Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury

A randomized, controlled, experimental study

Sebastian Rehberg, Yusuke Yamamoto, Eva Bartha, Linda Sousse, Collette Jonkam, Yong Zhu, Lillian D. Traber, Robert A. Cox, Daniel L. Traber, Perenlei Enkhbaatar

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Introduction: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model.Methods: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas.Results: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day.Conclusions: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.

Original languageEnglish (US)
Article numberR86
JournalCritical Care
Volume17
Issue number3
DOIs
StatePublished - May 11 2013

Fingerprint

Smoke Inhalation Injury
Antithrombins
Sheep
Inflammation
Oxygen Consumption
Water-Electrolyte Balance
Body Surface Area
p38 Mitogen-Activated Protein Kinases
Intravenous Infusions
Smoke
Stroke Volume
Peroxidase
Blood Vessels
Interleukin-6
Nitric Oxide
Neutrophils
Tumor Necrosis Factor-alpha
Heart Rate
Stroke
Cytokines

Keywords

  • Capillary leakage
  • Cardiovascular hemodynamics
  • Left ventricular dysfunction
  • Mitogen-activated protein kinase
  • Myocardial oxygen consumption
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury : A randomized, controlled, experimental study. / Rehberg, Sebastian; Yamamoto, Yusuke; Bartha, Eva; Sousse, Linda; Jonkam, Collette; Zhu, Yong; Traber, Lillian D.; Cox, Robert A.; Traber, Daniel L.; Enkhbaatar, Perenlei.

In: Critical Care, Vol. 17, No. 3, R86, 11.05.2013.

Research output: Contribution to journalArticle

Rehberg, Sebastian ; Yamamoto, Yusuke ; Bartha, Eva ; Sousse, Linda ; Jonkam, Collette ; Zhu, Yong ; Traber, Lillian D. ; Cox, Robert A. ; Traber, Daniel L. ; Enkhbaatar, Perenlei. / Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury : A randomized, controlled, experimental study. In: Critical Care. 2013 ; Vol. 17, No. 3.
@article{517c809f52db4335b8a7ba26e71effd7,
title = "Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: A randomized, controlled, experimental study",
abstract = "Introduction: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model.Methods: Following 40{\%} of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas.Results: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day.Conclusions: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.",
keywords = "Capillary leakage, Cardiovascular hemodynamics, Left ventricular dysfunction, Mitogen-activated protein kinase, Myocardial oxygen consumption, Tumor necrosis factor",
author = "Sebastian Rehberg and Yusuke Yamamoto and Eva Bartha and Linda Sousse and Collette Jonkam and Yong Zhu and Traber, {Lillian D.} and Cox, {Robert A.} and Traber, {Daniel L.} and Perenlei Enkhbaatar",
year = "2013",
month = "5",
day = "11",
doi = "10.1186/cc12712",
language = "English (US)",
volume = "17",
journal = "Critical Care",
issn = "1466-609X",
publisher = "Springer Science + Business Media",
number = "3",

}

TY - JOUR

T1 - Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury

T2 - A randomized, controlled, experimental study

AU - Rehberg, Sebastian

AU - Yamamoto, Yusuke

AU - Bartha, Eva

AU - Sousse, Linda

AU - Jonkam, Collette

AU - Zhu, Yong

AU - Traber, Lillian D.

AU - Cox, Robert A.

AU - Traber, Daniel L.

AU - Enkhbaatar, Perenlei

PY - 2013/5/11

Y1 - 2013/5/11

N2 - Introduction: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model.Methods: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas.Results: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day.Conclusions: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.

AB - Introduction: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model.Methods: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas.Results: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day.Conclusions: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.

KW - Capillary leakage

KW - Cardiovascular hemodynamics

KW - Left ventricular dysfunction

KW - Mitogen-activated protein kinase

KW - Myocardial oxygen consumption

KW - Tumor necrosis factor

UR - http://www.scopus.com/inward/record.url?scp=84877301986&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877301986&partnerID=8YFLogxK

U2 - 10.1186/cc12712

DO - 10.1186/cc12712

M3 - Article

VL - 17

JO - Critical Care

JF - Critical Care

SN - 1466-609X

IS - 3

M1 - R86

ER -