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CASE REPORT
Fentanyl-induced asystole in two dogs M. Jang, W.-G. Son and I. Lee Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
Fentanyl is used in small animals for perioperative analgesia during anaesthesia. Severe bradycardia and asystole were observed on bolus administration of a 3 µg/kg loading dose of fentanyl in two dogs under isoflurane anaesthesia. Premedication with 10 µg/kg glycopyrrolate did not prevent asystole in the first case; and although bradycardia was treated with 5 µg/kg glycopyrrolate administered intravenously in the second case, the heart rate continuously decreased and asystole subsequently developed. Asystole in both cases was quickly corrected by intravenous administration of 0·04 mg/ kg atropine and closed chest compressions. This case report describes asystole induced by fentanyl administration in isoflurane anaesthetised dogs. Atropine was more effective than glycopyrrolate in the treatment of fentanyl-induced asystole.
Journal of Small Animal Practice (2015) DOI: 10.1111/jsap.12312 Accepted: 30 October 2014
INTRODUCTION Fentanyl is a widely used pure mu opioid receptor agonist with rapid onset and short duration for the treatment of perioperative analgesia (Gurney 2012). Generally, cardiovascular stability is excellent with fentanyl, but bradycardia may be caused by opioid-induced medullary vagal stimulation (Lamont & Mathews 2007). Bradycardia may be significant with bolus doses, but is immediately responsive to anticholinergic treatment (Kerr 2007). Asystole has also been reported as a complication of fentanyl administration in human patients with known syncope and/or on multiple drugs (Kinsella & Tuckey 2001). This report describes two cases of asystole in dogs after bolus administration of fentanyl under isoflurane anaesthesia.
CASE HISTORIES Case 1 A one-year-old, 6·9 kg, male, shih tzu dog was referred to the Veterinary Medical Teaching Hospital of Seoul National University for closing a wedge osteotomy. The dog underwent a preoperative physical examination, complete blood cell count, serum chemistry and thoracic imaging. The results of the examinations were within their respective reference intervals. The dog was premedicated with 0·2 mg/kg midazolam intravenously (iv) (Midazolam; Bukwang Pharma) and anaesthesia was induced with 6 mg/kg propofol iv (Provive 1%; Claris) (Table 1). After intubation, anaesthesia was maintained with 2% isoflurane (Ifrane; Hana Pharma) in 2 L/minute oxygen Journal of Small Animal Practice
•
© 2015 British Small Animal Veterinary Association
delivered through a semi-closed circle system. Hartmann’s solution iv (HS; Daihan Pharma) was administered at a rate of 5 mL/kg/hour. Initial readings during surgical preparation were heart rate (HR) of 160 beats/minute, indirect mean arterial pressure (MAP) of 80 mmHg, respiratory rate of 15 breaths/ minute, end-tidal CO2 partial pressure (EtCO2) of 45 mmHg, pulse oximetry (SpO2) of 99% and end-tidal isoflurane concentration (ETiso) of 1·3% as recorded by a monitor (DatexOhmeda S/5; G.E. Healthcare). The dog was positioned in right lateral recumbency and a loading dose of 3 µg/kg fentanyl iv (Fentanyl citrate; Hana Pharma) was injected over 30 seconds. The electrocardiogram (ECG) showed an abrupt change from sinus rhythm to asystole within 30 seconds of the bolus injection of fentanyl. There was no ECG lead disconnection and no palpable femoral artery pulse.The vaporizer was turned off at this time and 0·04 mg/kg atropine iv (Atropine sulfate; Jeil Pharma) was administered, followed by closed chest compression. The HR immediately increased to 150 beats/minute and the MAP improved to 75 mmHg. The duration of asystole persisted for approximately 20 to 30 seconds according to the monitor. The recovery post extubation was uneventful. The surgery was postponed for 1 week as asystole occurred after fentanyl administration. One week later, anaesthesia was retried. The dog was premedicated with 10 µg/kg glycopyrrolate (Glycopyrrolate; Myungmun Pharma) half iv and half intramuscularly, and 0·2 mg/kg midazolam iv (Table 1). Anaesthesia was induced with 6 mg/kg propofol iv and maintained with 2% isoflurane in 2 L/minute oxygen delivered through a semi-closed system. Monitored values at 15 minutes after induction of anaesthesia were ETiso of 1·3%, HR of 180 beats/minute, MAP of 80 mmHg and SpO2 of 1
M. Jang et al.
Table 1. Anaesthetic procedures in two dogs Drugs
Case 1 First time
Premedications
Midazolam 0·2 mg/kg iv
Induction Maintenance Bradycardia and asystole Treatments
Propofol 6·0 mg/kg iv Isoflurane 30 seconds after fentanyl 3·0 µg/kg iv Discontinue isoflurane Atropine 0·04 mg/kg iv Closed chest compression
Responses
Immediate increase of heart rate
Case 2 Second time
Midazolam 0·2 mg/kg iv Glycopyrrolate 5·0 µg/kg iv Glycopyrrolate 5·0 µg/kg im Propofol 6·0 mg/kg iv Isoflurane 2 minutes after fentanyl 3·0 µg/kg iv Atropine 0·04 mg/kg iv
Acepromazine 0·01 mg/kg iv
Propofol 6·0 mg/kg iv Isoflurane 3 minutes after fentanyl 3·0 µg/kg iv Glycopyrrolate 5·0 µg/kg iv Discontinue isoflurane Atropine 0·04 mg/kg iv Closed chest compression No response to glycopyrrolate Immediate increase of heart rate
Immediate increase of heart rate
iv Intravenous administration, im Intramuscular administration
99%, and 3 µg/kg fentanyl iv was administered over 60 seconds. The HR gradually decreased to 50 beats/minute and asystole subsequently occurred 5 minutes after fentanyl administration. Asystole was observed on the ECG and there was no palpable femoral artery pulse. Atropine iv was administered at 0·04 mg/kg. The HR and MAP increased to 140 beats/minute and 75 mmHg, respectively. Anaesthesia was continued, as the period of asystole was brief and the dog’s vital signs returned to normal. After initiation of surgery, 0·05 mg/kg hydromorphone (Dilid; Hana Pharma) was administered iv and the remainder of the anaesthesia was uneventful. The dog recovered on completion of surgery, with no further problems. Case 2 A three-year-old, 14 kg, neutered male, cocker spaniel dog was referred for total ear canal ablation and lateral bulla osteotomy. The dog underwent a preoperative examination, and the results were unremarkable. The dog was premedicated with 0·01 mg/kg acepromazine iv (Sedaject; Samu Median) (Table 1). Anaesthesia was induced with 6 mg/kg propofol iv and maintained with 2% isoflurane in 2 L/minute oxygen delivered through a semi-closed circle system. HS iv was administered at a rate of 10 mL/kg/hour. Forty minutes later, before the surgery, an assessment revealed a HR of 150 beats/minute, direct MAP of 80 mmHg and ETiso of 1·3%. A loading dose of 3 µg/kg fentanyl iv was administered over 60 seconds followed by a 6 µg/kg/hour fentanyl infusion. Over the next 3 minutes, HR and MAP decreased from 150 to 90 beats/minute and 80 to 55 mmHg, respectively. Fentanyl infusion was discontinued at this time and 5 µg/kg glycopyrrolate iv was administered. Despite withdrawal of fentanyl, the HR continued to decrease to 40 beats/minute and asystole subsequently occurred. The vaporizer was turned off at this time and 0·04 mg/kg atropine iv was injected, followed by closed chest compression. The HR and MAP increased immediately to 140 beats/minute and 65 mmHg, respectively. The duration of asystole persisted for approximately 20 to 30 seconds according to the monitor. After initiation of surgery, 0·05 mg/kg hydromorphone iv was administered. The HR and MAP remained stable during the remainder of anaesthesia. The post extubation recovery was uneventful. 2
DISCUSSION Fentanyl, a mu opioid receptor agonist, is widely used for the treatment of intraoperative and postoperative pain. A loading dose of fentanyl, 3 to 5 µg/kg iv, is usually followed by a constant rate infusion (CRI) of 3 to 6 µg/kg/hour iv (Kerr 2007). Fentanyl infusion is known to cause a decrease in HR and/or mean arterial blood pressure, especially when used at a high dose CRI under general anaesthesia (Borer-Weir 2014). However, asystole following the administration of fentanyl in dogs has not been reported. There are several potential causes of bradycardia and asystole under general anaesthesia. Cardiac arrest under general anaesthesia is most commonly associated with respiratory and/or cardiac dysfunction, such as hypoxaemia, hypoventilation, hypotension, hypovolaemia, cardiac arrhythmia and drug interactions or overdose (Adams 2014). The cases in this study had severe bradycardia and asystole following fentanyl bolus administration despite no apparent underlying disease in either dog. There was no sudden change in vital signs before the fentanyl bolus administration, and the loading dose of fentanyl was as recommended. Although it is difficult to explain this asystole, it might be associated with a potent opioid bolus administration and interaction between the anaesthetic drugs. Severe bradycardia and asystole have been reported in human patients as a complication of induction of anaesthesia with fentanyl, propofol and/or succinylcholine (Dorrington 1989, Egan & Brock-Utne 1991). Administration of other potent opioids, such as alfentanil and sufentanil, and midazolam, has also been associated with asystole (Starr et al. 1986, Maryniak & Bishop 1987, Nordt & Clark 1997). Asystole was associated with many drugs used for the induction of anaesthesia in the previous case reports. Similarly, in both cases in the current study, anaesthesia was induced with 6 mg/kg propofol which was fairly high following premedications, and it was assumed that propofol and/or midazolam may have contributed to the asystole. Brachycephalic dogs have a higher vasovagal tonus index than other breeds (Doxey & Boswood 2004). A previous report showed that concurrent hydromorphone administration and tracheal extubation increased vagal tone, which led to bradycardia, asystole and Journal of Small Animal Practice
•
© 2015 British Small Animal Veterinary Association
Fentanyl-induced asystole in two dogs
sudden cardiopulmonary arrest (Mathews et al. 2011). The high vagal tone in the first case of this report may have made the dog more susceptible to vagally mediated responses following fentanyl administration, that lead to asystole (Mathews et al. 2011). Cardiac arrest under general anaesthesia may also be associated with specific types of procedures, anaesthetic errors and body repositioning (Adams 2014). Human patients who received remifentanil at induction reportedly had severe bradycardia that progressed to asystole immediately after laryngoscopy (Wang et al. 1998). However, in both cases in this study, fentanyl was administered at the recommended dose and the dogs did not undergo specific procedures, repositioning or movement when the asystole occurred. Increasing concentrations of isoflurane can cause significant decreases in cardiac output, arterial blood pressure and a decrease or increase in HR (Steffey & Mama 2007). Concurrent administration of a mu opioid receptor agonist can also potentiate cardiovascular changes. Fentanyl-induced bradycardia is more marked in anaesthetised than in conscious human patients, and can be minimised by slow administration of potent opioids (Saidman et al. 1984). Fentanyl bolus administration over 60 seconds under isoflurane anaesthesia in both study cases likely had a synergistic effect in initiating the asystole. Therefore, if loading doses of fentanyl are administered during inhalation anaesthesia, the fentanyl should be administered over several minutes or a lower dosage (1 to 2 µg/kg) may also be considered. The two dogs described in this study were administered an iv bolus of hydromorphone, a full agonist at the mu opioid receptor (Lamont & Mathews 2007), at the time of the initiation of surgery. However in these cases, hydromorphone given at the doses expected to result in perioperative analgesia did not induce asystole. This suggested that some characteristic of fentanyl, aside from its analgesic effects, was responsible for the asystole or else intraoperative atropine might have attenuated a vasovagal response induced by hydromorphone. Anticholinergic drugs are recommended for the treatment of vagally mediated bradycardia during anaesthesia (Dyson & James-Davies 1999). Atropine and glycopyrrolate competitively antagonise the effect of acetylcholine at the muscarinic receptor (Richards et al. 1989), and glycopyrrolate is preferable in patients at risk for tachycardia (Watney et al. 1987). However, in the first case, glycopyrrolate premedication did not prevent asystole. In the second case, although bradycardia was treated with glycopyrrolate, the HR continued to decrease until asystole occurred. Atropine iv coupled with closed chest cardiac compressions was successful in reversing the asystole in both cases. These differences were assumed to be because glycopyrrolate has a slower onset of action than atropine, and does not readily cross the blood-brain barrier (Richards et al. 1989). Clinically, if asystole develops in a dog following the administration of fentanyl and glycopyrrolate administration fails to prevent asystole, both very uncommon occurrences, drug contamination may be considered. However, the two cases occurred at intervals of 3 months and new fentanyl and glycopyrrolate ampoules in each case were used. Therefore, drug contamination is unlikely to have been unrelated to these cases. Journal of Small Animal Practice
•
© 2015 British Small Animal Veterinary Association
In conclusion, under inhalation anaesthesia, concurrent bolus administration of fentanyl can lead to asystole in dogs. Intravenous atropine and closed chest compressions are recommended rather than glycopyrrolate, on the rare occurrence of severe bradycardia and asystole after fentanyl administration under general anaesthesia. Acknowledgements This research was supported by the Basic Science Research Promotion program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science, and Technology (NRF-2011-0007777, NRF-2012-0002638), and the BK21 program and the Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University. Conflict of interest None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. References Adams, J. G. (2014) Cardiopulmonary cerebral resuscitation (CPCR). In: Veterinary Anaesthesia. 11th edn. Eds K. W. Clarke, C. M. Trim and L. W. Hall. Saunders, London, UK. pp 645-669 Borer-Weir, K. (2014) Analgesia. In: Veterinary Anaesthesia. 11th edn. Eds K. W. Clarke, C. M. Trim and L. W. Hall. Saunders, London, UK. pp 101-133 Dorrington, K. L. (1989) Asystole with convulsion following a subanaesthetic dose of propofol plus fentanyl. Anaesthesia 44, 658-659 Doxey, S. & Boswood, A. (2004) Differences between breeds of dog in a measure of heart rate variability. Veterinary Record 154, 713-717 Dyson, D. H. & James-Davies, R. (1999) Dose effect and benefits of glycopyrrolate in the treatment of bradycardia in anesthetized dogs. The Canadian Veterinary Journal 40, 327-331 Egan, T. D. & Brock-Utne, J. G. (1991) Asystole after anesthesia induction with a fentanyl, propofol, and succinylcholine sequence. Anesthesia & Analgesia 73, 818-820 Gurney, M. (2012) Pharmacological options for intra-operative and early postoperative analgesia: an update. Journal of Small Animal Practice 53, 377-386 Kerr, C. (2007) Pain management I: systemic analgesics. In: BSAVA Manual of Canine & Feline Anaesthesia & Analgesia. 2nd edn. Eds C. J. Seymour and T. Duke-Novakowski. BSAVA, Gloucester, UK. pp 89-103 Kinsella, S. M. & Tuckey, J. P. (2001) Perioperative bradycardia and asystole: relationship to vasovagal syncope and the Bezold-Jarisch reflex. British Journal of Anaesthesia 86, 859-868 Lamont, L. A. & Mathews, K. A. (2007) Opioids, nonsteroidal anti-inflammatories, and analgesic adjuvants. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia. 4th edn. Eds W. J. Tranquilli, J. C. Thurmon and K. A. Grimm. Blackwell Publishing, Ames, IA, USA. pp 241-271 Maryniak, J. K. & Bishop, V. A. (1987) Sinus arrest after alfentanil. British Journal of Anaesthesia 59, 390-391 Mathews, L. A., Killos, M. B. & Graham, L. F. (2011) Anesthesia case of the month. Journal of the American Veterinary Medical Association 239, 307-312 Nordt, S. P. & Clark, R. F. (1997) Midazolam: a review of therapeutic uses and toxicity. The Journal of Emergency Medicine 15, 357-365 Richards, D. L. S., Clutton, R. E. & Boyd, C. (1989) Electrocardiographic findings following intravenous glycopyrrolate to sedated dogs: a comparison with atropine. Veterinary Anaesthesia and Analgesia 16, 46-50 Saidman, L. J., Bovill, J. G., Sebel, P. S. & Stanley, T. H. (1984) Opioid analgesics in anesthesia: with special reference to their use in cardiovascular anesthesia. Anesthesiology 61, 731-755 Starr, N. J., Sethna, D. H. & Estafanous, F. G. (1986) Bradycardia and asystole following the rapid administration of sufentanil with vecuronium. Anesthesiology 64, 521-523 Steffey, E. P. & Mama, K. R. (2007) Inhalation anesthetics. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia. 4th edn. Eds W. J. Tranquilli, J. C. Thurmon and K. A. Grimm. Blackwell Publishing, Ames, IA, USA. pp 355-393 Wang, J., Winship, S. & Russell, G. (1998) Induction of anaesthesia with sevoflurane and low-dose remifentanil: asystole following laryngoscopy. British Journal of Anaesthesia 81, 994-995 Watney, G. C. G., Chambers, J. P. & Watkins, S. B. (1987) Antimuscarinic premedication in canine anaesthesia: a comparison of atropine, hyoscine and glycopyrrolate. Journal of Small Animal Practice 28, 1087-1094
3
CASE REPORT
Fentanyl-induced asystole in two dogs M. Jang, W.-G. Son and I. Lee Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
Fentanyl is used in small animals for perioperative analgesia during anaesthesia. Severe bradycardia and asystole were observed on bolus administration of a 3 µg/kg loading dose of fentanyl in two dogs under isoflurane anaesthesia. Premedication with 10 µg/kg glycopyrrolate did not prevent asystole in the first case; and although bradycardia was treated with 5 µg/kg glycopyrrolate administered intravenously in the second case, the heart rate continuously decreased and asystole subsequently developed. Asystole in both cases was quickly corrected by intravenous administration of 0·04 mg/ kg atropine and closed chest compressions. This case report describes asystole induced by fentanyl administration in isoflurane anaesthetised dogs. Atropine was more effective than glycopyrrolate in the treatment of fentanyl-induced asystole.
Journal of Small Animal Practice (2015) DOI: 10.1111/jsap.12312 Accepted: 30 October 2014
INTRODUCTION Fentanyl is a widely used pure mu opioid receptor agonist with rapid onset and short duration for the treatment of perioperative analgesia (Gurney 2012). Generally, cardiovascular stability is excellent with fentanyl, but bradycardia may be caused by opioid-induced medullary vagal stimulation (Lamont & Mathews 2007). Bradycardia may be significant with bolus doses, but is immediately responsive to anticholinergic treatment (Kerr 2007). Asystole has also been reported as a complication of fentanyl administration in human patients with known syncope and/or on multiple drugs (Kinsella & Tuckey 2001). This report describes two cases of asystole in dogs after bolus administration of fentanyl under isoflurane anaesthesia.
CASE HISTORIES Case 1 A one-year-old, 6·9 kg, male, shih tzu dog was referred to the Veterinary Medical Teaching Hospital of Seoul National University for closing a wedge osteotomy. The dog underwent a preoperative physical examination, complete blood cell count, serum chemistry and thoracic imaging. The results of the examinations were within their respective reference intervals. The dog was premedicated with 0·2 mg/kg midazolam intravenously (iv) (Midazolam; Bukwang Pharma) and anaesthesia was induced with 6 mg/kg propofol iv (Provive 1%; Claris) (Table 1). After intubation, anaesthesia was maintained with 2% isoflurane (Ifrane; Hana Pharma) in 2 L/minute oxygen Journal of Small Animal Practice
•
© 2015 British Small Animal Veterinary Association
delivered through a semi-closed circle system. Hartmann’s solution iv (HS; Daihan Pharma) was administered at a rate of 5 mL/kg/hour. Initial readings during surgical preparation were heart rate (HR) of 160 beats/minute, indirect mean arterial pressure (MAP) of 80 mmHg, respiratory rate of 15 breaths/ minute, end-tidal CO2 partial pressure (EtCO2) of 45 mmHg, pulse oximetry (SpO2) of 99% and end-tidal isoflurane concentration (ETiso) of 1·3% as recorded by a monitor (DatexOhmeda S/5; G.E. Healthcare). The dog was positioned in right lateral recumbency and a loading dose of 3 µg/kg fentanyl iv (Fentanyl citrate; Hana Pharma) was injected over 30 seconds. The electrocardiogram (ECG) showed an abrupt change from sinus rhythm to asystole within 30 seconds of the bolus injection of fentanyl. There was no ECG lead disconnection and no palpable femoral artery pulse.The vaporizer was turned off at this time and 0·04 mg/kg atropine iv (Atropine sulfate; Jeil Pharma) was administered, followed by closed chest compression. The HR immediately increased to 150 beats/minute and the MAP improved to 75 mmHg. The duration of asystole persisted for approximately 20 to 30 seconds according to the monitor. The recovery post extubation was uneventful. The surgery was postponed for 1 week as asystole occurred after fentanyl administration. One week later, anaesthesia was retried. The dog was premedicated with 10 µg/kg glycopyrrolate (Glycopyrrolate; Myungmun Pharma) half iv and half intramuscularly, and 0·2 mg/kg midazolam iv (Table 1). Anaesthesia was induced with 6 mg/kg propofol iv and maintained with 2% isoflurane in 2 L/minute oxygen delivered through a semi-closed system. Monitored values at 15 minutes after induction of anaesthesia were ETiso of 1·3%, HR of 180 beats/minute, MAP of 80 mmHg and SpO2 of 1
M. Jang et al.
Table 1. Anaesthetic procedures in two dogs Drugs
Case 1 First time
Premedications
Midazolam 0·2 mg/kg iv
Induction Maintenance Bradycardia and asystole Treatments
Propofol 6·0 mg/kg iv Isoflurane 30 seconds after fentanyl 3·0 µg/kg iv Discontinue isoflurane Atropine 0·04 mg/kg iv Closed chest compression
Responses
Immediate increase of heart rate
Case 2 Second time
Midazolam 0·2 mg/kg iv Glycopyrrolate 5·0 µg/kg iv Glycopyrrolate 5·0 µg/kg im Propofol 6·0 mg/kg iv Isoflurane 2 minutes after fentanyl 3·0 µg/kg iv Atropine 0·04 mg/kg iv
Acepromazine 0·01 mg/kg iv
Propofol 6·0 mg/kg iv Isoflurane 3 minutes after fentanyl 3·0 µg/kg iv Glycopyrrolate 5·0 µg/kg iv Discontinue isoflurane Atropine 0·04 mg/kg iv Closed chest compression No response to glycopyrrolate Immediate increase of heart rate
Immediate increase of heart rate
iv Intravenous administration, im Intramuscular administration
99%, and 3 µg/kg fentanyl iv was administered over 60 seconds. The HR gradually decreased to 50 beats/minute and asystole subsequently occurred 5 minutes after fentanyl administration. Asystole was observed on the ECG and there was no palpable femoral artery pulse. Atropine iv was administered at 0·04 mg/kg. The HR and MAP increased to 140 beats/minute and 75 mmHg, respectively. Anaesthesia was continued, as the period of asystole was brief and the dog’s vital signs returned to normal. After initiation of surgery, 0·05 mg/kg hydromorphone (Dilid; Hana Pharma) was administered iv and the remainder of the anaesthesia was uneventful. The dog recovered on completion of surgery, with no further problems. Case 2 A three-year-old, 14 kg, neutered male, cocker spaniel dog was referred for total ear canal ablation and lateral bulla osteotomy. The dog underwent a preoperative examination, and the results were unremarkable. The dog was premedicated with 0·01 mg/kg acepromazine iv (Sedaject; Samu Median) (Table 1). Anaesthesia was induced with 6 mg/kg propofol iv and maintained with 2% isoflurane in 2 L/minute oxygen delivered through a semi-closed circle system. HS iv was administered at a rate of 10 mL/kg/hour. Forty minutes later, before the surgery, an assessment revealed a HR of 150 beats/minute, direct MAP of 80 mmHg and ETiso of 1·3%. A loading dose of 3 µg/kg fentanyl iv was administered over 60 seconds followed by a 6 µg/kg/hour fentanyl infusion. Over the next 3 minutes, HR and MAP decreased from 150 to 90 beats/minute and 80 to 55 mmHg, respectively. Fentanyl infusion was discontinued at this time and 5 µg/kg glycopyrrolate iv was administered. Despite withdrawal of fentanyl, the HR continued to decrease to 40 beats/minute and asystole subsequently occurred. The vaporizer was turned off at this time and 0·04 mg/kg atropine iv was injected, followed by closed chest compression. The HR and MAP increased immediately to 140 beats/minute and 65 mmHg, respectively. The duration of asystole persisted for approximately 20 to 30 seconds according to the monitor. After initiation of surgery, 0·05 mg/kg hydromorphone iv was administered. The HR and MAP remained stable during the remainder of anaesthesia. The post extubation recovery was uneventful. 2
DISCUSSION Fentanyl, a mu opioid receptor agonist, is widely used for the treatment of intraoperative and postoperative pain. A loading dose of fentanyl, 3 to 5 µg/kg iv, is usually followed by a constant rate infusion (CRI) of 3 to 6 µg/kg/hour iv (Kerr 2007). Fentanyl infusion is known to cause a decrease in HR and/or mean arterial blood pressure, especially when used at a high dose CRI under general anaesthesia (Borer-Weir 2014). However, asystole following the administration of fentanyl in dogs has not been reported. There are several potential causes of bradycardia and asystole under general anaesthesia. Cardiac arrest under general anaesthesia is most commonly associated with respiratory and/or cardiac dysfunction, such as hypoxaemia, hypoventilation, hypotension, hypovolaemia, cardiac arrhythmia and drug interactions or overdose (Adams 2014). The cases in this study had severe bradycardia and asystole following fentanyl bolus administration despite no apparent underlying disease in either dog. There was no sudden change in vital signs before the fentanyl bolus administration, and the loading dose of fentanyl was as recommended. Although it is difficult to explain this asystole, it might be associated with a potent opioid bolus administration and interaction between the anaesthetic drugs. Severe bradycardia and asystole have been reported in human patients as a complication of induction of anaesthesia with fentanyl, propofol and/or succinylcholine (Dorrington 1989, Egan & Brock-Utne 1991). Administration of other potent opioids, such as alfentanil and sufentanil, and midazolam, has also been associated with asystole (Starr et al. 1986, Maryniak & Bishop 1987, Nordt & Clark 1997). Asystole was associated with many drugs used for the induction of anaesthesia in the previous case reports. Similarly, in both cases in the current study, anaesthesia was induced with 6 mg/kg propofol which was fairly high following premedications, and it was assumed that propofol and/or midazolam may have contributed to the asystole. Brachycephalic dogs have a higher vasovagal tonus index than other breeds (Doxey & Boswood 2004). A previous report showed that concurrent hydromorphone administration and tracheal extubation increased vagal tone, which led to bradycardia, asystole and Journal of Small Animal Practice
•
© 2015 British Small Animal Veterinary Association
Fentanyl-induced asystole in two dogs
sudden cardiopulmonary arrest (Mathews et al. 2011). The high vagal tone in the first case of this report may have made the dog more susceptible to vagally mediated responses following fentanyl administration, that lead to asystole (Mathews et al. 2011). Cardiac arrest under general anaesthesia may also be associated with specific types of procedures, anaesthetic errors and body repositioning (Adams 2014). Human patients who received remifentanil at induction reportedly had severe bradycardia that progressed to asystole immediately after laryngoscopy (Wang et al. 1998). However, in both cases in this study, fentanyl was administered at the recommended dose and the dogs did not undergo specific procedures, repositioning or movement when the asystole occurred. Increasing concentrations of isoflurane can cause significant decreases in cardiac output, arterial blood pressure and a decrease or increase in HR (Steffey & Mama 2007). Concurrent administration of a mu opioid receptor agonist can also potentiate cardiovascular changes. Fentanyl-induced bradycardia is more marked in anaesthetised than in conscious human patients, and can be minimised by slow administration of potent opioids (Saidman et al. 1984). Fentanyl bolus administration over 60 seconds under isoflurane anaesthesia in both study cases likely had a synergistic effect in initiating the asystole. Therefore, if loading doses of fentanyl are administered during inhalation anaesthesia, the fentanyl should be administered over several minutes or a lower dosage (1 to 2 µg/kg) may also be considered. The two dogs described in this study were administered an iv bolus of hydromorphone, a full agonist at the mu opioid receptor (Lamont & Mathews 2007), at the time of the initiation of surgery. However in these cases, hydromorphone given at the doses expected to result in perioperative analgesia did not induce asystole. This suggested that some characteristic of fentanyl, aside from its analgesic effects, was responsible for the asystole or else intraoperative atropine might have attenuated a vasovagal response induced by hydromorphone. Anticholinergic drugs are recommended for the treatment of vagally mediated bradycardia during anaesthesia (Dyson & James-Davies 1999). Atropine and glycopyrrolate competitively antagonise the effect of acetylcholine at the muscarinic receptor (Richards et al. 1989), and glycopyrrolate is preferable in patients at risk for tachycardia (Watney et al. 1987). However, in the first case, glycopyrrolate premedication did not prevent asystole. In the second case, although bradycardia was treated with glycopyrrolate, the HR continued to decrease until asystole occurred. Atropine iv coupled with closed chest cardiac compressions was successful in reversing the asystole in both cases. These differences were assumed to be because glycopyrrolate has a slower onset of action than atropine, and does not readily cross the blood-brain barrier (Richards et al. 1989). Clinically, if asystole develops in a dog following the administration of fentanyl and glycopyrrolate administration fails to prevent asystole, both very uncommon occurrences, drug contamination may be considered. However, the two cases occurred at intervals of 3 months and new fentanyl and glycopyrrolate ampoules in each case were used. Therefore, drug contamination is unlikely to have been unrelated to these cases. Journal of Small Animal Practice
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© 2015 British Small Animal Veterinary Association
In conclusion, under inhalation anaesthesia, concurrent bolus administration of fentanyl can lead to asystole in dogs. Intravenous atropine and closed chest compressions are recommended rather than glycopyrrolate, on the rare occurrence of severe bradycardia and asystole after fentanyl administration under general anaesthesia. Acknowledgements This research was supported by the Basic Science Research Promotion program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science, and Technology (NRF-2011-0007777, NRF-2012-0002638), and the BK21 program and the Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University. Conflict of interest None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. References Adams, J. G. (2014) Cardiopulmonary cerebral resuscitation (CPCR). In: Veterinary Anaesthesia. 11th edn. Eds K. W. Clarke, C. M. Trim and L. W. Hall. Saunders, London, UK. pp 645-669 Borer-Weir, K. (2014) Analgesia. In: Veterinary Anaesthesia. 11th edn. Eds K. W. Clarke, C. M. Trim and L. W. Hall. Saunders, London, UK. pp 101-133 Dorrington, K. L. (1989) Asystole with convulsion following a subanaesthetic dose of propofol plus fentanyl. Anaesthesia 44, 658-659 Doxey, S. & Boswood, A. (2004) Differences between breeds of dog in a measure of heart rate variability. Veterinary Record 154, 713-717 Dyson, D. H. & James-Davies, R. (1999) Dose effect and benefits of glycopyrrolate in the treatment of bradycardia in anesthetized dogs. The Canadian Veterinary Journal 40, 327-331 Egan, T. D. & Brock-Utne, J. G. (1991) Asystole after anesthesia induction with a fentanyl, propofol, and succinylcholine sequence. Anesthesia & Analgesia 73, 818-820 Gurney, M. (2012) Pharmacological options for intra-operative and early postoperative analgesia: an update. Journal of Small Animal Practice 53, 377-386 Kerr, C. (2007) Pain management I: systemic analgesics. In: BSAVA Manual of Canine & Feline Anaesthesia & Analgesia. 2nd edn. Eds C. J. Seymour and T. Duke-Novakowski. BSAVA, Gloucester, UK. pp 89-103 Kinsella, S. M. & Tuckey, J. P. (2001) Perioperative bradycardia and asystole: relationship to vasovagal syncope and the Bezold-Jarisch reflex. British Journal of Anaesthesia 86, 859-868 Lamont, L. A. & Mathews, K. A. (2007) Opioids, nonsteroidal anti-inflammatories, and analgesic adjuvants. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia. 4th edn. Eds W. J. Tranquilli, J. C. Thurmon and K. A. Grimm. Blackwell Publishing, Ames, IA, USA. pp 241-271 Maryniak, J. K. & Bishop, V. A. (1987) Sinus arrest after alfentanil. British Journal of Anaesthesia 59, 390-391 Mathews, L. A., Killos, M. B. & Graham, L. F. (2011) Anesthesia case of the month. Journal of the American Veterinary Medical Association 239, 307-312 Nordt, S. P. & Clark, R. F. (1997) Midazolam: a review of therapeutic uses and toxicity. The Journal of Emergency Medicine 15, 357-365 Richards, D. L. S., Clutton, R. E. & Boyd, C. (1989) Electrocardiographic findings following intravenous glycopyrrolate to sedated dogs: a comparison with atropine. Veterinary Anaesthesia and Analgesia 16, 46-50 Saidman, L. J., Bovill, J. G., Sebel, P. S. & Stanley, T. H. (1984) Opioid analgesics in anesthesia: with special reference to their use in cardiovascular anesthesia. Anesthesiology 61, 731-755 Starr, N. J., Sethna, D. H. & Estafanous, F. G. (1986) Bradycardia and asystole following the rapid administration of sufentanil with vecuronium. Anesthesiology 64, 521-523 Steffey, E. P. & Mama, K. R. (2007) Inhalation anesthetics. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia. 4th edn. Eds W. J. Tranquilli, J. C. Thurmon and K. A. Grimm. Blackwell Publishing, Ames, IA, USA. pp 355-393 Wang, J., Winship, S. & Russell, G. (1998) Induction of anaesthesia with sevoflurane and low-dose remifentanil: asystole following laryngoscopy. British Journal of Anaesthesia 81, 994-995 Watney, G. C. G., Chambers, J. P. & Watkins, S. B. (1987) Antimuscarinic premedication in canine anaesthesia: a comparison of atropine, hyoscine and glycopyrrolate. Journal of Small Animal Practice 28, 1087-1094
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