1. Christopher Manacci, MSN, ACNP, CFRN Acute Care Nurse Practitioner Critical Care Transport Services The Cleveland Clinic Director, ACNP Flight Nursing Program National Flight Nurse Academy Case Western Reserve University October 26, 2008 Aichi Medical University College of Nursing

2.  Sepsis is a serious medical condition, involving acute organ dysfunction, resulting from an inflammatory and procoagulant response to a severe infection. Bernard, G., Vincent, J.L., Laterre, P.F., LaRosa, S.P., Dhainaut, J.F., et al. (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. The New England Journal of Medicine. 344(10), 699-709.

4.  Abrupt onset of ◦ Fever ◦ Chills ◦ Tachycardia ◦ Tachynpnea ◦ Altered mental status ◦ Hypotension

5.  Vasodilation  Low central filling pressures  Decreased intravascular volume  Reduction in peripheral vascular resistance  Loss of capillary integrity  Increase in cardiac output (initially) Green, G.B., Harris, I.S., Lin, G.A., & Moylan, K.C. (Eds). (2004) The Washington Manual. ST. Louis, MO: Washington University.

6.  Inflammation  Coagulation  Impaired fibrinolysis Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

7.  Sepsis ◦ SIRS + source of infection  Severe Sepsis ◦ Sepsis + organ dysfunction  Septic Shock ◦ Sepsis + hypotension unresponsive to two 20-30 cc/kg fluid challenge ◦ (SBP < 90mm Hg or 40mm below baseline)

8.  WBCs are generated  WBCs release proinflammatory cytokines (proteins that act as nonspecific mediators of inflammation).  Cytokines, such as tumor necrosis factor-alpha, attract neutrophils to the site of infection  Results in endothelial cellular injury. Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

9.  Cytokines stimulate the release of tissue factor from monocytes and endothelial cells.  The coagulation pathway is stimulated resulting in clot formation throughout the microvasculature.  Endothelial dysfunction(caused by the proinflammatory cytokines) decreases thrombomodulin (a protein that binds with thrombin) thus inhibiting the formation of a complex required to convert protein C to activated protein C (an important anti-inflammatory, antithrombotic and profibrinolytic molecule). Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

10.  Activated briefly until inhibited by increased levels of plasminogen activator inhibitor-1 (a protein that reduces fibrinolysis).  Fibrin is deposited in the microcirculation  Additional thrombin activates thrombin-activatable fibrinolysis indicator (potent inhibitor of the endrogenous fibrinolytic system).  Clots remain intact contributing to systemic impairment of microvasculature blood flow to vital organ, multiple organ dysfunction syndrome (MODS) and death. Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

11. Hypotension is caused by decreased vascular tone. Increased cardiac output leads to increased heart rate and end diastolic volumes despite overall myocardial depression. Green, G.B., Harris, I.S., Lin, G.A., & Moylan, K.C. (Eds). (2004) The Washington Manual. ST. Louis, MO: Washington University.

12.  A procoagulant state manifested: ◦ Decreased platelets ◦ Protein C deficiency ◦ Positive D-dimers Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

13.  The rate of death from severe sepsis ranges from 30-50% despite advances in critical care.  750,000 cases of sepsis annually in the U.S.  225,000 cases resulted in mortality. Balk, R.A, Ely, E.W., Goyette, R.E. (2001) Sepsis Handbook. Vanderbilt University Medical Center.

14.  Mortality within 30 days: ◦ ~20-35% of pts with severe sepsis ◦ ~40-60% of pts with septic shock ◦ ~100% of pts with refractory septic shock Braunwald, E., Fauci, A.S., Kasper, D.L. et al. (2002). Harrison’s manual of medicine. USA: McGraw Hill. Dunser, M.W., Mayr, A.J., Ulmer, H. et al. (2003). Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized controlled study. Circulation. 107, 2313- 2319. Van Haren, F.M.P., Rozendaal, F.W., & Vander Hoeven, J.G. (2003). The effect of vasopressin on gastric perfusion in catecholamine-dependent patients in septic shock. Chest. 124, 2256-2260.

15.  Sepsis has continued to rise each year since 1979 and is expected to continue it’s upward trend.  Increasing rates due to: ◦ Increasing number of elderly patients ◦ Increase in immunocompromised patients ◦ Increase in use of invasive procedures ◦ Increased number of resistant microorganisms ◦ Failure diagnose in a timely manner Balk, R.A, Ely, E.W., Goyette, R.E. (2001) Sepsis Handbook. Vanderbilt University Medical Center. Bernard, G., Vincent, J.L., Laterre, P.F., LaRosa, S.P., Dhainaut, J.F., et al. (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. The New England Journal of Medicine. 344(10), 699-709.

16.  Systemic Inflammatory Response Syndrome (SIRS)  The patient must have two or more of these symptoms: ◦ Core temp below 96.8 F (36 C) or above 100.4 F (38 C) ◦ Elevated heart rate (greater than 90 beats/min) ◦ Respiratory rate greater than 20 breaths/min or PaCO2 less than 32 mm Hg ◦ WBC less than 4,000 cells/mm3 or greater than 12,000 cells/ mm3 Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

17.  Sepsis ◦ Known or suspected infection, plus two or more SIRS criteria. Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

18.  Severe Sepsis ◦ Sepsis plus organ dysfunction.  Lactic acidosis  Oliguria  Acute change in mental status Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

19.  4.) Septic Shock ◦ Acute circulatory failure and persistent hypotension despite fluid resuscitation, not explained by other causes. Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1). 38-43.

20.  No reliable laboratory data. Must rely on signs and symptoms.  Laboratory may include ◦ Leukocytosis with left shift ◦ Thrombocytopenia ◦ Hyperbilirubinemia ◦ Proteinuria ◦ Leukopenia ◦ Respiratory alkalosis (early) ◦ Metabolic acidosis (later) Braunwald, E., Fauci, A.S., Kasper, D.L. et al. (2002). Harrison’s manual of medicine. USA: McGraw Hill.

21.  Definitive diagnosis requires isolation of microorganisms from the blood or from a local site of infection.  At least two blood samples should be obtained for culture from different venipuncture sites.  If blood cultures are negative the diagnosis depends on Gram’s stain and culture of the primary site of infection or of secondarily infected cutaneous tissue. Braunwald, E., Fauci, A.S., Kasper, D.L. et al. (2002). Harrison’s manual of medicine. USA: McGraw Hill.

22.  Lactate !!! ◦ Rivers estimated 60-70% of his patients qualified with an elevated lactate ◦ Lactate risk stratifies infected patients Shapiro N. Serum lactate as a predictor of mortality in Emergency Department patients with infection. Ann Emerg Med. 2005;45:524-528.

26.  Initial decrease in systemic vascular resistance and MAP ◦ Ventilatory Support ◦ Hemodynamic Support  Provide volume replacement  Consider vasopressors (norepinephrine) ◦ Treat the infection  Antibiotics  Surgical drainage of abscesses Green, G.B., Harris, I.S., Lin, G.A., & Moylan, K.C. (Eds). (2004) The Washington Manual. ST. Louis, MO: Washington University. Lee, C.S. (2006). Role of exogenous arginine vasopressin in the management of catecholamine-refractory septic shock. Critical Care Nurse. 26(6). 17-23.

27. ◦ Discover the source  Blood, urine and sputum cultures  Paranasal sinuses  Abscesses or pelvic fluid collections  Consider urethral and IV catheters and wounds

28.  The response of volume replacement and catecholamine vasopressors is often temporary in septic shock and may require more aggressive treatment options.  Extremely high mortality rate (close to 100%) Dunser, M.W., Mayr, A.J., Ulmer, H. et al. (2003). Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized controlled study. Circulation. 107, 2313- 2319. Van Haren, F.M.P., Rozendaal, F.W., & Vander Hoeven, J.G. (2003). The effect of vasopressin on gastric perfusion in catecholamine-dependent patients in septic shock. Chest. 124, 2256-2260.

29.  Although initially effective in achieving hemodynamic stability, high dose catecholamines are associated with several adverse effects and do not significantly improve outcome measures in refractory septic shock. Patel, F.M., Chittock, D.R., Russell, J.A., & Walley, K.R. (2002). Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 96, 576-582. Tsuneyoshi, I., Ymada, H. Kakihana, Y. et al. (2001). Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Critical Care Medicine. 29, 487-493.

30.  Recombinant Human Activated Protein C  aka [Drotrecogin alfa (activated)], Xigris ◦ Antithrombotic ◦ Antiinflammatory ◦ Profibrinolytic Significantly reduces mortality in patients with severe sepsis. Bernard, G., Vincent, J.L., Laterre, P.F., LaRosa, S.P., Dhainaut, J.F., et al. (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. The New England Journal of Medicine. 344(10), 699-709.

31.  Exogenous arginine vasopressin ◦ Maintains cardiovascular homeostasis by regulating serum osmolality. ◦ Use in conjunction with norepinephrine ◦ Acts as a catecholamine-independent vasoconstrictor in states of physiological shock ◦ Benefits- increased MAP, decrease in norepinephrine requirement, increased urine output, ◦ Adverse Effects-bradycardia, decrease in oxygen delivery, and decreased cardiac index Lee, C.S. (2006). Role of exogenous arginine vasopressin in the management of catecholamine-refractory septic shock. Critical Care Nurse. 26(6). 17-23.

32.  Glucocorticoid supplementation (hydrocortisone)  Indicated only in the rare instance of adrenal insufficiency  Suspect in cases of: ◦ Refractory Hypotension ◦ Neisseria meningitidis bacteria ◦ Disseminated tuberculosis ◦ Prior glucocorticoid use ◦ AIDS Braunwald, E., Fauci, A.S., Kasper, D.L. et al. (2002). Harrison’s manual of medicine. USA: McGraw Hill. Green, G.B., Harris, I.S., Lin, G.A., & Moylan, K.C. (Eds). (2004) The Washington Manual. ST. Louis, MO: Washington University.

33.  Best opportunity to reduce morbidity and mortality from sepsis ◦ Minimize number of invasive procedures ◦ Limit use and duration of indwelling vascular and bladder catheters ◦ Reduce the incidence and duration or profound neutropenia ◦ Aggressively treat localized infection ◦ Immunize patients as appropriate Braunwald, E., Fauci, A.S., Kasper, D.L. et al. (2002). Harrison’s manual of medicine. USA: McGraw Hill.

34.  Balk, R.A, Ely, E.W., Goyette, R.E. (2001) Sepsis handbook. Vanderbilt University Medical Center.  Bernard, G., Vincent, J.L., Laterre, P.F., LaRosa, S.P., Dhainaut, J.F., et al. (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. The New England Journal of Medicine. 344(10), 699-709.  Braunwald, E., Fauci, A.S., Kasper, D.L. et al. (2002). Harrison’s manual of medicine. USA: McGraw Hill.  Cheek, D.J., McGehee-Smith, H., Cunneen, J., & Cartwright, M. (2005). Sepsis: Taking a deeper look. Nursing 2005. 35(1), 38-43.  Dunser, M.W., Mayr, A.J., Ulmer, H. et al. (2003). Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized controlled study. Circulation. 107, 2313-2319.

35.  Green, G.B., Harris, I.S., Lin, G.A., & Moylan, K.C. (Eds). (2004) The Washington Manual. ST. Louis, MO: Washington University.  Lee, C.S. (2006). Role of exogenous arginine vasopressin in the management of catecholamine-refractory septic shock. Critical Care Nurse. 26(6). 17-23.  Patel, F.M., Chittock, D.R., Russell, J.A., & Walley, K.R. (2002). Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 96, 576-582.  Tsuneyoshi, I., Ymada, H. Kakihana, Y. et al. (2001). Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Critical Care Medicine. 29, 487-493.  Van Haren, F.M.P., Rozendaal, F.W., & Vander Hoeven, J.G. (2003). The effect of vasopressin on gastric perfusion in catecholamine-dependent patients in septic shock. Chest. 124, 2256-2260.