Malignant hyperthermia (MH) is a life-threatening hypermetabolic condition triggered by inhalational anesthetics and succinylcholine and characterized by nonspecific signs including tachycardia, hypercarbia, respiratory and metabolic acidosis, muscular rigidity, myoglobinuria, rhabdomyolysis, hyperkalemia, hemodynamic instability, and coagulopathy.1 Diagnosis can be particularly difficult in the setting of cardiopulmonary bypass (CPB) because many of the signs of MH are masked by CPB. There is even evidence that hypothermia can delay the presentation of MH, with subsequent fulminant MH after rewarming.2 We are aware of 20 cases of MH reported in the setting of CPB.2–7 In only 1 did the patient receive dantrolene before the initiation of CPB.4 One other describes signs of MH before CPB, but dantrolene was not given until after initiation of CPB.3 Among pediatric cases, all 3 were diagnosed postoperatively.5,6,8 This is the first reported case of MH in a pediatric patient suspected before CPB and treated on CPB.
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DESCRIPTION OF CASE
We report the case of a 10-year-old boy (weight, 48 kg; height, 144 cm) with congenital aortic stenosis going for aortic valve replacement. He previously underwent uncomplicated balloon valvuloplasty under general anesthesia as an infant at an outside institution. The specific anesthetic used is not known. The patient had no other previous anesthetics and no known family history of anesthetic complications. He was not on any medications. He recently developed progressive and symptomatic aortic insufficiency, including dyspnea on exertion. A preoperative echocardiogram demonstrated moderate aortic stenosis, moderate to severe aortic regurgitation, and moderate dilation of the left ventricle. The patient was therefore brought to the operating room for aortic valve replacement.
After obtaining preinduction peripheral intravenous access, the patient was induced with intravenous midazolam 0.06 mg/kg, fentanyl 3 µg/kg, etomidate 0.3 mg/kg, and rocuronium 1 mg/kg. The trachea was intubated with direct laryngoscopy and anesthesia maintained with sevoflurane 1.0%–1.4%, while a radial arterial line and right internal jugular central venous catheter were placed. During catheter placement, the heart rate was 65–70 beats per minute (bpm). It gradually rose to 95–100 bpm before incision. The patient’s temperature, initially 35.5°C by nasopharyngeal probe, quickly climbed to 37.7°C despite the forced air warming blanket being off. At the time of incision, an arterial blood gas showed no gradient between Etco2 and Paco2 (38 mm Hg).
During the time until CPB, minute ventilation was incrementally increased from 5.4 to 9.2 L/min to maintain Etco2 35–39 mm Hg. Heart rate gradually increased to 120 bpm despite increasing inhaled sevoflurane to 3.2% and administering an additional 3 µg/kg fentanyl. CPB was initiated 45 minutes after incision. An arterial blood gas showed a lactate of 3.5 mmol/L, up from 1.9 mmol/L at the time of incision. The base deficit was 1.1. Given suspicion for MH, sevoflurane was discontinued and propofol (125 µg·kg−1·minute−1) was started for maintenance of anesthesia; volatile anesthetics were never used while on CPB. The surgeon noted that the patient’s chest was hot to the touch, despite attempts to cool the patient to 28°C. The urine was dark, and copious pink frothy sputum was suctioned from the endotracheal tube. Laboratory studies sent at this time later resulted showing creatine phosphokinase of 905 units/L (reference range, 56–433 units/L) and urine myoglobin of 60 µg/L (reference range, <28 µg/L). Paco2 had risen from 38 mm Hg at the initiation of CPB to 54 mm Hg, despite increasing the sweep from 0.9 to 2 L/min.
An initial dantrolene bolus of 2.5 mg/kg was given and an infusion (0.25 mg·kg−1·hour−1) was started. After 30 minutes, a second dantrolene bolus of 1.5 mg/kg was given, as the lactate had risen to 4.5 mmol/L and the Paco2 remained elevated (47 mm Hg). The patient was separated from CPB 1 hour after the initial dantrolene bolus, requiring dopamine (5–8 µg·kg−1·minute−1) and epinephrine (0.03 µg·kg−1·minute−1) for inotropic support. A third dantrolene bolus of 2.5 mg/kg was given just after separation from CPB, at which time the Paco2 and lactate remained elevated at 47 mm Hg and 4.3 mmol/L, respectively. The remainder of surgery was uneventful, and the patient was transferred to the intensive care unit intubated and on a dantrolene infusion. Although rigidity could not be appreciated, examination intraoperatively was limited given position and surgical drapes. By the time of undraping, the patient had received several doses of dantrolene.
Postoperatively, his lactate was 11.1 mmol/L, creatine phosphokinase 1585 units/L, and base excess −12 mmol/L. After arrival to the intensive care unit, dantrolene was interrupted for 4 hours, during which time the temperature rose from 36.6 to 38.6°C; the temperature normalized after restarting dantrolene. Dantrolene was continued until the morning of postoperative day 2. By that time, the lactate had normalized (1.2 mmol/L), the creatine phosphokinase had down-trended (518 units/L), and the myoglobinuria had resolved. He was extubated on postoperative day 2 and discharged from the hospital on postoperative day 5. The remainder of his recovery was unremarkable.
The presumed diagnosis of MH and administration of dantrolene on CPB have only been reported in a few cases. Quinn et al9 reports an adult patient undergoing mitral valve replacement in which diagnosis of MH was based on hypercarbia, hyperkalemia, and difficulty maintaining hypothermia on CPB. Another case involves an adult patient undergoing mitral valve repair. Diagnosis was based on worsening base deficit, elevated Paco2 despite elevated sweeps, and rising temperature.10 A third case involves diagnosis based on difficulty ventilating due to high airway pressures and hypercarbia despite elevated minute ventilation.3 Only 1 case describes the decision to treat before the initiation of CPB.4 Hyperthermia, tachycardia, and hypotension were the diagnostic signs in this case.
The first signs exhibited in the pre-CPB timeframe in our case included slight hyperthermia, hypercarbia despite increasing minute ventilation, and gradually developing tachycardia despite increased sevoflurane and additional fentanyl. Our initial blood gas demonstrated no gradient between Etco2 and Paco2, indicative of a state of high carbon dioxide production, as may occur in the highly metabolic state of MH. Myoglobinuria (suspected clinically and later laboratory confirmed) and elevated lactate further contributed to our decision to treat with dantrolene just after CPB initiation. Although we are limited in that our patient did not undergo caffeine halothane contracture testing, the likelihood of MH is “almost certain” according to the MH Clinical Grading Scale described by Larach et al.1 The differential diagnosis for MH includes neuroleptic malignant syndrome and serotonin syndrome; however, the patient was not on any triggering medications preoperatively. Of note, although the patient had no family history of anesthetic complications, no additional family history was discovered after postoperative discussion with the family.
There are only 3 case reports involving MH in the setting of CPB in pediatric patients. In 1, a 5-month-old infant undergoing ventricular septal defect repair had a missed diagnosis and expired postoperatively.5 In another, a 2-year-old patient undergoing tetralogy of Fallot repair exhibited hypercarbia and tachycardia before CPB. These events were attributed to other factors, and the diagnosis of MH was finally made on postoperative day 2 when a creatine kinase level of 3740 units resulted.8 Delayed diagnosis in another pediatric case resulted in permanent neurological injury.6 Comparatively, the time interval between first signs and the decision to treat with dantrolene in our case was quite short. No pediatric case involving treatment while on CPB has been reported.
Dosing dantrolene on CPB necessitates special consideration because most cases report the administration of multiple dantrolene boluses. Jonassen et al10 reported the administration of 2 boluses of 2.5 mg/kg while on CPB followed by a dantrolene infusion. Quinn et al9 noted giving 1 dantrolene bolus on CPB, followed by an additional bolus postoperatively when the patient demonstrated hyperthermia, increasing Etco2, and arterial desaturation.9 In the 1 case involving dantrolene administration before CPB, 1 mg/kg was given before CPB followed by 3 small (0.3 mg/kg) doses after initiation of CPB.4 In our case, 3 dantrolene boluses were administered totaling 6.5 mg/kg. An infusion was also started and continued for over 24 hours. This seemingly high dose of dantrolene may be due to the relatively high dilution of blood volume that occurs in pediatric patients on CPB. There may be an advantage to administering an initial dose before the dilution that takes place with CPB initiation, particularly in pediatric patients.
Identification of MH on CPB is difficult due to masking of clinical signs and a tendency to assume alternative causative factors. The hemodynamic and physiological changes during cardiac surgery may increase this tendency. Using signs in addition to persistent hypercarbia, we were able to arrive at a diagnosis of MH and administer treatment in a timely fashion. Treatment while on CPB may require additional doses of dantrolene given the blood dilution that occurs; this may be exaggerated in pediatric patients. Timely diagnosis and treatment in the setting of CPB are particularly important given the masked clinical signs, potential for fulminant MH on rewarming, and severe consequences of a missed diagnosis.
The authors acknowledge Richard McNeer, MD, PhD (Department of Anesthesiology, Jackson Memorial Hospital, Miami, FL), for his valuable feedback on this manuscript.
Name: Michael T. Kuntz, MD.
Contributions: This author helped search the literature, and prepare and write the manuscript.
Name: Amanda D. Saab, MD.
Contributions: This author helped prepare and write the manuscript.
This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.
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