Dose-finding study comparing three treatments of remifentanil in cats anesthetized with isoflurane undergoing ovariohysterectomy

Abstract

Objectives

Three infusion rates of remifentanil were used in isoflurane-anesthetized cats undergoing ovariohysterectomy. The aim of this study was to identify a dosage regimen that would provide optimal anesthetic and surgical conditions, as well as to compare cardiovascular response to surgical stimulation, postoperative analgesia, anesthetic duration and quality of recovery among the tested remifentanil infusion rates.

Methods

Twenty-seven client-owned, mixed-breed adult healthy female cats were randomized to receive remifentanil 0.1 µg/kg/min (REMI01), remifentanil 0.2 µg/kg/min (REMI02) or remifentanil 0.4 µg/kg/min (REMI04). After premedication with acepromazine and induction of anesthesia with propofol, cats were mechanically ventilated and anesthesia was maintained at approximately 1.0 minimum alveolar concentration (MAC) of isoflurane (1.63% end-tidal isoflurane [ET_ISO]). Remifentanil infusion rate was increased or decreased by 20% if blood pressure had increased or decreased by 20% from previous values. Pulse rate (PR), systolic arterial pressure (SAP), esophageal temperature, pulse oximetry, end-tidal partial pressure of CO₂ and ET_ISO were recorded at different time points during surgery. Meloxicam was administered before the end of surgery. Data within each treatment group were analyzed using a mixed-model ANOVA and Friedman’s test followed by the Wilcoxon signed rank test. Bonferroni or Dunnett’s post-hoc tests were used. The Kruskal-Wallis test followed by Dunn’s post-hoc test were used to compare data between groups; significance was set at P <0.05.

Results

Time to sternal recumbency and time to standing were significantly longer in REMI04 than in the other groups. SAP was higher when compared with baseline in REMI01 and REMI02 groups than in REMI04. No significant difference in PR among groups was observed. One cat in REMI01 and another in REMI02 required postoperative rescue analgesia.

Conclusion and relevance

The dosage regimen of 0.4 µg/kg/min seemed to be the most appropriate to be used in cats undergoing ovariohysterectomy and anesthetized with 1.0 MAC of isoflurane.

Introduction

The reduction of anesthetic doses achieved with balanced anesthetic techniques aims to decrease the incidence of adverse effects, with the ultimate goal of improving patient safety and outcome.^1,2 In veterinary practice, balanced anesthesia is commonly performed with the combination of inhalant anesthetics and systemic opioids.² However, it is debatable if opioids can decrease anesthetic requirements in cats because some studies were able to demonstrate reduction in the minimum alveolar concentration (MAC) when opioids were combined with inhalant anesthetics,^3–5 while others not.⁶ Nevertheless, MAC assesses only one endpoint of anesthesia (immobility),⁷ while other endpoints, such as sympathetic response to surgical stimulation, are clinically important but not well controlled by inhalant anesthetics.⁸ Conversely, the addition of opioid analgesics to general anesthetics can provide effective autonomic blockade.⁹ Consequently, clinical studies investigating the association of opioids to inhalant anesthetics are warranted to better define their clinical role in feline anesthesia.

Remifentanil is an ultra-short-acting synthetic µ-opioid receptor agonist degraded by non-specific plasma and tissue esterases, and has a rapid distribution and high clearance, making it appropriate for infusion regimens in cats.¹⁰ Clinical studies in cats demonstrated that remifentanil at a dosage of 0.3 µg/kg/min can reduce the requirements of isoflurane by 16%, on average.¹¹ It also provided satisfactory anesthesia in this species when a dosage of 0.2 µg/kg/min was combined with propofol.^12,13 However, only one dose of constant rate infusion of remifentanil has been investigated during surgical procedures in cats.^11–13

The aim of this study was to identify the remifentanil dosage regimen to be used in isoflurane-anesthetized cats undergoing ovariohysterectomy, which presented the best compromise between the following endpoints: (1) better control of the blood pressure response to surgical stimulation; (2) fewer requirements for increments in remifentanil infusion; (3) optimal surgical conditions; (4) postoperative analgesia; and (5) optimal anesthetic recovery duration and quality.

Materials and methods

Animals

This study was approved by the Institutional Animal Research Ethics Committee. Twenty-seven client-owned, mixed-breed adult healthy female cats scheduled for elective ovariohysterectomy were enrolled in this randomized, clinical trial. The owners of all cats provided written informed consent. Cats were considered healthy on the basis of medical history, physical examination, echocardiography, complete cell blood count and serum biochemistry analysis. Pregnant cats were excluded from the study. Food, but not water, was withheld 12 h before the surgery.

Anesthesia and instrumentation

Cats were intramuscularly premedicated with 0.05 mg/kg of acepromazine (Acepran; Vetnil). After 20 mins, the cephalic vein was catheterized and anesthesia was induced with 4 mg/kg propofol (Propovan; Cristalia Produtos Químicos Farmacêuticos) intravenously titrated to effect until there was no response to opening the mouth and visualization of the larynx with the laryngoscope. The larynx was instilled with 0.1 ml lidocaine (Xylestesin 2%; Cristalia Produtos Químicos Farmacêuticos) and intubation was performed with an appropriately sized, cuffed endotracheal tube. If necessary, additional propofol was used to allow intubation. End-tidal concentration of isoflurane (ET_ISO) and end-tidal partial pressure of carbon dioxide (P_ETCO2) was measured with a gas analyzer (LW6000; Digicare Biomedical Technology), calibrated before each experiment with a standard gas mixture provided by the manufacturer. The endotracheal tube was connected to a pediatric circle system and isoflurane (Isoflurane; Instituto BioChimico Indústria Farmacêutica) (1.0 MAC; 1.63% ET_ISO)¹⁴ was administered with oxygen during anesthesia maintenance. After orotracheal intubation, cats were positioned in dorsal recumbency on a thermal blanket for instrumentation and surgery. Mechanical ventilation was started with peak inspiratory pressure of 10 cmH₂O and respiratory rate adjusted to maintain normocapnia (P_ETCO2 25–37 mmHg).¹⁵ Two infusion pumps (model 670; Samtronic Indústria e Comércio) were used to deliver lactated Ringer’s solution (RL solution; Eurofarma) intravenously at 3 ml/kg/h and one of the dose regimens of remifentanil. Body temperature was monitored with an esophageal temperature probe. Pulse rate (PR) and systolic arterial pressure (SAP) were monitored using Doppler ultrasound (Model 811-B; Parks Medical Electronic) with the cuff placed around the antebrachium (cuff width was approximately 40% of the circumference of the limb). In case of hypotension prior surgery (SAP <90 mmHg), a fluid bolus of 5 ml/kg was administered over 15 mins. A continuous lead II electrocardiogram and pulse oximetry (SpO₂) with the probe positioned on the tongue were measured during the experiments.

Experimental treatments and surgery

Five minutes after induction of anesthesia, one of the three dose regimens of remifentanil (Ultiva; GlaxoSmithKline Brasil) was started. The dosage regimen for each cat was randomly selected (randomization.com) on the day of the experiment as one of the three investigated remifentanil treatments (0.1 µg/kg/min [REMI01; n = 9], 0.2 µg/kg/min [REMI02; n = 9] or 0.4 µg/kg/min [REMI04; n = 9]). Surgery was initiated between 5 and 7 mins after the beginning of remifentanil infusion. Anesthesia and surgery were managed in all cats by the same experienced anesthetist (MAKAG) and surgeon (PBAD). Ovariohysterectomy was performed in all cats by the midline approach.

Monitoring, data collection and remifentanil infusion adjustments

PR, SAP, SpO₂, P_ETCO2 and temperature were collected approximately 3 mins after remifentanil infusion rate had begun and immediately before skin incision (M_baseline), and at specific time points during surgery: end of skin incision (M_incisionSKIN), immediately after celiotomy (M_celiotomy), during traction and ligation (just before excision) of the right (M_tractionROV) and left ovary (M_tractionLOV), uterus clamping (M_clampUT), midpoint of abdominal wall closure (M_closeABDWALL) and midpoint of skin closure (M_closeSKIN).

If SAP increased by 20% or more from the previous time point, the surgical stimulus was immediately stopped and remifentanil infusion rate was increased by 20%. Then, a period of at least 3 mins was allowed before continuing surgery. This procedure was repeated as many times as needed to maintain SAP <20% higher than in the previous time point. Similarly, if SAP decreased by 20% from previously recorded values, remifentanil infusion was decreased by 20% and the same interval was allowed before continuing surgery. Remifentanil infusion was decreased to the initial rate for at least 3 mins prior to M_closeABDWALL and increased again as described previously, if necessary. This was performed because previous studies showed that maximal nociceptive stimulation occurs at M_tractionROV and M_tractionLOV.¹⁶ If movement was detected during any time point of the surgery, ET_ISO was increased and the cat excluded from the study.

Surgical conditions were assessed by the surgeon, blinded to the treatments, using an ordinal surgical rating scale adapted from Martini et al (Table 1).¹⁷

Table 1

Surgical condition rating scale (adapted from Martini et al)¹⁷

1	Extremely poor	Surgeon is unable to work because of coughing, bucking and/or movement. Abdominal wall extremely rigid. Unable to expose the ovarian pedicle
2	Poor	Surgeon is hampered by continuous muscle contractions. Moderate resistance to ovarian pedicle exposure. Poor abdominal muscle relaxation
3	Good	Acceptable surgical conditions with sporadic muscle contraction. Mild resistance to ovarian pedicle exposure. Good abdominal muscle relaxation
4	Optimal	Optimal surgical conditions with no muscle contraction. No resistance to ovarian pedicle exposure. Excellent abdominal muscle relaxation

After M_clampUT, 0.2 mg/kg meloxicam (Maxicam; Ourofino Saude Animal) was subcutaneously administered. Remifentanil and intravenous fluid infusions were discontinued at the end of the surgery.

Surgery time (time elapsed from the first incision until placement of the last suture), anesthesia time (time elapsed from injection of propofol to stopping isoflurane delivery) and extubation time (time elapsed between stopping isoflurane delivery and extubation) were recorded for each cat. Extubation was performed once swallowing reflex was detected. Quality of anesthetic recovery was assessed in each cat within 15 mins of extubation by a simple descriptive scale from 1 to 4 (Table 2).¹¹ During anesthetic recovery, time from extubation to first head lift, sternal recumbency and standing were recorded. Postoperative analgesia was assessed hourly in all cats for 3 h using Botucatu’s multimodal feline pain scale,¹⁸ starting 1 h after extubation. Cats with pain scores >8 received methadone 0.2 mg/kg intramuscularly. Anesthetic recovery quality and postoperative pain were assessed by the same non-blinded trained observer (MLM).

Table 2

Anesthetic recovery quality scale¹³

1	Excellent	Calm and comfortable, stretching, possible kneading with forepaws, ideal
2	Good	Comfortable but with mild agitation
3	Acceptable	Moderate agitation but acceptable, no thrashing or dysphoria
4	Poor	Thrashing, severe agitation, dysphoria, unacceptable

Statistical analysis

Data were analyzed using commercial software (SAS University Edition; SAS Institute). Normality of the data was evaluated by the Shapiro–Wilk test. Normally and non-normally distributed data were compared between and within treatment groups by a mixed-model ANOVA and Friedman’s test, respectively. A t-test or a Wilcoxon rank-test followed by a Bonferroni correction for multiple comparisons were used to compare normally or non-normally distributed data of each time point between groups, respectively. Dunnett’s test was used to compare the results from different time points with M_baseline. Kruskal–Wallis followed by Dunn’s post-hoc test were used to compare the non-parametric or non-normally distributed data (anesthesia and surgery times, recovery quality and surgical condition scores) between treatments. Results were expressed as mean ± SD (normally distributed) or median and range (non-normally distributed or non-parametric data) and all differences were considered to be significant at P <0.05.

Results

Age and body weight of the cats used in this study are presented in Table 3 and the anesthesia and surgery related results are presented in Table 4. The time required to sternal recumbency was longer in the REMI04 cats when compared with cats in the REMI01 (P = 0.0259) and REMI02 groups (P = 0.0038). Time to standing was longer in the REMI04 cats when compared with the REMI02 cats (P = 0.0094).

Table 3

Demographic data of cats undergoing ovariohysterectomy and anesthetized with isoflurane and three infusion rates of remifentanil

Group	Age (years)	Body weight (kg)
REMI01 (n = 9)	1.0 (1.0–2.0)	3.1 ± 0.8
REMI02 (n = 9)	1.5 (1.0–2.0)	3.2 ± 0.8
REMI04 (n = 9)	1.8 (1.0–5.0)	2.8 ± 0.5

Normally distributed data are expressed as mean ± SD and non-normally distributed or non-parametric data are expressed as median (range)

REMI01 = remifentanil 0.1 µg/kg/min; REMI02 = remifentanil 0.2 µg/kg/min; REMI04 = remifentanil 0.4 µg/kg/min

Table 4

Anesthesia and surgery-related results in cats undergoing ovariohysterectomy and anesthetized with isoflurane and three infusion rates of remifentanil

Group	Anesthesia time (mins)	Remifentanil infusion time (mins)	Surgery time (mins)	Extubation time (mins)	Time to first head lift (mins)	Time to sternal recumbency (mins)	Time to standing (mins)	Recovery quality	Surgical condition score
REMI01 (n = 9)	55.0 (44.0–67.0)	41.0 (33.0–60.0)	37.0 (26.0–51.0)	8.0 (6.0–13.0)	3.0 (1.0–5.0)	5.0 (1.0–9.0)	7.0 (3.0–12.0)	1 (1–3)	4 (1–4)
REMI02 (n = 9)	59.0 (43.0–67.0)	40.0 (32.0–49.0)	35.0 (26.0–46.0)	6.5 (4.0–11.0)	2.5 (1.0–7.0)	3.0 (1.0–7.0)	3.5 (3.0–11.0)	1 (1–2)	4 (2–4)
REMI04 (n = 9)	50.0 (45.0–64.0)	39.5 (33.0–52.0)	30.0 (28.0–49.0)	10.0 (4.0–13.0)	5.0 (2.0–18.0)	10.0 (4.0–18.0)*	12.0 (6.0–22.0)^†	1 (1–2)	4 (4–4)

All data are expressed as median (range)

Significantly higher in the REMI04 than in the REMI02 and REMI01 groups

†

Significantly higher in the REMI04 than in the REMI02 group

REMI01 = remifentanil 0.1 µg/kg/min; REMI02 = remifentanil 0.2 µg/kg/min; REMI04 = remifentanil 0.4 µg/kg/min

None of the cats included in this study presented motor response during surgery. Remifentanil requirements during anesthesia are presented in Table 5. Six cats in the REMI01 group and REMI02 and three cats in the REMI04 group had their infusion rates increased once at M_tractionROV. Two cats in the REMI01 group and one cat in the REMI02 group needed two increments of remifentanil at M_tractionLOV. Overall, the infusion rates of REMI01, REMI02, and REMI04 were 0.10 (0.10–0.14), 0.20 (0.20–0.28) and 0.40 (0.40–0.48) µg/kg/min, respectively. Two cats each in the REMI01 and REMI02 groups required rescue analgesia in the first hour of postoperative evaluation.

Table 5

Physiologic variables and remifentanil requirements recorded at different moments of surgery in isoflurane-anesthetized cats (n = 9/group) undergoing ovariohysterectomy receiving three infusion rates of remifentanil

Variables	Group	M_baseline	M_incisionSKIN	M_celiotomy	M_tractionROV	M_tractionLOV	M_clampUT	M_closeABDWALL	M_closeSKIN
SAP (mmHg)	REMI01	76 ± 11	77 ± 12	80 ± 14	102 ± 26*	97 ± 27*^†	88 ± 21*^†	78 ± 17	80 ± 21
	REMI02	72 ± 16	76 ± 16	77 ± 14	96 ± 19*	101 ± 24*^‡	81 ± 19	81 ± 12	78 ± 14
	REMI04	67 ± 12	67 ± 13	71 ± 13	87 ± 17*	75 ± 17	67 ± 10	69 ± 15	63 ± 18
PR (beats/min)	REMI01	129 ± 21	129 ± 23	136 ± 25	148 ± 22	153 ± 26	148 ± 23	145 ± 26	141 ± 27
	REMI02	115 ± 21	117 ± 22	118 ± 23	139 ± 23^‡	156 ± 27*	145 ± 20*	140 ± 18	130 ± 23
	REMI04	115 ± 28	116 ± 30	113 ± 30	135 ± 27	146 ± 27*	145 ± 29*	143 ± 32	138 ± 31
P_ETCO2 (mmHg)	REMI01	27 (25–35)	27 (25–35)	27 (25–36)	26 (25–36)	30 (25–36)	30 (25–36)	25 (25–38)	27 (26–38)
	REMI02	30 (25–35)	30 (25–35)	31 (25–35)	34 (25–36)	33 (25–36)	33 (26–35)	33 (25–35)	33 (25–35)
	REMI04	27 (25–34)	28 (25–34)	28 (25–34)	28 (25–33)	29 (25–33)	29 (27–33)	29 (26–33)	28 (27–32)
T (°C)	REMI01	36.9 ± 1.2	36.8 ± 1.1	36.7 ± 1.1	36.6 ± 1.1	36.6 ± 1.0	36.6 ± 0.9	36.6 ± 0.8	36.5 ± 0.8
	REMI02	37.4 ± 0.7	37.3 ± 0.7	37.2 ± 0.6	37.1 ± 0.6	37.0 ± 0.5	37.0 ± 0.6	36.9 ± 0.4	36.9 ± 0.4
	REMI04	37.3 ± 0.5	37.3 ± 0.5	37.2 ± 0.6	37.1 ± 0.5	37.0 ± 0.5	36.9 ± 0.5	36.9 ± 0.5	36.9 ± 0.5
SpO₂	REMI01	99 (98–99)	99 (98–99)	99 (98–99)	99 (97–99)	99 (97–99)	99 (97–99)	99 (96–99)	99 (95–99)
	REMI02	99 (98–100)	99 (98–100)	99 (98–100)	99 (98–99)	99 (98–99)	99 (98–99)	99 (98–99)	99 (98–99)
	REMI04	99 (97–99)	99 (97–99)	99 (97–99)	99 (98–100)	99 (99–100)	99 (98–100)	99 (98–99)	99 (98–99)
ET_ISO(%)	REMI01	1.55 ± 0.05	1.59 ± 0.08	1.59 ± 0.09	1.56 ± 0.07	1.58 ± 0.07	1.59 ± 0.05	1.58 ± 0.05	1.57 ± 0.05
	REMI02	1.58 ± 0.05	1.57 ± 0.04	1.60 ± 0.03	1.61 ± 0.03	1.60 ± 0.05	1.61 ± 0.03	1.63 ± 0.04	1.63 ± 0.03
	REMI04	1.58 ± 0.12	1.58 ± 0.12	1.58 ± 0.12	1.61 ± 0.05	1.62 ± 0.05	1.61 ± 0.04	1.62 ± 0.04	1.62 ± 0.04
CRI (µg/kg/min)	REMI01	0.10 (0.10–0.10)	0.10 (0.10–0.10)	0.10 (0.10–0.10)	0.12 (0.10–0.12)	0.12 (0.10–0.14)	0.12 (0.10–0.14)	0.10 (0.10–0.10)	0.10 (0.10–0.10)
	REMI02	0.20 (0.20–0.20)	0.20 (0.20–0.20)	0.20 (0.20–0.20)	0.20 (0.20–0.24)	0.20 (0.20–0.28)	0.20 (0.20–0.28)	0.20 (0.20–0.20)	0.20 (0.20–0.20)
	REMI04	0.40 (0.40–0.40)	0.40 (0.40–0.40)	0.40 (0.40–0.40)	0.40 (0.40–0.48)	0.40 (0.40–0.48)	0.40 (0.40–0.48)	0.40 (0.40–0.40)	0.40 (0.40–0.40)

Normally distributed data are expressed as mean ± SD and non-normally distributed data are expressed as median (range)

Significantly different from baseline values within the group (P <0.05)

†

Significantly higher in REMI01 than in the REMI04 group (P <0.05)

‡

Significantly higher in the REMI02 than in the REMI04 group (P <0.05)

M_baseline = immediately before skin incision; M_incisionSKIN = end of skin incision; M_celiotomy = immediately after celiotomy; M_tractionROV = during traction and ligation (just before excision) of the right ovary; M_tractionLOV = just before excision of left ovary; M_clampUT = uterus clamping; M_closeABDWALL = midpoint of abdominal wall closure; M_closeSKIN = midpoint of skin closure; SAP = systolic arterial pressure; REMI01 = remifentanil 0.1 µg/kg/min; REMI02 = remifentanil 0.2 µg/kg/min; REMI04 = remifentanil 0.4 µg/kg/min; PR = pulse rate; PETCO2 = end-tidal partial pressure of carbon dioxide; T = temperature; SpO₂ = pulse oximetry; ET_ISO = end-tidal concentration of isoflurane; CRI = constant rate infusion

There was no significant difference among groups and time points for ET_ISO, P_ETCO2, SpO₂ and temperature. SAP was higher when compared with baseline values at M_tractionROV in REMI01 (P = 0.0003), REMI02 (P = 0.0012) and REMI04 (P = 0.0097) cats, and at M_tractionLOV in REMI01 (P = 0.0117) and REMI02 (P = 0.0003) cats. Among groups, SAP was higher in REMI01 than REMI04 cats at M_tractionLOV (P = 0.0258) and M_clampUT (P = 0.0383), and REMI02 was higher than REMI04 at M_tractionLOV (P = 0.0041).

Most of the cats presented optimal surgical condition with no significant difference in the surgical condition scores among groups. In REMI01, one cat presented extremely poor surgical conditions and another presented poor surgical conditions. In REMI02 one cat presented poor and another presented good surgical conditions. All cats in the REMI04 group presented optimal surgical conditions.

Hypotension was observed during instrumentation in 16 cats (4/9 REMI01, 7/9 REMI02 and 5/9 REMI04). PR was higher compared with baseline values at M_tractionROV within the REMI02 groups (P = 0.0342) and at M_tractionLOV and at M_clampUT within the REMI02 (P = 0.0002, P = 0.0211) and REMI04 (P = 0.0113, P = 0.0245) groups. Decrements in remifentanil infusion due to a decrease in SAP by 20% were not performed in any of the groups.

Discussion

The main findings of this study were that in cats undergoing ovariohysterectomy, anesthetized with isoflurane and three doses of remifentanil; (1) increments in remifentanil dose in response to a 20% increase in SAP were required during the moments of more intense surgical stimulation (M_tractionROV, M_tractionLOV and M_clampUT) independently of the dose; (2) SAP and the requirements for intraoperative increments of remifentanil were lower in the cats in the REMI04 group than in REMI01 and REMI02 groups; (3) extremely poor surgical condition was observed in one cat with the lowest remifentanil dosage, while all cats that received the highest dosage presented optimal surgical conditions; (4) most of the cats presented good-to-excellent recovery quality, regardless of the dose, with only one cat in the REMI01 group showing moderate signs of agitation; (5) the time required to sternal recumbency and time to standing were longer in the REMI04 cats when compared with REMI01 and REMI02 cats; and (6) none of the cats in the REMI04 group required rescue analgesia, while two cats in the REMI01 and REMI02 groups received rescue analgesia in the first postoperative hour.

Isoflurane concentration was maintained fixed at approximately 1.0 MAC, which represents a light plane of anesthesia. However, remifentanil can decrease isoflurane MAC by up to 30% when doses between 0.25 and 1.0 µg/kg/min were used in cats.³ Consequently, 1.0 MAC used during the experiments was likely associated with a light-to-moderate plane of anesthesia where motor response to noxious stimulation was not expected. However, it was possible that the cats of different groups were at different depths of anesthesia for at least two reasons: (1) MAC reduction of 0.1 µg/kg/min was not assessed by Ferreira et al;³ and (2) cats can present a significant variability in MAC in the presence or not of an opioid.^3,6,19,20 Having the cats in variable depths of anesthesia does not seem to invalidate our results because the increase in blood pressure observed during noxious stimulation was not blunted by different levels of isoflurane anesthesia, even though blood pressure before noxious stimulation is high and low at lighter and deeper levels of anesthesia, respectively.⁸ Even though MAC was not individually determined in this study, none of the cats presented a motor response during surgery and the sympathetic response was present for the titration of the remifentanil infusion rate.

Independently of the remifentanil dose, increments of more than 20% in SAP were observed during more intense surgical stimulation, as observed in previous studies using the same surgery,^12,13 and in humans undergoing cardiac surgery.²¹ However, the dosage regimen of 0.4 µg/kg/min appeared to provide the best control of the blood pressure response to surgical stimulation in cats undergoing ovariohysterectomy for at least three reasons: (1) fewer adjustments in the remifentanil infusion rate were necessary at this rate when compared with REMI01 and REMI02; (2) SAP was higher in REMI02 than in REMI04 during one of the moments of more intense surgical stimulation (M_tractionLOV); and (3) SAP was not higher than baseline on M_tractionLOV only with this dosage regimen. However, there was a tendency towards more hypotension in the cats of the REMI04 group, especially in the moments of no or less intensity of noxious stimulation, as demonstrated by all cats having a SAP <90 mmHg during M_baseline. Despite the tendency for less hypotension in the REMI01 and REMI02 groups, their remifentanil dosage regimens were adjusted more often. The fixed ET_ISO used in the present study might have been caused a deeper plane of anesthesia in the cats of the REMI04 group because SAP was lower in this group than in the REMI01 and REMI02 groups. If this is true, hypotension can be minimized by decreasing ET_ISO when isoflurane is combined to 0.4 µg/kg/min of remifentanil in cats undergoing ovariohysterectomy. Alternatively, hypotension could have been minimized in these cats by the use of positive inotropes, such as dopamine.²² However, the use of dopamine in this study would have added a confounding factor because the criterion for adjustments in remifentanil infusion rate is based on changes in blood pressure, as performed in previous studies.^11–13 Even though higher doses of remifentanil can increase sympathetic tone in cats,³ the lower SAP in the cats in the REMI04 group could possibly be attributed to the dose-dependent decrease in blood pressure caused by a decrease in sympathetic activity observed with increasing doses of opioids in cats.²³

Although remifentanil has an extremely high clearance and short elimination half-life,¹⁰ the more prolonged time to sternal recumbency and standing, as well as no requirement for rescue analgesia in the cats of the REMI04 group, were probably caused by a higher plasma concentration of remifentanil in this group during the first hour after extubation, as demonstrated in dogs when a higher dose of remifentanil was administered.²⁴ Postoperative rescue analgesia is commonly needed when only a non-steroidal anti-inflammatory drug is used in cats submitted to ovariohysterectomy^25,26 as was observed in two cats of the REMI01 and REMI02 groups during the first postoperative hour. In addition, the hyperalgesia reported after higher doses of remifentanil in other species did not appear to happen in the REMI04 cats.^27,28 Even though remifentanil can be associated with excitement in cats, especially at higher doses,⁶ most of the cats presented recovery quality between excellent and good with only one cat in of REMI01 presenting moderate agitation and hyper-reflexia. These behavior patterns ameliorated significantly when the cat was left undisturbed in a quiet and dark room. Even though anesthetic recovery was longer in the cats in the REMI04 group, it did not seem to be of clinical significance as it took a median of 12 mins for the cats to reach standing position.

The blinded assessment of anesthesia recovery and postoperative analgesia was not possible owing to the lack of trained personal in all experiments and is an important limitation of this study because both assessments have a high degree of subjectivity. To minimize the bias associated with the non-blinded nature of the study, a numerical anesthetic recovery scale and a multidimensional pain scale with well-defined criteria for each category and specifically developed for cats were used which, in theory, could minimize the subjectivity of the assessment, especially for the postoperative pain.²⁹ In addition, the biases during these evaluations were also potentially diminished by the fact that the same evaluator with experience with the normal behavior of cats was responsible for the assessments. Finally, the main reasons to include the postoperative pain and recovery quality assessments were to possibly identify postoperative hyperalgesia and dysphoria, which were more expected with the use of higher doses of remifentanil. Consequently, the bias included by the non-blinded evaluator would be in the direction of identifying higher levels of postoperative pain and disphoria in the REMI04 group, which did not happen. An additional limitation of this study was the measurement of SAP with the Doppler ultrasound as Doppler can underestimate SAP.^30–32 However, it would only affect the detection of hypotension but not the number of increments of remifentanil necessary in each dosage regimen because the latter was based on the relative changes in SAP and not in its absolute values. Within the range of SAP observed in this study, the bias for SAP was relatively constant.^30–32 Alternatively, an oscillometric technique could be used to measure arterial blood pressure with the potential benefit of providing a better-defined parameter of hypotension: mean arterial pressure. However, the bias with this technique seems to be strongly dependent on the monitor used.^31–33

Most of the anesthesia-related dose-finding studies only investigate the effects in vital functions, perioperative pain control and recovery quality.^12,13,34 Nevertheless, an ideal anesthetic protocol should also provide optimal surgical conditions,¹ which was more consistently achieved in the cats in the REMI04 group.

Conclusions

The dosage regimen of 0.4 µg/kg/min seemed to be the most appropriate to be used during ovariohysterectomy in cats anesthetized with 1.0 MAC of isoflurane because it presented the best compromise between the control of blood pressure response to surgical stimulation, optimal surgical conditions, anesthetic recovery quality and postoperative analgesia.

Footnotes

Accepted: 9 March 2017

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) N^o 50501011.

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