Erythropoietin to Reduce Mortality in Traumatic Brain Injury: A Post-hoc Dose-effect Analysis

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Abstract

OBJECTIVE: We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI). BACKGROUND:: Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain. METHODS:: We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury. RESULTS:: There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.33–1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95% CI 0.12–0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95% CI 0.66–3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings. CONCLUSIONS:: This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma.

Original languageEnglish
Pages (from-to)585-589
Number of pages5
JournalAnnals of Surgery
Volume267
Issue number3
DOIs
Publication statusPublished - Mar 2018

Keywords

  • dose-response relationship
  • erythropoietin
  • mortality
  • traumatic brain injury

Cite this

@article{73cc26b750ba4c9cbc02afa088753208,
title = "Erythropoietin to Reduce Mortality in Traumatic Brain Injury: A Post-hoc Dose-effect Analysis",
abstract = "OBJECTIVE: We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI). BACKGROUND:: Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain. METHODS:: We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury. RESULTS:: There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95{\%} confidence interval (CI) 0.33–1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95{\%} CI 0.12–0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95{\%} CI 0.66–3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings. CONCLUSIONS:: This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma.",
keywords = "dose-response relationship, erythropoietin, mortality, traumatic brain injury",
author = "Dashiell Gantner and Michael Bailey and Jeffrey Presneill and French, {Craig J.} and Alistair Nichol and Lorraine Little and Rinaldo Bellomo",
year = "2018",
month = "3",
doi = "10.1097/SLA.0000000000002142",
language = "English",
volume = "267",
pages = "585--589",
journal = "Annals of Surgery",
issn = "0003-4932",
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TY - JOUR

T1 - Erythropoietin to Reduce Mortality in Traumatic Brain Injury

T2 - A Post-hoc Dose-effect Analysis

AU - Gantner, Dashiell

AU - Bailey, Michael

AU - Presneill, Jeffrey

AU - French, Craig J.

AU - Nichol, Alistair

AU - Little, Lorraine

AU - Bellomo, Rinaldo

PY - 2018/3

Y1 - 2018/3

N2 - OBJECTIVE: We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI). BACKGROUND:: Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain. METHODS:: We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury. RESULTS:: There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.33–1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95% CI 0.12–0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95% CI 0.66–3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings. CONCLUSIONS:: This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma.

AB - OBJECTIVE: We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI). BACKGROUND:: Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain. METHODS:: We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury. RESULTS:: There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.33–1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95% CI 0.12–0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95% CI 0.66–3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings. CONCLUSIONS:: This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma.

KW - dose-response relationship

KW - erythropoietin

KW - mortality

KW - traumatic brain injury

UR - http://www.scopus.com/inward/record.url?scp=85011661872&partnerID=8YFLogxK

U2 - 10.1097/SLA.0000000000002142

DO - 10.1097/SLA.0000000000002142

M3 - Article

VL - 267

SP - 585

EP - 589

JO - Annals of Surgery

JF - Annals of Surgery

SN - 0003-4932

IS - 3

ER -