Frequency of steroid use
The overall frequency of steroid use in patients with shock was 35.7% (95% CI: 30.78, 40.62). The types of all steroids used along with their frequencies are shown in Table 3. The most commonly used steroid in the first 72 hours was hydrocortisone (81/130, 62.3%) followed by methylprednisolone (30/130, 23.1%), dexamethasone (18/130, 13.9%) and prednisone (1/130, 0.77). No patients received fludrocortisone. The frequency of hydrocortisone use within 72 hours of PICU admission was 22.3% (95% CI: 18.0, 26.5). The frequency of hydrocortisone use by centre varied from 19.0% to 30.9%.
Reasons for hydrocortisone and other steroid use
The reason for starting hydrocortisone within 72 hours of admission was documented in the chart for 50.6% (41/81) of patients with the reported indications for its use being hemodynamic instability (37/41), pre-medication (2/41), asthma (1) and post-operative transplant (1). Of the 40 patients in whom hemodynamic instability was documented as the reason for the administration of any steroid, 37 received hydrocortisone and three received methylprednisolone. Nineteen of the 40 patients (47.5%) with documented use of any steroid within 72 hours of admission for hemodynamic reasons had a primary discharge diagnosis other than septic shock. The primary diagnoses and reasons for steroid use in these patients are shown in Table 4.
Patterns of hydrocortisone use
The most commonly used dosing regimen for hydrocortisone was 4 mg/kg/day divided every 6 hours and the median cumulative dose was 23.1 mg/kg (IQR 3.6–80.0). No patient received a continuous infusion of hydrocortisone. The median time to administration of hydrocortisone from the time the patient was started on a vasoactive agent was 6.3 ± 15.1 hours (IQR 2.7–13.0) and the median duration of hydrocortisone use was 66.8 ± 15.1 hours (IQR 24.4–124.0). The duration of hydrocortisone use in post-operative cardiac surgery patients was shorter than those with septic shock (61.6 ± 11.0 versus 68.7 ± 17.2 hours, P = 0.038). Seventy-four of the 81 patients (91.4%) who received hydrocortisone received it within 24 hours of starting a vasoactive agent.
Factors associated with hydrocortisone use
Hydrocortisone was more commonly used in septic patients, (44.7%, 42/94; P < 0.0001; OR 4.78, 95% CI: 2.8, 8.1) and respiratory patients (36.8%, 7/19; P < 0.001, 95% CI: 1.15, 1.50) and least frequently used in cardiovascular surgery patients (12.0%, 15/125; P = 0.0007) with shock. Analysis of baseline characteristics of patients demonstrated that those who were administered hydrocortisone had higher PRISM scores (19, IQR, 11–24 versus 9, IQR, 5–16; P < 0.0001) and were more likely to have received greater than 60 ml/kg of fluid than those who did not receive hydrocortisone (59.3% versus 33.6%; P < 0.0001). Hydrocortisone was administered to 38 of the 64 patients (59.4%, 95% CI 47.2–70.6) with resistant shock (required 60 cc/kg of fluid and two or more vasoactive infusions).
Adrenal axis testing
Only 10/364 patients (2.7%) had adrenocorticotropic hormone stimulation testing conducted at any time during their admission and in only two of these patients (0.5%) was this performed prior to initiation of steroid therapy. Random cortisol values at the time of admission were only available in 14 patients (3.8%).
Clinical course of shock patients and corticosteroid use
In an unadjusted (univariate) analysis of the entire study cohort, taking centre specific effects into account, hydrocortisone use in shock patients was associated with an increase duration of vasoactive infusion use (64 versus 34 hours; hazard ratio (HR) 0.61, 95% CI: 0.51, 0.72; P < 0.0001) (Fig. 1), mechanical ventilation (6 versus 2 days; HR 0.68, 95% CI: 0.49, 0.94; P = 0.02), and PICU length of stay (7 versus 4 days; HR 0.71, 95% CI: 0.52, 0.97; P = 0.03)(Fig. 2). After correcting for age, gender, PRISM score, number of vasoactive infusions on admission and initial fluid resuscitation requirement using multiple logistic regression, only time on vasopressors remained significant (64 versus 34 hours; HR 0.70, 95% CI: 0.58, 0.84; P < 0.0001). The adjusted analysis also showed an increased time on vasopressors in respiratory patients who received hydrocortisone (52 versus 9.3 hours; HR 0.44, 95% CI: 0.29, 0.66; P = 0.0001) but not in septic or cardiac surgery patients (see Table 5).
Potential adverse events associated with hydrocortisone use
The incidence of adverse events in the entire study cohort and the septic, cardiac surgery and respiratory subgroups is shown in Table 6. In the entire cohort, after correcting for age, gender, illness severity, number of vasopressor infusions on admission and initial fluid resuscitation requirements there was an increase in the duration of GI prophylaxis used (8 versus 1.6 days; HR 0.74, 95% CI: 0.59, 0.92; P = 0.0057), the number of new positive cultures (24.7% versus 14.5%; OR 1.79, 95% CI: 1.58, 2.04; P < 0.0001) and the duration of antibiotic use (8 versus 3 days; HR 0.73, 95% CI: 0.59, 0.90; P = 0.003) in those who received hydrocortisone compared to those who did not. The increase in duration of gastrointestinal prophylaxis after adjustment for age, gender, illness severity, number of vasopressor infusions on admission and initial fluid resuscitation was also seen in respiratory patients (12 versus 0.6 days; HR 0.18, 95% CI: 0.11, 0.30; P < 0.0001) but not in septic or cardiac surgery patients. After adjustment for age, gender, illness severity, number of vasopressor infusions on admission and initial fluid resuscitation an increase in new positive cultures was seen in septic patients (21.4% versus 7.7%; OR 4.04, 95% CI: 1.17, 13.97; P = 0.03) but not in cardiac surgery patients.
Implications for a randomized controlled trial
Potential sample size calculations for a future randomized controlled trial of the effect of hydrocortisone in pediatric shock using time on vasopressors, duration of mechanical ventilation, PICU length of stay and PICU mortality as primary outcome measures are shown in Table 7.
This multi-centre Canadian study is the first to comprehensively assess the practice patterns and patient outcomes associated with steroid use in pediatric shock. We found that hydrocortisone was administered to 22.3% of all patients with shock and 59.4% of patients with refractory shock, defined as the requirement of 60 cc/kg of fluid and two or more vasoactive infusions. Hydrocortisone administration was associated with increased time on vasopressors, a trend towards increased PICU length of stay and an increased risk of new positive cultures in this population when adjusted for illness severity. Interestingly, despite the focus in the literature on the use of corticosteroids in shock from sepsis (2, 13, 19, 20), we found that hydrocortisone was also used in patients with hemodynamic instability from a variety of other etiologies including post-operative congenital heart surgery, trauma and respiratory diseases such as bronchiolitis.
The use of corticosteroids by physicians for patients with non-sepsis related hemodynamic instability may be the result of a combination of factors. To begin with, many critically ill patients present with systemic inflammatory responses (SIRS) regardless of their underlying diagnosis, leading to hypotension and shock. When these patients do not respond to fluid and vasopressor therapy, many critical care physicians believe that critical illness related corticosteroid insufficiency (CIRCI) may be contributory (7). CIRCI is a complex, multi-factorial condition resulting from different mechanisms (21–24) making it difficult to define and diagnose (10, 25) and therefore many physicians opt to treat this condition regardless of etiology empirically with steroids (7, 17). In addition, since the diagnosis of sepsis is not contingent upon having a proven infection (26) clinicians may use corticosteroids in patients initially suspected of having sepsis but who end up having other diagnoses.
The role of corticosteroids in patients with septic shock has been debated in the literature for over 40 years (27, 28). Although there is compelling physiologic rationale for the use of corticosteroids in these patients (11, 29–31), there have been no clinical trials demonstrating the benefit of corticosteroids in pediatric septic shock (32) and the two most recent adult studies on this issue found conflicting results (13, 19). Despite this, in our study, almost a quarter of all patients with shock and 44.7% of patients with septic shock received hydrocortisone. The patients given hydrocortisone had higher PRISM and inotrope scores and had received more fluid on admission than those who were not suggesting that severity of illness influences physicians’ decision to use corticosteroids despite a lack of evidence to support this practice. In fact, a recent study by Atkinson et al (20) actually found that corticosteroid use in pediatric septic shock was associated with an increased risk of mortality and a more complicated clinical course in all patients including those more severely affected.
In our overall study cohort, corticosteroid use was also associated with worse outcomes including increased time on vasopressors and an increased incidence of new positive cultures. Similar to the study by Atkinson et al, this association persisted even after correcting for illness severity, age and centre specific effects. In septic patients, corticosteroid use was not associated with increased time on vasopressors but was associated with a significant increase in new positive cultures and a trend towards a longer duration of antibiotic therapy. This association has not been previously reported in a pediatric cohort but is consistent with findings by Sprung et al who showed an increase in secondary infections with corticosteroid therapy in septic adult patients (13). These findings may be related to the delayed administration of corticosteroids in both Sprung's and our study (up to 72 hours) with recent literature suggesting an association of decreased mortality with earlier use of corticosteroids (33, 34) or may be a real side effect of corticosteroid use in this population.
Our data will help inform the conduct of a future corticosteroid trial in several ways. First of all, our study provides concrete estimates of the number of patients with shock in Canada which would provide researchers with realistic recruitment numbers. Secondly, we have shown that clinicians use hydrocortisone in patients with non-sepsis related shock states suggesting that consideration should be given to including these patients in future steroid trials. Thirdly, our study suggests that there may not be equipoise in many centres regarding the use of corticosteroids steroids in shock and that centre and physician specific practices will need to be carefully examined in determining sites for future studies. This study provides unique data that allow us to objectively determine the implications of clinically important endpoints in such a trial. It provides evidence that mortality would not be a practical outcome measure for a future North American based RCT (would require a sample size in the thousands) necessitating consideration of other outcome measures such as time on vasopressors or perhaps cost effectiveness (35).
There are several limitations to this study inherent in the nature of a retrospective design. The reason for hydrocortisone use was only documented in approximately half of the cases but it is unlikely that the reasons would differ from those in whom they were not documented. Secondly, there is the potential for ascertainment bias in the reporting of adverse events resulting in potential underestimation of their true incidence as well as the possibility of residual confounding leading to our findings. Finally, we were only able to report on associations and not causation.
Our study found that physicians administered hydrocortisone to almost one quarter of all patients with shock and almost 60% of patients with more severe shock. Hydrocortisone administration was not associated with a clear benefit but was associated with increased time on vasopressors and increased incidence of new positive cultures. These findings strongly support the need for a well-designed, randomized controlled trial on the effect of corticosteroids in pediatric shock to better delineate the risks and benefits of corticosteroid use in this population. The relatively low mortality rate in this patient population along with the short duration of mechanical ventilation and PICU length of stay may necessitate use of more pragmatic outcome measures such as time on vasopressors or economic cost evaluations for any future pediatric RCTs on this subject.
Canadian Critical Care Trials Group STRIPES Investigators: Institutions, site investigators, research coordinators and research assistants (numbers of enrolled patients are shown in parentheses) – Children's Hospital of Eastern Ontario, Ottawa, ON (108) – K. Menon, S. Bucking, C. Dass; McMaster Children's Hospital, Hamilton, ON (55) – K. Choong, L. Saunders; Children's Hospital of Western Ontario, London, ON (53) – J. Foster, L. Wherry; Hospital for Sick Children, Toronto (148) – J. Hutchison, T. Yavorska, J. Van Huyse.
We would also like to acknowledge Roxanne Ward for her role as study coordinator which involved supervision of study procedures, data acquisition and data verification.
1. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med
1996; 24 5:743–752.
2. Valoor HT, Singhi S, Jayashree M. Low-dose hydrocortisone
in pediatric septic shock
: an exploratory study in a third world setting. Pediatr Crit Care Med
2009; 10 1:121–125.
3. Slusher T, Gbadero D, Howard C, Lewison L, Giroir B, Toro L, Levin D, Holt E, McCracken G. Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis. Pediatr Infect Dis J
1996; 15 7:579–583.
4. Odetola FO, Gebremariam A, Freed GL. Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics
2007; 119 3:487–494.
5. Kissoon N, Carcillo JA, Espinosa V, Argent A, Devictor D, Madden M, Singhi S, Van Der V, Latour J. World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative. Pediatr Crit Care Med
2011; 12 5:494–503.
6. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, bd-Allah SA, Levy H, Angle R, Wang D, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet
2007; 369 9564:836–843.
7. Menon K, McNally JD, Choong K, Ward RE, Lawson ML, Ramsay T. A Survey of Stated Physician Practices and Beliefs on the Use of Steroids in Pediatric Fluid and/or Vasoactive Infusion-Dependent Shock
. Pediatr Crit Care Med
2013; 14 5:462–466.
8. Ando M, Park IS, Wada N, Takahashi Y. Steroid supplementation: a legitimate pharmacotherapy after neonatal open heart surgery. Ann Thorac Surg
2005; 80 5:1672–1678.
9. Choong K, Bohn D, Fraser DD, Gaboury I, Hutchison JS, Joffe AR, Litalien C, Menon K, McNamara P, Ward RE. Vasopressin in pediatric vasodilatory shock
: a multicenter randomized controlled trial. Am J Respir Crit Care Med
2009; 180 7:632–639.
10. Menon K, Ward RE, Lawson ML, Gaboury I, Hutchison JS, Hebert PC. A prospective multicenter study of adrenal function in critically ill children. Am J Respir Crit Care Med
2010; 182 2:246–251.
11. Sasidharan P. Role of corticosteroids
in neonatal blood pressure homeostasis. Clin Perinatol
1998; 25 3:723–740.
12. Hinshaw LB, Beller BK, Chang AC, Murray CK, Flournoy DJ, Passey RB, Archer LT. Corticosteroid/antibiotic treatment of adrenalectomized dogs challenged with lethal E. coli. Circ Shock
1985; 16 3:265–277.
13. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, et al. Hydrocortisone
therapy for patients with septic shock
. N Engl J Med
2008; 358 2:111–124.
14. Pasquali SK, Hall M, Li JS, Peterson ED, Jaggers J, Lodge AJ, Marino BS, Goodman DM, Shah SS. Corticosteroids
and outcome in children undergoing congenital heart surgery: analysis of the Pediatric Health Information Systems database. Circulation
2010; 122 21:2123–2130.
15. Costello JM, Graham DA, Morrow DF, Morrow J, Potter-Bynoe G, Sandora TJ, Pigula FA, Laussen PC. Risk factors for surgical site infection after cardiac surgery in children. Ann Thorac Surg
2010; 89 6:1833–1841.
16. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky MD, Sprung CL, Douglas IS, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock
, 2012. Intensive Care Med
2013; 39 2:165–228.
17. Menon K, Lawson M. Identification of adrenal insufficiency in pediatric critical illness
. Pediatr Crit Care Med
2007; 8 3:276–278.
18. Averill RF, Mullin RL, Steinbeck BA, Goldfield NI, Grant TM. Development of the ICD-10 procedure coding system (ICD-10-PCS). Top Health Inf Manage
2001; 21 3:54–88.
19. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al. Effect of treatment with low doses of hydrocortisone
and fludrocortisone on mortality in patients with septic shock
2002; 288 7:862–871.
20. Atkinson SJ, Cvijanovich NZ, Thomas NJ, Allen GL, Anas N, Bigham MT, Hall M, Freishtat RJ, Sen A, Meyer K, et al. Corticosteroids
and pediatric septic shock
outcomes: a risk stratified analysis. PLoS One
2014; 9 11:e112702.
21. den Brinker M, Joosten KF, Liem O, de Jong FH, Hop WC, Hazelzet JA, van Dijk M, Hokken-Koelega AC. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab
2005; 90 9:5110–5117.
22. Beishuizen A, Thijs LG, Vermes I. Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? Crit Care
2002; 6 5:434–438.
23. 2007; Cooper MS, Stewart PM. Adrenal insufficiency in critical illness: J Intensive Care Med. 22 6:348–362.
24. Peeters RP, Hagendorf A, Vanhorebeek I, Visser TJ, Klootwijk W, Mesotten D, Wouters PJ, Koper JW, de Jong FH, Feelders RA, et al. Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clin Endocrinol (Oxf)
2009; 71 1:145–153.
25. Annane D. Defining critical illness-related corticosteroid insufficiency: one step forward!. Crit Care Med
2010; 38 2:721–722.
26. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med
2005; 6 1:2–8.
27. Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De GR, Keh D, Kupfer Y, Oppert M, Meduri GU. Corticosteroids
in the treatment of severe sepsis and septic shock
in adults: a systematic review. JAMA
2009; 301 22:2362–2375.
28. Markovitz BP, Goodman DM, Watson RS, Bertoch D, Zimmerman J. A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Pediatr Crit Care Med
2005; 6 3:270–274.
29. Wehling M. Specific, nongenomic actions of steroid hormones. Annu Rev Physiol
30. Seri I, Evans J. Controversies in the diagnosis and management of hypotension in the newborn infant. Curr Opin Pediatr
2001; 13 2:116–123.
31. Munck A, Mendel DB, Smith LI, Orti E. Glucocorticoid receptors and actions. Am Rev Respir Dis
1991; 141 (2 Pt 2):S2–10.
32. Menon K, McNally D, Choong K, Sampson M. A systematic review and meta-analysis on the effect of steroids in pediatric shock
. Pediatr Crit Care Med
2013; 14 5:474–480.
33. Funk D, Doucette S, Pisipati A, Dodek P, Marshall JC, Kumar A. Low-dose corticosteroid treatment in septic shock
: a propensity-matching study*. Crit Care Med
2014; 42 11:2333–2341.
34. Katsenos CS, Antonopoulou AN, Apostolidou EN, Ioakeimidou A, Kalpakou GT, Papanikolaou MN, Pistiki AC, Mpalla MC, Paraschos MD, Patrani MA, et al. Early administration of hydrocortisone
replacement after the advent of septic shock
: impact on survival and immune response*. Crit Care Med
2014; 42 7:1651–1657.
35. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis*. Pediatr Crit Care Med
2013; 14 7:686–693.
Keywords:© 2015 by the Shock Society
Corticosteroids; hydrocortisone; pediatric critical care; pediatric critical illness; septic shock; shock