Erythropoietin does not alter serum profiles of neuronal and axonal biomarkers after traumatic brain injury

Findings from the Australian EPO-TBI clinical trial

Sarah C. Hellewell, Stefania Mondello, Alison Conquest, Gerry Shaw, Irina Madorsky, Jay V. Deng, Lorraine Little, Firas Kobeissy, Nicole Bye, Rinaldo Bellomo, David J. Cooper, Shirley Vallance, Jasmine Board, Maria C. Morganti-Kossmann

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups. Design: Single-center, prospective observational study. Setting: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia. Patients: Forty-four patients with moderate-to-severe traumatic brain injury. Interventions: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury. Measurements and Main Results: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain. Conclusions: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.

Original languageEnglish
Pages (from-to)554-561
Number of pages8
JournalCritical Care Medicine
Volume46
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • Biomarker
  • Erythropoietin
  • Phosphorylated neurofilament heavy-chain
  • Traumatic brain injury
  • Ubiquitin carboxy-terminal hydrolase L1

Cite this

Hellewell, Sarah C. ; Mondello, Stefania ; Conquest, Alison ; Shaw, Gerry ; Madorsky, Irina ; Deng, Jay V. ; Little, Lorraine ; Kobeissy, Firas ; Bye, Nicole ; Bellomo, Rinaldo ; Cooper, David J. ; Vallance, Shirley ; Board, Jasmine ; Morganti-Kossmann, Maria C. / Erythropoietin does not alter serum profiles of neuronal and axonal biomarkers after traumatic brain injury : Findings from the Australian EPO-TBI clinical trial. In: Critical Care Medicine. 2018 ; Vol. 46, No. 4. pp. 554-561.
@article{cdf0ec7047cf45258a27207c8f8eb6f2,
title = "Erythropoietin does not alter serum profiles of neuronal and axonal biomarkers after traumatic brain injury: Findings from the Australian EPO-TBI clinical trial",
abstract = "Objective: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups. Design: Single-center, prospective observational study. Setting: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia. Patients: Forty-four patients with moderate-to-severe traumatic brain injury. Interventions: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury. Measurements and Main Results: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain. Conclusions: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.",
keywords = "Biomarker, Erythropoietin, Phosphorylated neurofilament heavy-chain, Traumatic brain injury, Ubiquitin carboxy-terminal hydrolase L1",
author = "Hellewell, {Sarah C.} and Stefania Mondello and Alison Conquest and Gerry Shaw and Irina Madorsky and Deng, {Jay V.} and Lorraine Little and Firas Kobeissy and Nicole Bye and Rinaldo Bellomo and Cooper, {David J.} and Shirley Vallance and Jasmine Board and Morganti-Kossmann, {Maria C.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1097/CCM.0000000000002938",
language = "English",
volume = "46",
pages = "554--561",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams & Wilkins",
number = "4",

}

Erythropoietin does not alter serum profiles of neuronal and axonal biomarkers after traumatic brain injury : Findings from the Australian EPO-TBI clinical trial. / Hellewell, Sarah C.; Mondello, Stefania; Conquest, Alison; Shaw, Gerry; Madorsky, Irina; Deng, Jay V.; Little, Lorraine; Kobeissy, Firas; Bye, Nicole; Bellomo, Rinaldo; Cooper, David J.; Vallance, Shirley; Board, Jasmine; Morganti-Kossmann, Maria C.

In: Critical Care Medicine, Vol. 46, No. 4, 01.04.2018, p. 554-561.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Erythropoietin does not alter serum profiles of neuronal and axonal biomarkers after traumatic brain injury

T2 - Findings from the Australian EPO-TBI clinical trial

AU - Hellewell, Sarah C.

AU - Mondello, Stefania

AU - Conquest, Alison

AU - Shaw, Gerry

AU - Madorsky, Irina

AU - Deng, Jay V.

AU - Little, Lorraine

AU - Kobeissy, Firas

AU - Bye, Nicole

AU - Bellomo, Rinaldo

AU - Cooper, David J.

AU - Vallance, Shirley

AU - Board, Jasmine

AU - Morganti-Kossmann, Maria C.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Objective: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups. Design: Single-center, prospective observational study. Setting: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia. Patients: Forty-four patients with moderate-to-severe traumatic brain injury. Interventions: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury. Measurements and Main Results: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain. Conclusions: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.

AB - Objective: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups. Design: Single-center, prospective observational study. Setting: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia. Patients: Forty-four patients with moderate-to-severe traumatic brain injury. Interventions: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury. Measurements and Main Results: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain. Conclusions: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.

KW - Biomarker

KW - Erythropoietin

KW - Phosphorylated neurofilament heavy-chain

KW - Traumatic brain injury

KW - Ubiquitin carboxy-terminal hydrolase L1

UR - http://www.scopus.com/inward/record.url?scp=85047512120&partnerID=8YFLogxK

U2 - 10.1097/CCM.0000000000002938

DO - 10.1097/CCM.0000000000002938

M3 - Article

VL - 46

SP - 554

EP - 561

JO - Critical Care Medicine

JF - Critical Care Medicine

SN - 0090-3493

IS - 4

ER -