Hyperglycemia as an atypical finding of malignant hyperthermia: A case report and literature review

ABSTRACT

Malignant hyperthermia (MH) is a rare but life‐threatening disorder induced by volatile anesthetics or depolarizing muscle relaxants. Studies have reported the increased prevalence of hyperglycemia among patients susceptible to MH. Herein, we present the case of a 13‐month‐old toddler who had successfully undergone dextro‐transposition of the great arteries and required main and bilateral pulmonary artery augmentation because of residual pulmonary atresia. The patient exhibited atypical manifestations of MH including hyperglycemia with an inadequate insulin response during the perioperative period. The hyperglycemia resolved following administration of dantrolene, the antidote for MH. Research has associated intracellular calcium leaks with reduced glucose storage in human muscle. Metabolic alterations in patients susceptible to MH may predispose them to hyperglycemia during acute MH episodes.

A 13‐month‐old toddler presented with an atypical symptom – hyperglycemia – during a malignant hyperthermia crisis. During MH, hyperglycemia may result from intracellular calcium leakage in muscle cells, suggesting a potential association between MH susceptibility and hyperglycemia.

INTRODUCTION

Malignant hyperthermia (MH), a rare genetic disorder affecting skeletal muscle, is a progressive and life‐threatening hyperthermic condition that develops during general anesthesia ¹ . It is typically induced by inhaled anesthetics or depolarizing skeletal muscle relaxants. MH is characterized by a rapid, uncontrolled increase of sarcoplasmic Ca²⁺ within skeletal muscle ² . The incidence of MH ranges from 1 in 10,000 to 1 in 150,000 cases of general anesthesia induction ^{2 , 3} . The most common MH symptoms are sinus tachycardia, hypercarbia, and a rapid increase in body temperature ^{1 , 4} . Research has associated hyperglycemia with MH susceptibility; this association is likely attributable to increased intracellular calcium levels ⁵ . Elevated intracellular calcium levels result in the activation of enzymes that promote glycogenolysis while inhibiting glycogenesis, ultimately increasing the blood glucose level ⁶ . Herein, we present the case of a 13‐month‐old toddler with suspected MH who exhibited hyperglycemia with an inadequate insulin response during surgery.

CASE REPORT

A 13‐month‐old Taiwanese girl (height, 66 cm; weight, 5.8 kg) presented to our hospital with chronic heart failure and suspected residual pulmonary stenosis. At the age of 2 months, the patient had undergone total surgical correction of dextro‐transposition of the great arteries, a patent foramen ovale, ventricular septal defect, and patent ductus arteriosus. The patient had no anesthesia‐related complications or a family history of such complications. After admission to our hospital, she was scheduled for augmentation of the main and bilateral pulmonary arteries.

Anesthesia was induced with lidocaine, ketamine, fentanyl, and atracurium; sevoflurane was used as the primary volatile anesthetic. The patient's vital signs remained stable after anesthesia induction. Before cardiopulmonary bypass (CPB) was performed, her body temperature was mildly elevated (oral temperature: 37.9°C). Arterial blood gas analysis performed before CPB yielded results within normal ranges (Table 1). Cooling was initiated with cannulation, and the patient's lowest body temperature was 31°C. CPB was initiated 3 h after anesthesia induction. Two hour after the initiation of CPB, following the intracardiac procedure, the patient's body temperature gradually increased, reaching 36.5°C over the next 2 h (rewarming period).

Table 1.

Preoperative and perioperative arterial blood gas analysis

Time	pH	PaO2, mmHg	PaCO2, mmHg	Na, mmol/L	K, mmol/L	Free Ca, mmol/L	HCT, %	Lac, mmol/L	Be, mmol/L	HCO3, mmol/L	Glu, mg/dL
Normal range	7.35–7.45	80–100	30–45	135–145	3.5–5.5	1.1–1.4	33–39	0.5–2.2	−2 to +2	20–26	10–110 (fasting)
Pre‐operative	7.39	39	43	132	5.1	1.11	49	–	0.7	26.0	–
Operation Day 12:40 (induction)	7.392	101.3	40.1	131.2	4.39	1.19	43	1.1	0.3	24.6	171
Operation Day 14:05 (CPB onset)	7.411	146.9	34.5	132.0	4.36	1.15	35	1.4	−1.3	22.1	169
Operation Day 18:52 (weaning CPB)	7.284	92.9	55.0	138.1	3.31	1.21	35	2.3	−0.6	26.3	357
Operation Day 20:51	7.291	91.6	56.7	141.0	3.78	1.13	30	3.2	0.8	27.6	362
Operation Day 21:33	7.326	154.1	42.0	139.0	4.58	1.10	30	5.1	−4.1	22.1	429
Operation Day 22:22	7.239	155	46.1	139.2	4.86	1.17	37	7.4	−7.8	19.9	–*
Operation Day 22:48	7.244	209.3	50.4	141.2	4.90	1.17	36	7.7	−5.5	22.0	498
Operation Day 23:24 (Leaving OR)	7.264	138.9	39.5	140.3	5.16	1.16	36	7.7	−9.2	18.0	361

^*Finger sugar higher than upper limit.

After CPB, the patient developed tachycardia. Her EtCO₂ increased from 48 to 50 mmHg. Arterial blood gas analysis revealed mixed metabolic and respiratory acidosis (Table 1). In addition, marked hyperglycemia was observed. Human regular insulin, 1 unit (0.15 units/kg), was administered via intravenous slow drip; however, the patient remained unresponsive to insulin therapy. Arterial blood gas analysis and blood glucose levels were monitored at 30‐min intervals. A total of four doses of regular insulin were administered over a 4‐h period; however, hyperglycemia persisted after treatment. Additionally, the hypotension persisted despite continuous inotropic support with dopamine and milrinone. Approximately 4 h after the termination of CPB, the patient's body temperature was 39.0°C. The metabolic acidosis and hyperglycemia progressively worsened, as indicated by arterial blood gas analyses. Although MH was suspected because of hypercapnia and hyperthermia, the slow progression of symptoms and the absence of muscle rigidity reduced the likelihood of MH.

Upon admission to the PICU, the patient showed tachycardia with hypotension under inotropic agent supports, with body temperature, 39.6°C; and Glasgow Coma Scale score, E1VTM3. Arterial blood gas analysis indicated metabolic acidosis (Table 2). At 30 min after PICU admission, the patient's body temperature had increased to 40.8°C, and dark urine was observed (Figure 1). The patient's serum creatine kinase level was mildly elevated (1,451 U/L).

Table 2.

Postoperative Arterial blood gas analysis

Time	pH	PaO2, mmHg	PaCO2, mmHg	Na, mmol/L	K, mmol/L	Free Ca, mmol/L	HCT, %	Lac, mmol/L	Be, mmol/L	HCO3, mmol/L	Glu, mg/dL
Normal range	7.35–7.45	80–100	30–45	135–145	3.5–5.5	1.1–1.4	33–39	0.5–2.2	−2 to +2	20–26	10–110 (fasting)
Post‐operation Day 1 00:47 (entering PICU)	7.32	83	28	142	5.0	0.83	38	9.21	−10.3	14.4	320
Post‐operation Day 1 01:23	7.30	76	37	144	4.3	1.37	37	10.57	−7.6	18.2	193
Post‐operation Day 1 02:00 (dantrolene given)	7.43	117	29	142	3.5	1.04	32	–	−4.3	19.2	125
Post‐operation Day 1 02:35	7.48	153	27	140	3.7	1.02	33	8.68	−2.5	20.1	–
Post‐operation Day 1 03:02	7.46	126	26	141	3.5	0.93	30	–	−4.4	18.5	–
Post‐operation Day 1 03:35	7.49	136	26	142	3.8	0.87	29	9.94	−2.8	19.8	–
Post‐operation Day 1 04:29	7.51	83	28	142	4.3	0.98	32	–	−0.1	22.3	–
Post‐operation Day 1 05:44	7.49	107	30	138	4.4	1.07	42	4.55	0.2	22.9	–

Figure 1.

Dark urine noted after the surgery.

Malignant hyperthermia was suspected; therefore, intravenous dantrolene was administered at a dose of 15 mg (2.5 mg/kg), in accordance with the United States FDA recommendation for infants, children, and adolescents: initial dose of 2.5 mg/kg, followed by 1 or 2.5 mg/kg every 5 min as frequently as needed until treatment goals are reached. The patient's body temperature decreased to 38.2°C within 40 min. Then, dantrolene was continuously infused at a rate of 1.33 mg/h. Arterial blood gas analysis revealed gradual improvement following the dantrolene administration (Table 2). At 6 h after PICU admission, improvements were noted in the patient's vital signs (heart rate, 120 bpm; blood pressure, 107/58 mmHg) and consciousness level (Glasgow Coma Scale score, E4VTM6). No further episodes of hyperglycemia occurred.

DISCUSSION

Although genetic testing was not performed, the patient's clinical presentation strongly suggested “almost certain” MH, which was classified based on the clinical grading scale [4]. A retrospective analysis of data from the North American Malignant Hyperthermia Registry for pediatric patients (age <18 years) indicated that sinus tachycardia (73.1%), hypercarbia (68.6%), and a rapid increase in body temperature (48.5%) are the most common manifestations. Infants and toddlers (0–24 months) are more likely to exhibit cutaneous mottling, have a higher peak lactate level, and have a lower peak creatine kinase level compared with older individuals [7]. Our patient had a high lactate level (10.0 mmol/L), a low peak creatine kinase level (1,651 U/L), tea‐colored urine, sinus tachycardia, and hyperthermia without muscle rigidity.

An atypical finding in our case was hyperglycemia with poor responsiveness to insulin therapy. A retrospective study reported that 42% of all MH‐susceptible (MHS) patients exhibited hyperglycemia, a proportion higher than that observed in the general population. The high prevalence of hyperglycemia in MHS patients was positively correlated with their muscle response to caffeine and halothane, suggesting that calcium imbalance influences glycemic control. An animal study demonstrated glucose intolerance in MHS mice [5], which was mitigated with dantrolene, a drug that stabilizes intracellular calcium levels. Muscle cells in MHS mice exhibited impaired insulin signaling, as evidenced by reduced protein kinase B phosphorylation. This impairment likely leads to chronic hyperglycemia because skeletal muscle facilitates insulin‐mediated glucose uptake [5].

Our findings suggest that MHS patients are at increased risk of abnormal glucose metabolism. At the molecular level, intracellular calcium leakage in muscle cells disrupts glucose metabolism, potentially contributing to the high prevalence of hyperglycemia in MHS patients. During an MH episode, increased cytosolic calcium levels activate enzymes that promote glycogenolysis and inhibit glycogenesis, leading to an elevated blood glucose level. This cascade can occur in MHS patients even in the absence of an acute MH episode, resulting in chronic hyperglycemia. Calcium imbalance also reduces the number of glucose transporters in muscle cells, further impairing glucose uptake and exacerbating insulin resistance. These metabolic alterations may predispose MHS patients to hyperglycemia during both acute and chronic MH crises [6]. Animal experiments demonstrated that both elevating and reducing intracellular calcium levels beyond the physiological level markedly reduced insulin‐stimulated glucose uptake in MHS mice. Additionally, exposure of MHS neurons to isoflurane further increased the intracellular calcium level, exacerbating the already compromised insulin‐dependent glucose uptake, which led to reduced insulin‐stimulated glucose uptake during an MH episode [8].

In conclusion, our case highlights an atypical clinical presentation of MH with refractory hyperglycemia. During MH, hyperglycemia may result from intracellular calcium leakage in muscle cells. This case suggests a potential association between MHS and hyperglycemia, warranting further investigation into the mechanisms that link MHS to glucose metabolism abnormalities.

DISCLOSURE

Approval of the research protocol: N/A.

Informed consent: Written informed consent for publication will be submitted with the manuscript.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.