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Hypothermic Total Liquid Ventilation After Experimental Aspiration Rambaud et al. Ann. Intensive Care (2018) 8:57 https://doi.org/10.1186/s13613-018-0404-8 RESEARCH Open Access Hypothermic total liquid ventilation after experimental aspiration‑associated acute respiratory distress syndrome Jérôme Rambaud1,2, Fanny Lidouren1, Michaël Sage3, Matthias Kohlhauer1, Mathieu Nadeau3, Étienne Fortin‑Pellerin3, Philippe Micheau3, Luca Zilberstein1, Nicolas Mongardon1,4, Jean‑Damien Ricard5, Megumi Terada6, Patrick Bruneval6, Alain Berdeaux1, Bijan Ghaleh1, Hervé Walti1 and Renaud Tissier1* Abstract Background: Ultrafast cooling by total liquid ventilation (TLV) provides potent cardio- and neuroprotection after experimental cardiac arrest. However, this was evaluated in animals with no initial lung injury, whereas out-of-hospital cardiac arrest is frequently associated with early-onset pneumonia, which may lead to acute respiratory distress syn‑ drome (ARDS). Here, our objective was to determine whether hypothermic TLV could be safe or even benefcial in an aspiration-associated ARDS animal model. Methods: ARDS was induced in anesthetized rabbits through a two-hits model including the intra-tracheal admin‑ istration of a pH 1 solution mimicking gastric content and subsequent gaseous non-protective ventilation during 90 min (tidal volume= [Vt] 10 ml/kg with positive end-expiration pressure [PEEP] 0 ­cmH O). After this initial period, = = 2 animals either received lung protective gas ventilation (LPV; Vt 8 ml/kg and PEEP 5 ­cmH2O) under normother‑ mic conditions, or hypothermic TLV (TLV; Vt 8 ml/kg and end-=expiratory volume = 15 ml/kg). Both strategies were applied for 120 min with a continuous monitoring= of respiratory and cardiovascular= parameters. Animals were then euthanized for pulmonary histological analyses. Results: Eight rabbits were included in each group. Before randomization, all animals elicited ARDS with arte‑ rial oxygen partial pressure over inhaled oxygen fraction ratios ­(PaO2/FiO2) below 100 mmHg, as well as decreased lung compliance. After randomization, body temperature rapidly decreased in TLV versus LPV group (32.6 0.6 vs. 38.2 0.4 °C after 15 min). Static lung compliance and gas exchanges were not signifcantly diferent in the± TLV versus ± LPV group ­(PaO2/FiO2 62 4 vs. 52 8 mmHg at the end of the procedure, respectively). Mean arterial pressure and arterial bicarbonates levels= ±were signifcantly± higher in TLV versus LPV. Histological analysis also showed signifcantly lower infammation in TLV versus LPV group (median histological score 3 vs. 4.5/5, respectively; p 0.03). = = Conclusion: Hypothermic TLV can be safely induced in rabbits during aspiration-associated ARDS. It modifed neither gas exchanges nor respiratory mechanics but reduced lung infammation and hemodynamic failure in comparison with LPV. Since hypothermic TLV was previously shown to provide neuro- and cardio protective efects after cardiac arrest, these fndings suggest a possible use of TLV in the settings of cardiac arrest-associated ARDS. Keywords: ARDS, Pneumonia, Aspiration, Total liquid ventilation, Hypothermia, Cardiac arrest *Correspondence: renaud.tissier@vet‑alfort.fr 1 U955 – IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d’Alfort, 7 avenue du Général de Gaulle, 94700 Maisons‑Alfort, France Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Rambaud et al. Ann. Intensive Care (2018) 8:57 Page 2 of 9 Background min. Positive end-expiratory pressure (PEEP) was set at After out-of-hospital cardiac arrest and successful resus- 5 cmH2O. Peripheral catheters were inserted into the ear citation, a post-cardiac arrest syndrome occurs and marginal vein and artery for blood sampling and pressure makes patients prone to infectious complications [1, 2]. monitoring, respectively. Temperature probes were also Among them, early-onset pneumonia afects up to two- inserted into the rectum and esophagus. Anesthesia was thirds of successfully resuscitated patients and are mainly maintained with additional administration of pentobarbi- related to aspiration. In this setting, aspiration pneumo- tal (5 mg/kg/h i.v.). nia deteriorates pulmonary function and has negative impact on outcome [1–3]. More dramatically, aspiration Experimental protocol pneumonia can culminate into acute respiratory distress After stabilization, rabbits were paralyzed by vecuronium syndrome (ARDS). For instance, around six percent of bromide (0.4 mg/kg/h, i.v.). ARDS was induced with a the patients resuscitated after out-of-hospital cardiac two-hits injury including an intra-tracheal administra- arrest present ARDS [4–6]. tion of 4 ml/kg of an aqueous solution at pH = 1 and a Hypothermic total liquid ventilation (TLV) could be period of conventional non-protective gas ventilation. an interesting alternative to conventional ventilation in Te acid solution was administered slowly into the tra- the context of cardiac arrest-associated aspiration pneu- cheal tube, while animals were manipulated in order to monia since this technique has been previously shown to improve lung distribution. Conventional non-protective limit the post-cardiac arrest syndrome in animal studies ventilation consisted in mechanical ventilation with tidal [7–11]. During TLV, the lungs can be alternatively flled volumes set at 10 ml/kg and PEEP at 0 cmH2O. Inhaled and emptied by perfuorocarbons, authorizing lung lav- fraction of oxygen (FiO2) was increased to 100%. Conven- age as well as gas and thermal exchanges. Tis approach tional non-protective ventilation was maintained during provides ultrafast cooling [12] and powerful neuro- and 90 min according to preliminary experiments demon- cardioprotection after cardiac arrest, as well as attenua- strating an optimal balance between the occurrence of tion of multi-organ dysfunction after low perfusion states reproducible ARDS and the need for a sufcient survival [7–11]. and follow-up after group allocation. Body temperature In the context of aspiration-associated ARDS, hypo- was maintained around 38.5 °C throughout ARDS induc- thermic TLV might also provide benefts per se through tion phase. lung lavage or anti-infammatory efects of liquid venti- After the period of conventional ventilation, animals lation [13–18]. Conversely, one would also argue that were randomly allocated to a group treated by lung pro- TLV could increase the risk of ventilation-induced tective gas ventilation (LPV) or TLV for 120 min (Fig. 1). injury when initiated after such lung injury. Our previ- In the LPV group, tidal volume was set at 8 ml/kg with ous reports with hypothermic TLV were indeed done in PEEP = 5 cmH2O. Such tidal volumes used are slightly animal models of cardiac with very controlled conditions higher that the recommended volumes for humans with preventing accidental aspiration. Accordingly, the goal of ARDS. However, lower tidal volumes are currently rec- the present study was to investigate whether TLV could ommended in rabbits. Body temperature was maintained be safely induced in a model of aspiration-associated at 38.5 °C using heating pads in the LPV group. In the ARDS and whether it modifes gas exchanges, respiratory TLV group, animals were ventilated with a dedicated mechanics, hemodynamic status or pulmonary infam- prototype of liquid ventilator continuously controlling matory response in rabbits. liquid pressures and volumes (Inolivent-5, Université de Sherbrooke, QC, Canada) [16, 19]. Tey were submit- Methods ted to hypothermia with a target temperature of 33 °C Te animal instrumentation and the ensuing experiments [7–11, 20, 21]. Lungs were initially flled with 13 ml/kg were approved by the institutional review board for ani- of perfuoro-n-octane (PFO, C8F18; F2-chemical®, Pres- mal research (project 04585-04 evaluated by the “Ethical ton, Lancashire, UK). Tidal volume was set at 8-10 ml/ committee Anses-Enva-UPEC”). kg and respiratory frequency at 9 cycles/min. Te pul- monary end-expiratory volumes of PFO were increased Animal instrumentation to reach 15–20 ml/kg. Te temperature of the liquid Male New Zealand rabbits (2.5–3.5 kg) were anesthe- was initially set at 20 °C and progressively increased in tized using zolazepam, tiletamine and pentobarbital (all order to maintain body core temperature at 33 °C. Static 20–30 mg/kg i.v.). After intubation, they were artifcially lung compliance was calculated by dividing tidal volume ventilated with inspired fraction of oxygen (FiO2) of 30% by the diference between airways pressures between (SAR-830P, CWE Inc., Ardmore, USA). Tidal volume end-inspiratory and end-expiratory pauses. Pause pres- was set at 8 mL/kg and respiratory rate at 30 cycles/ sures were calculated after valve closures at the end of Rambaud et al. Ann. Intensive Care (2018) 8:57 Page 3 of 9 Fig. 1 Schematic representation of the experimental protocol. ARDS acute respiratory distress syndrome; PEEP positive end‑expiratory pressure inspiration and expiration, respectively. Mean values Statistical analysis were obtained with at least 3 cycles. After 120 min of Data were expressed as mean ± SEM. Hemodynamic, LPV or TLV, animals were weaned back to conventional respiratory and biochemical variables
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