QT Prolongation During Therapeutic Hypothermia of Sudden Cardiac Arrest Patients Does Not Cause Predisposition to Ventricular Arrhythmias

DOI: 10.19102/icrm.2012.031104

DAVID N. GACHOKA, MD, MUJEEB SHEIKH, MD, YOUSEF AL AHWEL, MD, BLAIR P. GRUBB, MD, FACC, JEFFREY HAMMERSLEY, MD, SADIK KHUDER, PhD and YOUSUF KANJWAL, MD, FACC

University of Toledo Medical Center, Electrophysiology Section, Division of Cardiology, Department of Medicine, University of Toledo, College of Medicine, Toledo, OH

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ABSTRACT. Background: Therapeutic hypothermia (TH) used in patients with sudden cardiac arrest prolongs QT interval and potentially predisposes patients to increased risk of ventricular arrhythmias. Our aim was to investigate whether QT interval prolongation in patients receiving TH is associated with increased risk of ventricular arrhythmias. Methods: In a retrospective study, we identified patients who received TH after cardiac arrest. We measured the QT and corrected QT (QTc) interval before institution of therapeutic hypothermia (group I) and compared it with the QT, QTc interval during cooling (group II) and after rewarming (group III). We also analyzed electronic medical records, electrocardiograms, and continuous telemetry strips for possible sustained ventricular tachycardia, ventricular fibrillation, or torsade de pointes. Results: A total of 55 patients with mean age of 61±15 (34 males) were analyzed. The mean QTc at baseline was 478±43 ms, during hypothermia 528±65 ms (p = 0.0001), and 471±69.5 ms after the cooling protocol was stopped (p = 0.0001). This increase in QTc interval during the cooling phase was similar in both genders. No cases of torsade de pointes or ventricular tachycardia were observed throughout the cooling phase. Conclusion: Prolongation of QT interval during TH does not lead to any significant ventricular arrhythmias. The role of TH in promoting electrical myocardial stability despite prolonging repolarization needs to be studied further.

KEYWORDS. Ventricular arrhythmia, QT interval, electrocardiogram, sudden cardiac death, therapeutic hypothermia.

The authors report no conflicts of interest for the published content.
Manuscript received June 14, 2012, final version accepted July 20, 2012.

Address correspondence to: David N. Gachoka, MD, Resident, Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH 43614. E-mail: gachokad@gmail.com

Introduction

Randomized clinical trials have shown that therapeutic hypothermia (TH) can limit neurologic injury and improve outcomes in patients admitted with out-of-hospital sudden cardiac arrest.^1,2 Nonetheless, this therapy can predispose many to complications. Multiple electrocardiographic abnormalities have been reported during controlled hypothermia, including prolongation of QT interval, and this remains a great concern. Early experimental animal studies have shown that exposure to low body temperatures (<30°C) can lead to electrocardiographic repolarization abnormalities and cause predisposition to ventricular fibrillation.^3,4 This has also been observed in patients who have been exposed to low temperatures as a result of accidental hypothermia.^5,6 In recent large prospective observational registry data of 986 patients undergoing TH, (13%) had sinus bradycardia, (9%) ventricular tachycardia, (9%) had atrial fibrillation, and (7%) ventricular fibrillation.⁷ The study reported these findings as adverse events and did not provide an association with QT prolongation. Since this was an observational study, the cause of such events could not be ascertained. It still remains unclear whether the incidence of lethal arrhythmias in the patient population studied above was due to underlying clinical disorder, electrolytes abnormality or repolarization changes induced by hypothermia. In summary, ventricular tachycardia and fibrillation during TH have been less well reported in literature.⁸ We wanted to investigate whether QT prolongation in patients undergoing TH would predispose them to significant ventricular arrhythmias.

Methods

This was a retrospective electronic medical record review study approved by the Institutional Review Board. The sample consisted of 55 patients (34 men) with a mean age of 61±15 years admitted to the medical and surgical intensive care unit of the University of Toledo Medical Center (UTMC) between August 2008 and October 2011 and treated with endovascular hypothermia. Inclusion and exclusion criteria were based on the UTMC medical and surgery intensive care unit induced hypothermia protocol for an unconscious/intubated patient who had out-of-hospital cardiac arrest. Our protocol is a modified version of the San Francisco General Hospital Hypothermia Treatment after Cardiac Arrest Protocol and included age greater than 18 years, persistent coma as evidenced by no eye opening to pain after resuscitation or Glasgow comma scale of 9, spontaneous systolic blood pressure of at least 90 mmHg, or with fluids and pressors. Exclusion criteria included pregnancy, cardiopulmonary resuscitation (CPR) more than 45 min, persistent malignant dysrhythmias, severe coagulopathy or terminal illness that precludes aggressive resuscitation, other causes of coma, and a prior do not resuscitate (DNR) code status. Clinical and laboratory data were obtained by reviewing the patient’s electronic medical records. Electrocardiographic tracings previously taken using a MAC 5500 electrocardiogram (ECG) machine manufactured by General Electric were obtained from the electronic medical records. The ECG timing in relation to hypothermia was confirmed from intensive care unit flow sheets. All the electrocardiograms were measured with a 25 mm/s paper speed and standardization of 1.0 mV/1.0 cm. The ECGs were taken before commencement of hypothermia, during moderate hypothermia at a temperature of 33°C±0.5, and 24 h after cooling at a temperature above 36.5°C, and were analyzed independently by two cardiologists: a general cardiologist and an electrophysiologist. The QTc value was calculated using the Bazzett formula (QTc = QT/√(R–R). A kappa agreement of 0.83 was calculated using Cohen’s formula. Endovascular catheters manufactured by Innercool^® therapies (San Diego, CA) and a Philips Therapeutics Innercool^® machine (San Diego, CA) were used for hypothermia treatment.

Statistical analysis

Descriptive statistics were used to summarize the data by age, gender, race, and comorbid conditions. A mixed model ANOVA was used to examine QTc changes before, during, and after hypothermia treatment. Fisher’s exact test was used to evaluate rhythm changes during hypothermia treatment. All the statistical analyses were conducted using SAS (SAS Institute, Cary, NC). p-Values ≤0.05 were considered statistically significant. Kappa agreement was calculated using the Cohen’s formula.

Results

We analyzed a total of 357 patients who had been admitted to UTMC Intensive Care Unit with cardiac arrest between August 2008 and November 2011. Of these patients, 55 had been treated with the endovascular hypothermia protocol as outlined in the methods section (Table 1).

Of the 55 patients treated with the hypothermia protocol, 34 patients (61.8%) were male. Forty-seven patients (85.4%) were Caucasian, seven (12.7%) African–Americans, and one (1.8%) was an Asian male. Twenty-eight patients (50.9%) had a history of coronary artery disease, and seven (12.7%) had already undergone a coronary artery bypass graft. Thirty-one patients (56.4%) had an initial rhythm of either ventricular fibrillation or ventricular tachycardia, 16 (29.1%) had pulseless electrical activity (PEA), and eight (14.5%) were found in asystole at the time of resuscitation. Six patients (10%) had been using potentially QT prolonging medications before admission, whereas 12 patients (21.8%) had hyperkalemia on admission. Forty-seven patients (85.5%) had more than two risk factors associated with myocardial infarction. These factors include age, male sex, hypertension, diabetes mellitus, family history, smoking, and high cholesterol.

In both sexes, there were significant QTc changes from a mean of 478±43.5 ms before cooling to 528±64.8 ms during cooling (p = 0.0001). In males, the mean QTc was 476.1±47.3 ms before hypothermia and increased to 517±60.2 ms during hypothermia (p = 0.0008); in females the mean QTc was 481.3±37.5 ms before hypothermia and increased to 546±69.4 ms (p = 0.0001) during hypothermia. However, the slope of the increase in QTc values was similar in both genders (p = 0.394). On rewarming, the overall mean QTc value shortened to 471±69.5 ms for all patients, 465±46.5 for males, and 479±82.9 for females, with p-values of 0.9881, 0.1828 and 0.4862 respectively when compared to pre-TH values (Table 2 and Figure 1).

Discussion

The incidence of out-of-hospital sudden cardiac death in the industrialized countries is between 35.7 and 128.3 cases per 100,000 with an average of 62 cases per year, which translates to about 300,000 people in the USA.⁹ The survival rate of out-of-hospital sudden cardiac arrest is very poor, with less than half of the victims who develop return of spontaneous circulation (ROSC) surviving to leave the hospital alive.^9,10

Currently hypothermia is defined as core body temperature (rectal, esophageal, or tympanic) less than 35°C.^5,6,11 An accepted grading system of hypothermia based on body core temperature establishes three categories: mild (32–35°C), moderate (28–32°C), and severe (<28°C).⁸ After the publication of two landmark trials, the International Liaison Committee on Resuscitation recommended the use of therapeutic hypothermia in out-of-hospital sudden cardiac arrest patients.^1,2 Since then, therapeutic hypothermia has become the standard of care for unconscious patients after ROSC following CPR.¹⁰

Reduction of body temperature induces characteristic physical and electrophysiological changes. These changes include reduced shivering, slurred speech, amnesia, confusion, apathy, joint stiffness, loss of fine motor skills, and ataxia.⁸ Electrophysiological changes including heart rate reduction appear secondary to reduction in the diastolic depolarization rate at the sinoatrial node cells, resulting in slow conduction and manifesting as prolongation of the PR interval, the QRS complex, and the QT interval.¹² During TH, QT prolongs and is inversely correlated with a decrease in temperature, as shown in Table 2 and Figure 1. This is consistent with other previous studies.^4,5,13,14 In a case series of four patients receiving TH, Khan et al¹³ noted a significant negative correlation between QTc interval and body temperature. Although in this study QTc increased to >460 ms in all four patients, none of them developed torsade de pointes or any other type of ventricular arrhythmia. Their findings were similar to our larger cohort of patients, despite significant QTc prolongation of >700 ms identified in one patient in our study (Table 3). Notable is the finding that some of our study patients had increased baseline QTc interval before implementation of cooling. This finding could not be entirely attributed to TH and may have been a consequence of cardiac arrest, genetic predisposition, or medication that was used during resuscitation. What is intriguing about these findings is that if this range of QTc resulted from other causes, including medication used in the treatment of patients with sudden cardiac arrest during TH, it would highly predispose patients to increased risk of ventricular arrhythmia.^15–17 Tortorici et al¹⁸ have explored the idea of altered drug metabolism, elimination, and response during hypothermia to explain their reduced impact on myocardial physiology during TH. This concept may explain the above finding in our study. We identified one patient who had a diagnosis of long QT syndrome by a prior genetic study carried out by our facility. Surprisingly enough, even with this genetic predisposition for arrhythmia, this patient did not develop ventricular arrhythmia during TH. Recently, a prospective study by Storm et al¹⁴ reported an 8.8% (n = 34) incidence of non-sustained ventricular tachycardia during TH that resolved without additional treatment. Similar to our study, the authors did not report any incidence of torsade de pointes despite a significantly prolonged QTc interval of 564.47 ms (Interquantile range (IQR) 512.41–590.00; p = 0.0001; n = 34). In another prior observational registry data review involving 650 patients 462 of whom received TH, documented adverse events of cardiac arrhythmia were ventricular fibrillation in 12 (3%), ventricular tachycardia in eight (2%) and pulseless electrical activity (PEA) in one (0.2%) patient (8). These findings were reported as adverse events of TH, and no correlation was made to the QT interval prolongation effect of TH. Earlier, a prospective study by Oddo et al¹⁰ had also reported the incidence of non-sustained VT and atrial fibrillation as major complications of TH without correlating these findings to QT interval prolongation. Lack of recurrent arrhythmia despite QT prolongation has been suggested to result from the cardiac cell membrane stabilizing property of hypothermia.^19,20 In experimental cerebral ischemia, TH has also been shown to slow the depletion of intracellular adenosine triphosphate, suppress the production of reactive oxygen species, and inhibit the activation of apoptosis, a process that may be similar for cardiomyocytes protection.^21,22 Some authors have even postulated that TH does slow down cellular metabolism, thereby reducing oxygen demand and increasing tolerance to the accumulation of metabolic waste which is cardioprotective.^23–25 This benefit is however lost at lower temperatures (<30°C), particularly if also associated with electrolyte imbalance. Arrhythmias starting as atrial fibrillation at these low temperatures are like a warning sign of impending development of difficult to treat ventricular arrhythmias and should prompt immediate patient rewarming.²⁵ The protection against ventricular arrhythmia offered by TH despite QT prolongation is therefore very intriguing and needs to be studied further.

Limitations

Several limitations were identified in our study. First, the study sample size is small and retrospective. Second, short episodes of torsade de pointes may have been missed, despite continuous telemetry during the entire hospital stay. Finally, a small increase in QTc interval can be caused by other confounding variables, including electrolyte imbalances, antiarrhythmic therapy routinely used during cardiac resuscitation, or genetic predisposition, which we could not entirely rule out.

Conclusion

Prolongation of the QT interval during TH does not lead to significant ventricular arrhythmias.

References

1. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557–563. [CrossRef] [PubMed]
2. Nolan JP, Morley PT, Hoek TL, Hickey RW. Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation. Resuscitation 2003; 57:231–235. [PubMed]
3. Vassallo SU, Delaney KA, Hoffman RS, Slater W, Goldfrank LR. A prospective evaluation of the electrocardiographic manifestations of hypothermia. Acad Emerg Med 1999; 6:1121–1126. [CrossRef] [PubMed]
4. Wynne NA, Fuller JA, Szekely P. Electrocardiographic changes in hypothermia. Br Heart J 1960; 22:642–646. [PubMed]
5. de Souza D, Riera AR, Bombig MT, Francisco YA, Brollo L, Filho BL, et al. Electrocardiographic changes by accidental hypothermia in an urban and a tropical region. J Electrocardiol 2007; 40:47–52. [CrossRef] [PubMed]
6. Mattu A, Brady WJ, Perron AD. Electrocardiographic manifestations of hypothermia. Am J Emerg Med 2002; 20:314–326. [CrossRef] [PubMed]
7. Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009; 53:926–934. [CrossRef] [PubMed]
8. Aslam AF, Aslam AK, Vasavada BC, Khan IA. Hypothermia: evaluation, electrocardiographic manifestations, and management. Am J Med 2006; 119:297–301. [CrossRef] [PubMed]
9. Flint AC, Hemphill JC, Bonovich DC. Therapeutic hypothermia after cardiac arrest: performance characteristics and safety of surface cooling with or without endovascular cooling. Neurocrit Care 2007; 7:109–118. [CrossRef] [PubMed]
10. Oddo M, Schaller MD, Feihl F, Ribordy V, Liaudet L. From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 2006; 34:1865–1873. [CrossRef] [PubMed]
11. Graham CA, McNaughton GW, Wyatt JP. The electrocardiogram in hypothermia. Wilderness Environ Med 2001; 12:232–235. [PubMed]
12. Emslie-Smith D, Sladden GE, Stirling GR. The significance of changes in the electrocardiogram in hypothermia. Br Heart J 1959; 21:343–351. [PubMed]
13. Khan JN, Prasad N, Glancy JM. QTc prolongation during therapeutic hypothermia: are we giving it the attention it deserves? Europace 2010; 12:266–270. [CrossRef] [PubMed]
14. Storm C, Hasper D, Nee J, Joerres A, Schefold JC, Kaufmann J, et al. Severe QTc prolongation under mild hypothermia treatment and incidence of arrhythmias after cardiac arrest—a prospective study in 34 survivors with continuous Holter ECG. Resuscitation 2011; 82:859–862. [CrossRef] [PubMed]
15. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010; 70:16–23. Epub 2010/07/21. [CrossRef] [PubMed]
16. Elming H, Sonne J, Lublin HK. The importance of the QT interval: a review of the literature. Acta Psychiatr Scand 2003; 107:96–101. [CrossRef] [PubMed]
17. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003; 89:1363–72. [PubMed]
18. Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med 2007; 35:2196–2204. [CrossRef] [PubMed]
19. Rhee BJ, Zhang Y, Boddicker KA, Davies LR, Kerber RE. Effect of hypothermia on transthoracic defibrillation in a swine model. Resuscitation 2005; 65:79–85. [CrossRef] [PubMed]
20. Boddicker KA, Zhang Y, Zimmerman MB, Davies LR, Kerber RE. Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation 2005; 111:3195–201. [CrossRef] [PubMed]
21. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 2008; 88:581–609. [CrossRef] [PubMed]
22. Otake H, Shite J, Paredes OL, Shinke T, Yoshikawa R, Tanino Y, et al. Catheter-based transcoronary myocardial hypothermia attenuates arrhythmia and myocardial necrosis in pigs with acute myocardial infarction. J Am Coll Cardiol 2007; 49:250–260. [CrossRef] [PubMed]
23. Ning XH, Chen SH, Xu CS, Li L, Yao LY, Qian K, et al. Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis. J Appl Physiol 2002; 92:2200–2207. [CrossRef] [PubMed]
24. Hale SL, Kloner RA. Mild hypothermia as a cardioprotective approach for acute myocardial infarction: laboratory to clinical application. J Cardiovasc Pharmacol Ther 2011; 16:131–139. [CrossRef] [PubMed]
25. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 2009; 37(Suppl):S186–202. [CrossRef] [PubMed]