1 Series: JAMA Clinical Guidelines Synopsis 1 2 Title: Corticosteroids for Sepsis, Acute Respiratory Distress Syndrome, or Community Acquired 3 Pneumonia 4 5 Authors: Peggy B. Leung, MD1; Andrew M. Davis, MD, MPH2; Joshua Davis, MD,3 6 7 Affiliations: 8 9 1Division of General Internal Medicine, Weill Cornell Medicine, New York, New York 10 2Section of General Internal Medicine, University of Chicago, Chicago, Illinois 11 3Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, New 12 York 13 14 Guideline Title: 15 16 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory 17 Distress Syndrome, and Community-Acquired Pneumonia 18 19 Release date: Jan 2024 20 21 Developer and funding source: 22 23 Society of Critical Care Medicine (SCCM) 24 25 Target population: Critical Care and Internal Medicine physicians 26 27 Selected Recommendations: 28 29 ● Administer corticosteroids to adult patients with septic shock (conditional 30 recommendation, low certainty evidence) at a daily dose <400mg hydrocortisone 31 equivalent (strong recommendation, moderate certainty evidence) 32 ● Administer corticosteroids to adult hospitalized patients with acute respiratory 33 distress syndrome (conditional recommendation, moderate certainty evidence) 34 ● Administer corticosteroids to adult patients hospitalized with severe bacterial 35 community-acquired pneumonia (strong recommendation, moderate certainty 36 evidence) 37 38 Word count: 1179 words 39 40 References: 4 references 41 2 Summary of the Clinical Problem 42 43 Many acutely ill patients, including those hospitalized with severe pulmonary infections, 44 have a dysregulated systemic inflammatory response, characterized by hypothalamic-pituitary-45 adrenal axis dysfunction, altered cortisol metabolism, and tissue corticosteroid resistance.1 Given 46 the growing body of evidence regarding corticosteroid use in critical illness, the guideline sought 47 to provide updated recommendations on corticosteroid use for adults with sepsis, acute 48 respiratory distress syndrome (ARDS), and community acquired pneumonia (CAP).2 49 50 Characteristics of the Guideline Source 51 52 This guideline was developed and funded solely by the Society of Critical Care Medicine 53 (SCCM), and also sponsored by the Endocrine Society. An international, interdisciplinary expert 54 panel was selected by the SCCM Board of Regents. A comprehensive literature review identified 55 82 randomized clinical trials (RCTs) published prior to October 2022 to inform the guideline 56 recommendations, using Grading of Recommendations Assessment, Development, and 57 Evaluation (GRADE) methodology. All panel members disclosed potential financial and non-58 financial conflicts of interest (see eTable).2 59 60 Evidence Base 61 62 Recommendations were based on 46 RCTs evaluating the effect on mortality or length of 63 intensive care unit (ICU) stay for adult patients with sepsis or septic shock treated with 64 corticosteroids compared with placebo or standard of care. Among these studies, the most 65 common corticosteroid dosing regimen in patients with septic shock was hydrocortisone 200 mg 66 IV per day (continuous infusion or divided every 6 hours) with or without enteral fludrocortisone 67 50 μg daily for 7 days or until ICU discharge. However, the dosage, type, and duration of 68 3 corticosteroids were variable (even including tapering regimens) in these RCTs, and the studies 69 aggregated in this panel’s meta-analysis included participants with sepsis and septic shock, 70 regardless of infection source. 71 The panel made: 1) a conditional recommendation to administer corticosteroids to adult 72 patients with septic shock and 2) a strong recommendation not to administer high dose/short 73 duration corticosteroids (daily dose >400mg hydrocortisone equivalent for less than 3 days) for 74 adult patients with septic shock. 75 To assess mortality in the ICU and mortality at 14 - 30 days, the guideline evaluated 39 76 trials (9,632 participants) that randomized patients with sepsis and septic shock to corticosteroid 77 vs placebo or usual care, and reported moderate certainty evidence of a reduction in mortality 78 with steroids [steroids 27.4% vs placebo or usual care 29.7%; risk ratio (RR) 0.93, 95% CI 0.88-79 0.98].2 Based on 9 studies (6,438 participants), use of corticosteroids may reduce 60-day to 1-80 year mortality vs placebo (35.2% vs 37.2%; RR 0.94, 95% CI 0.89 – 1.0, low certainty 81 evidence).2 Also, compared with placebo or no corticosteroids, corticosteroid use was associated 82 with higher rates of shock reversal (72.4% vs 62.7%; RR 1.24; 95% CI 1.11-1.38, high certainty 83 evidence) and greater reductions in organ dysfunction, defined as a lower Sequential Organ 84 Failure Assessment score (mean difference (MD) -1.41, 95% CI -1.87 to -0.96 at 7 days, high 85 certainty evidence). Corticosteroid use was associated with reduced length of stay in the ICU 86 (MD 0.60 days fewer, 95% CI -1.48 to 0.27 days more) and in the hospital (MD 0.74 days fewer, 87 95% CI, -2.06 to 0.57 days more). Adverse effects associated with steroid use with at least 88 moderate certainty evidence were hyperglycemia (33.1% vs 29.1%; RR 1.13, 95% CI 1.08 - 89 1.18), and hypernatremia (5.9% vs 4.0%; RR 1.64, 95% CI 1.32-2.03).2 90 4 A planned subgroup analysis compared corticosteroid use for > 3 days vs ≤3 d a y s t o 91 p l a c e b o o r n o c o r t i c o s t e r o i d u s e (25 s t u d i e s u s e d f i xe d s t e r o i d d o s e s 92 < 400 mg /d , 12 u s e d we i g h t - b a s e d d o s i n g , a n d 1 d i d n o t r e p o r t t h e d o s e ) 93 o n 28- d a y mo r t a l i t y f r o m s e p s i s a n d s e p t i c s h o c k ; d u r a t i o n > 3 d a y s 94 wa s a s s o c i a t e d wi t h a mi l d b e n e f i t i n mo r t a l i t y (RR 0.92; 95% CI 0.87-95 0.98), wh e r e a s d u r a t i o n ≤3 d a y s d i d n o t s h o w r e d u c e d mo r t a l i t y (RR 96 0.90; 95% CI 0.59- 1.37).2 97 The strong recommendation not to administer high dose corticosteroids (greater than 400 98 mg per day of hydrocortisone equivalent) for short duration (less than 3 days), was based on 99 contemporaneous and historical trials suggesting a potential elevated risk of hyperglycemia and 100 secondary infections from short high-dose courses of steroids, without significant improvements 101 in mortality in patients with septic shock.2 102 Based on 16 randomized studies (2,740 patients) of 28-day mortality in critically ill 103 adults with ARDS, this guideline issued a conditional recommendation (moderate certainty) for 104 administration of corticosteroids (mortality with corticosteroids 35.8% vs mortality without 105 corticosteroids 44.6%; RR 0.82, 95% CI 0.72-0.95).2 A longer course of corticosteroids (more 106 than 7 days) in those with ARDS was associated with higher rates of survival than a shorter 107 course (7 days or less), p value for subgroup interaction 0.04, moderate credibility. Steroid 108 dosing regimens varied across studies from 40 mg/d to 2 mg/kg/d IV methylprednisolone 109 equivalents, with a duration of 7 to 30 days.2 Corticosteroid use was associated with fewer days 110 of mechanical ventilation and a shorter hospital length of stay (both with low certainty evidence). 111 This guideline also provided an important update about use of corticosteroids in adults 112 with bacterial community acquired pneumonia (CAP) based on 18 RCTs (4,567 patients) 113 5 comparing hospital mortality for adults with suspected or probable CAP, including those with 114 severe and less severe disease. Definitions of severe CAP varied among these studies and 115 included the American Thoracic Society/Infectious Diseases Society of America Criteria3, the 116 Pulmonary Severity Index score group IV or V, and other clinical criteria associated with severe 117 CAP such as septic shock, mechanical ventilation, hypoxemia and confusion. Based on the 12 118 RCT in those with severe bacterial CAP (2,133 patients), this guideline provides a strong 119 recommendation for use of corticosteroids in adults hospitalized with severe bacterial CAP 120 (corticosteroids 10.4% mortality vs 17.2% in controls; RR 0.62, 95% CI 0.45-0.85). 121 Corticosteroids probably also reduce the need for invasive mechanical ventilation 122 (corticosteroids 5.1% vs usual care 8.9%; RR 0.56, 95% CI 0.42-0.74) in adults hospitalized with 123 severe and less severe CAP.2 In the 7 RCT of patients with less severe CAP (2,434 patients), 124 there was no difference in mortality (corticosteroids 8.6% mortality vs usual care 8.1%; RR 1.08, 125 95% CI 0.83-1.42). 126 127 Discussion 128 129 Compared to the 2017 guidelines4, the 2024 update provides: 1) a conditional 130 recommendation for broader use of corticosteroids in septic shock (not isolated to septic shock 131 unresponsive to both fluid and moderate- to high-dose vasopressor therapy), 2) a conditional 132 recommendation for use of corticosteroids in patients with ARDS of all degrees of severity (no 133 longer focused on solely early moderate to severe ARDS), and 3) a strong recommendation for 134 use of corticosteroids in patients with severe CAP (in contrast to the prior conditional 135 recommendation in hospitalized patients with CAP). 136 137 Areas for Future Research 138 139 6 Upcoming data from ongoing trials such as HYDRO-SHIP (NCT05354778), a 140 multicenter RCT investigating hydrocortisone use in critically ill patients with nosocomial 141 pneumonia, may inform corticosteroid use in severe hospital-acquired pneumonia. Additionally, 142 a phase 3 trial, COLOSSEUM (NCT03745664) is assessing whether corticosteroid use in 143 patients hospitalized with CAP reduces myocardial injury, as assessed by serum high-sensitivity 144 cardiac T Troponin. Additional research is required: 1) to better define critical illness related 145 corticosteroid insufficiency including greater understanding of its relevance in managing the 146 various phenotypes and genotypes of sepsis and critical illness, and 2) to evaluate optimal doses 147 and duration of corticosteroid when used in sepsis, ARDS, and CAP. 148 https://classic.clinicaltrials.gov/ct2/show/NCT05354778?term=NCT05354778&draw=2&rank=1 https://classic.clinicaltrials.gov/ct2/show/NCT03745664?term=NCT03745664&draw=2&rank=1 7 References 149 1) Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency 150 (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical 151 Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). 152 Intensive Care Med. 2017;43(12):1781-1792. 153 2) Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused Update: Guidelines on Use of 154 Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-155 Acquired Pneumonia. Crit Care Med. Published online January 19, 2024. 156 3) Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with 157 Community-acquired Pneumonia. An Official Clinical Practice Guideline of the 158 American Thoracic Society and Infectious Diseases Society of America. Am J Respir 159 Crit Care Med. 2019;200(7):e45. 160 4) Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and 161 management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill 162 patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of 163 Intensive Care Medicine (ESICM) 2017 [published correction appears in Intensive Care 164 Med. 2018 Feb 23;:]. Intensive Care Med. 2017;43(12):1751-1763. 165 166 167 168 169 170 171 172 173 8 eTable. Guideline Ratinga 174 175 Standard Rating Establish Transparency Good Management of conflict of interest in the Guideline Development Group (GDG) Fair GDG composition Good Clinical practice guideline-systematic review intersection Good Establishing evidence foundations and rating strength for each of the guideline recommendations Fair Articulation of recommendations Fair External Review Good Updating Fair Implementation Issues Fair aCifu AS, Davis AM, and Livingston EH. Introducing JAMA Clinical Guidelines Synopsis. JAMA. 2014 Sep 176 24;312(12):1208-1209. 177 178 https://jamanetwork.com/journals/jama/fullarticle/1906589 https://jamanetwork.com/journals/jama/fullarticle/1906589