Top

Published in:

Open Access 01-06-2013 | Research

Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study

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

Published in: Critical Care | Issue 3/2013

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.

Available only for authorised users

Horton JW: Left ventricular contractile dysfunction as a complication of thermal injury. Shock. 2004, 22: 495-507. 10.1097/01.shk.0000145205.51682.c3.CrossRefPubMed

Horton JW, Garcia NM, White DJ, Keffer J: Postburn cardiac contractile function and biochemical markers of postburn cardiac injury. J Am Coll Surg. 1995, 181: 289-298.PubMed

Muller-Werdan U, Buerke M, Ebelt H, Heinroth KM, Herklotz A, Loppnow H, Ruß M, Schlegel F, Schlitt A, Schmidt HB, Söffker G, Werdan K: Septic cardiomyopathy - a not yet discovered cardiomyopathy?. Exp Clin Cardiol. 2006, 11: 226-236.PubMedCentralPubMed

Lin CY, Wu CK, Yeong EK, Lin HH, Huang YT, Lee JK, Lin YH, Chiang FT, Tang YB, Tsai CT: Prognostic significance of left ventricular diastolic function in burn patients. Shock. 2012, 37: 457-462.CrossRefPubMed

Jeschke MG, Gauglitz GG, Kulp GA, Finnerty CC, Williams FN, Kraft R, Suman OE, Mlcak RP, Herndon DN: Long-term persistance of the pathophysiologic response to severe burn injury. PLoS One. 2011, 6: e21245-10.1371/journal.pone.0021245.PubMedCentralCrossRefPubMed

Zhang JP, Ying X, Liang WY, Luo ZH, Yang ZC, Huang YS, Wang WC: Apoptosis in cardiac myocytes during the early stage after severe burn. J Trauma. 2008, 65: 401-408. 10.1097/TA.0b013e31817cf732. discussion 408CrossRefPubMed

Carlson DL, Horton JW: Cardiac molecular signaling after burn trauma. J Burn Care Res. 2006, 27: 669-675. 10.1097/01.BCR.0000237955.28090.41.CrossRefPubMed

White J, Carlson DL, Thompson M, Maass DL, Sanders B, Giroir B, Horton JW: Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma. Am J Physiol Heart Circ Physiol. 2003, 285: H1616-1625.CrossRefPubMed

Dunzendorfer S, Kaneider N, Rabensteiner A, Meierhofer C, Reinisch C, Romisch J, Wiedermann CJ: Cell-surface heparan sulfate proteoglycan-mediated regulation of human neutrophil migration by the serpin antithrombin III. Blood. 2001, 97: 1079-1085. 10.1182/blood.V97.4.1079.CrossRefPubMed

10.

Enkhbaatar P, Esechie A, Wang J, Cox RA, Nakano Y, Hamahata A, Lange M, Traber LD, Prough DS, Herndon DN, Traber DL: Combined anticoagulants ameliorate acute lung injury in sheep after burn and smoke inhalation. Clin Sci (Lond). 2008, 114: 321-329. 10.1042/CS20070254.CrossRef

11.

Sun HM, Hong LZ, Shen XK, Lin XQ, Song Y, Shi Y: Antithrombin-III without concomitant heparin improves endotoxin-induced acute lung injury rats by inhibiting the activation of mitogen-activated protein kinase. Chin Med J (Engl). 2009, 122: 2466-2471.

12.

Komura H, Uchiba M, Mizuochi Y, Arai M, Harada N, Katsuya H, Okajima K: Antithrombin inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by monocytes in vitro through inhibition of Egr-1 expression. J Thromb Haemost. 2008, 6: 499-507. 10.1111/j.1538-7836.2007.02869.x.CrossRefPubMed

13.

Kowal-Vern A, Walenga JM, McGill V, Gamelli RL: The impact of antithrombin (H) concentrate infusions on pulmonary function in the acute phase of thermal injury. Burns. 2001, 27: 52-60. 10.1016/S0305-4179(00)00057-7.CrossRefPubMed

14.

Niedermayr M, Schramm W, Kamolz L, Andel D, Romer W, Hoerauf K, Zimpfer M, Andel H: Antithrombin deficiency and its relationship to severe burns. Burns. 2007, 33: 173-178. 10.1016/j.burns.2006.06.011.CrossRefPubMed

15.

Lavrentieva A, Kontakiotis T, Bitzani M, Papaioannou-Gaki G, Parlapani A, Thomareis O, Tsotsolis N, Giala MA: Early coagulation disorders after severe burn injury: impact on mortality. Intensive Care Med. 2008, 34: 700-706. 10.1007/s00134-007-0976-5.CrossRefPubMed

16.

Lange M, Connelly R, Traber DL, Hamahata A, Cox RA, Nakano Y, Bansal K, Esechie A, von Borzyskowski S, Jonkam C, Traber LD, Hawkins HK, Herndon DN, Enkhbaatar P: Combined neuronal and inducible nitric oxide synthase inhibition in ovine acute lung injury. Crit Care Med. 2009, 37: 223-229. 10.1097/CCM.0b013e3181926104.PubMedCentralCrossRefPubMed

17.

Enkhbaatar P, Connelly R, Wang J, Nakano Y, Lange M, Hamahata A, Horvath E, Szabo C, Jaroch S, Holscher P, Hillmann M, Traber LD, Schmalstieg FC, Herndon DN, Traber DL: Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury. Crit Care Med. 2009, 37: 208-214. 10.1097/CCM.0b013e318193226a.CrossRefPubMed

18.

Baxter CR, Shires T: Physiological response to crystalloid resuscitation of severe burns. Ann N Y Acad Sci. 1968, 150: 874-894. 10.1111/j.1749-6632.1968.tb14738.x.CrossRefPubMed

19.

Gobel FL, Norstrom LA, Nelson RR, Jorgensen CR, Wang Y: The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation. 1978, 57: 549-556. 10.1161/01.CIR.57.3.549.CrossRefPubMed

20.

Adams HR, Baxter CR, Izenberg SD: Decreased contractility and compliance of the left ventricle as complications of thermal trauma. Am Heart J. 1984, 108: 1477-1487. 10.1016/0002-8703(84)90695-1.CrossRefPubMed

21.

Soejima K, Schmalstieg FC, Sakurai H, Traber LD, Traber DL: Pathophysiological analysis of combined burn and smoke inhalation injuries in sheep. Am J Physiol Lung Cell Mol Physiol. 2001, 280: L1233-1241.PubMed

22.

Traber DL, Enkhbaatar P: Thermal lung injury and acute smoke inhalation. Fishman's Pulmonary Diseases and Disorders. Edited by: Fishman DA. 2008, New York: McGraw-Hill Medical Publishing Company, 4

23.

Williams FN, Herndon DN, Suman OE, Lee JO, Norbury WB, Branski LK, Mlcak RP, Jeschke MG: Changes in cardiac physiology after severe burn injury. J Burn Care Res. 2011, 32: 269-274. 10.1097/BCR.0b013e31820aafcf.PubMedCentralCrossRefPubMed

24.

Lavrentieva A, Kontakiotis T, Bitzani M, Parlapani A, Thomareis O, Scourtis H, Tsotsolis N, Lazaridis L, Giala MA: The efficacy of antithrombin administration in the acute phase of burn injury. Thromb Haemost. 2008, 100: 286-290.PubMed

25.

Makita H, Nishimura M, Miyamoto K, Nakano T, Tanino Y, Hirokawa J, Nishihira J, Kawakami Y: Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation. Am J Respir Crit Care Med. 1998, 158: 573-579. 10.1164/ajrccm.158.2.9707086.CrossRefPubMed

26.

Kaneider NC, Forster E, Mosheimer B, Sturn DH, Wiedermann CJ: Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. Thromb Haemost. 2003, 90: 1150-1157.PubMed

27.

Ballard-Croft C, White DJ, Maass DL, Hybki DP, Horton JW: Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-alpha. Am J Physiol Heart Circ Physiol. 2001, 280: H1970-1981.PubMed

28.

Cao W, Xie YH, Li XQ, Zhang XK, Chen YT, Kang R, Chen X, Miao S, Wang SW: Burn-induced apoptosis of cardiomyocytes is survivin dependent and regulated by PI3K/Akt, p38 MAPK and ERK pathways. Basic Res Cardiol. 2011, 106: 1207-1220. 10.1007/s00395-011-0199-3.CrossRefPubMed

29.

Lv GF, Dong ML, Hu DH, Zhang WF, Wang YC, Tang CW, Zhu XX: Insulin-mediated inhibition of p38 mitogen-activated protein kinase protects cardiomyocytes in severe burns. J Burn Care Res. 2011, 32: 591-599. 10.1097/BCR.0b013e31822dc3f2.CrossRefPubMed

30.

Justus AC, Roussev R, Norcross JL, Faulk WP: Antithrombin binding by human umbilical vein endothelial cells: effects of exogenous heparin. Thromb Res. 1995, 79: 175-186. 10.1016/0049-3848(95)00103-X.CrossRefPubMed

31.

Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, Thompson M, Giroir B: Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation. 1998, 97: 1375-1381. 10.1161/01.CIR.97.14.1375.CrossRefPubMed

32.

Giroir BP, Horton JW, White DJ, McIntyre KL, Lin CQ: Inhibition of tumor necrosis factor prevents myocardial dysfunction during burn shock. Am J Physiol. 1994, 267: H118-124.PubMed

33.

Wu CK, Lee JK, Chiang FT, Yang CH, Huang SW, Hwang JJ, Lin JL, Tseng CD, Chen JJ, Tsai CT: Plasma levels of tumor necrosis factor-alpha and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase. Crit Care Med. 2011, 39: 984-992. 10.1097/CCM.0b013e31820a91b9.CrossRefPubMed

34.

Muller-Werdan U, Engelmann H, Werdan K: Cardiodepression by tumor necrosis factor-alpha. Eur Cytokine Netw. 1998, 9: 689-691.PubMed

35.

Soejima K, Schmalstieg FC, Traber LD, Szabo C, Salzman A, Traber DL: Role of nitric oxide in myocardial dysfunction after combined burn and smoke inhalation injury. Burns. 2001, 27: 809-815. 10.1016/S0305-4179(01)00051-1.CrossRefPubMed

36.

Belba M, Aleksi A, Nezha I, Tafaj S, Shtylla M, Belba G: Net fluid accumulation and outcome. A randomized clinical trial. Ann Burns Fire Disasters. 2009, 22: 16-21.PubMedCentralPubMed

37.

Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D: Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006, 34: 344-353. 10.1097/01.CCM.0000194725.48928.3A.CrossRefPubMed

38.

Chappell D, Jacob M, Hofmann-Kiefer K, Rehm M, Welsch U, Conzen P, Becker BF: Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc Res. 2009, 83: 388-396. 10.1093/cvr/cvp097.CrossRefPubMed

39.

Uchiba M, Okajima K, Kaun C, Wojta J, Binder BR: Inhibition of the endothelial cell activation by antithrombin in vitro. Thromb Haemost. 2004, 92: 1420-1427.PubMed

Title: Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study
Authors: Sebastian Rehberg
Yusuke Yamamoto
Eva Bartha
Linda E Sousse
Collette Jonkam
Yong Zhu
Lillian D Traber
Robert A Cox
Daniel L Traber
Perenlei Enkhbaatar
Publication date: 01-06-2013
Publisher: BioMed Central
Published in: Critical Care / Issue 3/2013
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/cc12712

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study

Abstract

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2013

Measuring and reporting glycemic control in clinical trials: building a path to consensus

Intimacy or utility? Organ donation and the choice between palliation and ventilation

Impact of arterial load on the agreement between pulse pressure analysis and esophageal Doppler

Early alterations of B cells in patients with septic shock

Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations

A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis