Remifentanil constant rate infusion reduces propofol and isoflurane requirements in spontaneously breathing dogs undergoing orthopaedic surgery
MeSH keywords:dogs, isoflurane, propofol, remifentanil
Opioids are used in orthopaedic surgery in humans for their antinociceptive effects. Remifentanil has not been used in dogs extensively. The objectives of this study were to evaluate the sparing effects of remifentanil constant rate infusion on propofol and isoflurane, in spontaneously breathing dogs. Fifty-four client-owned dogs, scheduled for ortho- paedic surgery were premedicated with acepromazine (0.05 mg kg-1 IM), pethidine (3 mg kg-1 IM), and carprofen (4 mg kg-1 IM). They were randomly allocated into two groups: Group R (n=37) received a bolus of remifentanil (3 μg kg-1) followed by a constant rate infusion (0.4 μg kg-1 min-1). Group P (n=17) received normal saline at the same volume rates. Five minutes after the bolus administration of remifentanil, 0.5 mg kg-1 propofol was administered, at incremental doses, to induce anaesthesia and the trachea was intubated. Isoflurane in 100% oxygen was used to maintain anaes- thesia. During surgery, arterial blood pressure, heart rate, arterial saturation of haemoglobin, inspired and end-tidal carbon dioxide (CO2), isoflurane and oxygen (O2) concentrations, and respiratory rate were recorded every 5 min. For each dog, the area under the curve was calculated and standardized by the duration of anaesthesia for the end-tidal isoflurane concentration sand the end-tidal CO2.
The total propofol dose for induction was significantly (p<0.0005) lower [0.71 (0-1.5) mg kg-1] in group R compared to group P [3 (0.5-8.7) mg kg-1]. Group R required significantly (p<0.0005) less isoflurane for maintenance of anaesthesia [ETiso 0.7% (0.3-1.1%)] compared to group P [1.3% (1.2-1.6%)]. Remifentanil administration may be a useful adjunct to propofol induction and isoflurane inhalant anaesthesia, providing analgesia and reduction of doses of these anaesthetics.
Opioids are commonly used for analgesia during orthopaedic surgery in human patients, as well as in dogs, because pre- and intra-operative use of opioids prevents central nervous system hypersensitization, reduces postoperative requirements for analgesics and improves overall recovery from surgical procedures (Woolf & Chong 1993, KuKanich & Wiese 2015). Remifentanil is an ultra-short-acting pure μ opioid receptor agonist, with a terminal half-life of 6 minutes in dogs (Hoke et al. 1997). Unlike other opioids, remifentanil undergoes widespread metabolism by blood and tissue non-specific esterases and almost 90% of the metabolites is excreted in the urine (Feldman et al. 1991, Egan 1998). It has been shown that amongst all tissues examined in dogs, the muscles, intestines, and brain exhibited the highest extraction ratios (Chism & Rickert 1996, Hoke et al. 1997). As a result, compared with other phenylpiperidine derivatives, such as fentanyl, remifentanil has a shorter duration of action and does not accumulate after several hours of intravenous infusion. Although, remifentanil is extensively protein bound, it has a low pKa, and thus the diffusible (unbound, unionized) fraction is high. This together with its moderate lipid solubility, make remifentanil a rapid-onset opioid (Egan 1998, Egan 2000).
Remifentanil can be used when rapid patient recovery is desirable, like in cases of neuroanaesthesia or outpatient procedures, in humans (Vuyk et al. 1997, Egan 1998, Lee et al. 2010). Patients that receive remifentanil during anaesthesia for its opioid effect are able to regain their spontaneous ventilation only a few minutes after cessation of the infusion (i.e. cardiac surgery), and this is due to the drugs pharmacokinetic profile. This characteristic of the drug permits even high infusion rates of opioid administration intra-operatively with early discontinuation of mechanical ventilation (Vuyk et al. 1997). Due to their short acting pharmacokinetic behaviour, remifentanil and other sedatives and analgesic drugs, have facilitated improvements in anaesthesia, when used as part of a balanced anaesthetic protocol during noxious surgical procedures in combination with major anaesthetic agents (Michelsen & Hug 1996).
The purpose of this study was to evaluate the effect of remifentanil on the induction dose of propofol, as well as the intra-operative requirements of isoflurane in dogs undergoing orthopaedic surgery. The hypothesis was that remifentanil would reduce these requirements.
Materials and methods
This was a prospective, blinded, randomized, placebo-controlled study, approved by the Ethical Committee of our Institution. In all cases informed consent was obtained from the owners. Fifty-four dogs, 31 males and 23 females, 2 (0.6-12) years old [median (minimum-maximum)], weighing 13 (5-30) kg, scheduled for elective orthopaedic surgery (status-ASA 2-3) were used. All dogs were fasted before induction of anaesthesia for approximately 6 hours if the last meal was canned food, or overnight, if this consisted of dry food. They had free access to water up to 2 hours before induction of anaesthesia.
All dogs were premedicated with acepromazine (Acepromazine, Alfasan, Netherlands) (0.05 mg kg-1 intramuscularly-IM), pethidine (Pethidine hydrochloride, State Formulary of Greece, Greece) (3 mg kg-1 IM), and carprofen (Rimadyl, Pfizer, Scotland, UK) (4 mg kg-1 subcutaneously). After 30 min, an indwelling catheter was placed in the cephalic vein, and the administration of 10 mL kg-1 h-1 of Lactated Ringer’s solution commenced, which lasted until the end of surgery.
The dogs were randomly allocated into two groups, in a 2:1 ratio. Dogs of the first group (group R, n=37) received a bolus of remifentanil (Ultiva, GlaxoSmithKline, Greece) (3 μg kg-1 intravenously-IV) followed immediately by a constant rate infusion (CRI, 0.4 μg kg-1 min-1 IV). Dogs of the other group (group P, n=17) received normal saline at the same volume rates IV. The CRI in both groups was continued throughout surgery and was ceased about 10-15 minutes before the end of the procedure. The anaesthetist monitoring the dogs intraoperatively was blinded as to the treatments. Five minutes after the administration of remifentanil, propofol (Propofol, Fresenius Kabi, Greece) was administered at incremental doses of 0.5 mg kg-1 IV (hand injection) for induction of anaesthesia until intubation of the trachea was possible (based on the lack of laryngeal reflexes) and the trachea was then intubated. Propofol induction and intubation of the trachea was always carried out by the same anaesthetist (IS) who was blinded to the treatment (remifentanil or saline). Isoflurane (Isoflurane, Merial, Italy) in oxygen was used for maintenance of anaesthesia. The dial of the vaporizer was originally set to deliver 2% isoflurane, and within a few minutes it was adjusted to achieve an appropriate depth of surgical anaesthesia, based on assessment of eye globe position, palpebral and limb withdrawal reflex, as well jaw muscles tone, and standard anaesthetic monitoring of the cardiovascular and respiratory systems. Then, the surgical site was aseptically prepared, and the dog was moved to the operating theatre. The same team of surgeons performed all operations.
Just after induction of anaesthesia and throughout surgery, systolic, diastolic, and mean arterial blood pressure (indirectly, oscillometric method), electrocardiogram, SpO2 (PC Scout, SpaceLabs Medical Inc., USA), inspired and end-tidal carbon dioxide (CO2 - side stream), isoflurane and oxygen (O2) concentrations, and respiratory rate (Capnomac Ultima, Datex-Engstrom, Finland) were constantly monitored and recorded every 5 min. Inadequate depth of anaesthesia was defined as an increase of heart rate and/or mean arterial blood pressure and/or respiratory rate of more than 10% from baseline values (i.e. 5 minutes before surgical stimulation), which was associated with surgical stimulation. This was treated with an increase in the end-tidal isoflurane concentration of about 0.1%-0.3%. If this proved to be ineffective in reducing the heart rate and/or mean arterial blood pressure and/or respiratory rate within 2-3 minutes, fentanyl (Fentanyl, Janssen, Belgium) was administered intravenously (rescue analgesia) at a dose rate of 2-3 μg kg-1, and the animal was excluded from the study. Upon completion of surgery, the administration of isoflurane and the infusion of remifentanil or control solution ceased.
The total dose of propofol per kg of body weight required for induction and the end-tidal concentration of isoflurane required to maintain anaesthesia throughout surgery were recorded. The time between cessation of the administration of anaesthetics and extubation was recorded as the recovery time. Additional analgesia was provided 10-15 min before the end of surgery by administration of morphine (0.2 mg kg-1, IM) (Morphine hydrochloride, State Formulary of Greece, Greece) or pethidine (3 mg kg-1, IM) or fentanyl CRI. The selection of the analgesic drug was based on the type of surgery and severity of the anticipated pain. To reduce inter-observer variability, the same anaesthetist (IS) anaesthetized all animals.
For each dog, the area under the curve (AUC) was calculated and standardized, i.e. divided by the duration of anaesthesia (AUCst) for the mean arterial blood pressure, the end-tidal isoflurane concentrations (ETiso) and the end-tidal CO2 (ETCO2) (Matthews et al. 1990). For the evaluation of normality, the Shapiro-Wilk test of normality was used. The Mann-Whitney test was used to statistically compare age, weight, duration of anaesthesia, recovery time, total propofol dose per kg, mean arterial blood pressure, ETisoAUCst, and ETCO2AUCst between the two groups. The chi-square test was used to compare categorical variables (groups assignment, type of surgery). A p value less than 0.05 was considered significant. For all statistical tests the IBM SPSS Statistics for Mac, V.24.0 (IBM Corp., Armonk, USA) computer software was used. An a priori sample size calculation revealed that anticipating an effect size of about 0.75 a sample size of 48 (for propofol dose reduction) and 53 (for isoflurane concentration reduction) would be needed in order to achieve a 0.8 statistical power.
Anaesthesia lasted for 110 (55-210) [median (min-max)] min in group R and 135 (45-165) min in group P. Recovery time was 5 (1-10) and 10 (1-20) min in group R and group P, respectively. The two groups did not differ significantly with regard to age (p=0.42), weight (p=0.22), duration of anaesthesia (p=0.24), recovery time (p=0.24), and type of orthopaedic surgery (p=0.17). The total propofol dose for induction was significantly (p<0.0005) lower [0.5 (0-1.5) mg kg-1] in group R compared to group P [3 (0.5-8.5) mg kg-1]. In group R, three dogs were tracheally intubated without any use of propofol. Group R dogs required significantly (p<0.0005) less isoflurane to maintain anaesthesia [AUCstETiso 0.7% (0.3-1.1%)] than group P [1.3% (1.2-1.6%)] dogs. Group R animals had significantly (p<0.0005) higher AUCstETCO2 levels [6.4 (2.36-7.57) kPa, 48 (17.7-56.8) mmHg] compared to group P [4.79 (3.57-6.49) kPa, 35.9 (26.8-48.7) mmHg] animals. Mean arterial blood pressure differed statistically non-significantly (p=0.12) between group R [84.3 (69-101) mmHg] and group P [76.8 (62-82) mmHg] (Table 1). In one dog in group P, heart rate increased from 90 to 112 just after the initial surgical stimulation. An increase of the isoflurane vaporiser dial from 2% to 2.2% resulted in the reduction of the heart rate below 100, throughout surgery. No rescue analgesia was administered to any animal in either group, intraoperatively.
In the present study, the remifentanil sparing effect on propofol requirements for induction was dramatic (about 86% reduction). Dogs that received remifentanil needed significantly lower doses of propofol for induction of anaesthesia than the placebo group and three dogs were intubated without any need for use of propofol. These findings are in agreement with the results of a similar study in humans, in which only 54% of the patients receiving low infusion rates of remifentanil for sedation were supplemented with propofol, in an intensive care unit (Muellejans et al. 2006).
The isoflurane requirements for maintenance of anaesthesia were also reduced (about 47%). This finding comes in agreement with the findings of another study in dogs that underwent orthopaedic surgery, in which remifentanil infusion reduced isoflurane requirements for surgical anaesthesia during orthopaedic surgery (Allweiler et al. 2007). In that study, remifentanil at the high infusion rates (0.25 μg kg-1 min-1) reduced the concentration of isoflurane by up to 50%, i.e. from 1.28%±0.13 to 0.65%±0.16. This finding also is in accordance with the results of a study in humans, in which anaesthesia was maintained with sevoflurane and two different CRI doses of remifentanil were used (Florkiewicz et al. 2015). Inhalational agent requirements were slightly lower in the high remifentanil infusion rate group compared to the lower rate group. Our findings also agree with the results of a study in which remifentanil had satisfactory sparing effects on the MAC of enflurane inhalant anaesthesia in dogs (Michelsen et al. 1996). A study in cats found that a combination of ketamine-remifentanil CRI can be administered to reduce isoflurane requirements (Steagall et al. 2015). A CRI of remifentanil alone reduced isoflurane requirements, but the reduction was smaller (about 16%). This is probably attributed to the ceiling effect of remifentanil in cats, which limits the reduction in the MAC of isoflurane (Ferreira et al. 2009). In our study, although the mean arterial blood pressure was higher in group R, this was statistically non-significant, probably because of the small sample size. Thus, the remifentanil associated reduction of the isoflurane requirements was not accompanied by an increase of the mean arterial blood pressure.
It is noteworthy that the dogs that received remifentanil in the present study had significantly elevated end-tidal CO2 values. This is probably a direct effect of remifentanil depressing respiratory function (Allweiler et al. 2007). Although one dog developed hypercapnia (up to 7.57 kPa-56.9 mmHg), no mechanical ventilation was applied, since hypercapnia lasted for only 10 minutes. Furthermore, a slight increase in ETCO2 may be considered to be beneficial (permissive hypercapnia) (McDonell & Kerr 2015).
In this study, remifentanil bolus was administered before the commencement of the CRI. As long as the elimination half-life of remifentanil is very short, this practice seems reasonable in order to achieve a therapeutic blood plasma level of the drug, well before the beginning of the surgical stimulation. In our case, no rescue analgesia was use, thus it can be assumed that this technique could be applied in a clinical setting.
Remifentanil constant rate infusion successfully reduced propofol and isoflurane requirements for induction and maintenance of anaesthesia, respectively, in spontaneously breathing dogs undergoing orthopaedic surgery. Remifentanil may contribute to a balanced anaesthetic protocol and reduce unwanted effects of high-dose anaesthetic drugs administration. However, this reduction of the unwanted effects has to be evaluated in practice with appropriate clinical trials.
Conflict of interest
The authors declare no conflicts of interest.
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