Lecture notes, lectures 1-9 - Pathophysiology Nursing

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Lecture notes, lectures 1-9 - Complete
Integrated Pathophysiology for Nursing (McMaster University)
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Patho- Module 1
The Stress Response
What is Stress?
-Stress is a response, not something that happens to us.
-There are external influences (or stressors) that alter your homeostatic balance.
-The stressor, the stress response, and the pathophysiological sequelae.
THE STRESSORS
-Stressors can be positive (Eustressors).

-Stressors can be negative (Distressors).
-Stressors a e eutral a d these do ’t e essarily lead to stress u til we ha ge the i to a negative or
positive stressor.
EXTERNAL STIMULI
-External stimuli are external demands that trigger reactions.

- Stressors can be categorized into three different factors.
1. Quantity
-negative consequences due to an accumulation of stressors
-EX. Holmes and Rahe Stress Scale
2. Quality
-could be a major change that affects a lot of people (wars or economic depression)
-could be a major change that a affects few people (divorce)
-could be a daily hassle

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3. Duration
-can be acute or time limited (job interview)
-could be sequential (changes that follow divorce)
-could be chronic-intermittent (periodic family arguments)
-could be chronic
PHYSIOLOGICAL RESPONSE- three key areas
࿿࿿࿿¢151 Perception or emotion- frustration, anger, and fear can lead to the hormonal release.
࿿࿿࿿¢152 Primary Hormones involved are:

-Glucocorticoids: mainly cortisol
-Mineralcorticoids: primarily aldosterone
-Catecholamines: epinephrine, norepinephrine, and a small amount of dopamine.
0 Consequences
BODY’S RESPONSE TO STRESS
The Adrenal Glands (Retroperitoneal glands)
-They are comprised of three main layers.
0 The outer layer is The Capsule. This is a tough, fibrous capsule enclosed in fat for protection.
1 The Adrenal Cortex forms the bulk of the gland and makes up 80-90% of the gland. This layer
has three divisions or zones.
0 Outer Layer: Zona Glomerulosa- this produces primarily aldosterone. 95% of the
mineralocortecoid produced is in the form of aldosterone. This is key for regurgitating sodium
and potassium secretion and retention. Aldosterone is the key component of the rennin-
angiotensin aldosterone pathway for volume and blood pressure control. Aldosterone plays a
role with the pH balance, as it facilitates the excretion of hydrogen ions. If someone has too
much aldosterone excreted (aldosteronism), it is usually related to the neoplasms (an abnormal

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mass of tissue that results when cells divide more than they should or not die when they
should). The person will present with hypertension, and edema due to the high sodium. A
decrease in potassium will cause muscle weakness or paralysis. If too little aldosterone is
secreted, it can lead to hypotension. Dehydration can be common, decreased sodium,
increased potassium, and potential weight loss.
0 Middle Layer: Zona Faciculate- 95% of the gluco-corticoid secreted is in the form of
cortisol. Cortisol is released with ATCH (adrenocorticotrophin) stimulation and there is negative
feedback with increased cortisol levels. Adrenocorticotropic hormone is made in the corticotroph
cells of the anterior pituitary gland. It is secreted in several intermittent pulses during the day into the
bloodstream and transported around the body. Once adrenocorticotropic hormone reaches the adrenal
glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher
levels of cortisol in the blood. Cortisol, also known as hydrocortisone is the major stress hormone. It is
important to understand that cortisol is secreted during periods of stress and it is essential for our
survival. Cortisol increases blood glucose by decreasing peripheral uptake and promoting
gluconeogenesis. It acts synergistically with glucagon and epinephrine. It decreases insulin sensitivity.
This should help understand why well controlled diabetes are harder to control in the hospital
setting and their control often improves when they go home. It increases protein synthesis in the liver
but also promotes the catabolism (breakdown) in the muscles. Cortisol promotes lipolysis in the
extremities and there seems to be important acute and long term effects on the fatty acid breakdown.
In the acute stage, cortisol promotes the breakdown of fatty acids to be used as a source of
energy. However in the long term with sustained cortisol levels, the body starts to redistribute fat or
promote lipogenesis in the face and trunk area (Cushingoid signs). A other key role of ortisol is that it’s
an anti-inflammatory and an immunosupression.
Cortisol Effects:
Insufficient Cortisol -
Addiso ’s disease
Excessive Cortisol -
Cushi g’s disease

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0 Inner Layer: Zona Reticularis- Gonadocorticoids are made here. They are considered
very weak androgens. Primarily DHEA (dehydroepiandrosterone) and DHEA sulphate can be
converted to testosterone or in females, estrogen. If too much DHEA is secreted, it can lead to
an increase in facial hair. (PCOS- polycystic ovarian syndrome).
23 Lastly the innermost layer is the Adrenal Medulla, which is more like a knot of nervous tissue
and is part of the sympathetic nervous system accounting for 10-20% of the gland. The Adrenal
Medulla is made up of chromaffins cells called pheochromocytes. It has a rich blood supply and
a rich nerve supply. Epinephrine and norepinephrine are secreted and epinephrine is 10 times
more potent here. Adrenal Medulla also has key links to the autonomic sympathetic(fight or
flight) nervous system.

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Adrenal Gland Hormones Summary

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PHYSIOLOGICAL RESPONSE: HPA (HYPOTHALAMIC-PITUITARY-ADRENAL) AXIS
-Stressors activate the limbic system and parts of the cerebral cortex, to ultimately stimulate
the hypothalamus.
HYPOTHALAMUS
5888 The hypothalamus is the clearing house for many homeostasis controls.
5889
5890 It releases corticotrophin releasing hormone, and this stimulates the
sympathetic nervous system by the locus ceruleus.
5891 When CRH is released, it stimulates the Anterior Pituitary to release ACTH
(adrenal corticotropic hormone). ACTH is responsible for releasing cortisol from
the adrenal gland
5892 SIDE NOTE: Cortisol, the stress hormone is essential for general adaptation to
stress in the body, and plays a crucial role in cardiovascular, metabolic, and
immunological balances. As it circulates in the blood, most 90-95% is bound to the
cortisol-binding
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globulin and a small amount is bound to albumin. This protects the cortisol from being
cleared in the liver, but it must become unbound to be physiologically active.
23 When activated by stress, the hypothalamus also stimulates the locus ceruleus. This
area located in the brain stem is the integrating centre for the autonomic nervous
system, as norepinephrine is synthesized here.
24 In response to stress, after norepinephrine is synthesized, it goes from the locus
ceruleus by the afferent pathways back to the hypothalamus limbic system,
hippocampus and cerebral cortex.
25 When the sympathetic nervous system is activated, it releases epinephrine and
norepinephrine from the adrenal gland. These catecholamines allow the body to
support increases physical activity and rapid production of ATP.
26 Epinephrine will increase the glucose available in the body by gluconeogenesis and this
will limit the uptake of peripheral glu ose, plus will also li it the pa reas’ produ tio
of insulin resulting in hyperglycemia. Epinephrine also causes broncho-dilation, promote
lipolysis, and increase heart rate.
5888 Other hormones are also released from the anterior pituitary in
response to hypothalamic stimulation.
5888 Beta endorphins- increased levels reduce pain sensations.
5889 Prolactin- released during stress
5890 Growth hormone- increases amounts affect protein, lipid, and
carbohydrate metabolism and also counters the effects of insulin.
-The stimulation of the Posterior Pituitary releases ADH (anti-diuretic hormone or

vasopressin). This helps the retention of sodium and water.

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YOUTUBE VIDEO ON THE STRESS RESPONSE-

https://www.youtube.com/watch?v=BIfK0L8xDP0&feature=player_detailpage
In stressful situation, the body switches in its autonomic nervous system and
neurobiological processes in an attempt to maintain homeostasis. In the brain, the
hypothalamus is connected to the pituitary gland. The hypothalamus stimulated by the
sympathetic nervous system releases the hormone CRF. The CRF activates the pituitary gland to
release the ACTH hormone; this in turn alerts the adrenal glands. The adrenal glands are
located on top of each kidney. The ACTH from the pituitary gland stimulates the adrenal cortex
to release cortisol. At the same time, neurons in the hypothalamus signal the medulla to
release epinephrine (adrenaline) and norepinephrine. These hormones then push the body into
hyper alertness.
Short-Term Stress and Long-Term Chronic Stress Feedback
-Short term feedback occurs at the hypothalamus in the anterior pituitary gland. Normally with
the activation of the hypothalamus, there is a negative feedback system that decreases further
release of cortisol. This increased level of cortisol inhibits the hypothalamus from releasing
more CRF and the anterior pituitary from releasing more ACTH.
-in the Long-term stress, negative feedback becomes blunted or desensitized and becomes no
longer responsive to increased levels cortisol thus enabling the hypothalamus to release more
CRF and the anterior pituitary to release ACTH.

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dknfve

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Module 2: Alterations in Hormonal Regulation – Diabetes
Diabetes Mellitus Part 1

This module will cover Type 1 and Type 2 Diabetes, as well as briefly addressing
gestational diabetes. Learning about the disease of diabetes requires you to have a basic
understanding of the anatomy and physiology of the pancreas, liver, and the regular
hormonal influences on these organs. I will cover the basics of the anatomy and
physiology as it relates to diabetes mellitus. This includes glucose, fat, and protein
metabolism, pancreas, hormones of the endocrine pancreas, glucose regulating hormones,
the action of insulin on cells.
I have included some recommended readings from the School of Nursing’s

science textbooks. There is a lot of content in this module. Some of should be a review from
previous science courses and some of it will be new or add on to previous learning. The
overall aim of this module is to provide the basic science content related to diabetes so that
you are then able to apply it into clinical practice. Remember, you will have further
opportunity to discuss and apply this content in tutorial sessions and clinical setting. Please
note that there is a reference list at the PowerPoint presentation and specific references for
each slide are found in the notes section of each slide. Also, the term diabetes will be used
interchangeably with diabetes mellitus in this presentation.
Diabetes actually means the excessive excretion of urine. Diabetes mellitus

refers to the disorder of carbohydrate, fat and protein metabolism with absolute or
relative insulin deficiency. Diabetes insipidus will not be covered in this module.
Learning Outcomes
At the end of this module, you should be able to:
23 Describe current Canadian trends in the prevalence diabetes mellitus
24 Describe the etiology of diabetes comparing type 1 & 2 DM and gestational
diabetes
25 Describe glucose, fat and protein metabolism
26 Identify glucose-regulating hormones and describe their function
27 Describe the pathophysiology of type 1 and type 2 diabetes mellitus
28 Link the pathogenesis of DM to the clinical manifestations and evaluation of the
disease
29 Provide scientific rationale for interventions
30 Provide scientific rationale for patient teaching
Complication of diabetes mellitus will be very briefly discussed. The second module on
diabetes mellitus will cover in detail, the acute and chronic complications of the disease.

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Prevalence of Diabetes
According to the National Diabetes Surveillance System in Canada:
23 In 2006/07 prevalence of diagnosed diabetes increased by 4% from the previous
year and 21% from 2002/03 to 2006/07
24 Type 2 DM accounts for app. 90% of diabetes cases
23 Type 1 DM accounts for another 10% with gestational diabetes
mellitus and others making up the remaining
25 2 million (1 in 16) Canadians are diagnosed with diabetes (2006/07)
26 > 9 million Canadians live with diabetes or prediabetes
23 As future nurses, I hope that this statistic and the previous
one leads you to recognize the opportunity and need for
health education to address prediabetes
27 Prevalence 6.2% (5.9% females, 6.2% males)
23 Aged one year and older
28 Prevalence of diabetes lower in children than adults
23 The prevalence among children and adolescents is 0.3% while that
of the adult is 6.4%.
24 Among adults, the prevalence increases with age from about 2%
of adults in their 30s, peaking at 23% or 1 in 5 adults aged 75-79
years old
29 Personal costs of premature death and complications
23 Include reduced quality of life, an increased rate of heart
disease, stroke, kidney disease, blindness, amputation, and
erectile dysfunction
24 A staggering 80% of people with diabetes will die as a result of
heart disease or stroke
25 Canadian adults with diabetes are twice as likely to
die prematurely
26 Type 1 diabetic’s life expectancy may be shortened by as much as
15 yrs
27 Type 2 diabetic’s life expectancy may be shortened by 5-10 yrs
30 Financial burden
23 There is tremendous personal societal financial burden to diabetes
24 A diabetic incurs medical cost that are 2-3 times higher than
someone without diabetes
5888 Personal annual medical cost $1000 - $15 000
5889 Diabetes estimated to cost $16.9 billion/year by 2020
Etiology Type 1 DM
Type 1 Diabetes Mellitus is characterized into two types:
23 Autoimmune Type 1A
23 accounts for 90-95% of T1D cases
24 Idiopathic Type 1B

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Autoimmune Type 1A
23 In type 1A there is a autoimmune mediated specific loss of beta cells in the
pancreatic islets Langerhans
23 As a whole, T1D includes cases of diabetes that are primarily the
result of beta cells destruction which leads to absolute insulin
deficiency and is prone to ketoacidosis. This is believed to be the
result of genetic-environment interaction.
24 Genetic-environment interaction
25 Genes
23 There is research underway looking at the genetic susceptibility
to T1D
24 The strongest association and most studied is the inheriting
Major histocompatibility complex (MHC) on chromosome 6
25 In particular, HLA-DR 3 and HLA-DR 4 is associated with an
increased risk of Type 1A diabetes, that is 20-40 times higher than
that of the general population
26 It should be noted that some specific human leukocyte antigens are
thought to decrease the risk of developing T1D, including HLA-
DR 2
27 There is also an insulin gene which regulates beta cell replication
and function on chromosome 11, which is worth mentioning
28 There are polymorphisms of multiple genes that have been
identified as influencing the risk of Type 1A diabetes that will not
be identified in this module
29 In most cases, there is likely a polygenic inheritance of T1D,
meaning that susceptible individuals have more than one genetic
polymorphism
30 Between 10-13% of individuals with newly diagnosed T1D have
a first degree relative with T1D
31 Identifying genes that predispose individuals to diabetes has many
advantages but also carries many ethical and legal issues
32 A discussion of the pros and cons of the genetic testing is beyond
the scope of this module, but definitely worth thinking about as it
becomes more and more prevalent and relevant to most clinical
practice areas
23 MHC genes on chromosome 6 encode for human leukocyte antigens
HLA-DQ and HLA-DR
24 Chromosome 11- insulin gene regulating beta cell replication & function
24 Autoantibodies specific to beta cell destruction include: insulin autoantibodies,
islet cell autoantibodies, antibodies directed at other islet autoantigens
(glutamic acid decarboxylase-GAD & tyrosine phosphatase IA-2)
25 Environmental factors: drugs & chemicals; nutritional intake; viruses
23 As mentioned before, environmental factors interact with genes
24 Certain chemicals such as Alloxan, Streptozotocin, and Vacor as
well as certain drugs such as Pentamadine have been associated
with T1D

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5888 Nutritional intake of Bovine milk and high levels of

Nitrosamines has also been linked to T1D
5889 Lastly, viruses have also been linked to T1D
5890 40% of individuals with congenital rubella infection develop
T1D later
5891 Persistent Cytomegalovirus infection appears relevant in
some cases of T1D while mumps and Coxsackievirus’ seem
to have small effect on the development of T1D
5892 There is a seasonal distribution with more new cases
recorded in the Fall and Winter in the Northern Hemisphere
5893 This supports the idea that there is a gene environment
interaction which causes Type 1A diabetes to manifest
5894 There is a small number of adults estimated at approximately
10% classified as having T2D who appear to have immune-
mediated destruction of beta cells who actually fall into the
category of Type 1A D
5895 The term used to describe this sub-population is
Latent Autoimmune Disease in Adult (LADA)
5896 Otherwise, T1D is diagnosed in childhood for the most part
5897 Diagnosis peaks at 12 years of age and is rare before 9
months of age
Etiology Type 1 DM
The second subgroup of T1D is Idiopathic Type 1B diabetes. It is sometimes also
called Non-Immune Type 1 Diabetes.
Idiopathic Type 1B
5888 No evidence of autoimmunity
5889 Accounts for <10% of those with T1D
5890 Strong genetic component to type 1B diabetes
5891 Most affected individuals are of African or Asian descent
5892 Affected individuals have varying degrees of insulin deficiency that can come
and go which leads to --> episodic ketoacidosis
Etiology Type 2 DM
T2D is a heterogeneous condition:
23 Characterized by hyperglycemia, insulin resistance and relative impairment
of insulin secretion (insulin deficiency)
24 Type 2 diabetes range from predominant insulin resistance with relative insulin
deficiency to a predominant secretory defect with insulin resistance
25 The edeology of type 2 diabetes is thought to involve environment-genetic
interaction
O The ideology of T2D is thought to involve an environmental genetic
interaction
O 15-25% of first degree relatives of people with T2D will develop either
impaired glucose tolerance or diabetes

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23 There is a 2-4 fold increase of T2D associated with a positive family

history
24 Genes: genetic defects of beta cell function; genetic defects in insulin
synthesis, secretion and action
23 Variance of genes have been identified that increase the risk of T2D
24 Many of them fall in the category of genetic defects of beta cell
function and genetic defects in insulin synthesis, secretion and action
25 Others include genes that encode proteins for pancreatic development,
amyloid deposition in beta cells, cellular insulin resistance, and
impaired regulation of gluconeogenesis
25 Risk factors for T2D include: age, obesity, hypertension, physical inactivity and
family history
26 + metabolic syndrome (high risk of developing T2D and associated
cardiovascular complications)
23 Furthermore, there is a high risk of developing T2D and associated
cardiovascular complications with metabolic syndrome
24 Metabolic syndrome will be discussed a little bit later in this module
27 T2D Occurs mostly in adults however there is an increasing prevalence in
children as childhood obesity rates climb
23 Canadian Aboriginal Children are particularly affected
24 Canadian data regarding the prevalence of T2D is limited US data
suggests a 10-30 fold increase in T2D in children over the past 10-15
years
Etiology GDM & Other

Gestational Diabetes Mellitus
5888 Any degree of glucose intolerance with onset or first recognition
during pregnancy
O Pre-gestational diabetes refers to pregnancy in persons with preexisting
diabetes
5889 Exact etiology of glucose intolerance in gestational diabetes is unknown.
However, a combination of insulin resistance and impaired insulin secretion
are most definitely contributing factors
O Risk factors for gestational diabetes include: older age, family history,
history of glucose intolerance, obesity, membership in certain ethnic or
racial groups, history of poor obstetric outcomes, and infant weighing
>9 pounds
O Diagnosis is made based on the gestational diabetes screen which is a 50g
glucose load followed by a plasma glucose level, one hour later
O Diagnosis of gestational diabetes is made based on different lab values for
non-pregnant individuals
O For specific values, refer to the Canadian Diabetes Association Clinical
Practice Guidelines
O Untreated gestational diabetes leads to increased maternal and perinatal
morbidity while the well managed is associated with outcomes similar to
control populations

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23 In the US, Canada and Europe, T2D accounts for over 80% of cases
of diabetes
24 T1D accounts for another 5-10% while the remaining causes are
classified as other
Other
5888 Specific genetically defined forms of diabetes include genetic defects of beta
cell function and genetic defects in insulin action
5889 One specific group of genetically defined form of diabetes is maturity
onset diabetes of the young, also known as “modi”
O These individuals present at a young age, have mild disease due to beta
cell dysfunction, with some insulin production, and inherit the disease via
autosomal dominant transmission
O There is normal insulin sensitivity in individuals with Modi
O There have been 6 different genetic abnormalities identified that are
responsible for beta-cell function impairment
O Modi Type 2 and 3 account for 65% and 15% of the cases respectably
O It should be noted that these genetic abnormalities are often now referred
to their specific descriptions of known genetic defects instead of Modi
subtypes
5888 i.e. Modi 2 encompasses over a dozen mutations in the
glucose-kinase gene on chromosome 7
5890 Diabetes associated with the exocrine pancreas or endocrinopathies
5888 Endocrinopathies like Cushing’s Syndrome or acromegaly
result in diabetogenic effects due to excess hormone levels
5889 Diabetes induced by infections, drugs or chemicals
5888 There are also specific genetic syndromes sometimes associated with
diabetes like Down Syndrome and uncommon forms of immune-mediated
diabetes like Stiff Man Syndrome
5890 The Etiology identifies of the “Other” section vary and may be more type
1 in nature with beta cell destruction and absolute insulin deficiency, or more type
2 in nature with relative insulin deficiency
5891 When classifying diabetes, it is important to understand the underlying
etiology to understand how the disease manifests and the corresponding
management
5892 Table 42-2 in Porth pathophysiology textbook summarizes the
etiologic classification of DM in a very concise manner
5893 For a more detailed etiologic classification of DM, you may refer to appendix
1 in the 2008 Canadian Diabetes Association Clinical Practice Guidelines
5894 It is not necessary to recall all of the other specific types, but you need
to be aware of them]
5895 I would expect that you would be able to explain why someone with Cushing’s
Syndrome is at higher risk for developing diabetes as this is drawn on previous
knowledge of the effects of cortisol on glucose and insulin

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Glucose Metabolism
23 The physiological concepts of glucose, fat, and protein metabolism are key
to understanding the pathophysiology and complications of DM
24 Glucose is a 6 carbon molecule that is a very efficient fuel, breaking down into
CO2 and H2O when metabolized in the presence of oxygen
25 Brain & nervous system rely almost solely on glucose as a fuel source
5888 Other tissues and organ systems can use other sources of non-
carbohydrate fuel such as fatty acids and ketones
5889 The brain isn’t able to synthesize glucose or store more than a few
minutes of glucose supply, therefore a continuous supply of glucose from
the circulation is required to maintain normal cerebral function
5889 Fasting blood glucose (FBG) is tightly regulated between 4.4-5.0 mmol/L in
non-diabetics
5890 Insulin is secreted by beta cells in the pancreas in response to rising blood glucose
5891 After a meal is ingested, ~ 2/3 glucose is stored in the liver as glycogen
5892 Between meals, the liver releases glucose by breaking down glycogen in a
process called glycogenolysis to maintain normal glycemia between meals
5893 Once the liver & skeletal muscles are saturated with glycogen, additional
glucose is converted into fatty acids by the liver and then stored as triglycerides
in adipose tissue
5894 The liver also synthesizes glucose from non-carbohydrate sources such as
amino acids, glycerol, and lactic acid in a process called gluconeogenesis
Protein Metabolism
23 Proteins are essential for the formation of all body structures, including
genes, enzymes, contractile structures in muscle, matrix of bone, and
hemoglobin of RBCs
24 Amino acids are the building blocks of proteins
25 There is a limited capacity for the storage of excess amino acids
23 Most stored amino acids are contained in body proteins
24 Amino acids not needed for protein synthesis are converted to fatty acids, ketones
or glucose and then stored or used as metabolic fuel
25 Amino acids broken down from proteins are used as a major substrate
for gluconeogenesis when metabolic needs exceed food intake
Fat Metabolism
0 Fat is the most efficient form of fuel storage yielding 9kcals/g of stored energy
compared with 4 kcals/g yielded by stored carbohydrates and proteins
1 Approximately 30-35% of calories are obtained from fat in a normal Canadian
diet
O 55% are obtained from carbohydrates
O About 15% are obtained from protein
2 Many carbohydrates consumed in the diet are converted to triglycerides and
then stored in adipose tissue
3 Triglyceride = 3 fatty acids linked by glycerol molecule

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0 Lipase is an enzyme that breaks down triglycerides into its 4 components

when fat is required for fuel
1 Glycerol is then used in glycolytic pathway (glycolysis) and can be used with
glucose to produce energy or to produce glucose alone
2 Fatty acids are transported to tissues to be used interchangeably with glucose for
energy in almost all body cells EXCEPT the brain, nervous system, and RBCs
3 Liver converts left over fatty acids into ketones and releases them into
the bloodstream
4 Question: What happens when large amounts of ketones (which are organic acids)
are released into the bloodstream?
O Answer: ketoacidosis
Putting It All Together

0 Let’s look at a diagram representing glucose, fat, and protein metabolism
and storage
1 Glucose is a necessary and very efficient fuel used in our bodies
0 Remember: the brain requires a constant supply of glucose from the
circulation to maintain normal cerebral function
1 After a meal is consumed, the pancreas releases insulin in response to increasing
plasma glucose
0 This allows glucose to enter cells and be used
1 This will be discussed in a couple of slides
2 Glucose that isn’t needed will go to the liver and be stored as glycogen
3 Glycogen is converted back to glucose between meals to maintain normal
glycaemia in a process called glycogenolysis
4 When the liver and skeletal muscles are saturated with glycogen, additional
glucose is converted into fatty acids by the liver and then stored as triglycerides
in adipose tissue
5 Many carbohydrates consumes are converted into triglycerides and stored
in adipose tissue
6 Remember: almost all body cells can use fatty acids as an energy source and fat
is the most efficient form of fuel storage
7 Amino acids are the building blocks of proteins  proteins are essential for
the formation of all body structures
8 Proteins are broken down into amino acids for gluconeogenesis when metabolic
needs exceed carbohydrate availability
9 Glucose is stored in skeletal muscle as glycogen

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The Pancreas
0 The endocrine pancreas is largely responsible for the hormonal control of blood
glucose
1 The pancreas is an organ located behind the stomach between the spleen and
duodenum
2 It is made up of 2 components:
23 The endocrine pancreas
23 Makes up about 1-2% of the pancreas’ volume
24 Secretes hormones that regulate most of the
carbohydrate metabolism in the body
25 Made up of the Islet of Langerhans
23 The pancreatic Islets are made up of beta cells (secrete
insulin and amylin), alpha cells (secrete glucagon), and
delta cells (secrete somatostatin)
24 The exocrine pancreas
23 Produces digestive juices which are secreted into the duodenum
24 The Acini cells make up the exocrine pancreas
25 As mentioned before, these cells secrete digestive juices into
the duodenum via the pancreatic duct
Endocrine Pancreas Hormones

5888 Insulin is the only direct hormone to have a direct effect on lowering blood
glucose levels. It is important to understand the effect of insulin as insulin
resistance in T2 diabetes is one of the main pathophysiological features.
Understanding how insulin is synthesized, secreted and its action on cells will
help you to better understand the clinical consequences of a breakdown in any
of these areas.
5889 The active form of insulin is composed of two polypeptide chains – A chain
and B chain. Active insulin is formed from pro-insulin which is composed of
active insulin and a biologically inactive connecting peptide
5890 The following is a picture of proinsulin. Note the A and B chain are joined by
the connecting peptide. The cleaving of the connecting peptide results in
proinsulin being converted to insulin. Both active insulin and inactive C-peptide
chain are packaged into secretory granules and releases from the beta cell at the
same time. Clinically, it is possible to measure serum C-peptide to assess beta
cell function and the need for insulin therapy.

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Insulin is released from beta cells in response to blood glucose. Blood glucose enters the
beta cell by means of the glucose transporter. It is metabolized to form adenosine
triphosphate or ATP through phosphorylation by an enzyme called glucokinase. ATP is
needed to close the K+ channels and depolarize the cell. Once the beta cell is
depolarized the calcium channels can open and insulin is secreted. Therefore, insulin
secretion is decreased when blood glucose levels are lower and increased when blood
glucose levels are higher. Insulin response is biphasic with the first release of insulin
peaking 3-5 minutes post food ingestion and returning to baseline within 2-3 hours.
During the first phase, stored preformed insulin is secreted. The second phase begins
around 2 minutes and continues to increase slowly for at least 60 minutes or until the
stimulus ceases. The insulin released in the second phase is newly synthesized insulin.
From a broad perspective insulin has three main actions:
23 Promotes uptake of glucose by target cells and increases glycogen synthesis
24 Prevents fat and glycogen breakdown
25 Inhibits gluconeogenesis and increases protein synthesis
As plasma glucose increases insulin is secreted by the beta cells and enters the portal
circulation. Once in the liver 50% is used or degraded. The ½ life is approximately 15
minutes once it is released into circulation. To initiate the effector on target tissue insulin
23 binds to a membrane receptor (2) The membrane receptor is composed of 2 subunits,
the alpha subunit (3) that extends outside of the cell membrane and where insulin binds
and the smaller beta subunit (4) that is predominantly inside the cell membrane. The beta
subunit contains kinase enzyme (5) that activates with insulin binding. The kinase
enzyme results in autophosphorylation (6) of the beta subunit which in turn activates
some enzymes and inactivates others. This causes the desired intracellular effect of
insulin on glucose, fat and protein metabolism as well as cell growth. Specifically
insulin receptor substrates 1-4 (7) causes glucose transport (8), fatty acid synthesis (9),
protein synthesis (10), glycogen synthesis (11), cell growth and survival (12) and amino
acid/ electrolyte transport (13) cell membranes are almost impermeable to glucose and
therefore require a special carrier called a glucose transporter to move glucose from the
blood into the cell. There is a family of glucose transporters. Glucose transporter 4 or
GLUT4 (14) is the insulin-dependent glucose transporter for skeletal muscle and adipose
tissue. It is stimulated by insulin to move from its inactive site to the cell membrane (15)
where it facilitates glucose entry (16). GLUT-2 is the major transporter for glucose into
beta and liver cells. GLUT-1 is present in all tissues and does not require the actions of
insulin. It is important in the transport of glucose into cells of the nervous system. All of
these glucose transporters move glucose across the cell membrane at a faster rate than
would occur with diffusion alone. Mitogen activated protein kinase signaling cascade
5888 promotes cell growth and differentiation as well as gene expression.

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DIABETES PART 3
Endocrine Pancreas Hormones

 Insulin Amylin is released at the same time as insulin
-Promotes uptake of glucose by target by beta cells. It regulates blood sugar by
cells and increases glycogen synthesis delaying nutrient uptake through inhibition of
-Prevents fat and glycogen breakdown gastric emptying and suppressing glucagon
Inhibits gluconeogenesis and secretion after meals. Overall, it has
increases protein synthesis antihyperglycemic and satiety effects.
 Amylin
-Regulates blood sugar by delaying
nutrient uptake through inhibition of
gastric emptying and suppressing
glucagon secretion after meals
-Satiety effect, overall
antihyperglycemia effect
Endocrine Pancreas Hormones Glucagon is a polypeptide molecule produced
 Glucagon by the alpha cells and works opposite to

-Initiates glycogenolysis in the liver insulin. Like insulin, it travels to the liver via
-Increases transport of AA into liver the portal circulation. It exerts its main
and stimulates gluconeogenesis function in the liver. Glucagon maintains blood
 Somatostatin sugar levels between meals by initiating
-Decreases GI activity and inhibits glycogenolysis in the liver and increasing
release of insulin/glucagon  extend transport of amino acids into the liver and
time for food to be absorbed and stimulating gluconeogenesis. When there are
extend the use of absorbed nutrients high levels of glucagon, glucagon activates
by tissues adipose cell lipase making fatty acids available
for use as an alternative source of energy. In
addition, glucagon can also have an inotropic
effect, enhance bile secretion and inhibit
gastric acid secretion at high levels.
Somatostatis is released by delta cells in the
endocrine pancreas. Almost all aspects related
to food ingestion stimulate somatostatin
secretion. Main activities of somatostatin are to
decrease GI activity and inhibit release of
insulin and glucagon. This causes an extended
time for food to be absorbed and extends the
use of absorbed nutrients by tissues.

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Counter-Regulatory Hormones I want to briefly review how counter regulatory

23 Counter-regulatory hormones hormones affect blood glucose. These
counteract the storage functions of hormones can have a profound effect on both
insulin in regulating blood glucose the pathophysiology of diabetes as well as
levels during periods of fasting, some of the complications of diabetes.
exercise, stress Counter-regulatory hormones counteract the
23 Epinephrine storage functions of insulin in regulating the
24 Growth hormone blood glucose levels during periods of fasting,
25 Glucocorticoids (specifically exercise and stress. Therefore, these are
cortisol) situations that either limit glucose intake or
26 Glucagon deplete glucose stores.
As you know, epinephrine is one of the
catecholamines released by the adrenal
medulla when stimulated by the sympathetic
nervous system. It is particularly active in the
stress response. It causes transient
hyperglycemia by promoting gluconeogenesis
and glycogenolysis in the liver, and inhibits
glycogen formation as well as increasing the
breakdown of muscle glycogen stores. It also
inhibits insulin release from beta cells which
decreases glucose uptake in muscles and other
organs. This preserves glucose for the brain.
Glucose released by muscle glycogen is not
released into the blood, however the
mobilization of these stores for muscle use
conserves blood glucose for use by other
tissues that rely almost solely on glucose for
energy, like the brain and the nervous system.
Epinephrine stimulates lipolysis by freeing
triglycerides and fatty acids from adipose
tissue. It also inhibits the degradation of
circulating cholesterol to bile acids. Growth
hormone increases protein synthesis in all cells
of the body, stimulates lipolysis and
antagonizes the effects of insulin. It also
decreases cellular uptake in use of glucose. A
disease called acromagalae, which is
characterized by the hypersecretion of growth
hormone that can result in glucose intolerance
or the development of diabetes mellitus. For
those with diabetes, an increase in growth
hormone, which occurs in periods of stress and
growth for children, can lead to the full
spectrum of metabolic abnormalities associated

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with poor regulation, even though insulin

treatment may be optimized. Glucocorticoids,
specifically cortisol, are synthesized in the
adrenal cortex. Glucocorticoids refer to steroid
hormones that have direct effects on
carbohydrate metabolism. One of the main
effects of cortisol is to stimulate
gluconeogenesis. Glucocorticoids also
moderately decrease the use of glucose by
tissues. Remember that almost any type of
stress causes the release of corticotrophin
releasing hormones (CRH) from the
hypothalamus, which stimulates the anterior
pituitary gland to release adrenocorticotrophic
hormone (ACTH), which then signals the
adrenal gland to increase secretion of cortisol.
Outside the liver, glucocorticoids stimulate
protein catabolism and inhibit amino acid
uptake in protein syntheses. Increased cortisol
complicates diabetes. Glucagon, which has
already been discussed, is also considered a
counter-regulatory hormone. It is important to
remember that counter-regulatory hormones
play an essential role in glucose homeostasis,
especially in times of stress and hypoglycemia.
Unfortunately, when there is persistent stress
or hypersecretion of these hormones, for other
reasons, there are consequences which can lead
to dysfunction of glucose metabolism.
Definitions The Canadian Diabetes Association defines

 “Diabetes mellitus is a metabolic diabetes mellitus as is a metabolic disorder
disorder characterized by the presence characterized by the presence of
of hyperglycemia due to defective hyperglycemia due to defective insulin
insulin secretion, defective insulin secretion, defective insulin action or both. The
action or both. The chronic chronic hyperglycemia of diabetes is
hyperglycemia of diabetes is associated with significant long-term sequelae,
associated with significant long-term particularly damage, dysfunction and failure of
sequelae, particularly damage, various organs – especially the kidneys, eyes,
dysfunction and failure of various nerves, heart and blood vessels. Another term,
organs – especially the kidneys, eyes, which is often used in the literature is
nerves, heart and blood vessels” dysglycemia. Dysglycemia is a qualitative term
 “Dysglycemia is a qualitative term used to describe blood glucose (BG) that is
used to describe blood glucose (BG) abnormal without defining a threshold. The
that is abnormal without defining a adoption of this term reflects uncertainty about
threshold. The adoption of this term optimal BG ranges and the current

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reflects uncertainty about optimal BG understanding that cardiovascular (CV) risk

ranges and the current understanding and mortality risk exist in people with even
that cardiovascular (CV) risk and slightly elevated BG levels.
mortality risk exist in people with
even slightly elevated BG levels”
Pathophysiology Type 1 DM Type one diabetes is a catabolic disorder

 Catabolic disorder characterized by: characterized by an absolute lack of insulin,
- Absolute lack of insulin hyperglycemia and a breakdown of fats and
- Hyperglycemia proteins for energy instead of carbohydrates.
- Breakdown of fats and The pathophysiology of type one diabetes,
proteins particularly the absolute lack of insulin, makes
 Prone to ketoacidosis these patients prone to ketoacidosis. As
 Autoimmune disorder (genetics and previously discussed, type one A diabetes is an
environmental triggering event  T- autoimmune disorder where genetics and
lymphocyte mediated hypersensitivity environmental triggering event leads to T-
reaction against some beta cell lymphocyte mediated hypersensitivity reaction
antigen against some beta cell antigen. Remember, that
 Destruction of beta cells: in idiopathic type one B diabetes, there is beta
1. Lymphocyte and macrophage cell destruction, however, no evidence of
infiltration of the islets resulting in autoimmunity exists. For the remainder of the
inflammation (insulitis) and islet discussion about type one diabetes, I will be
beta cell death speaking to you about type one A diabetes. The
2. Production of autoantibodies destruction of beta cells is two fold.
against islet cells, insulin, a) First, there is lymphocyte and
glutamic acid decarboxylase macrophage infiltration of the islets
(GAD) and other cytoplasmic which results in inflammation or
proteins insulitis and islet beta cell death
b) Secondly, there is production of
autoantibodies against islet cells,
insulin, glutamic acid decarboxylase
(GAD) and other cytoplasmic proteins.
Glutamic acid decarboxylase ia an
enzyme in beta cells that is involved in
glucagon synthesis
Putting it Together: Type 1 DM Now, I will put the pathophysiology together

in a visual representation for the pathology for
type one diabetes. A genetic predisposition and
environmental factors causes autoantigens to
form on insulin-producing beta cells and
circulates in the blood stream and lymphatics.
Processing and presentation of autoantigen
presenting cells occurs as the autoantigen
circulates through the body. T-helper 1
lymphocytes are activated when circulating

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autoantigens are ingested by antigen presenting

cells. T-helper 1 lymphocytes secrete
interpuron which activates macrophages and
stimulates the release of inflammatory
cytokines like IL-1 etc. These inflammatory
cytokines cause beta cell destruction and
apoptosis. Activated T-helper 1 lymphocytes
also secrete IL-2 (interleukin) which activates
beta cell autoantigen specific T-lymphocytes.
This leads to the destruction of beta cells with
decreased insulin. Activation of T helper 2
lymphocytes causes the secretion of IL-4,
which stimulates B-lymphocytes to proliferate
and produce antibodies. These autoantibodies
contribute to the destruction of beta cells and
decreased insulin secretion. Therefore, there is
dysfunction in both humoral and cell mediated
immunity. One last point to mention regarding
the pathophysiology of diabetes type one is the
relative inactivity of T-regulatory cells.
Remember, T-regulatory cells usually act to
inhibit the immune response. There have been
mutations affecting these cells noted in a rare
form of diabetes called neonatal diabetes.
Further research is needed to investigate the
role, or lack thereof, of T-regulatory cells.

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Pathophysiology Type 2 DM Like type 1 Diabetes, there is a genetic

23 Genes and environmental predisposition as well as environmental
influences insulin resistance + influences that result in the basic
abnormal insulin secretion by beta pathophysiological mechanisms of diabetes
cells + increased glucose production type 2. These include insulin resistance,
by the liver = Type 2 DM abnormal secretion of insulin by beta cells, and
24 Relative insulin deficiency required increased glucose production by the liver.
25 Compensatory hyperinsulinemia Many genes have been identified as being
26 Beta cell dysfunction associated with type 2 diabetes. They include
23 Relative insulin deficiency those that code for beta cell mass, beta cell
24 Decrease in beta cell mass, function, pro-insulin and insulin molecular
abnormal function of beta structure, insulin receptors, hepatic synthesis
cells or some combination of glucose, glucagon synthesis, and cellular
25 Progressive decrease in responsiveness to insulin stimulation. It is
the weight and number of important to understand that a relative insulin
beta cells deficiency is required to develop type 2
-Glucolipotoxic beta Diabetes. This means that beta cell dysfunction
cells undergo apoptotic death is always present in some extent with type two
-Adipokineleptin decreases insulin diabetes. Many individuals have risk factors
synthesis in beta cells for type 2 Diabetes including obesity,
-Inflammatory cytokines (i.e. TNF- metabolic syndrome, hypertension, and are
alpha and IL-beta) toxic to beta cells insulin resistant; however, it is only those who
-Beta cell exhaustion associated are genetically predisposed to beta cell
with intracellular oxidative stress and dysfunction who will develop type 2 diabetes.
endoplasmic reticulum dysfunction Compensatory hyperinsulinemia, caused by
 beta cell apoptosis insulin resistance, prevents the clinical
appearance of diabetes for many years;
eventually, beta cell dysfunction leads to a
relative insulin deficiency, hyperglycemia and
type 2 diabetes. Let’s look at beta cell
dysfunction in more detail. As you know, beta
cell dysfunction causes a relative insulin
deficiency in type two diabetes. The
dysfunction may be a result of a decrease in
beta cell mass, abnormal function of beta cells
or some combination of these. Either way,
there is a progressive decrease in the weight
and number of beta cells. This happens for the
following reasons: beta cells are extremely
sensitive to high levels of glucosyntry fatty
acids and undergo apoptotic death in these so
called glucolipotoxic conditions;
adipokineleptin decreases insulin synthesis in
beta cells; inflammatory cytokines, like TNF-
alpha and IL-beta which are released from

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adipocytes, are toxic to beta cells; lastly, there

is beta cell exhaustion from increased demand
for insulin biosynthesis which is associated
with intracellular oxidative stress and
endoplasmic reticulum dysfunction. This has
also been implicated in beta cell apoptosis.
Pathophysiology of Type 2 DM Let’s look at insulin resistance in more detail.

 Insulin resistance Insulin resistance is the suboptimal response of
-Suboptimal response of insulin- insulin-sensitive tissues to insulin. These
sensitive tissues to insulin insulin sensitive tissues include liver, muscle
-Abnormality of insulin molecule, and adipose tissue. The mechanisms of insulin
high amounts of insulin antagonists, resistance include an abnormality of the insulin
down-regulation of insulin receptor, molecule, high amounts of insulin antagonists,
decreased or abnormal activation of down regulation of insulin receptor, decreased
postreceptor kinases and alteration of or abnormal activation of postreceptor kinases
glucose transporter proteins and alteration of glucose transporter proteins.
 Obesity Based on your understanding of insulin and
-Contributor to insulin resistance and counter-regulatory hormones, you should be
beta cell dysfunction able to understand why each of these
-Increased adipokines and pathologic mechanisms may lead to insulin
expression of peroxisome proliferator- resistance. Obesity is present in 60%-80% of
activated receptor gamma (PPAR) individuals with type 2 Diabetes, and 90% of
-Elevated serum FFAs, intracellular those with type 2 Diabetes are overweight.
deposits of triglycerides and Obesity is a significant contributor to both
cholesterol insulin resistance and beta cell dysfunction
-Inflammatory cytokines (i.e. TNF- through the following mechanisms: there are
alpha, IL-6) released from adipocytes increased adipokines which are produced in
-Hyperinsulinemia and decreased adipose tissue, a nuclear receptor called
receptor density peroxisome proliferator-activated receptor
gamma is highly expressed in adipose tissue
and responsible for the changes in adipokines;
these include increased levels of serumleptin
and resistin, and decreased levels of
adiponectin. Adiponectin increases tissue
sensitivity to insulin and appears to have
antidiabetic , anti-inflammatory and
antiathrogenic affects. These changes in
adipokines have an overall effect of decreased
insulin sensitivity. A class of drugs called
thyasoladindions modulate the activity of
peroxisome proliferator-activated receptor
(PPAR) gamma, and are used to treat type 2
diabetics. Elevated serum free fatty acids,
intracellular deposits of triglycerides and
cholesterol interfere with intracellular insulin

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signaling and decrease tissue response to

insulin. Lipotoxicity causes altered insulin
secretion within the beta cell. Elevated free
fatty acids inhibit glucose uptake and glycogen
storage in the peripheral tissues, causing
insulin resistance and glucose underutilization.
Lastly, elevation of free fatty acids and
triglycerides reduces hepatic insulin sensitivity,
leading to increased hepatic glucose production
and hyperglycemia. This is heightened in the
fasting state. Inflammatory cytokines, like
TNF-alpha and IL-6, are released from
adipocytes and contribute to insulin resistance
through a post-receptor mechanism. Lastly,
obesity is correlated with hyperinsulinemia and
decreased receptor density.
Metabolic Syndrome In a joint statement between the American

NCEP ATP III Criteria for a DX of diabetes association and the European
metabolic syndrome association for the study of diabetes metabolic
syndrome is described as a clustering of
Three or more of the following specific cardiovascular disease risk factors
1. Abdominal obesity: waist whose underlying pathophysiology is thought
circumference > 88cm in women to be related to insulin resistance. Therefore,
or .102 cm in men insulin resistance seems to play a role in, not
2. Triglycerides > or equal to only the pathophysiology of type 2 Diabetes,
1.7mmol/L but other metabolic abnormalities as well.
3. HDL < 1.3mmol/L in women or These include obesity, high levels of
<1.0mmol/L in men plasmatoryglycerides and low levels of high
4. Blood pressure > 130/85 mmHg density lipoproteins, hypertension, systemic
5. Fasting plasma glucose 5.7- inflammation detected by measuring plasma
7.0mmol/L CRP and other inflammatory mediators,
abnormal fibrinolysis, abnormal function of the
vascular endothelium and macrovascular
diseases such as coronary artery,
cerebrovascular and prolifartery disease.
Although it is a term that is often used in the
literature and clinical context, the paper
outlining the joint statement by the American
diabetes association and the European
association for the study of diabetes cautioned
practitioners to not treat the patient based on
whether they meet criteria for metabolic
syndrome, but to evaluate and treat each
cardiovascular disease risk factor
independently of a metabolic syndrome

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diagnosis. Furthermore, there is no universal

consensus on metabolic syndrome criteria. The
world health organization and international
diabetes federation have outlined criteria where
insulin resistance is a requisite. The following
is criteria outlined in the third report of the
National Cholesterol Education Program
(NCEP 3) Adult Treatment Panel which
provides an operational definition based on
risk determinants and is intended to be used to
ensure consistency in North American clinical
practice when diagnosing metabolic syndrome.
Metabolic syndrome is diagnosed when the
patient meets three or more of the following
criteria: abnormal obesity, which means a
waist circumference greater than 88
centimeters in women or greater than 102
centimeters in men; triglycerides greater or
equal to 1.7 mmol/L; HDL less than
1.3mmol/L in women or less than 1.0 mmol/L
in men; blood pressure greater than 130/85
mmHg; and fasting plasma glucose between
5.7-7.0 mmol/L. The take home message is
that insulin resistance and metabolic syndrome
are associated, and the associated
cardiovascular risk must each be evaluated and
treated either within the context of a type 2
diabetes diagnosis or not.
Putting it All Together Type 2 DM Now, I will pull the pathophysiology together
in a visual representation of the patho of type 2
Diabetes. Diet an inactivity, as well as genetic
predisposition, leads to obesity. Obesity leads
to a deraignment of adipokines, increased free
fatty acids and release of inflammatory
cytokines from adipocytes. This compilation of
mechanisms contributes to insulin resistance.
When there is a resistance to insulin, the
demand for insulin synthesis increases. This
leads to hyperinsulinemia. The clinical
appearance of diabetes was avoided for many
years due to compensatory hyperinsulinemia.
The result is damaging tissue effects without
hyperglycemia or insulin resistance without
diabetes. Remember that these individuals
often meet criteria for metabolic syndrome and

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should be treated accordingly. Genetic

predisposition for beta cell dysfunction leads to
hypoinsulinemia. Genetic predisposition may
also lead to insulin resistance. Remember that
insulin resistance causes an increased demand
for insulin synthesis and beta cell exhaustion
associated with intracellular oxidative stress
and endoplasmic reticulum dysfunction leads
to beta cell apoptosis. Lipotoxic conditions and
inflammatory cytokines have a direct toxic
effect to beta cells. As you already know,
glucagon is a hormone produced in the alpha
cells of the pancreas, and stimulates
glycogenolysis and gluconeogenesis in the
liver, thereby increasing plasma glucose.
Normally, glucagon release is inhibited by
hyperglycemia. Pancreatic alpha cells are less
responsive to glucose inhibition in type 2
diabetes. This causes increased glucagon
secretion and contributes to hyperglycemia in
type 2 diabetes. Decreased amylin activity
parallels the reduction in insulin secretion.
There is also amyloid deposition in the
pancreas, which contributes to islet cell
dysfunction. Amylin also normally inhibits
glucagon secretion. Incretins are peptides
released in the GI tract when food is ingested.
They bind to receptors on beta cells and
increases synthesis and secretion of insulin in
response to glucose levels. In type 2 diabetes,
incretin activity is decreased which impairs
beta cell function. There are drugs approved in
the US aimed at augmenting one of the incretin
peptides and inhibiting an enzyme that
inactivates them. These drugs are not approved
for use in Canada. Lastly, ghrelin is a peptide
produced in the stomach and pancreatic islets
that stimulates growth hormone secretion that
is involved in homeostasis regulation of
energy, glucose, GI motility and secretions.
Ghrelin has an effect on insulin, however the
effect is unclear. Decreased levels of
circulating ghrelin have been associated with
insulin resistance and increased fasting insulin
levels.

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Counter-Regulatory Mechanisms in
DM There are two mechanisms that I will mention
Somogyi Effect related to counter-regulatory hormones. The
5888 Insulin induced first is the somogyi effect. The somogyi effect
hypoglycemia followed by rebound is characterized by insulin-induced
hyperglycemia hypoglycemia followed by rebound
5889 Hypoglycemia stimulates hyperglycemia. The hypoglycemia state
glucose stimulates glucose counter-regulatory
counter-regulatory hormones hormones like catecholamines, glucagon,
Dawn Phenomenon cortisol and growth hormone as part of a
23 Hyperglycemia btwn 0500- compensatory mechanism. These hormones
0900 without hypoglycemia cause hyperglycemia and produce some degree
24 Disruption of normal of insulin resistance. The cycle occurs when
circadian rhythm for glucose hyperglycemia and insulin resistance is treated
25 Nocturnal elevations of with larger doses of insulin. Management to
growth hormone prevent hypoglycemia and subsequent counter-
regulatory mechanisms activation includes
redistribution of dietary carbohydrates and
altering insulin dose or time of administration.
Somogyi effect usually occurs in type 1
diabetes, however it can occur in type two
diabetes if insulin is prescribed. The second

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mechanism related to counter-regulatory

hormones and diabetes is the dawn
phenomenon. It is characterized by
hyperglycemia between 5 and 9 am without
preceding hypoglycemia. One possible cause is
if there is a change in the normal circadian
rhythm for glucose tolerance in diabetes.
Glucose is normally higher in the later part of
the morning. Also, it appears to be related to
nocturnal elevations of growth hormone.
Management includes altering the time and
dose of insulin.
Complications There are acute and chronic complicatiosn of

Acute: diabetes. Acute complications include
- Hypoglycemia hypoglycemia, diabetes ketoacidosis,
- Diabetes ketoacidosis hyperosmolar hyperglycemic nonketotic
- Hyperosmolar hyperglycemic syndrome. Chronic complications can be
nonketotic syndrome categorized as micro or macrovascular disease.
Microvascular disease includes retinopathy,
Chronic: neuropathy, and nephropathy. Macrovascular
- Microvascular disease disease includes coronary artery disease,
- Retinopathy cerebrovascular disease, and peripheral
- Neuropathy vascular disease. The second module of the
- Nephropathy diabetes series will review in detail the
- Macrovascular disease pathophysiology, clinical manisfestations,
- CAD management, and nursing considerations for
- Cerebrovascular disease each of these complications. Note that the
- PVD questions related to this module will not test
you on the complications of diabetes.
Clinical Manisfestations Both type 1 and type 2 diabetes evolve over

- Polyuria time and eventually to a point where there is
- Polydipsia either a relative or absolute deficiency of
- Polyphagia insulin, which results in some common clinical
- Body mass manisfestations. Unless specifically mentioned,
- Weight loss (type 1 DM) these manisfestations can be present in either
- Obesity (type 2 DM) type 1 or type 2 diabetes. Polyuria, which
- Blurred vision means excessive urination, occurs as the
- Fatigue excessive glucose filtered by the glomeruli of
- Paresthesias the kidneys exceeds the amount which can be
- Infections reabsorbed by the renal tubules and glucose
acts as an osmotic diuretic. Polydipsia, or
excessive thirst, is a result of intracellular
dehydration, which occurs as hyperglycemia
pulls water out of body cells, including those in

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the hypothalamic thirst centre. Furthermore,

polyuria contributes to dehydration.
Polyphagia, or excessive hunger, usually does
not occur in type 2 diabetics. In type 1
diabetes, it is the result of cellular starvation
and the depletion of cellular stores of
carbohydrates, fats, and proteins. This
depletion corresponds with increased hunger.
Body mass is often affected in diabetes.
Weight loss, despite normal or increased
appetite, is common in uncontrolled type 1
diabetes. This occurs for two reasons. First: the
loss of fluids through osmotic diuresis:
vomiting during periods of ketoacidosis may
exaggerate the weight loss due to fluid loss.
Secondly: the absolute insulin deficiency leads
to the loss of body tissue as fat and proteins are
used for energy as a result of insulin
deficiency. Obesity is common in diabetes. As
already mentioned, over 90% of individuals
with type 2 diabetes are overweight, and 60-
80% are classified as obese. Genetics may have
a role in obesity, however life style and
nutrition contribute significantly. Blurred
vision occurs with exposure of the lens and
retina to hyperosmolar fluids. Fatigue is the
result of lowered plasma volume. Poor use of
food products due to metabolic changes and
possibly sleep loss from severe nocturia.
Paresthesias occurs due to dysfunction of
peripheral sensory nerves, called peripheral
vascular disease. Infections can occur due to
entry into a person with peripheral vascular
disease that was not attended to. Candida or
yeast infections are common causes of
vulvovaginitis and balanitis. Signs and
symptoms related to diabetes will be
heightened in individuals whose blood sugar is
not managed well. Non-compliance with
lifestyle, dietary, or pharmacological
interventions leads to persistence of clinical
manisfestations as well as complications listed
on the previous slide.

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Diagnostic Tests The diagnosis of diabetes mellitus is based on

- Fasting Blood Glucose (FBG) the result of blood tests measuring plasma
- Fasting for at least 8 hours glucose. Fasting blood glucose is the preferred
- Normal = < 6.0 mmol/L; Impaired diagnostic test for diabetes. It requires that the
FBG = individual fasts for at least 8 hours. Normal
6.1 – 6.9 mmol/L plasma glucose is less than 6.0 mmol per liter.
- Diabetes = > 7.0 mmol/L on 2 Impaired fasting blood glucose ranges between
occasions 6.1 to 6.9 mmol per liter. And a diagnosis of
- OR Random Blood Glucose Test diabetes is made if the fasting blood glucose is
- No regard to time or last meal greater than or equal to 7.0 mmol per liter on
- >= 11.1 mmol/L + clinical two occasions. A random blood glucose test
manisfestations can be done without regard to the time or last
of DM = DM meal. A finding of greater than or equal to 11.1
- OR Oral Glucose Tolerance Test mmol per liter plus classical clinical
(OGTT) manisfestations of diabetes like polyuria,
- Measures plasma glucose response to polydipsia, and unexplained weight loss meets
75g the criteria for diagnosis of diabetes mellitus.
concentrated glucose solution at 1 Lastly, an oral glucose tolerance test (OGTT)
and 2 measures plasma glucose response to 75 grams
hours of concentrated glucose solution at 1 and 2
- >= 11.1 mmol/L = DM hours post-glucose load. A diagnosis of
diabetes mellitus is made for a finding of
greater than or equal to 11.1 mmol per liter
SLIDE 34 Diagnostic Tests Capillary blood glucose monitoring is the gold
- Capillary Blood Glucose Monitoring standard for monitoring diabetes at home. It

- Uses capillary blood, reagent strip uses capillary blood from pricking the finger or
and forearm, and the blood is placed on a reagent
glucometer to determine glucose strip, and the strip is entered into the
levels glucometer to determine capillary blood
(uses whole blood, lab uses plasma) glucose. Whole blood is used, which gives
- Hemoglobin A1C results which are 10 to 15 percent lower than
- Measures glycosylation of when plasma is used in laboratory tests.
hemoglobin by Newer glucometers can be calibrated to give
glucose to provide an index of plasma values. Either way, the diabetic must
blood know whether the glucometer or strips provide
glucose levels over the course of 6- whole blood or plasma results. Hemaglobin
12 A1C has become a part of the standard care
weeks and management of diabetes. A goal of less
- Goal < 7% than 7% is outlined in the Canadian Diabetes
- Urine Tests Association 2008 Clinical Practice Guidelines.
- Glucose Remember than hemoglobin does not require
- Ketones insulin for glucose entry into red blood cells.
- Genetic studies, autoantibodies Therefore, the rate at which glucose becomes

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attached to hemoglobin is dependent upon

blood glucose levels. During a red blood cell’s
120 day life span, they become glycated to
become A1A, A1B, and A1C. Glycosylation of
hemoglobin is essentially irreversible and
individuals with hyperglycemia will have a
higher percentage of glycosylated hemoglobin.
Hemoglobin A1C has been found to be useful
in screening for chronic hyperglycemia and
assessing the effectiveness of therapy. Urine
tests can be used to measure glucose or
ketones. Remember that in uncontrolled or
poorly controlled diabetes, hyperglycemia will
persist, and when the renal threshold for
glucose reabsorption is reached, glycosuria
ensues. Ketones are the metabolic end-products
of fat metabolism. Normally ketones are
completely metabolized, but when fat
metabolism is the predominant source of
energy, excessive amounts of ketones are
formed and excreted through the urine. This
occurs in diabetic ketoacidosis. Lastly, as
discussed in the beginning of this module, the
role of genetics in diabetes is being studied.
Genetic testing and testing for plasma
autoantibodies specific to diabetes can be done
in certain circumstances.
Pharmacological Therapy – Insulin Insulin therapy is required in the management

- Insulin therapy required in type 1 dm of type 1 diabetes and many people with type 2
may be required in type 2 dm diabetes will eventually require some form of
- Administered by injection or insulin therapy. Insulin can be administered by
inhalation injection or inhalation. Injection routes include
- Destroyed in GI Tract subcutaneous and intravenous. Intravenous
- Insulin primarily produced by insulin therapy is used in hospital settings.
recombinant DNA technology to be Only regular insulin can be given
identical to human insulin or modified intravenously. Also, regular insulin can bind to
to alter pharmacokinetics (insulin plastic IV tubing, and therefore the insulin
analogues) solution is often run through the tubing for a
- Intensive treatment of type 1 diabetes period of time before attaching to the patient. If
- Basal/bolus insulin regimens or you are required to do this is clinical, there
CSII should be a policy or protocol for you to
- CBG checks follow. Inhaled insulin is approved in Canada
- Meal planning but it isn’t commercially available yet. In
- Hypoglycemia studies, it was used as a rapid acting insulin in
- Teaching: care and use of insulin; combination with 1 or 2 subcutaneous

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prevention, recognition, and treatment injections of long acting insulin doses. The
of hypoglycemia; sick-day study results are promising. Finding that in
management; adjustments for food adults equivalent glycemic control was
intake (i.e. carb counting) and physical achieved with reducing fasting plasma glucose
activity; CBG levels and increased patient satisfaction. The
short-term safety data suggests no significant
pulmonary dysfunction. However, it is
recommended that it not be used in patients
with abnormal baseline spirometry. Insulin is
destroyed in the GI tract, and therefore it
cannot be given orally. Insulin preparations are
primarily produced by recombinant DNA
technology to be identical to human insulin or
modified to alter pharmacokinetics. Those
preparations are called insulin analogs. The
diabetes control and complications trial
concluded that intensive treatment of type 1
diabetes through basal and bolus insulin
regimens or continuous subcutaneous insulin
infusion as well as capillary blood glucose
checks and meal planning significantly delayed
the onset and slowed the progression of
microvascular and macrovascular
complications. Those that achieved near
normal glucose levels could expect a 50 – 75
percent reduction in the risk of development or
progression of retinopathy, neuropathy, and
nephropathy after 8 to 9 years. An intermediate
acting or long acting insulin analog, given once
or twice daily provides basal insulin. A short
acting or rapid acting insulin analog given at
each meal provides bolus or prandial insulin.
For continuous subcutaneous insulin infusions,
insulin aspart and lispro (both rapid acting
insulin analogs) were shown to be superior to
regular insulin, by providing post-prandial
glycemic control and reducing hypoglycemia.
Hypoglycemia is a major obstacle for
achieving glycemic targets. It can have
negative social and emotional impacts, as well
as significant physical consequences, such as
confusion, coma, or seizure. Unfortunately,
less stringent glycemic goals must be used
when there is a significant risk of
hypoglycemia. The healthcare team will work
diligently with the diabetic to provide the

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safest insulin therapy to achieve the best

glycemic target. Although insulin causes the
hypoglycemia, the influence of lifestyle factors
is significant. The Canadian Diabetes
Association reports in the 2008 clinical
practice guidelines that deviations from
recommended or appropriate self-management
behaviors, such as eating less food, taking
more insulin, and engaging in more activity
accounts for 85% of hypoglycemic episodes.
Any individual who is prescribed insulin
therapy should be taught how to care and use
the insulin; the prevention, recognition, and
treatment of hypoglycemia; what to do when
they are sick, how to make adjustments for
food intake and physical activity; and how to
perform capillary blood glucose monitoring.
Activity Profiles of Insulin Preparations The following is a list of preparations used in

in Canada Canada. They are categorized based on their
duration of action. Note that pre-mixed insulin
*refer to diagram below* preparations are available, however, they are
usually not suitable for intensive treatment in
type 1 diabetes.

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Pharmacologic Therapy – Oral Insulin secretagogues include sulfonylurea

Antidiabetic Agents and non-solfunylurea agents. Sulfonylureas
act by binding to the sulfonylurea receptor
23 Insulin secretagogues on the beta cell, which is linked to ATP
24 Biguanides sensitive potassium channels. This causes
25 Alpha-glucosidase inhibitors the potassium channels to close and
26 DPP (depeptidyl peptidase)-4 inhibitor depolarization to occur. An influx of calcium
27 Thiazolidinediones ions and insulin secretion ensues. Non-
sulfonylurea insulin secretagogues require
28 Weight loss agent, such as orlistat glucose to close ATP dependent potassium
(Xenical) or sibutramine (Meridia), can be channels and subsequent insulin release
used as an adjunct pharmacology therapy through the same mechanism as the
in the management of type 2 DM sulfonylurea agents. To visualize this in a
diagram refer to figure 42-4 on page 1008 in
your textbook. Insulin secretagogues can
cause hypoglycemia, and patients should be
educated on how to avoid, recognize, and
manage hypoglycemic episodes. Biguanides
inhibit hepatic glucose production and
increase the insulin

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sensitivity in peripheral tissues. Metformin

is the only biguanide available in Canada.
Alpha-glucosidase inhibitors are used
when insulin secretagogues or metformin
are not affective in decreasing post-
prandial hypoglycemia. Alpha-glucosidase
is an enzyme which breaks down complex
carbohydrates in the small intestine. By
inhibiting this enzyme, the breakdown of
complex carbohydrates is delayed, thus
blunting the post-prandial increase in
plasma glucose and insulin levels.
Hypoglycemia can occur when alpha-
glucosidase inhibitors are used in
conjuction with sulfonylurea agents. If this
does occur, glucose which is dextrose but
not sucrose (table sugar), should be used as
sucrose breakdown may be blocked by the
action of alpha-glucosidase inhibitors.
Dipeptidyl-peptidase -4 inhibitor promotes
the activity of incretins by inhibiting
dipeptidyl-peptidase -4 enzymes, which
degrade the main incretins GLP-1 and
glucose dependent insulinotropic
polypeptide. Remember that these incretins
are released following a meal and stimulate
insulin secretion from the beta cells.
Thiazolidinediones or TZDs are the only
class of drugs that target insulin resistance.
They do this by binding to the nuclear
peroxisome proliferator activated receptor
(PPAR) gamma that is highly expressed in
adipose tissue, and seems to be responsible
for the changes to adipokines in type 2
diabetes. These changes include: increased
levels of serum leptin and resistin, and
more importantly decreased levels of
adiponectin. Adiponectin increases tissue
sensitivity to insulin, and appears to have
an anti-diabetic, anti-inflammatory, and
anti-atherogenic effects. TZDs modulate
the activity of peroxisome proliferator
activated receptor gamma, specifically
increasing adipocyte production of
adiponectin. The mechanism for TZDs is
complex and not entirely understood,

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however, other beneficial effects include: a

decrease in free fatty acids and
triglycerides, a decrease in blood pressure
and inflammatory mediators like
fibrinogen and psoriatic protein, and pro-
coagulation factors. Lastly, weight loss
agents such as orlistat and sibutramine can
be used as an adjunct pharmacology
therapy in the management of type 2
diabetes mellitus. Table 42-6 on page 1022
of the textbook provides a great overview
of the oral antidiabetic agents including:
dose, duration, schedule, and mechanism
of action. Also, the section of
pharmacological management of type 2
diabetes and the Canadian diabetes
association 2008 clinical practice
guidelines provide an algorithm for the
management of type 2 diabetes with
specific targets, advantages, and
disadvantages of specific classes of drugs.
Metabolic Dysfunction The following is a visual representation of

the metabolic dysfunction in type 2
diabetes. The second part is the same
diagram, but with the addition of the oral
antidiabetic agents shown where they exert
their action. Note that incretin and amalin
analogues are not available in Canada, and
they were not discussed.

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Patient Teaching Patient teaching is geared towards teaching

- Lifestyle people how to manage their diabetes. It is
- Nutrition/Diet broken down into five main components.
- Medications Lifestyle: including healthy self-
- Avoiding/recognizing complications management behaviours related to physical
- Equipment (use, cost) activity, smoking cessation, and self-
monitoring of blood glucose, should be
- Multi-disciplinary/inter-professional team promoted. Nutrition/diet: play a
significant role in the management of
diabetes. Although not reviewed in this
module, an individualized diet, which
meets nutritional requirements and
minimizes saturated fat and cholesterol,
should be advised. A registered dietitian
plays a key role in providing an

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individualized plan and adjusting the

components of carbohydrates, fats, and
protein as required.
Initial guidelines may include a diet made
up of: 45-60% carbs, 20-35% fat, and 10-
35% protein. Medications: education
regarding medications, including insulin
and oral antidiabetic agents, is key for the
patient in order to avoid and recognize
complications. Avoiding/recognizing
complications: includes both acute and
chronic complications. This decreases
mortality and morbidity, and hopefully
increase quality of life. Equipment:
including the use and cost can be a
significant part of teaching. This includes
but is not limited to: teaching SC
injections, self-monitoring of blood
glucose, using capillary poke and
glucometer, and insulin pumps. Lastly, a
multi-disciplinary or inter-professional
team is necessary to meet all of the needs
of the patient.
Conclusion In conclusion, diabetes carries a significant
- Diabetes carries a significant personal and personal and societal burden. Diabetics are
societal burden a heterogenous and diverse group that
- Heterogenous and diverse groups require individualized treatment plans.
requiring individualized treatment plans Both type 1 and type 2 diabetes occur via
- Both type 1 and type 2 occur via genetic genetic predisposition and environmental
predisposition and environmental influences. As obesity rates continue to
influences. climb, type 2 diabetes will also increase in
- As obesity rates continue to climb, type 2 prevalence. There are multiple co-
diabetes rates will also increase morbidities in diabetes. There is a decrease
- Multiple co-morbidities in diabetes in complications if glucose levels remain
- Decrease in complications IF glucose near normal levels, that is, a hemoglobin
levels remain near normal levels (Hgb A1C A1C of less than 7. There are special
< 7 TARGET) populations that were not discussed in this
- Special populations not discussed in this module, but they require special
module, but require special consideration: consideration. These include: pediatrics,
pediatrics, pregnant women, and elderly pregnant women, and the elderly.

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Additional helpful info from the discussion board

Adiponectin is a adipokine that is present in your adipose tissues and is involved in
regulating glucose levels and fatty acid breakdown. In humans, plasma levels of
adiponectin are significantly lower in insulin-resistant states including type 2 diabetes.
Adiponectin increases the tissues sensitivity to insulin.
Increased levels of serum Leptin and Resistin and decreased levels of Adiponectin
cause insulin resistance (this takes place in patients with obesity, which is why obesity
can cause insulin resistance and is a risk factor for Type 2 DM).
PPAR Gamma regulates glucose metabolism and fatty acid storage, and is responsible
for adipokine changes in Type 2 DM.
Thiazolidinediones are drugs that target insulin resistance (the only class of drugs) by
binding to PPAR Gamma. This drug is used to treat Type 2 DM. The drug increases
insulin sensitivity by acting on adipose, muscle and liver to utilize glucose and
decrease glucose production.
SO, if that is still confusing, the way I understand it is that Adipokines (Leptin and
Adipolectin) are regulating glucose levels, PPAR Gamma comes around and messes
things up by changing adipokines. Therefore, we give Thiazolidinediones to bind to
PPAR Gamma so that it can't mess around with adipokines and cause Insulin

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Module 3: Inflammation and Immunity
Inflammation and Immunity

When you encounter a condition ending with a suffix “itis,” you will know that inflammation is
at the heart of this disease process.
At the end of this module:

5888 Define inflammation
5889 List the goals of inflammation
5890 Identify common causes of inflammation
5891 Review the roles of cells of inflammation
5892 Discuss the vascular and cellular changes of the inflammatory response
5893 Discuss the role of inflammatory mediators
5894 Differentiate between acute and chronic inflammation
5895 List and describe the five cardinal signs of inflammation
5896 Briefly discuss the role of inflammation in atherosclerosis
Let’s now look at some of the types of inflammation.
Human Defense Mechanisms

5888 Specific (aka the Immune Response)
5889 Non-specific (aka the Inflammatory Response)
Inflammation can be innate, meaning naturel or present at birth, or acquired, evolving over time after
birth. We’re all born with the same innate abilities to protect ourselves. But each one of us
will vary in our ability to acquire immunity, based on our individual experiences with exposure
to pathogens and foreign antigens over our lifetime. We will all develop our own unique immune
systems tailored just for us. There are 3 types of dense mechanisms.
23 Natural Barriers (First line of defense)

23 Include the epithelial layer of the skin and mucous membranes lining
the gastrointestinal, genitourinary and respiratory tract
24 Called naturel, physical barriers
25 Physical barriers can include mechanical and chemical types
26 Mechanical means of ridding the body of pathogens and includes sloughing ,
sneezing, coughing, vomiting, urinating, and ciliary action of the respiratory tract
27 Most skin temperatures discourage the growth of bacteria
28 Chemical barriers include mucous, perspAiration, saliva, tears and earwax that
trap and kill microorganisms
29 Some of these barriers contain enzymes, fatty and lactic acids, and
antimicrobial proteins that destroy bacteria
30 Our own normal bacteria flora are capable of producing chemicals to keep
pathogens at bay
24 Inflammation (Second line of defense)

25 Immunity (Third line of defense)

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5888 Acquired, specific and adaptive ability

5889 Over time, our immune system develops specific antibodies designed
to target certain antigens and this defense mechanism has memory
5890 This means that on first exposure to an antigen, our immune
system makes antibodies targeted toward that antigen
5891 Then, upon subsequent exposure to that same antigen, those antibodies
that match the antigen will be called to action to fight of new infection
In your readings, you will also come across terms like “humoral” and “cellular” in
reference to inflammation and immunity. These terms simply tell us where the inflammatory
response originates.
23 Humoral
5888 Implies that the response comes from the blood or plasma components
5889 Humoral response in inflammation involves complement factors
5890 In immunity, it involves in the formation and action of antibodies
5889 Cellular
5888 Refers to a cell-derived process
5889 In inflammation, the involved cells are neutrophils and macrophages
5890 In the immune response, we’re talking about lymphocytes

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Inflammation
Here are two definitions of inflammation:
23 A protective response designed to eliminate the initial cause of injury, remove damaged
tissue and generate new tissue (Porth, pg. 363)
24 The biochemical and cellular response of vascularized tissue to injury; designed
to protect the body from further injury (McCance, pg. 186)
It’s important to emphasize the vascularized feature of inflammation to indicate that

inflammation occurs in tissues and other organs that are vascularized or perfused with blood.
Goals of Inflammation
5888 Move required components to the site of injury
23 Movement of all the necessary blood and cellular components to the site of injury
or insult
24 Deliver nutrients to the site of injury
23 Delivery of nutrients and blood cells to eradicate the offender
25 Dilute, confine and/or eliminate injurious agents
23 Dilution, confinement and elimination of the offending agents
26 Stimulate and assist the immune system
23 Stimulation and facilitation of components of the immune system
27 Promote healing and generation of new tissue
23 Promotion of healing with generation of new tissue
How are these goal accomplished? There are 3 major events that occur pretty much
simultaneously and include:
5888 Increased metabolic rate
23 When called upon to fight injury or infection, cells step up their usual
daily routines and increase production of necessary items for the battle
24 As a result, we increase our heat production, our oxygen and glucose consumption,
and our production of wastes
24 Dilation of blood vessels
23 Help speed up delivery of the inflammatory components to the sight of injury
25 Increased permeability
23 Allows the movement of white cells, specifically neutrophils, proteins and
nutrients out of the blood vessels and into the tissue where they can go to work
Causes of Inflammation
Some of the many cases of inflammation include microbes, immune reactions between antigen
and antibody, trauma, burns, physical or chemical agents and tissue necrosis. Other causes of
inflammation include temperature extremes, oxygen deprivation, nutrient deprivation, genetic
or immune defects, and ionizing radiation.

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Acute Inflammation
Acute inflammation is a response to injury or insult that occurs:
5888 Early and quick
23 We’re talking minutes to hours
24 Triggered by a variety of stimuli
25 Mediated by many factors
26 Short duration
27 Self-limiting
Think about the last time you cut yourself, how many days did it take to heal? Likely not very
long. One of the key features of acute inflammation is its non-specificity. In other words, if you
stub your toe today, and cut your finger next month, the same processes will occur with the
finger as those that occurred with the toe, regardless of the cause. The inflammatory system is
not terribly particular about where or how the injury occurred. It has a job to do and goes to
work pretty quickly in much the same way, every time.
5888 Non-specific
5889 Two phases (vascular and cellular)
Acute inflammation will have one of two outcomes:
23 Results in healing or chronic inflammation
Cells involved in Inflammation

Before we examine the processes involved in inflammation, it would first be helpful to review
the functions and roles of the cells involved in these processes. Normally, cells float within our
blood vessels continuously and harmoniously. In response to inflammation though, each cell
type springs into action to perform a very specific function.
There are number biochemical mediators released from mast cells, plasma proteins and dying
cells which trigger the production of “adhesion molecules” on the surface of many cells.
Adhesion molecules cause these cells to stick to, or “adhere” to the endothelium.
Endothelial cells
This is a picture of a normal endothelial cell layer lining a
blood vessel. Note how each endothelial cell lines up right
next to its neighbors, leaving virtually no space in between
the cells. This format prevents molecules and particles
from exiting the vascular space under normal conditions.
5888 Endothelial cells line the walls of blood vessels and normally maintain very close
contact with each other
5889 The space between them is very tight, limiting the movement of the cells and
particles across the vessel wall
5890 In addition to this traffic-control function, endothelial cells also:
23 produce antiplatelet and antithrombotic agents to prevent formation of clots,
24 Produce vasoconstrictors and vasodilators to regulate flow
25 Regulate leukocyte extravasation/movement through the use of adhesion
molecules

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5888 Regulate immune cell proliferation through secretion of colony-

stimulating factors
5889 Participate in the repair process through angiogenesis and
formation of an extracellular matrix
Platelets
23 Platelets are cells also referred to as thrombocytes and they circulate passively
until activated by products of tissue degradation, like collagen, thrombin, and
platelet activating factor
24 Primary role is hemostasis (stemming of blood flow)
25 Once activated, they produce potent inflammatory mediators which result in
increased vascular permeability, chemotaxis, chemical attraction, adhesive and
protolithic properties of the endothelium
Neutrophils
Neutrophils are cells representing one type of granulocyte, so named because enzymes
containing lysosomal granules are found within their cytoplasm and are considered the
chief phagocytic leukocytes.
Early in the inflammatory response, about 90 minutes to 6-12 hours post injury, these cells are
attracted to the site of injury by chemotactic factors. On their surface, are found a number of
different receptors, each designed to recognize and interact with certain substances such as
bacterial glycoproteins, microbes, cytokines and chemokines.
Because of their lysosomal enzymes, they are called upon to destroy invaders and remove
subsequent debris. Once they themselves die off, they become exudate or pus. In the presence of
inflammation, neutrophils are released from bone marrow and the neutrophil count will rise.
They are relatively short-lived because they are incapable of division. When they die off, they
release macrophage chemotactic factor to attract macrophages to the site of injury.
In the presence of severe inflammation, as the demand for neutrophils increases, the bone marrow
can’t quite keep up and releases immature neutrophils called “bands.” When the band
count is elevated on a CBC, we then know that the bone marrow is overworked and is
working valiantly to keep up with an ongoing inflammatory process.
5888 As granulocytes, they are the main phagocytic leukocytes

5889 They contain lysosomes filled with enzymes, meant to destroy invaders
5890 They are short-lived and release macrophage chemotactic factor and become
pus upon their death
Monocytes/macrophages
Like the neutrophils, monocytes are also leukocytes derived from bone marrow, but contain
larger and fewer lysosomes than their counterparts. They too express receptors that interact with
a variety of substances. Typically, monocytes exit the circulation in response to inflammation
and take up residence in various tissues as the more mature macrophage. Monocytes are then
considered to be the immature form of macrophages.

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Macrophages are named according to their tissue location. Some examples include Kupffer cells
in the liver, Alveolar macrophages in the lung, and Microglia in the brain. Macrophages arrive at
the site of inflammation a little later than the neutrophils; about 24-48 hours post injury.
Eventually, they replace the neutrophils as they die off. Macrophages are often associated with
chronic inflammation because they are somewhat sluggish.
Monocytes and macrophages differ somewhat from neutrophils in other ways too. They produce
very potent vasoactive mediators, like prostaglandins, leukotrienes, platelet activating factor,
inflammatory cytokines and growth factor, and they engulf more material than neutrophils. Their
lifespan is 3-4x longer than neutrophils and they also interact with the immune system.
Macrophages are responsive to lymphokines from T-cells which enhance their efficacy and work
with the immune system by processing and presenting antigens to lymphocytes and by
promoting wound healing.
23 Monocytes are leukocytes that also contain lysosomes

24 They respond to inflammation and take up residence in the tissues as the
mature macrophage
25 They arrive later than, and eventually replace neutrophils
26 They produce vasoactive mediators and engulf more material than neutrophils
27 Their lifespan is 3-4x longer than neutrophils and they also interact with the immune
system
Eosinophils:
5888 Eosinophils are granulocytes with many lysosomes, containing biochemical
mediators of inflammation and are prominent in the allergic response and hypersensitivity
disorders
5889 They are also particularly good at tackling parasitic infections
5890 Like their counterparts, eosinophils circulate in the blood until they are needed to
respond to insult of injury
5891 Then, the migrate to the tissues where they modulate release of inflammatory
mediators and degrade vasoactive molecules, controlling the vascular effects of
histamine and serotonin
5892 In other words, eosinophils lend some balance to the inflammatory response
Basophils:
5888 Very similar in function to eosinophils
5889 They too produce lipid mediators and cytokines to produce an inflammatory
response
5890 They too are important in the allergic and hypersensitivity reactions
5891 They also interact with the immune system by binding to immune globulin E
through receptors on their cell’s surface
5892 These actions triggers the release of histamine and vasoactive agents
6
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Mast Cells:
0 In just a few moments, we will be discussing the role and function of mast cells
in great detail
1 Suffice it to say they are considered the most important activators of
the inflammatory response by performing two functions:
O Degranulation
O Synthesis of new mediators
Mediators of Inflammation
0 Before we look at the details of the inflammatory response, let’s first look at the
role and functions of those factors that mediate the inflammatory response
1 A number of processes occur simultaneously and interdependently during the
inflammatory response
2 These include:
0 Mast cell degranulation
1 Activation of 3 plasma protein systems
2 Release of cell derived mediators
Mast Cells
Introduction:
5888 Mast cells are located in connective tissue close to a blood vessel and are
prevalent along the mucosa of the lung and the GI tract and the dermis of the skin
5889 These cells don’t mature until they leave the circulation and settle in nearby
tissues
5890 They are considered the most important activators in the inflammatory response
5891 Mast cells produce lipid mediators and cytokines that induce inflammation
5892 They contain within their cytoplasm some pre-formed granules
5893 On this slide, you are able to view the process of mast cell degranulation
(feel free to click on it at any time)
23 Degranulation
5888 http://www.youtube.com/watch?v=eVBqMXMIFnM&feature=related
(animation only, no audio)
24 Synthesis
5888 When activated, mast cells release their granular contents which can
include substances like histamine, serotonin, chemotactic factors, enzymes,
produglycans, proteases, and cytokines like tumenucorsis factor alpha, and
interleukin 6, in the circulation and exert their effects immediately
5889 They also synthesize lipid mediators from cell membrane precursors,
such as prostaglandins and platelet activating factor, such as prostaglandins and
platelet activating factor, and stimulate cytokine and chemokine (leukotrienes)
synthesis by other cells such as monocytes and macrophages (we’ll look at
the function of these other cells shortly)
5890 Mast cells are especially important in the inflammatory response
related to hypersensitivity and allergies

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5888 They work with the immune system by binding to one of the immune
globulins, lgE to trigger the release of histamine and vasoactive substances from
basophils
5889 Finally, mast cells are responsible for the release of eosinophil
chemotactic factor (ECFA), which serves to attract the eosinophils to the site of
inflammation
Functions of the Mast Cell

23 This very busy diagram lists all of the important functions of the mast cell
24 On the left side of the slide, we see the mediators released from the mast cell
25 On the right side of the slide, we see the wide variety of inflammatory mediators
synthesized by the mast cell
26 The effects of each are also shown here
(Diagram on next page)
8
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Plasma Protein Systems

Introduction:
23 There are three interrelated plasma protein systems that normally exist in an inactive state
24 These plasma derived mediators of inflammation are synthesized in the liver and include
coagulation factors and complement proteins
25 Many of these protein components are enzymes that circulate in an inactive or
‘proenzyme’ state
26 Activation of a proenzyme by infection or injury creates a cascade type effect
27 Components of these plasma protein systems are usually short-lived and are rapidly
deactivated
28 There are three, each with a specific goal within the inflammatory
process: 1. Complement (cell lysis)
23 Components of the complement system include 20 different proteins labelled C1

through C9 and make up about 10 % of the total circulating proteins in the body
24 They are capable of direct destruction of pathogens or can activate and work with
other components of the inflammatory response to effect the same result
25 As proenzymes are activated, a cascade forms, which plays an important role
in immunity and inflammation
10

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23 Complement fragments contribute to the inflammatory response by

causing vasodilation, increasing vascular permeability, and enhancing
activity of phagocytes
24 It is not necessary to memorize the names and functions of each of these proteins,
but there are some key players in this cascade with very important roles and I will
mention a few of these
25 C3 and C5 activation is the most important piece of this cascade
23 Activation of C3 and C5 results in formation of opsonins,
chemotactic factors, and anaphylatoxins
24 Recall that opsonins coat that bacteria and tag them for destruction
25 Chemotactic factors attract other components of inflammation to
the injury site
26 Anaphylatoxins trigger all or some of the symptoms of anaphylaxis
26 The most potent components with chemotactic and anaphylatoxic properties
are C3a and C3b
27 C5a also exhibits chemotactic and anaphylatoxic properties
28 Other important components are C2b, which causes vasodilation and increased
vascular permeability, C4a which also acts as an anaphylatoxin inducing mast cell
degranulation with release of histamine
29 What’s most important to appreciate about this cascade is the final
endpoint, which is the formation of the Membrane Attack Complex
(MAC), which is composed of components C5 through C9
23 Its job is to create holes in the membrane of pathogens, allowing entry of
water causing the cells to explode
30 Another interesting feature that you can see in this diagram, is that there are three
possible avenues though which the component cascade can be activated
23 The classical pathway is activated by antibodies and requires at least 2
antigen-antibody complexes to initiate the cascade. Thus the immune
system can take advantage of this option for destruction of bacteria
24 The lectin pathway is activated by bacterial carbohydrates and is similar to
the classical pathway but no antibodies are required
25 The alternative pathway is activated by gram-negative bacterial and fungal
cell wall polysaccharides termed endotoxins, no antibodies are required,
and it begins the activation of C3b and merges with the classical pathway
at C5
31 In summary, the complement cascade is activated in three ways and have four
major effects
23 Opsonisation
24 Mast cell degranulation through anaphylatoxic activity
25 Leukocyte chemotaxis
26 Cell lysis
32 Mediates inflammation
33 Destroys pathogens directly
34 Activates and collaborates with other plasma protein systems
35 C3 and C5 are most important
36 Endpoint: Membrane Attack Complex (MAC)
11

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5888 Clotting/coagulation cascade (formation of fibrin

clots) O Activated by 2 pathways
5888 Activated by substances released during tissue destruction and

infection
5889 As you can see there are two pathways, intrinsic and
extrinsic that converge at the place where factor 10 becomes 10a
5890 Factor 10a and thrombin both act to provide the link
between the coagulation system and inflammation
5891 Inflammation is enhanced by many of the byproducts of fragments
that are produced during the clotting cascade
5888 i.e. during fibrin production, fibrinogen releases
fibrinopeptides that are chemotactic for neutrophils, cause
increased vascular permeability, and enhance the effect of
bradykinin from the Kinin cascade
5889 similarly plasmin works with the complement cascade to
activate C3a and C5a, causing the release of histamine
enhancing the inflammatory response
5890 factor 12a is also called precalicreen activator, an
enzyme that activates precalicreen in the Kinin cascade
5891 thus you can clearly see the interdependent relationship
between the three plasma protein systems
5892 stimulation of one cascade leads to stimulation of
some of the components of the others, designed to enhance
the overall inflammatory response
5893 the primary goal of the clotting system then is to produce a
fibrous clot
12

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23 the fibrous network that forms serves to prevent the spread of

infection by trapping the offending agent and retaining it at the site
of inflammatory activity to prevent bleeding and to provide the
framework for eventual healing and repair
5888 Makes a fibrous mesh network
5889 Traps exudate, organisms and invaders
5890 Prevents spread to other tissues
5891 Prepares for healing
5892 Endpoint: fibrous clot
5889 Kinin (vasodilation, vascular permeability and pain)
23 Interacts closely with the clotting system

24 Both the clotting system and the Kinin system are initiated by the activated
factor 12 or factor 12a
25 In this cascade, vasoactive peptides are generated from plasma proteins
called kininogens by the action of proteases called kalicreins
23 Kalicreins can be found in tissue and body fluids including saliva,
tears, sweat, urine, feces
24 The end result is the production of bradykinin which increases
vasodilation, increased vascular permeability, smooth muscle contraction,
enhances leukocyte chemotaxis, and stimulates pain receptors
26 Effects of bradykinin are very similar to histamine although the effect are
much shorter in duration as Kinins are eventually degraded by kininases to
maintain homeostasis
27 Bradykinin seems to have a greater importance during the latter phases
of inflammation
28 Results in the release of bradykinin which causes:
23 Vasodilation
24 Pain
13

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5888 Extravascular, smooth muscle contraction

5889 Increased vascular permeability
5890 Leukocyte chemotaxis
5888 Short lived
Three Plasma Protein Systems

5888 In this diagram, you should be able to clearly see the interdependent relationship
between all three plasma protein systems (Diagram on next page)
5889 Note the presence of Hageman factor as the initiator of the Kinin system
5888 Hageman factor activates the following 4 components of the plasma
protein systems:
5888 Clotting cascade through factor XI (11)
5889 Fibrinolytic system through conversion of plasminogen
5890 Kinin system by pre-kalikrein activator
5891 C1 in the complement cascade
5889 It is important to also consider the concept of homeostasis when considering
how the plasma protein systems influence the inflammatory response
5890 Imagine how we would feel if the plasma protein system effects were stimulated
without some measure of control
5888 We would be in a constant state of inflammation leading to much
discomfort
5889 Of course we do have mechanisms in place to control the effects of
inflammation so that they are self-limiting
5890 This is the concept of homeostasis defined as:
5888 The steady state an organism tries to maintain by self-
regulating adjustments
5889 In order to temper these inflammatory effects brought on by the
activation of the protein plasma systems, there are a great number of
circulating enzymes whose sole purpose is to inactivate the components of
the plasma protein systems, thus turning off the inflammatory response
when it is no longer required
5890 This is how we are able to maintain balance and control to
prevent injury to the tissues
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Inflammatory Mediators
23 This diagram reveals the vast array of inflammatory-derived mediators
24 On the left side, we see the plasma=derived mediators that are synthesized in the liver
25 We have just discussed the roles of those proteins in reviewing the plasma protein
systems
26 Now it’s time to turn our attention to the components to the right side
27 Those are referred to as cell-derived mediators of inflammation
28 It is important to note that cell-derived mediators are derived from pre-formed cells, like
mast cells, platelets, and neutrophils and macrophages, or newly synthesized in
response to need from leukocytes, macrophages, lymphocytes, and endothelial cells
29 Let’s look at some of these mediators produced in response to injury
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Cell Derived Mediators of Inflammation

Inflammatory Mediators are responsible for the wide variety of clinical manifestations seen with the
inflammatory response. In the normal state, cell derived mediators are held within intracellular
granules to be secreted at a time when the body is in need of protection from invaders or injury. We
are also capable of synthesizing additional mediators based upon need. The major sources of these
mediators include platelets, neutrophils, monocytes and macrophages and mast cells, endothelial
cells, smooth muscle, fibroblasts and most epithelial cells.
23 Several types of mediators exist and the can act on one, or several targets, and have
different effects on different types of cells. Most of these mediators are short lived
(think about homeostasis) as they are inactivated by enzymes, scavenged and
degraded. Let’s look at the properties and functions of these mediators in turn
5888 Histamine – vasodilation, increased vascular permeability, increased
adherence of leukocytes to the endothelium and bronchoconstriction
O Histamine is found in many places including well-perfused connective
tissue, circulating platelets and vasophills, and within mast cell granules
where it is released in response to trauma and immune reactions
involving in immunoglobulin E. Histamine binds to H1 receptors on
endothelial cells, causing vasodilation which helps to increase blood flow
to the microcirculation. It also contributes to increased vascular
permeability by causing retraction of endothelial cells and capillaries and
stimulates increased adherence of leukocytes to the endothelial.
Histamine also has some negative consequences as it causes smooth
muscle constriction of the bronchioles making breathing difficult on acute
inflammatory reactions. Thankfully, antihistamine, or H1 receptor
antagonist, medications are capable of binding to the H1 receptor to
compete with histamine to antagonize the many affects of the acute
inflammatory response
5889 Serotonin – smooth muscle contraction, small blood vessel dilation,
increased vascular permeability
O Serotonin is very similar to histamine in that it is released mainly by mast
cells, vasophills and platelets, and causes smooth muscle contraction,
small blood vessel dilation and increased vascular permeability
5890 Lysosomal Enzymes – fuse with phagocytes to destroy invaders
23 Lysosomal enzymes are small membrane enclosed sacs that contain very
powerful enzymes. These lysosomes are capable of fusing with
phagocytes for the purpose of destroying foreign invaders
24 Arachidonic Acid Metabolites – facilitate production of prostaglandins and
leukotrienes
23 Arachidonic metabolites are fatty acids found in phospholipids of the
cell membrane. They are released from mast cells and initiate complex
reactions that lead to the production of other inflammatory mediators
like prostaglandins and leukotrienes
25 Prostaglandins – induce inflammation, enhance effects of histamine and other
mediators, vasodilation, bronchoconstriction, increased neutrophil
chemotexis, cause pain and fever
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23 Prostaglandins are synthesized from arachidonic acid metabolites and

serve to induce inflammation and enhance the effects of histamine and
other inflammatory mediators. They promote vasodilation and
bronchoconstriction, and increase neutrophil chemotaxis, and cause
pain through direct action on nerves and fever. The use of aspirin and
non-steroidal anti-inflammatory drugs counteract this effect by
inhibiting prostaglandin synthesis
5889 Thromboxane A2 – platelet aggregation, bronchochonstriction,
vasoconstriction
23 Throboxane A2 are produced primarily by platelets at the site of injury,
and promotes platelet aggregation, bronchoconstriction and
vasoconstriction
5890 Leukotrienes – increased vascular permeability, smooth muscle
contraction, pulmonary constriction, affect adhesion, properties of
endothelial cells and extravasation, chemotaxis of neutrophils, eosinophils,
and monocytes
23 Leukotrienes have a similar function to histamine and are synthesized while
histamine is busy at work. They increase vascular permeability, induce
smooth muscle contraction and constrict pulmonary airways, thus playing a
major role in mediation of asthma and anaphylaxis. In addition, they affect
the adhesion properties of endothelial cells, and extravasation and
chemotaxis of neutrophils, eosinphils and monocytes. Leukotrienes, because
of their late start, help to prolong the inflammatory response
5891 Platelet Activating Factor – platelet aggregation, activation of
neutrophils, chemoattractant of eosinophils
23 Platelet activating factor is generated from lipids stored in the cell
membrane and induce platelet aggregation. It also serves to activate
neutrophils and potentially acts as a chemoattractant for eosinophils
5892 Cytokines/Chemokines – modulate the inflammatory response by other
cells
23 Cytokines and chemokines are proteins that play a role in both acute and
chronic inflammation and immunity. They are either pro-inflammatory or
anti-inflammatory. Again, remember the concept of homeostasis. They are
produced by many cell types including activated macrophages and
lymphocytes, endothelium, epithelium and connective tissue, and
modulate the inflammatory response by many other cells by travelling and
binding to and affecting the function of those target cells. There are
literally hundreds of examples of cytokines and chemokines. A few
examples of cytokines and their roles are shown on the diagram. For more
details on the many specific cytokines and chemokines, please refer to the
attachment for this module entitled: “Cytokines and Chemokines PDF”
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5888 Nitric Oxide – smooth muscle relaxation, antagonizes platelet

adhesion, aggregation and degranulation, regulates recruitment of
leukocytes
O Nitric oxide is produced by the endothelial cells and causes smooth muscle
relaxation and antagonizes platelet adhesion, aggregation and
degranulation. It also plays a role in regulating the recruitment of
leukocytes. Blocking of nitric oxide production promotes leukocyte
rolling and adhesion to capillary venules. Delivery of nitric oxide induces
leukocyte recruitment therefore production of nitric oxide reduces the
cellular phase of inflammation. Impaired production of nitric oxide is
implication in the inflammatory changes associated with atherosclerosis
and also has some antimicrobial properties
5889 Oxygen-Derived Free Radicals – at low levels, increases expression of
cytokines and adhesion molecules; at high levels, can damage endothelium with
increased vascular permeability
O Oxygen-free radicals are often released by leukocytes after exposure to
microbes, cytokines and immune complexes, ordering the phagocytic
process. Releasing of low levels increases the expression of cytokines
and endothelial adhesion molecules, enhancing the inflammatory process.
At high levels, they can cause significant damage to the endothelium
leading to increased permability
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Depiction of the Inflammatory Response
Shows the steps of injury to clinical manifestation
Two Phases of Inflammation

23 Introduction: Two phases of inflammation
O Vascular
O Cellular
23 We learned earlier in this module that there are two phases of
inflammation: vascular and cellular. We will look at both
separately, beginning with the vascular phase
24 Vascular – changes in vessel diameter leads to increased blood flow to the area of
injury
O Vasoconstriction (brief)
O Vasodilation, increased blood flow to area
O Slowing of blood flow velocity
O Increased hydrostatic pressure
O Heat and redness
With any injury to tissue, there is an initial, brief period of arteriolar vasoconstriction, followed by
a more profound vasodilation of the vessel. With vasodilation, the increased vessel size encourages
increased volume of blood to the area of injury and velocity of blood flow slows,
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increasing hydrostatic pressure. Biochemical mediators causes retraction of the endothelial cells,
increasing spaces between each cell resulting in increased vascular permeability as large proteins
now leave the vessel, move into the extravascular space, they take fluid along with them. Blood
then becomes more viscous, further slowing velocity of flow and leukocytes begin to stick to the
endothelium and then migrate out to the site of injury. To review then, the three major changes in
the microcirculation during the vascular response to inflammation include: brief vasoconstriction
followed by vasodilation, increased capillary permeability and movement of leukocytes into the
tissues. This process leads to the five cardinal signs of inflammation: heat, redness, edema, pain
and loss of function
5888 Cellular – leukocytes and other cells migrate from the circulation to the
tissue to eliminate offending agent
Permeability Changes
Examples of chemical mediators that bind to endothelial mediators to cause retraction include
histamine, bradykinins and leukotrienes etc. When mediators bind to receptors on endothelial
cells, the cells begin to retract leaving wide gaps between them. As a result, proteins and
molecules that were once too big to squeeze between the endothelial cells can now leave the
vessel quite freely taking water along with them. Loss of water into the extravascular space leads
to a decrease in osmotic pressure within the blood vessel and edema of the tissues. The
individual will also experience discomfort and quite possible impaired function. Also, with a
loss of fluid from the intravascular space comes increased blood viscosity. The blood becomes
thick and sluggish, leading to a slower flow. Now the leukocytes are much more able to stick to
the endothelium and prepare to leave the area to travel to the site of injury
5888 Binding of mediators to endothelial receptors
5889 Endothelial cell retraction
5890 Loss of proteins and water into tissue
5891 Decreased osmotic pressure
5892 Edema, pain and impaired function
5893 Increased blood viscosity
5894 Low velocity flow
5895 Leukocytes stick to endothelium
Vasodilation and Increased Permeability

23 Highlights the vascular phase of inflammation
24 The first picture on the left shows a normal capillary with very tight
endothelial cell junctions. No large particles are allowed to pass through under
normal conditions
25 In the second picture however, you can see that the vessel has become dilated and
the gaps between endothelial cells have widened. As a result of this vasodilation
and increased capillary permeability, proteins and inflammatory components are
permitted to pass through the vessel into the tissues where they are needed
26 One very helpful tip is to remind you that wherever protein goes, water follows.
Thus it makes sense then that the blood left behind in the vessel becomes much
more viscous and sticky, and the fluid leaking from the vessel into the tissues
causes an accumulation of extravascular fluid or edema in the tissues
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Vascular Changes of Inflammation

5888 Image depicts the original arteriolar vasoconstriction, followed by
vasodilation and increased capillary permeability, with resultant leakage of
proteins, cells and fluid out of the vascular space into the tissues
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Cellular Phase of Inflammation

Now let’s discuss the cellular phase of inflammation. Several simultaneous events occur
during the vascular and cellular phases of inflammation
23 Endothelial lining changes
23 As previously mentioned, the endothelial lining undergoes changes, which
results in increased vascular permeability, and loss of fluids and
substances into the tissue. How this occurs is an interesting process
involving a series of simultaneous steps. Let’s first look at the process
of leukocyte emigration
24 Leukocytes head to the site of injury (emigration)
25 Chemical mediators are released from tissue cells (mast cells and macrophages)
23 During normal conditions, cells float within the blood vessel continuously
and the endothelium secretes nitric oxide causing vasodilation and limiting
the sticking of cells to itself. Again, think of the concept of homeostasis.
During inflammation, as biochemical mediators are released from mast
cells, activation of plasma proteins are released from dying cells and
cause production of adhesion molecules on the surface of many cells
involved in inflammation. These adhesion molecules cause certain cells,
like leukocytes and platelets, to become sticky and they adhere to the
endothelial wall
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Emigration of Leukocytes
5888 Initially, leukocytes are “recruited” to the site of injury and facilitated
to linger there, by the slowing of blood flow. They line up and move alone the
endothelial wall (rolling) and “adhere” to it, with the help of those adhesion
molecules we talked about earlier. Some of the adhesion molecules are
“selectins”, “integrins”, and members of the lg superfamily (ICAM-1, ICAM-2
and VCAM-1) and are found on both leukocyte and endothelial cell walls and are
complementary, meaning they fit together like a lock and key. Then, through a
process called “chemotaxis”, leukocytes are encouraged to move into the tissue
where the injury has occurred
5888 In this slide you can click on each term to view the definition.
Initially, as leukocytes are recruited to the site of injury, they move along
the endothelial wall and are facilitated to linger there by the slowing of
blood flow. They then line up and adhere to the endothelium with the help
of those adhesion molecules we talked about earlier. Some examples of
adhesion molecules are selectins, integrins, and members of the
immuneglobulin superfamily (ICAM-1, ICAM-2 and VCAM-1) and are
found on both leukocyte and endothelial cell walls and are complementary,
meaning they fit together like a lock and key. Then, through a process
called chemotaxis, leukocytes are encouraged to move into the tissue
where the injury has occurred
5889 Magination – Leukocytes move along the endothelial wall
5890 Adhesion – leukocytes stick to the endothelium with the help of
adhesion molecules
5891 Transmigration – leukocytes move to the site of injury in response to
chemotactic factors
5892 Chemotaxis – a response involving cell orientation or cell movement that
is either toward (positive chemotaxis) or away from (negative chemotaxis) a
chemical stimulus
Margination, Adhesion and Transmigration

23 Leukocytes and endothelium interact via adhesion molecules
23 As we learned earlier, as blood volume to the injury increases, hydrostatic
pressure also increases and velocity of blood flow slows. Leukocytes, or
white blood cells in the area, tend to linger here for a bit. Again, to review,
the release of cytokines, the communication signals, cause the
endothelium to express adhesion molecules that bind to leukocytes,
tethering them to the endothelium wall further leading to sluggish forward
movement of these cells
24 Slow movement
25 Tight adherence
26 Migration along the vessel periphery
27 Movement through cell junctions
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23 As leukocytes slow down, they adhere to the endothelial surface via

intercellular adhesion molecules or ICAMs. Once attached to the ICAMs,
the endothelial cells begin to separate and leukocytes work their way, via
pseudopod like movements, through these junctions. This process is
called transmigration and is encouraged by a process called chemotaxis
Margination, Adhesion and Transmigration

This diagram clearly shows the process of leukocyte margination, rolling, tethering, adhesion,
and transmigration in response to inflammation
Chemotaxis
Feel free to click on this link http://www.gluegrant.org/chemotaxis.htm to view an animated
image of neutrophil chemotaxis
5888 A dynamic process
5889 Cells move in response to chemical gradients
5890 Chemotactic factors are also called “chemoaattractants”
5888 Chemotaxis is a dynamic process of directed cell migration. When
leukocytes leave the capillary, they move in response to a chemical
gradient caused by chemokines, bacterial and cellular debris, and protein
fragments derived from the compliment system. Both immune and non-
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immune cells ensure that leukocytes move in the appropriate direction.

Chemotactic factors, also called chemoattractants, cause directional
movement of cells towards the site of injury. Examples of chemotactic
factors include neutrophil chemotactic factor and eosinophil
chemotactic factor, and these are both contained in mast cells
Chemotaxis
This is another depiction of the process of chemotaxis
Leukocyte Activation and Phagocytosis

23 Opsonization of microbes
24 Activation of major phagocytes (granulocytes and monocytes/macrophages)
25 Formation of pseudopods
26 Engulfment of bacteria and cell debris
27 Degradation of lysozomal enzymes
23 Some offending microbes are tagged or opsonized by a compliment factor
know as C3B, and by various antibodies of the immune system.
Opsinization enhances recognition and binding activity of the phagocytes,
acting like glue between the phagocyte and the target. Major phagocytes
including monocytes, neutrophils and tissue macrophages are activated by
injured tissue, which triggers the leukocyte response for
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phagocytosis and cell killing. Neutrophils are then activated to form

pseudopods that will encircle the offending organism or debris. Then,
the phagocyte will fuse with an intracellular lysosome to will form a
phagolysosome which will release its enzymes and oxygen radicals
to attack and destroy the offending microbe
Phagocytosis Process Review

Here is a list of all the steps involved in phagocytosis. The process of phagocytosis begins with
margination, or the slowing or adherence of leukocytes (mainly neutrophils) to the endothelium).
They move along the periphery of the blood vessels and they accumulate in clusters. Their goal
now is to find the target and phagocytise or destroy it by capture or digestion. The plasma
membrane of the phagocyte extends into finger-like projections, through the gaps between
individual endothelial cells, and leaves the blood vessel by digesting the basement membrane and
squeezing between the cells. Now the phagocyte migrates or moves towards the target which has
been opsonized by complement C3b or antibodies that have tagged or marked the target cell to
make it more recognizable to the phagocyte and to allow for enhanced adherence to the
phagocyte. Upon reaching the target, the phagocyte uses the finger-like projections to surround
and engulf the target. This engulfment creates a new vacuole containing the target (called a
phagosome). This phagosome fuses with the lysosome to form a phagolysosome. Finally, the
enzymes contained within the phagolysosome work on the destruction and digestion of the target.
Once phagocytes have destroyed the foreign material, they die and become exudate or pus.
Phagocyte products exit via the lymphatics.
5888 Margination
23 Leukocytes slow migration, adhere tightly to the endothelium and move along
the periphery of the blood vessels where they accumulate
24 Pseudopod Formation
23 A process in which the plasma membrane of the phagocyte extends in finger-like
projections
25 Diapedesis
23 Movement of leukocytes through the widened junction between endothelial
cells into the tissue
26 Migration
23 Phagocytes move toward the target
27 Opsonization
23 A process whereby adherence is enhanced between the phagocyte and the target
cell
28 Engulfment
23 A process in which the phagocyte pseudopods surround and encircle the target,
forming an intracellular phagocytic vacuole, or “phagosome”
29 Fusion with lysosome
23 A process whereby the phagosome merges with a lysosome to form a
phagolysosome
30 Destruction
23 The target is destroyed; the ultimate goal of phagocytosis
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5888 Once phagocytes have destroyed the foreign material, they themselves die
off and become exudate (pus). Phagocytic products exit via the lymphatics
Phagocytosis
Here is a diagram illustrating all of the steps involved in the activity of a phagocyte. In addition,
you can see the formation of a phagosome, when a microorganism is engulfed by the phagocyte.
When phagocytes die, the lysosomal contents are released and these can be toxic to surrounding
tissues, causing: increased permeability, chemotaxis for monocytes, connective tissue breakdown,
and activation of the plasma protein systems. In order to avoid toxicity, alpha 1-antitrypsin (a
plasma protein from the liver) is released and it inhibits the destructive effects. Feel free to have a
look at the video on the next slide which shows all of the effects of phagocytosis.
Phagocytosis Video
http://www.youtube.com/watch?v=7VQU28itVVw
In phagocytosis, phagocytes are attracted to the areas of invasion by chemical products of the
microorganism, possible lipids released by injured mammalian cells, or by components of the
complement system. The phagocyte moves into the area of invasion and then attaches to the
microorganism. The attachment is mediated by a variety of surface attachers, including antibody
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lipopolysaccharide and complement receptors. For example, the C3b component of complement
codes bacteria or other particles, and then binds to C3b receptors on the phagocyte. This process
of coding to enhance phagocytosis is called opsonisation. The microorganism is then engulfed by
the phagocyte into a vacuole known as a phagosome. Vesicles in the cytoplasm, called
lysosomes, fuse with the phagosome, releasing digestive enzymes (such as lysozyme and
proteases) into the phagosome. The structure resulting from this fusion is called a
phagolysosome. Inside the phagolysosome, microorganisms are killed and digested. Finally, the
digested contents of the phagolysosome are eliminated from the phagocyte by exocytosis.
Local Manifestations of Inflammation

Now that we have discussed acute inflammation in great detail, let’s see if you can identify the
pathophysiological processes that cause each of these clinical manifestations of inflammation:
23 Heat
5888 Caused by vasodilation and increased movement of blood to site of injury
5889 Redness
5888 Caused by vasodilation and increased movement of blood to site of injury
5890 Edema
5888 Caused by vasodilation, increased movement of blood to site of injury,
increased capillary permeability, leakage of proteins and cells out of the
endothelial wall taking water with it; results in increased fluid in the tissues
5891 Pain
5888 Increased fluid in tissues causes pain; as well prostaglandins act directly
on nerve endings to cause pain and the end product of the kinin system
(bradykinin) also contributes to the pain response
5892 Pus
5888 As neutrophils die off, their contents become exudate (pus)
5893 Clot
5888 Initiation of the clotting cascade results in formation of a
thrombus; acts to sequester invaders in the areas of injury
5894 Loss of Function
5888 May be due to edema and pain
Chronic Inflammation
23 Longer lasting
24 Preceded by acute inflammation
25 Organism resistance
26 Formulation of granulomas
Sometimes the acute and inflammatory process does not lead to healing and repair as quickly as
we would like. After a two week period, the inflammatory process is now considered to be
chronic as opposed to acute. Some organisms, like mycobacteria and tuberculosis, have waxy
cell walls that are not well phagocytised. Therefore, inflammation persists. Other organisms (like
leprosy, syphilis, and brucellosis) can survive within microphages. Others release tissue-toxic
chemicals upon their death. Granulomatous inflammation is characterized by infiltration of
lymphocytes and microphages. The body isolates the site and walls it off. Granuloma is
encapsulated by fibrous deposits and can become calcified. Some of these infections include:
listeria, brucella, histoplasmosis, and parasitic infections like schistosomiasis and toxoplasmosis.
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When you view the next slide, you will be able to view an animation of the inflammatory
process, and you can also open the attachment where you will have access to a chart on the
inflammatory process.
Overview of Inflammation Video

Inflammation is the protective reaction of vascularized tissue to local injury. Acute inflammation
is the early (almost immediate) reaction of tissue to the injury, and it is the first phase of wound
healing. Acute inflammation can be triggered by cell or tissue damage, or by the presence of
dead cells or noxious agents such as bacteria. Acute inflammation typically occurs before the
immune response becomes established, and aims primarily at removing the injury-causing agent
and limiting the extent of tissue damage.
Acute inflammation occurs in two overlapping stages: vascular and cellular. In the vascular stage,
arterioles and venules near the site of injury constrict briefly and then dilate. Dilation promotes
congestion while an accompanying increase in capillary permeability leads to the movement of
fluid into the affected tissue, resulting in the five classic signs of inflammation: redness, swelling,
heat, pain, and loss of function. As fluid leaves the capillaries, the blood remaining in circulation
becomes more viscous  it flows more slowly and clotting occurs. The cellular stage of acute
inflammation is initiated by the movement of phagocytic white blood cells or leukocytes into the
area of injury. The leukocytes begin to adhere to the vessel wall, and then in a process called
emigration, they squeeze through the wall and into the inflamed tissue. The leukocytes wander
through the tissue, guided by chemical signals in a process called chemotaxis. The cellular stage
culminates in the leukocytes engulfing and degrading the bacteria and cellular debris in a process
called phagocytosis. Products of phagocytosis, along with plasma and blood cells, form exudates
which accumulate, causing swelling and pain. Exudates are composed of serous fluid, red blood
cells, fibrinogen or tissue debris, and white blood cell breakdown products. Concurrent with the
events of the vascular and cellular stages, chemical mediators release bioactive agents that act to
mediate the inflammatory response. Mediators are derived from the cells or from the plasma.
One of the first mediators of an inflammatory response is a cell derived mediator: histamine.
Histamine is found in high concentrations in the mast cells of connective tissues adjacent to blood
vessels, as well as in blood basophils and platelets. Histamine is released in response to a variety of
stimuli, and causes dilation and increased permeability of capillaries. Serotonin, another cell-
derived mediator, performs similar actions. The three major plasma derived mediators are present in
the plasma in precursor forms that must be activated, usually by a series of proteolytic enzymes. The
kinins increase capillary permeability and stimulate pain receptors. The clotting system traps
exudates, microorganisms, and foreign bodies. The complement cascade causes vasodilation,
promotes leukocyte chemotaxis, and augments phagocytosis. Acute
inflammation comprises a variety of complex responses to injury that, together, lay the
groundwork for the next stages of the body’s recovery: immune response and tissue repair.
Inflammation and Atherosclerosis

5888 Endothelial injury or excess LDLs
5889 Turning on of adhesion molecules
5890 Leukocytes (monocytes) become sticky
5891 Oxidation of LDLs
5892 Signal to macrophage
5893 Triggering of inflammatory response
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23 Release of mediators (arachidonic acid-like compounds, prostaglandins, leukotrienes) and

cytokines
Now that we have examined the basic concepts of the inflammatory response, let’s look at
one particular disease and the role that inflammation plays in its progression.
Recall the normal endothelium that we looked at earlier. Remember that the junctions between
endothelial cells are normally tight. With injury or elevated cholesterol (especially LDLs)
monocytes become sticky and attach to the endothelium in response to adhesion molecule
expression. As a result, the endothelium begins to produce far less antithrombotic and
vasodilating cytokines. Inflammatory cytokines and growth factors are released and monocytes
begin to move into the endothelium, and platelets become activated. Macrophages emerge from
monocytes (remember how monocytes mature and become macrophages), and free radicals are
released. LDLs then undergo the process of oxidation. Microphages consume the LDLs, which
transforms them into foam cells. Foam cells release growth factors and cytokines that further
the process of atherogenesis (development of atherosclerosis). Oxidation of LDLs provides one
signal that is recognized by surface receptors on the macrophage and the inflammatory response
is triggered, causing further endothelial injury. Phagocytes are stimulated, and they release
mediators which are arachidonic acid-like compounds or prostaglandins or leukotrienes, causing
changes in surrounding tissue. The phagocytes also release protein mediators, such as cytokines,
which interact with local tissue cells in a pro or anti inflammatory way.

5888 Communication between innate and adaptive immune response
5889 Processing and presentation of antigen to immune cells
5890 T cells communicate with innate immune system
5891 Destruction of antigen
5892 T cells communicate with B cells
5893 Formation of a lineage of cells SPECIFIC to this
Meanwhile, there is a fair bit of communication between the innate and adaptive immune
responses. Normally, antigen processing cells of the immune system patrol the environment
looking for foreign invaders. When found, these cells process and present them to other cells of
the immune system. In the presence of inflammation caused by endothelial injury and oxidation
of LDLs, T lymphocytes from the immune system are also attracted the site of injury by
chemoattractants, and respond to the presence of adhesion molecules that subsequently form. T
cells communicate with the innate immune system and some cells are able to destroy the
antigen. So in this way, both the inflammatory and immune responses cooperate in an effort to
deal with the process of atherogenesis.

23 Platelet stimulation and activation
24 Proliferation and migration of smooth muscle cells
25 Turning on of adhesion molecules by innate and adaptive immune systems
With endothelial injury, the subendothelium is exposed to blood components and platelets adhere and
aggregate at the site of injury. This is followed by smooth muscle proliferation. Smooth
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muscle proliferation causes the endothelial layer to pouch out, making the lumen of the
vessel smaller. To see a diagram depicting smooth muscle proliferation, look below:

5888 Formation of lipid core
5889 Formation of protective fibrous cap
5890 Lymphocyte signals halt collagen formation on cap
5891 Overexpression of enzymes eat away at the protective cap
5892 Signals produce prothrombogenic mediators
5893 Formation of a clot
5894 Occlusion of vessel
5895 Infarction of myocardium
As lipids continue to accumulate beneath the endothelial layer, a hard lipid core is formed.
Lymphocytes send a signal to the smooth muscle cells to halt formation of collagen. At the same
time, there is an over-expression of enzymes that begin to eat away at the protective fibrous cap.
Atherosclerotic plaques are now considered to be unstable or vulnerable, as they can rupture or
fissure, which encourages the formation of an occlusive thrombus. Lesions become complicated
once they begin to fissure or rupture. Signals are then produced that encourage formation of
prothrombogenic mediators. Blood flowing over the lesion is filled with platelets that adhere to
the lesion, and a thrombus is formed (aided by an expression of pro-coagulated factors). This
thrombus serves to occlude the blood vessel, either partially or fully, resulting in pain, angina, or
myocardial infarction. According to recent research, inflammation appears to be at the heart of
coronary artery disease or atherosclerosis. Knowing this gives scientists more input as to find
new ways to predict and prevent this insidious disease.
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Conclusion
Now that we have discussed the basics of inflammation, think about some of the inflammatory
conditions you may have encountered so far. Have you ever had a sliver in your finger or
developed a blister touching something too hot? Now you should be able to list each of the
clinical manifestations you may have seen (redness, swelling, blistering, pain, pus), and explain
the pathophysiological processes responsible for the clinical manifestations.
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Module 4: Depression
Statistics
Mood disorders are disorders of emotion, including mania and depression. 10% of
Canadians are affected. These disorders are highly underdiagnosed and undertreated. Depression
is among the leading cause of disability worldwide, with approximately 8% of adults
experiencing major depressive episodes at some time in their lives. Suicide is estimated to be the
cause of death in up to 15% of individuals with major depressive disorder. The prevalence of
major depression among women is double that in men. It is thought that the reason for this is that
women are more apt to recognize mental health issues and go to their doctor.
In research conducted by the National Institute for Mental Health, they found that when
speaking to men in focus groups, depression often becomes masked. For example, in sematic
complaints, like migraines, back pain, or irritable bowel syndrome, it is therefore often not
recognized as depression. The true neurological basis for the increased prevalence in women is
unknown, but is also thought to be related to differences in hormonal status, or stress response
systems, or to sexual differences between the sexes in any of several brain areas. The prevalence
of bipolar disorder or manic depression is approximately 1% in the population at large,
approximately equally distributed between men and women.
Learning Outcomes
Objectives for today are:
23 To gain a basic understanding of the pathophysiology ofdepression
24 To describe the risk factors and symptoms of depression
25 To understand the process of neurotransmission
26 To identify which neurotransmitters are implicated indepression and how they work
27 To explain the anatomical changes associated withdepression
28 To describe the neuroendocrine system changes associatedwith depression
29 To identify treatments for depression includingpharmacological and non-pharmacological
therapies anddescribe how
DSM-IV-TR Criteria for Depression

Mood disorders are disorders of emotion including mania and depression. For this module, we
will be focusing on Depressive Disorders which are commonly divided into two categories:
5888 Major Depressive Disorder which is characterized by a persistent unpleasant
mood
5889 Dysthymia which is characterized by chronic mild depressive
symptoms (so the symptoms are the same, they’re just in a milder form in
dysthymia)
The DSM 4 Diagnostic Criteria for a Major Depressive Disorder include the simultaneous
presence of 5 or more of the following symptoms during a 2 week period. These represent a
change from previous functioning.
Major Depressive Disorder

2 Depressed mood
3 Anhedonia (inability to experience pleasure)
4 Feelings of worthlessness or excessive guilt
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concentration
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agitation or retardation, insomnia or hypersomnia, decreased libido
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appetite
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suicide ideation
Sub Classifications of Depression

I will not be focusing on these sub classifications. Several medical illnesses such as diabetes,
heart disease, autoimmune disorders and pain are common comorbid diagnoses.
0 Melancholic features, atypical depression
1 Depression with psychotic features
2 Depression with catatonic features
3 Postpartum specifier
4 Dysthymia
Risk Factors for Depression

The following is a list of risk factors or environmental in-life history events that can contribute
to the etiology of depression.
0 Childhood emotional, physical, and sexual abuses
1 Prior episode of depression
2 Family history of depressive disorder
3 Lack of social support
4 Stressful life event
5 Current substance abuse
6 Economic difficulties
Etiology of Depression
The etiology of depression is:
23 Multi-factorial
24 Dynamic interplay amongst:
O Genetic predisposition
O Environment
O Life history O
Development
O Biological challenges
Much of the research in the past 40 years has focused on the deficits in the
neurotransmitter systems. It is currently believed that major depressive disorders arise
from the complex interactions of genes and environmental factors.
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Brain Math
Pathophysiology is the study of what happens at the cellular level to cause disease. For
the pathophysiology of mental illness, we are talking about what happens inside the brain. That portion
of the central nervous system is contained within the cranium. So let’s do a little bit of
brain math. There are about 100 billion neurons or nerve cells, and 10-50 trillion neuroglia which
support the nerve cells in the brain. The brain has a mass of about 1300 grams or 3 pounds in
adults. On average, each neuron performs 1000 synapses with other neurons. The total numbers
of synapses is about 1000 trillion, which is larger than the number of stars in the galaxy. Just from
these numbers, you can conclude that the brain is a very complex organ and it is quite complex to
try and understand how it works and what happens at the cellular level, or in this case, the level of
the neuron to cause depression.
Genetic-Environment Interaction
So now, let’s talk about the genetic component of depression. Major depression is
more common amongst first degree relatives than the general population. Family, twin, and
adoption studies suggest the hereditary component to the etiology of mood disorders.
Hereditability for depression has been estimated from twin studies as 31-42% with a substantial
contribution of environmental effects unique to individuals of 58-67%. So again, the cause is
partly genetics and partly environment.
Scientist have not identified a gene or a series of genes that cause depression, rather
certain variations in genes, called polymorphisms may increase the risk for depression. Genes
can predispose individuals to major depressive disorder in many ways. For example, genes help
control the metabolism of neurotransmitters and their receptors, the number of particular types
of neurons and their synaptic connections, the intracellular transduction of neuronal signals, and
the speed with which all of these can change in response to environmental stressors.
The serotonin transporter gene is the most studied in major depressive disorder. This
gene is of interest because it contains a polymorphism that gives rise to two different alleles,
long and short. As you know, people usually have two copies of each gene in their DNA.
Therefore, a person can be homozygous for the long allele, homozygous for the short allele, or
heterozygous, one long and one short. The short allele slows down the synthesis of the serotonin
transporter. This is thought to reduce the speed with which serotonin neurons can adapt to
changes in their stimulation.
Serotonin is one of the neurotransmitters implicated in depression and we will talk about
this in more detail a little later on. At present, it just important to remember that the short allele in a
serotonin transporter gene slows down the synthesis of the serotonin transporter, leading to the
dysregulation of serotonin, and that this process has been implicated for depression.
Genetic Predisposition: Brain Derived Nerotropic Factor (BDNF)

BDNF is also implicated in depression. BDNF is a growth factor that:
23 Plays an Important role in birth, survival and maturation of brain cells
during development
O As described in the article, BDNF is a protein found in high concentrations in the
brain. BDNF is important for neuronal cell growth and well as the synaptic

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changes that occur throughout a person’s life. BDNF contributes to

these processes by:
5888 Activating DNA binding factors that stimulate genes involved in serotonin
function
Genes such as the serotonin transporter and tryptophan hydrolase, the serotonin synthesizing
gene. Activation of serotonin receptors in turn, stimulates the expression of the BDNF gene.
During brain development, this cyclic process promotes outgrowth, synapse formation, and
survival of serotonin neurons and the eventual innervations of multiple brain regions. The
ability of the serotonin system to adapt and change in response to various stimuli continues to be
influenced by BDNF throughout life. It is believed that BDNF may be the link between stress,
neurogenesis, and hippocampal atrophy in depression. It’s important to remember that:
5888 People diagnosed with major depressive disorder have lower levels of BDNF
It’s also important to note here that BDNF may be not only related to depression, but to
multiple psychiatric disorders.
BDNF: val/met genotype

As described in the review article, a common polymorphism in the gene that codes for
BDNF produces alleles called val and met. This polymorphism affects the intracellular transport
and secretion of BDNF.
23 Val and met alleles in gene that codes for BDNF
People with met allele have been found to have a relatively small hippocampus at birth,
hippocampal activity at rest, hippocampal hyper activation during learning, and relatively poor
hippocampus dependent memory function. The hippocampus is significant to depression because
it is believed to module the cognitive aspects of depression such as memory impairments, and
feelings of hopelessness, guilt, doom, and suicidality. Studies have found that the met allele in
addition to having the short allele of the serotonin transporter in psychosocial stress increases
vulnerability to depression.
5888 People with met allele increases a person’s vulnerability to depression
Further evidence has found low levels of BDNF in hippocampus and prefrontal cortex of
symptomatic depressed patients. Serum studies have shown that serum levels of BDNF are abnormally
low in patients with major depressive disorder. We don’t normally test BDNF levels
in our patient to diagnose them with depression. Depression is diagnosed based on the DSM-IV
symptoms previously mentioned. It is important for scientists to know about BDNF so they can
try to figure out the best way to increase these levels when treating patients with depression.
Neurobiological Theory
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So far, we have discussed the pathophysiology of depression as being related to a genetic

hereditability of a polymorphism of a short allele which slows down the synthesis of a serotonin
transporter, a genetic hereditability of the polymorphism of the met allele in the gene that codes
for BDNF and will now turn to neurobiological theory which suggest that major depression is
caused by deficiency or dysregulation in the central nervous system concentration or neural
transmitters.
The noradrenergic and serotonergic systems which originate deep in the brain and fan out
over almost the entire brain and modulate many areas of feeling, thinking, and behaving are
implicated in depression. Take a moment now to review the source and effect of brain
neuromediators included in the table. From this table, you will see that norepinephrine and
serotonin under activity is thought to be involved the development of depression.

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Neurotransmission
5888 As you’ll likely remember from A & P and pharmacology courses,
nerve cells communicate with one another by a process called
neurotransmission
5889 Nerve cells communicate by electrochemical signals which cross the point at
which two neurons meet of the synapse
5890 Chemical substances, called neurotransmitters, are released from the axonal
terminal from one neuron, which is called the presynaptic cell
5891 The neurotransmitter then crosses the synapse and binds to the receptors
of the postsynaptic cells and causes and excitatory or inhibitory action
5892 Take a moment to watch the YouTube video “The Brain: Emotions, Neurons,
Neurotransmitters” by David Suzuki
5893 YouTube video:
23 Underneath the newfangled cortex, the brain stem, the limbic system,
and the basal ganglia date back to the mastodons, the dinosaurs, and the
first amphibians
24 In humans, the old parts of the brain oversee emotions and help
build memories
25 They control HR and breathing
26 They also form intimate connections with the new brain: the cortex
27 Less than a ¼ inch thick, the cortex is the brain’s crowning glory
28 Among its roles, the cortex is our reality check: it filters and orders the
outside world for us; it allows us to see, touch, hear, and speak
29 The cortex is also the human thinking cap: all our plans, thoughts and ideas
originate in this layer
30 The cortex is packed with nerve cells. About 2/3 of all our neurons operate
here
31 A piece of cortex tissue, no larger than a pinhead, can house 30 000 of these
cells
32 Each neuron has a job: to communicate with other neurons
33 The brain works by forming networks with these cells
34 The long spiny branches of the network create a neural forest of
astounding intricacy
35 Neurons use these communication lines to communicate with each other
via electrical and chemical signals
36 Here under a microscope are two neurons linking up
37 Though it may look like they fuse together, neurons don’t actually
touch each other
38 A closer look reveals that a tiny gap, called a synapse, separates their
branches: this is where a neurons passes one message to the next
39 The message comes from small sacks that store chemical molecules
40 When stimulated, these sacs release their molecules which cross the
cell membrane synaptic gap and the electric zap allows this to happen
41 Meanwhile, the receiving neuron has special receptor sites for the
incoming molecules
42 These receptor sites bind with the molecules causing special gates to open up

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5888 The gates let in a flood of charged particles, sodium and potassium
ions, which start up a new neuroelectrical signal in the receiving neuron
5889 This simple chain of events – an electrical zap followed by chemical
changes followed by another electrical zap – is the basis of all brain
activity (it’s how neurons speak to each other)
5890 This is the key to the brain’s complexity: there are a hundred million
neurons in the brain; each neuron processes its information then hooks up
with as many as 50 000 other neurons to send and receive messages
23 A hundred billion neurons times 50 000 connections: it’s this
complexity that allows us to think imaginatively
24 On their own, neurons aren’t very bright, but put them all together in a
small space and let them start communicating with one another, and you
start to get brain storms
25 The trillions of neural networks, like an improvisation of an orchestra, create
new ideas and connect different thoughts in a whimsical and sometimes
inspired fashion
26 It is this impromptu ability to produce new things in our brains that allows
us to progress
Neurotransmission
5888 From the video and your previous science courses, you know that
neurotransmission involves several discreet steps
5889 Many of you will remember these steps and may want to skip the next 2
slides which are here as a review of your prior learning regarding
neurotransmission
5890 As a review, neurotransmission involves:
23 The synthesis of a transmitter substance
24 Storage and release of the transmitter
25 Binding of the transmitter to receptors on the postsynaptic membrane
26 Removal of the transmitter from the synaptic cleft
Synaptic Transmission: Neurotransmitter Synthesis & Release

23 We can now look at neurotransmission in a little more detail here
24 Neurotransmitters are typically stored in the vesicles in the presynaptic axonal
terminal and released by the process of exocytosis
5888 Synthesis and Release
23 The first step in synaptic transmission is synthesis and release
24 Neurotransmitters are synthesized in the presynaptic neuron, and then
stored in synaptic vesicles
25 Communication between the two neurons begins with the nerve
impulse that stimulates the presynaptic neuron, followed by
movement of the synaptic vesicle to the cell membrane, and
release of the neurotransmitter into the synaptic cleft

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23 Receptor Binding
5888 The second step of synaptic transmission is receptor binding
5889 Once released from the presynaptic neuron, the
neurotransmitter moves across the synaptic cleft and binds to
receptors on the postsynaptic neuron
5890 The actions of a neurotransmitter is determined by the
type of receptor – excitatory or inhibitory – to which it binds
5891 Binding of a neurotransmitter to a receptor from an excitatory
function often results in the opening of an ion channel, such as
the sodium channel
5892 Many presynaptic neurons also have receptors to
which a neurotransmitter binds
5893 The presynaptic receptor functions in a negative feedback
manner to inhibit further release of the neurotransmitter

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23 Neurotransmitter Removal
5888 The third step in synaptic transmission is neurotransmitter removal
5889 Precise control of synaptic function relies on the rapid removal
of the neurotransmitter from the receptor site
5890 A released neurotransmitter can be:
23 Taken back up into the neuron in a process called reuptake
24 Diffused out of the synaptic cleft
25 Broken down by enzymes into inactive substances or metabolites

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Biogenic Amine Hypothesis

23 Serotonin &Norepinephrine
O Decreased levels
5888 The biogenic amine hypothesis suggests that decreased levels of
neurotransmitters serotonin and norepinephrine in the synaptic cleft –
due to either decreased presynaptic release or decreased postsynaptic
sensitivity – is the underlying process of depression
5889 It is believed that a reduction in serotonin synthesis may
result in depression, but also that depression may result in a
reduction of serotonin synthesis (we have a bit of a “chicken
and egg” theory going on here)
5890 We know that when serotonin levels are depleted
experimentally In humans by oral treatment by decreasing the level
of tryptophan (a precursor to serotonin), healthy individuals
without a personal or family history of major depressive disorder
tend to not show any mood changes while persons in who have
been successfully treated with serotonin reuptake inhibitors will
relapse into depression
5891 This research has shown that lowering serotonin factors
doesn’t induce depression in all people, thus supporting the
genetic environmental factors we had previously discussed
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5888 Dopamine
5888 Decreased in depression
5889 Increased in mania
23 Dopamine activity has also been implicated in mood disorders with
decreased activity in depression and increased activity in mania
24 Studies show that the frequency of depression is higher in patients
with Parkinson’s Disease, which is caused by lower rates of
dopamine production in the substantia nigra
Neurophysiology of Symptoms: Prefrontal Cortex

0 Introduction:
23 Research into brain anatomy has shown that the effects of genetics,
environment and deficiencies or dysregulation of the CNS concentrations of
neurotransmitters causes anatomic changes in many areas of the brain
1 Prefrontal Cortex:
23 The prefrontal cortex is part of the cerebral cortex, which covers the
outermost part of the brain which is the most evolved portion of our brain
24 It is described as the chief administrator of the brain and is responsible for
planning, problem solving, intellectual insight, judgement and expression
of emotion (regulates thinking and mood) and has extensive connections
with deeper parts of the brain
25 In some cases of familial major depressive disorder and bipolar disorder,
PET and MRI scan studies have demonstrated a reduction in the volume of
grey matter in the prefrontal cortex , with an associated decrease in activity
in that region
26 The prefrontal cortex is reduced and less active because of a decrease in
the neurotransmission of serotonin and norepinephrine and alterations in
the neurotransmission of dopamine in this area
27 There has also been found to be a decrease in BDNF in the prefrontal
cortex\this decrease in neurotransmitter activity leads to a decrease
in neuronal volume because pathways are not being used
28 So density of these pathways decreases and there is a pruning of these
pathways
2 What is a PET scan?
23 Positron Emission Tomography
24 The variable brain tissue uptake of an infused radioactive substance
25 Drugs can be infused to study neurotransmitter receptor activity
or concentration in the brain
3 What is an MRI?
23 Magnetic Resonance Imaging
24 Helps to diagnose structural abnormalities of the brain and can distinguish
between grey and white matter
4 What is Grey Matter?
23 Remember from A&P that white matter is composed primarily of myelinated
axons which are axons surrounded by a multilayered lipid and protein covering
which electrically insulates the axon of a neuron and increases the

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speed of nerve impulse conduction (Tortora, pg. 423), as compared to grey

matter which contains neuronal cell bodies, dendrites, unmyelinated axons,
axon terminals and neuroglia
PREFRONTAL
Neurophysiology of Symptoms: Frontal and Temporal Lobes

23 The temporal lobe integrates and interprets somatic or bodily, visual, and auditory
information that is critical for recognition of the familiar as well as appropriate
interpretation of and response to social contexts
24 Part of an appropriate social response in the accurate interpretation of emotions
and the ability to respond with the socially appropriate level of emotionality and
language
25 The temporal lobe is responsible for the modulation and fine-tuning of emotion
appropriate to the level of intensity
26 It is responsible for planning, problem-solving, intellectual insight, judgement,
and expression of emotion
27 Parts of the limbic system, which regulate our emotional behaviour, are housed
in the temporal lobe
28 Physiologically, PET and MRI studies show evidence of decreased functioning in
the frontal and temporal lobes
29 Once again, dysregulation of serotonin, norepinephrine, and dopamine are the
culprits in these regions of the brain
30 It is not known if these anatomical changes are a cause or an effect of depression
because the activity returns to normal with the resolutions of the symptoms

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Neurophysiology of Symptoms: Amygdala

5888 The amygdala is located in the medial temporal lobe in the primitive part of our
brain
5888 It receives neuronal signals from the temporal and occipital lobes of the
cortex and communicates with the hypothalamus and other parts of the limbic
system. The amygdala helps the person relate to the surrounding environment
and pattern appropriate behaviour. The amygdala is important in emotional
function and regulation, the modulation of affective responses in social
settings, as well as sexual arousal, aggression and fear responses
24 Increased blood flow and oxygen consumption during depression
25 Abnormal neurodevelopment
5888 The amygdala tends to have increased blood flow and oxygen
consumption during depression. The striatum and amygdala, and related brain
areas are important in emotional memory and are believed to mediate the
anhadonia, or decreased drive and reward for pleasurable activities, anxiety,
and reduce motivation symptoms of depression
Neurophysiology of Symptoms: Limbic System

23 Limbic System and basal ganglia are involved in the development of mood disorders
24 The amygdala is part of the limbic system which is a primitive area deep in our brain that
regulates our emotional behavior
O The limbic system includes the hippocampus, parahippocampalgyrus,
cingulate gyrus, amygdala, and a bridge-like structure called the fornix, which
connects the hippocampus and the hypothalamus. Higher and lower brain
centers communicate with the limbic system to link thoughts and autonomic
nervous system responses to emotions

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5888 The limbic system includes the hippocampus, parahippocampalgyrus, cingulate

gyrus, amygdala, and a bridge-like structure called the fornix, which connects the
hippocampus and the hypothalamus
O Neurologic disorders of the limbic system and basal ganglia are also involved
in the development of mood disorders. The neocortex and hippocampus are
thought to mediate cognitive aspects of depression, such as memory
impairments and feelings of worthlessness, hopelessness, guilt, doom and
suicidality. Disregulation and neuroanatomical changes in the hypothalamus
are believed to be responsible for neurovegetative symptoms of depression,
including too much or too little sleep, appetite and energy, as well as a loss of
interest in sex and other pleasurable activities. Serotonin, norepinephrine and
dopamine are the active neurotransmitters in these regions of the brain. Their
disregulation is what causes the overactivity of the amygdala, and when these
neurotransmitters are disregulated, they are no longer able to do their job
well. This results in an overall abnormality of connectivity within the limbic
system and may also explain symptoms of emotional lability, irritability, and
suicidality
The Neuroendocrine System: Hypothalmic-Pituitary-Adrenal Axis (HPA)

23 People with depression also have increased levels of:
O CRF
O Cortisol
24 With childhood stress:
5888 Chronic disinhibition of HPA axis
5889 Exaggerated stress response as adults

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Major depressive disorder is also associated with multiple endocrine alterations, particularly in
the hypothalamic-pituitary-adrenal or HPA axis. As you will remember from the stress response
module, stress is perceived by the cortex of the brain and transmitted to the deeper regions of the
hypothalamus where corticotrophin releasing factor, or CRF, is released onto pituitary receptors.
This stimulus results in the secretion of corticotrophin into the plasma, stimulation of
corticotrophin receptors in the adrenal cortex, and release of cortisol into the blood. There is
considerable evidence that both cortisol and CRF are involved in depression. Research has
demonstrated that patients with depression may have elevated cortisol levels in plasma, elevated
levels in cerebral spinal fluid, and increased levels of CRF mRNA and protein in limbic brain
regions. Research has shown that sensitivity of the hypothalamus to feedback signals for the
shutdown of CRF release is about half in severely depressed patients. Disturbances in the
function of the HPA axis in depression cause cortisol levels to spike erratically throughout the
day. In the non-depressed person, cortisol levels are usually flat from late in the afternoon until a
few hours before dawn when they begin to rise. In research cited, in the non-depressed person,
serum B, D and F levels do not lower with the exposure of stress. In research with people with
major depressive disorder, stress activated the amygdala and norepinephrine systems, causing
symptoms of increased vigilance and fear, and people with an exaggerated stress response and
increased levels of CRF and norepinephrine in the plasma. Also, people exposed to childhood
stress had an exaggerated stress response as adults. In the depressed person, cortisol levels
return to the normal pattern as depression resolves

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Other Changes in Depression

We will now talk about other physical changes that occur with depression
23 Changes in pathways that influence the activity of neurotransmitters:
O Thyroid function
5888 Depression has an effect on thyroid function. In 5-10% of persons
with depression, when tested, have a decreased thyroid function.
Depressed patients with decreased thyroid function are given thyroid
replacement therapy in order to reverse this process and speed up their
ability to metabolize and respond to treatment with antidepressant
medication.
5888 Sleep-wake cycle

23 Alteration of the sleep-wake cycle is common in many mental illnesses
including depression. It is often one of the prodromal or early warning signs
of relapse. Research into the sleep-wake cycle in people with depression has
shown that the normal sleep cycle is often rebursed in depressed individuals
where the person reaches deep sleep later in the cycle. Malitonin, which is
produced by the pineal gland, is thought to help regulate the sleep-wake
cycle. The pineal gland synthesizes and releases
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malitonin at night. This rhythm of sleep wake is regulated by the circadian

clock
23 Circadian rhythms
5888 Circadian rhythms are cyclic patterns of sleep and wakefulness
which are integrated in the 24-hour light-dark-solar day and are related to
the monthly patterns of the moon. Circadian rhythms function is to
provide a temporal organization for physiologic processes and
behaviours to promote effective adaptation to our environment. This
involves regular cycles of sleep and waking, and body functions such as
temperature regulation and hormone secretion based on changes in the
24-hour light-dark-solar day. Research has shown that some patients with
depression have circadian abnormalities of mood, sleep, temperature and
neuroendocrine secretion. The sleep cycle usually reverts to normal after
the resolution of depression although this may take weeks to months. It is
important that a person with depression attempts to normalize the sleep-
wake cycle. Initially in treatment, sedative medication may be used and
patients are taught sleep hygiene techniques, for example to decrease the
use of alcohol and other stimulants before bedtime
24 Cytokine dysregulation
5888 Psychoneuroimmunology is a recent area of research into a diverse
group of proteins known as chemical messengers between immune cells.
These messengers, called cytokines, signal the brain and serve as
mediators between immune and nerve cells. Dysregulation of cytokines
can result in adverse effects and may manifest in symptoms of major
depression and related disorders. Research shows that depression is
common in infectious and autoimmune diseases. Research has also shown
that exposure to cytokines induces depressive symptoms and cytokine
secretion is increased in major depression. We also know that
antidepressants have anti-inflammatory effects and have been used to treat
chronic pain. As was previously mentioned, depression often is masked as
physical illness and it is believed that there can actually be physical pain
associated with depression. This is thought to be because serotonin is a
pain modulating neurotransmitter and the release of endorphins is
centrally mediated by serotonin. It makes sense that decreases in the
availability and action of serotonin at the nerve synapse may be
manifested as increased subjective experiences of pain and complaints of
physical symptoms of which may be indicative of a depressive illness

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Other Theories of Causation: Environmental

These theories focus on the individualized, environmental exposure component of depression
and exposure to stressors that are believed to trigger the HPA axis. It is believed that the way a
person interprets their environment and thinks about themselves can induce and perpetuate
depressive symptoms
5888 Psychodynamic factors
5888 Involve distorted negative beliefs and thoughts about the self, the
environment and the future that can induce and perpetuate depressive
symptoms
5889 Negative beliefs
24 Behavioural Factors
5888 Involve a severe reduction in rewarding activities or an increase of
unpleasant events in one’s life that result in depression, and a further
restriction of activity decreasing the likelihood of experiencing pleasurable
activities and intensifying a mood disturbance
5889 Decrease in pleasurable activities
25 Developmental Factors
5888 Involve loss of a parent or lack of emotional adequate parenting that may
delay or prohibit the realization of appropriate developmental milestones
5889 Parenting
26 Family Distress
5888 Involves a disruption in family dynamics involving maladaptive circular
patterns in family interactions that contribute to the onset of depression in family
members
27 Social Factors
5888 Adverse or traumatic life events, especially those that involve the loss
of an important human relationship or role in life that is followed by a
depression
Treatment: Antidepressant Drugs

SSRIs
MAOIs
TCAs
Novel or Dual antidepressant drugs
It is believed that antidepressant treatments may increase synaptic sprouting or rewiring of
connections, which are disregulated at the synapse. If you think about the phrase “if you don’t
use it, you lose it”, this can also apply to what happens at the synapse. Without treatment for
depression, synaptic pruning means that when connections between nerve cells are not used,
nerve cells atrophy and volume decreases. With treatment, connections are once again used
and formed, and brain volume in the areas implicated in depression increase. Antidepressant
medications are used to treat depression. Their clinical antidepressive effects occur only after
chronic administration of days to weeks. In general, these drugs normalize levels of serotonin,
dopamine, and norepinephrine in the brain, and thus, their neurotransmission at the synapse.
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Antidepressants also increase levels of BDNF, and affect synaptic plasticity by increasing the
activity of neurotransmitters in the synapse and nerve cell volume. Antidepressant response
takes days to weeks because it requires sufficient time for the levels of BDNF to gradually rise
and exert synaptic and nerve cell sprouting. The classification of antidepressant drugs includes
the following types: selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase
inhibitors (MAOIs), tricyclics (TCAs), and novel or dual antidepressants.
Selective Serotonin Reuptake Inhibitors (SSRIs)
The next five slides are included as a review from your pharmacology course on the
mechanism of action of antidepressant medications.
Selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin. They do this by
the following five steps:
Serotonin or 5-HT is released into the synapse
Serotonin (5-HT) binds to its postsynaptic receptor
Serotonin (5-HT) binds to its presynaptic receptor
This reuptake of serotonin results in less serotonin being released
SSRIs block the reuptake of serotonin, and therefore, more will be available in the
synaptic cleft.
Serotonin is a neurotransmitter (plays a major role in mood changes) that is transmitted from the presynaptic cleft to the postsynaptic cleft. The
serotonin can bind to the receptors on the postsynaptic cleft, or it can go through the transporter on the presynaptic cleft (the presynaptic
receptor) to be reuptaken into it. SSRIs block the transporters, so that there is more free-floating serotonin available in the synapse.

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Monoamine Oxidase Inhibitors (MAOIs)
Monoamine oxidase inhibitors (MAOIs) block the degradation of norepinephrine and serotonin.
They do this by the following four steps:
Norepinephrine is released into the synapse

Norepinephrine binds with its postsynaptic receptor
The action of norepinephrine is terminated by the enzymes monoamine oxidase and
catecholamine o-methyl transferase
The monoamine oxidase is inhibited, and norepinephrine is not broken down as quickly,
and therefore its action is prolonged.

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Tricyclic Antidepressants (TCAs)
Tricyclic antidepressants (TCAs) inhibit the uptake of norepinephrine and serotonin into the
presynaptic terminal, allowing norepinephrine and serotonin to accumulate in the synapse,
and thus enhance their action.
Novel or Dual Antidepressants

See attachment in the top corner for the “venlafaxine animation”
This animation illustrates the mechanism of action of venlafaxine at both the molecular
and tissue level
Dual medications, like SNRIs, block the reuptake of serotonin and norepinephrine.
Venlafaxine (Effexor) is a wildly prescribed antidepressant that is classified as a

serotonin/norepinephrine reuptake inhibitor (SNRI). The drug exerts its antidepressant effects by
inhibiting the neuronal reuptake of both serotonin and norepinephrine, which causes an increase in
neurotransmitter activity in certain regions of the brain. Both venlafaxine and its metabolite also
have weak inhibitory effects on the reuptake of dopamine. Because venlafaxine is selective for
serotonin receptors, it does not typically exhibit the cardiovascular, sedative, and anti-cholinergic
side effects seen by other classes of antidepressants. Clinically, venlafaxine improves symptoms
associated with major depression and melancholia (a severe form of depression marked by insomnia,
psychomotor changes, and guilt). SNRIs are also used in the treatment of

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anxiety disorders, obsessive compulsive disorder, attention deficit disorder, ADHD, and chronic
neuropathic pain.
https://avenue.cllmcmaster.ca/content/enforced/109399-
NURSING_2LA2_hellipb_T3_13/Depression/data/downloads/venlafaxine.html
Antidepressant Medications
Take a moment now to review the typical and atypical antidepressant medications, their generic
names, mechanism of action, therapeutic effect, key side effects, and serious interactions.
Non-pharmacological Treatment: Electroconvulsive Therapy (ECT)

We will now discuss the non-pharmacological therapies for depression. These therapies are
believed to work in a similar fashion to antidepressant medications, promoting increased
connectivity at the synapse and nerve cell growth.
Electroconvulsive therapy (ECT) is a procedure that electrically stimulates a generalized seizure

and has a 70-90% effective treatment rate for depression. It was introduced in Italy in 1938, and

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is one of the oldest treatments available and is safely used today. Every year, over 1 million
people in the world receive ECT. It is given under a general anaesthetic with complete muscle
relaxation, because the motor component of the seizure does not contribute to the therapeutic
effects of the treatment. A brief electric current is passed through the brain to produce a
generalized seizure lasting 25-150 seconds. The patient doesn’t feel the stimulus or recall the
procedure. On average, 6-8 treatments are given in 2-day intervals over a period of 2-4 weeks.
After symptoms have improved, antidepressant medications are used to prevent relapse. The
exact mechanism of the antidepressant mechanism of the ECT remains unclear. It is known to
down-regulate B-adrenergic receptors in much the same way as antidepressant medications,
therefore lowering the stress response. Down-regulation occurs when there are excess chemical
messengers and the number of active receptors decreases. ECT produces an up-regulation in
serotonin. Up-regulation occurs when there is a deficiency in the messenger. In this case, there is
less serotonin, so the number of active receptors for serotonin increases. ECT increases the influx
of calcium in the brain and has effects on second messenger systems. The first messengers in
depression are the neurotransmitters. Second messengers are involved in converting the chemical
signal into a physiological one that moves the nerve impulse across the nerve cell and onto the
next nerve cell. ECT has also been shown to up-regulate levels of BDNF. After symptoms have
improved, antidepressant medications are used to prevent relapse. The use of ECT is limited by
its invasive nature, namely the requirement of the general anaesthetic, and risk of retrograde
amnesia which may be irreversible in some patients. Because of its invasive nature, ECT is
currently only indicated for patients whose depression is resistant to conventional treatments.
Other Non-Pharmacological Treatments

Light Therapy (photo-therapy)
Uses artificial light to influence the production of melatonin and the function of the
catecholamine systems
Melatonin is a hormone that is produced by the pineal gland and thought to regulate the
sleep-wake cycle and possibly circadian rhythm
Artificial light is believed to trigger a shift in the patients’ circadian rhythm to an
earlier time
Exposure to this light source has produced improvement and relief of depressive
symptoms for significant numbers of seasonally depressed individuals
It produces no change for individuals who are not seasonally depressed
Vagal Nerve and Transcranial Magnetic Stimulation

Neurostimulation techniques, such as vagal nerve stimulation, deep brain stimulation, and
transcranial magnetic stimulation, have been recently developed. These techniques are
considered treatments for cases of depression that do not respond to medications or ECT.
Vagal Nerve Stimulation (VNS)

Involves using an implanted stimulator that sends electric impulses to the left vagas nerve in
the neck via a lead wire implanted under the skin
It is believed that VNS has antidepressant properties via its effects on the locus coeruleus, an
area in the brain stem from which norepinephrine neurons originate

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Deep Brain Stimulation

Involves the implantation of electrodes which are connected to a surgically implanted
impulse generator that delivers electrical stimulation to the ventral striatum which
has been found to have functional dysregulation in depression
The ventral striatum is connectionally associated with the limbic structures
Transcranial Magnetic Stimulation

Involves stimulation of the dorsolateral prefrontal cortex by using weak electric currents
which are induced in the tissue by rapidly changing magnetic fields or electromagnetic
induction
In this way, brain activity can be triggered in the prefrontal cortex, which has decreased
volume and activity in depression
Vagal nerve and transcranial magnetic stimulation have been improved in Canada for the
treatment of major depressive disorder, and deep brain stimulation is still under experimental
investigation.
Psychotherapy Focused
Psychotherapy helps to reduce the stressors that trigger episodes. It is thought that by reducing
stressors and negative thinking, the abnormal activity of the neurotransmitters indicated in
depression and the stress response can both be reduced. Aiding in a more normal functioning of
BDNF, neurotransmission, neuro-endocrine abnormalities, and reduction and/or prevention of
the neuro-anatomical changes of depression.
Specifically, cognitive behavioural therapy is psychotherapy focused on identifying,
analyzing, and ultimately changing the habitually inflexible and negative cognitions
about oneself, others, and the world that occur with depression
The use of cognitive therapy in the acute phase of treatment may be considered first line
treatment for mildly to moderately depressed outpatients
Especially helpful for patients with a history of childhood adversity or recent stress
Future Directions for Research

Current treatments for depression are very successful, but we can always learn more and try
to do better. Future directions for research currently involve:
New drugs that target: CRF (corticotropin releasing factor), the dopamine system, and the
glutamate system which normally stimulates the growth of BDNF and neuro-plasticity, but if
too much glutamate is released in the stress response, this can cause neuro-toxicity.
Other future studies of significance involve research into other polymorphisms with effects
on patients’ responses to antidepressants, resulting from allelic variations in other
genes with roles in the serotonin system, HPA axis, CRF and norepinephrine system,
liver enzymes involved in drug metabolism.
Current and future research also needs to focus on looking at the impact of an
individual’s psychosocial environment on brain chemistry, activity, and anatomy.

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Summary
In summary, we have talked about the pathophysiology of mental illness, focusing on depression.
We have explored symptoms, risk factors, etiology, neurotransmission, neuroanatomical changes,
neuromodulatory system changes, treatments (including medications, ECT, and other non-
pharmacological approaches), and briefly explored future directions for research.
We should be able to recognize when patients may be depressed and we should know the
importance of early detection and intervention involving treatments that not only manage the
symptoms, but can actually prevent the neuroanatomical changes in the brain from further
deterioration. We should also think about risk factors and the huge role that the stress response
and environment play in the formation of a mood disorder. We should know the importance of
helping our patients manage their stress, and we need to focus on prevention of risk factors
associated with depression.

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Module 5: Fluid and Electrolyte Imbalances
Objectives
At the conclusion of this self-study module, students should be able to:
describe the mechanisms of fluid balance and imbalance at the capillary level
discuss Na+ and H2O balance and imbalances in terms of physiologic mechanisms,
possiblecauses, manifestations, and possible diagnostic measures and treatment
describe disorders of K+ balance
briefly discuss disorders of calcium, phosphate, and magnesium balance
This lecture will focus primarily on fluid imbalances rather than the mechanisms of maintaining
fluid balance that you studied last year in Anatomy and Physiology. The presentation will help
you to link physiology and pathophysiology to clinical situations to what you might assess and
to what interventions might be appropriate.
Are You Ready For This Unit?

To understand fluid and electrolyte imbalances, you need to know how the body regulates fluid
balance.
Renal physiology;
The basics of fluid balance;
And the basics of electrolytes in body fluids.
It’s important that you remember your Anatomy and Physiology. It would be helpful for you to
review renal physiology (including glomerular filtration and tubular reabsorption and secretion),
the basics of body fluid balance (including fluid compartments and the regulation of fluid gains
and losses), and to review the basics of electrolytes distribution and functions.
Resources For Review

Tortora&Derrickson, 12th edition, Chapters 26 and 27
See attachment: Anatomy and physiology lectures on renal physiology and fluids and
electrolytes
O “Tubular Function.pdf”
O “Creating urine and measuring renal function.pdf”
Porth Pathophysiology, 1st Canadian edition, chapter 30
More Resources For Review

Diffusion
Active Transport
Osmosis
Click here (on the link below) to review and test your knowledge
http://www.merlot.org/merlot/viewMaterial.htm?id=417233
Diffusion, Osmosis and Active Transport (From the link above)

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Introduction
Fluids and solutes move continually throughout the body
in order to maintain homeostasis.
Cellular Movement
Membranes that separate the intracellular, interstitial and
intravascular compartments are semipermeable. Some,
but not all, solutes are able to pass through these
membranes. Three forms of cellular movement are shown
below.
Diffusion
Passivetransport of
solutes across cell
membranes from an
area of higher
concentration
to one of lower
concentration.
This movement
continues until
equilibrium is
reached on both
sides of the
membrane.
Osmosis
Passive transport of
fluid across cell
membranes from an
area of higher
concentration to one of
lower concentration.
This movement
continues until
equilibrium is reached
on both sides of the
membrane.
Active Transport
Active transport of
solutes across cell
membranes from an area of lower concentration to one of higher concentration. Like swimming
upstream, this requires energy – in this case, adenosine triphosphate (ATP).

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Pressures:
Hydrostatic
Colloidal osmotic (oncotic)
Click here to review and test your knowledge
http://www.merlot.org/merlot/viewMaterial.htm?id=417242
Inside the Body: Fluid Pressures and Processes (From the link above)
Here’s your challenge: Fluid in your body is constantly in motion in an attempt to maintain
balance, or homeostasis. Many types of illness can upset this balance by creating fluid excess
or deficit in the intravascular or interstitial compartments.
Goal: Your body’s goal is to prevent the accumulation of fluid in these compartments.
How is this achieved? Your body has to ensure that fluid leaving circulation and the amount of
fluid returning to circulation is equal.
Let’s shift gears for a moment and compare the soaker‐ hose to a capillary. Both are long, narrow,
flexible tubes with hollow centers. Both are semi permeable. Both have clearly defined ends where fluid enters
and exits. Just as you controlled the flow of water in this exercise, your body controls the continuous
movement of water, nutrients and waste products between the capillary and the interstitial space.
This movement is regulated by two pressures, and two processes. We’ll talk about the
pressures first, and then describe the processes.

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Key Factors:
Hydrostatic pressure pushes water out of, or into, the capillaries. Oncotic pressure pulls water out
of, or into, the capillaries. Because of the differing pressures, the process “begins” at the
arterial end of the capillary and ends at the venous end.
Think back to the garden hose and what happened to the flow of water when you adjusted the
faucet. Now, replace the faucet with the heart, and the hose with a capillary. What would you
expect to happen in the capillaries if you ran up a flight of stairs? If you meditated or relaxed? If
you suffered an injury, such as a bite, burn or cut? If something in your body prevented the
normal flow of blood and nutrients? Remember how the flow of water increased when you
turned the faucet on high? Running up stairs, exercising or doing anything that increases your
activity level causes your heart to pump harder and faster. This increases hydrostatic pressure in
the capillaries. When we adjusted the faucet so less water flowed, more remained inside the hose.
Some studies show that meditation and other deep breathing relaxation exercises may slow the
beating of the heart. As a result cardiac force, and subsequently hydrostatic pressure, decreases.
Twisting the hose caused obstruction, increasing the flow of water at one end, and preventing
itfrom moving to the other. Likewise, a blood clot or other form of obstruction in the body
creates additional hydrostatic pressure at one end of the capillary and significantly reduced flow
in the other. Increasing the size of the holes in the hose allowed more water to leave. In your
body forms of trauma, such as those experienced during injury or illness, damage capillaries and
initiate the inflammatory process. This causes the endothelial cells that line the capillary wall to
contract, creating spaces through which fluid and proteins, such as albumin, leak into the
interstitial space.
Arterial End
Capillary filtration is the process that unloads materials for the tissues at the arterial end of the
capillary. Just like the part of the hose that is closest to the faucet, hydrostatic pressure is highest
at this end of the capillary. Capillary hydrostatic pressure, caused by the pumping of the heart,
pushes fluid out of the capillary into the interstitial space. In addition, as the number of Na
molecules increase in the interstitial space, interstitial osmotic pressure pulls fluid from the
capillary to dilute these particles.
Venous End
Due to the loss of fluid at the arterial end, hydrostatic pressure falls as it reaches this end of the
capillary. Reabsorption is the process that picks up materials for transport at the venous end of
the capillary. Capillary oncotic pressure, caused by the presence of plasma proteins (especially
albumin) and Na, is now greater (due to loss of fluid) and pulls water out of the interstitial
space and back into the capillary. In addition, interstitial fluid hydrostatic pressure which is now
greater due to the increased fluid present, pushes water from the interstitial space into the
capillary.
Key Points
At the venous end, capillary hydrostatic pressure < capillary osmotic pressure and fluid
moves from the interstitial space back into the capillary (termed reabsorption) Net movement
favors water and solutes being passed back into the capillary where they are less concentrated.

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Summary
As blood circulates, two types of pressure cause fluids (primarily) and solutes (sometimes) to
move between the capillaries and the interstitial space. When hydrostatic pressure is higher
inside the capillary than in the interstitial compartment that surrounds it, this pressure pushes
fluids out of the capillary. When oncotic pressure is higher in the capillaries than in the
interstitial compartment, oncotic pressure pulls fluid back into the capillary. Since large solutes
cannot pass through capillary walls, the solute buildup induces osmosis. Small amounts of
extra fluid that leave the capillary move into the lymphatic vessels and are eventually
recirculated by the heart. The difference in pressure at opposing ends of the capillary is known
as the pressure gradient.
As I mentioned, it’s important for you to understand the ways in which fluids and solutes
move in the body, including the pressures that govern fluid movement. The links provided here
are short reviews of each of these topics, each accompanied by a 10 questions quiz.
Fluid Balance at the Capillary Level

Just to be sure you’re ready to look at fluid imbalances, let’s quickly review the
mechanisms of fluid balance at the level of capillary. Fluid balance at the level of capillary
relies of the balance between opposing forces. The pushing force of hydrostatic pressure and
the pulling force of oncotic pressure.
Capillary Hydrostatic Pressure “Push”
At the arterial end of the capillary, hydrostatic pressure is higher than the oncotic pressure in the
capillary so fluid moves or is pushed out into the interstitial space. Current research shows that
the interstitial hydrostatic pressure had a small negative value and contributes slightly to the
movement of fluid from the capillary to the tissue.

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Capillary Colloidal Osmotic Pressure “Pull”
Toward the venous end of the capillary, much of the fluid has moved into the interstitial space,
leaving the solutes, in particular, the plasma proteins, behind. This creates higher capillary
osmotic pressure, which effectively pulls fluid from the interstitial space back into the vessel.
Some particles, such as glucose and electrolytes, move from the vessel into the interstitial
space and create interstitial colloidal osmotic pressure, pulling a small amount of fluid into the
interstitial space.
Capillary Fluid Balance
Excess interstitial fluid is taken up by the lymphatics and returned to the central circulation.

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Capillary Fluid Balance

To review, fluid balance is determined by the push and pull of fluid across the semipermeable
capillary membrane. It is important to remember that the normal movement of fluid depends
on the integrity of the capillary membrane.
Imbalance: Increased Capillary Hydrostatic Pressure
Fluid imbalances at the capillary level can be due to several alterations in the normal fluid
movement. First, increased capillary hydrostatic pressure can cause higher amounts of fluid
to leave the capillary. If the hydrostatic pressure continues to be high at the venous end of the
capillary, net fluid movement will be out of the capillary.
Imbalance: Increased Capillary Hydrostatic Pressure

Increased fluid pressure O
Hypertension
Increased fluid volume
Na+ and H2O retention
Back-up of blood flow
DVT
Increased hydrostatic capillary pressure can result from hypertension or from an increase in fluid
volume, for example, in the case of sodium and water retention. Hydrostatic pressure also
increases if there is any back up of blood flow, for example, a DVT might obstruct venous blood
flow, resulting in higher than normal pressure at the venous end of the capillary.

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Imbalance: Decreased Capillary Colloidal Osmotic Pressure
The second thing that can go wrong with the fluid balance is the lack of sufficient capillary oncotic
pressure to pull fluid back into the intravascular space at the venous end of the capillary.
Imbalance: Decreased Capillary Colloidal Osmotic Pressure

Low serum albumin
Because albumin is the most prevalent colloid or solid in the plasma, any clinical situation that
results in decreased albumin can result in the decrease of capillary oncotic pressure. Common
medical diagnoses associated with low albumin are burns, liver disease, malnutrition, and
excessive wound drainage.
Imbalance: Increased Interstitial Colloidal Osmotic Pressure

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The third mechanism that causes fluid imbalance at the capillary is increased interstitial
colloidal osmotic pressure. When solutes or particles escape from the vessel into the interstitial
fluid, they will take fluid with them and hold that fluid in the interstitial space.
Imbalance: Increased Interstitial Colloidal Osmotic Pressure

“Leaky capillaries”
As you know, the capillary membrane should allow only some solutes to escape. Capillary
permeability increases in response to the chemical mediators of the inflammatory process.
Imbalance: Increased Tissue Hydrostatic Pressure
Finally, the fourth mechanism that results in fluid imbalance at the level of the capillary is an
increased tissue hydrostatic pressure.
Imbalance: Increased Tissue Hydrostatic Pressure

Obstruction of lymph flow O
Lymphedema
Also creates increased interstitial colloidal osmotic pressure
This can happen when the lymphatics are obstructed for some reason and do not remove excess
fluid and is complicated by increased tissue oncotic pressure, which continues to pull fluid
from the vessel. Lymphatic obstruction can occur in liver disease or because of physical
obstruction from surgery.

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Edema represents an increase in fluid in the interstitial place. Here is another way of looking at
the mechanisms that cause edema. Increased capillary hydrostatic pressure causes fluid to move
into the tissue, creating edema. A decrease in plasma proteins results in decreased capillary
oncotic pressure. The lack of pull factors means that fluid remains in the interstitial space instead
of moving back to the vessel. This is edema. Leaky capillaries or increased capillary
permeability results in the loss of intravascular proteins and other solids into the interstitial space.
This movement is accompanied by fluid and the solutes keep the fluids in the interstitial space.
That’s edema. Lymphatic obstruction results in decreased absorption of interstitial
fluid, and therefore, edema.
Edema or Third-Spacing?
Edema = interstitial fluid accumulation
Third-spacing = transcellular fluid accumulation
You know that edema is the accumulation of fluid in the interstitial space. Sometimes, fluid
becomes trapped in another compartment. The transcellular compartment is a small subdivision of
the extracellular fluid compartment. It includes various body spaces, such as joint spaces, the
pericardial and pleural cavities, the peritoneum, and ocular fluid. Normally, fluid moves in and out
of transcellular spaces using the same mechanisms that I’ve just discussed. When fluid shifts
into the transcelluar space and cannot be pushed or pulled out of that space, or when there is
obstruction to lymphatic flow, fluid becomes trapped in the transcellular space. We call this
third-spacing. As with edema, this fluid is not readily available for exchange with the rest of the
ECF, so is called nonfunctional fluid.
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Manifestations of Edema
The signs and symptoms and the effects of edema are determined by its location.
Brain
In the brain, edema is most frequently associated with infections or trauma, both of which initiate
an inflammatory response. Because the skull is an enclosed space with little room for extra fluid,
cerebral edema is life-threatening. Signs of increased intracranial pressure include headache,
altered level of consciousness or a coma, abnormal pupil size or reflexive response, changes in
patterns in respiration, and changes in muscle tone and abnormal posturing.
Airway
Swelling of the airway constitutes an acute life threatening condition. It is frequently due to an
inflammatory response to allergens or microorganisms. Airway swelling may result in difficulty
swallowing, anxiety, stridor, and possible airway obstruction and asphyxia.
Lungs
When fluid is forced out of the capillaries at the level of the lungs and accumulates around the
alveoli, the result is the decrease in gas exchange and the decrease in the ability of the lungs
to inflate. Manifestations may vary according to the cause and location of the fluid shift, but
will certainly include dyspnea. Patients may also have anxiety or restlessness, diminished
breath sounds and or crackles on auscultation.
Abdomen
The term for fluid that collects in the peritoneal cavity is ascites. This is an example of third-
spacing. Perhaps this accumulation is due to the increased intravascular hydrostatic pressure that
results when the portal vein is affected by liver cirrhosis or perhaps results from a significant
inflammatory response to something like an abdominal tumour or pancreatitis. You might see an
increase of abdominal girth and a protruding umbilicus. Your client might complain about
abdominal discomfort and if the accumulation of fluid is considerable, of shortness of breath
when the expansion of the diaphragm is impeded by fluid.
Intestine
Clients may also experience a third-space loss of fluid inside the lumen and wall of the
intestine if the intestine is obstructed.
Peripheral edema
Often due to the obstruction of venous blood flow, which increases the capillary hydrostatic
pressure, or to obstruction in lymphatic drainage, peripheral edema can occur predominantly in the
lower extremities in ambulatory patients. In bedridden patients, this edema can occur in the
sacral area. In both cases, this is referred to as dependent edema. Edema that is related to salt retention,
which I’ll discuss in a few minutes, is usually pitting edema. When a finger is pressed
into the edematous area, the fluid in the soft tissue shifts and when the finger is removed, a pit is
evident. Overt edema is only apparent after a significant amount of fluid has collected.
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Treatment of Edema
What you do depends on why the edema occurred O
Correct the problem
O Control the underlying mechanism
O Treat symptoms
O Supportive measures
In general, doctors, nurses and other members of the health care team need to determine the
mechanisms underlying a client’s edema and then to treat accordingly to correct or control the
cause. For example, if the edema is related to malnutrition and the lack of albumin, an obvious
solution to the problem would be to ensure that the client consumes adequate amounts of protein.
The answer isn’t always that easy though, perhaps the mechanism responsible for edema is the
lack of albumin intravascularly, but the reason for that problem is that a massive inflammatory
response has created increased capillary permeability, so protein is leaking from the vessels. The
treatment of this problem would be more complex. Perhaps the client would require transfusions of
albumin or other colloid solutions to increase the capillary oncotic pressure. But unless the problem
of increased capillary permeability is resolved, albumin will continue to move to the
interstitial space and will take fluid with it, increasing the edema. The problem will be further
complicated by the body’s fluid conserving mechanisms, which I’ll talk about in more detail
soon. The kidneys will conserve water and sodium, effectively increasing the
capillary hydrostatic pressure and again, increasing the edema.
Diuretic therapy is commonly used when there is increased extracellular fluid volume. One
example of this would be clients with hypertension. Often the treatment of edema includes
implementation of supportive measures. For example, a pregnant female client who has
swelling of her ankles due to increased hydrostatic pressure may be taught to keep her legs
elevated whenever possible and to be sure to avoid standing for extended period of time. Clients
who have peripheral edema due to heart disease may be advised to wear supportive stockings to
increase interstitial fluid pressure, thereby providing some resistance to the movement of fluid
from the capillary to the interstitial space.
Maintaining Na+ & H20 Balance

ECF levels of water and sodium
Maintaining vascular volume
Edema and third-space fluid shifts are examples of loss of intravascular fluid volume. Before I
discuss other fluid losses and gains, other imbalances and body water balance, I think it will be
helpful to quickly review the mechanisms the body uses to regulate body water. As you already
know, the movement of body fluids between the intracellular and extracellular fluid
compartments depends on the extracellular fluid levels of water and of sodium, the primary solute in
the ECF. Let’s quickly review the ways in which the body responds to alterations in
body water balance. The first thing to remember is that the major regulator of sodium and water
balance is the amount of circulating blood volume. Our bodies continually strive to maintain
adequate vascular volume to effectively perfuse tissues, supplying them with nutrients and
removing wastes.
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Fluid Balance Receptors

Osmoreceptors
Baroreceptors
Next, a quick reminder about the two types of receptors or sensors that pick up messages in the
body about the adequacy of our circulating fluid volume. Osmoreceptors located in the
hypothalamus keep track of the osmolality or the concentration of the blood. Remember too,
that sodium is the predominantly osmotically active particle in the blood. Baroreceptors are
sensors that are located in the blood vessel walls and in the kidneys. These receptors measure
the stretch in the vessel walls that is produced by blood volume and blood pressure.
+
Maintaining Na & H2O Balance
There are several mechanisms of fluid balance that the body uses in response to
messages from the osmoreceptors and baroreceptors:
O Thirst
O ADH
O Sympathetic nervous system
O R-A-A-S (renin-angiotensin-aldosterone system)
O Natriuretic Peptides
Thirst and ADH

Thirst:
Thirst is a primary regulator if water intake
Normally we drink without being reminded by the thirst mechanism
Sometimes our bodies experience unanticipated increases of blood volume or increases in
osmolality that alert the body to take corrective action
For example, if you eat a lot of salty food, your thirst mechanism will prompt you to
drink more
O That’s one reason for your local drinking establishment to offer free
peanuts of pretzels
Thirst develops with even a small change in fluid volume of osmolality
ADH:
A second mechanism of fluid regulation of ADH (antidiuretic hormone)
This is also referred to as vasopressin
ADH is made in the hypothalamus but stored in the posterior pituitary
When the hypothalamus senses low blood volume or increased osmolality, it sends
signals to the posterior pituitary to release ADH
As its name implies, antidiuretic hormone acts on the kidney tubules to retain water and
therefore increases blood volume and reduces serum osmolality
Note the feedback loop in the diagram – once the problem has been corrected, they
hypothalamus gets the message and stops the cycle
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Sympathetic Nervous System

The sympathetic nervous system responds to changes in arterial blood pressure and
blood volume in several ways:
1. GFR
First by regulating the constriction and dilation of the afferent and efferent
arterioles in the kidneys, the amount of glomerular filtrate can be controlled
If the SNS is stimulated, the afferent arterioles will constrict, limiting the amount of
blood flow to the kidney and lowering glomerular filtration pressure
Tubular reabsorption
Second, sympathetic activity regulates the reabsorption of sodium
Renin release
Third, stimulation of the SNS results in the release of renin, which we’ll discuss
further in the next slide
R-A-A-S
The next hormonal regulator of fluid balance is the renin-angiotensin-aldosterone
system (R-A-A-S)
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If the circulating blood volume drops, there is less blood flow to the glomerulus, so less
renal perfusion pressure
The juxtaglomerular cells in the kidney sense the reduces stretch of the afferent arteriole
because of reduced blood flow
This causes and increase in release of renin, which acts as an enzyme to convert
angiotensinogen into angiotensin 1
Angiotensin 1 is converted to angiotensin 2 (the active angiotensin) by ACE
(angiotensin converting enzyme)
The now active angiotensin 2 acts directly on the kidney tubules to increase sodium
reabsorption
It also stimulates the production of aldosterone in the adrenals
Aldosterone works in the distal tubule of the kidney to promote exchange of sodium and
potassium
O Sodium is reabsorbed and potassium is lost
When sodium is reabsorbed, it brings water with it resulting in an increase on
circulating blood volume
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Natriuretic Peptides
Natriuretic peptides provide a counterbalance to the activity of baroreceptors, ADH, and
the R-A-A-S
ANP and BNP
Respond to increased blood pressure/volume
In response to an increase in blood volume, these cells cause the kidney to
increase sodium and water excretion by suppressing renin levels, decreasing
aldosterone release, and causing vasodilation
+
Counter-regulatory: excretion of Na and water
Risk for Fluid Imbalance

Now that you’re back up to speed with where body the fluid is, how it moves, and
how it’s regulated, let’s relate that knowledge to who might be at greater risk for
fluid imbalances
Infants
Infants have a higher percentage of body water than adults and more than half of
their total body water is in the extracellular compartment
Infants ingest and excrete a relatively higher amount of water daily than do
adults
In fact, an infant may exchange up to half his daily extracellular fluid. This
means that infants have a smaller reserve of body fluids than adults
The daily fluid exchange is greater in infants because of their high metabolic
rate
Another reason that infants are at risk for fluid imbalances is the inability of
their immature kidneys to concentrate urine efficiently
Finally, infants lose a relatively greater fluid loss through the skin than adults
because of their proportionately greater body surface area
Both infants and young child have immature homeostatic regulating
mechanisms, so don’t respond as efficiently as adults to small changes in
fluid balance
Elderly
Aging kidneys experience a decrease in glomeruli and a decrease in the
glomerular filtration rate
There is a decrease in ability to concentrate urine
They are slower to respond to sodium and water imbalances, including having a
decreased response to ADH and a decrease in secretion of aldosterone
The elderly have a reduction in total body water
Research has shown that thirst sensation decreases with age. Fluid intake therefore
is not necessarily irregulated with thirst, but instead can be associated with
food intake
If an elderly individual is eating poorly, it is possible that he or she is also
drinking poorly
Obese
Obese individuals are at risk for fluid imbalances because their percentage of
total body water is much less than that of a lean individual
This means that they have less body water to lose
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Ill
Also at risk for fluid imbalances is anyone who is sick
Perhaps the risk is due to an increased intake of fluid
Perhaps the problem is an increased of fluid losses through fever, vomiting, or
diarrhea
Anyone who experiences an inflammatory response will experience
intravascular fluid loss due to increased capillary permeability
Remember that even if the fluid loss is not external, such as that which occurs
with vomiting, fluid that is not where it’s supposed to be can result in
dehydration
Assessing Fluid Balance

Introduction
When I talked about manifestations of edema, I mentioned a number of ways in which
you would assess your client
I’d like to look more broadly now at how you would assess for fluid balance
This part of the nurse’s role is logical given that nurses are often the primary contact
for clients in the community and are with hospitalized comments more than any other
member of the healthcare team
Accurate, ongoing assessment is also vital in detecting fluid and electrolyte imbalances
early
Understanding the reasons behind the signs and symptoms helps nurses to know what
changes are relevant and what interventions might be appropriate
In the sections that follow, I’ll help you link the pathophysiology of the imbalance
to the clinical manifestations I’ll describe
Thirst, mucous membranes, turgor, tearing

May indicate fluid imbalance
I’ve already discussed the importance of the subjective symptom of thirst as an
indicator of alterations in body fluid and electrolyte balance
A dry mouth could be due to a fluid volume deficit or might simply be the result of
mouth breathing
The trick to determine the difference is to look in areas where cheeks and gums meet
In mouth breathing, these areas will remain moist
In fluid volume deficits, they will be dry
Skin turgor, the elasticity of the skin that allows it to return to its normal position after its
been pinched, might be a helpful assessment
In individuals with fluid volume deficit, the skin flattens more slowly after a
pinch is released
When you check skin turgor, remember that the test measures not just interstitial fluid
volume but also skin elasticity
Older clients or those with recent weight loss may show signs of decreased skin
elasticity
Obese infants might maintain their skin turgor even when in fluid volume deficit
Because tissue turgor varies considerably with age, nutritional status and even race or
complexion, it might not be the best indicator of imbalances
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In infants tearing is considered a reliable indicator of fluid volume with decreased

tearing in patients with volume deficit
Pulse and BP
Reliable indicators
Tachycardia is usually the early sign of decreased vascular volume
Alterations in pulse rate, regularity, and volume are present in several types of fluid or
electrolyte imbalance
The client’s blood pressure can also provide information about fluid volume status
Sometimes in suspected fluid volume imbalances, we take the BP when the client is
lying and standing
Accurate systolic and diastolic readings are very important
Edema
Generalized, localized, dependent
Edema, excessive amounts of interstitial fluid, will not become apparent until the
interstitial fluid volume has increased by at least 2.5 L
As I mentioned in a previous slide, you need to be sure to check for edema that is
generalized, localized, and dependent
Don’t forget manifestations of pulmonary edema, pracholsyndismia, and of peritoneal
third spacing, possibly increased abdominal girth
Weight
Daily weighing of patients with actual or suspected fluid balance problems is of great
clinical importance
Rapid changes in weight reflect changes in body fluid volume
It is easy to weight a client and body weight measurements are generally accurate and
intake and output measurements
To minimize inaccuracies, clients should be weighed first thing in the morning before
breakfast but after voiding in the same scale and in the same or similar clothing
Intake/output; urine concentration

Normally urine output in an adult is 1000 to 2000 mL/day or 40 to 80 mL/hour
Although it is very important to monitor urine output, it is equally important to
remember all other sources of measurable output and to recall that insensible losses
in some patients can be considerable
Of course you also have to know how much fluid the client is receiving from all sources
Nurses should initiate careful intake and output records for any patient with a real or
potential fluid or electrolyte imbalance
Urine concentration, specific gravity, measures the ability of the kidneys to concentrate
urine
In a fluid volume deficit, the body conserves water so solutes are excreted in a small,
concentrated urine volume
It is important to note though that high urine levels of unexpected solutes such as
glucose or albumin for example will falsely elevate specific gravity readings
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Neuromuscular signs
Some disturbances in body fluids or electrolyte balance will create central and/or
peripheral effects:
O Headache
O Anxiety
O Changes in levels of consciousness
O Twitching
Some of these changes can be vague and if you use your knowledge of the
pathophysiology of the specific deficit or excess, they will make sense to you
I’ll talk about some of these signs as the lecture proceeds
+
Disorders of Na and H2O Balance
Now that we’ve looked at how the body regulates fluid balance, who is at risk for fluid
imbalances, and what to assess fluid balance, let’s begin to look at what can go wrong
Remember that sodium and the chloride and bicarbonate anions that are associated with
sodium accounts for most of the osmotic activity in the ECF
When we look at imbalances in the body, we always talk about changes in both sodium
and water
These imbalances can be divided into two main categories:
Proportionate changes in sodium and water
Changes in which gains or losses are of both sodium and water in proportion
Changes which are isotonic
Disproportionate changes in sodium and water
Changes in which sodium or water are gained or lost so that their normal
concentrations are altered
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+
Disorders of Na and H2O Balance
Let’s look at proportionate changes/isotonic changes first
Isotonic changes can also be divided into two categories:
Proportionate losses of sodium and water
Proportionate gains of sodium and water
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Isotonic Fluid Volume Deficit: Causes

Inadequate Intake
Fluid unavailable or withheld
Thirst mechanism impaired
Excessive Output
Lost through the skin
Lost to third spacing
Lost to the GI tract
Lost through the kidneys
When both sodium and water are lost, an isotonic fluid volume deficit exists. Plasma electrolyte
concentrations remain unchanged, but the circulating fluid volume has decreased. A deficit of
extracellular body fluid can occur for many reasons. Perhaps fluid intake has decreased, either
because fluids are not available or because they are intentionally being withheld. Perhaps the
individual’s sensation of thirst is impaired. Or instead of inadequate intake, perhaps there is an
abnormally large output of fluid. Fluid can be lost through the skin due to fever, to exposure to
heat or due to wounds or burns. Fluid can be lost to the circulation when it because trapped in a
third space, such as the peritoneum or the intestine. Fluid is readily lost through the
gastrointestinal tract. In a single day, up to 10L of fluid are secreted into the gastrointestinal tract.
Most of this is usually reabsorbed, but vomiting or diarrhea can result in both large losses and an
increased secretion of fluid to the GI tract. And fluid can be lost through the kidneys due to,
perhaps, diseases or to drug therapy such as diuretics that result in impaired sodium and water
reabsorption.
Isotonic Fluid Volume Deficit: Manifestation

Thirst (maybe)
What will your assessments reveal if your client is in fluid volume deficit? You will remember
that the body responds to even small decreases in total fluid volume by initiating the thirst response.
I have said “maybe” on this slide because, as I have already mentioned, thirst response
can be unreliable in the elderly and is not easily assessed in infants
Decrease in body weight (maybe)

When fluid volume is lost from the body, there is a decrease in body weight. A liter of water
weighs one kilogram. To accurately reflect fluid losses or gains, you must ensure to take care
when weighing your client. As I have mentioned in the previous slide, it is important to
remember that fluid volume deficit does not always result in a decrease in body weight. If the
fluid is lost to the third space, it still contributes to body weight even though it does not
contribute to functional fluid volume.
Decreased urine output; increased SG, osmolality

When the baroreceptors sense a decrease in vascular volume, they will send a message to the
pituitary to initiate a compensatory secretion of ADH. As you know, ADH causes an increased
reabsorption of water and sodium, which results in decreased urine output. As output decreases,
urine is more concentrated. The specific gravity and osmolality rise.
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Sunken eyes (maybe)

When vascular volume decreases, fluid will move from the interstitial space in an attempt to
improve vascular volume. When tissues lose fluid, they lose their resiliency. The eyes can look sunken,
and skin or tissue turgor decreases. Again, I have put “maybe” in brackets. Sunken eyes
and decreased skin turgor are not reliable indicators of dehydration in elderly individuals due to
the loss of skin elasticity due to aging.
Loss of skin turgor (maybe)
Infants: tearing
In infants, contraction of fluid volume and the body’s efforts to conserve vascular volume
can be seen in a decrease in tearing.
Changes in blood pressure

When the blood volume declines, the blood pressure decreases. One the early signs of fluid
deficit is postural hypotension: a drop in blood pressure on standing. As the BP drops, the heart
rate will increase and the pulse will become weak and thready. In severe volume depletion, the
body experiences hypovolemic shock with vascular collapse
Changes in pulse
Hct BUN
As sodium and water are decreased, the red blood cells and blood uria nitrogen (BUN) become
more concentrated.
Isotonic Fluid Volume Deficit: Treatment

The treatment of hypovolemia is straightforward and very important.
Replace the fluid
Because hypovolemia can cause renal damage and circulatory collapse, it is very important
to replace lost fluid promptly. When IV therapy is required, isotonic losses are replaced
with isotonic fluids, like normal saline or lactated ringer’s solution
Treat the cause
Replacing fluid is critical, but it is also just treating the symptoms. The health care team
must also determine the underlying cause of the fluid loss and take measures to
correct the problem.
Isotonic Fluid Volume Excess: Causes

Inadequate elimination
Excessive intake
When sodium and water are retained in proportion an isotonic fluid volume excess results. Both
the extracellular fluid compartments expand, the vascular volume and the interstitial fluid volume.
This type of excess is unusual in healthy individuals because the body’s compensatory
mechanisms for dealing with excess volume are usually sufficient to restore fluid balance.
Hypervolemia can occur when the body is unable to eliminate appropriate amounts of fluid due to
poor kidney function. If the heart is unable to effectively pump, decreased blood flow to the kidneys
will result in fluid retention. An increase in the amount of sodium ingested will result in
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an increase in water retention as well. Normally, the body will eliminate excess, but if the
kidneys or heart are not adequately able to do their jobs, hypervolemia may result. It is also interesting
to note that sometimes the health care team plays a part in a client’s hypervolemia. If
excessive amounts of IV fluid are given, or if the fluids are given quickly, the body may not be
able to manage the increase in circulating volume.
Isotonic Fluid Volume Excess: Manifestation

Weight gain
Changes in body weight can indicate fluid overload. Watch your client to gain weight
over a short period of time.
Edema
As a result of increased hydrostatic pressure, hypervolemia results in edema
Distended neck veins
The increase in vascular volume can be seen in distended neck veins and in a full,
bounding pulse
Bounding pulse
Respiratory symptoms
When the fluid accumulates in the lungs, the client will show signs of respiratory
distress. Listen for crackles and watch for a productive cough.
Decrease in BUN and hematocrit
And just the opposite of a fluid volume deficit, in hypervolemia, the BUN and
hematocrit levels will decrease when both are diluted.
Isotonic Fluid Volume Excess: Treatment

Treatment of hypervolemia revolves around three things:
Stop increasing the volume
First, stop increasing the fluid volume. This can be done by restricting fluid intake and
restricting sodium intake. If IV fluids are contributing to fluid overload, careful
attention must be paid to the solution and the rate of administration.
Start decreasing the volume
To help decrease the excess fluid volume, diuretics can be give to increase sodium
and therefore water elimination.
Treat the cause
As for hypovolemia, it is important to try to determine the reason for the volume excess,
so the treatment of the problem, not just the symptoms, can be initiated if possible.
For example, heart failure might be treated with digoxin, which strengthens cardiac
contractions and can increase kidney perfusion.
Disorders of Na+ and H2O Balance

Hypo- and hypervolemia are conditions in which sodium and water are lost or gained in their
normal proportions. But sometimes, fluid imbalances are not proportionate. Sometimes,
either sodium or water is lost or gain independently of the other, resulting in changes of
sodium concentration. That is, either hypernatremia or hyponatremia. These
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changes produce change in the osmolality of the extracellular fluid and result in
fluid shifts between the ECF and ICF
Hyponatremia
Shift of concentration of sodium
This is defined as a plasma concentration of sodium of less that 135mmol/L.
Hyponatremia is a deficit of sodium in relation to the amount of body water. There
are two reasons that the concentration of sodium drops. Either there is too little
sodium in the ECF or there is too much water.
O Too little ECF sodium
Not enough intake
A deficiency of sodium can be the result of too little sodium intake. This
is uncommon in our North American society where excessive sodium
intake is a common risk factor for many health problems.
Too much sodium loss

The excessive loss of sodium is often related to renal problems. You know
that the kidneys should preserve sodium through the use of
aldosterone. Failure to do so may indicate renal impairment or adrenal
insufficiency, or perhaps, might indicate loss of sodium due to diuretic
use. Sodium is also lost through sweating and GI losses such as
vomiting, diarrhea or nasogastric suction. Fluid is also lost in this
manner but comparatively more sodium than water can be lost.
Sometimes, the problem is compounded when the client replaces
losses with water as opposed to solutions containing electrolytes.
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Too much ECF water

Osmotic pull
Blood sodium can be diluted when too much fluid moves to or stays in
the vascular space. If other osmotically active particles in the blood
stream increase intravascular osmotic pull. Fluid will move into the
vessel. An example of the is hyperglycemia.
Water retention
When hyponatremia is the result of too much water, generally the
kidneys are at fault. For example, high levels of ADH result in water
retention. This is, in fact, very common in the post operative period
and can be made worse if clients are then given electrolyte free IV
fluids such as dextrose in water. Sometimes, the high ADH levels are
through inappropriate secretion; mixed up messages in the body. This
is a syndrome known as “Syndrome of Inappropriate ADH
Secretion” or SIADH. Finally, water retention can also be caused by
some medications, including several antipsychotic medications.
Hyponatremia is a problem that is commonly seen in hospitals and
also in the elderly outpatient population.
Hyponatremia: Manifestations
Variable symptoms
The manifestations of hyponatremia really depend on the cause of the problem and the
speed of onset. If the onset is gradual, there may be few signs.
Fluid shifts to cells: brain swelling
Because of decreased vascular osmotic pressure, hyponatremia results in fluid shifts
from the extracellular space into the cells. When cells in the brain swell, clients will
have headaches. With further swelling, there will be changes in the level of
consciousness and coma. Fluid shifts into the GI tract result in diarrhea.
Inadequate sodium: neuromuscular effects
You will remember the role that sodium plays in the transmission of impulses in
nerve and muscle fibers. When sodium levels are too low, clients will experience
muscle cramping, weakness, fatigue, and tremors.
Labs: decreased serum osmolality
Lab values show decreased serum osmolality and a decrease in hematocrit and BUN,
because of the dilution of these substances by lots of extra fluid.
Hyponatremia: Treatment
Determine and treat the cause
As with other fluid and electrolyte imbalances, it’s important for members of the
health care team to determine the cause of the patient’s hyponatremia and fix
it if possible. Sometimes, that is not possible and we treat the symptoms of the
problem instead.
Decrease the fluid excess
If there is water excess, clients will be placed on fluid restrictions. If it is medication that is
causing the water intoxication, that medication should be stopped. If the client
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is hypervolemic, it may necessary to limit both water intake and salt intake until
the cause of the problem has been determined and treated.
Maybe replace some sodium
If hyponatremia is severe, it is possible that the physician will order oral or IV sodium
replacements. If that is the case, this treatment should be gradual in order to avoid huge
shifts of fluid that would occur in response to suddenly higher sodium levels.
Monitor carefully
Finally, it is important for nurses to monitor patients closely. You’ll want to
monitor vital signs, neurological status, intake and output, and daily weight, all of
which will provide important information about the client’s fluid balance
status. And of course, you will monitor lab values as well.
Hypernatremia
Shift of concentration of sodium O
Too much ECF sodium
Too much intake
O Too little ECF water
Insufficient intake
Abnormal water loss
Hypernatremia is defined as a serum sodium concentration of more than 145 mmol/L. Again,
remember that this means that there has been a change in concentration of sodium in the blood.
The high levels of sodium can be caused by too much sodium in the ECF or by too little water.
Hypernatremia is rarely caused by too much sodium intake. As you’ll remember, increased
sodium creates an increase in the osmolality of the blood, which stimulates thirst. That means
that hypernatremia should not persist unless there is no access to fluid. Rarely, the administration
of IV fluids or of sodium bicarbonate in specific medical treatments will result in hypernatremia.
More commonly, hypernatremia is caused by water loss. Clients lose water through insensible
losses, through the skin or lungs when they experience fever, heatstroke, or respiratory illnesses.
Significant amounts of fluid can be lost when a client has diarrhea. In all these cases, sodium is
also lost, but if the proportion of sodium loss is less than that of water loss, the client will have
hypernatremia. Sometimes clients lose extraordinary amounts of water through osmotic diuresis.
That means that at the level of the kidney, loss of particles into the filtrate will cause a related
loss of water. One example of this is the renal loss of glucose that occurs when blood glucose
levels are high.
Hypernatremia: Manifestations
Shrunken cells
Brain cells
Skin and mucous membranes
Volume depletion
Lab values
Don’t forget thirst!
The manifestations of hypernatremia are all related to the increased osmolality of the blood, but
symptoms depend on why the osmolality is increased. For example, if the problem is an increase
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in sodium, fluid will shift from the intracellular compartment to the vasculature because of the
osmotic pull. This results in shrunken cells. Shrunken brain cells are not happy cells. Your client
will be restless, confused, and weak. If the imbalance is not corrected, symptoms will worsen
(stupors, seizures, and coma). In addition, (remembering the role of sodium in the transmission
of nerve and muscle impulses), you should look for signs of neuromuscular excitability, such as
twitching. When water is lost in greater proportion than sodium, your client will also show signs
of volume depletion, such as dry mucous membranes and orthostatic hypotension. Lab values
will show an increase in sodium concentration and an increase in osmolality. And of course, your
client will be thirsty.
Hypernatremia: Treatment
Decrease the salt
Increase the fluid
Correct slowly
Once again, the treatment of this sodium and water imbalance sounds simple  either add
water or remove salt. As I’ve just discussed, it’s not common that the cause of
hypernatremia is
excessive intake of sodium since our bodies crave the fluid that would dilute the sodium. So that
leaves us looking at treating the loss of fluid that is responsible for most cases of hypernatremia.
Oral rehydration solution is widely available in grocery stores.. It contains glucose and
electrolytes (along with water) and is recommended for treating dehydration. IV solutions can
also be used. Care must be taken to ensure serum osmolality is corrected slowly. A sudden
decrease in osmolality would cause fluids to shift quickly to brain cells, causing cerebral edema
and potentially permanent neurological damage.
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Summary of Na+ and H2O Imbalances
Fluid volume status and the distribution of fluids between the intracellular and extracellular
compartments depend on water and sodium balance. The body will always try to preserve blood
volume so it can effectively nourish tissues. Fluid volume shifts in which both sodium and water
are lost or gained in equal proportion are called isotonic imbalances. An isotonic loss is called
fluid volume deficit or dehydration. An isotonic gain results in fluid volume excess.
Sometimes, sodium and water are lost in unequal/disproportionate amounts, creating an
imbalance in serum osmolality. Hyponatremia is the decrease in osmolality that occurs when
there is proportionately too much water. Hypernatremia is just the opposite  it is an increase in
osmolality due to proportionately too little water. The manifestations of each imbalance are the
result of the shift of fluids associated with the problem. The treatment of each imbalance is
always to correct the problem that caused it and to treat the symptoms that result from changes in
osmolality and fluid shift.
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Potassium Imbalances
Major intracellular cation
Normal concentration in the cells: O
140 to 150 mmol/L
We measure the ECF concentration: O
3.5 to 5 mmol/L
Normal concentrations are vital
Balance is carefully regulated
As you know, potassium is the major intracellular cation and plays a big role in regulating many
body functions. Particularly important is the role that potassium plays in regulating membrane
potentials, controlling the excitability of nerve and muscle cells, and the contractility of
muscles. When we look at manifestations of potassium imbalance, knowing the role it plays in
the body will help you understand what to assess. Most of us receive adequate amounts of
potassium in our diets. We lose potassium primarily through renal excretion.
Potassium Imbalances: Hypokalemia

Too little potassium intake
Too much potassium output
Shifts between intracellular and extracellular compartments
Hypokalemia is a decrease in plasma potassium levels below 3.5 mmol/L. It can occur for a
number of reasons. First, an individual may have an inadequate intake of potassium. This is a
reasonably common cause of low potassium levels. Adults require at least 40 mmol of potassium
a day to balance renal losses. People whose intake of food (in general) is low will also take in
too little potassium. People on fad diets may not eat specific potassium-rich foods. The elderly
are at risk for inadequate potassium intake if they are unable to purchase, prepare, and eat
potassium-rich foods. Hospitalized patients who are receiving IV fluids might have hypokalemia
if they receive solutions that do not contain potassium.
Hypokalemia can also be caused by excessive losses of potassium. Potassium can be lost
through the kidneys, either when aldosterone levels are high, or quite frequently because of
diuretic use. Many thiazide and loop diuretics increase the loss of potassium in the urine.
Potassium is also normally lost through the GI tract. Losses can become excessive through
vomiting, diarrhea, or gastro-intestinal suctioning.
Movement of potassium from the extracellular space into the intracellular space will
decrease potassium levels. Insulin promotes movement of potassium into the cells, as do a
number of medications such as bronchodilators and decongestants.
Hypokalemia: Manifestations
Kidneys
GI tract
Skeletal muscles
Cardiovascular system
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A deficit in potassium can affect physiological functioning in many ways. Most clients will not
show signs of hypokalemia until potassium levels fall below 3.0 mmol/L. Signs are usually
gradual in onset so detecting the problem might take some time. When the kidneys try to
conserve potassium it creates an inability for them to concentrate urine. Output increases and
therefore the plasma osmolality increases and the client will experience thirst. In the GI tract,
potassium deficit alters normal peristalsis, so clients may have anorexia, nausea, or vomiting.
Decrease in smooth muscle activity can cause constipation, or in severe cases, paralytic ileus
(intestinal obstruction). Abnormal muscle contractility in skeletal muscles can cause fatigue,
weakness, and muscle cramping. But it is the cardiovascular system that shows the most serious
(even life-threatening) effects of hypokalemia. Too little potassium interferes with normal
electrical activity and contractility, so patients may experience postural hypotension and cardiac
arrhythmias.
Hypokalemia: Treatments
Prevention
Replacement O
Oral O
Iv
Correct slowly
The best treatment for hypokalemia is prevention. Patients at risk, particularly patients who are on
potassium-wasting diuretics, should be taught to ingest foods with a high potassium content. Once
a deficit in potassium has occurred it is difficult to adequately treat with high potassium foods
alone. Frequently, clients are prescribed oral potassium supplements, which will slowly correct the
problem. When oral supplements are contra-indicated or when the deficit is severe,
potassium may be added to an IV solution. Nurses need to be aware of all precautions necessary
when administering any potassium replacement. As you’ll see in the next few slides, too much
potassium is also a big problem.
Potassium Imbalances: Hyperkalemia

Too rapid administration
Too little output
Shifts between intracellular and extracellular compartments
Hyperkalemia is defined as plasma levels of potassium higher than 5.0 mmol/L. This is not
a common problem but it can be serious. There are three causes of hyperkalemia.
It is difficult to create hyperkalemia when treating low potassium levels with oral supplements
because the kidneys will excrete any overload. However, if IV potassium-containing solutions are
administered rapidly, (especially in clients whose kidney function is impaired), hyperkalemia
can result. In hospitalized patients, potassium- containing solutions should not be started until
the healthcare team is sure that the client’s kidney function is adequate.
The most common cause of hyperkalemia is decreased renal function – usually renal failure.
In addition, a decrease in aldosterone will cause elimination of sodium with an accompanying
decrease in the elimination of potassium.
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The movement of potassium out of the cells and into the plasma will also cause hyperkalemia.
This movement can occur in response to tissue injury. In periods of acidosis, the body tries to
compensate for a high number of hydrogen ions by shifting them into the cells. In exchange,
potassium ions will move out of the cells and into the plasma. In times of acidosis, renal
function is decreased which furthers the retention of potassium.
Hyperkalemia: Manifestations
GI
Neuromuscular
Cardiovascular
The signs of hyperkalemia are often not noticeable until plasma levels exceed 6.0 mmol/L. When
they do occur, they are related to problems of neuromuscular excitability. In the GI tract, you’ll see
nausea and vomiting, as for hypokalemia, but this time you’ll see cramping and diarrhea.
Clients will have weakness, dizziness, and muscle cramps, but might also have abnormal
sensations (paresthesia). The most serious problem associated with hyperkalemia is cardiac.
Because of problems with conductivity, the heart rate may slow. ECG changes will occur, and if
the excess is severe, ventricular fibrillation and cardiac arrest may occur.
Hyperkalemia: Treatment
Restrict intake
Promote excretion
The treatment of hyperkalemia depends on how quickly the potassium rate has risen and how
high it is. Sometimes treatment can be limited to restricting dietary potassium, particularly in
salt-substitutes, or discontinuing medications that promote potassium retention, such as
potassium-sparing diuretics. If potassium levels require more aggressive treatment, clients can be
prescribed oral solutions, which will remove potassium by exchanging sodium for potassium in
the intestinal tract. In severe hyperkalemia, when there are neuromuscular or ECG changes,
clients may require more aggressive treatment that helps to move potassium back into the cells
or to promote renal excretion.
Calcium, Phosphorous, and Magnesium Imbalances

Regulated by Vitamin D, parathyroid hormone, and calcitonin
Normal Ca++ 2.1-2.6 mmol/L
Neuromuscular and cardiovascular manifestations of imbalances
Calcium, phosphorous, and magnesium are also very important cations in the body. Not very
much of each of these three ions is available in the ECF, but the amounts are vital. You’ll
remember the role that vitamin D and parathyroid hormone play in regulating ECF levels
of these substances. Also recall that calcitonin removes calcium from the extracellular
fluid. It would be helpful for you to review the manifestations of hypo and hypercalcemia.
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Fluid and Electrolyte Imbalances: Summary

Imbalance at the level of the capillary
Sodium and water imbalances – proportionate and disproportionate O
Causes, manifestations, and treatment
Potassium imbalances
Causes, manifestations, and treatment
We’ve looked at the mechanism of fluid imbalance at the level of the capillary that result in
edema. I’ve talked about isotonic imbalances of sodium and water and I’ve covered hypo and
hypernatremia. This module also covered potassium imbalances.
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Module 2: Alterations in Respiratory Function- Asthma

Asthma
This is the first of two modules on obstructive airway diseases. This module will cover the
disease of asthma. Learning about the disease of asthma requires you to have a basic
understanding of the anatomy and physiology of the respiratory system and inflammation. I
recommend that you review chapter 23 in the Tortora and Derrickson A&P textbook. I will cover
the drugs used for asthma in this module. To supplement this information please review chapter
29 of the Adams pharmacology textbook, specifically pages 369-379. Required readings for this
lecture from your Forth pathophysiology textbook are in chapters 17, 18, 19, 27 and 29. Specific
pages and further required readings are listed on the next 2 slides. There is a brief tutorial on
asthma available to you on the CD that came with your Porth pathophysiology textbook. There is
a lot of content in this module, some of it should be a review from previous science courses and
some of it will be new or add on to previous learning. The overall aim of this module is to
provide basic science content related to asthma so that you are then able to apply it to clinical
practice. Remember, you will have further opportunity to discuss and apply this content in
tutorial sessions and in the clinical setting. Please note that there is a reference list at the end of
the power point presentation, specific references for each slide are found in the notes section of
each slide. Also, the term asthma attack and acute exacerbation of asthma are used
interchangeably throughout the module.
Concepts in Action Animations - Asthma

The respiratory system is composed of airway passages, the lungs, and the associated blood
vessels. The purpose of the respiratory system is to provide for oxygen and carbon
dioxide exchange between air and blood. Respiration consists of three distinct processes.
Ventilation is the movement of air from the atmosphere into and out of the lungs. Air
must be taken in through the upper airway passages comprising the nose, nasal passages,
mouth, pharynx, and larynx. The air then proceeds from there into the lower airway
consisting of the trachea, the bronchi, and bronchioles of the lungs. The process of taking
air in is called inspiration. Perfusion is the movement of blood through the lungs.
Diffusion is the movement of gases between the roughly one million alveoli or air-filled sacs
within the lungs and the capillaries that supply the alveoli. In diffusion, gases move
across the alveolar capillary membrane. Oxygen moves from the air that is in the alveoli
into the blood flowing through the pulmonary capillaries. Carbon dioxide passes from
the blood into the alveoli. Completing the respiration process, the carbon dioxide is
expelled through expiration. If respiration is impeded, gas exchange cannot occur.
The body’s supply of oxygen becomes insufficient for its needs and carbon dioxide
cannot be expelled from the blood.
Asthma is a chronic reactive airway disorder characterized by increased resistance to airflow

due to episodic airway obstruction. Asthma involves inflammation of the airways,
bronchospasm, increased mucus secretion and injury to the mucosal lining of the
airways. Asthma can be characterized as extrinsic or intrinsic, based on the factors that
trigger the disorder.

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Extrinsic, atopic asthma is initiated by a type one hypersensitivity response to an extrinsic

antigen. An antigen binds with a mast cell, and causes mast cell degranulation with
release of histamine, leukotrienes, interleukins, and prostaglandins, resulting in
inflammation and bronchospasm. This airway inflammation in turn produces airway
edema, epithelial injury, and impaired mucociliary function.
Intrinsic, non-atopic asthma is initiated by diverse non-immune mechanisms; however,

many people have overlapping symptoms. Intrinsic asthma is triggered by irritant
receptors and vagal reflex. Intrinsic asthma is often triggered by viral infections, inhaled
irritants, NSAIDs, sulfites, and emotional stress.
Asthma usually has its onset in childhood or adolescence; however, adults may develop
asthma without a previous history of the disease. Asthma arises from a complex
interaction between heredity and environmental factors, and manifests as acute attacks.
The early phase or acute responsive asthma occurs within 10-20 minutes of exposure to a
trigger. Mast cells, which in people with asthma, are in a pre-sensitized state, react to
antigens and release histamine, leukotrienes, interleukins, and prostaglandins. With
airborne antigens, the antigen binds to the mast cells on the mucosal surface of the
airway. The release of inflammatory mediators leads to infiltration of inflammatory cells
and allows the antigens to reach the sub-mucosal mast cells. In addition, direct
stimulation of parasympathetic receptors causes bronchospasm, and increased vascular
permeability causes mucosal edema and increased mucus secretions. As airway
obstruction progresses, expiration becomes prolonged.
Late phase response develops 4-8 hours after exposure to an asthmatic trigger. Release of
inflammatory mediators induces the migration and activation of other inflammatory cells,
basophils, eosinophils, and neutrophils. The late phase response involves inflammation,
increased airway responsiveness, and renewed bronchospasm. These symptoms lead to
further airflow limitations and continued heightened airway responsiveness. This sequence
prolongs the asthma attack and sets into motion a vicious cycle of exacerbations including
additional edema, epithelial injury, and impaired mucociliary function.
Treatment for all asthma patients is approached in two ways: through control of factors
contributing to asthma severity and through pharmacologic treatment. If exposure to
triggers can’t be avoided, then pharmacologic treatment is usually needed. This can
include corticosteroids, bronchodilators, mast cell stabilizers, beta-agonists, and
anticholinergic drugs.
In summary, asthma is a chronic reactive airway disorder characterized by increased

resistance to airflow due to obstruction of the airway passages. Asthma involves a
hypersensitivity reaction to stimuli and the release of chemical mediators from pre-
sensitized mast cells, leading to a vicious cycle of edema, epithelial injury, and impaired
mucociliary function.

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Learning Outcomes
Describe current Canadian trends in the prevalence of asthma.
Describe the etiology of asthma.
Describe the pathophysiology of asthma.
Link the pathogenesis of asthma to the clinical manifestations and evaluation of the disease.
Clinical manifestations are the signs and symptoms of the disease.
Evaluation of the disease includes assessment findings, laboratory results, radiological
findings, pulmonary function texts, and peak flow measurement. Remember that the
evaluation findings are objective signs of a disease.
Provide scientific rationale for interventions.
Specifically understanding the mechanism of action of the various drugs used to treat
asthma.
Provide scientific rationale for patient teaching.
Provide key points.
Prevalence: The Faces of Asthma

Canadians >12 y.o. (Statistics Canada) O
2,362,902 (2008)
O 2 249 703(2005)
NLSCY data 2000/01:
586 000 (13.4%) children aged 11 and under
Higher prevalence in boys and women
Childhood asthma rates highest in Atlantic provinces, lowest in British Columbia and
Prairie Provinces
Rates are steadily increasing around the world
The prevalence of physician diagnosed asthma among Canadians 12 years and older has
increased from over 2.2 million in 2005 to over 2.3 million in 2008. This represents between 8
and 9 percent of the Canadian population aged 12 and over. It is important to identify
populations where the prevalence of asthma is different than that of the general population. In
Canada, the prevalence of asthma of off-reserve aboriginal people 12 years of age and over is
higher than that of the general population at 11.9%.
The National Longitudinal Survey in Children and Youth (NLSCY) is a longitudinal study of
Canadian children that began in 1994. The study provides information about health,
development, and social environments of the participants from birth to early adulthood. Data
from the NLSCY found that 586 000 Canadian children aged 11 and under had been diagnosed
with asthma. This represents 13.4% of Canadian children aged 11 and under. Overall, this is a
statistically significant increase from 1994/95 data where 11.1% of Canadian children under 11
years of age had been diagnosed with asthma. However, when broken down into age groups,
the increase was only significant for children aged 5 and younger and children aged 10 and 11.
Despite the increase in childhood asthma, the prevalence of asthma attacks has decreased from
51% to 39% between 1994/95 and 2000/01 data of 0-11 year old Canadian children.
The prevalence of physician diagnosed asthma among adults is also increasing. Specifically,
there has been a 60% increase in women aged 35-44 years, 80% increase in women aged 45-64

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years, and 41% increase in men aged 35-44 years between 1994/95 and 2005. Other important
epidemiological facts are that there is a higher prevalence in boys and adult women, that
childhood asthma rates are highest in Atlantic Provinces and lowest in the British Columbia and
Prairie Provinces, and that the prevalence is steadily increasing in both children and adults in
most countries around the world, including Canada. It is encouraging to note that despite
increasing prevalence, asthma mortality rates have steadily declined in Canada since 1987. This
is consistent with other developed nations. Although asthma continues to be a major cause of
hospitalization in children in Canada, hospitalization rates have also decreased in children and
adults along with ER visits. This is attributed to the appropriate use of asthma practice
guidelines and active involvement of patients and their families.
Etiology
What triggers asthma? What causes the disease?
The etiology of asthma is multi-modal and most often without a singular cause
Childhood asthma
Longitudinal studies have suggested that in childhood asthma, susceptibility is
determined during fetal development and the first 3-5 years of life
Risk factors for developing childhood asthma include:
Family history of allergy and allergic disorders (hay fever, asthma, eczema)
The genetic basis of asthma is complicated and multifactorial as there have been
several genetic loci and a variety of different chromosomes implicated in the
pathogenesis of asthma
There have actually been more than 100 genes identified that may have played a
role in the susceptibility and pathogenesis of asthma
Some of these genes influence the production of IL-4. IL-5, IL-13, IgE, eosinophils,
mast cells, adrenergic receptors, leukotrienes, and bronchohyperresponsiveness
In particular the gene Atom 33 has been associated with asthma and
bronchohyperresponsiveness
High exposure to airborne allergens

i.e. pets, house dustmites, cochroaches, mold in the first 2 years of life
Exposure to tobacco smoke in utero or early in life

The NLSCY found that Canadian children living in households whose either
parents smoked daily are significantly more likely to develop and be
diagnosed with asthma than children who develop in non-smoking households
Low birth rate and respiratory distress syndrome (RDS)

The NLSCY has not found any relationship between household income and
childhood asthma
Similarly with those children with asthma, the likelihood of having an asthma
attack within the past year was not related to household income

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It is important to note that the NLSCY has not found a difference in the prevalence of
asthma between urban and rural areas
This is in contrast to findings in other countries, specifically the USA where the
prevalence of asthma is significantly higher in urban areas
Adult onset asthma risk factors include:

Occupational exposures to low molecular weight sensitizers (i.e. isocyanates)
Exposure to infectious agents, allergens or pollution
Although atmospheric pollution itself is unlikely to be the primary cause of asthma in
the absence of other risk factors
For women: smoking, obesity, hormonal influences
Definition of Asthma
Before we move on to discussing the pathophysiology of asthma, let’s review the
definition:
“Asthma is characterized by paroxysmal or persistent symptoms, such as dyspnea
chest tightness, wheezing, sputum production and cough associated with variable
airflow limitation and airway hyperresponsiveness to endogenous or exogenous stimuli.
Inflammation and its resultant effects on airway structure are considered the main
mechanisms leading to the development and persistence of asthma” (Becker et al.,
2005, p. S3-S4)
This descriptive definition is used in both adult and pediatric Canadian consensus
guidelines and has not changed in over a decade
Asthma can be classified as mild, moderate, or severe
It can vary greatly from one patient to another and symptoms may be transient,
intermittent, or persistent
Other definitions include that the lower airway obstruction is usually reversible which is in
contrast with other obstructive airway diseases such as COPD
Pathophysiology
First, I am going to talk about specific concepts listed here before we look at a couple of
images to pull it all together. Specifically for the next several slides I will:
inflammation
Identify the specific inflammatory mediators involved
Bronchospasm
Discuss the causes and effects of hyperresponsiveness of bronchial smooth
muscle resulting in bronchospasm
Increased mucus production
Discuss the causes and effects of mucous hypersecretion
Airway remodelling
Discuss injury to the mucosal lining as it relates to airway remodelling
Let’s begin by comparing extrinsic vs. intrinsic asthma and describing the early and
late phases associated with intrinsic asthma

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Triggers
Extrinsic asthma (atopic/allergy asthma)
Extrinsic asthma, also known as atopic or allergic asthma, is a Type 1 IgE mediated
hypersensitivity reaction resulting from an exposure to an extrinsic antigen or allergen
Intrinsic asthma (non-atopic asthma)

Intrinsic asthma, also known as non-atopic asthma, results from a variety of triggers
listed here
O Respiratory tract infections (*viral)
O Exercise
O Hyperventilation
O Cold air, weather changes
O Drugs & chemicals
O Irritants
O Hormonal changes & emotional upsets
O Airborne pollutants
O GERD
Most individuals with asthma have a combination of extrinsic and intrinsic asthma
The pathophysiology of intrinsic asthma is not as well understood or straightforward as
extrinsic asthma
There are different explanations for why a non-atopic trigger may cause bronchospasm
and subsequently an acute asthma exacerbation
O For example, it is thought that bronchospasm by way of parasympathetic
stimulation through vago pathways may initiate an exacerbation of asthma
and asthma symptoms for triggers such as inhaled irritants, emotional factors,
and hormonal changes
Other possible explanations that link intrinsic asthma triggers to asthma clinical
manifestations can be found in your Porth textbook on pages 682 and 683
Either way, the major pathologic feature of both types of asthma is inflammation, the
result of hyperresponsiveness of the airways
Let’s look a bit more closely at the early and late phases of intrinsic asthma
Note that intrinsic asthma generally has the same cell involvement, including mast cell
and immune activation
Early Phase Response

Occurs within 10-20 min of triggering stimuli and can last up to 2 hrs
Allergen binds to preformed IgE on sensitized mast cells on mucosal surface of airways
Mast cell activation releasing inflammatory mediators
Mast cell activation results in the release of pre-formed granules, specifically:
Histamine, chemotactic chemokines, ILs and tumernucrosis factor
alpha This immediate response is called mast cell degranulation
Mast cells also begin synthesising leukotrienes, prostaglandin D2,
cytokines, platelet activating factor for a release in the late phase
response
These inflammatory mediators cause:
Infiltration of inflammatory cells
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Opening of mucosal intercellular junction, allowing access to sub-mucosal mast

cells, which results in further inflammation
Increase mucus secretion
Increased vascular permeability
Bronchoconstriction
It should also be noted that dendritic cells may receive antigen at this time, that will be
processed and presented later in the late phase response to naïve lymphocytes in the
lymph nodes or memory T-helper 2 cells in the airway mucosa
This will result in further immune activation
Late Phase Response

Occurs 4-8 hrs. after triggering stimuli, and may persist for days or even weeks
Release of inflammatory mediators causes recruitment and persistent activation of
neutrophils, eosinophils, basophils, T lymphocytes (specifically T-helper 2
lymphocytes) triggered earlier by chemotactic factors and upregulation of
endothelial adhesion molecules
These inflammatory cells cause epithelial injury and edema, increased mucus changes in
mucociliary functions resulting in accumulation of mucus and increased airway
responsiveness and bronchospasm
Epithelial damage and impaired mucociliary function is caused because of direct toxic effects
of cellular products, specifically from eosinophils such as major basic protein
In turn, this injury causes local nerve endings to be stimulated through autonomic
pathways, which may cause further bronchoconstriction and mucosecretion
Macrophages are also activated in the respiratory tract during the late phase
Inflammatory Cells
The following is an overview of the specific inflammatory mediators involved
You should have a basic understanding of the role of each of these mediators in the
inflammatory process and in the pathogenesis of asthma
You may find it helpful to review Ch. 17 and Ch. 18 in your Porth Pathophysiology
textbook as a description provided in this presentation are limited to how these
mediators are relevant to the pathophysiology of asthma
Mast Cells
Mast cells are cellular bags of granules found in large numbers in the skin and linings of the
GI and respiratory tract
They are activated by several means, including physical injury, chemical agents,
immunological and infections means
As discussed previously they degranulate, releasing histamine, chemotactic factors and
cytokines which cause an immediate effect
The activated mast cells also begins synthesizing inflammatory mediators derived from
plasma membrane lipids such as platelet activating factor, prostaglandin D2 and
leukotrienes as well as cytokines and growth factors which result in the long term
response
Now let’s look at each of these mast cell-derived mediators
Histamine
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A potent vasodilator that causes increased vascular permeability through

retraction of endothelial cells
Also causes smooth muscle to retract, causing bronchoconstriction when
stimulated in the bronchi – this is particularly important in the
pathogenesis of asthma
Leukotrienes
Their functions are similar and complementary to that of histamine
Are more potent, stimulate slower, and have more prolonged effects
compared to histamine
Systenoleukotrienes, LTc4, LTd4, and LTe4 cause slow and sustained
constriction of the bronchioles which is important in the pathogenesis
of asthma
Prostaglandin D2
Causes vasodilation, increased vascular permeability, and
bronchoconstriction
Chemotactic chemokines
Are cytokines that attract immune and inflammatory cells
They primarily function to attract leukocytes
Cytokines
Defined on pg. 372 in your Porth Pathophysiology textbook as “proteins
that modulate the functions of other cells”
Tumernucrosis factor alpha, IL-4, IL-5, IL-8, and IL-18 are key
mediators in the pathogenesis of asthma
Tumerucrosis factor alpha increases the migration and activation of
inflammatory cells, specifically eosinophils and neutrophils, and
contributes to airway remodelling
Tumerucrosis factor alpha also causes endothelial cells to express
adhesion molecules
Tumerucrosis factor alpha and IL-1 alter muscarinic receptor function,
resulting in increased levels of Ach which causes bronchial smooth
muscle contraction and mucous secretion
IL-4, IL-5, IL-8, and IL-18 are T-helper 2 cytokines
IL-4 stimulates activation, proliferation, and production of antigen-
specific IgE by B cells
IL-5 activates and promotes eosinophil activity
IL-8 causes a more exaggerated inflammatory response through
activation of basophils, neutrophils and eosinophils
IL-13 impairs the clearance of mucous, contributes to
bronchoconstriction, and increases fibroblast secretion

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Platelet activating factor

Induces platelet aggregation, increases vascular permeability through
endothelial cell retraction, activates neutrophils, and is a potent
eosinophil chemoattractant
In the respiratory system it causes bronchospasm, eosinophil infiltration,
and non-specific bronchial hyperreactivity
Cytokines (i.e. TNF-alpha, IL-4, IL-5) [We have already discussed the following specific
cytokines]
Cysteinyl Leukotrienes
Although we have discussed the role of leukotrienes, it is important to note
that cysteinyl leukotrienes, which are mostly produced by mast cells,
eosinophils, and basophils, are the leukotrienes that play a major role in
the pathophysiology of asthma. They were initially called slow reacting
substance of anaphylaxis due to their effect on bronchial smooth muscle
of slow and prolonged contraction and hence bronchoconstriction
T Lymphocytes (Th2)
.
T-lymphocytes, specifically T-helper 2 lymphocytes play an important role
in the pathogenesis of extrinsic asthma. T-helper 2 lymphocytes act as
growth factors for mast cells, as well as recruiting and activating
eosinophils by stimulating the differentiation of B-cells into the IgE-
producing plasma cells. In asthmatic patients, T-cell differentiation is
skewed towards T-helper 2 phenotype cells
Leukocytes (Leukocytes, such as eosinophils, basophils, neutrophils, lymphocytes

and macrophages, are also known as white blood cells. Neutrophils, eosinophils
and basophils are also known as granulocytes)
Neutrophils: Neutrophils are the first on scene and the predominant
phagocytes in the early inflammatory phase
Eosinophils In the pathogenesis of allergic asthma, eosinophils have an
important role by controlling the release of specific mediators for mast
cells
Basophils: Like mast cells, basophils bind to IgE which is secreted by
plasma cells and release histamine and mediators of inflammation such
as IL-4
Lymphocytes: Remember that lymphocytes are T and B cells
Macrophages: Macrophages arrive after neutrophils, which means in the
pathogenesis of asthma, they arrive in the late phase response

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Bronchospasm
Bronchospasm is the result of the action of several mediators listed here
Histamine (early phase)
Leukotrienes (late phase)
PAF (Platelet aggravating factor)
Prostaglandins
Autonomic Nervous System Dysregulation (PNS): Also, the parasympathetic control
of the airway function appears to not function properly due to heightened
responsiveness to cholinergic mediators. This is caused by an alteration of
muscarinic receptor function by TNF-alpha and IL-1, leading to an increase in
acetylcholine which causes bronchial smooth muscle contraction and further mucus
secretion
O Cholinergic mediators responsiveness increases
Mucus Hypersecretion
Mucus hypersecretion is a major pathophysiological feature of asthma
Goblet cell hyperplasia and submucosal gland hypertrophy- submucosal glands and
goblet cells produce mucus in the airways. Both sources are affected in patients with
asthma, resulting in goblet cell hyperplasia and submucosal gland hypertrophy
Mucus secretion triggered by the inflammatory response- Mucus secretion is
triggered by the inflammatory response
Leukotrienes stimulate increased mucus secretion- Leukotrienes are known to
stimulate mucus production
Th2 release IL-9 and IL-13  upregulate mucus production in asthmatic patients-IL-9
and IL-13 are the two more relevant cytokines that upregulate mucus secretion.
Other mediators that may have a role in mucus hypersecretion are TNF-alpha, IL-
1beta and ligands of the epidermal growth factor receptor
Airway obstruction by mucus plugs d/t mucus hypersecretion + increased plasma
exudation  increased airway hyperresponsiveness- The more damaging the effect of
mucus hypersecretion is airway obstruction by mucus plugs which is caused by mucus
hypersecretion and increased plasma exudation. Mucus hypersecretion may also
increase airway hyperresponsiveness. Furthermore, impaired mucociliary function
worsens the situation as the ability to clear the mucus is impaired
Airway Remodelling
Appears to occur in parallel with inflammation
Airway remodelling is recognized as one of the major contributors in the
pathogenesis of asthma. These structural changes in the airway wall probably
occur in parallel with inflammation, meaning that more inflammation equals more
airway remodelling. Therefore, airway remodelling begins early on in the disease
process of asthma and declining lung function, which is attributed to airway
remodelling, is found in young children as well as new asthmatic. Changes to the
airway due to inflammation may include submucosal infiltration with activated
lymphocytes and eosinophils, mast cell activation, epithelial changes and
basement membrane thickening. In more severe asthma,
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goblet cell hyperplasia and smooth muscle hypertrophy and hyperplasia

along with mucus plugging are common
Increase in goblet cells, hyperplasia and hypertrophy of smooth muscle cells 
thickened smooth muscle cell layer, increased airway deposition of collagen and
other proteins  thickening of the lamina reticularis with subepithelial fibrosis
and increased vascularity in the airway wall
Review of literature on airway remodelling; there are many factors that influence
airway remodelling. TNF-alpha, cysteinyl leukotrienes being major
contributors
Putting it all Together

The following is a summary of the pathophysiology of an asthma attack or acute
exacerbation of asthma. It does not take the early or late phase responses into account.
A trigger in the form of an allergen or irritant exposure causes mast cell degranulation
and release of vasoactive mediators and chemotactic mediators. The mast cell will
release histamine immediately and synthesize other vasoactive mediators for later
release. As you know, these include leukotrienes, prostaglandin D2, platelet-activating
factor. These vasoactive mediators result in vasodilation, increased capillary
permability and broncho constriction. The trigger also causes immune activation and T-
helper 2 cells release IL-4 which stimulates B-cell activation proliferation and
production of antigen specific IgE. IgE also causes mast cell degranulation. Mast cells
release chemotactic mediators, which cause cellular infiltration of other inflammatory
cells, specifically neutrophils, eosinophils, lymphocytes and cytokines. Autonomic
dysregulaiton results from alterations to muscarinic receptor function by TNF-alpha
and IL-1 causing bronchoconstriction and mucosecretion. Epithelial injury and airway
remodelling occurs because of persistant inflammation and toxic effects of eosinophils,
leukotrienes and TNF-alpha. The result of both vasoactive mediators and inflammatory
cellular infiltration is bronchospasm, vascular congestion, mucus secretion, impaired
mucociliary function, thickening of airway walls and increased contractile response of
bronchial smooth muscle with resulting bronchial hyperresponsiveness and obstruction
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Putting it All Together

From Porth textbook on page 683
Depicts the early and late phase responses and does not show the activation of T-
helper 2 lymphocytes
A – the immediate or early phase response is triggered by activation of presensitized
IgE coated mast cells. Mast cell degranulation results in the release of inflammatory
mediators that increase mucus production, open mucosal intercellular junctions with
exposure of submucosal mast cells to the antigen and cause bronchospasm
B – the late phase response involves the release of other inflammatory mediators,
recruitment of neutrophils, eosinophils and basophils, increased vascular
permeability, epithelial cell injury with decreased mucociliary function and
increased airway responsiveness and bronchospasm
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Clinical Manifestations
Signs are objective findings assessed or measured by a health care provider
Symptoms are subjective in nature and reported by the patient
Signs Symptoms
Physical assessment findings Dyspnea/SOB
Lab results Chest tightness
Radiological findings Cough
Pulmonary function tests “Noisy breathing”; wheezing
Peak flow monitoring Increased sputum
In the asthmatic patient, dyspnea is a result of the inability to adequately ventilate and
an abnormal ventilation-perfusion relationship where parts of the lung that are
well-perfused are not adequately ventilated
Chest tightness results from air trapping and resultant hyperinflation of the lungs
The symptom of cough results as the asthmatic patient tries to clear his or her
airway of mucus. In the absence of a respiratory infection, the cough
will initially be nonproduction during an asthma attack
Wheezing is the result of the passing of air through narrowed airways. Initially,
wheezing will be expiratory as the obstruction is in the lower airways. The clinical
manifestations during an asthma attack are related to narrow airways because of
lower airway obstruction due to bronchospasm, edema of the bronchial mucosal
and mucus hypersecretion
Air becoming trapped with impaired expiration as the obstruction worsens and air
flows to the less resistant portions because ventilation is uneven. The lungs become
hyperinflated, putting respiratory muscles at a disadvantage. As hyperinflation
progresses, alveolar hypoventilation occurs as gas exchange is impeded by
increasing intrapleural and alveolar gas pressure causing ventilation-perfusion
mismatch. Mucus also inhibits alveolar ventilation
Hyperventilation is triggered by lung receptors responding to increasing lung volume
and alveolar hypoxia. This hypoxia causes vasoconstriction which in turn decreased
vascular perfusion contributing to the ventilation-perfusion mismatch.
Hyperventilation causes a decrease in serum carbon dioxide, resulting in respiratory
alkalosis usually accompanied with hypoxemia
Work of breathing increases as the asthmatic patient breathes close to their functional
residual capacity, worsening dyspnea and increasing oxygen demands; fatigue
ensues. The cough becomes less effective due to air trapping and inspiration
occurring at higher residual lung volumes. Worsening hypoxemia and retention of
carbon dioxide with associated respiratory acidosis will result if the airway
production insists. Respiratory failure ensues with worsening respiratory acidosis
and hypoxemia
It should be noted that during full remission, asthmatic patients are asymptomatic
and pulmonary function tests are usually normal
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Physical Assessment Findings

Inspection  increased work of breathing, use of accessory muscles, prolonged
expiration, wheezing, cough, inability to maintain a conversation
Auscultation  wheezing, distant breath sounds, other adventitious breath sounds
such as crackles d/t infection
Vital signs  tachypnea, tachycardia, decreased oxygen saturations (hypoxemia)
As a nurse, physical assessment findings are key to providing safe and quality care to your
patients. If your patient is in respiratory distress and can barely talk to you, you will forego
reviewing their peak flow results or reviewing chest x-ray results for the time-being, as this
patient requires immediate support and you require assistance from the health care team,
particularly respiratory therapists and physicians. As you know, a thorough examination is
comprised of four assessment techniques: inspection, percussion, palpation, and
auscultation. I am going to discuss common findings when observing an asthmatic patient or
auscultating lung fields. In the clinical setting, percussion is often not done in a respiratory
assessment. Palpation may be done to assess perfusion of the skin by determining skin
temperature and capillary refill, or assessing for pain, masses, or crepitus of the chest. Upon
inspection, you may note: increased work of breathing, use of accessory muscles, prolonged
expiration, wheezing, cough, and an inability to maintain a conversation. Upon auscultation,
you may note: wheezing, distant breath sounds, or other adventitious breath sounds such as
crackles, which may be related to an infection. Remember that quiet or distant breath sounds
mean that air is not moving. In comparion, you can be sure that there is at least some
movement of air when you hear wheezing. If you cannot hear any breath sounds, you must
intervene and seek help from appropriate members of the health care team. For the vital
signs, you may note: tachypnea, tachycardia, and decreased oxygen saturation meaning
hypoxemia. You should be able to link each of these assessment findings to the
pathophysiology of asthma. The only one that we have not discussed is tachycardia.
Tachycardia may be the result of anxiety, stress, and/or the use of quick relief medications
like Ventolin. Think about why Ventolin may cause tachycardia. It will be evident in a few
slides when we talk about the pharmacology of drugs used in the management of asthma.
Laboratory Values
Arterial blood gases
Initially  respiratory alkalosis d/t hyperventilation +/- hypoxemia
Progresses to respiratory acidosis + hypoxemia
Can you analyze these ABGs?
pH 7.50, pCO2 29, HCO3- 22, pO2 76
pH is high, which indicates alkalosis; pCO2 is low; bicarbonate is
normal; pO2 is low, which indicates hypoxemia
This blood gas is analyzed as respiratory alkalosis with
hypoxemia
pH 7.32, pCO2 49, HCO3- 27, pO2 70
pH is low, which indicates acidosis; pCO2 is high; bicarbonate is
normal; pO2 is low, which indicates hypoxemia
This blood gas is analyzed as respiratory acidosis with
hypoxemia
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Normal values:
pH: 7.35-7.45; pCO2: 35-45
HCO3: 22-26; pO2: 80-100
The most helpful laboratory result in the asthmatic patient is an arterial blood gas. The
arterial blood gas provides information about ventilation through pCO2 values.
Hyperventilation will initially cause respiratory alkalosis, which may be accompanied with
hypoxemia or a low pO2 during an asthma attack. With persistent worsening of ventilation
and ventilation-perfusion mismatch, the patient will progress to respiratory acidosis due to
hypercapnia (retention of carbon dioxide). These acid base imbalances and hypoxemia can
be addressed with oxygen administration and pharmacologic therapy to open the airways
and improve ventilation. Mechanical ventilation and critical care management is required for
severe respiratory acidosis and hypoxemia.
Chest X-ray
Hyperinflation
+/- Flattening of the hemidiaphragms
Note any signs of infection
It is common for a chest x-ray to be done as part of the work-up for a patient in respiratory
distress, such as an asthmatic patient experiencing an acute exacerbation of the disease.
Hyperinflation plus or minus flattening of the hemidiaphragms are common radiological
findings on chest x-rays. The chest x-ray may also provide information on whether or not
there is a respiratory infection component as well. If a bacterial respiratory infection is
suspected or confirmed, antibiotics are warranted. If a viral respiratory infection is
suspected or confirmed, antibiotics are NOT warranted. Remember that a viral infection is a
more common trigger than a bacterial respiratory infection.
Pulmonary Function Tests

“Spirometry offers the single most objective measurement of lung
function available” (Conner & Meng, 2003, p. 571)
Bronchial provocation tests using histamine methacholine or non-pharmacologic
agent (i.e. cold air)
Bronchia responsiveness and bronchial obstruction should be reversible following
administration of short-acting bronchodilator (B2 agonist) in asthmatic patients
FVC, FEV1, FEV1/FVC, PEF, FEV 25-75%
Pulmonary function tests using spirometry may be used in the initial diagnosis of asthma,
monitoring ongoing response to therapy, assessing airway function, and to validate peak
flow monitoring. Connor and Meng (2003) state that “Spirometry offers the single most
objective measurement of lung function available.” Bronchial provocation tests use
histamine, methacholine, or exposure to a non-pharmacologic agent, such as cold air, to cause a
bronchoconstriction. Methacholine is a cholinergic agonist, which means that it acts on the
parasympathetic nervous system and causes bronchoconstriction. Airway obstruction is
assessed following bronchial provocation using baseline and post-beta agonist measurements of
forced vital capacity (FVC), forced expiratory volume in one second
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(FEV1), the ratio of FEV1 to FVC (FEV1/FVC), and forced expiratory volume between
25 and 75 percent. Reversible airway obstruction is confirmed when the data shows a 12%
or greater improvement. Peak expiratory flow (PEF) can be used to validate peak flow
monitoring results if the value is multiplied by 60. Spirometry does have the potential to
yield other measurements not discussed in this module.
Peak Flow Monitoring

Assesses peak expiratory flow (PEF) by comparing to patient’s personal best
Measure PEF around the same time each day
The best of three readings should be recorded
Green zone: PEF > 80% of personal best
Yellow zone: PEF 50-80% of personal best
Red zone: PEF < 50% of personal best
Peak flow monitoring measures the peak expiratory flow (PEF), which is how quickly a
person can exhale. It can be done at home using a hand-held device, which compares the result
to the patient’s personal best. It should be measured around the same time each day
and the best of three readings should be recorded. The following image is of a school age
boy using a home peak flow monitor.
A PEF greater than 80% of personal best indicates that the person is in the “green zone” and
that their asthma is well controlled. A PEF between 50 and 80% of personal best indicates that
the person is in the “yellow zone” and caution should be taken. The person should use
their short-acting bronchodilator and repeat peak expiratory flow measurement. The patient
should contact their health care provider if their peak flow rates do not return to the green zone.
A PEF less than 50% of personal best indicates that the person is in the “red zone”,
which indicates medical alert. The person should take their short-acting bronchodilator and
increase if needed. The person should seek medical attention and/or call 911.
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Pharmacologic Therapy
Long-term Control Medications O
Inhaled corticosteroids
i.e. Fluticasone (Flovent)
O Long-acting beta-2 agonist
i.e. Salmetrol (Serevent)
O Leukotriene modifiers
i.e. Montelukast (Singulair)
O Systemic corticosteroids
i.e. Prednisone
Mast cell stabilizers
i.e. Cromolyn (Intal)
Monoclonal antibody
i.e. Omalizumab (Xolair)
Quick Relief Medications

Bronchodilators
Beta-2 Agonist
i.e. Albuterol (Ventolin)
Anticholinergic
i.e. Ipratropium (Atrovent)
Systemic corticosteroids
i.e. Prednisone
Pharmacologic therapy is key to the management of asthma. Common medications used for
asthma are listed here. Medications used for asthma can be separated into two categories: long
term control medications that address inflammation and airway obstruction, and quick relief
medications that reverse acute airflow obstruction. All of the medications listed here are given
by inhalation, except for monoclonal antibody medications, which are given subcutaneously.
Note that I have given examples for each class of medication. The name in
brackets is the trade name and the other is the generic name. Other medications exist in each of
these classes. Let’s first look at the quick relief medications. Both beta-2 agonists and
anticholinergic inhalation medications result in bronchodilation. Beta-2 agonists, like
salbutamol, act on beta-2 pulmonary receptors, which increases levels of cyclic adenosine
monophosphate and relaxes smooth muscle. Although these medications are relatively
selective for beta-2 receptors in the lungs, they can affect beta-1 receptors in the heart,
causing tachycardia. Anticholinergic medications, such as ipratropium, inhibit muscarinic
cholinergic receptors, producing vagotone of the airways, which results in bronchodilation.
Systemic corticosteroids are sometimes used in severe asthma exacerbations. Corticosteroid
medications block the cyclooxygenase and lipoxygenase pathways in the inflammatory
process. The mechanism of action of corticosteroids is to decrease inflammation by
suppression of polymorpho-nuclear leukocytes and fibroblasts, as well as reducing capillary
permeability. Long acting beta-2 agonists function in the same way as short acting beta-2
agonists, but last longer. Leukotriene modifiers interfere with leukotriene action, which has
been well described in this module. Mast cell stabilizers stabilize the membrane of the
sensitized mast cell after an antigen-IGE interaction, preventing the release of inflammatory
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mediators, such as histamine. Lastly, monoclonal antibody subcutaneous injections is anti-

IGE antibody that prevents binding of IGE to basophils and mast cells. There are specific
Canadian guidelines that outline step-by-step how and when these medications should be
prescribed that is beyond the scope of this module. However, it should be noted that inhaled
corticosteroids are the medication of choice for all individuals with persistent asthma. Also,
those with persistent asthma should always have a quick relief medication on hand. Beta-2
agonist inhalations are the preferred quick relief medications to be used with
anticholinergic medications as adjuvant therapy. The side effects and nursing considerations
for each of these medications is also very important.
Lipoxygenase and Cyclooxygenase Pathways
This image depicts the lipoxygenase and cyclooxygenase pathways and identifies where
corticosteroid medications, leukotriene modifiers, and NSAIDs exert their actions.
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Patient Teaching
Patient teaching should include the following points. The nurse should teach the patient to:
Minuet
Avoid triggers and recognize signs of an impending asthma attack
Participate in the development of a written action plan for medication titration and
symptom management
Use peak flow monitoring
Take their medications as prescribed (medication adherence)
Use proper inhaler technique and use an appropriate medication delivery device
Conclusion
To conclude, the prevalence of asthma is increasing in Canada and worldwide. The etiology
and triggers are multi-factoral. Inflammation and airway hyperresposiveness are the major
pathologic features of both intrinsic and extrinsic asthma. Pharmacoogic interventions are
aimed at decreasing inflammation and addressing bronchoconstriction. And remember,
asthma can be effectively managed using best practice guidelines.
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Module 3: Childhood Obesity
Childhood Obesity
This module will discuss the issue of childhood obesity. Prevalence of obesity is so high that the
World Health Organization (WHO) and Centres for Disease Control and Prevention (CDC) now
refer to the obesity epidemic. The World Watch Institute released a report in the year 2000
stating, for the first time in human history, the number of overweight people rivals the number of
underweight people. Even more concerning than the fact that one third of U.S. adults are
considered obese, is that rates of childhood obesity have tripled since 1980 in the U.S. This same
trend is occurring globally. According to the WHO, 22 million children under 5 are estimated to
be overweight worldwide.
Special Report in NEJM

A special report in the March 2005 edition of the New England Journal of Medicine warned that:
“Unless effective population-level interventions to reduce obesity are developed, the steady rise
in life expectancy observed in the modern era may soon come to an end and the youth of today may,
on average, live less healthy and possibly even shorter lives than their parents.” (Olshansky
et al. 2005)
This is pretty frightening news considering that we as a society are used to ever-lengthening
lifespans because of better living conditions and medical advances. Now there is even talk of a
double cohort of cardiovascular patients. Parents and their children could, in the future, be
vying for a limited number of hospital beds, similar to the way high school students were
competing for university admissions for the 2003/2004 academic year.
This module will discuss:

The size and scope of the problem
Some of which I’ve already discussed
The complex factors leading to childhood obesity
Factors that may begin even before birth, depending on the conditions in the
intrauterine environment
The physiological dangers of obesity that continues into adulthood
Obese children that grow into obese adults face the risk of myriad of different
chronic health conditions that will tax the health care system and impact very
negatively on their future quality of life.
Programs and resources for dealing with this problem
Finally we will talk with an expert in the field of treatment of childhood obesity and
discuss some of the programs and resources for dealing with this problem.
The biological benefits of changes in diet and exercise
Benefits to health of changing lifestyle to include a better diet and more activity
will be included in this section.

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Canadian Statistics
Approximately 26% of Canadian children ages 2-17 years old are currently overweight or
obese
Approximately 1/3 of normal weight 20 year olds will become overweight within 8 years
Approximately 1/3 of overweight 20 year olds will become obese within 8 years
If this trend continues, in 20 years we can expect 70% of the 35-44 year olds in Canada to be
overweight or obese vs. 57% who are currently overweight or obese.
I’ve already mentioned some of the U.S. and global statistics about childhood obesity. Now
we will talk about what is happening right here at home. According to the Childhood Obesity
Foundation Website, data from the most recent Canadian Community Health Survey conducted
in 2004 shows that 26% (1.6 million) Canadian children ages 2-17 are overweight or obese.
Many obese children and adolescents do not outgrow this condition. Data from these studies
show that obese children aged 10-13 have an 80% chance of becoming obese adults. Many more
children who are not overweight or obese will gain excess weight in adulthood. Trends in weight
gain forecast that approximately 1/3 of normal weight 20 year olds will become overweight
within 8 years and approximately 1/3 of overweight 20 year olds will become obese within 8
years. If this trend continues, in 20 years, we can expect 70% of the 35-44 year olds in Canada to
be overweight or obese vs. 57% who are currently overweight or obese. The burden on the health
care system due to obesity related illnesses will be enormous, which is why there is so much at
stake in halting these trends now.
Definitions
Body mass index is used to define overweight and obesity in adults O
An adult with a BMI>30 kg/m2 is considered obese
The Centres for Disease Control and Prevention (CDC) growth charts are used to assess
weight in children in the U.S.
O At or above the 95th percentile for BMI for their gender and age is considered
obese
The World Health Organization (WHO) charts are recommended for use with Canadian
children, as of 2010
At or above the 97th percentile for their age and gender is considered obese for 5-19 year old
group
See attachment “DC_HealthProGrowthGuideE.pdf”
Overweight and obesity in adults is measured using body mass index, a person’s weight in kg
divided by the square of their height in m squared. The adult ideal for BMI lies between 18.5 and
24.9 kg/m^2. Overweight is defined as 25-30 kg/m^2 and over 30 kg/m^2 is considered obese.
Because children grow at different rates based on age and because they also vary in growth
patterns by gender, ideal weight is based on growth charts. You will likely see a number of different
measurement styles, but they will all be based on growth charts specific for a child’s
age and gender. The U.S. uses the Centres for Disease Control and Prevention (CDC) growth
charts. Plotting a child’s BMI on the growth chart appropriate for age and gender will allow
you to see what percentile the child’s weight falls within. Children with BMIs below the 5th
th
percentile are considered underweight, while those whose BMI falls on or between the 5 and

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th th
85 percentile are at their ideal weight. Children whose BMI is above the 85 but below the
th th
95 percentile are overweight for their age. Obesity is defined as a BMI at or above the 95
percentile for age and gender. This year, the Dietitians of Canada in cooperation with the
Canadian Pediatrics Society, the College of Family Physicians of Canada, and the Community
Health Nurses of Canada recommended the adoption of the World Health Organization (WHO)
growth charts as the gold standard for assessing growth in Canadian children. These are thought
to more accurately affect growth in Canadian children and were created based on populations in
a number of different countries. The cut-offs for these charts are broken into three categories for
children. There are a set of parameters from birth to age 2, from ages 2-5 years, and ages 5-19
th
years. In this latter category, overweight is assessed as BMI for age above the 85 percentile,
th
specific for gender. While criteria for obesity is BMI for age above the 97 percentile and
th
severe obesity is above the 99.9 percentile. For more information on criteria within the other
age categories, please see the Dietitians of Canada document in the attachments tab.
Statistics Canada Data
In Canada, adolescents are the age group most affected by overweight and obesity. From
1978/79 to 2004, the proportion of overweight children between 2 and 6 remain the same,
although obesity, previously unseen in this age group, rose to 6% in this category in 2004. Rates
doubled in those in the 6-11 year old age group and again, obesity appeared where had not been
seen before. Obesity in the 12-17 year old age group tripled while the proportion of overweight
and obese just over doubled since the previous measurement in 1978/79. Some of the factors
identified with obesity risk by the Canadian Community Health Survey were more than 2 hours
of screen time per day, either T.V. viewing, computer time, or video gaming, and the
consumption of less than 5 servings of fruits and vegetables per day.

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Causal Web
Obesity is caused by an imbalance between energy in, in the form of intake of nutrient dense
food, and energy out, in the form of activity level. This seems like a simple concept but there are
many more factors involved, as illustrated by the complexity of this causal web. There are many
variables that dictate what the intake/output ratio will look like. Obesity is therefore not a simple
problem with a single cause and there are no simple solutions. Conditions in the family and
home as well as the availability of facilities for leisure time activities can have an impact. Public
transportation, safety and quality of health care can also contribute. Education level may impact
food and nutrition choices regionally or nationally. National perspective on education, health
care and nutrition can also complicate the picture. Internationally, media and particularly food
advertising are especially important for child nutrition. As you can see, all of these factors are
interconnected and create the complexity of factors that affect childhood obesity.

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Breaking News
January 6, 2004
30% of U.S. children will eat fast food today.
6,212 children and adolescents over five years of age
children who eat fast food consume 187 additional calories daily
six pounds of weight gain per year!
One of the results of our busy lifestyles is the rise in consumption of fast food. A study in the
U.S. in 2004 established that of a population of adolescents and children over 5 years of age,
30% eat fast food each day. That fast food meal adds an extra 187 calories, which totals a
whopping 6 pounds of weight gain over the course of a year.
Other Factors involved

A previous slide showed the web of interrelated factors that can determine a
child’s weight.
Ethnicity is a factor since overweight and obesity occurs more often in the African-,
Hispanic- and Native-American populations than in Caucasian children in the U.S.;
Aboriginal children are more often affected in Canada (See attachment “Obesity risk
and ethnicity.pdf”)
The biggest predictive factor in childhood obesity appears to be obesity in one or both
parents and is related more strongly with maternal obesity.
Ethnicity and genetics can also collude to cause obesity. Certain populations are more
susceptible to becoming obese, which is why the proportion of obese individuals amongst First
Nation Peoples and those of Hispanic and African descents are so high. Adolescent males of
Hispanic descent and adolescent African American females appear to be especially predisposed
to development of obesity, given the right conditions. Genetics plays its part in the development
of obesity as well. The biggest predictive factor in childhood obesity appears to be obesity in one
or both parents. It is more strongly related with maternal obesity, but genetics are not the whole
story. Children obviously consume the same diet as their parents and have also been shown to
mirror their activity level.
Parents may not see the problem

See attachment “Invisible childhood obesity.pdf” and “Dr. Jeffrey Schwimmer - QoL
for obese children JAMA 2003 URL link”
Studies have shown that parents may not recognize that their child is overweight and may not be
aware of the associated health consequences and the seriousness of the situation. Since parents are
responsible for food purchases and meal preparations, their lack of awareness may worsen the
problem. Parents have the greatest opportunity to make the lifestyle changes necessary to ensure the
health of their children. But refusal to recognize the problem may lead to continued
weight gain over the remaining childhood years and maintenance of overweight or obese status into
adulthood. Besides the risks to the child’s health, their quality of life may suffer, due to the
extra pounds. When Dr. Jeffrey Schwimmer and his associates examined Quality of Life

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questionnaires from children and adolescent who were healthy and of normal weight, obese
children, and pediatric cancer patients, they were surprised to find that the obese
children’s’ scores were similar to those of the cancer patients.
The Economist
This slide is a magazine cover from the year 2003. The
frightening thing about this is that we have evolved into
humans over thousands of years yet it has only taken a
few decades to develop into an overweight society. In
2003, there were only 4 of the U.S. states that obesity
levels over 25%. The government statistics for 2008, the
last year reported, show 19 states with obesity levels
between 25-30% and 6 states with obese populations
greater than 30%. The article in the Economist, the
magazine that the cover image was taken from, talks
about days gone by,
when the rich were fat and the poor were thin as
opposed to today’s situation where the rich are thin
and the poor are fat and there is great concern over the
epidemic of obesity that is sweeping the globe. The authors blame evolution for designing us to
store energy for lean times and since we have not experienced lean times in recent memory, our
bodies continue to store the excess energy we take in and our waistlines continue to expand.
Childhood Obesity Cartoon

This cartoon depicts another of the societal
problems, adding to the burden of childhood
obesity. Before the advent of personal
computers and video games, children were
far more active. After school was the time to
play ball in the park, or hide and seek in your
neighbourhood. Now many children go home
and play video games, watch T.V. or use a
personal computer for entertainment. The
problem with inactivity is compounded by
the fact that playing video games or watching
T.V. is often accompanied by snacking with
high-fat, calorie-dense foods.

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The Trouble with FAT

Obesity can lead to poor self-esteem and in some cases depression. But an additional and perhaps
more serious health issue is the dysregulation of body systems leading to chronic illnesses. Those
who are obese are more likely to be diagnosed with cancer, liver disease, osteoarthritis, stroke,
type II diabetes and any of a number of cardio-vascular diseases.
For years, adipose tissue, the main storage depot for triglycerides which are the most common
form of lipid consumed in a meal was considered somewhat passive. All that changed a little
over a decade ago when it was discovered that adipose tissue synthesizes and secretes a number
of substances, including hormones and inflammatory molecules, now referred to as adipokines.
These secreted substances allow different tissues in the body to interact to maintain lipid
homeostasis. However, constant overconsumption of food, especially high-fat diets, causes
dysregulation of this homeostasis and leads to the pathologies discussed in the different
sections of this slide. As you will learn in the following slide, this chronic exposure of tissues to
high levels of lipids and their sometimes toxic metabolic byproducts is now considered to be
the root cause of many of the health problems associated with obesity. Click on each of the
buttons to learn about the pathophysiology of each of these diseases related to obesity.

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Stroke
Visceral adiposity (fat deposited around central organs) is associated with higher risk of
stroke
This effect was shown independent of cardiovascular risk factors.
Those younger than 65 had the greatest increase in risk from central obesity
Obesity is a known risk factor for cardio-vascular disease in general, but manifestation as
ischemic stroke is less clear. A recent study showed that again it is central obesity that causes the
greatest risk. Chance of stroke was examined the Northern Manhattan Stroke Study with respect
to waist to hip ratio. There was an association shown with ischemic stroke and waist to hip ratio,
even after correcting for confounding factors. Greater waist to hip ratio increases the risk of
ischemic stroke in both men and women, although risk was greater in men. This effect seemed to
be independent of the atherosclerotic risk factors so there may be some other mechanism
involved in this association. Risk of stroke from greater waist to hip ratio was shown at all ages
but there appeared to be greater risk among those younger than 65.
Type II Diabetes
Insulin resistance is common in obesity, but can be reversed by lifestyle changes
Hyperinsulinemia, due to resistance eventually leads to hyperglycemia and diabetes if not
corrected
Hyperglycemia and altered blood flow may lead to retinopathy and blindness
As will be explained
further in the next
slide, obesity may
lead to type II
diabetes over time,
first due to
dysregulated lipid
metabolism which
then causes insulin
resistance. This
insulin resistance may
eventually lead to
hyperglycemia, when
the pancreas fails to
be able to produce
sufficient insulin to
affect glucose uptake
in cells.
Hyperglycemia along
with altered blood
flow and vascular endothelial damage may lead to diabetic retinopathy and eventual blindness.
Type II diabetes will be further explained in one of the other pathophysiology modules.
Vascular Diseases
Dyslipidemia, common in obesity leads to atherosclerosis

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Inactivity compounds the problem

Narrowed and less flexible vessels can lead to angina, myocardial infarction or stroke
Obesity and inactivity are two of

the biggest risk factors in the
development of atherosclerosis,
which can cause coronary artery
disease as well as peripheral
vascular disease. The altered lipid
metabolism that results from a
constant excess of nutrients as
well as a diet high in fat leads to a
lower level of high density
lipoproteins (HDL – good
cholesterol) and higher levels of
low density lipoproteins (LDL –
bad cholesterol) and triglycerides.
The inflammatory process that is
also a result of lipid dysregulation,
compounds the problem by
increasing the influx of
macrophages into the
vascular tissues, where they move LDL cholesterol from circulation, creating foam cells and
advancing the atherosclerotic process.
Liver Disease
Caused by fat deposition in liver cells
Fat deposits increase inflammatory activity, causing
fibrosis
Present in virtually all who are morbidly obese AND
diabetic
Over-nutrition leads to deposition of fat in liver cells. This fat

deposition is further enhanced by insulin resistance and other
consequences of overeating and inactivity. There is increased
risk of fatty liver disease amongst obese individuals and
diabetes patients. But it is present in nearly everyone who is
morbidly obese and diabetic. Although those with fatty liver
disease may start out asymptomatic, these fat deposits can lead
to increases in inflammatory activity, fibrosis and eventually
cirrhosis in some cases. Liver failure can result and the chances
of hepatocellular carcinoma are increased as well.

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Colon Cancer
High BMI is correlated with higher risk of colon cancer, especially in males
Increasing waist circumference is linked to increased risk in men and women
Apple shape (visceral or central adiposity) is associated with higher risk than pear shape
(subcutaneous fat deposits, usually around the hips and thighs)
Obesity increases the risk of colon cancer, especially central obesity. A high BMI was associated
with increased risk of colon cancer, especially in men, among the Framingham Study Cohort.
Waist circumference was even more strongly correlated with the chance of colon cancer and risk
was found to increase linearly with increasing waist size, in both men and women. It seems that
visceral adiposity or fat deposits around the central organs creates an even greater risk than
elevated BMI alone.
Osteoarthritis
Extra pounds add stress to bone and joints
Joints not affected by mechanical stress (such as hands) are also affected in the obese
Inflammatory molecules secreted by adipose tissue (adipokines) are likely responsible
Increased weight adds extra stress to bones and joints. Osteoarthritis used to be associated with
advanced age but is now being seen at earlier ages, as is diabetes (another former disease of old
age), especially in those with elevated BMIs. In addition to the mechanical stress by excess
weight, studies show that the adipokines secreted by adipose tissue mentioned earlier may have
a role to play in causing and advancing osteoarthritis. Investigation into inflammation related to
adipokines was instigated when it was noticed that there was also an increase osteoarthritis with
high BMI in non-weight-bearing joints, such as the hands. Inflammatory cytokines such as
tumour necrosis factor alpha (TNF-alpha) promote cartilage degradation and the advance of this
disease.
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Pathophysiology of Metabolic Syndrome
This slide examines the pathophysiological processes that underlie the chronic
conditions that cause obesity
As I mentioned in a previous slide, predisposition to obesity may occur even before a
child is born
If the mother is affected by gestational diabetes, this can have a profound effect on
the child’s propensity for weight gain down the road
In addition, children born large for gestational age (that is big babies) are
predisposed for obesity and diabetes
Paradoxically, babies born small for gestational age are also predisposed for
obesity and diabetes and they may manifest these characteristics usually
during adolescence when triggered by the environmental conditions of
inactivity and poor diet
It is thought that the fetal environment may permanently alter metabolic processes
to a more thrifty phenotype, so that glucose homeostasis malfunctions during
conditions of overabundance of nutrients
The result may be insulin resistance, increased risk of cardiovascular disease and
other evidence of metabolic syndrome
For more information on the link between small for gestation age and adiposity,
follow the link on the attachment to read the 2006 article on this subject in the
International Journal of Obesity
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As previously mentioned, ethnicity and genetic makeup in general may predispose

children to the pattern of weight gain that leads to central obesity and therefore
insulin resistance
We have also already discussed the contributions of both sedentary lifestyle and poor diet,
including intake of large amounts of saturated and trans fats to both central obesity and
insulin resistance
One other predisposition to insulin resistance that have not been yet discussed is the
onset of puberty
O Puberty results in reduced insulin sensitivity and a compensatory increase in
insulin secretion
O This was first discovered because of the increase by about 30% for insulin by
Type 1 diabetics entering puberty
O Non-diabetic children and adolescents were then tested for insulin sensitivity,
and it was found to be true for all children entering puberty
O This is a transitory situation and insulin sensitivity and secretion returns to
normal once the child has reached full adolescence
Dyslipidemia
Constant excess caloric intake leads to an increase in the size of adipocytes, the cells in
adipose or fat tissue
I mentioned previously that this tissue secretes adipokines, a combination of hormones
and cytokines (which are small immune system molecules such as TNFα)
Enlarged adipocytes filled with fat produce and secrete excess adipokines and this
causes problems in normal lipid metabolism
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The enlarged adipocytes also have little capacity to take in more lipids so that the fat
may begin to be deposited into the muscle cells
The excess TNFα causes an increase in free fatty acids in the blood stream by
causing some of the fat in the adipose tissue to break down
This cytokine also inhibits the clearance of VLDL, which is the main transporter of
triglycerides and some cholesterol in the bloodstream
The lipoproteins, which you will hear more about in pharmacology related to cholesterol
transport (atherosclerosis and heart disease), are the body’s mechanism for
transporting lipids or fats through the bloodstream (which is a water-based system)
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Dyslipidemia
TNFα is also involved in increased production of more VLDL by the liver and
lowering of levels of HDL (good cholesterol) in the circulation in response to increased
adiposity or weight gain (See step 1)
All of these extracirculating triglycerides and free fatty acids interfere with insulin
signalling in muscle and liver tissue (See step 2)
Insulin, released by the pancreas after a meal, binds to receptors on cells in the muscle
and liver and signals the cells to take up the glucose that is flooding into the
bloodstream from the digestive system (See step 3)
Binding of insulin leads to signalling of the cells, that allows the cells to take up glucose
(See step 4)
High concentrations of free fatty acids in the blood interfere with this signalling,
preventing the cells from taking up glucose in response to the insulin (See step 5
&6)
This is the beginning of insulin resistance (See step 5 &6)
The pancreas produces greater and greater quantities of insulin in response to this
insulin resistance (See step 7)
The pancreas is able to overproduce insulin to compensate for insulin resistance for a
while which is why the first signs of impending Type 2 Diabetes are elevated
triglycerides and insulin levels (See step 7)
At this point, the individual would also have impaired glucose tolerance since the body
has to produce so much insulin to allow the cells to take up glucose (See step 8)
Eventually the beta cells become exhausted from producing all this extra insulin, and
this is the point at which glucose levels in the blood being to rise and hyperglycemia
results (See step 8)
Step 1
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Step 2
Step 3
Step 4
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Step 5
Step 6
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Step 7
Step 8
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Pathophysiology of Metabolic Syndrome
Type 2 Diabetes
So you can see that the process leading to Type 2 diabetes happens over a period of
years this results from the metabolic disturbances that occur when the body is
constantly overwhelmed by trying to deal with an overabundance of food, especially
when this is compounded by a lack of activity or sedentary lifestyle
This dyslipidemia, or disturbed lipid metabolism, also greatly increases the risk for
cardiovascular disease
As I have mentioned,
The levels of good cholesterol drop
The levels of triglycerides are elevated and this is true of LDL (bad cholesterol)
Atherosclerotic process:
You will see that oxidation of this excess LDL in the bloodstream, is taken up by
immune cells that deposit in the artery beginning the atherosclerotic process
This process can begin very early in those eating a diet high in fat, especially
saturated and trans fats
Fatty streaks, which are the first signs of the atherosclerotic process, have been
found in coronary arteries in children younger than nine years of age
Hypertension
Blood pressure is maintained in the body through the RAAS (renin-angiotensin-

aldosterone-system) as shown in the picture below from the pharmacology textbook
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Adipocytes have also been shown to release angiotensinogen, along with the other
adipokines previously mentioned and the amount is related to adiposity
Body mass index (BMI) is positively correlated with plasma concentrations of
angiotensinogen, as well as renin and angiotensin converting enzyme (ACE) activity
This research has elucidated the link between obesity and hypertension
Acanthosis nigricans
This is a picture of a patient with Acanthosis nigricans, a condition common in obesity

usually caused by insulin resistance
It is an area of hyperpigmentation usually found in body folds such as at the back of the
neck under the arms, and in the groin area
It can appear brown to black and is an area of thicker velvety skin
Once the underlying cause is treated, usually through diet change and increase in
activity, the skin problem is resolved
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PCOS and NAFLD
Polycystic ovary syndrome (PCOS) is associated with obesity, hyperandrogenism, and

again with hyperinsulinemia related to insulin resistance
O Hyperandrogenism results in excess body hair, acne, and often elevated levels of
testosterone
O Failure of ovulation appears to be the cause of cysts that develop on the ovaries
and the condition is usually accompanied by menstrual irregularities
O You can find more information on PCOS on page 1099 in the pathophysiology
textbook
Non-alcoholic fatty liver disease (NAFLD) is related to hyperlipidemia, obesity, and
insulin resistance
O Non-alcoholic fatty liver disease is related to obesity as well and may be caused
by dysregulation of lipid metabolism
O This condition can be asymptomatic but may eventually progress to cirrhosis
and could ultimately lead to liver failure
O Page 928 of the pathophysiology text discusses this disease in greater detail
Both conditions improve with weight loss and exercise
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Alden’s Case
Let’s consider Aden’s case

He is an 11 year old boy who has left friends bind because of the recent split from his
parents, which has resulted in the move to a new school
He has therefore been less active and has taken comfort in food
Because his father sees him infrequently, he tends to indulge him and adds to
Alden’s weight problem by taking him out to eat fast food as a treat
His father denies that his son has a weight problem but his mother is concerned for
Alden’s health
A plot of this BMI on the age and appropriate gender CDC growth chart shows that he is
th
above the 99 percentile, which would put him in the obese category
Cause of his mother’s concern, this physician may refer him to a program to address
his diet and inactivity
In the following slides, you will learn about a program such as this, that is one of the few
that exist in Canada offered right here in McMaster University Medical Centre
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Randy Calvert – Clinical Background
Today we’re going to talk to Randy Calvert, who is the program manager of
the ambulatory clinic at McMaster University
Randy has graciously agreed to talking with us because he has a rich background
dealing with child health
Randy, first of all, could you briefly describe your clinical background and perhaps
some of your experience with the children’s exercise and nutrition centre?
Sure. First of all thanks for inviting me to talk about something that is near and
dear to my heart
I’ve been involved with childhood obesity for nearly 20 years
I started at the children’s exercise and nutrition centre after graduating in my
Masters for physiology and pharmacology and back in those days I was
the exercise physiologist at the clinic up at Chedoke
And what that meant was that I did all the exercise testing in the 2 exercise labs
that we had there
Over the years I moved away from a clinical function and today I’m responsible for
about 22 clinical programs within McMaster’s Children’s Hospital at
McMaster University Medical Centre
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Randy Calvert
Question: Randy, could you tell us little bit more about the Children’s Exercise and
Nutrition Center?
Answer: The Children’s Exercise and Nutrition Center is founded by Doctor 27 years ago. He
came to McMaster on a sabbatical from Israel, and he had a keen interest in developing a unique
program that involved exercise medicine in the treatment and rehabilitation of children. His
program really started to involve kids with asthma and diabetes and muscular dystrophy and so
on; and over time, we began to receive more and more referrals for overweight kids. So, over the
last 17 or 18 years, working with the clinical staff, we’ve worked to develop one of the only
extensive weight management programs for kids and families in Canada.
Randy Calvert
Question: Maybe you could tell us a little bit about how children are referred to this
program and what specific tests do you order once they have been referred to the
program?
Answer: Sure. We receive between 30 to 50 referrals per month, from community physicians and
pediatricians, and to date we don’t have a catchment area. We’re willing to see families from as far
as they’re willing to commute to their program once a month. We’ve had families come very
commonly that drive 2-2.5 hours each way for their visits. More recently, we’ve had a family
that joined the program that lives in Thunder Bay that actually fly down to Hamilton once every
about six weeks, Once people are referred to the program, we invite them to come to a program
orientation session. That orientation session started for two reasons: first of all, it helped with
efficiency of the program and to try and prevent us from having a waitlist; because we believe
that it is important when someone’s interested and engaged in making a lifestyle change, we
need to engage them in the program as soon as possible, otherwise they might lose that interest. The
other reason we started that orientation program was because, consistently, we’d have only 50-60%
of the people we’d invite for visits would actually show up to their appointments. So, we had a
lot of staff that were not very busy for certain times of the week because patients weren’t
showing up for their visits; so that’s where the orientation session really came from. The
orientation session is an opportunity for families to come, and we do it in a group setting, to come
and learn all about what they can expect to do and see while they’re attending the program;
and at that session, we talk about the fact that this needs to be a family project, and this is really their
program and the clinical staff that they’ll work with which includes a registered dietician, a
kinesiologist, a behaviour therapist, and exercise physiologist, and a physician. They are really
apart of the family’s team because the program is developed specifically around individual
family needs, and we go at a pace that will match their success.
Randy Calvert
Question: Randy, maybe you could tell us what the parents can expect to get out of the
orientation session and what kinds of messages they can get to take home and use?
Answer: At orientation, we really talk about the process, we talk about the fact that the lifestyle change
that they’re going to be involved in is really all about behavioural modification. We talk about the fact
that we don’t put anyone on a diet because will work as long as they stay on the diet, and the typical
pattern we see in many adults is that we lose a lot of weight while we’re on a
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diet and as soon as we’ve lost that weight, they don’t have to diet anymore and go back to their
old habits and behaviours, and they tend to gain all that weight they’ve lost, plus gain a little
more just for posterity’s sake. So, at the end of orientation, hopefully families understand the
process. We will see them monthly for approximately a year; that would be the average length of
our treatment program. And then we follow up for a second year where we see them three times;
just to make sure they’re doing okay while they’re not involved in their programs specifically.
That ranges anywhere from 8 visits to sometimes 24 visits of treatment where we try to
encourage families to develop a program that meets their needs, and sometimes it takes a little bit
longer to have successful behaviour change implemented.
Changes in Lifestyle
As was mentioned in the interview clip you just watched, modification of eating behaviours is a
goal of the Children’s Exercise and Nutrition Center program. This must be accomplished
gradually and result in a permanent change in dietary choices in order to be effective. Choosing to
be physically active after school and breaking the habit of sitting in front of the TV with and
unhealthy snack is one way to modify a behaviour that leads to excess weight gain
Failure in Diets
This slide depicts the reason that diets fail and the reason why they’re not recommended as part of
the program of the Children’s Exercise and Nutrition Center (CENC). Basil metabolic rate
drops in response to a decrease in availability of food through dieting. This causes weight to be
quickly re-gained when previous food levels are reinstated. The only way to permanently reduce
weight is to change the eating behaviours for good, as well as increasing levels of physical
activity.
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Randy Calvert – Physiological Tests

Question: When you do see them, are there physiological tests that you have done?
Answer: Yup. What will happen when they come for their first visit is they’ll meet the
physician and have a family medical history performed. Typically, we will order a lipid panel,
and an insulin and blood glucose panel – that would be common for all. Some of the other kids,
depending on comorbidities, may require a little bit more extensive blood work and we try to
encourage the kids to do that in the hospital here so we have good access to the results. We also
do measurement of percent body fat in conjunction with height and weight. Height and weight
tells us a lot and enables us to plot their values on a growth chart to be able to show them their
progress. But percent body fat is a more sensitive measure. We will expect all kids involved in
the program to continue to gain both height and weight over the time, because as they grow
taller, they get more muscle and bones. The percent body fat measurement gives us a better
indication of success in their program. In the past, we have used underwater weighing as a gold
standard for body composition measurement, and it is very time consuming and difficult test for
kids under about 9 years of age to do successfully; so over the years we have adopted to use
bioelectrical impedance. Bioelectrical impedance is really a measurement of body water and
there is a reverse calculation that will calculate percent body fat from that. We do that
measurement every two months and that’s really what we’re looking for as success in the
program is a reduction in percent body fat. We also do fitness tests on all the kids who come into the
program. Like a stress test that we would do on an adult that we’re concerned about cardiac
issues, the first time we do that exercise test is really to show us and the families that it is safe for
their children to be physically active at some vigorous levels. That very first visit, we measure
electrocardiogram and blood pressure, and we also measure pulmonary function before and after
the exercise test because approximately 60-80% of all the kids referred to the program come with
a complaint of exercise induced asthma, and 90% of the time we rule out that condition with that
first exercise test. We will repeat that fitness test every three months and we’ll be able to tell the
kids how dramatically their fitness is improving. Many of the kids we’ve seen in the program
lead very sedentary lives so with modest increases in physical activity, their fitness can go up 20-
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30% in a three month period. We find that it’s really encouraging for the kids and their families
to realize that “with a little bit of work, we see a huge difference in our fitness level.”
Sometimes, that’s the first glimpse of success that they have because to change percent body fat
or to change current weight trajectory sometimes takes longer than three months to occur in
most families.
Normal Values
These charts provide normal values for lipids and glucose, determined by blood work. The
normal lipid values for adults are those quoted in the Heart and Stroke Foundation publication
“Living with Cholesterol”. The lipid values for children were taken from an article entitled
“Screening and Management of Hyperlipidemia in Children” and are the values used by the
CENC to assess pediatric dyslipidemia. The glucose values are taken from the Canadian Diabetes
Association publication “Managing your Blood Glucose”, and apply to adults as well as
children and teens. All these documents are available or may be linked to by clicking on the
attachment’s tab. The values for triglycerides and LDL cholesterol would likely be higher in
obese children and teens. The glucose levels could be normal or high, depending on the degree of
metabolic derangements. The value for HDL cholesterol would likely be lower. High levels of
LDL cholesterol and low levels of HDL cholesterol could lead to deposition of oxidized LDL
cholesterol in the artery walls, the beginnings of atherosclerosis, which would put these
individuals at higher risk for heart disease in the coming years. High triglyceride levels would
compound the problem of glucose and insulin dysregulation, and could eventually lead to type II
diabetes if left unchecked. As mentioned, abnormal values for lipids and glucose are seen in
about 70% of program participants, so even though some participants are deemed obese by their
height and weight, their blood may not show any metabolic abnormalities.
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Measurement of Body Composition

There are a number of ways to measure percent body fat. The gold standard is underwater
weighing, although it requires specialized equipment, and, as mentioned previously, is difficult
to do with children. Tricepts skinfold thickness test is not nearly as reliable and can vary
greatly depending on who was doing the measuring. Bioelectrical impedance can be done
easily using either a stand on device or a hand held one. This gives an accurate measure of body
fat, that correlates well with values derived by underwater weighing. So the stand on device
shown on the far right is that used during the CENC.
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Growth During Treatment

This chart is an actual chart from a participant in the CENC program. As the child grew taller,
they manage to maintain their weight with the help of the program staff. This resulted in their
coming into line with their expected weight over a period of about four years. Since they would
have gained a fair bit of bone and muscle over those four years, the percent body fat would
have dropped even though there was very little weight loss.
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Randy Calvert – Results and Exercise

Question: You mentioned you did some blood work and lipid panels and insulin and sugar;
can you tell us what kind of results you find and maybe what happens in conjunction with
those results and the fitness levels? What kind of results do you see and how does exercise
affect them?
Answer: Sure. I would say that probably 60-70% of all kids involved in the program would have
some abnormal values of cholesterol and triglycerides, probably the same proportion have some
level of hypertension, and within that group about 25% of the kids have either impaired fasting
glucose or impaired glucose tolerance. Of that, about 5% would be either in a state of pre-diabetes
or have true type II diabetes. All of that sounds very negative and we’re not sure what
the implications are of that in the future because obesity is a fairly new phenomenon for us. In
fact, up until about seven years ago we weren’t measuring lipid levels and so on in children
because we just made the assumption that they were fairy healthy kids. The good news is that
with modest increases in physical activity, we can reverse all of those – we can get lipid levels
back to normal we can reduce hypertension, we can reduce impaired glucose tolerance tests –
back to pretty much normal levels with not a lot of work.
Reversal of Metabolic Disorders

Exercise has been shown to increase insulin sensitivity and action, as well as to lower
hepatic glucose production
There is a body of literature supporting the value of increased activity, along
with weight maintenance. Exercise increases insulin sensitivity, even in
those with type II diabetes, as well as reducing glucose production by the
liver
Triglyceride levels after a high-fat meal were reduced if subject exercised first
Studies also show that exercise an hour after consumption of a high-fat
meal reduced blood triglyceride levels versus the high fat meal with no
exercise.
A combination of low-fat diet and exercise improved dyslipidemia
Finally, in studies of those with dyslipidemia, exercise combined with
low-fat diet was shown to improve blood lipid profile.
Glucose Uptake by the Glucose Transporter System

This is an illustration showing how glucose transporters translocate to the cell’s surface.
Glucose transporters migrate to the surface of muscle cells in response to signals
transmitted by insulin binding to its receptor. Translocation of these glucose transporters to
the cell surface has also been shown with exercise alone, independent of insulin binding.
This allows more glucose to be taken up by muscle cells to fuel further activity
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Randy Calvert – Goals of the Program

What are the goals of the program and how has the weight management and
nutritional education gotten across to the participants?
The overall goal of the program is to change current lifestyle behaviors. We try not to suggest
taking things away from kids and families. Instead, we try to substitute more healthy food
choices or more healthy activity choices for the not so healthy choices they had chosen previously.
This is because we know it’s easier to add things in a positive way than to take things
away in a negative way. Early on in the program, we talked to the kids and their families about the fact
that anything is okay in moderation. We won’t tell them to stop eating their favorite foods or
stop playing video games, because that’s just part of our normal society today. So the
goals of the program (over time) are to make some minor lifestyle changes on a monthly basis.
So when they come for each visit, they will typically go home after they set three goals. They’ll set
a physical activity goal, a nutrition goal, and a family goal. Families are really important in
this program because they enhance success rates when as many family members as possible will
support that goal achievement process. We don’t expect families to attend visits but we
encourage them to participate in the program at home. At the orientation session, I introduced the
families to this goal-setting process, and my message to the families is: this is your program and you
need to start today. Don’t wait until your first visit to the clinic. Usually I send them home
with three common recommendations that we make for most families.
We caution them on sweet drinks. When I talk to parents and inform them that even if a
product says it is 100% natural unsweetened juice, this doesn’t necessarily mean it’s a
healthy choice. In fact, it has the same amount of sugar as regular pop does. Many
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parents find this to be an extremely useful piece of information because they

had originally thought they were giving their children something healthy.
We tell them to become more physically active. We rarely talk about “exercise” in the
program because adults usually perceive this as going to the gym (going on an exercise bike,
running on a treadmill, lifting weights). Instead, we encourage physical activity, which means
outside play (we don’t have to buy fancy equipment or join programs).
Instead of going by the Canada’s physical activity guide (which says to partake in 45
minutes of physical activity daily), I encourage the families to start where they can. If
they can get 5 more minutes of physical activity today than they got yesterday, then
that’s a great place to start. We will encourage them to keep increasing this over time.
We need them to develop these goal setting parameters for ways in which they can have
success. So over a longer period of time, they will eventually meet the requirements of
Canada’s physical activity guideline.
We encourage families to not consume second portions at meal times. A trick that we use is
called the twenty-minute rule.  It can take up to 20 minutes for the brain to tell the
stomach that you’re full. So we encourage them to have one helping at meal times and
then wait 20 minutes, and if they truly feel hungry after that time, then we encourage
them to have some more food. But people have to learn to be honest to themselves. 90%
of the time after the 20 minute break, if a person can be honest with themselves and say
they feel satisfied and don’t take a second helping, that’s when they start to have
success in this program. Learning how to say no to yourself can be a real challenge for
many people.
Sweet Drinks
Forgoing sweet drinks is one of the pieces of nutritional advice offered in the CENC Program. As
mentioned, even 100% fruit juices contain a considerable amount of sugar. In a 12-ounce can of
pop, there are about 40 grams of sugar. The equivalent amount of orange juice contains about 33
grams of sugar. Apple juice has about 39 grams and grape juice juice has a whopping 58.5 grams of
sugar. Labeling on juices and other drinks may be confusing as well. On this label, we see that there
are 25 grams of sugar, but that quantity is per serving. The label lists the serving size as 8 ounces,
but the servings per container is 2. It is unlikely that someone would only drink
half of this bottle, so 50 grams of sugar are actually being consumed (and a total of 200 calories),
with very little nutritional value. Now we’ll go back and finish our interview with Randy
Calvert.
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Randy Calvert – Different Nutritional Choices

How do you encourage different nutritional
choices?
As I said earlier, it’s about a positive change. I can think of some good examples. If current
routine means that the child comes home from school, grabs a glass of pop and a bag of chips
and heads over to the TV to wait for dinner to be prepared, the dietician would say that we’re not going
to take that away, we’d rather substitute a less sweet drink for the pop, and maybe have an
apple before they have the chips. Over time, the kids will learn that after eating the apple and drinking
the less-sweet beverage, they’ll feel full, and they eventually won’t need the chips after that. Or
they’ll have much fewer chips, which really reduces the calories over time. It’s all about making
positive suggestions. We don’t focus on low-fat products because marketers are pretty
clever at getting us to buy the products that they want to sell to us, and many low-fat
products may have just as many or even more calories than the regular products. So we tell
them to eat regular foods, not specialized foods.
As far as physical activity goes, you mentioned that there was talk about increasing by 5
minutes a day. Can you give us some more information on how you encourage that and what the
benefits are to the whole family?
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Physical activity is probably the hardest thing to change in a family setting. When we send
families home with the three activity goals, we also give them a calendar, and tell them to use
stickers or checkboxes or whatever they like to keep track of their goals, and this is the only record
keeping we ask them to do. So the physical activity piece needs to be more creative. It’s
very easy to ask someone what kinds of physical activity they like and they may list off some sports,
but the more important question is “what kind of physical activity can you get right where you
live?” Do you have a sidewalk, do you have a park, do you have a basketball net in the driveway,
etc. We have to find something that they like to do, so that there’s a greater chance that they’ll
do it as often as they can. So we have to find out what the child would like to do as a form of
physical activity and hopefully their family supports them. It’s all about incorporating
fun and involving the family. I think because of all the media attention about unsafe streets,
parents have the perception of a lack of safety. So we encourage parents to be outside with their kids
and watch over them. They don’t even have to partake in the physical activity themselves,
although that would be a great thing to do. For example, I worked with this one girl who used to
come home from school, grab a snack, and sit in front of the TV until dinner was ready. One day
she decided she wanted to learn how to play basketball, so she asked her dad to put up a
basketball net in their driveway. So everyday, she would then play basketball after school until
dinner was ready.
The benefits of physical activity are two-fold. First of all, it gets kids outside enjoying things that
they like to do and experiencing new things. This may lead them to join different sports teams,
because typically, overweight children may be shunned at school and not invited to play sports
with their peers. The second advantage to physical activity is that while we’re outside being
physically active, we tend not to consume excess amounts of calories, which in my opinion is the
greatest aspect of physical activity.
Randy Calvert – Success Rate

What kind of success rate have you had with your program?
I did a formal study of the program over a two-year period, and we had a 70% success rate at that
time (after a one-year of follow-up). This study involved over 600 families, and this data is still
fairly consistent today. We measured success in two ways. We looked at success in changes in
body composition or lowering of percent body fat. And we looked at success in terms of a
calculation called the mathematical index. The mathematical index compares changes in body
composition using underwater weighing and by electrical impedance with a comparison of actual
height and weight changes over a monthly period. So the mathematical index compares the
actual and expected height and weight, multiplied by a factor of 10. And we tell the kids how many
points they’ve gained or lost at each visit. A positive point gain would mean they’ve had a
positive change in their growth, and that might be the result of a quicker height increase than
predicted or slower weight increase than predicted. So that 70% success rate holds
consistent, whether we look at percent body fat change or the mathematical index change.
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Summary
Action needs to be taken now to improve the health outcomes of this generation as they
enter adulthood
Consumption of excess calories, combined with inactivity, have led to the
“obesity epidemic”
These patterns can be changed, gradually, through education about diet and exercise
The whole family needs to be invested in this goal and the earlier they start, the better
Action needs to be taken sooner rather than later to change nutrition and activity behaviors that
could increase risk of cardiovascular disease, type 2 diabetes, and a host of other disorders in
adulthood. Eating patterns are set in childhood, so addressing them now is easier than addressing
them in adulthood, and this could possibly halt the obesity epidemic. Understanding the evidence
for good nutrition and lots of activity could aid you in modifying these behaviors through
education of children that you work with. It is also important to note that the behaviors of the
whole family need to change and they must all be invested in the goals of improved health.
Aiden and his family could benefit greatly by following guidelines from a program such as that
offered by CENC. His parents would both have to change nutritional habits and encourage Aiden
to become more active (perhaps by engaging in his favorite activities with him). Along with reducing
the future risks to Aiden’s health and the health of his family, it is likely that his self-
esteem and confidence would improve, making it easier for him to make friends in his
new environment.
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MODULE 2B: COPD
COPD
This is the second of two modules on obstructive airway diseases. This module will cover the
disease of Chronic Obstructive Pulmonary Disease (COPD). Learning about the disease of
COPD requires you to have a basic understanding of the anatomy and physiology of the
respiratory system. You may also find it helpful to review concepts related to genetics and
inflammation. I have not included any specific readings on these topics but you can find
content related to inflammation and genetics Porth Pathophysiology textbook. I will briefly
review the pharmacological agents used to treat COPD and highlight key points related to
pharmacotherapies for COPD. There is a lot of content in this module, some of it should be a
review from previous science courses and some of it will be new or add on to previous
learning. The overall aim of this module is to provide basic science content related to COPD so
that you are then able to apply it to clinical practice.
Additional Resources
Barnes, P.J. & Celli, B.R. (2009). Systemic manifestations and comorbidities of COPD.
European Respiratory Journal, 33, 1165-1185.
Canadian Lung Association, http://www.lung.ca/diseases-maladies/copd-mpoc_e.php O
Up to date information on lung diseases in Canada including COPD.
O Intended audience of the website are patients and the general public, however,
you will find much of the information helpful as nursing students.
O Specifically, you may want to look at the personal stories of COPD patients and
health care professionals. Also, there is information on community supports and
the BreathWorks program is worth checking out.
Kuebler, K.K., Buchsel, P.C. & Balkstra, C.R. (2008). Differentiating chronic obstructive
airway disease from asthma. Journal of the American Academy of Nurse Practitioners,
20, 445-454.
O Compares COPD and asthma in terms of epidemiology, etiology, pathophysiology,
clinical manifestations, disease evaluation, and pharmacologic interventions. This
article should supplement your readings about drugs for obstructive airway
diseases by identifying and providing rationale for which drugs are used for
asthma and for which drugs are used for COPD
RNAO. (2010). Nursing Care of Dyspnea: The 6th Vital Sign in Individuals with Chronic
Obstructive Pulmonary. Available online:
http://www.rnao.org/Storage/67/6135_REVISED_BPG_COPD.pdf
Learning Outcomes
Describe current Canadian epidemiology related to COPD.
Describe the etiology of COPD.
Compare asthma and COPD.
Describe the pathophysiology of COPD.
I will discuss chronic bronchitis, emphysema, and inflammation.
Link the pathogenesis of COPD to the clinical manifestations and evaluation of the disease.
Provide scientific rationale for interventions.

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Specifically, oxygen therapy, pharmacotherapy, and pulmonary rehabilitation.

Provide scientific rationale for patient teaching.
COPD in Canada
COPD underdiagnosed, affects at least 700 000 adults, app. 4.4% Canadians aged 35
years or older
4th leading cause of death in females, 5th in males
Higher prevalence in women except for the > or =75 years age group
Mortality rates increasing
Mortality rates higher in men (4.5/100 000) than females (2.8/100 000)
COPD is a major respiratory disease in Canada that is often preventable and can be treated but
remains underdiagnosed. It is thought that the prevalence of COPD is underestimated because
those with early symptoms of COPD are not recognized and/or do not seek treatment. COPD
affects at least 700 000 adults which is approximately 4.4% of Canadians aged 35 years or older.
In contrast, COPD affects a much higher percentage of off-reserve Aboriginal people at 7.9%.
COPD is the 4th leading cause of death in females and 5th in males. There is a higher
prevalence in women except for the aged 75 years and older group. Over the past 15 years,
mortality rates have increased, especially for women. Mortality rates are higher in males
(4.5/100 000) than females (2.8/100 000). Mortality rates may be actually higher than reported
because two complications of COPD, pneumonia and congestive heart failure, may be listed as
the cause of death instead of COPD. Also, it is predicted that as new epidemiological data
emerges, the mortality rates in women will be higher than for men.
th
COPD is also a major cause of death worldwide. In the United States, it is the 4 leading cause
th
of death and it is the 6 leading cause of death worldwide. Like Canada, the mortality and
morbidity are increasing around the world. The burden of COPD from a health, economical, and
societal cost is significant. Hospitalizations, ER visits, pharmacotherapy, pulmonary
rehabilitation, oxygen therapy, missed work days are but a few of the items that were studied in
the confronting COPD survey in North America and Europe which studied the burden of COPD
in different countries. Among major chronic illnesses in Canada, COPD now accounts for the
highest rating of hospital admissions. Hospitalization for an acute exasperation of COPD are on
average 10 days in length and cost about $10 000. A conservative estimate of the total cost of
COPD hospitalizations in Canada is 1.5 billion dollars per year. It is beyond the scope of this
lecture to go into further detail about the actual costs of care. But I have listed the reference
from the confronting COPD survey as well as a more recent report from the Canadian Thoracic
Society for those who may be interested.
Etiology
Cigarette smoking
#1 cause of COPD, 15-20% smokers -> COPD dx; 80-90% dx COPD have hx of
smoking
Toxic to cells in lungs + impairs mechanisms responsible for lung tissue repair
Genetics

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Genetic susceptibilities – polymorphisms of genes that code for TNF, surfactant,

proteases and antiproteases
Inherited mutation in alpha-1 antitrypsin gene -> AAT deficiency
Heterogeneous nature of COPD attributed to multiple genetic & environmental
factors as well as gene-gene & gene-environment interactions (i.e. epigenetics)
Cigarette smoking is the leading cause of COPD. 15-20% of smokers will be diagnosed with
COPD. This does not take into account smokers who have yet to be diagnosed with COPD. An
average smoker loses lung function at twice the rate of a non-smoker. This means that smoking
adults lose lung function at a more rapid rate as they age in comparison to non-smokers. Loss of
lung function is associated with an increased mortality. Adolescents who begin smoking before
they are finished growing will inhibit maximal lung development. Smoking is common in people
diagnosed with COPD as 80-90% of them have a history of smoking. Smoking is toxic to cells
in the lungs and also impairs the mechanisms that are responsible for lung tissue repair. It is
important to note that both active and passive smoking have been implicated in COPD.
Genetics also play a contributory factor to developing COPD. Genetic susceptibilities have
been identified. Polymorphisms of genes that code for Tumour Necrosis Factor (TNF),
surfactant, proteases and antiproteases are examples. Also, a hereditary deficiency of alpha-1
antitrypsin may result in early onset of severe COPD. The onset and severity is worsened by
smoking. Alpha-1 antitrypsin will be discussed further when I describe the pathophysiology of
emphysema. The heterogeneous nature of COPD can be attributed to multiple genetic and
environmental factors as well as gene-to-gene and gene-to-environment interactions, known as
epigenetics. We will be looking at different phenotypes of COPD after the next slide. Genetics
have a role in how these phenotypes are expressed and how gene-environment interactions
contribute to disease manifestations such as exacerbations.
Environmental
Long-term inhalational exposure to: occupational dusts/chemicals; indoor
pollution from heating and cooking with biomass fuels; outdoor pollution
Other risk factors
Severe childhood respiratory infections, asthma, airway hyper-responsiveness,
nutritional compromise, impairment of fetal development resulting in low
birth weight, infants who develop bronchopulmonary dysplasia
Environmental risk factors include long-term inhalational exposure to: occupational dusts or
chemicals, indoor pollution from heating and cooking with biomass fuels, and outdoor pollution.
Other risk factors include: severe childhood respiratory infections, asthma, airway hyper-
responsiveness, nutritional compromise, impairment of fetal development resulting in low birth
weight, and infants who develop bronchopulmonary dysplasia. Although the risk factors listed on
this slide are relevant to the etiology of COPD, the most important etiologic factor is cigarette
smoking.

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COPD Phenotypes
Chronic bronchitis
Airway inflammation & obstruction of the major and small airways
Chronic productive cough for at least 3 consecutive months over 2 consecutive
years (Pooler, 2010, p. 688)
Emphysema
Loss of lung elasticity & abnormal enlargement of the airspaces distal to the
terminal bronchioles with destruction of the alveolar walls & capillary beds
(Pooler, 2010, p. 686).
Bronchiectasis
Permanent dilation of the bronchi and bronchioles
Caused by destruction of the muscle and elastic supporting tissue d/t vicious
cycles of infection & inflammation (Pooler, 2010, p. 691)
Asthma (obstructive airway disease)
COPD is not a single disorder. Rather, it is a group of disorders that are characterized by airflow
limitation. These different phenotypes may overlap and include chronic bronchitis, emphysema,
and bronchiectasis. Chronic bronchitis is characterized by airway inflammation and obstruction
of the major and small airways. A history of a chronic productive cough for at least 3
consecutive months over 2 consecutive years is required for clinical diagnosis.
Emphysema is characterized by loss of lung elasticity and abnormal enlargement of the airspaces
distal to the terminal bronchioles with destruction of the alveolar walls and capillary beds.
Bronchiectasis is an uncommon form of COPD characterized by permanent dilation of the
bronchi and bronchioles. It is caused by the destruction of the muscle and elastic supporting
tissue due to vicious cycles of infection and inflammation. This lecture will not go into any
further detail about bronchiectasis. If it is of interest to you, you will find information on pages
691 and 692 of your Porth Pathophysiology textbook. These readings are not of testable
material. Asthma is a chronic inflammatory airway disorder where lung function is often
normalized in the absence of triggers especially early on in the disease prior to significant
airway remodeling. Asthma is usually not classified under COPD, but together, asthma and
COPD can be called obstructive airway diseases.
Comparing Asthma & COPD

Asthma COPD
Age of onset Occurs anytime often in childhood Occurs midlife
Smoking Hx Usually nonsmokers Usually smokers
Usual Etiology Immunologic stimuli, family hx Tobacco smoke or other air pollution
asthma
Airflow Airflow limitation usually reversible Airflow limitation not fully
limitation reversible
Past medical Hx allergies, sinusitis, resp. Hx allergies & sinusitis rare, hx resp.
hx infections, nasal polyps infections
Clinical Episodic wheeze with chest tightness, Persistent or worsening dyspnea,
features cough & dyspnea chronic cough
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Inflammation Acute eosinophilic inflammation Neutrophil & macrophage induced

features inflammation
Pathologic Fragile epithelium, thickening of Squamous metaplasia of epithelium,
changes basement membrane, mucus gland parenchymal destruction, mucus
metaplasia & enlargement gland metaplasia & enlargement
Before we look at the pathophysiology of COPD, let’s take a moment to compare asthma and
COPD. The course of asthma is usually intermittent while that of COPD is chronic and progressive.
The age of onset for asthma is anytime in childhood and COPD is usually in midlife. Asthma usually
has no smoking history while COPD usually has a smoking history. The usual etiology for asthma is
an immunologic stimuli and family history of asthma. That of COPD is tobacco smoke or other air
pollution. Airflow limitation is usually reversible in asthma while airflow limitation is not fully
reversible in COPD. Past medical history for asthma often includes a history of allergies, sinusitis,
respiratory infections, and nasal polyps. The past medical history in COPD does not usually include
a history of allergies and sinusitis is rare, however, there is a history of respiratory infections. The
clinical features for asthma include episodic wheeze with chest tightness, cough and dyspnea. The
clinical features for COPD include persistent or worsening dyspnea and chronic cough. Acute
eosinophilic inflammation is characteristic of asthma, while neutrophil and macrophage induced
inflammation is characteristic of COPD. Pathologic changes of asthma include a fragile epithelium,
thickening of basement membrane, mucus gland metaplasia and enlargement. The pathologic
changes of COPD include squamous metaplasia of epithelium, parenchymal destruction, mucus
gland metaplasia and enlargement.
Now let’s define COPD then look at the pathophysiology of COPD in detail.
Defining COPD
The Canadian Thoracic Society defines COPD as “a respiratory disorder largely
caused by smoking, characterized by progressive, partially reversible airway
obstruction and lung hyperinflation, systemic manifestations, and increasing frequency
and severity of exacerbations”
COPD is characterized by persistent inflammation of airways, lung parenchyma and its
vasculature
The pathophysiological hallmark of COPD is expiratory flow limitation
Airflow Limitation Mechanisms

The foremost important mechanisms for airflow limitations are listed here, any of
which can occur in either asthma or COPD:
O Loss of lung elastic recoil
Occurs with emphysema due to protease-mediated degradation of
connective tissue elements in the lungs
Peribronchiolar fibrosis
Occurs due to an imbalance between the lungs’ repair and
defence mechanisms
Fibrosis of the small airways contributes to airway remodelling, which is a
key factor of the development of the irreversible airflow limitation seen
in COPD

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Fromer and Cooper define airways remodelling as “the persistent

changes that occur within the structural components of the airways in
response to inflammation”
Increased airway secretions
In COPD there is mucus hyperplasia and increased expression of mucin
genes
Inflammation and occident injury play a role in mucus hypersecretion
Airway smooth muscle
Increased tone in airway smooth muscle due to hyperreactivity of the
bronchi with bronchoconstriction due to persistent inflammation
Even if tone is not increased in persons with COPD, their airways are
narrowed resulting in an increase in airway resistance
Relaxing airway smooth muscle with bronchodilators will have a
beneficial effect on airflow whether there is an increase in tone or not
Chronic Bronchitis
People diagnosed with COPD usually have some degree of both emphysema and
chronic bronchitis
I am going to first discuss chronic bronchitis and emphysema separately in order to
provide a clear description for each of these diseases
Inflammation of the airway epithelium
Chronic bronchitis is the result of inflammation of the airway epithelium and
mucus hypersecretion due to inspired irritants like tobacco, or air pollution
Hypersecretion in the large airways is the first feature of chronic bronchitis
Mucus hypersecretion
The mucus produced is not only more tenacious than normal, but there is also an
increase in the size and number of mucous glands & goblet cells in the airway
epithelium
Ciliary function impaired
This reduces mucus clearance
Increased risk of pulmonary and bacterial colonization
There is an increased risk in pulmonary infection and injury, as the
lungs’ defence mechanisms are compromised
Bacterial colonization may occur
Bacteria such as hemopholis influenza and streptococcus pneumonia can be
embedded in airway secretions
Infection and injury cause further mucus production and inflammation
Recurrent infection and persistent inflammation result in bronchospasm and
eventual permanent narrowing of the airways
Thick mucus and hypertrophied bronchial smooth muscle leads to airway obstruction
Air trapping can result as the airways collapse early in expiration when the airways are
narrowed, trapping gas in distal portions of the lung
Airway obstruction causes ventilation-perfusion mismatch, hypercapnia, and
hypoxemia
Significant hypoxemia will lead to polycythemia (the over production of RBCs) and
cyanosis

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Eventually if not reversed, hypoxemia will lead to hypertension and cor pulmonale
(enlargement of the right ventricle) which will in turn right heart failure
Thick mucushypertrophied bronchial smooth muscle  airway obstruction
ventilation-perfusion mismatch + hypoxemia  polycythemia, cyanosis  cor
pulmonale
Emphysema
Emphysema is characterized by the breakdown of elastin in the alveolar septa and
bronchial walls as well as breakdown of alveolar and bronchial wall components
by proteases
O Proteases are enzymes that digest proteins
This occurs due to an imbalance between proteases and antiproteases as a result of
increased protease activity and inhibition of an abnormal endogenous protease
activity in the lung
O The leading cause for this is airway epithelial inflammation from toxins in
tobacco, smoke, or airway pollution
O Proteases are released from neutrophils, alveolar macrophages, and other
inflammatory cells
O Examples of the most important proteases activated in emphysema elastases,
cathapsisns, and matrix metaloprotease
O Normally antiproteases, such as alpha 1 antitrypsin, inhibit the activity of
proteases in the lungs
O However, antiproteases production and release is inadequate in smokers that
develop COPD
O Primary emphysema is commonly linked to an inherited deficiency of alpha 1
antitrypsin and accounts for approximately 1-3% of emphysema cases
O Primary emphysema often develops in individuals who develop the disease
before age 40 or in their early 40s and do not have a history of smoking
O Persons with inherited alpha 1 antitrypsin deficiency with a history of smoking
are even more susceptible to developing emphysema
O I will talk about the genetics of alpha 1 antitrypsin deficiency on the next slide
Septal destruction in the alveoli destroys portions of the pulmonary capillary bed
causing ventilation-perfusion mismatch and hypoxemia
Decreased elastic recoil in bronchial walls contributes to air trapping
I will talk about air trapping in further detail in a couple of slides
There is an abnormal enlargement of gas exchange airways called “acini” due to
air trapping
An increase in residual volume and total lung capacity (TLC) are inevitable with air
trapping
Also persistent inflammation of the airways can result in hyperreactivity of the bronchi
with bronchoconstriction

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The following is a diagram which depicts the protease/antiprotease mechanisms of

emphysema
The protease identified in the diagram is elastase and the antiprotease is the alpha-1-
antitrypsin
Smoking or air pollution initiates an inflammatory response
Inflammatory cells, specifically neutrophils and alveolar macrophages, release elastase
The action of elastase is normally inhibited by alpha-1-antitrypsin
However as inflammation persists, there is a decrease in alpha-1-antitrypsin activity
In turn, there is destruction of the elastic fibres of the lung resulting in emphysema
In the case of inherited alpha-1-antitrypsin deficiency, there is limited amount of alpha-1-
antytripsin to counteract the action of elastase release
The result is destruction of elastic fibres in the lung and eventual emphysema
The amount of alpha-1-antitrypsin is determined by a pair of co-dominants genes named
protein inhibitor genes
There are more than 75 mutations of the gene, which are inherited as an autosomal
recessive disorder
The most serious alpha-1-antitrypsin deficiency is caused by the Piz variant, which is
found in 5% of the population
Homozygous individuals who carry two Piz genes only have 15-20% of the normal
plasma concentration of alpha-1-antitrypsin and have a 70-80% likelihood of
developing emphysema
The sites of involvement of emphysema determine whether it is called centriacinar or
panacinar emphysema
The most common form is centriacinar emphysema, where the destruction is confined to the
terminal and respiratory bronchioles
In panacinar emphysema, there is involvement of the peripheral alveoli and later the
more central bronchioles
This form is more common in individuals with inherited alpha-1-antitrypsin deficiency
Centriacinar emphysema often involves the upper parts of the lung, while panacinar
emphysema tends to occur in the lower parts of the lung

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Air Trapping/Hyperinflation
When air trapping occurs airways are pulled open during inspiration, allowing gas to
flow past obstruction caused by narrowed airways in mucus plugs
However during expiration decreased elastic recoil of the bronchiole walls causes the
airways to collapse, preventing normal expiratory flow
On physical exam, the person with hyperinflated lungs due to air trapping will have the
appearance of a barrel chest as illustrated in the picture below
The expanded thorax puts the respiratory muscles at a mechanical disadvantage,
resulting decreased tidal volume, hypoventilation and hypercapnia
Although both chronic bronchitis and emphysema contribute to air trapping , it is usually
associated more with emphysema as the loss of elastic recoil due to destruction of
lung tissue significantly prevents normal expiratory flow

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Inflammation
The following two slides highlight the key points about inflammation in the
pathophysiology of COPD
I won’t be going into detail describing the general function of the common
inflammatory cells. Instead, I will be describing their predominant effects in COPD
If you need to review basic inflammation terminology, you will find chapters 17 and 18 in
your Porth pathophysiology textbook helpful
Inflammation is a central feature in the pathophysiology of COPD
Leads to damage & remodelling of the lung parenchyma  airflow limitation
As you know there are two types of immunity: innate and adaptive
Innate immunity is activated at all stages of COPD, and adaptive immunity activated in
more severe disease
Cytokines mediate both types of immunity
Dendritic cells likely link innate and adaptive immunity in COPD
10

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Inflammation cont.
Lymphocytes
There is an increase in lymphocytes
Neutrophils, macrophages, CD8+ lymphocytes are thought to be the most important
inflammatory cells in COPD
There is also an increase in CD4 T-lymphocytes and B cells
Neutrophils:
Neutrophils release proteases, specifically neutrophil-elastase-cathapsin-G,
proteinase 3, matrix-metalloproteinase 8, and matrix-metalloproteinase 9
Elastins, cathapsins, and matrix-metalloproteinase are the most important
proteases involved in emphysema
Macrophages and CD8+ lymphocytes:
Macrophages release inflammatory mediators that activate neutrophils and CD8 T-
lymphocytes
Macrophages also release proteases, specifically matrix-metalloproteinase and
cathapsins
CD4+ lymphocytes and B-cells:
CD4 T-lymphocytes activate B-cells and B-cells are involved in antibody
production
Pro-inflammatory cytokines:
There is an increase in the following pro-inflammatory cytokines:
O TNF- α (tumeronecrosis factor alpha)
Increases expression of adhesion molecules on leukocytes and
endothelial cells
Up-regulates other pro-inflammatory cytokines like IL-1 and IL-6
It is especially increased during exacerbations and in persons with COPD
and associated weight loss
IL-1β
Activates macrophages to secrete inflammatory cytokines, chemokines,
and matrix-metalloproteinase
IL-6
It is a link between innate and acquired immunity
Stimulates C-reactive protein release from the liver
IL-32
It is a newly described pro-inflammatory cytokine and is correlated with
disease severity
Thymic stromal lymphopoietin (TSLP)
It belongs to the IL-7 family
It plays a key role in dendritic cell programming by stimulating specific
chemokines which then attract T-helper lymphocytes and cytotoxic T-
lymphocytes
T-cell cytokines
These secrete pro-inflammatory cytokines, sometimes termed
lymphokines
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Chemokines
Induce leukocyte chemotaxis, specifically promoting neutrophil activation and
migration
Growth factors
Contribute to airway remodelling
Dec. anti-inflammatory cytokines (i.e. IL-10)
cytokines can also have inhibitory or anti-inflammatory effects
One such cytokine is IL-10, which is reduced in the sputum of persons with
COPD
IL-10 is a potent anti-inflammatory cytokine that inhibits TNF-α, IL-1β,
granulocyte-macrophage-colony-stimulating factor, chemokines, and matrix-
metalloproteinase – all of which are increased in COPD
Systemic Inflammation
There is a systemic component to COPD, in terms of systemic inflammation, systemic
manifestations and comorbidities. The airflow obstruction characteristic of COPD has
significant effects on cardiac function and gas exchange with systemic consequences.
There are two schools of though related to COPD and systemic involvement. In the first
view, systemic manifestations and comorbildities are a result of a systemic spill over of
the inflammatory and respiratory events occurring in the lungs. In the second view, the
pulmonary manifestations are simply one form of expression of a systemic inflammatory
state where there is multiple organ compromise
2 views
Inflammation “spill-over” from lungs [Therapy should be primarily directed to
the lungs]
COPD systemic inflammatory disease in which lungs are one form of expression
[Therapy should be shifted to the systemic inflammatory state]
Either way, research is underway in both of these views. Currently, most treatments
are directed to the lungs. What is known is that systemic inflammation appears to
relate to an accelerated decline in lung function and is increased during
exacerbations
Cytokines associated with muscle involvement: IL-6, TNF-alpha, IL-1beta, chemokines
(specifically CXCL8 or IL-8) [The following cytokines have been linked to either
muscle weakness, skeletal muscle atrophy or cachexia. IL-6, TNF-alpha, IL-1beta and
chemokines; all of these cytokines except IL-1beta have increased plasma
concentrations]
Leptin
Leptin is an adipokine which is a cytokine derived from fat cells. Leptin plays an
important role in regulating energy and is decreased in persons with COPD
12

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Systemic Inflammation continued

Acute phase proteins linked to COPD symptoms and severity: CRP, fibrinogen, serum
amyloid A, surfactant protein D
The following acute phase proteins, plasma concentrations can be increased in
persons with COPD, particularly during exaserbations. Increased CRP has been
linked to health and exercise capacity and appears to be a significant predictor of
BMI. If CRP remains high two weeks after an exacerbation, there is a likelihood
of recurrent exacerbation. Fibrinogen plasma concentrations are increased with
frequent exacerbations. Worse expiratory volume in one second and increased
risk of hospitalization with COPD was linked with elevated plasma fibrinogen.
An elevated serum amyloid A during an exacerbation correlated with the severity
of exacerbations. Lastly, surfactant protein D better related disease severity and
symptoms in CRP. Both CRP and fibrinogen have been associated with
increased cardiac comorbidity
Systemic manifestations and comorbidities: skeletal muscle weakness, cachexia, lung
cancer, pulmonary hypertension, ischemic heart disease, cardiac failure, osteoporosis,
normocytic anemia, diabetes, obstructive sleep apnea and depression
Systemic inflammation can contribute to the following systemic manifestations and
comorbidities of COPD: skeletal muscle weakness, cachexia, ischemic heart
disease, cardiac failure, osteoporosis, diabetes, normocytic anemia and
depression. Lung cancer, pulmonary hypertension and obstructive sleep apnea
are also comorbidities of COPD, but are not usually related to systemic
inflammation
Putting it all Together

Tobacco, smoke or air pollution causes inflammation of the airway epithelium
Inflammation results in the infiltration of inflammatory cells and release of cytokines. These
inflammatory cells and mediators have systemic effects including muscle weakness and
weight loss as well as inhibition of normal endogenous antiproteases in the lungs
Bronchial inflammation and irritation persists which leads to chronic bronchitis. It is
important to note that airway remodeling causes fibrosis around small airways which
is though to be a major mechanism to progressive irreversible airway narrowing
Protease mediated degradation of connective tissue elements, specifically elastin, leads to
emphysema and the destruction of alveolar septa and loss of elastic recoil of bronchial
walls
Chronic bronchitis and emphysema cause airway obstruction with air trapping, loss of
surface area for gas exchange, and persons with diseases have frequent exacerbations
often due to infections and bronchospasm
Clinically, the person with COPD complains of dyspnea or SOB and a cough, which is
often productive. Hypoxemia, hypercapnia, and cor pulmonale are often manifested as
the disease progresses. Remember that since COPD is not one singular disease
process, clinical features often differ between patients
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Inherited alpha-1 antitrypsin that results in emphysema is due to the same protease-
antiprotease imbalance that occurs with smoking etiology
The limited endogenous alpha-1 antitrypsin results in increase protease activity leading to the
development of emphysema and air trapping, loss of surface area for gas excahange and
frequent exaserbations
Clinically, the person will experience dyspnea, hypoxemia and hypercapnia. Cough and
cor pulmonale are usually linked to chronic bronchitis
I also want to mention a concept that I really didn’t discuss which is the role of oxidative
stress which occurs as a direct result from cigarette smoke which contains numerous
oxidants as well as from inflammatory cells which release reactive oxygen species.
There is an oxidant-antioxidant imbalance. Other factors that can have an effect on
oxidant-antioxidant imbalance in the pathogenesis of COPD are respiratory infections,
genetic factors and dietary factors. Oxidative stress contributes to the damage that occurs
in the lungs. Furthermore, oxidative stress is considered to be the cause of corticosteroid
resistance in COPD. Also, muscle dysfunction in COPD has been strongly associated
with enhanced oxidative stress
14

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Acute Exacerbations (AECOPD)

“Acute changes in symptoms (cough, dyspnea and sputum production) beyond what is
considered normal variability in a patient” (Fromer and Cooper, 2008, p. 1231)
Etiology – ½ infectious (viral more frequent than bacterial, 1/3 unknown, other triggers
include CHF, PE, exposure to allergens and irritants
Half of acute exacerbations of COPD are infectious. Viral infections seem to be more
common than bacterial, however it is difficult to establish what bacterial
pathogen has caused the exacerbation as chronic bacterial colonization of the
airways is common in COPD. Also, there can be both a viral and bacterial
component to exacerbations. It appears that there is an increased risk of acute
exacerbations of COPD with new strain acquisition. The etiology of 1/3 of
AECOPD is unkown. Other triggers of AECOPD include congestive heart
failure, pulmonary embolis and exposure to allergens and irritants
Viral – rhinoviruses, RSV
The most frequently involved respiratory viruses in acute exacerbations are
rhinoviruses, or the common cold, and RSV. Others include influenza viruses,
coronaviruses, parainfluenza viruses, and human metapneumoviruses
Bacterial – haemophilus influenza and haemophilus species, Moraxella catarrhalis and
streptococcus pneumonia
Probable bacterial pathogens include haemophilus influenza, and other haemophilus
species, Moraxella catarrhalis and streptococcus pneumonia. Others to consider,
especially in a complicated exacerbation (which means COPD with risk factors),
are klebsiella species and other gram negative bacteria and pseudomonas species
Common signs and symptoms of AECOPD include breathlessness, wheezing, chest
tightness, increased cough and sputum production, change of colour and tenacity of
sputum and fever. Others include tachycardia, tachypnea, malaise, insomnia, fatigue,
depression, and confusion. Exercise intolerance and fever may present prior to
exacerbation
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AECOPD continued
Management Prevention
Initiate or increase bronchodilator Smoking cessation

therapy
If no improvement, admit to hospital Vaccinations [Specifically annual influenza vaccine, and

pneumococcal vaccine every 5-10 years. Annual influenza
vaccine reduces morbidity and mortality or the disease by as
much as 50% in elderly patients, and hospitalization rates
are reduced by as much as 39% in persons with chronic lung
disease. Although the benefit of pneumococcal vaccine is less
well established, the Canadian Thoracic Society
recommendations are that it be given at least once, and
possible repeated every 5-10 years]
Oxygen; combo therapy B-agonists Self-management education [Reinforcement of self-

and anticholinergics; PO, IV, inhaled management education]
corticosteroids [Administering oxygen,
combination therapy of beta-2 agonists
and anticholinergics, and oral,
intravenous or inhaled corticosteroids]
Consider intravenous Regular long-acting bronchodilator therapy in [may be

methylxanthines, antibiotics, NIPPV prescribed in] moderate to severe COPD
[the medical team may consider IV
methylxanthines, antibiotics,
noninvasive positive pressure
ventilation]
Tx comorbidities prn [important to Regular ICS/LABA combo in moderate to severe COPD with
treat comorbidities as needed] 1 or more AECOPD/year [Regular inhaled corticosteroid and
long-acting beta-2 agonist combination therapy may be
prescribed in moderate to severe COPD with one or more
acute exacerbations per year]
Oral corticosteroid therapy for AECOPD [Initiation of oral
16

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corticosteroid therapy for acute exacerbations]
Pulmonary rehabilitation
Clinical Manifestations
The signs are objective findings assessed or measured by a health care provider
To interpret clinical manifestations, it requires an understanding of the underlying
physiology and/or pathophysiology
Symptoms are subjective in nature are reported by the patient. Of course, symptoms may be
observed by the health care provider as well, such as cough and sputum production
Signs Symptoms
Physical assessment findings Dyspnea/SOB [The subjective sensation of

being unable to get enough air. Dyspnea may
be caused by disturbances in ventilation, gas
exchange or ventilation-perfusion
relationships, as well as increased work of
breathing or diseases that damage the lung
parenchyma. All of these causes are possible
with COPD]
Lab results (including arterial blood gases) Fatigue [Fatigue and exercise intolerance
occurs as breathing with effort depletes energy
stores]
Radiological findings Exercise intolerance
Pulmonary function tests Cough [Cough is a reflex that is stimulated in

COPD by excessive secretions and/or inhaled
irritants]
Sputum production [Sputum production is

caused by inflammation in the airways]
Wheezing [Wheezing occurs as air passes

through narrowed airways]
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The RNAO best practice guideline titled Nursing Care of Dyspnea: The Sixth Vital Sign in
Individuals with COPD provides a detailed summary of the assessment of an individual
with COPD and dyspnea on page nine
Possible Abnormal PA Findings

VS: +/- fever, hypoventilation, tachycardia, hypoxemia
Cardiac: edema, increased JVP
Respiratory: barrel chest, increased work of breathing, use of accessory muscles, pursed lip
breathing, cyanosis, hyper-resonant sound with percussion, crackles, wheezes
Other: muscle weakness, muscle wasting, cachexia, finger clubbing
This slide will review the common abnormal physical assessment findings, focusing mostly on
the vital signs and the cardio-respiratory assessments. A fever may be present, indicating an
infection. Now is the time to think back to your lecture on inflammation and remember what
causes fever. Hypoventilation (decreased respiratory rate) is often seen due to prolonged
expiratory phase. Tachycardia may be present and related to several mechanisms, including
fever, use of beta-2 agonist puffer, and hypovolemia should always be considered with
tachycardia.
Blood pressure shouldn’t be affected. If you receive an abnormal result, consider
hypovolemia or sepsis for hypotension and a history of high blood pressure for hypertension.
Oxygen saturations are often measured with vital signs. Hypoxemia may be present related
to inadequate gas exchange in COPD.
If there is cardiac involvement, you may note edema or an increased jugular venous pressure.
Although a person with COPD warrants a head to toe assessment, one may argue that the most
important system to assess is the respiratory system.
First you want to inspect the person. Note their work of breathing, use of accessory muscles,
shape of chest, and colour. We have already talked about the cause of barrel chest. Increased
work of breathing and use of accessory muscles occurs as the person with COPD attempts to
improve ventilation. Often, the person is sitting in a tripod position, which is used to facilitate
use of the sternocleidomastoid scalene and intercostal muscles. Pursed lip breathing helps to
prevent expiratory airway collapse. Cyanosis is caused by hypoxemia.
Next, you want to palpate and percuss. With air-trapping, the chest has a hyper-resonant sound
with percussion. Palpation is not frequently done. Next you want to auscultate. Crackles are
caused by abnormal secretions, mucus, or fluid in the airways. Wheezing occurs as air passes
through narrowed airways. Inspiratory wheezing is usually \associated with upper airway
obstruction and expiratory wheezing is usually associated with lower airway obstruction.
Other abnormal physical assessment findings include: muscles weakness, muscle wasting,
cachexia, and finger clubbing. We have already discussed the possible causes for muscle
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weakness, wasting, and cachexia. Clubbing of the fingers is associated with diseases
that interfere with oxygen (such as COPD).
Signs Continued
Labs
ABG: hypoxemia, hypercapnia, acidosis with severe disease, or respiratory failure
CBC: elevated leukocytes, anemia
Elevated cytokines and acute phase problems
Chest X-ray
Hyperinflation
Flattening of the hemidiaphragms
Note presence of atelectasis, pulmonary edema, areas of consolidation,
cardiomegaly
Evidence of infection
The above are common laboratory findings. In the arterial blood gas, it may show: hypoxemia,
hypercapnia, acidosis with severe disease, or respiratory failure. Respiratory failure is defined
as inadequate gas exchange. This means hypoxemia in which partial pressure of arterial oxygen
is less than or equal to 50 mmHg, or hypercapnia in which partial pressure of arterial carbon
dioxide is greater than 50 mmHg with a pH less than or equal to 7.25. The CBC may show
elevated leuokocytes and anemia, and there may also be elevated cytokines and acute phase
proteins. When reviewing the chest x-ray report, hyperinflation and flattening of the
hemidiaphragms is consistent with air-trapping in COPD. Also, note if there is any report of
atelectasis, pulmonary edema, areas of consolidation, cardiomegaly, or evidence of infection.
Pulmonary Function Tests

Spirometry is the standard assessment tool for dx, staging, and monitoring of COPD
FEV1 < 80% indicates more advanced disease
FVC not always reduced in early stages of COPD
FEV1/FVC post-bronchodilator < 0.70 confirms airflow limitation
Spirometry is the standard assessment tool for diagnosis, staging, and monitoring of COPD.
Current COPD guidelines recommend that spirometry should be performed on any patient who
has a history of exposure to risk factors for COPD, a history of chronic respiratory illness, or
chronic symptoms of cough, sputum production, or dyspnea. Forced expiratory volume in one
second (FEV1) is the volume of air forcibly exhaled during the first second of expiration after
maximal inspiration. An FEV1 of less than 80% predicted indicates more advanced disease.
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Forced vital capacity (FVC) is the maximum volume of air exhaled until the lungs are
emptied. FVC is not always reduced in the early stages of COPD. The ratio of FEV1 and FVC
(FEV1/FVC) is used to assess lung function. If this ratio is less than 0.70 post bronchodilator
therapy, it confirms airflow limitation.
Oxygen Therapy
Usually used in stage IV COPD (very severe disease)
Long-term continuous therapy, during exercise or prn to relieve episodes of acute
dyspnea
Improves pulmonary hypertension, increases exercise capacity & lung function, improves
the mental and emotional states, increases survival in persons with chronic respiratory
failure
NIPPV is considered during severe exacerbations or in persons with chronic hypercapnic
respiratory failure
Oxygen therapy is usually used in stage 4 COPD, which is described as very severe disease with
chronic respiratory failure. It can be delivered as long-term continuous therapy during exercise or
as need to relieve episodes of acute dyspnea. Long-term therapy oxygen, which is 15 hours per
day or more, to achieve an oxygen saturation of 90% or higher offers a survival advantage to
persons with stable COPD with severe hypoxemia. Severe hypoxemia is defined as a partial
pressure of arterial oxygen of 55 mmHg or less, or when partial pressure of arterial oxygen is
less than 60 mmHg in the presence of bilateral ankle edema, cor pulmonale, or hematocrit
greater than 56%. Oxygen therapy has been shown to improve pulmonary hypertension, increase
exercise capacity and lung function, improve the mental and emotional state of a person with
COPD, and increase survival in persons with chronic respiratory failure. Non-invasive positive
pressure ventilation (NIPPV) can be considered during severe exacerbations or in persons with
chronic hypercapnic respiratory failure, although it is not considered standard of care for persons
with COPD.
Pharmacology
Bronchodilators
Inhaled Anticholinergics
Inhaled Beta-2 Adrenergic Receptor Agonists
Combination inhalations
Corticosteroids
Inhalation
Oral
Other: Methylxanthines (i.e. aminophylline and theophylline); mucolytics
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Bronchodilators are the main pharmacological therapy for COPD. They are available in both
short and long acting formulations. Inhaled anticholinergics decrease bronchoconstriction by
reducing muscle tone. They also decrease glandular mucous. They inhibit acetylcholine from
first interacting with cholinergic M1 and M3 receptors in the airway’s smooth muscle that
controls bronchoconstriction and secondly the glands that produce mucous secretions. They
are generally well tolerated but should be used with caution in persons with glaucoma or
prostate symptoms. Dry mouth occurs in approximately 10 – 14% of people who use an
inhaled anticholinergic and it is the most common side effect.
Inhaled beta-2 adrenergic receptor agonists cause bronchodilation by acting on the beta-2
adrenergic receptors located in the smooth muscle of the airways. When these receptors are
stimulated, there is an increase in the production of cyclic adenosine monophosphate, which
inhibits bronchoconstriction. Long acting beta-2 adrenergic receptor agonists, such as Formeterol
and Salmeterol, are recommended as maintenance therapies for the long-term prevention and
reduction of COPD related symptoms.
There are several combination inhalation therapies that combine inhaled anticholinergics with
corticosteroids. The trade names do not provide information as to what is in the inhalation. It
is important to identify the generic names and what they are prior to administering
combination inhalation therapy.
Corticosteroids as monotherapy are usually not effective in COPD due to corticosteroid

resistance caused by the effects of oxidative and nitrative stress in COPD lungs. Current
guidelines recommend inhalation corticosteroid therapy for the treatment of patients with
advanced COPD, meaning an FEV1 less than 50% predicted who experience repeated
exacerbations. Combine inhaled corticosteroid therapy and long-acting beta-2 agonists have been
shown to reduce the decline in lung function in a recent study. Oral corticosteroids are often used
for severe exacerbations.
Other pharmacologic agents used include: methylxanthines, which are used as third line
treatment after inhaled anticholinergics or inhaled beta-2 agonists or when treating
exacerbations. Mucolytics can also be used, especially in patients with significant
mucous hypersecretion.
Pulmonary Rehabilitation
Reduces symptoms (specifically improves dyspnea, exercise endurance), improves quality
of life, increases physical and emotional participation in ADL, decreased risk of
hospitalization following AECOPD
Goal – “restore a patient to the fullest medical, emotional, social, and vocational status
possible” (Fromer & Cooper, 2008, p. 1230)
3 components: exercise training (aerobic and resistance exercises), nutritional counseling,
and patient education
All persons with COPD should maintain an active lifestyle. Pulmonary rehabilitation should be
offered and encouraged for those who continue to have dyspnea and exercise limitations despite
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pharmacotherapy. Pulmonary rehabilitation reduces symptoms. It has been shown to significantly

improve dyspnea, exercise endurance, and quality of life. It also increases physical and emotional
participation in activities of daily living, and decreases the risk of hospitalization following an
acute exacerbation of COPD. The goal of pulmonary rehabilitation as stated by
Fromer and Cooper is to “restore a patient to their fullest medical, emotional,
social, and vocational status possible”.
There are three main components of pulmonary rehabilitation: exercise training (aerobic
and resistance exercises), nutritional counseling, and patient education.
Peripheral muscle dysfunction is extensively studied but the mechanisms for decreased
exercise capacity, skeletal muscle weakness, and cachexia are still poorly understood.
However, both inactivity and inflammation play a role in this peripheral muscle dysfunction.
Pulmonary rehabilitation addresses the inactivity.
Patient Education
SMOKING CESSATION!!!
Self-management programs
Effective inhaler technique
Early recognition and treatment of acute exacerbations
Nutritional counseling
Encourage an active lifestyle
Identification of community resources
End-of-life issues
Patient education includes the following. Smoking cessation is the only intervention shown
to slow the rate of lung function decline. Smoking cessation counseling is key to a person’s
success. Self-management programs, along with smoking cessation, have been shown to reduce
health resources utilization related to the management of acute exacerbations. Effective inhaler
technique ensures adequate drug delivery. Early recognition and treatment of acute exacerbations
can help to avoid more severe exacerbations.
Others include: Nutritional counseling (as part of pulmonary rehabilitation), encourage an active
lifestyle, and helping a person identify community resources required to assist them with
activities of daily living or other needs. COPD is a progressive disease for which there is no cure.
When appropriate, end of life issues should be discussed.
Conclusion
To conclude, COPD is expected to become the third leading cause of death worldwide by 2020.
Although several etiologies exist, smoking remains the primary cause of COPD. Asthma and
COPD are fundamentally different, although there are similarities in clinical manifestations and
pharmacologic treatments of these diseases. Airflow obstruction and inflammation affects more
than just the lungs. There are several systemic manifestations and comorbidities that must be
considered when caring for a patient with COPD. Infection is the main cause of acute
exacerbations of COPD. Pharmacology is aimed at improving air flow. Pulmonary rehabilitation
is very beneficial. Smoking cessation is the only intervention to the rate of lung function decline.
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Module 4: Delirium
Learning Outcomes
Define delirium as a clinical syndrome
Discuss the importance of delirium as a predictor of increased mortality in the elderly
hospitalized population
Distinguish between delirium and other neuropsychiatric illnesses
Identify the subtypes of delirium and their associated characteristics
Describe the screening tools available to diagnose delirium
Identify the predisposing and precipitating factors that increase a patient’s risk
for delirium
Discuss the pathophysiology of delirium
Describe the intervention protocols used to prevent and manage delirium in the
hospitalized elderly population
Delirium
Acute decline in the cognitive processes of the brain
Most commonly associated with hospitalized patients aged 65 years and older
Cognitive function fluctuates throughout the day
Wide range of symptoms and patient characteristics
2/3 of cases go unreported
Delirium is a common, life-threatening and potentially preventable clinical syndrome induced by

a variety of physical causes. It is often defined as an acute decline in the cognitive processes of
the brain, namely attention and cognition. It is most strongly associated with hospitalized
patients who are 65 years of age or older. Patients with delirium may exhibit periods of
inattention, disorganized thinking, changes in level of consciousness, disorientation, delusions,
perceptual disturbances, as well as impaired memory, speech, sleep, and psychomotor activity.
These changes in cognitive function can fluctuate in severity throughout the day and as such,
delirium is often under-recognized and undertreated. It is estimated that two thirds of patients
with delirium go unreported. This can be attributed to both the syndromes fluctuating nature and
the wide range of symptoms and patient characteristics associated with the syndrome. Some
clinicians continue to use the term “confusional state” or encephalopathy when diagnosing
delirium, further complicating the proper identification, management, and treatment of this
life-threatening syndrome.
Delirium
Linked to poor clinical outcomes
Marker for severe illness and mortality O 1
year mortality rate of 35 – 40%
Initiates a cascade of pathophysiological changes that lead to: O
Loss of independence
O Increased risk of morbidity and death
O Increased health care costs

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Yet, only 40% of health care workers routinely screen for delirium in at risk patients
As mentioned earlier, delirium frequently accompanies acute illness in hospitalized elderly

patients. Historically, delirium was accepted as a harmless process, however data collected from
the past 15 years has shown that this clinical syndrome is relaying to poor clinical outcomes and
should be regarded as a marker for severe illness and mortality. In North America, delirium
complicates the hospital stays of approximately 20% of patients 65 years of age and older. More
concerning is the evidence that the one year mortality rate associated with cases of delirium in
the elderly is 35-40%.
Current studies investigating delirium and its outcomes suggest that the development of delirium
in the hospitalized elderly initiates of events that culminate in a loss of a patients independence
and an increased risk of morbidity and mortality. There are also associated increases in health
care costs due to longer hospital stays, rehabilitation, and the need for formal home health care or
long term institutionalized care. Despite this evidence, it is estimated that only 40% of clinicians
routinely screen for delirium in hospitalized elderly patients.
Diagnostic Criteria for Delirium

A. Disturbance of consciousness (e.g., reduced clarity of awareness of the environment)
with reduced ability to focus, sustain or shift attention
B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the

development of a perceptual disturbance that is not better accounted for by a preexisting,
established or evolving dementia
C. The disturbance develops over a short period of time (usually hours to days) and tends to
fluctuate during the course of the day
D. There is evidence from the history, physical examination or laboratory findings that the
disturbance is caused by the direct physiological consequences of a general medical condition
Currently, the DSM4 defines delirium by the presence of disturbed consciousness and a change
in cognition or the development of a perceptual disturbance that is not better accounted for by a
preexisting, established or evolving dementia. This disturbance in consciousness must develop
over a short period of time as you fluctuate during the course of the day. Moreover, there must be
evidence from clinical history, physical examination and/or laboratory findings that the
disturbance is caused by the direct physiological consequences of a general medical condition.

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Clinical Features of Delirium

In addition to the core symptoms outlined by the DSM4, the clinical features shown below
are also hallmark characteristics of delirium.
Acute Onset
Occurs abruptly, usually over a period of hours or days
Reliable information often needed to ascertain the time course of onset
Fluctuating Course
Symptoms tend to come and go or increase and decrease in severity over a 24-hr period
Characteristic lucid intervals
Inattention
Difficulty focusing, sustaining, and shifting attention
Difficulty maintain conversation or following commands
Disorganized Thinking
Manifested by disorganized or incoherent speech
Rambling or irrelevant conversation or an unclear or illogical flow of ideas
Altered level of consciousness

Clouding of consciousness, with reduced clarity of awareness of the environment
Cognitive deficits
Typically global or multiple deficits in cognition, including disorientation, memory
deficits, and language impairment
Perceptual Disturbances
Illusions or hallucinations in about 30% of patients
Psychomotor Disturbances:
Psychomotor variants of delirium
Hyperactive: marked by agitation and vigilance
Hypoactive: marked by lethargy, with a markedly decrease level of motor activity
Mixed
Altered sleep-wake cycles

Characteristic sleep-cycle disturbances
Typically daytime drowsiness, nighttime insomnia, fragmented sleep, anxiety,
depression, irritability, apathy, anger, or euphoria
Emotional disturbances
Common
Manifested by intermittent and labile symptoms of fear, paranoia, anxiety, depression,
irritability, apathy, anger, or euphoria

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Delirium, Dementia & Depression
Feature Delirium Dementia Depression

Onset Acute (often at twilight) Chronic, insidious Coincides with life changes,
often abrupt
Course Short, diurinal fluctuations; Long, symptoms Diurinal effects (worse in
worse at night & on progressive, yet stable over morning), situational
awakening time, no diurinal effects fluctuations
Progression Abrupt Slow but even Variable (rapid-slow)
Duration Hours to less than 1 month, Months to years At least 2 weeks, but can be
seldom longer months to years
Awareness Reduced Clear Clear
Alertness Fluctuates; lethargic or Generally normal Normal
hyper-vigilant
Attention Impaired, fluctuates Generally normal Minimal impairments, but
distractible
Orientation Impaired, fluctuates in May be impaired Selective disorientation
severity
Memory Impaired – recent & Impaired- recent & remote Selective or patchy
immediate
Thinking Disorganized, distorted, Thoughts impoverished, Intact but with themes of
fragmented, incoherent words difficult to find, poor hopelessness or self-
judgment deprecation
Perception Distorted; delusions & Misperceptions often absent Intact; delusions &
hallucinations, difficulty hallucinations absent except
distinguishing between in severe cases
reality & misperceptions
While reviewing the clinical features of delirium listed in the previous slide, you may have
noticed that many of the symptoms observed in patients with delirium are also observed in
patients with other neuropsychiatric diseases or medical illnesses. This likely represents another
reason as to why patients with delirium may be difficult to identify, especially to an
inexperienced health care worker. Consequently, it is crucial that the health care team perform
both a careful and detailed history and physical examination of the patient, to distinguish
between delirium and other types of mental illness or dementia. As discussed earlier, in cases of
delirium, the onset of altered consciousness, cognitive disturbance or hallucinations is typically
acute and present in a context of medical illness or surgery or medication change. To the
untrained eye, these features can sometimes be mistaken for a psychotic disorder, especially
when auditory and visual hallucinations predominate. In such cases, it is important to remember
that schizophrenia tends to have a gradual onset and appears in late adolescents or early
adulthood. It is also preceded by a phase of social isolation that lasts weeks to months.
Moreover, disorientation and fluctuations in level of consciousness are rare in schizophrenia,
but is a hallmark feature of delirium.
Delirium may also be mistaken for dementia. In patients with dementia, the client’s level of
consciousness is typically intact and inattention is either absent or mild, when compared to other
cognitive deficits. Patients with dementia rarely exhibit fluctuations in their cognitive function,

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another distinguishing feature between dementia and delirium. Finally, delirium may also be
mistaken for depression, especially when the patient’s symptoms are hypoactive in nature.
Unlike delirium, depression has a more gradual onset of psychomotor slowing and the cognitive
deficits tend to reflect disinterest as opposed to the disorientation commonly seen in patients with
delirium.
Types of Delirium
Hyperactive
Restlessness, constant movement, agitation
Insomnia, hyper-vigilance, irritability, rapid speech
May be mistaken for schizophrenia, bipolar disorder, or agitated dementia
Hypoactive
Slowing or lack of movement, paucity of speech, unresponsiveness
May be mistaken for depression
Most common form of delirium
Associated with a higher mortality
Mixed
Alternating hyperactive and hypoactive states
Adding to its complexity, delirium exists in three different subtypes: hyperactive, hypoactive,
and mixed subtypes. Hyperactive delirium is often characterized by symptoms of restlessness,
constant movement, and agitation. Insomnia, hyper-vigilance, irritability, distractibility, rapid
speech, uncooperativeness and wandering behaviour are also observed. Given these features,
the hyperactive subtype of delirium may often be mistaken for schizophrenia, bipolar disorder,
or agitated dementia.
In contrast, a slowing or lack of movement, a paucity of speech with or without prompting, and
unresponsiveness characterize hypoactive delirium. Apathy and decreased alertness are also typical
in patients with the hypoactive subtype of delirium. Not surprisingly, it is this subtype that is often
mistaken for depression. The hypoactive subtype of delirium is more common in the elderly, with
more than 50% of elderly hospitalized patients presenting with the hypoactive form
of this syndrome. Due to its almost silent nature, this form of delirium is the most difficult for
clinicians to identify, especially if the patient’s baseline or normal behaviour was never
established.
The mixed subtype of delirium is characterized by alternating hyperactive and hypoactive

states. Of the three subtypes, those with severe hypoactive delirium have the lowest 6 month
survival rate. This may be because those with hyperactive delirium are more likely to be
referred to a psychiatrist and receive appropriate therapy or interventions due to the more
disruptive and potentially self-harming nature of the subtype. In contrast, hypoactive delirium
maybe mistaken for compliance, fatigue, or simply behaviours incorrectly ascribed to old age.

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Screening for delirium

Introduction: The questions associated with the CAM Instrument are listed under the bullets below.
For most questions, a “yes” or “no” answer by the health care professional is all that is
required.
Since the vast majority of elderly patients fall into the hypoactive delirium subtype, the risk of
not identifying a patient with delirium is high. Given that unmanaged delirium is associated
with a significant risk of mortality in the first year, the use of effective screening tools for the
diagnosis of delirium is critical. The Confusion Assessment Method Instrument, or CAM, has
been widely accepted as the most useful scale for diagnosing delirium. This screening tool
diagnoses the delirious state by a yes or no answer to a 4-point algorithm based on the DMS-IV
criteria. Proper use of this instrument has the potential to enhance the detection of delirium in
hospital settings and reduce the number of delirious patients who go undiagnosed or
undertreated. For those patients who are intubated or ventilated, this scale has been adapted so
that direct communication is not required. This instrument is called the CAM-ICU. While the
CAM instrument is an excellent means to diagnose delirium, it is not able to rate symptom
severity. As such, the delirium rating scale is often used to rate symptom severity, follow the course
of the syndrome, and assess whether the patient’s symptoms are improving with treatment
interventions.
Confusion Assessment Method Instrument

Acute Onset: Is there evidence of an acute change in mental status from the
client’s baseline?
Inattention
a) Did the client have difficulty focusing attention, for example, being easily distractible,
or having difficulty keeping track of what was being said?
Not present at any time during interview
Present at some time during interview, but mild in form
Present at some time during interview, in marked form
Uncertain
(If present or abnormal) Did this behaviour fluctuate during the interview, that is, tend
to come and go or increase and decrease in severity?
Yes □No □ Uncertain □ Not applicable
(If present or abnormal) Please describe this behaviour.
Disorganized Thinking: Was the client’s thinking disorganized or incoherent, such as
rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable
switching from subject to subject?
Altered Level of Consciousness: Overall, how would you rate this client’s level of
consciousness?
Alert (normal)
Vigilant (hyperalert, overly sensitive to environmental stimuli, startled very easily
Lethargic (drowsy, easily aroused)
Stupor (difficult to arouse)
Coma (unarousable)
Uncertain

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Disorientation: Was the client disoriented at any time during the interview, such as
thinking that he or she was somewhere other than the hospital, using the wrong bed,
or misjudging the time of day?
Memory Impairment: Did the client demonstrate any memory problems during the
interview, such as inability to remember events in the hospital or difficulty remembering
instructions?
Perceptual Disturbances: Did the client have any evidence of perceptual disturbances, for
example, hallucinations, illusions, or misinterpretations (such as thinking something
was moving where it was not)?
Psychomotor Agitation & Retardation
Psychomotor agitation Part 1: At any time during the interview, did the client have an unusually
increases level of motor activity, such as restlessness, picking bedclothes, tapping fingers, or
making frequent sudden changes in position?
Psychomotor retardation Part 2: At any time during the interview, did the client have an
unusually decrease level of motor activity, such as sluggishness, staring into space, staying in
one position for a long time, or moving very slowly?
Altered Sleep-Wake Cycle: Did the client have evidence of disturbance of the sleep-
wake cycle, such as excessive daytime sleepiness with insomnia at night?
Scoring: To have a positive CAM result, the client must have:

1/ Presence of acute onset and fluctuating course AND 2/Inattention
AND EITHER
3/Disorganized thinking OR 4/Altered level of consciousness
Causes of delirium
Introduction: Delirium is rarely caused by a single factor. Rather, it is multifactorial and involves a
complex interaction between the vulnerable patient and their exposure to precipitating factors.
Predisposing factors include any baseline characteristic present at the time of admission that is
patient-dependent. Predisposing factors make the patient vulnerable to delirium and can thus be
considered predictive of those at risk for developing the syndrome. In contrast,
precipitating factors refer to any noxious insults, or factors related to hospitalization, that contributes to
a patient’s risk of developing delirium. In 1993 and 1996 Inouye et al. showed that
the effects of baseline and precipitating factors on the risk for developing delirium are
cumulative. Specifically, they showed that the presence of 3 or more delirium risk factors
increases the odds that an individual will develop delirium by 60%. In line of this evidence, it is
unlikely that addressing only one risk factor would result delirium in an elderly hospitalized
patient. Consequently, all factors – predisposing and precipitating – should be addressed.
Fortunately, most of the risk factors outlined in these two tables are modifiable and amenable for
intervention. We will discuss the different types of intervention used to prevent and manage
delirium later on in the module.

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PREDISPOSING FACTORS: Baseline PRECIPITATING FACTORS: Noxious insults or

characteristics present at the time of admission factors related to hospitalization
(patient-dependent) (environment/illness dependent)
Demographic characteristics Drugs
 Age of 65 years or older  Severe hypnotics
 Male sex  Narcotics
 Anticholinergic drugs
 Treatment with multiple drugs – related to a
2.9 times increased risk for delirium
 Alcohol or drug withdrawal
Cognitive status Primary neurologic diseases
 Dementia  Stroke, particularly non-dominant
 Cognitive impairment – related to a 2.82 times  hemispheric
increased risk for delirium Intracranial bleeding
 History of delirium  Meningitis or encephalitis
 Depression
Functional status Incurrent illness
 Functional dependence  Infections
 Immobility  Latrogenic complications
 Low level of activity  Hypoxia
 History of falls  Shock
 Fever or hypothermia
 Anemia
 Dehydration
 Poor nutritional status
 Low serum albumin level – related to a 4
times increased risk for delirium
 Metabolic derangements (i.e. electrolyte,
glucose, acid-base)
Sensory impairment Surgery
 Visual impairment – related to a 3.52 times  Orthopedic surgery
 increased risk for delirium  Cardiac surgery
Hearing impairment  Prolonged cardiopulmonary bypass
 Non-cardiac surgery
Decreased oral intake Environmental
 Dehydration – related to a 2.02 times increased  Admission to an intensive care unit
 risk for delirium  Use of physical restraints – related to a 4.4
Malnutrition times increased risk for delirium
 Use of bladder catheter – related to a 2.4
times increased risk for delirium
 Use of multiple procedures
 Pain & Emotional stress
Drugs Prolonged sleep deprivation
 Treatment with multiple psychoactive drugs

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Treatment with many drugs

Alcohol abuse
Co-existing medical conditions
Severe illness – related to a 3.49 times
increased risk for delirium
Multiple co-existing conditions
Chronic renal or hepatic disease
History of stroke
Neurologic disease
Metabolic derangements
Fracture or trauma
Terminal illness
Infections with human immunodeficiency virus
Causes of delirium: Predisposing and Precipitating Factors

As discussed in the previous slide, it is the interrelationship between predisposing and
precipitating factors that puts a patient at risk for developing delirium. While each factor has its
own independent effect, this synergy between the vulnerable patient and their exposure to
noxious stimuli represents a strong predictive model of which hospitalized patients are most at
risk for delirium. Based on the model outlined on this slide, patients who are highly vulnerable
to delirium (such as those with dementia) will develop delirium after exposure to a minor insult
(such as a single dose of a sedative drug). In contrast, in patients who are not vulnerable or
predisposed to delirium, the condition will only manifest after exposure to a number of noxious
insults (such as general anesthesia, major surgery, and multiple psychoactive medications).
Taken together, this information can be used which patients are at either a high or low risk for
developing delirium in the first 9 days of their hospital stay. With this information in hand,
interventions for the prevention of delirium can then be targeted to those at risk for delirium

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Multifactorial model of delirium

As discussed previously, a wide variety of factors or noxious insults can precipitate delirium.
Similarly, a wide variety of factors can influence a patient’s vulnerability to developing
delirium in response to a noxious stimulus. For example, in elderly patients, age is a predisposing
factor. However, for young to middle age adults age is a protective factor. Similarly, poor cognitive
function – even full-blown dementia – is a predisposing factor for delirium whereas healthy
cognitive function, or cognitive reserve, reduces a patient’s risk for delirium by exerting a
protective effect. The same can be said for sensation – good hearing and vision are protective
factors against delirium while hearing or visual impairments increase a person’s risk for
developing delirium, especially in a hospital setting. Not surprisingly, overall health influences
the risk of developing delirium. Those that are healthy and fit are at reduced risk for
developing delirium in response to a noxious stimulus than those who are of poorer health and
weaker functional status
Pathophysiology of Delirium
Pathophysiology of delirium is poorly understood

Unfortunately, the pathophysiology of delirium remains poorly understood for a
number of reasons:
O Inattention and impaired cognition are difficult to define
First, the core features of delirium (inattention and impaired cognition)
are difficult to define.
Fluctuating course is a hallmark feature of the disease
Second, the fluctuating course of this syndrome and its diverse clinical
symptoms make delirium difficult to recognize.
Multiple and interacting risk factors

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Third, delirium can be caused by a multitude of risk factors reflecting a

complex interaction between environmental and individual factors.
Inaccessibility of the CNS to scientific investigation
Finally, the overall inaccessibility of the central nervous system limits
scientific investigation into the possible neurobiological correlates of
delirium. However, it is evident from the clinical features of delirium
that this syndrome manifests from a strong link between the brain and
the body. Delirium occurs when physical stressors affect a vulnerable
patient. As such, there must be a link between the physiological
changes in the body and the cognitive changes that constitutes
delirium.
Current working hypotheses:

Neuroinflammatory
The leading hypothesis for the pathogenesis of delirium focuses on the
roles of inflammation and neurotransmitter dysregulation on brain
function.
Neurotransmitter dysregulation
Neuroinflammatory Hypothesis of Delirium
Systemic inflammation
Systemic inflammation is a predominant features of many surgical and medical
conditions associated with delirium, especially when tissue destruction and/or
infection is involved
Predominant feature of many surgical and medical conditions associated
with delirium
Delirium
For example, delirium is a presenting clinical feature of sepsis, UTIs, pneumonia,
myocardial infarction, fractures, hepatitis, burns, and also commonly appears in
complications following major surgical procedures. All of these medical or surgical
conditions share a common thread, the release and production of pro-inflammatory
mediators into the systemic circulation. As such, there appears to be a strong link
between delirium and inflammation.
Clinical features of sepsis, UTIs, pneumonia, myocardial infarctions,
fractures etc.
All of these conditions share a common thread
Release and production of pro-inflammatory mediators into the
systemic circulation
Delirious patients have higher blood plasma levels of inflammatory cytokines than
patients without delirium
This suggestion is supported by the clinical evidence that patients with post-operative
delirium have higher circulating blood levels of inflammatory cytokines than patients
without delirium

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It is wildly accepted that cells within the brain (neurons, glia and astrocytes) react to the
presence of peripheral immune cells in the systemic circulation. Activation of the brain
by peripheral immune cells leads to the production of cytokines, neuronal cell
proliferation and activation of the HPA axis. These changes allow the CNS to help
combat acute infections in the body. Unfortunately, it is these changes that may
contribute to the pathogenesis of delirium. Peripheral immune cells are able to gain
access to the brain by altering the expression of tight junction proteins that help form the
blood brain barrier. These changes lead to the increase in permeability of the blood brain
barrier, and allow for the recruitment and infiltration of blood-derived leukocytes and
other inflammatory agents into brain tissue. Once inside the brain, these pro-
inflammatory agents activate endothelial cells, microglia and astrocytes. Activation of the
microglia induces morphological changes and initiates the production of pro-
inflammatory cytokines such as IL-1, IL-2 and TNF-alpha. Changes within the microglia,
in turn, modulate the activity of adjacent endothelial cells, astrocytes and neurons,
impacting cerebral blood flow, signal propagation and neuronal excitability. It is
hypothesized that these changes in neurotransmission and cerebral blood flow contribute
to the pathogenesis of delirium. This hypothesis is supported by recent neuroimaging
studies that show a 42% reduction in overall cerebral blood flow in patients with
delirium. The symptoms of inattention and decreased cognitive function observed in
patients with delirium may be associated with decreased cerebral blood flow. Reduced
blood supply to the brain impairs the supply of oxygen and glucose, both of which are
essential to proper cognitive functioning.

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While the neuroinflammatory hypothesis of delirium cannot fully account for all the clinical
features associated with this syndrome, it does provide an explanation of how peripheral
changes in the body such as surgery, infection, and medical illness can affect brain
function and increase a patient’s risk for developing delirium. Moreover, this
hypothesis offer insight as to why elderly patients are more vulnerable to delirium, since
neuroanatomical studies have shown the presence of enlarged and damaged microglia in
the brains of elderly, non-delirious patients. The finding of microglia cells undergo age-
related functional and structural changes suggest that the elderly brain may exist in a pro-
inflammatory state that is primed, and thus more vulnerable to noxious insults, which
results in decreased cerebral blood flow and neurotransmitter dysfunction associated with
delirium

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Provides an explanation as to how peripheral changes in the body may affect brain
function and increase a patient’s risk for developing delirium
Offers insight as to why elderly patients are more vulnerable to delirium
Neuroanatomical studies revealed the presence of enlarged and damaged
microglia in elderly non-delirious patients
Elderly brain may exist in a pro-inflammatory state that is “primed” and
vulnerable to noxious insults
Cholinergic Hypothesis of Delirium
In addition to its effects on cerebral blood flow, neuroinflammation has been shown to
induce a cholinergic deficit in the brain. As you will have learned in other courses,
namely pharmacology, acetylcholine plays an important role in memory and cognition.
Consequently, decreased levels of acetylcholine in the brain would be somewhat
expected in patients presenting with delirium. The finding that anticholinergic drugs
cause delirium in healthy adults, and are even more likely to cause delirium in the
elderly population, supports this hypothesis. In fact, most drug-induced episodes of
delirium are associated with a medication that possesses anticholinergic activity. For
example, isofluorine anesthesia decreases acetylcholine release in most regions,
providing a rational as to why most elderly patients experience delirium while in post-
operative recovery. Opiate drugs, such as morphine, are also a common cause of drug-
induced delirium. Opiate administration induces an increase in dopamine levels, which
then leads to a corresponding decrease in acetylcholine levels within the brain. This
finding is commonly observed with dopaminergic drugs, because dopamine has an
inhibitory effect on acetylcholine release. As such, dopamine antagonists have been
shown to effectively treat some of the symptoms associated with delirium.
Acetylcholine
Memory and cognition
Patients with delirium show reduced brain cholinergic activity
Anticholinergic drugs cause delirium in healthy adults and the elderly population
Dopamine
Inhibitory effect on cholinergic activity
Dopamine agonists induce delirium
Dopamine antagonists treat some of the symptoms associated with delirium
Cholinergic Hypothesis of Delirium
In further support of the cholinergic hypothesis of delirium, studies have shown that medical
conditions that precipitate delirium, such as hypoxia and hypoglycemia, decrease
acetylcholine synthesis in the CNS. Moreover, clinical investigations have shown that
higher levels of serum anticholinergic activity are associated with an increased risk of
delirium of both medical and surgical in-patients. Other studies have also implicated a
role in serotonin, GABA, glutamate and melatonin as neuromodulators of the
dopaminergic and cholinergic neurotransmitter system. While both the
neuroinflammatory and cholinergic hypotheses of delirium provide insight into the

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biological mechanisms that underlie this syndrome, it is evident that neither hypothesis
can fully explain all of the characteristic features of delirium. Again, this is likely due to
the fact that delirium is associated with multiple, interacting, heterogeneous risk
factors. As such, it is unlikely that a single neurobiological pathway is responsible for
this syndrome.
Many precipitating factors for delirium decrease acetylcholine synthesis in the brain
High levels of serum anticholinergic activity are associated with an increased risk of
delirium
Neuroinflammatory and cholinergic hypothesis of delirium
Provide insight into the biological mechanisms that underlie delirium
However neither hypothesis can fully explain all of the characteristic features of
delirium
Delirium Prevention
Delirium is the most common preventable adverse event among the hospitalized elderly
population. It is estimated that 30-40% of delirium cases are preventable. As such, some experts
suggest that delirium rates should be used as an indicator of an institution’s overall quality of
health care. As discussed earlier, many elements of hospital care contribute to the development of
delirium. Adverse effects to medications, complications of invasive procedures, immobilization,
dehydration, the use of bladder catheters, and sleep deprivation, just to name a
few. Fortunately, most of these risk factors are modifiable. As such, prevention is the most effective
means to decrease the frequency of delirium and it’s complications. In 1999, it was
shown that targeted interventions to prevent delirium reduced the risk of the syndrome by 40%
in hospitalized elderly patients compared to patients who received a standard level of care. Such
interventions were also shown to reduce delirium duration, so therefore they should be used to
manage a delirious patient once the syndrome has manifested. In this study, the following risk
factors were targeted:
Cognitive impairment
Orientation Protocol  Board with names of care-team members and day’s
schedule; communication to reorient to surroundings
Therapeutic Activities Protocol  Cognitively stimulating activities three times daily
(e.g. discussion of current events, structured reminiscence, or word games)
Sleep deprivation
Non-pharmacological Sleep Protocol  At bedtime, warm drink (milk or herbal
tea), relaxation tapes or music, and back massage
Sleep Enhancement Protocol  Unit-wide noise reduction strategies (e.g. silent pill
crushers, vibrating beepers, and quiet hallways) and schedule adjustments to
allow sleep (e.g. rescheduling of medications and procedures)
Immobility
Early Mobilization Protocol  Ambulation or active range-of-motion exercises
three times daily; minimal use of immobilizing equipment (e.g. bladder
catheters or physical restraints)
Visual impairment

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Vision Protocol  Visual aids (e.g. glasses or magnifying lenses) and adaptive
equipment (e.g. large illuminated telephone key pads, large-print books, and
fluorescent tape on call bell), with daily reinforcement of their use
Hearing impairment
Hearing Protocol  Portable amplifying devices, earwax disimpaction, and special
communication techniques, with daily reinforcement of these adaptations
Dehydration
Dehydration Protocol  Early recognition of dehydration and volume repletion
(i.e. encouragement of oral intake of fluids)
Delirium Management
The flow chart identifies the key strategies that should be used by the health care team to both
prevent and manage delirium in the elderly hospitalized population. Upon admission, all elderly
patients should be started on intervention protocols to prevent the development of delirium.
Formal cognitive testing with confusion assessment method instrument should be performed to
establish base-line cognitive performance in all elderly patients, and identify any subtle cases of
hypoactive delirium. When a patient is admitted with confusion, the severity of change in mental
status should be determined. If no history is available, delirium should be assumed. Failing to do
so is the leading cause of missing a diagnosis of delirium. All patients should be awoken during
rounds and evaluated daily for delirium.
Monitor Cognitive Function

Perform formal cognitive assessment
Establish baseline cognitive function and recent changes
Monitor patient for changes in mental status
Acute Onset
Hallmark feature of delirium
If the patient’s status has deteriorated overtime, and the changes are more
chronic in nature, the possibility of dementia should be explored
Identify and Address Predisposing and Precipitating Factors

When investigating the underlying cause of delirium, the healthcare team should be
aware of atypical presentations of many diseases in the elderly, including
myocardial infarction, infection, and respiratory failure
Delirium is often a sole manifestation of a serious underlying disease in this
population
Initial Evaluation
Obtain history (including alcohol and benzodiazepine use)
Obtain vital signs
Perform physical and neurological examination
Order selected laboratory tests
Search for occult infection

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Review Medications and Remove or Alter Potentially Harmful Drugs

All pre-admission and current medications should be reviewed. Even long-term
medications can contribute to delirium and they should be re-evaluated.
Review the use of prescription drugs, as-needed drugs, over-the-counter drugs,
herbal remedies
Identify psychoactive effects and drug interactions
Change harmful dugs to a less noxious alternative
Use lower doses of potentially harmful drugs
Try non-pharmacologic approaches
Potential Contributing Factor Identified?

Yes  Evaluate and treat as approach for each contributing factor
No  Order lab tests (thyroid function tests, measurement of drug levels,
toxicology screen, measurement of ammonia or cortisol levels, vitamin b12
deficiency, and arterial blood gas levels), perform electrocardiography,
neuroimaging, and lumbar puncture/electroencephalography
Provide Supportive Care and Prevent Complications

Protect airway, prevent aspiration
Maintain volume status
Provide nutritional support
Provide skin care, prevent pressure sores
Use mobilization, prevent deep venous thrombosis, pulmonary embolus
Non-Pharmacologic Treatment Strategies

Continue delirium prevention
Reorient patient, encourage family involvement (use calenders, clocks, and
familiar objects from home)
Use sitters
Avoid use of physical restraints and foley catheters
Use nonpharm approaches for agitation: music, massage, relaxation techniques
Use of eyeglasses, hearing aids, and interpreters
Maintain patient’s mobility and self-care ability
Normalize sleep-wake cycle, discourage naps, aim for uninterrupted period of
sleep at night
At night, have patient sleep in a quiet room with low-level lighting
Pharmacologic Management
Reserve this approach for patients with severe agitation at risk for interruption of
essential medical care (e.g. intubation) or for patients who pose safety hazard to
themselves or staff
Start low doses and adjust until effect achieved
Maintain effective dose for 2-3 days
Prevention of Delirium

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Coordinating schedules for drug administration, obtaining vital signs, and

performing procedures during the night will provide patients with an
uninterrupted period for sleep. Opening blinds and promoting wakefulness
and mobility during the daytime can also encourage normal sleep-wake cycles
Address risk factors for delirium
Provide orienting communication
Encourage early mobilization
Use visual and hearing aids
Prevent dehydration
Avoid psychoactive drugs
Pharmacological Management of Delirium
Antipsychotic drugs
Low dose haloperidol
Atypical antipsychotic s
Increased risk of mortality with atypical antipsychotic use
Physicians should prescribe with caution
Non-pharmacological therapies should always be attempted first

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Antipsychotics are the drug class of choice for the treatment of delirium. Both low does
haloperidol treatment and atypical antipsychotic therapy are effective in managing the symptoms
of delirium. High dose haloperidol therapy should be avoided due to the increased risk of extra-
parameter side effects. In 2008, the Federal Drug Agency in the United States issued a black box
warning on atypical antipsychotic drugs. A meta-analysis of 17 placebo control trials revealed a
1.7 times increased risk of death in drug treated patients, compared to placebo controlled
patients. In these studies, mortality was most commonly associated with cardiovascular effects of
atypical antipsychotic drugs and the risk of aspiration pneumonia due to over-sedation. As such,
clinicians need to use careful judgment when prescribing for delirium, as the majority of patients
are elderly and medically compromised. The dose and duration of therapy should always be
minimized for this patient population.
Delirium & Dementia
Dementia is the leading predisposing risk factor for delirium

Dementia and delirium are associated with decreased cerebral blood flow, cholinergic
deficiency, and inflammation
50% of delirium cases persist after discharge, from months to years
Delirium worsens dementia and accelerates the patient’s loss of independence
May serve as an early warning sign of dementia
While delirium and dementia are two distinct conditions, there is significant evidence to suggest
that delirium and dementia are highly interrelated. First, dementia is the leading risk factor for
delirium. Two thirds of delirium cases occur in patients with dementia. This finding suggests that
dementia is a significant predisposing factor for delirium and it is also highly vulnerable to minor
insults. Second, both conditions are associated with decreased cerebral blood flow, acetylcholine
deficiency, and inflammation, suggesting overlapping neurobiological mechanisms. Thirdly, in
some patients, delirium can last from months to years, lowering the boundaries between delirium
and dementia. In fact, 50% of delirium cases persist after discharge. Persistant delirium is
associated with worse long-term cognitive and functional outcomes, and is 2.3 times more likely
to occur in patients with underlying dementia. Interestingly, the most significant risk factor for
persistent delirium is the use of physical restraints. The use of restraints leads to increased
agitation, immobility, functional decline, incontinence, pressure ulcers, asphyxiation (deficient
supply of oxygen to the body from being unable to breathe normally), and in some cases, cardiac
arrest. As such, physical restraints should not be used for older people with delirium, especially
those with agitated dementia. In those with dementia, delirium worsens functional status, accelerates
the patient’s loss of independence, and is associated with poor outcomes. Patients
with dementia never return to their baseline mental state after an episode of delirium and are
more likely to experience delirium in the future. Taken together, this evidence suggests that
delirium may serve as an important means to identify patients in the early stages of dementia
or mild cognitive decline.
Conclusion

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Delirium is a complex neuropsychiatric syndrome that primarily affects the hospitalized

elderly
Linked to significant morbidity and mortality
Health care providers must be able to identify the predisposing and precipitating risk
factors for delirium
Interventions are able to both prevent and manage this condition
Pathophysiology of delirium remains unknown, however it is likely to involve more than
one neurobiological mechanism
Delirium is often under-recognized and undertreated in the clinical setting. Given the significant
morbidity and mortality associated with delirium, all health care providers should understand the
clinical features of delirium, the predisposing and precipitating factors associated with it, and the
interventions available to both prevent and manage delirium in hospitalized patients. Structured
diagnostic instruments and scales to follow symptom severity have improved both the
identification and management of delirium. However, little is known about the pathophysiology
and underlying neurobiology of this condition. While both the neuroinflammatory and
cholinergic hypotheses for delirium have merit, future research into the neuro and atomical
correlates between human cognitive function and cellular brain mechanisms should shed some
light in this AREA.

Lecture notes, lectures 1-9 - Pathophysiology Nursing

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Lecture notes, lectures 1-9 - Pathophysiology Nursing

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Lecture notes, lectures 1-9 - Complete

Integrated Pathophysiology for Nursing (McMaster University)

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The Stress Response

-Stress is a response, not something that happens to us.

-The stressor, the stress response, and the pathophysiological sequelae.

-Stressors can be positive (Eustressors).

-External stimuli are external demands that trigger reactions.

-negative consequences due to an accumulation of stressors

-EX. Holmes and Rahe Stress Scale

-could be a major change that a affects few people (divorce)

-could be a daily hassle

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-can be acute or time limited (job interview)

-could be sequential (changes that follow divorce)

-could be chronic-intermittent (periodic family arguments)

PHYSIOLOGICAL RESPONSE- three key areas

࿿࿿࿿¢152 Primary Hormones involved are:

BODY’S RESPONSE TO STRESS

The Adrenal Glands (Retroperitoneal glands)

-They are comprised of three main layers.

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Adrenal Gland Hormones Summary

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PHYSIOLOGICAL RESPONSE: HPA (HYPOTHALAMIC-PITUITARY-ADRENAL) AXIS

-The stimulation of the Posterior Pituitary releases ADH (anti-diuretic hormone or

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YOUTUBE VIDEO ON THE STRESS RESPONSE-

Short-Term Stress and Long-Term Chronic Stress Feedback

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Module 2: Alterations in Hormonal Regulation – Diabetes

Diabetes Mellitus Part 1

I have included some recommended readings from the School of Nursing’s

Diabetes actually means the excessive excretion of urine. Diabetes mellitus

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5888 Nutritional intake of Bovine milk and high levels of

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23 There is a 2-4 fold increase of T2D associated with a positive family

Etiology GDM & Other

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0 Lipase is an enzyme that breaks down triglycerides into its 4 components

Putting It All Together

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Endocrine Pancreas Hormones

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Endocrine Pancreas Hormones

Endocrine Pancreas Hormones Glucagon is a polypeptide molecule produced

 Glucagon by the alpha cells and works opposite to

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Counter-Regulatory Hormones I want to briefly review how counter regulatory

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with poor regulation, even though insulin

Definitions The Canadian Diabetes Association defines