Noncardiogenic Pulmonary Edema and Rhabdomyolysis after Protamine Administration in a Patient with Unrecognized McArdle's Disease 

A 2-yr-old boy was scheduled for repair of tetralogy of Fallot. He had not been hospitalized previously and required no prior palliation. His room air oxygen saturation fluctuated between 80% and 85%. There was no family history of myopathies or reactions to anesthesia. Anesthesia was accomplished with halothane supplemented with fentanyl and pancuronium. Right radial arterial and internal jugular central venous catheters were inserted percutaneously. Intraoperative transesophageal echocardiography was used with the aid of a pediatric biplane transducer (Hewlett Packard, Andover, MA). The repair consisted of closure of the ventricular septal defect, right ventricular infundibulectomy, and patch enlargement of the right ventricular outflow tract under full CPB at moderate hypothermia (rectal temperature, 28 [degree sign]C). The patient was then rewarmed over 30 min to a rectal temperature of 37.5 [degree sign]C, maintaining a temperature gradient less than 10 [degree sign]C, with a maximum blood temperature from the CPB machine of 39 [degree sign]C. After placement of a left atrial pressure catheter and institution of mechanical ventilation, separation from CPB was then achieved without inotropes. Left atrial pressure was 5–10 mmHg, and central venous pressure was 5–9 mmHg. After hemodynamic stability was achieved, protamine sulfate was administered over 15 min. Ten minutes later, pink frothy sputum appeared in the endotracheal tube with a concomitant decrease in oxygenation and increased airway pressures. Left atrial pressure remained normal, whereas the central venous pressure increased to 15 mmHg. Transesophageal echocardiography showed good biventricular function, no residual ventricular septal defect, and no mitral regurgitation. Direct simultaneous pressure obtained from both the right ventricle and pulmonary artery showed a residual gradient of 10 mmHg, which was considered acceptable. Methylprednisolone, cimetidine, and diphenhydramine were administered together with a continuous infusion of epinephrine. Over the next couple of hours, the patient's rectal temperature increased to 39.5 [degree sign]C, and myoglobin was detected in the urine. A chest radiograph obtained in the intensive care unit was consistent with pulmonary edema. End-tidal carbon dioxide and Pa^CO(2) increased with a corresponding acidosis, but after initial adjustments in minute ventilation, they remained stable. The serum creatinine kinase value was 5,000 U and, together with myoglobinuria, established the diagnosis of rhabdomyolysis. Despite the lack of muscle rigidity and further increases in Pa^CO(2) and temperature, malignant hyperthermia was suspected because the patient had received halothane. A 2.5-mg/kg dose of dantrolene was administered without response. The patient developed progressive renal failure followed by sepsis. A skeletal muscle biopsy performed on the fifth postoperative day showed the absence of skeletal myophosphorylase with accumulation of tissue glycogen, findings typically compatible with the diagnosis of McArdle's disease (Figure 1). The patient died on the tenth hospital day.

This unfortunate patient developed three relatively uncommon complications that have been described after cardiac surgery: hyperthermia, rhabdomyolysis, and NCPE. Rebound hyperthermia may occur after CPB. The average increase in temperature is on the order of 1 [degree sign]C/hr and peaks 6 hr after CPB. [3] Mechanisms involved in heat production in the early postoperative period include return of muscle activity, the exothermic action of catecholamines, and circulating endogenous pyrogens released from leukocytes during CPB. The increase in temperature is rarely beyond 39 [degree sign]C, but occasionally higher temperatures can occur. [4] Malignant hyperthermia has been described after CPB. [5] The diagnosis may be obscured by the temperature changes during CPB, but it is manifested by a hyperkinetic syndrome in the early postoperative period. Malignant hyperthermia is associated with persistent mixed acidosis, progressive elevation of carbon dioxide, muscle rigidity, and rhabdomyolysis. Dantrolene administration results in dramatic resolution of the syndrome. Malignant hyperthermia was initially considered in this patient because of his exposure to halothane. However, the absence of muscle rigidity and CO²elevation, and the lack of response to dantrolene made the diagnosis of malignant hyperthermia unlikely.

Rhabdomyolysis without hyperthermia can occur as a consequence of CPB as a result of inadequate blood flow to the muscle with consequent cell breakdown and myoglobin release. [6–8] Prolonged CPB and femoral cannulation are considered risk factors, particularly in children. Patients with McArdle's disease are particularly prone to rhabdomyolysis and acute renal failure. [9] In this disorder, glycogen accumulation results from a lack of glycogen breakdown to free glucose available for glycolytic pathways because of a deficiency of skeletal muscle myophosphorylase. [10] Because glucose is not available as a source of adenosine triphosphate, the cells progressively lose adenosine triphosphate and become acidotic. Lactate production is impaired; thus, the characteristic increase in serum lactate that occurs during exercise is blunted. [11] The clinical presentation is that of myalgias and myoglobinuria, sometimes progressing to frank rhabdomyolysis and renal failure. [12] During general anesthesia, these patients are prone to hypoglycemia, and, if energy demands of the skeletal muscle are high, rhabdomyolysis may ensue. The intraoperative care of patients with McArdle's disease involves the supply of exogenous glucose and maintenance of adequate blood flow to the systemic circulation. Of interest, it is thought that patients with McArdle's disease are protected against malignant hyperthermia because the skeletal muscle cannot undergo spastic contracture; however, at least one patient with McArdle's disease was found to have a positive halothane caffeine contracture test. [13] The occurrence of NCPE after CPB has been described. [14] Although protamine was initially implicated, it is evident that this syndrome may occur also as a consequence of CPB in the absence of protamine or after transfusion. [15] The cause of protamine-associated NCPE is multifactorial, but it is thought to be the result of an anaphylactoid reaction or polycation injury with damage to the pulmonary capillaries, leading to pulmonary hypertension. [1,16] Protamine has also been implicated in the development of hyperthermia and rhabdomyolysis after CPB. [2] The postulated mechanism is similar to that of NCPE. Why some patients respond with lung injury while others develop muscle breakdown after protamine administration is not entirely known. Protamine is a basic protein that, when combined with heparin, may trigger an abnormal immune/inflammatory response in genetically susceptible patients.

In summary, we believe that an adverse reaction to protamine is the more likely diagnosis to explain the occurrence of hyperthermia, NCPE, and rhabdomyolysis in this patient. The presence of McArdle's disease may have rendered this patient more susceptible to skeletal muscle injury when increased energy demand ensued, thus resulting in massive rhabdomyolysis and renal failure.