A Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study-Associations With Acute Kidney Injury and Mortality

Markus B Skrifvars, Michael Bailey, Elizabeth Moore, Johan Mårtensson, Craig French, Jeffrey Presneill, Alistair Nichol, Lorraine Little, Jacques Duranteau, Olivier Huet, Samir Haddad, Yaseen M Arabi, Colin McArthur, David James Cooper, Stepani Bendel, Rinaldo Bellomo, Erythropoietin in Traumatic Brain Injury (EPO-TBI) Investigators and the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group, Markus B Skrifvars, Michael Bailey, Elizabeth Moore, Johan Mårtensson, Craig French, Jeffrey Presneill, Alistair Nichol, Lorraine Little, Jacques Duranteau, Olivier Huet, Samir Haddad, Yaseen M Arabi, Colin McArthur, David James Cooper, Stepani Bendel, Rinaldo Bellomo, Erythropoietin in Traumatic Brain Injury (EPO-TBI) Investigators and the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group

Abstract

Objectives: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown.

Design: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use.

Setting: Twenty-nine university-affiliated teaching hospitals in seven countries.

Patients: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline.

Interventions: None.

Measurements and main results: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death.

Conclusions: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.

Conflict of interest statement

Dr. Skrifvars reports having received a research grant from GE Healthcare, travel reimbursements, and lecture fees from BARD Medical (Ireland), and he received personal research funding from Medicinska Understodsforeningen Liv och Halsa, Finska Läkaresallskapet, Sigrid Juselius Stiftelse, and Svenska Kulturfonden. Dr. Presneill’s institution received funding from the Australian National Health and Medical Research Council (NHMRC) (project grant ID 545902); he received support from the Victorian Transport Accident Commission (project grant ID D162); and he disclosed off-label product use of erythropoietin trial in traumatic brain injury. Dr. Nichol has received support from the Health Research Board of Ireland. Dr. Little received support for article research from the NHMRC, and she also disclosed off-label product use of Epoetin alfa. Drs. McArthur’s and Cooper’s institutions received funding from the NHMRC. Dr. Cooper’s institution received funding from the Transport Accident Commission and Pressura Neuro. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.

Figures

Figure 1.
Figure 1.
Flow chart of the development of acute kidney injury (AKI) by Kidney Disease Improving Global Outcome (KDIGO) beyond day 3 in patients who did and did not receive early mannitol and remained in the ICU.
Figure 2.
Figure 2.
Cumulative proportion of patients with acute kidney injury (AKI) after day 2 indexed by early use of mannitol. HR = hazard ratio, KDIGO = Kidney Disease Improving Global Outcome.

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