Abstract
BackgroundThere is controversy around the prescription of adjunct corticosteroids in patients with fluid-refractory septic shock, and studies provide mixed results, showing benefit, no benefit, and harm. Traditional means for evaluating whether a patient receives corticosteroids relied on anecdotal experience or measurement of serum cortisol production following stimulation. We set out to measure both serum cortisol and the intracellular signaling receptor for cortisol, the glucocorticoid receptor (GCR), in this group of patients.MethodsWe enrolled pediatric patients admitted to the pediatric intensive care unit with a diagnosis of systemic inflammatory response syndrome (SIRS), sepsis, or septic shock as well as healthy controls. We measured serum cortisol concentration and GCR expression by flow cytometry in peripheral blood leukocytes on the day of admission and day 3.ResultsWe enrolled 164 patients for analysis. There was no difference between GCR expression comparing SIRS, sepsis, and septic shock. When all patients with septic shock were compared, those patients with a complicated course, defined as two or more organ failures at day 7 or death by day 28, had lower expression of GCR in all peripheral blood leukocytes. Further analysis suggested that patients with the combination of low GCR and high serum cortisol had higher rates of complicated course (75%) compared with the other three possible combinations of GCR and cortisol levels: low GCR and low cortisol (33%), high GCR and high cortisol (33%), and high GCR and low cortisol (13%; P <0.05).ConclusionsWe show that decreased expression of the GCR correlated with poor outcome from septic shock, particularly in those patients with high serum cortisol. This is consistent with findings from transcriptional studies showing that downregulation of GCR signaling genes portends worse outcome.
Highlights
There is controversy around the prescription of adjunct corticosteroids in patients with fluid-refractory septic shock, and studies provide mixed results, showing benefit, no benefit, and harm
Patients not older than 18 years of age admitted to the pediatric intensive care unit (PICU) and meeting pediatric-specific consensus criteria for systemic inflammatory response syndrome (SIRS), sepsis, or septic shock were eligible for enrollment
The finding of low expression of glucocorticoid receptor (GCR) in patients with a complicated course matches previous studies showing that patients with downregulation of this axis have worse outcomes
Summary
There is controversy around the prescription of adjunct corticosteroids in patients with fluid-refractory septic shock, and studies provide mixed results, showing benefit, no benefit, and harm. Heterogeneity among patients with septic shock has resulted in our inability to clearly show beneficial interventions beyond antibiotics and supportive care This is nowhere more obvious than in our current practice of prescribing adjunctive corticosteroids for patients with refractory septic shock. Some studies have suggested benefit [6], but subsequent trials have not been able to confirm these findings [7], whereas other studies suggest that there may be harm due to administration of corticosteroids [8,9,10,11] This was further reiterated with two recent large studies published side by side in the New England Journal of Medicine, again showing conflicting results [12, 13]. Until a more definitive trial can better categorize patients into more than just septic shock or no septic shock, we are unlikely to be able to resolve this question
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