sepsis : pathophysiology and treatment sepsis : pathophysiology and treatment zainab abdulla april...

Sepsis :Sepsis :Pathophysiology and Pathophysiology and

TreatmentTreatment

Zainab AbdullaZainab Abdulla

April 25, 2006April 25, 2006

►DefinitionsDefinitions►EpidemiologyEpidemiology►PathophysiologyPathophysiology►TreatmentTreatment►Future directionsFuture directions

DefinitionsDefinitionsSystemic Inflammatory ResponseSystemic Inflammatory Response

Syndrome (SIRS) :Syndrome (SIRS) :► Systemic inflammatory response to various Systemic inflammatory response to various

stresses.stresses.► Meets 2 or more of the following criteria :Meets 2 or more of the following criteria :

Temperature of >38C/<36degree CTemperature of >38C/<36degree C Heart rate of more than 90 beats/minHeart rate of more than 90 beats/min RR >20 breaths/min or PaCo2 <32mmHgRR >20 breaths/min or PaCo2 <32mmHg WBC >12,000/mm3 or <4000/mm3WBC >12,000/mm3 or <4000/mm3

DefinitionsDefinitionsSEPSIS :SEPSIS :► Evidence of SIRS accompanied by known or suspected Evidence of SIRS accompanied by known or suspected

infection.infection.

Severe SEPSIS :Severe SEPSIS :► Sepsis accompanied by hypoperfusion or organ Sepsis accompanied by hypoperfusion or organ

dysfunction.dysfunction.► Cardiovascular : Cardiovascular :

SBP<90mmhg/MAP<70 for at least 1 hr despite SBP<90mmhg/MAP<70 for at least 1 hr despite adequate volume adequate volume resuscitation or the use of vasopressors to achieve the same goals.resuscitation or the use of vasopressors to achieve the same goals.

► Renal : Renal : Urine output <0.5ml/kg/hr or Acute Renal Failure.Urine output <0.5ml/kg/hr or Acute Renal Failure.

► Pulmonary : Pulmonary : PaO2/FiO2 <250if other organ dysfuncton is present or <200 if the PaO2/FiO2 <250if other organ dysfuncton is present or <200 if the

lungs is the only dysfunctional organ.lungs is the only dysfunctional organ.

Severe SEPSIS (contd) :Severe SEPSIS (contd) :► Gastrointestinal : Gastrointestinal :

Hepatic dysfunction (hyperbilirubinemia,Elevated transaminasesHepatic dysfunction (hyperbilirubinemia,Elevated transaminases► CNS : CNS :

Alteration in Mental status (delirium)Alteration in Mental status (delirium)► Hematologic : Hematologic :

Platelet count of <80,000/mm3 or decreased by 50% over 3 Platelet count of <80,000/mm3 or decreased by 50% over 3 days/DICdays/DIC

► Metabolic : Metabolic : PH<7.30 or base deficit >5.0mmol/LPH<7.30 or base deficit >5.0mmol/L Plasma lactate >1.5 upper limit of normal.Plasma lactate >1.5 upper limit of normal.

Septic Shock :Septic Shock :► Severe Sepsis with persistent hypoperfusion or Severe Sepsis with persistent hypoperfusion or

hypotension despite adequate fluid resuscitationhypotension despite adequate fluid resuscitation

DefinitionsDefinitions

EpidemiologyEpidemiology

► Current estimates suggest that over 750,000 cases of Current estimates suggest that over 750,000 cases of Sepsis are diagnosed annually, resulting in more than Sepsis are diagnosed annually, resulting in more than 200,000 deaths.200,000 deaths.

► The incidence rate for Sepsis has been increasing over the The incidence rate for Sepsis has been increasing over the past two decades, driving an increase in the number of past two decades, driving an increase in the number of deaths despite a decline in case-fatality rates.deaths despite a decline in case-fatality rates.

► Sepsis is the tenth leading cause of death in the United Sepsis is the tenth leading cause of death in the United States and accounts for more than 17 billion dollars in States and accounts for more than 17 billion dollars in direct healthcare expenditures.direct healthcare expenditures.

► Risk factors include age > 65 years, male, non-whites. Risk factors include age > 65 years, male, non-whites. ► A primary site of infection cannot be established in 10% of A primary site of infection cannot be established in 10% of

patients with severe Sepsis/SIRS.patients with severe Sepsis/SIRS.

Epidemiology:Epidemiology:

Epidemiology : Mortality rateEpidemiology : Mortality rate

Epidemiology : Causative Epidemiology : Causative organismorganism

Pathophysiology of SepsisPathophysiology of Sepsis


Disorder Due to Uncontrolled Inflammation?Disorder Due to Uncontrolled Inflammation?

► Increased inflamatory mediators like IL-1, TNF, Increased inflamatory mediators like IL-1, TNF, IL-6.IL-6.

► Based on animal studies.Based on animal studies.► In a study in children with meningococcemia, TNF In a study in children with meningococcemia, TNF

levels directly correlated with mortality.levels directly correlated with mortality.► Clinical trials involving TNF anagonist, antiendotoxin Clinical trials involving TNF anagonist, antiendotoxin

antibodies, IL-1 receptor antagonists, cortocosteroids antibodies, IL-1 receptor antagonists, cortocosteroids failed to show any benefits.failed to show any benefits.

► Patients with RA treated with TNF antagonist develop Patients with RA treated with TNF antagonist develop infectious complications.infectious complications.

Pathogenesis of SepsisPathogenesis of Sepsis

Failure of Immune System to EliminateFailure of Immune System to EliminateMicroorganism?Microorganism?

► Shift from inflammatory (ThI) to antiinflammatory Shift from inflammatory (ThI) to antiinflammatory response (Th2).response (Th2).

► Anergy.Anergy.► Apotosis of B cells, T cells, Dendritic cells.Apotosis of B cells, T cells, Dendritic cells.► Loss of macrophage expression of MHC Class I Loss of macrophage expression of MHC Class I

and co-stimulatory molecules. and co-stimulatory molecules. ► Immunosuppressive effect of apoptotic cells.Immunosuppressive effect of apoptotic cells.



The dark stained regions are concentrations of B cells in lymphoid follicles The dark stained regions are concentrations of B cells in lymphoid follicles that are visible to the naked eye. The patients with Sepsis have that are visible to the naked eye. The patients with Sepsis have dramatically smaller and fewer lymphoid follicles than the patients with dramatically smaller and fewer lymphoid follicles than the patients with trauma.trauma.


Factors that influence Immune Response :Factors that influence Immune Response :

► Genetic factors, polymorphisms in cytokine genes, Genetic factors, polymorphisms in cytokine genes, TLR4 mutations, MBP.TLR4 mutations, MBP.

► Type of organism, virulence, size of inoculum.Type of organism, virulence, size of inoculum.► Host Factors : Host Factors :

Age, Nutritional status, Coexisting illness, COPD, Age, Nutritional status, Coexisting illness, COPD, CHF, Cancer, DM, Immunodeficiency.CHF, Cancer, DM, Immunodeficiency.

► Therapeutic efforts to modify the host immune response Therapeutic efforts to modify the host immune response in critical illness will require a more thorough in critical illness will require a more thorough understanding of the cytokine milieu and the factors that understanding of the cytokine milieu and the factors that determine their production. determine their production.

Multiple Organ Dysfunction Syndrome Multiple Organ Dysfunction Syndrome (MODS)(MODS)

► MODS occurs late and is the most common cause MODS occurs late and is the most common cause of death in patients with Sepsis.of death in patients with Sepsis.

► Lactic acidosis led investigators to think that this is Lactic acidosis led investigators to think that this is due to tissue ischaemia.due to tissue ischaemia.

► Minimal cell death in postmortem samples taken Minimal cell death in postmortem samples taken from the failed organs of patients with Sepsis. from the failed organs of patients with Sepsis.

► Recovery from Sepsis is associated with near Recovery from Sepsis is associated with near complete recovery of organ function, even in complete recovery of organ function, even in organs whose cells have poor regenerative organs whose cells have poor regenerative capacity. capacity.

► Increased tissue oxygen tensions in various Increased tissue oxygen tensions in various organs (muscle, gut, bladder) in animals and organs (muscle, gut, bladder) in animals and patients with Sepsis.patients with Sepsis.

Mitochondrial DysfunctionMitochondrial Dysfunction ► Mitochondria use > 90% of total body oxygen consumption Mitochondria use > 90% of total body oxygen consumption

for Adenosine TriPhosphate (ATP) generation, a for Adenosine TriPhosphate (ATP) generation, a bioenergetic abnormality is implied.bioenergetic abnormality is implied.

► Cell and animal data have shown that nitric oxide (and its Cell and animal data have shown that nitric oxide (and its metabolites peroxynitrite), produced in considerable excess metabolites peroxynitrite), produced in considerable excess in patients with Sepsis, can affect oxidative in patients with Sepsis, can affect oxidative phosphorylation by inhibiting several of its component phosphorylation by inhibiting several of its component respiratory enzymes.respiratory enzymes.

► In cell models, the antioxidant GSH has a protective role In cell models, the antioxidant GSH has a protective role against mitochondrial inhibition, particularly for complex I. against mitochondrial inhibition, particularly for complex I. Human data are scarce but supportive of these findings.Human data are scarce but supportive of these findings.

MODS : MODS : PossiblePossible Explanations Explanations

Increased cellular apoptosisIncreased cellular apoptosis

► Extensive apoptosis of lymphoid cells is a prominent Extensive apoptosis of lymphoid cells is a prominent feature of Sepsis in both human patients and mice.feature of Sepsis in both human patients and mice.

► Neither apoptosis nor necrosis are prominent features in Neither apoptosis nor necrosis are prominent features in other organs (notably the lungs, liver or kidneys) that are other organs (notably the lungs, liver or kidneys) that are commonly involved in cases of MODS.commonly involved in cases of MODS.

MODS : Possible ExplanationsMODS : Possible Explanations

Derangements in epithelialDerangements in epithelial

cellular physiologycellular physiology

► Derangements in epithelial cellular physiology lead to Derangements in epithelial cellular physiology lead to organ dysfunction responsible for late-phase mortality in organ dysfunction responsible for late-phase mortality in Sepsis (e.g., membrane pumps, TJ’s, cytoskeletal proteins, Sepsis (e.g., membrane pumps, TJ’s, cytoskeletal proteins, and cell-surface receptors). and cell-surface receptors).

Late acting mediators of SepsisLate acting mediators of Sepsis

► HMGB1 (high mobility group box 1) was identified as a late-acting, HMGB1 (high mobility group box 1) was identified as a late-acting, cytokine-like mediator of inflammation and lethality in an animal cytokine-like mediator of inflammation and lethality in an animal model of endotoxemia and Sepsis.model of endotoxemia and Sepsis.

► Neutralizing antibodies against HMGB1 confer significant protection Neutralizing antibodies against HMGB1 confer significant protection against LPS- or Sepsis-induced mortality.against LPS- or Sepsis-induced mortality.

► It is elevated in late phase of Sepsis, suggesting that this may play a It is elevated in late phase of Sepsis, suggesting that this may play a role in pathogenesis of MODS.role in pathogenesis of MODS.

► Ethyl pyruvate and certain cholinergic agonists, which inhibits Ethyl pyruvate and certain cholinergic agonists, which inhibits HMGB1 are therapeutic in various animal models of Sepsis even HMGB1 are therapeutic in various animal models of Sepsis even when given well after the onset of symptoms.when given well after the onset of symptoms.

► Increased levels of MIF have been demonstrated in both the plasma Increased levels of MIF have been demonstrated in both the plasma and alveoli of patients with ARDS, suggesting that it may play a role and alveoli of patients with ARDS, suggesting that it may play a role in the pathogenesis of Sepsis induced organ dysfunction.in the pathogenesis of Sepsis induced organ dysfunction.

► Although it is unlikely that any single mechanism can account for all Although it is unlikely that any single mechanism can account for all forms of organ failure in MODS, it is plausible that some key forms of organ failure in MODS, it is plausible that some key molecular events are common factors contributing to cellular molecular events are common factors contributing to cellular dysfunction in multiple tissues. dysfunction in multiple tissues.

MODS : Possible ExplanationsMODS : Possible Explanations

MODSMODS

Treatment of SepsisTreatment of Sepsis► Early recognition of the Sepsis syndrome.Early recognition of the Sepsis syndrome.► Prompt administration of broad-spectrum Prompt administration of broad-spectrum

antibiotics.antibiotics.► Surgical intervention when indicated.Surgical intervention when indicated.► Aggressive supportive care in intensive care units.Aggressive supportive care in intensive care units.► SteroidsSteroids► Tight glycemic control.Tight glycemic control.► Activated protein CActivated protein C► Newer therapies.Newer therapies.

Eradication of InfectionEradication of Infection► Identification of septic focus (history, physical examination, Identification of septic focus (history, physical examination,

imaging, cultures). Blood cultures, urine culture, sputum imaging, cultures). Blood cultures, urine culture, sputum culture, abscess culture.culture, abscess culture.

► I.V. antibiotics should be initiated as soon as cultures are I.V. antibiotics should be initiated as soon as cultures are drawn.drawn.

► Patients with severe Sepsis should receive broadspectrum Patients with severe Sepsis should receive broadspectrum antibiotic covering both gram positive and gram negative antibiotic covering both gram positive and gram negative organism.organism.

► Empiric antifungal drug if patient had received antimicrobial Empiric antifungal drug if patient had received antimicrobial treatment. Neutropenic patients, DM, Chronic steroids.treatment. Neutropenic patients, DM, Chronic steroids.

► There is limited evidence to support the use of combination There is limited evidence to support the use of combination therapy except in neutropenic patients.therapy except in neutropenic patients.

► Many experts would also consider extended spectrum beta-Many experts would also consider extended spectrum beta-lactamase inhibitor to be effective.lactamase inhibitor to be effective.

► In centers with high prevalence of MRSA, Vancomycin In centers with high prevalence of MRSA, Vancomycin should be added if they have IV catheter and develop severe should be added if they have IV catheter and develop severe Sepsis.Sepsis.

Choice of AntibioticsChoice of AntibioticsIf pseudomonas is an unlikely pathogen, combineIf pseudomonas is an unlikely pathogen, combinevancomycinvancomycin with one of the following: with one of the following:► Cephalosporin, 3rd or 4th generation (e.g., Cephalosporin, 3rd or 4th generation (e.g., ceftriaxoneceftriaxone, , cefotaximecefotaxime, or , or

cefepimecefepime).).► Beta-lactam/beta-lactamase inhibitor (e.g., Beta-lactam/beta-lactamase inhibitor (e.g., ampicillin-sulbactamampicillin-sulbactam).).► Fluroquinolones (eg., Levofloxacin, gatifloxacin, moxifloxacin.)Fluroquinolones (eg., Levofloxacin, gatifloxacin, moxifloxacin.)

If pseudomonas is suspected, combine If pseudomonas is suspected, combine vancomycin with two with twoof the following :of the following :► Antipseudomonal cephalosporin (e.g., Antipseudomonal cephalosporin (e.g., cefepimecefepime, , ceftazidimeceftazidime, or , or

cefoperazone).cefoperazone).► Antipseudomonal carbapenem (eg, imipenem, Antipseudomonal carbapenem (eg, imipenem, meropenemmeropenem).).► Antipseudomonal beta-lactam/beta-lactamase inhibitor (e.g., pipercillin-Antipseudomonal beta-lactam/beta-lactamase inhibitor (e.g., pipercillin-

tazobactam,tazobactam,ticarcillin-clavulanateticarcillin-clavulanate).).► Aminoglycoside (e.g., Aminoglycoside (e.g., gentamicingentamicin, , amikacinamikacin, , tobramycintobramycin).).► Fluoroquinolone with good anti-pseudomonal activity (e.g., Fluoroquinolone with good anti-pseudomonal activity (e.g.,

ciprofloxacinciprofloxacin).).► Monobactam (e.g., Monobactam (e.g., aztreonamaztreonam). ).

Antibiotics dosing Antibiotics dosing

► Dosage for intravenous administration (normal Dosage for intravenous administration (normal renal function).renal function).

► Imipenem-cilastin 0.5g q 6hImipenem-cilastin 0.5g q 6h► Meropenem 1.0g q 8hMeropenem 1.0g q 8h► Piperacillin-tazobactam 3.375gq 4h or 4.5 g q 6hPiperacillin-tazobactam 3.375gq 4h or 4.5 g q 6h► Cefepime1-2 q 8hrCefepime1-2 q 8hr► Gatifloxacin 400mg iv q dGatifloxacin 400mg iv q d► Ceftriaxone 2.0g q 24hrCeftriaxone 2.0g q 24hr► Levofloxacin500mg q dLevofloxacin500mg q d

AirwayAirwayAssess the airway, respiration, and Assess the airway, respiration, and

perfusionperfusion

► ARDS/ALI causes respiratory failure in patients ARDS/ALI causes respiratory failure in patients with severe Sepsis.with severe Sepsis.

► Supplemental oxygenation, Ventilator for Supplemental oxygenation, Ventilator for respiratory failure, airway protection. respiratory failure, airway protection.

► Etomidate can cause adrenal insufficiency via Etomidate can cause adrenal insufficiency via inhibition of glucocorticoid synthesis, which may inhibition of glucocorticoid synthesis, which may contribute to increased mortality in patients with contribute to increased mortality in patients with Sepsis.Sepsis.

Treatment of HypotensionTreatment of Hypotension► Volume Resuscitation: Volume Resuscitation:

Hypotension in severe Sepsis and septic shock results from a loss of Hypotension in severe Sepsis and septic shock results from a loss of plasma volume into the interstitial space, decreases in vascular tone, and plasma volume into the interstitial space, decreases in vascular tone, and myocardial depression.myocardial depression.

An arterial catheter may be inserted if blood pressure is labile.An arterial catheter may be inserted if blood pressure is labile.

► Intravenous fluids : Crystalloids vs. Colloids.Intravenous fluids : Crystalloids vs. Colloids. Goals for initial resuscitation include :Goals for initial resuscitation include :

► Central venous pressure 8 to 12 mmHg.Central venous pressure 8 to 12 mmHg.► Mean arterial pressure 65 mmHg.Mean arterial pressure 65 mmHg.► Urine output 0.5 mL per kg per hr.Urine output 0.5 mL per kg per hr.► Central venous or mixed venous oxygen saturation 70%.Central venous or mixed venous oxygen saturation 70%.► Pulmonary capillary wedge pressure exceeds 18 mmHg.Pulmonary capillary wedge pressure exceeds 18 mmHg.► Volume status, tissue perfusion, blood pressure, and the presence or absence Volume status, tissue perfusion, blood pressure, and the presence or absence

of pulmonary edema must be assessed before and after each bolus.of pulmonary edema must be assessed before and after each bolus.

► Pressors, if above measures fail. Pressors, if above measures fail. ► PRBC’s.PRBC’s.

CoticosteroidsCoticosteroids► Anti-inflammatory actions such as inhibiting the production of Anti-inflammatory actions such as inhibiting the production of

proinflammatory cytokines, enhancing the release of anti-inflammatory proinflammatory cytokines, enhancing the release of anti-inflammatory mediators.mediators.

► Decreasing the function and migration of inflammatory cells.Decreasing the function and migration of inflammatory cells.► Maintains BP by upregulation of adrenergic receptors. Maintains BP by upregulation of adrenergic receptors. ► Patients with Septic shock has relative adrenal insufficiency despite Patients with Septic shock has relative adrenal insufficiency despite

elevated levels of cortisol.elevated levels of cortisol.► Cosyntropin stim test – Cortisol of < 9mcg/dl identifies patients with Cosyntropin stim test – Cortisol of < 9mcg/dl identifies patients with

relative adrenal insufficiency. relative adrenal insufficiency. ► In 2001, studies showed that physiologic doses of steroids are useful in In 2001, studies showed that physiologic doses of steroids are useful in

patients with refractory shock.patients with refractory shock.► Administration of replacement-dose corticosteroids(50mg of Administration of replacement-dose corticosteroids(50mg of

Hydrocortisone IV q 6hrs with fludrocortisone 50mcg NGTfor 7 days) Hydrocortisone IV q 6hrs with fludrocortisone 50mcg NGTfor 7 days) improved refractory hypotension and (63% vs 73% mortality; improved refractory hypotension and (63% vs 73% mortality; P P = = 0.02),in patients with relative adrenal insufficiency.0.02),in patients with relative adrenal insufficiency.

► But only in patients with relative adrenal insufficiency (defined as an But only in patients with relative adrenal insufficiency (defined as an increase of serum cortisol in response to the corticotropin stimulation increase of serum cortisol in response to the corticotropin stimulation test of 9 mg/dL or less).test of 9 mg/dL or less).

► Unanswered questions :Unanswered questions :

What defines adrenal dysfunction? High dose ACTH, What defines adrenal dysfunction? High dose ACTH, Low dose ACTH test?Low dose ACTH test?

How long should treatment continue once shock has How long should treatment continue once shock has resolved? resolved?

Taper Steroids?Taper Steroids? Role of Fludrocortisone?Role of Fludrocortisone?

Role of CoticosteroidsRole of Coticosteroids

TreatmentTreatment

Tight Glycemic controlTight Glycemic control

► A decreased release of insulin, increased release of hormones with A decreased release of insulin, increased release of hormones with effects countering insulin, and increased insulin resistance combine to effects countering insulin, and increased insulin resistance combine to produce stress hyperglycemia in many critically ill patients.produce stress hyperglycemia in many critically ill patients.

► Hyperglycemia diminishes the ability of neutrophils and macrophages Hyperglycemia diminishes the ability of neutrophils and macrophages to combat infections. Also insulin possesses antiapoptotic effects.to combat infections. Also insulin possesses antiapoptotic effects.

► A large, single-center, randomized trial of more than 1500 critically ill A large, single-center, randomized trial of more than 1500 critically ill patients demonstrated that, maintaining serum glucose levels between patients demonstrated that, maintaining serum glucose levels between 80 and 110 mg/dL (mean morning glucose of 103 mg/dL) through the 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%; use of a continuous insulin infusion decreased mortality (4.6% vs 8%; P P < 0.04), development of renal failure (< 0.04), development of renal failure (P P = 0.04), and episodes of = 0.04), and episodes of septicemia (septicemia (P P = 0.003), compared with conventional treatment (mean = 0.003), compared with conventional treatment (mean morning glucose of 153 mg/dL.morning glucose of 153 mg/dL.

► Physicians liberalize their insulin treatment to keep blood glucose Physicians liberalize their insulin treatment to keep blood glucose levels less than 150 mg/dL due to concerns of hypoglycemia.levels less than 150 mg/dL due to concerns of hypoglycemia.

► Studies are needed to determine whether less tight control of blood Studies are needed to determine whether less tight control of blood glucose — for example, a blood glucose level of 120 to 160 mg per 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.deciliter (6.7 to 8.9 mmol per liter) — provides similar benefits.

Activated Protein CActivated Protein C

► Mechanism of action:Mechanism of action: antithrombotic, antiinflammatory, profibrinolytic.antithrombotic, antiinflammatory, profibrinolytic.

► PROWESS Trial:PROWESS Trial: 1690 randomly assigned to placebo or DAA, 28-day mortality rate was 1690 randomly assigned to placebo or DAA, 28-day mortality rate was

significantly lower in the drotrecogin-treated group (24.7% vs. 30.8%).significantly lower in the drotrecogin-treated group (24.7% vs. 30.8%).► rhAPC decreased mortality rates consistently across all rhAPC decreased mortality rates consistently across all

demographic subgroups defined by age, sex, race, and demographic subgroups defined by age, sex, race, and geographic region of treatment, compared with placebo.geographic region of treatment, compared with placebo.

► In 2001, FDA approved the use of drotrecogin alfa (activated In 2001, FDA approved the use of drotrecogin alfa (activated DAA ) for the treatment of severe Sepsis.DAA ) for the treatment of severe Sepsis.

► DAA produced the largest benefit in the sickest subgroups, with DAA produced the largest benefit in the sickest subgroups, with an absolute mortality reduction of 7.4% in patients with more an absolute mortality reduction of 7.4% in patients with more than one organ dysfunction and 13% (than one organ dysfunction and 13% (P P = 0.0002) in patients = 0.0002) in patients with APACHE II scores totaling more than 24.with APACHE II scores totaling more than 24.

► The treatment was effective regardless of age, severity of The treatment was effective regardless of age, severity of illness, the number of dysfunctional organs or systems, the site illness, the number of dysfunctional organs or systems, the site of infection (pulmonary or extrapulmonary), and the type of of infection (pulmonary or extrapulmonary), and the type of infecting organism (gram-positive, gram-negative, or mixed.infecting organism (gram-positive, gram-negative, or mixed.


Drawbacks:Drawbacks:

► Change in study protocol, drug preparations, APACHE scoring.Change in study protocol, drug preparations, APACHE scoring.► Increased risk of bleeding Increased risk of bleeding includingincluding fatal intracranial hemorrhage, in fatal intracranial hemorrhage, in

patients receiving DAA.patients receiving DAA.► The study excluded these groups of patients :The study excluded these groups of patients :

Higher risk of bleeding, INR > 3.0, hypercoaguble states.Higher risk of bleeding, INR > 3.0, hypercoaguble states. Chronic liver disease, pancreatitis.Chronic liver disease, pancreatitis. Chronic renal failure who were dependent on dialysis.Chronic renal failure who were dependent on dialysis. Recent surgery, organ-transplant recipients, HIV with CD4 < 50 cells.Recent surgery, organ-transplant recipients, HIV with CD4 < 50 cells. Patients with thrombocytopenia (defined as a platelet count of less than Patients with thrombocytopenia (defined as a platelet count of less than

30,000 per cubic mm). 30,000 per cubic mm). Those who had taken acetylsalicylic acid at a dose of > 650 mg per day Those who had taken acetylsalicylic acid at a dose of > 650 mg per day

within three days before the study.within three days before the study. Age <18 years, weight > 135kg.Age <18 years, weight > 135kg.

► Many patients with severe Sepsis meet one or more of these criteria. Many patients with severe Sepsis meet one or more of these criteria. ► Further studies will be needed to assess the safety of activated protein Further studies will be needed to assess the safety of activated protein

C in these groups of patients. C in these groups of patients.


Adjunctive therapiesAdjunctive therapiesTNF antagonist.TNF antagonist.► Murine anticlonal antibody.Murine anticlonal antibody.► NORASEPTII RCT 1879 patients randomly assigned to murine NORASEPTII RCT 1879 patients randomly assigned to murine

monoclonal antibodies (40.7% vs42.8%), effective in patients with a IL-monoclonal antibodies (40.7% vs42.8%), effective in patients with a IL-6 > 1000pg/ml.6 > 1000pg/ml.

► Two large phase III studies are currently underway to determine the Two large phase III studies are currently underway to determine the effects of the murine IgG3 monoclonal antibody to TNF-a and of the effects of the murine IgG3 monoclonal antibody to TNF-a and of the p55 TNF receptor fusion protein construct in patients with Sepsis.p55 TNF receptor fusion protein construct in patients with Sepsis.

Pentoxyphylline.Pentoxyphylline.► Inhibits synthesis of TNF.Inhibits synthesis of TNF.► Inhibits neutrophil activation and downregulates adhesion molecules.Inhibits neutrophil activation and downregulates adhesion molecules.► Randomized placebo controlled trial 51 patients pentoxyphylline vs Randomized placebo controlled trial 51 patients pentoxyphylline vs

saline infusion (30% vs. 33%)saline infusion (30% vs. 33%)► A decrease in the multiple organ dysfunction score, which was noted at A decrease in the multiple organ dysfunction score, which was noted at

day 4 and reached statistical significance (day 4 and reached statistical significance (PP < 0.05) at day 14 in the < 0.05) at day 14 in the patients who received pentoxifylline.patients who received pentoxifylline.

► Pentoxifylline significantly affects the synthesis of TNF and IL-6 as well Pentoxifylline significantly affects the synthesis of TNF and IL-6 as well as reduces the mortality rate in premature infants with Sepsis. as reduces the mortality rate in premature infants with Sepsis.

IL -1 receptor AntagonistIL -1 receptor Antagonist

► IL-1 induces fever, constitutional symptoms, and hypotension.IL-1 induces fever, constitutional symptoms, and hypotension.► An initial trial of IL-1 receptor antagonist in 99 human subjects An initial trial of IL-1 receptor antagonist in 99 human subjects

demonstrated a dose-dependent improvement in 28-day mortality demonstrated a dose-dependent improvement in 28-day mortality (44% vs. 16% ) correlated with IL-6 levels.(44% vs. 16% ) correlated with IL-6 levels.

► A subsequent trial with 893 patients with Sepsis syndrome revealed a A subsequent trial with 893 patients with Sepsis syndrome revealed a trend towards improved 28-day mortality that did not achieve statistical trend towards improved 28-day mortality that did not achieve statistical significance, although a retrospective analysis of the data suggested significance, although a retrospective analysis of the data suggested that those patients with the highest predicted mortality (24% or greater) that those patients with the highest predicted mortality (24% or greater) benefited most from the treatment and experienced a significant benefited most from the treatment and experienced a significant reduction in mortality at 28 days (45% in the placebo group versus 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; 35% in the patients receiving 2 mg/kg/h of IL-1 receptor antagonist; PP = = 0.005).0.005).

Adjunctive therapiesAdjunctive therapies

Interleukin-10Interleukin-10

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

► Decrease serum concentrations of TNF and IL-1.Decrease serum concentrations of TNF and IL-1.► In experimental animal models, administration of exogenous IL-10 In experimental animal models, administration of exogenous IL-10

protected against death in the setting of endotoxemia and protected against death in the setting of endotoxemia and staphylococcal enterotoxin injection .Alternatively, antibodies directed staphylococcal enterotoxin injection .Alternatively, antibodies directed against IL-10 will increase mortality in a similar clinical situation.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 Further studies are needed to define the utility of IL-10 in the treatment of Sepsis. of Sepsis.



HA-1AHA-1A

► Multicenter trials involving more than 1500 patients randomly assigned Multicenter trials involving more than 1500 patients randomly assigned to HA-1A or placebo within six hours of the onset of septic shock, the to HA-1A or placebo within six hours of the onset of septic shock, the antibody had no effect upon 14-day mortality.antibody had no effect upon 14-day mortality.

► Monoclonal antibody TLR-2Inhibition of toll-like receptor (TLR)-2 with a Monoclonal antibody TLR-2Inhibition of toll-like receptor (TLR)-2 with a neutralizing antibody successfully prevented lethal septic shock in a neutralizing antibody successfully prevented lethal septic shock in a murine model, even when given three hours after initiation of systemic murine model, even when given three hours after initiation of systemic inflammation.inflammation.


Cytokine agents:Cytokine agents:► Interferon-gamma Interferon-gamma

In patients with defective monocyte functions, shown In patients with defective monocyte functions, shown benefit, needs larger trials.benefit, needs larger trials.

► Granulocyte colony stimulating factorGranulocyte colony stimulating factor Studies not shown benefit in RCT of non neutropenic Studies not shown benefit in RCT of non neutropenic

patients.patients.

► Granulocyte-macrophage colony stimulating factor Granulocyte-macrophage colony stimulating factor Small phase 11 trial in 18 septic patients did not show Small phase 11 trial in 18 septic patients did not show

any benefit.any benefit.


► Anti-MIF antibodyAnti-MIF antibody MIF levels correlate with outcome among patients with MIF levels correlate with outcome among patients with

Sepsis, and human trials of anti-MIF antibody therapy are Sepsis, and human trials of anti-MIF antibody therapy are underway.underway.

► Antithrombin Antithrombin There was no significant benefit in mortality in patients There was no significant benefit in mortality in patients

receiving AT at 28, 56, or 90 days, or in survival time receiving AT at 28, 56, or 90 days, or in survival time within the intensive care unit.within the intensive care unit.

► Tissue factor pathway inhibitor Tissue factor pathway inhibitor Serine protease inhibitor that impairs the ability of tissue Serine protease inhibitor that impairs the ability of tissue

factor (thromboplastin) to initiate the coagulation cascade factor (thromboplastin) to initiate the coagulation cascade large multicenter randomized controlled trial (OPTIMIST) large multicenter randomized controlled trial (OPTIMIST) failed to show any improvement in outcome when patients failed to show any improvement in outcome when patients treated with tifacogin were compared to control patients.treated with tifacogin were compared to control patients.

Potential TherapiesPotential Therapies

► Antibodies against complement-activation product C5a decreased the Antibodies against complement-activation product C5a decreased the frequency of bacteremia, prevented apoptosis, and improved survival.frequency of bacteremia, prevented apoptosis, and improved survival.

► Antibodies against macrophage migration inhibitory factor protected Antibodies against macrophage migration inhibitory factor protected mice from peritonitis. mice from peritonitis.

► Strategies that block apoptosis of lymphocytes or gastrointestinal Strategies that block apoptosis of lymphocytes or gastrointestinal epithelial cells have improved survival in experimental models of epithelial cells have improved survival in experimental models of Sepsis.Sepsis.

► Mice with Sepsis that are deficient in poly–ADP–ribose polymerase 1 Mice with Sepsis that are deficient in poly–ADP–ribose polymerase 1 (PARP) have improved survival, and administration of a PARP inhibitor (PARP) have improved survival, and administration of a PARP inhibitor was beneficial in pig models.was beneficial in pig models.

► Electrical stimulation of the vagus nerve protects against endotoxic Electrical stimulation of the vagus nerve protects against endotoxic shock.shock.

► HMGB1, neutralizing antibodies against HMGB1 confer significant HMGB1, neutralizing antibodies against HMGB1 confer significant protection against LPS- or Sepsis-induced mortality.protection against LPS- or Sepsis-induced mortality.

Conclusions…Conclusions…

► The incidence of Sepsis is increasing.The incidence of Sepsis is increasing.► Possible contributing factors : Possible contributing factors :

Use of antibiotics leading to microbial resistanceUse of antibiotics leading to microbial resistance More invasive proceduresMore invasive procedures Increasing use of immunosuppressants.Increasing use of immunosuppressants.

► There have been new insights into the There have been new insights into the pathogenesis of Sepsis which could be potential pathogenesis of Sepsis which could be potential therapeutic targets in the future.therapeutic targets in the future.

► Treatment of Sepsis includes early institution of Treatment of Sepsis includes early institution of antibiotics, volume resuscitation, tight glycemic antibiotics, volume resuscitation, tight glycemic control, steroids protein C when indicated.control, steroids protein C when indicated.

BibliographyBibliography► The Pathophysiology and Treatment of Sepsis, NEJMThe Pathophysiology and Treatment of Sepsis, NEJM► The Treatment of Severe Group A Streptococcal InfectionsThe Treatment of Severe Group A Streptococcal Infections Anna Anna Norrby-TeglundNorrby-Teglund, PhD, PhD, , S. S. RagnarRagnar

NorrbyNorrby, MD, PhD, FRCP, MD, PhD, FRCP, and , and Donald E. Low, MD, FRCPCDonald E. Low, MD, FRCPC ► Pathophysiology of Sepsis Pathophysiology of Sepsis William J William J SibbaldSibbald, MD, FRCPC, MD, FRCPC

RemiRemi NeviereNeviere, MD, MD► The Multiple Organ Dysfunction Syndrome and Late-phase Mortality in SepsisThe Multiple Organ Dysfunction Syndrome and Late-phase Mortality in Sepsis Joshua A. Joshua A. EnglertEnglert

, MD, MD and and Mitchell P. Fink, MDMitchell P. Fink, MD ► Current Infectious Disease ReportsCurrent Infectious Disease Reports 2005, 2005, 77:335-341:335-341

► Epidemiology of Sepsis: Recent AdvancesEpidemiology of Sepsis: Recent Advances Pajman Danai and Greg S. Martin Pajman Danai and Greg S. Martin ► Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with

septic shock. AUAnnane D; Sebille V; Charpentier C; Bollaert PE; Francois B; Korach JM; Capellier G; septic shock. AUAnnane D; Sebille V; Charpentier C; Bollaert PE; Francois B; Korach JM; Capellier G; Cohen Y; Azoulay E; Troche G; Chaumet-Riffaut P; Bellissant E SOJAMA 2002 Aug 21;288.Cohen Y; Azoulay E; Troche G; Chaumet-Riffaut P; Bellissant E SOJAMA 2002 Aug 21;288.

► Advances in Sepsis TreatmentAdvances in Sepsis Treatment Todd W. Rice and Gordon R. Bernard Todd W. Rice and Gordon R. Bernard ► Mitochondrial Dysfunction in Sepsis David Brealey and Mervyn Singer Mitochondrial Dysfunction in Sepsis David Brealey and Mervyn Singer Can Enterococcal Infections Can Enterococcal Infections

Initiate Sepsis Syndrome?Initiate Sepsis Syndrome? Peter Linden Peter Linden ► Adjunctive Therapies for Sepsis and Septic ShockAdjunctive Therapies for Sepsis and Septic Shock Gregory Breen and Allan R. Tunkel Gregory Breen and Allan R. Tunkel ► Efficacy and safety of recombinant human activated protein C for severe Sepsis.Efficacy and safety of recombinant human activated protein C for severe Sepsis. N Engl J MedN Engl J Med

2001, 2001, 344344:699-709 :699-709 ► Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients

with septic shock.with septic shock. JAMA 2002, JAMA 2002, 288288:862-871:862-871 ► Intensive insulin therapy in critically ill patients.Intensive insulin therapy in critically ill patients. N Engl J Med 2001, N Engl J Med 2001, 345345:1359-1367.:1359-1367. ► The epidemiology of Sepsis in the United States from 1979 through 2000.The epidemiology of Sepsis in the United States from 1979 through 2000. N Engl J Med 2003, N Engl J Med 2003,

348348:1546-1554:1546-1554

DiscussionDiscussion

sepsis : pathophysiology and treatment sepsis : pathophysiology and treatment zainab abdulla april...

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cases of sepsis

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t cells

host immune response

host factors

concentrations of b

apotosis of b cells

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