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Postoperative malignant hyperthermia (MH) is a very rare phenomena. It is generally observed within less than an hour after discontinuation of the anesthetic trigger. Present case describes rare delayed postoperative presentation of MH after off-pump coronary bypass surgery. Prompt recognition and immediate treatment with dantrolene can effectively treat the fatal syndrome. Family education and genetic counseling should be encouraged.
Malignant hyperthermia (MH) is pharmacogenetic syndrome inherited in an autosomal dominant way. Mutations in genes coding for calcium channel proteins (RYR1) and receptors (dihydropyridine) are responsible for MH susceptibility in 30–50% of the cases.[1,2] The incidence of MH episodes in the general population is estimated as 1:100,000 administered anesthetics. This may be an underestimated prevalence as unrecognized, mild, or atypical reactions occur due to variable penetrance of the inherited trait.[4,5] The occurrence of MH has been reported in all ethnic groups in all parts of the world. About 45–52% of reported events has been seen in children below 19 years of age.[4,6]
Sixty-eight-year-old gentleman presented with retrosternal chest discomfort since 10 days. He was evaluated thoroughly at our center and found to have severe triple vessel coronary artery disease. He was scheduled for coronary artery bypass grafting (CABG) surgery. Preoperative history was not suggestive of any use of antipsychotic medications nor any medical illness or any previous anesthesia exposure. There was no history suggestive of any muscle disorders in his family. Anesthesia induction was done with intravenous (IV) injection fentanyl 2 mcg/kg, midazolam 0.03 mg/kg, and propofol 2 mg/kg with inhalation agent sevoflurane. The patient was intubated by using IV injection of rocuronium 1 mg/kg. Anesthesia was maintained by inhalational agent isoflurane 2–3% keeping bispectral index 40–60. Intraoperatively, dexmedetomidine infusion 0.5 mcg/kg/h along with intermittent fentanyl doses were used for analgesia. Muscle relaxant vecuronium was used intermittently. Off-pump CABG was done successfully. Total surgical duration was 3.5 h. Patient's temperature remained between 35°C and 36°C intraoperatively. End-tidal carbon dioxide (ETCO2) was between 30 and 35 mm Hg with mechanical ventilation at tidal volume 10 ml/kg and respiratory rate of 12/min. Intraoperatively, metabolic or respiratory acidosis or electrolytes imbalance was not noticed with lactate level of 0.5 mmol/L. After the skin closure, isoflurane inhalation was stopped and propofol infusion 150 mcg/kg/min was started for sedation before shifting the patient to the cardiac recovery room. Patient's ETCO2 started rising from 35 to 65 mmHg with the same ventilatory setting 60 min after the completion of surgery. Temperature showed rising trend from 36°C to 38.8°C. Generalized muscle rigidity was observed including masseter muscle spasm despite using vecuronium. Arterial blood gas analysis revealed mixed respiratory and metabolic acidosis with raised lactate level of 5 mmol/L (pH 7.20, PaCO2 62 mmHg, and base excess – 9 mEq/L). Heart rate was 110/min and mean arterial blood pressure of 70 mmHg was maintained with an infusion of noradrenaline 0.5 mcg/kg/min. Electrocardiogram showed sinus tachycardia with intermittent appearance of premature ventricular contractions. Serum potassium increased from 3.8 to 4.9 mEq/L. Any fault in ventilator machine and breathing circuit were checked and ruled out. Ventilator settings were adjusted to normalize ETCO2. Cooling blanket and cold saline were used to decrease the core body temperature. IV frusemide 1 mg/kg was injected to augment urine output to decrease the probability of acute tubular necrosis induced by suspected myoglobinuria. Considering clinical suspicion of MH, IV dantrolene 1 mg/kg was administered within 30 min of noticing the symptoms. Patient's limb rigidity decreased to some extent and temperature dropped to 38.2°C. Oral dantrolene 50 mg qid was started due to nonavailability of IV dantrolene. Patient's creatinine phosphokinase (CPK) enzyme level was raised. The patient was mechanically ventilated for another 2 days. Patient was extubated on the 3rd postoperative day, as the muscle rigidity reduced significantly and temperature normalized with good hemodynamic stability without any inotropic support. Oral dantrolene was stopped after the 3rd day. CPK enzyme showed decreasing trend [Figure 1]. Postoperative course after the event was stable and smooth. Patient and his family members were counseled about the event occurred and advised about genetic testing for MH. Patient was given anesthesia summary at the time of discharge stating MH occurrence and its management.
Closest differential diagnosis with features of muscle rigidity and hyperthermia is a neuroleptic malignant syndrome, which was ruled out in the present case due to the absence of history of antipsychotic medications. Our patient had a rise in CPK more than 5000 IU/L. Normal increase in CPK after cardiac or great vessel surgeries can be up to 1100 IU/L. As per the clinical grading scale (CGS), clinical features of the present case scored 58 which suggests it was an almost certain case of MH [Figure 2]. MH in the present case is diagnosis by exclusion, and it was reaffirmed by the disappearance of symptoms after dantrolene therapy. We could not perform muscle biopsy to confirm the diagnosis. Liver function tests were monitored and found to be normal during dantrolene therapy.
In the present case, features of MH appeared 1 h postoperatively. The case was managed successfully using IV dantrolene initially followed by the oral form of dantrolene.
MH susceptible (MHS), patient when exposed to triggering anesthetic agents, causes uncontrolled intracellular release of calcium in skeletal muscle with resultant sustained muscle contraction. Such muscular hypermetabolic state produces rigidity, hyperthermia, and acidosis [Figure 3].
Intraoperative clinical diagnosis of MH may be difficult due to the nonspecific nature of MH clinical signs and symptoms. Larach et al. devised the CGS as a set of clinical diagnostic criteria for MH. As per the scale, clinical features of the present case scored 53 which suggests it was an almost certain case of MH. Cases developing MH during cardiopulmonary bypass (CPB) in cardiac surgery have been reported.[9,10] However, classical features of MH are obscured and disguised by the hypothermic CPB.
Postoperative MH is very rare (<2% of all cases) and generally observed within less than an hour after discontinuation of the anesthetic trigger. After reviewing published cases of MH, North American Malignant Hyperthermia Registry (NAMHR) found postoperative MH is a rare event which happened in 10 of 528 suspected MH cases (1.9%) reported to the NAMHR. None of these cases had hyperthermia as an initial presenting sign. NAMHR suggested that initial postoperative fever without signs of hypermetabolism is unlikely to be MH. Postoperative MH cases presenting more than 1 h after discontinuation of anesthesia should warrant investigation of alternative diagnoses. Firstenberg et al. reported a successfully treated case of delayed MH after 4.5 h of isoflurane inhalational anesthesia in a case of on-pump CABG. MH cases have presented in a delayed or atypical manner with a latency of 0–40 min in the postoperative period.[12,14]
Considering rapidly, progressive, and fulminant course of MH, it is essential for the anesthesiologist to diagnose the condition as early as possible to minimize mortality and MH-related complications. Visoiu et al. have reported shorter MH onset time in the presence of halothane and after succinylcholine in all anesthetics. MH onset time was shorter during sevoflurane anesthesia than during isoflurane or desflurane in the human cohort of MH cases. Larach et al. observed cardiac dysfunction and level of consciousness change as the most common MH-related complications. More the time period between the first clinical sign and dantrolene administration, higher complication rate was observed. Other studies also suggested early dantrolene use can reduce the MH-related complications.[16,17] Riazi et al. reported more than 50 min delay in the administration of dantrolene raised complication rate to 100%. The most common complication in this study was renal dysfunction (14.7%). In the present case, we managed to administer dantrolene in 30 min after diagnosing the symptoms.
Dantrolene is recommended in the dose of 2.5 mg/kg every 5 min until a clinical improvement is seen.[19,20] Previous studies suggested that no dosing adjustments need to be made during CPB, as there is only a slight decrease in blood levels due to dilution. Improvement in symptoms is generally observed within 30–60 min. No clinical improvement even after administration of 10 mg/kg warrants a review of differential diagnosis.[19,20] Recrudescence of symptoms is observed in up to 25% of patients after successful treatment at a mean of 13 h (standard deviation, 13 h) after the initial reaction and commonly in patients with increased muscle mass.[21,22] Hence, it is suggested to continue dantrolene in maintenance doses (1 mg/kg IV every 4–6 h) for 24–48 h after the last noticed sign of acute MH.[21,23]
Dantrolene can cause a profound muscular weakness by interfering with the intracellular calcium handling.[23,24] Higher than recommended doses has been reported to have negative inotropic effects in animal studies.[25,26] Dantrolene can also cause fatal and nonfatal hepatic failure after long-term use.[27,28] Shih et al. described that intraoperative administration of low-dose dantrolene, 1.2 mg/kg, was effective in treating hyperthermia, hypercapnia, and hyperkalemia. In the present case, we also used IV dantrolene in the low dose of 1 mg/kg successfully and oral dantrolene for 48 h to prevent the recurrence.
Use of oral dantrolene in MH has been reported anecdotally.[30,31,32] Oral dantrolene sodium is well absorbed and achieves peak blood levels 3–6 h after ingestion. Oral dantrolene 5 mg/kg (divided 3–4 times a day) can attain acceptable plasma level of the drug.
Dantrolene was stopped in our case when the following criteria were met: Core temp is <38°C, metabolic stability for 24 h, muscle is no longer rigid, creatine kinase is decreasing, and no evidence of myoglobinuria.
Complications such as hypercarbia, hyperthermia, electrolyte abnormalities, and arrhythmias should be managed with conventional measures, like mechanical ventilation, systemic cooling, and anti-arrhythmic drugs. Cardiac surgical patients are generally prone to develop an acute renal injury. Rhabdomyolysis in untreated MH can cause myoglobin-induced kidney damage. Aggressive fluid replacement with crystalloids and adequate diuresis can decrease the risk of myoglobin precipitation in renal tubules. Excessive physical activity in a hot, humid environment can trigger MHS human beings. Patients with a preexisting fever are more prone to develop an episode of MH. Role of heat in triggering MH in human beings is not known, however a modulating effect on a developing crisis must be presumed. Rapid and exaggerated rewarming during CPB can be a potential risk factor. Slow rewarming till 36°C is advisable. Core temperature should be maintained <36°C during the postoperative period in MHS patients. Gasoline vapors and serotonin receptor agonists are also said to be potential trigger agents.[36,37] Usefulness of CPB has been reported in noncardiac surgery patients who had MH episode during general anesthesia. The advantages of CPB in MH patients include ultrafiltration, temperature control, normalization of electrolytes, control of acidosis, cytokine removal, and supporting the circulation of the patient. Witherspoon have reported the use of extracorporeal membrane oxygenation for cardiac failure due to hypermetabolic episode possibly caused by MH.
Anesthesia can be safely given to MHS patients with nontriggering agents. Close monitoring of minute ventilation, ETCO2 levels, and core body temperature should be done in MHS patients. MH triggering agents are inhalational halogenated anesthetics (e.g., sevoflurane, desflurane, isoflurane, enflurane, and halothane) and depolarizing muscle relaxant like succinylcholine. Safe agents that can be safely administered to MHS patients include - all IV sedatives and anesthetic including propofol, dexmedetomidine, ketamine, etomidate, and barbiturates. All local anesthetics (e.g., ropivacaine, lidocaine, and bupivacaine), nondepolarizing neuromuscular blockers (e.g., atracurium, vecuronium, and rocuronium), analgesics and anxiolytics (opioids and benzodiazepines), and inhalational agents limited to nitrous oxide and xenon are safe. Perioperative dantrolene for prophylaxis is not recommended by the Malignant Hyperthermia Association of the United States.
After recovery from MH episode, all details should be noted in anesthesia discharge summary and patient and family should be counseled specifically about the following points - avoid anesthesia with triggering agents, avoid exercise in excessive heat which can be a triggering event. Inform family members of the possible MH reaction, as MHS is a genetic condition.
Recognizing these genetically-susceptible individuals is the mainstay of prevention.
Avoiding anesthetic triggers and prompt use of dantrolene during acute event occurs have decreased the mortality due to MH from historic rates of 70% to about 5%.[41,42] The present case describe a rare delayed postoperative presentation of MH after off-pump coronary bypass surgery. Prompt recognition and immediate treatment with low dose IV dantrolene followed by oral form can effectively reverse potentially fatal syndrome. Family education and genetic counseling should be encouraged.
There are no conflicts of interest.