Testing the waters*

Science …requires testing of its ideas …to see if predictions are borne out by experiment …the testing of theories can be considered to distinguish science from other creative fields. —DC Giancoli, Physics, Upper Saddle River, NJ, Prentice Hall, 1995, p 3 For the most part, pediatric intensivists behave as an independent bunch, similar to a community of cats. On the other hand, critical care therapeutics from adult experience frequently migrate into the pediatric intensive care unit (PICU), often with meager evidence of either safety or efficacy in children. In this respect, the metaphor is more appropriately sheep rather than cats. This behavior likely reflects burgeoning pediatric critical care clinical and outcomes research, compared with more established adult research in these areas. No example better exemplifies this situation than the use of corticosteroids as adjunctive therapy for severe sepsis. Interestingly, the origins of rigorous clinical research in adult critical care can be traced to the 1980s, when several randomized, double-blinded, placebo-controlled trials were conducted to assess high-dose, short-duration methylprednisolone for septic shock. Although these studies demonstrated no benefit, and perhaps harm, they established a new, more rigorous standard for attempting to generate evidence-based critical care medicine (1–3). In this issue of Pediatric Critical Care Medicine, Menon and Lawson (4) report survey data regarding views of Canadian pediatric intensivists on the question of adjunctive corticosteroid therapy for children with severe sepsis. This type of information is vital in terms of eventual interventional trial design. Completed survey data were received from 84% (59/70) of intensivists practicing in 16 tertiary PICUs in Canada during 2004. Moreover, survey data also were received from 75% (43/57) of pediatric endocrinologists who provided consultation in Canadian PICUs during this interval. The authors acknowledge that the survey did not distinguish among absolute adrenal insufficiency (e.g., congenital adrenal hyperplasia), so-called relative adrenal insufficiency (in the setting of severe stress, such as sepsis), and inadequate adrenal reserve (requires a corticotrophin stimulation test). Although opinions varied widely, most Canadian pediatric intensivists would use a serum cortisol concentration <138 nM (5 μg/dL) as their definition of adrenal insufficiency, while Canadian pediatric endocrinologists prefer a definition of serum cortisol <500 nM (<18.1 μg/dL) after standard-dose corticotropin adrenal stimulation. Interestingly, 12% of the intensivists preferred to diagnose (and treat) adrenal insufficiency using clinical findings only. Without pediatric evidence of either safety or efficacy, 51% of Canadian pediatric intensivists would treat sepsis-related hypotension with corticosteroids. Surprisingly, 81% of Canadian pediatric endocrinologists would never or only occasionally prescribe corticosteroids for this same indication. In a related investigation conducted in the United Kingdom, Hildebrandt and colleagues (5) surveyed their pediatric intensivist colleagues regarding the use of adjunctive corticosteroids for pediatric severe sepsis. Among 25 PICUs, 13 (52%) returned the mailed survey, and the authors followed up with the other 12 units by telephone. For severe sepsis, 76% of the PICUs used corticosteroids regularly, 84% in the setting of vasoactive-inotropic refractory hypotension associated with sepsis. Usually (79%) hydrocortisone was the corticosteroid of choice, and it was administered without testing for adrenal sufficiency 42% of the time. For PICUs that undertook laboratory testing for adrenal sufficiency, there was wide variation for what was considered abnormal. Although all units regarded their prescribed dose of corticosteroids as stress or physiologic, significant variability in dosing also was reported. Czaja and Zimmerman (6) conducted a similar informal survey of pediatric intensivists who subscribe to the PICUList e-mail-forum digest. The questionnaire was posted at http://pedsccm.wustl.edu/research/trials/shipss_questionnaire.doc. Respondents numbered 65. In describing why a physician would prescribe corticosteroids to children with severe sepsis, 62% cited adult evidence, 8% cited pediatric evidence, and 30% cited personal preference. Nearly half of the respondents (48%) ordered no cortisol laboratory testing before prescribing corticosteroids for sepsis, whereas 21% relied on random cortisol levels and 31% preferred corticotropin stimulation testing. Again, despite lack of pediatric evidence for safety and efficacy of adjunctive corticosteroid therapy for severe sepsis, 68% of respondents noted that they would not participate in a clinical trial examining this question if a bailout study design was not used (i.e., administration of corticosteroids at the discretion of the primary intensivist as a life-saving measure). Several pediatric studies have linked increasing sepsis severity with decreasing random baseline serum cortisol levels (7–13). Two pediatric investigations have reported that children exhibiting a suboptimal increase in serum cortisol after corticotropin administration require more intense hemodynamic resuscitation, but no relationship to mortality could be established (9, 13). Admittedly, relatively small numbers of children were included in each of these pediatric investigations. Despite a transition from industrial corticosteroid dosing for severe sepsis to the currently popular low-dose, stress-dose, or physiologic-replacement corticosteroid dose, controversy continues to abound regarding the benefit of even this approach. Initial, small, adult trials using this tactic appeared to demonstrate hastened resolution of septic shock associated with decreased mortality (14–18). Subsequently, a substantially larger trial with 299 subjects demonstrated faster resolution of organ dysfunction, including septic shock, and significantly reduced mortality in an a priori defined subgroup with <9 μg/dL (250 nM) increment in serum cortisol after standard-dose corticotropin administration (74% of the total subjects enrolled) (19). Unfortunately, this investigation was subsequently found to be flawed by a report that a significant number of subjects had received etomidate for sedation during intubation (20). Etomidate inhibits 11-β hydroxylase, the rate-limiting enzyme in cortisol synthesis (21, 22). A definitive trial, CORTICUS, was designed and conducted as a logical follow-up (23). Although results of this pivotal study have only been reported in abstract form (24), it appears that even stress-dose hydrocortisone is not a panacea for adults with septic shock. Three small corticosteroid interventional trials in pediatric sepsis are also inconclusive (25–27). Multiple studies have confirmed that stress-dose corticosteroids hasten resolution from septic shock (14, 15, 18, 28–30). However, as illogical as it seems, resolution of septic shock may not be a clinically meaningful surrogate marker for mortality associated with sepsis. This was ascertained in the definitive trial of a nonselective inhibitor of inducible nitric oxide synthase; it hastened resolution of septic shock but was associated with increased mortality (31–33). In fact, corticosteroid supplementation for recalcitrant septic shock may hasten resolution of septic shock (34–36), but its pronounced gluconeogenic activity may augment hyperglycemia that, if inadequately controlled, may contribute to increased morbidity and mortality (37–41). It remains unclear whether the correct population is being targeted for corticosteroid supplementation during sepsis. Identifying this population would maximize the beneficial effects of corticosteroids, while minimizing adverse effects. Herein likely lies the value of the correct test to identify the target population. Among intensive care providers, this testing has traditionally involved two points of view: a) a stress such as severe sepsis should be sufficient stimulus for adrenal stimulation and, accordingly, a random serum cortisol should suffice to identify those individuals not mounting an appropriate adrenal stress response (42); and b) formal corticotropin stimulation testing best identifies individuals likely to benefit from corticosteroid supplementation (36). The latter approach is made more complex by arguments for standard-dose (145 μg/m2, 250 μg maximum) vs. low-dose corticotropin (1 μg) (43). A recent study in adults indicates that individuals with a random baseline serum cortisol of <10 μg/dL (278 nM) or those with an increment <9 μg/dL (250 nM) after standard dose corticotropin are likely to benefit from corticosteroid supplementation, but those with a random baseline level >44 μg/dL (1,222 nM) or those with an increment >16.8 μg/dL (467 nM) after standard-dose corticotropin appear cortisol sufficient and are unlikely to benefit from cortisol supplementation (44). Overriding all of this is an evolving consensus among endocrinologists that free (rather than total) cortisol more closely reflects the degree of stress and best identifies patients who are most likely to benefit from corticosteroid supplementation (45, 46). Studies such as the one presented by Menon and Lawson (4) should remind pediatric intensivists that we have an academic and, more importantly, patient responsibility to generate our own evidence-based medicine regarding the rational use of adjunctive corticosteroid for severe pediatric sepsis. Jerry J. Zimmerman, MD, PhD, FCCM Pediatric Critical Care Medicine Seattle Children's Hospital University of Washington School of Medicine Seattle, WA

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