Addison’s disease

Lower Mortality in Patients Treated with Hydrocortisone for Severe Community-Acquired Pneumonia

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In contrast to findings from a recent meta-analysis, this study showed patients were less likely to die if hydrocortisone was started early.

Are corticosteroids beneficial for patients with community-acquired pneumonia (CAP)? Earlier this year, a randomized, controlled trial of patients with severe CAP showed no benefit for steroids (Intensive Care Med 2022; 48:1009. opens in new tab). Just last month, a meta-analysis of 16 randomized trials also showed no effect on mortality (NEJM JW Gen Med Apr 15 2023 and Chest 2023; 163:484). Interestingly though, the meta-analysis showed that patients treated with corticosteroids were less likely to need intubation.

French investigators randomized 800 patients who were admitted to the intensive care unit with severe CAP to receive hydrocortisone (intravenous 200 mg daily) or placebo. Patients began treatment within 24 hours of developing severe CAP and were treated for 4 days and then tapered over 4 or 10 days depending on clinical improvement. About one quarter of patients were intubated at enrollment, and 40% were receiving high-flow nasal cannula oxygen. No standardized microbiologic investigation was done.

This trial began prior to the pandemic, and enrollment was halted in March 2020. Mortality at 28 days was significantly lower with hydrocortisone than with placebo (6% vs. 12%); this benefit persisted at 90 days. The hydrocortisone group was also less likely to require mechanical ventilation and less likely to develop shock. Hyperglycemia was more common in patients treated with hydrocortisone, but other adverse events were similar between groups.

Comment

Completely reconciling this body of literature is hard, but it seems that glucocorticoids lower the need for mechanical ventilation in patients with severe CAP — an outcome that reasonably could drive a mortality benefit. It will be interesting to see how the guidelines evolve, given that they currently recommend steroids only in CAP patients with septic shock (NEJM JW Gen Med Dec 1 2019 and Am J Respir Crit Care Med 2019; 200:45). I will have a lower threshold to administer hydrocortisone to patients admitted to the ICU with severe CAP.

Continuous subcutaneous hydrocortisone infusion viable option to normalize cortisol.

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Continuous subcutaneous hydrocortisone infusion was a safe approach for decreasing adrenocorticotropic hormone and cortisol levels to a normal circadian level with minimal adverse effects on glucocorticoid metabolism compared with conventional oral hydrocortisone replacement therapy, according to results in a prospective crossover study.

  • These data suggest a physiological glucocorticoid replacement therapy may be beneficial and that the infusion may become an option for patients with poorly controlled levels such as those with Addison’s disease, according to Marianne Øksnes, MD, of the department of clinical science and department of medicine at the University of Bergen in Norway, and colleagues.

Patients with Addison’s disease (n=33) were assessed at baseline and after 8 and 12 weeks in each treatment arm, according to data.

The infusion allowed the normalization of adrenocorticotropic hormone (ACTH) and cortisol levels, and 24-hour salivary cortisol curves appeared to reach normal circadian variation, the researchers wrote.

“This study shows that [continuous subcutaneous hydrocortisone infusion] can safely re-establish the circadian cortisol rhythm and normalize morningACTH levels in [Addison’s disease] patients, which is in sharp contrast to the typical daytime cortisol peaks and troughs and elevated morning ACTH seen with [oral hydrocortisone] treatment,” researchers wrote.

The oral hydrocortisone yielded major alterations in glucocorticoid metabolites and metabolic enzyme activities, according to researchers. However, the infusion appeared to restore glucocorticoid metabolism close to normal.

No significant between-treatment differences were observed in sleep outcomes, according to data.

Additional studies are warranted to determine further ultradian rhythm improvement outcomes for patients with Addison’s disease.

Ipilimumab-induced autoimmune adrenalitis.

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A 56-year-old woman presented with fatigue and headache after receiving four doses of ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4, for the treatment of metastatic melanoma. Low morning serum concentrations of corticotropin (<1·1 pmol/L [reference range 2·2—13·2 pmol/L]) and cortisol (41·4 nmol/L [reference range 165·5—662·2 nmol/L]), combined with pituitary enlargement, were consistent with hypophysitis-related secondary adrenal insufficiency.

adrenal

Treatment with a replacement dose of hydrocortisone was initiated. Before ipilimumab treatment, her adrenal glands (circled) were normal in size (figure A). A subsequent surveillance CT scan of the abdomen showed bilateral enlargement of adrenal glands (figure B). Her serum cortisol and aldosterone concentrations did not respond to cosyntropin stimulation, which indicated primary adrenal insufficiency. 6 weeks later, her adrenal glands normalised in size (figure C). The dynamic size change of the adrenal glands suggests ipilimumab-related autoimmune adrenalitis. Although secondary adrenal insufficiency is a fairly common endocrinopathy related to ipilimumab treatment, the identification of primary adrenal insufficiency that could coexist with secondary adrenal insufficiency is important.

Source: Lancet

 

Still No Reason Not to Use Single-Dose Etomidate for RSI in Septic Patients.

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This meta-analysis was flawed, and the authors’ conclusion that etomidate use is linked to increased mortality is faulty.

Researchers performed a meta-analysis to assess the effects of single-dose etomidate used for rapid sequence intubation (RSI) on the adrenal axis and mortality in septic patients. They included only studies that were randomized or prospective observational, had a control group, and reported data on mortality and adrenal insufficiency as determined by cosyntropin stimulation testing. Ten studies involving a total of 1623 patients were included in the analysis; of these, five evaluated mortality (865 patients) and seven evaluated adrenal insufficiency (1303 patients). Of the five mortality studies, only two included patients who were randomized to etomidate versus an alternative agent — neither showed a mortality difference. Of the three studies without etomidate randomization, only one reported a mortality difference.

The authors report that patients receiving etomidate had a higher risk of mortality (pooled relative risk, 1.20) and adrenal insufficiency (pooled RR, 1.33).

Comment: The entire mortality effect comes from a single study in which patients were not randomized for etomidate. We reviewed that secondary analysis of etomidate use previously and found it sorely lacking (JW Emerg Med Dec 18 2009). Four of the five mortality studies, including the three with the highest methodology scores, failed to show any effect of single dose etomidate on the primary outcome of mortality. The authors correctly note that “the quality of literature investigating etomidate in severe sepsis and septic shock is limited in both quantitative and qualitative fashions.”

Meta-analyses of methodologically flawed trials are no more valuable than the trials themselves. Until a sufficiently sized, properly randomized, controlled trial of single-dose etomidate shows harm, etomidate remains one of the safest options for RSI, particularly in patients at risk for hypotension.

Source:Journal Watch Emergency Medicine