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Determining an optimum propofol infusion rate for induction of anaesthesia in healthy dogs: a randomized clinical trial

Published:January 04, 2022DOI:https://doi.org/10.1016/j.vaa.2021.07.006

      Abstract

      Objective

      To determine an optimum infusion rate of propofol that permitted rapid tracheal intubation while minimizing the duration of postinduction apnoea.

      Study design

      Prospective, randomized, blinded clinical trial.

      Animals

      A total of 60 client-owned dogs presented for elective neutering and radiography.

      Methods

      Dogs were randomly allocated to one of five groups (groups A–E) to have propofol at an infusion rate of 0.5, 1, 2, 3, or 4 mg kg–1 minute–1, respectively, following intramuscular premedication with methadone 0.5 mg kg–1 and dexmedetomidine 5 μg kg–1. Propofol administration was stopped when adequate conditions for tracheal intubation were identified. Time to tracheal intubation and duration of apnoea were recorded. If oxygen haemoglobin saturation decreased to < 90%, manual ventilation was initiated. A one-way analysis of covariance was conducted to compare the effect of propofol infusion rate on duration of apnoea and intubation time whilst controlling for covariates, followed by post hoc tests. The significance level was set at p < 0.05.

      Results

      Propofol infusion rate had a significant effect on duration of apnoea (p = 0.004) and intubation time (p < 0.001) after controlling for bodyweight and sedation scores, respectively. The adjusted means (± standard error) of duration of apnoea were significantly shorter in groups A and B (49 ± 39 and 67 ± 37 seconds, respectively) than in groups C, D and E (207 ± 34, 192 ± 36 and 196 ± 34 seconds, respectively). Group B (115 ± 10 seconds) had a significantly shorter intubation time than group A (201 ± 10 seconds, p < 0.001).

      Conclusions and clinical relevance

      An infusion rate of 1.0 mg kg–1 minute–1 (group B) appears to offer the optimal compromise between speed of induction and duration of postinduction apnoea.

      Keywords

      Introduction

      Propofol is an alkyl phenol used for rapid induction of general anaesthesia. A rapid recovery from anaesthesia then occurs owing to redistribution (
      • Goodman N.W.
      • Black A.M.S.
      • Carter J.A.
      Some ventilatory effects of propofol as sole anaesthetic agent.
      ;
      • Morgan D.W.
      • Legge K.
      Clinical evaluation of propofol as an intravenous anaesthetic agent in cats and dogs.
      ). It has market authorization for induction of anaesthesia at 1.0–4.0 mg kg–1 in premedicated dogs, or 6.5 mg kg–1 in unpremedicated dogs (
      • Morgan D.W.
      • Legge K.
      Clinical evaluation of propofol as an intravenous anaesthetic agent in cats and dogs.
      ;
      • Zoetis UK Limited
      PropoFlo Plus 10mg/mL datasheet.
      ). The current recommendation in the datasheet is to administer a calculated dose to effect over 10–40 seconds (
      • Zoetis UK Limited
      PropoFlo Plus 10mg/mL datasheet.
      ). In clinical practice, incremental boluses of propofol are often administered, although little definitive guidance exists, and administration techniques differ significantly between clinicians.
      The optimum delivery of an induction agent (in terms of administration technique, rate and dose) should result in rapid loss of consciousness with no or minimal adverse effects. A time delay between drug injection and loss of consciousness arises while the cardiovascular system transports the drug to the brain where the clinical effect occurs. This delay often results in the delivered dose exceeding the minimum dose required to achieve loss of consciousness, as the drug continues to be injected until an adequate anaesthetic plane is reached (
      • Kazama T.
      • Ikeda K.
      • Morita K.
      • et al.
      Investigation of effective anesthesia induction doses using a wide range of infusion rates with undiluted and diluted propofol.
      ).
      Adverse effects associated with propofol administration are dose dependent. Postinduction apnoea is the most common adverse event following propofol administration, occurring with an incidence of 85–100% in studies conducted in humans and dogs. Apnoea results from a reduction in central inspiratory drive and ventilatory responses to carbon dioxide (
      • Goodman N.W.
      • Black A.M.S.
      • Carter J.A.
      Some ventilatory effects of propofol as sole anaesthetic agent.
      ;
      • Grounds R.M.
      • Maxwell D.L.
      • Taylor M.B.
      • et al.
      Acute ventilatory changes during IV induction of anaesthesia with thiopentone or propofol in man.
      ;
      • Smith J.A.
      • Gaynor J.S.
      • Bednarski R.M.
      • Muir W.W.
      Adverse effects of administration of propofol with various preanaesthetic regimens in dogs.
      ;
      • Muir W.W.
      • Gadawski J.E.
      Respiratory depression and apnea induced by propofol in dogs.
      ;
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Postinduction apnoea in dogs premedicated with acepromazine or dexmedetomidine and anaesthetised with alfaxalone or propofol.
      ,
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      ). However, postinduction apnoea rarely led to cyanosis if dogs were provided with supplemental oxygen at induction (
      • Smith J.A.
      • Gaynor J.S.
      • Bednarski R.M.
      • Muir W.W.
      Adverse effects of administration of propofol with various preanaesthetic regimens in dogs.
      ;
      • McNally E.M.
      • Robertson S.A.
      • Pablo L.S.
      Comparison of time to desaturation between preoxygenated and nonpreoxygenated dogs following sedation with acepromazine maleate and morphine and induction of anesthesia with propofol.
      ). Another adverse effect associated with propofol administration is decreased mean arterial blood pressure owing to a reduction in systemic vascular resistance and a slight decrease in heart rate (HR) (
      • Suarez M.A.
      • Dzikiti B.T.
      • Stegmann F.G.
      • Hartman M.
      Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs.
      ;
      • Henao-Guerrero N.
      • Ricco C.H.
      Comparison of the cardiorespiratory effects of a combination of ketamine and propofol, propofol alone, or a combination of ketamine and diazepam before and after induction of anaesthesia in dogs sedated with acepromazine and oxymorphone.
      ).
      The propofol infusion rate affects the dose required to induce anaesthesia (
      • Stokes D.N.
      • Hutton P.
      Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
      ;
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      ), induction time (
      • Rolly G.
      • Versichelen L.
      • Huyghe L.
      • Mugroop H.
      Effect of speed of injection on induction of anaesthesia using propofol.
      ;
      • Gillies G.W.
      • Lees N.W.
      The effects of speed of injection on induction with propofol. A comparison with etomidate.
      ;
      • Stokes D.N.
      • Hutton P.
      Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
      ) and the duration of apnoea (
      • Gillies G.W.
      • Lees N.W.
      The effects of speed of injection on induction with propofol. A comparison with etomidate.
      ;
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      ) in humans and animals. In humans, slower administration was associated with a lower incidence of apnoea, but longer induction times (
      • Rolly G.
      • Versichelen L.
      • Huyghe L.
      • Mugroop H.
      Effect of speed of injection on induction of anaesthesia using propofol.
      ;
      • Gillies G.W.
      • Lees N.W.
      The effects of speed of injection on induction with propofol. A comparison with etomidate.
      ;
      • Stokes D.N.
      • Hutton P.
      Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
      ). Currently, it is unknown which infusion rate produces the most favourable combination of induction speed while minimizing postinduction apnoea by dose reduction in healthy dogs.
      The aim of this study was to determine an optimum infusion rate of propofol that permitted rapid tracheal intubation while minimizing the duration of postinduction apnoea in healthy dogs. We hypothesized that the optimum infusion rate would lie between the previously described 1 mg kg–1 minute–1 and 4 mg kg–1 minute–1 (
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      ;
      • Zoetis UK Limited
      PropoFlo Plus 10mg/mL datasheet.
      ).

      Materials and methods

      Animals

      All American Society of Anesthesiologists (ASA) score I dogs presenting for elective neutering or elective radiography for hip scoring at the Queen’s Veterinary School Hospital, UK, between November 2017 and July 2019 were recruited. Brachycephalic breeds, animals on concurrent medication or with a history of regurgitation were excluded. Informed owner consent was obtained, and the project was approved by the University of Cambridge Animal Welfare and Ethical Review Body (AWERB), UK (ref CR 246).

      Study protocol

      The progression of all animals included in this study are shown in Fig. 1. Dogs were randomized to one of five groups using a random number generator (Excel 2010; Microsoft Corporation, WA, USA). Each group was administered a different propofol infusion rate for induction of anaesthesia: group A, 0.5 mg kg–1 minute–1; group B, 1.0 mg kg–1 minute–1; group C, 2.0 mg kg–1 minute–1; group D, 3.0 mg kg–1 minute–1; and group E, 4.0 mg kg–1 minute–1. Signalment and planned procedure were recorded for each animal. An independent person calculated the propofol infusion rate (mL hour–1) allocated to each dog and programmed the rate into the syringe driver (Alaris GH; Cardinal Health, Switzerland) before obscuring the display from view. A total of 6 mg kg–1 propofol (10 mg mL–1; Propoflo Plus; Zoetis, UK) was drawn up and set up with an extension set (V-green extension; Vygon, France).
      Figure 1
      Figure 1CONSORT (CONsolidated Standards of Reporting Trials 2010) flow diagram outlining the progression of all animals in this randomized controlled study to identify an optimum propofol infusion rate for the induction of anaesthesia in healthy dogs.
      All animals underwent a physical examination before premedication with 0.5 mg kg–1 methadone (Synthadon; Animalcare, UK) and 5 μg kg–1 dexmedetomidine (Dexdomitor; Orion Pharma, UK) by deep intramuscular injection into the cervical muscles. An intravenous 22 or 20 gauge cephalic cannula (Jelco; Smiths Medical International, UK) with T-connector (Bionector T-connector LL; Vygon) was inserted 15 minutes after premedication. At 30 minutes after premedication, each animal was assigned a sedation score between 0 (not sedated) and 21 (profound sedation) by the same observer (KW) familiar with the subjective scoring system assessment tool (
      • Grint N.J.
      • Burford J.
      • Dugdale A.H.A.
      Does pethidine affect the cardiovascular and sedative effects of dexmedetomidine in dogs?.
      ; Appendix SA). Oxygen was supplemented via face mask (Face mask clear with diaphragm; J.A.K Medical, UK) at 4 L minute–1 for 5 minutes before starting the allocated propofol infusion.
      The same anaesthetist (KW), blinded to the assigned propofol infusion rate, intubated the trachea of all animals using an endotracheal tube (ETT) (Surgivet; Smiths Medical, UK) appropriate to the animal’s size. Once the dog was unable to support its own head and the palpebral reflex and jaw tone were absent, the propofol infusion was stopped. If there was no resistance to gentle tongue traction, tracheal intubation was attempted. In the event of unsuccessful tracheal intubation (indicated by coughing or resistance to passage of the ETT), the infusion was restarted until tongue retraction was possible and a second attempt at tracheal intubation was made. Animals were excluded from the study if two unsuccessful attempts occurred.
      Once the trachea was intubated, the ETT was connected via a capnograph adapter (Clear-therm HMEF with luer port; Intersurgical Inc, NY, USA) to a breathing system delivering oxygen at 2 L minute–1. The ETT cuff was inflated guided by pilot balloon palpation. No further manipulation of the animal was permitted until spontaneous breathing occurred, at which point an end-tidal carbon dioxide reading was recorded. Once spontaneous breathing occurred, a positive pressure leak test guided further ETT cuff inflation and isoflurane (IsoFlo; Zoetis) delivery commenced.
      A second observer, also blinded to the propofol infusion rate, started a stopwatch (Adanac 3000; Marathon, UK) the moment the syringe driver was activated. They recorded the time the infusion was stopped, tracheal intubation was achieved and the first spontaneous breath. The latter was defined as the first visible chest excursion.
      Throughout the induction of anaesthesia, HR and respiratory rates were monitored manually using a stethoscope. Systolic, mean (MAP) and diastolic arterial blood pressure were monitored using an oscillometric blood pressure cuff applied to the animal’s pelvic limb distal to the hock (PetMap Graphical II; Ramsey Medical Inc and CardioCommand Inc., FL, USA). A pulse oximeter probe (Avante Waveline Nano-V2; DRE Veterinary, KY, USA) was placed on the tongue to measure haemoglobin oxygen saturation (SpO2). Recordings were taken before premedication, at the end of preoxygenation (preinduction), after tracheal intubation and immediately after the first breath observed after completion of endotracheal intubation. Animals with SpO2 < 90% received manual ventilation at 4 breaths minute–1 to a pressure of 12–15 cmH2O until saturation increased to 95% or spontaneous breathing occurred.
      The total propofol dose administered was calculated by subtracting the residual volume in the syringe and 1.4 mL from the extension set, from the original volume drawn up. The difference in MAP before induction and after tracheal intubation was also calculated. Intubation time was recorded as the time taken from starting the infusion to successful tracheal intubation. Duration of apnoea was recorded as the time from tracheal intubation to the first breath observed after completion of endotracheal intubation. For any animals that desaturated and required manual ventilation, duration of apnoea was determined as the time taken from tracheal intubation to initiation of manual ventilation; this is included in subsequent analysis. Any adverse event or intervention was recorded.

      Statistical analysis

      A sample size calculation based on a previous study comparing propofol infusion rate and duration of apnoea (
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      ) was performed. When considering an effect size of 0.4 minutes for duration of apnoea, 12 dogs per group would be required to achieve a power of 80% and an α of 0.05.
      All statistical analyses were performed using the software R version 4.0.2 for Mac (R Foundation for Statistical Computing, Austria; http://www.r-project.org). The significance level was set at p < 0.05. Distribution of data was assessed by Shapiro-Wilk test for numeric variables within groups. Equality of variance was tested using Levene’s test. Data are summarized as mean ± standard deviation for normally distributed data or median (range) for non-normally distributed data. Either one-way analyses of variance or Kruskal-Wallis tests followed by post hoc pairwise comparisons were used to assess differences among groups in terms of the following variables: age, sedation score, bodyweight, change in blood pressure and total dose of propofol.
      Outliers [above upper quartile + 1.5∗interquartile range (IQR) or below lower quartile – 1.5∗IQR] were identified for duration of apnoea and intubation time by group. One-way analyses of covariance were performed to determine the effect of propofol infusion rate on duration of apnoea and intubation time after controlling for selected covariates and is presented as adjusted means ± standard error. Covariates were selected based on linearity with the dependent variables with p < 0.05. Post hoc tests were then performed for pairwise comparisons among groups with Bonferroni multiple testing correction.

      Results

      A total of 62 dogs were enrolled in the study, with a median age of 22 (8–112) months and a median bodyweight of 11.5 (3–44.3) kg. Prior to induction of anaesthesia, one animal was withdrawn owing to bradycardia (HR = 27 beats minute–1, sinus rhythm) following premedication and the dog was given atipamezole. Another was withdrawn owing to cannula failure during propofol administration (Fig. 1). Of the 60 animals that completed the study, 21 presented for ovariohysterectomy, 21 for laparoscopic ovariectomy, and 17 for castration and one for hip scoring. Each group contained 12 animals, and tracheal intubation was successful at the first attempt in all animals. Desaturation (SpO2 values of 84–87%) occurred in three dogs (5%) in group D requiring manual ventilation at 96, 394 and 404 seconds after tracheal intubation, respectively.
      The mean dose of propofol, duration of apnoea and intubation time were significantly different among groups (p < 0.001, p = 0.017 and p < 0.001, respectively), whereas age, bodyweight, sedation score and blood pressure difference were not (p = 0.697, p = 0.722, p = 0.956, and p = 0.456, respectively). Distribution of results for duration of apnoea and intubation time are shown in Fig. 2. There were six outliers identified: three in group A, two in group B and one in group D.
      Figure 2
      Figure 2Box and whisker plots showing the distribution of duration of apnoea and time to tracheal intubation for five different propofol infusion rates used for the induction of anaesthesia in 60 healthy dogs following intramuscular premedication with methadone 0.5 mg kg–1 and dexmedetomidine 5 μg kg–1. There were 12 dogs per group: group A, propofol infusion rate 0.5 mg kg–1 minute–1; group B, 1 mg kg–1 minute–1; group C, 2 mg kg–1 minute–1; group D, 3 mg kg–1 minute–1; group E, 4 mg kg–1 minute–1. The whiskers demonstrate the range; the boxes show the interquartile range; the line in the box is the median. Outliers are marked as dots. Significance is set at p < 0.05. Significantly different from groups C–E. Significantly different from groups B–E.
      The total dose of propofol administered to induce anaesthesia was significantly less in group B (2.1 ± 0.5 mg kg–1) than in groups C (3.4 ± 0.9 mg kg–1; p = 0.037), D (3.8 ± 0.8 mg kg–1; p = 0.003) and E (3.9 ± 1.3 mg kg–1; p = 0.004), with no significant difference from group A (1.6 ± 0.8 mg kg–1; p = 0.917).
      Bodyweight (p = 0.034) and sedation score (p = 0.026) were identified as covariates for duration of apnoea and intubation time, respectively. Propofol infusion rate had significant effects on duration of apnoea [F (4,48) = 4.403, p = 0.004] and intubation time [F (4,48) = 23.103, p < 0.001] after controlling for body weight and sedation score, respectively. Subsequent post hoc pairwise comparisons between the adjusted means identified that groups A and B had a significantly shorter duration of apnoea than groups C–E, with no significant difference between groups A and B (Table 1). Intubation time was significantly shorter in group B than in group A, with no significant difference in groups C–E (Table 2).
      Table 1Pairwise comparisons of duration of apnoea between five different propofol infusion rates. A total of 60 dogs were included, 12 in each group. A one-way analysis of covariance was conducted with bodyweight identified as a covariate and is presented as adjusted mean ± standard error. The significance identified by post hoc pairwise comparisons with Bonferroni multiple testing correction between groups are shown. Propofol infusion rate: group A, 0.5 mg kg–1 minute–1; group B, 1 mg kg–1 minute–1; group C, 2 mg kg–1 minute–1; group D, 3 mg kg–1 minute–1; group E, 4 mg kg–1 minute–1
      Group (p)
      GroupDuration of apnoea (seconds)ABCDE
      A49 ± 390.7320.004
      Significance level was set at p < 0.05.
      0.010
      Significance level was set at p < 0.05.
      0.007
      Significance level was set at p < 0.05.
      B67 ± 370.008
      Significance level was set at p < 0.05.
      0.020
      Significance level was set at p < 0.05.
      0.015
      Significance level was set at p < 0.05.
      C207 ± 340.7600.808
      D192 ± 360.946
      E196 ± 34
      Significance level was set at p < 0.05.
      Table 2Pairwise comparisons of intubation time between different propofol infusion rates. A total of 60 dogs were included, with 12 per group. A one-way analysis of covariance was conducted with sedation score identified as a covariate and is presented as adjusted mean ± standard error. The significance identified by post hoc pairwise comparisons with Bonferroni multiple testing correction between groups are shown. Propofol infusion rate: group A, 0.5 mg kg–1 minute–1; group B, 1 mg kg–1 minute–1; group C, 2 mg kg–1 minute–1; group D, 3 mg kg–1 minute–1; group E, 4 mg kg–1 minute–1
      Group (p)
      GroupIntubation time (seconds)ABCDE
      A201 ± 10< 0.0001
      Significance level was set at p < 0.05.
      < 0.0001
      Significance level was set at p < 0.05.
      < 0.0001
      Significance level was set at p < 0.05.
      < 0.0001
      Significance level was set at p < 0.05.
      B115 ± 100.9130.1130.055
      C113 ± 90.1210.053
      D93 ± 90.204
      E76 ± 9
      Significance level was set at p < 0.05.

      Discussion

      A propofol infusion rate of 1.0 mg kg–1 minute–1 is optimal for the induction of general anaesthesia in healthy dogs sedated with methadone and dexmedetomidine. Both 0.5 and 1.0 mg kg–1 minute–1 rates were associated with significantly reduced propofol induction doses and shorter postinduction apnoea than higher rates. However, 1 mg kg–1 minute–1 resulted in a significantly shorter time to tracheal intubation than 0.5 mg kg–1 minute–1.
      Shorter tracheal intubation times were achieved with faster infusion rates in the present study, although no statistical difference was found between 1 mg kg–1 minute–1 and higher rates. There appears, therefore, to be no benefit in administering propofol infusions at a rate greater than 1.0 mg kg–1 minute–1 to hasten tracheal intubation in healthy animals. The more rapid onset of clinical effects can be explained by higher infusion rates more rapidly achieving greater concentration gradients between the arterial blood and the central nervous system (CNS) than slower infusion rates (
      • Stokes D.N.
      • Hutton P.
      Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
      ). However, there is also a positive association between the infusion rate and total propofol dose administered. In the present study, for the 1.0 and 4.0 mg kg–1 minute–1 infusion rates, the total doses administered mirror those reported by
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      (1.8 ± 0.6 and 4.1 ± 0.7 mg kg–1, respectively). The association between higher infusion rates and larger propofol doses suggests that the transfer of drug to the effect site (CNS) is not solely dependent on drug concentration gradients, but also on rate-limiting kinetics described as the ‘biophase delay’ (
      • Stokes D.N.
      • Hutton P.
      Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
      ;
      • Larrson J.
      • Wahlstrom G.
      Optimum rate of administration of propofol for induction of anaesthesia in rats.
      ). The biophase delay arises as a result of a set transport time limiting the uptake to the effect site, permitting even slow infusion rates of propofol to achieve a sufficient and sustained concentration gradient. In addition, the effect site concentration for the clinical measures of drug effect is independent of the rate of increase of the effect site concentration (
      • Doufas A.G.
      • Bakhshandeh M.
      • Bjorksten A.R.
      • et al.
      Induction speed is not a determinant of propofol pharmacodynamics.
      ). Therefore, faster propofol infusion rates result in plasma accumulation and a relative overdose, prior to the onset of clinical signs.
      The present study mirrors findings in humans and dogs, where slower propofol infusion rates were associated with reduced incidences and durations of postinduction apnoea (
      • Rolly G.
      • Versichelen L.
      • Huyghe L.
      • Mugroop H.
      Effect of speed of injection on induction of anaesthesia using propofol.
      ;
      • Goodman N.W.
      • Black A.M.S.
      • Carter J.A.
      Some ventilatory effects of propofol as sole anaesthetic agent.
      ;
      • Gillies G.W.
      • Lees N.W.
      The effects of speed of injection on induction with propofol. A comparison with etomidate.
      ;
      • Berthoud M.C.
      • McLaughlan G.A.
      • Broome I.J.
      • et al.
      Comparison of infusion rates of three I.V. anesthetic agents for induction in elderly patients.
      ;
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      ).
      This probably occurs as slow infusion rates are less likely to overshoot the dose required, and therefore cause fewer dose-dependent adverse effects (
      • Stokes D.N.
      • Hutton P.
      Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
      ;
      • Ludbrook G.L.
      • Upton R.N.
      A physiological model of induction of anaesthesia with propofol in sheep. 2. Model analysis and implications for dose requirements.
      ;
      • Ludbrook G.L.
      • Upton R.N.
      • Grant C.
      • Martinez A.
      The effect of rate of administration on brain concentrations of propofol in sheep.
      ). The duration of postinduction apnoea reported by
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      was shorter for 1.0 mg kg–1 minute–1 and longer for 4.0 mg kg–1 minute–1 (10 ± 18 and 287 ± 125 seconds, respectively) than in the present study. This could be related to individual anaesthetist variability, timing of tracheal intubation and study design, such as criteria dictating when the propofol infusion should cease. In the present study, the propofol infusion was stopped when the plane of anaesthesia was deemed adequate for tracheal intubation, while in the study reported by
      • Bigby S.E.
      • Beths T.
      • Bauquier S.
      • Carter J.E.
      Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.
      the infusion was continued until successful tracheal intubation was achieved. The decision to alter the protocol was taken to reflect clinical practice.
      Covariance was identified between duration of apnoea and bodyweight, as well as intubation time and sedation score. Although no significant difference was identified between groups, there was variation within each group for these variables. In addition, although infusion rates are calculated based on bodyweight, physiological processes including metabolic rate and drug metabolism are more closely correlated to body surface area (
      • El Edelbi R.
      • Lindemalm S.
      • Eksborg S.
      Estimation of body surface area in various childhood ages – validation of the Mosteller formula.
      ;
      • Nam A.
      • Kim S.M.
      • Jeong J.W.
      • et al.
      Comparison of body surface area-based and weight-based dosing format for oral prednisolone administration in small and large-breed dogs.
      ). This may account for the covariance identified in the present study.
      The effect of propofol on blood pressure was minimal and not significantly different between groups. Significant decreases in arterial blood pressure and systemic vascular resistance have been reported in humans and veterinary species following propofol administration (
      • Fairfield J.
      • Dritsas A.
      • Beale R.
      Haemodynamic effects of propofol: Induction with 2.5 mg kg-1.
      ;
      • Hug Jr, C.C.
      • McLeskey C.H.
      • Nahrwold M.L.
      • et al.
      Hemodynamic effects of propofol: data from over 25,000 patients.
      ;
      • Smith J.A.
      • Gaynor J.S.
      • Bednarski R.M.
      • Muir W.W.
      Adverse effects of administration of propofol with various preanaesthetic regimens in dogs.
      ;
      • Zheng D.
      • Upton R.N.
      • Martinez A.M.
      • et al.
      The influence of the bolus injection rate of propofol on its cardiovascular effects and peak blood concentrations in sheep.
      ;
      • Suarez M.A.
      • Dzikiti B.T.
      • Stegmann F.G.
      • Hartman M.
      Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs.
      ;
      • Henao-Guerrero N.
      • Ricco C.H.
      Comparison of the cardiorespiratory effects of a combination of ketamine and propofol, propofol alone, or a combination of ketamine and diazepam before and after induction of anaesthesia in dogs sedated with acepromazine and oxymorphone.
      ;
      • de Wit F.
      • van Vliet A.L.
      • de Wilde R.B.
      • et al.
      The effect of propofol on haemodynamics: cardiac output, venous return, mean systemic filling pressure, and vascular resistances.
      ;
      • Cattai A.
      • Rabozzi R.
      • Ferasin H.
      • et al.
      Haemodynamic changes during propofol induction in dogs: new findings and approach of monitoring.
      ). In sheep,
      • Zheng D.
      • Upton R.N.
      • Martinez A.M.
      • et al.
      The influence of the bolus injection rate of propofol on its cardiovascular effects and peak blood concentrations in sheep.
      identified a correlation between propofol plasma concentration and the magnitude of blood pressure decline, with the greatest reduction seen in cases receiving propofol at high injection speeds. Similarly, in acepromazine-premedicated dogs,
      • Cattai A.
      • Rabozzi R.
      • Ferasin H.
      • et al.
      Haemodynamic changes during propofol induction in dogs: new findings and approach of monitoring.
      identified maximal cardiovascular depression 50–60 seconds after propofol administration, with the magnitude related to propofol plasma concentration. The fact that these effects were not observed in the present study could be explained by the use of lower infusion rates than the 10 mg kg–1 minute–1 reported by
      • Cattai A.
      • Rabozzi R.
      • Ferasin H.
      • et al.
      Haemodynamic changes during propofol induction in dogs: new findings and approach of monitoring.
      . Furthermore, we did not administer acepromazine, which may exacerbate hypotension by contributing to vasodilation (
      • Smith J.A.
      • Gaynor J.S.
      • Bednarski R.M.
      • Muir W.W.
      Adverse effects of administration of propofol with various preanaesthetic regimens in dogs.
      ;
      • Maddison J.
      • Page S.
      • Church S.
      Small Animal Clinical Pharmacology.
      ). In addition, dexmedetomidine-mediated vasoconstriction may have helped to maintain vascular tone in animals in the present study (
      • Robinson B.J.
      • Ebert T.J.
      • O’Brien T.J.
      • et al.
      Mechanisms whereby propofol mediates peripheral vasodilation in humans.
      ;
      • Ohata H.
      • Iida H.
      • Dohi S.
      • Watanabe Y.
      Intravenous dexmedetomidine inhibits cerebrovascular dilation induced by isoflurane and sevoflurane in dogs.
      ). Effects of rate of administration on blood pressure may be more readily elucidated if potent vasoconstrictors such as α2-adrenoceptor agonist drugs are not used prior to administration of propofol.
      In the present study, the mean duration of apnoea in dogs given 0.5 and 1.0 mg kg–1 minute–1 propofol infusion rates was shorter than desaturation times (69.6 ± 10.6 seconds for dogs breathing room air and 297.8 ± 42.0 seconds for dogs receiving oxygen supplementation) reported by
      • McNally E.M.
      • Robertson S.A.
      • Pablo L.S.
      Comparison of time to desaturation between preoxygenated and nonpreoxygenated dogs following sedation with acepromazine maleate and morphine and induction of anesthesia with propofol.
      . This suggests that slower infusion rates would be particularly beneficial in animals that do not tolerate preoxygenation. In the present study, three animals desaturated and required manual ventilation despite preoxygenation. All three animals received high doses of propofol at faster infusion rates. Desaturation occurred early after induction in one dog, and this may be linked to a sampling error, such as compression of lingual vessels or ambient light interference; while two dogs developed prolonged postinduction apnoea and probably desaturated owing to hypoventilation.
      The present study has several limitations. The setup using a T-connector as a cannula attachment was a limitation. Although the T-connector has a volume of 0.3 mL, this additional volume introduced a delay between starting the infusion and the drug reaching the animal. This is most relevant in smaller animals at slower infusion speeds. However, as there was no difference in weight among groups, the impact on the data should have been minimal. In future, the connector could be primed with propofol in addition to the extension line, or the timer only started when propofol visibly reached the animal. Another limitation was the use of subjectively defined time points guiding decisions about when to stop propofol administration or determine what constituted a first breath. The first breath was recorded as the first visible chest excursion. During the study, it became apparent not all animals continued to breathe once the first chest excursion had occurred, while others initially breathed very shallowly. However, as the same blinded observers determined what constituted the first breath and decided when the infusion should stop, the impact of subjective decisions was minimized. Another limitation of the study design was the inclusion of animals requiring ventilation following desaturation. If this intervention had not been initiated, apnoea would have continued in these three animals. Therefore, duration of apnoea would have been longer in their respective groups if no intervention was made. Finally, physiological monitoring was noninvasive relying on oscillometric blood pressure and SpO2 rather than direct arterial pressure measurements or blood gas sampling. This type of monitoring was most relevant to daily clinical practice for ASA I animals undergoing neutering and imaging procedures.
      In conclusion, a 1.0 mg kg–1 minute–1 infusion rate offers the best compromise between speed of induction and duration of postinduction apnoea in healthy dogs. Differences in the distribution pharmacokinetics between propofol infusions and boluses are reported (
      • Stokes D.N.
      • Hutton P.
      Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
      ). Therefore, further studies should compare the optimum infusion rate (1.0 mg kg–1 minute–1) we identified with incremental low dose (1–1.5 mg kg–1) bolus administration of propofol to facilitate tracheal intubation. This may identify whether the optimal induction dose of propofol is less using bolus administration as compared with the slow continuous administration used in this study.

      Authors’ contributions

      KW: data collection, statistical analysis and interpretation of the data, manuscript preparation. KL: experimental design, data collection, manuscript preparation. NCL: statistical analysis and interpretation of the data, manuscript preparation. SEB: experimental design and manuscript preparation.

      Conflict of interest statement

      The authors declare no conflict of interest

      Acknowledgements

      Thank you to Jennifer E. Carter, University of Melbourne, Australia, for the original concept. This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

      Supporting Information

      The following are the Supplementary data to this article:

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