Resus Blog: Stress Dose Steroids
Case presentation:
A 64-year-old female was brought in from her nursing facility for altered mental status. The nursing home states that over the last 24 hours, the patient has had worsening lethargy and became relatively unresponsive earlier today. Upon arrival to the emergency department, the patient was noted to have a blood pressure of 83/57 with a heart rate of 67. Patient required nasal cannula support at 5 L during which time she was saturating 97%. After judicious volume resuscitation, vasopressors were started and titrated up to near maximal doses of norepinephrine, vasopressin, and epinephrine to maintain MAPs of 55-60. The patient's initial blood gas came back with a metabolic acidosis and a lactate level of 17.1. The patient had a history of recent UTIs and was empirically started on vancomycin and piperacillin-tazobactam. A repeat venous full panel showed worsening acidemia with mixed respiratory and metabolic components with a pH of 6.90. Patient was successfully intubated for expected respiratory failure.
Standard of care in sepsis:
Sepsis and the treatment of septic shock is an area of significant controversy and ongoing evolution of treatment. In this patient, vasopressors to treat hypotension, antibiotics and source control form the backbone of treatment as sepsis is suspected. Moderate volume resuscitation if the patient does not have contraindications or true hypovolemia is also generally accepted standard of care. What adjunctive treatments to utilize is more controversial. HAT (hydrocortisone, ascorbic acid, thiamine) therapy is one treatment that has been previously proposed but it is not definitive whether all the components are effective [1]. This post will focus on the aspect that this author believes has the strongest evidence to be included in the ED management of septic shock: corticosteroids.
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Should stress dose steroids be part of the initial standard of care in ED management of septic shock:
Controversy over the use of steroids in septic shock comes both from underpowered early trials and complicated mechanisms of action of corticosteroids. It is well established that corticosteroids bind to glucocorticoid receptors, translocate to the nucleus, and have modulatory effects on specific nuclear mechanisms to have downstream effects on cytokine production but dose, duration and which glucocorticoid receptors are targeted all play a role in the net downstream effect [2,3]. In septic shock, the desirable effects are largely in the decreased capillary permeability but there has also been concerns raised about increased risks of super-infection due to corticosteroids effects on neutrophil trafficking and general immunosuppression. Early underpowered trials, particularly the Corticus trial with an sample size of 499 patients, did show a modest increase in the risk of superinfection with steroids but no effect on mortality [4]. Since then, significantly stronger trials as well as meta-analyses have not shown the risk of superinfection to be clinically significant [4–6]. In addition to the empiric data on corticosteroid safety in sepsis, it is also worth noting that the stress-doses of steroids used in septic shock are largely equivalent to those routinely used without harm in other diseases such as COPD.
Equally important to the demonstration of safety is whether corticosteroids result in a clinically significant improvement in outcomes in septic shock which the largest and most recent trials, the ADRENAL and APROCCHSS trial, both showed [5,7]. The ADRENAL trial was a 3800 patient, multicenter randomized control trial comparing continuous 200mg/day hydrocortisone versus placebo both with standard of care otherwise [5]. The 2018 study demonstrated no difference in the primary outcome of 90-day mortality but did show statistically significant decreases in days to resolution of shock, time to cessation of mechanical ventilation and days to discharge from ICU with hydrocortisone. The APROCCHSS trial had a number of complications with design changes and statistical manipulation but is the only trial to show a statistically significant difference in 90-day mortality with steroids albeit with a miniscule fragility index [8] on that statistic. APROCCHSS was also a double-blinded, multi-center RCT that compared hydrocortisone 50mgq6 plus fludrocortisone 50mcg once with placebo. As the only major trial using a mineralocorticoid as well as the only one to show mortality benefits, it is difficult to interpret these findings in the broader picture of septic shock but together with the ADRENAL trial and a large metanalysis of the numerous smaller previous trials [6], there is significant independently corroborated evidence that stress-dose steroids do improve clinically significant metrics such as time to ICU discharge, length of shock and time on mechanical ventilation even if mortality is a difficult endpoint to statistically prove given the low incidence and high variability in patients with septic shock. It is important to note that these effect sizes are not profound compared with those achieved by standard of care treatment and that corticosteroids represent an adjunctive rather than preemptive treatment.
Case Conclusions:
The patient continued management of their septic shock in the ED with ventilatory and pressor support. The patient was additionally treated with hydrocortisone 100mgq12, thiamine 500mg and 450units of sodium bicarbonate. Patient was admitted to the MICU where pressors and ventilatory support were weaned with extubation at hospital day 4 and full removal of pressor support at hospital day 6. The patient was discharged back to her nursing home with return to baseline activity after 10 days of hospitalization.
Take home conclusions:
Patients with septic shock requiring a vasopressor for support likely benefit in clinically significant ways from early stress-dose steroids without clinically significant adverse effects.
POST BY: BRIAN FORT (MS4, CWRU)
FACULTY EDITING BY: DR. COLIN MCCLOSKEY (EM-INTENSIVIST)
References
Moskowitz, A. et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit. Care 22, 283 (2018).
Ramamoorthy, S. & Cidlowski, J. A. Corticosteroids-Mechanisms of Action in Health and Disease. Rheum. Dis. Clin. North Am. 42, 15–31 (2016).
McKay, L. I. & Cidlowski, J. A. Physiologic and Pharmacologic Effects of Corticosteroids. Holl.-Frei Cancer Med. 6th Ed. (2003).
Sprung, C. L. et al. Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358, 111–124 (2008).
Venkatesh, B. et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N. Engl. J. Med. 378, 797–808 (2018).
Sligl, W. I., Milner, D. A., Jr., Sundar, S., Mphatswe, W. & Majumdar, S. R. Safety and Efficacy of Corticosteroids for the Treatment of Septic Shock: A Systematic Review and Meta-Analysis. Clin. Infect. Dis. 49, 93–101 (2009).
Annane, D. et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N. Engl. J. Med. 378, 809–818 (2018).
Ridgeon, E. E. et al. The Fragility Index in Multicenter Randomized Controlled Critical Care Trials. Crit. Care Med. 44, 1278–1284 (2016)
Keh, D. et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA 316, 1775–1785 (2016).