Effect of 6% hydroxyethyl starch 130/0.4 on kidney and haemostatic function in cardiac surgical patients: a randomised controlled trial

Abstract

Whether third-generation hydroxyethyl starch solutions provoke kidney injury or haemostatic abnormalities in patients having cardiac surgery remains unclear. We tested the hypotheses that intra-operative administration of a third-generation starch does not worsen postoperative kidney function or haemostasis in cardiac surgical patients compared with human albumin 5%. This triple-blind, non-inferiority, clinical trial randomly allocated patients aged 40-85 who underwent elective aortic valve replacement, with or without coronary artery bypass grafting, to plasma volume replacement with 6% starch 130/0.4 vs. 5% human albumin. Our primary outcome was postoperative urinary neutrophil gelatinase-associated lipocalin concentrations, a sensitive and early marker of postoperative kidney injury. Secondarily, we evaluated urinary interleukin-18; acute kidney injury using creatinine RIFLE criteria, coagulation measures, platelet count and function. Non-inferiority (delta 15%) was assessed with correction for multiple comparisons. We enrolled 141 patients (69 starch, 72 albumin) as planned. Results of the primary analysis demonstrated that postoperative urine neutrophil gelatinase-associated lipocalin (median (IQR [range])) was slightly lower with hydroxyethyl starch (5 (1-68 [0-996]) ng.ml^-1 ) vs. albumin (5 (2-74 [0-1604]) ng.ml^-1 ), although not non-inferior [ratio of geometric means (95%CI) 0.91 (0.57, 1.44); p = 0.15] due to higher than expected variability. Urine interleukin-18 concentrations were reduced, but interleukin-18 and kidney injury were again not non-inferior. Of 11 individual coagulation measures, platelet count and function, nine were non-inferior to albumin. Two remaining measures, thromboelastographic R value and arachidonic acid-induced platelet aggregation, were clinically similar but with wide confidence intervals. Starch administration during cardiac surgery produced similar observed effects on postoperative kidney function, coagulation, platelet count and platelet function compared with albumin, though greater than expected variability and wide confidence intervals precluded the conclusion of non-inferiority. Long-term mortality and kidney function appeared similar between starch and albumin.

Trial registration: ClinicalTrials.gov NCT02192502.

Keywords: cardiac surgery; hydroxyethyl starch; urinary interleukin-18; urinary neutrophil gelatinase-associated lipocalin.

Figure 1

CONSORT patient flow diagram

Figure 2

Urinary concentrations of (a) neutrophil gelatinase‐associated lipocalin (NGAL) and (b) interleukin‐18 (IL‐18) at baseline, 1 h after surgery (postop 1 h) and 24 h after surgery (postop 24 h) are shown.

Figure 3

Non‐inferiority (NI) tests on the primary and secondary outcomes. Non‐inferiority was claimed if p < 0.021 for urinary NGAL, or p < 0.013 for urinary IL‐18 and AKI, defined by RIFLE categories: Risk, Injury or Failure. HES, Third‐generation hydroxyethyl starch; NGAL, urinary neutrophil gelatinase‐associated lipocalin; IL‐18, urinary interleukin‐18; AKI, acute kidney injury assessed as Risk, Injury or Failure by RIFLE classification based on creatinine values vs. No Risk.

Figure 4

Forest plot of non‐inferiority tests on coagulation and platelet function. The estimated difference of HES compared with albumin is shown as a square and error bars indicate the 95%CI. Non‐inferiority delta is 15% of the control group mean. Non‐inferiority of each outcome was claimed if p < 0.025. NI, non‐inferiority; PT, prothrombin time; aPTT, activated partial thromboplastin time; PLT, platelet count; AA, arachidonic acid; ADP, adenosine diphosphate; TEG, thromboelastogram; R value, reaction time; K value, kinetics; LY 30, amplitude at 30 min; MA, maximum amplitude.