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Sepsis :

Pathophysiology and
Treatment
Department of Internal Medicine
Medical Faculty
UNISSULA
► Definitions
► Epidemiology
► Pathophysiology
► Treatment
► Future directions
Definitions
Systemic Inflammatory Response
Syndrome (SIRS) :
► Systemic inflammatory response to various
stresses.
► Meets 2 or more of the following criteria (
harus dipenuhi kriteria 2 atau lebih) :
 Temperature of >38 degree C/<36 degree C
 Heart rate of more than 90 beats/min
 RR >20 breaths/min or PaCo2 <32mmHg
 WBC (white blood cell) >12,000/mm3 or
<4000/mm3
Definitions
SEPSIS :
► Evidence of SIRS accompanied by known or suspected
infection.

Severe SEPSIS :
► Sepsis accompanied by hypoperfusion or organ
dysfunction.
► Cardiovascular :
 SBP<90 mmHg/MAP<70 for at least 1 hr despite adequate volume
resuscitation or the use of vasopressors to achieve the same goals.
► Renal :
 Urine output <0.5ml/kg/hr or Acute Renal Failure.
► Pulmonary :
 PaO2/FiO2 <250if other organ dysfuncton is present or <200 if the
lungs is the only dysfunctional organ.
Definitions
Severe SEPSIS (contd) :
► Gastrointestinal :
 Hepatic dysfunction (hyperbilirubinemia,Elevated transaminases
► CNS :
 Alteration in Mental status (delirium)
► Hematologic :
 Platelet count of <80,000/mm3 or decreased by 50% over 3
days/DIC
► Metabolic :
 PH<7.30 or base deficit >5.0mmol/L
 Plasma lactate >1.5 upper limit of normal.

Septic Shock :
► Severe Sepsis with persistent hypoperfusion or
hypotension despite adequate fluid resuscitation
Epidemiology
► Current estimates suggest that over 750,000 cases of
Sepsis are diagnosed annually, resulting in more than
200,000 deaths.
► The incidence rate for Sepsis has been increasing over the
past two decades, driving an increase in the number of
deaths despite a decline in case-fatality rates.
► Sepsis is the tenth leading cause of death in the United
States and accounts for more than 17 billion dollars in
direct healthcare expenditures.
► Risk factors include age > 65 years, male, non-whites.
► A primary site of infection cannot be established in 10% of
patients with severe Sepsis/SIRS.
Consesnsus definition
 2016
a. Sepsis yang baru : tidak ada istilah severe , sepsis adalah kondisi yang
mengancam jiwa , karena ada infeksi yang menyebabkan disregulasi dan
disfungsi organ
- Kriteria 2016 : ada disfungsi organ  peningkatan 2 poin atau lebih
dari SOFA score
- Pasien yang butuh perawatan lama : dipake qSHOFA ( hipotensi ,
gangguan status mental dan takipneu)
b. Septic shoke  adanya gangguan sirkulasi atau selauler/metabolik ,
kriteria klinis :
1. hipotensi persisten  yang sudah diperbaiki
2. Kadar laktat tinggi
-
Epidemiology:
Epidemiology : Mortality rate
Epidemiology

Gram positive bacteria


Gram negative bacteria
Fungi
Martin et al, NEJM 2003; 348:1546
Pathophysiology of Sepsis
Pathophysiology of Sepsis
Disorder Due to Uncontrolled Inflammation?

► Increased inflamatory mediators like IL-1, TNF,


IL-6.
► Based on animal studies.
► In a study in children with meningococcemia, TNF
levels directly correlated with mortality.
► Clinical trials involving TNF anagonist,
antiendotoxin antibodies, IL-1 receptor
antagonists, cortocosteroids failed to show any
benefits.
► Patients with RA treated with TNF antagonist
develop infectious complications.
Pathogenesis of Sepsis
Pathophysiology of Sepsis
Failure of Immune System to Eliminate
Microorganism?

► Shiftfrom inflammatory (ThI) to antiinflammatory


response (Th2).
► Anergy.
► Apotosis of B cells, T cells, Dendritic cells.
► Loss of macrophage expression of MHC Class I
and co-stimulatory molecules.
► Immunosuppressive effect of apoptotic cells.
Pathogenesis of Sepsis
Pathogenesis of Sepsis
Pathogenesis of Sepsis

The dark stained regions are concentrations of B cells in lymphoid follicles


that are visible to the naked eye. The patients with Sepsis have
dramatically smaller and fewer lymphoid follicles than the patients with
trauma.
Pathogenesis of Sepsis
Factors that influence Immune Response :

► Genetic factors, polymorphisms in cytokine genes,


TLR4 mutations, MBP.
► Type of organism, virulence, size of inoculum.
► Host Factors :
 Age, Nutritional status, Coexisting illness,
COPD, CHF, Cancer, DM, Immunodeficiency.
► Therapeutic efforts to modify the host immune
response in critical illness will require a more
thorough understanding of the cytokine milieu and
the factors that determine their production.
Multiple Organ Dysfunction Syndrome
(MODS)
► MODS occurs late and is the most common cause
of death in patients with Sepsis.
► Lactic acidosis led investigators to think that this is
due to tissue ischaemia.
► Minimal cell death in postmortem samples taken
from the failed organs of patients with Sepsis.
► Recovery from Sepsis is associated with near
complete recovery of organ function, even in
organs whose cells have poor regenerative
capacity.
► Increased tissue oxygen tensions in various
organs (muscle, gut, bladder) in animals and
patients with Sepsis.
MODS : Possible Explanations

Mitochondrial Dysfunction

► Mitochondria use > 90% of total body oxygen consumption


for Adenosine TriPhosphate (ATP) generation, a
bioenergetic abnormality is implied.
► Cell and animal data have shown that nitric oxide (and its
metabolites peroxynitrite), produced in considerable
excess in patients with Sepsis, can affect oxidative
phosphorylation by inhibiting several of its component
respiratory enzymes.
► In cell models, the antioxidant GSH has a protective role
against mitochondrial inhibition, particularly for complex I.
Human data are scarce but supportive of these findings.
MODS : Possible Explanations
Increased cellular apoptosis
► Extensive apoptosis of lymphoid cells is a prominent
feature of Sepsis in both human patients and mice.
► Neither apoptosis nor necrosis are prominent features in
other organs (notably the lungs, liver or kidneys) that are
commonly involved in cases of MODS.

Derangements in epithelial
cellular physiology

► Derangements in epithelial cellular physiology lead to


organ dysfunction responsible for late-phase mortality in
Sepsis (e.g., membrane pumps, TJ’s, cytoskeletal proteins,
and cell-surface receptors).
MODS : Possible Explanations
Late acting mediators of Sepsis
► HMGB1 (high mobility group box 1) was identified as a late-acting,
cytokine-like mediator of inflammation and lethality in an animal
model of endotoxemia and Sepsis.
► Neutralizing antibodies against HMGB1 confer significant protection
against LPS- or Sepsis-induced mortality.
► It is elevated in late phase of Sepsis, suggesting that this may play a
role in pathogenesis of MODS.
► Ethyl pyruvate and certain cholinergic agonists, which inhibits
HMGB1 are therapeutic in various animal models of Sepsis even
when given well after the onset of symptoms.
► Increased levels of MIF have been demonstrated in both the plasma
and alveoli of patients with ARDS, suggesting that it may play a role
in the pathogenesis of Sepsis induced organ dysfunction.
► Although it is unlikely that any single mechanism can account for all
forms of organ failure in MODS, it is plausible that some key
molecular events are common factors contributing to cellular
dysfunction in multiple tissues.
MODS
SEPSIS AND ENDOTOXEMIA

AVP and Insulin Activated


Hydrocortisone Protein C

Hypotension,
Increased Hyperglycemia Disseminated
Catecholamines and Intravascular
Pressor Resistance to Coagulation
Norepinephrine and
Angiotensin II
Glomerular and
Renal WBC Dysfunction
Vascular
Ischemia and Inflammation
Microthrombosis

Early Hydrocortisone
Resuscitation

ACUTE RENAL FAILURE


Surviving Sepsis Implementation:
“Care Bundles”
• 6 Hour Sepsis Bundle
1. Measure serum lactate ► 24 Hour Bundle
2. Blood cultures prior to Abx 1. Steroids as needed
3. Broad spectrum Abx (3hrs) 2. APC if indicated
4. If hypotensive or lactate>4 3. Tight glycemic
 Fluid bolus
control
 Vasopressors for MAP> 65
5. If persistent BP<65 or 4. Maintain plateau
Lactate >4 pressure <30
 Achieve CVP>8
 SVO2 >65
Sepsis Resuscitation Bundle
► The following steps should be completed as soon as possible (within 6 hours) after
identification of a patient that has a positive SIRS screening
► Serum lactate measured
► Blood Cultures obtained
Appropriate antibiotics administered
► If Lactate >4, SBP<90 or SBP decreased >30 mm Hg (Severe Sepsis):
► Give 20 ml/kg IVF bolus and assess need for CVP monitoring
► If responsive to fluids
 continue aggressive IVFs as indicated
 recheck lactate q 4 hours X 3
 consider SAC transfer
► If unresponsive to fluids
 Transfer to MICU

► Place arterial and central lines


 Repeat fluid bolus 0.5-1L until CVP 8-12 mm Hg
► Apply vasopressors for hypotension not responding to initial fluid resuscitation to
maintain mean arterial pressure > 65 mmHg
Treatment of Sepsis
► Early recognition of the Sepsis syndrome.
► Prompt administration of broad-spectrum
antibiotics.
► Surgical intervention when indicated.
► Aggressive supportive care in intensive care units.
► Steroids
► Tight glycemic control.
► Activated protein C
► Newer therapies.
Eradication of Infection
► Identification of septic focus (history, physical examination,
imaging, cultures). Blood cultures, urine culture, sputum
culture, abscess culture.
► I.V. antibiotics should be initiated as soon as cultures are
drawn.
► Patients with severe Sepsis should receive broadspectrum
antibiotic covering both gram positive and gram negative
organism.
► Empiric antifungal drug if patient had received antimicrobial
treatment. Neutropenic patients, DM, Chronic steroids.
► There is limited evidence to support the use of combination
therapy except in neutropenic patients.
► Many experts would also consider extended spectrum
beta-lactamase inhibitor to be effective.
► In centers with high prevalence of MRSA, Vancomycin
should be added if they have IV catheter and develop
severe Sepsis.
Choice of Antibiotics
If pseudomonas is an unlikely pathogen, combine
vancomycin with one of the following:
► Cephalosporin, 3rd or 4th generation (e.g., ceftriaxone, cefotaxime, or
cefepime).
► Beta-lactam/beta-lactamase inhibitor (e.g., ampicillin-sulbactam).
► Fluroquinolones (eg., Levofloxacin, gatifloxacin, moxifloxacin.)

If pseudomonas is suspected, combine vancomycin with two


of the following :
► Antipseudomonal cephalosporin (e.g., cefepime, ceftazidime, or
cefoperazone).
► Antipseudomonal carbapenem (eg, imipenem, meropenem).
► Antipseudomonal beta-lactam/beta-lactamase inhibitor (e.g., pipercillin-
tazobactam,ticarcillin-clavulanate).
► Aminoglycoside (e.g., gentamicin, amikacin, tobramycin).
► Fluoroquinolone with good anti-pseudomonal activity (e.g.,
ciprofloxacin).
► Monobactam (e.g., aztreonam).
Antibiotics dosing
► Dosage for intravenous administration (normal
renal function).
► Imipenem-cilastin 0.5 g q 6h
► Meropenem 1.0 g q 8h
► Piperacillin-tazobactam 3.375 g q 4h or 4.5 g q 6h
► Cefepime1-2 q 8hr
► Gatifloxacin 400 mg iv q d
► Ceftriaxone 2.0 g q 24hr
► Levofloxacin500 mg q d
Airway
Assess the airway, respiration, and
perfusion

► ARDS/ALI causes respiratory failure in patients


with severe Sepsis.
► Supplemental oxygenation, Ventilator for
respiratory failure, airway protection.
► Etomidate can cause adrenal insufficiency via
inhibition of glucocorticoid synthesis, which may
contribute to increased mortality in patients with
Sepsis.
Treatment of Hypotension
► Volume Resuscitation:
 Hypotension in severe Sepsis and septic shock results from a loss of
plasma volume into the interstitial space, decreases in vascular tone, and
myocardial depression.
 An arterial catheter may be inserted if blood pressure is labile.

► Intravenous fluids : Crystalloids vs. Colloids.


 Goals for initial resuscitation include :
► Central venous pressure 8 to 12 mmHg.
► Mean arterial pressure 65 mmHg.
► Urine output 0.5 mL per kg per hr.
► Central venous or mixed venous oxygen saturation 70%.
► Pulmonary capillary wedge pressure exceeds 18 mmHg.
► Volume status, tissue perfusion, blood pressure, and the presence or absence
of pulmonary edema must be assessed before and after each bolus.

► Pressors, if above measures fail.


► PRBC’s.
Fluid Therapy

► No mortality difference between colloid vs. crystalloid


► In severe sepsis patients (N=1218): mortality 35.3%
(NS) vs. 30.7% (alb)… 95% CI .74-1.02 p=0.09
Corticosteroids
► Anti-inflammatory actions such as inhibiting the production of
proinflammatory cytokines, enhancing the release of anti-inflammatory
mediators.
► Decreasing the function and migration of inflammatory cells.
► Maintains BP by upregulation of adrenergic receptors.
► Patients with Septic shock has relative adrenal insufficiency despite
elevated levels of cortisol.
► Cosyntropin stim test – Cortisol of < 9 mcg/dl identifies patients with
relative adrenal insufficiency.
► In 2001, studies showed that physiologic doses of steroids are useful in
patients with refractory shock.
► Administration of replacement-dose corticosteroids (50 mg of
Hydrocortisone IV q 6hrs with fludrocortisone 50mcg NGTfor 7 days)
improved refractory hypotension and (63% vs 73% mortality; P =
0.02),in patients with relative adrenal insufficiency.
► But only in patients with relative adrenal insufficiency (defined as an
increase of serum cortisol in response to the corticotropin stimulation
test of 9 mg/dL or less).
Treatment
Tight Glycemic control
► A decreased release of insulin, increased release of hormones with
effects countering insulin, and increased insulin resistance combine to
produce stress hyperglycemia in many critically ill patients.
► Hyperglycemia diminishes the ability of neutrophils and macrophages
to combat infections. Also insulin possesses antiapoptotic effects.
► A large, single-center, randomized trial of more than 1500 critically ill
patients demonstrated that, maintaining serum glucose levels between
80 and 110 mg/dL (mean morning glucose of 103 mg/dL) through the
use of a continuous insulin infusion decreased mortality (4.6% vs 8%;
P < 0.04), development of renal failure (P = 0.04), and episodes of
septicemia (P = 0.003), compared with conventional treatment (mean
morning glucose of 153 mg/dL.
► Physicians liberalize their insulin treatment to keep blood glucose
levels less than 150 mg/dL due to concerns of hypoglycemia.
► Studies are needed to determine whether less tight control of blood
glucose — for example, a blood glucose level of 120 to 160 mg per
deciliter (6.7 to 8.9 mmol per liter) — provides similar benefits.
Activated Protein C
Activated Protein C
► Mechanism of action:
 antithrombotic, antiinflammatory, profibrinolytic.
► PROWESS Trial:
 1690 randomly assigned to placebo or DAA, 28-day mortality rate was
significantly lower in the drotrecogin-treated group (24.7% vs. 30.8%).
► rhAPC decreased mortality rates consistently across all
demographic subgroups defined by age, sex, race, and
geographic region of treatment, compared with placebo.
► In 2001, FDA approved the use of drotrecogin alfa (activated
DAA ) for the treatment of severe Sepsis.
► DAA produced the largest benefit in the sickest subgroups, with
an absolute mortality reduction of 7.4% in patients with more
than one organ dysfunction and 13% (P = 0.0002) in patients
with APACHE II scores totaling more than 24.
► The treatment was effective regardless of age, severity of
illness, the number of dysfunctional organs or systems, the site
of infection (pulmonary or extrapulmonary), and the type of
infecting organism (gram-positive, gram-negative, or mixed.
Activated Protein C
Drawbacks:

► Change in study protocol, drug preparations, APACHE scoring.


► Increased risk of bleeding including fatal intracranial hemorrhage, in
patients receiving DAA.
► The study excluded these groups of patients :
 Higher risk of bleeding, INR > 3.0, hypercoaguble states.
 Chronic liver disease, pancreatitis.
 Chronic renal failure who were dependent on dialysis.
 Recent surgery, organ-transplant recipients, HIV with CD4 < 50 cells.
 Patients with thrombocytopenia (defined as a platelet count of less than
30,000 per cubic mm).
 Those who had taken acetylsalicylic acid at a dose of > 650 mg per day
within three days before the study.
 Age <18 years, weight > 135kg.
► Many patients with severe Sepsis meet one or more of these criteria.
► Further studies will be needed to assess the safety of activated protein
C in these groups of patients.
Adjunctive therapies
TNF antagonist.
► Murine anticlonal antibody.
► NORASEPTII RCT 1879 patients randomly assigned to murine
monoclonal antibodies (40.7% vs42.8%), effective in patients with a IL-
6 > 1000pg/ml.
► Two large phase III studies are currently underway to determine the
effects of the murine IgG3 monoclonal antibody to TNF-a and of the
p55 TNF receptor fusion protein construct in patients with Sepsis.

Pentoxyphylline.
► Inhibits synthesis of TNF.
► Inhibits neutrophil activation and downregulates adhesion molecules.
► Randomized placebo controlled trial 51 patients pentoxyphylline vs
saline infusion (30% vs. 33%)
► A decrease in the multiple organ dysfunction score, which was noted at
day 4 and reached statistical significance (P < 0.05) at day 14 in the
patients who received pentoxifylline.
► Pentoxifylline significantly affects the synthesis of TNF and IL-6 as well
as reduces the mortality rate in premature infants with Sepsis.
Adjunctive therapies
IL -1 receptor Antagonist

► IL-1 induces fever, constitutional symptoms, and hypotension.


► An initial trial of IL-1 receptor antagonist in 99 human subjects
demonstrated a dose-dependent improvement in 28-day mortality (44%
vs. 16% ) correlated with IL-6 levels.
► A subsequent trial with 893 patients with Sepsis syndrome revealed a
trend towards improved 28-day mortality that did not achieve statistical
significance, although a retrospective analysis of the data suggested
that those patients with the highest predicted mortality (24% or greater)
benefited most from the treatment and experienced a significant
reduction in mortality at 28 days (45% in the placebo group versus 35%
in the patients receiving 2 mg/kg/h of IL-1 receptor antagonist; P =
0.005).
Adjunctive therapies
Interleukin-10

► Interleukin-10 is a prominent mediator of the anti-inflammatory cascade


► Decrease serum concentrations of TNF and IL-1.
► In experimental animal models, administration of exogenous IL-10
protected against death in the setting of endotoxemia and
staphylococcal enterotoxin injection .Alternatively, antibodies directed
against IL-10 will increase mortality in a similar clinical situation.
► Further studies are needed to define the utility of IL-10 in the treatment
of Sepsis.
Adjunctive therapies

HA-1A

► Multicenter trials involving more than 1500 patients randomly assigned


to HA-1A or placebo within six hours of the onset of septic shock, the
antibody had no effect upon 14-day mortality.
► Monoclonal antibody TLR-2Inhibition of toll-like receptor (TLR)-2 with a
neutralizing antibody successfully prevented lethal septic shock in a
murine model, even when given three hours after initiation of systemic
inflammation.
Adjunctive therapies

Cytokine agents:
► Interferon-gamma
 In patients with defective monocyte functions, shown
benefit, needs larger trials.
► Granulocyte colony stimulating factor
 Studies not shown benefit in RCT of non neutropenic
patients.
► Granulocyte-macrophage colony stimulating factor
 Small phase 11 trial in 18 septic patients did not show
any benefit.
Adjunctive therapies
► Anti-MIF antibody
 MIF levels correlate with outcome among patients with Sepsis, and
human trials of anti-MIF antibody therapy are underway.
► Antithrombin
 There was no significant benefit in mortality in patients receiving
AT at 28, 56, or 90 days, or in survival time within the intensive
care unit.
► Tissue factor pathway inhibitor
 Serine protease inhibitor that impairs the ability of tissue factor
(thromboplastin) to initiate the coagulation cascade large
multicenter randomized controlled trial (OPTIMIST) failed to show
any improvement in outcome when patients treated with tifacogin
were compared to control patients.
Potential Therapies
► Antibodies against complement-activation product C5a decreased the
frequency of bacteremia, prevented apoptosis, and improved survival.
► Antibodies against macrophage migration inhibitory factor protected
mice from peritonitis.
► Strategies that block apoptosis of lymphocytes or gastrointestinal
epithelial cells have improved survival in experimental models of
Sepsis.
► Mice with Sepsis that are deficient in poly–ADP–ribose polymerase 1
(PARP) have improved survival, and administration of a PARP inhibitor
was beneficial in pig models.
► Electrical stimulation of the vagus nerve protects against endotoxic
shock.
► HMGB1, neutralizing antibodies against HMGB1 confer significant
protection against LPS- or Sepsis-induced mortality.
Conclusions…
► The incidence of Sepsis is increasing.
► Possible contributing factors :
 Use of antibiotics leading to microbial resistance
 More invasive procedures
 Increasing use of immunosuppressants.
► There have been new insights into the pathogenesis of
Sepsis which could be potential therapeutic targets in the
future.
► Treatment of Sepsis includes early institution of
antibiotics, volume resuscitation, tight glycemic control,
steroids protein C when indicated.