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Evaluation of a midazolam-ketamine-xylazine infusion for total intravenous anesthesia in horses

John A. E. Hubbell DVM, MS1, Turi K. Aarnes DVM, MS2, Phillip Lerche BVSc, PhD3, and Richard M. Bednarski DVM, MS4
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  • 1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 2 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 3 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 4 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

Abstract

Objective—To evaluate the use of midazolam, ketamine, and xylazine for total IV anesthesia (TIVA) in horses.

Animals—6 healthy Thoroughbred mares.

Procedures—Horses were sedated with xylazine (1.0 mg/kg, IV). Anesthesia was induced with midazolam (0.1 mg/kg, IV) followed by ketamine (2.2 mg/kg, IV) and was maintained with an IV infusion of midazolam (0.002 mg/kg/min), ketamine (0.03 mg/kg/min), and xylazine (0.016 mg/kg/min). Horses underwent surgical manipulation and injection of the palmar digital nerves; duration of the infusion was 60 minutes. Additional ketamine (0.2 to 0.4 mg/kg, IV) was administered if a horse moved its head or limbs during procedures. Cardiopulmonary and arterial blood variables were measured prior to anesthesia; at 10, 20, 30, 45, and 60 minutes during infusion; and 10 minutes after horses stood during recovery. Recovery quality was assessed by use of a numeric (1 to 10) scale with 1 as an optimal score.

Results—Anesthesia was produced for 70 minutes after induction; supplemental ketamine administration was required in 4 horses. Heart rate, respiratory rate, arterial blood pressures, and cardiac output remained similar to preanesthetic values throughout TIVA. Arterial partial pressure of oxygen and oxygen saturation of arterial hemoglobin were significantly decreased from preanesthetic values throughout anesthesia; oxygen delivery was significantly decreased at 10- to 30-minute time points. Each horse stood on its first attempt, and median recovery score was 2.

Conclusions and Clinical Relevance—Midazolam, ketamine, and xylazine in combination produced TIVA in horses. Further studies to investigate various dosages for midazolam and ketamine or the substitution of other α2-adrenoceptor for xylazine are warranted.

Abstract

Objective—To evaluate the use of midazolam, ketamine, and xylazine for total IV anesthesia (TIVA) in horses.

Animals—6 healthy Thoroughbred mares.

Procedures—Horses were sedated with xylazine (1.0 mg/kg, IV). Anesthesia was induced with midazolam (0.1 mg/kg, IV) followed by ketamine (2.2 mg/kg, IV) and was maintained with an IV infusion of midazolam (0.002 mg/kg/min), ketamine (0.03 mg/kg/min), and xylazine (0.016 mg/kg/min). Horses underwent surgical manipulation and injection of the palmar digital nerves; duration of the infusion was 60 minutes. Additional ketamine (0.2 to 0.4 mg/kg, IV) was administered if a horse moved its head or limbs during procedures. Cardiopulmonary and arterial blood variables were measured prior to anesthesia; at 10, 20, 30, 45, and 60 minutes during infusion; and 10 minutes after horses stood during recovery. Recovery quality was assessed by use of a numeric (1 to 10) scale with 1 as an optimal score.

Results—Anesthesia was produced for 70 minutes after induction; supplemental ketamine administration was required in 4 horses. Heart rate, respiratory rate, arterial blood pressures, and cardiac output remained similar to preanesthetic values throughout TIVA. Arterial partial pressure of oxygen and oxygen saturation of arterial hemoglobin were significantly decreased from preanesthetic values throughout anesthesia; oxygen delivery was significantly decreased at 10- to 30-minute time points. Each horse stood on its first attempt, and median recovery score was 2.

Conclusions and Clinical Relevance—Midazolam, ketamine, and xylazine in combination produced TIVA in horses. Further studies to investigate various dosages for midazolam and ketamine or the substitution of other α2-adrenoceptor for xylazine are warranted.

Equine veterinarians frequently anesthetize horses, with > 80% performing short-term anesthesia (duration, 20 minutes) on a weekly basis and approximately 45% performing long-term anesthesia (> 30 minutes) at least monthly.1 Infusion of GKX is the most commonly used technique for long-term anesthesia, particularly when anesthesia is performed outside of the hospital setting.1 Guaifenesin is a centrally acting skeletal muscle relaxant that can be used alone to produce restraint, lateral recumbency, and immobilization.2 The combination of guaifenesin, α2-adrenoceptor agonists, and ketamine is frequently used to produce anesthesia.3–9 Large volumes of dilute formulations of guaifenesin (5% and 10%) are frequently used for this purpose because more concentrated solutions can cause vascular endothelial damage and hemolysis and are also prone to precipitation.10–12 Currently, no solution of guaifenesin for injection is manufactured commercially in the United States; thus, veterinarians must purchase guaifenesin powder and compound it on an as-needed basis.

Benzodiazepines, including diazepam, climazolam, zolazepam, and midazolam, produce muscle relaxant, anxiolytic, and hypnotic effects by binding to inhibitory gamma-amino butyric acid receptor sites in the brainstem reticular formation and spinal cord.13 Benzodiazepines produce minimal cardiopulmonary effects in adult horses and have been used as replacements for guaifenesin.14 Diazepam, administered in sequence with xylazine and ketamine, is more convenient to use than GKX infusion and produces comparable short-term anesthesia.15 Climazolam, in combination with ketamine, has been used to maintain anesthesia in ponies premedicated with acepromazine and xylazine.16 Zolazepam is combined with tiletamine, a dissociogenic drug, in a proprietary combination approved for use in dogs and cats.17 The combination has been used in horses sedated with α2-adrenoceptor agonists to produce TIVA for 30 to 40 minutes.18–20 Midazolam, a water-soluble benzodiazepine, causes lowering of the head and moderate ataxia in horses.21 The combination of midazolam and ketamine compared favorably with the combination of guaifenesin and ketamine when used IV for induction of anesthesia maintained with isoflurane in 1 study22; the end-tidal isoflurane concentration required to maintain anesthesia was significantly lower after induction of anesthesia with midazolam and ketamine, and the quality of recovery was not different between groups. However, ataxia was evident during anesthetic recovery after administration of midazolam and ketamine in combination with isoflurane if anesthetic durations were < 75 minutes. Midazolam, in combination with ketamine and medetomidine, has been used to produce TIVA of approximately 40 minutes' duration in horses, with good to excellent recoveries.23 Cardiovascular depression was judged to be mild, but supplemental oxygen administration was suggested to improve oxygenation.23 In 2 other studies,24,25 midazolam and ketamine in combination with either detomidine, xylazine, or medetomidine reduced the dose requirement for inhalation anesthesia in horses undergoing surgery.

The purpose of the present study was to determine whether MKX infusion is a suitable alternative to GKX infusion to produce TIVA for 60 minutes in horses. Midazolam is widely used for anesthesic induction in humans and is available as a generic drug. Midazolam and ketamine are chemically compatible when mixed, with no reduction in potency for either drug for up to 97 hours.26 The substitution of midazolam for guaifenesin would result in a more easily compounded solution and could be administered at a smaller volume, potentially eliminating the adverse vascular and hematologic effects associated with guaifenesin administration.

Materials and Methods

Study population—Six mature Thoroughbred mares (mean body weight, 496 kg; range, 422 to 577 kg) were enrolled in the study. The horses were part of a group maintained by the university for pharmacological studies. The horses were determined to be healthy prior to the start of the study on the basis of a physical examination by a veterinarian and the results of a CBC and serum biochemical analysis. The horses were anesthetized for another study involving surgical exposure of the palmar digital nerves of both forelimbs below the metacarpophalangeal joint. The study protocols and procedures were approved by the Institutional Animal Care and Use Committee of The Ohio State University.

Experimental protocol—Food, but not water, was withheld from horses for approximately 6 hours prior to anesthesia and surgery. On the day of the experiment, hair over both jugular veins and a transverse facial artery was clipped and the skin was aseptically prepared for placement of IV and intracardiac catheters. A 2% lidocainea solution (1 mL/site) was injected SC at 2 sites over the right jugular vein, at 1 site over the left jugular vein, and over the prepared transverse facial artery.

A 14-gauge polytetrafluoroethylene catheterb was inserted in the left jugular vein for administration of anesthetic drugs. Two 8F catheter introducersc were separately placed in the right jugular vein to facilitate the placement of 2 catheters: a 7F specialized thermistor with a balloon-tipped quadruple lumen catheterd was positioned so that its distal tip lay in the pulmonary artery for measurement of CO by use of thermodilutione and MPAP, and a 110-cm polyethylene 240 catheterf was positioned so that its distal tip lay in the right atrium for injection of 1 mL of iced 5% dextrose solutiong/15 kg for CO determinations and MRAP measurement. A 20-gauge, 1.25-inch catheterh was percutaneously inserted in a transverse facial artery for measurement of SAP, DAP, and MAP and collection of heparinized arterial blood samples for analysis of pH and blood gas values. Positioning of all catheters was confirmed by the visualization of characteristic cardiac chamber or vessel pressure waveforms by attaching each catheter to an appropriately calibrated pressure transducer.i The scapulohumeral joint and the sternum were used as zero-pressure reference points when the horse was standing and in right lateral recumbency, respectively. At least 3 injections were administered for CO determination, and the mean value was calculated. A base-apex ECGj was used to determine HR and heart rhythm. Respiratory rate was determined by observing chest excursions.

Horses were left undisturbed for ≥ 10 minutes after catheter placement. Baseline values of HR, RR, CO, SAP, MAP, DAP, MPAP, and MRAP were then measured, and arterial blood samples were obtained for determination of baseline values of the following variables: pH; blood gases; concentrations of lactate, sodium, potassium, chloride, and calcium; and Sao2.k Oxygen delivery (mL of O2/kg/min) was calculated by use of the following equation: 10 × CO × (1.39 × hemoglobin concentration × Sao2 + [0.003 × Pao2])/body weight. Cardiac index was calculated by use of the following equation: CO/body weight.

Five minutes after baseline values were obtained, xylazinel (1.0 mg/kg, IV) was administered for sedation and horses were moved to a padded induction stall and positioned behind a restraining door for anesthetic induction. Five minutes after xylazine administration, midazolamm (0.1 mg/kg, IV) was administered, followed immediately by ketaminen (2.2 mg/kg, IV). Once recumbent, horses were positioned in lateral recumbency and orotracheal intubation was performed with a 26-mm internal diameter endotracheal tube. Horses were lifted by use of limb hobbles attached to a motorized hoist and positioned in right lateral recumbency on an appropriately padded table. Ten minutes after anesthetic induction, the MKX infusion (midazolam [0.002 mg/kg/min], ketamine [0.03 mg/kg/min], and xylazine [0.016 mg/kg/min]) was begun to maintain anesthesia. The drugs were administered by use of separate infusion pumps connected via a 3-way adapter into an IV administration set that delivered Ringer's solutiono at a rate of 1 L/h. Horses breathed spontaneously.

A tourniquet was placed midway between the carpus and the metacarpophalangeal joint on each forelimb, and the hair was clipped and skin aseptically prepared over each palmar digital nerve. Incisions (2 cm) were made in the skin to expose each palmar digital nerve; these were then isolated and exteriorized for intraneural injection of 0.5 mL of an investigational long-acting local anesthetic substance for purposes of another study. The incisions were closed routinely, tourniquets were removed, and bandages were applied. Total surgical time was approximately 45 minutes.

Horses were continuously observed for any response to positioning, manipulation, or surgical stimulation. Ketamine (0.2 to 0.4 mg/kg, IV) was administered if a horse moved its head or limbs during the procedures. Cardiopulmonary measurements were made and recorded, and samples of arterial blood were collected anaerobically 10, 20, 30, 45, and 60 minutes after the start of MKX infusion. The infusion was stopped 70 minutes after anesthetic induction (duration of infusion, 60 minutes), and a final arterial blood sample was collected 10 minutes after the horses stood. Samples of arterial blood were stored on ice and analyzed within 2 hours after collection.

Horses were transported to a padded recovery stall by use of a hobble and hoist system after the MKX infusion was discontinued, and the 60-minute measurements and sample collection were completed. Horses were positioned in right lateral recumbency on a 25-cm-thick foam pad, the lights were dimmed, and a towel was placed over the left eye. The endotracheal tube was removed when the horse resumed spontaneous swallowing. Recovery data were recorded for later evaluation. The duration from disconnection of the infusion to the times of first movement, extubation, first attempt at sternal recumbency, sternal recumbency, first attempt to stand, and standing were recorded as well as the number of attempts to stand. The quality of recovery was assessed by 4 independent observers (JAEH, TKA, PL, and RMB) either in real time or using video recordings and was scored on a 10-point scale (1 = stands on first attempt with clean effort and no body sway or weight shifting; 2 = stands on first attempt with little to moderate effort and slight body sway or shifting; 3 = stands on first or second attempt with great effort and marked shifting once standing; 4 = 2 or 3 attempts to stand with a strong effort on the last attempt and slight shifting once standing; 5 = 2 or 3 attempts to stand and marked instability once standing; 6 = several weak attempts to stand and marked instability once standing; 7 = several weak attempts to stand, the horse resumes recumbency, and minor shifting is observed once standing; 8 = several weak attempts to stand, and the horse falls easily or resumes recumbency and incurs minor injury; 9 = several violent attempts to stand, and the horse falls or resumes recumbency and incurs minor injury; 10 = several violent attempts to stand, the horse falls or resumes recumbency, and major injury is incurred by the horse or personnel).

Statistical analysis—Cardiovascular and blood data were evaluated for normal distribution by use of a Kolmogorov-Smirnov normality test and were determined to be normally distributed. A 1-way repeated-measures ANOVA and Tukey-Kramer posttest were used to evaluate effects of time on the variables of interest. Values of P < 0.05 were considered significant. Hemodynamic and pulmonary data are reported as mean ± SD. Timed recovery data are reported as mean ± SD for parametric data or median (range) for nonparametric data. Recovery score and number of attempts to stand are reported as median (range).

Results

All 6 horses completed the study. One horse required sedation (total dose of xylazine, 300 mg, IV) to facilitate catheter placement; once catheters were in place, the experimental procedure for this horse was started 40 minutes after xylazine administration. One horse had signs of abdominal discomfort and distention 2 hours after recovery from anesthesia. Displacement of the large colon was diagnosed via rectal palpation, and surgical correction was performed. The horse recovered uneventfully after correction of the displacement.

During the MKX infusion, 4 of 6 horses required additional administration of ketamine. One horse received supplemental ketamine administration IV 3 times (200 mg at 20 and 24 minutes and 100 mg at 60 minutes, as measured from the start of infusion). Three horses each received additional ketamine IV once (200 mg at 36 minutes in one horse, 200 mg at 59 minutes in another, and 250 mg at 59 minutes in the third horse, with each duration measured from the start of infusion). Supplemental ketamine was administered because of movement associated with stimulation (manipulation of a palmar digital nerve; n = 4) or transportation and positioning for recovery (1). Anesthesia was sufficient for placement of drapes, towel clamps, and tourniquets and for creating skin incisions in all horses.

Compared with baseline values, MRAP was significantly increased 10 minutes after the MKX infusion was started but was not significantly different from baseline at other time points (Table 1). Heart rate, RR, SAP, MAP, DAP, MPAP, CO, and cardiac index were not significantly different from baseline at any time point evaluated, and oxygen delivery was significantly decreased, compared with baseline values, at the 10-, 20-, and 30-minute measurements.

Table 1—

Mean ± SD cardiopulmonary variables in 6 healthy Thoroughbred mares that underwent TIVA maintained with an MKX infusion (midazolam [0.002 mg/kg/min], ketamine [0.03 mg/kg/min], and xylazine [0.016 mg/kg/min]) for surgical manipulation and injection of the palmar digital nerves (total duration of anesthesia, 70 minutes).

 Time*
VariableBaseline10 minutes20 minutes30 minutes45 minutes60 minutes10 minutes after standing
HR (beats/min)32 ± 828 ± 328 ± 427 ± 327 ± 329 ± 433 ± 4
RR (breaths/min)15 ± 216 ± 816 ± 517 ± 515 ± 715 ± 412 ± 3
SAP (mm Hg)145 ± 10178 ± 34170 ± 30184 ± 24180 ± 21183 ± 15141 ± 33
MAP (mm Hg)117 ± 13136 ± 17136 ± 19141 ± 17138 ± 13141 ± 9111 ± 22
DAP (mm Hg)98 ± 16112 ± 13112 ± 14114 ± 14113 ± 10117 ± 1092 ± 17
MRAP (mm Hg)13 ± 318 ± 317 ± 417 ± 417 ± 316 ± 416 ± 3
MPAP (mm Hg)26 ± 426 ± 425 ± 527 ± 826 ± 825 ± 726 ± 6
CO (L/min)36.2 ± 8.927.2 ± 6.026.5 ± 6.627.8 ± 5.831.3 ± 4.333.0 ± 6.935.0 ± 6.6
Cardiac index (mL/kg/min)73.7 ± 20.154.8 ± 9.453.2 ± 9.455.7 ± 7.663.1 ± 4.266.4 ± 10.170.6 ± 10.5
Oxygen delivery (mL/kg/min)11.4 ± 3.37.0 ± 1.37.4 ± 3.26.1 ± 1.58.5 ± 1.18.8 ± 1.49.7 ± 1.4

Baseline values were obtained 5 minutes prior to xylazine administration for preanesthetic sedation. Remaining values were obtained from 10 to 60 minutes after the MKX infusion was started (10 minutes after anesthetic induction) and 10 minutes after horses stood during recovery.

Value is significantly (P < 0.05) different from the baseline value for this variable.

Arterial pH and Paco2 were not different from baseline values at any time point. Values for Pao2 and Sao2 were significantly decreased, compared with baseline, for the duration of the MKX infusion and had returned to approximate baseline values 10 minutes after horses stood (Table 2). Plasma hemoglobin concentration was significantly decreased, compared with the baseline concentration, 30 minutes after the start of the infusion. Sodium and chloride concentrations were significantly decreased at the 30- to 60-minute time points, and calcium concentration was significantly decreased for the duration of the infusion, compared with the respective baseline values. Ten minutes after horses stood, calcium and chloride concentrations were significantly decreased and potassium concentration was significantly increased from baseline concentrations. Lactate concentration was also significantly increased, compared with baseline values, at 60 minutes and 10 minutes after the horses stood.

Table 2—

Mean ± SD arterial blood sample variables in the same horses in Table 1.

 Time*
VariableBaseline10 minutes20 minutes30 minutes45 minutes60 minutes10 minutes after standing
pH7.47 ± 0.027.46 ± 0.047.46 ± 0.037.49 ± 0.067.46 ± 0.047.49 ± 0.077.46 ± 0.02
Paco2 (mm Hg)37.3 ± 1.839.9 ± 5.339.4 ± 4.436.2 ± 6.140.4 ± 5.336.6 ± 6.241.1 ± 1.4
Pao2 (mm Hg)114.5 ± 12.568.1 ± 19.063.2 ± 9.066.4 ± 10.056.8 ± 9.063.6 ± 12.3112.0 ± 15.0
Sao2 (%)97.7 ± 3.592.3 ± 3.491.9 ± 2.793.7 ± 3.389.6 ± 3.592.8 ± 3.797.6 ± 3.0
Hemoglobin (g/dL)11.1 ± 0.89.8 ± 0.910.3 ± 3.28.3 ± 1.710.6 ± 0.910.2 ± 1.410.0 ± 1.3
Potassium (mmol/L)3.5 ± 0.33.4 ± 0.23.3 ± 0.33.3 ± 0.23.4 ± 0.23.5 ± 0.33.9 ± 0.4
Sodium (mmol/L)134 ± 1133 ± 1133 ± 2132 ± 1132 ± 1131 ± 2132 ± 2
Calcium (mg/dL)5.7 ± 0.25.5 ± 0.35.4 ± 0.25.4 ± 0.25.4 ± 0.25.4 ± 0.25.3 ± 0.2
Chloride (mmol/L)99.1 ± 1.598.3 ± 1.698.0 ± 2.097.5 ± 1.996.8 ± 2.196.6 ± 1.696.5 ± 1.7
Lactate (mmol/L)0.8 ± 0.51.0 ± 0.31.0 ± 0.41.1 ± 0.31.1 ± 0.41.3 ± 0.31.5 ± 0.7

See Table 1 for key.

All horses stood on the first attempt, and the median recovery score was 2 (range, 2 to 3). Extubation was performed for all horses ≤ 11 minutes after the MKX infusion was discontinued, but there was considerable variability in the other recovery times evaluated (Table 3). One horse stood 90 minutes after the end of the MKX infusion. For this horse, the lighting level was increased at 60 minutes and the noise level was increased at 75 minutes (by an attendant slapping the wall with his or her hand) as measured from the end of the infusion. The handlers physically prompted the horse to assume sternal recumbency 90 minutes after the end of the infusion, at which time it stood spontaneously.

Table 3—

Recovery variables for the same horses in Table 1.

VariableMean ± SD or median (range) value
Time to first movement (min)2 (0–3)
Time to extubation (min)6 ± 2.7
Time to first attempt to sternal recumbency (min)37 ± 29.4
Time to sternal recumbency (min)48.8 ± 31.2
Time to first attempt to stand (min)49.7 ± 31.1
Time to standing (min)49.7 ± 31.1
No. of attempts to stand1 (—)
Recovery score2 (2–3)

Timed recovery data are reported as mean ± SD or median (range) values as measured from the time that the MKX infusion was disconnected. Number of attempts to stand and recovery score are reported as median (range); quality of recovery was assessed in real time or by use of video recordings and scored on a 10-point scale, in which 1 = stands on first attempt with clean effort and no body sway or weight shifting and 10 = several violent attempts to stand, horse falls or resumes recumbency, and major injury is incurred by horse or personnel.

— = Not applicable.

Discussion

An MKX infusion may be a suitable alternative to GKX infusion to produce TIVA in horses. Infusion of MKX safely produced TIVA for 70 minutes with minimal cardiovascular depression. Ventilation was maintained at preanesthetic values, but Pao2 and Sao2 decreased significantly from baseline to values similar to those reported previously for TIVA in equids.5,7,23 Supplemental administration of ketamine was required for some horses when surgical stimulation was most intense (ie, during nerve manipulation) or at the end of the infusion to facilitate safe positioning in a recovery stall. All horses stood on their first attempt.

In the present study, MKX infusion produced a light plane of surgical anesthesia as determined by the lack of reaction to skin incisions and the occurrence of limb movement (2/6 horses) when the palmar digital nerves were manipulated (a painful stimulation).27 The dose of midazolam administered IV in sequence with xylazine and ketamine for induction of anesthesia was within the range of recommended doses.22,23,28 In previous studies23–25 involving midazolam-combination infusions in horses, midazolam was delivered at lower infusion rates (0.02 to 0.08 mg/kg/h) but higher doses of ketamine or α2-adrenoceptor agonists other than xylazine were incorporated, or the infusion was used as a supplement to inhalation anesthesia. For the present study, we chose infusion rates for ketamine and xylazine that were similar to those used in a previous study4 (2.2 and 1.1 mg/kg/h for ketamine and xylazine, respectively) in which GKX was used to maintain anesthesia for surgery. Starting the MKX infusion immediately after anesthetic induction could have resulted in the maintenance of higher drug concentrations and lessened the requirement for supplemental ketamine administration. We started the MKX infusion 10 minutes after anesthetic induction, following positioning for surgery and placement of monitoring equipment to standardize data collection time intervals. Others have reported the use of higher infusion rates for ketamine (3.2 mg/kg/h) or the substitution of other α2-adrenoceptor agonists for xylazine with good results.7–9 In clinical practice, typical responses to evidence of insufficient anesthesia include bolus administration of ketamine or an increase in the rate of a combined drug infusion. In the present study, bolus administration of ketamine was sufficient to prevent movement in response to stimulation and did not appear to cause deterioration of cardiopulmonary indices. Increased ketamine infusion rates could potentially be used instead, but their safety in combination with midazolam and xylazine was not evaluated in the present study. The use of other α2-adrenoceptor agonists in combination with midazolam and ketamine should be further evaluated.

Cardiovascular indices, including HR, SAP, MAP, DAP, CO, and cardiac index, did not differ from pre-anesthetic baseline values at any evaluated time point during MKX infusion. Maintenance of good cardiovascular function is a recognized advantage of most TIVA techniques that include ketamine,3–9 and our results suggest that MKX infusion is comparable. Mean right atrial pressure was significantly (P < 0.05) increased 10 minutes after the start of the infusion. However, apparently increased MRAP values at other time points were not significantly different from baseline and were not thought to be clinically relevant. Increases in MRAP have been associated with lateral recumbency (the position of horses in the present study throughout the infusion) and with α2-adrenoceptor agonist administration.29,30

Indices of oxygenation, including Pao2 and Sao2 at the 10- to 60-minute time points and oxygen delivery at 10, 20, and 30 minutes, were significantly lower during the MKX infusion than were those prior to or after anesthesia and recumbency. Decreases in Pao2 and Sao2 frequently occur when horses are anesthetized and placed in lateral recumbency without supplemental oxygen administration.5,7,23 Potential causes of hypoxemia (Pao2 < 60 mm Hg) in anesthetized horses include hypoventilation, intrapulmonary vascular shunting, and ventilation-perfusion mismatching. Alveolar ventilation, as assessed by use of Pao2 during anesthesia in the present study, was not significantly different from preanesthetic baseline values and was likely attributable to intrapulmonary vascular shunting and ventilation-perfusion mismatching. Hypoxemia caused by ventilation-perfusion mismatching associated with TIVA can be treated by increasing inspired oxygen tensions, but hypoventilation may occur.31 To mimic anesthesia in the field, in which oxygen is not routinely administered, we elected not to administer supplemental oxygen in horses during the experimental protocol.

Oxygen delivery was significantly (P < 0.05) decreased at 10, 20, and 30 minutes after the MKX infusion was started. Minimum requirements for oxygen delivery have not been established for horses, but arterial lactate concentrations (an index of anaerobic metabolism) were increased at the 60-minute time point and 10 minutes after the horses stood, compared with preanesthetic baseline concentrations. Although increased, lactate concentrations remained within normal limits (< 2 mmol/L), but further increases might be anticipated if the duration of TIVA were to be extended.32 Oxygen supplementation has been recommended particularly when horses are anesthetized for > 60 minutes33 and would likely be of benefit in horses anesthetized with MKX infusion. Changes in other plasma constituents (eg, sodium and chloride) were consistent with results of a previous study34 and, although significant, remained within previously reported ranges.

In the study reported here, each horse stood on the first attempt, with slight or moderate to marked swaying or weight shifting once standing. Greater ataxia in recovery might have been anticipated on the basis of a previous study22 that incorporated a single dose of midazolam as part of an anesthetic induction regimen prior to isoflurane anesthesia. Apparent differences between the present study and that study22 may have been related to differences in the depth of anesthesia, drugs administered contemporaneously, or scales used to assess ataxia. The differences call attention to the need to determine the pharmacokinetics of midazolam. In the present study, 1 horse remained in lateral recumbency for 90 minutes in the recovery stall, then stood when prompted. Each horse moved from lateral recumbency to standing with only a brief pause in sternal recumbency. Although it is possible that the large colon displacement that occurred in 1 horse after anesthesia was related to the anesthesia or to stress associated with the procedures, the authors believe it is unlikely that it was associated with any specific anesthetic agent.

Midazolam-ketamine-xylazine infusion may be a suitable alternative to GKX infusion for TIVA in horses. Further studies investigating various dosages for the constituents of MKX infusion or substitutions of other α2-adrenoceptor agonists for xylazine are warranted, with the goal of developing an optimal combination for TIVA in horses.

ABBREVIATIONS

CO

Cardiac output

DAP

Diastolic arterial blood pressure

GKX

Guaifenesin, ketamine, and xylazine

HR

Heart rate

MAP

Mean arterial blood pressure

MKX

Midazolam, ketamine, and xylazine

MPAP

Mean pulmonary arterial pressure

MRAP

Mean right atrial pressure

RR

Respiratory rate

Sao2

Oxygen saturation of arterial hemoglobin

SAP

Systolic arterial blood pressure

TIVA

Total IV anesthesia

a.

Lidocaine, Vedco Inc, St Joseph, Mo.

b.

Intracath, Parke, Davis & Co, Sandy, Utah.

c.

Catheter introducers CL-07811, Arrow International Inc, Reading, Pa.

d.

Thermodilution balloon catheter AI-07067, Arrow International Inc, Reading, Pa.

e.

Cardiomax III, Columbus Instruments, Columbus, Ohio.

f.

Intramedic PE-240 tubing, Becton, Dickinson & Co, Sparks, Md.

g.

Dextrose 5% in water, Baxter Healthcare Corp, Deerfield, Ill.

h.

Surflo catheter, Terumo Medical Corp, Elkton, Md.

i.

TruWave disposable pressure transducer, Edwards Lifesciences LLC, Irvine, Calif.

j.

Datascope Passport Model EL, Datascope Corp, Paramus, NJ.

k.

ABL 725, Radiometer America, Westlake, Ohio.

l.

Xylazine, Vedco Inc, St Joseph, Mo.

m.

Midazolam, Hospira Inc, Lake Forest, Ill.

n.

Ketamine, Ketaset, Fort Dodge Animal Health, Fort Dodge, Iowa.

o.

Lactated Ringer's solution, Baxter Healthcare Corp, Deerfield, Ill.

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Contributor Notes

The authors thank Carl O'Brien, Dr. Christine Pariseau, Dr. Akikazu Ishihara, and Dr. Alicia Bertone for assistance with the instrumentation and collection of data.

Address correspondence to Dr. Hubbell (john.hubbell@cvm.osu.edu).