Abstract
Although sedation is frequently used to facilitate patient compliance in feline echocardiography, the effects of sedative drugs on echocardiographic variables have been poorly documented. This study investigated the effects of two sedation protocols on echocardiographic indices in healthy cats, with special emphasis on the assessment of left atrial size and function, as well as left ventricular diastolic performance. Seven cats underwent echocardiography (transthoracic two-dimensional, spectral Doppler, color flow Doppler and tissue Doppler imaging) before and after sedation with both acepromazine (0.1 mg/kg IM) and butorphanol (0.25 mg/kg IM), or acepromazine (0.1 mg/kg IM), butorphanol (0.25 mg/kg IM) and ketamine (1.5 mg/kg IV). Heart rate increased significantly following acepromazine/butorphanol/ketamine (mean ± SD of increase, 40 ± 26 beats/min) and non-invasive systolic blood pressure decreased significantly following acepromazine/butorphanol (mean ± SD of decrease, 12 ± 19 mmHg). The majority of echocardiographic variables were not significantly different after sedation compared with baseline values. Both sedation protocols resulted in mildly decreased left ventricular end-diastolic dimension and mildly increased left ventricular end-diastolic wall thickness. This study therefore failed to demonstrate clinically meaningful effects of these sedation protocols on echocardiographic measurements, suggesting that sedation with acepromazine, butorphanol and/or ketamine can be used to facilitate echocardiography in healthy cats.
Introduction
In feline echocardiography, administration of sedation is sometimes necessary to ensure patient compliance, to avoid overt stress and to allow for high quality recordings.1–5 Common sedative choices in cats include opioids, such as butorphanol or buprenorphine; phenothiazine neuroleptics, such as acepromazine; and dissociative anesthetics, such as ketamine. Although acepromazine6–10 and ketamine2,4,10–12 have been widely utilized as sedatives to facilitate echocardiography in dogs and cats, their effects on echocardiographic variables have been poorly documented.1–3,13,14 Moreover, the majority of previous studies have investigated only two-dimensional echocardiography (2-DE) and motion-mode (M-mode) variables of left ventricular (LV) size and systolic function. To the our knowledge, there are no published reports on the effects of sedation on echocardiographic measurements of left atrial (LA) size and LV diastolic function in cats.
Diastolic dysfunction is an important component in the pathophysiology of feline cardiomyopathy.4,15 Echocardiographic assessment of diastolic function generally involves a combination of 2-DE variables, including measures of LA and LV size and wall thickness;4,15–17 pulsed-wave Doppler variables of transmitral and pulmonary venous flow;4,16,18 and pulsed-wave tissue Doppler imaging (TDI) indices of lateral and septal mitral annulus motion.16,18–20
The purpose of the present study was to investigate the effects of two different sedation protocols commonly used in veterinary practice on various echocardiographic variables in healthy cats. We placed special emphasis on the assessment of LA size and function, as well as LV diastolic performance. Our hypothesis was that a combination of acepromazine and butorphanol (Ace/But) or a combination of acepromazine, butorphanol, and ketamine (Ace/But/Ket) would have no effect on echocardiographic variables of left heart size and function, despite an anticipated decrease in blood pressure (Ace/But) and increase in heart rate (Ace/But/Ket). We tested this null hypothesis against the alternative hypothesis that sedation would significantly affect echocardiographic measurements.
Materials and methods
Subjects and study design
The study protocol was approved by the Institutional Animal Care and Use Committee at the University of Missouri, College of Veterinary Medicine. Seven adult, purpose-bred domestic shorthair cats aged 1–3 years and weighing 3.6–4.5 kg were used for this study. Prior to the beginning of the study, the cats were deemed healthy based on a comprehensive physical examination, complete blood count, blood biochemistry profile, urinalysis, heartworm antibody test, non-invasive blood pressure measurement, electrocardiography and echocardiography.
Prior to the sedation study, inter-operator recording variability was investigated for selected echocardiographic variables. The cats were sedated with acepromazine (0.1 mg/kg IM: Acepromazine Maleate Injection; Boehringer Ingelheim Vetmedica) and imaged 30– 60 min following sedation. Cats were randomly assigned to two groups and imaged by two experienced echocardiographers (KES and VLF) sequentially in a fully crossed design. Each echocardiographer was blinded to the other’s echocardiogram results. Measurements were performed by a single observer (KES).
The sedation study was then conducted after a 6-day washout period. Baseline echocardiograms were performed for each cat without sedation. The cats were then randomly assigned to two treatment groups in a fully crossed study design with a 4–6 day washout period in between the echocardiographic studies. Treatment consisted of sedation with one of two protocols: Ace/But, consisting of acepromazine (0.1 mg/kg IM) and butorphanol (0.25 mg/kg IM: Torbugesic; Fort Dodge Animal Health); or Ace/But/Ket, consisting of acepromazine (0.1 mg/kg IM), butorphanol (0.25 mg/kg IM) and ketamine (1.5 mg/kg IV: KetaVed; Vedco). Cats were imaged 30–60 min following sedation. All echocardiograms were performed by a single recorder (VLF) and measured by a single operator (KES), both of whom were blinded to treatment group.
Echocardiography
Echocardiographic examinations were performed using a SSA-380A Powervision echocardiographic system (Toshiba) coupled to 7- and 5-MHz phased array sector transducers (PSK-70 LT and PSK-50 LT; Toshiba). Cats underwent repeated transthoracic 2-DE, spectral Doppler, color flow Doppler and TDI echocardiographic examinations using standard methods described previously. 16,17,21,22 Echocardiography images were stored digitally in an integrated image storing system (TomTec) and also on videotape (Sony Videokassette Recorder, Model SVO-9500 MD; Sony). Images were measured manually using digital calipers. All reported measurements were averaged over five observations of sufficient technical quality.
Assessment of LA size and function was performed using previously described methods 17 from standard right parasternal long-axis and short-axis views. Variables measured included maximum and minimum LA septal-to-free wall dimension (LADmax and LADmin) and maximum and minimum LA area (LAAmax and LAAmin), with the latter acquired from the same imaging views and by tracing the endocardial border of the LA proper excluding the ostia of the pulmonary veins. LA fractional shortening (LA-FS) was calculated using the formula: [LADmax-LADmin]/LADmax × 100%. LA fractional area change (FAC) was calculated using the formula: [LAAmax-LAAmin]/LAAmax × 100%. Additionally, LA diameter in diastole (LAD) and aortic diameter in diastole (Ao) were measured from a right parasternal short-axis view, and the ratio between LA to Ao was calculated (LAD/Ao). 22
Assessment of LV size and systolic function was performed using standard right parasternal short and long-axis views, and a left apical parasternal long-axis view.6,16,23,24 Variables measured included LV dimension at end-systole and end-diastole (LVDs and LVDd), LV posterior wall thickness at end-systole and end-diastole (LVPWs and LVPWd), and interventricular septal thickness at end-systole and end-diastole (IVSs and IVSd). LV luminal area at end-systole and end-diastole at the level of the chordae tendineae (LVAs and LVAd) was measured from right parasternal short-axis images. LV ejection time (ET) was measured from a pulsed- wave Doppler aortic outflow signal obtained from a subcostal view. LV ejection fraction (LV-EF) was determined using the modified single plane Simpson’s method of disks and images acquired from a right parasternal four-chamber long-axis view optimized for the LV.24–26 LV segmental shortening fraction (LV-SF = [LVDd-LVDs]/LVDd × 100%) and LV shortening area (LV-SA = [LVAd – LVAs]/LVAd × 100%) were calculated.
Transmitral and pulmonary venous flow was recorded using pulsed-wave Doppler and a left apical parasternal long-axis view.16,18 Variables measured included isovolumic relaxation time (IVRT), LV flow propagation velocity (Vp), peak velocity of early diastolic transmitral flow (Peak E), deceleration time of early diastolic transmitral flow (DTE), peak velocity of late diastolic transmitral flow (Peak A), duration of late diastolic transmitral flow (Adur), peak velocity of pulmonary vein systolic flow (Peak S), peak velocity of pulmonary vein diastolic flow (Peak D), peak velocity of pulmonary vein reversal flow at atrial contraction (Peak AR) and duration of pulmonary vein reversal flow at atrial contraction (ARdur). Ratios between Peak E to Peak A (E/A), Peak S to Peak D (S/D) and duration of A to duration of AR (Adur/ARdur) were calculated. The index of LV myocardial performance (IMP) was also calculated. 27
TDI was performed with the highest available transducer frequency to record the velocity of mitral annulus motion from a left apical parasternal long-axis view optimized for the LV inflow tract.16,18,28 The following variables were measured for both the lateral (lat) and septal (sept) mitral valve annulus: isovolumic relaxation time (IVRT), peak early diastolic velocity (Peak Ea) and peak late diastolic velocity (Peak Aa). Ratios between Peak Ea to Peak Aa (Ea/Aa) and Peak E to Peak Ea (E/Ea) were also calculated for both the lateral and septal mitral valve annulus.
Statistical analysis
Statistical analysis was performed with commercially available software [Graph Pad Prism (GraphPad Software) and SAS version 9.1 (SAS Institute)]. Inter-observer recording variability was quantified using the formula: Coefficient of variation (CV) = mean difference between measurements/average of measurements × 100%.
Distribution of variables was tested for normality using the Shapiro-Wilk test at the α = 0.05 level. Mean and SD for individual echocardiographic variables were calculated. A generalized linear mixed effects model was used to analyze the effects of treatment on variables. The latter included the following as fixed effects: treatment (Ace/But and Ace/But/Ket), sequence of treatment (Ace/But followed by Ace/But/Ket or vice versa), time period (first, second and third measurement period), and interaction of treatment and time. The model included cats as a random effect. The Bonferroni correction was used for multiple comparisons. For variables showing a significant treatment effect, the model was repeated using heart rate as a time-varying covariate to identify any independent effect of heart rate on echocardiographic variables. Significance level was set at P <0.05.
Results
Study cats were healthy domestic shorthair cats (four spayed females, three castrated males) with a mean age of 1.6 years (SD 0.79, range 1–3) and a mean body weight of 4.1 kg (SD 0.37, range 3.6–4.5).
Results concerning inter-observer recording variability of selected echocardiographic variables are summarized in Tables 1–3. Recording variability ranged from 0.5–16.8%. Variability was highest for LA-FAC (16.8%), Peak Aa lat (14.7%) and Vp (14.1%), and lowest for LVDd (0.50%), LV-SF (0.57%) and IMP (0.8%).
Table 1.
Echocardiographic variables (mean ± SD) of left atrial size and function before and after sedation in seven healthy cats
| Variable | Baseline | Ace/But | Ace/But/Ket | CV (%) |
|---|---|---|---|---|
| Heart rate (beats/min) | 192 ± 21 | 204 ± 25 | 232 ± 27 † ‡ | 5.83 |
| LADmax (cm) | 1.23 ± 0.13 | 1.14 ± 0.09* | 1.16 ± 0.08 | 3.22 |
| LA-FS (%) | 23 ± 2.0 | 21 ± 3.0 | 25 ± 7.0 | 10.3 |
| LAAmax (cm2) | 1.47 ± 0.30 | 1.39 ± 0.18 | 1.42 ± 0.22 | 1.5 |
| LA-FAC (%) | 35 ± 5.0 | 33 ± 6.0 | 41 ± 9.0 ‡ | 16.8 |
| LAD (cm) | 1.03 ± 0.07 | 1.06 ± 0.13 | 0.97 ± 0.03 | nd |
| Ao (cm) | 0.79 ± 0.06 | 0.83 ± 0.12 | 0.79 ± 0.11 | nd |
| LAD/Ao | 1.32 ± 0.14 | 1.25 ± 0.25 | 1.29 ± 0.14 | nd |
| Peak A (m/s) | 0.49 ± 0.16 | 0.43 ± 0.11 | 0.49 ± 0.11 | 2.64 |
| Peak AR (m/s) | 0.15 ± 0.03 | 0.17 ± 0.05 | 0.22 ± 0.04† ‡ | 6.59 |
| Adur (ms) | 58 ± 7.0 | 58 ± 7.0 | 56 ± 5.0 | nd |
| ARdur (ms) | 38 ± 4.0 | 36 ± 5.0 | 40 ± 5.0 | nd |
| Adur/ARdur | 1.53 ± 0.28 | 1.63 ± 0.34 | 1.44 ± 0.11 | 8.01 |
| Peak Aa sept (cm/s) | 6.1 ± 1.7 | 7.2 ± 2.3 | 6.8 ± 1.6 | 2.17 |
| Peak Aa lat (cm/s) | 6.1 ± 1.6 | 6.0 ± 2.3 | 6.8 ± 1.7 | 14.7 |
Bold values indicate statistical significance
Significant (P <0.05) differences between Ace/But and baseline
Significant (P <0.05) differences between Ace/But/Ket and baseline
Significant (P <0.05) differences between Ace/But/Ket and Ace/But Ace = acepromazine (0.1 mg/kg IM), But = butorphanol (0.25 mg/kg IM), Ket = ketamine (1.5 mg/kg IV), CV = coefficient of variation (recording variability), nd = not determined, LADmax = maximum left atrial septal-to-free wall dimension, LA-FS = left atrial fractional shortening, LAAmax = maximum left atrial area, LA-FAC = left atrial fractional area change, LAD = short-axis left atrial diameter in diastole, Ao = short axis aortic diameter in diastole, LAD/Ao = ratio between LAD to Ao, Peak A = peak velocity of late diastolic transmitral flow, Peak AR = peak velocity of pulmonary vein reversal flow at atrial contraction, A duration = duration of A, AR duration = duration of AR, Adur/ARdur = ratio between duration of A to duration of AR, Peak Aa = peak late diastolic velocity of mitral valve annulus motion, sept = measured at septal mitral annulus, lat = measured at lateral mitral annulus
Table 2.
Echocardiographic variables (mean ± SD) of left ventricular size and systolic function before and after sedation in seven healthy cats
| Variable | Baseline | Ace/But | Ace/But/Ket | CV (%) |
|---|---|---|---|---|
| LVDd (cm) | 1.41 ± 0.16 | 1.25 ± 0.11* | 1.27 ± 0.18† | 0.50 |
| LVDs (cm) | 0.85 ± 0.14 | 0.71 ± 0.12 | 0.75 ± 0.12 | 1.07 |
| IVSd (cm) | 0.31 ± 0.03 | 0.34 ± 0.04 | 0.32 ± 0.04 | nd |
| IVSs (cm) | 0.45 ± 0.04 | 0.51 ± 0.05 | 0.50 ± 0.06 | nd |
| LVPWd (cm) | 0.34 ± 0.03 | 0.38 ± 0.02* | 0.39 ± 0.02† | nd |
| LVPWs (cm) | 0.55 ± 0.06 | 0.59 ± 0.06 | 0.61 ± 0.06 | nd |
| LVAd (cm2) | 2.09 ± 0.34 | 1.70 ± 0.18* | 1.66 ± 0.29† | nd |
| LVAs (cm2) | 0.82 ± 0.13 | 0.69 ± 0.10 | 0.77 ± 0.21 | nd |
| LV-SA (%) | 60 ± 3 | 59 ± 4 | 56 ± 5 | 3.90 |
| LV-SF (%) | 40 ± 6 | 44 ± 4 | 41 ± 6 | 0.57 |
| LV-EF (%) | 62 ± 1.8 | 68 ± 2.9* | 60 ± 5.2‡ | 3.02 |
| Peak Ao (m/s) | 0.89 ± 0.19 | 0.84 ± 0.20 | 0.85 ± 0.19 | nd |
| ET (ms) | 139 ± 18.6 | 133 ± 9.9 | 129 ± 14.5 | nd |
| IMP | 0.49 ± 0.18 | 0.47 ± 0.29 | 0.43 ± 0.16 | 0.80 |
| Peak S (m/s) | 0.36 ± 0.05 | 0.44 ± 0.19 | 0.53 ± 0.12 | 0.92 |
| Peak Sa sept (cm/s) | 8.6 ± 1.6 | 8.0 ± 2.3 | 8.1 ± 2.3 | 3.67 |
| Peak Sa lat (cm/s) | 6.6 ± 1.1 | 7.7 ± 2.4 | 8.5 ± 2.5 | nd |
Bold values indicate statistical significance
Significant (P <0.05) differences between Ace/But and baseline
Significant (P <0.05) differences between Ace/But/Ket and baseline
Significant (P <0.05) differences between Ace/But/Ket and Ace/But
LVDd = left ventricular dimension, IVS = interventricular septal thickness, LVPW = left ventricular posterior wall thickness, LVA = left ventricular area measured at the level of the chordae tendinae, LV-SA = left ventricular shortening area, LV-SF = left ventricular shortening fraction, LV-EF = left ventricular ejection fraction, Peak Ao = peak aortic flow velocity, ET = left ventricular ejection time, IMP = index of myocardial performance, Peak S = peak velocity of pulmonary vein systolic flow, Peak Sa = peak systolic velocity of mitral valve annulus motion, d = measured at end-diastole, s = measured at end-systole, nd = not determined
Table 3.
Echocardiographic variables (mean ± SD) of left ventricular diastolic function before and after sedation in seven healthy cats
| Variable | Baseline | Ace/But | Ace/But/Ket | CV (%) |
|---|---|---|---|---|
| IVRT (ms) | 46 ± 3.0 | 47 ± 6.0 | 46 ± 11 | 4.10 |
| IVRT sept (ms) | 47 ± 7.0 | 50 ± 12 | 42 ± 10 | 8.32 |
| IVRT lat (ms) | 51 ± 3.0 | 48 ± 7.0 | 47 ± 10 | 1.29 |
| Vp (cm/s) | 81 ± 17 | 86 ± 10 | 80 ± 17 | 14.1 |
| Peak E (m/s) | 0.62 ± 0.09 | 0.67 ± 0.12 | 0.69 ± 0.16 | 5.85 |
| DTE (ms) | 52 ± 3.0 | 52 ± 8.0 | 52 ± 6.0 | 4.49 |
| E/A | 1.33 ± 0.29 | 1.64 ± 0.42 | 1.43 ± 0.48 | 7.08 |
| E/Vp | 0.79 ± 0.22 | 0.76 ± 0.09 | 0.83 ± 0.19 | n.d. |
| Peak D (m/s) | 0.33 ± 0.27 | 0.30 ± 0.28 | 0.26 ± 0.25 | 3.73 |
| S/D | 1.09 ± 0.33 | 1.32 ± 0.49 | 1.70 ± 0.80 | 2.52 |
| Peak Ea sept (cm/s) | 7.5 ± 2.6 | 6.4 ± 1.6 | 7.9 ± 3.6 | 3.42 |
| Ea/Aa sept | 0.93 ± 0.20 | 0.87 ± 0.36 | 0.81 ± 0.30 | 4.57 |
| Peak Ea lat (cm/s) | 8.1 ± 2.1 | 7.9 ± 2.9 | 8.7 ± 3.3 | 7.36 |
| Ea/Aa lat | 1.36 ± 0.36 | 1.23 ± 0.50 | 1.04 ± 0.54 | 12.3 |
| E/Ea sept | 8.7 ± 1.7 | 10.8 ± 1.6 | 9.9 ± 3.5 | 10.6 |
| E/Ea lat | 8.5 ± 3.4 | 9.7 ± 4.8 | 8.6 ± 2.5 | 1.31 |
IVRT = isovolumic relaxation time, Vp = left ventricular flow propagation velocity, Peak E = peak velocity of early diastolic transmitral flow, DTE = deceleration time of early diastolic transmitral flow, E/A = ratio between Peak E to Peak A, E/Vp = ratio between peak E to Vp, Peak D = peak velocity of pulmonary vein diastolic flow, S/D = ratio between Peak S to Peak D, Peak Ea = peak early diastolic velocity for mitral valve annulus motion, Ea/Aa = ratio between Peak Ea to Peak Aa, E/Ea = ratio between Peak E to Peak Ea
Heart rate (mean ± SD) was 192 ± 21 beats/min prior to sedation, 204 ± 25 beats/min after sedation with Ace/But and 232 ± 27 beats/min after sedation with Ace/But/Ket. Heart rate after sedation with Ace/But/Ket was significantly higher than heart rate prior to sedation (P <0.01) or after sedation with Ace/But (P <0.01). Non-invasive systolic blood pressure (SBP, mean ± SD) was 120 ± 20 mmHg prior to sedation, 109 ± 11 mmHg after sedation with Ace/But and 114 ± 9 mmHg after sedation with Ace/But/Ket. SBP after sedation with Ace/But was significantly lower than SBP prior to sedation (P = 0.01) but was not significantly different from SBP after sedation with Ace/But/Ket (P = 0.36).
Results for variables of LA size and function, LV size and systolic function, and LV diastolic function are displayed in Tables 1–3, respectively. The majority of variables showed no statistically significant differences between baseline and either sedation protocol. The following variables were significantly different from baseline following sedation with Ace/But: LADmax, LVDd, and LVAd (decreased) and LVPWd and LV-EF (increased). The following variables were significantly different from baseline following sedation with Ace/But/Ket: LVDd and LVAd (decreased) and LVPWd and Peak AR (increased). The following variables were significantly different between the Ace/But protocol and the Ace/But/Ket protocol: Peak AR and LA-FAC (higher with Ace/But/Ket), and LV-EF (higher with Ace/But).
Treatment differences for some variables approached, but did not reach, statistical significance (0.05 < P <0.08 ). These variables included: LADmax with Ace/But/Ket compared with baseline (P = 0.0505); LA-FAC with Ace/But/Ket compared with baseline (P = 0.0768); Peak S with Ace/But/Ket compared with baseline (P = 0.0591); IVRT sept with Ace/But/Ket compared with Ace/But (P = 0.0616); and E/Ea with Ace/But compared with baseline (P = 0.052).
For variables that were significantly different from baseline or between treatments, the statistical model was repeated using heart rate as a time-varying covariate. The effect of heart rate did not reach statistical significance for any of the variables (all P >0.10). Moreover, with the exception of one variable, the addition of heart rate to the mixed model did not affect the level of significance previously achieved with the original model (not including heart rate).
Discussion
This study identified only minimal changes of echocardiographic variables in healthy cats following sedation with Ace/But or Ace/But/Ket. Heart rate increased following sedation with Ace/But/Ket and SBP decreased following sedation with Ace/But. Several echocardiographic variables increased or decreased following one or both sedation protocols; however, while these differences were statistically significant, the magnitude of change in these variables was low and likely not clinically relevant. Based on the findings of this study, we failed to reject our null hypothesis.
In the clinical setting, echocardiography is preferentially performed on awake animals; however, feline behavior sometimes necessitates the use of sedation to facilitate a quantifiable echocardiographic examination, and to reduce examination stress for both the cat and the examiners. Many sedative and anesthetic drugs also influence the cardiovascular system, which may alter echocardiographic measurements. Anesthetics, in particular, are unsuitable for echocardiographic examinations. For instance, previous studies have demonstrated that anesthesia with sodium pentobarbital in cats results in clinically relevant decreased indices of preload (eg, LVDd) and systolic function [eg, LV-SF and velocity of circumferential fiber shortening (VcF)] with a minimal effect on heart rate, resulting in decreased cardiac output.29,30 The inhalation anesthetic isoflurane causes variation in heart rate and dose-dependent hypotension, and may, therefore, affect echocardiographic measures. 31
Butorphanol is a κ-opioid agonist and μ-opioid antagonist which exerts its sedative effects through direct stimulation of opioid receptors. It is widely used as a first-line sedative for animals with heart disease owing to its wide therapeutic window, lack of significant cardiovascular effects and relatively short duration. 32 Although butorphanol has been used in a number of published sedation protocols for feline echocardiography,8,9,18,33,34 to our knowledge, no studies have specifically evaluated the effects of butorphanol on echocardiographic variables. In our experience, butorphanol alone does not induce sufficient sedation in many healthy cats undergoing echocardiography. Consequently, both sedation protocols used in this study included butorphanol with acepromazine, a combination that produces more reliable sedation. Thus, in this study, it was not possible to isolate the effects of butorphanol from those of acepromazine.
Acepromazine is a phenothiazine neuroleptic that inhibits central dopamine-2 receptors, causing sedation and tranquilization. Peripherally, acepromazine causes a non-specific α-adrenergic blockade, which leads to vasodilation and subsequent decrease in systemic vascular resistance and SBP. Acepromazine also desensitizes the heart to the effects of catecholamines. In the present study, SBP was significantly decreased following sedation with Ace/But, consistent with the vasodilatory properties of acepromazine. However, the magnitude of SBP decline, at least in these healthy cats, was not clinically relevant.
No previous studies have specifically investigated the effects of acepromazine in feline echocardiography. However, research in horses has demonstrated that acepromazine had no effects on echocardiographic indices of ventricular function or severity of valvular regurgitation. Horses treated with acepromazine did show mild increases in pulmonary artery and aortic diameter, consistent with afterload reduction and compensatory increase in stroke volume.35,36
Ketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist that functions as a dissociative anesthetic. Ketamine itself causes direct myocardial depression; however, it also stimulates central adrenergic centers and decreases re-uptake of norepinephrine, resulting in sympathomimetic effects. 32 Administration of ketamine should, therefore, result in increased heart rate, cardiac output, mean arterial pressure and central venous pressure. Ketamine also increases myocardial workload and myocardial oxygen demand. In the present study, heart rate was significantly higher after sedation with Ace/But/Ket compared with baseline or sedation with Ace/But — consistent with ketamine’s sympathomimetic and positive chronotropic effects. The Ace/But/Ket sedation protocol did not result in a significant increase in SBP from baseline, possibly because any vasoconstrictive effects of ketamine were offset by vasodilation from acepromazine.
A limited number of studies have investigated the effects of ketamine on echocardiographic indices in cats. DeMadron and Bonagura 3 found that a combination of 0.3 mg/cat acepromazine IM and 7.5 to 12 mg/kg ketamine IM had minimal effects on most 2-DE variables of LV systolic function in healthy cats. However, this study was designed to establish reference echocardiographic values for cats, rather than to evaluate the specific effects of sedation; therefore, treatment groups were not randomized and no crossover occurred. Fox and Bond 2 found that cats sedated with 1.5–2.5 mg/kg ketamine IV had higher heart rates, increased LV systolic function, and shorter LV ejection time compared with values reported for unanesthetized cats in other studies; however, this study did not include a control group of unsedated cats for comparison. Dummel et al 13 found that ketamine at 3–5 mg/kg IM decreased LVDd and LV-SF while increasing LA size compared with a separate control group of unsedated cats. Finally, Jacobs and Knight 1 reported that administration of 3–5 mg/kg ketamine IM caused an increased heart rate and decreased LV-SF and VcF compared with the same cats measured when awake. Therefore, these studies suggest that ketamine causes increased heart rate and decreased systolic myocardial function. However, these studies measured only 2-DE and M-mode indices of cardiac function. One additional study 14 investigated the effects of ketamine on Doppler echocardiographic indices of transvalvular flow velocities and found that ketamine did not significantly alter measurements of transmitral or pulmonary venous flow.
In the present study, a small number of echocardiographic indices were affected by sedation with both Ace/But and Ace/But/Ket. Following either protocol, LVDd and LVAd were decreased from baseline, and LVPWd was increased from baseline. The pattern of change in these variables suggests that sedation with Ace/But or Ace/But/Ket decreases preload in healthy cats. Because these effects were seen following both sedation protocols, it is reasonable to conclude that the decrease in preload was related to non-specific vasodilation associated with acepromazine. However, these findings are also similar to effects seen with ketamine alone in previous studies.13,37 Of importance is the potential impact of reduced preload on measurements of wall thickness. While the absolute values of LVPWd were relatively small, there was a trend for diastolic wall thickness to increase with ‘progressive sedation’ and this change achieved statistical significance from the unsedated state (Table 2). The mean difference in diastolic wall thickness was 0.5 mm — a value that could be significant when applying the label of ‘hypertrophic’ to a sedated cat. This effect is likely owing to reduced preload which may lead to ‘pseudohypertrophy’ in cats. 38
Several echocardiographic variables were affected differently by sedation with Ace/But compared with Ace/But/Ket. LV-EF was increased from baseline following Ace/But, but not following Ace/But/Ket. This suggests that acepromazine may increase LV systolic function as a result of either increased preload, decreased afterload or a combination of these mechanisms, but this effect was not apparent after the addition of ketamine. However, owing to the study design of adding ketamine to the Ace/But, it is impossible to isolate the specific effects of ketamine in this study group. LA-FAC was significantly higher following Ace/But/Ket compared with Ace/But, but failed to reach statistical significance when compared with baseline (P = 0.0768). Additionally, Peak AR was increased following Ace/But/Ket compared with Ace/But or baseline. LA-FAC is an index of LA booster pump function and Peak AR is also correlated with LA systolic function.16,18 These findings therefore suggest that ketamine may have mild stimulating effects on LA mechanical function.
Previous studies have demonstrated that heart rate can influence echocardiographic variables independent of the direct effects of sedatives and anesthetics. Increased heart rate has been associated with decreased cardiac chamber size and increased LV systolic function. 37 Because sedation with Ace/But/Ket resulted in a significant increase in heart rate, it may be important to separate the secondary effects of increased heart rate from the primary effects of the sedatives. Statistical analysis using heart rate as a time-varying covariate revealed that the effects on echocardiographic variables observed with the Ace/But/Ket sedation protocol were independent of changes in heart rate. This suggests that the echocardiographic effects of ketamine are related to intrinsic properties of the drug itself, rather than simply to ketamine’s positive chronotropic effects.
Limitations
This study has several limitations. First, the number of cats was small which limits the power of statistical analysis. Second, our study subjects were healthy cats. It is possible that sedation may influence variables of LA and LV size and function differently in cats with cardiac disease. Also, because our subjects were healthy cats, this study did not address the safety and potential adverse effects of administering butorphanol, acepromazine or ketamine to cats with cardiac disease. Clinicians should exercise caution when administering any drug that modulates the cardiovascular system to cats with heart disease. Third, our study subjects were young cats (age 1–3 years), whilst the median age for cats with acquired heart disease is higher. 39 It is possible that sedation may have different effects on echocardiographic variables in older cats. Finally, our study investigated only the possible effects of inter-operator recording variability, but did not specifically address intra-operator recording variability or measurement variability. Previous studies by our group 17 and from other laboratories16,28,40 have more comprehensively investigated the effects of observer variation in feline echocardiography and have repeatedly documented low measurement variability.
In conclusion, the results of this study suggest that sedation with Ace/But and Ace/But/Ket at the doses used failed to produce clinically meaningful changes in echocardiographic variables of LA and LV size and function, particularly indices of LV filling and diastolic function. Accepting that mild changes in LV preload and wall thickness may be observed, sedation with Ace/But or Ace/But/Ket can be used to facilitate echocardiography in healthy cats.
Acknowledgments
The authors acknowledge Edward Durham and Dan Hatfield for technical assistance and Dr Xiaobai Li (Center for Biostatistics, Office of Health Sciences, The Ohio State University, Columbus, OH 43210, USA) for providing expertise with statistical analysis.
Footnotes
Funding: Dr Schober was supported by funds from the Max Kade Foundation, New York City, NY, USA.
The authors do not have any potential conflicts of interest to declare.
Accepted: 11 April 2012
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