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Hyperthermia Requiring Prolonged Administration of High-Dose Dantrolene in the Postoperative Period

DeRuyter, Marie L. MD; Wedel, Denise J. MD; Berge, Keith H. MD

Case Reports

Department of Anesthesiology, Mayo Foundation, Rochester, Minnesota.

Accepted for publication November 18, 1994.

Address correspondence and reprint requests to Denise J. Wedel, MD, Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Malignant hyperthermia (MH) is a pharmacogenetic side effect of general anesthesia. There are wide variations in clinical presentation, anesthetic history, symptoms and timing of episodes, and responses to treatment. Episodes of MH have been reported in patients with a history of multiple uneventful triggering anesthetics [1-3]. Furthermore, the clinical presentation can be delayed into the postoperative period [4,5]. There have also been rare reports of prolonged episodes requiring large doses of dantrolene [6-8]. We report a case of delayed triggering requiring prolonged treatment with dantrolene in a patient who had undergone two previous major surgical procedures. MH was subsequently confirmed by in vitro contracture testing.

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Case Report

An 80-kg, 31-yr-old man presented with recurrent hemangiopericytoma for a left occipital craniotomy. Prior to this hospitalization, the patient had undergone two stereotactic brain biopsies with intravenous (IV) sedation (fentanyl, midazolam, and propofol) without complication. He had also received two reportedly uneventful general anesthetics, one for a craniotomy and one for a thoracotomy and pleurodesis. Subsequent review of anesthetic and hospital records from these procedures revealed no evidence of a MH episode. His medical history was negative other than for mild asthma treated with Proventil inhaler (Schering Corp., Kenilworth, NJ) as needed.

General anesthesia was induced at 8:00 AM (Day 1) with thiopental, vecuronium, and fentanyl IV and was maintained with oxygen, isoflurane, and intermittent IV boluses of fentanyl and pancuronium. Standard monitors for this procedure included radial arterial and central venous catheters and transesophageal echocardiography. He was positioned semi-sitting at 30 degrees. During the 8-h anesthetic, expiratory isoflurane concentrations ranged from 0.5% to 1.2% and end-tidal carbon dioxide (ETCO2) ranged from 27 to 32 mm Hg. Esophageal temperature gradually rose from 35.4 degrees C at induction to 37.1 degrees C at the end of the procedure. Heart rate (HR) ranged from 70 to 90 bpm and arterial blood pressure (BP) remained stable throughout the procedure.

During the last hour of surgery, the isoflurane was discontinued and a propofol infusion at 100 micro gram centered dot kg-1 centered dot h-1 was started. At that time, the vital signs were stable and the ETCO2 was 33 mm Hg. At the end of the surgery, the neuromuscular block was reversed with neostigmine and glycopyrrolate IV and propofol was discontinued. The patient did not respond to painful stimuli and was transferred to radiology for an emergent computed tomography (CT) scan of the head during which time the propofol infusion was restarted. The CT scan revealed significant pneumocephalus without hemorrhage; therefore the patient was taken back to the operating room for a twist drill evacuation. Anesthesia was maintained with propofol, isoflurane (expiratory concentrations ranged 0.5%-0.7%), and oxygen. Vital signs were stable, but the ETCO2 had increased to 45 mm Hg. The patient's temperature was not monitored during this 15-min procedure.

The patient was transferred to the postanesthesia care unit (PACU) at 5:00 PM, tracheally intubated and mechanically ventilated. The vital signs on arrival were BP 110/80 mm Hg, HR 100 bpm, Sao2 99%, and tympanic membrane (TM) temperature 37.5 degrees C. The first arterial blood gas (ABG) drawn on PACU admission showed a mixed metabolic/respiratory acidosis: PaCO2 58 mm Hg, pHa 7.19, base excess (BE) -6 mEq/L, HCO3 23 mEq/L, and Pao2 489 mm Hg, with a minute ventilation of 15 L. While waiting for the results of this initial ABG, the TM temperature increased to 38.6 degrees C. A diagnosis of probable MH was made and an initial dose of dantrolene 3 mg/kg IV was given while the patient was placed on a cooling blanket. After dantrolene administration, the metabolic and respiratory acidosis improved (PaCO2 43 mm Hg, pHa 7.38, BE 1 mEq/L, HCO3 25 mEq/L); however, the TM temperature had continued to increase to 38.9 degrees C. A further 1 mg/kg of dantrolene IV resulted in a temperature decrease to 37.9 degrees C. During the next 2 h vital signs and ABGs remained stable; however, the TM temperature again increased to 38.7 degrees C. This temperature increase was treated with a further 2 mg/kg of dantrolene IV. Throughout this period, active cooling, neuromuscular block, and elective mechanical hyperventilation were continued.

The patient was transferred to the neurosurgical intensive care unit with a TM temperature of 37.7 degrees C. He was paralyzed with vecuronium to assist ventilation, and a propofol infusion was begun. Scheduled doses of 1 mg/kg IV of dantrolene were ordered every 6 h. ABGs on arrival were PaCO2 51 mm Hg, pHa 7.36, BE 3 mEq/L, HCO3 29 mEq/L. The initial creatine kinase (CK) 5 h after surgery was 1549 U/L (normal range, 52-336) with a serum lactate of 5.4 mmol/L (normal range, 0.93-1.65). The patient was placed on a cooling blanket.

At 12:30 AM (Day 2), the patient's chest wall musculature was noted to be rigid and the lungs difficult to ventilate. Bladder temperature increased from 37.5 to 38.5 degrees C, and there was an increase in PaCO2 from 32 to 40 mm Hg with no change in ventilator settings. A CK drawn at this time was 2640 U/L. A diagnosis of MH recrudescence was made and dantrolene 3 mg/kg IV was given with additional vecuronium to assist with ventilation. Both temperature and PaCO2 returned to normal after treatment. During the next 36 h the patient had several further episodes of chest wall rigidity and transient temperature fluctuations which would temporarily correct with bolus dantrolene doses (3-4 mg/kg). Laboratory values during these episodes documented increases in CK, serum myoglobin (0.247 ng/mL; normal range, 0-0.09) and lactate levels. Because of these episodes, the intermittent dose of dantrolene (2 mg/kg every 6 h) was changed to a continuous infusion.

An electroencephalogram obtained during an episode of chest wall rigidity indicated no seizure activity, and a repeat CT scan of the head showed no evidence of intracranial bleeding. Thyroid studies and chest radiograph were normal.

The vital signs remained stable for the next 24 h and the CK and lactate levels were decreasing. The dantrolene infusion was decreased to 1 mg centered dot kg-1 centered dot 6 h-1 on the afternoon of Day 3. During the evening the patient had an increase in temperature to 38.4 degrees C and a slight increase in CK to 2566 U/L. The ABG at that time was unchanged. A chest radiograph showed a new pulmonary infiltrate in the right lower base and his white blood cell count was slightly increased to 14,500 cells. It was not clear whether the increase in temperature was due to a pneumonia or a recrudescence of MH. The patient was started on antibiotics and the dantrolene dose was increased to 2 mg centered dot kg-1 centered dot 6 h-1 IV.

On the morning of Day 4, the dantrolene infusion was again decreased to 1 mg centered dot kg-1 centered dot 6 h-1 IV. Core temperature was intermittently mildly increased. The CK had decreased to 872 U/L, and it was thought that the increase of temperature was most likely pulmonary in origin, since the white count had increased to 17,000 cells and the right lower lobe infiltrate on chest radiograph had worsened.

The dantrolene infusion was discontinued on Day 5. The patient had received a total dose of 39 mg/kg IV dantrolene over 4 days. The muscle relaxant and sedation were slowly weaned, and the patient was allowed to awaken. His trachea was extubated the next day. His temperature and white blood cell count decreased and his chest radiograph improved. The patient continued to improve after tracheal extubation.

Approximately 3 mo later, the patient underwent a vastus lateralis muscle biopsy for in vitro contracture testing. The test was conducted according to the North American MH Registry Group protocol [9]. Six bundles were tested with 3% halothane, two with 2% halothane, and six with incremental doses of caffeine. Two muscle bundles had abnormal contractures during halothane administration (1.02 g with 3% halothane and 0.8 g with 2% halothane). A third bundle had a 200-mg increase at 2 mM caffeine. These findings were consistent with MH susceptibility. Examination of frozen sections of muscle showed nonspecific abnormalities consisting of small focal decreases of oxidative enzyme activity.

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Variations in MH presentation can complicate diagnosis and treatment. This case report demonstrates delayed clinical presentation of MH in a patient who had had two previous prolonged anesthetics without difficulty as well as recrudescence, in spite of high-dose dantrolene. The patient was later proven to be MH susceptible by in vitro contracture testing.

MH has been reported to occur in patients with a history of a previous uneventful anesthetic [1,2]. In a recent review of 503 cases of MH, 24% of the adults and 17.5% of the pediatric patients had a median of two prior general anesthetics without complications. In most of these cases, volatile anesthetics and depolarizing and nondepolarizing muscle relaxants were used [3]. In our case, the patient had a thoracotomy, a craniotomy, and two brain biopsies without incident.

There have been several case reports of delayed postoperative triggering up to 11 h after anesthesia [4,5]. The etiology is uncertain, but postsurgical stress may be a factor. MH has also been reported in susceptible patients who underwent "safe" anesthesia (without triggering drugs) with stress again being postulated as the etiology [7,10,11]. The described episodes are inconclusive, and may represent residual effects from the anesthetic or other factors. Our patient had an 8-h procedure which included continuous ETCO2 and temperature monitoring. There was no evidence of a hypermetabolic state during surgery. The patient was transferred for a radiologic procedure at which time HR, BP, and pulse oximetry were monitored and remained stable. However, once the patient arrived in the PACU, he was clearly in a hypermetabolic state as documented by initial ABGs, temperature, and vital signs. Our patient may have triggered during transfer to radiology or during the second anesthetic for the evacuation of the pneumocephalus. Stress should not have been a significant factor, since the patient was sedated continuously throughout the early postoperative period.

There have been case reports of large doses of dantrolene required for treatment of MH [6,7]. An explanation for these large doses is not found readily. Blank and Boggs [8] reported 42 mg/kg of dantrolene was needed to overcome severe muscle rigidity in a 6-yr-old, 25-kg female [4]. They postulated that decreases in blood flow to the affected muscles during rigidity might have resulted in a decrease in the amount of drug delivered. It is possible that adequate blood levels of dantrolene are not attained initially with the loading dose [6]. The standard recommendation for dantrolene treatment in MH is 2.5 mg/kg initially with additional doses up to 10 mg/kg if symptoms do not resolve, followed by IV maintenance doses of 1 mg centered dot kg-1 centered dot 6 h-1 for 24-48 h.

Our patient's metabolic acidosis and increase in temperature responded to the initial 5 mg/kg of dantrolene in the PACU. However, 6 h later he developed episodes of muscle rigidity associated with increases in temperature, PaCO2, CK, lactate, and serum myoglobin thought to be recrudescence of MH. Dantrolene blood levels were not measured in our patient; however, all drug was delivered IV through a central line, so issues of variable absorption associated with oral ingestion are not applicable. Muscle rigidity and temperature quickly corrected after each dose of dantrolene, and once the patient was placed on a continuous infusion the episodes subsided, suggesting that decreased perfusion of affected muscles was not an issue. Prolonged anesthetic exposure to isoflurane may theoretically result in tissue deposition, with gradual redistribution resulting in continued triggering in the postoperative period. However, our patient received very low doses of a volatile anesthetic during the surgical procedure and had a lean body mass with minimal fat stores.

Other possible etiologies for the postoperative problems in our patient were considered. An electroencephalogram obtained on Day 2 showed no seizure activity. A CT scan of the head excluded hemorrhage or other intracranial etiologies for the temperature increase. Thyroid studies were normal.

The temperature increase on Day 2 was thought to be secondary to recrudescence of MH because it coincided with the muscle rigidity and increases in CK, lactate, serum myoglobin, and PaCO2. On Day 3, the muscle rigidity resolved but the patient continued to have temperature and CK increases. At this point the chest radiograph, which previously had been clear, showed an infiltrate and the white cell count was increased. This process worsened during the time that the episodes of MH appeared to be subsiding, but was not thought to have been a factor during the first two postoperative days.

This case represents an unusual presentation of MH for several reasons: the patient had undergone two prolonged anesthetics prior to this exposure without triggering, the onset was delayed, and a large dose of dantrolene was required for treatment. The postoperative course was confounded by a late developing pulmonary infection. Several case reports have presented these problems individually, but in most cases the patients have not had a diagnosis of MH confirmed by muscle biopsy. The administration of dantrolene via continuous infusion may result in more consistent blood levels and a decreased risk of recrudescence.

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