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Association of Hydroxyethyl Starch Administration with Mortality and Acute Kidney Injury in Critically Ill Patietns Requiring Volume Resuscitaion: A Systematic Review and Meta-Analysis
Study Question: What is the efficacy and potential harm of hydroxyethyl starch (HES) solutions compared with other resuscitation fluids in critically ill patients requiring acute volume resuscitation?
Study Description: This was a meta-analysis of randomized controlled trials including adult critically ill patients receiving a HES compared with another colloid (including albumin, gelatin, or plasma) or crystalloid for acute fluid resuscitation. While similar meta-analyses have been conducted in past, a repooling of data was warranted in light of the retraction of 88 articles published by one author (J. Boldt), some of which involved this area of study, in 2011 due to fabrication of data and failure to attain institutional review board approval. Like earlier analyses, the primary outcomes were mortality and the incidence of acute kidney injury. Secondary outcomes included incidence of renal recovery and major bleeding, transfusion of red blood cells, allergic reactions, ICU and hospital length of stay (LOS), and duration of mechanical ventilation.
Results: A total of 38 trials enrolling 10,974 patients were included. Thirty-five studies reported mortality for 10,880 patients with a pooled risk ratio (RR) for death among patients randomized to receive HES of 1.07 (95% CI 1.00 to 1.14). However, when the seven Boldt et al. trials that remain published (not retracted in 2011) were excluded, findings of 28 trials including 10,290 patients found HES was significantly associated with increased death (RR 1.09; 95% CI 1.02 to 1.17; absolute risk (AR) 1.51%; 95% CI 0.02% to 3.00%). The 7 trials by Boldt et al. were excluded from further analysis of primary and secondary outcomes due to measured statistical heterogeneity coupled with the history of retractions of other trials conducted by this investigator. Ten trials reported incidence of renal replacement therapy for 9,258 patients and found a significant relationship between HES and risk of renal replacement therapy (RR 1.32; 95% CI 1.15 to 1.50; AR 3.12%; 95% CI 0.47% to 5.78%). There were no reports on incidence of renal recovery. Only one trial including 800 patients reported incidence of major hemorrhage and found no difference. However, results from five trials enrolling 1,482 patients showed a significantly higher rate of red blood cell transfusions with HES (RR 1.42; 95% CI 1.15 to 1.75). No differences were found in duration of mechanical ventilation or hospital and ICU LOS.
Conclusions: HES solutions were associated with a significant increased risk of mortality and acute kidney injury. Clinical use of HES solutions for acute volume resuscitation is not warranted due to serious safety concerns.
Perspective: The use of HES persists in some areas in spite of concerns about safety, a lack of clear clinical superiority, and significant cost. This review did not assess efficacy beyond impact on mortality, but it does highlight an unfavorable safety profile. The further use of HES solutions in clinical practice warrants careful consideration and caution.