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  • Elevated plasma levels of TIMP-3 are associated with a higher risk of acute respiratory distress syndrome and death following severe isolated traumatic brain injury

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Original article
Elevated plasma levels of TIMP-3 are associated with a higher risk of acute respiratory distress syndrome and death following severe isolated traumatic brain injury
  1. Carolyn M Hendrickson1,
  2. Stuart L Gibb2,3,
  3. Byron Y Miyazawa2,3,4,
  4. Sheila M Keating3,
  5. Erin Ross1,
  6. Amanda S Conroy4,
  7. Carolyn S Calfee1,
  8. Shibani Pati2,3,
  9. Mitchell J Cohen4,5
  1. 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA
  2. 2 Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA
  3. 3 Blood Systems Research Institute, San Francisco, California, USA
  4. 4 Department of Surgery, University of California San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, California, USA
  5. 5 Department of Surgery, University of Colorado, Denver, Colorado, USA
  1. Correspondence to Dr Carolyn M Hendrickson, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA; carolyn.hendrickson{at}ucsf.edu

Abstract

Background Complications after injury, such as acute respiratory distress syndrome (ARDS), are common after traumatic brain injury (TBI) and associated with poor clinical outcomes. The mechanisms driving non-neurologic organ dysfunction after TBI are not well understood. Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) is a regulator of matrix metalloproteinase activity, inflammation, and vascular permeability, and hence has plausibility as a biomarker for the systemic response to TBI.

Methods In a retrospective study of 182 patients with severe isolated TBI, we measured TIMP-3 in plasma obtained on emergency department arrival. We used non-parametric tests and logistic regression analyses to test the association of TIMP-3 with the incidence of ARDS within 8 days of admission and in-hospital mortality.

Results TIMP-3 was significantly higher among subjects who developed ARDS compared with those who did not (median 2810 pg/mL vs.2260 pg/mL, p=0.008), and significantly higher among subjects who died than among those who survived to discharge (median 2960 pg/mL vs.2080 pg/mL, p<0.001). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of ARDS increased significantly, OR 1.5 (95% CI 1.1 to 2.1). This association was only attenuated in multivariate models, OR 1.4 (95% CI 1.0 to 2.0). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of death increased significantly, OR 1.7 (95% CI 1.2 to 2.3). The magnitude of this association was greater in a multivariate model adjusted for markers of injury severity, OR 1.9 (95% CI 1.2 to 2.8).

Discussion TIMP-3 may play an important role in the biology of the systemic response to brain injury in humans. Along with clinical and demographic data, early measurements of plasma biomarkers such as TIMP-3 may help identify patients at higher risk of ARDS and death after severe isolated TBI.

Level of evidence III.

  • ARDS
  • TBI

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/tsaco-2018-000171

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    Footnotes

    • CMH and SLG are joint first authors.

    • Contributors CMH made substantial contributions to the conception and study design of the work, the data acquisition and analysis, the interpretation of data, and drafting and critical revisions of the article. SLG made substantial contributions to the conception and study design of the work, the data acquisition and analysis, the interpretation of data, and drafting and critical revisions of the article. BYM made substantial contributions to the study design of the work, the data acquisition, the interpretation of data, and critical revisions of the article. SMK made substantial contributions to the data acquisition and analysis, the interpretation of data, and critical revisions of the article. ER made substantial contributions to the data acquisition, the interpretation of data, and critical revisions of the article. ASC made substantial contributions to the data acquisition, the interpretation of data, and critical revisions of the article. CSC made substantial contributions to the study design of the work, the data acquisition, the interpretation of data, and drafting and critical revisions of the article. SP made substantial contributions to the conception and study design of the work, the data acquisition and analysis, the interpretation of data, and drafting and critical revisions of the article. MJC made substantial contributions to the conception and study design of the work, the data acquisition and analysis, the interpretation of data, and drafting and critical revisions of the article. All of the above listed authors of this project have provided approval of the submitted article and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CMH and SLG are joint first authors and contributed equally to the study design, data acquisition and analysis, and drafting and critical revisions of the article. CMH is the corresponding author.

    • Funding This study was funded by the National Institute of Health (NIH) General Medical Sciences (grant numbers NIH GM-085689) and National Heart, Lung, and Blood Institute (R01 110969, T32 HL007185-37, F32 HL124911, and K23 HL133495), and the US Department of Defense (grant number W911NF-10-1-0384). This publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF-CTSI Grant Number UL1 TR001872. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval The University of California San Francisco IRB approved this study.

    • Provenance and peer review Not commissioned; externally peer reviewed.