Recurrent malignant hyperthermia after scoliosis correction surgery
Corresponding authors: Man Huang, Email:huangman@zju.edu.cn
Received: 2023-06-10 Accepted: 2023-10-18
Cite this article
Junfeng Su, Man Huang.
Malignant hyperthermia (MH) is a genetic disorder of skeletal muscle cells that affects muscle cytoplasmic calcium homeostasis, with high mortality and low morbidity. Generally, it presents with non-specific signs of a hypermetabolic response, including high fever, tachycardia, and elevated end-tidal carbon dioxide (ETCO2). The successful treatment lies in the timely recognition and early use of dantrolene.[1] As an inhibitor of Ca2+ release through ryanodine receptor (RYR) channels, the skeletal muscle relaxant dantrolene has proven to be both a valuable experimental probe of intracellular Ca2+ signaling and a lifesaving treatment for MH.[2] Dominant mutations in the skeletal muscle RYR1 gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD).[3] CCD is an inherited neuromuscular disorder characterized by central cores on muscle biopsy and clinical features of a congenital myopathy. It typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness, especially in the hip girdle.[4] MH phenotypes may be affected significantly by mutation type.[5] Recurrence occurred in 20% of patients surviving a clinical MH episode in the North American Malignant Hyperthermia Registry, and it was not associated with the initial dose of dantrolene.[6]
CASE
A 15-year-old boy (weight 43 kg, body mass index [BMI] 25.95 kg/m2) underwent posterior spinal osteotomy, correction, and fusion fixation for congenital scoliosis. He was otherwise healthy and took no medication routinely. He underwent safe anesthesia for surgical extension of the right Achilles tendon last year. There was no family history of anesthesia side effects, and his father had undergone a safe anesthesia process for posterior spinal osteotomy, correction, and fusion fixation for congenital scoliosis. His preoperative blood pressure was 107/70 mmHg (1 mmHg=0.133 kPa), heart rate was 113 beats/min (sinus rhythm), and body temperature was 36.6 °C. A rapid sequence induction was performed with 10 mg lidocaine, 2 mg midazolam, 30 μg sufentanil, 12 mg etomidate, and 40 mg rocuronium.
Three hours after the beginning of operation, an unexplained and unexpected increase in ETCO2 (maximum 61 mmHg), heart rate (maximum 102 beats/min), and temperature (maximum 39.2 ℃) (supplementary Figure 1) alerted the anesthesiologist to the possibility of MH onset because conventional medication therapy proved ineffective. The patient only showed shivering; neither hemodynamic instability nor severe acidosis occurred on arterial blood gas analysis. Since MH was suspected, the anesthesiologist changed the sodium lime and the anesthesia apparatus, the blood samples were examined for complete blood count, cardiac enzyme panel, coagulation spectrum, electrolyte analysis, and blood gas analysis, and dantrolene was obtained from outside the hospital when the operation had been over for 25 min. Dantrolene 40 mg was given for intravenous injection. After 20 min, the ETCO2 decreased to 38 mmHg, his body temperature dropped to 38.3 ℃, his muscles were relaxed, his vital signs returned to normal, and he was transferred to the intensive care unit (ICU) for further treatment. The patient’s MH clinical grading score (CGS), which indicates a suspected clinical MH event, was 63 (> 50). The likelihood of MH is almost certain.[7]
After ICU admission, his shivering recurred, accompanied by a fever, an increased level of ETCO2, increased creatine kinase (CK), prolonged prothrombin time (PT), increased heart rate and blood pressure, and decreased oxygenation. The dantrolene dose was increased from 40 mg every 6 h to 60 mg every 6 h to improve symptoms during the administration of propofol and midazolam for sedation and sufentanil for analgesia. Cough difficulty and mild limb muscle weakness (upper limb muscle strength level 4, lower limb muscle strength level 3) occurred after the tracheal intubation was removed on the 8th day after the operation.
Until the 10th day, the shivering was relieved, and the dose of dantrolene was reduced to 40 mg every 6 h. On the 11th day after the procedure, his spirit and oxygen improved, without trembling, and the dantrolene injection was stopped. Thus far, the total dantrolene dosage was 2,440 mg (Table 1).
Table 1. Patient's condition after operation
Date (after operation) | Shivering frequency | Tmax (℃) | ETCO2max (mmHg) | CKmax | Sedation | Respiratory support | Dantrolene usage | Dantrolene dose (mg) |
---|---|---|---|---|---|---|---|---|
D0 (ICU admission) | No shivering | 37.1 | 45 | 1,591 | Propofol+remifentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 100%, PEEP: 5 cmH2O, SpO2 ≥94% | 40 mg iv. Q6h (1 iv) | 40 |
D1 | 5 times, continued for 1 min per time | 37.7 | 43 | 6,450 | Propofol+remifentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 40%, PEEP: 5 cmH2O, SpO2 ≥94% | 40 mg iv. Q6h (4 iv) & 40 mg bolus | 200 |
D2 | 5 times, continued for 1 min, 1 min, 2 min, 1 min, and 10 min, respectively | 39.5 | 54 | 8,310 | Midazolam+remifentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 40%, PEEP: 5 cmH2O, SpO2 ≥94% | 40 mg iv. Q6h (4 iv) | 160 |
D3 | 2 times, continued for 10 min, and 30 min, respectively | 38.5 | 56 | 8,060 | Midazolam+remifentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94% | 40 mg bolus (2 iv) & 40 mg iv. Q6h (3 iv) | 200 |
D4 | 4 times, continued for 30 min, 30 min, 30 min, and 50 min, respectively | 38.0 | 58 | 4,210 | Propofol+midazolam+remifentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94% | 60 mg iv. Q6h (4 iv) & 60 mg bolus | 300 |
D5 | 1 time, continued for 15 min | 38.8 | 55 | 3,500 | Propofol+midazolam+sufentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94% | 60 mg iv. Q6h (4 iv) | 240 |
D6 | 4 times, continued for 5 min, 6 min, 5 min, and 5 min, respectively | 38.6 | 51 | 2,700 | Propofol+midazolam+sufentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94% | 60 mg iv. Q6h (3 iv) & iv.vp. 10 mg/h for 3 h | 210 |
D7 | 5 times, continued for 7 min, 20 min, 10 min, 10 min, and 12 min respectively | 38.9 | 56 | 2,700 | Propofol+midazolam+sufentanil RASS score: -4 to -2 | Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94% | iv.vp. 10 mg/h for 7 h & 60 mg iv. Q6h (4 iv) | 310 |
D8 | 3 times, continued for 12 min, 6 min, and 8 min, respectively | 38.0 | 53 | 12,330 | Desist from sedation | Removal of endotracheal intubation & high-flow oxygen therapy (flow rate 35 L/min, oxygen concentration 40%, SpO2 ≥94%) | 60 mg iv. Q6h (4 iv) | 240 |
D9 | Persistent weak shivering for 120 min | 39.3 | - | 12,800 | - | High-flow oxygen therapy (flow rate 35L/min, oxygen concentration 50%-100%, SpO2 ≥94%) | 60 mg iv. Q6h (4 iv) | 240 |
D10 | Shivering for 10 min, persistent weak shivering for hours | 38.9 | - | 8,020 | - | Sat beside the bed (for rehabilitation exercise) for 30 min in the late morning with nasal catheter oxygen inhalation 5 L /min, SpO2 91%-95%, and continued to tremble in the afternoon, then high-flow oxygen therapy (flow rate 25 L/min, oxygen concentration 50%-55%, SpO2 ≥94%) | 60 mg iv. Q6h (2 iv) & 40 mg iv. Q6h (2 iv) | 200 |
D11 | No shivering | 37.7 | - | 3,700 | - | Nasal catheter oxygen inhalation 5 L /min, SPO2 ≥94% | 60 mg bolus & 40 mg bolus then stop dosing | 100 |
D12 | No shivering | 37.3 | - | - | - | Nasal catheter oxygen inhalation 5 L/min, SpO2 ≥94% | - | 0 |
D13 | No shivering | 36.9 | - | - | - | Nasal catheter oxygen inhalation 5 L/min, SpO2 ≥94% | - | 0 |
D14 (left ICU) | Weak shivering (head and limbs) improved automatically in a few minutes | 37.4 | - | - | - | Nasal catheter oxygen inhalation 5 L/min, SpO2 ≥94% Transfered to orthopedic ward | - | 0 |
D15-D35 | No shivering | <37.5 | - | D15 (920) D19 (645) | Nasal catheter oxygen inhalation 3 L/min, SpO2 ≥94% (D15); no oxygen inhalation (D16-D35) | - | 0 |
ICU: intensive care unit; ETCO2: end-tidal carbon dioxide; T: temperature; CK: creatine kinase; RASS: Richmond Agitation-Sedation Scale; PEEP: positive end-expiratory pressure; FiO2: fraction of inspiration O2; SpO2: peripheral capillary oxygen saturation; iv: intravenous.
Genetic detection of his peripheral blood samples during hospitalization showed a heterozygous missense mutation of the RYR1 gene (NM_000540.3): c.7523G > A (p. Arg2508His), exon 47. The same mutation was detected in his father’s peripheral blood samples. Electromyography (EMG) suggested myogenic changes. He was diagnosed with CCD caused by the RYR1 mutation, treated with idebenone, and finally discharged from the hospital on the 35th day of hospitalization without complications. Wang et al[8] reported that the clinical diagnostic scale of MH can provide clues for clinical diagnosis. Caffeine-halothane contracture tests (CHCTs) can also be used to confirm the diagnosis of MH in Chinese individuals, although they have different genetic backgrounds from Westerners. However, the patient and his family refused further testing for CHCT.
DISCUSSION
MH is rare, but the mortality was high until dantrolene was identified as an effective medication. The morbidity is estimated to be between 1/30,000 and 1/10,000 in adults or between 1/250,000 and 1/100,000 in children, depending on location and age, with no difference regarding ethnicity, but men are more common than women. The prevalence of gene mutations ranges from 1/3,000 to 1/2,000, and individuals do not exhibit MH events before administering multiple anesthetics.[9] Dantrolene was synthesized in 1967[10] and initially used for muscle relaxation treatment of skeletal muscle spasms.[11] It has been approved for clinical therapy for MH since animal experiments in the 1970s found that it has a beneficial effect. ETCO2’s universal detection and patient counseling and testing have reduced MH mortality from 80% in the 1960s to less than 5% in the 1970s in European countries and the USA.[9,12] The situation improved until October 2020, when dantrolene for injection, China’s first generic drug, was approved for sale in China.
In contrast, in Wu et al’s study, limb muscle weakness was present in all patients with C-terminal mutations.[13] In this case, the patient, who was detected as having a non-C-terminal mutation, as his father did, was asymptomatic before the surgery but showed cough difficulty and mild limb muscle weakness without muscle atrophy after recurrent MH and using sedation and dantrolene. The recurrence was marked by shivering, increased body temperature, higher ETCO2, and tachycardia (supplementary video), with CGS >4.[7,14] Short et al[14] suggested two possibilities: shivering may indicate the initiation of MH or reactivation of the MH response in association with subtherapy or the absence of dantrolene. We eliminated interference factors, that is, an electroencephalogram showed no seizure activity. A head CT scan excluded hemorrhage or other intracranial etiologies. Thyroid studies were normal. We failed to prevent and stop the recurrence, even though we gave a repeat dose of dantrolene, approximately 1.0-1.4 mg/kg, every 6 h after the first dose according to the drug’s elimination half-life, until two weeks later.[15] However, we are unable to detect its blood concentration and are unsure whether the effective plasma concentration of dantrolene can prevent the recurrence of MH according to this case.
Most individuals susceptible to MH have a defect in the RYR1 gene (MHS1 form) on chromosome 19, which regulates the synthesis of the ryanodine receptor one protein. There are more than 400 mutations associated with this gene, 34 of which are linked to MH.[9] Specific genetic defects that are prone to MH may affect the likelihood of recurrence. Robinson et al[5] reported the influence of specific RYR1 mutations on the severity of the MH phenotype. RYR1 mutations are clustered geographically; this genetic susceptibility to recurrence has implications for the applicability to Asian patients because these findings were based on North American patients.[16] The patient’s MH phenotype in our case may be related to his RYR1 mutations (c.7523G > A). More data will be needed to verify this hypothesis in the future.
CONCLUSIONS
The prompt recognition and proper management of MH are critical in preventing life-threatening complications, with particular attention needed to recurrence. Non-C-terminal mutations (c.7523G >A) may increase the likelihood of recurrence. The relationship between effective plasma concentrations of dantrolene and recurrence is worthy of further exploration.
Funding: None.
Ethical approval: The patient gave his informed consent.
Conflicts of interest: None.
Contributors: All authors contributed significantly to the writing and revision of this manuscript and approved the final version.
All the supplementary files in this paper are available at http://wjem.com.cn.
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