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From the Departments of *Anesthesiology and Pathology, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
Address correspondence and reprint requests to Lynn M. Broadman, MD, Department of Anesthesiology, Children's Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213. Address e-mail to lbroadman{at}aol.com.
Abstract
An 8-mo-old infant born at 24-wk of gestation died unexpectedly 12 h after his ninth uneventful general anesthetic. Preoperatively, he required low-flow nasal oxygen due to bronchopulmonary dysplasia, chronic diuretic therapy, and IV alimentation. As planned preoperatively, the infant remained tracheally intubated after his elective surgery and went to the Neonatal Intensive Care Unit in stable condition. However, over the next 6 h, he developed fever. The diagnosis of postoperative sepsis was considered. One hour before his death his temperature reached 43°C. Autopsy documented Duchenne's muscular dystrophy and renal tubules containing myoglobin.
We uneventfully anesthetized an 8-mo-old, 4.1 kg former premature infant for the ninth time with sevoflurane, air, oxygen, and fentanyl. His gestational age was 24 wk, and his birth weight was 660 g. His neonatal course was complicated by respiratory distress syndrome, bronchopulmonary dysplasia (BPD), patent ductus arteriosus, a grade III interventricular hemorrhage, blindness secondary to retinopathy of prematurity, necrotizing enterocolitis, and sepsis. The infant had a resting tachycardia of 140–160 bpm in the neonatal intensive care unit (NICU) before the induction of anesthesia. Tachycardia continued throughout his anesthesia and surgery. Markedly increased end-tidal CO2 (ET-CO2) of 60–70 torr was observed throughout his surgery, which could not be corrected by increasing fresh gas flows or minute ventilation. The infant remained stable throughout the operative and early postoperative periods. However, 6 h into the postoperative period, he developed hypokalemia, metabolic acidosis, and a fever of 38°C. The initial clinical impression was postoperative sepsis. Despite rigorous antibiotic therapy and cardiovascular support, his temperature increased to 43°C and he died 12 h after his readmission to the NICU. After his death, the infant's family revealed for the first time that there was a family history of Duchenne's muscular dystrophy (DMD). At postmortem, it was confirmed that the infant also had DMD.
CASE REPORT
An 8-mo-old, 4.1-kg male infant died 12 h after undergoing an uneventful general anesthetic with sevoflurane, air, fentanyl, and oxygen for the closure of an ileostomy. His parents agreed to the publication of this case report. The infant had undergone eight previous uneventful general anesthetics with volatile anesthetics (Table 1). His ninth and final anesthetic was similar, in that all these anesthetics included sevoflurane and/or isoflurane, and were supplemented with opioids. A depolarizing muscle relaxant was not used during any of these anesthetics.
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This infant was born at 24 wk of gestation with a birth weight of 660 g. His neonatal course was complicated by respiratory distress syndrome, BPD, patent ductus arteriosus, a grade III-interventricular hemorrhage, blindness secondary to retinopathy of prematurity, necrotizing enterocolitis, and sepsis. At the time of this final anesthetic and surgery, the patient was 56 wk postconceptual age and weighed 4.1 kg. The infant's current medical management included IV hyperalimentation through a functional Broviac® catheter, oxygen via a nasal cannula to produce a transcutaneous oxygen saturation of about 91%. He required an occasional dose of furosemide. He also received GoLYTELY and enemas in preparation for his ileostomy closure. A capillary blood gas 3 days before surgery demonstrated a mixed metabolic alkalosis and respiratory acidosis (pH 7.28, Pco2 45, Po2 50, base excess +5). One day before surgery, the infant's metabolic panel was sodium, 140 meq/L; potassium, 3.6 meq/L; chloride, 90 meq/L; bicarbonate, 31 meq/L; blood urea nitrogen, 71 mg/dL; and creatinine, 0.8 mg/dL. At the start of the anesthetic, the infant's vital signs were: heart rate 160 bpm, arterial blood pressure 90/50 mm Hg, and respiratory rate 20 breaths per minute.
In the operating room, general anesthesia was induced with propofol and tracheal intubation was facilitated with rocuronium. Anesthesia was maintained with sevoflurane, oxygen, and air. Routine intraoperative monitoring was performed. Throughout the entire operative procedure, the infant's ET-CO2 was markedly elevated (60–70 torr), and ET-CO2 was unresponsive to changes in ventilation rate, increased fresh gas flows, and depth of anesthesia. Mechanical rather than manual ventilation was used. In addition, he had a persistent tachycardia of 140–160 bpm preoperatively and operatively. The infant's heart rate was not altered during surgery by either deepening the anesthetic with fentanyl and increased concentrations of inspired sevoflurane or by administering IV fluids (15 mL · kg–1 · h–1 of lactated Ringer's solution and 30 mL of 5% albumin, as well as 19 mL/h of IV alimentation solution). There was no evidence of increased oxygen consumption at any time during anesthesia. The total duration of anesthesia and surgery was 3 h and 20 min.
Upon completion of the surgical procedure, the patient was transported back to the NICU with an endotracheal tube in place. He continued to receive mechanical ventilatory support, as planned preoperatively. On arrival in the NICU, his axillary temperature was 36.8°C, heart rate was 173 bpm, and arterial blood pressure was 86/43 mm Hg. The infant remained stable during the initial postoperative period, but over the ensuing 12 h, he developed a profound hypokalemia (K+: 2.3 meq/L), hypocalcemia (ICa2+: 0.5 meq/L, normal 0.9–1.1 meq/L), hypomagnesemia (Mg2+: 1.0–1.1 meq/L, normal 1.7–2.5 meq/L), a progressive metabolic acidosis, and no urine output. The infant's temperature began to increase 5 h postoperatively. Six hours postoperatively, his forehead skin temperature was >38°C. There was increased serum creatinine (1.1 mg/dL) and evidence of a coagulopathy developed with prothrombin time of 25.9 s, activated partial thromboplastin time of 93.7 s, and an international normalized ratio of 2.4. In addition, new onset left-sided focal seizure activity occurred and was controlled with IV phenobarbital.
Acute sepsis was the clinical diagnosis entertained by the neonatal team. Antibiotic therapy was instituted initially with vancomycin and ceftazidime (Fortaz®). When there was further clinical deterioration, antibiotic therapy was changed to piperacillin with tazobactam (Zosyn®). After 8 h in the NICU, the infant became hypotensive and required ionotropic support with dopamine and epinephrine, and increased ventilatory support. The infant's rectal temperature reached a maximum of 43°C 11 h postoperatively. A surgical consultant found the abdomen to be unremarkable. An arterial blood gas 12 h after the surgery was pH 7.09, Pco2 79, Po2 72, HCO3 24 meq/L, with base excess –8 meq/L. Blood cultures drawn at that time were later found to be negative. The baby continued to deteriorate even with continued intensive therapy. During the last hour of his life, a transthoracic echocardiogram was performed demonstrating poor contractility of both ventricles in the presence of both dopamine and epinephrine continuous infusions. Ultimately, the infant became bradycardic (heart rate <50 bpm). Ventilatory support was withdrawn after consultation with the child's parents and he was held by his parents until he died. After the infant's death, the mother revealed for the first time that her brother and her uncle had both died of DMD, and she requested that special muscle staining be performed during the autopsy to determine if the baby also had DMD.
Postmortem examination demonstrated significant changes in the skeletal muscle (Fig. 1). No evidence of fiber-type grouping or type-specific atrophy, red ragged fibers, or central cores was seen on special staining. Immunohistochemical stain for the dystrophin rod domain (dys1) (Fig. 2) and for the dystrophin c-terminus (dys2) yielded no normal staining (Fig. 3). Immunohistochemical staining for merosin, adhalin, and dysferlin all showed normal staining patterns. These skeletal muscle findings were consistent with DMD.
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Kidney sections revealed numerous dilated tubules with focal tubular epithelial damage and intraluminal red cell and proteinaceous debris: an immunohistochemical stain for myoglobin was positive in some of the dilated tubules. Postmortem serum creatine kinase and lactate dehydrogenase were both elevated at 21,093 and 21,393 IU, respectively. Other postmortem findings included multiple tissue hematomas and petechiae, cholestatic hepatomegaly, pulmonary hypertension, and BPD. There was no evidence of recent bleeding in the brain. One of the postmortem blood cultures was positive for coagulase-negative Staphylococcus, which was not considered a contributory pathogen in this case.
DISCUSSION
This critically ill infant died <24 h after receiving a propofol, fentanyl, sevoflurane, and rocuronium anesthetic. During and after surgery, he had increased ET-CO2, not responsive to ventilatory changes, and tachycardia. Several hours later, his temperature increased to a critical level (1) and hypokalemia, rhabdomyolysis, and renal failure ensued. His death was initially presumed to be due to sepsis. After the death of this infant, the family history of DMD was first discussed. Autopsy confirmed the presence of DMD.
DMD occurs in 1 of 3500 live male births. It may be asymptomatic before the age of 5 yr. Anesthesia is usually uncomplicated in the presence of this condition, but exposure to anesthesia can exacerbate the chronic rhabdomyolysis characteristic of DMD. As a result, hyperkalemic cardiac arrest can occur during or after anesthesia in children with DMD. In the absence of relevant family history, there are few signs of occult DMD that can be observed in infants and young children. Resting tachycardia is common (2) in patients with DMD and is suggestive of early neuroautonomic dysfunction (3). Common electrocardiographic abnormalities include biventricular hypertrophy, tall R-waves in the right precordium, and deep Q-waves in limb and left precordial leads. However, cardiomyopathies do not usually occur in DMD patients younger than 10-yr-of-age (4). In this infant, tachycardia was present and persistent, but readily attributed to his pulmonary disease and preoperative dehydration.
DMD patients with perioperative cardiac arrest may have hyperkalemia and metabolic acidosis as a result of the egress of intracellular fluid from muscle into their blood (5–7). Succinylcholine is expected to cause hyperkalemia in DMD patients. Rare case reports demonstrated that hyperkalemic cardiac arrest can also occur in patients with DMD in the absence of succinylcholine (2,7). In contrast, the infant in this case report had hypokalemia, which required rigorous potassium replacement. Chronic potassium depletion has been shown to increase the risk of rhabdomyolysis, especially during subclinical muscle breakdown (8–10). This infant had been receiving chronic diuretic therapy, and it is likely that there was underlying total body potassium depletion.
Rhabdomyolysis is caused by mechanisms that affect muscle metabolism and muscle membrane integrity (10,11). Causative factors include infection, extremes of temperature (1,12), toxins, metabolic myopathies (13), and muscular dystrophies. In many patients, the cause of rhabdomyolysis cannot be identified (14). This infant is the youngest DMD patient reported to have died within 24 h of surgery, and the only known DMD patient to have experienced eight previous uneventful anesthetics with potent inhaled anesthetics. In this patient, the diagnosis of rhabdomyolysis was made as the result of the postmortem examination. DMD can be definitively diagnosed, as it was in this case, by staining postmortem muscle for dystrophin and excluding other myopathies. Adverse anesthetic events can occur in patients with other myopathies, even in the absence of potent inhaled anesthetics (15). Staining postmortem muscle for dystrophin is a highly sensitive test for DMD. Genetic tests of DMD should be applied preoperatively whenever there is a positive family history of this disease.
Since the presence of DMD is a sufficient explanation for the observed events in this case, the diagnosis and approximate cause of death that is most appropriate for this infant is DMD with rhabdomyolysis and an associated critical fever. We have no further explanation why these complications were not observed after any of the previous eight general anesthetics. We agree with a recent discussion of the safety of inhaled anesthetics in patients with muscular dystrophy (16) in that, rather than prohibiting the administration of volatile anesthetics for a large proportion of apparently healthy pediatric patients, better screening of pediatric patients with medical problems should be performed. Pediatric anesthesiologists must routinely inquire about family medical history as well as previous anesthetic experiences of all family members. The mother of this infant did not reveal the deaths of two male relatives from DMD while her son was alive. Possibly her reticence was due to the perception that there was a stigma attached to the presence of this familial disease or because of her lack of awareness of the serious complications that can occur after anesthesia in patients with DMD. Clearly, she is at risk due to her status as a carrier of DMD. Genetic counseling and referral of the mother to a cardiologist are important interventions for this family.
Footnotes
Accepted for publication June 20, 2007.
Dr. Peter J. Davis, Section Editor for Pediatric Anesthesiology, was received from all editorial decision related to this manuscript.
REFERENCES
2 (merosin) deficiency in the absence of a triggering agent. Ped Anesth 2006;16:462–5This article has been cited by other articles:
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  A. Choiniere Could This Be Malignant Hyperthermia? Anesth. Analg., April 1, 2008; 106(4): 1327 - 1328. [Full Text] [PDF]
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