UPDATES IN SEPSIS MANAGEMENT Shannon Fry, Pharm.D. Critical Care Pharmacy Specialist St. Joseph Medical Center ShannonFry@fhshealth.org DISCLOSURE I have no financial relationships to disclose OBJECTIVES At the completion of this program, the participant will be able to: Describe the 2012 Sepsis Campaign Guidelines List new sepsis management trials Cite evidence for recent updates to the 2012 Surviving Sepsis Campaign Guidelines Critically analyze new evidence regarding sepsis management and its place in therapy guidance 1
SELF-ASSESSMENT QUESTIONS What guideline updates have been released by the Surviving Sepsis Campaign Committee? How have the ProCESS, ARISE and ProMISe studies influenced the 2012 Surviving Sepsis Campaign Guidelines? What have the conclusions been of recent trials regarding early goal-directed therapy in sepsis management? How does the newest evidence in sepsis management influence the use of the current Surviving Sepsis Campaign Guidelines? SURVIVING SEPSIS GUIDELINE REVIEW SEPSIS Definitions The presence of infection together with systemic manifestations of infection SIRS plus infection Severe sepsis is sepsis associated with organ dysfunction or tissue hypoperfusion Septic shock is sepsis-induced hypotension persisting despite adequate fluid resuscitation Sepsis-induced tissue hypoprofusion is hypoperfusion persisting after initial fluid challenge or blood lactate 4 2
GRADING Quality of evidence A- high quality B- intermediate C- low D- very low Case series or expert opinion Strength of recommendation 1- strong recommendation We recommend 2- weak recommendation We suggest SURVIVING SEPSIS CAMPAIGN 1 A collaboration between the U.S. Society of Critical Care Medicine (SCCM), the European Society of Intensive Care Medicine, and the International Sepsis Forum Consensus committee of 65 international experts representing 26 international organizations Last updated 2012 Continues to recommend early goal-directed therapy INITIAL RESUSCITATION, SCREENING AND DIAGNOSIS Goals for resuscitation (1C): CVP 8-12 MAP 65 UOP 0.5 ml/kg/hr ScvO2 70% or SvO2 65% Resuscitation should target normalization of lactate levels in facilities that do not have the capability to target central venous oxygenation saturation (2C) Screening processes should occur to assist in early sepsis identification (1C) Cultures should be obtained before antimicrobial therapy initiation (1C) Diagnostic assays could be utilized in patients at risk for fungal sepsis (2B-C) 3
INFECTION ISSUES: ANTIMICROBIAL THERAPY Administration of effective IV antimicrobial within the first hour of recognition of septic shock and severe sepsis (1C) Regimen should be assessed daily for potential de-escalation (1B) Empiric combination therapy should be considered in neutropenic patients, or those with risk factors for MDROs (2B) Typical duration of therapy 7-10 days (2C) Procalcitonin should not be used as a diagnostic tool for severe sepsis (2C) Low procalcitonin levels can be used as a marker for discontinuation of empiric antibiotics INFECTION ISSUES: SOURCE CONTROL AND INFECTION PREVENTION Recommends rapid diagnosis and intervention as appropriate for source control (1C) Digestive tract and oropharyngeal decontamination may be investigated to reduce VAP (2B) Oral chlorhexidine gluconate FLUID THERAPY The use of crystalloids for initial fluid resuscitation is recommended (1B) Albumin may be added to the initial fluid resuscitation (2C) Hydroxyethyl startches (hetastarches) with molecular weight greater than 200 daltons or a degree of substitution more than 0.4 should not be used (1B) The initial fluid challenge in suspected hypovolemic patents should be 1 L or more to achieve a minimum of 30 ml/kg (1C 4
VASOPRESSORS AND INOTROPIC THERAPY Norepinephrine is identified as the first-choice vasopressor (1B) Epinephrine may be added or substituted (2B) Vasopressin 0.03 units/minute may be added (UG) Dopamine is identified as an alternative vasopressor in patients at very low risk of arrhythmias, and with a low cardiac output and/or heart rate (2C) Dobutamine may be started or added to a vasopressor in the presence of myocardial dysfunction or ongoing signs of hypoperfusion (1C) STEROIDS IV corticosteroids should not be used if fluid resuscitation or vasopressor therapy is able to restore hemodynamic stability (2C) When hemodynamic stability cannot be achieved, hydrocortisone 200 mg daily as a continuous infusion is recommended (2C-D) No value to ACTH stimulation testing (2B) OTHER SUPPORTIVE THERAPIES Blood product administration based on labs (1B-2D) Mechanical ventilation of sepsis-induced ARDS Higher levels of PEEP are recommended (2C) Recruitment maneuvers may be used in patients with severe hypoxemia on high PEEP and FiO2 (2C) Prone position can be considered for patients with PaO2/FiO2 ratios < 100 (2B) Conservative fluid use when tissue hypoprofusion is not present (1C) Recommend against beta 2-agonist use without indication (1B) Glycemic control to goal glucose levels 180 (1A) Recommends enteral feeding over parenteral nutrition for first 7 days (2B) 5
SURVIVING SEPSIS CAMPAIGN BUNDLES To be completed within 3 hours Measure lactate level Obtain blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30 ml/kg crystalloids for hypotension or lactate 4 To be completed within 6 hours Initiate vasopressors for hypotension not responsive to initial fluid resuscitation to maintain a MAP 65 If persistent arterial hypotension despite volume resuscitation, or initial lactate 4, measure CVP and ScvO2 Remeasure lactate if initial was elevated RECENT RESEARCH EARLY GOAL-DIRECTED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEPTIC SHOCK 2 Primary basis for EGDT 2001 randomized study enrolling 263 patients Patients received either 6 hour EGDT or standard therapy Primary outcome: hospital mortality Results: EGDT mortality 30.5%; standard therapy 46.5% P=0.009 Significant decrease in mortality seen with EGDT 6
PROCESS TRIAL 3 2014 randomized study enrolling 1341 patients Patients randomized to one of three groups for comparison Protocol-based EGDT Protocol-based standard therapy Usual care Primary outcome: 60-day in-hospital mortality Results: EGDT mortality 21%, PBST mortality 18.2%, UC mortality 18.9% Found no significant difference in outcomes between groups ARISE TRIAL 4 2014 randomized study enrolling 1600 patients Patients randomized to received either EGDT or usual care Primary outcome: 90-day all-cause mortality Results: EGDT mortality 18.6%, UC mortality 18.8% Found mortality benefit from EGDT META-ANALYSIS 5 2014 review Effect of goal-directed therapy on mortality 13 trials including 2,525 patients Did not include the ARISE Trial GDT significantly reduced overall mortality RR 0.83 (95% CI 0.71-0.96) Subgroup analysis Only EGDT (within first 6 hours) had mortality benefit RR 0.77 (95% CI 0.67-0.89) VS RR 0.92 (95% CI 0.69-1.24) 7
PROMISE TRIAL 6 2015 randomized trial enrolling 1260 English patients Patients randomized to 6-hour EGDT protocol or usual care Primary outcome: 90-day all-cause mortality Results: EGDT mortality 29.5%, UC mortality 29.2% Found no significant mortality benefit with EGDT EGDT was associated with increased costs IMPRESS STUDY 7 2015 prospective, observational, quality improvement study Examined the effects of compliance with the 3- hour and 6-hour Surviving Sepsis Campaign bundles on outcomes 1,794 patients from 62 countries Overall compliance with all 3 hour bundle metrics was 19% Associated with improved hospital mortality (20 vs 31%, p<0.001) 6 hour bundle matric compliance was 36% Associated with improved hospital mortality (22 vs 32%, p< 0.001) Compliance with bundles significantly decreased mortality APPLYING THE LITERATURE 8
SURVIVING SEPSIS CAMPAIGN BUNDLES UPDATES To be completed within 3 hours Measure lactate level Obtain blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30 ml/kg crystalloids for hypotension or lactate 4 To be completed within 6 hours Initiate vasopressors for hypotension not responsive to initial fluid resuscitation to maintain a MAP 65 If persistent arterial hypotension despite volume resuscitation, or initial lactate 4, reassess volume status and tissue perfusion by either: Repeat focused exam by provider, including vital signs, cardiopulmonary review, capillary refill, pulse, and skin findings, OR Two of the following: measure CVP, measure ScvO2, bedside cardiac echo, or dynamic assessment of fluid responsiveness via passive leg raise for fluid challenge Remeasure lactate if initial was elevated EGDT- WHERE DO WE GO NOW? Is EGDT debunked? Critically review the literature What is usual care? Has this changed? External validity APACHE II scores Mortality rates ROLE OF EGDT Beneficial elements that are now part of usual care Early detection Antibiotics within 1 hour Adequate fluid resuscitation Elements that may not be necessary Oximetric monitoring Inotropes Others? 9
CMS REQUIREMENTS CMS REQUIREMENTS Implemented October 1, 2015 Within 3 hours of severe sepsis presentation Lactate level Blood cultures drawn prior to antibiotics Broad spectrum antibiotics Administer 30 ml/kg crystalloid fluids for hypotension or lactate 4 Within 6 hours Repeat lactate if initial level >2 IF persistent hypotension after fluids Vasopressors to maintain MAP 65 mmhg Repeat volume status and tissue perfusion assessment Also required if initial lactate was 4 CMS REQUIREMENTS The terms severe sepsis or septic shock must be used to clearly define time zero Any delineation from protocol must be supported by patient or family refusal of treatment For patients with septic shock, repeat volume status and tissue perfusion assessment can be done in 2 ways: Focused provider exam documenting vital signs, cardiopulmonary exam, capillary refill, peripheral pulses, skin color and circulation Two of the following: CVP measurement, ScvO2 measurement, bedside cardiac echo, passive leg raise or fluid challenge 10
SUMMARY SUMMARY Guidelines recommend early goal-direct therapy New data may suggests lack of benefit from EGDT Confounded by the definition of standard of care CMS requirements follow EGDT SELF-ASSESSMENT QUESTIONS What guideline updates have been released by the Surviving Sepsis Campaign Committee? How have the ProCESS, ARISE and ProMISe studies influenced the 2012 Surviving Sepsis Campaign Guidelines? What have the conclusions been of recent trials regarding early goal-directed therapy in sepsis management? How does the newest evidence in sepsis management influence the use of current Surviving Sepsis Campaign Guidelines? 11
QUESTIONS? REFERENCES 1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. 2. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. 3. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. 4. ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. 5. Gu WJ, Wang F, Bakker J, Tang L, Liu JC. The effect of goal-directed therapy on mortality in patients with sepsis - earlier is better: a meta-analysis of randomized controlled trials. Crit Care. 2014 Oct 20;18(5):570. 6. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM; ProMISe Trial Investigators. Trial of early, goaldirected resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. 7. Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D, Divatia J, Du B, Evans L, Ferrer R, Girardis M, Koulenti D, Machado F, Simpson SQ, Tan CC, Wittebole X, Levy M. The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med. 2015 Sep;41(9):1620-8. 12