A 7-month-old male Siberian Husky was referred to the Veterinary Teaching Hospital at the University of Berne because of nonambulatory tetraparesis. The dog had an acute onset of hind limb weakness 3 days prior to referral. The referring veterinarian initiated treatment with meloxicam (0.2 mg/kg [0.09 mg/lb], IV, q 24 h) soon after the onset of the clinical signs, but no improvement was observed.
During physical examination at our veterinary teaching hospital (day 0), the dog was nonambulatory with tetraparesis; however, postural reactions were within anticipated limits. The dog had generalized weakness and a decrease in muscle tone, especially in the hind limbs and neck. Assessment of spinal reflexes revealed generalized hyporeflexia. Panniculus and perineal reflexes were difficult to evoke. Cranial nerve evaluation revealed a decrease in sensation and jaw tone. Results of a serum biochemical analysis and CBC revealed CK activity (181 U/mL; reference range, 64 to 390 U/mL) within the reference range, hypoalbuminemia, and leukocytosis. Urine analysis results revealed severe myoglobinuria. Thoracic radiography revealed moderate interstitial changes in the lungs, involving primarily the caudodorsal lung fields, which was compatible with a diagnosis of early stage interstitial pneumonia. Initial differential diagnoses included myasthenia gravis, myopathy, and neuropathy.
General anesthesia was required to perform electrodiagnostic testing on day 1. Physical examination prior to anesthesia revealed a slightly high rectal temperature (39.1°C [102.4°F]; reference range, 38° to 38.5°C [100° to 101°F]), and an increase in expiratory sounds was detected during auscultation of the caudodorsal lung fields on both sides of the thorax. Following intravenous catheterization, the dog was premedicated with butorphanol tartrate (0.3 mg/kg [0.14 mg/lb], IV). General anesthesia was induced with propofol (2 mg/kg [0.9 mg/lb], IV) administered to effect to allow endotracheal intubation. The endotracheal tube was then connected to a circle breathing system, and administration of isoflurane in 100% oxygen was begun. The vaporizer setting was adjusted to achieve an adequate plane of anesthesia. An isotonic crystalloid solutiona was administered IV at a rate of 10 mL/kg/h (4.5 mL/lb/h). Blood pressure was measured via a noninvasive oscillometric technique. The dog was connected to an ECG machine and a capnometer.b Heart rate, SAP, DAP, MAP, RR, and Petco2 were monitored and recorded at 5-minute intervals.
Electrodiagnostic testing (repetitive nerve stimulation, electromyography, and nerve conduction velocity) was conducted on the left side of the body of the anesthetized dog. Structures evaluated included the muscles of the trunk and limbs and the peroneal nerve. Results for all the electrodiagnostic tests were within reference limits. These results, in addition to negative results for the acetylcholine-receptor antibody and edrophonium tests, ruled out myasthenia gravis and most other neuropathies or myopathies as possible diagnoses.
Forty minutes after initiation of isoflurane administration, a moderate increase in Petco2 (65.4 mm Hg; reference range, 35 to 45 mm Hg) was observed, and the rectal temperature increased to 39.6°C (103.3°F). Isoflurane administration was discontinued immediately, the endotracheal tube was disconnected from the breathing system, and pure oxygen was administered until the dog recovered from anesthesia. The dog's rectal temperature 5 minutes after the discontinuation of isoflurane was 40°C (104°F). Active cooling of the body core was performed by application of ice packs to the body surface and alcohol to the foot pads until the rectal temperature was reduced to 39.1°C. A venous blood gas analysis performed 90 minutes after the discontinuation of isoflurane revealed a decreased venous Pco2 (33.2 mm Hg; reference range, 37 to 47 mm Hg) and electrolyte values within reference ranges.
The dog's condition deteriorated during the next 4 days. On day 5, the dog was anesthetized again to obtain muscle and nerve biopsy specimens for diagnostic purposes. Physical examination prior to anesthesia revealed an increase in inspiratory and expiratory sounds for both lungs. Rectal temperature was 39.3°C (102.7°F), and serum biochemical analysis revealed a large increase in CK (55,030 U/mL) and liver enzyme values (aspartate transaminase, 3,946 U/mL [reference range, 20 to 73 U/mL]; alanine transaminase, 1,642 U/mL [reference range, 24 to 124 U/mL]; and glutamate dehydrogenase, 11 U/mL [reference range, 1 to 7 U/mL]). After premedication with fentanyl (10 μg/kg, IV), the dog was preoxygenated by use of a flow-by ventilation technique for 5 minutes. Anesthesia was induced with propofol (2.5 mg/kg [1.2 mg/lb], IV), which was slowly administered to effect to allow endotracheal intubation. The circle breathing system was flushed with fresh oxygen at a flow rate of 10 L/min for 5 minutes before being connected to the endotracheal tube. Once the system was connected, the dog was administered only 100% oxygen through the circle breathing system. Anesthesia was maintained with propofol (0.4 mg/kg/min [0.18 mg/lb/min], IV) and fentanyl (10 μg/kg/min, IV) administered via CRI. Blood pressure was measured invasively via a catheter placed in a metatarsal artery. The dog was connected to an ECG machine and an end-tidal gas analyzer,c and HR, SAP, DAP, MAP, RR, and Petco2 were monitored and recorded at 5-minute intervals. An isotonic crystalloid solutiona was administered IV at a rate of 10 mL/kg/h. Even though the circle breathing system was purged before being used on this dog, the end-tidal gas analyzer recorded an FiIso of 0.3%.
Ten minutes after induction, the dog developed severe hypercapnia (Petco2, 100 mm Hg) and hyperthermia (40.3°C [104.5°F]). The dog's HR was 130 beats/min, SAP was 145 mm Hg (reference range, 100 to 130 mm Hg), DAP was 80 mm Hg (reference range, 60 to 80 mm Hg), MAP was 95 mm Hg (reference range, 80 to 100 mm Hg), and RR was 60 breaths/min. Intermittent positive-pressure ventilation was started 30 minutes after intubation by use of a volume-controlled ventilator set to deliver a mean tidal volume of 20 mL/kg (9.1 mL/lb) at an RR of 20 breaths/min. This resulted in a peak inspiratory pressure of 20 cm H2O. At this point, SAP was 125 mm Hg, DAP was 60 mm Hg, and MAP was 90 mm Hg. To reduce the core body temperature, cold crystalloid solutions were administered IV, the abdomen was shaved, and towel-covered ice packs were applied to the skin of the abdomen. The rectal temperature continued to increase. Thirty minutes after beginning mechanically controlled ventilation (60 minutes after intubation), Petco2 decreased substantially (Table 1). Sixty minutes after beginning mechanical ventilation (90 minutes after intubation), the dog was weaned from the ventilator and allowed to breath spontaneously through the circle breathing system; Petco2 increased from 55 to 63 mm Hg. Despite aggressive cooling measures, the rectal temperature continued to increase to 41.6°C (106.9°F). Because dantrolene was not available in the hospital, acepromazine maleate was administered (10 μg/kg, IV) to facilitate a decrease in body temperature by the induction of vasodilation. Twenty minutes after administration of acepromazine, rectal temperature was 41.2°C (106.2°F). Administration of propofol and fentanyl was discontinued 140 minutes after intubation, and the fraction of inspired oxygen was decreased by the addition of 50% room air to the fresh gas flow. Because the dog was able to maintain an arterial oxygen saturation > 97%, it was disconnected from the circle breathing system and allowed to recover from anesthesia in the intensive care unit of the hospital. Oxygen supplementation (1.5 to 2 L/min) was provided via a double nasal catheter. Rectal temperature at extubation was 38.8°C (101.8°F). Serum biochemical analysis of a sample obtained at the time of recovery revealed marked increases in CK (180,950 U/mL) and liver enzyme activities (aspartate transaminase, 7,940 U/mL; alanine transaminase, 2,005 U/mL; and glutamate dehydrogenase, 13 U/mL). Oxygen supplementation was discontinued when the dog could maintain arterial oxygen saturation > 95% while breathing room air, which was approximately 24 hours after the end of anesthesia. The dog was treated with clindamycin (12 mg/kg [5.5 mg/lb], PO, q 12 h) and metronidazole (12 mg/kg, PO, q 12 h) for 8 days after recovery from anesthesia. Crystalloid solutions were also administered IV at an infusion rate of 2 mL/kg/h for 4 days starting at day 5.
Data recorded for a 7-month-old male Siberian Husky with nonambulatory tetraparesis while it was anesthetized for the second time within 5 days; the dog developed severe MH during the anesthetic episode.
| Time after intubation (min) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Variable | Reference range | 30* | 60 | 90† | 120 | 150‡ | 180§ | 210§ |
| Arterial blood pH | 7.37–7.43 | 7.16 | 7.26 | 7.10 | 7.10 | 7.13 | 7.30 | 7.25 |
| Inspired fraction of oxygen (%) | 21–100 | 97 | 90 | 90 | 90 | 90 | 30 | 30 |
| Pao2(mm Hg) | 95–108 | 109.4 | 107.6 | 153.3 | 159.1 | 168.2 | 54.3 | 75.8 |
| Arterial oxygen saturation (%) | 97–100 | 96.4 | 97.1 | 98.1 | 98.3 | 98.5 | 84.6 | 92.7 |
| Petco2 (mm Hg) | 35–45 | 69.9 | 54.9 | 63.2 | 80.5 | 86.5 | 50.4 | 56.4 |
| Paco2(mm Hg) | 34–40 | 75 | 57.1 | 92.7 | 81.5 | 81.7 | 52.8 | 60.1 |
| Rectal temperature (°C [°F]) | 38–38.5 (100–101) | 40.3 (104.5) | 41.0 (105.8) | 41.6 (106.9) | 41.2 (106.2) | 40.0(104) | 38.8(101.8) | 38.6(101.5) |
| HR(beats/min) | 70–110 | 140 | 125 | 135 | 132 | 115 | 120 | 120 |
| MAP (mm Hg) | 80–100 | 98 | 110 | 95 | 98 | 80 | — | — |
Anesthesia was induced and maintained with a CRI of propofol and fentanyl until 140 minutes after intubation at which time the administration of both drugs was discontinued.
Beginning of mechanical ventilation.
Weaning from the ventilator and administration of acepromazine.
Reduction of the inspired fraction of oxygen to 50%.
Administration of supplemental oxygen via nasal catheter.
— = Not determined.
Histologic examination of muscle and nerve biopsy specimens did not reveal any pathological abnormality. A genetic test (PCR assay) to determine whether the dog had a mutation of the RYR1 gene, a genetic disorder associated with MH, yielded negative results. On the basis of clinical features, and because other neuromuscular disorders that might have provoked similar clinical signs had been excluded, we concluded this dog was most likely affected by a channelopathy-based muscle disorder.
The clinical condition of the dog progressively improved, and the dog was discharged to the owner after 13 days of hospitalization. At the time of discharge, the dog had a good appetite and was ambulatory, although it still had signs of tetraparesis. Three months after discharge, the owner reported that the dog was clinically normal.
Discussion
Malignant hyperthermia is an autosomal dominant pharmacogenetic disorder of skeletal muscle typically triggered by halogenated volatile anesthetics and depolarizing muscle relaxants.1,2 In dogs, susceptibility to MH is thought to be caused by a mutation of RYR1,1 the gene mediating calcium-release channels in skeletal muscle, which results in altered regulation of calcium within skeletal muscle fibers. The most common clinical features of MH in dogs are hypercarbia, hyperthermia, and cardiac arrhythmias, with increased production of carbon dioxide being the most prominent sign. Moderate metabolic acidosis and myoglobinuria may also develop. In contrast to MH in pigs, other clinical signs such as lactic acidosis and muscle rigidity are not typically observed in dogs with MH.1,2
The present case report provides a description of an unusual manifestation of MH in a dog in which no mutation of the RYR1 gene was detected, which resulted in the speculation that the MH was caused by a muscle channelopathy. The dog was anesthetized twice within a 5-day period. It is interesting that the more severe, life-threatening manifestation of MH happened the second time the dog was anesthetized, during which injectable anesthetic agents thought to be less likely to trigger MH were used. In contrast, isoflurane (a compound associated with triggering MH) was used the first time the dog was anesthetized but caused only moderate hypercarbia and mild hyperthermia.
One possible explanation for the severe manifestation of MH the second time the dog was anesthetized might be poor preparation of the anesthesia machine. New guidelines for the preparation of an anesthesia machine before usage with human patients susceptible to MH3 require decontamination of the apparatus by the removal of the vaporizer and the replacement of each part of the machine that might have been in contact with a volatile agent. The gas flow circuit should be flushed with fresh gas at a rate of 10 L/min for a minimum of 10 minutes, with the recommendation that newer machines need a substantially longer time to flush out any residual inhalation anesthetic agent, compared with the time needed to flush out old-style machines. The goal during decontamination of an anesthesia machine is to achieve a residual anesthetic concentration < 5 ppm. The anesthesia machine used for the dog in the present report was flushed for only 5 minutes, the vaporizer was not removed, and the components of the breathing system were not replaced. As a result, the gas analyzer still measured an FiIso of 0.3% for the first few minutes during which supplemental oxygen was provided to the dog via the breathing system.
In MH-susceptible patients, even a small FiIso can trigger the syndrome.3 However, this does not explain the reason that the manifestation of MH was more severe with such a low FiIso (0.3%), compared with the reaction to much higher values of FiIso (1.5% to 2%) recorded during the first anesthetic episode. Furthermore, this dog had negative results when tested for a mutation of the RYR1 gene, a defect that is commonly associated with MH following the administration of halogen-based anesthetic agents such as isoflurane.
Because the dog had an MH-like syndrome when it was anesthetized with isoflurane, the use of propofol and fentanyl administered via CRI was chosen for induction and maintenance of anesthesia in the dog the second time it was anesthetized. This decision was made on the basis that, among the nonvolatile compounds, propofol and opioids are considered the safest injectable agents for the anesthetic management of MH-susceptible patients.2,3
In pigs and dogs, volatile anesthetics trigger MH by increasing the efflux of calcium ions from the sarcoplastic reticulum, which is a process mediated by the RYR1 gene.1,2 An in vitro study4 performed on human skeletal muscle cells revealed that propofol does not activate RYR1-mediated calcium ion channels and therefore cannot directly trigger MH like volatile anesthetics do. However, propofol and volatile anesthetics have similar effects on calcium ion-AT Pase channel activity at the level of the sarcoplastic reticulum of skeletal muscle.4 A study5 performed in vitro on human astrocytoma cells revealed that propofol affects intracellular calcium homeostasis by increasing calcium ion concentrations in mitochondria. Severe MH characterized by a marked increase in body temperature and a hypermetabolic state has been reported in a woman anesthetized with a CRI of propofol and fentanyl but no exposure to inhaled anesthetics.6 The authors of that report6 hypothesized that propofol as well as inhalation anesthetics might be triggering agents for MH. Administration of opioids has also been reported to cause increases in body temperature and hypercapnia in cats7 and dogs8 under certain conditions.
Although it is possible that propofol or fentanyl aided in triggering the MH in the dog reported here, we believe the MH was more likely caused by preexisting conditions in the dog. The presence of an intercurrent genetic muscle disease2 can put an animal at risk for developing a perianesthetic MH-like syndrome, irrespective of the animal's genetic makeup and the anesthetic protocol used. In human patients, there is a link between the perianesthetic manifestation of MH and the presence of several genetic-based disorders involving the skeletal muscle ion channels that are broadly known as ion channelopathies.3,9–12 The dog of the present report was most likely affected by a channelopathy involving the skeletal muscle cells, which resulted in severe myopathy and extreme muscle weakness. It is therefore hypothesized that the channelopathy was the primary cause of MH in this dog, and the severity of MH the second time the dog was anesthetized was attributable to the compromised clinical condition of the dog, rather than the anesthetic agents used. We believe that anesthetizing the dog, independent of the anesthetic agents used, altered the activity of the calcium ion channels in the skeletal muscle and triggered the clinical manifestation of MH.
Dantrolene is currently the recommended therapeutic agent for the treatment of MH.2,3 It is an intracellular calcium antagonist that has skeletal muscle relaxant properties and should be administered immediately after the recognition of MH.2 Unfortunately, because of its high cost and the low incidence of MH as an anesthesia-related complication, dantrolene is not always available in all veterinary institutions. We decided to administer acepromazine as a palliative treatment to facilitate decreasing the body temperature. Although acepromazine has no effects on the intracellular calcium regulation of skeletal myocytes and cannot be considered an alternative to dantrolene in the management of MH, this sedative drug can be effective in decreasing body temperature. Acepromazine induces hypothermia by acting at the central level by depleting the concentration of catecholamines in the thermoregulatory center of the hypothalamus and at the peripheral level by blocking α1-adrenergic receptors, the latter of which results in vasodilation and loss of body heat.13 To our knowledge, the use of acepromazine for decreasing body temperature during MH has not been described in human or veterinary patients; however, if dantrolene is not available, administration of acepromazine might be considered as an option for the palliative treatment of hyperthermia until dantrolene can be obtained.
In the dog reported here, clinical signs were evident as episodic attacks and resolved without specific treatment. Little is known about the clinical syndrome and prognosis of channelopathies in skeletal muscle in dogs. However, many muscle channelopathies, such as periodic paralyses, myotonic syndromes, and congenital myasthenic syndrome, described in humans are characterized by recurrent attacks of muscle weakness and can progress to the inability to stand, often followed by spontaneous resolution of the clinical condition.14
Every patient affected by a genetic muscle disorder should be considered at risk for developing perianesthetic MH. For safe anesthetic management of these patients, adequate decontamination of the anesthetic machine and the use of anesthetic agents not associated with MH for the induction and maintenance of anesthesia are necessary. Also, sufficient quantities of dantrolene should be available when MH-susceptible patients are anesthetized.
ABBREVIATIONS
| CK | Creatine kinase |
| CRI | Constant rate infusion |
| DAP | Diastolic arterial pressure |
| FIIso | Inspired fraction of isoflurane |
| HR | Heart rate |
| MAP | Mean arterial pressure |
| MH | Malignant hyperthermia |
| Petco2 | End-tidal partial pressure of carbon dioxide |
| SAP | Systolic arterial pressure |
| RR | Respiratory rate |
Plasma-Lyte A, Baxter AG, Volketswil, Switzerland.
Datex Normocap, Datex-Ohmeda GmbH, Duisburg, Germany.
Datex Ohmeda, Anandic Medical System AG, Berne, Switzerland.
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