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A Brief Period of Hypothermia Induced by Total Liquid Ventilation Decreases End-Organ Damage and Multiorgan Failure Induced by Aortic Cross-Clamping

Mongardon, Nicolas MD, MSc; Kohlhauer, Matthias DVM, MSc; Lidouren, Fanny BSc; Hauet, Thierry MD, PhD; Giraud, Sébastien PhD; Hutin, Alice MD, MSc; Costes, Bruno PhD; Barau, Caroline PharmD, PhD; Bruneval, Patrick MD, PhD; Micheau, Philippe PhD; Cariou, Alain MD, PhD; Dhonneur, Gilles MD, PhD; Berdeaux, Alain MD, PhD; Ghaleh, Bijan PharmD, PhD; Tissier, Renaud DVM, PhD

doi: 10.1213/ANE.0000000000001432
Critical Care and Resuscitation: Original Laboratory Research Report

BACKGROUND: In animal models, whole-body cooling reduces end-organ injury after cardiac arrest and other hypoperfusion states. The benefits of cooling in humans, however, are uncertain, possibly because detrimental effects of prolonged cooling may offset any potential benefit. Total liquid ventilation (TLV) provides both ultrafast cooling and rewarming. In previous reports, ultrafast cooling with TLV potently reduced neurological injury after experimental cardiac arrest in animals. We hypothesized that a brief period of rapid cooling and rewarming via TLV could also mitigate multiorgan failure (MOF) after ischemia-reperfusion induced by aortic cross-clamping.

METHODS: Anesthetized rabbits were submitted to 30 minutes of supraceliac aortic cross-clamping followed by 300 minutes of reperfusion. They were allocated either to a normothermic procedure with conventional ventilation (control group) or to hypothermic TLV (33°C) before, during, and after cross-clamping (pre-clamp, per-clamp, and post-clamp groups, respectively). In all TLV groups, hypothermia was maintained for 75 minutes and switched to a rewarming mode before resumption to conventional mechanical ventilation. End points included cardiovascular, renal, liver, and inflammatory parameters measured 300 minutes after reperfusion.

RESULTS: In the normothermic (control) group, ischemia-reperfusion injury produced evidence of MOF including severe vasoplegia, low cardiac output, acute kidney injury, and liver failure. In the TLV group, we observed gradual improvements in cardiac output in post-clamp, per-clamp, and pre-clamp groups versus control (53 ± 8, 64 ± 12, and 90 ± 24 vs 36 ± 23 mL/min/kg after 300 minutes of reperfusion, respectively). Liver biomarker levels were also lower in pre-clamp and per-clamp groups versus control. However, acute kidney injury was prevented in pre-clamp, and to a limited extent in per-clamp groups, but not in the post-clamp group. For instance, creatinine clearance was 4.8 ± 3.1 and 0.5 ± 0.6 mL/kg/min at the end of the follow-up in pre-clamp versus control animals (P = .0004). Histological examinations of the heart, kidney, liver, and jejunum in TLV and control groups also demonstrated reduced injury with TLV.

CONCLUSIONS: A brief period of ultrafast cooling with TLV followed by rapid rewarming attenuated biochemical and histological markers of MOF after aortic cross-clamping. Cardiovascular and liver dysfunctions were limited by a brief period of hypothermic TLV, even when started after reperfusion. Conversely, acute kidney injury was limited only when hypothermia was started before reperfusion. Further work is needed to determine the clinical significance of our results and to identify the optimal duration and timing of TLV-induced hypothermia for end-organ protection in hypoperfusion states.

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From the *Inserm, U955, Equipe 3, Créteil, France; Université Paris Est, UMR_S 955, UPEC, DHU A-TVB, Créteil, France; Université Paris Est, Ecole Nationale Vétérinaire Alfort, Maisons Alfort, France; §Service d’ Anesthésie et des Réanimations Chirurgicales, DHU A-TVB, Hôpitaux Universitaires Henri Mondor, Assistance Publique – Hôpitaux de Paris, Créteil, France; Inserm, U1082, Poitiers, France; ¶Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France; #CHU de Poitiers, Service de Biochimie, Poitiers, France; **Inserm, UMR 970, Paris Cardiovascular Research Center, Paris, France; ††Université de Sherbrooke, Sherbrooke, Canada; and ‡‡Service de Réanimation Médicale, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.

Accepted for publication May 3, 2016.

Funding: This study was supported by a grant from the Region Ile-de France (CORDDIM) and grant DBS20140930781 from the Fondation pour la Recherche Médicale (FRM).

Conflict of Interest: See Disclosures at the end of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

This report was previously presented, in part, at the following medical congresses: European Resuscitation Council (May 15–17, 2014, Bilbao, Spain); Société Française d’Anesthésie Réanimation (September 18–21, 2014, Paris, France); and American Society of Anesthesiology (October 11–15, 2014, New Orleans, LA).

Reprints will not be available from the authors.

Address correspondence to Renaud Tissier, DVM, PhD, Inserm, Unité 955, Ecole Nationale Vétérinaire d’Alfort, 7 Ave. du Général de Gaulle, 94704 Maisons-Alfort cedex, France. Address e-mail to

© 2016 International Anesthesia Research Society