Total Intravenous Anesthesia in Association with a Constant Rate Infusion of Fentanyl-Lidocaine-Ketamine in Female Dogs
Corresponding author: Monzem S, College of Veterinary Medicine, Federal University of Mato Grosso, (Fernando Corrêa da Costa avenue, nº 2367 – 78060- 900, Cuiabá, Mato Grosso) Brazil. Email: email@example.com
Fentanyl, lidocaine, or ketamine can be used in association with a total intravenous anesthesia (TIVA) with propofol [1-3]. The use of fentanyl-lidocaine-ketamine (FLK) reduced the minimum alveolar concentration of isoflurane by 97% in dogs  and fentanyl (loading dose [LD] 0.005 mg kg-1 and constant rate infusion [CRI] 0.0001 mg kg-1 hr-1) decreased the propofol induction dose and the minimum infusion rate (MIR) in dogs . Lidocaine (LD 1.5 mg kg-1 and CRI 15 mg kg-1 hr-1) did not reduce the MIR of propofol . The combination of lidocaine (LD 1.5 mg kg-1 and CRI 15 mg kg-1 hr-1) with ketamine (LD 1 mg kg-1 and CRI 6 mg kg-1 hr-1), however, reduced the MIR by 37%, but cardiovascular depression could not be avoided . In dogs, a CRI of propofol-ketamine (1:1 mg mL-1) promotes a significant reduction in the propofol CRI, with an elevated heart rate and mean arterial pressure; however, it worsens pulmonary function .
In this study, we tested the hypothesis if FLK can be associated with a propofol CRI, and if this combination could avoid perisurgical cardiopulmonary depression. The aim of this work was to evaluate the cardiopulmonary parameters of female dogs which were anesthetized with a propofol TIVA, combined with a CRI of FLK while undergoing an ovariohysterectomy.
Materials and methods
This study was conducted in agreement with the Ethical Principles for Animal Research, established by the National Council for Control of Animal Experimentation. This project was approved by the Institutional Committee for ethics in the use of Animals (Federal University of Mato Grosso-UFMT), number 23108.036572/14-0.
Eight female mongrel dogs (Mean values ± standard deviation of age =2±1 years, and weight = 12±6 kg), originating from the Veterinary Hospital of the Federal University of Mato Grosso underwent ovariohysterectomies. The animals were selected after client permission, as well as clinical and laboratory examination; importantly, all animals were classified as American Society of Anesthesiology class I. They were hospitalized 24 h prior to the procedure to clip the hair for surgical access, in the cranial aspect of the thoracic limbs for venous access, and on the medial aspect of the tarsus and metatarsus of the pelvic limb for arterial access.
After 12 hours of continuous fasting and no water for six hours, the following baseline parameters were recorded: heart rate (HR), via auscultation with a stethoscope; respiratory rate (fR), by counting the movements of the intercostal muscles; systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressures, using the noninvasive oscillometric method (petMAP® Ramsey Medical Inc. and Cardio Command Inc, Tampa, Florida, USA). Arterial blood from the femoral artery was collected anaerobically and percutaneously using a heparinized syringe, in order to immediately measure the arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), arterial pH, and bicarbonate (HCO3), using the hemogasometry apparatus (Cobas 121b, Roche Diagnóstica Ltda, Taquara, Rio de Janeiro, Brazil). Premedication with 0.03 mg kg-1 of intramuscular acepromazine (Acepran® Vetnil, Louveira, São Paulo, Brazil) was administered in semitendinosus. After 30 minutes, the venous accesses were obtained aseptically by the insertion of 20 G catheters in the left and right cephalic veins. Antibiotic prophylaxis was performed using 30 mg kg-1 of intravenous (IV) cephalothin sodium (ABL antibióticos do Brasil, São Paulo, SP, Brazil).
The loading dose of FLK 0.0036 mg kg-1 of fentanyl (Fentanest® Cristália, São Paulo, São Paulo, Brazil), 3 mg kg-1 lidocaine (Xylestesin® Cristália, São Paulo, São Paulo, Brazil), and 0.6 mg kg-1 ketamine (Ketamin® Cristália, São Paulo, São Paulo, Brazil)] was administered IV over 60 seconds in the same syringe. This was immediately followed by the induction of anesthesia using propofol (Propovan® Cristália, Brazil) until the loss of the eyelid reflex and rotation of the medioventral rotation of the eye were observed; then, the CRI of FLK was started, using 0.0036 mg kg-1 hr-1 of fentanyl, 3.0 mg kg-1 hr-1 of lidocaine, and 0.6 mg kg-1 hr-1 of ketamine, concomitant with 0.24mg kg-1 minute-1 of propofol CRI. The FLK was diluted in 500 mL of Lactated Ringer’s solution, such that the solution contained 0.18 mg fentanyl, 150 mg lidocaine, and 30 mg ketamine, and was infused using a peristaltic infusion pump (Pump: 600I Mindray Veterinary. Nanjing, Jiangsu, China) through the right cephalic vein at a rate of 10 mL kg-1 hr-1. The propofol CRI was infused using a syringe infusion pump (Insight: EFF311, Insight Equipamentos Científicos, Ribeirão Preto, São Paulo, Brazil.) through the left cephalic vein. After tracheal intubation with an orotracheal tube, the animal was connected to a circle rebreathing delivery system with 100% oxygen at 1 L minute-1 and maintained under spontaneous ventilation.
Anesthetic Monitoring and Maintenance
A multi-parameter monitor (Dash 4000, GE Healthcare, Milwaukee, Wisconsin, USA) was used for the measurement of cardiopulmonary parameters during the intraoperative period. The sidestream capnograph was positioned between the orotracheal tube and the breathing system to measure end-tidal carbon dioxide levels (EtCO2) and fR. A pulse oximeter was placed on the tongue to measure arterial hemoglobin oxygen saturation (SaO2). A percutaneous catheter was inserted in the metatarsal artery, which was connected to a disposable transducer, flushed with heparinized saline solution, and zeroed to atmospheric pressure at the height of the manubrium to measure the HR, SAP, DAP, and MAP. The cardiopulmonary variables and dose of propofol CRI were repeatedly measured intraoperatively and were recorded at 5 (T5) and 15 (T15) minutes after anesthetic induction, after skin (T20) and musculature (T30) incision, during clamping of the left (T40) and right (T50) pedicle, and the body of the uterus (T60), at the end of closure of the abdominal wall (T70), and at the end of skin suturing (T80). An arterial blood gas analysis was performed at T50 and T80.
The propofol CRI was increased (0.1 mg kg-1minute-1) or decreased (0.05 mg kg-1minute-1) to maintain the surgical anesthetic plane, with goals of an absent eyelid reflex, rotation of the eyeball medially, and an absence of movement, this was in addition to maintenance of cardiovascular variables within the physiological values of the species. All CRI infusions were discontinued at the end of surgery and the animals were monitored each 60 minutes through Glasgow scale for the next six hours. After 0.02 mg kg-1 of meloxicam (Ouro Fino, Cravinhos, SP, Brazil) was administrated subcutaneously.
Statistical analyses were performed using R software (2013, version 3.2.0). An analysis of variance was performed, followed by the Kolmogorov-Smirnov test for the normality of errors, and the Scott-Knott test for the comparison of means across time points. The differences were considered to be significant when p <0.05.
Propofol CRI rate, HR, SaO2, EtCO2 and HCO3 were not significantly different across time points (Table 1). Arterial blood pressures decreased from the baseline values. SAP decreased between T5-T30 and increased thereafter from T40-T80, but remained below baseline values. DAP only decreased between T5-T30. MAP decreased between T5-T30 and T70-T80 (Table 1).
fR decreased from baseline between T5-T15 and T60-T80. PaCO2 increased from the baseline value, PaO2 increased at T50 and T80, and pH was consistently lower than the baseline value (Table 1).
Table 1: Mean values ± standard deviation of intraoperative variables in female dogs which underwent an elective ovariohysterectomy under total intravenous anesthesia performed with a loading dose of fentanyl-lidocaine-ketamine (0.0036; 3.0 and 0.6 mg kg-1 , respectively) followed by propofol induction and a continuous infusion of propofol and fentanyl-lidocaine-ketamine (0.0036; 3.0 and 0.6 mg kg-1 hr-1 respectively). Different letters at the same line indicate difference among time.
Baseline: Baseline values; (T5 and T15): 5 and 15 minutes after anesthetic induction; (T20 and T30) after skin and musculature incision, (T40, 50, and 60) during clamping of the pedicle of the left, right, and body of the uterus; (T70 and T80) end of laparorrhaphy and of skin suture.
Abbreviations: propofol constant rate infusion (propofol CRI), heart rate (HR), systolic arterial blood pressure (SAP), diastolic arterial blood pressure (DAP), mean arterial blood pressure (MAP), respiratory rate (fR), arterial hemoglobin oxygen saturation (SaO2), end-tidal carbon dioxide levels (EtCO2), arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), arterial pH (pH), bicarbonate (HCO3).
In the present study the doses used for the FLK were based on the study by Aguado et al. . And the initial dose for propofol CRI was reduced by 30% compared with the dose reported by Gasparini et al . Who used a CRI of propofol at 0.34 mg kg-1 minute– associated with ketamine. This reduction was enough for maintaining of anesthetic plane and not needed to be increased. The mean propofol CRI across all time points, in our study, was 0.24±0.1 mg kg-1 minute-1, which is less than the doses previously described by Gasparini 2009  and Intelisano 2008  (0.37 mg kg-1 minute-1) for the association of propofol and ketamine in an ovariohysterectomy. Furthermore, FLK is a multimodal analgesia because of block different receptors in the pain pathway [8, 9]. And because of this analgesic mechanism requires a CRI of propofol lower than other studies.
The arterial blood pressure decreased after the loading dose of FLK and the initial induction with propofol; the reduction of this parameter by these drugs has been cited as a characteristic of TIVA [5, 2]. When the effect of the loading dose and induction diminished, and traction was applied to the pedicle during clamping, the arterial blood pressure increased as a consequence of a higher autonomic response [6, 9, 10]. These values were not considered to be indicative of excessive hypotension, or hypertension because SAP and MAP were <160 or <140 mmHg and >80 or >60 mmHg, respectively . And are not closely with pain because of the animals was under surgical anesthetic plane, the blood pressure increased but HR and the CRI of propofol did not increased .
The increase at PaO2 happened because of the increase in fraction of O2 given through circle rebreathing delivery system with 100% of O2 . SaO2 demonstrated that animals did not have hypoxia, but the loading dose of FLK combined with propofol induction depressed fR; the blood gas analyses showed respiratory depression . The values of PaCO2 were high, but acceptable; the increase induced respiratory acidosis with a consequent drop in pH and increase in bicarbonate as a compensatory mechanism [6, 11, 12]. Notably, FLK and TIVA depress the respiratory center and may be cited as the primary cause of respiratory acidosis .
A limitation of the study is that we attempted to measure baseline values for invasive blood pressure, using anesthesia with propofol to perform arterial access one day before the procedure; however, this failed because in some cases we lost the signal of the artery. Moreover, the anesthesia with propofol could interfere in obtaining a true baseline measurement. Despite being known that ocillometric pressure is not the gold standard this technic was chosen to measure baselines values because of is not trustworthy with invasive blood pressure during hypotension, and baselines blood pressure values for health animals are not hypotension .
FLK CRI combined with propofol TIVA resulted in depressed pulmonary function, concomitant with light hypotension in dogs undergoing elective surgery. However, this may be a suitable protocol for TIVA if the intraoperative parameters are closely monitored.
The present work was carried out with the support of the coordination of improvement of personnel of superior level – Brazil (CAPES) and Veterinary Hospital of Federal University of Mato Grosso.
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