Abstract
Objective
To determine the cardiopulmonary effects of oral trazodone before isoflurane anesthesia in systemically healthy horses.
Methods
12 horses donated for euthanasia (from August 2022 through June 2023) due to conditions unrelated to the cardiovascular system were included in this prospective, randomized, controlled trial. Horses were assigned to receive oral trazodone (6 mg/kg; n = 7) or corn syrup (n = 5) 1 hour before xylazine (1 mg/kg, IV) sedation, ketamine (2.2 mg/kg, IV) and propofol (0.7 mg/kg, IV) induction, and anesthetic maintenance with inhaled isoflurane (target 1.6% expired) for 75 minutes. Dobutamine (1 μg/kg/min, IV) was administered during the last 15 minutes of anesthesia before euthanasia. The primary outcome cardiac index (CI; saline thermodilution technique) was recorded at baseline, 1 hour after oral dosing, after sedation and induction, and every 15 minutes under anesthesia. Data were compared between groups using a mixed model.
Results
All 12 horses completed the study. No significant differences were observed between groups at all time points except after dobutamine infusion, where CI (mean ± SD) was significantly higher in the trazodone group (66.2 ± 16.8 mL/min/kg) than the control group (46.8 ± 6.6 mL/min/kg). One horse in the trazodone group displayed signs of colic after dosing, with markedly reduced CI during anesthesia compared to all other horses.
Conclusions
Oral trazodone before isoflurane anesthesia in healthy horses produced variable cardiovascular function, including profound cardiovascular depression in 1 horse.
Clinical Relevance
Profound individual cardiovascular responses may be seen with routine preanesthetic trazodone in horses.
Horses may be given oral trazodone to facilitate stall rest and reduce anxiety in a hospital setting, including before general anesthesia. Trazodone is a serotonin receptor antagonist and reuptake inhibitor that has diverse receptor targets, including α1-adrenergic receptor antagonist (α1-antagonist) actions.1 Concern exists regarding the potential for hypotension associated with trazodone’s α1-antagonist and possible vasodilatory effect2 in combination with the cardiovascular depression associated with inhalant anesthetics in horses.
Effects on heart rate (HR), vascular tone, and cardiac contractility have been documented with trazodone in anesthetized dogs.3–5 Moreover, arrhythmias and sinus tachycardia have been reported with oral trazodone in horses.6,7 At the authors’ institution, tachycardia and hypotension have been observed in some anesthetized horses given trazodone before anesthesia to promote anxiolysis, prompting questions about trazodone’s interaction with anesthetic drugs in this species.
From a search of the literature, no published studies have investigated cardiopulmonary function in horses given oral trazodone before general anesthesia. Given the significance of maintaining hemodynamic stability in horses for optimal anesthetic recovery,8,9 it was decided to study the effects of 6 mg/kg oral trazodone given 1 hour before xylazine sedation, followed by anesthetic induction with ketamine and propofol, and maintenance of anesthesia with isoflurane in systemically healthy horses. Additionally, the effects of concurrent dobutamine infusion were studied. It was hypothesized that trazodone-treated horses would show a reduction in systemic arterial blood pressure due to decreases in vascular tone and that cardiac output (CO) would be increased as compared to anesthetized control horses. A secondary hypothesis was that this difference in CO would be augmented by the IV infusion of dobutamine.
Methods
Animals
The study protocol was approved by the Colorado State University IACUC (protocol #3150). Horses considered systemically healthy based on physical examination, including thorough cardiorespiratory auscultation, CBC, and serum chemistry, were included in the study. Horses exhibiting any systemic illness or significant abnormalities in cardiorespiratory auscultation, CBC, or serum chemistry were excluded. Horses were donated with written informed consent for all study procedures, followed by euthanasia due to incurable conditions unrelated to the cardiovascular system (primarily chronic lameness but also ocular squamous cell carcinoma, penile carcinoma, and blindness due to recurrent uveitis). Horses were housed in box stalls at least 1 night before the experiment to acclimate to the hospital environment. They were provided free-choice grass/alfalfa mix hay and water, which were not withheld before anesthesia.
A sample size of 5 horses/treatment group was determined using a power analysis for a difference in CO between treatments of 30% considered clinically significant, an estimated SD of 15%, and a power of 80%. Two additional horses were added to the trazodone treatment group to account for variability in drug response.
Instrumentation and data collection
On the morning of the experiment, body mass and baseline physical examination variables (HR, respiratory rate [fR], and rectal temperature) were collected on each horse. A 14-gauge, 13.3-cm catheter was then placed percutaneously in the left jugular vein for drug and fluid delivery after SC infiltration of lidocaine 2% (3 mL). Similarly, 2 8-French introducers were inserted into the right jugular vein to allow the passage of a 7-French, 100-mm right atrial catheter and a 7.5-French, 100-mm pulmonary artery catheter. The position of these catheters was confirmed by characteristic pressure tracings visible when the catheters were connected to a blood pressure transducer and a multiparametric anesthetic monitor. Transducer accuracy was verified using a mercury manometer over a range of pressures (0 to 200 mm Hg) prior to the study. The transducers were zeroed to atmospheric pressure and positioned level with the point of the shoulder. Catheters were secured in place with tape and bandage material.
Once instrumented, baseline CO was measured in all horses while standing quietly in the stall using the saline thermodilution technique. Briefly, 1 mL/15 kg body mass iced saline solution 0.9% sodium chloride (0.1 to 0.6 °C) was injected via the right atrial catheter at 35 mL/s using a power injector. A computer used the changes in blood temperature measured at the tip of the pulmonary artery catheter and the known injectate temperature to calculate CO using the Stewart-Hamilton equation and an automated computation constant. Because a 10-mL injectate volume was known to the computer, the results were then adjusted for the difference in actual injectate volume. The injection was conducted 4 times, and the mean of the closest 3 values was recorded as the CO measurement for that time point. All results were indexed to body mass as cardiac index (CI). Mean right atrial pressure (RAP), pulmonary arterial pressure (PAP), and pulmonary artery temperature were also recorded.
Each horse was then randomly allocated (graphpad.com/quickcalcs) via simple random sampling to either the trazodone (n = 7) or control group (n = 5). In the trazodone group, horses were given oral trazodone (6 mg/kg; trazodone hydrochloride tablet; Zydus Pharmaceuticals Inc) using a 60-mL catheter-tip syringe. Tablets were ground with a mortar and pestle and immediately mixed with corn syrup (10 mL) and water (20 mL) for administration, which was performed by 1 author (RCH). Control horses were given only water (30 mL) and corn syrup (10 mL). Whether the full contents of the syringe were successfully administered was recorded. One hour later, HR, fR, and rectal temperature were recorded. Notes on horse behavior (signs of sweating, pawing, sedation, recumbency, etc) were also recorded. Cardiac index, RAP, and PAP measurements were performed. Horses were then immediately brought to the anesthetic induction area.
Anesthesia and data collection
An experimental timeline is provided in Figure 1. The investigators were not blinded to the horses’ assigned treatment group due to limitations in study personnel availability and budget constraints requiring all study personnel to directly assist with each horse’s restraint, instrumentation, anesthesia, and data collection. Horses were brought to the anesthesia induction box and given xylazine (1 mg/kg, IV). Two minutes later, HR, fR, CI, RAP, and PAP were measured. Immediately afterward, horses were given ketamine (2.2 mg/kg, IV) and propofol (0.7 mg/kg, IV) to induce general anesthesia. Orotracheal intubation was performed with a cuffed endotracheal tube. Horses were temporarily positioned in right lateral recumbency for the measurement of postinduction HR, fR, CI, RAP, and PAP. After these data were collected, horses were hoisted into the operating room and placed in dorsal recumbency on a padded table. The endotracheal tube was attached to a large animal breathing circuit, and anesthesia was maintained with isoflurane in 100% oxygen. The target end-tidal isoflurane concentration (FÉIso) was 1.6% (1.2 times the reported MAC for horses), which was subsequently corrected for barometric pressure at the study location.10 The accuracy of the gas analyzer within the anesthetic monitor was confirmed before the study with standard gases (compressed isoflurane 0.5%, 1%, 1.5%, 2%, and 3% balance nitrogen).
Study timeline for 12 horses randomly allocated to receive oral trazodone (n = 7) or plain corn syrup (n = 5) prior to sedation with IV xylazine, anesthetic induction with ketamine and propofol, and anesthetic maintenance with isoflurane. Time points (Ts) are T0 (connection to circuit) and T15, T30, T45, T60, and T75 minutes of anesthesia. B = Baseline. CI = Cardiac index. FÉIso = End-tidal isoflurane concentration. HR = Heart rate. MAP = Mean arterial pressure. PAP = Mean pulmonary artery pressure. PD = Postdose. PI = Postinduction. PX = Postxylazine. RAP = Mean right atrial pressure. SVRI = Systemic vascular resistance index.
Citation: American Journal of Veterinary Research 86, 6; 10.2460/ajvr.25.01.0029
Mechanical ventilation was started immediately, with a tidal volume of 15 mL/kg, 2.5-second inspiratory time, and fR (2 to 5 breaths/min; inspiratory-to-expiratory ratio, 1:4.8 to 1:12) to maintain the PaCO2 between 45 and 55 mm Hg (6.0 to 7.3 kPa) as measured by arterial blood gas analysis.
Horses were instrumented with a 3-lead base-apex ECG, pulse oximeter probe, sidestream capnography, and direct arterial blood pressure measurement via a 20-gauge, 4.8-cm catheter in the left facial artery. Isotonic fluid (5 mL/kg/h, IV) was infused continuously throughout anesthesia using a fluid pump. From connection to the anesthetic circuit to time 60 minutes, no additional drugs were given to the horses. After measurements were taken at time 60 minutes, an infusion of dobutamine (1 µg/kg/min, IV) was delivered until the end of anesthesia at time 75 minutes.
At 15, 30, 45, 60, and 75 minutes of anesthesia, HR, pulmonary artery temperature, CI, RAP, and PAP; systolic, diastolic, and mean arterial pressure (MAP); and FÉIso were recorded. Systemic vascular resistance was calculated using CO, RAP, and MAP and indexed to body mass as systemic vascular resistance index (SVRI).
Arterial blood samples were taken and analyzed for PaO2, PaCO2, pH, base excess, bicarbonate, glucose, lactate, and creatinine. Simultaneous mixed venous blood samples were collected to calculate oxygen consumption (V˙O2), oxygen delivery (DO2), and oxygen extraction (EO2). Horses were euthanized using sodium pentobarbital (19,500 mg/horse, IV) after the last measurements at time 75 minutes.
Plasma drug concentration analysis
In trazodone-treated horses, venous blood samples were collected for plasma trazodone concentration analysis. Samples were collected 1 hour after trazodone administration (postdose), immediately after anesthetic induction, and at times 15, 30, 45, 60, and 75 minutes of anesthesia. Samples were placed in sodium heparin tubes and centrifuged for 5 minutes to separate plasma. Plasma was stored at −80 °C until analysis was performed using previously described techniques.11
Statistical analysis
Analysis was performed using commercial software. Summary statistics (mean, SD, SE, minimum, median, and maximum) were calculated for each variable and time point, and residual diagnostic plots were made to evaluate model assumptions of normality and equal variance.
A mixed model was fit separately for the primary outcome of interest (CI) in addition to several secondary outcomes (HR, fR, systolic arterial pressure, diastolic arterial pressure, MAP, RAP, PAP, SVRI, V˙O2, DO2, EO2, temperature, FÉIso, pH, PaCO2, PaO2, bicarbonate, base excess, lactate, creatine, and glucose). A Bonferroni adjustment was applied for all variables except CI and MAP in order to control for multiple testing. Treatment (control or trazodone), time, and treatment*time interaction were included as fixed effects and to account for repeated measures; horse was included as a random effect. For MAP, a log transformation was used to satisfy model assumptions. Analyses of CI, MAP, DO2, EO2, V˙O2, and SVRI would be conducted with and without results for horses that had any adverse reactions after receiving the assigned treatment or whose cardiovascular data were strong outliers from all other horses. Those responses that showed evidence of treatment or treatment*time interaction based on ANOVA F tests (with Bonferroni adjustment) were considered for further pairwise comparisons. Specifically, comparisons between groups (control vs trazodone) were performed at each time point. Evidence of a statistical difference was considered with values of P < .05.
Results
Twelve adult horses (5 Quarter Horses, 2 Paint horses, 2 Arabians, 1 Thoroughbred, 1 Appaloosa, and 1 Pony of the Americas, of which 5 were mares and 7 geldings), 15.5 ± 5.0 years old with a body mass of 461 ± 72 kg [mean ± SD], were included in our study from August 2022 through June 2023. All horses completed the study and were successfully given the entire contents of the oral dosing syringe. No horses in the control group showed any change in behavior after dosing. In the trazodone group, all horses displayed signs of mild sedation (eg, moving less in stall, less reactive to external stimuli, head lowered slightly, resting a hind leg). Three of the 7 horses given trazodone became mildly sweaty (damp to the touch), and 1 of these 3 horses also had fine muscle fasciculations. A 17-year-old Quarter Horse gelding (horse #2), donated due to lameness associated with osteoarthritis, exhibited a more profound response to trazodone. Approximately 15 minutes postdosing, it became laterally recumbent, displayed moderate muscle tremors and profound sweating, and showed apparent distress and signs of colic (pawing, flank watching, and multiple changes in position).
Figure 2 shows cardiovascular comparisons between groups, with data from horse #2 presented separately. Statistical evidence of differences between groups was only found for CI at time 75 minutes (after dobutamine administration), where trazodone-treated horses had a significantly higher CI (trazodone 66.2 ± 16.8 vs control 46.8 ± 6.6 mL/min/kg; P = .0012). This result is from the analysis excluding horse #2 and does not extend to the analysis including horse #2. Except for CI, the conclusions on statistical significance were unchanged whether horse #2 was included or excluded from the analysis. The results for selected arterial blood variables and body temperature values are shown in Tables 1 and 2. Trazodone plasma concentrations over time for 7 horses in the trazodone group are provided in Figure 3.
Mean (bar) ± SD (whisker) for (A) HR, (B) CI, (C) SVRI, (D) MAP, (E) oxygen consumption, (F) oxygen delivery, (G) PAP, and (H) oxygen extraction in 12 horses given 6 mg/kg of trazodone (solid dark bar; n = 7) or corn syrup (control, light solid bar; n = 5) orally. Following treatment, horses were sedated with xylazine (1 mg/kg, IV), and anesthesia was induced with ketamine (2.5 mg/kg, IV) and propofol (0.7 mg/kg, IV) and maintained for 75 minutes with isoflurane (1.6% target expired concentration). Dobutamine (1 μg/kg/min, IV) infusion was initiated after the measurement at T60 and continued to the end of anesthesia at T75. Horse #2 showed signs of distress after trazodone administration. Anesthetized data for this horse differed markedly from other horses and are presented separately for comparison (dotted bar). Baseline (predose), PD, PX, PI, and T15, T30, T45, T60, and T75 minutes of anesthesia are shown. A mixed model was fit for each response variable. To control for multiple testing, response variables that showed evidence of treatment or treatment*time interaction based on Bonferroni-adjusted ANOVA F tests were considered for further pairwise comparisons. Based on these criteria, only pairwise comparisons for cardiac index were performed. For other variables, we provide descriptive statistics. *Significant difference (P < .05) between control and trazodone group at that time point.
Citation: American Journal of Veterinary Research 86, 6; 10.2460/ajvr.25.01.0029
Arterial blood gas variables from 12 horses given 6 mg/kg of trazodone (n = 7) or corn syrup (control; n = 5) orally.
| Time points | |||||
|---|---|---|---|---|---|
| Variable/treatment | 15 minutes | 30 minutes | 45 minutes | 60 minutes | 75 minutes |
| pH | |||||
| Control | 7.40 ± 0.01 | 7.40 ± 0.02 | 7.40 ± 0.02 | 7.38 ± 0.02 | 7.35 ± 0.03 |
| Trazodone | 7.36 ± 0.02 | 7.37 ± 0.03 | 7.38 ± 0.03 | 7.37 ± 0.02 | 7.34 ± 0.04 |
| PaCO2 (mm Hg) | |||||
| Control | 46 ± 4 | 47 ± 2 | 48 ± 1 | 51 ± 3 | 60 ± 3 |
| Trazodone | 53 ± 3 | 53 ± 4 | 54 ± 3 | 54 ± 3 | 59 ± 4 |
| HCO3− (mmol/L) | |||||
| Control | 27.3 ± 1.7 | 28.1 ± 1.2 | 28.4 ± 1.4 | 28.8 ± 1.4 | 29.4 ± 1.9 |
| Trazodone | 29.5 ± 0.5 | 29.9 ± 0.8 | 30.3 ± 0.9 | 30.6 ± 0.6 | 30.9 ± 0.9 |
| BE (mmol/L) | |||||
| Control | 3.0 ± 1.5 | 3.9 ± 1.7 | 4.0 ± 1.9 | 3.9 ± 1.8 | 3.6 ± 2.2 |
| Trazodone | 3.5 ± 1.7 | 4.0 ± 1.6 | 4.5 ± 1.4 | 4.9 ± 1.6 | 4.4 ± 1.7 |
| PaO2 (mm Hg) | |||||
| Control | 290 ± 72 | 294 ± 63 | 287 ± 73 | 272 ± 89 | 271 ± 60 |
| Trazodone | 238 ± 75 | 239 ± 86 | 228 ± 87 | 236 ± 95 | 242 ± 83 |
| Lactate (mmol/L) | |||||
| Control | 1.0 ± 0.3 | 1.1 ± 0.2 | 1.1 ± 0.3 | 1.2 ± 0.3 | 1.3 ± 0.3 |
| Trazodone | 1.1 ± 0.2 | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.3 |
| Creatinine (µmol/L) | |||||
| Control | 1.2 ± 0.3 | 1.3 ± 0.2 | 1.4 ± 0.3 | 1.4 ± 0.3 | 1.4 ± 0.3 |
| Trazodone | 1.0 ± 0.2 | 1.1 ± 0.2 | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.2 |
| Glucose (mg/dL) | |||||
| Control | 142 ± 16 | 140 ± 19 | 136 ± 23 | 135 ± 25 | 133 ± 27 |
| Trazodone | 144 ± 29 | 145 ± 29 | 147 ± 33 | 146 ± 35 | 144 ± 38 |
BE = Base excess. HCO3− = Bicarbonate. NA = Not applicable.
One hour following treatment, horses were sedated with xylazine (1 mg/kg, IV), and anesthesia was induced with ketamine (2.5 mg/kg, IV) and propofol (0.7 mg/kg, IV) and maintained for 75 minutes with isoflurane (1.6% target expired concentration). Dobutamine (1 μg/kg/min, IV) infusion was initiated after the measurement at time 60 and continued to the end of anesthesia at time 75. Time points 15, 30, 45, 60, and 75 minutes of anesthesia are shown. Data are mean ± SD. To control for multiple testing, response variables that showed evidence of treatment or treatment*time interaction based on Bonferroni-adjusted ANOVA F tests were considered for further pairwise comparisons. For all variables presented here, we provide descriptive statistics.
Body temperature data from 12 horses anesthetized as described in Table 1.
| Time points | Treatment | Temperature (°C) |
|---|---|---|
| Baseline | Control | 37.3 ± 0.3 |
| Trazodone | 37.6 ± 0.36 | |
| Postdose | Control | 37.5 ± 0.3 |
| Trazodone | 37.1 ± 0.7 | |
| Postxylazine | Control | 37.5 ± 0.3 |
| Trazodone | 37.0 ± 0.4 | |
| 15 min | Control | 36.9 ± 0.3 |
| Trazodone | 35.9 ± 1.0a | |
| 30 min | Control | 36.9 ± 0.2 |
| Trazodone | 35.9 ± 0.9a | |
| 45 min | Control | 36.9 ± 0.2 |
| Trazodone | 35.8 ± 1.0a | |
| 60 min | Control | 36.8 ± 0.3 |
| Trazodone | 35.6 ± 1.1a | |
| 75 min | Control | 36.4 ± 0.3 |
| Trazodone | 35.2 ± 1.1a |
Indicates evidence of a difference between groups at that time point (P < .05).
Baseline (predose), postdose, postxylazine, postinduction, and time points 15, 30, 45, 60, and 75 minutes of anesthesia are shown. Data are mean ± SD. To control for multiple testing, response variables that showed evidence of treatment or treatment*time interaction based on Bonferroni-adjusted ANOVA F tests were considered for further pairwise comparisons. Based on these criteria, pairwise comparisons for temperature were performed.
Trazodone plasma concentration profiles for 7 horses given 6 mg/kg of oral trazodone. One hour after treatment, horses were sedated with xylazine (1 mg/kg, IV), and anesthesia was induced with ketamine (2.5 mg/kg, IV) and propofol (0.7 mg/kg, IV) and maintained for 75 minutes with isoflurane (1.6% target expired concentration). Dobutamine (1 μg/kg/min, IV) infusion was initiated after the measurement at T60 and continued to the end of anesthesia at T75. Data for PD, PI, and T15, T30, T45, T60, and T75 minutes of anesthesia are shown.
Citation: American Journal of Veterinary Research 86, 6; 10.2460/ajvr.25.01.0029
Discussion
The findings of this study provide an initial description of cardiopulmonary effects seen in systemically healthy horses when oral trazodone at 6 mg/kg is administered approximately 1 hour prior to xylazine sedation, anesthetic induction with ketamine and propofol, and short-term maintenance with inhaled isoflurane. While the addition of dobutamine improved CI to a significantly greater degree in trazodone horses (with the exclusion of horse #2), major differences in MAP (a clinical indicator of cardiovascular stability under anesthesia) between control and treatment horses were not observed. Overall, anesthesia in both groups was clinically indistinguishable. However, the presence of 1 trazodone treatment horse (horse #2) with dramatic hemodynamic changes under anesthesia, including markedly lower CI and DO2 with increased SVRI, provides cause for concern when broadly recommending the safety of trazodone in horses before inhalant anesthesia.
Several significant limitations in this study exist that prevent wide extrapolation of the results and ultimate conclusions on the safety of trazodone prior to general anesthesia in horses. The small sample size and variability in pharmacodynamic responses to trazodone that are evident in the literature as well as this study are likely a major limitation. It is not clear whether the cardiovascular responses seen in horse #2 are seen occasionally or rarely or were simply unique to this specific horse. A larger number of horses subjected to the treatment conditions may have helped determine this, but budget constraints did not allow the enrollment of additional horses in this study. Additionally, our sample size estimation was based only on 1 primary outcome of interest (CO or CI). However, additional outcomes are presented to provide a more comprehensive evaluation of the effects of trazodone in anesthetized horses. To mitigate the risk of type I errors due to multiple comparisons, Bonferroni correction was employed. The statistical power for detecting changes in other outcomes is likely insufficient. There is a risk of type II errors, where caution should be taken when interpreting the results for outcomes other than CI.
Our study looked at a single dose of trazodone given at a specific time frame in relation to a relatively simplistic sedation, induction, and anesthetic maintenance protocol. This dose was chosen as it constitutes a “midrange” dose from clinical experience at our institution and was based on prior literature.6,7,11 The time frame relative to the ultimate anesthetic induction was chosen based on a time to maximum concentration of 0.75 ± 0.53 hours found in a prior study11 performed at our institution using the same trazodone dosing and delivery method. It is impossible to determine whether similar results would be seen with different doses of trazodone, different administration times, and/or the addition of other drugs to the protocol that alter vascular tone, such as acepromazine, which is commonly used in equine anesthesia. Additionally, the short (75 minute) anesthetic period does not reflect all clinical anesthesia scenarios. For example, xylazine doses are often based on an individual horse’s sedation response, and by giving a set dose (1 mg/kg) without titration, we were unable to determine if trazodone reduced the preanesthetic sedation requirement in our population. However, this single uniform dose was chosen to limit variability in cardiovascular responses during the early anesthetic period, and a recent study12 has shown trazodone at 6 mg/kg PO did not appear to reduce xylazine requirements for standing sedation in horses.
Unfortunately, the study was also not blinded due to personnel availability, and this provides a source of bias that cannot be discounted, including observer bias, particularly in the behavioral results. Further blinded studies are warranted to confirm our findings. Horses donated for euthanasia also never represent a uniform population, which likely introduced additional variability into this study. Experimental horses were euthanized prior to recovery due to both the nature of their inclusion in this study (donated for scientific purposes because of incurable conditions, primarily orthopedic disease) and an expectation of profound hypotension given the study’s chosen isoflurane dose. Therefore, the effects of trazodone on the quality of anesthetic recovery could not be determined. Further investigation is required to assess the effects of oral trazodone during recovery, including changes in time, quality, and level of ataxia. Significant limitations taken into consideration, the authors believe that the information provided is a valuable first investigation into possible cardiopulmonary effects when trazodone is used prior to inhalant anesthesia in horses as this has not been described previously.
Trazodone has α1-antagonist effects and might be expected to produce decreases in SVRI leading to hypotension in anesthetized horses. In anesthetized dogs, dose-dependent hypotensive effects of oral or IV trazodone are described.3,4 In awake cats, oral trazodone decreased systolic blood pressure,10 and severe hypotension unresponsive to fluid therapy was reported in human medicine after trazodone overdose.13 In this study, horses in both trazodone and control groups experienced clinically unacceptable hypotension (MAP well below 60 mm Hg) when exposed to surgical doses of isoflurane in dorsal recumbency, without surgical stimulation, and in the absence of inotropic support. It has been well established that isoflurane causes dose-dependent cardiovascular depression in horses and that the addition of mechanical ventilation as performed in this study further depresses cardiovascular function.14–16 Therefore, the comparison of cardiovascular function between groups was considered more meaningful than exact values at each time point.
As expected, CI and MAP improved in both groups with the addition of a dobutamine infusion. Dobutamine is β1- and β2-adrenergic receptor agonist, which has been shown to dose-dependently increase CI and decrease SVRI in healthy horses under general anesthesia.17–19 The greater improvement in CI in the trazodone group could be mainly associated with the increases in contractility from dobutamine and further decrease in afterload by trazodone, resulting in increases in stroke volume. We were unable to demonstrate statistical evidence of differences in SVRI between groups at any time point; however, both mean SVRI and MAP were lower in the trazodone group after dobutamine infusion. However, the sample size in our study (which was calculated based on differences in CO) may have been too small to allow this difference to reach significance. Indeed, body temperature was significantly lower in trazodone horses under anesthesia. This is similar to previous reports11,20 for awake horses and may be a result of sweating but may also reflect lower overall SVRI and core-to-periphery temperature loss. Using a post hoc power calculation based on potential differences in SVRI, we likely needed upwards of 10 to 15 horses/group to determine significance given a clinically significant difference in SVRI and a moderately wide population SD.
With the exception of horse #2, all horses in the trazodone group showed mild sedation, and some had only minor side effects (haircoat damp to the touch from mild sweating, very fine muscle fasciculations) reported in other studies with varying doses (2.5 to 10 mg/kg) of oral trazodone. More dramatic responses, such as profuse sweating, muscle tremors, and signs of colic, were displayed by horse #2. Colic, fever, and soft manure after trazodone at 10 mg/kg PO were described in a horse in 1 study.6 Similarly, transient arrhythmias, tachycardia, and possible prolongation of the QT interval have also been reported.6,7,20 It is apparent from this and previous studies that there is a distinct individual variation in response, and it is unclear whether plasma trazodone concentrations played a significant role; while horse #2 maintained higher than average plasma concentrations of trazodone throughout the study, their data were not dissimilar to horse #9, which did not experience any dramatic behavioral effects and whose cardiopulmonary function fitted closely with all other horses. Additionally, large variations in trazodone plasma concentrations were seen in the study horses despite all horses receiving the entire contents of the dosing syringe successfully. Although all horses receiving trazodone became mildly sedate with the dose and delivery method, cardiovascular responses did not appear to correlate with plasma concentrations. Wide SDs in plasma concentrations of trazodone after oral dosing in horses have been seen in prior studies.6,7,11,20 One reason in this study may be the route of administration (oral dosing syringe vs nasogastric intubation). Even though horses appeared to receive the entire dose, spillage or retention in the mouth is certainly possible. A previously suggested and very plausible explanation for differences in trazodone metabolism between horses is potential genetic polymorphisms in the cytochrome P450 enzymes responsible for trazodone metabolism,20 which may be especially likely in equine studies with nonuniform populations.
This is the first study in which a horse with such a response was subsequently anesthetized and cardiopulmonary function was evaluated. Outside of study circumstances, the authors would have chosen not to anesthetize horse #2 for an elective procedure given the profound preanesthetic behavior. We find it important to note that while horse #2 experienced extreme reductions in CI when exposed to isoflurane, which did not improve with the addition of dobutamine, their HR remained within normal limits and their MAP comparable to group values due to an increase in SVRI. Interestingly, their arterial blood gas and lactate values similarly did not differ from the group overall. This is concerning because in a clinical case, MAP, HR, and blood gas analysis are primary tools available to the anesthetist for assessing overall patient stability. In this horse, these values could have provided a false sense of security about overall cardiovascular function.
The effects seen in horse #2 are the opposite of what would be expected from the α1-antagonist effects of trazodone. However, trazodone acts at many receptors, including 5-HT (serotonin), H1 (histamine), and the serotonin reuptake transporter.1 Trazodone itself has been associated with prolonged a QT interval in humans, as have other H1 receptor antagonists. First-generation H1 receptor antagonists have also been associated with sometimes fatal ventricular arrhythmias.21,22 Neither occurred in the horse in this study, so it is not clear whether these receptor effects played a role in his response. Though the horse was donated for osteoarthritis, it is also possible that horse #2 had an underlying condition undetectable on physical examination and preanesthetic bloodwork that ultimately led to these complications. This is unknown as a full postmortem examination was not performed due to budget constraints. Additionally, it is unclear whether gross or histologic changes that might have been seen on postmortem examination would have been confounded by the horse having experienced over an hour of severe anesthetic hypotension (which was seen in all study horses).
In conclusion, our results do not provide a clear recommendation of the safety of a single dose of oral trazodone at 6 mg/kg prior to xylazine sedation, anesthetic induction with ketamine and propofol, and 75 minutes of isoflurane maintenance (with and without dobutamine infusion). Although many of our trazodone-treated horses had similar cardiopulmonary function to control horses, the presence of 1 trazodone-treated horse with severe cardiovascular depression leads the authors to caution that profound individual responses (including severe cardiovascular depression) may be seen.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
This project was funded by the Colorado Racing Commission/Equine Foundation Funds via the Colorado State University College Research Council.
ORCID
T. Kazama https://orcid.org/0009-0005-6641-9802
R. C. Hector https://orcid.org/0000-0002-0599-5057
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