Journal Club Podcast #43: May 2018
A brief look at the evidence for and against the use of steroids in patients sepsis and septic shock...
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Article 2: Keh D, Trips E, Marx G, et al; SepNet–Critical Care Trials Group. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016 Nov 1;316(17):1775-1785. Answer Key.
Article 3: Venkatesh B, Finfer S, Cohen J, et al; 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. Answer Key.
You’re working the weekend shift in TCC when you get a page: triage patient to 3L for low BP. You meet the patient in the room and find a critically ill-appearing 55-year-old female with one week of cough and increased shortness of breath. Her vital signs are:
SpO2 89% on room air
She is struggling to breathe, getting out 2 to 3 word sentences, and is oriented only to self. You immediately ask the nurses to get two large-bore IVs and hang two liters of normal saline on pressure bags while you prepare to intubate. Following intubation (during which you administer two boluses of phenylephrine, 100 mcg each, for dropping blood pressure), you get a stat portable chest x-ray showing multifocal pneumonia. After your initial two liters of fluid have been administered, followed by a third (and broad-spectrum antibiotics), the patient’s blood pressure is still only 80/45.
You place a right-sided internal jugular central line under ultrasound guidance and start a norepinephrine drip. Your deftly placed arterial line begins to demonstrate an improved BP and MAP and you find the patient a bed in the medical ICU. As the patient is being transferred, you begin to wonder whether steroids would be beneficial in this patient with clear septic shock. After all, you know that much of the problem in sepsis is the inflammatory response, which would theoretically be mitigated by steroid administration. You begin to search the literature and realize this has been a controversial topic dating back over 10 years...
Population: Adults patients with either severe sepsis without septic shock of with septic shock.
Intervention: IV steroids, administered as an intermittent bolus or a continuous infusion.
Comparison: Placebo and standard of care.
Outcome: Mortality, resolution of septic shock, development of septic shock, ICU and hospital length of stay, duration of mechanical ventilation, need for renal replacement therapy.
PubMed was searched using the terms “steroids AND sepsis” and limiting the results to clinical trials (https://tinyurl.com/y9wswub5). This strategy yielded 363 studies, from which the four most relevant articles were chosen. The Cochrane Database of Systematic Reviews was also searched in an attempt to find a meta-analysis of results, but no such article was identified.
In 2002, a landmark study published in JAMA (Annane 2002) demonstrated a significant reduction in 28-day mortality with the use of low-dose steroids among patients with septic shock who did not respond appropriately to a corticotropin stimulation test (adjusted odds ratio [OR] 0.54, 95% CI 0.31-0.97). Despite adjusting outcomes for baseline characteristics in this randomized controlled trial (with no difference in outcomes looking at raw data), the authors concluded that steroids were beneficial in non-responders. Since this study was published, several studies have been conducted to reevaluate the effects of steroids on the course of septic shock. We looked at four such articles, including two high-impact articles published earlier this year.
In 2008, the CORTICUS trial was published as a follow-up to the initial 2002 study. This international, multicenter trial again evaluated the efficacy of steroids in both corticotropin non-responders and responders with septic shock, and found no difference in 28-day mortality among either group (relative risk [RR] 1.09, 95% CI 0.77 to 1.52 and RR 1.09, 95% CI 0.84-1.41, respectively). The authors therefore concluded that “hydrocortisone cannot be recommended as general adjuvant therapy for septic shock (vasopressor responsive), nor can corticotropin testing be recommended to determine which patients should receive hydrocortisone therapy.”
Given the different outcomes observed in these two early studies, further research has since been completed to attempt to obtain a more definitive answer. Earlier this year, two studies were published in the New England Journal of Medicine, again with differing results. The ADRENAL study enrolled 3800 patients with septic shock requiring mechanical ventilation, but did not test corticotropin responsiveness. Patients were randomized to either placebo or a continuous infusion of hydrocortisone for up to 7 days, and there was no difference in 90-day mortality between the groups (OR 0.95, 95% CI 0.82-1.10). Similar to the CORTICUS trial, they did find a faster time to resolution of shock in the hydrocortisone group (median 3 vs. 4 days; hazard ratio [HR] 1.32, 95% CI 1.23-1.41), but this again is of unclear importance to the patient.
The APPROCCHSS trial, published soon after the ADRENAL trial, again enrolled patients with septic shock, but was designed to test the efficacy of both combined hydrocortisone-fludrocortisone therapy AND drotrecogin alfa. As drotrecogin alfa was removed from the market several years into the study, an adjustment was made and the study ended with a two-parallel-group design. Unfortunately, due to this adjustment, the study was halted twice for prolonged periods, and hence was completed over a seven-year period, during which multiple changes in the management of sepsis occurred (see Journal Club July 2015, Journal Club October 2010). While this trial found a decrease in 90-day all-cause mortality with steroid administration (RR 0.88, 95% CI 0.78-0.99) its logistical issues make these results difficult to interpret.
While these studies had differing results, the APPROCCHSS study at least suggests that it is reasonable to administer stress-dose steroids to patients with sepsis and refractory shock, as in this study, only patients requiring vasopressors for at least 6 hours were eligible for enrollment. This is likely not a significant change from current management in many ICUs.
An additional study was identified that looked at the ability of steroids to prevent progression to shock in patient with severe sepsis (the HYPRESS trial). A total of 353 patients with sepsis and evidence of organ dysfunction without shock were enrolled and randomized to received placebo (mannitol) or a continuous infusion of hydrocortisone for 5 days, followed by a taper. There was no significant difference in rates of progression to shock between the two groups (absolute risk reduction [ARR] -1.8%, 95% CI -10.7% to 7.2%), or in 28-day, 90-day, 180-day, ICU, or in-hospital mortality. There was also no difference in ICU or hospital length of stay, need for mechanical ventilation, or need for renal replacement therapy. This final study suggests no benefit with the administration of steroids in patients with sepsis but without shock.