Abstract
Neonatal foals may require prolonged sedation to permit ventilatory support in the first few days of life. The objective of this study was to evaluate and compare the cardiopulmonary effects and clinical recovery characteristics of 2 sedative/analgesia protocols in healthy foals receiving assisted ventilation. Foals were randomized to receive dexmedetomidine, butorphanol, and propofol (DBP) or midazolam, butorphanol, and propofol (MBP) during a 24-hour period. Infusion rates of dexmedetomidine, midazolam, and propofol were adjusted and propofol boluses administered according to set protocols to maintain optimal sedation and muscle relaxation. Ventilatory support variables were adjusted to preset targets. Physiologic variables were recorded, cardiac output (CO) measured (thermodilution), and arterial and mixed venous blood collected for gas analysis at intervals up to 24 hours. Foals in group DBP received dexmedetomidine [2.4 ± 0.5 μg/kg body weight (BW) per hour], butorphanol (13 μg/kg BW per hour), and propofol (6.97 ± 0.86 mg/kg BW per hour), whereas foals in group MBP received midazolam (0.14 ± 0.04 mg/kg BW per hour), butorphanol (13 μg/kg BW per hour), and propofol (5.98 ± 1.33 mg/kg BW per hour). Foals in the DBP group received significantly more propofol boluses (9.0 ± 3.0) than those in the MBP group (4.0 ± 2.0). Although physiologic variables remained within acceptable limits, heart rate (HR), mean arterial pressure (MAP), and cardiac index (CI) were lower in foals in the DBP group than in the MBP group. Times to sternal recumbency, standing, and nursing were significantly shorter in the DBP than MBP group. We found that MBP and DBP protocols are suitable to assist ventilatory support in neonatal foals, although MBP results in a prolonged recovery compared to DBP.
Résumé
Les poulains nouveau-nés peuvent nécessiter une sédation prolongée pour permettre une assistance ventilatoire au cours des premiers jours de vie. L’objectif de cette étude était d’évaluer et de comparer les effets cardio-pulmonaires et les caractéristiques de récupération clinique de deux protocoles sédatifs/analgésiques chez des poulains sains recevant une ventilation assistée. Les poulains ont été randomisés pour recevoir de la dexmédétomidine, du butorphanol et du propofol (DBP) ou du midazolam, du butorphanol et du propofol (MBP) pendant une période de 24 heures. Les débits de perfusion de dexmédétomidine, de midazolam et de propofol ont été ajustés et des bolus de propofol ont été administrés selon des protocoles définis pour maintenir une sédation et une relaxation musculaire optimales. Les variables d’assistance ventilatoire ont été ajustées à des cibles prédéfinies. Les variables physiologiques ont été enregistrées, le débit cardiaque (CO) mesuré (thermodilution) et le sang artériel et veineux mixte prélevé pour analyse des gaz à des intervalles allant jusqu’à 24 h. Les poulains du groupe DBP ont reçu de la dexmédétomidine [2,4 ± 0,5 μg/kg de poids corporel (PC) par heure], du butorphanol (13 μg/kg de PC par heure) et du propofol (6,97 ± 0,86 mg/kg de PC par heure), tandis que les poulains du groupe MBP ont reçu du midazolam (0,14 ± 0,04 mg/kg de PC par heure), du butorphanol (13 μg/kg de PC par heure) et du propofol (5,98 ± 1,33 mg/kg de PC par heure). Les poulains du groupe DBP ont reçu significativement plus de bolus de propofol (9,0 ± 3,0) que ceux du groupe MBP (4,0 ± 2,0). Bien que les variables physiologiques soient restées dans des limites acceptables, la fréquence cardiaque (FC), la pression artérielle moyenne (MAP) et l’index cardiaque (IC) étaient plus faibles chez les poulains du groupe DBP que dans le groupe MBP. Les temps de décubitus sternal, de station debout et d’allaitement étaient significativement plus courts dans le groupe DBP que dans le groupe MBP. Nous avons constaté que les protocoles MBP et DBP sont adaptés pour assister l’assistance ventilatoire chez les poulains nouveau-nés, bien que le MBP entraîne une récupération prolongée par rapport au DBP.
(Traduit par Docteur Serge Messier)
Introduction
Neonatal foals may require ventilatory support due to primary pulmonary conditions, including bacterial or viral pneumonia and/or secondary to neurological pathology, such as neonatal encephalopathy, that result in respiratory failure (1). Sedation and analgesia may be needed in foals requiring ventilatory support to reduce agitation, minimize the risk of accidental extubation, and improve the foal’s overall level of comfort. Although the use of sedative protocols for management of human patients requiring prolonged ventilatory support has been shown to improve outcome and is therefore recommended (2,3), no protocols for use in neonatal foals have been reported to date.
Sedative regimens commonly used in the critical care setting to facilitate mechanical ventilation in humans and veterinary species include infusions of opioids, benzodiazepines, alpha-2 agonists, and short-acting anesthetics such as propofol (3–5). Inappropriate use of sedatives and analgesics in human patients has been linked to prolonged periods of mechanical ventilation and stays in the intensive care unit (ICU) (6). Rapid recovery from the sedative and muscle relaxant effects of any drug protocol is important in the neonatal foal to ensure strong spontaneous ventilation and mobility that permit reintroduction and acceptance by the mare and return to nursing.
The ideal sedative protocol for mechanical ventilation of neonatal foals would provide cardiovascular stability, effective sedation, and rapid recovery after its discontinuation. Although there are studies evaluating the effects of alpha-2 agonists, benzodiazepines, butorphanol, ketamine, propofol, and alfaxalone in foals (7–12), there are no prospective studies evaluating combination protocols for long-term sedation or anesthesia at planes suitable to permit ventilatory support in neonatal foals.
The objective of this investigation was to evaluate and compare the cardiopulmonary effects and clinical recovery characteristics of a 24-hour infusion of a combination of dexmedetomidine, butorphanol, and propofol (DPB) and midazolam, butorphanol, and propofol (MBP) in healthy foals receiving assisted ventilation.
Materials and methods
Animals
Ten pony foals, 3 to 5 d old (9 female, 1 male) and weighing 34.4 kg ± 5.6 kg (mean ± SD) were used. Foals were randomly assigned to the MBP group (n = 5) or DBP group (n = 5). Foals were considered healthy based on physical examination, complete blood (cell) count (CBC), serum biochemistry, fibrinogen, serum immunoglobulin (IgG), and 2-view thoracic radiographs obtained before enrollment. The institutional Animal Care Committee at the University of Guelph approved the study, which conformed to the standards of the Canadian Council on Animal Care.
Instrumentation and monitoring
Foals were gently restrained in standing position and a viscous gel containing 2% lidocaine (Xylocaine; AstraZeneca Canada, Mississauga, Ontario) was applied to a ventral nasal meatus. Foals were nasotracheally intubated with a silicone nasotracheal tube (8 to 10 mm internal diameter, 50 to 55 cm in length) and anesthetized with isoflurane (AErrane; Baxter Corporation, Mississauga, Ontario) delivered in oxygen via a universal F-circuit attached to an anesthetic machine. The foals were placed in lateral recumbency following induction of anesthesia and anesthesia was maintained with isoflurane delivered to effect (end-tidal isoflurane of 1.2% to 1.5%) while breathing spontaneously.
An 8.5-Fr introducer (Intro-Flex Percutaneous Sheath Introducer Kit; Edwards Lifesciences, Irvine, California, USA) was placed in a jugular vein to allow introduction of a 7-Fr thermodilution catheter (Swan-Ganz; Edwards Lifesciences) into the pulmonary artery. The distal port of the catheter was positioned in the pulmonary artery using fluoroscopic guidance. The distal port of the thermodilution catheter was used to collect mixed-venous blood samples and measure core body temperature, pulmonary artery occlusion pressure, and mean pulmonary artery pressure. The proximal port of the thermodilution catheter was used to measure central venous pressure and cardiac output (CO).
An 18-gauge, 4.78-cm catheter was placed in a cephalic vein for administering a balanced electrolyte solution and infusion of sedative drugs. A 20-gauge, 4.78-cm catheter was placed in the lateral metatarsal artery to allow direct measurement of arterial blood pressure and sampling of arterial blood for analysis. Cardiac output (CO) was measured with the thermodilution technique with a multi-parameter monitor (S/5 Critical Care Monitor; Datex Ohmeda, GE Healthcare, Helsinki, Finland) using 10 mL injectate of 5% dextrose chilled to 1 to 2°C. Three measurements with < 10% variation were taken at each time point and averaged to obtain the value for the given time point. Foals were further monitored with a 3-lead electrocardiogram (ECG) and pulse oximeter.
An indwelling urinary catheter was placed to collect and measure urine volume and specific gravity. A 14-Fr, 50-inch enteral feeding tube was placed nasogastrically and foals were fed milk replacer (FoalLac; Land O’Lakes, St. Paul, Minnesota, USA) at 4-hour intervals over the 24-hour period. The total volume of milk replacer administered over the 24-hour study period was equivalent to 20% of the foal’s body weight. A forced air warmer was used to maintain core body temperature, with the goal of achieving a core body temperature of 37 to 38.5°C.
Experimental design
Following instrumentation, foals were placed in sternal recumbency, using soft padding to maintain their position. The foal’s forelimbs were flexed at the olecranon and carpi and the hind limbs were positioned on one side of the foal. An isotonic balanced electrolyte solution (Plasma-Lyte A; Baxter) was initiated at a rate of 4 mL/kg body weight (BW) per hour. When indicated, dextrose (50%) was added to the intravenous fluids to create 1% incremental increases in dextrose concentration in order to maintain the foal’s blood glucose at 3.5 to 6.0 mmoL/L. Butorphanol (Torbugesic; Ayerst Laboratories, Montreal, Quebec) was administered intravenously as a bolus of 0.02 mg/kg BW per hour, followed immediately by a constant-rate infusion (CRI) delivered at 13 μg/kg BW per hour. Twenty minutes after end-tidal isoflurane levels had stabilized, baseline physiologic data were recorded, cardiac output was measured, and blood samples were obtained for analysis (Time 0).
Isoflurane was then discontinued and 1 of the 2 sedative protocols was initiated. The proximal end of the endotracheal tube was connected to the ventilator circuit and the ventilator (Evita 4; Draeger Medical AG, Lubeck, Germany) was turned on with the settings as outlined in the section on ventilation. Variables, including carbon dioxide in exhaled air (EtCO2), airway pressures [peak, mean, positive end-expiratory pressure (PEEP)], minute ventilation, frequency, and compliance and resistance, were displayed on the ventilator.
In the DBP protocol, dexmedetomidine (Dexdomitor; Pfizer Animal Health, Montreal, Quebec) was administered intravenously at a dose of 1.5 μg/kg BW delivered over 2 min, followed by an infusion started at 1.5 μg/kg BW per hour. In protocol MBP, midazolam (Midazolam; Sandoz, Boucherville, Quebec) was administered intravenously at a dose of 0.1 mg/kg BW delivered over 2 min, followed by an infusion started at 0.1 mg/kg BW per hour. In both protocols, butorphanol was continued at 13 μg/kg BW per hour and propofol administration (Diprivan 1%; AstraZeneca Canada) was started at 6.0 mg/kg BW per hour, IV.
Infusion rates of dexmedetomidine, midazolam, and propofol were adjusted according to the doses outlined in Table I. This was done by 1 of 2 investigators (CK or LA) based on the foal’s clinical signs. These signs included muscle tone, movement, patient-ventilator synchrony, palpebral reflexes, and eye position. Indications that sedation was inadequate included strong muscle tone with movement and patient-ventilator asynchrony. Minor spontaneous movement such as limb flexion was not considered an indication of inadequate sedation. The lack of a palpebral reflex, central eye position, or tear production or change in eye position over time indicated that sedation was excessive. If rigorous spontaneous movement occurred, propofol was administered as a bolus in 1 mg/kg BW increments to effect, in addition to changing the infusion rates. Throughout the study, 20 min was allowed to elapse between infusion adjustments so the level of sedation could stabilize.
Table I.
Baseline infusion doses and protocol for adjusting administration of dexmedetomidine, butorphanol, and propofol (DBP, n = 5) or midazolam, butorphanol, and propofol (MBP, n = 5) to clinically healthy neonatal foals during a 24-hour period of assisted ventilation.
| Baseline infusion doses | |
|---|---|
|
| |
| DBP | MBP |
| Dexmedetomidine 1.5 μg/kg BW per hour | Midazolam 0.1 μg/kg BW per hour |
| Butorphanol 13 μg/kg BW per hour | Butorphanol 13 μg/kg BW per hour |
| Propofol 6 mg/kg BW per hour | Propofol 6 mg/kg BW per hour |
| If inadequate sedation while receiving baseline doses | ||
|---|---|---|
|
| ||
| DBP | MBP | |
| Step 1 | Increase dexmedetomidine to 3 μg/kg BW per hour | Increase midazolam to 0.2 mg/kg BW per hour |
| Step 2 | Increase propofol to 7.5 mg/kg BW per hour | Increase propofol 7.5 mg/kg BW per hour |
| Step 3 | Increase propofol to 9 mg/kg BW per hour | Increase propofol to 9 mg/kg BW per hour |
| Step 4 | Increase dexmedetomidine to 4.5 μg/kg BW per hour | Increase midazolam to 0.3 mg/kg BW per hour |
Note: If excessive sedation is observed after any step, drug doses are changed in reverse order until foal is receiving baseline infusion rates.
| If excessive sedation while receiving baseline doses | ||
|---|---|---|
|
| ||
| DBP | MBP | |
| Step 1 | Reduce propofol to 4.5 mg/kg BW per hour | Reduce propofol to 4.5 mg/kg BW per hour |
| Step 2 | Reduce propofol to 3.0 mg/kg BW per hour | Reduce propofol to 3.0 mg/kg BW per hour |
| Step 3 | Reduce dexmedetomidine to 0.75 μg/kg BW per hour | Reduce midazolam to 0.05 mg/kg BW per hour |
| Step 4 | Reduce propofol to 1.5 mg/kg BW per hour | Reduce propofol to 1.5 mg/kg BW per hour |
| Step 5 | Discontinue propofol | Discontinue propofol |
Note: If inadequate sedation is observed after any step, drug doses are changed in reverse order until foal is receiving baseline infusion rates.
Body temperature, heart rate (HR), blood pressures, ventilatory settings, respiratory variables, and drug-infusion rates were monitored continuously and recorded every 30 min. The volume of urine collected and the urine specific gravity were measured every hour. Cardiac output was measured and mixed venous and arterial blood samples were obtained simultaneously for hematocrit (HCT), total solids (TS), glucose, and gas analysis and recorded at 1, 4, 8, 12, 16, 20, and 24 h from the start of ventilation. Hemodynamic variables were calculated by use of standard equations (13,14). Foals were repositioned by moving their hind limbs to their other side every 4 h after physiologic variables were recorded.
All drug infusions were discontinued 24 h after initiation of positive pressure ventilation. At the first evidence of ventilator-patient asynchrony, positive pressure ventilation was stopped and the endotracheal tube was disconnected from the ventilator circuit. The following times were recorded: from discontinuation of the drug infusions until the foal was removed from ventilatory support, extubated, able to maintain sternal recumbency, and capable of standing with and without assistance. When foals were capable of standing without assistance, they were returned to their mares and the time from extubation to nursing was recorded. Catheters were subsequently removed and foals were observed in the hospital for a minimum of 24 h before being discharged.
Ventilation
Foals were ventilated using synchronized intermittent mandatory ventilation volume-targeted mode, with automated flow and a positive end-expiratory pressure of 5 cmH2O applied throughout the study. Spirometry capabilities of the ventilator allowed ventilatory variables to be measured. Tidal volume was set at 8 to 10 mL/kg with a respiratory rate of 12 to 16 breaths/min to maintain arterial partial pressure of carbon dioxide (PaCO2) at 45 to 55 mmHg. The fraction of inspired oxygen (FiO2) was initially set to 0.35 and was adjusted to maintain arterial partial pressure of oxygen (PaO2) at 80 to 200 mmHg. Routine ventilation management was applied, including placing a heat and moisture exchanger between the patient and the breathing system and suctioning the nasotracheal tube every 6 h.
Statistical analysis
Statistical analysis was carried out using standard statistical software (SAS, version 9.4; SAS Institute, Cary, North Carolina, USA). Normality of the data was assessed graphically, through analysis of residuals and the Shapiro-Wilk test. A 2-way analysis of variance (ANOVA) for repeated measures was used to determine differences in physiologic variables measured over time. The results of the 2-way ANOVA are provided in the Supplemental Table.
The main effects of treatment and time and treatment by time interaction were included in the model. If the overall F test was significant for a treatment by time interaction, a post-hoc adjustment based on the multivariate t distribution was used to control the family-wise error rate of multiple treatment comparisons made at each time. Dunnett’s post-hoc analysis was used to compare values within the groups back to baseline. Student’s t-tests were conducted on single measurement values, including ventilatory variables, administered drug doses, and recovery times. Time to discontinue ventilator assistance was analyzed using Wilcoxon 2-sample test. All data are reported as mean ± standard deviation and all P-values < 0.05 were considered statistically significant.
Results
The mean infusion drug doses for butorphanol, propofol, dexmedetomidine, and midazolam, the number of propofol boluses administered over the 24-hour study period, and the total dose of propofol (including both infusion and boluses) are provided in Table II. Although the mean dose of propofol over the study period was not different between groups, foals receiving protocol DBP required a significantly greater number of propofol boluses than foals receiving protocol MBP in order to maintain an adequate plane of sedation.
Table II.
Infusion rates and bolus doses (mean ± SD) of drugs administered to healthy neonatal foals receiving dexmedetomidine, butorphanol, and propofol (DBP, n = 5) or midazolam, butorphanol, and propofol (MBP, n = 5) during a 24-hour period of assisted ventilation.
| DBP | MBP | |
|---|---|---|
| Dexmedetomidine (μg/kg BW per hour) | 2.4 ± 0.5 | |
| Midazolam (mg/kg BW per hour) | 0.14 ± 0.04 | |
| Butorphanol (μg/kg BW per hour) | 13 | 13 |
| Propofol infusion rate (mg/kg BW per hour)a | 6.78 ± 0.48 | 5.76 ± 1.38 |
| Propofol boluses-number | 9 ± 3† | 4 ± 2 |
| Propofol bolus dose (mg/kg) | 1.14 ± 0.15 | 1.05 ± 0.07 |
| Total propofol (mg/kg per hour)b | 6.97 ± 0.86 | 5.98 ± 1.32 |
Values differ significantly between treatments (P < 0.05).
Propofol infusion rate represents the rate of propofol administered by infusion only.
Total propofol includes the amount of propofol administered by infusion and bolus.
Cardiovascular and hematologic variables are displayed in Figure 1 and Table III. Heart rate (HR) and cardiac index (CI) were significantly greater than baseline values in foals receiving MBP during the first half of the infusion period, whereas heart rate was significantly lower than BL in foals receiving DBP during the initial infusion period.
Figure 1.
A — Heart rate (HR), B — cardiac index (CI), C — mean arterial pressure (MAP), and D — oxygen delivery (DO2) in mechanically ventilated clinically healthy neonatal foals receiving dexmedetomidine, butorphanol, and propofol (protocol DBP, □) or midazolam, butorphanol, and propofol (protocol MBP, ◆) over a 24-hour period. Data represent mean ± SD.
* Within a group, value differs significantly from baseline (P < 0.05).
† Within a time point, values differ significantly between treatments (P < 0.05).
Table III.
Cardiovascular and hematologic variables (mean ± SD values) determined in spontaneously breathing, clinically healthy neonatal foals receiving 1.2% end-tidal isoflurane (Time 0) followed by a 24-hour period of assisted ventilation while receiving dexmedetomidine, butorphanol, and propofol (DBP, n = 5) or midazolam, butorphanol, and propofol (MBP, n = 5).
| Variable | Time (h) | |||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| 0 | 1 | 4 | 8 | 12 | 16 | 20 | 24 | |
| SAP (mmHg) | ||||||||
| DBP | 95.8 ± 11.9 | 133.0 ± 16.6* | 106.8 ± 8.1 | 108.8 ± 9.8 | 102.8 ± 6.9 | 103.4 ± 23.1 | 101.6 ± 16.5 | 99.4 ± 13.6 |
| MBP | 88.4 ± 12.9 | 119.6 ± 22.0* | 129.0 ± 20.9* | 118.4 ± 9.0* | 115.4 ± 11.1* | 111.2 ± 28.6* | 122.2 ± 5.2* | 124.6 ± 11.3* |
| DAP (mmHg) | ||||||||
| DBP | 49.6 ± 9.8 | 60.4 ± 15.3 | 47.2 ± 5.1 | 47.2 ± 5.1 | 46.8 ± 2.2 | 48.2 ± 9.7 | 48.2 ± 8.7 | 41.4 ± 2.7 |
| MBP | 44.6 ± 5.0 | 66.4 ± 11.0* | 65.2 ± 9.9*† | 59.6 ± 9.5*† | 54.4 ± 11.1 | 52.2 ± 5.2 | 57.4 ± 8.2* | 60.6 ± 12.7*† |
| CVP (mmHg) | ||||||||
| DBP | 7.2 ± 1.1 | 8.4 ± 1.7 | 5.4 ± 1.1 | 5.2 ± 2.6 | 5.0 ± 1.2 | 7.2 ± 3.5 | 7.0 ± 3.1 | 5.8 ± 0.8 |
| MBP | 7.2 ± 1.8 | 6.6 ± 0.5* | 7.2 ± 0.8* | 6.4 ± 0.9 | 5.8 ± 1.3 | 6.4 ± 1.7 | 5.4 ± 1.5 | 5.8 ± 1.3 |
| MPAP (mmHg) | ||||||||
| DBP | 25.8 ± 3.7 | 32.5 ± 1.3 | 24.4 ± 3.6 | 26.4 ± 1.9 | 27.0 ± 6.1 | 26.0 ± 4.3 | 24.3 ± 5.1 | 24.0 ± 2.4 |
| MBP | 23.6 ± 3.7 | 28.4 ± 2.1 | 24.2 ± 4.3 | 26.4 ± 5.4 | 21.2 ± 8.0 | 21.4 ± 4.7 | 20.0 ± 4.4 | 19.4 ± 4.2 |
| PAOP (mmHg) | ||||||||
| DBP | 11.0 ± 1.2 | 11.3 ± 1.3 | 11.0 ± 1.6 | 12.3 ± 2.2 | 9.0 ± 1.8 | 11.0 ± 2.0 | 9.5 ± 3.1 | 10.8 ± 2.2 |
| MBP | 9.0 ± 2.0 | 10.8 ± 0.5 | 10.6 ± 2.2 | 11.2 ± 2.2* | 9.6 ± 1.1 | 12.0 ± 0.7* | 10.6 ± 1.5 | 10.6 ± 1.3 |
| SI (mL/beat/kg) | ||||||||
| DBP | 2.1 ± 0.3 | 2.6 ± 0.3* | 2.0 ± 0.2 | 2.0 ± 0.3 | 1.9 ± 0.3 | 1.7 ± 0.4* | 1.7 ± 0.3* | 1.8 ± 0.3 |
| MBP | 2.1 ± 0.3 | 2.6 ± 0.3* | 2.1 ± 0.3 | 2.2 ± 0.3 | 1.9 ± 0.4 | 2.2 ± 0.3 | 2.0 ± 0.3 | 2.1 ± 0.3 |
| SVRI (dynes.s/cm5/kg) | ||||||||
| DBP | 20.6 ± 4.7 | 27.1 ± 5.9* | 30.2 ± 7.3* | 28.0 ± 7.4* | 25.4 ± 3.7* | 26.9 ± 7.0* | 26.9 ± 6.8* | 23.0 ± 5.9* |
| MBP | 27.1 ± 13.7 | 34.0 ± 15.9 | 29.6 ± 14.9 | 29.2 ± 11.8 | 28.7 ± 11.4 | 29.3 ± 14.4 | 33.2 ± 12.5* | 32.9 ± 12.1* |
| PVRI (dynes.s/cm5/kg) | ||||||||
| DBP | 8.7 ± 6.1 | 8.1 ± 2.9 | 6.5 ± 2.7 | 7.0 ± 1.7 | 8.4 ± 3.8 | 6.9 ± 3.7 | 5.3 ± 4.0 | 5.5 ± 4.3 |
| MBP | 8.0 ± 4.9 | 6.9 ± 2.3 | 4.4 ± 1.3 | 5.4 ± 1.6 | 5.9 ± 1.6 | 4.0 ± 2.1 | 4.3 ± 2.3 | 3.7 ± 1.9 |
| VO2 (mL/min/kg) | ||||||||
| DBP | 6.2 ± 2.6 | 6.4 ± 1.3 | 6.2 ± 2.0 | 5.3 ± 2.0 | 9.2 ± 4.4 | 7.7 ± 0.7 | 8.4 ± 2.8 | 8.1 ± 1.9 |
| MBP | 6.4 ± 6.7 | 8.8 ± 4.0 | 5.0 ± 3.0 | 8.6 ± 6.6 | 5.6 ± 2.9 | 8.2 ± 2.6 | 5.8 ± 0.7 | 5.2 ± 3.1 |
| HCT (%) | ||||||||
| DBP | 36.5 ± 2.4 | 35.7 ± 0.6 | 37.2 ± 4.4 | 35.8 ± 3.9 | 36.8 ± 6.0 | 35.8 ± 3.9 | 36.6 ± 3.2 | 38.3 ± 3.6 |
| MBP | 33.5 ± 0.7 | 34.0 ± 3.5 | 33.0 ± 2.5 | 34.0 ± 1.9 | 31.3 ± 4.9 | 31.3 ± 2.3 | 33.0 ± 3.6 | 33.0 ± 2.0 |
| TS (g/dL) | ||||||||
| DBP | 7.2 ± 0.5 | 6.9 ± 0.4 | 7.4 ± 1.0 | 7.3 ± 0.9 | 7.3 ± 0.4 | 6.2 ± 1.7 | 7.5 ± 0.6 | 7.8 ± 0.1 |
| MBP | 7.5 ± 0.3 | 7.5 ± 0.3 | 7.1 ± 0.4 | 7.3 ± 0.3 | 6.7 ± 0.5 | 6.7 ± 0.1 | 7.3 ± 0.7 | 7.3 ± 0.8 |
| Lactate (mmoL/L) | ||||||||
| DBP | 2.0 ± 0.3 | 2.1 ± 0.2 | 1.7 ± 0.3 | 1.5 ± 0.2 | 1.8 ± 0.3 | 1.9 ± 0.3 | 1.8 ± 0.3 | 1.7 ± 0.3 |
| MBP | 1.3 ± 0.2 | 1.3 ± 0.3 | 1.1 ± 0.2 | 1.0 ± 0.1 | 1.0 ± 0.1 | 1.0 ± 0.1 | 1.0 ± 0.1 | 0.9 ± 0.2 |
| Temperature (°C) | ||||||||
| DBP | 37.1 ± 0.4 | 36.8 ± 0.3 | 36.4 ± 0.6 | 36.7 ± 0.7 | 37.1 ± 0.9 | 37.7 ± 0.8 | 38.0 ± 0.3 | 38.0 ± 0.5 |
| MBP | 37.0 ± 0.7 | 37.3 ± 0.7 | 38.3 ± 0.3*† | 38.2 ± 0.3*† | 37.8 ± 0.4 | 37.8 ± 0.4 | 38.0 ± 0.3* | 37.9 ± 0.2 |
Within a group, value differs significantly from baseline (P < 0.05).
Within a time point, values differ significantly between treatments (P-values).
SAP — systolic arterial pressure; DAP — diastolic arterial pressure; CVP — central venous pressure; MPAP — mean pulmonary arterial pressure; PAOP — pulmonary artery occlusion pressure; SI — stroke index; SVRI — systemic vascular resistance index; PVRI — pulmonary vascular resistance index; VO2 — oxygen consumption; HCT — hematocrit; TS — total solids.
Heart rate and CI were both significantly higher in foals receiving the MBP than those in the DBP group during the first 12 h of the study. Changes in oxygen delivery (DO2) relative to baseline followed a similar pattern as HR and CI, with values being higher than BL in the MBP and lower than BL in the DBP group.
Mean arterial pressure (MAP) increased relative to baseline in both groups, although significant changes were present only in foals receiving MBP. There were no significant differences relative to baseline or between treatment groups in oxygen consumption (VO2), pulmonary vascular resistance index (PVRI), mean pulmonary arterial pressure (MPAP), hematocrit (HCT), total solids (TS), and lactate. Body temperature was significantly higher than baseline in the MBP group at 4, 8, and 20 h. There were significant differences in body temperature between groups at 4 and 8 h only.
There were no significant differences between treatment groups in blood gas values, ventilator settings, and respiratory variables recorded during the 24-hour period. These are outlined in Table IV.
Table IV.
Ventilator setting and respiratory variables (mean ± SD) in clinically healthy neonatal foals receiving dexmedetomidine-butorphanol-propofol (DBP, n = 5) or midazolam-butorphanol-propofol (MBP, n = 5) during a 24-hour period of assisted ventilation.
| DBP | MBP | |
|---|---|---|
| Vt (mL/kg) | 12.4 ± 1.0 | 12.3 ± 2.0 |
| VE (mL/min/kg) | 157.4 ± 26.8 | 141.1 ± 19.1 |
| Respiratory rate (breaths/min) | 14 ± 2 | 13 ± 2 |
| PIP (cmH2O) | 13.5 ± 0.5 | 13.0 ± 0.9 |
| PEEP (cmH2O) | 5.0 ± 0.1 | 5.0 ± 0.1 |
| FiO2 (%) | 30.5 ± 1.7 | 30.1 ± 2.9 |
| PaO2 (mmHg) | 183.6 ± 22.1 | 170.8 ± 22.1 |
| PaCO2 (mmHg) | 52.6 ± 3.7 | 53.2 ± 3.7 |
| Resistance (cmH2O/L/s) | 8.6 ± 0.8 | 11.3 ± 2.3 |
| Compliance (mL/cmH2O) | 57.4 ± 8.7 | 61.3 ± 11.5 |
Vt — tidal ventilation; VE — minute ventiltation; PIP — peak inspiratory pressure; PEEP — positive end expiratory pressure; FiO2 — fraction of inspired oxygen; PaO2 — partial pressure of oxygen; PaCO2 — partial pressure of carbon dioxide.
The mean volume of urine collected over the 24-hour period was significantly higher in foals receiving protocol MBP (5.49 ± 0.64 mL/kg BW per hour) than in foals receiving DBP (3.31 ± 1.6 mL/kg BW per hour). There was a trend for the foals in the DBP group to have a higher urine output in the first 6 h of the study and a lower urine output in the remaining time period compared to the foals in the MBP, although differences in urine volume between groups at specific times did not achieve statistical significance. There were no differences in urine specific gravity between groups.
All recovery times, except for time to extubation, were significantly shorter in foals in the DBP group than those in the MBP group. Recovery times are reported in Table V.
Table V.
Time in minutes (mean ± SD) following discontinuation of drug administration to indices of recovery in clinically healthy neonatal foals receiving dexmedetomidine-butorphanol-propofol (DBP, n = 5) or midazolam-butorphanol-propofol (MBP, n = 5) during a 24-hour period of assisted ventilation.
| DBP | MBP | |
|---|---|---|
| Spontaneous ventilation | 3.0 ± 3.5† | 3.8 ± 4.8 |
| Extubation | 4.2 ± 3.3 | 12.5 ± 10.6 |
| Sternal recumbency | 22.4 ± 11.0† | 110.2 ± 41.6 |
| Standing with assistance | 39.5 ± 19.4† | 142.2 ± 67.8 |
| Standing unassisted | 64.0 ± 10.4† | 254.6 ± 42.8 |
| Nursing | 92.3 ± 30.6† | 211.5 ± 47.7 |
Within a variable, value differs significantly between treatments (P < 0.05).
Discussion
This study describes 2 different protocols for assisted ventilation in foals, while maintaining cardiovascular variables within ranges typically recorded in healthy foals that are sedated or at a light plane of anesthesia (11,12,15). The DBP protocol resulted in a relatively fast recovery and return to normal activities, with foals being able to stand unassisted approximately 1 h after the drug infusion was terminated. Although foals receiving MBP had a favorable cardiovascular status throughout the study period, the time to resume normal activities was substantially longer than that observed in those receiving DBP. This may result in the MBP protocol being less desirable than the DBP.
The goal of this study was to achieve a degree of depression of the central nervous system (CNS) in foals that permitted ventilatory support, but did not prevent minor movement, such as limb flexion and stretching. While multiple agents were used in both protocols tested, the focus of the study was to evaluate and compare protocols containing a benzodiazepine or an alpha-2 agonist, as these 2 groups of sedative agents are most often used for sedative purposes in foals (16,17). Midazolam was the benzodiazepine chosen for this study due to its water-soluble properties and lack of association with accumulation of propylene glycol, whereas dexmedetomidine was the alpha-2 agonist selected due to its reported short half-life and rapid redistribution, at least in mature veterinary species and humans (16,18). To the authors’ knowledge, the pharmacokinetic properties of midazolam or dexmedetomidine have not been reported in foals. Doses of the sedatives were therefore based on the reported relative clinical sedative properties of these 2 agents in foals and adult horses (11).
Midazolam is considered more potent than diazepam in human patients, but such comparative potency studies have not been conducted in veterinary species and recommended dose ranges for midazolam and diazepam are similar (16,19). Dexmedetomidine is considerably more potent than xylazine and, based on the literature in adult horses, it was estimated that a dose of 3 μg/kg BW was similar in sedative effects to 0.8 mg/kg BW of xylazine and 0.2 mg/kg BW of midazolam (18,20).
As foals in this study were being transferred from an inhalant-based anesthesia to an intravenous regimen, conservative doses of 1.5 μg/kg BW of dexmedetomidine and 0.1 mg/kg BW of midazolam were selected as the initial bolus doses. The infusion doses of the sedatives were similarly selected based on studies in foals, adult horses, and critically ill human patients (21–23). Based on our findings, the sedative doses selected at the onset of the study were roughly equivalent, based on the subsequent change in dexmedetomidine and midazolam administration rates. Specifically, the mean dose of both sedative agents was slightly above the initial rate of infusion for both groups. Furthermore, the rate of administration of propofol was similar between groups. The number of propofol bolus doses was significantly higher in the group receiving dexmedetomidine, however, and although not significant, the propofol infusion rate was also greater in this group.
The latter findings may suggest that the relative degree of CNS depression with the chosen dose of dexmedetomidine was somewhat less than that achieved with midazolam. Based on our results, a slightly higher dose of dexmedetomidine might be selected in clinical practice to reduce the dose of propofol required to achieve adequate CNS depression to facilitate ventilation, although the cardiovascular effects of this approach are unknown at this time. Although a constant infusion dose of midazolam was set in our protocol, with adjustments based on the clinical signs, our results would suggest that the dose of midazolam should be reduced over time if a rapid recovery is desired. Although pharmacokinetics of the agents studied were not evaluated in this study, the slow return to normal activities observed in the foals receiving midazolam was likely a result of accumulation of midazolam over time (24).
In clinical practice, sedation of critically ill foals with a benzodiazepine or alpha-2 agonist alone might be suitable to permit ventilatory support. In this study with healthy foals, we chose to include both propofol and butorphanol in order to reduce the total dose of sedative agents required and to ensure that adequate restraint was achieved to safely manage the patients during the study period. Propofol, administered as an infusion, was chosen, due to its short half-life and rapid clearance. It has previously been administered as an infusion for sedation or anesthesia for prolonged ventilatory support in humans and other veterinary species and as an anesthetic in foals undergoing diagnostic imaging (3,4,8,25). The initial infusion dose of propofol was selected based on the latter studies.
Although foals in this study were healthy and had only minimal instrumentation, it was elected to add butorphanol, as it would likely be added to a protocol in clinical patients due to its analgesic properties and potential beneficial effect on nursing behavior during recovery from sedation (10). The dose rate chosen was based on doses previously reported in adult horses (26).
In this study, the investigators chose to collect baseline hemodynamic variables while the foals were positioned in sternal recumbency and receiving isoflurane delivered at an inhaled concentration to maintain a light plane of anesthesia. Although there are no studies reporting the cardiopulmonary effects of isoflurane (1.2% end-tidal) alone in foals under 5 d of age, the values observed were similar to those previously reported in 7- to 10-day-old foals receiving isoflurane (1.0% to 1.1% end-tidal) following anesthetic induction with an injectable regime (11).
When considering the hemodynamic variables of the 2 injectable regimens relative to baseline, the influence of isoflurane on the baseline measurements should be taken into account. In addition, the hemodynamic effects of isoflurane may have also impacted the initial response to the injectable drugs. It is important to note, however, that the study took place over a 24-hour time period and the effects of isoflurane 1 h after its discontinuation were likely minimal at the time of the first cardiac output measurement. Although the protocols used in the current study have not previously been evaluated in foals, some of the differences in cardiovascular variables observed in this study are consistent with those previously reported in studies evaluating alpha-2 adrenergic agonists and benzodiazepines in horses (11,27). The cardiovascular effects of alpha-2 adrenergic agonists administered as an intravenous bolus have been well-documented in adult horses and are typified by reductions in heart rate and cardiac output, increases in systemic vascular resistance, and an initial rise in blood pressure, followed by a more prolonged decrease to values similar or below baseline values (15,27).
In contrast, it has been shown that cardiovascular effects of benzodiazepines on heart rate (HR), cardiac output (CO), or mean aortic pressure (MAP) in horses are not significant, even at supra-clinical doses (28). The foals receiving dexmedetomidine in this study (DBP group) had lower HR and cardiac index (CI) values than foals receiving the protocol containing midazolam (MBP group). The lower CI with protocol DBP also resulted in lower oxygen delivery (DO2) compared to protocol MBP. Fortunately, in this group of healthy foals, the difference in DO2 did not appear to result in compromised global tissue oxygenation, as blood lactate remained unchanged over time in both treatment groups. This finding is particularly relevant as oxygen debt, which is indicated by elevated blood lactate, is associated with reduced survival in critically ill foals (29).
In this study, foals receiving dexmedetomidine as a constant rate infusion did not have the characteristic dramatic increase in blood pressure typically observed when alpha-2 agonists are administered. The immaturity of the foals’ vascular system due to their very young age or the concurrent administration of propofol may have blunted the vascular response to the alpha-2 agonist in this study. A decreased central sympathetic outflow secondary to central alpha-2 receptor activation may also have contributed to the systemic arterial pressures observed in the foals receiving dexmedetomidine (30). Similar systemic arterial pressures were recorded in slightly older foals receiving a constant rate infusion of dexmedetomidine at 1 μg/kg BW per hour in combination with alfaxalone and remifentanyl (12).
It has been shown that alpha-2 agonists increase urine output in adult horses, even when horses are deprived of food and water (31– 33). To date, these studies have examined the effects over shorter periods of time than that of the present study (31–33). Although foals receiving dexmedetomidine had a significantly lower urine volume over the 24-hour period than foals receiving midazolam, there was a trend toward increased urine output in the first 6 h. The small sample size in the present study may have contributed to the lack of differences during the early period of the study. The subsequent reduced urine output in horses receiving an infusion of alpha-2 agonists over a 24-hour period is, as yet, unreported. Further evaluation is warranted of the impact of various sedative regimens, particularly those administered over a prolonged period, on urine output and hydration status to assist both nutritional and fluid therapy in foals in the clinical setting.
The rapid recovery observed in foals in the DBP group is consistent with other studies that reported rapid recoveries in foals receiving propofol infusions after premedication with xylazine and in horses and ponies anesthetized with infusions of medetomidine and propofol (25,34,35). Although it took longer for foals in the MBP group to recover, this might be shortened by using flumazenil, which is a benzodiazepine antagonist, to reverse the sedative effects of midazolam.
When drawing conclusions related to the relative benefits of the protocols described in this study, it is appropriate to draw attention to the fact that the individuals responsible for adjusting the foals’ depth of anesthesia by adjusting the rate of drug infusion were not blinded to the treatment groups. To standardize the assessment of foals’ depth of anesthesia, criteria used to trigger changes in drug infusion rates were based on signs typically used in a clinical setting, including movement, patient-ventilator synchrony, and eye position and followed a standardized protocol (Table I). Although this limitation in study design is recognized, it was not feasible to have an additional observer throughout the entire 24-hour study period due to costs and available personnel. Although this may limit the strength of the comparisons between groups, the study adds significantly to the literature by providing 2 sedative protocols, including the drug doses administered and the resulting cardiovascular effects, as well as the recovery characteristics associated with each protocol.
Overall, this study provides clinicians with 2 potential sedative protocols to facilitate prolonged sedation in foals requiring ventilatory support. Although the protocol using midazolam resulted in suitable sedation and acceptable physiologic changes, clinicians need to be aware of the potential for a lengthy recovery period when this agent is used in foals for a prolonged period at the doses evaluated in this study.
Supplementary Information
Supplemental Table.
Results of the 2-way ANOVA for repeated measures for cardiovascular and hematologic variables measured over time. P-values for the main effects of treatment and time and treatment by time interaction were included in the analysis.
| P-value | P-value | P-value | |
|---|---|---|---|
| Variable | Time | Treatment | Treatment by time |
| HR (beats/min) | 0.4371 | 0.1804 | 0.0001 |
| CI (mL/kg/min) | 0.0877 | 0.0018 | 0.0011 |
| MAP (mmHg) | 0.0003 | 0.0152 | < 0.0001 |
| DO2(mL/min/kg) | 0.0385 | 0.2814 | < 0.0001 |
| SAP (mmHg) | 0.0002 | 0.0859 | 0.2188 |
| DAP (mmHg) | < 0.0001 | < 0.0122 | < 0.0001 |
| CVP (mmHg) | < 0.0001 | 0.8037 | < 0.0001 |
| MPAP (mmHg) | 0.0526 | 0.1048 | 0.6612 |
| PAOP (mmHg) | 0.0005 | 0.7320 | 0.6047 |
| SI (mL/beat/kg) | < 0.0001 | 0.1664 | 0.0960 |
| SVRI (dynes.s/cm5/kg) | 0.0011 | 0.7916 | 0.2534 |
| PVRI (dynes.s/cm5/kg) | 0.1131 | 0.4441 | 0.9927 |
| VO2 (mL/min/kg) | 0.8854 | 0.5871 | 0.3281 |
| HCT (%) | 0.6460 | 0.05575 | 0.1409 |
| TS (g/dL) | 0.0865 | 0.2618 | 0.3130 |
| Lactate (mmoL/L) | 0.0586 | 0.0754 | 0.2497 |
| Temperature (°C) | < 0.0047 | < 0.0001 | < 0.0001 |
HR — heart rate; CI — cardiac index; MAP — mean arterial pressure; DO2 — oxygen delivery; SAP — systolic arterial pressure; DAP — diastolic arterial pressure; CVP — central venous pressure; MPAP — mean pulmonary arterial pressure; PAOP — pulmonary artery occlusion pressure; SI — stroke index; SVRI — systemic vascular resistance index; PVRI — pulmonary vascular resistance index; VO2 — oxygen consumption; HCT — hematocrit; TS — transferrin saturation.
Acknowledgment
This project was supported by the Ontario Ministry of Agriculture, Food and Rural Affairs.
Footnotes
This article was presented in September 2016 at the 2016 Annual Meeting of the American College of Veterinary Anesthesia and Analgesia in Grapevine, Texas.
References
- 1.Palmer JE. Ventilatory support of the critically ill foal. Vet Clin North Am Equine Pract. 2005;21:457–486. doi: 10.1016/j.cveq.2005.04.002. [DOI] [PubMed] [Google Scholar]
- 2.Mehta S, Burry L, Fischer S, et al. Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients. Crit Care Med. 2006;34:374–380. doi: 10.1097/01.ccm.0000196830.61965.f1. [DOI] [PubMed] [Google Scholar]
- 3.Payen JF, Chanques G, Mantz J, et al. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: A prospective multicenter patient-based study. Anesthesiology. 2007;106:687–695. doi: 10.1097/01.anes.0000264747.09017.da. [DOI] [PubMed] [Google Scholar]
- 4.Ethier MR, Mathews KA, Valverde A, et al. Evaluation of the efficacy and safety for use of two sedation and analgesic protocols to facilitate assisted ventilation of healthy dogs. Am J Vet Res. 2008;69:1351–1359. doi: 10.2460/ajvr.69.10.1351. [DOI] [PubMed] [Google Scholar]
- 5.McPherson C. Sedation and analgesia in mechanically ventilated preterm neonates: Continue standard of care or experiment? J Pediatr Pharmacol Ther. 2012;17:351–364. doi: 10.5863/1551-6776-17.4.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Riker RR, Fraser GL. Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit. Pharmacotherapy. 2005;25:8S–18S. doi: 10.1592/phco.2005.25.5_part_2.8s. [DOI] [PubMed] [Google Scholar]
- 7.Norman WM, Court MH, Greenblatt DJ. Age-related changes in the pharmacokinetic disposition of diazepam in foals. Am J Vet Res. 1997;58:878–880. [PubMed] [Google Scholar]
- 8.Chaffin MK, Walker MA, McArthur NH, Perris EE, Matthews NS. Magnetic resonance imaging of the brain of normal neonatal foals. Vet Radiol Ultrasound. 1997;38:102–111. doi: 10.1111/j.1740-8261.1997.tb00823.x. [DOI] [PubMed] [Google Scholar]
- 9.Naylor JM, Garven E, Fraser L. A comparison of romifidine and xylazine in foals: The effects on sedation and analgesia. Equine Vet Educ. 1997;9:329–334. [Google Scholar]
- 10.Arguedas MG, Hines MT, Papich MG, Farnsworth KD, Sellon DC. Pharmacokinetics of butorphanol and evaluation of physiologic and behavioral effects after intravenous and intramuscular administration to neonatal foals. J Vet Intern Med. 2008;22:1417–1426. doi: 10.1111/j.1939-1676.2008.0200.x. [DOI] [PubMed] [Google Scholar]
- 11.Kerr CL, Bouré LP, Pearce SG, McDonell W. Cardiopulmonary effects of diazepam-ketamine-isoflurane or xylazine-ketamine-isoflurane during abdominal surgery in foals. Am J Vet Res. 2009;70:574–580. doi: 10.2460/ajvr.70.5.574. [DOI] [PubMed] [Google Scholar]
- 12.Jones T, Bracamonte JL, Ambros B, Duke-Novakovski T. Total intravenous anesthesia with alfaxalone, demedetomidine, and remifentanil in healthy foals undergoing abdominal surgery. Vet Anaesth Analg. 2019;46:315–324. doi: 10.1016/j.vaa.2019.01.003. [DOI] [PubMed] [Google Scholar]
- 13.Boyd CJ, McDonell WN, Valliant A. Comparative hemodynamic effects of halothane and halothane-acepromazine at equipotent doses in dogs. Can J Vet Res. 1991;55:107–112. [PMC free article] [PubMed] [Google Scholar]
- 14.Haskins S, Pascoe PJ, Ilkiw JE, Fudge J, Hopper K, Aldrich J. Reference cardiopulmonary values in normal dogs. Comp Med. 2005;55:156–161. [PubMed] [Google Scholar]
- 15.Carter SW, Robertson SA, Steel CJ, Jourdenais DA. Cardiopulmonary effects of xylazine sedation in the foal. Equine Vet J. 1990;22:384–388. doi: 10.1111/j.2042-3306.1990.tb04300.x. [DOI] [PubMed] [Google Scholar]
- 16.Taylor PM, Clark KW. Handbook of Equine Anaesthesia. 2nd ed. Toronto, Ontario: Saunders; 2007. Sedation and premedication; pp. 17–32. [Google Scholar]
- 17.Fischer B, Clark-Price S. Anesthesia of the equine neonate in health and disease. Vet Clin North Am Equine Pract. 2015;31:567–585. doi: 10.1016/j.cveq.2015.09.002. [DOI] [PubMed] [Google Scholar]
- 18.Bettschart-Wolfensberger R, Freeman SL, Bowen IM, et al. Cardiopulmonary effects and pharmacokinetics of i.v. dexmedetomidine in ponies. Equine Vet J. 2005;37:60–64. doi: 10.2746/0425164054406801. [DOI] [PubMed] [Google Scholar]
- 19.Nuotto EJ, Korttila KT, Lichtor JL, Ostman PL, Rupani G. Sedation and recovery of psychomotor function after intravenous administration of various doses of midazolam and diazepam. Anesth Analg. 1992;74:265–271. doi: 10.1213/00000539-199202000-00017. [DOI] [PubMed] [Google Scholar]
- 20.Bryant CE, England GC, Clarke KW. Comparison of the sedative effects of medetomidine and xylazine in horses. Vet Rec. 1991;129:421–423. doi: 10.1136/vr.129.19.421. [DOI] [PubMed] [Google Scholar]
- 21.Wilkins PA. How to use midazolam to control equine neonatal seizures. Proc Annual AAEP Conv; 2005; Seattle, Washington. p. 279. [Google Scholar]
- 22.Marcilla MG, Schauvliege S, Segaert S, Duchateau L, Gasthuys F. Influence of a constant rate infusion of dexmedetomidine on cardiopulmonary function and recovery quality in isoflurane anaesthetized horses. Vet Anaesth Analg. 2012;39:49–58. doi: 10.1111/j.1467-2995.2011.00672.x. [DOI] [PubMed] [Google Scholar]
- 23.Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA. 2009;301:489–499. doi: 10.1001/jama.2009.56. [DOI] [PubMed] [Google Scholar]
- 24.Hubbell JAE, Kelly EM, Aarnes TK, et al. Pharmacokinetics of midazolam after intravenous administration to horses. Equine Vet J. 2013;45:721–725. doi: 10.1111/evj.12049. [DOI] [PubMed] [Google Scholar]
- 25.Matthews NS, Chaffin MK, Erickson SW, Overhulse WA. Propofol anesthesia for non-surgical procedures of neonatal foals. Equine Pract. 1995;17:15–20. [Google Scholar]
- 26.Sellon DC, Roberts MC, Blikslager AT, Ulibarri C, Papich MG. Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy. J Vet Intern Med. 2004;18:555–563. doi: 10.1892/0891-6640(2004)18<555:eocrii>2.0.co;2. [DOI] [PubMed] [Google Scholar]
- 27.Bettschart-Wolfensberger R, Bettschart RW, Vainio O, Marlin D, Clarke KW. Cardiopulmonary effects of a two hour medetomidine infusion and its antagonism by atipamezole in horses and ponies. J Vet Anaesth. 1999;26:8–12. [Google Scholar]
- 28.Muir WW, Sams RA, Huffman RH, Noonan JS. Pharmacodynamic and pharmacokinetic properties of diazepam in horses. Am J Vet Res. 1982;43:1756–1762. [PubMed] [Google Scholar]
- 29.Borchers A, Wilkins PA, Marsh PM, et al. Sequential L-lactate concentration in hospitalised equine neonates: A prospective multicentre study. Equine Vet J Suppl. 2013;45:2–7. doi: 10.1111/evj.12165. [DOI] [PubMed] [Google Scholar]
- 30.Langer SZ. Presynaptic regulation of catecholamines. Pharmacol Rev. 1980;32:337–362. [PubMed] [Google Scholar]
- 31.Thurmon JC, Steffey EP, Zinkl JG, Woliner M, Howland D., Jr Xylazine causes transient dose-related hyperglycemia and increased urine volumes in mares. Am J Vet Res. 1984;45:224–227. [PubMed] [Google Scholar]
- 32.Trim C, Hanson RR. Effects of xylazine on renal function and plasma glucose in ponies. Vet Rec. 1986;118:65–67. doi: 10.1136/vr.118.3.65. [DOI] [PubMed] [Google Scholar]
- 33.Nuñez E, Steffey EP, Ocampo L, Rodriquez A, Garcia AA. Effects of alpha2-adrenergic receptor agonists on urine production in horses deprived of food and water. Am J Vet Res. 2004;65:1342–1346. doi: 10.2460/ajvr.2004.65.1342. [DOI] [PubMed] [Google Scholar]
- 34.Bettschart-Wolfensberger R, Bowen IM, Freeman SL, Weller R, Clarke KW. Medetomidine-ketamine anaesthesia induction followed by medetomidine-propofol in ponies: Infusion rates and cardiopulmonary side effects. Equine Vet J. 2003;35:308–313. doi: 10.2746/042516403776148354. [DOI] [PubMed] [Google Scholar]
- 35.Bettschart-Wolfensberger R, Kalchofner K, Neges K, Kästner S, Fürst A. Total intravenous anaesthesia in horses using medetomidine and propofol. Vet Anaesth Analg. 2005;32:348–354. doi: 10.1111/j.1467-2995.2005.00202.x. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Table.
Results of the 2-way ANOVA for repeated measures for cardiovascular and hematologic variables measured over time. P-values for the main effects of treatment and time and treatment by time interaction were included in the analysis.
| P-value | P-value | P-value | |
|---|---|---|---|
| Variable | Time | Treatment | Treatment by time |
| HR (beats/min) | 0.4371 | 0.1804 | 0.0001 |
| CI (mL/kg/min) | 0.0877 | 0.0018 | 0.0011 |
| MAP (mmHg) | 0.0003 | 0.0152 | < 0.0001 |
| DO2(mL/min/kg) | 0.0385 | 0.2814 | < 0.0001 |
| SAP (mmHg) | 0.0002 | 0.0859 | 0.2188 |
| DAP (mmHg) | < 0.0001 | < 0.0122 | < 0.0001 |
| CVP (mmHg) | < 0.0001 | 0.8037 | < 0.0001 |
| MPAP (mmHg) | 0.0526 | 0.1048 | 0.6612 |
| PAOP (mmHg) | 0.0005 | 0.7320 | 0.6047 |
| SI (mL/beat/kg) | < 0.0001 | 0.1664 | 0.0960 |
| SVRI (dynes.s/cm5/kg) | 0.0011 | 0.7916 | 0.2534 |
| PVRI (dynes.s/cm5/kg) | 0.1131 | 0.4441 | 0.9927 |
| VO2 (mL/min/kg) | 0.8854 | 0.5871 | 0.3281 |
| HCT (%) | 0.6460 | 0.05575 | 0.1409 |
| TS (g/dL) | 0.0865 | 0.2618 | 0.3130 |
| Lactate (mmoL/L) | 0.0586 | 0.0754 | 0.2497 |
| Temperature (°C) | < 0.0047 | < 0.0001 | < 0.0001 |
HR — heart rate; CI — cardiac index; MAP — mean arterial pressure; DO2 — oxygen delivery; SAP — systolic arterial pressure; DAP — diastolic arterial pressure; CVP — central venous pressure; MPAP — mean pulmonary arterial pressure; PAOP — pulmonary artery occlusion pressure; SI — stroke index; SVRI — systemic vascular resistance index; PVRI — pulmonary vascular resistance index; VO2 — oxygen consumption; HCT — hematocrit; TS — transferrin saturation.