Suspected malignant hyperthermia in a young Chinese patient undergoing a micro varicocelectomy surgery

To the Editor: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscles that presents as an acute hypermetabolic state triggered by depolarizing muscle relaxants and volatile anesthetics in susceptible individuals.[1] The reported incidence of MH reaction ranged from 1:250,000 to 1:10,000.[1] However, the exact incidence in the Asian population remains unknown. A recent report suggested that the incidence of MH in Japan was 1 to 2 per 100,000 anesthetics,[2] which was similar to that in Western countries. In China, there are only a few reported cases, which may be attributed to incomplete records, and the actual incidence might be higher.[3,4] In China, between January 1978 and March 2004, only 34 cases of MH were recorded.[5] Due to the lack of the effective drug dantrolene, the mortality rate at that time was 73.5%.[5] Here, we reported the onset and treatment of a patient with suspected MH. A 29-year-old man with American Society of Anesthesiologist grade 1, a height of 172 cm, and a weight of 65 kg was scheduled for bilateral microvaricocelectomy surgery under general anesthesia (GA). Informed consent and the authorization to use and disclose protected health information was obtained from the patient. The patient had bilateral varicocele (left III°, right II°), hypospadias, and urethral stricture. He had no history of any chronic diseases, allergies, surgeries, and medication use. He and his family members had never been exposed to GA. All pre-operative laboratory examination indices were within the normal range. On December 4, 2020, the patient entered the operating room (OR) after adequate pre-operative preparation. At 13:35, intravenous anesthesia was administered with the following formulation: 20 μg sufentanil (Yichang Humanwell Pharmaceutical, Yichang, Hubei, China); 120 mg propofol (Fresenius Kabi AB, Uppsala, Sweden); 3 mg cisatracurium (Heng Rui Pharmaceutical, Lianyungang, Jiangsu, China); and 50 mg succinylcholine (Shanghai Xudong Haipu Pharmaceutical, Shanghai, China). The patient developed significant limb muscular rigidity without masseter spasm after administration, which was relieved spontaneously. A volume-controlled breathing mode was set after the laryngeal mask airway (LMA) was successfully established. The ventilator parameters were as follows: tidal volume (Vt), 500 mL; ventilation frequency, 12/min; and 70% oxygen. Combined anesthesia was performed using desflurane (1.0–1.1 Minimum Alveolar Concention, Baxter Healthcare, Guayama, Puerto Rico) and remifentanil (0.1 μg·kg−1·min−1, National Pharmaceutical Industry, Langfang, Hebei, China). Sufentanil (10 μg) intravenous injection (I.V.) was administered once every hour to maintain the depth of anesthesia. The first alarm about end-tidal carbon dioxide (EtCO2) rising (>45 mmHg) went off at 14:25 [Supplementary Figure 1, https://links.lww.com/CM9/B279]. EtCO2 began to increase rapidly at 14:40. By 14:50, the patient's temperature was 37.3 oC, while the EtCO2 was 67 mmHg. Rapid manual ventilation did not reduce it. Blood gas analysis revealed a pH of 7.24 and an arterial partial pressure of carbon dioxide (PaCO2) of 69.3 mmHg [Supplementary Figure 1, https://links.lww.com/CM9/B279]. We thus suspected muscular problems, immediately turned off the desflurane volatilizer, and rapidly adjusted the ventilation flow rate to 10 L/min, Vt to 600 mL and a ventilation frequency to 16/ min. At the same time, LMA was changed to endotracheal intubation and total intravenous anesthesia was initiated. At 15:00, the EtCO2 had increased to 99 mmHg, which was the maximum that the anesthesia station (Primus, Grager Medical Equipment Shanghai Branch, Shanghai, China) could display. The temperature was also elevated to 38.5 oC, which was 1.2 oC higher than 10 min earlier. We declared an MH emergency, suspended the surgery, and initiated a rescue. For more accurate monitoring, a nasal temperature monitoring tube and arterial puncture were performed, followed by the establishment of central venous access. We used an intravenous drip of 0.9% sodium chloride solution (NS) at 4 oC both in the peripheral venous (rapidly) and central venous (slowly), an ice compress, and an alcohol scrubbing bath to cool the patient. Additionally, an ice cap was used to protect the brain. Full ventilation was maintained to remove CO2. All of these were done in 5 min. EtCO2 began to drop at 15:02, but the temperature was still rising until peaked at 15:10, reaching 38.9 oC, and then dropped. Then followed by an i.v. of methylprednisolone (40 mg, Pfizer Manufacturing Belgium NV, Brussels, Belgium) and furosemide (20 mg, Shanghai Harvest Pharmaceutical, Shanghai, China). Blood gas at 15:15 had a pH of 7.28 and a PaCO2 of 58.3 mmHg, both of which were improved. We removed all cooling measures by 16:18. Ventilator parameters were adjusted back at 16:25. The tracheal tube was successfully removed at 17:00 when the patient regained consciousness. During the anesthesia, the patient's heart rate (HR) increased to 100 to 110 beats per minute (bpm) for half an hour when the temperature was abnormal. The pH value decreased when EtCO2 was increasing. Other blood gas values were all normal, especially cK+ and base excess [Supplementary Table 1, https://links.lww.com/CM9/B279]. Finally, a left varicocelectomy surgery was performed under a microscope, abandoning the right side. The total anesthesia time was 3.5 h, while the total fluid volume was 2500 mL (lactate Ringer's solution, 1500 mL; 4 °C NS, 1000 mL). The urine volume in operating room was 900 mL and its color was light yellow. In the post-anesthesia care unit (PACU), we received the venous blood test report extracted at 16:30, which indicated the following: creatine kinase isoenzyme (CK-MB), 9.6 ng/ mL; myoglobin, >3948 ng/mL; creatine phosphokinase (CPK), >1600 U/ L; and creatinine (Cr), 102.3 μmol/L [Supplementary Table 1, https://links.lww.com/CM9/B279]. From 18:20, the patient's HR and temperature increased again. While ice packs and 4 oC NS in peripheral intravenous drops could only maintain the HR and temperature at approximately 100 bpm and 37.6 to 37.7 oC, respectively. However, the patient did not complain of any discomfort. The electrocardiogram (ECG) at 20:00 indicated a complete right bundle branch block [Supplementary Table 2, https://links.lww.com/CM9/B279]. We, therefore, suspected that the MH symptoms had recurred and started an initial dose of 1.85 mg/kg dantrolene followed by a maintenance dose (0.15 mg·kg−1·h−1) through an intravenous pump. The MH symptom continued to improve. At 1:30 on December 5, we received blood reports drawn at 0:00, indicating that CK-MB improved to 12.5 ng/mL. Additionally, the thromboelastogram test [Supplementary Figure 2, https://links.lww.com/CM9/B279], blood routine, blood coagulation routine, and other electrolyte biochemical tests were all normal. At 1:45, we escorted the patient to the intensive care unit (ICU). In the ICU, the patient continued to be treated according to the plan [Supplementary Table 3, https://links.lww.com/CM9/B279] we made and was monitored closely. Dantrolene administration was stopped 24 h after the first MH onset. The patient was transferred to the general ward on December 8. On the morning of December 9, the patient complained of muscle soreness in the limbs, especially in the bilateral thighs. We measured the muscle strength as grade IV, whereas the patient's pre-operative muscle strength was grade V. On December 10, all the blood indicators and ECG returned to normal. On December 12, the patient was discharged with a grade IV muscle strength. In this case, anesthesia induction was performed with the depolarizing muscle relaxant succinylcholine, which was administered after cisatracurium. The patient developed severe transient extremity muscle tremor, which manifested as bilateral forearm flexion and lifting. These should have been eliminated by cisatracurium. The anesthetic desflurane was used for maintenance. Thus, it was not clear which drug was responsible for MH. However, because the patient's EtCO2 was slowly elevated, desflurane was more likely to have caused the MH.[1] MH broke out 65 min after induction, which was consistent with the median onset time of 70 min (21.5–143.5 min) in male patients previously reported.[6] The first symptom was a rapid increase in EtCO2 and body temperature. EtCO2 peaked within 20 min, while the temperature increased by 1.2 °C within 10 min before cooling measures were taken. In addition, the patient was accompanied by hypercapnia and tachycardia at the beginning of MH. Effective cooling measures may play a crucial role, particularly intravenous drip of cold saline from the central vein, which was successful and bold. To prevent hypothermic cardiac arrest, we administered a slow drip from the internal jugular vein, which has proved to be very effective in reducing the patient's core temperature. Fortunately, the MH symptoms reversed within 10 min. Due to the rapid response and reversal, the patient's electrolytes and blood coagulation indicators were normal, and no serious complications occurred. However, when MH was first suspected, we did not replace the anesthesia station that was not contaminated with inhalants according to the guidelines,[7] which resulted in some desflurane residue in the pipeline during the entire rescue process. Among the test indicators, we measured a peak CPK and myoglobin levels of nearly 4000 ng/mL 1 h after MH symptom remission. This, along with the rising temperature, was evidence of rhabdomyolysis in the patient. Subsequently, the patient presented with signs of myocardial injury, which manifested as abnormal ECG and elevated CK-MB and brain natriuretic peptide (116 pg/mL); a short-term decrease in renal function, which manifested as a slight increase in Cr of 102.3 μmol/L over a short period of time [Supplementary Table 1, https://links.lww.com/CM9/B279]; and the sequelae of rhabdomyolysis that persisted until discharge, which decreased to grade IV in limb muscle strength. Unfortunately, there was no urine myoglobin monitoring program in the laboratory of our hospital; therefore, we could not determine whether this patient had myoglobinuria. Urine can only be compared between the operating room and PACU by the naked eye [Supplementary Figure 3, https://links.lww.com/CM9/B279]. We suspect that the patient may have had mild myoglobinuria based on the color contrast. In addition, we did not communicate with the clinical laboratory about the blood dilution before testing CPK, which might explain why the value appeared with fuzzy results, such as >1600 U/L.This could have led to a possible underestimate of Clinical Grading Scale (CGS) scores. The CGS was designed to estimate the qualitative likelihood of MH and predict MH susceptibility in 1994.[8,9] It also applied to Chinese people.[8] According to the scoring criteria, the CGS score of this case was 63 points [Supplementary Tables 4 and 5, https://links.lww.com/CM9/B279], with an MH rank of 6, and a description of likelihood of almost certainty. Although CGS as a possibility assessment could not replace the established in vitro contracture test (IVCT),[10] we abandoned IVCT due to its invasive nature and the patient's will. The clinical pathway of MH resulted in significant advances in genetic diagnosis.[11,12] This makes genetic testing a more acceptable option. The RYR1 and CACNA1S genes which showed definitive association with MH were tested in this case, but both were negative. In addition, no related family members, in this case, were known to have received GA or foreign ancestry. Therefore, the family history of this case was unknown. This patient had hypospadias. As reported in the literature,[1,12] MH often occurred in people with diseases such as hernia and scoliosis. These may be risk factors for MH. To date, dantrolene is the only drug used for the treatment of MH, which can reduce mortality from 80% to 6–10%.[13] However, dantrolene has been approved for use in China for less than two months, and the drug was not supplied to our hospital.[14] In this case, when the MH emergency was activated, we contacted the drug preparation site in Shanghai (Shanghai Zhongshan Hospital Affiliated with Fudan University). The first batch of dantrolene was delivered to our hospital 1 h later, with a total of 200 mg (20 mg /vial, 10 vials, Livzon Pharmaceutical Group Inc., Ningxia, China). At that time, the patient's MH symptoms were in remission. When the symptoms returned and the initial dose of dantrolene was decided to be used at 20:00, we contacted the West China Hospital Affiliated with Sichuan University, which was 1500 km away. The second batch was not delivered until 5:00 of the following day. Considering the continuity of medication, we did not use the initial dose of 2.0 to 2.5 mg/kg recommended by European Malignant Hyperthermia Group guidelines,[13] but administered 120 mg (1.85 mg/kg) in accordance with the Japanese Society of Anesthesiologists guidelines.[2] Similarly, the maintenance dose was adjusted to 10 mg/h (0.15 mg/kg). Although there were some shortcomings in the rescue and testing methods, the patient was treated successfully. MH is rare in China. With the development of international communication and the convergence of Eastern and Western genes, MH is expected to increase in China. An effective team, rapid response, and bold cooling measures played a vital role in the treatment of our MH case. We hope that this may provide a reference for the treatment of MH in China in the future. Conflicts of interest None. Funding The study was supported by grants from Clinical Research Innovation Plan of Shanghai General Hospital (No. KD031-ly01), Clinical Research Innovation Plan of Shanghai General Hospital (No. CTCCR-2021C21).