Introduction
(Article introduction authored by ICU Editorial Team)
The utilization of corticosteroids in the management of sepsis and septic shock has remained contentious despite extensive examination through randomized controlled trials (RCTs), systematic reviews, and meta-analyses. While some previous analyses hint at a potential reduction in mortality, the evidence supporting this claim is often characterized by low certainty.
Conversely, more robust evidence suggests that corticosteroids can effectively reverse shock and ameliorate organ dysfunction when compared to standard care or placebo.
However, critical uncertainties persist, particularly regarding which specific patient populations might derive greater benefits from corticosteroid therapy and whether variations in dosage, duration, or type of corticosteroid impact treatment outcomes.
In light of these ongoing uncertainties, recent years have seen a surge in new RCTs investigating the efficacy and safety of corticosteroids in patients with sepsis and septic shock.
By incorporating the findings from these latest studies, the objective is to enhance the precision of evidence summaries and provide clinicians with clearer guidance on the appropriate use of corticosteroids in treating sepsis, ultimately striving to improve patient outcomes in this critical condition.
Methods
The study protocol was registered on Open Science Framework, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Eligibility criteria included randomized controlled trials (RCTs) examining corticosteroid use in critically ill adults and pediatric patients with sepsis or septic shock, while excluding case reports and observational studies.
Data collection encompassed trial characteristics, patient demographics, intervention details, and various outcomes such as mortality, shock reversal, and adverse events.
Risk of bias was assessed using the modified Cochrane tool, and statistical methods included pairwise and dose-response meta-analyses.
A comprehensive search strategy was conducted to identify relevant studies, updated from a previous review, covering trials published from January 1, 2018, to January 1, 2023.
Two independent reviewers screened titles and abstracts, followed by full-text screening for potentially relevant studies. Data extraction involved collecting information on trial characteristics and outcome measures.
Subgroup analyses were conducted based on corticosteroid type, patient demographics, and treatment duration.
Additionally, sensitivity analyses were performed, including meta-regression and dose-response meta-analysis.
The certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to provide a comprehensive understanding of corticosteroid efficacy and safety in sepsis and septic shock management.
Results
Trial Selection and Characteristics
The search yielded 1702 unique citations, identifying 11 new eligible RCTs since the previous review. Among these, seven RCTs evaluated combination therapy with corticosteroid, ascorbic acid, and thiamine, which were not included in the primary analysis.
Including these, a total of 45 RCTs were included in the updated analysis, comprising 42 trials from the previous review and three new RCTs. Of these, seven trials were included in a secondary sensitivity analysis. Among the 45 RCTs, 20 were multicenter and 25 were single center.
Twenty-seven trials focused on patients with septic shock, while others included patients with community-acquired pneumonia (CAP), acute respiratory distress syndrome (ARDS), or both.
The most commonly used corticosteroid compound was hydrocortisone, with varying doses employed across studies. All included studies enrolled patients based on previous Sepsis 1 or Sepsis 2 diagnostic criteria.
Risk of Bias
We judged 22 trials (48.8%) to be at high or probably high risk of bias. Eight were at risk of bias due to issues arising from allocation concealment, eight due to bias arising from lack of blinding, seven due to bias arising from missing data, seven due to bias arising from selective reporting, and seven due to bias arising from deviations from the intended interventions.
Mortality
We found that corticosteroids probably reduce short-term mortality and may reduce long-term mortality
Discussion
In summary, our meta-analysis suggests that corticosteroids likely reduce mortality in adult patients with sepsis, irrespective of shock status, while also improving shock reversal and organ dysfunction within one week of treatment initiation.
However, the use of corticosteroids may be associated with increased risks of hypernatremia, hyperglycemia, and neuromuscular weakness, although these findings were based on low-certainty evidence.
The dose-response analysis indicates that approximately 260 mg/d of hydrocortisone or equivalent is optimal, with most evidence derived from studies using hydrocortisone at relatively low doses.
The inclusion of new trials in this updated review has enhanced the precision of effect estimates, particularly regarding short-term mortality, which now excludes harm.
While corticosteroids are conditionally recommended in adult patients with septic shock according to the most recent Surviving Sepsis Campaign guidelines, the role of corticosteroids in children with sepsis remains uncertain, with limited evidence available.
Moreover, combination therapy with ascorbic acid and thiamine does not appear to confer additional benefits and may even be harmful.
Future research should focus on clarifying the long-term effects of corticosteroids on mortality and systematically assessing adverse outcomes.
Biomarkers such as cystatin C, proenkephalin, TIMP2, IGFBP7, and plasma neutrophil gelatinase-associated lipocalin can aid in detecting AKI. Bedside Doppler ultrasound can assess renal perfusion, and the renal resistive index (RRI) may predict AKI.
Urinalysis and urine microscopy, especially evaluating cast elements and tubule epithelial cells, contribute to identifying sepsis-associated AKI. These tools collectively enhance early detection of AKI in septic patients.
Conclusion
Corticosteroids probably reduce mortality, increase shock reversal, and decrease SOFA scores in patients with sepsis.
Corticosteroids probably increase hypernatremia and hyperglycemia and may increase neuromuscular weakness. Dose-response meta-analysis suggested the optimal dosage to be 260 mg/d of hydrocortisone or equivalent.
Source: Pitre, Tyler MD, MA1; Drover, Katherine2; Chaudhuri, Dipayan MD, MSc3,4; Zeraaktkar, Dena PhD3,5; Menon, Kusum MD, MSc6; Gershengorn, Hayley B. MD7,8; Jayaprakash, Namita MD9; Spencer-Segal, Joanna L. MD, PhD10; Pastores, Stephen M. MD11; Nei, Andrea M. PharmD12; Annane, Djillali MD, PhD13; Rochwerg, Bram MD, MSc3,4. Corticosteroids in Sepsis and Septic Shock: A Systematic Review, Pairwise, and Dose-Response Meta-Analysis. Critical Care Explorations 6(1):p e1000, January 2024. | DOI: 10.1097/CCE.0000000000001000
