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A. Definitions [2]

  1. Sepsis syndrome is divided into stages
    1. This will help stratify patients for prognosis
    2. Help to insure uniformity in enrolling patients in trials for therapy
  2. Systemic Inflammatory Response Syndrome (SIRS)
    1. Clinical Response due to non-specific injury
    2. Includes at least 2 of the following:
    3. Temperature >38°C or <36°C
    4. Heart Rate (HR) > 90bpm
    5. Respirations >20 breaths per minute or pCO2 <32mm Hg
    6. White blood cells (WBC) <4K/µL or >12K/µL or at least 10% immature (band) neutrophils
    7. Earliest stage of sepsis syndrome continuum
    8. Risk for progression to more severe syndromes correlates with number of criteria
  3. Sepsis
    1. SIRS with documented infection OR empiric antibiotic treatment for possible infection
    2. Similar prognosis is seen whether culture is positive or negative
  4. Severe Sepsis
    1. Sepsis associated with organ dysfunction, hypoperfusion abnormalities, or hypotension
    2. Lactate levels should be elevated or acute renal failure (ARF) present
  5. Septic Shock
    [Figure] "Starling Curve for Septic Shock"
    1. Sepsis-induced hypotension despite fluid resuscitation + evidence of hypoperfusion
    2. This definition has remained farily constant
    3. Nearly 70% of patients with this diagnosis have positive blood culture [4]
    4. Patients with positive blood cultures have similar mortality to those without cultures
  6. Multiple-Organ Dysfunction Syndrome (MODS)
    1. Refers specifically to the organ dysfunction which occurs in SIRS
    2. Presence of altered organ function in acutely ill patients, leading to loss of homeostasis
    3. SIRS or sepsis can progress to MODS
    4. Kidney, liver, and heart are major initial organs affected
    5. Renal insufficiency, hepatic dysfunction (transaminase elevation) most common
    6. Reduced cardiac output observed

B. Epidemiology [4]

  1. Increasing numbers of cases over past 20 years
  2. About 750,000 cases in USA in 2005
  3. Annual Incidence 1995-2000
    1. Overall: 240/100,000 population
    2. Whites: 186/100,000
    3. Blacks: 378/100,000
    4. Other: 370/100,000
  4. Average age ~60 years
  5. Length of hospital stay 11.8±2.6 days
  6. Organisms (Year 2000)
    1. Gram positive bacteria: 52.1%
    2. Gram negative bacteria: 37.6%
    3. Polymicrobial: 4.7%
    4. Anaerobes: 1.0%
    5. Fungi: 4.6%
  7. Most patients have no (66%) or one (25%) organ failure at time of diagnosis
  8. 30-Day Mortality by Severity
    1. SIRS: ~7% mortality
    2. Sepsis: ~15%
    3. Severe Sepsis: ~25%
    4. Septic Shock: ~65%
    5. Single organ involvement - 30% mortality
    6. Two organs involved - 60% mortality
    7. Three or more ogans involved - 90% mortality
    8. For every organ/system failure, ~20% increase in mortality

C. Etiology

  1. Culture Positive
    1. Usually Gram Negative (Enterobactereacaea and Pseudomonas) Sepsis (~40%)
    2. S. aureus (or Streptococcal) Toxic Shock Toxin
    3. S. aureus and S. epidermidus are most common gram positives (~26%)
    4. Enterococcus and Strep. pneumoniae each account for ~5% of cases
    5. Unusual - fungal (Candida ssp in majority)
    6. Biological Warfare - Anthrax (Bacillus anthracis) - spore forming rod; pneumonia
    7. Parasitemia - very uncommon in USA
  2. Culture Negative
    1. Previous antibiotics
    2. Pancreatitis
    3. Trauma
    4. Malignancy
    5. Failure to culture organism
    6. Gram negative infections at non-bloodstream sites may lead to syndrome
  3. Majority of infectious causes originate in lungs
    1. Urinary Tract also common
    2. Skin and soft tissue infections (increasing)

D. Pathophysiology [2,6,9,51]

  1. Sepsis was originally thought to be purely an "abnormal" response to infection or insult
    1. Gram negative (lipopolysaccharide) and gram positive (lipoteichoic acids) bacterial products most commonly initiate the process
    2. Now believed to be related to inappropriate immune/inflammatory response to stimulus
    3. Initial overzealous response followed by immune failure (massive apoptosis)
    4. Thus, overall host response pattern is critical to development and outcome in sepsis
    5. Mitochondrial dysfunction with reduced ATP levels correlate with clinical outcomes [8,10]
    6. Reduced mitochondrial production and cell utilization of ATP may be adaptive in severe disease, reducing long term organ dysfunction (but increasing short term dysfunction) [8]
    7. Interaction of clotting system and immune system critically important in pathogenesis
    8. Neutrophil activation and trafficking into tissues may be critical component [6]
    9. Anticoagulants may be particularly helpful in sepsis
  2. Cytokine Cascades in Sepsis
    1. Both pro- and anti-inflammatory cytokine classes are overexpressed and secreted
    2. Initially, tumor necrosis factor alpha (TNFa) and interleukin 1 (IL-1) are produced
    3. IL1ß and TNFa appear to be the most important early mediators in human sepsis
    4. These cytokines have broad effects on immune cells, endothelium, neutrophils
    5. IL-6, IL-8 and IL-10, oxygen radicals are produced
    6. Neutrophil trafficking into tissues due to chemokine stimulation important [6]
    7. High serum IL-10 and reduced TNFa levels correlate strongly with poor outcome [11]
    8. Very high serum IL-10 levels may be most important late marker for poor outcome [9]
    9. TNFa promoter polymorphism influences TNFa levels during sepsis [12]
    10. Cytokines may induce reduction in activity of mitochondria and reduction in ATP [8]
  3. Clinical Measurements of Cytokines [14]
    1. IL1ß, IL1ra, IL6, and TNFa are increased
    2. The TNFa-2 promoter polymorphism in TNFa gene leads to increased production of TNFa
    3. TNFa-2 polymorphism has been linked to increased susceptibility to and death from sepsis, with risk ~3.7X increased compared with TNFa-1 allele [12]
    4. Increased levels of TNFa in response to inflammatory stimuli may lead to further increases in IL1 and IL6, overzealous inflammation, and worsened outcome
    5. IL6 and IL1-receptor antagonist elevations predict outcome in neonatal sepsis [15]
    6. These markers are more helpful than soluble ICAM and CRP in predicting outcome
  4. Regulation of Vessel Diameter [16]
    1. Vasodilator overproduction and vasoconstrictor insensitivity present
    2. Nitric oxide (NO) is major vasodilator produced by endothelium and immune cells
    3. Atrial natriuretic factor (ANF), another vasodilator, also plays a role
    4. IL1ß, IL6, TNFa, many other cytokines stimulate NO production
    5. These cytokines activate inducible nitric oxide synthetase (iNOS) early in process
    6. NO activates K(ATP) and K(Ca) channels leading to hyperpolarized endothelium
    7. Localized NO production at nidus of infection correlates with IL1ß and TNFa levels [17]
    8. Upregulation of inducible NO synthetase (iNOS) triggers apoptosis of neurons in cardiovascular autonomic (sympathetic) centers which exacerbates hypotension [3]
    9. Mitochondrial dysfunction correlates with NO overproduction [10]
    10. Vasodilatory prostaglandins, leukotrienes, and bradykin are released
    11. Hyperpolarized endothelium is insensitive to vasoconstrictors
    12. Relative vasopressin (ADH) deficiency is also present in vasodilatory shock
  5. Cardiovascular System Effects
    [Figure] "Starling Curve for Septic Shock"
    1. With vasodilation, afterload is reduced and cardiac output can increase
    2. Venous return is also reduced which leads to reduction in cardiac output
    3. Eventually, blood pressure is compromised and organ hypoperfusion occurs
    4. Compensatory activation of renin-angiotensin-aldosterone system (RAAS) occurs
    5. But endothelium is resistant to constriction by angiotensin or alpha-adrenergic agonists
    6. Vasopressin levels initially elevated, but stores are rapidly depleted
    7. Therefore, relative vasopressin insufficiency is present
    8. Vasopressin blocks K(ATP) channels and helps return endothelium to normal state
    9. Infusion of vasopressin (analogs) can improve blood pressure resistant to other pressors
    10. Cardiovascular sympathetic autonomic dysfunction can exacerbate hypotension [50]
  6. Acute Renal Failure (ARF)
    1. Commonly accompanies severe sepsis and septic shock
    2. ARF occurs in ~6% of intensive care unit patients, ~50% due to sepsis syndromes [38]
    3. Initially, kidney including tubules are intact and sense vasodilation
    4. Result is sodium and water retention with fractional sodium excretion (FeNa) <1%
    5. Compensatory activation of RAAS likely leads to severe renal arteriolar vasoconstriction
    6. With reduced systemic perfusion pressures and activated RAAS, kidney becomes ischemic
    7. Ischemia leads to ARF, usually as acute tubular necrosis (ATN)
    8. Cortisol, vasopressin, maintaining hematocrit >30%, glucose control can reduce ATN
    9. Fednoldopam, a dopamine DA-1 agonist, reduced acute kidney injury and death in critical illness in a meta-analysis and should be considered strongly [56]
  7. Cortisol Levels [18]
    1. Baseline cortisol levels usually >20µg/dL (normal 5-15µg/dL)
    2. Absolute cortisol level <34µg/dL is associated with good outcomes
    3. Impaired response to corticotropin (ACTH stimulation gives <9µg/dL increase in cortisol level at 30-60 minutes) is associated with increased mortality
    4. Combination of baseline and stimulated cortisol levels provides reasonably good prognostic information
    5. Patients with relatively poor cortisol responses may benefit from glucocorticoids
    6. Serum free cortisol levels are abnormally low in ~40% of acutely ill patients and these may benefit from exogenous glucocorticoids [50]
    7. Low dose hydrocortisone for 5-7 days may be beneficial in all vasopressor-dependent patients with septic shock [30]
  8. Abnormalities in Severe Sepsis
    [Figure] "Oxygen Dissociation Curve"
    1. Usually associated with ARDS (see below)
    2. High progression to multi-organ system failure
    3. Disseminated intravascular coagulopathy (DIC)
    4. Oxygen demand increased but abnormal shunting is increased; shift in O2 dissociation
    5. MVO2 is actually increased consistent with reduced oxygen consumption
    6. Thrombocytopenia - multiple etiologies
    7. Platelet Activating Factor and proteases are released
    8. Inappropriately low levels of vasopressin
    9. Insensitivity to vasoconstrictors due primarily to nitric oxide overproduction
    10. Hyperglycemia is a poor prognostic sign in severe sepsis
    11. Aggressive insulin therapy correlated with good outcomes
    12. Good glucose control probably more important than insulin itself for good outcomes [48]
    13. Strict glucose control associated with maintenance of normal hepatocyte mitochondrial ultrastructure and function in critically ill patients [39]
  9. DIC [2]
    1. Multiple intravascular fibrin clots form
    2. Lead to marked consumption of coagulation proteins
    3. Both intrinsic and extrinsic coagulation pathways are depleted
    4. Prothrombin and partial thromboplastin time prolonged
    5. Clots broken down rapidly leads to increased D-dimers and fibrin degradation products
    6. Activated protein C is beneficial in sepsis (see below)
    7. Likely that coagulopathy is a major driver in severe sepsis

E. Diagnosis

  1. Fever often with Chills and/or Rigors
  2. Tachycardia
  3. Tachypnea
  4. Hypotension - later stages (failed compensation)
  5. Absent Jugular Venous Distension
    1. May be helpful in distinguishing cardiogenic from septic shock states
    2. Cardiogenic shock characterized by high preload (elevated atrial pressures)
    3. Sepsis syndromes characterized by reduced preload
  6. Leukocytosis with
    1. Neutrophils: band or immature forms prominant ("Left Shift")
    2. Leukopenia and/or lymphopenia may also occur, particularly in severe syndrome
  7. Elderly patients have fewer early symptoms of sepsis than younger patients
  8. Typical Organ / System Failures in Sepsis [9]
    1. Pulmonary Dysfunction is most common (~30% have frank ARDS)
    2. Cardiovascular failure (shock, lactic acidosis) is also very common
    3. Renal Dysfunction [51]
    4. Gastrointestinal Dysfunction / Catabolic Nutritional Deficits
    5. Coagulopathies
    6. Altered Consciousness / Delirium
    7. Anemia common in critically ill patients (iatrogenic and pathophysiologic)
  9. Biomarkers [5]
    1. No specific serum or urine markers of sepsis to date
    2. C-reactive protein (CRP) elevated; cutoff 70mg/L: 76% sensitivity, 67% specificity
    3. Procalcitonin also elevated: 84% sensitivity, 70% specificity (also useful in COPD) [55]
    4. Soluble TREM-1 elevated; cutoff 60ng/mL: 96% sensitivity, 89% specificity
    5. TREM-1 is triggering receptor on myeloid cells 1
    6. TREM-1 is shed from membrane of active phagocytes during inflammation, infection

F. Current Treatment [2,9]

  1. Overview [2]
    1. Early, goal directed therapy to reduce tissue hypoxia
    2. Lung protective ventilation
    3. Broad-spectrum antibiotics
    4. Possibly activated protein C
    5. Two or three sets of blood cultures PRIOR to beginning antibiotics if at all possible
  2. Cardiovascular Monitoring
    1. Central venous catheter and arterial pressure catheter usually recommended
    2. Critical to monitor central venous pressure (CVP) and central venous oxygen saturation (ScvO2) or mixed venous oxygen (MVO2) levels
    3. Pulmonary artery (Swann-Ganz) catheter (PAC) was previously recommended
    4. Allows calculation of cardiac output (CO) and Systemic Vascular Resistance (SVR)
    5. PAC associated with no benefit or increased mortality in several studies
    6. PAC are not currently recommended for general use
    7. PAC may be helpful when more than one form of shock are present
    8. PAC may be helpful to optimzie care in sepsis with pre-existing severe cardiac dysfunction
  3. Goal-Directed Cardiovascular Support [21]
    1. Goal directed therapy towards central venous pressure (CVP), mean arterial pressure (MAP), central venous oxygen saturation (ScvO2)
    2. Targets: CVP 8-12mmHg, MAP 65-95mmHg, ScvO2 >70% recommended
    3. Goal directed therapy associated with 30.5% versus usual care 46.5% in-hospital mortality [21]
    4. Maintain CVP at 8-12 mm Hg with crystalloids (IV fluids)
    5. Add vasopressors for mean arterial pressure (MAP) <65 mm Hg
    6. If central venous oxygenation <70%, transfuse to hematocrit >30%
    7. Dobutamine is added if above parameters did not yield central venous oxygenation >70%
    8. Overall, blood transfusion in critically ill patients associated with increased mortality [22,23]
    9. For septic shock, norepinephrine+dobutamine had similar outcomes (~50% mortality at 90 days) to epinephrine in direct comparison of inotropic support [57]
  4. Other Vasopressor Agents
    1. Dopamine (Intropin®) - high dose (>10µg/kg/min) with inotropic and alpha-agonist activity usually first line therapy
    2. Norepinephrine (NE, Levophed®) - usually second line after dopamine for septic shock
    3. Vasopressin low dose (0.01-0.03U/minute) added to NE showed trends for reduced 90 day mortality (43.9% versus 49.6%, p=0.11) versus NE alone in septic shock [58]
    4. Phenylephrine (Neosynephrine® - pure alpha agonist for vasoconstriction with no inotropic activity; induces a high incidence of renal insufficiency
    5. Epinephrine (Adrenaline) - no benefit over high dose dopamine, increased lactate
    6. Terlipressin (Glypressin®) - long acting vasopressin analog, raises blood pressure in norepinephrine resistant shock without rebound hypotension [31]
    7. High dose dexamethasone (16mg IV bolus) may improve blood pressure in some patients [31]
    8. Amrinone, milronone, and dobutamine are rarely helpful in sepsis even with depressed cardiac output due to vasodilatatory actions of these drugs
    9. Low dose hydrocortisone may be beneficial in vasopressor-dependent patients regardless of their cortisol levels [30]
  5. Glucocorticoids and Mineralocorticoids
    1. Many patients with sepsis have adrenal insufficiency
    2. Glucocorticoids benefit patients with relative adrenal insufficiency and sepsis [18,32]
    3. Glucocorticoids + mineralocorticoids must be given to patients with adrenal insufficiency
    4. Hydrocortisone 50-100mg q6-8 hours +50µg/d fludrocortisone given until shock resolved [32,33]
    5. Mineralocortoid replacement in adrenally insufficient septic shock patients beneficial [32]
  6. Broad Spectrum Antibiotics [20]
    1. Time to initiation of broad-specturm antibiotics in severe sepsis related to mortality; thus rapid initiation of therapy is critical [7]
    2. Initial antibiotic choices are critical to improving survival; initial coverage failure is associated with 1.8X increased risk of death [49]
    3. Choice of drug based on probable source of infection, gram stained smears, immune status of patient, and local patterns of bacterial resistance
    4. Two to 4 drugs are used empirically usually including cephalopsorin+aminoglycoisde
    5. Third or 4th generation cephalosporins (cefotaxime, ceftriaxone, ceftazidime, ceftizoxime, cefepime) are strongly recommended as basis for therapy
    6. Ticarcillin-clavulonate (Timentin®) or piperacillin-tazobactam (Zosyn®) have better anaerobe coverage than cephalosporins
    7. Imipenem or meropenem can also be used in place of cephalosporins and have broader activity including anaerobic coverage
    8. Aminoglycosides should be given early even with renal disease
    9. Fluoroquinolones also give rapid kill and are strongly recommended and can be used in ß-lactam allergic patients
    10. Vancomycin should be added if skin is suspected source or Staphylococci likely
    11. Rifampin may be added to vancomycin for for severe staph or pneumococcal infections
    12. Double gram-negative antibiotic coverage for severe, hospital acquired infections
    13. Similar broad coverage is required in neutropenic patients
    14. Metronidazole preferable over clindamycin for bowel anaerobes
    15. Aztreonam may be used in patients with renal disease who cannot tolerate prolonged aminoglycosides
    16. Once culture and susceptibility results are obtained, narrow coverage as appropriate [32]
    17. Treatment with intravenous agents for at least 7-14 days is generally recommended
  7. Activated Protein C (Drotrecogin alpha, Xigris®) [25,26,27]
    1. Anticoagulant, fibrinolytic, and anti-inflammatory activities
    2. In 1690 patients with severe sepsis or shock, reduced mortality from 30.8 to 24.7%
    3. Suggests that coagulopathy is a primary driver in severe sepsis
    4. Well tolerated with slight increase in serious bleeding (3.5% versus 2.0%) in adults
    5. Showed no benefit and increased bleeding events in patients with severe sepsis and low risk of death; should not be used in these patients [1,19]
    6. No efficacy benefit and slightly increased bleeding risk in pediatric sepsis patients [36]
    7. Given as continuous infusion 24µg/kg/hr IV for 96 hours
    8. Cost-effective (<$30K/life year gained) in patients with APACHE II score >24 [28]
    9. Optimal utility is still being investigated [29]
    10. High-dose antithrombin+heparin of no benefit in severe sepsis
  8. Respiratory Support [52,53]
    1. May be complicated by capillary leak syndrome (ARDS) and/or septic emboli
    2. Lungs in sepsis are particularly susceptible to barotrauma
    3. Overdistension of lungs leads to significant inflammatory / cytokine responses [54]
    4. Lung protective ventilation is now standard recommendation
    5. Tidal volumes ~6mL/kg and mean plateau pressures <25-30cm are essential
    6. Protective ventilation uses tidal volume <6mL/kg, permissive hypercapnia, preference for pressure limited ventilatory modes and other changes
    7. Protective ventilation had better in 28 day survival and weaning from mechanical ventilation
  9. Renal Failure
    1. Acute Tubular Necrosis (ATN) is most common type of renal failure in sepsis
    2. Close monitoring for ATN / renal dsyfunction is critical
    3. General use of diuretics in critically ill patients with ATN is discouraged [34]
    4. Low dose dopamine (2-4µg/kg/min) may help spare kidneys when tolerated
    5. No clear data showing improved outcome with dopamine once ATN has begun
    6. Adequate volume repletion with 0.45% saline
    7. Patients may need renal replacement therapy with hemodialysis or hemoperfusion
    8. Intermittent hemodialysis appears to be as effective as continuous venous hemofiltration in patients with ARF associated with MODS [37]
    9. Intensive renal support in critically ill patients with renal failure did not improve outcomes compared with less intensive dialysis with continuous renal replacement at 20mL/kg/hr [59]
  10. Intensive Insulin Therapy [24]
    1. Hyperglycemia associated with metabolic dysfunction, poor outcomes
    2. Hyperglycemia at least in part in exacerbating mitochondrial dysfunction [39]
    3. Insulin may be used to maintain glucose <110mg/dL
    4. Intensive insulin therapy associated with 40-55% reduction in mortality in critically ill, ventilated, surgical instensive care unit patients
    5. Most effective in patients with hospital stays >5 days
    6. Reduction in hospital stay, infections, transfusions, ARF
    7. Intensive insulin therapy associated with maintenance of normal mitochondrial function [39]
  11. Selective Digestive Decontamination (SDD) [46,47]
    1. Gut bacteria may seed bloodstream in critically ill patients
    2. Prophylactic SDD has been used to reduce bacterial loads in gut
    3. Likely reduces hospital stay and mortality in critically ill patients
    4. Prophylaxis often uses ciprofloxacin 400mg IV q12 and oral antibiotic mixture
    5. Intravenous cefotaxime 1gm q6 hours may be used instead of ciprofloxacin
    6. Oral mixture q6 hours: gentamicin 80mg, polymyxin B 50mg, vancomycin 125mg
    7. Polymyxin E, tobramycin, amphotericin B can be used for enteral/oral decontamination
    8. Patients also receive stress ulcer prolphylaxis with sucralfate 1.5gm qid 3 hours post SDD
    9. SDTD reduced ICU and overall mortality in medical and surgical patients [47]
    10. Strongly consider SDD in critically ill patients at high risk for bacteremia
  12. Nutrition
    1. Patients should receive enteral or parenteral nutrition early in course
    2. Albumin and Transferrin levels are good overall markers of nutriation and disease status
    3. Insulin used to maintain normal range glucose regulation (see above) [24]
  13. Intravenous Immunoglobulin (IVIg) [13]
    1. May have activity against infectious organisms causing sepsis
    2. Meta-analysis showed ~25% survival benefit with administration of IVIg in sepsis
    3. Severe sepsis or septic shock showed greater benefit than less severe disease
    4. Dose is 1gm/kg body weight IV for >2 days
    5. Large ranodmized controlled trial is needed to document effects

G. Experimental Therapies [9]

  1. Anti-Endotoxin Antibodies
    1. Several nti-endotoxin Abs showed no overall benefit in septic shock
    2. Rather, data suggest that endotoxin initiates, but does not maintain, inflammation
  2. Anticytokine Therapies
    1. Anti-TNFa antibody has no overall benefit on 28 day mortality in sepsis [15]
    2. Soluble TNF-Receptors (bind and therby block TNFa function)
    3. Soluble p55-TNF-R reduced mortality in highest dose in only severe sepsis [2]
    4. IL1ß-receptor blockers (antibodies, receptor antagonists) are not effective
    5. Thus, blockade of TNFa (and perhaps other inflammatory cytokines) may be detrimental
  3. Nitric Oxide Inhibition [40]
    1. Non-specific nitric oxide inhibitors may improve hypotension
    2. Inhibitors specific for inducible nitric oxide synthetase are being developed
    3. Nitric oxide may play a central role in causing or mediating hypotension in sepsis
    4. Preliminary data suggest that nitric oxide inhibition may reduce survival in shock [31]
  4. Bradykinin Antagonist (Deltibant) [41]
    1. Bradykinin mediates many of the symptoms/signs in sepsis
    2. Deltibant is a competitive antagonist that blocks B2 subset of bradykinin receptors
    3. In a Phase II trial in Sepsis, Deltibant had no overall effect on 28 day survival
    4. However, in patients with gram negative sepsis, highest dose improved survival
  5. Interferon Gamma 1b
    1. During course of sepsis, anti-inflammatory cytokines are produced at high levels
    2. These cytokines include IL-4, IL-10, and others
    3. Anti-inflammatory cytokines block macrophage activation and HLA-DR expression
    4. This is called "immunoparalysis", and may explain some aspects of sepsis
    5. In fact, patients with highly eleved IL-10 levels have poor outcome [11]
    6. Interferon (IFN) Gamma 1b can reverse macrophage inhibition
    7. IFN gamma 1b induces HLA-DR, IL-6 and TNFa from macrophages
    8. Trials are ongoing to assess activity in sepsis patients
  6. Cyclooxygenase (Prostaglandin Synthetase) Inhibition [43]
    1. Animal model data show improvement with non-steroidal anti-inflammatory drugs
    2. Ibuprofen treated sepsis patients had reduced prostacyclin, thromboxane, heart rate, oxygen consumption, lactate, and body temperature
    3. Ibuprofen treated sepsis patients had 37% survival versus 40% for placebo at 30 days
    4. This was not significant in a study of 224 ibuprofen patients and 231 placebo
    5. The overall 30 day mortality rate in septic patients exluded from the study was 40%
  7. Tissue Factor Pathway Inhibitor (TFPI) [44]
    1. TFPI is a receptor for Factor VII which blocks Factor Xa directly
    2. Blocks the "alternative" coagulation pathway through blocking Factor VIIa/TF complex
    3. Tifacogin is recombinant human TFPI with activity in Phase 2 and 3 sepsis trials
    4. In Phase 3 sepsis patients with coagulopathy (INR at least 1.2), no mortality improvement
  8. Platelet activating factor (PAF) antagonists - disappointing phase 2 and 3 results [45]
  9. Additional Agents in Development
    1. Antioxidants
    2. Bactericidal Permeability increasing protein (BPI) - promising phase 2 data
    3. Thromboxane antagonists

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