Discussion
MH is a well-known but potentially lethal disorder that is triggered by volatile anesthetics and depolarizing muscle relaxants. Most of the patients who suffered MH were reported having a genetic defect in the RYR1 gene which was associated with disordered calcium channel function and disease. This adolescent patient we reported was also diagnosed as CCD with RYR1 mutations and occurred MH postoperatively even absence of volatile anesthetics and depolarizing muscle relaxants. Dantrolene is the only clinically available agent for the specific treatment and is established to decrease the mortality of MH to <10%(2). To monitor the effectiveness and safety of intravenous dantrolene during fulminant malignant hyperthermia, the blood samples were collected and plasma concentrations of dantrolene were measured.
As an orphan drug, studies focusing on PK parameters of dantrolene injection were limited worldwide. Besides, a gap existed between the enrolled volunteers/ patients and our patients both in the demographic characteristics and physical status, making the generalizability border of available data vague. There was only one population PK model reported previously, by assuming one single compartment, the parameters were from 27±5 yr old, weighted 70±12 kg healthy adults (4). However, the simulated dantrolene plasma concentrations for our adolescent patient (14-year-old, 48kg) showed poor goodness of fit compared with the measured ones. Also, the parameters using the non-compartmental method from another study were calculated from 3.6±51.3 yr old, weighted 17.4±4.9 kg malignant hyperthermia susceptible children during anesthesia(6).
The pharmacokinetic parameters, i.e., CL only based on renal clearance, for dantrolene administration in this adolescent patient presenting as 0.33 mL/(min*kg) is lower to those reported previously both in healthy adults (0.43±0.043 mL/(min*kg) (4) and in malignant hyperthermia susceptible children (0.64±0.18 mL/(min*kg) (6). Because of the high myoglobin concentrations, an acute kidney injury during malignant hyperthermia attack might occur, followed by a slow elimination of dantrolene. Moreover, a coefficient of variation might lie in the methods for the measurement of dantrolene among different studies.
Owing to the patient’s complicated with massive rhabdomyolysis, early institution of CVVH even PE seems important(7). However, until now, there was no recommendation about how to adjust the dosage of dantrolene during and after CVVH/PE, and to our knowledge. This case is the first one to explore the pharmacodynamics during CVVH/PE. Although CL increased from 0.33 mL/(min*kg) to 0.42 mL/(min*kg) during the PE period and even elevated to 0.51 mL/(min*kg) during CVVH and PE period, considering the safety and cost-effectiveness, together with the accumulation of dantrolene, a loading dose of 2.5 mg/kg dantrolene after PE period seems unnecessary. Further studies are needed to explore either a safe accumulated dose limit for avoiding dantrolene-induced cardiotoxicity or the mechanism of the toxicity.