Severe Sepsis: Pathophysiology, Diagnosis, And Treatment

Severe Sepsis: Pathophysiology,Diagnosis, and TreatmentMichael J. Mosier, MD, FACSAssistant Professor of SurgeryLoyola University Medical CenterJanuary 24, 2013

Epidemiology Severe sepsis (acute organ dysfunction secondary to infection) andseptic shock (severe sepsis plus hypotension not reversed with fluidresuscitation) are major healthcare problems, affecting millions aroundthe world each year, killing 1-2 in 4, and increasing in incidence.Angus, Crit Care Med 2001Dellinger, Crit Care Med 2003Martin, N Engl J Med 2003Dombrovskiy, Crit Care Med 2007

Epidemiology Every year, severe sepsis strikes about 750,000 Americans. Between 28-50% will die-far more than the number of US deaths fromprostate cancer, breast cancer, and AIDS combined. The number of sepsis cases per year has been on the rise in the US. An estimated 17 Billion is spent annually to treat sepsis in the US. Sepsis Fact Sheet www.nigms.nih.gov/education/factsheet sepsis.htm

Epidemiology One of the main challenges in sepsis treatment is diagnosis. Often the diagnosis is made late with significant effects on patientoutcomes. Current research focuses on: Improving earlier diagnosis Improved understanding of the inflammatory response How best to treat the syndrome and at what points treatments are mosteffective.

Surviving Sepsis Campaign: InternationalGuidelines In 2004, and again in 2008 an international group of expertsrepresenting 11 organizations, published the 1st and 2nd internationallyaccepted guidelines to improve outcomes in severe sepsis and septicshock. Dellinger, Crit Care Med 2004 Dellinger, Crit Care Med 2008 In February, the 2012 guidelines will be jointly published in IntensiveCare Medicine and Critical Care Medicine. www.survivingsepsis.org

How did we get here? An early influential study Early Goal Directed Therapy (EGDT): Rivers, NEJM 2001 Randomly assigned 263 pts who presented to an urban ED with severesepsis or septic shock to receive either 6 hrs of EGDT or SC before ICU. In-hospital mortality was 30.5% in EGDT and 46.5% w/ SC. At 7-72 hrs, EDGT pts had a significantly higher mean ScVO2 (70.4 vs.65.3%), lower lactate (3.0 vs. 3.9mmol/L), lower BD (2.0 vs. 5.1mmol/L),and a higher pH (7.40 vs. 7.36). APACHE II scores were lower over the same period, indicating lesssevere organ dysfunction (13.0 vs. 15.9)

Efforts to improve outcomes: Do guidelines andbundles improve outcome? Multiple studies have shown that EGDT and guidelines can improvemortality in severe sepsis and septic shock. Micek, Crit Care Med 2006; Castellano-Ortega, Crit Care Med 2010 Nguyen, Crit Care 2011; Lin, Shock 2006 BUT, achieving improvements in mortality requires energy, physicianbuy-in, monitoring, feedback, and QI efforts. Unfortunately many studies demonstrate that bundle compliance isoften low (6%) and simply applying a sepsis bundle did notsignificantly improve compliance (21.1% to 13.7% at 24 and 36months). Shiramizo, PLoS One 2011

Pathophysiology of Sepsis

Pathophysiology of sepsis associated coagulopathy(SAC) Sepsis is associated with hemostatic changes that range fromhypercoagulility to systemic clotting activation with massive thrombinand fibrin formation, eventually leading to consumption of plateletsand acute disseminated intravascular coagulation (DIC). DIC following sepsis is considered to be a condition where advancedhypercoagulability and suppressed fibrinolysis cause a decompensatedfailure of the coagulation system. Widespread thrombosis in the microcirculation can contribute to acuteorgan dysfunction or MODS. Levi, Semin Thromb Hemost 2010Semeraro, Mediterr J Hematol Infect Dis 2010

Pathophysiology of sepsis associated coagulopathy(SAC) Fibrin deposition in small and midsize vessels of various organs hasresulted in ischemia and necrosis. Levi, Clin Chest Med 2008 Experimental bacteremia or endotoxemia causes intra andextravascular fibrin deposition in kidneys, lungs, liver, brain, and otherorgans. Kessler, Blood 1997 Levi, Clin Chest Med 2008

Why sepsis associated coagulopathy matters DIC is an independent predictor of organ failure and mortality inpatients with sepsis. Fourrier, Chest 1992 Dhainaut, J Thromb Haemost 2004 Thrombocytopenia is an independent predictor of ICU mortality andhas been shown to be a stronger predictor of ICU mortality thanAPACHE II or MODS score. Vanderschueren, Crit Care Med 2000 Strauss, Crit Care Med 2002

Pathophysiology of sepsis associated coagulopathy(SAC) The pathophysiology of sepsis-associated DIC is extremely complexand extensively studied. The Key event is the systemic inflammatory response to the infectiousagent. Extensive cross talk exists between the coagulation system and theinflammatory response.

Pathophysiology of sepsis associated thrombusformation The causative agent and the associated inflammatory response drivefibrin formation and deposition by several simultaneously actingmechanisms: Up-regulation of procoagulant pathways Down-regulation of physiologic anticoagulants Suppression of fibrinolysis Levi, Semin Thromb Hemost 2010Semeraro, Mediterr J Hematol Infect Dis 2010 Levi, Clin Chest Med 2008

The role of Tissue Factor (TF) In the 1990s it became apparent that the principal initiator ofthrombin generation in sepsis is tissue factor. Van Deventer, Blood 1990 Van der Poll, NEJM 1990 Nullification of the TF-factor VIIa pathway by monoclonalantibodies directed against TF resulted in a complete inhibition ofthrombin generation in endotoxin challenged chimpanzees andprevented DIC and mortality in baboons infused with E. coli. Taylor, Circ Shock 1991 Levi, J Clin Invest 1994Biemond, Thromb Haemost 1995

The role of Tissue Factor (TF) While endothelial cells and mononuclear phagocytes synthesize TF inresponse to a wide variety of conditions, TF expression has beenshown in neutrophils, eosinophils, and activated platelets. Some studies suggest these cells acquire TF rather than synthesize it,by binding TF-expressing microparticles (MP).

So which cell is the main trigger for coagulation? While all mentioned cells might contribute to the aberrant expressionof TF, most studies point to activated monocytes-macrophages asthe main triggers of blood coagulation during sepsis. Further support for the prominent role of monocytes-macrophagescomes from studies investigating the role of MP. MP are small phospholipid vesicles released from cells that carrysurface proteins and are associated with thrombosis andinflammation.

Is there a potential benefit to inhibition of TF? Selective inhibition of TF expressed by non-hematopoietic cellssubstantially reduces the clotting activation in endotoxemic mice. Pawlinski, Thromb Res 2010 Pawlinski, Blood 2010 As the role of ECs and vascular smooth muscle cells remainsuncertain, it is likely that TF up-regulation in parenchymal cells oftarget organs contributes to clotting coagulation during sepsis. Additionally, TF is cleaved from the EC surface and higher elevatedblood levels are reported in pts with severe sepsis with organdysfunction than those without organ dysfunction. Iba, J Jpn Assoc Acute Med 1995

Impairment of anticoagulant pathways in sepsis Three main anticoagulant pathways regulate activation of coagulation: Antithrombin (AT) The Protein C system Tissue Factor Pathway Inhibitor (TFPI)

Impairment of anticoagulant pathways in sepsis:Antithrombin During severe inflammation AT levels are markedly decreased due toconsumption, impaired synthesis, and degradation by elastase fromactivated neutrophils. Vary, Am J Physiol 1992Seitz, Eur J Haematol 1989 Prospective clinical trials have shown a marked decrease in AT precedesthe clinical manifestations of infection, indicating that AT may beinvolved in the early stages of coagulation activation during sepsis. Mesters, Blood 1996Levi, Clin Chest Med 2008 Similarly, elevated levels of TAT have been found in early sepsis. Iba, J Abd Emerg Med 1996

Impairment of anticoagulant pathways in sepsis:Protein C Endothelial dysfunction is even more important in impairment of theProtein C system. Under physiologic conditions, Protein C is activated by thrombin boundto the EC membrane-associated thrombomodulin (TM). During severe inflammation, Protein C levels are decreased fromimpaired synthesis and degradation by neutrophil elastase, and thesystem is defective due to down-regulation of TM at the endothelialsurface, mediated by proinflammatory cytokines (TNF- and IL-1 . Vary, Am J Physiol 1992Eckle, Biol Chem Hoppe Seyler 1991 Nawroth, J Exp Med 1986

Impairment of anticoagulant pathways in sepsis:Protein C: Thrombomodulin In sepsis, both the synthesis and recycling of TM are inhibited,therefore its expression on the endothelial cell surface is suppressed by40-80%. Maruyama, J Biol Chem 1991 TM is cleaved from the EC and TM levels found in blood have beensignificantly elevated in septic patients with MODS. Moore, J Clin Invest 1987

Activation of Protein C and degradation ofthrombomodulin (TM)

Changes in endothelial cell after stimulation ofthrombin receptor by thrombin

The significance of PC deficiency Acquired severe PC deficiency has been associated with early death. Macias, Crit Care Med 2004 APC plasma levels vary markedly in patients with severe sepsis andare significantly higher in survivors, suggesting that endogenous APCserves protective functions. Liaw, Blood 2004 APC has inflammation modulating effects, including down-regulationof cytokines and TF in activated leukocytes, antioxidant properties,anti-apototic activity and prevention of loss of endothelial barrierfunction. Mosnier, Blood 2007; Esmon J Exp Med 2002; Okajima, Immunol Rev 2001

Impairment of anticoagulant pathways in sepsis:TFPI TFPI is the third inhibitory mechanism of thrombin generation and isthe main inhibitor of the TF-factor VIIa complex, binding to the TFfactor VIIa complex and factor Xa. Broze, Biochemistry 1990 Animal models have shown decreased TFPI expression in ECs ofseveral organs. Anti-TFPI antibodies increase fibrin accumulation. Tang, Am J Pathol 2007 TFPI under expression coupled with TF up-regulation, might augmentlocal procoagulant potential, promoting fibrin deposition in tissues.

Impairment of anticoagulant pathways in sepsis:TFPI: a potential treatment? Administration of recombinant TFPI has been shown to blockinflammation-induced thrombin generation in humans. High concentrations of TFPI may be capable of significantlymodulating TF-mediated coagulation. Creasey, J Clin Invest 1993De Jonge, Blood 2000

Plasminogen activator inhibitor-1 (PAI-1) mediatedinhibition of fibrinolysis in sepsis At the time of maximal activation of coagulation in sepsis, thefibrinolytic system is largely shut off. The acute fibrinolytic response to inflammation is the release ofplasminogen activators, particularly tissue plasminogen activator (t-PA),however, this increase in plasminogen activation and subsequentplasmin generation is counteracted by a delayed but sustained increasein PAI-1. Van der Poll, J Exp Med 1991Biemond, Clin Sci (London) 1995 This results in a complete inhibition of fibrinolysis, inadequate fibrinremoval, and microvascular thrombosis.

Suppression of fibrinolysis (hypofibrinolysis) A sustained increase in plasma PAI-1 has been consistently reported inSemeraro, Mediterr J Hematol Infect Dis 2010human sepsis. Elevated PAI-1 levels have been found to correlate with lactate as wellas incidence and severity of organ dysfunction, and persisted in nonsurvivors in small studies of pts in septic shock. Thus a coagulation/fibrinolysis imbalance may contribute to tissuehypoxygenation. Hartemink, J Clin Pathol 2010 Iba, J Jpn Assoc Acute Med 1994 Further evidence of this imbalance: Thrombin causes resistance tofibrinolysis by forming more compact and less permeable clot and byactivating thrombin-activatable fibrinolysis inhibitor (TAFI).

Changes in endothelial function in sepsis