SCCM Resource Library-34-The Effect of Early Corticosteroid Therapy on Outcomes in Children With Septic Shock

Video Transcription

Hello, my name is Dr. Nikki Camps and I'm a Pediatric Critical Care Fellow at the University of Wisconsin.  Today, I'll be talking about our study titled The Association of Corticosteroid Therapy with Clinical and Health-Related Quality of Life Outcomes in Children with Septic Shock.  None of the authors have any real or potential conflicts of interest to disclose. Sepsis remains one of the leading causes of death worldwide.  Every three seconds, a person dies of sepsis. These staggering statistics have supported the development of global sepsis care initiatives such as the Surviving Sepsis Campaign.  Given the low mortality rate in pediatric patients in resource-rich nations, it is very difficult to complete an adequately powered trial with mortality as the primary outcome.  In addition, there is a growing appreciation of the significant persistent morbidity these patients suffer.  Thus, investigating determinants of patient-centered outcomes such as functional status and health-related  quality of life following a severe sepsis event is a growing area of interest. There continues to be significant interest in adjunctive therapies for the treatment  of sepsis in both adults and pediatrics. Steroids are commonly used in hopes of improving hemodynamic stability of these patients.  However, there remains significant controversy due to the lack of reliable, reproducible, and generalizable data to support their use, especially in pediatrics.  Significant side effects attributed to steroids such as hyperglycemia, secondary infections,  GI bleeding, poor wound healing, and myopathy have the potential to contribute to the morbidity a patient suffers.  Given this risk and lack of clear benefit, we need to investigate how adjunctive corticosteroid therapy affects morbidity outcomes in pediatric septic shock.  Through my mentor, Dr. Pailin Cengiz, I was presented with the opportunity to examine this question using data acquired from the Life After Pediatric Sepsis Evaluation or  LAPS investigation led by Dr. Jerry Zimmerman. The objective of our study was to investigate the association of early adjunctive corticosteroid  therapy with morbidity outcomes in pediatric patients hospitalized with septic shock. Our primary outcomes were duration of pressure support, mortality at month one, survival  without new morbidity based on a change of functional status score from baseline to discharge, and quality of life at month one.  Also investigated were the secondary outcomes of hospital-free days, PICU-free days, severity and duration of organ failure while in the PICU, which was measured by the sum of PILOD  scores, and ventilator-free days. Our study design was a retrospective cohort analysis of the aforementioned LAPS database.  LAPS was a large, multi-institutional, NIH-funded descriptive investigation that was designed  to evaluate the functional status and health-related quality of life in children hospitalized for community-acquired septic shock requiring vasopressor support.  Functional status scores and health-related quality of life evaluations were gathered at baseline and over the course of a year following the event.  This large trial collected a wealth of data on 392 children and showed that 35 percent  of these patients suffered a severe deterioration of health-related quality of life that persisted for at least a year following the sepsis event.  For this secondary analysis, we excluded patients that had no reasonable chance of receiving  steroids or not receiving steroids, such as patients with absolute adrenal insufficiency,  profound vasoplegia, and patients at an institution where adjunctive steroid therapy seemed to be standard of care.  The treatment group was defined as any patient in which hydrocortisone or methylprednisolone therapy was initiated on study days zero to three.  Patients that did not receive either of those medications on days zero to three were placed into the no-treatment group.  To best control for potentially confounding variables associated with the decision to start steroids and outcomes, we compared the two groups using a propensity score-weighted  analysis. Propensity scoring methods are increasingly used statistical analysis techniques that  are used in retrospective studies in an attempt to mimic the randomization of subjects in randomized control trials.  The first step is to assign each subject a propensity score, which is a score from zero to one based on how likely that subject is to receive the therapy in question.  This score is based on predetermined baseline characteristics called covariates, or subject  characteristics identified as potential confounding variables, such as demographics and illness severity.  In propensity weighting, each subject is then given a certain weight so that the treatment group and non-treatment group are balanced in terms of these confounders.  Once balance is achieved, the outcomes are compared between the two groups. If confounding variables were successfully identified and balance was achieved between  the two groups, any difference in outcomes can then be attributed to the treatment in question.  For our study, we controlled for the following covariates, sex, clinical institution, age, risk of mortality, highest pressure support, and highest organ dysfunction score in the  first 24 hours. Moving on to our results, 323 out of 392 patients met study criteria. 150 out of these 323, or 46%, received either hydrocortisone or methylprednisolone on study  days 0, 1, 2, or 3. Prior to propensity weighting, it was obvious that the steroid group was more severely ill  with a higher risk of mortality, pressure support, and organ dysfunction. However, with propensity weighting, we were able to achieve successful balancing of the  groups with less than 0.1 standard deviations of difference between the two groups for all covariates, which was our goal.  And what we found was that there was no demonstrable difference in the duration of pressure support,  mortality, functional status, or health-related quality of life at month one between the two groups.  As for our secondary outcomes, no significant difference was found in PICU-free days, hospital-free days, organ failure, or ventilator-free days between the two groups.  So in summary, our study was unable to demonstrate any difference, positive or negative, associated  with early adjunctive corticosteroid therapy in pediatric patients with septic shock.  Our results are similar to previous retrospective studies in children that have failed to demonstrate  a clinically meaningful benefit of this therapy, such as improved mortality, quality of life, or utilization of health care resources.  The strengths of this investigation is that this is the largest study and really one of the very few studies to specifically examine the association of early corticosteroid therapy  with functional and health-related quality of life outcomes in pediatric patients with septic shock.  The data from the LAPS trial were prospectively gathered as part of a large, multi-institutional study.  And by using a propensity-weighting analysis technique, we were able to significantly reduce the effect of confounders, such as illness severity, that have clouded similar studies  in the past. Of course, this was not a gold-standard, blinded, randomized control trial, so there are significant limitations to our analysis.  The covariates we chose as potential confounders associated with both corticosteroid therapy  use and mortality were chosen a priori, which is an opportunity to introduce bias by potentially missing key confounders or by falsely identifying a variable as a confounder.  Covariates identified were chosen based on risk of mortality, not on risk of deterioration in functional outcomes. That is because this data is not yet available.  Retrospectively, it was impossible to isolate the effect of hydrocortisone, as the steroid  recommended in the treatment of septic shock, as methylprednisolone was usually given around the same time and at five times the hydrocortisone equivalent dose.  Additionally, there were likely patients in the new treatment group that received other steroids throughout their course.  We were unable to control for the steroid dose and duration. And lastly, evaluating long-term outcomes is difficult, as there was significant loss  to follow-up and additional steroid exposure in that time period could not be controlled for. So where do we go next?  This question will remain unanswered until we have adequately powered prospectively collected data in randomized patients.  Luckily, currently enrolling, the Stress Hydrocortisone in Pediatric Septic Shock, or SHPS, trial  is a large, double-blinded, randomized control trial that will examine the potential benefits  and risks of adjunctive hydrocortisone therapy in children with fluid and vasoactive inotropic refractory shock.  Importantly, SHPS will also seek to prospectively validate the sepsis endotyping methodology  and the variable response to adjunctive corticosteroid therapy developed by Dr. Hector Wong and colleagues.  To conclude, this large, retrospective cohort analysis did not reveal any significant benefit  or positive or negative associated with early adjunctive corticosteroid therapy on duration of pressure support, mortality, functional status, or health-related quality of life  in U.S. children suffering a septic shock event. This may have been due to sample size, limitation of the vasoactive inotropic score reporting,  and the retrospective nature of our analysis. While we did not evaluate for the incidence of side effects in this study, the lack of  clear benefit should continue to caution providers in the use of corticosteroids until better data are acquired.  I want to thank my dedicated mentors, Dr. Cengiz and Dr. Zimmerman, the wonderful statisticians at the LAPS Data Coordinating Center, Ron and Russ, and all those that participated  in the LAPS trial. I would like to thank the NIH for funding the study and FCCM for giving me the opportunity to share my research with you all.  I will be happy to answer any questions. Thank you all for attending, and I hope you enjoy the rest of Congress.

Video Summary

Dr. Nikki Camps, a Pediatric Critical Care Fellow at the University of Wisconsin, presented a study on the association of corticosteroid therapy with clinical and health-related outcomes in children with septic shock. The study aimed to investigate the impact of corticosteroid therapy on morbidity outcomes in pediatric patients with septic shock. The results showed that there was no significant difference in duration of pressure support, mortality, functional status, or health-related quality of life between the group receiving corticosteroid therapy and the group not receiving it. These findings add to previous studies that have also failed to demonstrate a meaningful benefit of corticosteroid therapy in pediatric septic shock.

Asset Subtitle

Pediatrics, Sepsis, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Nicole Kamps

Introduction/Hypothesis: Corticosteroids are commonly used in the treatment of pediatric septic shock without clear evidence of the impact on mortality and morbidity. This study examined the effect of early corticosteroid therapy on the following outcomes in children hospitalized for septic shock: duration of vasoactive-inotropic support (VIS), survival (short-term, without new morbidity), health-related quality of life at month 1, ventilator, hospital and PICU-free days, and severity and duration of organ failure in the PICU.

Methods: This was a retrospective cohort analysis of data obtained from the prospective, descriptive Life After Pediatric Sepsis Evaluation (LAPSE) study that was conducted 2013-2017 across 12 US academic PICUs and included children with community-acquired septic shock requiring VIS and PICU admission. Patients were excluded if they were immunocompromised due to chronic corticosteroid use or if there was no reasonable chance that they would or would not receive corticosteroid therapy (institution standard of care, first day PELOD-2 score of 0, or first day VIS score >60). Outcomes in those who received either hydrocortisone or methylprednisolone on study days 0-3 were compared to those who did not using a propensity score-weighted analysis that controlled for age, sex, study site, and first day PRISM-IV, PELOD-2, and VIS scores.

Results: 323/392 children met inclusion criteria. 150/323 received early corticosteroid therapy. The two groups were successfully balanced based on subjects' propensity scores with an absolute standardized difference of <0.10 for the potentially confounding variables detailed above. No statistically significant differences between the groups were detected for any of the outcome measures.

Conclusions: This is the first study to examine the effect of early corticosteroid therapy on mortality and morbidity among children with septic shock. After adjusting for variables with the potential to confound the relationship between early corticosteroid therapy and clinically meaningful endpoints, there was no improvement in outcomes with this therapy. Results from this propensity analysis justify clinical equipoise regarding corticosteroids for pediatric septic shock, and ascertain the need for a well-designed clinical trial to rigorously examine benefit/risk for this intervention.

Meta Tag

Content Type Presentation

Knowledge Area Pediatrics

Knowledge Area Sepsis

Knowledge Level Advanced

Membership Level Select

Tag Shock

Tag Inflammation

Year 2021

Keywords

corticosteroid therapy

septic shock

morbidity outcomes

pediatric patients

previous studies

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