1. Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis/Septic Shock Resident Education Program R. Phillip Dellinger, MD Mitchell M. Levy, MD Janice L. Zimmerman, MD Graham Ramsay, MD For the Surviving Sepsis Campaign

2. Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe Sepsis and Septic Shock Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, and the SSC Management Guidelines Committee Crit Care Med. 2004;32:858-873 Intensive Care Med. 2004;30:536-555 available online at www.springerlink.com www.sccm.org www.sepsisforum.com

3. Initial Resuscitation of Sepsis-induced Tissue Hypoperfusion

6. Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003;31:946-955. See discussion on next slide

7. The physiological changes occurring in patients with severe sepsis and septic shock are myriad and include changes that are clearly detrimental such as decreased contractility of the left and right ventricle, increased venous capacitance, increased pulmonary vascular resistance, and capillary leak. Increased ventricular compliance and sinus tachycardia are likely adaptive responses allowing the ventricle to maintain, and even manifest increased cardiac input, following volume resuscitation in despite decreased contractility. The decreased arteriolar resistance may also be adaptive, although when profound, produces detrimental and potentially lethal hypotension.

8. During Septic Shock See discussion on next slide 10 days post shock Diastole Systole Diastole Systole Images used with permission from Joseph E. Parrillo, MD

9. This slide demonstrates radionuclide angiography in a patient during septic shock and following recovery. The top left panel shows end-diastole and demonstrates increased diastolic size of the ventricles (increased compliance), which is thought to be an adaptive mechanism. The top right image shows end-systole in this patient demonstrating a very low ejection fraction (little change in chamber size compared to end-diastole). The bottom two frames following recovery demonstrate a decrease in end-diastole volume, smaller ventricle at end systole, and therefore significant improvement in ejection fraction.

10. Effects of Dopamine, Norepinephrine, and Epinephrine on the Splanchnic Circulation in Septic Shock See discussion on next slide Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best? Crit Care Med. 2003;31:1659-1667.

11. Considerable data (such as that shown on the previous slide) indicates that epinephrine, although a combined inotrope/vasopressor, is not the best initial vasopressor of choice because of concerns with decrease in splanchnic blood flow. The study above comparing dopamine, norepinephrine, and epinephrine in moderate shock, and norepinephrine and epinephrine in severe shock supports epinephrine-induced decrease in splanchnic blood flow.

14. The Importance of Early Goal-Directed Therapy for Sepsis-induced Hypoperfusion See discussion on next slide Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377. In-hospital mortality (all patients) 0 10 20 30 40 50 60 Standard therapy EGDT 28-day mortality 60-day mortality NNT to prevent 1 event (death) = 6 - 8 Mortality (%)

15. The recommendations for initial resuscitation are centered around the Rivers trial (above) of early goal-directed therapy, which showed significant improvement in (a) hospital mortality, (b) 28-day mortality, and (c) 60-day mortality.

24. Photograph used with permission from Janice L. Zimmerman, MD

25. EKG tracing reproduced with permission from Janice L. Zimmerman, MD

26. This picture demonstrates a 38-year-old man with pharyngitis who presents with high fever, leukocytosis, hypotension, elevated BUN/creatinine, and early evidence of coagulopathy who now has redness and swelling of the anterior neck and chest pain. An EKG obtained in this patient demonstrates a diffuse ST segment elevation (or PR depression) diagnostic of pericarditis, and in this case indicating the presence of mediastinitis requiring urgent operative drainage of the mediastinum in order to prevent mortality.

29. Alternative of using mixed venous oxyhemoglobin saturation from pulmonary artery catheter instead of central venous O2 saturation from CVP catheter

30. Reinhart K, et al. Intensive Care Med. 2004;30:1572-1578.

31. ScvO2 closely paralleled SvO2 but averaged 5 – 7% higher Reinhart K, et al. Intensive Care Med. 2004;30:1572-1578.

32. A central line is inserted in the right neck. CVP is 12 mm Hg. MAP is 70 mm Hg with vasopressor support. Lab results reveal elevated BUN and creatinine. Arterial gases reveal pH 7.22, PaCO2 28 torr, and PaO2 65 torr. Hematocrit is 32% and saturation is 94% with supplement oxygen. The central venous O2 saturation is 60%.

36. Changing pH Has Limited Value See discussion on next slide Treatment Before After NaHCO3 (2 mEq/kg) pH 7.22 7.36 PAOP 15 17 Cardiac output 6.7 7.5 0.9% NaCl pH 7.24 7.23 PAOP 14 17 Cardiac output 6.6 7.3 Cooper DJ, et al. Ann Intern Med. 1990;112:492-498.

37. Cooper and colleagues compared equimolar amounts of sodium bicarbonate and normal saline in patients with vasopressor requiring lactic acidosis (pH range down to 7.15 with mean 7.23) and demonstrated that although pH was significantly increased with bicarbonate versus normal saline there was no difference in cardiac output. There was also no difference between the two groups as to weaning of vasopressors.

39. Circulating Vasopressin Levels in Septic Shock Figure 2, page 1755 reproduced with permission from Sharshar T, Blanchard A, Paillard M, et al. Circulating vasopressin levels in septic shock. Crit Care Med. 2003;31:1752-1758. See discussion on next slide

40. Vasopressin levels are elevated during the initial presentation of septic shock and then decrease to basal levels over the next 48 to 96 hours. Since vasopressin levels are expected to be a normal body response to hypotension, this occurrence has been labeled as relative vasopressin deficiency and has led to the use of vasopressin in patients with septic shock.

43. Steroid Therapy Figure 2A, page 867, reproduced with permission from Annane D, S ébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862-871. See discussion on next slide

44. The largest randomized prospective trial done to study the effect of stress-dose steroids in septic shock is the “French multi-center trial,” which targeted “apriori” patients who did not respond to ATCH stimulation as the group that would likely benefit from steroid therapy (slide shows results in that group). This group represented 77% of the population, and in this group significant improvement in survival by Kaplan-Meier curve with logistic regression adjustment for other variables influencing survival was shown.

45. Figure 2 and Figure 3, page 648, reproduced with permission from Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645-650. Figure 2 and Figure 3, page 727, reproduced with permission from Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27:723-732. See discussion on next slide P = .045 P = .007

46. Single center studies also support significant clinical benefit as to morbidities and/or mortality.

48. Results: 28-day All-cause Mortality Primary analysis results 2-sided p-value 0.005 Adjusted relative risk reduction 19.4% Increase in odds of survival 38.1% Adapted from Table 4, page 704, with permission from Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709. 35 30 25 20 15 10 5 0 30.8% 24.7% Placebo (n - 840) Drotrecogin alfa (activated) (n = 850) Mortality (%) 6.1% absolute reduction in mortality

49. Activated protein C when administered in a blinded, randomized fashion to over 1,600 patients with severe sepsis and septic shock produced a 6.1% absolute reduction in mortality.

54. www.survivingsepsis.org 

55. A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis—hypotension, hypoperfusion, and organ dysfunction. Crit Care Med. 2004;320(Suppl):S595-S597.

56. Actual title of painting is “Hercules Kills Cerberus,” by Renato Pettinato, 2001. Painting hangs in Zuccaro Place in Agira, Sicily, Italy. Used with permission of artist and the Rubolotto family.