Surviving Sepsis Campaign Guidelines for Management of Severe

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

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

Initial Resuscitation of Sepsisinduced Tissue Hypoperfusion

Sepsis-induced Tissue Hypoperfusion Persistent hypotension after initial fluid bolus of 20 ml/kg crystalloid or colloid equivalent Lactate > 4. 0 mmol/liter

A 62 -year-old man comes to the emergency department with altered mental status, tachycardia, tachypnea, and hypotension (BP 64/38 mm Hg). He has fever with leukocytosis, platelet count 75, 000, and INR 2. 0. A fluid bolus is being administered. Which adrenergic agents are most appropriate to maintain blood during fluid bolus and following fluid bolus if hypotension persists? ? A. B. C. D. Dopamine or epinephrine Epinephrine or vasopressin Vasopressin or norepinephrine Norepinephrine or dopamine

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

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.

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

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.

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.

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.

Vasopressors Either norepinephrine or dopamine administered through a central catheter is the initial vasopressor or choice. • Failure of fluid resuscitation • During fluid resuscitation

Following 2 liters of crystalloid infusion, the patient continues to require vasopressors to maintain systolic blood pressure of 90 mm Hg. Which one of the following is the most important intervention? A. B. C. D. Infusion of 300 - 500 ml of colloid over 30 minutes Obtain an estimate of left heart filling pressures Administration of stress dose steroids Administration of rh APC

The Importance of Early Goal-Directed Therapy for Sepsis-induced Hypoperfusion See discussion on next slide NNT to prevent 1 event (death) = 6 - 8 60 Mortality (%) 50 Standard therapy EGDT 40 30 20 10 0 In-hospital mortality (all patients) 28 -day mortality 60 -day mortality 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.

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.

Initial Resuscitation of Persistent Hypotension or Lactate > 4 mm/L Insertion of CVP catheter Goal: Central venous pressure: > 8 mm Hg

Fluid Therapy Fluid resuscitation may consist of natural or artificial colloids or crystalloids.

Antibiotics Selection depends on: • • Presumed site of infection Gram stain results Suspected or known organism (includes risk for fungal infection) Resistance patterns of the hospital

Diagnosis Appropriate cultures Minimum two blood cultures • one percutaneous • one from each vascular access 48 hours

Antibiotic Therapy Begin intravenous antibiotics within first hour of recognition of severe sepsis.

Antibiotic Therapy One or more drugs active against likely bacterial or fungal pathogens. Consider microorganism susceptibility patterns in the community and hospital.

Antibiotic Therapy Reassess antimicrobial regimen at 48 - 72 hours • • Microbiologic and clinical data Narrow-spectrum antibiotics Noninfectious cause identified Prevent resistance, reduce toxicity, reduce costs

Source Control Evaluate patient for a focused infection amendable to source control measures including abscess drainage or tissue debridement. • Move rapidly • Consider physiologic upset of measure • Intravascular access devices

Photograph used with permission from Janice L. Zimmerman, MD

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

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.

Which of these options is a goal of initial resuscitation that has been demonstrated to decrease mortality in sepsisinduced tissue hypoperfusion? A. B. C. D. Heart rate < 90/min Mean arterial pressure > 65 mm Hg Normalization of lactate Central venous saturation 70%

Guidelines for the Management of Septic Shock Initial Resuscitation Goals : Central venous (superior vena cava) oxyhemoglobin saturation 70%

Alternative of using mixed venous oxyhemoglobin saturation from pulmonary artery catheter instead of central venous O 2 saturation from CVP catheter

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

Scv. O 2 closely paralleled Sv. O 2 but averaged 5 – 7% higher Reinhart K, et al. Intensive Care Med. 2004; 30: 1572 -1578.

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 p. H 7. 22, Pa. CO 2 28 torr, and Pa. O 2 65 torr. Hematocrit is 32% and saturation is 94% with supplement oxygen. The central venous O 2 saturation is 60%.

Which one of the following is most appropriate at this time? A. B. C. D. Packed red blood cells Intravenous bicarbonate Dobutamine Diuresis

Initial Resuscitation Goals: Central venous or mixed venous O 2 sat < 70% after CVP of 8 – 12 mm Hg Packed RBCs to Hct 30% Dobutamine to max 20 g/kg/min

Bicarbonate Therapy Bicarbonate therapy not recommended to improve hemodynamics in patients with lactate induced p. H > 7. 15 Cooper, et al. Ann Intern Med. 1990; 112: 492 -498. Mathieu, et al. Crit Care Med. 1991; 19: 1352 -1356.

Changing p. H Has Limited Value See discussion on next slide Treatment Na. HCO 3 (2 m. Eq/kg) p. H PAOP Cardiac output 0. 9% Na. Cl p. H PAOP Cardiac output Before After 7. 22 15 6. 7 7. 36 17 7. 5 7. 24 14 6. 6 7. 23 17 7. 3 Cooper DJ, et al. Ann Intern Med. 1990; 112: 492 -498.

Cooper and colleagues compared equimolar amounts of sodium bicarbonate and normal saline in patients with vasopressor requiring lactic acidosis (p. H range down to 7. 15 with mean 7. 23) and demonstrated that although p. H 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.

Dobutamine is begun and titrated to 10 g/kg/min with central venous O 2 sat measurement increasing to 72%. CVP is 12 mm Hg. Norepinephrine is being administered at 5 ug/min with a MAP of 70. Repeat laboratory values include platelet count of 55, 000/mm 3 and INR 2. 5. Patient is intubated and mechanically ventilated for ARDS. FIO 2 is 1. 0, PEEP is 10 cm H 2 O with PAO 2 of 70 mm Hg. Which one of the following is least indicated at this time? A. B. C. D. Increase in end-expiratory pressure Administration of stress dose steroids Administration of rh APC Administration of vasopressin

Circulating Vasopressin Levels in Septic Shock See discussion on next slide 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.

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.

Vasopressin and Septic Shock Vasopressin levels · Sustained in cardiogenic shock · Fall over time in septic shock When administered in septic shock, decreases or eliminates requirements of traditional pressors A concern is that as a pure vasopressor expected to decrease stroke volume and cardiac output

Vasopressors Vasopressin Not a replacement for norepinephrine or dopamine as a first-line agent Consider in refractory shock despite high-dose conventional vasopressors If used, administer at 0. 01 - 0. 04 units/minute in adults

Steroid Therapy See discussion on next slide Figure 2 A, page 867, reproduced with permission from Annane D, Sébille 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.

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.

See discussion on next slide P =. 045 P =. 007 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.

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

Steroids Treat patients who still require vasopressors despite fluid replacement with hydrocortisone 200 - 300 mg/day, for seven days in three or four divided doses or by continuous infusion.

Results: 28 -day All-cause Mortality 2 -sided p-value Adjusted relative risk reduction Increase in odds of survival Primary analysis results 0. 005 19. 4% 38. 1% 35 30. 8% 30 24. 7% Mortality (%) 25 20 15 10 Placebo (n - 840) Drotrecogin alfa (activated) (n = 850) 5 0 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. 6. 1% absolute reduction in mortality

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.

Patient Selection for rh. APC Full support patient Infection induced organ/system dysfunction as a cause of high risk of death

Recombinant Human Activated Protein C (rh. APC) High risk of death - Any of the following: • • APACHE II 25 Sepsis-induced multiple organ failure Septic shock Sepsis induced ARDS No absolute contraindications Weigh relative contraindications

Sepsis Resuscitation Bundle Serum lactate measured. Blood cultures obtained prior to antibiotic administration. From the time of presentation, broad-spectrum antibiotics administered within three hours for ED admissions and one hour for non-ED ICU admissions. In the event of hypotension: • Minimum of 20 ml/kg of crystalloid (or colloid equivalent) delivered. • For hypotension not responding to volume resuscitation, vasopressors employed to maintain mean arterial pressure (MAP) > 65 mm Hg. In the event of persistent arterial hypotension refractory to volume resuscitation (septic shock) and/or initial lactate > 4 mmol/L (36 mg/dl): • Central venous pressure (CVP) of > 8 mm Hg achieved. • Central venous oxygen saturation (Scv. O 2) of > 70% achieved. * *Achieving a mixed venous oxygen saturation (Sv. O 2) of 65% is an acceptable alternative.

Sepsis Management Bundle Low-dose steroids administered for septic shock in accordance with a standardized ICU policy. Drotrecogin alfa (activated) administered in accordance with a standardized ICU policy. Glucose control maintained > lower limit of normal, but < 150 mg/dl (8. 3 mmol/L). For mechanically ventilated patients inspiratory plateau pressures maintained < 30 cm H 2 O.

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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): S 595 -S 597.

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.

References Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32: 858 -873. Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003; 31: 946 -955. 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. Annane D, Sebille 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: 862871.

References 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. Cohen J, Brun-Buisson C, Torres A, et al. Diagnosis of infection in sepsis: an evidence-based review. Crit Care Med. 2004; 32: S 466 -S 494. Bochud PY, Bonten M, Marchetti O, et al. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004; 32: S 495 -S 512. Marshall JC, Maier RV, Jimenez M, et al. Source control in the management of severe sepsis and septic shock: an evidencebased review. Crit Care Med. 2004; 32: S 513 -S 526.