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Sepsis : Pathophysiology and Treatment Zainab Abdulla April 25, 2006
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Definitions Epidemiology Pathophysiology Treatment Future directions
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Definitions Systemic Inflammatory Response Syndrome (SIRS) : Systemic inflammatory response to various stresses. Meets 2 or more of the following criteria : Temperature of >38C/<36degree C Heart rate of more than 90 beats/min RR >20 breaths/min or PaCo2 <32mmHg WBC >12,000/mm3 or <4000/mm3
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Definitions SEPSIS : Evidence of SIRS accompanied by known or suspected infection. Severe SEPSIS : Sepsis accompanied by hypoperfusion or organ dysfunction. Cardiovascular : SBP<90mmhg/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.
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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 Definitions
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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.
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Epidemiology:
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Epidemiology : Mortality rate
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Epidemiology : Causative organism
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Pathophysiology of Sepsis
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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.
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Pathogenesis of Sepsis
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Failure of Immune System to Eliminate Microorganism? Shift from 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. Pathophysiology of Sepsis
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Pathogenesis of Sepsis
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Pathogenesis of Sepsis
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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.
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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.
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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.
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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
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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. MODS : Possible Explanations 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).
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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 : Possible Explanations
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MODS
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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.
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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.
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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).
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Antibiotics dosing Dosage for intravenous administration (normal renal function). Imipenem-cilastin 0.5g q 6h Meropenem 1.0g q 8h Piperacillin-tazobactam 3.375gq 4h or 4.5 g q 6h Cefepime1-2 q 8hr Gatifloxacin 400mg iv q d Ceftriaxone 2.0g q 24hr Levofloxacin500mg q d
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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.
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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.
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Coticosteroids 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 < 9mcg/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(50mg 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).
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Unanswered questions : What defines adrenal dysfunction? High dose ACTH, Low dose ACTH test? How long should treatment continue once shock has resolved? Taper Steroids? Role of Fludrocortisone? Role of Coticosteroids
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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.
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Activated Protein C
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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
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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. Activated Protein C
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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.
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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
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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
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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.
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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.
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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.
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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.
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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.
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Bibliography The Pathophysiology and Treatment of Sepsis, NEJM The Treatment of Severe Group A Streptococcal Infections Anna Norrby-Teglund, PhD, S. Ragnar Norrby, MD, PhD, FRCP, and Donald E. Low, MD, FRCPC Pathophysiology of Sepsis William J Sibbald, MD, FRCPC Remi Neviere, MD The Multiple Organ Dysfunction Syndrome and Late-phase Mortality in Sepsis Joshua A. Englert, MD and Mitchell P. Fink, MD Current Infectious Disease Reports 2005, 7:335-341 Epidemiology of Sepsis: Recent Advances Pajman Danai and Greg S. Martin 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; Cohen Y; Azoulay E; Troche G; Chaumet-Riffaut P; Bellissant E SOJAMA 2002 Aug 21;288. Advances in Sepsis Treatment Todd W. Rice and Gordon R. Bernard Mitochondrial Dysfunction in Sepsis David Brealey and Mervyn Singer Can Enterococcal Infections Initiate Sepsis Syndrome? Peter Linden Adjunctive Therapies for Sepsis and Septic Shock Gregory Breen and Allan R. Tunkel Efficacy and safety of recombinant human activated protein C for severe Sepsis. N Engl J Med 2001, 344:699-709 Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002, 288:862-871 Intensive insulin therapy in critically ill patients. N Engl J Med 2001, 345:1359-1367. The epidemiology of Sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348:1546-1554
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Discussion