We thank Dr. Rusyniak et al. for their critical comments on our study about the induction of malignant hyperthermia (MH) in susceptible swine by 3,4-methylenedioxymethamphetamine (MDMA) (“ecstasy”).1However, some of the criticisms of our study must be relativized.
First, to our knowledge, this is the first controlled study investigating the association between MDMA-induced hypermetabolic syndrome and MH. MH crisis is an acute clinical complication; therefore, the experimental setting for this study was following the clinical situation, and diagnosis of MH in our experiment could only be based on clinical parameters. The definition of the clinical cutoff parameters for MH crisis in our study was following the recommendations for clinical diagnosis of human MH crisis and previous animal studies. Increasing doses of MDMA induced a hypermetabolic state in MH-susceptible (MHS) as well as MH-normal (MHN) swine. However, the changes in the MHN swine after receiving a higher dose of MDMA (12 mg/kg) were moderate compared with the changes in MHS swine after 8 mg/kg MDMA, and all MHS swine fulfilled the defined criteria for MH.
The only known differentiation between MHS and MHN swine is the presence of the Arg615-Cys point mutation on chromosome 6 leading to a functional impairment of the skeletal muscle ryanodine receptor (RyR1). We share the opinion of Dr. Rusyniak et al. that MDMA-induced hypermetabolism is not solely mediated through RyR1 complexes. However, the different reactions of MHS and MHN swine in our study are an indirect hint for activation of RyR1 after in vivo MDMA administration. The current study was aimed to prove whether MDMA is capable of inducing an MH syndrome, not to clarify the exact pathomechanism, i.e. , a possible mediation via the RyR1. Whether the RyR1 activation could be attributed to a direct effect of MDMA at the skeletal muscle or to a secondary effect of central stimulation, hyperthermia, or an MDMA-metabolite must therefore be clarified in future studies.
The definition of an MH “trigger” is not as clear as mentioned in the letter of Dr. Rusyniak et al. From a clinical point of view, an MH trigger is a substance that is able to induce an MH crisis in a genetically determined individual in a clinically relevant dosage without any relevant cofactors. Following this definition, MDMA triggered MH in MHS swine in our study. We agree that cumulative intravenous administration of MDMA is not the common method of MDMA abuse. However, this course of action and measurement of corresponding MDMA plasma concentrations allowed us to determine a dose response and to underline the clinical relevance.
The therapeutic regimen of MDMA-induced MH in our study was based on the standard clinical therapy of MH. Standardized therapy of MH in the MHS swine performed with dantrolene, sodium bicarbonate, and hyperventilation partly removed the clinical signs of MH immediately. The body temperature of the swine remained unchanged 15 min after therapy induction. We agree that the short observation time without the possibility to detect changes in body temperature was a weakness in our study design.
Whether administration of dantrolene is useful in all patients with MDMA-induced hyperthermia could not be answered by our study. However, in a life-threatening clinical situation, “simple hyperthermia” could not be distinguished from “true malignant hyperthermia.” Therefore, in our opinion, dantrolene might be a lifesaving therapy option, and consequently, administration of dantrolene should be considered with respect to patient safety in cases of MDMA-mediated hyperthermic syndrome.
* University Hospital Hamburg-Eppendorf, Hamburg, Germany. email@example.com