Medycyna Wet. 2010, 66 (1) 37
Praca oryginalna Original paper
Veterinary anaesthesiology has improved notably in recent years thanks to developments in identifying new safe drugs as induction agents. Currently several small animals worldwide receive an inhalation-based anaesthesia. Hence, there is a growing interest in the general effects of drugs used during premedication or as induction agents for inhalation anaesthesia. Barbi-turates and propofol are among the drugs most com-monly used for inducing inhalation anaesthesia. Unfor-tunately, several adverse respiratory and cardiovascu-lar effects following the administration of these drugs have been described (13, 14).
The use of water-soluble benzodiazepine midazo-lam is well established in human anaesthesia as a pre-medicant, anxiolytic and anaesthetic induction agent. Notably, midazolam has been used successfully in patients in intensive care units in hospitals to cause unconsciousness (1, 22). Midazolam has been shown to have superior sedative effects (15) and to be less likely to produce phlebitis than diazepam following intravenous administration (5). Midazolam is
hydro-xylated by cytochrome and its metabolites are sub-sequently glucuronidated and excreted in the urine (4, 7, 16, 18). In dogs, midazolam has been shown to act as a mild sedative when administered alone, and with a synergistic interaction when given with other drugs, including medetomidine, xylazine, butorphanol, ace-promazine, and buprenorphine (3, 8, 9, 17, 19, 24).
The aim of the study was to evaluate midazolam as an intravenous induction agent for inhalation anaesthe-sia in the routine castration of dogs and to investigate the dose required for induction as well as its effects on the dogs general conditions, arterial blood gas and acid-base balance.
Material and methods
Animals. A total of 24 male dogs of various breeds were studied, ranging in age from 1 to 11 years and in weight from 5 to 27 kg. Dogs were recruited at the Department and Clinic of Animal Surgery, University of Life Sciences in Lublin, Poland. The hematological and biochemical exa-minations were performed. Dogs did not show any clinical
Intravenous midazolam as an induction agent
for inhalation anaesthesia in dogs
ANDRZEJ ÆWIEK, IRENEUSZ BALICKI*, DOROTA RÓ¯AÑSKA*Gilmore Veterinary Practice, 52-54 High Street Standish, Wigan, England,
*Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, G³êboka 30, 20-612 Lublin, Poland
Æwiek A., Balicki I., Ró¿añska D.
Intravenous midazolam as an induction agent for inhalation anaesthesia in dogs
Summary
The aim of this study was to evaluate midazolam as an intravenous induction agent for inhalation anaesthe-sia in the routine castration of dogs. Investigations concerned the dose required for induction as well as its effects on the dogs general condition, arterial blood gas and acid-base balance. A total of 24 male dogs of various breeds were studied, ranging in age from 1 to 11 years and in weight from 5 to 27 kg. Dogs were recruited at the Department and Clinics of Animal Surgery, University of Life Sciences in Lublin, Poland. The dogs were premedicated intramuscularly with xylazine and atropine sulphate at dose rates of 2 mg/kg and 0.05 mg/kg respectively. Twenty minutes after premedication, midazolam was administered by intravenous infusion. Intravenous midazolam proved useful as an induction agent for inhalation anaesthesia. The dose used was dependent on the animals reaction. The induction of anaesthesia with midazolam was successful and enabled endotracheal intubation and inhalation anaesthesia with a halothane-oxygen mixture. The appli-cation of midazolam with halothane, however, led to transitory disturbances in systemic acid-base balance due to gas exchange abnormalities. The median effective dose of midazolam for the induction of anaesthesia was 0.46 mg/kg i.v. Postoperatively, a full recovery of consciousness and motor functions was rapidly achieved in all dogs. Further studies on midazolam as an intravenous induction agent for inhalation anaesthesia in the dog are warranted.
Medycyna Wet. 2010, 66 (1) 38
symptoms of disease before surgery. Food was withheld for 12 hours prior to the induction of anaesthesia. Anaes-thesia was performed prior to a routine castration.
Anaesthesia. The dogs were premedicated with intra-muscular xylazine (Rometar, Spofa, Czech Republic) and atropine sulphate (Atropinum sulfuricum, WZF Polfa, Poland) at dose rates of 2 mg/kg and 0.05 mg/kg, respecti-vely. At 20 minutes after premedication, midazolam (Mi-danium, WZF Polfa, Poland) was administered by intra-venous infusion. Dosage of midazolam depended on the individual response to anaesthesia (suppression of palpebral, corneal, and toe-pinch reflexes). Dogs were intubated, and halothane oxygen mixture (Narcotan, Leciwa, Czech Re-public) was administered for approximately 5 minutes at 3.5% followed by 10 minutes at 1.5%. Closed-circuit inha-lation anesthesia was used. The operating time for routine castration was 10 to 15 minutes. Halothane was administe-red for another fifteen minutes and then withdrawn. Dogs received oxygen for 5-10 minutes and were therafter dis-connected from the anaesthetic machine. When recovery of the first reflexes occurred, the endotracheal tube was removed.
Clinical evaluation. The depth of anaesthesia was evalu-ated based on the suppression of superficial sensibility and palpebral, corneal, and toe-pinch reflexes. Body tempera-ture, heart and respiratory rates were monitored in all dogs before the administration of anaesthetics, as well as at 15, 25, 40 and 60 minutes thereafter. Arterial blood gas varia-bles were measured in fifteen dogs. The following parame-ters were determined: pH, actual bicarbonate (HCO3 act.),
standard base excess (SBE), partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), and arterial blood oxygen saturation (SatO2). Arterial blood gas measurements were performed on blood samples taken from the femoral artery and collected into disposable syringes containing heparin. Determinations were performed before the administration of anaesthetics, as well as at 15, 25, 40
and 60 minutes thereafter. All analyses were performed with a blood gas analyzer (Model 238; Ciba Corning Diagno-stics Corp., Norwood, MA, USA).
Data analysis. Data are expressed as means ± standard deviations (SD) and compared using Students t-test. Cor-relations were evaluated for statistical significance with Pearsons test. A two-tailed P value < 0.05 was considered as significant in all the analyses.
Results and discussion
Between 10 and 15 minutes following premedication, all animals exhibited symptoms of sedation. The dogs rested in a recumbent position and showed a decre-ased response to external stimuli. Following the ad-ministration of xylazine, the vomiting reflex was ob-served in 20% of the dogs. Table 1 depicts the mean dose of midazolam used for the induction of inhala-tion anaesthesia, as well as the correlainhala-tion coefficients with age and body weight. After the administration of midazolam, muscles became relaxed, the animals lost consciousness, and superficial sensibility was lost. About 20% of the dogs preserved the corneal reflex.
During the 15-minute inhalation anaesthesia with a halothane-oxygen mixture, superficial sensitivity as well as palpebral, corneal, and toe-pinch reflexes were eliminated. When halothane administration was stop-ped, the ability to respond to external stimuli was re-gained in 12 minutes on average. The return of motor functions (dogs trying to assume sternal recumbency or standing position) occurred at approximately 24 minutes following the discontinuation of anaesthesia. Changes in body temperature, as well as heart and respiratory rates during anaesthesia are displayed in Tab. 2. Following premedication with xylazine and atropine, body temperature increased significantly from baseline. After the administration of midazolam, body temperature decreased and then stabilized during inha-lation anaesthesia with halo-thane. A further significant decrease was observed at minute 60 following preme-dication. Heart rate decre-ased significantly at minute 15 following premedication. Heart rate reached its peak at minute 25, and then decre-ased costantly but insigni-ficantly. As can be seen in Tab. 2, at minute 15 follo-wing premedication respira-tory rates of the dogs began to decrease.
Table 3 shows changes in arterial blood gas parameters during the procedure. There was a significant reduction in blood pH at minute 40
Explanation: * no significant correlation was observed between midazolam dose and age or body weight
Tab. 1. Dosage of midazolam in the study: correlation analysis with age and body weight. Time for return of consciousness and motor function is also reported
e s o d m a l o z a d i M )t h g i e w y d o b g k / g m ( * s t n e i c if f e o c n o it a l e rr o C Timeforreturn e g A Bodyweight ofressitpmounsile(mstionuetexste)rnal ofm(omtoirnufutensc)itons 6 0 . 0 ± 6 4 . 0 0.09 0.16 12.21±2.37 24.16±4.0 Explanations: * p < 0.05; ** p < 0.01; *** p < 0.001
Tab. 2. Effect of anaesthesia on body temperature, heart and respiratory rates at different time points (x ± SD) s e l b a ir a V Timepoint(minutes) 0 15 25 40 60 y d o B ( e r u t a r e p m e t ° )C 38.79±0.42 39.14±0.43** 39.02±0.49 38.63±0.58 38.01±0.64** e t a r tr a e H ) n i m /f ( 121.38±32.90 82.00±29.66** 134.62±51.72 120.85±19.58 100.46±19.34 e t a r y r o t a ri p s e R ) n i m /f ( 28.85±6.68 18.69±7.87** 17.69±9.72** 13.85±3.80*** 15.15±11.20**
Medycyna Wet. 2010, 66 (1) 39
following anaesthesia. Blood pH returned to normal values at minute 60. PaCO2 was found to be signifi-cantly increased at minutes 25, 40 and 60. The peak in PaCO2 was observed at minute 40. Similarly, a signi-ficant increase in HCO3act. was observed at minutes
25, 40 and 60. On the other hand, PaO2 decreased significantly at minute 25, then peaked at minute 40 as a result of oxygen administration during inhalation anaesthesia. A significant decrease of PaO2 to a criti-cal level was observed at minute 60. No significant fluctuations in SatO2 were noted during the 60-minute observation period.
To the best of our knowledge, no study has yet been reported on the potential usefulness of midazolam as an induction agent for inhalation anaesthesia in the dog. Our findings provide evidence that the induction of anaesthesia by intravenous midazolam was successful and enabled safe endotracheal intubation. The dose used depended on the animals reaction and averaged 0.46 mg/kg, thereby remaining within the recommen-ded therapeutic dosing range of 0.2 to 0.5 mg/kg (7). No significant correlation was observed between the dose of midazolam and the dogs age and body weight. In general, the time required to regain consciousness after anesthesia is heavily influenced by the anaesthe-sia-inducing agent. In this regard, the use of antago-nists is often necessary to reduce the time of returning to full consciousness. In the present study, with mida-zolam induction, consciousness was rapidly regained, so the use of an antagonist could be avoided.
Heart rate depression induced by xylazine is well-known (11, 20, 21, 25, 26). It has been suggested that arrhythmia and bradycardia following xylazine admi-nistration may be due to an increase in cardiac vagal tone (7). Atropine may be used to prevent the xylazi-ne-induced bradycardia and arrhythmia, but intense hypertension produced by the combination of these two drugs is a serious adverse effect (2, 7). Our previous observations (unpublished data) have shown that atro-pine used before xylazine does not seem to prevent bradycardia.
In veterinary medicine, benzodiazepines are most commonly used as anticonvulsants and as
co-induc-tion agents in combinaco-induc-tion with other anesthetics. Notably, they have minimal depressant effects on cardiopulmonary function. Although diazepam may cause a dose-dependent increase in heart rate in sheep (12), no chan-ges in heart rate were observed following the administration of midazolam (0.1 mg/kg) in dogs (6). On the other hand, a com-bination of medetomidine and midazolam may result in signi-ficant bradycardia (9). In this study, we observed an increase in heart rate following the administration of midazo-lam. After the application of inhalation anaesthesia, there was a decrease in heart rate due to halothane. In general, the mean heart rate has been found to decre-ase with halothane exposure in a dose-dependent fashion (18). Previous data from our group have indi-cated that the application of halothane 1.5% or 3.5% results in a reduced heart rate. It has been suggested that bradycardia caused by halothane may be partly due to increased vagal activity (15).
Although it has been suggested that xylazine at an average dose led to a slight decrease in breathing frequency (23), a study by Komar et al. (11) reported a significant decrease in the respiratory rate after xyla-zine administration at 3 mg/kg i.m. Similar results were obtained by Wasak (26). In our study, there was a sig-nificant reduction in respiratory rate following the application of xylazine at 2 mg/kg i.m. Inhalation anaesthesia induction with midazolam resulted in apnoea, and the application of halothane contributed to a further decrease in breathing frequency. Changes in the acid-base balance occurred as a consequence of these respiratory disturbances. Premedication and induction of anaesthesia resulted in a non-significant decrease in pH, whereas pH decreased significantly at minute 40 following the application of halothane. Although the termination of anaesthesia was followed by an increase in pH, PaCO2 was found to be signifi-cantly increased throughout the entire procedure. The observed changes in pH were due to short term minor disturbances in gas exchange. Previous studies did not show significant alterations of acid-base balance and blood gas oxygenation following the administration of a medetomidine-midazolam combination (9). We hypothesize that the increase in actual bicarbonate as observed at minutes 25, 40, and 60 in our study was a metabolic mechanism compensatory to respiratory depression. Breathing depression resulted in a signifi-cant decrease in the partial pressure of arterial oxygen that persisted until the end of the procedure. In the light of these data, hypoventilation due to anaesthetics should be considered as the primary cause of the ob-served alterations in acid-base balance.
Explanations: HCO3: bicarbonate; SBE: standard base excess, PaCO2: partial pressure of
carbon dioxide; PaO2: partial pressure of oxygen, SatO2: arterial blood oxygen saturation;
* p < 0.05, ** p < 0.01, *** p < 0.001
Tab. 3. Effect of anaesthesia on arterial blood gas variables (x ± SD)
s e l b a ir a V Timepoint(minutes) 0 25 40 60 H p 7.34±0.05 7.31±0.03 7.30±0.04* 7.32±0.04 O C a P 2(mmHg) 31.11±3.95 36.78±4.47* 41.11±9.32** 37.33±4.87** O C H 3ac.t(mmo/l)l 18.87±1.75 19.63±1.49* 20.03±1.56* 20.79±1.18** O a P 2(mmHg) 103.13±4.91 85.88±9.57* 268.00±29.87* 84.25±13.96* O t a S 2(%) 97.14±0.60 94.29±1.62 98.90±1.84 94.19±4.02 )l /l o m m ( E B S 7.53±2.27 6.18±2.28* 5.51±3.07* 4.68±1.76*
Medycyna Wet. 2010, 66 (1) 40
Conclusions
Intravenous midazolam proved useful as an induc-tion agent for inhalainduc-tion anaesthesia. The dose used was dependent on the animals reaction. Induction of anaesthesia by midazolam was successful and enabled endotracheal intubation. The application of midazo-lam with halothane, however, led to transitory distur-bances in systemic acid-base balance due to gas exchange abnormalities. The median effective dose of midazolam for the induction of anaesthesia was 0.46 mg/kg. Postoperatively, a full recovery of conscious-ness and motor functions was rapidly achieved in all dogs. Further studies on midazolam as an intravenous induction agent for inhalation anaesthesia in the dog are warranted.
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Authors address: dr hab. Ireneusz Balicki, ul. G³êboka 30, 20-612 Lublin; e-mail: irbal@poczta.onet.pl
