Anesth Analg 2004;99:435-437
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000130395.93107.15
ANESTHETIC PHARMACOLOGY
Volatile Anesthetics and Succinylcholine in Cardiac Ryanodine Receptor Defects
Heikki Swan, MD*,
Päivi J. Laitinen, MSc , and
Lauri Toivonen, MD*
Departments of *Cardiology and
Medicine, Helsinki University Central Hospital, Helsinki, Finland
Address correspondence and reprint requests to Heikki Swan, MD, Helsinki University Hospital, Department of Cardiology, PL 340, Haartmaninkatu 4, FIN-00029 HUS, Helsinki, Finland. Address e-mail to heikki.swan{at}helsinki.fi
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Abstract
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Familial polymorphic (catecholaminergic) ventricular tachycardia is an arrhythmogenic cardiac disorder caused by mutations of the myocardial isoform of the ryanodine receptor gene (RyR2). Mutations of the corresponding gene in the skeletal muscle (RyR1) predispose its carriers to malignant hyperthermia upon use of volatile anesthetics or succinylcholine, which further deteriorate the inherited intracellular calcium release disorder. We report a series of patients with cardiac RyR defects who underwent general anesthesia without complications. Succinylcholine and volatile anesthetics did not have a clinically significant effect on RyR2 defects.
IMPLICATIONS: We report a series of patients with cardiac ryanodine receptor (RyR) defects who had general anesthesia. Succinylcholine and volatile anesthetics do not seem to have a clinically significant effect on cardiac RyR2. This suggests an isoform-specific effect of these compounds on the RyR1 calcium channel, the mutations of which are associated with malignant hyperthermia.
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Introduction
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Mutations of ryanodine receptor (RyR) genes predispose patients to malignant hyperthermia (MH), central core disease, and familial polymorphic or catecholaminergic ventricular tachycardia. MH is a rare but life-threatening complication of general anesthesia that occurs upon the administration of volatile anesthetics or depolarizing muscle relaxants (1). Predisposition to MH is of heterogeneous origin, but in a considerable proportion of cases, it results from mutations in the skeletal muscle calcium-release channel gene known as RyR1 (2). RyRs are intracellular calcium channels that regulate the release of Ca2+ from the endoplasmic reticulum in skeletal muscle and other cells. Different isoforms of RyR are expressed in different tissues; RyR1 is the skeletal muscle isoform, and mutations in this gene also cause central core disease (3).
The cardiac isoform of RyR, RyR2, is responsible for the coupling of cardiomyocytes’ electrical excitation and their mechanical contraction (4). Mutations in RyR2 cause alterations in intracellular calcium release from the sarcoplasmic reticulum (SR) and enhanced ventricular depolarization. The consequent disease, familial polymorphic or catecholaminergic ventricular tachycardia, is clinically manifested as successive ventricular premature complexes and sudden death upon increased sympathetic tone, e.g., during physical exercise or emotional stress (5–7). This disease is often highly malignant: the mortality increases up to 30% by the age of 30 yr.
In MH, an increase in myoplasmic free [Ca2+] follows the administration of anesthetics, but the exact mechanism of how those either enhance the activation of or prevent the inactivation of Ca2+ release from the SR is unknown. Because the very individuals who carry the RyR1 mutation have a predisposition to MH, it is reasonable to postulate that succinylcholine and volatile anesthetics interfere with the intracellular RyR-mediated intracellular calcium release. Indeed, halothane increased the Ca2+ release from cardiac SR preparations in several experimental studies (8), but no reports on in vivo effects in RyR2 mutation carriers have been reported, because these mutations have been discovered recently.
Volatile anesthetics depress the L-type calcium currents in human atrial myocytes (9) and have a negative inotropic effect on the heart (10). Because of close structural similarities of skeletal and cardiac RyR isoforms, volatile anesthetics could also affect the cardiac RyR function and be potentially proarrhythmic to RyR2 carriers, just as they predispose RyR1 carriers to MH.
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Methods
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We reviewed the case histories of 30 patients who had familial polymorphic ventricular tachycardia. They were members of three families that had been thoroughly examined in genetic linkage and mutation identification studies during the years 1993 to 2002 (5,6). Altogether, 30 patients manifested ventricular arrhythmias during the exercise stress test. Each of them was a carrier of RYR2 gene mutations (P2328S, V4653F, and Q4201R). Nine had experienced one or more episodes of syncopal spell. In addition, the history of 16 other family members who had died suddenly before the age of 35 yr was obtained from relatives and from medical and forensic pathology records.
The study was approved by the ethical review board. All patients gave informed consent for the review of their medical history. Medical records were obtained from the treating hospitals. Data were collected (by HS) on the administered medications and the observed heart rhythm disturbances and other complications during the general anesthesia and subsequent recovery phase. In addition to electrocardiogram, arterial blood pressure, and heart rate monitoring, CO2 was monitored in 8 of 13 operated patients.
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Results
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Thirteen patients (six men and seven women) had undergone general anesthesia at least once, and four had done so twice or more. The mean age of the patients at the time of general anesthesia was 26 ± 18 yr (range, 3–52 yr). Because diagnosis of most patients was first made recently because of the systematic family screening, only one of the patients was receiving ß-antiadrenergic medication at the time of general anesthesia. None of the family members who had died suddenly had undergone general anesthesia preceding their death.
A summary of the anesthetics used is presented in Table 1. Succinylcholine had been administered seven times to five patients and volatile anesthetics to eight patients. None developed hyperthermia or hypercapnia. Ventricular arrhythmias—i.e., ventricular premature complexes and bigeminy, arrhythmias typical to RyR2 patients—were reported in only one patient, who received enflurane. Her heart rate was temporarily 120 bpm at the time of arrhythmias. However, the anesthesia and operation were performed without complications. The combination of succinylcholine and a volatile anesthetic had been used successfully in four patients.
In addition, cardiac catheterization, which was performed in 12 patients under local anesthesia with lidocaine, and included an electrophysiologic study during infusion of epinephrine 0.05 µg/kg of body weight per minute, was uneventful in all patients. None of the 16 cases of sudden death was related to anesthesia or surgical procedures in these patients.
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Discussion
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This assessment indicated that general anesthesia has been a safe procedure for familial polymorphic or catecholaminergic ventricular tachycardia patients. Although succinylcholine and volatile anesthetics can have life-threatening consequences on skeletal muscle calcium metabolism when RyR function is impaired because of an underlying gene defect in RyR1, these drugs do not seem to have a clinically significant effect on cardiac intracellular calcium release or uptake, even if they are administered to patients carrying cardiac RyR2 disorder. This suggests a gene isoform-specific effect of these anesthetics on RyR1. This difference in calcium-release mechanisms between skeletal and cardiac muscle SR is further supported by the fact that dantrolene, which inhibits calcium release from skeletal muscle SR, does not have an influence on cardiomyocyte SR functions in in vitro studies (11). However, it is not likely that the absence of deleterious effects on RyR2 would be mutation specific, because in both RyR1 and RyR2 genes, the reported disease-causing mutations seem to cluster into the same regions of the genes (6,7).
Prophylactic ß-antiadrenergic medication is now being prescribed to all symptomatic RyR2 patients. This therapy seems to have a favorable effect in terms of diminishing occurrence of symptoms and mortality, although the medication does not necessarily completely abolish the appearance of ventricular premature complexes. Although familial polymorphic ventricular tachycardia patients are prone to cardiac events upon mental stress, the surgical procedures reviewed in this study were not associated with malignant arrhythmias or cardiac arrests, even though most of the patients were without ß-antiadrenergic medication.
We conclude that the clinical experience of patients with familial polymorphic ventricular tachycardia suggests that volatile anesthetics and succinylcholine have different effects on intracellular calcium release in skeletal and cardiac RyRs, suggesting a gene isoform-specific effect of these drugs.
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References
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- Ørding H. Investigation of malignant hyperthermia susceptibility in Denmark. Dan Med Bull 1996; 43: 111–25.[Web of Science][Medline]
- Gillard EF, Otsu K, Fujii J, et al. A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 1991; 11: 751–5.[Web of Science][Medline]
- McCarthy TV, Quane KA, Lynch PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat 2000; 15: 410–7.[Web of Science][Medline]
- Lewartowski B. Excitation-contraction coupling in cardiac muscle revisited. J Physiol Pharmacol 2000; 51: 371–86.[Web of Science][Medline]
- Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999; 34: 2035–42.[Abstract/Free Full Text]
- Laitinen P, Brown KM, Piippo K, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 2001; 103: 485–90.[Abstract/Free Full Text]
- Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001; 103: 196–201.[Abstract/Free Full Text]
- Zucchi R, Ronca-Testoni S. The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacol Rev 1997; 49: 1–51.[Abstract/Free Full Text]
- Hüneke R, Jüngling E, Skasa M, et al. Effects of the anesthetic gases xenon, halothane, and isoflurane on calcium and potassium currents in human atrial cardiomyocytes. Anesthesiology 2001; 95: 999–1006.[Web of Science][Medline]
- Hanouz JL, Massetti M, Guesne G, et al. In vitro effects of desflurane, sevoflurane, isoflurane, and halothane in isolated human atria. Anesthesiology 2000; 92: 116–24.[Web of Science][Medline]
- Fratea S, Langeron O, Lecarpentier Y, Coriat P. In vitro effects of dantrolene on rat myocardium. Anesthesiology 1997; 86: 205–15.[Web of Science][Medline]
Accepted for publication February 20, 2004.
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Abstract
Introduction
