Management of Sepsis: In a Sea of Changes Where Are We Now? No conflicts to disclose. Learning objectives

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1 Management of Sepsis: In a Sea of Changes Where Are We Now? Eric Schmidt, MD Associate Professor Pulmonary Sciences and Critical Care Medicine Denver Health Medical Center University of Colorado School of Medicine No conflicts to disclose Learning objectives To understand the (historical) challenges in therapeutically targeting sepsis pathogenesis To understand the role of fluid resuscitation approaches in sepsis To understand the use of steroids as an adjunctive treatment for sepsis

2 Case #1: Patient M.R. 52 year old Hispanic female presents to the ED 10 days after cholecystectomy; complains of fever, back pain T 39.2 C, BP 75/30, HR 130 Fatigued and confused, with left flank tenderness Urinalysis: 4+ WBC A central line is placed, 3 L bolus lactated Ringer s administered, and blood cultures drawn MAP improves to 65 mm Hg, but remains tachycardic CVP 6 mm Hg, creatinine 1.3 mg/dl, hemoglobin 9 g/dl What s next? (a) Give more balanced crystalloids until CVP > 8 mm Hg (b) Check central venous oxygenation (c) Give vancomycin, then cefepime (d) Give cefepime, then vancomycin Patient M.R., continued. Despite early antibiotics and intravenous fluid resuscitation, M.R. s hemodynamic status deterioriates. She now requires max-dose norepinephrine and vasopressin to maintain mean arterial pressures at ~60. She is now oliguric. Lab work reveals increasing anion gap, elevated BUN/Cr, a random cortisol of 40 mg/dl, and a post-cosyntropin (60 min) cortisol of 43 mg/dl. What s next? (a) Give hydrocortisone, as M.R. is adrenally insufficient (b) Give hydrocortisone, as M.R. is relatively adrenally insufficient (c) Do not give hydrocortisone, M.R. is cosyntropin-responsive (d) Giving hydrocortisone has no clinical impact, regardless of adrenal responsiveness Learning objectives To understand the (historical) challenges in therapeutically targeting sepsis pathogenesis To understand the role of fluid resuscitation approaches in sepsis To understand the use of steroids as an adjunctive treatment for sepsis

3 The Ancient Riddle of Sepsis Ukhedu Majno G. JID 1991 Exogenous ukhedu? 1862: Discovery of 3000 B.C. papyrus describing case series of traumatic injuries Development of wound purulence/putrefaction ( ryt ) was predictive of fever, death Egyptian medicine aimed at preventing ryt Treating wounds with dressings impregnated with honey or wine Bacteriostatic! Surgical evacuation of ryt Botero et al. Intech 2012 Ancient Greece

4 Ancient Greece Two forms of biological degradation: Galen: Pus bonum et laudabile Majno G. JID 1991 Ancient Greece Two forms of biological degradation: Majno G. JID 1991 Baron RM AJRCMB 2005

5 Baron RM AJRCMB 2005 Baron RM AJRCMB 2005 Sepsis How sepsis kills Organ Failure Severe Sepsis/ Septic Shock Hospital mortality Mackenzie I, Lever A BMJ 2007;335:

6 Modern burden of sepsis EPIC-II: (Vincent et al. JAMA 2009) One day, multinational cross-sectional study of 14,414 patients (1,265 ICUs) 46-60% of all ICU patients were actively infected ICON: (Vincent et al. Lancet Respir Med 2014) Ten-day, multinational cross-sectional study of 10,069 ICU patients 29.5% of ICU patients had active sepsis In-hospital mortality of 35.3%; worse in low-income countries 55% of U.S. in-hospital deaths are attributed to sepsis (Liu et al. JAMA 2014) Patient M.R. 52 year old Hispanic female presents to the ED 10 days after cholecystectomy; complains of fever, back pain T 39.2 C, BP 75/30, HR 130 Fatigued and confused, with left flank tenderness Urinalysis: 4+ WBC A central line is placed, 3 L bolus lactated Ringer s administered, and blood cultures drawn MAP improves to 65 mm Hg, but remains tachycardic CVP 6 mm Hg, creatinine 1.3 mg/dl, hemoglobin 9 g/dl What s next? (a) Give more balanced crystalloids until CVP > 8 mm Hg (b) Check central venous oxygenation (c) Give vancomycin, then cefepime (d) Give cefepime, then vancomycin How sepsis kills Sepsis Organ Failure Severe Sepsis/ Septic Shock Hospital mortality Mackenzie I, Lever A BMJ 2007;335:

7 Acute onset severe hypoxemia Noncardiogenic, neutrophilic edema High mortality, morbidity Commonly triggered by sepsis Acute respiratory distress syndrome (ARDS) Septic ARDS Ware and Matthay NEJM 2000 How does sepsis cause ARDS?

8 How does sepsis cause ARDS? How does sepsis cause ARDS? Baron RM AJRCMB 2005

9 Inciting insult of lung inflammation? Danger hypothesis (Matzinger, Ann Rev Immunol. 1994) Molecular patterns of pathogens are sensed by pattern receptors Pathogen-associated molecular patterns, PAMPs Lipopolysaccharide (LPS) Toll-like receptor 4 Resident cell (macrophage, etc.) Inflammatory cytokines (e.g. TNF-α) PAMP Pattern receptor Inflammatory response Therapeutic targeting of lung inflammation pathogenesis PAMP or DAMP Pattern receptor Inflammatory response Potential approaches? 1. Neutralize the PAMPs/DAMPs 2. Inhibit the pattern receptor 3. Suppress inflammatory cytokines 4. Block other contributors to inflammation? 1. Neutralize the PAMPs/DAMPs Hemofiltration of PAMPs Polymixin B immobilized fiber (PMX-DHP) Binds LPS (and perhaps activated neutrophils) Kotaski and Giamarellos-Bourboulis, Exp Op Emerg Drug 2012 Pickkers and Payen Int Care Med 2017

10 1. Neutralize the PAMPs/DAMPs Hemofiltration of PAMPs Polymixin B immobilized fiber (PMX-DHP) Binds LPS (and perhaps activated neutrophils) Kotaski and Giamarellos-Bourboulis, Exp Op Emerg Drug 2012 EUPHAS study (Cruz DN et al. JAMA 2009) Patients undergoing emergent surgery for intraabdominal infection Randomized to usual care (34 pts) or 2 sessions of hemofiltration plus usual care (34 pts) EUPHAS outcomes Cruz et al. JAMA 2009 ABDOMIX trial (2015) Payen et al. Crit Care Med 2015

11 Euphrates trial (started 2014) Original goal was to enroll 360 patients in US and Canada Had sham hemoperfusion control group Size increased to 650 patients after interim analysis Larger than every other study of hemoperfusion combined! Study stopped by company (Spectral Medical) at 446 patients due to futility Stock prices dropped by 81% in one day 2. Block pattern receptors TLR4 Eritoran Opal et al. JAMA patients in 197 ICUs No difference in any outcomes (28.1% Eritoran mortality vs 26.9% in placebo) TAK-242 Rice et al. Crit Care Med ICUs worldwide Study stopped early (274 patients) due to futility: no change in IL-6, no change in survival 3. Block inflammatory cytokines Neutralizing antibodies Decoy receptors Natanson C et al. Crit Care Med 1998

12 4. Block contributors to inflammation Nutrition? Omega-3 polyunsaturated fatty acids OMEGA (Rice et al. JAMA 2011) Potential harm!» Increased ventilator days, ICU LOS, organ failure» Trend towards increased 60 day mortality (26.6% v. 17.6%, p = 0.054) Glutamine/antioxidants? Heyland et al. NEJM 2013 Harm! Glutamine supplementation worsened 6 month mortality Coagulation cascade? Activated Protein C (APC) Anti-inflammatory in multiple animal models of sepsis, ALI PROWESS (Bernard et al NEJM 2001) 1,690 patients with severe sepsis randomized to APC x 96 hours vs placebo Survival (%) Placebo APC p = % risk of major bleeding (p = 0.06) FDA, based on their own subgroup analysis of risk:benefits, approved APC for APACHE II 25 ( 2 organ failure) FDA-mandated follow-up studies ADDRESS (Abraham et al. NEJM 2005) No benefit to patients with APACHE II < 25 Increased risk of major bleeding! (3.9%) ENHANCE (Vincent JL et al. Crit Care Med 2005) Open-labeled study; bleeding risk 6.2%!

13 PROWESS-SHOCK (Ranieri et al. NEJM 2012) Severe septic shock (APACHE II > 25, more than one organ failure) Is targeting sepsis pathogenesis impossible? No immunotherapy to date has convincingly (randomized, controlled trial) demonstrated benefit in interrupting/abrogating pathophysiologic processes of sepsis onset Infection Timing of antibiotics in sepsis Mortality increases incrementally during a delay in antibiotic administration after sepsis 7.6% increase in mortality per hour Kumar et al Crit Care Med 2006

14 Importance of early antibiotics in preventing septic lung injury ALI No ALI Crit Care Med 2008 Practical considerations to antibiotic administration Goal? Antibiotics should be administered within 1 hour of sepsis diagnosis (Surviving Sepsis Campaign, Dellinger et al. CCM 2013) Cannot be prospectively tested (unethical to randomized patients to delayed antibiotic administration) but could we test earlier antibiotic administration? Pre-hospital antibiotics? PHANTASi trial (Lancet Resp Med 2018) 25 regional ambulance services in the Netherlands 2698 patients with suspected sepsis (suspected infection and SIRS) randomized to either usual care in ambulance or 2000 mg IV ceftriaxone plus usual care in ambulance

15 The continuing challenge of sepsis Ancient Egypt: Apply honey, wine to injuries to prevent ryt Today: Give antibiotics before sepsis progresses Learning objectives To understand the (historical) challenges in therapeutically targeting sepsis pathogenesis To understand the role of fluid resuscitation approaches in sepsis To understand the use of steroids as an adjunctive treatment for sepsis

16 Modifiable factors re: fluid resuscitation? Type of fluid resuscitation Protocolized resuscitation? Modifiable factors re: fluid resuscitation? Type of fluid resuscitation Protocolized resuscitation? Crystalloids vs. colloids SAFE study (Finfer et al. NEJM 2004) 7000 ICU patients randomized to saline vs. 4% albumin for fluid resuscitation No differences in outcomes at 28 days Trend towards benefit of albumin in sepsis subgroup, but such differences between subgroups frequently occur by chance and only specifically designed and appropriately powered studies can determine whether any such treatment effects are real.

17 Crystalloids vs. colloids SAFE study investigators get bored, decide to publish post-hoc analysis anyway (SAFE study investigators, Intensive Care Med 2010) Trend towards benefit in patients with severe sepsis (p = 0.09, as first noted in SAFE) Multivariate subgroup analysis on patients with complete records (75.5%), albumin had significant benefit (OR 0.71, p = 0.03) Surviving Sepsis Guidelines: Consider giving albumin if large volumes of crystalloid have already been given Crystalloids vs. colloids NEVER GIVE HYDROXYETHYL STARCH CRYSTMAS study: No difference between 6% 130/0.4 HES and saline (Guidet et al. Crit Care 2012) CHEST study: No difference in mortality, but increased dialysis need in HES patients (Myurgh et al. NEJM 2012) 6S study: Worsened mortality in HES compared to Ringer s acetate (51% vs. 43%), increased need for dialysis (Perner et al. NEJM 2012) Balanced fluids vs. normal saline Normal saline can cause acidosis Balanced fluids buffered by acetate or lactate Plasmalyte, LR Young et al. JAMA 2015 ANZCIS study of 2278 ICU patients (only 4% had sepsis); randomized to NS vs. plasmalyte Received 1 liter of plasmalyte prior to randomization After randomization, received roughly 2 liters of saline vs. 2 liters of plasmalyte No difference in renal failure, other outcomes

18 Single center, 5 ICU study Cluster-randomization, crossover (monthly) 15,802 critically ill adults received either saline or balanced crystalloids for all fluid needs 15% of patients had sepsis Primary outcome: composite of death, need for RRT, persistent AKI weighted equally? Modifiable factors re: fluid resuscitation? Type of fluid resuscitation Protocolized resuscitation?

19 VOLUME RESUSCITATE Crystalloid or colloid to CVP 8-12 mm Hg 1 st 6 hours (in ER) Control group Transfer to ICU Rivers et al NEJM 2001 OPTIMIZE BP Vasopressors or vasodilators to MAP mm Hg Intervention group MAXIMIZE O 2 DELIVERY If ScvO 2 < 70%... Transfuse PRBC until HCT > 30 If ScvO 2 still < 70%... Start inotropes Success at achieving goals in first 6 h? Goal Usual care Intervention VOLUME RESUSCITATE CVP 8-12 mm Hg 10.5 ± 6.8 mm Hg 11.7 ± 5.1 mm Hg OPTIMIZE BP MAP mm Hg 81 ± 16 mm Hg 88 ± 16 mm Hg MAXIMIZE O 2 DELIVERY Rivers et al NEJM 2001 ScvO 2 > 70% 65.4 ± 15.5 % 71.6 ± 10.2 % Mean ± SD In-hospital mortality 28-day mortality 60-day mortality EGDT outcomes? Usual care Intervention 46.5% 30.5% 49.2% 33.3% 56.9% 44.3% p < 0.05 p < 0.05 p < 0.05 Conclusion: A protocol aimed at optimizing volume status, blood pressure, and oxygen delivery early in sepsis improves survival Rivers et al NEJM 2001

20 Potential problems with EGDT? Rivers study Single center, single ER Single center studies often show exaggerated treatment effects (Dechartres Ann Int Med 2011) Nearly all validation studies of EGDT have been observational studies of implementation of sepsis bundles (Schmidt GA Chest 2010) Potential problems with EGDT? Rivers study Very high mortality in control arm Schmidt GA. Chest 2010 Potential problems with EGDT? Rivers study Potential conflict of interest

21 Potential problems with EGDT? CVP terrible at predicting volume responsiveness preload reserve : An increase in cardiac index > 15% after a 500 cc colloid bolus Michard et al AJRCCM 2000 Only 1/27 articles reviewed showed that CVP is an accurate measure of volume responsiveness Study discussing resuscitation of 7 exsanguinating mares (Magdesian KG et al. 2006) Potential problems with EGDT? Can overaggressive fluid resuscitation be harmful? FACTT study (ARDS Network, NEJM 2006) Fluid-conservative strategy improved pulmonary function/recovery in ARDS FEAST trial (Maitland et al. NEJM 2011) African children with severe febrile illness (57% malaria) Bolus administration of fluids increased mortality at 48 hours (RR 1.45) VASST post-hoc analysis (Boyd et al. Crit Care Med 2011) Cumulative fluid balance at 12 hours and 4 days directly correlated with mortality, even after controlling for age and severity of illness Low CVP at 12 hours associated with improved survival! CLOVERS study (PETAL Network) 2018

22 Single center Concerns with EGDT! Inexplicably high mortality Financial conflict of interest Biologic implausibility of CVP as measure of volume status Harm of overaggressive fluid resuscitation (and transfusion) Re-assessing EGDT Three major, multicenter studies performed to test EGDT ProCESS: Protocolized Care for Early Septic Shock (1,935 patients) ARISE: Australasian Resuscitation in Sepsis Evaluation (1,600 patients) ProMISe: Protocolized Management of Sepsis (1,260 patients) Rivers mocks the need for further studies: These trials include an experimental ProCESS of prospectively observing a highly lethal disease without the ProMISe that one preventable death of a loved one will not ARISE (Rivers, Chest 2010) 31 Emergency Departments in the United States Compared three groups Protocol based, EGDT therapy (439 patients) Protocol based, Standard therapy (446 patients) Standard care (456 patients)

23 Outcomes? 1588 patients with septic shock Randomized to EGDT or usual care x 6 hours

24 1260 patients in England Randomized to EGDT or usual care x 6 hours Why does EGDT no longer work? The perils of the single-center study Intensive insulin control Van den Berghe et. al, NEJM 2006 NICE-SUGAR, NEJM 2009 Has the general practice of critical care improved? Sedation cessation studies Kress et. al, NEJM 2000 Mehta et. al, JAMA 2012

25 1588 patients with septic shock Randomized to EGDT or usual care x 6 hours Before randomization, patients received empiric antibiotics: Mean door to antibiotic time 70 min (EGDT), 67 min (usual care) Sooo..how should we fluid resuscitate our septic patients? Balanced crystalloids > saline Initial bolus of 30 ml/kg crystalloid appears standard-of-care for now Use physiological responsiveness (subject to debate) to guide additional fluid boluses Learning objectives To understand the (historical) challenges in therapeutically targeting sepsis pathogenesis To understand the role of fluid resuscitation approaches in sepsis To understand the use of steroids as an adjunctive treatment for sepsis

26 Use of steroids in sepsis? (1) Attempt at immunosuppression (2) Attempt at adrenal supplementation Use of steroids in sepsis? (1) Attempt at immunosuppression (2) Attempt at adrenal supplementation 1970 s: High dose steroids beneficial in septic shock Schumer Ann Surg s: Benefit disputed by larger trials Sprung et al. NEJM 1984: No benefit VA Sepsis Cooperative NEJM 1987: No benefit Meta-analysis (Cronin Crit Care Med 1995) Potential harm in patients with uncontrolled infection

27 Use of steroids in sepsis? (1) Attempt at immunosuppression (2) Attempt at adrenal supplementation Stress dose Steroids Addresses relative adrenal insufficiency as opposed to adrenal insufficiency Adrenals work, but are maxed out (< 9 µg/dl or less increase with cosyntropin) Annane et al. JAMA ICUs across France Randomized pts with septic shock to placebo vs. hydrocortisone (50 mg q 6) plus fludrocortisone (50 µg daily via NG tube). Outcome? 28 day survival Annane et al. JAMA 2002

28 CORTICUS Sprung et al. NEJM patients with septic shock randomized to hydrocortisone vs. placebo x 5 days Less sick (mortality 31.5% in control) than Annane s study (mortality 63% in control) No survival benefit, regardless of cosyntropin response Hastened resolution of shock (in cosyntropin responders!), at cost of increased infections (OR 2.78 for recurrent septic shock in all patients) ADRENAL Venkatesh et al. NEJM mechanically-ventilated septic shock patients admitted to ICUs within the ANZICS cooperative Placebo mortality 28.8% Randomized to continuous infusion hydrocortisone (200 mg/d) or placebo No benefit in 90 day survival Hydrocortisone led to faster resolution of shock (3 days vs. 4 days), fewer ICU days (10 days vs. 12 days), slightly improved MAPs (5.39 mm Hg) Quicker liberation from ventilator, but increased need for reintubation No change in bacteremia APROCCHSS study Annane again! (Annane et al. NEJM 2018) 1241 septic shock patients randomized between 2008 and 2015 to (2x2) to hydrocortisone/fludrocortisone vs. placebo or activated protein C vs. placebo. Placebo mortality 49.1%! Hydrocortisone/fludrocortisone groups had improved 90 day survival (43.1% vs. 49.1%) Hastened resolution of sepsis Hastened weaning from ventilator, but still no change in ventilator free days (reintubations?) No evidence of increased infection, septic shock

29 Stress dose Remember! Treating relative adrenal insufficiency steroid immunosuppression Learning objectives To understand the (historical) challenges in therapeutically targeting sepsis pathogenesis To understand the role of fluid resuscitation approaches in sepsis To understand the use of steroids as an adjunctive treatment for sepsis Case #1: Patient M.R. 52 year old Hispanic female presents to the ED 10 days after cholecystectomy; complains of fever, back pain T 39.2 C, BP 75/30, HR 130 Fatigued and confused, with left flank tenderness Urinalysis: 4+ WBC A central line is placed, 3 L bolus lactated Ringer s administered, and blood cultures drawn MAP improves to 65 mm Hg, but remains tachycardic CVP 6 mm Hg, creatinine 1.3 mg/dl, hemoglobin 9 g/dl What s next? (a) Give more balanced crystalloids until CVP > 8 mm Hg (b) Check central venous oxygenation (c) Give vancomycin, then cefepime (d) Give cefepime, then vancomycin

30 Patient M.R. 52 year old Hispanic female presents to the ED 10 days after cholecystectomy; complains of fever, back pain T 39.2 C, BP 75/30, HR 130 Fatigued and confused, with left flank tenderness Urinalysis: 4+ WBC A central line is placed, 3 L bolus lactated Ringer s administered, and blood cultures drawn MAP improves to 65 mm Hg, but remains tachycardic CVP 6 mm Hg, creatinine 1.3 mg/dl, hemoglobin 9 g/dl What s next? (a) Give more balanced crystalloids until CVP > 8 mm Hg (b) Check central venous oxygenation (c) Give vancomycin, then cefepime (d) Give cefepime, then vancomycin Patient M.R., continued. Despite early antibiotics and intravenous fluid resuscitation, M.R. s hemodynamic status deterioriates. She now requires max-dose norepinephrine and vasopressin to maintain mean arterial pressures at ~60. She is now oliguric. Lab work reveals increasing anion gap, elevated BUN/Cr, a random cortisol of 40 mg/dl, and a post-cosyntropin (60 min) cortisol of 43 mg/dl. What s next? (a) Give hydrocortisone, as M.R. is adrenally insufficient (b) Give hydrocortisone, as M.R. is relatively adrenally insufficient (c) Do not give hydrocortisone, M.R. is cosyntropin-responsive (d) Giving hydrocortisone has no clinical impact, regardless of adrenal responsiveness Patient M.R., continued. Despite early antibiotics and intravenous fluid resuscitation, M.R. s hemodynamic status deterioriates. She now requires max-dose norepinephrine and vasopressin to maintain mean arterial pressures at ~60. She is now oliguric. Lab work reveals increasing anion gap, elevated BUN/Cr, a random cortisol of 40 mg/dl, and a post-cosyntropin (60 min) cortisol of 43 mg/dl. What s next? (a) Give hydrocortisone, as M.R. is adrenally insufficient (b) Give hydrocortisone, as M.R. is relatively adrenally insufficient (c) Do not give hydrocortisone, M.R. is cosyntropin-responsive (d) Giving hydrocortisone has no clinical impact, regardless of adrenal responsiveness

31 Thank you