The Safety of Dantrolene in a Patient with a Severe Cardiomyopathy Requiring a Heart Transplant

To the Editor: We studied the cardiovascular and respiratory effects of dantrolene in a 14-yr-old, 65-kg male adolescent with central core disease and a severely dilated cardiomyopathy necessitating cardiac transplantation. Central core disease is a skeletal myopathy with its gene closely linked to the malignant hyperthermia (MH) gene on chromosome 19 [1,2]. Because patients with central core disease commonly test positive for MH susceptibility, dantrolene and a non-MH-triggering anesthetic were used. However, there are significant concerns about the safe use of dantrolene in patients with preexisting skeletal muscle weakness and poor cardiac contractility due to the fact that it can cause mild to moderate skeletal muscle weakness [3] and a negative inotropic action in vitro [4,5]. Although hemodynamic depression is not normally evident in vivo when cardiovascular function is normal and compensatory hemodynamic reflexes are active [6], there have been no reports of dantrolene's cardiovascular effects either prior to or during large-dose fentanyl anesthesia in patients with greatly reduced cardiac contractility secondary to severe cardiomyopathy. In our patient, dantrolene (2.4 mg/kg) was infused over 1 h just prior to the induction of anesthesia. During the infusion, while breathing room air, the patient felt progressively weaker, complained of difficulty breathing, and became slightly lethargic but maintained SpO2 98%-100%. At the completion of the infusion, the forced vital capacity decreased from 1.9 to 1.0 L, the PaO2 declined from 104 to 73 mm Hg, and the PaCO2 remained unchanged. Heart rate, arterial blood pressure; pulmonary artery systolic, diastolic, and wedge pressure; and cardiac output all remained unchanged or slightly increased after this dantrolene infusion. Similarly, induction of anesthesia with 124 micro g/kg of fentanyl and vecuronium was hemodynamically well tolerated, as was a second dose of dantrolene (1.2 mg/kg) over the 15 min just prior to institution of bypass and a third dose (2.4 mg/kg) 8 h after successful completion of the orthotopic heart transplant (Figure 1). No intra- or postoperative triggering of MH occurred.Figure 1: Relationship between systolic blood pressure and dantrolene plasma concentrations. The first and third doses of dantrolene were infused over 1 h, and the second dose was infused over 15 min. After the completion of the first dantrolene infusion at 1 PM, fentanyl 124 micro g/kg was injected over 10 min.As shown in Figure 1, the first and second dantrolene infusions produced plasma levels in the range of 4-5 micro g/mL, which exceeded the 2.5-3.0 micro g/mL concentrations of dantrolene that have been determined to prevent MH crises and also correlate with maximum depression of the skeletal muscle twitch response [7]. The third infusion increased plasma concentrations to more than 11 micro g/mL. Hence, this case provides strong evidence that high therapeutic blood concentrations of dantrolene do not produce hemodynamic instability in patients with a severe cardiomyopathy either before or after the blunting of cardiovascular reflexes with the administration of large-dose fentanyl and that supratherapeutic blood levels of dantrolene are well tolerated in a newly transplanted heart. Douglas E. Koehntop, MD David S. Beebe, MD Kumar G. Belani, MD Department of Anesthesiology; University of Minnesota Hospital and Clinic; Minneapolis, Mn 55455