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.