Feature Review Article

A history of adjunctive treatment for pediatric sepsis: Moving beyond pulp fiction toward evidence-based medicine

Jerry J. Zimmerman, MD, PhD, FCCM

Objectives: To review the history of clinical use of corticoste- pituitary, adrenal disease), the safety and efficacy of stress-dose roids with particular reference to adjunctive therapy for severe as general adjunctive therapy for pediatric septic shock pediatric sepsis and, in this context, to provide an overview of have not been established. Glucocorticoid administration does what is known, what is not known, and what research questions add potential risk to critically ill children. In particular, although are particularly relevant at this time. adjunctive may hasten resolution of unstable he- Data Source: Literature review using PubMed, cross-refer- modynamics in septic shock, this may occur at the metabolic cost enced article citations, and the Internet. of hyperglycemia. Clinical practice that fosters innovative therapy Conclusions: The history of use in clinical med- (off-label use) over research probably represents bad medical and icine has been colorful, noisy, and always controversial. Thera- social policy. Accordingly, pediatric critical care researchers have peutic corticosteroid indications that initially seemed rational a responsibility to generate pediatric-specific evidence-based have frequently been refuted on closer, rigorous clinical trial medicine for adjunctive corticosteroid therapy for severe sepsis in inspection. Although it may be prudent to provide stress-dose children. (Pediatr Crit Care Med 2007; 8:530–539) steroids to children with septic shock who are clinically at risk for KEY WORDS: Thomas Addison; corticosteroids; ; hydro- adrenal insufficiency (chronic or recent steroid use, purpura ful- ; sepsis; septic shock; children; pediatric critical care minans, etomidate or administration, hypothalamic, medicine; corticotropin; bacterial meningitis; history of medicine

ovels written for the mass Birth of Endocrinology monograph titled On the Constitutional market, intended to be “a and Local Effects of Disease of the Supra- good read,”—often exciting, Although the adrenal glands were first renal Capsules (4). This work represented titillating, thrilling. Histori- described by Eustachio in 1563 (1), most Addison’s initiation into the formal study N discussions regarding the medical use of cally they have been very popular but of endocrinology (5). Although Addison’s critically sneered at as being of subliter- steroids begin with a discussion of work involving adrenal failure was criti- ary quality. The earliest ones were the Thomas Addison (Fig. 1), who graduated cized locally, a colleague in Paris, Ar- dime novels of the nineteenth century, as a medical doctor from the University of mand Trousseau, also recognized clinical printed on newsprint (hence “pulp” fic- Edinburgh in 1815 (2). That same year, adrenal failure and provided the eponym, tion) and sold for ten cents. Westerns, Addison moved to London to work in the Addison’s disease (6). stories of adventure, even the Horatio Lock Hospital. There, under the tutelage In conjunction with Dr. Richard Alger novels, all were forms of pulp fic- of Thomas Bateman, Addison became in- Bright, Addison took note of people dying tion.—R Harris, A Glossary of Literary terested in diseases of the skin; eventually with damage to their suprarenal capsules Terms, 1997 this interest would lead him to describe (adrenal glands). He first reported his ob- the alterations in skin pigmentation that servations in a lecture delivered in 1849 are characteristic of Addison’s disease. In titled “Anemia—disease of the supra re- 1817, Addison enrolled as a physician stu- nal capsules.” In 1866, E. H. Greenhow From the Division of Critical Care Medicine, Seattle dent at Guy’s Hospital in London, and by published a case series of adrenal failure Children’s Hospital, University of Washington School of 1819 he was elected to the Royal College associated with death. His survey in- Medicine, Seattle, WA. of Physicians. During the next 2 decades, cluded essentially all cases collected Dr. Zimmerman’s salary supported, in part, by NIH/NICHD 5 U10 HD049945, Collaborative Pediatric Addison had the good fortune to work throughout Europe. In conjunction with Critical Care Research Network. with Dr. Richard Bright and Dr. Thomas his Croonian Lectures delivered to the The author has not disclosed any potential con- Hodgkin (3), both lecturers at Guy’s Hos- Pathologic Society, Greenhow published flicts of interest. pital on the subject of practical medicine. a book titled Addison’s Disease in 1875, For information regarding this article, E-mail: Addison subsequently collaborated with [email protected] essentially a compilation of the clinical Copyright © 2007 by the Society of Critical Care Bright to write a textbook of medicine experience with Addison’s disease to that Medicine and the World Federation of Pediatric Inten- titled Elements of the Practice of Medi- date (7). Addison’s early work identified sive and Critical Care Societies cine, published in 1839. In 1855, Addison the constellation of clinical signs and DOI: 10.1097/01.PCC.0000288710.11834.E6 published a monumental endocrinology symptoms associated with adrenal dam-

530 Pediatr Crit Care Med 2007 Vol. 8, No. 6 philic adenomas of the pituitary gland. A curred in 1911 with a report in The Lan- description of hypothalamus-pituitary- cet by Rupert Waterhouse (26), who was a adrenal function and glucocorticoid se- pathologist and assistant physician at the cretion was recorded by Selye (18) in Royal United Hospital in Bath, England. 1936, when he noted adrenal hypertro- In this article Waterhouse described clin- phy, gastric ulceration, and thymolym- ical purpura fulminans and its associa- phatic dysplasia as the classic triad of the tion with acute hemorrhagic necrosis of stress response. the adrenal glands (suprarenal apoplexy). During the following several years, a Steroid Hormone Characterization Copenhagen pediatrician, Carl Friderich- Also during the 1930s, numerous ad- sen (27), published his observations on renal steroid compounds were being iso- nearly 30 similar clinical cases, calling lated and structures identified in the lab- the syndrome nebennier-enapoplexie bei oratories of Thadeus Reichstein, Edward kleinen Kindern (adrenal apoplexy in Calvin Kendall, and Phillip Showalter small children). In 1934, Bamatter (28) Figure 1. Thomas Addison. Figure accessed on Jan- Hench (19). These pioneer physiology coined the term Waterhouse-Friderich- uary 10, 2007, at http://www.iqb.es/historiamedicina/ sen syndrome in honor of the first two personas/addison.htm. Printed with permission. chemists were awarded the Nobel Prize for Physiology in Medicine in 1950 for describers. Writing again in 1955, Fri- their combined work related to steroid derichsen (29) reported on an additional hormone characterization of the adrenal 250 cases. He noted the association with age and promoted his recognition as the cortex, which ultimately culminated in meningotoxemia. He also indicated that “father” of the field of endocrinology. the isolation and identification of corti- before 1938, all detailed cases had been sone as a novel compound in 1935 (20). fatal, but with the advent of sulfonamides Early Adrenal Initial synthesis of compound E (corti- and penicillin, case reports of survival Physiology/Biochemistry sone) was achieved in the laboratories of were now beginning to appear in the lit- the Mayo Foundation and Merck and erature (29). Numerous experiments in the early Company when a practical method was 1900s demonstrated the key role of the achieved to introduce a hydroxyl moiety Cortisone Treatment of Clinical adrenal glands in maintaining normal he- to carbon 17 of the steroid framework Shock modynamics. Some cases of clinical (21). By 1948, sufficient quantities of cor- shock were found to be associated with tisone were isolated in Kendall’s and Sar- During the early 1950s, with frequent hemorrhage of the adrenal gland, as re- rett’s laboratories to be used in small clinical and necropsy evidence for adrenal ported in 1934 (8). Based on these obser- clinical investigations. During the next 2 insufficiency associated with meningo- vations, some types of shock were actu- decades the various steroidogenic en- coccemia, children with evidence of cir- ally attributed to so-called adrenal zymes were isolated, characterized, and culatory collapse in shock were being exhaustion (9, 10). Subsequent experi- subsequently cloned. routinely treated with cortisone. Based ments confirmed the importance of the primarily on results of impressive animal adrenal cortex. Investigators at the Uni- Initial Steroid Clinical Trials experiments (described previously), corti- versity of Buffalo (11) and Princeton (12) costeroids were routinely used for ad- were the first to prepare extracts of adre- In September 1948, Hench et al. (22) junctive treatment of sepsis in the 1950s nal cortex and subsequently use these administered the first injections of corti- and 1960s (30). The first clinical evidence preparations to relieve adrenal insuffi- sone acetate to patients with rheumatoid suggesting the use of therapeutic corti- ciency symptoms in both adrenalecto- arthritis and rheumatic fever, demon- costeroids for severe generalized infec- mized animals and patients with Addi- strating clinically the anti-inflammatory/ tions was published by Hahn et al. (31) in son’s disease. Swingle et al. (13) reported immunosuppressive properties of corti- 1951. A summary of a trial that enrolled 82 that preparations of adrenal cortex ex- sone. In 1952, corticosteroids were pediatric and adult subjects with severe in- tract were effective in treating shock in shown to reduce granulocyte adherence fection was published by Jahn et al. (32) in terms of restoring circulating blood vol- to vascular epithelium after an inflamma- 1954. More than half of the subjects were ume, relieving hemoconcentration, in- tory stimulus using the classic ear cham- children, infected primarily with Hae- creasing blood pressure, and restoring ber model (23). By November 1950, cor- mophilus influenzae and Neisseria menin- but ,%33ف kidney function, including increased ex- tisone was available to physicians gitidis. Overall mortality was cretion of both potassium and ammonia throughout the United States through the investigators noted, “There is no ques- and retention of both sodium and chlo- supply houses, and translational re- tion that the administration of ACTH or ride. Later studies, like those of Hinshaw search permitted the first treatment of cortisone in sufficient amounts to patients et al. (14–16) using similar animal mod- congenital adrenal hyperplasia orches- with severe infections will result in rapid els, demonstrated that corticosteroid re- trated by both Crigler and Wilkins (24) and striking clinical improvement.” Multi- placement in conjunction with antibiot- and Bartter et al. (25) with cortisone. ple small clinical investigations examining ics resulted in improved survival in Infection-Associated Adrenal corticosteroids in this clinical setting were adrenalectomized dogs challenged with conducted between 1950 and 1971, but Apoplexy lethal doses of bacteria. In 1932 Harvey good clinical trial design was absent (33). Cushing (17) described the multiple clin- Probably the first link between adrenal More than a decade passed before the first ical manifestations associated with baso- pathology and critical care medicine oc- prospective, randomized, placebo-con-

Pediatr Crit Care Med 2007 Vol. 8, No. 6 531 trolled trial of in sepsis was fluid lactate and protein levels. A subse- Regarding pneumococcal meningitis, there conducted, by Bennett et al (34). quent study by Odio et al. (44) that en- was no consensus for the use of adjunctive rolled 101 infants with culture-proven corticosteroids. Here the committee ex- Steroids for Sepsis—Burgeoning bacterial meningitis confirmed the bene- plained that insufficient data are available Strict Critical Care Clinical ficial effect of in this set- demonstrating a clear benefit in children. If Research Design ting. Twelve hours following enrollment, used, corticosteroids should be administered those children treated with dexametha- before or concurrent with the first dose of Primarily base on the study by sone demonstrated decreased cerebral antibiotic. No recommendations were pro- Schumer (35), high-dose spinal fluid tumor necrosis factor and vided for cases of meningococcal meningitis. became accepted therapy for septic shock platelet-activating factor, whereas those in the late 1970s and early 1980s, al- children receiving placebo actually dem- Invocation of Relativity in the though an earlier study that enrolled onstrated increases in cerebral spinal Adrenal Response to Stress: both children and adults demonstrated fluid inflammatory markers. Again, re- Pediatric Data no benefits of hydrocortisone in patients duction in neurosensory hearing loss, as with severe sepsis (36). This era might be assessed at 15 months following enroll- Sepsis and associated systemic inflam- described as the industrial dosing revolu- ment, was apparent in the dexamethasone- matory response represent a common tion of corticosteroids as adjunctive treat- treated children. In their discussion, the cause of acute so-called relative adrenal ment of severe sepsis. Dose of glucocor- authors emphasized the importance of ad- insufficiency and dysfunctional adrenal ticoid, typically , was ministering the dexamethasone before ini- reserve in adults (51–60) as well as chil- high, generally 30 mg/kg, and duration of tiation of antibiotics. Other clinical trials dren (61–65). In adults with severe sep- dosing short, typically Յ1 day. During subsequently reported a beneficial effect of sis, Annane et al. (58) reported that non- this time, rigorous clinical trial design dexamethasone in both adult and pediatric survivors demonstrated higher basal emerged in critical care medicine. Re- meningitis (45–47). Beneficial affects were plasma cortisol concentrations compared sults of three such trials, all published in confirmed for not only the most common with survivors and also exhibited dimin- the New England Journal of Medicine, bacterial pathogen, namely H. influenzae, ished cortisol response to corticotropin. ascertained that high-dose, short-dura- but also for Streptococcus pneumoniae and A study of Brazilian children with severe tion methylprednisolone did not decrease N. meningitidis. A subsequent meta- sepsis by Pizarro et al. (65) seemed to sepsis mortality and might be associated analysis of 11 studies examining dexameth- indicate similar findings, with the high- with serious adverse side effects, such as asone therapy for childhood bacterial men- est mortality (53%) noted in a group of gastrointestinal hemorrhage (37–39). Re- ingitis from 1988 to 1996 concluded that 15 children with random total baseline views of the clinical trials using high- adjunctive dexamethasone therapy was cortisol Ͼ20 ␮g/dL but incremental in- dose corticosteroids, administered as a clearly beneficial in terms of reducing sen- crease in cortisol following corticotropin single dose during the initial hours of sory neural hearing loss secondary to H. Ͻ9 ␮g/. septic shock, concluded that this ap- influenzae B meningitis, and if dexameth- However, for pediatric patients with proach likely conferred no beneficial ef- asone was initiated with or before antibiotic meningococcemia (n ϭ 96), significantly fect on mortality (40–42). An additional therapies, a suggested benefit for pneumo- lower cortisol levels were identified by important conclusion of the meta- coccal meningitis was also apparent (48). Riordan et al. (61) in those patients who analyses of these early steroid sepsis trials Dexamethasone treatment led to more died (median 38.5, range 16–74) com- was the need for methodologically rigor- rapid resolution of initial fever but was as- pared with those who survived (median ous experimental design in future studies sociated with a greater incidence of second- 45.3, range 16–186 ␮g/dL, p Ͻ .05), al- (40–42). ary fevers as well as gastrointestinal bleed- though absolute adrenal failure (serum ing. Similarly, a Cochrane review that cortisol Ͻ5 ␮g/dL) was not noted. Two of Steroids as Adjunctive included 18 studies enrolling 1,853 sub- three children with levels Ͻ18 ␮g/dL and Treatment for Bacterial jects concluded that overall adjunctive cor- hypotension died. No association of cor- Meningitis ticosteroids were associated with a lower tisol levels with meningococcal severity case fatality rate as well as lower incidence scores or shock status could be ascer- Enthusiasm for the use of adjunctive of sensory neural hearing loss and long- tained, but lower cortisol levels and steroids for sepsis was heightened during term neurologic sequelae (49). In this re- higher adrenocorticotropic hormone lev- the late 1980s when reports began to view, adverse events were not noted to be els were characteristic of those who died. appear extolling the benefits of dexa- significantly increased with the use of cor- In a similar smaller study of children therapy for bacterial menin- ticosteroids. The 27th Edition of the Red with meningococcemia (n ϭ 33) con- gitis. An initial report summarizing two Book (2006 Report of the Committee of ducted by Hatherill et al. (62), no statis- clinical investigations that enrolled a to- Infectious Diseases, American Academy of tical relationship could be claimed re- tal of 200 infants by Lebel et al. (43) Pediatrics) (50) states that dexamethasone garding cortisol levels and outcome, indicated that children with meningitis may be beneficial for infants and children although survivors demonstrated numer- who received dexamethasone became afe- with H. influenzae meningitis in terms of ically higher basal and corticotropin- brile earlier and in addition were less reducing the risk of neurologic sequelae, stimulated minus basal (⌬) cortisol levels likely to acquire moderate or severe neu- specifically neurologic hearing loss, if given compared with nonsurvivors. Children rosensory hearing loss. These clinical ef- before or concurrent with the first dose of exhibiting a ⌬ cortisol Ͻ7.2 ␮g/dL had fects were correlated with faster normal- antibiotics. The Committee noted that significantly higher Pediatric Risk of ization of cerebral spinal fluid glucose there is likely no benefit if dexamethasone Mortality scores and required more vaso- and faster decrease in cerebral spinal is given Ͼ1 hr following the antibiotic. active-inotropic support compared with

532 Pediatr Crit Care Med 2007 Vol. 8, No. 6 children who had a more robust ⌬ corti- nal response to intense stress, such as sure and systemic vascular resistance and sol response. In another study of pediat- severe sepsis (55, 60, 70). Moreover, a decrease in heart rate, cardiac index, ric meningococcal disease, by van Hamrahian et al. (71) pointed out that and norepinephrine requirement. Shock Woensel et al. (66), relatively lower levels quantification of total vs. free cortisol will reversal in the cortisol-treated group was of cortisol and higher levels of adrenocor- generate different answers particularly in faster than in the placebo group. Cortisol ticotropic hormone were associated with patients with hypoalbuminemia. Re- treatment (but not placebo) was associated a more severe disease course. Accord- cently, Annane et al. (72) used the gold with a reduction of plasma nitrite/nitrate ingly, serum cortisol levels of 45.7 Ϯ 5.1, standard overnight stimula- (following 3 days of cortisol treatment, se- 36.9 Ϯ 1.5, and 22.5 Ϯ 3.0 ␮g/dL were tion test to assess the diagnostic value of rum nitrite/nitrate concentrations de- p ϭ .009), which was ,%32ف recorded for children with meningococ- the standard (high-dose) corticotropin creased by cal meningitis, meningococcal sepsis, stimulation test in relation to defining correlated with a reduction in need for va- and fulminant meningococcal sepsis, re- the prevalence of sepsis-associated rela- sopressor support. Biomarkers of proin- spectively. In this study, levels of inter- tive adrenal insufficiency. Baseline serum flammation (IL-6, IL-8), endothelial activa- leukin (IL)-6, IL-8, and IL-10 also corre- cortisol Յ10 ␮g/dL, corticotropin-stimu- tion (soluble E-selectin), neutrophil lated with disease severity. Yet another lated minus basal (⌬) cortisol Ͻ9 ␮g/dL, activation (CD11b, CD64 expression), and study of severe pediatric meningococcal and (derived) free cortisol Ͻ2 ␮g/dL were anti-inflammation (soluble tumor necrosis disease (n ϭ 62) by de Kleijn et al. (67) found to be associated with positive like- factor receptors, IL-10) were all attenuated confirmed that low serum cortisol and lihood ratios of ϱ, 8.46, and 9.50, respec- during cortisol administration. However, high adrenocorticotropic hormone levels tively. As defined by metyrapone testing, blood monocyte human leukocyte anti- were associated with poor outcome as the best predictors of adrenal insuffi- gen-DR expression was only minimally de- median serum cortisol levels of 41.7 ciency were baseline cortisol Ͻ10 ␮g/dL pressed (no immune paralysis). Measures of (range 26.5–77.4), 35.9 (range 10.6– or ⌬ cortisol Ͻ9 ␮g/dL, whereas the best in vitro phagocytosis and IL-12 were in- 89.3), and 23.5 (range 11.5–37.8) ␮g/dL predictors of normal adrenal response creased. Rebound hemodynamic and im- were recorded for children with sepsis were baseline cortisol Ն44 ␮g/dL or ⌬ munologic effects were appreciated with survival, septic shock survival, and septic cortisol Ն16.8 ␮g/dL. withdrawal of hydrocortisone on day 3, shock nonsurvival, respectively. More re- Even in the presence of elevated prompting the investigators to suggest cently, an investigation by Önebli- plasma cortisol concentration, relative weaning of steroid dosing for patients with Mungan et al. (68) examining generic pe- local cortisol insufficiency may occur at severe sepsis, as opposed to abrupt with- diatric sepsis (n ϭ 102) also found a sites of inflammation (corticosteroid re- drawal. In this important clinical biological relationship between lower serum corti- sistance syndrome) secondary to 1) deple- plausibility study of stress cortisol for septic sol levels and more severe disease. In this tion of corticosteroid-binding globulin; shock, baseline serum total cortisol levels study, serum cortisol levels of 29.4 Ϯ 1.5 2) activation of 11-␤-hydroxysteroid de- ranged from 30 to 40 ␮g/dL and increased (range 7–46), 30.8 Ϯ 0.8 (range 20–45), hydrogenase (type 2); 3) depression of approximately five-fold above this baseline and 10.4 Ϯ 1.5 (range 2–19) ␮g/dL were glucocorticoid receptors; 4) diminution during cortisol administration. characteristic of nonseptic control chil- of receptor affinity for cortisol; and 5) With reference to children, endogenous dren, children with sepsis (mortality elevation of antiglucocorticoid com- cortisol secretion increases approximately 26%), and children with septic shock pounds or receptors (73). four-fold in the setting of meningococcal (mortality 71%), respectively. Serum cor- disease (66–68, 83). Accordingly, to mimic tisol levels in survivors and nonsurvivors Stress-Dose Cortisol the body’s stress response, a dose of hydro- Ϯ Ϯ ␮ were 33.9 0.9 and 19.7 1.8 g/dL, Replacement for Severe Sepsis cortisone equivalent to four times the nor- respectively (p Ͻ .01). Most recently, mal cortisol secretion has been recom- Sarthi et al. (69) assessed 30 children In an effort to therapeutically address mended (61, 84). with septic shock for adequacy of adrenal the concept of relative adrenal insuffi- A landmark trial of adjunctive low- function using low-dose (1 ␮g) cortico- ciency and/or inadequate adrenal reserve, dose hydrocortisone plus fludrocortisone tropin stimulation. Thirty percent dem- more recent interventional investigations for adults (n ϭ 299) with septic shock onstrated cosyntropin-stimulated minus have examined provision of low or so- was conducted in France by Annane (85) basal cortisol (⌬) concentrations Ͻ9 ␮g/ called stress-dosing of cortisol as adjunc- and rekindled interest in endocrinology dL. These children with inadequate adre- tive therapy for septic shock and severe and metabolism within the field of criti- nal reserve exhibited a higher incidence sepsis, with the knowledge that cortisol cal care medicine. This investigation of catecholamine refractory shock but no can restore the vascular responsiveness demonstrated faster resolution of septic difference in mortality compared with to catecholamines in adults with septic shock and organ dysfunction in general children with adequate adrenal reserve (74) and hemorrhagic shock (75). An for subjects receiving replacement ste- based on this low-dose corticotropin overview summary of seven such studies roids. Moreover, a significant decrease in relative) was reported ,%20ف) stimulation test. generally confirms the benefit of stress- mortality dose cortisol in hastening hemodynamic for subjects demonstrating a ⌬ cortisol Semantics Turn Out to Be Very stability in the setting of adult septic Ͻ9 ␮g/dL at enrollment. Unfortunately, Important shock (76–82). this trial was tainted with subsequent In a double-blind, crossover investiga- knowledge that a significant number of Comparisons of studies correlating ad- tion involving 40 adults with septic shock subjects had been intubated with etomi- renal status with outcome are hampered conducted by Keh and Sprung (79), hy- date (70), which is known to inhibit 11- by lack of consensus regarding what con- drocortisone treatment was associated ␤-hydroxylase, a rate-limiting enzyme in stitutes a sufficient vs. insufficient adre- with an increase in mean arterial pres- the synthesis of cortisol (86, 87). With

Pediatr Crit Care Med 2007 Vol. 8, No. 6 533 this discussion came recommendations testing cannot be recommended to guide are meager. A randomized, double-blind to discontinue the use of etomidate in the hydrocortisone therapy. Adjunctive hy- trial of adjunctive cortisol for dengue intensive care unit (88) or alternatively drocortisone may have a role for adult shock syndrome (n ϭ 98 total, 48 of provide hydrocortisone replacement if septic shock that persists for Ͼ1hrde- whom received cortisol) by Min et al. (97) etomidate is used (89). spite aggressive fluid and vasoactive- reported a case fatality rate of 19% in the With this suggestion that stress-dose inotropic resuscitation. steroid group and 44% in the placebo cortisol might be beneficial for adults A meta-analysis of 505 septic adults group (illness severity, age, and gender with septic shock (85), a larger interna- included in steroid replacement trials be- matched). Later, a prospective observa- tional trial, CORTICUS, was designed fore the CORTICUS investigation simi- tional trial of nine children with dengue (90). As with the previous investigation, larly reported that low-dose corticoste- shock treated with high-dose methyl- the primary outcome measure was all- roids can reduce vasoactive-inotropic (nine of nine) and mannitol cause 28-day mortality in subjects who infusion requirements and hasten the re- (six of nine) conducted by Futrakul et al. exhibited a corticotropin stimulated mi- versal of shock (92). Other meta-analyses, (98) reported improved hemodynamics in nus baseline serum cortisol increment of examining several trials of adjunctive glu- seven patients. However, a subsequent Ͻ9 ␮g/dL. This investigation was slated cocorticoid therapy for adults with sepsis, study by Sumarmo et al. (99) yielded op- to enroll 800 adults with sepsis from 2002 all conducted before the CORTICUS inves- posite conclusions. Mortality, duration of to 2005 at 52 European performance tigation, concluded that 1) short-course, shock, and volume of fluid resuscitation sites, but the trial was halted for futility high-dose glucocorticoid therapy decreases were virtually identical in the two illness following enrollment of 500 subjects survival and hence is not recommended for severity-, age-, and gender-matched (91). Cortisol (no fludrocortisone in this severe sepsis; 2) a 5- to 7-day course of groups of children with dengue shock study) or placebo was prescribed at 50 mg low-dose cortisol with rapid weaning im- (n ϭ 97 total), treated with cortisol (n ϭ intravenously every 6 hrs for 5 days fol- proves survival and hastens shock reversal for 47, 50 mg/kg once) or placebo (n ϭ 50). lowed by a rapid wean. Although has- adults with vasoactive-inotropic infusion de- Similarly, Tassniyom et al. (100) con- tened resolution of shock occurred in the pendent septic shock; and 3) in the absence of ducted a randomized, controlled trial of a group receiving corticosteroids (3.1 vs. vasoactive-inotropic infusion requirement, single dose of methylprednisolone (30 5.7 days), no benefit in terms of reduced corticosteroids should not be used to treat mg/kg) vs. placebo among 63 children mortality was noted either for the total sepsis (79, 92–96) (Fig. 2). If patients from with dengue shock. Baseline characteris- cohort or for subjects with ⌬ cortisol Ͻ9 the CORTICUS trial are included in one tics between the two groups were very -of the total population). such meta-analysis (94), there is no benefit similar. Mortality was 12.5% in the meth %50ف) ␮g/dL Nosocomial infection, new sepsis, new of adjunctive steroids in reducing septic ylprednisolone group and 12.9% in the septic shock, and measures of hypergly- shock mortality (G Benard, Sepsis Contro- placebo group. In addition, no differences cemia were significantly more prevalent versies, Society of Critical Care Medicine in organ dysfunction between groups in the hydrocortisone-treated group. 2007 Annual Scientific Symposium). could be ascertained. From a study of Principal investigator for the CORTICUS African children with sepsis, Slusher et trial, Charles Sprung, surmised that rou- Insufficient Pediatric Data al. (101) concluded that moderate-dose tine adjunctive hydrocortisone for adult dexamethasone (0.05 mg/kg every 8 hrs septic shock cannot be recommended and Clinical trials examining adjunctive for 2 days, with the initial dose delivered that corticotropin adrenal stimulation corticosteroid therapy for pediatric sepsis before antibiotics) did not improve sur-

Figure 2. Relative risk of all-cause 28-day mortality in septic shock patients treated with low-dose or high-dose corticosteroids. Marker size is proportional to the percentage weight of the study. Horizontal lines, 95% confidence interval (CI); diamonds, pooled analysis; horizontal diamond width, 95% CI. Adapted with permission from Keh and Sprung (79).

534 Pediatr Crit Care Med 2007 Vol. 8, No. 6 Table 1. Steroid use and mortality for pediatric severe sepsis Hastened Gluconeo- Shock genesis Mortality Resolution Hyperglycemia

Received Concurrent Steroids? Died (%) Lived (%) Crude OR (95% CI) Total

Neonates Yes 427 (29) 1,050 (71) 2.29 (1.94, 2.71) 1,477 Figure 3. Adjunctive corticosteroids for severe No 289 (15) 1,627 (85) 1,916 Totals 716 (21) 2,677 (79) 3,393 sepsis: a question of balance. Nonneonates Yes 521 (30) 1,209 (70) 1.60 (1.37, 1.88) 1,730 No 333 (21) 1,237 (79) 1,570 cium mobilization, impaired insulin ac- Totals 854 (26) 2,446 (74) 3,300 tion and associated hyperglycemia, and perhaps alterations in brain development OR, odds ratio; CI, confidence interval. (107). Although adjunctive corticoste- roids for severe sepsis may hasten reso- vival to discharge, time to hemodynamic diatric intensive care unit days, hospital lution of unstable hemodynamics (76– stability, hospital length of stay, or dura- days, hospital costs) (103). 82), this may occur at the metabolic risk tion of fever. Other adult investigations have con- of hyperglycemia (Fig. 3). Augmentation One retrospective cohort study by cluded that results of corticotropin stim- of gluconeogenesis and anti-insulin ef- Markovitz et al. (102) using the Pediatric ulation testing does not predict hemody- fects of cortisol are of particular concern, Health Information System database ex- namic improvement with adjunctive given adult data indicating the significant amined factors associated with outcome corticosteroids for patients with vasoac- risk of nosocomial sepsis, multiple organ in children with severe sepsis as opera- tive-inotropic-dependent septic shock dysfunction syndrome, and death associ- tionally defined by a combination of in- (104); that administration of adjunctive ated with hyperglycemia (108, 109). Risk fection plus need for a vasoactive- corticosteroids to critically ill patients of hyperglycemia and associated in- inotropic infusion and mechanical based on arbitrary baseline or incremen- creased mortality secondary to the glu- ventilation. Among the 6,693 children tal serum cortisol concentrations does coneogenic effects of cortisol deserve meeting this definition of severe sepsis, not improve survival (105); and that cor- close scrutiny in children as well (110– mortality was 30% for children who re- ticosteroid use in the intensive care unit 112). ceived steroids compared with 18% for is associated with increased rate of infec- Steroid treatment for disease states those who did not (crude odds ratio 1.9; tion, increased days of mechanical venti- can be associated with worse outcomes: 95% confidence interval, 1.7, 2.2) (Table 1). lation, increased intensive care unit Early, prolonged dexamethasone pre- Similarly, children who received steroids length of stay, and a trend toward in- scribed to decrease the incidence and se- required longer duration of vasoactive- creased mortality (106). verity of bronchopulmonary dysplasia inotropic infusion and mechanical venti- may increase the incidence of cerebral lation support and required a signifi- Evidence-Based Medicine palsy (113). Methylprednisolone pre- cantly longer pediatric intensive care unit Means Doing the Experiment scribed in the setting of traumatic brain length of stay and hospital length of stay. injury actually increased mortality and A crucial liability of this investigation re- Although it seems prudent to provide morbidity (114). Methylprednisolone pre- lated to lack of illness severity data. How- stress-dose steroids to children with sep- scribed to reduce the incidence and se- ever, an important conclusion from this tic shock clinically at risk for stress adre- verity of acute respiratory distress syn- epidemiologic study using the Pediatric nal insufficiency (chronic steroid use, re- drome fibroproliferative disease was Health Information System administra- cent steroid use, purpura fulminans, associated with significantly increased tive database was that no evidence exists etomidate or ketoconazole administra- 60- and 180-day mortality for patients indicating that steroids are associated tion, hypothalamic, pituitary, adrenal dis- who were enrolled Ն14 days after the with improved outcome in critically ill ease) as suggested by the Task Force for onset of acute respiratory distress syn- children with sepsis. Although steroids Hemodynamic Support of Pediatric and drome (115). Although methylpred- may have been given preferentially to Neonatal Sepsis, American College of nisolone increased the number of venti- more severely ill children, their use was Critical Care Medicine (65), safety and lator-free and vasopressor-free days associated with increased mortality. The efficacy of stress-dose steroids as general during the first 28 days following enroll- authors emphasized that clinicians adjunctive therapy for pediatric septic ment, it was also associated with a higher should maintain equipoise on the ques- shock have not been established. Provi- rate of neuromuscular weakness. tion of adjunctive steroid therapy for pe- sion of stress-dose cortisol may be bene- Existing clinical guidelines for hemo- diatric sepsis pending prospective ran- ficial or even life-saving in children with dynamic support of pediatric and neona- domized clinical trials. Preliminary an insufficient adrenal response to severe tal patients in septic shock are clear to single-institution data suggest that even stress, such as sepsis. However, pediatric point out, “Studies are required to deter- controlling for illness severity, adjunctive evidence-based data for this indication mine whether American College of Criti- corticosteroids administered to children currently do not exist. cal Care Medicine guidelines for hemody- with sepsis syndrome do not improve Glucocorticoid administration does namic support of pediatric and neonatal outcomes (mortality, mechanical ventila- add potential risk to critically ill children, septic shock will be implemented and as- tor days, vasoactive-inotropic infusion including antianabolic effects, attenuated sociated with improved outcome” (65). days) or reduce resource utilization (pe- immunity, depressed wound healing, cal- Although it is highly desirable to develop

Pediatr Crit Care Med 2007 Vol. 8, No. 6 535 evidence-based guidelines for use of ad- trials of sepsis, as faster resolution of History reveals a long and colorful tale junctive corticosteroids for pediatric se- shock does not necessarily correlate with of the use of steroids in clinical medicine vere sepsis, three significant barriers im- reduced mortality (102, 123, 124). authored by bedside physicians and Nobel pair design and implementation of The third barrier is substantial lack of laureates alike. The road to Oz, as the clinical trials to support or refute this clinical equipoise regarding the benefit metaphor for evidence-based medicine notion. and safety of adjunctive corticosteroid for regarding use of adjunctive steroids for The first barrier includes existing, pediatric severe sepsis. Several relevant pediatric sepsis, may be arduous, even widely variable, but emphatic practices re- comments are appropriate at this junc- treacherous, but it is time for pediatric garding use of adjunctive corticosteroids ture: Usual care, not linked to strong intensivists to attend to the significant for severe sepsis in children. Surveys con- evidence is ephemeral and very subject to task of generating pediatric evidence- ducted in the United Kingdom (116), Can- secular change. migrate into pedi- based medicine in this area: 1) Establish ada (117), and the United States (118) have atric use from adult experience, often by data and then consensus what consti- confirmed that significant controversy and with meager evidence of safety and effi- tutes an inadequate adrenal response to no consensus exist regarding the method cacy. However, in the absence of a well- severe stress and how this is best quanti- for assessing adequacy of the adrenal stress defined clinical practice (wide variation fied; and 2) identify the true benefit/risk response and regarding treatment of appar- that is largely unexplained), it is reason- ratio associated with corticosteroid ad- ent adrenal insufficiency (indication, drug, able to randomize (in a clinical trial) two ministration in critically ill children, by dose, duration). well-founded yet competing beneficial assessing both short- and long-term mor- The second barrier is lack of an appro- treatment strategies (with or without bidities. International multicenter pedi- priate, consensus-determined, clinically corticosteroid) that lie within the bound- atric critical care research networks (e.g., meaningful primary outcome measure aries of competent or good care. Australia and New Zealand Intensive Care for pediatric sepsis interventional trials. Society Study Group, Canadian Critical Because of a significantly lower mortality What Next Along the Yellow Care Trials Group, Collaborative Pediat- in children with severe sepsis (approxi- Brick Road? ric Critical Care Research Network [CPC- mately 15% to 20%), conduct of a sepsis CRN], European Society of Pediatric and interventional trial with reduction of Several aspects of the current use of Neonatal Intensive Care [ESPNIC], In- mortality as the primary end point is un- stress-dose corticosteroids for pediatric dian Pediatric Intensive Care Group, In- realistic, as thousands of patients would severe sepsis are unsatisfactory: Safety ternational Group on Mechanical Venti- be required for both arms of an investi- and efficacy are unproven; wide practice lation, Pediatric Acute Lung Injury and gation for an expected 20% relative treat- variability exists; risks of adverse events Sepsis Investigators [PALISI], UK Pediat- ment effect (119). At first, consideration in children, such as hyperglycemia, my- ric Intensive Care Society Study Group, of hastened resolution of septic shock opathy/neuropathy, and nosocomial in- WFPICCS [World Federation of Pediatric might seem an appropriate surrogate fections, are unknown; and there is po- Intensive and Critical Care Societies] clinical outcome measure for corticoste- tential for increased risk of mortality. (Sepsis Initiative) are now a reality. We roid interventional trials. Many pediatric Anecdotes is not the plural of evi- can do this. intensivists reflexively initiate stress-dose dence. Off-label use of corticosteroids cortisol in the setting of volume and vaso- could be argued to represent bad clinical active-inotropic infusion recalcitrant septic practice: Dosing regimens are typically REFERENCES shock (116). Compromised endothelial in- extrapolated and variable among practi- tegrity, systemic vasoplegia, impaired car- tioners, every patient is an experiment 1. 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