Ultrafast and whole-body cooling with total liquid ventilation induces favorable neurological and cardiac outcomes after cardiac arrest in rabbits

Abstract

Background: In animal models of cardiac arrest, the benefit afforded by hypothermia is closely linked to the rapidity of the decrease in body temperature after resuscitation. Because total liquid ventilation (TLV) with temperature-controlled perfluorocarbons induces a very rapid and generalized cooling, we aimed to determine whether this could limit the post-cardiac arrest syndrome in a rabbit model. We especially focused on neurological, cardiac, pulmonary, liver and kidney dysfunctions.

Methods and results: Anesthetized rabbits were submitted to either 5 or 10 minutes of untreated ventricular fibrillation. After cardiopulmonary resuscitation and resumption of a spontaneous circulation, the animals underwent either normothermic life support (control) or therapeutic hypothermia induced by TLV. The latter procedure decreased esophageal and tympanic temperatures to 32°C to 33°C within only 10 minutes. After rewarming, the animals submitted to TLV exhibited an attenuated neurological dysfunction and decreased mortality 7 days later compared with control. The neuroprotective effect of TLV was confirmed by a significant reduction in brain histological damages. We also observed limitation of myocardial necrosis, along with a decrease in troponin I release and a reduced myocardial caspase 3 activity, with TLV. The beneficial effects of TLV were directly related to the rapidity of hypothermia induction because neither conventional cooling (cold saline infusion plus external cooling) nor normothermic TLV elicited a similar protection.

Conclusions: Ultrafast cooling instituted by TLV exerts potent neurological and cardiac protection in an experimental model of cardiac arrest in rabbits. This could be a relevant approach to provide a global and protective hypothermia against the post-cardiac arrest syndrome.

Figure 1. Experimental protocol

CA, cardiac arrest; TLV, total liquid ventilation initiated; H-TLV, hypothermic TLV; N-TLV, normothermic TLV; Saline, hypothermia induced by intravenous administration of cold saline combined to external cooling; ROSC, resumption of spontaneous circulation.

Figure 2

Panel A: Examples of normal or pathological histological appearances of the kidney, liver and lungs in the TLV and control groups, respectively. In kidney, lesions consisted in dilated regenerative proximal tubules (arrows, bar=120 μm). In liver, we observed systematized clarification of hepatocytes (arrows, bar=120 μm). In lungs, lesions were congestion and serous edema (arrows in the left lung panel, bar=120 μm) or foci of bronchopneumonia (arrows in the right lung panel, bar=120 μm). Panel B: Histological scores of alteration in kidney, liver and lungs of rabbits from the different groups. For lungs, we assessed two separate scores for cardiogenic lesions and infection complications, respectively. Open circles represents individual scores and the thick line represents the median value of corresponding group. * p<0.05 vs corresponding control; TLV, total liquid ventilation; H-TLV, hypothermic TLV; N-TLV, normothermic TLV; Saline, hypothermia induced by intravenous administration of cold saline combined to external cooling.

Figure 3

Panel A: Examples of normal or pathological histological appearances of the brain and the heart in the TLV and control groups, respectively. In brain, ischemic disorders consisted in ischemic pyramidal cells with pycnotic nucleus in the hippocampus (arrows, bar=30 μm), in laminar necrosis of Purkinje cells in the cerebellum (arrows, bar=30 μm) or in numerous ischemic neurons in the cortex (arrows, bar=30 μm), respectively. In the myocardium, we observed foci of cardiomyocytes necrosis (arrows, bar=120 μm). Panel B: Histological scores of alteration in the brain and heart of rabbits from the different groups. Open circles represents individual scores and the thick line represents the median value of the corresponding group. * p<0.05 vs corresponding control; TLV, total liquid ventilation; H-TLV, hypothermic TLV; N-TLV, normothermic TLV; Saline, hypothermia induced by intravenous administration of cold saline combined to external cooling.

Figure 4. Esophageal, tympanic and rectal temperatures in the different experimental groups

* p<0.05 vs corresponding control; n=10 in each experimental group; TLV, total liquid ventilation; H-TLV, hypothermic TLV; N-TLV, normothermic TLV; Saline, hypothermia induced by intravenous administration of cold saline combined to external cooling.

Figure 5. Blood pH, pCO2 and pO2 in the different experimental groups

* p<0.05 vs corresponding control; n=10 in each experimental group; TLV, total liquid ventilation; H-TLV, hypothermic TLV; N-TLV, normothermic TLV; Saline, hypothermia induced by intravenous administration of cold saline combined to external cooling.

Figure 6

Panels A and B: Neurological dysfunction scores at days 1, 2 and 7 following resuscitation in the different experimental groups submitted to 5 min or 10 min of cardiac arrest, respectively. Open circles represent individual scores and the thick line represents the median value of the corresponding group. Only animals achieving resumption of spontaneous circulation were included. Panels C and D: Kaplan-Meyer survival curves in the different experimental groups submitted to 5 min or 10 min of cardiac arrest, respectively. Only animals achieving resumption of spontaneous circulation were included. * p<0.05 vs corresponding control; TLV, total liquid ventilation; H-TLV, hypothermic TLV; N-TLV, normothermic TLV; Saline, hypothermia induced by intravenous administration of cold saline combined to external cooling.