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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.

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 renaud.tissier@vet-alfort.fr.

Multiorgan failure (MOF) is a common feature of ischemia-reperfusion injury in critical care.1,2 Because cardiovascular and renal dysfunction largely predominate, MOF treatment is mostly limited to hemodynamic optimization and renal replacement therapies.3 In the setting of ischemia-reperfusion injury, hypothermia has anti-inflammatory, antiapoptotic, and antioxidant properties and may improve outcomes.4 However, hypothermia has been mostly studied after single-organ ischemia or after experimental cardiac arrest. Here, we used an original model of aortic cross-clamping and abdominal ischemia-reperfusion injury in rabbits. This model produces an intense inflammatory response and severe liver and kidney injury.5,6

Early induction of hypothermia has demonstrated benefits after experimental cardiac arrest7,8 or myocardial ischemia.9 Total liquid ventilation (TLV) induces ultrafast whole-body cooling and hypothermia.10–13 Through instillation of temperature-controlled perfluorocarbons, TLV uses the lung as a heat exchanger while maintaining normal gas exchange and lung integrity.10,14,15 We previously demonstrated cardiac or neurological benefits with hypothermic TLV (HTLV) in animal models of cardiac arrest.10–13 Importantly, TLV also allows rapid warming, potentially mitigating adverse effects of prolonged cooling. We hypothesized that a brief period of HTLV followed by rapid rewarming would mitigate MOF after experimental ischemia-reperfusion induced by supraceliac abdominal aorta cross-clamping (ie, cardiovascular dysfunction, inflammatory response, as well as liver and renal failures). To test our hypothesis, we submitted rabbits to 30 minutes of aortic cross-clamping with HTLV being started before, during, or after ischemia and lasting for 75 minutes. Outcomes included circulatory, liver, and renal dysfunction and systemic markers of inflammation.

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METHODS

The animal instrumentation and the ensuing experiments were approved by the institutional review board for animal research (ComEth AnSES/ENVA/UPEC no. 16), in accordance with French official regulations.

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Animal Preparation, Aortic Occlusion, and Reperfusion

As previously described,12,13 male New Zealand rabbits (2.5–3.5 kg) were anesthetized using zolazepam, tiletamine, and pentobarbital (all 20–30 mg/kg IV). After intubation, mechanical ventilation was begun (FIO2 = 30%), and anesthesia was maintained with additional administration of pentobarbital (5–10 mg/kg/h). Electrocardiogram and arterial blood pressure in the right carotid artery were continuously recorded (HEM version 3.5; Notocord, Croissy-sur-Seine, France). After thoracotomy, a flowprobe was placed around the ascending aorta to measure cardiac output (PS-Series Probes, Transonic, Ithaca, NY). The chest was then closed in layers, and a median laparotomy was performed. Temperature probes were inserted behind the left kidney, as well as in the ear, rectum, and esophagus. All animals received heparin (100 IU/kg IV), and supraceliac aorta was then occluded with a vascular clamp. Occlusion was released after 30 minutes of aortic cross-clamping. Animals were then monitored for 300 minutes. These durations were determined after preliminary data determining the balance between severity of MOF and need for follow-up. Longer durations of ischemia (>40 minutes) were too severe with rapid shock and death (n = 3). Conversely, shorter durations (20 minutes) were not sufficient to produce reproducible decrease in cardiac output in control conditions (n = 4). The intravenous infusion of norepinephrine was permitted throughout reperfusion to target a mean arterial pressure of 70 mm Hg. Saline was administered throughout the experiment (5 mL/kg IV after intubation; 10 mL/kg IV at the onset of reperfusion; 10 mL/kg/h throughout follow-up). After the 300-minute reperfusion period, animals were euthanized.

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Experimental Protocol

Figure 1

Figure 1

As illustrated in Figure 1A, rabbits were randomly assigned to 1 of the 4 experimental groups. In the control group, temperature was maintained at about 38.5°C with a heating pad, and animals underwent conventional mechanical ventilation throughout the protocol. In the pre-clamp group, ultrafast cooling by TLV was induced 15 minutes before aortic cross-clamping with a target temperature fixed at 33°C. TLV was delivered by a liquid ventilator (Inolivent, Université de Sherbrooke, Canada) and initiated by instilling 13 mL/kg perfluorooctane (F2 Chemicals, Preston, UK) into the lungs. Liquid ventilator settings were tidal volume of 10 mL/kg, a ventilatory frequency of 8 cycles/min, and a pulmonary expiratory pause pressure of 5 cm H2O. Hypothermia was then maintained at 33°C using TLV for 75 minutes. TLV was then switched to a rewarming mode by an increase in perfluorooctane temperature (42°C). After 30 minutes of rewarming, perfluorooctane was drained from animal lungs by a prolonged expiration. The liquid ventilator was then disconnected, and animals were shifted to conventional mechanical ventilation. Body temperature was subsequently maintained at 38.5°C with heating pad until the end of the reperfusion period. In the per-clamp and post-clamp groups, similar procedures were performed with HTLV applied 15 minutes after aortic occlusion and 15 minutes after reperfusion, respectively. In all cases, HTLV was maintained for 75 minutes before being switched to the 30-minute rewarming period and then to conventional ventilation.

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Investigated Parameters During the Follow-Up

In addition to continuous hemodynamic and temperature monitoring, blood samples were withdrawn at baseline and 30, 120, and 300 minutes after reperfusion for blood gases and biochemical analyses. As previously described,13 acute kidney injury was evaluated using urine output, creatinine urinary clearance, blood creatinine, and sodium levels (Cobas Bio Analyzer; Roche-Diagnostics, Mannheim, Germany), blood and urinary neutrophil gelatinase-associated lipocalin (NGAL), blood and urinary kidney injury molecule (KIM-1; BlueGene, Shanghai, China), blood and urinary osmolarity (Roebling Osmometer, Burladingen, Germany), blood and urinary γ-glutamyl transpeptidase (γ-GT), urinary N-acetyl-β-(D)-glucosaminidase (NAG), and β2-microglobulin (Roche Diagnostic, Mannheim, Germany). All urinary dosages were normalized to urinary creatinine levels as a common denominator. Fractional sodium excretion was calculated as [urinary sodium × plasma creatinine]/[urinary creatinine × plasma sodium]. Renal failure index was also calculated as [urinary sodium × plasma creatinine]/[urinary creatinine]. Hepatic function was evaluated through the determination of blood aspartate aminotransferase, alanine aminotransferase (ALAT), and urinary liver-fatty acid-binding protein levels (L-FABP).

We also measured blood mRNA levels for markers of immunity, inflammation, or hypoxia using real-time quantitative reverse transcription polymerase chain reaction, as previously described.12 We assessed the expression of interleukins (IL)-1β, -8, and -10; tumor necrosis factor-α (TNF-α); heme oxygenase 1 (HO-1); and hypoxia-inducible factor-1α (HIF-1α).

At the end of the protocol, tissue samples were withdrawn from heart, kidneys, liver, and jejunum; fixed in formaldehyde (4%); stained with hematoxylin-eosin-saffron; and evaluated by conventional light microscopy.

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Statistical Methodology

Data were expressed as mean ± standard deviation. Hemodynamic and biochemical parameters were compared between different groups using a 2-way analysis of variance for repeated measures followed by a Tukey test, if necessary. Post hoc comparisons were only made between groups at baseline and 30, 120, and 300 minutes after reperfusion. Significant differences were determined at P ≤ .01.

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RESULTS

Effect of TLV on Cooling, Rewarming, and Gas Exchanges

Table 1

Table 1

In total, we studied 38 rabbits. Seven rabbits were excluded for technical reasons (eg, hemorrhage or technical issues with the cardiac flowprobe). Thirty-one rabbits underwent the entire experimental protocol (10 controls and 7 each in pre-clamp per-clamp, and post-clamp groups, respectively). Whereas the body temperature remained stable throughout the study period in the control group, HTLV reduced abdominal temperature to 33°C within 15 minutes after the onset of TLV (Figure 1B). At the end of the 75-minute hypothermic period, rewarming was also achieved very rapidly by TLV (eg, <30 minutes for abdominal temperature). Tympanic, rectal, and esophageal temperatures showed similar kinetic patterns (data not shown). As shown in Table 1, blood gases at 30 minutes after reperfusion remained within usual values during TLV. However, a transient increase in carbon dioxide levels was noted in all TLV groups versus control (P = .0002, .0003, and .0012 in pre-clamp, per-clamp, and post-clamp groups versus control at 30 minutes after reperfusion).

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Effect of TLV on Cardiovascular Parameters

Figure 2

Figure 2

As shown in Figure 2, heart rate decreased during the hypothermic phases in all HTLV groups compared with control (P < .0001 at 30 minutes of reperfusion in pre-clamp, per-clamp, and post-clamp groups versus control). Control animals experienced a 60% decrease in cardiac output at the end of the reperfusion period compared with baseline (36 ± 23 vs 90 ± 12 mL/min/kg). Conversely, cardiac output was improved in the pre-clamp group compared with control (eg, 90 ± 24 mL/min/kg at 300 minutes of reperfusion; P = .0001) and with a lower extent in per-clamp and post-clamp groups (Figure 2). Vasopressor requirements to maintain arterial blood pressure of >70 mm Hg were also dramatically different with higher doses of norepinephrine in the control group compared with pre-clamp (12.4 ± 11.7 vs 1.6 ± 0.5 µg/kg/min at the end of the follow-up; P < .0001). In per-clamp and post-clamp groups, intermediate requirements were observed (2.9 ± 2.4 and 9.0 ± 8.6 µg/kg/min, respectively; P < .0001 and NS versus control). In a similar manner, metabolic acidosis was significantly attenuated in the pre-clamp group compared with control when assessed by bicarbonate blood levels (Table 1; P = .0007).

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Effects of TLV on Organ Failures

As shown in Table 2 and Figures 3 and 4, acute kidney injury was attenuated by HTLV in the pre-clamp group compared with control. As an example, creatinine clearance was preserved in pre-clamp but not in per-clamp and post-clamp groups compared with control (Figure 3). Urinary osmolarity, fractional excretion of sodium, and renal failure index were also preserved in the pre-clamp group, to a limited extent in the per-clamp group, and not in post-clamp group. Plasma (Table 2) or urinary (Figure 4) markers of renal tubular necrosis (NGAL, KIM-1, NAG, γ-GT, and β2-microglobulin) also were attenuated in the pre-clamp group and to a limited extent in the per-clamp group. Urinary output was not significantly different among groups, despite increasing values from control to post-clamp, per-clamp, and pre-clamp groups (0.03 ± 0.03, 0.08 ± 0.12, 0.07 ± 0.05, and 0.11 ± 0.05 mL/min, respectively).

Table 2

Table 2

Figure 3

Figure 3

Figure 4

Figure 4

As shown in Table 2, rabbits receiving HTLV demonstrated less hepatic injury than controls. For example, plasma levels of ALAT were lower in pre-clamp and per-clamp versus control animals (P = .0002 and .0003, respectively). Urinary L-FABP levels, which reflect hepatocyte lysis but also kidney and intestinal injuries, were also significantly lower in HTLV groups compared with control.

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Effect of HTLV on Inflammatory Response

Figure 5

Figure 5

As illustrated in Figure 5, blood transcription levels of IL-1β, IL-8, IL-10, TNF-α, and interferon-β were dramatically increased after reperfusion (t = 300 minutes) compared with baseline. This increase was not significantly attenuated in pre-clamp, per-clamp, and post-clamp groups compared with controls. At the end of the protocol, HO-1 and HIF-1α levels also were increased compared with baseline, with no significant difference among groups. A trend toward lower HIF-1α levels was observed in HTLV groups versus control.

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Evaluation of Organ Morphology at the End of the Follow-Up

Figure 6

Figure 6

To confirm end-organ injury/preservation at the end of the reperfusion period, we performed histological analysis in the 2 “extreme” groups, that is, control and pre-clamp groups (n = 4 in each group). As shown in Figure 6A to 6C, we observed several foci of inflammation and uni- or paucicellular necrosis in the hearts of control, but not pre-clamp rabbits. Renal samples in control rabbits also exhibited foci of tubular necrosis and tubular dilation (Figure 6D). In one control rabbit, severe lesions with thrombotic microangiopathy and disseminated intravascular coagulation also were observed (Figure 6E). In contrast, renal samples in the pre-clamp group remained normal (Figure 6F). In the liver, control rabbits had mild centrilobular congestion (Figure 6G) or macrovacuolar steatosis (Figure 6H), while pre-clamp rabbits appeared normal (Figure 6I). Finally, the jejunum of control rabbits exhibited severe villous atrophy in the mucosa layer (Figure 6J) and massive inflammation and congestion in the lamina propria (Figure 6K), while pre-clamp rabbits did not (Figure 6L).

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DISCUSSION

In this study, we found that a brief period of ultrafast cooling by TLV followed by rapid rewarming mitigates heart, kidney, and liver dysfunction after experimental aortic cross-clamping. Our data suggest that a focused window of application may be as effective as prolonged cooling as functional, histological, and biomarker evidence of end-organ damage was virtually abolished by preischemic cooling and even attenuated when cooling was induced during the ischemic period. When induced postischemia, cardiovascular and liver failures were attenuated, but the severity of acute kidney injury remained almost unchanged. Although the anti-ischemic effects of hypothermia have already been well investigated, this study demonstrates that a brief episode of controlled hypothermia could be sufficient to attenuate or block the deleterious cascades of ischemia/reperfusion. By doing so, potential deleterious effects of prolonged hypothermia such as infection, electrolyte disorders, and coagulation abnormalities may be avoided.

To induce ischemia-reperfusion and MOF, we used a supraceliac aortic cross-clamp model. This model induced a severe vasoplegia and decrease in cardiac output. MOF was also characterized by the high burden of inflammatory biomarkers, including IL-1β, IL-8, IL-10, HIF-1α, and HO-1. In our model, HTLV attenuated the shock state, even when induced during aortic cross-clamping. That the benefit persisted after only a brief period of hypothermia and rapid rewarming suggests that the well-known hemodynamic effects of hypothermia11,16–18 are not only because of hypothermia-induced increases in systemic vascular resistance and stroke volume.16,19,20

We also investigated the inflammatory response as a major feature of MOF. Interestingly, regardless of the timing of hypothermia, all HTLV groups exhibited a similar and nonsignificant effect on inflammatory or hypoxic responses. This finding suggests that HTLV exerted its protective effect on MOF more via direct organ protection than by an anti-inflammatory effect, which differs from previous studies finding that hypothermia dramatically attenuates inflammation during septic shock,21 improved survival after cecal ligature and puncture,22 and suppressed inflammation during experimental endotoxemia.23 Because plasma cytokine levels may not be the most relevant markers of inflammation in our study, further work is needed to clarify the effect of hypothermia on organ cytokine levels.24

Regarding acute kidney injury, the protective effects of HTLV were mostly observed with early application. Acute kidney injury was not prevented by hypothermia induced after ischemia, suggesting that the kidney is very sensitive to ischemia induced by this model. Our finding is consistent with previous findings in rabbits submitted to experimental cardiac arrest, in which HTLV attenuated acute kidney injury when instituted rapidly after cardiopulmonary resuscitation.13

Beyond cardiac and renal dysfunction, we also found that TLV decreased plasma levels of liver enzymes, suggesting a reduction in hepatic injury. However, the effect of HTLV was again minor when started after reperfusion, suggesting that hepatic and renal responses were similar. Changes in gut histology were also blunted in pre-clamp animals when compared with nonhypothermic controls.

Our findings underline the importance of the timing of hypothermia, in particular regarding liver and renal dysfunction. In the post-clamp group, hypothermia was induced only 15 minutes after reperfusion, but this time lag was enough to compromise most of the benefit compared with earlier initiation. Failure to attenuate organ failure may be because adverse effects of ischemia and reperfusion occur immediately. In clinical studies, the target temperature of hypothermia is typically achieved more than 3 to 6 hours after initiation,25 even with prehospital cooling.26 This relatively late application may not prevent the acute phase of ischemia-reperfusion and could explain why mild hypothermia (33°C) improved outcomes in animal models10–13 but not in humans after cardiac arrest where cooling may be delayed.25 As example, HTLV has demonstrated its capacity to reach temperature level <34°C in <15 minutes in rabbits,10–13 newborn,27 and juvenile lambs28 and also in large animals including 40-kg pigs.29 This original strategy can now be instituted through original liquid ventilators, which are currently being developed.27–29 In addition to the ultrafast cooling property, the ability to rewarming rapidly, and possible pulmonary benefits of liquid ventilation,30 may also be benefits of TLV.28

In this study, we did not compare the effect of TLV to other cooling strategies because our primary goal was to evaluate the effect of a brief period of hypothermia followed by rapid rewarming with TLV. However, in previous work,10–12 we found that HTLV cooled body core to 32°C in 10 minutes in rabbits submitted to 8 minutes of ventricular fibrillation with concomitant coronary artery occlusion, whereas external cooling and cold saline infusion strategies required 30 to 45 minutes.11 We found that this delay in achieving hypothermia dramatically increased mortality compared with HTLV (30% vs 80%). In experimental reports, strategies such as convective-immersion surface cooling31,32 or cold aortic flush33 have been proposed to accelerate cooling. Although such techniques may not be as effective in larger animals, cooling with HTLV is effective independent of body weight.29 In addition, strategies such as peritoneal dialysis, cardiopulmonary bypass, or endovascular devices are invasive, whereas TLV requires only a specific ventilator and an endotracheal tube.

Another limitation of this study is that high aortic cross-clamping is usually not performed without concomitant bypass or selective distal perfusion during scheduled vascular surgery. The clinical relevance of our model is thus limited at this stage, and our results should not be extrapolated to other hypoperfusion syndromes such as sepsis or cardiac arrest. We also did not assess the effects of hypothermia on neurologic function and cannot extrapolate our results to brain or spinal cord preservation. The window of protection with hypothermia may differ for spine protection, as previously shown with delayed cooling after 15 minutes of aortic cross-clamp ischemia in rabbits.34 However, our goal was to demonstrate that a brief window of hypothermia followed by rewarming is able to mitigate end-organ injury because of ischemia/reperfusion. More work will be required to identify which organs benefit, the optimal initiation time and duration of hypothermia with TLV, and the mechanism of benefit. Another limitation is related to the design of the study, which includes a defined hypothermia duration and rapid rewarming in all HTLV groups. Although this approach allowed a more reliable comparison between groups, the short duration of hypothermia also may have limited some of the benefit of HTLV. Whether stronger effects could be observed with longer hypothermia durations remain to be elucidated. Alternatively, a short duration of hypothermia may limit adverse effects of prolonged hypothermia, such as infectious susceptibility and electrolytic disorders.35,36 In addition, one could speculate that some of the benefits observed with HTLV were related to noncooling effects of TLV such as an anti-inflammatory effect.37 However, in an animal model of cardiac arrest, we found that TLV did not exhibit benefit when induced in a normothermic manner.10

In conclusion, ultrafast hypothermia with TLV reduced MOF after aortic cross-clamping. However, protective effects differed depending on the organ system and the time that HTLV was initiated initiation. Cardiovascular dysfunction and liver dysfunction were attenuated by hypothermia, even when performed after ischemic injury. Conversely, hypothermia provided no benefit on renal function when applied after the onset of reperfusion. More work is needed to better understand the place and ideal window for the application of hypothermia in the treatment of MOF.

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DISCLOSURES

Name: Nicolas Mongardon, MD, MSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Nicolas Mongardon reported no conflicts of interest.

Name: Matthias Kohlhauer, DVM, MSc.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Matthias Kohlhauer reported no conflicts of interest.

Name: Fanny Lidouren, BSc.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Fanny Lidouren reported no conflicts of interest.

Name: Thierry Hauet, MD, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Thierry Hauet reported no conflicts of interest.

Name: Sébastien Giraud, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Sébastien Giraud reported no conflicts of interest.

Name: Alice Hutin, MD, MSc.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Alice Hutin reported no conflicts of interest.

Name: Bruno Costes, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Bruno Costes reported no conflicts of interest.

Name: Caroline Barau, PharmD, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Caroline Barau reported no conflicts of interest.

Name: Patrick Bruneval, MD, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Patrick Bruneval reported no conflicts of interest.

Name: Philippe Micheau, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Philippe Micheau is named as inventor on 2 patents related to liquid ventilator (US 7726311; WO 2014205548).

Name: Alain Cariou, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Conflicts of Interest: Alain Cariou reported no conflicts of interest.

Name: Gilles Dhonneur, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Conflicts of Interest: Gilles Dhonneur reported no conflicts of interest.

Name: Alain Berdeaux, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Conflicts of Interest: Alain Berdeaux is named as an inventor on a patent application on cooling with liquid ventilation (US 13/039415).

Name: Bijan Ghaleh, PharmD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Conflicts of Interest: Bijan Ghaleh reported no conflicts of interest.

Name: Renaud Tissier, DVM, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Conflicts of Interest: Renaud Tissier is named as an inventor on a patent application on cooling with liquid ventilation (US 13/039415).

This manuscript was handled by: Avery Tung, MD, FCCM.

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ACKNOWLEDGMENTS

The authors gratefully acknowledge Natacha Martin for excellent technical support.

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