Case Presentation
A 14-year-old boy with a 7-year history of progressively worsening
cervical lordosis deformity was hospitalized and planned for elective
cervical spine surgery. His muscle biopsy was performed and the
pathological diagnosis was central core disease (CCD). Subsequent
genetic testing revealed mutations in RYR1(NM 001042723)
c.11120A>G and c.12227C>T (figure 1).
On presentation, this 42-kg-weight patient was afebrile with normal
vital signs, while his laboratory tests, ECG, and Chest X-ray were
within normal limits. He later underwent posterior cervical C3-T3 soft
tissue release, pedical screw internal fixation and fusion, and
excessive lordosis deformity. Owing to his mutations encoding for
abnormal RYR1 receptors, total intravenous anesthesia with propofol and
remifentanil was used throughout the operation. Neither volatile
anesthetic agents nor succinylcholine was administered during the
uneventful surgical procedure. The intraoperative plasma CK, CK-MB, and
myoglobin were all within the normal range. The patient was transferred
to the intensive care unit (ICU) after surgery for further observation.
The patient arrived in ICU and routine monitors were applied, showing
normal vital signs and body temperature: BP 110/70mmHg, HR
50~60bpm, SpO2 100%,
axillary temperature
35.0℃.
Analgesia-sedation during the mechanical ventilation was maintained with
propofol (1~1.5 mg/kg) and butorphanol
(0.2~0.25 mg/h). After 90 minutes of mechanical
ventilation, the patient developed a sudden onset sinus tachycardia of
140~160 bpm while his arterial blood pressure increased
to 120~130/70~80 mmHg. The patient began
to appear with masseter muscle rigidity (MMR) and generalized muscle
rigidity intermittently, accompanied by an increase in axillary
temperature from 36.0℃ to 39.4℃.
Arterial blood gases showed mixed metabolic and respiratory acidosis
with hyperkalemia (pH 7.236, PaCO2 52.3mmHg,
K+ 4.38mmHg, Lac 5.7mmol/L). A clinical diagnosis of
fulminant MH was made according to the clinical grading scale (CGS) (3).
The MH crisis treatment workflow was started immediately and dantrolene
sodium (NDC 42023-123-06, Par Pharmaceutical Companies, Inc., USA) was
administered at the initial dose of 2.5 mg/kg which was followed by a
maintenance dose of 0.25 mg/kg/h (Supplementary Table 1). The inspired
oxygen fraction increased to 100% immediately, meanwhile increased
respiratory rate and tidal volume to maximize ventilation and lower the
PaCO2. Physical cooling was conducted including an ice
cap as well as a reducing the temperature carpet. Then
PaCO2 declined to 28.7 mmHg and the axillary temperature
dropped to 38.1℃. However, the status of the patient deteriorated over
the next 24 hours, MMR could still be observed intermittently, with
creatine phosphokinase (CK), serum myoglobin (Mb), urine myoglobin
(UMb), and lactate dehydrogenase (LDH) increasing progressively. Maximal
plasma concentrations of CK and Mb were 3303 IU/L and 579 ng/mL,
respectively. Accordingly, the diagnosis of rhabdomyolysis syndrome was
ascertained for the patient. Continuous veno-venous hemofiltration
(CVVH) was then initiated, 17 hours after the start of the event.
Analgesia-sedation treatments, bedside CVVH (AQUARIUS, Nikkiso Europe,
Langenhagen, Germany), the hemofilter (HF1200) was a 1.25
m2 glycerin-free polysulfone-membrane Polyflux
(Medivators, Minnesota, USA). The replacement solution was a
bicarbonate-based solution containing 1.91 mg/ml glucose and 0.02 mg/ml
magnesium, while the predilution and postdilution rates were both 1000
ml/h. Blood flow and fluid loss rates were 180 mL/min and 200 ml/h,
respectively. The rectification of acid intoxication, urine
alkalization, as well as several supportive treatments was performed at
the same time and dantrolene sodium was discontinued. After administered
CVVH for nearly 36 hours, the values of CK, Mb, and LDH decrease slowly,
while his muscle tremors still occurred intermittently throughout those
continuous treatments mentioned above. Due to the poor effect during
CRRT, his rhabdomyolysis syndrome was treated with plasma exchange (PE).
The plasma filter was a 0.6 m2 polyurethane-membrane
Polyflux (Fresenius, Bad Homburg, Germany). Plasma rate and total
volumes were 1000 mL/min and 3000ml, respectively.
Artery blood samples were collected before and after PE and followed by
the blood samples collected after dantrolene administration for up to
12h (at minutes 0, 15, 30, 60, 120, 240, 360 for the first bolus as 2.5
mg/kg dantrolene, and at minutes 0, 30, 120, 240, 360 for the second
bolus as 1 mg/ kg dantrolene). Plasma was separated by centrifuge and
stored at -80℃ until assayed.
The plasma concentrations of dantrolene were measured simultaneously by
using a validated high-performance liquid chromatography (Shimadzu
LC-30A; Shimadzu, JP) coupled with tandem mass spectrometry (ABSciex
4000+ triple quadrupole system, ABSciex Corp., USA)
assay method. Data were acquired and processed by Analyst 1.6.2 software
(ABSciex Corp.). A 50μL plasma sample was extracted by protein
precipitation.
A reported population PK model, with the parameters from healthy adults,
was applied for predicting dantrolene plasma concentrations (4). For all
calculations, NONMEM software (version 7.3.0, ICON Development
Solutions) was used. However, the predictions matched with the measured
values only nearby the lower limit, suggesting new pharmacokinetic
parameters for dantrolene should be developed, which might be fit for
adolescents with PE/ CVVH (Figure 2). Thus, PK analysis was performed by
using a nonlinear mixed-effects model. Data were analyzed using a
first-order conditional estimation method (5). One- and two-compartment
models with first-order absorption and linear elimination were
investigated to determine the optimal structural model. The clearance
(CL) and volume of distribution (Vd) of dantrolene were characterized
and estimated. Because we only have one patient, the inter-individual
variability was fixed as 0 and no covariate was retained in the final
model.
A one-compartment model with first-order absorption and elimination was
sufficient to characterize dantrolene pharmacokinetics. The parameter
estimate for dantrolene CL was 0.43 mL/(min*kg) and for Vd was 0.61
L/kg, and Table 1, Figure 3 shows the details. The CL was significantly
affected by CVVH and PE.