Sepsis and septic shock Pathophysiology

Introduction

Infection is defined as a pathologic process caused by invasion of normally sterile tissue

or fluid or body cavity by pathogenic or potentially pathogenic microorganisms

Definitions - Bacteremia
 Presence of bacteria in the blood, as evidenced by positive blood culture

Definitions - Septicemia
 Presence of microbes or their toxins in blood

Definitions - SIRS
 SIRS can occur in response to a variety of severe clinical insults & is defined by
presence of two or more of following conditions
 Temperature higher than 38° C or lower than 36° C
 Tachycardia – HR > 90 beats per minute
 Tachypnea – RR > 20 breaths per minute or a Paco2 lower than 32 mm Hg
 White blood cell count > 12,000 cells/mm3 or < 4000 cells/mm3

Definitions - Sepsis
 Sepsis occurs when SIRS is caused by infection
OR
 SIRS that has a proven or suspected microbial etiology
Definitions – Severe sepsis
 Severe sepsis is sepsis with associated organ dysfunction, hypoperfusion, or
hypotension
OR
 Sepsis with one or more signs of organ dysfunction

Definitions – Severe sepsis

 CVS – SBP < 90mm hg OR MAP < 70mm hg (that respondes to iv fluid
adminstration)
 Renal system - urine output < 0.5 mL/kg/hr
 Respiratory - PaO2/FIO2 < 250
 Unexplained metabolic acidosis

Definitions – Septic shock

 Septic shock is defined by presence of sepsis-induced hypotension (SBP - < 90
mm Hg or a reduction of more than 40 mm Hg from baseline in absence of other causes
for hypotension), despite adequate fluid resuscitation along with presence of perfusion
abnormalities
Definitions – MODS
 Dysfunction of more than one organ, requiring intervention to maintain
homeostasis
Second consensus conference – 2001

Diagnostic criteria for sepsis

 Infection, documented or suspected, and some of the following Diagnostic criteria
for sepsis
General variable
 Fever (core temperature > 38.3°C)
 Hypothermia (core temperature < 36°C)
 Heart rate > 90 /min or > 2 SD above normal value for age
 Tachypnea
 Altered mental status
 Significant edema or positive fluid balance ( >20 mL/kg over 24 hrs)
 Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of
diabetes

Inflammatory variables
 Leukocytosis (WBC count >12,000 cells/mm3)
 Leukopenia (WBC count 4000 cells/mm3)
 Normal WBC count with > 10% immature forms
 Plasma C-reactive protein > 2 SD above normal value
 Plasma procalcitonin > 2 SD above normal value

Hemodynamic variables
 Arterial hypotension (SBP < 90 mm Hg, MAP < 70mm hg, or an SBP decrease >
40 mm Hg in adults or < 2 SD below normal for age)

Organ dysfunction variables

 Arterial hypoxemia (PaO2/FIO2 < 300)
 Acute oliguria (urine output < 0.5 ml/kg/hr or 45 mmol/L for at least 2 hrs despite
adequate fluid resuscitation)
 Creatinine increase > 0.5 mg/dL
 Coagulation abnormalities (INR > 1.5 or aPTT > 60 secs)
 Ileus (absent bowel sounds)
 Thrombocytopenia (platelet count < 100,000 cells/mm3)
 Hyperbilirubinemia (plasma total bilirubin > 4 mg/dL or 70 mmol/L)

Tissue perfusion variables

 Hyperlactatemia (>1 mmol/L)
 Decreased capillary refill or mottling
Diagnostic criteria for sepsis in the pediatric population
Signs and symptoms of inflammation plus infection with hyper- or hypothermia (rectal
temperature >38.5 or < 35°C), tachycardia (may be absent in hypothermic patients), and
at least one of the following indications of altered organ function: altered mental status,
hypoxemia, increased serum lactate level, or bounding pulses

EPIDEMIOLOGY
 Currently, gram-positive bacteria are predominant pathogens in severe sepsis
 The incidence of sepsis due to fungal organisms has increased substantially over
last 20 years
 The most common sites of infection are respiratory system,bloodstream, &
genitourinary tract

PATHOPHYSIOLOGY
 Severe sepsis is the end result of complex interactions between infecting
organisms & host response
 Important components of this host response in early phases of sepsis are immune
system, activation of inflammatory cascade & alterations in hemostasis
 In later stages, organ failure, immunosuppression & apoptosis play important
pathophysiologic roles
 Characteristics of both infecting organism & host response influence outcome of
sepsis
 Virulence factors, high burden of infection & resistance to antibiotics are all
organism characteristics associated with higher risk of severe sepsis

Immune response

 The immune response to infection takes place through actions of two pathways
 Innate immune system
 Adaptive immune system
 Goal of innate immune system is to provide protection in first minutes to hours
after an infectious challenge
 Although it was initially thought to be a nonspecific response, research has
demonstrated that the innate immune system recognizes pathogens by means of pattern-
recognition receptors called Toll-like receptors
 These receptors bind to highly conserved structures on microorganisms, which are
not easily altered by microbes to evade detection & are present on broad groups of
organisms
 Current understanding of TLRs suggests that immune cells use different TLRs to
detect several features of an organism & generate a tailored response to invading
pathogen
Immune response
 Activation of TLRs by microorganisms stimulates signaling pathways that
increase production of
 Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α),
interleukin-1β (IL-1β) & nuclear factor-κB
 Anti-inflammatory cytokines, such as IL-10
 Upregulation of microbial killing mechanisms, such as production of reactive
nitrogen species

1- Adaptive immune system

 Amplifies response initiated by innate immune system with a higher degree of
specificity
 Microorganisms stimulate specific cell-mediated & humoral adaptive immune
responses
 Two types of lymphocytes, B cells & T cells, play an important role
 Adaptive immune responses (humoral and cellular) require days to develop
 In case of reexposure to same pathogen, they can elicit a faster response
 CD4+ T cells are divided into two types,
 Type 1 helper T (Th1) cells
 Type 2 helper T (Th2) cells
 Factors such as type of organism, site of infection & burden of infection influence
response elicited by T cells
 Th1 cells secrete proinflammatory cytokines (TNF-α and interleukin-1β)
 Th2 cells anti-inflammatory cytokines (IL-4 and IL-10)
 B lymphocytes are responsible for releasing immunoglobulins in response to
microorganisms
 These immunoglobulins bind to organism-specific antigens & enhance their
recognition & destruction by other immune cells (natural killer cells and neutrophils)

Role of Inflammation

 For many years, prevailing theory has been that sepsis is result of an uncontrolled
inflammatory response
 Animal models of sepsis that used large doses of endotoxin or bacteria created a
“cytokine storm”
 Early blockage of this cytokine storm resulted in improvements in mortality
 Most human patients with sepsis, however, have a complex host response that
involves activation of both proinflammatory and anti-inflammatory cascades
 The interplay among proinflammatory cytokines, anti-inflammatory cytokines, &
cytokine inhibitors is a dynamic process that influences host response to sepsis
 Proinflammatory cytokines such as TNF-α & IL-1β increase early in sepsis &
have overlapping & synergistic effects in further stimulating inflammatory cascade
 Proinflammatory cytokines
 Activate monocytes, macrophages & neutrophils
 An important role in development of clinical abnormalities such as
• Fever, hypotension, capillary leakage with decreased intravascular volume &
myocardial depression
 Anti-inflammatory cytokines in sepsis is still not fully understood
 Current understanding - sepsis-induced multiple organ failure & death may be
caused, in part, by a shift to an anti-inflammatory phenotype & by apoptosis of key
immune cells
 This shift is driven partially by increased levels of anti-inflammatory cytokines &
results from a shift in helper T-cell populations (from Th1 to Th2)

Alterations of Hemostasis

 Balance is altered by a rise in procoagulant factors paired with a drop in

anticoagulant factors
 Under normal conditions intraluminal vascular surface has anticoagulant
properties
 During sepsis, stimulation from cytokines promotes expression of tissue factor on
endothelial cells, monocytes & neutrophils
 Tissue factor triggers extrinsic coagulation pathway by activating factor VII
 Activation of extrinsic pathway leads to formation of thrombin
 The intrinsic pathway is triggered by activation of factor XI & leads to
amplification of coagulation cascade with further formation of thrombin
 Excessive coagulation is normally counterbalanced by several anticoagulant
factors
 Anticoagulant factors such as antithrombin III, activated protein C, protein S &
tissue factor pathway inhibitor are decreased in sepsis
 These circumstances push hemostatic balance toward procoagulant state
 Activation of coagulation cascade leads to a consumption of coagulation factors
 The clinical expression of this phenomenon is disseminated intravascular
coagulation (DIC)
 DIC is characterized by a consumptive coagulopathy, which can raise the risk of
bleeding but more commonly in sepsis causes damage by raising the risk of thrombosis
 In sepsis excessive formation of fibrin from thrombin, compounded by
suppression of fibrinolysis & impairment of anticoagulant pathways, leads to widespread
formation of microthrombi
 It has been proposed that these microthrombi cause microcirculatory alterations &
play an integral role in pathogenesis of organ failure

Septic shock

 Shock is defined as failure of cardiovascular system to maintain effective tissue

perfusion
 When shock develops because of a systemic inflammatory response to infection,
it is termed septic shock

PATHOGENESIS
 Septic shock results when infectious microorganisms in bloodstream induce a
profound inflammatory response causing hemodynamic decompensation
 Pathogenesis involves a complex response of cellular activation that triggers
release of a multitude of proinflammatory mediators
 This inflammatory response causes activation of leukocytes & endothelial cells,
as well as activation of coagulation system
 Excessive inflammatory response that characterizes septic shock is driven
primarily by cytokines tumor necrosis factor alpha (TNF-α) & interleukin-1 (IL-1), which
are produced by monocytes in response to an infection
 Although TNF and IL-1 are central to pathophysiology of septic shock,a number
of other vital mediators are also known to play a major role including high-mobility
group box 1 (HMGB1) protein
 Although systemic inflammatory response of sepsis triggers profound
macrocirculatory & microcirculatory changes that impair tissue perfusion, another
important mechanism playing a role in development of acute organ dysfunction in septic
shock is apoptosis (programmed cell death)
 Accelerated apoptosis is a pivotal pathogenic event in this disease

CLINICAL PRESENTATION
 Patients with septic shock will typically manifest signs of systemic inflammation
 Fever
 Tachycardia
 Tachypnea
 Elevation of the white blood cell count

 Although absence of arterial hypotension does not necessarily exclude possibility

of subclinical tissue hypoperfusion,the hallmark of septic shock is arterial hypotension
despite adequate volume resuscitation requiring vasoactive drugs for hemodynamic
support
 Other signs of potential tissue hypoperfusion may include
 Lactic acidosis
 Oliguria
 Encephalopathy
 Diminished capillary refill in the extremities
 Patients with septic shock typically have multiple organ system dysfunctions;
clinical evidence of other organ system dysfunction may range from subtle abnormalities
to overt organ failure
 Multiorgan system involvement in sepsis may include cardiovascular, respiratory,
renal, central nervous system, hepatic, metabolic, or hematologic dysfunction
 Respiratory system - acute lung injury or, in extreme cases, acute respiratory
distress syndrome (ARDS)
 Sepsis-induced renal dysfunction - oliguria & may progress to acute renal failure
requiring dialysis
 Central nervous system dysfunction - encephalopathy, which may range from
mild cognitive impairment to overt coma
 Cholestasis is a common manifestation of hepatic dysfunction in sepsis, but in the
presence of severe shock, ischemic hepatitis (“shock liver”) may occur
 Metabolic derangements of septic shock include a loss of glycemic control (both
hyperglycemia and hypoglycemia) & metabolic acidosis
 Septic shock is commonly associated with a consumptive coagulopathy, which is
likely present in almost all patients at least subclinically but may also manifest clinically
with
 Thrombocytopenia
 Prolongation of prothrombin time
 Disseminated intravascular coagulation

HEMODYNAMIC PROFILE OF SEPTIC SHOCK

 The hemodynamic profile of septic shock is the most complex hemodynamic

profile of all shock etiologies
 Septic shock may have features of
 Hypovolemic shock (poor cardiac filling secondary to severe systemic capillary
leak) and increased venous capacitance
 Cardiogenic shock (severe sepsis-induced myocardial depression)
 Distributive shock (tissue hypoperfusion in the face of an adequate cardiac
output)

Septic shock

 In septic shock, left ventricular blood return is reduced because of a combination

of capillary leak, increased venous capacitance (VC), & increased pulmonary vascular
resistance
 Stroke volume is further compromised by a sepsis-induced decrease in left & right
ventricular (RV) contractility
 Tachycardia & increased left ventricular compliance serve as countermeasures to
combat low cardiac output, latter by increasing left ventricular preload
 However, cardiac output remains low to normal
 Finally, a decrease in arteriolar (systemic vascular) resistance allows a higher
stroke volume at any given contractility & left ventricular filling state, but also potential
for severe hypotension despite restoration of adequate left ventricular filling
Septic shock - Fluid resuscitation
 Aggressive fluid resuscitation compensates for capillary leak, increased venous
capacitance & increased pulmonary vascular resistance by re-establishing adequate left
ventricular blood return
 Decreased arteriolar resistance (AR), tachycardia & increased left ventricular
compliance compensate for decreased ejection fraction
 Ejection fraction increases as left ventricular filling increases
 The net result is that after adequate volume resuscitation, most patients with
severe sepsis have a high cardiac output & low systemic vascular resistance state

Hypovolemia

 As proinflammatory mediators are released into circulation, this causes injury to

integrity of endothelial cell surface throughout systemic microvasculature, resulting in
severe capillary leak & extravasation of fluid into tissues
 Venodilation also compromises venous return
 These are major factors in producing hypovolemia in patient with septic shock
 Septic shock patient may have a markedly decreased cardiac preload, especially in
the initial phase of therapy
 Aggressive resuscitation with intravenous volume expansion modulates
hemodynamic profile of septic shock & allows patient to achieve a hyperdynamic (i.e.,
high cardiac output) state
 Combination of a decreased preload & myocardial depression means that in early
phase of sepsis resuscitation, patients may initially be hypodynamic (i.e., have low
cardiac output) prior to receiving adequate volume resuscitation
 Capillary leak is an ongoing process in course of septic shock therapy, &
therefore hypovolemia may reoccur later in course of disease, even after adequate
cardiac filling has been initially achieved
 Fluid balance (input of intravenous fluids & output of urine) is often an unreliable
parameter for assessing adequacy of fluid resuscitation in septic shock

Myocardial Dysfunction
 Septic shock is associated with depression of biventricular function with a
decrease in ejection fraction
 Ventricular dilation occurs as a compensatory mechanism & raises end-diastolic
volume so that stroke volume can be preserved
 When myocardial dysfunction occurs, a high CO can still be achieved in many
circumstances because of biventricular dilation, tachycardia & arteriolar dilation, as long
as patient is adequately volume resuscitated & does not have a preexisting
cardiomyopathy or severe cardiac suppression

Myocardial Dysfunction
 Most important inflammatory mediators that induce myocardial depression are
TNF-α, IL-1, & nitric oxide
 Coronary blood flow is typically normal or increased in septic shock
 Although coronary blood flow can be diminished by severe arterial hypotension
that compromises coronary perfusion pressure,myocardial ischemia does not appear to be
causative factor of depression in myocardial performance
 Nearly half of patients with septic shock will have echocardiographic evidence of
depressed systolic function, even in absence of preexisting cardiac disease
 However, myocardial depression is typically not judged to be predominant feature
of septic shock hemodynamic profile
 For majority of patients, aggressive volume resuscitation to restore adequate
cardiac filling pressures will be enough to achieve a reasonable cardiac output

Distributive Shock

 Septic shock is characterized by peripheral maldistribution of blood flow to

tissues so that tissue hypoperfusion abnormalities can still persist despite a normal or
high cardiac output - this is called “distributive shock”
 This maldistribution of blood flow may occur at both microcirculatory &
macrocirculatory levels
 At the level of macrocirculation, autoregulation of blood flow within any single
organ system in a normal host can typically maintain effective tissue perfusion over a
wide range of systemic pressures (usually ranging from a MAP of 50 mm Hg to 150 mm
Hg)
 However, there is heterogeneity of blood flow distribution throughout body in
septic shock because of preferential shunting of blood flow to “vital” organs (e.g., brain,
myocardium)
 Gastrointestinal tract may be earliest organ system to experience tissue
hypoperfusion in septic shock, as blood is shunted away from splanchnic circulation in
order to preserve blood flow elsewhere
 Ischemic injury to gastrointestinal tract may be a source of ongoing systemic
inflammation in septic shock

MICROCIRCULATORY & MITOCHONDRIAL DYSFUNCTION

 After restoration of adequate cardiac filling pressures & optimal CO in pts with
septic shock, tissue hypoxia may still occur via a number of pathogenic mechanisms
 These mechanisms of tissue hypoxia in face of a normal or a supranormal CO
may be caused by either
 Microcirculatory failure
 Mitochondrial dysfunction

Microcirculatory Dysfunction

 Microcirculatory dysfunction is a pivotal element of pathogenesis of septic shock

 Macrocirculation - regulate global distribution of blood flow throughout body
 Microcirculation - controls delivery of blood flow to tissues
 Causes of microcirculatory flow alterations in sepsis are multifactorial
 Pan-endothelial cell injury increases microvascular permeability with influx of
proinflammatory cells into tissues; this is hypothesized to be an important pathogenic
step in development of acute system organ dysfunction in sepsis

 Leukocyte adhesion - microvessel endothelial surface - impedes microcirculatory

blood flow
 Endothelial injury also triggers - coagulation cascade,resulting in fibrin deposition
& microvascular thrombosis that may further impair microcirculatory flow
 All of these mechanisms collectively contribute to microcirculatory “failure” in
septic shock

Mitochondrial Dysfunction

 Cellular utilization of oxygen can be markedly impaired in septic shock even after
effective restoration of blood flow to tissues has been achieved, & this has been termed
cytopathic hypoxia
 Proposed mechanisms that result in cytopathic hypoxia in sepsis include
 Diminished delivery of pyruvate into mitochondria
 Inhibition of mitochondrial enzymes
 Activation of poly-adenosine phosphate-ribosyl polymerase (PARP)

MANAGEMENT OF SEPSIS & SEPTIC SHOCK

Management - guidelines

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2008