Arrhythmogenicity of hypothermia - a large animal model of hypothermia (original) (raw)
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Critical Care Medicine, 2012
udden death resulting from cardiac arrest (CA) is a leading cause of death in the United States, Canada, and Europe (1-3). It accounts for as many as 50% of deaths in patients with heart disease (4). Despite efforts to improve outcomes from CA, the overall survival rate remains dismal (5, 6). Although the initial success of cardiopulmonary resuscitation (CPR) is approximately 39%, the majority of victims die within 72 hrs of hospital admission (7, 8). Patients successfully resuscitated after CA often present with what is now termed "postresuscitation disease" (9). Severe postresuscitation heart contractile failure has been implicated as one of the most important mechanisms causing these fatal outcomes (10, 11). Indeed, it is brain cellular injury after cerebral ischemia and after reperfusion that accounts for as many as 60% of disabilities in the small number of patients resuscitated after CA that survive to hospital discharge (12, 13). The greatest postresuscitation emphasis has therefore been on minimizing myocardial dysfunction together with the aim to preserve neurologic function (14). Among all postresuscitation care interventions suggested and/or recommended as providing the most persuasive benefits both for the brain and the heart is the use of therapeutic hypothermia (TH) (15-17). When the body temperature is reduced to 32-34°C, which is initiated during CPR or immediately after resuscitation, neurologic outcomes are significantly improved (18-21). The postresuscitation period is marked by hemodynamic instability and Objective: Therapeutic hypothermia initiated with cardiopulmonary resuscitation improves neurologic outcomes and survival after prolonged cardiac arrest. However, the potential mechanism by which hypothermia improves neurologic outcomes remains unclear. In the current study, we investigated the effect of rapid head cooling on 96-hr neurologic outcomes and survival by heart rate variability analysis in a pig model of prolonged cardiac arrest. Design: Prospective randomized controlled animal study. Setting: University-affiliated research laboratory. Subjects: Yorkshire-X domestic pigs (Sus scrofa). Interventions: A protocol of 10 mins of untreated ventricular fibrillation followed by 5 mins of cardiopulmonary resuscitation in a pig model of cardiac arrest was used in this study. Sixteen male domestic pigs weighing between 39 and 45 kg were randomized into two groups, hypothermia (n ؍ 8) and control (n ؍ 8). For the hypothermia group, intranasal-induced head cooling was initiated with cardiopulmonary resuscitation and persisted for 4 hrs after resuscitation. For the control group, cardiopulmonary resuscitation was started with normothermia. Measurements and Main Results: Time and frequency domain heart rate variability was calculated in 5-min sections of electrocardiographic recordings at baseline and 4 hrs after resuscitation. Neurologic outcomes were evaluated every 24 hrs during the 96-hr postresuscitation observation period. No differences in the baseline measurement and resuscitation outcome were observed between the groups. However, the 96-hr cerebral performance categories of the hypothermic group were significantly lower than control (1.0 ؎ 0.0 vs. 4.0 ؎ 1.9, p ؍ .003). Four hrs after resuscitation, mean RR interval, heart rate variability triangular index, and normalized verylow-frequency power were restored to baseline in the hypothermia group. Square root of the mean squared differences of successive RR intervals and SD of instantaneous RR intervals were significantly improved in the cooled animals compared with controls. A significant correlation between 4-hr heart rate variability and 96-hr cerebral performance category was observed in this study. Conclusion: Selective head cooling maintains a certain level of autonomic nervous system function in this pig model of cardiac arrest. The preserved heart rate variability during postresuscitation hypothermia was associated with favorable 96-hr neurologic recovery and survival.
Journal of Translational Medicine, 2015
Introduction: Mild therapeutic hypothermia (MTH) is being used after cardiac arrest for its expected improvement in neurological outcome. Safety of MTH concerning inducibility of malignant arrhythmias has not been satisfactorily demonstrated. This study compares inducibility of ventricular fibrillation (VF) before and after induction of MTH in a whole body swine model and evaluates possible interaction with changing potassium plasma levels. Methods: The extracorporeal cooling was introduced in fully anesthetized swine (n = 6) to provide MTH. Inducibility of VF was studied by programmed ventricular stimulation three times in each animal under the following: during normothermia (NT), after reaching the core temperature of 32°C (HT) and after another 60 minutes of stable hypothermia (HT60). Inducibility of VF, effective refractory period of the ventricles (ERP), QTc interval and potassium plasma levels were measured. Results: Starting at normothermia of 38.7 (IQR 38.2; 39.8)°C, HT was achieved within 54 (39; 59) minutes and the core temperature was further maintained constant. Overall, the inducibility of VF was 100% (18/18 attempts) at NT, 83% (15/18) after reaching HT (P = 0.23) and 39% (7/18) at HT60 (P = 0.0001) using the same protocol. Similarly, ERP prolonged from 140 (130; 150) ms at NT to 206 (190; 220) ms when reaching HT (P < 0.001) and remained 206 (193; 220) ms at HT60. QTc interval was inversely proportional to the core temperature and extended from 376 (362; 395) at NT to 570 (545; 599) ms at HT. Potassium plasma level changed spontaneously: decreased during cooling from 4.1 (3.9; 4.8) to 3.7 (3.4; 4.1) mmol/L at HT (P < 0.01), then began to increase and returned to baseline level at HT60 (4.6 (4.4; 5.0) mmol/L, P = NS). Conclusions: According to our swine model, MTH does not increase the risk of VF induction by ventricular pacing in healthy hearts. Moreover, when combined with normokalemia, MTH exerts an antiarrhythmic effect despite prolonged QTc interval.
Hypothermia and cardiac electrophysiology: a systematic review of clinical and experimental data
Cardiovascular Research, 2018
Moderate therapeutic hypothermia procedures are used in post-cardiac arrest care, while in surgical procedures, lower core temperatures are often utilized to provide cerebral protection. Involuntary reduction of core body temperature takes place in accidental hypothermia and ventricular arrhythmias are recognized as a principal cause for a high mortality rate in these patients. We assessed both clinical and experimental literature through a systematic literature search in the PubMed database, to review the effect of hypothermia on cardiac electrophysiology. From included studies, there is common experimental and clinical evidence that progressive cooling will induce changes in cardiac electrophysiology. The QT interval is prolonged and appears more sensitive to decreases in temperature than the QRS interval. Severe hypothermia is associated with more pronounced changes, some of which are proarrhythmic. This is supported clinically where severe accidental hypothermia is commonly asso...
Circulation Journal, 2009
Background: Therapeutic hypothermia (TH, 30°C) protects the brain from hypoxic injury. However, TH may potentiate the occurrence of lethal ventricular fibrillation (VF), although the mechanism remains unclear. The present study explored the hypothesis that TH enhances wavebreaks during VF and S1 pacing, facilitates pacinginduced spatially discordant alternans (SDA), and increases the vulnerability of pacing-induced VF. Methods and Results: Using an optical mapping system, epicardial activations of VF were studied in 7 Langendorff-perfused isolated rabbit hearts at baseline (37°C), TH (30°C), and rewarming (37°C). Action potential duration (APD)/conduction velocity (CV) restitution and APD alternans (n=6 hearts) were determined by S1 pacing at these 3 stages. During TH, there was a higher percentage of VF duration containing epicardial repetitive activities (spatiotemporal periodicity) (P<0.001). However, TH increased phase singularity number (wavebreaks) during VF (P<0.05) and S1 pacing (P<0.05). TH resulted in earlier onset of APD alternans (P<0.001), which was predominantly SDA (P<0.05), and increased pacing-induced VF episodes (P<0.05). TH also decreased CV, shortened wavelength, and enhanced APD dispersion and the spatial heterogeneity of CV restitution. Conclusions: TH (30°C) increased the vulnerability of pacing-induced VF by (1) facilitating wavebreaks during VF and S1 pacing, and (2) enhancing proarrhythmic electrophysiological parameters, including promoting earlier onset of APD alternans (predominantly SDA) during S1 pacing.
Hypokalemia during the cooling phase of therapeutic hypothermia and its impact on arrhythmogenesis
Resuscitation, 2010
Background: Mild to moderate therapeutic hypothermia (TH) has been shown to improve survival and neurological outcome in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation (VF) as the presenting rhythm. This approach entails the management of physiological variables which fall outside the realm of conventional critical cardiac care. Management of serum potassium fluxes remains pivotal in the avoidance of lethal ventricular arrhythmia. Methods: We retrospectively analyzed potassium variability with TH and performed correlative analysis of QT intervals and the incidence of ventricular arrhythmia. Results: We enrolled 94 sequential patients with OHCA, and serum potassium was followed intensively. The average initial potassium value was 3.9 ± 0.7 mmol l −1 and decreased to a nadir of 3.2 ± 0.7 mmol l −1 at 10 h after initiation of cooling (p < 0.001). Eleven patients developed sustained polymorphic ventricular tachycardia (PVT) with eight of these occurring during the cooling phase. The corrected QT interval prolonged in relation to the development of hypothermia (p < 0.001). Hypokalemia was significantly associated with the development of PVT (p = 0.002), with this arrhythmia being most likely to develop in patients with serum potassium values of less than 2.5 mmol l −1 (p = 0.002). Rebound hyperkalemia did not reach concerning levels (maximum 4.26 ± 0.8 mmol l −1 at 40 h) and was not associated with the occurrence of ventricular arrhythmia. Furthermore, repletion of serum potassium did not correlate with the development of ventricular arrhythmia. Conclusions: Therapeutic hypothermia is associated with a significant decline in serum potassium during cooling. Hypothermic core temperatures do not appear to protect against ventricular arrhythmia in the context of severe hypokalemia and cautious supplementation to maintain potassium at 3.0 mmol l −1 appears to be both safe and effective.
The effect of various stages of hypothermia on the ECG
Cardiovascular Endocrinology, 2016
Serial ECGs showing leads V4, V5, V6 of a hypothermic patient at 36°C (a), 31°C (b), and 29.6°C (c). Notice the increase in amplitude of the Osborn wave as the core body temperature decreases. (a-c) Reproduced from Omar and Abdelmalak [19] with permission and modification from the Cleveland Clinic Foundation, 2011 The Cleveland Clinic Foundation, all rights reserved.
Cardiac arrhythmia induced by hypothermia in a cardiac model in vitro
Journal of Electrocardiology, 2013
Patients that have survived Out-of-Hospital Cardiac Arrest usually develop some degree of neurological problems. A common treatment to mitigate neurological damage is mild therapeutic hypothermia (MTH). However, MTH has adverse effects, including arrhythmia. In order to explore the mechanisms of arrhythmia linked to MTH, we took measures on a temperature controlled experimental model which simulates MTH. These measures consisted of extracellular potential of cardiac culture on a multi-electrode array and we analysed them in terms of nonlinear dynamics. The results showed that cardiac arrhythmia is induced around temperature 35°C (spiral waves at T~35°C against plane waves at other temperatures). A period-doubling phenomenon is also observed around T=35°C, confirmed with the analysis methods. All results showed that 35°C is a critical temperature triggering arrhythmia. This suggests that the re-warming / cooling speed could affect the arrhythmia generation after MTH.
Electrocardiographic changes during therapeutic hypothermia: observational data from a single centre
Acta medica Lituanica, 2020
Background. Therapeutic hypothermia is recommended to reduce the risk of hypoxic brain damage and improve short-term survival after cardiac arrest. It also temporarily affects the cardiac conduction system. The aim of this study was to evaluate electrocardiographic changes during therapeutic hypothermia and their impact on the outcome. Materials and methods. This retrospective analysis involved 26 patients who underwent therapeutic hypothermia after cardiac arrest in Vilnius University Hospital Santaros Klinikos from 2011 to 2015. Results. During cooling, a significant reduction in the heart rate (p = 0.013), shortening of QRS complex duration (p = 0.041), and prolongation of the QTc interval (p < 0.001) were observed. During the cooling period, five patients had subtle Osborn waves, which disappeared after rewarming. The association between electrocardiographic changes during cooling and unfavourable neurological outcome or in-hospital mortality was non-significant. Conclusions....
The therapeutic hypothermia (under 34˝C´32˝C during 12´24h) can help reduce cerebral oxygen demand and improve neurological outcomes after the cardiac arrest. However it can have many adverse effects. The cardiac arrhythmia generation represents an important part among these adverse effects. In order to study the arrhythmia generation after therapeutic hypothermia, an experimental cardiomyocytes model is used. The experiments showed that at 35˝C, the acquired extracellular potential of the culture are characterized by period-doubling phenomenon. Spiral waves are observed as well in this case. The results suggested that the global dynamics of therapeutic hypothermia after cardiac arrest can be represented by a Pitchfork bifurcation, which could explain the different ratio of arrhythmia among the adverse effects after this therapy. A variable speed of cooling / rewarming, especially when passing 35˝C, would help reduce the post-hypothermia arrhythmia.
In Vitro Arrhythmia Generation by Mild Hypothermia-a Pitchfork Bifurcation Type Process
The neurological damage after cardiac arrest (CA) constitutes a big challenge of hospital discharge. The therapeutic hypothermia (34 • C − 32 • C) has shown its benefit to reduce cerebral oxygen demand and improve neurological outcomes after the cardiac arrest. However, it can have many adverse effects, among them the cardiac arrhythmia generation represents an important part (up to 34%, according different clinical studies). Monolayer cardiac culture is prepared with cardiomyocytes from newborn rat directly on the multi-electrodes array, which allows acquiring the extracellular potential of the culture. The temperature range is 37 • C − 30 • C − 37 • C, representing the cooling and rewarming process in the therapeutic hypothermia. Experiments showed that at 35 • C, the acquired signals are characterized by period-doubling phenomenon, compared to signals at other temperatures. Spiral waves, commonly considered as a sign of cardiac arrhythmia, are observed in the reconstructed activation map. With an approach from nonlinear dynamics, phase space reconstruction, it is shown that at 35 • C, the trajectories of these signals formed a spatial bifurcation, even trifurcation. Another transit point is found between 30 • C − 33 • C, which agreed with other clinical studies that induced hypothermia after cardiac arrest should not be below 32 • C. The process of therapeutic hypothermia after cardiac arrest can be represented by a Pitchfork bifurcation type process, which could explain the different ratio of arrhythmia among the adverse effects after this therapy. This nonlinear dynamics suggests that a variable speed of cooling / rewarming, especially when passing 35 • C, would help to decrease the ratio of post-hypothermia arrhythmia and then improve the hospital output.