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CARDIOVASCULAR ANESTHESIA

Malignant Hyperthermia Following Systemic Rewarming After Hypothermic Cardiopulmonary Bypass

Adam D. Lichtman, MD^*, and Charles Oribabor, MD

Department of *Anesthesiology, Weill-Cornell Medical Center, New York, New York; and Cardiothoracic Intensive Care Unit, New York Methodist Hospital, Brooklyn, New York

Address correspondence and reprint requests to Adam Lichtman, MD, 356 Clinton Street #2, Brooklyn NY 11231. Address e-mail to divemd{at}att.net.

	Abstract

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Malignant hyperthermia (MH) is a rare hypermetabolic disorder of skeletal muscle that can be fatal if not recognized and treated aggressively. We describe a patient with a suspected family history of MH who developed hyperpyrexia, acidosis, and hypermetabolism after cardiac surgery despite a nontriggering anesthetic. No drugs were identified as being causative and we theorize that systemic rewarming was the inciting cause of MH in this MH-susceptible individual via a mechanism similar to heat stroke.

	Introduction

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Malignant hyperthermia (MH) is a rare hypermetabolic disorder of skeletal muscle that is often inherited as an autosomal dominant trait and that appears on exposure to potent inhaled anesthetics and depolarizing muscle relaxants. If not treated quickly and aggressively MH results in extremely high mortality.

Several case reports have been published which describe patients who developed MH during or after cardiopulmonary bypass (CPB). The common theme in these reports is unexplained hyperthermia, acidosis, and hypercarbia. There are no reports, however, of patients who received a nontriggering anesthetic and developed MH post-CPB.

	Case Report

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The patient, a 54-yr-old 105-kg male, underwent elective coronary artery bypass grafting (CABG) with hypothermic CPB and developed MH postoperatively.

Initially, the patient presented for evaluation before outpatient shoulder surgery. On routine electrocardiogram, nonspecific ST-T changes were noted. This prompted further work-up, and the patient underwent cardiac catheterization that revealed triple vessel coronary artery disease and a normal ejection fraction. His medical history included only hypertension. He took no medications preoperatively (including statins or neuroleptics) and was asymptomatic from a cardiac standpoint. His anesthetic evaluation was significant for a family history of a sister and a nephew having "almost died" during anesthesia; both were assumed to have MH as a result of intraoperative hyperpyrexia, hypotension, cardiovascular collapse, and acidosis. Unfortunately, the diagnosis of MH was not confirmed in either case, as neither muscle biopsies nor genetic testing were performed. The patient’s surgical history included an uneventful nontriggering anesthetic 2 yr earlier.

Because of the presumptive family history of MH, a nontriggering anesthetic was chosen. The night before surgery, following standard procedures, the anesthesia and CPB machines were cleaned to deliver a nontriggering anesthetic. The MH cart was checked and the anesthesia machine was secured to prevent accidental use. Intensive care unit (ICU) staff were instructed on the signs/symptoms and treatment of MH.

After this preparation, the patient was taken to the operating room and after the placement of invasive monitors, general endotracheal anesthesia was induced using a combination of sodium thiopental (250 mg), fentanyl (750 µg), and vecuronium (12 mg). The patient was maintained on a propofol infusion (100 µg/kg/min) with supplemental fentanyl, midazolam, and vecuronium as needed. Arterial blood gas analyses were performed every hour (every 15 min on CPB) and his core temperature was monitored continuously. During the anesthetic there was no evidence of metabolic acidosis or hyperthermia. Coronary artery graft placement was accomplished using hypothermic (32°C) CPB with cardioplegic arrest. This technique was chosen due to surgeon preference despite the potential risk of rewarming as a MH trigger. After graft placement, the patient was rewarmed and separated easily from CPB without the need for inotropes or phosphodiesterase inhibitors. The post-CPB vital signs were normal sinus rhythm at 82 bpm, arterial blood pressure of 116/84 mm Hg, Sao₂ of 100%, pulmonary artery pressures of 22/16 mm Hg, central venous pressure 8 mm Hg, cardiac output of 5.5 L/m, and mixed venous oxygen saturation (Mvo₂) of 76%. Protamine was administered uneventfully and neither vasopressor drugs nor calcium were required to treat protamine hypotension. The patient was taken, fully ventilated with complete neuromuscular blockade, to the ICU. Upon arrival to the ICU, hemodynamics, Mvo₂, and temperature were all within normal limits. No blood transfusions were administered during surgery and the patient received two doses of prophylactic antibiotics intraoperatively.

Approximately 1 h postoperatively the patient’s Mvo₂ decreased from 80% to the 40s. Abdominal rigidity with purple striae and skin mottling were noted. Over the next few minutes the patient’s temperature began to increase, reaching 101°F with generalized muscle rigidity. At this time the patient continued to be fully paralyzed and sedated. No shivering or tonic/clonic activity was noted. Arterial blood gas analyses at this time demonstrated the classic combined respiratory and metabolic acidosis (Fig. 1). More concerning was a venous blood gas collected at the same time that demonstrated a Pco₂ of 72 mm Hg and a Po₂ of 36 mm Hg with an Fio₂ of 0.5.

View larger version (58K): [in this window] [in a new window]   Figure 1. Postoperative arterial blood gas analyses.

A presumed diagnosis of MH was made and the patient was treated accordingly. Serial creatinine kinase (CK) levels were determined acutely and then every 12 h to monitor for signs of rhabdomyolysis (Fig. 2). Initial therapy included placing the patient on 100% oxygen, increasing the controlled minute ventilation (from 12 L/min to 25 L/min), and cooling. Aggressive IV hydration was begun with normal saline and furosemide was given to promote brisk urine output. Dantrolene was ordered and approximately 20 min after the first signs of MH manifested 2 mg/kg of dantrolene was administered IV. After cooling and dantrolene administration, the patient’s temperature, Mvo₂ saturation, and arterial blood gases improved dramatically. Over the following hour, the cardiac output decreased from 5 L/m to 2.8 L/m, the Mvo₂ decreased from 70% to 45%, and the patient’s temperature again increased to 101°F. Atrial pacing at a rate of 80 bpm, epinephrine (2 µg/min), and norepinephrine (5 µg/min) infusions were begun to improve the patient’s hemodynamic status. These pharmacological manipulations resulted in no improvement in either the cardiac output or the Mvo₂, and an additional 2 mg/kg of dantrolene was administered. After this additional dantrolene the Mvo₂ saturation and cardiac output improved so that the norepinephrine infusion was discontinued. Muscle rigidity still was noted in the forearms and the small muscles of the hands and a supplementary dose of 4 mg/kg of dantrolene was administered. Within 4 h of the initial presentation of MH and administration of dantrolene the hyperpyrexia, acidosis, hemodynamic derangements, and muscle rigidity resolved (Fig. 3). Dantrolene 2 mg/kg was given every 6 h and whenever there were decreases in the Mvo₂ or increases in temperature over 99°F. Based on this strategy, in the first 24 h postoperatively a total dose of 16 mg/kg of dantrolene was administered. After treatment, the patient’s arterial blood gas values remained stable and serum creatinine never changed from baseline. He maintained good urine output that continued for the remainder of his admission.

View larger version (73K): [in this window] [in a new window]   Figure 2. Postoperative creatinine kinase values.

View larger version (73K): [in this window] [in a new window]   Figure 3. Temperature, Mvo2 saturation, and response to dantrolene.

The patient remained tracheally intubated/sedated and was extubated uneventfully on the morning of postoperative day two. IV dantrolene was continued every 6 h and oral dantrolene therapy was initiated on postoperative day 3. The postoperative course remained uneventful with oral dantrolene being continued for 4 days after the discontinuation of IV therapy and the patient was discharged to home on postoperative day 10. On discharge from the hospital the patient’s only complaints were profound muscle weakness and nausea associated with oral dantrolene. The patient and his immediate family were counseled extensively regarding MH, the need for medical emergency bracelets, and the location of the nearest testing center for muscle biopsies and genetic testing.

	Discussion

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We report a case of a patient with a family history suggestive of MH undergoing cardiac surgery who developed MH after hypothermic CPB and a nontriggering anesthetic. Several such cases have been reported; however, none has included patients with a presumed history of MH receiving a nontriggering anesthetic (1,2). The classic drugs implicated in the development of MH include the inhaled anesthetics and succinylcholine. Neuroleptic drugs such as haloperidol are associated with neuroleptic malignant syndrome, which manifests several of the signs of MH (hyperpyrexia, hypermetabolic state, and rhabdomyolysis). Other drugs, such as the cholesterol-decreasing statins, can cause rhabdomyolysis. However, increase in CK is not associated with the hyperpyrexia and severe combined acidosis seen in MH. Several drugs commonly used in cardiac surgery have been implicated in the development of MH. These include phosphodiesterase inhibitors and heparin (3). Of these two drugs, this patient only received heparin. Heparin containing the preservative 4-Chloro-m-cresol (4-CmC) has been associated with MH in MH-susceptible swine. However, this does not appear to be clinically relevant, as 200–300 times the dose used clinically is required to elicit this response (4).

One possible explanation for the development of MH in this patient is the use of hypothermia for myocardial protection. Although beneficial from a cardioprotective standpoint, it is problematic in patients with MH. In animal models active rewarming is a trigger for MH (5).

In this case report no drug was identified as a trigger of MH leaving only rewarming and the stress of surgery as possible inciting factors. This hypothesis appears to be supported in clinical practice and animal models (6). Several different species of animals (most notably pigs) develop the classic signs of MH when administered succinylcholine or inhaled anesthetics. They also develop MH in the presence of a stress or a hypermetabolic state (7). In humans, a similar syndrome called the "human stress syndrome" has been implicated in the rhabdomyolysis and hyperpyrexia of heat stroke and in the deaths of healthy young military personnel in training (8,9). In each case, the constellation of signs including hyperpyrexia and the metabolic derangements seen are consistent with MH. Our theory is further supported by the association between MH and heat-related exertional illness (10,11).

In this patient, the first sign of MH was a precipitous decrease in the Mvo₂ saturation as determined by continuous Mvo₂ saturation monitoring. Continuous Mvo₂ saturation measurement proved useful, as it provided an early indication as to the severity of the patient’s MH and acted as a real-time guide to therapy. Immediate improvements in the Mvo₂ saturation and cardiac output after dantrolene therapy were noted, and additional dantrolene was administered using the Mvo₂ saturation as a treatment end-point.

Several items in this patient’s postoperative course were atypical, such as the peak and timing of the CK levels as well as the time to presentation of the signs of MH. Because of muscle breakdown, one would expect an early increase and high peak in CK levels after an acute episode of MH. However, this may not always occur. Antognini (12), in his review of 157 patents who developed MH signs and symptoms and who were tested positive for MH susceptibility, identified a subset that did not mount a large increase in CK levels despite positive susceptibility testing. Of these patients, the 84% who were not given succinylcholine and who developed MH had CK levels <10,000 IU. Notably, one subset who developed clinical MH and received dantrolene had normal CK levels. These data suggest that CK levels may not correlate with the severity of an MH episode. However, high CK levels are correlated with rhabdomyolysis and renal failure and should therefore be quantified in any patient suspected of MH. The fact that our patient’s CK levels peaked on the fourth postoperative day is also unusual. The normal time course would be expected to be within the first 24-48 hours. Perhaps this muscular patient began to leak large quantities of CK only after he began ambulation late on day 3. The CKs continued to increase on day 4 as he continued to mobilize muscular stores, which then approached normal in the days after washout.

Although described in animals, there are no human cases of MH after systemic warming or induced hyperthemia. There is, however, a clear association between MH and heat-related illness. Therefore, in MH-susceptible patients requiring cardiac surgery, normothermia and off-pump CABG might be considered an alternative to traditional hypothermic CPB. Using this hypothesis, the avoidance of active warming might have prevented MH in this patient. This was not considered for our patient because of the absence of agreed-upon evidence that off-pump CABG is on par with traditional CABG.

Because our patient refused testing for MH, we cannot state with certainty that he developed MH. However, despite using a nontriggering anesthetic this patient developed the hypermetabolic syndrome consistent with MH that resolved after treatment with dantrolene and represents the first reported case of suspected MH being triggered by active rewarming after hypothermia.

	Footnotes

 
Accepted for publication September 9, 2005.

	References

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4. Wappler F, Scholz J, Fiege M, et al. 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine. Anesthesiology 1999;90:1733–40.[Web of Science][Medline]
5. Denborough M, Hopkinson KC, O’Brien RO, et al. Overheating alone can trigger malignant hyperthermia in piglets. Anaesth Intensive Care 1996;24:348–54.[Web of Science][Medline]
6. Feuerman T, Gade GF, Reynolds RJ. Stress-induced malignant hyperthermia in a head-injured patient. Neurosurg 1988;68:297–9.
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8. Jardon OM. Physiologic stress, heat stroke, malignant hyperthermia: a perspective. Military Med 1982;147:8–14.
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11. Bendahan D, Kozak-Ribbens G, Confort-Gouny S, et al. A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 2001;93:683–9.[Abstract/Free Full Text]
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Lichtman, A. D. Articles by Oribabor, C. Search for Related Content PubMed PubMed Citation Articles by Lichtman, A. D. Articles by Oribabor, C.