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Co-induction of anaesthesia with alfaxalone and midazolam in dogs: a randomized, blinded clinical trial
Veterinary Anaesthesia and Analgesia 2019, 46, 613e619
https://doi.org/10.1016/j.vaa.2019.03.009
RESEARCH PAPER
Co-induction of anaesthesia with alfaxalone and midazolam in dogs: a randomized, blinded clinical trial Chris Millera, Ellen Hughesb & Matt Gurneya a
Northwest Veterinary Specialists, Sutton Weaver, Cheshire, United Kingdom
b
College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Correspondence: Chris Miller, Small Animal Hospital, University of Glasgow, 464, Bearsden Road, Glasgow G61 1QH United Kingdom. E-mail: [email protected]
Abstract Objective To qualitatively assess the co-induction of anaesthesia with midazolam and alfaxalone and to determine cardiovascular or respiratory alterations compared with alfaxalone alone. Study design A randomized, blinded, clinical trial. Animals A total of 29 American Society of Anesthesiologists grade I or II, client-owned dogs undergoing elective orthopaedic or soft tissue surgery. e1
Methods All dogs received 0.02 mg kg acepromazine and 0.3 mg kge1 methadone intramuscularly 30 minutes prior to anaesthesia. Measurements of heart rate (HR), respiratory frequency and blood pressure (BP) were assessed pre-induction and at 0, 2 and 5 minutes post-induction. Anaesthesia was induced with 0.5 mg kge1 alfaxalone followed by either 0.4 mg kge1 midazolam intravenously (group M) or an equal volume of saline (group S). Conditions were assessed for intubation and further boluses of 0.25 mg kge1 alfaxalone were given as required. Response to co-induction, ease of intubation and quality of induction were scored, and total dose of alfaxalone required for intubation was recorded. Repeated measures one-way analysis of variance with post hoc Tukey’s test was used to assess within group changes over time and Student t tests were used to compare between groups. Incidence of apnoea was assessed using a Fisher’s exact test. Data are shown as mean ± standard deviation. Results Group M included 14 dogs and group S 15 dogs. There was a significant difference in the total dose of alfaxalone required for intubation, 0.65 ± 0.20 mg kge1 group M and 0.94 ± 0.26 mg kge1 group S (p ¼ 0.002). Apnoea occurred significantly more frequently in group M (p ¼ 0.007). There were no clinically significant differences in HR or BP at the measured time points between groups.
Conclusions and clinical relevance Co-induction with midazolam had significant alfaxalone-sparing effects with no clinically detectable cardiovascular changes. Apnoea is common after co-induction. Keywords alfaxalone, apnoea, co-induction, dogs, midazolam. Introduction Alfaxalone is a neuroactive progesterone-derived steroid that acts on gamma-aminobutyric acid (GABA) receptors within the central nervous system resulting in unconsciousness and muscle relaxation (Albertson et al. 1992). It has a rapid onset and short duration of action, making it an ideal induction agent (Ferre et al. 2006). Adverse effects of alfaxalone are dose-dependent and include an increase in heart rate (HR), hypoventilation and apnoea (Muir et al. 2008). In unpremedicated dogs, alfaxalone administered intravenously (IV) at 6 mg kge1 and 20 mg kge1 caused a significant increase in HR compared with baseline. However, this change was not observed at an alfaxalone dose of 2 mg kge1. A significant decrease in systolic blood pressure (SAP) was also demonstrated at doses between 2 mg kg e1 and 20 mg kge1 (Muir et al. 2008), whereas Maney et al. (2013) reported no significant cardiovascular changes in unpremedicated dogs following induction of anaesthesia with alfaxalone (mean dose 2.6 mg kge1). These studies demonstrate that although high (supraclinical) doses of alfaxalone cause cardiovascular effects, these effects are not significant at clinically recommended doses of up to 2 mg kge1 in the healthy dog (Summary of Product Characteristics, Jurox UK Ltd, UK). Alfaxalone at 2.6 mg kge1in unpremedicated dogs caused a significant but clinically acceptable increase in arterial pressure of carbon dioxide immediately following drug administration (Maney et al. 2013). Apnoea may be seen using 2 mg kge1 alfaxalone, while higher doses, up to 20 mg kge1, increases the duration of apnoea (Muir et al. 2008). Speed of
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Alfaxalone midazolam co-induction in dogs C Miller et al.
alfaxalone injection may influence postinduction apnoea with a faster rate of administration, 2 mg kge1 minutee1, resulting in a higher incidence of apnoea than with a rate of 0.5 mg kge1 minutee1 (Bigby et al. 2017). Co-induction, the use of more than one drug in combination or sequence, is a commonly used technique to reduce the total dose of induction agent required and potentially reduce the number or severity of associated side effects (Anderson & Robb 1998). Commonly used co-induction drugs include opioids (Covey-Crump & Murison 2008) and benzodiazepines (Short & Chui 1991; Hopkins et al. 2014). Recent studies have demonstrated significant alfaxalone- and propofol-sparing effects when combined with varying doses of midazolam (Liao et al. 2017; Mu~ noz et al. 2017; Italiano & Robinson 2018; Zapata et al. 2018). This study examined whether the administration of midazolam following administration of a subhypnotic dose of alfaxalone would reduce the total dose of alfaxalone required for endotracheal intubation. A secondary aim was to determine whether there was a difference in the observed cardiorespiratory effects between this co-induction technique versus the use of alfaxalone alone. It was hypothesized that midazolam administered as a coinduction agent would reduce the total dose of alfaxalone required for intubation, with a reduction in the magnitude of cardiorespiratory depressant effects. Materials and methods Ethical approval for the study was granted by the Animal Health Trust Ethics committee (AHT_42_2015). An Animal Test Certificate (Type S) was obtained from the Veterinary Medicines Directorate for the use of midazolam (Hypnovel 5 mg mLe1; Roche Products Ltd, UK) in dogs. Informed owner consent was obtained for each dog before inclusion in the study. All dogs included in the study were American Society of Anesthesiologists (ASA) grade I or II, based on clinical examination and medical history, and were undergoing general anaesthesia for elective orthopaedic or soft tissue surgery. Aggressive or excessively boisterous dogs were excluded from the study. A full clinical examination was performed prior to anaesthesia, HR and respiratory rate (fR) were assessed by auscultation and rectal temperature measurements were recorded. Body condition score was assessed using a previously published scale (body condition score; WSAVA 2013). All dogs were premedicated with acepromazine (0.02 mg kge1, ACP; Elanco Animal Health, UK) and methadone (0.3 mg kge1, Comfortan; Dechra Veterinary Products, UK) mixed in the same syringe via injection into the lumbar epaxial muscles 30 minutes before the induction of anaesthesia. 614
Dogs were randomly assigned via a lottery system to one of the two groups: group M received midazolam (0.4 mg kge1) as a co-induction agent and group S received an equal volume of saline (0.08 mL kge1). Co-induction agents were drawn up into a syringe labelled ‘test drug’ by an assistant. The primary investigator was blinded to the allocated group and administered all drugs, performed endotracheal intubation, assigned scores (Table 1) and recorded measurements (Tables 2e4). Level of sedation was graded 30 minutes after premedication in dogs using a composite scoring scale as described in Table 1 (Covey-Crump & Murison 2008). An IV cannula (Jelco; Smiths Medical, UK) was placed into a cephalic vein. Prior to induction of anaesthesia, the lungs of the dogs were pre-oxygenated for 3 minutes via a tight-fitting mask with an oxygen flow of 3 L minutee1. During pre-oxygenation preinduction measurements of HR and fR were taken. Blood pressure (BP) was assessed by an oscillometric method (Cardell; Midmark Animal Health, OH, USA) using an appropriately sized cuff placed around the antebrachium. Alfaxalone (2 mg kge1, Alfaxan; Jurox UK Ltd, UK) was drawn into a labelled syringe and induction of anaesthesia was initiated with alfaxalone (0.5 mg kge1) given manually over 30 seconds. The IV cannula was flushed with heparinized saline, and then midazolam or saline, group M or S, respectively, was given by the investigator over 30 seconds followed by further heparinized saline. The response to the co-induction agent was immediately scored according to the scale detailed in Table 1 and conditions for intubation including loss of palpebral reflex, ventromedial rotation of the eye and loss of jaw tone were assessed. If conditions were unsuitable immediately following assessment, a further alfaxalone (0.25 mg kge1) bolus was given over 15 seconds and intubation conditions were reassessed. This was repeated until intubation was possible. The total dose of alfaxalone required for intubation was recorded. A laryngoscope was used to depress the base of the tongue and visualize the larynx with the dog in sternal recumbency. Endotracheal intubation was performed with an appropriately sized endotracheal tube (ETT) and the quality of induction and ease of intubation were scored based on the scale in Table 1. Following endotracheal intubation, the ETT cuff was inflated and the ETT was connected to an appropriate breathing system. Anaesthesia was maintained using isoflurane (IsoFlo; Abbott Animal Health, UK) vaporised in 100% oxygen and the vaporiser was initially set to deliver 2% isoflurane. Further measurements of HR assessed by electrocardiography, fR assessed by visualizing thoracic excursions and BP [SAP, mean (MAP) and diastolic blood pressure (DAP)] assessed by oscillometry were taken at 0, 2 and 5 minutes after intubation (T0, T2 and T5, respectively). Other monitoring
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., 46, 613e619
Alfaxalone midazolam co-induction in dogs C Miller et al. Table 1 Description of scales for scoring sedation, co-induction, intubation and quality of induction (Covey-Crump & Murison 2008).
Sedation score
Co-induction score
Intubation score
Quality score
Score
Description
0 1 2 3 0 1 2 0 1 2 3 0 1 2 3
No effect Mild sedation (quieter than before injection but still bright and active) Moderate sedation (quiet, reluctant to move, possibly slightly ataxic) Profound sedation (unable to walk) Sedation (more sedated than before co-induction agent) No change (compared with before injection) Excitement (more activity than before injection) Smooth (no swallowing, coughing, tongue or jaw movements) Fair (some tongue movement, slight cough) Poor (marked tongue movement, swallowing or coughing) Very poor (as 2 but required additional alfaxalone and second attempt) Smooth (without excitement) Fair (slight excitement, muscle twitching or movement of limbs) Poor (marked excitement, muscle twitching, paddling of limbs) Very poor (severe excitement plus vocalization)
Reprinted from Covey-Crump and Murison (2008). © Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd.
devices such as a pulse oximeter were attached to the patient. Periods of apnoea longer than 30 seconds were recorded and managed via intermittent manual ventilation using the reservoir bag of the anaesthetic breathing system at a rate of 3 breaths minutee1 until spontaneous ventilation resumed. Statistical analysis Statistical analyses were performed using GraphPad Prism version 8.0.1 for Windows, GraphPad Software, CA, USA (www.graphpad.com). Data were assessed for normality using the D'Agostino-Pearson omnibus K2 test. Between-group differences were analysed using Student t tests for normally distributed data (HR, SAP, MAP and DAP) and ManneWhitney U test for nonparametric data (fR, sedation, co-induction, intubation and quality scores). Within-group comparisons for normally distributed data were analysed using repeated measures one-way analysis of variance with Tukey’s post hoc test. Within-group comparisons for nonTable 2 Mean ± standard deviation of age, body mass, heart rate (HR) and respiratory rate (fR) and median (range) of body condition score (BCS) of dogs in alfaxalone-midazolam (group M) and alfaxalone-saline (group S) groups.
Age (years) Body mass (kg) BCS HR (beats minutee1) fR (breaths minutee1)
Group M
Group S
p*
5.5 ± 3.3 23.5 ± 12.8 6 (5.5e8) 107 ± 27 27 ± 9
4.2 ± 2.8 21.3 ± 10 6 (5e7) 118 ± 28 28 ± 7
0.281 0.610 0.791 0.312 0.932
* Probability of statistical difference between groups. A value of p < 0.05 considered significant.
normally distributed data (fR) were analysed using Friedman test and Dunn’s post hoc test. For the purposes of analyses, apnoea was categorized as 0 breaths minutee1. Presence or absence of apnoea was also compared as a categorical variable using Fisher’s exact test. Level of significance was set at a p < 0.05. Data are presented as mean ± standard deviation (SD) or median and range. A post hoc power calculation using the calculated means and SDs showed sufficient power (>0.9) to detect a significant difference in alfaxalone dose between the groups with an alpha of 0.05. Results Group M comprised 14 dogs (7 female and 7 male) and group S comprised 15 dogs (9 female and 6 male). One dog in group M was excluded because further premedication was required to enable IV cannula placement. There were no significant differences between groups in age, mass, body condition score, HR and fR measured prior to premedication administration (Table 2).
Table 3 Median (range) of scores assigned as defined in Table 1 to dogs and incidence of apnoea in alfaxalone-midazolam (group M) and alfaxalone-saline (group S) groups.
Sedation score Co-induction score Intubation score Quality score Apnoea
Group M
Group S
p*
1 (1e2) 0 (0e2) 0 (0e1) 0 (0e1) 8/14
1 (1e3) 1 (0e1) 1 (0e3) 0 (0e2) 1/15
0.990 0.014 0.016 0.200 0.007
* Probability of statistical difference between groups. A value of p < 0.05 considered significant.
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., 46, 613e619
615
Alfaxalone midazolam co-induction in dogs C Miller et al. Table 4 Mean ± standard deviation of heart rate (HR), systolic blood pressure (SAP), mean blood pressure (MAP), diastolic blood pressure (DAP), respiratory rate (fR) and alfaxalone dose required for intubation (total alfaxalone) of dogs in alfaxalone-midazolam (group M) and alfaxalone-saline (group S) groups; before induction of anaesthesia (Pre), immediately following intubation (T0) and 2 minutes (T2) and 5 minutes (T5) following intubation.
HR (beats minutee1) Pre T0 T2 T5 SAP (mmHg) Pre T0 T2 T5 MAP (mmHg) Pre T0 T2 T5 DAP (mmHg) Pre T0 T2 T5 fR (breaths minutee1) Pre T0 T2 T5 Total alfaxalone (mg kge1)
Group M
Group S
96 ± 33 122 ± 45y 116 ± 34 119 ± 33
107 123 113 112
± ± ± ±
28 41 35 33
0.310 0.824 0.668 0.590
± ± ± ±
128 140 134 117
± ± ± ±
20 36 33 21
0.629 0.904 0.069 0.405
103 ± 20 104 ± 29 101 ± 35 83 ± 20
0.893 0.524 0.240 0.609
± ± ± ±
0.467 0.794 0.614 0.859
128 138 119 115
14 30 9 14
p*
Discussion 103 ± 13 109 ± 29 89 ± 12y 83 ± 14y,z 79 90 69 63
± ± ± ±
20 29 16 16y,z
40 ± 26 9 ± 16y 9 ± 11y 13 ± 9 0.65 ± 0.20
88 89 72 62
31 19 22 20y,z
26 ± 7 24 ± 9 17 ± 14 21 ± 11 0.94 ± 0.26
0.105 <0.001 0.068 0.181 0.002
y
Significant differences (p 0.05) compared with Pre values within group. Significant differences (p 0.05) compared with T0 values within group. Probability of statistical difference between groups. A value of p < 0.05 considered significant. z
*
Following premedication, there were no differences in sedation scores between the groups, but dogs in group M were more sedated following administration of the co-induction agent than group S (p ¼ 0.014). Intubation was significantly smoother in group M than in group S (p ¼ 0.016), but the overall quality of induction was similar between the groups. Mild excitement was seen in 2/14 dogs in group M and 5/15 dogs in group S, with one dog in group S showing marked excitement, but overall quality of induction was similar between the groups (p ¼ 0.200; Table 3). Changes in HR, fR and BP during the study period are presented in Table 4. Within group M, there was a significant increase in HR compared with pre-induction measurements at T0 but at no other time points. There were no significant differences in HR between groups at any other time point. There were no significant differences in SAP both within groups over time or 616
between groups. In group M, MAP decreased with a significantly lower MAP at T2 and T5 than at pre-induction measurements; however, there were no differences between groups at any time point. DAP decreased in both groups with significantly lower DAP within each group at T5, but there were no significant differences between groups at any time points. In group S, there were no significant changes in fR at any time point but fR was significantly lower within group M than pre-induction measurements at T0 (p ¼ 0.034) and T2 (p ¼ 0.021). fR was significantly different between groups at T0 (p < 0.001). Apnoea following induction of anaesthesia was significantly more common in group M than in group S (8/14 versus 0/15 respectively; p ¼ 0.007). Significantly less alfaxalone was required for endotracheal intubation in group M than in group S: 0.65 ± 0.2 mg kge1 versus 0.94 ± 0.26 mg kge1, respectively; (p ¼ 0.002).
This study demonstrates that midazolam (0.4 mg kge1) following an initial bolus of alfaxalone (0.5 mg kge1) has significant alfaxalone-sparing effects, with clinically insignificant cardiovascular effects but with significant respiratory depression and a higher incidence of apnoea. Previous studies in dogs have demonstrated a variable induction agent-sparing effect of midazolam that was both sequence dependent (S anchez et al. 2013) and dose dependent (Robinson & Borer-Weir 2013). Several recent studies have also demonstrated the significant alfaxalone-sparing effects of midazolam in healthy dogs (Liao et al. 2017; Mu~ noz et al. 2017; Italiano & Robinson 2018; Zapata et al. 2018). The reduction in the dose of alfaxalone in our study (24%) was less than that previously reported in studies using a similar protocol (35%, Italiano & Robinson 2018; 62%, Mu~ noz et al. 2017) but similar to another (Liao et al. 2017). Several explanations could account for these differences, such as difference in drugs used for premedication and consequently the degree of sedation prior to induction. Numerous studies have investigated the sequence of administration of co-induction agents (Covey-Crump & Murison 2008; S anchez et al. 2013; Zapata et al. 2018) and demonstrated that administration of midazolam following an initial bolus dose of an induction agent provides greater induction agent-sparing effects. One reason for administering induction agent prior to midazolam is to minimize any potential excitement or disinhibition following midazolam administration to a poorly sedated dog (Covey-Crump & Murison 2008). S anchez et al. (2013) demonstrated fewer excitatory phenomena and greater propofol-sparing effects when an initial bolus of propofol was given before midazolam. In our study, mild excitement was seen in two dogs following administration of midazolam and, moreover, a recent study demonstrated a significantly higher incidence of excitable
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., 46, 613e619
Alfaxalone midazolam co-induction in dogs C Miller et al.
behavioural changes when midazolam was given prior to alfaxalone (Zapata et al. 2018) In our study in group S, a lower total dose of alfaxalone was required for intubation than recommended guidelines (Summary of Product Characteristics, Jurox UK Ltd, UK) and studies reporting the induction dose in unpremedicated (Rodríguez et al. 2012) and premedicated dogs (Herbert et al. 2013; Pinelas et al. 2014). Manufacturer recommendations state that in premedicated dogs, the calculated dose of alfaxalone (2 mg kge1) should be given over 60 seconds. A previous study has demonstrated that slow administration of the induction agent can have significant alfaxalone- and propofol-sparing effects in dogs (Bigby et al. 2017). In our study, both premedication and the relatively slow rate of administration of alfaxalone could account for the comparatively low doses of alfaxalone required in group S. Another factor could be the principle of priming (Kumar et al. 2006). Giving a low subhypnotic dose of induction agent slowly prior to more rapid administration of induction agent has been shown to reduce total induction agent required for intubation (Stokes & Hutton 1991). The low total induction dose of alfaxalone in both groups could be attributed to this phenomenon. In this study, HR did not differ significantly between the groups, but HR was significantly higher at T0 than at preinduction measurements in group M. BP tended to decrease over time, but no hypotension was detected (Ruffato et al. 2015) at any time point in either group despite statistically significant differences within group M. There were no significant differences between groups, at any time point. It would appear from this study that the alfaxalone-sparing effect of midazolam does not result in any cardiovascular benefits. However, clinically significant cardiovascular benefits may not be apparent due to the comparatively low doses of alfaxalone required in both groups. Midazolam is considered to have minimal cardiovascular effects but can decrease myocardial contractility, systemic vascular resistance and preload when supraclinical doses are given (Jones et al. 1979). A previous study assessing midazolam-propofol co-induction demonstrated similar decreases in arterial BP (Hopkins et al. 2014) to our study using a lower dose of midazolam (0.2 mg kge1). Further work is required to determine if these changes are dose dependent. Decreasing BP following induction of anaesthesia in both groups could be accounted for by the transition to inhalational anaesthesia, which is known to cause a dosedependent vasodilation and hypotension (Steffey & Howland 1977). Premedication with acepromazine, which also causes vasodilation, may have contributed to the decrease in BP (Pruneau et al. 1984). In humans, midazolam is a respiratory depressant and causes hypoventilation by a reduction in tidal volume (Castro et al. 2017), but it is described as having minimal respiratory effects in dogs (Clarke & Trim 2013). However, in this study
apnoea occurred more frequently in group M with a relatively high incidence of 8 out of 14 dogs (57%). Both dose (Muir et al. 2008) and rate of administration of alfaxalone (Amengual et al. 2013; Bigby et al. 2017) have been associated with apnoea. However, the incidence of apnoea following coinduction with midazolam varies between studies. One study reported that apnoea occurred in 13 out of 90 dogs, but use of midazolam was not associated with apnoea more frequently than diazepam or control groups (Italiano & Robinson 2018). However, in comparison with our study, similar incidences of apnoea have been reported by other authors (Mu~ noz et al. 2017, Zapata et al. 2018). The higher incidence of apnoea in group M than group S in our study could be explained by the higher initial bolus of alfaxalone [0.5 mg kge1 versus 0.25 mg kge1 (Mu~ noz et al. 2017)] and a possible synergistic effect between the alfaxalone and midazolam as they both act at the GABA receptor (Skerritt and Johnston, 1983; Albertson et al. 1992). This higher initial alfaxalone dose, when combined with the midazolam, could result in a deeper plane of anaesthesia and more pronounced respiratory depression. Unlike the studies by Mu~ noz et al. (2017) and Zapata et al. (2018), no dogs in group S experienced apnoea; this result was contrary to their findings. Possible explanations could be differences in premedication and the different initial doses of alfaxalone prior to midazolam, 0.25 mg kge1 (Mu~ noz et al. 2017) and 0.5 mg kge1 (Zapata et al. 2018). Periods of apnoea were not associated with any clinically significant desaturation of haemoglobin as measured by pulse oximetry (data not included) and apnoea was managed with intermittent manual ventilation until spontaneous ventilation resumed. All animals tolerated pre-oxygenation prior to induction of anaesthesia, and this may have helped to reduce any potential desaturation events. In this study, we investigated midazolam (0.4 mg kge1) for co-induction because this dose was found to have the greatest propofol-sparing effects in a dose finding study (Robinson & Borer-Weir 2013). However, a recent study investigating coinduction with midazolam and alfaxalone showed that a midazolam dose higher than 0.3 mg kge1 had no advantage in terms of alfaxalone-sparing effects (Italiano & Robinson 2018). The dose used in our study was found to have a similar incidence of apnoea compared with 0.3 mg kge1 (Mu~ noz et al. 2017) and similar clinically acceptable changes in BP. This suggests that there are no additional benefits to using a higher dose of midazolam. Given the clinical nature of this study, there are several limitations. First, nonvalidated scoring systems were used. However, these scoring systems were adapted from previous studies, which may allow for more direct comparison between subsequent studies. The use of oscillometry to measure BP may have resulted in less accuracy in the measurements when compared with an invasive technique. A further limitation is the study population, which included only healthy dogs
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Alfaxalone midazolam co-induction in dogs C Miller et al.
undergoing anaesthesia for routine surgery. The use of coinduction techniques is often most applicable to animals assigned ASA grade III or above to minimize the negative side effects of induction agents, but studies are lacking in this population of dogs. Changes in BP seen after midazolam may be more pronounced and potentially detrimental in higher-risk anaesthetic patients. Use of midazolam (10 mg kge1) in experimentally hypovolaemic dogs showed more significant decreases in BP than normovolaemic dogs (Adams et al. 1985). An important distinction needs to be made about the significance of our findings. A lower dose of alfaxalone was required in group M; however, the potential cardiovascular benefits of using a lower total dose of induction agent were not apparent in this study. At all time points following induction of anaesthesia, cardiovascular variables were within clinically acceptable ranges and did not differ between groups. The use of midazolam for co-induction using the protocol in this study had a higher incidence of apnoea, which may be more clinically significant. In conclusion, midazolam following an initial alfaxalone bolus had significant alfaxalone-sparing effects, followed by a smoother intubation with mild, clinically acceptable cardiovascular changes. Incidence of apnoea was higher in the midazolam group, which should be taken into consideration when using midazolam as a co-induction agent. Acknowledgements The authors would like to thank the clients for their consent, and the nursing and surgical team at NWVS for their help and support. Authors' contributions CM: study design, data collection and preparation of the manuscript. MG: study design and preparation of the manuscript. EH: statistical analysis and preparation of the manuscript. Conflict of interest statement Authors declare no conflict of interest. References Adams P, Gelman S, Reves JG et al. (1985) Midazolam pharmacodynamics and pharmacokinetics during acute hypovolaemia. Anesthesiology 63, 140e146. Albertson TE, Walby WF, Joy RM (1992) Modification of GABAmediated inhibition by various injectable anesthetics. Anesthesiology 77, 488e499. Amengual M, Flaherty D, Auckburally A et al. (2013) An evaluation of anaesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone. Vet Anaesth Analg 40, 115e123. 618
Anderson L, Robb H (1998) A comparison of midazolam co-induction with propofol predosing for induction of anaesthesia,. Anaesth 53, 1117e1129. Bigby SE, Beths T, Bauquier S, Carter JE et al. (2017) Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs. Vet Anaesth Analg 44, 1267e1275. Castro LN, Mehta JH, Brayanov JB, Mullen GJ et al. (2017) Quantification of respiratory depression during pre-operative administration of midazolam using a non-invasive respiratory volume monitor. PLoS One 12e0172750. Clarke KW, Trim CM (2013) Anaesthesia of the dog. In: Veterinary Anaesthesia (11th edn). Saunders, UK. pp. 405e498. Covey-Crump GL, Murison PJ (2008) Fentanyl or midazolam for coinduction of anaesthesia with propofol in dogs. Vet Anaesth Analg 35, 463e472. Ferre PJ, Pasloske K, Whittem T et al. (2006) Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU. Vet Anaesth Analg 33, 229e236. Herbert GL, Bowlt KL, Ford-Fennah V et al. (2013) Alfaxalone for total intravenous anaesthesia in dogs undergoing ovariohysterectomy: A comparison of premedication with acepromazine or dexmedetomidine. Vet Anaesth Analg 40, 124e133. Hopkins A, Giuffrida M, Larenza MP (2014) Midazolam, as a coinduction agent, has propofol sparing effects but also decreases systolic blood pressure in healthy dogs. Vet Anaesth Analg 41, 64e72. Italiano M, Robinson R (2018) Effect of benzodiazepines on the dose of alfaxalone needed to endotracheal intubation in healthy dogs. Vet Anaesth Analg 45, 720e728. Jones DJ, Stehling LC, Zauder HL (1979) Cardiovascular responses to diazepam and midazolam maleate in the dog. Anaesth 51, 430e434. Kumar A, Sanikop CS, Kotur PF (2006) Effect of priming principle on the induction dose requirements of propofol - a randomized clinical trial. Indian J Anaesth 50 (4), 282e287. Liao PT, Sinclair M, Valverde A et al. (2017) Induction dose and recovery quality of propofol and alfaxalone with or without midazolam coinduction followed by total intravenous anesthesia in dogs. Vet Anaesth Analg 44, 1016e1026. Maney JK, Shepard MK, Braun C et al. (2013) A comparison of cardiopulmonary and anesthetic effects of an induction dose of alfaxalone or propofol in dogs. Vet Anaesth Analg 40, 237e244. Mu~ noz KA, Robertson SA, Wilson DV (2017) Alfaxalone alone or combined with midazolam or ketamine in dogs: intubation dose and select physiologic effects. Vet Anaesth Analg 44, 766e774. Muir W, Lerche P, Wiese A et al. (2008) Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs. Vet Anaesth Analg 35, 451e462. Pinelas R, Alibhai HI, Mathis A et al. (2014) Effects of different doses of dexmedetomidine on anaesthetic induction with alfaxalone e a clinical trial. Vet Anaesth Analg 41, 378e385. Pruneau D, Mainguy Y, Roy F (1984) Trifluoperazine antagonizes postsynaptic a1 but not a2 adrenoceptor mediated pressor responses in the rat. Eur J Pharm 105, 343e346.
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Alfaxalone midazolam co-induction in dogs C Miller et al. Robinson R, Borer-Weir K (2013) A dose titration study into the effects of diazepam or midazolam on the propofol dose requirements for induction of general anaesthesia in client owned dogs, premedicated with methadone and acepromazine. Vet Anaesth Analg 40, 455e463. Rodríguez JM, Mu~ noz-Rasc on P, Navarrete-Calvo R et al. (2012) Comparison of the cardiopulmonary parameters after induction of anaesthesia with alphaxalone or etomidate in dogs. Vet Anaesth Analg 39, 357e365. Ruffato M, Novello L, Clark L (2015) What is the definition of intraoperative hypotension in dogs? Results from a survey of diplomates of the ACVAA and ECVAA. Vet Anaesth Analg 42, 55e64. S anchez A, Belda E, Escobar M et al. (2013) Effects of altering the sequence of midazolam and propofol during co-induction of anaesthesia. Vet Anaesth Analg 40, 359e366. Short TG, Chui PT (1991) Propofol and midazolam act synergistically in combination. Br J Anaesth 67, 539e545.
Skerritt JH, Johnston GA (1983) Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol 89, 193e198. Steffey EP, Howland D (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833e1836. Stokes DN, Hutton P (1991) Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics. Anaesth Analg 83, 578e583. WSAVA (2013) Global Nutrition Committee, Body Condition Score. https://www.wsava.org/WSAVA/media/Arpita-and-Emma-editori al/Body-Condition-Score-Dog.pdf. (Accessed 12 December 2018). Zapata A, Laredo FG, Escobar M et al. (2018) Effects of midazolam before or after alfaxalone for co-induction of anaesthesia in healthy dogs. Vet Anaesth Analg 45, 609e617. Received 28 August 2018; accepted 1 March 2019. Available online 8 June 2019
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https://doi.org/10.1016/j.vaa.2019.03.009
RESEARCH PAPER
Co-induction of anaesthesia with alfaxalone and midazolam in dogs: a randomized, blinded clinical trial Chris Millera, Ellen Hughesb & Matt Gurneya a
Northwest Veterinary Specialists, Sutton Weaver, Cheshire, United Kingdom
b
College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Correspondence: Chris Miller, Small Animal Hospital, University of Glasgow, 464, Bearsden Road, Glasgow G61 1QH United Kingdom. E-mail: [email protected]
Abstract Objective To qualitatively assess the co-induction of anaesthesia with midazolam and alfaxalone and to determine cardiovascular or respiratory alterations compared with alfaxalone alone. Study design A randomized, blinded, clinical trial. Animals A total of 29 American Society of Anesthesiologists grade I or II, client-owned dogs undergoing elective orthopaedic or soft tissue surgery. e1
Methods All dogs received 0.02 mg kg acepromazine and 0.3 mg kge1 methadone intramuscularly 30 minutes prior to anaesthesia. Measurements of heart rate (HR), respiratory frequency and blood pressure (BP) were assessed pre-induction and at 0, 2 and 5 minutes post-induction. Anaesthesia was induced with 0.5 mg kge1 alfaxalone followed by either 0.4 mg kge1 midazolam intravenously (group M) or an equal volume of saline (group S). Conditions were assessed for intubation and further boluses of 0.25 mg kge1 alfaxalone were given as required. Response to co-induction, ease of intubation and quality of induction were scored, and total dose of alfaxalone required for intubation was recorded. Repeated measures one-way analysis of variance with post hoc Tukey’s test was used to assess within group changes over time and Student t tests were used to compare between groups. Incidence of apnoea was assessed using a Fisher’s exact test. Data are shown as mean ± standard deviation. Results Group M included 14 dogs and group S 15 dogs. There was a significant difference in the total dose of alfaxalone required for intubation, 0.65 ± 0.20 mg kge1 group M and 0.94 ± 0.26 mg kge1 group S (p ¼ 0.002). Apnoea occurred significantly more frequently in group M (p ¼ 0.007). There were no clinically significant differences in HR or BP at the measured time points between groups.
Conclusions and clinical relevance Co-induction with midazolam had significant alfaxalone-sparing effects with no clinically detectable cardiovascular changes. Apnoea is common after co-induction. Keywords alfaxalone, apnoea, co-induction, dogs, midazolam. Introduction Alfaxalone is a neuroactive progesterone-derived steroid that acts on gamma-aminobutyric acid (GABA) receptors within the central nervous system resulting in unconsciousness and muscle relaxation (Albertson et al. 1992). It has a rapid onset and short duration of action, making it an ideal induction agent (Ferre et al. 2006). Adverse effects of alfaxalone are dose-dependent and include an increase in heart rate (HR), hypoventilation and apnoea (Muir et al. 2008). In unpremedicated dogs, alfaxalone administered intravenously (IV) at 6 mg kge1 and 20 mg kge1 caused a significant increase in HR compared with baseline. However, this change was not observed at an alfaxalone dose of 2 mg kge1. A significant decrease in systolic blood pressure (SAP) was also demonstrated at doses between 2 mg kg e1 and 20 mg kge1 (Muir et al. 2008), whereas Maney et al. (2013) reported no significant cardiovascular changes in unpremedicated dogs following induction of anaesthesia with alfaxalone (mean dose 2.6 mg kge1). These studies demonstrate that although high (supraclinical) doses of alfaxalone cause cardiovascular effects, these effects are not significant at clinically recommended doses of up to 2 mg kge1 in the healthy dog (Summary of Product Characteristics, Jurox UK Ltd, UK). Alfaxalone at 2.6 mg kge1in unpremedicated dogs caused a significant but clinically acceptable increase in arterial pressure of carbon dioxide immediately following drug administration (Maney et al. 2013). Apnoea may be seen using 2 mg kge1 alfaxalone, while higher doses, up to 20 mg kge1, increases the duration of apnoea (Muir et al. 2008). Speed of
613
Alfaxalone midazolam co-induction in dogs C Miller et al.
alfaxalone injection may influence postinduction apnoea with a faster rate of administration, 2 mg kge1 minutee1, resulting in a higher incidence of apnoea than with a rate of 0.5 mg kge1 minutee1 (Bigby et al. 2017). Co-induction, the use of more than one drug in combination or sequence, is a commonly used technique to reduce the total dose of induction agent required and potentially reduce the number or severity of associated side effects (Anderson & Robb 1998). Commonly used co-induction drugs include opioids (Covey-Crump & Murison 2008) and benzodiazepines (Short & Chui 1991; Hopkins et al. 2014). Recent studies have demonstrated significant alfaxalone- and propofol-sparing effects when combined with varying doses of midazolam (Liao et al. 2017; Mu~ noz et al. 2017; Italiano & Robinson 2018; Zapata et al. 2018). This study examined whether the administration of midazolam following administration of a subhypnotic dose of alfaxalone would reduce the total dose of alfaxalone required for endotracheal intubation. A secondary aim was to determine whether there was a difference in the observed cardiorespiratory effects between this co-induction technique versus the use of alfaxalone alone. It was hypothesized that midazolam administered as a coinduction agent would reduce the total dose of alfaxalone required for intubation, with a reduction in the magnitude of cardiorespiratory depressant effects. Materials and methods Ethical approval for the study was granted by the Animal Health Trust Ethics committee (AHT_42_2015). An Animal Test Certificate (Type S) was obtained from the Veterinary Medicines Directorate for the use of midazolam (Hypnovel 5 mg mLe1; Roche Products Ltd, UK) in dogs. Informed owner consent was obtained for each dog before inclusion in the study. All dogs included in the study were American Society of Anesthesiologists (ASA) grade I or II, based on clinical examination and medical history, and were undergoing general anaesthesia for elective orthopaedic or soft tissue surgery. Aggressive or excessively boisterous dogs were excluded from the study. A full clinical examination was performed prior to anaesthesia, HR and respiratory rate (fR) were assessed by auscultation and rectal temperature measurements were recorded. Body condition score was assessed using a previously published scale (body condition score; WSAVA 2013). All dogs were premedicated with acepromazine (0.02 mg kge1, ACP; Elanco Animal Health, UK) and methadone (0.3 mg kge1, Comfortan; Dechra Veterinary Products, UK) mixed in the same syringe via injection into the lumbar epaxial muscles 30 minutes before the induction of anaesthesia. 614
Dogs were randomly assigned via a lottery system to one of the two groups: group M received midazolam (0.4 mg kge1) as a co-induction agent and group S received an equal volume of saline (0.08 mL kge1). Co-induction agents were drawn up into a syringe labelled ‘test drug’ by an assistant. The primary investigator was blinded to the allocated group and administered all drugs, performed endotracheal intubation, assigned scores (Table 1) and recorded measurements (Tables 2e4). Level of sedation was graded 30 minutes after premedication in dogs using a composite scoring scale as described in Table 1 (Covey-Crump & Murison 2008). An IV cannula (Jelco; Smiths Medical, UK) was placed into a cephalic vein. Prior to induction of anaesthesia, the lungs of the dogs were pre-oxygenated for 3 minutes via a tight-fitting mask with an oxygen flow of 3 L minutee1. During pre-oxygenation preinduction measurements of HR and fR were taken. Blood pressure (BP) was assessed by an oscillometric method (Cardell; Midmark Animal Health, OH, USA) using an appropriately sized cuff placed around the antebrachium. Alfaxalone (2 mg kge1, Alfaxan; Jurox UK Ltd, UK) was drawn into a labelled syringe and induction of anaesthesia was initiated with alfaxalone (0.5 mg kge1) given manually over 30 seconds. The IV cannula was flushed with heparinized saline, and then midazolam or saline, group M or S, respectively, was given by the investigator over 30 seconds followed by further heparinized saline. The response to the co-induction agent was immediately scored according to the scale detailed in Table 1 and conditions for intubation including loss of palpebral reflex, ventromedial rotation of the eye and loss of jaw tone were assessed. If conditions were unsuitable immediately following assessment, a further alfaxalone (0.25 mg kge1) bolus was given over 15 seconds and intubation conditions were reassessed. This was repeated until intubation was possible. The total dose of alfaxalone required for intubation was recorded. A laryngoscope was used to depress the base of the tongue and visualize the larynx with the dog in sternal recumbency. Endotracheal intubation was performed with an appropriately sized endotracheal tube (ETT) and the quality of induction and ease of intubation were scored based on the scale in Table 1. Following endotracheal intubation, the ETT cuff was inflated and the ETT was connected to an appropriate breathing system. Anaesthesia was maintained using isoflurane (IsoFlo; Abbott Animal Health, UK) vaporised in 100% oxygen and the vaporiser was initially set to deliver 2% isoflurane. Further measurements of HR assessed by electrocardiography, fR assessed by visualizing thoracic excursions and BP [SAP, mean (MAP) and diastolic blood pressure (DAP)] assessed by oscillometry were taken at 0, 2 and 5 minutes after intubation (T0, T2 and T5, respectively). Other monitoring
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., 46, 613e619
Alfaxalone midazolam co-induction in dogs C Miller et al. Table 1 Description of scales for scoring sedation, co-induction, intubation and quality of induction (Covey-Crump & Murison 2008).
Sedation score
Co-induction score
Intubation score
Quality score
Score
Description
0 1 2 3 0 1 2 0 1 2 3 0 1 2 3
No effect Mild sedation (quieter than before injection but still bright and active) Moderate sedation (quiet, reluctant to move, possibly slightly ataxic) Profound sedation (unable to walk) Sedation (more sedated than before co-induction agent) No change (compared with before injection) Excitement (more activity than before injection) Smooth (no swallowing, coughing, tongue or jaw movements) Fair (some tongue movement, slight cough) Poor (marked tongue movement, swallowing or coughing) Very poor (as 2 but required additional alfaxalone and second attempt) Smooth (without excitement) Fair (slight excitement, muscle twitching or movement of limbs) Poor (marked excitement, muscle twitching, paddling of limbs) Very poor (severe excitement plus vocalization)
Reprinted from Covey-Crump and Murison (2008). © Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd.
devices such as a pulse oximeter were attached to the patient. Periods of apnoea longer than 30 seconds were recorded and managed via intermittent manual ventilation using the reservoir bag of the anaesthetic breathing system at a rate of 3 breaths minutee1 until spontaneous ventilation resumed. Statistical analysis Statistical analyses were performed using GraphPad Prism version 8.0.1 for Windows, GraphPad Software, CA, USA (www.graphpad.com). Data were assessed for normality using the D'Agostino-Pearson omnibus K2 test. Between-group differences were analysed using Student t tests for normally distributed data (HR, SAP, MAP and DAP) and ManneWhitney U test for nonparametric data (fR, sedation, co-induction, intubation and quality scores). Within-group comparisons for normally distributed data were analysed using repeated measures one-way analysis of variance with Tukey’s post hoc test. Within-group comparisons for nonTable 2 Mean ± standard deviation of age, body mass, heart rate (HR) and respiratory rate (fR) and median (range) of body condition score (BCS) of dogs in alfaxalone-midazolam (group M) and alfaxalone-saline (group S) groups.
Age (years) Body mass (kg) BCS HR (beats minutee1) fR (breaths minutee1)
Group M
Group S
p*
5.5 ± 3.3 23.5 ± 12.8 6 (5.5e8) 107 ± 27 27 ± 9
4.2 ± 2.8 21.3 ± 10 6 (5e7) 118 ± 28 28 ± 7
0.281 0.610 0.791 0.312 0.932
* Probability of statistical difference between groups. A value of p < 0.05 considered significant.
normally distributed data (fR) were analysed using Friedman test and Dunn’s post hoc test. For the purposes of analyses, apnoea was categorized as 0 breaths minutee1. Presence or absence of apnoea was also compared as a categorical variable using Fisher’s exact test. Level of significance was set at a p < 0.05. Data are presented as mean ± standard deviation (SD) or median and range. A post hoc power calculation using the calculated means and SDs showed sufficient power (>0.9) to detect a significant difference in alfaxalone dose between the groups with an alpha of 0.05. Results Group M comprised 14 dogs (7 female and 7 male) and group S comprised 15 dogs (9 female and 6 male). One dog in group M was excluded because further premedication was required to enable IV cannula placement. There were no significant differences between groups in age, mass, body condition score, HR and fR measured prior to premedication administration (Table 2).
Table 3 Median (range) of scores assigned as defined in Table 1 to dogs and incidence of apnoea in alfaxalone-midazolam (group M) and alfaxalone-saline (group S) groups.
Sedation score Co-induction score Intubation score Quality score Apnoea
Group M
Group S
p*
1 (1e2) 0 (0e2) 0 (0e1) 0 (0e1) 8/14
1 (1e3) 1 (0e1) 1 (0e3) 0 (0e2) 1/15
0.990 0.014 0.016 0.200 0.007
* Probability of statistical difference between groups. A value of p < 0.05 considered significant.
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., 46, 613e619
615
Alfaxalone midazolam co-induction in dogs C Miller et al. Table 4 Mean ± standard deviation of heart rate (HR), systolic blood pressure (SAP), mean blood pressure (MAP), diastolic blood pressure (DAP), respiratory rate (fR) and alfaxalone dose required for intubation (total alfaxalone) of dogs in alfaxalone-midazolam (group M) and alfaxalone-saline (group S) groups; before induction of anaesthesia (Pre), immediately following intubation (T0) and 2 minutes (T2) and 5 minutes (T5) following intubation.
HR (beats minutee1) Pre T0 T2 T5 SAP (mmHg) Pre T0 T2 T5 MAP (mmHg) Pre T0 T2 T5 DAP (mmHg) Pre T0 T2 T5 fR (breaths minutee1) Pre T0 T2 T5 Total alfaxalone (mg kge1)
Group M
Group S
96 ± 33 122 ± 45y 116 ± 34 119 ± 33
107 123 113 112
± ± ± ±
28 41 35 33
0.310 0.824 0.668 0.590
± ± ± ±
128 140 134 117
± ± ± ±
20 36 33 21
0.629 0.904 0.069 0.405
103 ± 20 104 ± 29 101 ± 35 83 ± 20
0.893 0.524 0.240 0.609
± ± ± ±
0.467 0.794 0.614 0.859
128 138 119 115
14 30 9 14
p*
Discussion 103 ± 13 109 ± 29 89 ± 12y 83 ± 14y,z 79 90 69 63
± ± ± ±
20 29 16 16y,z
40 ± 26 9 ± 16y 9 ± 11y 13 ± 9 0.65 ± 0.20
88 89 72 62
31 19 22 20y,z
26 ± 7 24 ± 9 17 ± 14 21 ± 11 0.94 ± 0.26
0.105 <0.001 0.068 0.181 0.002
y
Significant differences (p 0.05) compared with Pre values within group. Significant differences (p 0.05) compared with T0 values within group. Probability of statistical difference between groups. A value of p < 0.05 considered significant. z
*
Following premedication, there were no differences in sedation scores between the groups, but dogs in group M were more sedated following administration of the co-induction agent than group S (p ¼ 0.014). Intubation was significantly smoother in group M than in group S (p ¼ 0.016), but the overall quality of induction was similar between the groups. Mild excitement was seen in 2/14 dogs in group M and 5/15 dogs in group S, with one dog in group S showing marked excitement, but overall quality of induction was similar between the groups (p ¼ 0.200; Table 3). Changes in HR, fR and BP during the study period are presented in Table 4. Within group M, there was a significant increase in HR compared with pre-induction measurements at T0 but at no other time points. There were no significant differences in HR between groups at any other time point. There were no significant differences in SAP both within groups over time or 616
between groups. In group M, MAP decreased with a significantly lower MAP at T2 and T5 than at pre-induction measurements; however, there were no differences between groups at any time point. DAP decreased in both groups with significantly lower DAP within each group at T5, but there were no significant differences between groups at any time points. In group S, there were no significant changes in fR at any time point but fR was significantly lower within group M than pre-induction measurements at T0 (p ¼ 0.034) and T2 (p ¼ 0.021). fR was significantly different between groups at T0 (p < 0.001). Apnoea following induction of anaesthesia was significantly more common in group M than in group S (8/14 versus 0/15 respectively; p ¼ 0.007). Significantly less alfaxalone was required for endotracheal intubation in group M than in group S: 0.65 ± 0.2 mg kge1 versus 0.94 ± 0.26 mg kge1, respectively; (p ¼ 0.002).
This study demonstrates that midazolam (0.4 mg kge1) following an initial bolus of alfaxalone (0.5 mg kge1) has significant alfaxalone-sparing effects, with clinically insignificant cardiovascular effects but with significant respiratory depression and a higher incidence of apnoea. Previous studies in dogs have demonstrated a variable induction agent-sparing effect of midazolam that was both sequence dependent (S anchez et al. 2013) and dose dependent (Robinson & Borer-Weir 2013). Several recent studies have also demonstrated the significant alfaxalone-sparing effects of midazolam in healthy dogs (Liao et al. 2017; Mu~ noz et al. 2017; Italiano & Robinson 2018; Zapata et al. 2018). The reduction in the dose of alfaxalone in our study (24%) was less than that previously reported in studies using a similar protocol (35%, Italiano & Robinson 2018; 62%, Mu~ noz et al. 2017) but similar to another (Liao et al. 2017). Several explanations could account for these differences, such as difference in drugs used for premedication and consequently the degree of sedation prior to induction. Numerous studies have investigated the sequence of administration of co-induction agents (Covey-Crump & Murison 2008; S anchez et al. 2013; Zapata et al. 2018) and demonstrated that administration of midazolam following an initial bolus dose of an induction agent provides greater induction agent-sparing effects. One reason for administering induction agent prior to midazolam is to minimize any potential excitement or disinhibition following midazolam administration to a poorly sedated dog (Covey-Crump & Murison 2008). S anchez et al. (2013) demonstrated fewer excitatory phenomena and greater propofol-sparing effects when an initial bolus of propofol was given before midazolam. In our study, mild excitement was seen in two dogs following administration of midazolam and, moreover, a recent study demonstrated a significantly higher incidence of excitable
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., 46, 613e619
Alfaxalone midazolam co-induction in dogs C Miller et al.
behavioural changes when midazolam was given prior to alfaxalone (Zapata et al. 2018) In our study in group S, a lower total dose of alfaxalone was required for intubation than recommended guidelines (Summary of Product Characteristics, Jurox UK Ltd, UK) and studies reporting the induction dose in unpremedicated (Rodríguez et al. 2012) and premedicated dogs (Herbert et al. 2013; Pinelas et al. 2014). Manufacturer recommendations state that in premedicated dogs, the calculated dose of alfaxalone (2 mg kge1) should be given over 60 seconds. A previous study has demonstrated that slow administration of the induction agent can have significant alfaxalone- and propofol-sparing effects in dogs (Bigby et al. 2017). In our study, both premedication and the relatively slow rate of administration of alfaxalone could account for the comparatively low doses of alfaxalone required in group S. Another factor could be the principle of priming (Kumar et al. 2006). Giving a low subhypnotic dose of induction agent slowly prior to more rapid administration of induction agent has been shown to reduce total induction agent required for intubation (Stokes & Hutton 1991). The low total induction dose of alfaxalone in both groups could be attributed to this phenomenon. In this study, HR did not differ significantly between the groups, but HR was significantly higher at T0 than at preinduction measurements in group M. BP tended to decrease over time, but no hypotension was detected (Ruffato et al. 2015) at any time point in either group despite statistically significant differences within group M. There were no significant differences between groups, at any time point. It would appear from this study that the alfaxalone-sparing effect of midazolam does not result in any cardiovascular benefits. However, clinically significant cardiovascular benefits may not be apparent due to the comparatively low doses of alfaxalone required in both groups. Midazolam is considered to have minimal cardiovascular effects but can decrease myocardial contractility, systemic vascular resistance and preload when supraclinical doses are given (Jones et al. 1979). A previous study assessing midazolam-propofol co-induction demonstrated similar decreases in arterial BP (Hopkins et al. 2014) to our study using a lower dose of midazolam (0.2 mg kge1). Further work is required to determine if these changes are dose dependent. Decreasing BP following induction of anaesthesia in both groups could be accounted for by the transition to inhalational anaesthesia, which is known to cause a dosedependent vasodilation and hypotension (Steffey & Howland 1977). Premedication with acepromazine, which also causes vasodilation, may have contributed to the decrease in BP (Pruneau et al. 1984). In humans, midazolam is a respiratory depressant and causes hypoventilation by a reduction in tidal volume (Castro et al. 2017), but it is described as having minimal respiratory effects in dogs (Clarke & Trim 2013). However, in this study
apnoea occurred more frequently in group M with a relatively high incidence of 8 out of 14 dogs (57%). Both dose (Muir et al. 2008) and rate of administration of alfaxalone (Amengual et al. 2013; Bigby et al. 2017) have been associated with apnoea. However, the incidence of apnoea following coinduction with midazolam varies between studies. One study reported that apnoea occurred in 13 out of 90 dogs, but use of midazolam was not associated with apnoea more frequently than diazepam or control groups (Italiano & Robinson 2018). However, in comparison with our study, similar incidences of apnoea have been reported by other authors (Mu~ noz et al. 2017, Zapata et al. 2018). The higher incidence of apnoea in group M than group S in our study could be explained by the higher initial bolus of alfaxalone [0.5 mg kge1 versus 0.25 mg kge1 (Mu~ noz et al. 2017)] and a possible synergistic effect between the alfaxalone and midazolam as they both act at the GABA receptor (Skerritt and Johnston, 1983; Albertson et al. 1992). This higher initial alfaxalone dose, when combined with the midazolam, could result in a deeper plane of anaesthesia and more pronounced respiratory depression. Unlike the studies by Mu~ noz et al. (2017) and Zapata et al. (2018), no dogs in group S experienced apnoea; this result was contrary to their findings. Possible explanations could be differences in premedication and the different initial doses of alfaxalone prior to midazolam, 0.25 mg kge1 (Mu~ noz et al. 2017) and 0.5 mg kge1 (Zapata et al. 2018). Periods of apnoea were not associated with any clinically significant desaturation of haemoglobin as measured by pulse oximetry (data not included) and apnoea was managed with intermittent manual ventilation until spontaneous ventilation resumed. All animals tolerated pre-oxygenation prior to induction of anaesthesia, and this may have helped to reduce any potential desaturation events. In this study, we investigated midazolam (0.4 mg kge1) for co-induction because this dose was found to have the greatest propofol-sparing effects in a dose finding study (Robinson & Borer-Weir 2013). However, a recent study investigating coinduction with midazolam and alfaxalone showed that a midazolam dose higher than 0.3 mg kge1 had no advantage in terms of alfaxalone-sparing effects (Italiano & Robinson 2018). The dose used in our study was found to have a similar incidence of apnoea compared with 0.3 mg kge1 (Mu~ noz et al. 2017) and similar clinically acceptable changes in BP. This suggests that there are no additional benefits to using a higher dose of midazolam. Given the clinical nature of this study, there are several limitations. First, nonvalidated scoring systems were used. However, these scoring systems were adapted from previous studies, which may allow for more direct comparison between subsequent studies. The use of oscillometry to measure BP may have resulted in less accuracy in the measurements when compared with an invasive technique. A further limitation is the study population, which included only healthy dogs
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Alfaxalone midazolam co-induction in dogs C Miller et al.
undergoing anaesthesia for routine surgery. The use of coinduction techniques is often most applicable to animals assigned ASA grade III or above to minimize the negative side effects of induction agents, but studies are lacking in this population of dogs. Changes in BP seen after midazolam may be more pronounced and potentially detrimental in higher-risk anaesthetic patients. Use of midazolam (10 mg kge1) in experimentally hypovolaemic dogs showed more significant decreases in BP than normovolaemic dogs (Adams et al. 1985). An important distinction needs to be made about the significance of our findings. A lower dose of alfaxalone was required in group M; however, the potential cardiovascular benefits of using a lower total dose of induction agent were not apparent in this study. At all time points following induction of anaesthesia, cardiovascular variables were within clinically acceptable ranges and did not differ between groups. The use of midazolam for co-induction using the protocol in this study had a higher incidence of apnoea, which may be more clinically significant. In conclusion, midazolam following an initial alfaxalone bolus had significant alfaxalone-sparing effects, followed by a smoother intubation with mild, clinically acceptable cardiovascular changes. Incidence of apnoea was higher in the midazolam group, which should be taken into consideration when using midazolam as a co-induction agent. Acknowledgements The authors would like to thank the clients for their consent, and the nursing and surgical team at NWVS for their help and support. Authors' contributions CM: study design, data collection and preparation of the manuscript. MG: study design and preparation of the manuscript. EH: statistical analysis and preparation of the manuscript. Conflict of interest statement Authors declare no conflict of interest. References Adams P, Gelman S, Reves JG et al. (1985) Midazolam pharmacodynamics and pharmacokinetics during acute hypovolaemia. Anesthesiology 63, 140e146. Albertson TE, Walby WF, Joy RM (1992) Modification of GABAmediated inhibition by various injectable anesthetics. Anesthesiology 77, 488e499. Amengual M, Flaherty D, Auckburally A et al. (2013) An evaluation of anaesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone. Vet Anaesth Analg 40, 115e123. 618
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