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.