Intra-operative hyperthermia in a young Angus bull with a fatal outcome

Abstract

A healthy, 9-month-old black Angus bull was presented for elective penile-preputial translocation and caudal epididymectomy. After premedication and induction, general anesthesia was maintained with inhalant anesthetic. Over an hour into the anesthetic period the bull developed severe hyperthermia and hypercapnia that resulted in fatality despite treatment efforts.

Case description

A 9-month-old black Angus bull weighing 350 kg was presented for elective penile-preputial translocation and caudal epididymectomy. The animal was feral, but to the clinician’s knowledge was healthy. For the anesthesia, the bull was run in to a mobile head gate and a left jugular catheter was placed using a 14-gauge, 13.3-cm catheter (BD Angiocath; Infusion Therapy Systems, Sandy, Utah, USA). Preoperative blood gas evaluation revealed no abnormalities. For sedation, 0.1 mg/kg of xylazine (Rompun; Bayer Animal Health, Mississauga, Ontario) was administered intravenously (IV) and 5 min later anesthesia was induced with a 5% solution of guaifenesin (Guaifenesin Powder; Galenova, St. Hyacinthe, Quebec), 34 mg/kg body weight (BW) and ketamine (Ketaset; Zoetis, Kirkland, Quebec), 3 mg/kg BW, IV. A 20-mm internal diameter cuffed endotracheal tube was placed and connected with a circle system to a large animal anesthesic machine for maintenance of anesthesia with isoflurane (AErrane; Baxter Corporation, Mississauga, Ontario) vaporized with pure oxygen. The bull was positioned in dorsal recumbency on a padded surgery table (Haico; Loimaa, Finland). Intermittent positive pressure ventilation was applied with a tidal volume of 4 L/min, a respiratory rate of 7 breaths/min, and peak inspiratory pressure (PIP) of 18 cm H₂O. A 22-gauge, 2.5-cm catheter (BD Insyte-W; Infusion Therapy Systems) was placed in the auricular artery and connected to a pressure transducer, previously calibrated and zeroed at the height of the manubrium. Advanced monitoring using a multiparameter monitor (Cardiocap 5; Datex-Ohmeda, Wisconsin, USA) included direct blood pressure, sidestream capnography, end-tidal inhalant concentration, and electrocardiography. Isotonic fluids (LRS, Baxter Corporation, Mississauga, Ontario) were administered IV at 5 mL/kg BW per hour and additional analgesia was provided with lidocaine (Lidocaine 2%; Baxter Corporation), 2 mg/kg BW, IV, administered at 15 min post-induction.

Physiologic parameters recorded during anesthesia are presented in Table 1. At 30 min post-induction the bull’s cardio-respiratory function and anesthetic depth were considered adequate and an arterial blood gas revealed no significant abnormalities (Table 2). At 75 min post-induction a progressive increase in heart rate from 55 to 70 beats/min and an end-tidal carbon dioxide (ETCO₂) from 38 to 60 mmHg was noticed, which caused the bull to start bucking the ventilator. A second arterial blood gas revealed a respiratory acidosis with moderate elevation in arterial CO₂ and a decrease in the arterial O₂ tension (Table 2). A nasopharyngeal temperature probe was placed and revealed mild hyperthermia (39.5°C). Active cooling was initiated using ice packs and the ventilator settings were adjusted to a tidal volume of 7 L/min and respiratory rate of 12 breaths/min, resulting in a PIP of 40 cm H₂O. The surgery was in progress and there was no possibility to stop the procedure due to the invasiveness of the dissection at the time. Up to 120 min post-induction ETCO₂, temperature, and heart rate had progressively and dramatically increased with presence of ventricular tachycardia, a decrease in mean arterial blood pressure and signs of cyanosis. The arrhythmia was nonresponsive to treatment with 3 boluses of lidocaine (700 mg, IV, q10min). The anesthetic machine was also noted to become “hot–to–touch.” As a result of these changes the delivery of isoflurane was discontinued, a different machine was used, and the patient was ventilated with 100% oxygen from then on. The patient was started on dobutamine (Dobutamine; Sandoz, Boucherville, Quebec), 0.5 μg/kg BW per min, IV, and the fluid rate increased to free flow to support arterial blood pressure. At 140 min post-induction the heart rate increased to 155 beats/min, the ETCO₂ was 218 mmHg, and the body temperature 43.5°C; the patient then developed ventricular fibrillation which progressed to asystole.

Table 1.

Physiologic parameters during anesthesia

Time from induction (min)	30	75	120	140
Heart rate (beats/min)	55	70	120	155
End-tidal CO2 (mmHg)	38	60	150	218
Respiratory rate (breaths/min)	7	7	12	12
Mean arterial pressure (mmHg)	70	70	40	38
Temperature (°C)	NR	39.5	40.5	43.5
End-tidal isoflurane (%)	1.5	1.5	NR	NR

NR — not recorded.

Table 2.

Arterial blood gas values during anesthesia

Time from induction (min)	30	75
pH	7.469	7.268
PaO2 (mmHg)	449	247
PaCO2 (mmHg)	39.7	66.4
HCO3− (mmol/L)	24.1	25.7
ABE (mmol/L)	4.8	3.0
Na+ (mmol/L)	138	143
K+ (mmol/L)	3.8	4.3
Cl− (mmol/L)	100	103
Lactate (mmol/L)	1.1	3.3

ABE — actual base excess.

Discussion

Malignant hyperthermia is a pharmacogenetic disorder that has been previously reported in a number of species including pigs (1), horses (2,3), dogs (4,5), and cats (6). Most reported clinical cases in veterinary species have resulted in fatality. Malignant hyperthermia is associated with genetic mutations in the ryanodine receptor (RYR1) (1,3,4,7), which is the calcium release channel of the sarcoplasmic reticulum that regulates calcium levels within the myoplasm (3).

Malignant hyperthermia has not been reported in anesthetized cattle. A non-fatal exercise-induced bovine malignant hyperthermia was reported in a group of anxious and hyper-active Brangus cattle of both genders (8). The syndrome was apparent by 1 mo of age and displayed throughout the lives of the cattle. These animals were triggered by noise or induced physical activity and when stressed developed acute hyperthermia, hyperventilation, metabolic acidosis, hyperglycemia, hyperlactatemia, and progressed from tremors to muscle rigidity with associated increases in creatine kinase activity for up to 24 h (8). These signs are similar to those reported for pigs with porcine stress syndrome (malignant hyperthermia), except that in pigs it tends to be fatal (9).

Malignant hyperthermia is initiated by a triggering factor such as halogenated inhalant anesthetics, depolarizing neuromuscular blocking agents, and stress (6). The animal enters a hypermetabolic state secondary to the triggering event, which is the result of excessive amounts of calcium being released from the sarcoplasmic reticulum in skeletal muscle cells, which promotes sustained skeletal muscle contracture and a rapid increase in cell metabolism (10,11). Diagnosis in veterinary patients is typically presumptive based on the affected patient exhibiting at least 3 of the following clinical findings: hyperthermia, hypercapnia, cardiac arrhythmias, muscle rigidity, and acidosis (6,10,11). The bull in the present case developed all but one of these signs, progressing from hypercapnia, hyperthermia, and acidosis, to arrhythmias and death. Rigidity was not obvious during the event. Progression of the syndrome varies between species; in pigs, signs develop within minutes of exposure to the triggering factor (11), whereas horses (3), dogs (5), and cats (6), require longer. Similar to our bull, clinical manifestations in a halothane-anesthetized horse were slow to progress over a period of 140 min (2).

Malignant hyperthermia has not been reported in anesthetized cattle. Beef cattle with phenotypic traits of double muscling (hereditary muscular hypertrophy) and normal carriers of this trait, exhibit at the histological and ultrastructural level conditions also seen in heavily muscled pigs with malignant hyperthermia (12). Red blood cells from double muscled animals and normal carriers for the gene, undergoing osmotic response tests, have an increased rate of hemolysis compared to red blood cells from normal cattle, indicating that there is an association between the erythrocytic osmotic response and the presence of the gene for double muscling (13). An increased rate of hemolysis was also observed in Belgian Landrace pigs that reacted positive to a halothane test for malignant hyperthermia, compared with control pigs (14). The Angus breed has identified individuals as carriers for the double muscled mutation (15,16), present in double-muscled cattle breeds, such as Belgian Blue and Piedmontese. The mutation is present in the sequence of the myostatin gene, which is a member of the transforming growth factor β superfamily, essential for proper regulation of skeletal muscle mass, and when the mutation is present results in an increase in muscle mass (15). The mutation consists of an 11-nucleotide deletion in the third exon of the gene.

The reason for the malignant hyperthermia-like reaction in the bull in this report is uncertain and to the authors’ knowledge, this is the first documented report of a malignant hyperthermia crisis in a bovine species under general anesthesia. Our suspicion is based on research that has shown that malignant hyperthermia reactions are possible in cattle (8) and that double muscled individuals or carriers for this mutation have red blood cells that react similar to pigs that are positive for malignant hyperthermia (13,14). Carriers for the double muscled mutation have been identified in the Angus breed (15,16).

The outcome of this case was fatal despite supportive treatment. The most important step for treatment of malignant hyperthermia under general anesthesia is rapid identification and immediate removal of the triggering factor. In most cases this includes discontinuation and elimination of the inhalant anesthetic, either by flushing the anesthetic circuit with 100% oxygen or utilization of a new anesthetic machine that does not have residual inhalant through the system (10). We did not proceed with urgency, as malignant hyperthermia had not been reported in cattle and the onset of signs did not occur until late during the maintenance of anesthesia. Active cooling is recommended via alcohol baths, ice packs, fans, chilled intravenous fluids and ice-fluid lavage of body cavities (10) and was instituted in our case using ice packs, but the size of the bull limited the benefits of this procedure. Intravenous fluid therapy should be continued, or initiated ideally with a balanced electrolyte solution not containing calcium (5,10); we continued the administration of a calcium-free solution at free flow. The patient should be started on intermittent positive pressure ventilation and hyperventilated in an attempt to improve hypercapnia (10). Despite our efforts at increasing minute ventilation, the ETCO₂ continued to rise and contributed to ventricular arrhythmias. Lidocaine was administered with the goal of slowing the ventricular rate and improving cardiac output; however, lidocaine can result in elevated myoplasmic calcium content, thus exacerbating the syndrome, which makes the use of procainamide a better option (5,10).

Dantrolene is the drug of choice in malignant hyperthermia, to control the adverse effects of excessive intracellular calcium release from the sarcoplasmic reticulum (5). We recognized the importance of administering dantrolene to this bull at the time of the event, but due to its infrequent use and cost, our hospital pharmacy does not keep dantrolene in stock. The surgery team was informed of the events and advised of the possible fatal outcome for this patient.

In summary, to the authors’ knowledge, this is the first documented case of a fatal malignant hyperthermia crisis in a bull under inhalant anesthesia. The clinical manifestation of the syndrome described seemed to progress similar to what has been described in horses. It is not known what the underlying mechanism is and if affected cattle share a similar genetic mutation within the ryanodine receptor as reported in other animal species. Animals suspected to be experiencing a malignant hyperthermia crisis should be treated supportively based on the recommendations outlined for other affected species. CVJ