Advancements in Sepsis

Objectives Advancements in Sepsis Brian Gilbert, PharmD PGY-1 Pharmacy Resident Jackson Memorial Hospital 3/13/2016 www.fshp.org Pharmacist objectives Review recent updates in resuscitation strategies Describe different monitoring updates Analyze appropriate use of adjuvant therapies Pharmacy Technician objectives Describe pathophysiology of sepsis Define systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock List guideline recommended sepsis treatment goals 3 Disclosure I have no disclosures to report. Epidemiology Sepsis is a leading cause of death in the U.S. and most common among ICU patients The associated cost of treating septic patients is rising with an estimated cost of $24 billion in 2013 Sepsis mortality rates have been reported as high as 60% End organ damage is the strongest predictor of mortality 2 Virulence. 2014 Jan 1; 5(1): 4 11 4 1

Risk Factors for Development of Sepsis Host Response to Sepsis Age Elderly Neonatal Immunocompromised Solid organ transplant HIV Diabetes Predisposing comorbidities COPD Cancers Recent hospitalization Prior antimicrobial exposure within past 30 days Prior hospitalization within past 90 days Ann Epidemiol. 2016 Jan;26(1):66-70 5 N Engl J Med 2013; 369:840-851 Inflammatory Mediators Pathophysiology of Organ Failure Pro-inflammatory Interleukin-1,6,12 TNFa Anti-inflammatory Interleukin-4,10 TGF-β 6 N Engl J Med 2013; 369:840-851 2

Sepsis As A Continuum? Systemic Inflammatory Response Syndrome (SIRS) Criteria Variable Fever Description >38 C or<36 C White blood cell count >12,000 or <4,000 Heart rate Tachypnea > 90 beats per minute > 20 breaths/min SIRS Sepsis Severe Sepsis Septic Shock Thrombocytopenia <100,000 Hyperlactatemia Creatinine >1 mmo/l Increase >0.5 mg/dl 9 11 Hot Off The Presses! Sepsis SIRS criteria + JAMA. 2016;315(8):801-810 10 http://www.gaspirtz.com/images/cartoons/bacteria.jpg JAMA. 2016;315(8):801-810 3

New Sepsis Definition Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection Variable Urine output Acute lung injury Acute lunginjury Creatinine Bilirubin Severe Sepsis Description <0.5 ml/kg/hr for more than 2 hours despite adequate fluid PaO2/FiO2 <250 in the absence of pneumonia PaO2/FiO2 <200 in the presence of pneumonia > 2.0 mg/dl > 2 mg/dl Platelet count < 100,000 INR > 1.5 JAMA. 2016;315(8):801-810 13 Sequential Organ Failure Assessment New Severe Sepsis The task force emphasis on life-threatening organ dysfunction is consistent with the view that cellular defects underlie physiologic and biochemical abnormalities within specific organ systems. Under this terminology, severe sepsis "becomes superfluous. JAMA. 2016;315(8):801-810 14 JAMA. 2016;315(8):801-810 16 4

Septic Shock Definitions Summary Sepsis + hypotension refractory to fluid resuscitation Complex disease state with poorest prognosis Old Classification SIRS nonspecific signs of inflammation Sepsis SIRS + suspected infection New Classification SOFA quantitative measure of organ failure Sepsis organ dysfunction caused by dysregulated host response to infection; SOFA >2 Severe sepsis sepsis induced organ failure Severesepsis all sepsis is associated with organ failure; therefore severe sepsis is redundant Septic shock sepsis inducedhypotension refractory to fluids Septic shock subsetof sepsis defined by persistent hypotension requiring vasopressors to maintain MAP = 65 mmhg despite adequate fluid resuscitation 19 New Septic Shock Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.persisting hypotension requiring vasopressors to maintain MAP=65 mmhg and having a serum lactate level > 3 mg/dl despite adequate volume resuscitation Current Recommended Surviving Sepsis Campaign Treatment Goals To be completed in 3 hours: Measure lactate level Obtain blood cultures prior to antibiotic administration Broad spectrum antibiotics Administer 30 ml/kg of crystalloids for hypotension or lactate > 4mmol/L To be completed in 6 hours: Apply vasopressors for fluid refractory hypotension Measure central venous pressure (CVP), central venous oxygen saturation (ScVO2) Re-measure lactate levels JAMA. 2016;315(8):801-810 18 20 5

Rivers et. al (2001) Foundation of early goal directed therapy (EGDT) EGDT group: received more fluids, vasopressors, and RBCs Mortality 28 day and 60 day mortality 30.5% vs. 46.5% in hospital mortality (p=0.009) The Rivers Trial The PROCESS Trial Randomized un-blinded controlled trial Objective: To determine effectiveness of EGDT Primary endpoint:60 day mortality N=1341 septic shock patients from 31 U.S. academic centers Three study groups: EGDT; protocolizedstandard therapy (PST); usual care N Engl J Med. 2001;345(19):1368-77. N Engl J Med 2014;370:1683-93 23 Recent Challenges to the Rivers Trial The PROCESS Trial The PROCESS Trial Results Group (n) 60 day mortality (%) Average ICU days 90 day mortality (%) The ARISE Trial EGDT (439) PST (446) Usual Care (456) 92 (21.0) 81 (18.2) p=0.83 86 (18.9) 5.1±6.3 5.1 ±7.1 p=0.63 4.7 ±5.8 129 (31.9) 128 (30.8) p=0.66 139 (33.7) The PROMISE Trial N Engl J Med 2014;370:1683-93 N Engl J Med 2014; 371:1496-1506 N Engl J Med 2015; 372:1301-131 22 N Engl J Med 2014;370:1683-93 24 6

The ARISE Trial The PROMISE Trial Randomized un-blinded controlled trial Randomized un-blinded controlled trial Objective: To determine effectiveness of EGDT Objective: To determine the effectiveness of EGDT Primary endpoint: 90 day mortality Primary endpoint: 90 day all cause mortality N=1591 septic shock patients from New Zealand and Australia N=1251 septic shock patients from the U.K. Two study groups: EGDT; usual care Two study groups: EGDT; usual care N Engl J Med 2014; 371:1496-1506 25 N Engl J Med 2015; 372:1301-131 27 The ARISE Trial Results The PROMISE Trial Results N Engl J Med 2014; 371:1496-1506 26 N Engl J Med 2015; 372:1301-131 28 7

EGDT Final Challenge Albumin Use in Septic Shock Meta-analysis; n=4735 Angus et al Rivers Trial (2001) Jones Trial (2010) PROCESS (2014) ARISE (2014) PROMISE (2015) Intensive Care Med. (2015) 41:1549 60 Results Mortality No difference between control group vs. EGDT p=0.90 Organ support Vasopressor use increased in EGDT group p<0.001 ICU length of stay EGDT was associated with higher ICU admission p<0.001 29 Increases oncotic pressure and increased intravascular volume Antioxidant and anti-inflammatory properties Acts as a buffer for acid-base equilibrium SSC recommends the use of albumin for severe sepsis and septic shock patients who require large volumes of crystalloids (grade 2C) N Engl J Med. 2014; 370(18):1683-93 31 Surviving Sepsis Campaign (SSC) Update ALBIOS Trial n=1795 Randomized controlled trial Objective: To establish effectiveness of daily albumin replacement in patients with severe sepsis Randomized to receive either crystalloids ±20% albumin daily Primary outcome: 28 day mortality 30 http://www.fabulousnurse.com/wp-content/uploads/2012/05/fun-with-nursing-cartoons-1024x760.jpg N Engl J Med. 2014; 370(18):1683-93 32 8

ALBIOS Results SEPSISPAM Trial Albumin Replacement Group No difference in 28 day mortality between both groups (p=0.94) Higher liver and coagulation SOFA sub-scores Shorter amount of time spent on vasopressors (p=0.007) Crystalloids Only Group No difference in time spent on mechanical ventilation, RRT, or reported acute kidney injuries No difference in ICU or hospital length of stay Lower cardiovascular SOFA subscore Multi-center open label randomized trial Objective: To determine if higher MAPs during septic shock would lead to lower mortality N=776 septic shock patients Patients were stratified into two groups; MAP (80-85) or MAP (65-70) N Engl J Med. 2014; 370(18):1683-93 33 N Engl J Med. 2014. Apr 24; 370(17):1583-93 35 Mean Arterial Pressure (MAP) in Sepsis Observational studies have shown association between MAP > 65 and good clinical outcomes Indirect sign of systemic perfusion Individualize to patients SEPSISPAM Results Outcome Lower Target; n (%) Higher Target; n (%) p Value 28 day mortality 132 (34.0) 142(36.6) 0.57 90 day mortality 164 (42.3) 170 (43.8) 0.74 Avg. days of vasopressor therapy 3.7 ± 3.2 4.7 ± 3.7 0.0001 Organ support at day 28 241 (62.1) 235 (60.6) 0.66 Rate of new onset A-fib 11 (2.8) 26(6.7) 0.02 Initial 6 hour SSC bundle calls for maintaining MAP > 65 Fluids Vasopressors 34 N Engl J Med. 2014. Apr 24; 370(17):1583-93 36 9

TRISS Trial Biomarkers SSC Recommendations are to transfuse patients in septic shock to maintain hematocrit > 30% in first 6 hours of resuscitation Hemoglobin should be maintained 7-9 g/dl in most patients Data is limited to support these recommendations n=998 patients Multicenter randomized parallel-group trial Stratified to receive transfusion based off their hemoglobin (<7 or <9) All transfusions consisted of one unit of packed red blood cells N Engl J Med. 2014. 371(15): 1381-91 37 39 TRISS Results ProcalcitoninRole in Sepsis Production is increased during bacterial infections Mixed data on its utility in critically ill patients SSC suggests that low procalcitonin(pct) can assist for the discontinuation of antibiotics (Low level of evidence; 2C) No consensus on cut off values or initial PCT value as it relates to sight and severity of sepsis Highly specific Low sensitivity N Engl J Med. 2014. 371(15): 1381-91 38 Am J Respir Crit Care Med. 2014 Nov 15;190(10) 40 10

Procalcitonin Selenium Shehabi et al. (2014); n=394 Blinded RCT PCT algorithm in critically ill adults with suspected sepsis or undifferentiated infection Primary outcome: Time to antibiotic cessation, hospital discharge or death Am J Respir Crit Care Med. 2014 Nov 15;190(10) PCT Algorithm 1) Cease antibiotics if: Initial or any subsequent PCT value is <0.10 ng/ml Initial or any subsequent PCT value is 0.1-0.25 ng/ml where infection is highly unlikely Subsequent PCT levels have decreased 90% of baseline 2) Asses antibiotic appropriateness and/or adequacy of source control if PCT level at 48 hours > 70% of baseline 41 Oxidative stress in the form of reactive oxygen species is associated with multi-organ failure Selenium is an important precursor in the development of free radical scavengers It causes positive immune modulation in vivo Serum selenium values are lower amongst septic patients SSC does not recommend the use of IV selenium (grade 2C) J Crit Care. 2014 Feb;29(1):150-6 43 Study Results Selenium Supplementation Study Group Intervention Mortality Benefit LOS Benefit MV Benefit Mishraet al (2007) Angstwurm etal (2007) Valenta et al (2011) Angstwurm et al (1999) Continuousinfusion of 474 μg x 3 days 1 mg bolus;then 1 mg continuous infusion x 14 days 1 mg bolus;then 1.5 mg continuous infusion x 14 days 535μg x 3 days 285 μg x 3 days 155 μg x 3 days No N/A N/A N/A Yes Yes N/A N/A Yes No No No Am J Respir Crit Care Med. 2014 Nov 15;190(10) 42 Crit Care, 11 (2007), p. R73 Crit Care Med, 26 (1998), pp. 1536 1544 Intensive Care Med, 27 (2001), pp. 91 100 Intensive Care Med, 37 (2011), pp. 808 815 J Crit Care. 2014 Feb;29(1):150-6 44 11

Ascorbic Acid (AA) Methylene Blue Proposed antioxidant and antiinflammatory effects on the microvasculature Enhanced cell signaling in vasculature cells Role in endogenous catecholamine synthesis SSC has no statement on the use of AA Improves vascular tone and perfusion to tissues Inhibits nitric oxide induced guanylate cyclase activation preventing smooth muscle relaxation Limited data on dose and duration SSC has no statement on the use of methylene blue in septic patients Critical Care 2015, 19:418 45 Pharmacotherapy 2010;30(7):702 715 47 Ascorbic Acid in the Literature Methylene Blue (MB) in the Literature Study; n Design Intervention Outcomes Nathenset al; 301 RCT AA 1 g PO TID Pulmonary morbidity, new MOF, LOS ven la on, LOS ICU Crimi et al; 105 RCT AA 500 mgq24h Ventilator-free days, 28-day mortality Collier at al; 2,727 QE* IV or PO AA 1 g TID Berger et al;102 RCT AA 2.7g IV x 1 days AA 1.6 g IV x 4 days Heylandet al;307 RCT AA1.5 g IV or PO q24h LOS ICU, LOS hospital, mortality ; OR 0.32, 95 % CI 0.22 to 0.46 New organ failure ND, new infections ND, LOS shorter in trauma, CRP in cardiac surgery and trauma, recovery of health a er discharge ND in 28-day mortality or length of stay Design Population MB Regimens Prospective randomized open-label, placebo controlled, single-center study Prospective randomized double blind, placebocontrolled,single-center study 20 patients diagnosed with septic shock treated with at least one vasopressor and no corticosteroids N= 10 MB N= 10 control 30 patients diagnosed with severe sepsis; patients receiving corticosteroids or inotropes were excluded N= 15 MB N= 15 control 2mg/kg infusion x 15 mins; 0.25 mg/kg/hr x 2 hours; 0.5 mg/kg/hrx 1 hour; 1 mg/kg/hr x 1 hour 0.5 mg/kg/hrinfusion over 6 hours QE; Quasi-experimental Each study had additional minerals, vitamins added to regimen ND; no difference Critical Care 2014, 18:460 46 Pharmacotherapy 2010;30(7):702 715 48 12

Methylene Blue Outcomes IVIG Increase in MAP Rationale for use is in toxic shock syndrome or refractory septic shock Decreased vasopressor requirements Neutralization of endotoxin and modification of cytokine release Increase in cardiac index SSC does not suggest the routine use of IVIG in adult patients with septic shock (grade 2B) Pharmacotherapy 2010;30(7):702 715 49 Crit Care Med 2007; 35:2693 2701 51 Sepsis Induced Immune Dysfunction SBITS Trial Randomized, double-blind placebo controlled, multi-center trial N=624 septic shock patients The primary objective was to determine if the administration of IVIG improved mortality among severe sepsis patients Patients were stratified to receive either: Placebo IVIG 0.6 g/kg on day 1; then 0.3 g/kg on day 2 J Clin Invest. 2016;126(1):23-31 50 Crit Care Med 2007; 35:2693 2701 52 13

SBITS Trial Results Conclusion The way we have defined sepsis has changed Outcome IVIG, n=321 Placebo, n=303 P value 28 day mortality 126(39.3%) 113 (37.3%) 0.6695 ICU LOS 26 days ± 38.9 22.9 ± 20.7 0.3946 Hospital LOS 55.4 ± 50.3 51.9 ± 38.6 0.4397 All aspects of EGDT are not needed when resuscitating a patient for septic shock Procalcitonin is a biomarker that still has mixed data which should be used with caution There are emerging adjuvant therapies which may prove beneficial for the treatment of septic shock Crit Care Med 2007; 35:2693 2701 53 55 Emerging Immune Modulating Therapies in Sepsis Assessment Question #1 Procalcitonin is a sensitive biomarker to identify someone who is septic True False J Clin Invest. 2016;126(1):23-31 54 56 14

Assessment Question #2 Selenium supplementation is appropriate to decrease length of stay in patients hospitalized for sepsis True False Advancements in Sepsis Brian Gilbert, PharmD PGY-1 Pharmacy Resident Jackson Memorial Hospital 3/13/2016 57 www.fshp.org Assessment Question #3 The use of a central venous catheter to measure ScVO2 is needed for all patients True False 58 15