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Hypothermic Total Liquid Ventilation Is Highly Protective Through Cerebral Hemodynamic Preservation and Sepsis-Like Mitigation After Asphyxial Cardiac Arrest*

Kohlhauer, Matthias DVM, MSc1,2,3; Lidouren, Fanny BSc1,2,3; Remy-Jouet, Isabelle PhD4; Mongardon, Nicolas MD, MSc1,2,3; Adam, Clovis MD5; Bruneval, Patrick MD6; Hocini, Hakim PhD2,7,8; Levy, Yves MD, PhD2,7,8; Blengio, Fabiola BSc2,7,8; Carli, Pierre MD, PhD9; Vivien, Benoit MD, PhD9; Ricard, Jean-Damien MD, PhD10,11; Micheau, Philippe PhD12,13; Walti, Hervé MD, PhD12,13; Nadeau, Mathieu MSc12,13; Robert, Raymond PhD12,13; Richard, Vincent PhD4; Mulder, Paul PharmD, PhD4; Maresca, David PhD14; Demené, Charlie PhD14; Pernot, Mathieu PhD14; Tanter, Mickael PhD14; Ghaleh, Bijan MD, PhD1,2,3; Berdeaux, Alain MD, PhD1,2,3; Tissier, Renaud DVM, PhD1,2,3

doi: 10.1097/CCM.0000000000001160
Online Laboratory Investigations

Objectives: Total liquid ventilation provides ultrafast and potently neuro- and cardioprotective cooling after shockable cardiac arrest and myocardial infarction in animals. Our goal was to decipher the effect of hypothermic total liquid ventilation on the systemic and cerebral response to asphyxial cardiac arrest using an original pressure- and volume-controlled ventilation strategy in rabbits.

Design: Randomized animal study.

Setting: Academic research laboratory.

Subjects: New Zealand Rabbits.

Interventions: Thirty-six rabbits were submitted to 13 minutes of asphyxia, leading to cardiac arrest. After resumption of spontaneous circulation, they underwent either normothermic life support (control group, n = 12) or hypothermia induced by either 30 minutes of total liquid ventilation (total liquid ventilation group, n = 12) or IV cold saline (conventional cooling group, n = 12).

Measurements and Main Results: Ultrafast cooling with total liquid ventilation (32°C within 5 min in the esophagus) dramatically attenuated the post–cardiac arrest syndrome regarding survival, neurologic dysfunction, and histologic lesions (brain, heart, kidneys, liver, and lungs). Final survival rate achieved 58% versus 0% and 8% in total liquid ventilation, control, and conventional cooling groups (p < 0.05), respectively. This was accompanied by an early preservation of the blood-brain barrier integrity and cerebral hemodynamics as well as reduction in the immediate reactive oxygen species production in the brain, heart, and kidneys after cardiac arrest. Later on, total liquid ventilation also mitigated the systemic inflammatory response through alteration of monocyte chemoattractant protein-1, interleukin-1β, and interleukin-8 transcripts levels compared with control. In the conventional cooling group, cooling was achieved more slowly (32°C within 90–120 min in the esophagus), providing none of the above-mentioned systemic or organ protection.

Conclusions: Ultrafast cooling by total liquid ventilation limits the post–cardiac arrest syndrome after asphyxial cardiac arrest in rabbits. This protection involves an early limitation in reactive oxidative species production, blood-brain barrier disruption, and delayed preservation against the systemic inflammatory response.

1Inserm, U955, Equipe 03, Créteil, France.

2Université Paris Est, UMR_S955, DHU A-TVB, UPEC, Créteil, France.

3Université Paris Est, Ecole Nationale Vétérinaire d’Alfort, Maisons-Alfort, France.

4Inserm, U1096, Rouen, France.

5Assistance Publique, Hôpitaux de Paris, Hôpital du Kremlin-Bicêtre, Service d’Anatomie Pathologique, Le Kremlin-Bicêtre, France.

6Inserm, U970, Paris, France.

7Inserm, U955, Equipe 16, Créteil, France.

8Vaccine Research Institute, Créteil, France.

9SAMU de Paris, Département d’Anesthésie Réanimation, Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes–Paris V, Paris, France.

10Inserm, IAME, 1137, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.

11Assistance Publique–Hôpitaux de Paris, Hôpital Louis Mourier, Service de Réanimation Médico-chirurgicale, Colombes, France.

12Department of Mechanical Engineering, University of Sherbrooke, QC, Canada.

13Department of Physiology, University of Sherbrooke, QC, Canada.

14Institut Langevin, CNRS UMR 7587, INSERM U979, ESPCI ParisTech, Paris, France.

*See also p. 2271.

This work was performed at Inserm, U955, Equipe 03; Université Paris Est; Université Paris Est, Ecole Nationale Vétérinaire d’Alfort; Inserm, U1096; Inserm, U955, Equipe 16.

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Supported, in part, by grant ABYSS-R12031JJ from the “Agence Nationale pour la Recherche” (Paris, France); grant PSR-SIIRI-757 from the “Ministère du Développement économique, de l’Innovation et de l’Exportation” (QC, Canada); grant from the Region Ile-de France (Cardiovasculaire-Obésité-Rein-Diabète – Domaine d’Intérêt Majeur); and grant DBS20140930781 from the “Fondation pour la Recherche Médicale.”

Dr. Adam consulted for the Sorin Group and lectured for Pfizer. Dr. Vivien served as a board member for Novartis, Lilly, and LFB and received support for the development of educational presentations from AstraZeneca and Lilly. Dr. Ricard served as a board member for Covidien (board on VAP prevention) and has stock in Fisher & Paykel (F&P covered expenses to attend scientific meetings). Dr. Tanter received grant support, consulted, and served as a board member. Dr. Berdeaux has a patent application. His institution received grant support from ANR (grant ABYSS-13/039,415). Dr. Tissier provided expert testimony for Expertises for French regulatory agencies. His institution has a patent (application 13/039,415) and received grant support from Agence Nationale pour la Recherche (grant ABYSS), Fondation pour la Recherche Médicale, and Association pour la Recherche et l'Etude des Maladies Cardiovasculaires. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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