Critical Care Pharmacist with special interests in trauma and surgery.
The Pre-brief
A 60-year-old male is brought from a nursing home to the emergency department after a mechanical fall. He suffers a severe traumatic brain injury with CT scans significant for subdural hematoma (SDH) and bilateral, multiple rib fractures. Due to inability to protect his airway rapid sequence intubation (RSI) was performed with etomidate and rocuronium. Twenty-four hours into his ICU admission, he develops septic shock secondary to pneumonia.
The question:
What is the role of corticosteroids in patients with septic shock?
The hypothalamic-pituitary-adrenal (HPA) axis is responsible for the release of glucocorticoids (cortisol) and mineralocorticoids (aldosterone) from the adrenal cortex during a stress response, such as the case of sepsis and septic shock.
Critically ill patients are at risk of a phenomenon that involves HPA axis dysfunction, also known as Critical Illness-related Corticosteroid Insufficiency (CIRCI). Most notably, in critically ill patients, CRICI can result in hypotension refractory to fluid resuscitation and vasopressor therapy.
What does the literature say?
Annane and colleagues1 sought to determine the efficacy of corticosteroids in septic shock, and found use of hydrocortisone plus fludrocortisone decreased the risk of death. This was followed by the CORTICUS2 trial, which found the use of hydrocortisone in patients with septic shock did not improve survival or reversal of shock. More recently, on a larger scale, the ADRENAL trial retested the hypothesis:
In addition, it is important to note if your intubated patient received etomidate for RSI. Etomidate is a commonly used anesthetic during RSI. Mechanistically, etomidate decreases the production of cortisol via inhibition of 11 beta-hydroxylase. A retrospective study(5) found septic patients who received etomidate for RSI were more likely to have hypotension (SPB <90 or MAP <60) compared to patients who did not receive etomidate within the first 24 hours. More recent meta-analyses(6,7) have found that single-dose etomidate does not increase ICU mortality. However, effects of adrenal insufficiency were noted.
The Debrief
CIRCI is associated with increased morbidity and mortality in critically ill patients. Based on the ADRENAL trial, it is reasonable to use corticosteroids in patients with septic shock. Although there was a non-significant decrease in 90-day mortality, there was a benefit in decreasing morbidity (ICU length of stay, duration of mechanical ventilation, need for blood transfusions). However, this trial does not address the benefit of corticosteroids in patients with refractory septic shock requiring higher doses of vasopressors or patients who received etomidate.
The 2021 SCCM guidelines recently updated their recommendations for use of corticosteroids in septic shock from weak, low quality of evidence to weak, moderate quality of evidence(8,9). The guidelines recommend adding corticosteroids if norepinephrine or epinephrine doses exceed > 0.25 mcg/kg/min at least 4 hours after initiation. If considered, the recommended dose is hydrocortisone 200 mg/day as a continuous infusion or as 50 mg IV every 6 hours.
Lastly, RSI medications are relevant for a number of reasons in addition to etomidate causing adrenal insufficiency, knowing the paralytic agent used can guide post-RSI analgesia and sedation management.
References
- Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71. doi: 10.1001/jama.288.7.862. Erratum in: JAMA. 2008 Oct 8;300(14):1652. Chaumet-Riffaut, Philippe [corrected to Chaumet-Riffaud, Philippe]. PMID: 12186604.
- Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366. PMID: 18184957.
- Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J; ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/NEJMoa1705835. Epub 2018 Jan 19. PMID: 29347874.
- Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D (2008) Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358:877–887
- Thompson Bastin ML, Baker SN, Weant KA. Effects of etomidate on adrenal suppression: a review of intubated septic patients. Hosp Pharm. 2014 Feb;49(2):177-83. doi: 10.1310/hpj4902-177. PMID: 24623871; PMCID: PMC3940683.
- Bruder EA, Ball IM, Ridi S, Pickett W, Hohl C. Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev. 2015 Jan 8;1(1):CD010225. doi: 10.1002/14651858.CD010225.pub2. PMID: 25568981; PMCID: PMC6517008.
- Gu WJ, Wang F, Tang L, Liu JC. Single-dose etomidate does not increase mortality in patients with sepsis: a systematic review and meta-analysis of randomized controlled trials and observational studies. Chest. 2015 Feb;147(2):335-346. doi: 10.1378/chest.14-1012. PMID: 25255427.
- Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Critical Care Medicine: November 2021 – Volume 49 – Issue 11 – p e1063-e1143 doi: 10.1097/CCM.0000000000005337
- Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers SC, Russell JA, Van den Berghe G. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017 Dec;45(12):2078-2088. doi: 10.1097/CCM.0000000000002737. PMID: 28938253.
