Abstract
The cardiovascular changes associated with anesthesia induced and maintained with romifidine/ketamine versus xylazine/ketamine were compared using 6 horses in a cross over design. Anesthesia was induced and maintained with romifidine (100 μg/kg, IV)/ketamine (2.0 mg/kg, IV) and ketamine (0.1 mg/kg/min, IV), respectively, in horses assigned to the romifidine/ketamine group. Horses assigned to the xylazine/ketamine group had anesthesia induced and maintained with xylazine (1.0 mg/kg, IV)/ketamine (2.0 mg/kg, IV) and a combination of xylazine (0.05 mg/kg/min, IV) and ketamine (0.1 mg/kg/min, IV), respectively. Cardiopulmonary variables were measured at intervals up to 40 min after induction. All horses showed effective sedation following intravenous romifidine or xylazine and achieved recumbency after ketamine administration. There were no significant differences between groups in heart rate, arterial oxygen partial pressures, arterial carbon dioxide partial pressures, cardiac index, stroke index, oxygen delivery, oxygen utilization, systemic vascular resistance, left ventricular work, or any of the measured systemic arterial blood pressures. Cardiac index and left ventricular work fell significantly from baseline while systemic vascular resistance increased from baseline in both groups. The oxygen utilization ratio was higher in the xylazine group at 5 and 15 min after induction. In conclusion, the combination of romifidine/ketamine results in similar cardiopulmonary alterations as a xylazine/ketamine regime, and is a suitable alternative for clinical anesthesia of the horse from a cardiopulmonary viewpoint.
Résumé
Les changements cardio-vasculaires associés à une anesthésie induite et maintenue avec la combinaison romifidine/ketamine ou la combinaison xylazine/ketamine ont été comparés chez 6 chevaux dans une étude avec schéma d’expériences croisées. Chez les chevaux du groupe romifidine/ketamine, l’anesthésie a été induite et maintenue, respectivement, avec romifidine (100 μg/kg, IV)/ketamine (2,0 mg/kg, IV) et ketamine (0,1 mg/kg/min, IV). Chez les chevaux du groupe xylazine/ketamine, l’anesthésie a été induite et maintenue, respectivement, avec xylazine (1,0 mg/kg, IV)/ketamine (2,0 mg/kg, IV) et une combinaison de xylazine (0,05 mg/kg/min, IV) et ketamine (0,1 mg/kg/min, IV). Les variables cardio-pulmonaires ont été mesurées à intervalles jusqu’à 40 min après l’induction. Tous les chevaux ont montré une sedation suite à l’administration intraveineuse de romifidine ou xylazine et étaient en décubitus après administration de ketamine. Aucune difference significative entre les groupes n’a été notée pour le rythme cardiaque, les pressions artérielles partielles en oxygène, les pressions artérielles partielles en dioxyde de carbone, l’index cardiaque, l’index systolique, l’apport en oxygène, la résistance vasculaire systémique, le travail du ventricule gauche, ou toutes les mesures des pressions artérielles sanguines systémiques. Dans les deux groupes, l’index cardiaque et le travail du ventricule gauche diminuèrent significativement par rapport aux données de base, alors que la résistance systémique vasculaire augmenta par rapport aux données de base. Le ratio d’utilisation de l’oxygène était plus élevé dans le groupe xylazine 5 et 15 min suivant l’induction. En conclusion, la combinaison romifidine/ketamine produit des modifications cardio-pulmonaires similaires à la combinaison xylazine/ketamine, et d’un point de vue cardio-pulmonaire est une alternative valable pour l’anesthésie clinique chez le cheval.
(Traduit par Docteur Serge Messier)
Introduction
In clinical practice, induction of anesthesia in adult horses is achieved exclusively through the administration of intravenous agents. In field situations anesthesia is generally maintained with injectable agents, whereas in a hospital setting the maintenance of anesthesia is often achieved using an inhalant system. The duration of action and quality of induction and recovery with a novel anesthetic anesthetic protocol are qualities that are important when a regime is evaluated for field use. At the same time, a protocol must produce minimal, or at least tolerable, cardiopulmonary changes to reach baseline requirements for consideration as an alternative to existing regimes.
Numerous combinations of agents have been employed in the equine for induction of anesthesia (1). In the last 15 y the greatest interest and emphasis for equine field anesthesia have been on various combinations of an α2-adrenergic agonist sedative/analgesic with a phencylidine (2–7). Cardiopulmonary investigations involving such combinations have been published and have shown favorable responses compared to the previous barbiturate-based anesthetic regimes (2). Xylazine/ketamine (X/K) was the first reported combination of this type (8) and remains the standard field anesthetic technique in North America (1).
Romifidine is the latest of the α2-adrenergic agonists to be developed as an equine sedative and preanesthetic agent (9–11). First studied in Germany, romifidine is presently licensed for use in horses in parts of Europe, the United Kingdom (UK), Canada, and Australia. The longer duration of action and the reduced ataxia horses demonstrate under romifidine sedation, when compared to xylazine, have raised interest in its usefulness as a preanesthetic agent (6,12–15). It has been demonstrated in horses, that diazepam/ketamine induced anesthesia following romifidine sedation resulted in an equivalent quality of anesthesia with a longer duration compared to that following xylazine premedication (9). Several studies have compared the cardiopulmonary effects of anesthesia maintained with halothane following romifidine or detomidine sedation in the horse (12,14). To date however, there has been no in depth comparative investigation evaluating the hemodynamic and respiratory effects of anesthesia induced and maintained with romifidine and ketamine versus xylazine and ketamine in the horse. The objective of this study was to determine the cardiopulmonary effects of a romifidine/ketamine (R/K) combination and to compare those changes to the alterations induced by X/K in horses. Anesthesia was maintained in horses in this study with an infusion of ketamine, with or without an α2-agent, to permit sequential cardiopulmonary measurements during a period of stable anesthesia, rather than as a design for a field anesthetic technique.
Materials and methods
Horses and experimental preparation
Six healthy horses ranging in age from 4 to 12 y and weighing between 406 to 515 kg (mean and standard error of means [sχ̄], 467 ± 16 kg) were used in this study. Horses were housed indoors for a minimum of 18 h prior to testing, of which the last 8 h were without feed. Access to water was provided until testing commenced. The institutional Animal Care Committee approved the experimental protocol and the guidelines by the Canadian Council on Animal Care were followed throughout the study.
Instrumentation and baseline measurements took place in standard equine stocks. Three 22 gauge stainless steel wires were placed sub-dermally under local anesthesia, in a standard base-apex position. Copper alligator clips were attached to the wires to permit lead I ECG recording. A 4-channel oscilloscope monitor system (PhysioControl VSMI; PhysioControl Corporation, Redpond, Washington, USA) recorded the electrocardiogram continuously. Two 8.5 F introducer catheters (Arrow Percutaneous Sheath Introducer Set; Arrow International, Reading, Pennsylvania, USA) were placed in a jugular vein to permit placement of catheters manufactured from 1.77 mm internal diameter polyethylene tubing in the right atrium and pulmonary artery (PE-260 Intramedic Polyethylene Tubing; Becton Dickinson, Parsippany, New Jersey, USA). The position of all intravascular catheters was determined by observation of the characteristic pressure waveform. The right atrial catheter was used to record right atrial pressures and to act as an intravenous (IV) access for drug administration. Mixed venous blood samples were collected from the pulmonary artery catheter. A 3rd introducer catheter was placed in the opposite jugular vein to allow insertion of a 130 cm long, 7 F thermistor catheter (Swan Ganz Flow Directed Thermodilution Catheter; American Edwards Laboratories, Irvine, California, USA) into the pulmonary artery. This catheter was used to record pulmonary artery pressure (PAP), body temperature, and measure cardiac output. Cardiac output was measured using a thermodilution technique, as previously described (16), with a computer system (Edwards Critical Care Cardiac Output Computer Model COM-2, version 2.2; Baxter Healthcare Corporation, Santa Ana, California, USA). Measurements were performed a minimum of 3 times, using an injectate volume of 60 mL of iced 5% dextrose in water. All cardiac output measurements were taken at end-expiration.
A 20 gauge catheter, 5.1 cm length (Insyte-W; Deseret Medical, Sandy, Utah, USA), was placed in the transverse facial artery for direct measurement of systemic arterial pressures and to obtain arterial blood samples for gas analysis. Arterial and venous blood samples for gas analysis were taken simultaneously throughout the study at end-expiration. All blood gas samples were stored on ice and analyzed within 1 h on an automated blood gas analyzer (ABL 500, Radiometer A/S; Bach-Simpson, Copenhagen, Denmark). The blood gas analyzer was calibrated daily with reference liquid samples (Qualichek, Radiometer A/S; Bach-Simpson) and throughout the measurement period with precision gases. Blood gas values were corrected to body temperature and arterial and venous hemoglobin saturations were calculated using a formula based on equine values (17) and these were used in subsequent analyses. Blood samples for arterial and venous hemoglobin analysis were withdrawn from the blood gas syringe after thorough mixing and were analyzed on a spectrophotometer using the cyanohemoglobin method.
The Swan-Ganz pulmonary artery catheter, right atrial catheter, and transverse facial artery catheters were intermittently connected to disposable pressure transducer systems (Spectramed DTX Pressure Transducer System; Spectramed, Critical Care Division, Orcnard, California, USA) and connected to the 4-channel oscilloscope monitor system in order to record appropriate pressures. The zero reference point for blood pressure measurements was taken to be the scapulohumeral joint when the horse was in the standing position and the manubrium when the horse was in lateral recumbency. Calibration of the pressure recording system was carried out at the start and end of each experimental period using a mercury manometer.
Experimental protocol
Each horse underwent 2 test procedures, with a minimum of 7 d separating the trials. The X/K protocol included premedication with xylazine (Rompun; Haver, Bayvet Division, Etobicoke, Ontario), 1.0 mg/kg, IV, followed in 5 min by the administration of ketamine (Ketalean; MTC Pharmaceuticals, Cambridge, Ontario), 2.0 mg/kg, IV. Once the horse achieved recumbency, 0.1 mg/kg/min of ketamine and 0.05 mg/kg/min of xylazine for 30 min was infused by IV. The R/K protocol included premedication with romifidine (Sedivet; Boehringer Ingelheim, Burlington, Ontario), 100 μg/kg, IV, followed in 10 min by the administration of ketamine (Ketalean), 2.0 mg/kg, IV. With this latter protocol, once horses achieved recumbency, they received an IV infusion of 0.1 mg/kg/min of ketamine over 30 min.
After instrumentation, prior to induction of anesthesia, a stabilization period of 5 to 20 min was allowed depending on the time required to achieve an acceptable resting heart rate (HR), defined as being below 55 beats/min. The HR (determined from the EKG trace recorded over 30 s), the presence of arrhythmias (determined from the EKG trace recorded over 30 s), respiratory rate (RR), central venous pressure (CVP), pulmonary artery pressure (PAP), body temperature, and systemic arterial pressures (systolic arterial blood pressure [SBP], mean arterial blood pressure [MBP], diastolic arterial blood pressure [DBP]) were recorded 5, 10, 15, and 20 min prior to the administration of the appropriate premedication agent. The frequency of second-degree atrioventricular heart blocks recorded was expressed as the percent of horses showing any second-degree atrioventricular heart block at each measurement period. Specifically, an EKG recording was printed for 30 s at each measurement period and was subsequently examined for the presence of second-degree atrioventricular heart blocks. Arterial and mixed venous blood gas samples were collected into heparinized syringes (Aspirator; Marquest Medical Products, Englewood, Colorado, USA) from the facial artery catheter and pulmonary artery catheter, respectively, at 5 and 20 min prior to premedication. Cardiac output measurements were performed, 5 and 20 min prior to premedication. Values for all variables recorded prior to premedication were averaged to obtain a mean baseline value.
After the administration of xylazine or romifidine, the horses were moved a short distance from the stocks, to a padded stall with a rubber floor for induction of anesthesia and subsequent measurements. As the horses became recumbent after ketamine administration (time 0 min), they were positioned in left lateral recumbency and orotracheal intubation was performed using a 26 mm internal diameter non-cuffed endotracheal tube. Throughout the period of anesthesia, oxygen was administered at 15 L/min by passive insufflation through a 10 mm external diameter tube placed 40 cm into the endotracheal tube.
Recording of HR, ECG sampling, RR, and blood pressures measurements were performed 2 and 5 min after the administration of ketamine, and at 5 min intervals thereafter until 40 min after the ketamine bolus administration. Cardiac output measurements, the recording of body temperature, and the collection of blood gas samples were included in the measurements recorded 5, 15, 25, and 40 min after ketamine administration. After the 40 min recording, the catheters and ECG leads were disconnected from the recording devices and the horses were allowed to recover.
Variables derived from the measured variables using methods previously described included, cardiac index (CI), stroke index (SI), left ventricular work (LVW), systemic vascular resistance (SVR), oxygen content of arterial blood (CaO2), oxygen content of mixed venous blood (CvO2), oxygen delivery (DO2) and oxygen uptake (VO2), and the oxygen utilization ratio (VO2/DO2) (18).
Statistical analysis
Statistical analysis of continuous data measured over time was performed using analysis of variance (ANOVA) for repeated measures with treatment and time as the main effects while controlling for animal effect, period, and carryover. In analyses that demonstrated a significant effect on time, a Dunnett’s test was performed. When a treatment-time interaction was present, a Tukey’s test was performed.
Results
All horses were effectively sedated after IV administration of romifidine or xylazine and achieved recumbency after ketamine administration. The depth of anesthesia permitted intubation in all horses under both regimes. The duration of anesthesia was such that cardiopulmonary measurements were possible for 35 min in 2 of the 12 trials and for 40 min in the remaining trials.
There were no differences between groups at baseline or at any subsequent time period for HR, SBP, MBP, DBP, PAP, CVP, SVR, and LVW (Table I, Figure 1). The percentage of horses that exhibited second-degree heart blocks at each sampling period ranged from 20% to 50% in the R/K group and from 0% to 20% in the X/K group. No other arrhythmias were observed. In general, there were significant changes in HR, SBP, MBP, DBP, and PAP in both groups after induction relative to baseline for variable periods of time. Specifically, relative to baseline, HR was lower in both the R/K and X/K groups from 2 to 40 min. In the X/K group, SBP was increased at 30 and 35 min, MBP was increased from 30 to 40 min, and DBP was elevated from 30 to 40 min relative to baseline. In the R/K group, SBP was increased at 2 min and DBP was increased at 2 and 5 min relative to baseline. At 2 and 5 min, PAP was higher than baseline in the R/K group. The CVP was increased at 5 to 40 min in both the R/K and X/K groups relative to baseline. Similarly, SVR was higher than baseline values in the R/K group at 5, 15, and 25 min, while the X/K group had a SVR higher than baseline from 5 to 40 min. The LVW was lower than baseline values at 5, 15, 25, and 40 min in both treatment groups.
Table I.
Hemodynamic variables following romifidine (100 μg/kg)/ketamine (2.0 mg/kg) induction, then maintained with ketamine (0.1 mg/kg/min) or xylazine (1.0 mg/kg)/ketamine (2.0 mg/kg) induction, followed by maintenance with xylazine (0.05 mg/kg/min)/ketamine (0.1 mg/kg/min)a
| Time after ketamine administration (min) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Variable | Tx | Baseline | 2 | 5 | 10 | 15 | 20 | 25 | 30 | 35 | 40 |
| HR (bpm) | R/K | 35.5 ± 5.6 | 25.0b ± 5.1 | 24.7b ± 4.2 | 24.3b ± 5.1 | 24.7b ± 5.1 | 24.7b ± 5.1 | 24.7b ± 6.4 | 26.3b ± 5.9 | 27.6b ± 6.4 | 26.0b ± 4.4 |
| X/K | 37.6 ± 11.3 | 29.2b ± 5.9 | 28.7b ± 6.6 | 28.0b ± 7.1 | 27.0b ± 5.1 | 27.3b ± 5.1 | 27.3b ± 3.9 | 28.3b ± 2.4 | 31.0b ± 4.7 | 29.0b ± 1.5 | |
| SABP (mmHg) | R/K | 141.7 ± 18.4 | 162.2b ± 26.9 | 154.5 ± 18.6 | 155.8 ± 17.6 | 153.8 ± 16.2 | 155.5 ± 11.3 | 150.7 ± 18.9 | 148.7 ± 14.9 | 146.8 ± 18.9 | 142.0 ± 15.0 |
| X/K | 148.8 ± 16.4 | 148.5 ± 26.9 | 149.7 ± 22.8 | 159.7 ± 28.7 | 162.8 ± 30.1 | 163.2 ± 21.8 | 168.7 ± 21.8 | 183.5b ± 26.0 | 185.3b ± 20.8 | 177.0 ± 19.8 | |
| DABP (mmHg) | R/K | 95.4 ± 14.2 | 116.2b ± 14.5 | 116.8b ± 29.1 | 112.8 ± 25.2 | 117.1 ± 22.3 | 114.8 ± 26.2 | 114.2 ± 25.5 | 113.7 ± 19.1 | 110.8 ± 19.6 | 106.3 ± 15.2 |
| X/K | 98.3 ± 15.4 | 103.0 ± 34.0 | 110.8 ± 22.3 | 116.2 ± 25.2 | 120.0 ± 26.5 | 123.2 ± 19.8 | 123.8 ± 11.3 | 135.0b ± 9.6 | 135.3b ± 9.1 | 131.0b ± 13.5 | |
| CVP (mmHg) | R/K | 1.9 ± 2.0 | 14.3b ± 3.7 | 14.2b ± 3.2 | 14.7b ± 3.2 | 14.7b ± 2.5 | 14.2b ± 2.5 | 13.5b ± 2.5 | 13.0b ± 3.4 | 12.2b ± 3.7 | 12.0b ± 3.2 |
| X/K | 2.3 ± 3.4 | 11.5b ± 6.1 | 9.2b ± 5.1 | 10.7b ± 6.9 | 11.8b ± 7.8 | 12.0b ± 7.3 | 13.2b ± 6.9 | 13.8b ± 6.9 | 13.5b ± 6.1 | 13.8b ± 7.8 | |
| PAP (mmHg) | R/K | 22.7 ± 1.9 | 31.0b ± 4.9 | 29.0b ± 3.9 | 27.7 ± 4.2 | 27.0 ± 3.7 | 28.3 ± 4.9 | 26.8 ± 4.2 | 27.2 ± 4.6 | 27.4 ± 4.6 | 29.0 ± 4.2 |
| X/K | 27.6 ± 4.2 | 21.0 ± 9.8 | 22.8 ± 8.1 | 26.2 ± 6.6 | 27.0 ± 7.1 | 29.8 ± 7.3 | 29.7 ± 7.6 | 31.0 ± 7.1 | 31.2 ± 7.8 | 30.0 ± 9.6 | |
| SI (mL/kg/beat) | R/K | 1.6 ± 0.2 | ND | 1.1b ± 0.2 | ND | 1.2b ± 0.2 | ND | 1.5b ± 0.5 | ND | ND | 1.3 ± 0.2 |
| X/K | 1.5 ± 0.2 | ND | 1.1b ± 0.2 | ND | 1.1b ± 0.2 | ND | 1.1b ± 0.5 | ND | ND | 1.3 ± 0.2 | |
| SVR (dynes·sec·cm–5) | R/K | 357.3 ± 112.2 | ND | 752.6b ± 204.5 | ND | 670.7b ± 149.2 | ND | 563.1b ± 207.2 | ND | ND | 552.1 ± 81.6 |
| X/K | 386.6 ± 112.7 | ND | 665.6b ± 181.0 | ND | 744.9b ± 201.1 | ND | 733.2b ± 169.0 | ND | ND | 602.4b ± 129.8 | |
| LVW (kg·m/min) | R/K | 40.6 ± 10.5 | ND | 22.2b ± 5.9 | ND | 22.9b ± 5.4 | ND | 27.5b ± 12.2 | ND | ND | 25.0b ± 5.8 |
| X/K | 39.6 ± 10.8 | ND | 23.5b ± 7.8 | ND | 23.7b ± 5.4 | ND | 26.1b ± 4.4 | ND | ND | 34.8b ± 6.9 | |
HR — Heart rate; SBP — Systolic blood pressure; DBP — Diastolic blood pressure; CVP — Central venous pressure; PAP — Pulmonary artery pressure; CO — Cardiac output; SI — Stroke index; SVR — Systemic vascular resistance; LVW — Left ventricular work; R/K — Romifidine/ketamine; X/K — Xylazine/ketamine; ND — Not determined
Mean ± s, n = 6, except at 40 mins for the romifidine group when n = 4
Significant difference relative to baseline (P < 0.05)
Figure 1.
Mean arterial blood pressure (± s) and cardiac index (± s) at baseline (BL) and during romfidine/ketamine (R/K) and xylazine/ketamine (X/K) anesthesia (5 to 40 min).
a Significant differences relative to baseline within a treatment group.
↑ Arrow indicates the end of the anesthetic infusion.
The CI was similar between groups, although relative to baseline, both indices were lower 5, 15, 25, and 40 min (Figure 1). Stroke index was lower than baseline for both groups at 5 to 25 min (Table I).
At 5, 15, and 25 min, arterial and venous hemoglobin were increased in the R/K group relative to baseline values and the X/K group (Table II). Compared to the X/K group, the arterial hemoglobin was higher in the R/K group at 5 and 15 min, while the venous hemoglobin was higher at 5, 15, and 25 min. Arterial oxygen content was higher for the R/K group at 5, 15, and 25 min relative to baseline, while it was only higher than baseline at 5 min in the X/K group (Table II). Relative to baseline, the venous oxygen content was increased at 5 and 15 min in the R/K group and from 5 to 25 min in the X/K group. The DO2 and VO2 were similar between groups; however, DO2 and VO2 were lower than baseline values from 5 to 40 min after induction in both groups (Table II, Figure 2). The VO2/DO2 was higher for the X/K group at 5 and 15 min compared to the R/K group and higher than baseline in the X/K group at 5 and 15 min (Figure 2).
Table II.
Arterial and venous blood gas variables following romifidine (100 μg/kg)/ketamine (2.0 mg/kg) induction followed by maintenance with ketamine (0.1 mg/kg/min) or xylazine (1.0 mg/kg)/ketamine (2.0 mg/kg) induction followed by maintenance with xylazine (0.05 mg/kg/min)/ketamine (0.1 mg/kg/min)a
| Time after ketamine administration | ||||||
|---|---|---|---|---|---|---|
| Variable | Tx | Baseline | 5 | 15 | 25 | 40 |
| RR (breaths/min) | R/K | 25.2 ± 18.6 | 16.8 ± 6.6 | 21.0 ± 9.3 | 21.0 ± 13.5 | 22.0 ± 10.6 |
| X/K | 20.1 ± 7.8 | 14.2 ± 13.0 | 13.3 ± 7.3 | 14.2 ± 7.3 | 12.8 ± 3.4 | |
| pHa | R/K | 7.42 ± 0.02 | 7.41b ± 0.05 | 7.40b ± 0.02 | 7.42 ± 0.02 | 7.42 ± 0.04 |
| X/K | 7.43 ± 0.02 | 7.39b ± 0.05 | 7.40b ± 0.05 | 7.40 ± 0.02 | 7.43 ± 0.05 | |
| PaO2 (mmHg) | R/K | 92.3 ± 5.6 | 89.9 ± 25.2 | 97.1 ± 34.3 | 101.9 ± 34.3 | 90.1 ± 43.6 |
| X/K | 93.1 ± 13.2 | 118.3 ± 63.2 | 125.8 ± 76.2 | 100.8 ± 52.7 | 79.8 ± 23.8 | |
| PaCO2 (mmHg) | R/K | 42.2 ± 1.5 | 44.6b ± 8.3 | 45.5b ± 2.9 | 43.5 ± 4.9 | 43.8 ± 5.4 |
| X/K | 42.8 ± 1.7 | 48.3b ± 5.6 | 47.8b ± 6.6 | 48.2 ± 2.9 | 44.5 ± 6.4 | |
| Hba (g/L) | R/K | 112.4 ± 16.1 | 146.2b,c ± 7.1 | 138.5b,c ± 1.2 | 131.2b ± 3.9 | 123.0 ± 3.0 |
| X/K | 111.7 ± 8.6 | 120.8 ± 11.8 | 119.7 ± 7.8 | 120.5 ± 6.9 | 121.0 ± 9.1 | |
| PvO2 (mmHg) | R/K | 31.8 ± 3.7 | 29.2b ± 2.0 | 31.5b ± 3.9 | 30.0 ± 3.2 | 31.3 ± 6.8 |
| X/K | 31.4 ± 3.9 | 26.4b ± 2.4 | 26.2 ± 3.9 | 27.7 ± 3.2 | 29.4 ± 3.4 | |
| Hbv (g/L) | R/K | 111.8 ± 12.0 | 151.8b,c ± 15.2 | 141.8b,c ± 15.2 | 135.2b,c ± 6.6 | 118.3 ± 1.6 |
| X/K | 112.5 ± 6.9 | 115.0 ± 8.8 | 118.3 ± 6.6 | 119.3 ± 6.4 | 121.2 ± 6.6 | |
| CaO2 (mL/L) | R/K | 154.57 ± 22.34 | 198.63b ± 11.71 | 187.81b ± 7.67 | 179.47b> ± 7.42 | 164.95 ± 7.16 |
| X/K | 153.68 ± 12.39 | 166.26b ± 13.91 | 165.56 ± 7.78 | 162.95 ± 9.55 | 162.57 ± 12.46 | |
| CvO2 (mL/L) | R/K | 105.45 ± 9.28 | 133.37b,c ± 11.44 | 132.34b,c ± 12.81 | 123.11c ± 8.94 | 112.48 ± 13.66 |
| X/K | 107.18 ± 16.70 | 91.18b ± 12.54 | 91.54b ± 9.82 | 99.28b ± 11.83 | 109.34 ± 15.33 | |
| VO2 (L/min) | R/K | 1.30 ± 0.51 | 0.83b ± 0.32 | 0.77b ± 0.24 | 0.98b ± 0.46 | 0.80b ± 0.08 |
| X/K | 1.14 ± 0.24 | 1.05b ± 0.24 | 0.98b ± 0.17 | 0.89b ± 0.15 | 0.96b ± 0.12 | |
R/K — romifidine/ketamine; X/K — xylazine/ketamine; RR — Respiratory rate; pHa — arterial pH; PaO2 — arterial oxygen partial pressure; PaCO2 — arterial carbon dioxide partial pressure; Bea — arterial base excess; Hba — arterial hemoglobin; PvO2 — venous oxygen partial pressure; Hbv — venous hemoglobin; CaO2 — arterial oxygen content; CvO2 — venous oxygen content; VO2 — oxygen utilization
Mean ± s, n = 6 except at 40 min when n = 4 for the R/K group
Significantly different from baseline (P < 0.05)
Significantly different from X/K (P < 0.05)
Figure 2.
Mean oxygen delivery (± s) and the oxygen utilization ratio (± s) at baseline (BL) and during romfidine/ketamine (R/K) and xylazine/ketamine (X/K) anesthesia (5 to 40 min).
a Significant differences relative to baseline within a treatment group.
b Significant differences between treatment groups.
↑ Arrow indicates the end of the anesthetic infusion.
Respiratory rate, PaO2, SaO2, PaCO2, and pHa showed no difference between treatment groups, although variables did change within a group relative to baseline values (Table 2).
Discussion
The observed hemodynamic and respiratory changes with the R/K combination were generally quite similar to the changes recorded with X/K in this study, and are comparable to other investigators reports with this type of anesthetic regime (2,7,8). The anesthetic protocols in this study differed not only in the α2-agonist used, but also in the length of time between the α2-agonist and ketamine administration and in regards to the contents of the anesthetic maintenance regimes. A longer period of time between α2-agonist and ketamine administration was used in the R/K group compared to the X/K group based on previous recommendations regarding the use of detomidine as a preanesthetic agent and the similar clinical characteristics of romifidine and detomidine (4,5,10). Specifically, Matthews and coworkers (5) reported an improved quality of induction with a 15 to 25 min interval versus the traditionally used 5 min interval between detomidine and ketamine administration. Based on our clinical experience with the use of romifidine as a preanesthetic agent and in an effort to minimize the impact of differences in protocols on subsequent cardiopulmonary measurements, we elected to use a 10 min interval between romifidine and ketamine in this investigation. As mentioned, maintenance of horses on an infusion of ketamine, with or without an α2-agent, was performed in this study to permit sequential cardiopulmonary measurements during a period of stable anesthesia, rather than as a design for a field anesthetic technique. For this study, we chose not to administer additional romifidine during the ketamine infusion period for the R/K group, in contrast to the xylazine given during the same period in the X/K group. This decision was based on the markedly longer period of sedation produced with romifidine versus xylazine (10) and the longer period of surgical anesthesia produced by romifidine/diazapem/ketamine versus xylazine/diazepam/ketamine, as shown in a previous study carried out in our laboratory (9). Recumbency periods are as short as 10 min following xylazine/ketamine single dose administration, a period of time that is too short to safely obtain stable thermodilution CO measurements. Using the chosen infusion regime, all horses remained recumbent for at least 35 min, which was a minimum of 5 min after the administration of ketamine or ketamine/xylazine infusion was terminated. The potential impact of the different infusion regimes used for the maintenance of anesthesia on the measured cardiopulmonary variables is discussed below.
A common response to intravenous administration of α2-adrenergic agonists is a marked reduction in HR frequently accompanied by second-degree heart blocks (3,7,11,19,20). When the administration of the α2-agonist is followed by an IV bolus of ketamine or tiletamine-zolazepam, however, HR tends to increase to an acceptable level and rhythm disturbances resolve (2,3,7,8,21,22). Mean rates for both groups fell into the 25 to 30 beats/min range following induction of anesthesia, values traditionally accepted as adequate during general anesthesia (23). There were individuals in both groups, however, whose rates fell as low as 18 beats/min. The frequency of rates below 25 beats/min was greater with R/K, with 3 of the 6 horses falling into this category at some point from 2 to 25 min of anesthesia, while only 1 of the 6 in the X/K group had rates less than 25 beats/min in this time interval. The bradycardia that is observed within minutes of administering an α2-agent intravenously is a result of an increase in parasympathetic tone on the heart. This latter increase is a result of a peripheral α2-receptor mediated increase in arterial blood pressure. The temporal pattern of a hypertensive response, followed within 2 min by bradycardia that can be blocked by anticholinergic agents, is strong support for parasympathetic mediated bradycardia (11,21). A reduced sympathetic outflow secondary to centrally mediated inhibition of norepinephrine release by presynaptic α2-receptor activation has also been suggested to contribute to the reduction in heart rate observed following α2-agonist administration (24). At this time, it is still controversial whether the cardiovascular effects of bradycardia warrant therapy with anticholinergics in horses (19).
Statistical analysis was not performed on the frequency of heart block due to the nature of the data (discrete data) and the small sample size. However, it is interesting to note the trend towards a higher frequency of heart blocks in the horses receiving romifidine compared to xylazine. Unfortunately few studies report the relative incidence of second-degree heart blocks with different α2-agonists and their significance on outcome is unknown. Second-degree heart blocks are observed in normal horses at rest and are considered to be a result of an increase in parasympathetic nervous system activity on the myocardial conduction pathyways rather than underlying structural cardiovascular disease (11,20). The presence of seconddegree heart blocks following the administration of α2-agonists, however, may result in a reduction in ventricular rate and may, therefore, contribute to a reduction in cardiac output.
Reports on cardiopulmonary changes associated with infusions of intravenous anesthetics vary with the specific drug combinations utilized, induction techniques, and instrumentation methods; however, they provide an interesting comparison for the experimental groups in this investigation (22,25,26). Greene and colleagues (25) performed the first in-depth cardiopulmonary evaluation on intravenous maintenance anesthesia in ponies. In this study, ponies received a mixture containing 2.3 mg/kg/min of guaifenesin, 0.025 mg/kg/min of xylazine, and 0.05 mg/kg/min of ketamine, whereas, in our investigation, horses induced with X/K received 0.05 mg/kg/min of xylazine and 0.1 mg/kg/min of ketamine, or 0.1 mg/kg/min of ketamine alone if induced with R/K. The ponies in the study by Greene and coworkers (25) showed no change in HR over the 120 min that they were maintained on an infusion. Unfortunately, the ponies were acutely instrumented under halothane/nitrous oxide anesthesia and baseline measurements were taken between inhalant and intravenous general anesthetics. In a similar maintenance protocol in a clinical investigation using 40 horses, Young and coworkers (26) observed that HR was decreased from the baseline values at 30 to 50 min during anesthesia, regardless of induction technique. Considering the longer-acting nature of romifidine and the higher dose of xylazine contained in the infusion in our study the lower HR observed in both groups during the anesthetic period is not unexpected and is consistent with the heart rates observed by McMurphy and coworkers (22), who evaluated a romifidine, guaifenesin, and ketamine combination in horses.
Consistent with previous reports involving α2-agonist/ketamine combinations, systemic blood pressures were well maintained in both treatment groups in this study (3,7–9,22). Several factors likely contributed to this latter outcome including an increase in systemic vascular resistance secondary to peripheral vasoconstriction associated with the intravenous administration of the α2-agonists (20). Ketamine, with its sympathomimetic effects, undoubtedly also contributed to the maintenance of pressures observed during the continuous infusion in both experimental groups in the present study. Investigators performing direct arterial measurements have shown mean arterial values ranging from 130 to 140 mmHg 5 min after induction of anesthesia with X/K in horses, which are very similar to the mean pressures of 128 and 118 mmHg reported with R/K and X/K in this study (3,8). Slightly lower values in this study may be attributed to the increased depth of anesthesia associated with the continuous infusion of drugs. In this study, 5 min after induction, the MBP in the R/K group was slightly higher than that of the X/K group. The former group of horses received no further administration of the α2-agonist during the infusion period, yet pressures never fell significantly below those of the xylazine group, suggesting the duration and potency of vasoconstriction with romifidine may be greater than that of xylazine. The X/K group in the present investigation showed a trend of increasing systemic arterial pressures after induction over the study period. As xylazine was included in this group’s maintenance infusion, the hypertensive effect of the α2-agonist likely contributed to the increase in pressures observed.
Central venous pressure, a measure of preload, increased in both groups to values previously reported with X/K (8). When used for sedative purposes, the α2-agents have been reported to markedly increase CVP, a response attributed to their bradycardic and venoconstrictive effects (8,20,27). An increase in SVR can occur secondary to an increase in sympathetic tone, stimulation of α-receptors in the periphery, or both. In the present study SVR increased to values close to double those of baseline values 5 min after induction and remained greater than 1.75 times the baseline values throughout the infusion period, thus maintaining systemic blood pressure despite decreased CI.
Cardiac index fell to approximately 50% to 55% of baseline values subsequent to the administration and the onset of recumbency with both regimes. The maintenance of SI at close to baseline values, despite a large fall in CI, suggests that bradycardia was the major source of the fall in CI. Muir and co-workers (8) reported a similar trend of decreasing HR, and maintenance of blood pressure with a fall in CI in horses induced with X/K. Values of CI in that study were markedly higher at baseline than those measured in the present investigation. In evaluating CI in conscious animals, close attention to resting HR and blood pressure is important, since excitement or nervousness in the animals at baseline recording may falsely elevate measured values. Muir and co-workers (8) actually describe the values obtained after induction with X/K as being more representative of resting values than their baseline values, due to mild excitement of their horses prior to induction. Cardiac index as measured by Greene and co-workers (24) in ponies on an infusion of X/K in guaifenesin followed the same pattern, with a significant fall after induction and a slow increase back to baseline. Left ventricular work, as calculated in the present study, fell as expected with a decrease in CI in both groups, since there was relatively little fluctuation in mean arterial pressures.
Hypoxemia and hypercarbia have both been shown to influence hemodyamics in horses under general anesthesia (28). Tracheal oxygen insufflation was provided to the horses during this investigation to increase the inspired oxygen content and minimize the probability of hypoxia occurring, since this could confound interpretation of cardiovascular changes. Maintenance of arterial hemoglobin saturation above 90% was achieved in all horses. It was elected not to support ventilation in horses in this study due to the confounding effects of intermittent positive pressure ventilation (IPPV). Fortunately, mean PaCO2 levels in this investigation remained below 50 mmHg in both groups, levels that should have minimal influence on the measured cardiovascular parameters. Arterial and venous oxygen contents were well maintained for both treatment groups, with the R/K group showing an increase in both parameters after induction relative to baseline. Arterial hemoglobin values paralleled this increase and is the major source contributing to the increased oxygen carrying capacity in this group. Previous investigations have reported decreases in the packed cell volume in horses following administration of xylazine; detomidine; or infusions of romifidine/ketamine/guaifenesin (20,22), which has been attributed to interstitial fluid redistribution into the vascular space, splenic sequestration of red blood cells due to a decrease in splenic sympathetic nerve activity, or both. The mechanism responsible for the increase in hemoglobin observed in the R/K group in this study is unknown; however, one could speculate that the degree of sympathetic inhibition was increased during anesthesia in this group, in part due to the lack of an α2-agonist in the maintenance infusion regime.
As a measure of the direct myocardial effects of anesthetic regimes, CI, SI, and LVW are poor criteria. They are influenced heavily by factors such as HR, preload, and afterload. Current research using more sophisticated indices for myocardial performance would suggest that α2-adrenoceptor activation does not produce an inherent reduction in myocardial performance (29). From a clinical point of view, perhaps the most important issue is in regard to the adequacy of tissue oxygen delivery, preferably at individual tissue regions. Measurement of regional tissue oxygen supply requires a very invasive study and is not, generally, performed. Knowledge of CO, along with arterial and venous oxygen contents, permits the calculation of DO2 and VO2 to allow for evaluation of global oxygen adequacy. With the consistency in the calculated oxygen contents (CaO2), DO2 paralleled CI showing a marked fall after the induction of anesthesia in both treatment groups. In the R/K group, VO2 tended to decrease, albeit insignificantly, and in the X/K group, this parameter changed little. Consequently, VO2/DO2 was significantly higher for the X/K group during anesthesia. In regard to the relatively higher VO2/DO2 values, mixed venous oxygen tension tended to be lower in the X/K group compared to the R/K group, although differences were not statistically significant. Presumably, this difference in the oxygen utilization ratio and the lower mixed venous oxygen tension in the X/K group are reflective of a less favorable oxygen supply versus utilization situation, than observed with R/K.
In conclusion, as used in the present study, a combination of R/K results in similar cardiopulmonary alterations as a X/K regime, and is a suitable alternative for clinical anesthesia of the horse from a cardiopulmonary viewpoint. Romifidine/ketamine produced a fall in HR and maintenance of systemic arterial pressures, while CI fell. The oxygen utilization ratio was well maintained with this regime and deterioration in respiratory function was minimal when horses were maintained on room air with oxygen insufflation.
Footnotes
Funding for the project was provided by Boehringer Ingelheim, Canada.
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