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Minimum alveolar concentration of isoflurane in dogs administered two morphine doses/Concentracao alveolar minima do isoflurano em caes tratados com duas doses de morfina.

Morphine has been used to provide analgesia/antinociception in dogs (MURPHY & HUG, 1992; KO et al., 2009; AGUADO et al., 2011; MONTEIRO et al., 2016). As with other [micro]-opioid agonists, morphine decreased the minimum alveolar concentration (MAC) of enflurane in a dose-related manner in dogs (MURPHY & HUG, 1992). Morphine also decreased the MAC of isoflurane ([ISO.sub.MAC]) in dogs, but to the authors' knowledge, only studies evaluating a single dose of the opioid were conducted (STEFFEY et al., 1994; KO et al., 2009). Moreover, in these previous studies, morphine was administered intravenously and only at high doses (1 to 2mg [kg.sup.-1]). In clinical practice, morphine is usually administered as premedication, at doses ranging from 0.1 to 1.0mg [kg.sup.-1], by intramuscular (IM) injection.

The present study evaluated the effects of IM 0.5mg [kg.sup.-1] ([MOR.sub.0.5]) and 1.0mg [kg.sup.-1] ([MOR.sub.1.0]) morphine premedication on the [ISO.sub.MAC] in dogs. The hypothesis was that morphine would decrease the [ISO.sub.MAC] in a dose-related manner.

Eighteen healthy female dogs scheduled for elective ovariohysterectomy (OH) were enrolled in the study. Any dog having clinical signs of systemic disease, abnormal laboratory data, or aged <6 months or >8 years was excluded from the study. The dogs were randomly administered IM 0.5mg [kg.sup.-1] or 1.0mg [kg.sup.-1] morphine (Dimorf, Cristalia) as premedication in the [MOR.sub.0.5] group and [MOR.sub.1.0] group, respectively.

Approximately 20 minutes after premedication, anesthesia was induced by administering propofol intravenously to allow endotracheal intubation. Dogs were positioned in dorsal recumbency on an electrical heating pad to maintain esophageal temperature between 37[degrees]C and 38[degrees]C. Anesthesia was maintained with isoflurane (Isoforine, Cristalia) in oxygen through a circle rebreathing system. Airway gases were sampled from between the endotracheal tube and the breathing system into an infrared gas analyzer (ILCA Sensor Module; Drager) to monitor the end-tidal carbon dioxide (ETC[O.sub.2]) and isoflurane (ETiso) concentrations. A standard calibration gas mixture (Agent/End-Tidal C[O.sub.2] Calibration Gas, Smiths Medical) was used to verify the calibration of the gas analyzer. Dogs were mechanically ventilated to maintain the ETC[O.sub.2] between 30 and 35mmHg. Intraoperative monitoring included heart rate (HR), indirect (oscillometric) systolic (SAP), mean (MAP) and diastolic (DAP) arterial blood pressures, ETC[O.sub.2] and esophageal temperature (Lifewindow 6000Vet, Digicare). The abovementioned variables were registered immediately before the noxious stimulus was delivered.

The noxious stimulus used for [ISO.sub.MAC] determination was delivered approximately 50 minutes after premedication with [MOR.sub.0.5] or [MOR.sub.1.0]. The [ISO.sub.MAC] was determined by the up-and-down method as reported in previous studies in dogs (AGUADO et al., 2011; MONTEIRO et al., 2016). The ETiso for the first dog in each group was set at 0.8%. On all occasions, an equilibration period of at least 15 minutes was allowed at the ETiso to be tested. Thereafter, the noxious stimulus was delivered: placement of four Backhaus towel clamps, a midline skin incision and subcutaneous tissue dissection. A single surgeon performed the noxious stimuli on all occasions. The response to noxious stimulus was classified as positive or negative if the dog did or did not move the head, trunk, or limbs within one minute after the stimulus. When a positive or negative response was observed, the ETiso to be tested in the subsequent dog from the same group was increased or decreased by 0.1%, respectively. Observation of opposite responses in two consecutive dogs (positive followed by negative or vice-versa) was defined as a crossover. The ETiso concentrations tested in four independent crossovers were used to calculate the [ISO.sub.MAC] value in each group by mathematical averaging. After evaluation of the response to the noxious stimulus, all dogs were administered 0.6mg [kg.sup.-1] S(+)-ketamine and 0.2mg [kg.sup.-1] meloxicam intravenously and the ETiso was increased to maintain surgical depth of anesthesia to perform the OH.

Data distribution was analyzed using the Shapiro-Wilk normality test. Differences between the groups in [ISO.sub.MAC], HR, SAP, MAP and DAP were compared by unpaired t test. A Mann Whitney test was used to compare propofol dose and age of dogs between groups. For all analyzes, a P value of <0.05 was considered significant.

Eighteen dogs completed the study (ten dogs in [MOR.sub.0.5] and eight dogs in [MOR.sub.1.0]). There were no significant differences between the groups for age, weight and propofol induction dose; median (interquartile range) for all 18 dogs were 12 months (12-42 months), 11.4kg (8.4-14.1kg) and 6.1 mg [kg.sup.-1] (5.1-7.0mg [kg.sup.-1]), respectively. There were no significant differences between the groups for temperature and ETC[O.sub.2]. Mean [+ or -] SD temperature and ETC[O.sub.2] for all 18 dogs were 37.1 [+ or -] 0.3[degrees]C and 32 [+ or -] 2mmHg. Values for MAP and DAP were significantly lower in [MOR.sub.1.0] than in [MOR.sub.0.5]: 50 [+ or -] 6mmHg versus 63 [+ or -] 10mmHg (P=0.008); 31 [+ or -] 7mmHg versus 40 [+ or -] 7mmHg (P=0.020), respectively. There was a trend for lower values of HR and SAP in [MOR.sub.1.0] than in [MOR.sub.0.5]: 59 [+ or -] 10beats [min.sup.-1] versus 74 [+ or -] 18beats [min.sup.-1] (P=0.056); 79 [+ or -] 8mmHg versus 93 [+ or -] 16mmHg (P=0.051), respectively. The mean [+ or -] SD calculated [ISO.sub.MAC] was 0.98 [+ or -] 0.15% in [MOR.sub.0.5] and 0.80 [+ or -] 0.08% in [MOR.sub.1.0] (Figure 1). The [ISO.sub.MAC] was 18% lower in [MOR.sub.1.0] compared with [MOR.sub.0.5] (P=0.010).

In a previous study, the [ISO.sub.MAC] determined in dogs was 1.20% (MONTEIRO et al., 2016). This previous study was performed in the same laboratory and using the same methodology of the present study. Because a control [ISO.sub.MAC] had already been determined in this previous study (MONTEIRO et al., 2016), we decided not to include a control group in the present study. In the study reported here, the estimated [ISO.sub.MAC] in the [MOR.sub.0.5] and [MOR.sub.1.0] groups is respectively 18% and 33% lower than the 1.20% value reported in the control group by MONTEIRO et al. (2016). The findings of the present study are in agreement with a previous study that demonstrated a dose dependent reduction on enflurane MAC by morphine in dogs (MURPHY & HUG JR, 1982).

In the present study, the noxious stimulus used for determination of the [ISO.sub.MAC] may not be considered a supramaximal stimulus (VALVERDE et al., 2003). Nevertheless, the reduction in the [ISO.sub.MAC] reported in a previous study (KO et al., 2009), which employed a supramaximal noxious stimulus for MAC determination in dogs administered 1.0mg [kg.sup.-1] morphine IV, was nearly the same compared to the [MOR.sub.1.0] group (34% versus 33%). These findings indicated that the up-and-down method employing dogs from clinical practice can be a good alternative for determination of the MAC sparing effect of sedative or analgesic drugs. However, other studies need to be performed to support this statement.

Pure [mu]-opioid agonists induce vagal stimulation on medullary centers and decrease in HR (LAUBIE et al., 1979). This effect was reported to be dose related such that progressively increasing doses of alfentanil decreased HR in a dose dependent manner in dogs (ARNDT et al., 1986). The finding that HR was lower in the [MOR.sub.1.0] group than in the [MOR.sub.0.5] group suggests that the higher dose of morphine induced a more pronounced vagal stimulation than the lower dose of the opioid in this study.

Based on mean values for each group, hypotension (MAP<60mmHg) was observed in [MOR.sub.1.0] but not in [MOR.sub.0.5]. This was an unexpected finding as isoflurane is known to induce dose related cardiovascular depression in dogs (PAGEL et al., 1991). Therefore, a higher MAP would be expected in [MOR.sub.1.0] than in [MOR.sub.0.5] because the [ISO.sub.MAC] was 18% lower in this group. The event of mild hypotension (MAP=50 [+ or -] 6mmHg) in [MOR.sub.1.0] might be considered a limitation of this study because hypotension decreased halothane MAC in dogs (TADIKONDA et al., 1981). In this previous study, the decrease in MAC was observed after a reduction in MAP from approximately 100mmHg to 60mmHg and the MAC was not evaluated in intermediate levels of MAP (TADIKONDA et al., 1981). In addition, the results from this previous study using halothane can not be extrapolated to isoflurane anesthesia. Further studies are necessary to evaluate the influence of different levels of MAP on the [ISO.sub.MAC]. In conclusion, results of this study suggest that IM premedication with morphine 0.5 and 1.0mg [kg.sup.-1] decreases the [ISO.sub.MAC] in a dose-related manner in dogs.

BIOETHICS AND BIOSSECURITY COMMITTEE APPROVAL

This study was approved by the Institutional Animal Care Committee (protocol 195/2011) and all owners gave their informed consent.

http://dx.doi.org/10.1590/0103-8478cr20170132

Received 03.01.17 Approved 07.22.17 Returned by the author 09.01.17

ACKNOWLEDGEMENTS

We thank Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) for providing a scholarship to Karina Coelho and Thais Bressan. Funding for this research was provided by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq).

REFERENCES

AGUADO, D. et al. Reduction of the minimum alveolar concentration of isoflurane in dogs using a constant rate of infusion of lidocaine-ketamine in combination with either morphine or fentanyl. Veterinary Journal, v.189, p.63-66, 2011. Available from: <http://www.ncbi.nlm.nih.gov/pubmed/20594878>. Accessed: Nov. 30, 2015. doi: 10.1016/j.tvjl.2010.05.029.

ARNDT, J.O. et al. Alfentanil's analgesic, respiratory, and cardiovascular actions in relation to dose and plasma concentration in unanesthetized dogs. Anesthesiology, v.64, p.345-352, 1986.

KO, J.C. et al. Effects of carprofen and morphine on the minimum alveolar concentration of isoflurane in dogs. Journal of theAmerican Animal Hospital Association, v.45, p.19-23, 2009. Available from: <http://wwwjaaha.org/doi/abs/10.5326/0450019?code=amah-site>. Accessed: Feb. 20, 2017. doi: 10.5326/0450019.

LAUBIE, M. et al. Vagal bradycardia produced by microinjections of morphine-like drugs into the nucleus ambiguus in anaesthetized dogs. European Journal Pharmacology, v.59, p.287-291, 1979. Available from: <https://www.ncbi.nlm.nih.gov/pubmed/?term=527649>. Accessed: Aug. 09, 2017. doi: 10.1016/0014-2999(79)90292-9.

MONTEIRO, E.R. et al. Effects of acepromazine-morphine and acepromazine-methadone premedication on the minimum alveolar concentration of isoflurane in dogs. Veterinary Anaesthesia and Analgesia, v.43, p.27-34, 2016. Available from: <http://www.ncbi. nlm.nih.gov/pubmed/25880906>. Accessed: Feb. 20, 2017. doi: 10.1111/vaa.12265.

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PAGEL, P.S. et al. Comparison of the systemic and coronary hemodynamic actions of desflurane, isoflurane, halothane, and enflurane in the chronically instrumented dog. Anesthesiology, v.74, p.539-551, 1991.

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Karina Coelho (1) Eduardo Raposo Monteiro (1, 2) * Thais Feres Bressan (1) Betania Souza Monteiro (1) Daniela Campagnol (1) Marcelo Meller Alievi (2)

(1) Escola de Medicina Veterinaria, Universidade Vila Velha (UVV), Vila Velha, ES, Brasil.

(2) Departamento de Medicina Animal, Faculdade de Veterinaria, Universidade Federal do Rio Grande do Sul (UFRGS), 91540 -000, Porto Alegre, RS, Brasil. E-mail: eduardo.monteiro@ufrgs.br. * Corresponding author.

Caption: Figure 1--Response (positive or negative) for each of the 18 anesthetized dogs at the respective end-tidal isoflurane concentration tested (ETiso). Before anesthetic induction with propofol, the dogs were administered 0.5mg [kg.sup.-1] morphine ([MOR.sub.0.5] group, n=10) or 1.0mg [kg.sup.-1] morphine ([MOR.sub.1.0] group, n=8). (+) indicates a positive response; (-) indicates a negative response; shaded squares indicate the crossovers. The horizontal lines indicate the calculated mean [ISO.sub.MAC] value.
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Author:Coelho, Karina; Monteiro, Eduardo Raposo; Bressan, Thais Feres; Monteiro, Betania Souza; Campagnol,
Publication:Ciencia Rural
Date:Nov 1, 2017
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