Α systematic review of the cardiopulmonary effects of alfaxalone when used as a main agent for induction and/or maintenance of anaesthesia in dogs

Authors

  • Maria Zioga DVM - Companion Animal Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece https://orcid.org/0000-0002-3595-0116
  • Symeon Papadopoulos DVM - Companion Animal Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece https://orcid.org/0000-0001-7813-5413
  • Aikaterini Pavlidou DVM - Companion Animal Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece https://orcid.org/0000-0003-0725-5818
  • Kyriaki Pavlidou DVM, PhD - Companion Animal Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
  • Ioannis Savvas DVM, PhD - Companion Animal Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece https://orcid.org/0000-0001-5575-7244

MeSH keywords:

alfaxalone, anaesthesia, dog

Abstract

Alfaxalone is a synthetic neuroactive steroid that has been used as an anaesthetic agent in humans, dogs, cats and other various veterinary species, as it provides smooth anaesthesia induction, adequate muscle relaxation and dose-dependant effects on the anaesthetic duration as well as the cardiopulmonary system. In order to comprehend the way alfaxalone affects both the cardiovascular and respiratory system of canine patients, the authors searched in PubMed, Google Scholar and Scopus for literature in which alfaxalone was used for induction and/or maintenance of anaesthesia. After the assessment of twenty-eight publications, twenty of them were excluded as they were studies that were either based on intramuscular administration, or combined alfaxalone with other anaesthetic agents, or were considered biased, or used inadequate measurements and/or sample size, or used higher doses than those recommended, or they were focusing on the effects of premedication. Eight were found to meet the criteria set and their results are thoroughly presented. The occurrence of apnoea seems to be the prime restriction in the use of alfaxalone as the main agent for induction and/or maintenance of anaesthesia, since the rest of the cardiopulmonary parameters are only slightly to moderately affected with a possibility of respiratory acidosis, a minor drop in arterial pressure and last but not least an increase in heart rate.

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Introduction

Alfaxalone (3a-hydroxy-5a-pregnane-11, 20-dione) is a water-insoluble, synthetic neuroactive steroid (Ferré et al. 2006), that may be used for the induction and maintenance of anaesthesia in small animals (Capik et al. 2019) and provides muscle relaxation by increasing the inhibition of gamma-amino-butyric acid type A-receptors (GABAA), through the enhance of the inhibitory effect of GABA (Bilgen Şen & Kiliç 2018). Despite the similar molecular structure with progesterone, alfaxalone is not known to have any hormonal activity. Its plasma protein binding is non-significant, and it is mainly metabolised in the liver, mostly through glucuronidation, with a half-life of approximately 30 minutes in dogs (Duke-Novakovski et al. 2016).

Alfaxalone has been used as an anaesthetic agent in humans (Althesin, GlaxoSmithKline, Middlesex, UK) as well as in dogs, cats and other various veterinary species (Saffan, Schering Plough Animal Health, Union, NJ, USA). As it was combined with alfadolone and solubilized with 20% castor oil, histamine-caused side-effects that were associated with the solubilizing agent were reported, such as hyperaemia of the ear pinnae or forepaw in cats and histamine-induced anaphylactoid reaction in dogs (Tamura et al. 2015), resulting in the withdrawal of both these drugs. In 2000, a new formulation of alfaxalone was developed for use in small animals, by solubilizing alfaxalone in 2-hydroxypropyl-beta cyclodextrin (Alfaxan-CD RTU, Jurox Pty. Ltd, Rutherford, Australia), which minimizes histamine release effects.

Alfaxalone produces smooth and rapid anaesthesia induction (within 30-60 seconds after intravenous injection), with excellent muscle relaxation, and dose-dependent changes in cardiovascular and respiratory variables as well as in the anaesthetic duration in dogs. When administrated intravenously, a bolus dose of 2 mg kg-1 provides an average duration of a 6-minute-long anaesthesia of adequate depth (Duke-Novakovski et al. 2016), which is sufficient to allow endotracheal intubation within 1 minute (Ferré et al. 2006). At the recommended dose of 2 mg kg-1, blood pressure changes are minor, and a countervailing brief increase of the heart rate is to be expected. Post induction apnoea is a possible side effect; however, a slow rate of administration will lower this risk significantly (Bigby et al. 2017). Cardiorespiratory parameters return to baseline within 15 minutes after the administration of the recommended induction dose (Duke-Novakovski et al. 2016).

Regarding the use of alfaxalone in maintaining anaesthesia, its rapid metabolism, and therefore clearance, results in a low tendency to accumulate in the tissues after repeated doses (Ferré et al. 2006, Muir et al. 2008), which makes it a suitable agent to be used in TIVA (total intravenous anaesthesia) protocols (Ambros et al. 2008). The maintenance dose is approximately 0.1 mg kg-1 min-1 in premedicated dogs and cats, although individual responses may vary. Mechanical ventilation is recommended in TIVA protocols. Therefore, as it is inadequate as an analgesic agent in painful procedures, appropriate analgesic administration is necessary. The recovery phase after alfaxalone administration can be associated with excitatory events, which are attenuated by the use of sedative pre-anaesthetic medication and by recovering the animal in a quiet room (Duke-Novakovski et al. 2016).

Intramuscular (IM) administration of alfaxalone alone or with other sedatives or analgesic agents has been used to produce sedation or general anaesthesia in various veterinary species, including dogs. Despite Alfaxan-CD not being approved for administration via this route, there are studies regarding IM administration in dogs, which report discomfort associated with large injection volumes, in addition to muscle tremors, pronounced limb extension, paddling and vocalization during recovery (Tamura et al. 2015).

Cardiopulmonary parameters are closely monitored during anaesthesia in order to assess the patient’s stability and decide the course of action. This systematic review aims to present the way alfaxalone affects both the cardiovascular and respiratory system, when used for induction and/or maintenance of anaesthesia, to help readers comprehend the extent in which those systems are being suppressed and, therefore, decide whether to include alfaxalone in their anaesthetic protocol, depending on the patient and the given circumstances.

The drug is not currently available in Greece.

Methods

The literature search included PubMed, Google Scholar and Scopus from 1 January 2000 to 28 February 2021 in English full-text scientific publications. The search terms used in all three search engines were: alfaxalone, dog, anaesthesia, cardiopulmonary effects, cardiorespiratory effects, cardiovascular effects and respiratory effects. Articles under evaluation were limited to English language only.

The criteria set for the selection were the intravenous administration of alfaxalone as a main agent for induction and/or maintenance of anaesthesia in dogs and report on its cardiorespiratory effects. The parameters examined include heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), cardiac output, arterial CO2 partial pressure (PaCO2), arterial O2 partial pressure (PaO2), arterial haemoglobin oxygen saturation (SaO2), end-tidal CO2 partial pressure (PE’CO2) and peripheral capillary haemoglobin oxygen saturation (SpO2). The occurrence of apnoea was also assessed. Twenty-eight publications were examined by three reviewers independently to evaluate if the criteria mentioned were met. Studies were excluded due to the following reasons: alfaxalone being administered intramuscularly, being combined with other anaesthetic agents, being used in higher doses than those recommended by the manufacturer, when the effects of premedication were the main focus, when they were considered biased and lastly when inadequate measurements and/or sample size were used.

Results

A total of eight publications out of twenty-eight were considered to be in agreement with the criteria set (Figure 1). Studies that were based on intramuscular administration of alfaxalone (n=4), combination of alfaxalone with other anaesthetic agents (n=7), studies that were either considered biased (n=1) or used inadequate measurements and/or sample size (n=5), studies that used higher doses than those recommended for clinical reasons (n=1) and studies that focused mainly on the effects of premedication (n=2) were excluded. In particular, in the studies Kato et al. 2020, Murdock et al. 2019, Cruz-Benedetti et al. 2018 and Lee et al. 2015 alfaxalone was administered solely intramuscularly. The studies Bustamante et al. 2020, Pinelas et al. 2014, Zapata et al. 2018, Seo et al. 2014, Quirós-Carmora et al. 2017, Carmona et al. 2016 and Miller, Hughes & Gurney 2019 were using additional anaesthetic agents. Furthermore, the study Keates & Whittem 2012 was found biased. The studies Hampton et al. 2019, Maney et al. 2013, Psatha et al. 2011, Okushima, Vettorato & Corletto 2014 and Pattanapon, Bootcha & Petchdee 2018 had inadequate sample size or measurements of the cardiopulmonary parameters, therefore the final results could not be considered credible. Muir et al. 2008 was excluded due to the use of higher doses than those recommended for clinical reasons. Lastly, Bigby et al. 2017 and Dehuisser et al. 2019 were rejected because they were mainly focused on the premedication that has been used.

The following eight publications were found suitable and were included in this systematic review: Rodríguez et al. 2012, Amengual et al. 2012, Bilgen Şen & Kiliç 2018, Bigby et al. 2017, Dehuisser et al. 2019, Ambros et al. 2008, Dehuisser et al. 2017 and Capik, Polkowska & Lukac 2019.

Figure 1. Flow diagram of excluded and included studies.

In the study “Comparison of the cardiopulmonary parameters after induction of anaesthesia with alfaxalone or etomidate in dogs” (Rodríguez et al. 2012), eight adult dogs were used. All animals were given alfaxalone or etomidate to induce anaesthesia with a washout period of 24 hours and were not subjected to any painful stimuli. Dogs were assigned randomly for induction of anaesthesia IV with alfaxalone (6 mg kg-1 IV) (treatment A) or etomidate (4 mg kg-1 IV) to effect (treatment E). Each drug was injected intravenously at a rate of 10% of total volume given every 6 seconds. Animals were allowed to breathe room air spontaneously. HR, SAP, DAP, MAP, cardiac output and respiratory rate (fR) were measured before induction (baseline), 30 seconds after induction (I30), 60 seconds after induction (I60), after intubation (It), one minute after intubation (T1) and then every 5 minutes. PE’CO2 was measured at the time points It, T1 and then every 5 minutes until extubation. Arterial and venous blood samples were taken before anaesthetic induction, after endotracheal intubation and then every 10 minutes until the trachea was extubated, to measure pH, PaCO2, PaO2, SaO2 and lactate concentration. The induction doses required were 2.91±0.41 mg kg-1and 4.15±0.7 mg kg-1 for treatment E and A, respectively. Significant differences between groups were found in HR at I30, I60, It, T1, T5, T10, T15 and T20, values being higher with treatment A. After induction, HR was non-significantly reduced in treatment E, whereas HR significantly increased in treatment A to reach a maximum difference at It (183±16 bpm from 127±16 bpm at baseline). Cardiac output was significantly lower in treatment E compared to treatment A from I30 to T20. Induction with alfaxalone reduced MAP from baseline (126±8 mmHg) at T5 (103±6 mmHg), T10 (103±9 mmHg), T15 (102±8mmHg) and T20 (104±8 mmHg), but the values remained within physiological range. The same situation was observed with SAP. fR did not differ between anaesthetics; however, it decreased significantly from I30 to T5 in treatment A. At It, PaO2 and SaO2 values were significantly reduced, displaying hypoxemic values in both treatments.

In the study “An evaluation of anaesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone” (Amengual et al. 2012), were included sixty client-owned dogs of various breeds American Society of Anaesthesiologists class I and II (ASA I and II) aged from 6 months to 8 years. Dogs were randomly allocated to either group P or group A and were given propofol or alfaxalone as an anaesthetic agent respectively. Sedation protocol comprised of acepromazine and meperidine. All dogs were pre-oxygenated for at least 3 minutes before the induction. Anaesthesia was induced in group P with 3 mg kg-1 IV propofol and in group A with 1.5 mg kg-1 IV alfaxalone, both administered over 5 seconds. Endotracheal intubation was attempted as soon as possible, and isoflurane (2%) was used to maintain anaesthesia. Intubation was not possible in two dogs (one of each group) and additional induction agents had to be administered. HR and fR were measured before premedication (baseline), immediately before induction and post-intubation and at 3- and 5- minutes post-intubation. SAP, DAP and MAP were recorded before induction and at times 0-, 3- and 5- minutes post-intubation. PE’CO2 and SpO2 were measured at 0-, 3- and 5-minutes post-intubation. Apnoea (defined as a lack of spontaneous breathing for 30 seconds or more) was observed in 17 dogs in group P and 14 dogs in group A. HR decreased in group P (-2±28 bpm) but increased in group A (14±33 bpm). However, it had already changed following pre-medication decreasing in group P (-14±24 bpm) and increasing in group A (3±19 bpm). SAP, DAP and MAP all decreased significantly over time with no significant difference between the two groups. Five dogs in group P and three in group A presented hypotension (MAP <60 mmHg). SaO2 was well maintained and the mean value was 100%. fR and PE’CO2 could not be recorded for apnoeic dogs and therefore analysis at individual time points was not considered appropriate.

In the study “General Anaesthesia in Geriatric Dogs with Propofol-Isoflurane, Propofol-Sevoflurane, Alphaxalone-Isoflurane, Alphaxalone-Sevoflurane and Their Comparison of Biochemical, Hemodynamic and Cardiopulmonary Effects” (Bilgen Şen & Kiliç 2018), forty geriatric dogs with an average age of 10.83 years were randomly assigned in four groups. After induction with propofol (6 mg kg-1 IV) anaesthesia was maintained with isoflurane in group 1 and sevoflurane in group 2. After induction with alfaxalone (3 mg kg-1 IV) in a few seconds, anaesthesia was maintained with isoflurane in group 3 and sevoflurane in group 4. Cardiopulmonary parameters (fR, HR, SpO2) were evaluated before anaesthesia and recorded. One dog in group 3 died in the 60th minute of anaesthesia due to respiratory arrest. The difference in HR between the groups was not significant. In groups that were given alfaxalone an increase in HR was observed with a maximum value at 5 minutes (142.6±9.15 bpm from 101±8.48 bpm at baseline in group 3, 130.2±7.12 bpm from 92±6.56 bpm at baseline in group 4). Arrhythmia was detected in two patients at 60 minutes after recovery in group 3 anaesthesia, both undergoing cataract surgery. fR showed a statistically significant decrease at the 5th minute in groups 3 and 4, but only one patient had apnoea after induction with alfaxalone. SpO2 in all anaesthetic protocols showed a statistically significant decrease in the 5th minute of anaesthesia.

In the study “Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnoea in dogs” (Bigby et al. 2017), participated thirty-two healthy client-owned dogs (ASA I), aged between 5 and 54 months. Dogs were randomly attributed to four groups, each group given a different combination of drug and administration rate (A-Slow, A-Fast, P-Slow, P-Fast). The Alfaxalone Slow (A-Slow) group was given alfaxalone IV at a rate of 0.5 mg kg-1 min-1 the Alfaxalone Fast (A-Fast) group was given alfaxalone IV at a rate of 2 mg kg-1 min-1 the Propofol Slow (P-Slow) group was administered propofol IV at a rate of 1 mg kg-1 min-1 and the Propofol Fast (P-Fast) group was administered propofol IV at a rate of 4 mg kg-1 min-1. All dogs were premedicated with methadone and dexmedetomidine and, after the completion of sedation, they were pre-oxygenated for 5 minutes. fRand HR were evaluated 30 minutes after premedication and throughout the induction of anaesthesia. The induction dose was for the A-Slow group 0.9±0.3 mg kg-1, for the A-Fast group 2.2±0.5 mg kg-1, for the P-Slow group 1.8±0.6 mg kg-1, and for the P-Fast group 4.1±0.7 mg kg-1. Three minutes after orotracheal intubation, fR, HR, SpO2, and PE’CO2 were measured and thereafter were constantly monitored every 5 minutes. Apnoea, that was defined as cessation of breathing for a period of 30 seconds or longer, occurred in 100% of dogs in the A-Fast and P-Fast groups, with a mean duration of 287±125 seconds and 247±125 seconds, respectively, and in 25% of dogs in the A-Slow and P-Slow groups, with a mean duration of 43±80 seconds and 10±18 seconds, respectively.

In the study “Alfaxalone total intravenous anaesthesia in dogs: pharmacokinetics, cardiovascular data and recovery characteristics” (Dehuisser et al. 2019), six intact female laboratory Beagles were included, aged 25.0±0.6 months. On the study day no premedication was administered. Anaesthesia was induced with 3 mg kg-1 alfaxalone IV, administered manually over 1 minute, and endotracheal intubation was performed. The alfaxalone constant rate infusion (CRI) was immediately administered at the rate of 0.15 mg kg-1 min-1 (manufacturer’s recommended infusion rate for unpremedicated dogs). The CRI was administered once for 90 minutes (short CRI) and once for 180 minutes (long CRI) with an interval period of 3 weeks. No surgical stimuli were performed. HR, SAP, DAP, MAP, SpO2, PECO2 and fR were measured immediately after induction (T0) and every 5 minutes throughout the anaesthesia. Mechanical ventilation was initiated in one dog during the protocol short CRI and in four dogs during protocol the long CRI due to high PE’CO2. A significant decrease in HR was found at 30 minutes (125±18 bpm for short CRI, 114±18 bpm for long CRI) compared with T0 (156±24 bpm for short CRI, 162±12 bpm for long CRI). The lowest SAP value was recorded at 60 minutes (126±20 mmHg from 157±22 mmHg at T0 for short CRI and 119±10 mmHg from 150±12 mmHg at T0 for long CRI). The lowest MAP value was observed at 30 minutes for short CRI (83±11 mmHg from 95±15 mmHg at T0). Long CRI protocol MAP also presented a maximum decrease at 30 minutes (80±6 mmHg from 94±8 mmHg at T0) as well as at 60 minutes.

In the study “Comparison of the anesthetic efficacy and cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-beta-cyclodextrin and propofol in dogs” (Ambros et al. 2008), six healthy crossbred laboratory young adult dogs, were all subjected to CRI anaesthesia both with propofol and alfaxalone with a washout period between the two of six days. All dogs were sedated with acepromazine and hydromorphone and after 30 minutes induction started with either propofol (4 mg kg-1 IV) or alfaxalone (2 mg kg-1 IV) administered over 60 seconds. Tracheal intubation was performed, and the dogs were allowed to spontaneously breathe 100% oxygen. CRI anaesthesia was then performed for 120 minutes with a rate of 0.25 mg kg-1 min-1 for propofol and 0.07 mg kg-1 min-1 for alfaxalone to maintain a light plane of anaesthesia. No painful simulations were performed. Measurements of SAP, DAP, MAP, mean pulmonary arterial pressure (MPAP), pulmonary artery wedge pressure (PAWP), right atrial pressure (RAP), HR, cardiac output, fR, arterial pH, PaCO2 and PaO2 were monitored. HR, SAP, DAP, MAP and cardiac output did not vary significantly between anaesthetics at any time. For the dogs in the alfaxalone group there was a slight increase in HR after induction, the cardiac output was well preserved and the decreased MAP, which was observed in both groups, was restored faster. fR, arterial pH, PaO2 and PaCO2 did not change significantly at any time. Arterial pH was significantly decreased 5 minutes (7.23±0.03) after induction until the end of anaesthesia, which was considered to indicate respiratory acidosis. PaCO2 was significantly higher only at 5 minutes (64.4±11.8 mmHg from 45.7±6.1 mmHg at baseline) after induction with alfaxalone which indicates a respiratory depression.

In the study “Cardiovascular effects, induction and recovery characteristics and alfaxalone dose assessment in alfaxalone versus alfaxalone-fentanyl total intravenous anaesthesia in dogs” (Dehuisser et al. 2017), were included 12 intact female experimental Beagles, aged 13±1 month and classified as ASA I. The dogs were randomly assigned to one of two TIVA protocols: group AF (alfaxalone-fentanyl) and group AP (alfaxalone). Premedication included dexmedetomidine and methadone. After 20 minutes, Group AF was co-induced with fentanyl (2 μg kg-1 IV), immediately followed by alfaxalone (2 mg kg-1 IV) administered manually over 1 minute. After endotracheal intubation, maintenance of anaesthesia was obtained by a variable rate infusion (VRI) of alfaxalone combined with a CRI of fentanyl using two syringe drivers. The alfaxalone VRI was started at a rate of 0.15 mg kg-1 min-1 and the fentanyl CRI was set at 10 μg kg-1 h-1. Group AP was administered saline, 0.04 ml kg-1, followed by alfaxalone 2 mg kg-1 over 1 minute and following intubation, anaesthesia was maintained by an alfaxalone VRI, starting at 0.15 mg kg-1, and a saline CRI. Mechanical ventilation was performed throughout the procedure to maintain PE’CO2 at a specific level. HR, SAP, DAP, MAP, SpO2, fR and PE’CO2 were monitored. VRI was either increased or decreased by 0.01 mg kg-1 min-1 when necessary. In group AP, three dogs were administered an additional IV bolus of alfaxalone to treat insufficient depth of anaesthesia. The dose rate required to maintain an adequate surgical plane of anaesthesia differed significantly between both groups (0.16±0.01 mg kg-1 min-1 in group AP versus 0.13 ± 0.01 mg kg-1 min-1 in group AF). Consequently, the total volume of alfaxalone needed for 210 minutes of anaesthesia was significantly lower in group AF than in group AP. Overall, HR, SAP, MAP and DAP were lower in group AF than in group AP (HR: 72±4 bpm versus 94±13 bpm, SAP: 134±11 mmHg versus 144±7 mmHg, MAP: 91±11 mmHg versus 105±6 mmHg, DAP 76±11 mmHg versus 91±7 mmHg, respectively). At the time of incision, HR, DAP and MAP were significantly increased in group AP compared with that in group AF. In group AP, HR was 91±17 bpm, DAP was 105±12 mmHg and MAP was 118±16 mmHg compared with 67±4 bpm, 75±6 mmHg and 91±8 mmHg, respectively, in group AF, remaining however within clinically acceptable limits.

In the study “A comparison of propofol and alfaxalone in a continuous rate infusion in dogs with mitral valve insufficiency” (Capik et al. 2019) seven client-owned Chihuahuas with second stage cardiac insufficiency (class II cardiac insufficiency according to the classification by the International Small Animal Cardiac Health Council), undergoing regular dental prophylaxis were included, aged from 9 to 14 years. All the dogs were treated with angiotensin converting enzyme inhibitors and diuretics. Dogs were administered propofol CRI for the procedure and with an interval of one-year alfaxalone CRI was used for the same purpose. The dogs were premedicated in both cases using midazolam, butorphanol and xylazine. After three minutes, anaesthesia was induced with 2 mg kg-1 IV and maintained with a CRI of 0.25 mg kg-1 min-1 of propofol, and with 2 mg kg-1 IV and 0.1 mg kg-1 min-1 of alfaxalone. Following the induction of anaesthesia, the dogs were immediately intubated to provide airway patency. CRI anaesthesia was conducted for one hour. HR, SAP, DAP, MAP, SpO2 and fR were monitored. Patients were electrocardiographically monitored for potential arrhythmia occurrence. The mean fR was insignificantly higher in the alfaxalone group. The SpO2 ranged from 96% to 98% in the propofol group and from 97% to 98% in the alfaxalone group. The heart rhythm was regular without episodes of arrhythmias in both groups. The mean HR was insignificantly higher in the alfaxalone group. One dog in the alfaxalone group remained tachycardic despite premedication. In the alfaxalone group the MAP was lower in comparison with the propofol anaesthesia (67.85 mmHg versus 71.71 mmHg at 10 minutes, 62.57 mmHg versus 66 mm Hg at 30 minutes and 62.71 mmHg versus 66.42 mmHg at 60 minutes for alfaxalone and propofol, respectively).

Discussion

In 2016, Chiu et al. published “The cardiopulmonary effects and quality of anaesthesia after induction with alfaxalone in 2-hydroxypropyl-β-cyclodextrin in dogs and cats: a systematic review”, where the cardiopulmonary effects of alfaxalone as an induction agent were reviewed in both dogs and cats, including 22 studies from 2001 until 20th May 2013. The database used for this systematic review consisted of Discovery, PubMed, Science Direct and Wiley Interscience. In order to collect data, there were also used studies that did not focus on the effects on the cardiopulmonary system. To the authors’ knowledge there is no other systematic review assessing the cardiopulmonary effects of alfaxalone as the main agent for induction and/or maintenance of anaesthesia, focusing only on canine patients.

Regarding materials and methods, all eight studies contained in this systematic review were based on randomised study design. Sample size and composition in addition to the procedures, to which the patients were subjected to, varied between the studies. In most anaesthetic protocols, patients were sedated before the induction of anaesthesia. It is important to highlight that the kind of sedative agents, as well as the dosage in which they were administered, has an effect both on the dosage of alfaxalone required to maintain anaesthesia and on alfaxalone’s effect on the recorded parameters. However, the duration of alfaxalone’s infusion, when used in CRI protocols, does not seem to significantly increase the risk of its side-effects on the cardiopulmonary system (Dehuisser et al. 2019).

Studies used considerably variable doses concerning the induction, depending on the administration rate and whether premedication was used. The lowest dose of 0.9±0.3 mg kg-1 of alfaxalone was used when administered slowly on premedicated dogs (Bigby et al. 2017). The highest dose of 4.15±0.7 mg kg-1 was used when administered slowly on non-premedicated dogs (Rodríguez et al. 2012). When used to maintain anaesthesia, similar doses on a scale of 0.1 mg kg-1 min-1 to 0.16 mg kg-1 min-1 (Dehuisser et al. 2017, Dehuisser et al. 2019, Capik et al. 2019) were used, excluding Ambros et al. 2008, in which 0.07 mg kg-1 min-1 were used to maintain a light plane of anaesthesia, with no painful stimuli applied.

The occurrence of apnoea, which is a considerable side-effect when alfaxalone is administered as an induction agent, was noted in three studies (Amengual et al. 2012, Bigby et al. 2017, Bilgen Şen & Kiliç 2018). The main factors that seem to contribute, not only to the appearance of apnoeic episodes, but also to their duration, are the rate of administration and the dosage of alfaxalone. On the contrary, the advanced age of the patients does not appear to increase the risk for this adverse reaction. In addition, it was observed that using a slow rate of administration the total dose required to facilitate intubation was significantly lower than that of the fast rate. The fRshowed a statistically significant decrease in some studies, but these declines were within physiological limits.

As far as blood gasses are concerned, measurements were made in arterial blood samples and a decrease in SaO2, PaO2, pH and an increase in PaCO2, indicating hypoxemia, acidosis and hypercapnia were clearly recorded in two studies (Ambros et al. 2008, Rodríguez et al. 2012). Where capnography was used there was mentioned an increase in PE’CO2. Although, two of the studies could not assess the changes in PE’CO2 because of apnoeic episodes (Amengual et al. 2012, Bigby et al. 2017), and in one study PE’CO2 was maintained stable using mechanical ventilation (Dehuisser et al. 2017). A SpO2 decrease was observed in two studies (Bilgen Şen & Kiliç 2018, Dehuisser et al. 2019), whereas a well maintained SpO2 was recorded in one study (Capik et al. 2019). As a consequence of the above, preoxygenation should be performed in order to avoid the possibility of hypoxemia after the induction of anaesthesia with alfaxalone, especially when it comes to haemodynamically unstable dogs or patients with a low PaO2. Furthermore, the prevention of hypoventilation is equally important via mechanical ventilation, so as to eliminate the risk of respiratory acidosis and hypercapnia (Ambros et al. 2008).

All studies recorded an increase in HR after induction, except for one study (Dehuisser et al. 2019), where a significant decrease in HR was mentioned at 30 minutes after induction, but an important limitation of this study is that cardiovascular variables were not recorded before induction of anaesthesia. Regarding arterial pressure, all three parameters (SAP, DAP, MAP) were slightly decreased. As a result, it seems that the use of alfaxalone is associated with an increase in HR, despite a decrease in MAP, suggesting that some baroreceptor reflex activity may be present after its administration (Amengual et al. 2012). Furthermore, the dose-dependent effect on blood pressure is presumed to be a result of vasodilation, since systemic vascular resistance index (SVRI) was significantly lower in two studies (Ambros et al. 2008, Rodríguez et al. 2012). Nevertheless, the mechanism of this effect of alfaxalone has not been completely defined yet.

Arrythmia was detected in two patients of one study (Bilgen Şen & Kiliç 2018), that were anesthetized for cataract surgery, and it is thought to be caused by their geriatric nature. Cardiac output was well preserved when monitored, which could indicate that alfaxalone has no or little negative effects on myocardial contractility (Ambros et al. 2008, Rodríguez et al. 2012). Moreover, alfaxalone has been found that might be useful as an anaesthetic agent in dogs with cardiological problems (Rodríguez et al. 2012, Capik et al. 2019), but its use might be contra-indicated in patients that cannot easily tolerate an excessive increase in heart rate. The use of premedication, the application of mechanical ventilation and the type of the surgical stimuli performed in each case may have an impact on the cardiovascular function.

Conclusions

In conclusion, a slow rate of administration of alfaxalone can prevent the occurrence of post-induction apnoea and can, additionally, contribute to a decrease of the total dose required to induce anaesthesia. In order to avoid respiratory depression, mechanical ventilation is suggested after endotracheal intubation and oxygen supplementation is advisable at the appropriate concentration per case, due to the possibility of hypoxemia. Concerning the cardiovascular parameters, an increase in HR and a slight decrease in arterial pressure is to be expected.

Overall, alfaxalone is considered to be a safe anaesthetic agent in clinical practice due to its rapid onset of activity and its high total body clearance. Although, the dose of administration for induction and/or maintenance of anaesthesia should be individualized, according to the case of each patient, taking in account its age, its ASA-status and the co-administration of other drugs. It is recommended to be combined with a proper analgesic protocol, when administered in painful procedures. Lastly, appropriate care should be taken during the recovery phase, where excitatory events may occur.

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2022-03-02

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Zioga, M., Papadopoulos, S., Pavlidou, A., Pavlidou, K. and Savvas, I. (2022) “Α systematic review of the cardiopulmonary effects of alfaxalone when used as a main agent for induction and/or maintenance of anaesthesia in dogs”, Hellenic Journal of Companion Animal Medicine, 10(2), pp. 80–95. Available at: https://ojs.hcavs.gr/index.php/hjcam/article/view/117 (Accessed: 11August2022).

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Systematic reviews

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