Intra-operative hyperthermia in a cat with a fatal outcome

Veterinary Anaesthesia and Analgesia, 2014, 41, 290–296

doi:10.1111/vaa.12097

CASE REPORT

Intra-operative hyperthermia in a cat with a fatal outcome Sarah M Thomson, Carolyn A Burton & Elizabeth A Armitage-Chan Davies Veterinary Specialists, Manor Farm Business Park, Hitchin, Herts, UK

Correspondence: Sarah M Thomson, Davies Veterinary Specialists, Manor Farm Business Park, Higham Gobion, Hitchin, Herts, SG5 3HR, UK. E-mail: [email protected] Present address: Elizabeth A Armitage-Chan, LIVE Centre, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, UK

Abstract History A four year old male neutered Domestic Short Hair cat presented for general anaesthesia for hind limb orthopaedic surgery. The cat had been anaesthetized four days previously with propofol and isoflurane and made an uneventful recovery. Physical Examination and Management On preanaesthetic examination the cat had a temperature of 38.9 °C and was otherwise healthy. After a premedication of acepromazine and pethidine, anaesthesia was induced with thiopental and maintained with isoflurane in oxygen 50% and nitrous oxide 50%. Increases in heart rate, respiratory rate, end tidal carbon dioxide tension and temperature were observed, occurring sequentially, from 110 to 175 minutes after anaesthetic induction. Despite ceasing all warming measures and attempting to cool the patient, body temperature continued to rapidly rise, reaching 42.5 °C and limb rigidity was observed. Isoflurane administration was stopped and esmolol was administered. Cardiac arrest occurred. Cardio-pulmonary cerebral resuscitation was commenced and a lateral thoracotomy was performed to allow cardiac compressions and internal defibrillation. Atropine, adrenaline, glucose and dopamine were administered and cold saline was instilled into the thoracic cavity. Follow-up Resuscitation was unsuccessful and the cat died. Conclusions A presumptive diagnosis of malignant hyperthermia was made. Malignant hyperthermia 290

should be considered, even if prior exposure to volatile inhalational anaesthesia was uneventful, and prompt and aggressive therapy instituted. Keywords cat, hyperthermia, isoflurane, malignant hyperthermia.

Introduction Hyperthermia results from increased heat production, the inability adequately to dissipate heat produced and, most frequently, a combination of both. Although unusual during anaesthesia, it may occur for a number reasons, the most lethal of which is malignant hyperthermia. Malignant hyperthermia (MH) is a syndrome which manifests when an individual with a genetic susceptibility is exposed to a trigger, such as volatile inhalational anaesthetic agents, succinylcholine or stress (Brunson & Hogan 2004). The incidence of MH in humans is not known, though is reported as between 1 in 4200 to 89,000 anaesthetics involving known triggering drugs (Ording 1985; Rosero et al. 2009; Glahn et al. 2010; Sumitani et al. 2011). It was documented in pigs in 1966 (Hall et al.), which became the experimental model for investigation of the syndrome. In the veterinary literature it has also been reported in horses (Manley et al. 1983; Klein et al. 1989; Aleman et al. 2005) and dogs (Nelson 1991; Adami et al. 2012). MH has been reported in two cats: one after halothane (Bellah et al. 1989) and another after halothane and decamethonium (de Jong et al. 1974). This is the first reported case of suspected MH associated with isoflurane use in a cat.

Fatal intra-operative hyperthermia in a cat SM Thomson et al.

Case history A four year old male neutered Domestic Short Hair cat weighing 5.2 kg, was presented for general anaesthesia and orthopaedic surgery to stabilise a left hock ligament rupture of eight days duration. The cat was anaesthetized using propofol and isoflurane four days previously at the referring veterinary practice for radiography, and was sedated on two occasions with medetomidine and butorphanol for dressing changes. A rectal temperature of 39.2 °C was recorded by the referring veterinary surgeon on first examination, prior to the administration of any drugs. During hospitalization for the week prior to referral the cat’s rectal temperature varied between 39.0 and 39.4 °C. On pre-anaesthetic assessment the cat had a heart rate (HR) of 140 beats minute 1, respiratory rate (fR) of 40 breaths minute 1 and rectal temperature of 38.9 °C. Acepromazine (ACP; Novartis, UK) 0.02 mg kg 1 and pethidine (Martindale Pharmaceuticals, UK) 3 mg kg 1 were administered by intramuscular (IM) injection and, 75 minutes later, anaesthesia was induced by thiopental 1.25% (Thiovet; Novartis) 10 mg kg 1 intravenously (IV) through a 22 gauge catheter (Jelco; Smiths Medical, UK) placed in the left cephalic vein. Topical lidocaine (Intubeaze; Arnolds, UK) was applied to the larynx, prior to placing a 4 mm internal diameter uncuffed endotracheal tube. A heat-moisture exchanger (Portex Thermovent 600; Smiths Medical) was connected and anaesthesia was maintained with the cat spontaneously breathing isoflurane (IsoFlo Vet; Schering-Plough, UK) vaporized in oxygen 100%, delivered via an Ayre’s T-piece with Jackson-Rees modification. In theatre, the cat was positioned in dorsal recumbency on an air warming device (Bair Hugger; Arizant, MN, USA), and nitrous oxide 50% was added to the administered anaesthetic gases 80 minutes after anaesthetic induction. Standard monitoring, using a multiparameter monitor (Kolormon Plus; Kontron Instruments, UK) was applied and included side-stream capnography, anaesthetic agent monitoring, pulse oximetry, oscillometric non-invasive blood pressure, electrocardiography and oesophageal temperature. Enrofloxacin (Baytril; Bayer, UK) 5 mg kg 1 subcutaneously and cefuroxime (Zinacef; GlaxoSmithKine, UK) 22 mg kg 1 IV were administered. Analgesia was morphine (Martindale Pharmaceuticals) 0.3 mg kg 1 IM at 30 minutes post-induction, repeated IV at 165 minutes post-induction and meloxicam (Metacam; Boehringer Ingelheim Vet-

medica, UK) 0.3 mg kg 1 IV. Fentanyl (Sublimaze; Janssen-Cilage Ltd, UK) was administered in response to a HR of 180 or more beats minute 1 in five boluses of 1–2.5 lg kg 1 IV to a total dose of 8.5 lg kg 1 between 95 and 160 minutes post-induction. Hartmann’s solution (Aquapharm No 11; Animalcare Ltd, UK) was infused at 10 mL kg 1 hour 1. A single bolus of gelatin (Haemaccel; Intervet, UK) 10 mL IV was administered at 135 minutes in response to 30 minutes of mild hypotension (mean arterial blood pressure (MAP) was 54 to 59 mmHg); MAP increased to 65 mmHg. Physiological data are summarized in Table 1. Heart rate was 180 beats minute 1 at 110 minutes and started to steadily increase despite fentanyl boluses, and reached 286 beats minute 1 at 170 minutes. At 140 minutes, fR increased from 22 to 32 breaths minute 1, and this was followed 10 minutes later by a sudden increase in end-tidal carbon dioxide (PE′CO2) from 4.26 to 7.45 kPa (32 to 56 mmHg). Body temperature started increasing from 36.2 °C at 75 minutes, to 38.9 °C at 140 minutes, rapidly reaching 42.5 °C at 175 minutes. Surgery was completed at 160 minutes and on removal of the drapes, generalized muscle rigidity was evident. Diagnosis and management Initial management, in response to tachycardia, consisted of additional fentanyl 2.5 lg kg 1 IV and morphine 0.3 mg kg 1 IV and increasing the fractional inspired isoflurane concentration. The air warming device was discontinued, heat moisture exchanger removed and ambient room temperature lowered. Despite these measures, 175 minutes after induction of anaesthesia, body temperature was 42.5 °C, HR was 286 beats minute 1 and muscular rigidity was evident in all limbs. Attempts to reduce body temperature with a cold water enema and external ice packs were unsuccessful. Isoflurane was stopped and intermittent positive pressure ventilation performed with 100% oxygen, although the breathing system was not changed. Esmolol (Brevibloc; Baxter, UK) 0.05 mg kg 1 was administered IV and the HR lowered from 256 to 82 beats minute 1. Asystole occurred at 195 minutes and external chest compressions were commenced. Five minutes later, a left lateral thoracotomy was performed to allow direct cardiac massage and cold sterile saline was instilled into the thoracic cavity. Ventricular fibrillation was evident, so two cycles of

© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 290–296

291

292

95

180

24

3.46 26 88 63 37.1 1.6 1st dose Fentanyl

80

145

21

3.72 28 – – 36.5 2 Start surgery

4.52 34 89 60 38.1 1.9 Gelatin

22

195

135

4.26 32 96 60 38.9 1.6 4th dose fentanyl

32

204

140

6.78 51 100 65 38.9 1.6

28

215

145

7.45 56 112 55 39.1 1.6

27

220

150

7.32 55 122 52 40.5 1.8 5th dose fentanyl. Stop active warming. End surgery

34

250

160

100 68 41.1 2 Morphine administered

30

252

165

– 42.4 0 Esmolol administered

–

–

– 42.0 2 Moved to radiology, muscle rigidity noted

IPPV

82

190

30

286

170

– 42.5 0 Cardiac arrest (start CPCR)

–

–

165

195

HR, heart rate; fR, respiratory rate; PE′CO2, end tidal carbon dioxide tension; SAP, systolic arterial blood pressure; MAP, mean arterial blood pressure; Temp, temperature; Iso, isoflurane vaporiser setting; – denotes variable not recorded; IPPV, intermittent positive pressure ventilation; CPCR, cardio-pulmonary cerebral resuscitation. Morphine (0.3 mg kg 1) administered at 30 (intramuscularly) and 165 (intravenously) minutes after induction. Fentanyl (doses administered IV) at 95 (1 lg kg 1), 105 (2 lg kg 1), 120 (2.5 lg kg 1), 140 (2.5 lg kg 1) and 160 (2.5 lg kg 1) minutes after induction.

HR (beats minute 1) fR (breaths minute 1) PE′CO2 (kPa) (mmHg) SAP (mmHg) MAP (mmHg) Temp (°C) Iso (%) Event

Time from induction (minutes)

Table 1 Measured variables at different significant time points during anaesthesia

Fatal intra-operative hyperthermia in a cat SM Thomson et al.

© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 290–296

Fatal intra-operative hyperthermia in a cat SM Thomson et al. internal cardiac defibrillation at 3 and 5 Joules (Lifepak 9, Medtronic Physio-Control, UK) were administered. Adrenaline (Hameln Pharmaceuticals, UK) 0.01 mg kg 1, atropine (Hameln Pharmaceuticals) 0.02 mg kg 1, glucose (Hameln Pharmaceuticals) 100 mg kg 1 and a dopamine (Martindale Pharmaceuticals) infusion were administered IV. A venous blood gas sample was collected 30 minutes after cardiac arrest and showed severe metabolic acidosis (pH = 6.945), low venous carbon dioxide tension (pCO2 = 2.14 kPa [16 mmHg]) and hyperkalaemia (K > 9.0 mmol L 1). Cardio-pulmonary cerebral resuscitation was ceased 5 minutes later, at 230 minutes post-anaesthetic induction, and the cat pronounced dead. Further blood collected post mortem revealed a creatine kinase (CK) of over 40,000 U L 1, aspartate transaminase of over 14,000 U L 1 and potassium (K+) of over 30 mmol L 1. Urine was negative for myoglobin. Fresh and formalin-fixed muscle biopsies collected post mortem from the right vastus lateralis and triceps muscles, showed no specific abnormalities or evidence of myopathy. Discussion MH is a pharmacogenetic disorder, associated with mutations in the ryanodine receptor gene (RYR1) in humans (Hopkins 2000), pigs (Fujii et al. 1991) dogs (Roberts et al. 2001) and horses (Aleman et al. 2009), and the dihydropyrindine receptor (CASANA1S) in humans (Hopkins 2000; Brunson & Hogan 2004). The triggering factor, which may include any volatile anaesthetic, succinylcholine or stress, disrupts skeletal muscle myocyte calcium homeostasis, by increasing calcium release from the sarcoplasmic reticulum. Intracellular calcium is increased, resulting in increased cellular metabolism and muscle rigidity (Halsall & Hopkins 2003). Carbon dioxide production increases and tachypnoea occurs in spontaneously ventilating patients, followed by hypercapnia. Tachycardia results from an increase in circulating catecholamines, released in response to a higher oxygen requirement. Heat is generated by muscle contraction and hypermetabolism (Hopkins 2000). In humans, MH is a syndrome with a spectrum of presentations from mild clinical signs, to the less commonly seen fulminant MH (Brunson & Hogan 2004). Variation in clinical presentations also occurs in animal species. Whilst pigs typically exhibit a rapid fulminant progression with muscle

rigidity, tachypnoea, hyperpnoea, hypercapnia, hyperthermia and cardiac arrhythmias (Brunson & Hogan 2004), a slow onset presentation at a second anaesthetic, has also been seen (KW Clarke personal communication). Slower onsets of MH reactions have occurred in horses, with tachycardia and tachypnoea preceding hyperthermia, reported after three hours of halothane anaesthesia (Manley et al. 1983). Descriptions of MH in dogs are an initial hypercapnia, before increases in HR, blood pressure and temperature (Nelson 1991). The diagnosis of MH is further complicated by associations with other channelopathies such as central core disease in humans (Brunson & Hogan 2004). Early recognition of a MH episode is essential to allow rapid treatment, and guidelines regarding the diagnosis and treatment of MH in humans have been recently published (Glahn et al. 2010). In veterinary patients, it has been suggested that a presumptive diagnosis of MH is made if at least three of the following clinical findings are present: cardiac arrhythmias, acidosis, hypercapnia, hyperthermia and muscle rigidity (Brunson & Hogan 2004); four of which were present in this cat. Tachycardia was the first abnormality observed, followed by tachypnoea, then an unexplained hypercapnia; all early clinical signs of MH in humans (Halsall & Hopkins 2003; Glahn et al. 2010). The one symptom of MH that was limited was the hypercapnia; There was a sudden 74.9% increase in PE′CO2 within ten minutes, which may have reflected increased CO2 production, but this reached only 7.45 kPa (56 mmHg), well below the values normally associated with MH, and which could have resulted from a reduced tidal volume associated with anaesthesia and the high dose opioid administration. However, the endotracheal tube was uncuffed, and leakage of respiratory gases around the tube, coupled with the high fresh gas flow rates used could have artificially lowered measured PE′CO2 and indeed the very low values of PE′CO2, early in anaesthesia (3.46 kPa, 26 mmHg) suggest that this was so (Table 1). An unexpectedly low venous carbon dioxide tension was evident on the blood sample collected 30 minutes after cardiac arrest. This was attributed to reduced cardiac output and cellular metabolism, associated with sampling late in the progression of the syndrome, just prior to death, but could simply have reflected lack of perfusion of the relevant peripheral tissues. Oesophageal temperature had steadily risen from 36.2 °C to 38.1 °C during anaesthesia, but rapidly increased by 4.4 °C over 40 minutes from the time

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Fatal intra-operative hyperthermia in a cat SM Thomson et al.

of tachypnoea. Rapid increases in body temperature are a late sign of MH in humans (Glahn et al. 2010). Because of the rarity of MH-type reactions in cats, other explanations for the observed changes, in particular the rapid increase in temperature, were considered. Differential diagnoses for tachycardia include inadequate depth of anaesthesia or analgesia, so initially opioids were administered and the fractional inspired concentration of isoflurane increased. Infection, anaphylactic reaction and phaeochromocytoma are other causes of tachycardia, but significant blood pressure variation would be expected, which did not occur in this cat. Opioid administration is a possible cause of hyperthermia in this cat, but the timing, progression and degree of hyperthermia in this cat makes this unlikely. Opioid related hyperthermia is reported in the post-anaesthetic period, with a highest mean temperature of 40.5 °C observed 2 hours after anaesthesia in one study; interestingly all these cats were hypothermic at extubation (Niedfeldt & Robertson 2006). Postanaesthetic hyperthermia is inversely associated with body temperature at extubation, suggesting a ‘rebound’ effect resulting from opioids increasing the hypothalamic set point (Adler et al. 1988; Posner et al. 2010). In addition, the degree of hyperthermia in this cat was greater than that reported with morphine (Posner et al. 2010), alfentanil (Ilkiw et al. 1997) or fentanyl (Gellasch et al. 2002). Overheating of the cat with the air warming device was a possibility, but considered unlikely as, in our experience, cats have not developed hyperthermia under anaesthesia with such devices. The initial presentation of this cat is different to a previously reported case of suspected MH in a 6 month old female Domestic Short Hair cat anaesthetized with halothane where the first signs, 50 minutes after induction of anaesthesia, were arrhythmias, bradycardia, hypotension and tachypnea (Bellah et al. 1989). Later signs of hyperthermia, with a rapid increase to 41.1 °C prior to cardiac arrest are similar, although there was no generalised muscle rigidity until extreme rigor mortis within five minutes of death (Bellah et al. 1989). The inhalational agent used can influence the speed of onset of MH, with halothane triggering a faster reaction than isoflurane in pigs (Wedel et al. 1993). This could explain the longer time interval of 140 minutes between starting isoflurane and first signs attributable to MH in this cat. In the other published report of MH in a cat, tachycardia, hypercapnia and hyperthermia occurred simultaneously, 10 minutes 294

after decamethonium administration during halothane anaesthesia (de Jong et al. 1974). Body temperature reached 44 °C and no generalised muscle rigidity exhibited, but, as with the case of Bellah et al. (1989), extreme rigor mortis occurred within ten minutes of death (de Jong et al. 1974) and this also occurred in the cat of our report. Muscle rigidity is an important clinical sign of MH, but due to the variability of this syndrome depending on the precise genetic mutation and species involved, is not always present. There are reports of muscle rigidity associated with MH in some dogs and horses, but not in others (Manley et al. 1983; Kirmayer et al. 1984; Adami et al. 2012). No specific abnormalities were identified on post mortem skeletal muscle biopsies, consistent with histological findings in MH susceptible humans and pigs (Gronert 1980), and MH case reports in a cat (Bellah et al. 1989) and dog (Adami et al. 2012). To definitively diagnose MH susceptibility in humans, in vitro contracture testing, where living muscle tissue is exposed to halothane and caffeine, is required (Urwyler et al. 2001). The testing can only be performed at specialist laboratories and was not practicable. Where a susceptibility to MH is identified, blood sampling is performed to test for genetic mutations. Analysis of the RYR1 gene in this cat ideally would have been performed. The short-acting beta blocker, esmolol, was administered to reduce HR and myocardial oxygen consumption, both of which increase during MH, due to beta-adrenergic receptor stimulation by catecholamines. Infusions of propranolol administered to pigs during episodes of MH reduced myocardial oxygen consumption to that of normal swine under anaesthesia (Gronert et al. 1978). Administration of esmolol did reduce HR, but was presumably administered too late in the course of the syndrome to have any beneficial effect on outcome. Hyperkalaemia, due to rhabomyolysis occurred in both previously reported cats with MH, (K+ = 10 mEq L 1 (Bellah et al. 1989), K = 9.5 mEq L 1 (de Jong et al. 1974)) and potassium was in excess of 9 mmol L 1 in this case. Blood was collected during resuscitation attempts and after cardiac defibrillation, which may have contributed to increasing serum potassium due to muscle damage. We assumed that the level of serum potassium rise was greater than would be expected from resuscitation and defibrillation. There is limited data available describing resuscitation-invoked hyperkalaemia, but a study of experimental dogs where ventricular

© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 290–296

Fatal intra-operative hyperthermia in a cat SM Thomson et al. fibrillation was induced prior to cardiac defibrillation and closed-chest cardio-pulmonary resuscitation showed a serum potassium increase from 4.3  0.6 to only 6.0  0.8 mEq L 1 (Niemann & Cairns 1999). Results of the blood sample collected after the cat died should be interpreted with caution due to changes post mortem. However CK can increase by 50 times the upper normal limit range of normal in MH (Halsall & Hopkins 2003) and a similar increase was evident in this cat. The pre-existing high body temperature (38.9– 39.4 °C) recorded on several occasions in this cat, was also reported prior to anaesthesia in a cat (39.2 °C) and dog (39.1–39.3 °C) which went on to develop MH (Bellah et al. 1989; Adami et al. 2012). An abnormality in heat dissipation between the core and periphery occurs in humans with a susceptibility to MH (Campbell et al. 1983). In addition there are suspicions of associations between exertional heat illness and susceptibility to MH (Capacchione & Muldoon 2009). Stress, a known trigger for MH in pigs, associated with hospitalization could also have contributed to the high body temperature. A susceptibility to MH should be considered when anaesthetizing animals with unexplained persistently high body temperatures. The previous two cats with MH reported in the literature (de Jong et al. 1974; Bellah et al. 1989) both died. A high mortality rate of 31% is also reported in horses with MH-like episodes (Aleman et al. 2005). In humans, the overall mortality rate for MH between 1940 and 1992 was 30%, but this has been reduced since the introduction of dantrolene (Strazis & Fox 1993). The cat of our report had been anaesthetized at least once before with isoflurane. In one study in humans, at least 20.9% of cases of MH had undergone a previous uneventful anaesthesia (Strazis & Fox 1993), so an unremarkable previous anaesthesia does not preclude the possibility of a MH episode occurring. This cat was young, at four years old; the ages of previously reported cats with MH were 6 months and ‘adult’. This is similar to the epidemiology of MH in humans, where 52.1% of cases of MH occurred in patients under 15 years of age (Strazis & Fox 1993). Rapid recognition of MH (or indeed hyperthermia of any cause) is essential in the management of MH. Isoflurane, the only recognised trigger agent used in this case, should have been discontinued immediately. Current guidelines do not advocate changing the breathing circuit or anaesthetic machine, to

avoid wasting time (Glahn et al. 2010). Other immediate measures include hyperventilating with 100% oxygen, stopping the surgery and converting to total intravenous anaesthesia (with no trigger agents). Dantrolene is an intracellular calcium antagonist, which is effective for the treatment of MH and in humans is administered IV at 2 mg kg 1 up to a total dose of 10 mg kg 1 (Halsall & Hopkins 2003). In humans, survivors of MH episodes were 2.73 times more likely to have received dantrolene that those that did not survive (Strazis & Fox 1993). Dantrolene was not available for use in this cat. Blood sampling allows the diagnosis and treatment of hyperkalaemia and acidosis resulting from MH, and could have been performed earlier in the management of this case. Conclusions The clinical signs exhibited by this cat are consistent with malignant hyperthermia, which should be considered as a potential cause of unexplained tachycardia, hyperventilation, hypercapnia, hyperthermia and muscle rigidity during the perioperative period. Acknowledgements The authors would like to thank the veterinary surgeons and veterinary nurses involved in the care of this case. References Adami C, Axiak S, Raith K et al. (2012) Unusual perianesthetic malignant hyperthermia in a dog. J Am Vet Med Assoc 240, 450–453. Adler MW, Geller EB, Rosow CE et al. (1988) The opioid system and temperature regulation. Annu Rev Pharmacol Toxicol 28, 429–449. Aleman M, Brosnan RJ, Williams DC et al. (2005) Malignant hyperthermia in a horse anesthetized with halothane. J Vet Int Med 19, 363–366. Aleman M, Nieto JE, Magdesian KG (2009) Malignant hyperthermia associated with ryanodine receptor 1 (C7360G) mutation in Quarter Horses. J Vet Int Med 23, 329–334. Bellah JR, Robertson SA, Buergelt CD et al. (1989) Suspected malignant hyperthermia after halothane anesthesia in a cat. Vet Surg 18, 483–488. Brunson DB, Hogan KJ (2004) Malignant hyperthermia: a syndrome not a disease. Vet Clin North Am Small Anim Pract 34, 1419–1433.

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