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A Cohort Study of Pediatric Shock: Frequency of Corticosteriod Use and Association with Clinical Outcomes

Menon, Kusum; McNally, J. Dayre; Choong, Karen; Lawson, Margaret L.; Ramsay, Tim; Wong, Hector R.the Canadian Critical Care Trials Group STRIPES Investigators

Shock: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches: November 2015 - Volume 44 - Issue 5 - p 402–409
doi: 10.1097/SHK.0000000000000355
Clinical Aspects
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Introduction: Pediatric shock is associated with significant morbidity and limited evidence suggests treatment with corticosteroids. The objective of this study was to describe practice patterns and outcomes associated with corticosteroid use in children with shock.

Methods: We conducted a retrospective, cohort study in four pediatric intensive care units (PICU) in Canada. Patients aged newborn to 17 years admitted to PICU with shock between January 2010 and June 2011 were eligible.

Results: 364 patients were included. The frequency of hydrocortisone administration was 22.3% overall (95% CI: 18.0, 26.5) and 59.4% in patients who received at least 60 cc/kg of fluid and were on two or more vasoactive agents. Patients administered hydrocortisone had higher PRISM scores (19, IQR 11–24 versus 9, IQR 5–16; P < 0.0001), higher inotrope scores (15, IQR 10–25 versus 7.5, IQR 3.3–10.6, P < 0.0001) and were more likely to have received 60 cc/kg of fluid resuscitation (59.3% versus 33.6%, OR 2.88, 95% CI: 2.09, 3.96). In an adjusted analysis, patients who received hydrocortisone spent more time on vasoactive infusions (64 versus 34 hours, hazard ratio 0.72, 95% CI: 0.62, 0.84) and had a higher incidence of positive cultures between day 4 and day 28 post admission (24.7% versus 14.5%, OR 1.79, 95% CI: 1.58, 2.04).

Conclusion: Hydrocortisone administration was associated with longer time on vasopressors and increased incidence of positive cultures even after correcting for illness severity. Caution should be exercised in administering hydrocortisone for shock until there is clear evidence for benefit in this patient population.

*Children's Hospital of Eastern Ontario, University of Ottawa

McMaster Children's Hospital, McMaster University

Ottawa Hospital Research Institute, University of Ottawa

§Cincinnati Children's Hospital Medical Center, University of Cincinnati

Address reprint requests to Dr. Kusum Menon, PICU, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario K1H 8L1. E-mail: menon@cheo.on.ca

Received 12 January, 2015

Revised 29 January, 2015

Accepted 4 February, 2015

This work was funded by a grant from the Physician Services Incorporated Foundation and no authors have any conflicts of interest to declare.

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INTRODUCTION

Shock is a serious form of cardiovascular failure associated with significant hypotension which may rapidly progress to multi-organ failure and death. Due to the unpredictable course of shock and relatively high risk of mortality, clinicians frequently report using steroids with the hope of improving outcome. In patients with sepsis, this condition is responsible for approximately 4% of pediatric intensive care unit (PICU) admissions (1), results in significant morbidity (2, 3) and carries a 2–17% mortality rate (4–6). Corticosteroid administration for pediatric shock has not been limited to sepsis (7) with published evidence documenting these practices (8–10). While there may be scientific rationale for administration of corticosteroids in certain patients with shock (2, 11, 12), there is limited pediatric clinical trial research demonstrating benefit and increasing evidence from other populations suggesting potential harm (13–15). In addition, the lack of a specific test or marker to determine which patients may benefit from exogenous corticosteroid administration along with non-specific clinical guidelines advocating their use (16) has resulted in variable bedside practices by clinicians (7, 17).

Given limited evidence, non-specific guidelines and emerging suggestions of harm, we sought to understand physician practices and outcomes related to use of corticosteroids in children with shock. The results of this study will help to determine if and where clinical equipoise exists on this issue and associations of corticosteroids with clinically important outcomes and adverse events in preparation for a much needed randomized controlled trial on the issue. The primary objective was to report on the frequency of hydrocortisone use in children who had received at least 60 cc/kg of fluid resuscitation or were on at least one vasoactive infusion. Secondary objectives were to report on hydrocortisone dosing regimens and factors associated with drug administration, including progression to fluid and/or catecholamine resistant shock (received at least 60 cc/kg of fluid resuscitation and on two or more vasoactive infusions). Finally, we sought to determine the frequency of clinically relevant outcomes and adverse events in this patient population amongst patients who did and did not receive hydrocortisone.

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MATERIALS AND METHODS

We conducted a large retrospective study in four academic PICUs in Ontario, Canada. Two centres had cardiac surgery programs, two centres performed organ transplants and all four centres had accredited pediatric critical care fellowships. None of the included centres had clinical practice guidelines in place for the use of steroids in the treatment of shock. Research Ethics Board approval was obtained at all sites and patient consent was not required.

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Study population

In order to identify all potential patients who may have received corticosteroids for the treatment of shock, we used case definitions based on the minimum thresholds for fluid resuscitation and vasoactive infusion requirements identified in our recent survey of PICU physicians in 15 Canadian centres (7). Our study cohort included any patient admitted to the PICU who 1) received at least 60 cc/kg of fluid resuscitation within a 6 hour period from the 6 hours prior to till 72 hours following PICU admission, and/or 2) any dose of dopamine, epinephrine, norepinephrine, milrinone, vasopressin and phenylephrine and 3) were between 0 days and 17 years of age. Patients less than 38 weeks corrected gestation were excluded. In addition to the above definition of shock, we also determined whether patients met or progressed to “resistant shock” defined as having received at least 60 cc/kg of fluid resuscitation and being on two or more vasoactive agents. These definitions were important as our previously published survey suggested equipoise in the use of steroids in less severe forms of shock with lack of equipoise in resistant shock (7).

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Study protocol

This study was powered for the primary outcome which was the frequency of hydrocortisone use within the first 72 hours in all patients with shock. Seventy-two hours was chosen based on Sprung et al who enrolled patients into their randomized controlled trial of corticosteroids in sepsis up to 72 hours following admission (13). Based on data provided from the participating sites and from Choong et al (9), the prevalence of shock and frequency of hydrocortisone use in shock were both estimated at 20%. A sample size of approximately 350–540 shock cases was targeted to allow an estimate of the true frequency of hydrocortisone use with a margin of error of ± 4.5%. We estimated that approximately 2000 PICU admissions would be needed. To achieve these numbers, three participating centres were asked to review the charts of all consecutive admissions over any one year period between January 1st, 2010 to June 30th, 2011. The eighteen month eligibility period was chosen to allow participating centres to identify a one year continuous interval within this time period over which a consistent charting method (electronic or paper) was used. The remaining one hospital reviewed charts from a 3 month period due to their larger number of admissions; this was required to obtain a similar number of patients per site, prevent unwanted bias from one centre and stay within budgetary restraints.

Trained research assistants collected data on standardized data collection forms. Definitions for patient diagnostic categories were established a priori using International Statistical Classification of Diseases (ICD) 10 codes (18). Baseline severity of illness measures collected on admission included Pediatric Risk of Mortality (PRISM) III score (1), fluid resuscitation and vasoactive infusion requirements and whether or not the patient was mechanically ventilated. The dosage, frequency and reason for prescription (when available) of all steroids used within the first 72 hours were recorded. Adverse effects recorded from the charts included gastrointestinal bleeding, use of insulin for hyperglycemia, and new infections defined by positive cultures from samples taken greater than 72 hours after admission.

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Statistical analysis

Statistical analysis was performed using SAS 9.3 (Cary, NC, USA). We determined the 95% confidence intervals around the frequency estimate of steroid use in the study population using the Wilson score with continuity correction. Frequency and proportion estimates are presented as point estimates with 95% confidence intervals. Descriptive statistics were used to describe hydrocortisone use, patient characteristics, clinically important outcomes and adverse events. Dichotomous and categorical variables were presented as numbers and percentages. Continuous variables were presented as medians and interquartile ranges (IQR). Age was dichotomized into ≤ or > one year of age based on the distribution of the population.

The Generalized Estimating Equations method was applied effects to determine associations between hydrocortisone use and dichotomous variables including patient demographics, PICU mortality, gastrointestinal bleeding, insulin infusion use and presence of positive cultures. This method was used as it incorporates centre specific effects into the analysis. Odds Ratios and their 95% confidence limits as well as P-values were calculated.

Cox model was used to examine the association between hydrocortisone use and time on vasopressors, days on mechanical ventilation, PICU length of stay, duration of gastrointestinal bleeding prophylaxis, and total days on antibiotics. Deaths were censored and cluster effect of centre was taken into consideration. Unadjusted and adjusted hazard ratios with their 95% confidence limits as well as P-values were presented.

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RESULTS

Study population

Two thousand, two hundred and seventy two PICU patients were screened of whom 364 met the case definition. Thirty-six of the included patients met fluid criteria alone (9.9%), 220 met vasoactive infusion criteria alone (60.4%) and 108 patients met both criteria (29.7%). Admission diagnostic categories are presented in Table 1. The most common admission diagnoses were post-operative cardiac surgery (34.3%, 125/364) and sepsis (25.8%, 94/364). Table 2 shows the admission characteristics presented as subgroups in those who did and did not receive hydrocortisone during the first 72 hours. The median PRISM score of the full cohort of 364 patients was 11 (IQR, 6–18), 71.7% were mechanically ventilated, 83.8% were receiving vasoactive infusions and 39.6% of patients had received ≥ 60 ml/kg of resuscitative fluids.

Table 1

Table 1

Table 2

Table 2

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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%.

Table 3

Table 3

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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.

Table 4

Table 4

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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.

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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).

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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%).

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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).

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Table 5

Table 5

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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.

Table 6

Table 6

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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.

Table 7

Table 7

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DISCUSSION

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.

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CONCLUSIONS

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.

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ACKNOWLEDGMENTS

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.

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Keywords:

Corticosteroids; hydrocortisone; pediatric critical care; pediatric critical illness; septic shock; shock

© 2015 by the Shock Society