A clinically utilized intravenous continuous rate infusion of diltiazem does not significantly decrease systolic function in healthy dogs

William H. Whitehouse Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Justin D. Thomason Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Dorothy A. Thompson-Butler Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Megan D. Kelley Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Natalia Cernicchiaro Center for Outcomes Research and Epidemiology and Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Matthew C. Tanner Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Abstract

OBJECTIVE

To determine if left ventricular systolic function on echocardiography, systemic blood pressure, and electrocardiography change with a clinically accepted intravenous (IV) diltiazem constant rate infusion (CRI) compared to a control.

ANIMALS

10 healthy client-owned adult dogs.

PROCEDURES

Prospective, masked, crossover study from May 27, 2021, to August 22, 2021. Dogs were randomized to receive diltiazem (loading dose of 240 μg/kg, IV followed by a CRI of 6 μg/kg/min for 300 minutes) or the same volume of 5% dextrose in water (D5W) administered IV followed by the opposite intervention after a 7-day washout. Blood pressure was monitored during each CRI, and echocardiographic and electrocardiographic studies were performed immediately before the CRI and during the last hour of the CRI.

RESULTS

Postdiltiazem systolic time interval (STI) (median, 0.30; range, 0.16 to 0.34) was significantly lower than post-D5W STI (median, 0.32; range, 0.22 to 0.40; P = .046). All other echocardiographic parameters did not differ significantly between each of the groups after receiving diltiazem or D5W. Systemic blood pressure did not change significantly with either diltiazem (P = .450) or D5W (P = .940), and none of the dogs became hypotensive at any point in the study. Expectedly, negative dromotropy was observed with diltiazem.

CLINICAL RELEVANCE

A significant decrease in left ventricular systolic function was not appreciated in healthy dogs receiving diltiazem at a clinically accepted intravenous infusion rate at this dosing regimen. Further studies are needed in dogs with cardiac disease.

Abstract

OBJECTIVE

To determine if left ventricular systolic function on echocardiography, systemic blood pressure, and electrocardiography change with a clinically accepted intravenous (IV) diltiazem constant rate infusion (CRI) compared to a control.

ANIMALS

10 healthy client-owned adult dogs.

PROCEDURES

Prospective, masked, crossover study from May 27, 2021, to August 22, 2021. Dogs were randomized to receive diltiazem (loading dose of 240 μg/kg, IV followed by a CRI of 6 μg/kg/min for 300 minutes) or the same volume of 5% dextrose in water (D5W) administered IV followed by the opposite intervention after a 7-day washout. Blood pressure was monitored during each CRI, and echocardiographic and electrocardiographic studies were performed immediately before the CRI and during the last hour of the CRI.

RESULTS

Postdiltiazem systolic time interval (STI) (median, 0.30; range, 0.16 to 0.34) was significantly lower than post-D5W STI (median, 0.32; range, 0.22 to 0.40; P = .046). All other echocardiographic parameters did not differ significantly between each of the groups after receiving diltiazem or D5W. Systemic blood pressure did not change significantly with either diltiazem (P = .450) or D5W (P = .940), and none of the dogs became hypotensive at any point in the study. Expectedly, negative dromotropy was observed with diltiazem.

CLINICAL RELEVANCE

A significant decrease in left ventricular systolic function was not appreciated in healthy dogs receiving diltiazem at a clinically accepted intravenous infusion rate at this dosing regimen. Further studies are needed in dogs with cardiac disease.

Introduction

Arrhythmias are an important cardiac emergency causing hemodynamic instability that may be life threatening. Supraventricular tachyarrhythmias are commonly treated with a beta-adrenergic receptor blocker, digoxin, or a calcium channel blocker (CCB; eg, diltiazem), alone or in combination.1 Atrial fibrillation, a type of supraventricular tachyarrhythmia, is reported to be the most common arrhythmia diagnosed in veterinary medicine,2 and most patients presenting with atrial fibrillation are in congestive heart failure.1 Beta-adrenergic receptor blockers are typically avoided in these patients due to their negative inotropic effects, especially in patients with dilated cardiomyopathy phenotype.3 Although digoxin may have some positive inotropic effects in dogs,4 it is not typically used in the acute setting due to its long time to steady state5 and narrow therapeutic index.4

Because of its rapid onset of action in heart rate control, diltiazem is commonly used in the emergency setting for acute management of supraventricular tachyarrhythmias. As a nondihydropyridine CCB, diltiazem has effects on the heart and not just the vasculature. Negative dromotropy and chronotropy are included within its favorable effects, which are primarily accomplished through the slowing of sinoatrial nodal activity and conduction through the atrioventricular nodal cells by blocking the inward movement of calcium via L-type channels.6 Unlike cardiac myocytes, these cells rely mostly on the inward movement of calcium as opposed to sodium for depolarization to threshold. However, intracellular calcium is needed for cardiac muscle contraction, and this blockade of calcium entry that would normally occur in cardiac myocytes may result in negative inotropy.

Supraventricular tachyarrhythmia management in the hospitalized patient may be performed using injectable diltiazem given as an IV bolus followed by a constant rate infusion (CRI).1,7 However, some clinicians may avoid this method due to concern for negative inotropy. The effects of injectable diltiazem on systolic function and cardiac output (CO) in dogs have been previously evaluated but only using protocols that are not typically employed in clinical patients. When given as a single IV bolus or short CRI with the assessment of cardiac function occurring ≤ 10 minutes after the start of the infusion, diltiazem does not affect left ventricular systolic function in dogs without cardiac disease.810 Cardiac assessment after short infusions may not be fully representative of the magnitude of effects in clinical patients since hemodynamic parameters may change with diltiazem CRI duration.11 Diltiazem may decrease left ventricular systolic function if high plasma levels are reached,12 and decreases in left ventricular systolic function are expected in a dose-dependent fashion.13 In addition, when given at supranormal doses of 30 to 90 μg/kg/min, diltiazem has the potential to cause a significant reduction in systemic blood pressure.11

Clinically used diltiazem continuous infusion rates for arrhythmia management are typically 2 to 6 μg/kg/min.14,15 Studies evaluating diltiazem’s inotropic effects in dogs at doses and durations used for clinical arrhythmia management are needed. The primary objective of this study was to determine if echocardiographic parameters of left ventricular systolic function change with a clinically used diltiazem infusion, compared to a control, in clinically healthy adult dogs. The secondary objectives were to assess changes in systemic blood pressure and electrocardiography with this infusion. We hypothesize that diltiazem at a clinically used dose will not significantly change markers of left ventricular systolic function, blood pressure, or electrocardiographic parameters in healthy dogs.

Materials and Methods

Animals

A prospective, randomized, masked, placebo-controlled crossover study was performed. Healthy client-owned dogs were recruited from May 2021 to August 2021 for this study. The study protocol (4496) was approved by the Institutional Animal Care and Use Committee at Kansas State University, and informed consent was obtained from all owners before enrollment. Dogs ≥ 1 year of age, weighing ≥ 10 kg, of any sex and reproductive status, and without evidence of underlying systemic disease based on history, physical examination, and initial screening diagnostics were eligible for enrollment. None of the study participants were receiving medications at home except for monthly heartworm and flea/tick preventatives.

Screening diagnostics

Diagnostic screening pertinent to this study included a complete blood count, serum biochemical profile, urinalysis, indirect blood pressure measurement, echocardiogram, and electrocardiogram. Initial enrollment of study participants occurred within 30 days of the first infusion. Dogs were fasted for 10 to 12 hours before presentation, but water was not restricted. The complete blood count, serum biochemical profile and urinalysis were performed by the Kansas State University Veterinary Health Center clinical pathology laboratory for each dog. Indirect blood pressure measurement was taken by Doppler sphygmomanometry according to the American College of Veterinary Internal Medicine consensus guidelines.16 Briefly, dogs were restrained in lateral recumbency, and 5 to 6 measurements were averaged after the first measurement was discarded from the upside forelimb at the level of the heart. Right versus left forelimb was not standardized among the entire cohort, but the same limb and protocol were used for future blood pressure measurements for each individual dog.

Echocardiographic assessment including continuous electrocardiographic assessment of left ventricular systolic function included fractional shortening (FS), ejection fraction, E-point septal separation, end-systolic volume index, and systolic time interval (STI) using standard imaging planes. The average of 3 cardiac cycles not synchronized with the respiratory cycle was recorded. Echocardiographic studies (Vivid-q Cardiovascular Ultrasound System; GE Healthcare) were performed by a single, board-certified veterinary cardiologist (JDT) who was blinded to the study interventions. Six-lead electrocardiographic studies (Burdick ELI 280 electrocardiograph; Mortara Instrument, Inc) were performed with dogs in right lateral recumbency following the echocardiograms. Electrocardiographic recordings were printed at a paper speed of 50 mm/s and 10 mm/mV to obtain the following values: heart rate, P-wave amplitude, P-wave duration, PR interval, R-wave amplitude, QRS duration, T-wave amplitude, and mean electrical axis. Electrocardiographic measurements were averaged from 5 complexes in lead II. Data on renal function including glomerular filtration rate, fractional excretion of sodium, and urine output were also collected on this study population and is reported separately.

Study design

Dogs were randomized to receive either an infusion of diltiazem (0.5% diltiazem hydrochloride injection; Akorn, Inc) or 5% dextrose in water (D5W) (5% dextrose injection USP; B. Braun Medical Inc) followed by the other treatment 7 days later allowing each dog to serve as its own negative control. Simple randomization was used to dictate the order of treatments with half of the dogs receiving diltiazem first (first 5 names drawn from a container). Starting times for each dog were staggered by approximately 20 minutes, and the order was based on arrival to the hospital each morning.

Dogs were fasted for 10 to 12 hours for each of the 2 infusions. Baseline echocardiographic and electrocardiographic variables were obtained within 1 hour before starting the infusions. For the first infusion, half of the dogs were randomized to receive diltiazem (IV bolus of 240 μg/kg followed by a CRI at 6 μg/kg/min for 300 minutes) and the other half to receive the same volume of D5W. This timeframe was selected based on time points chosen to concurrently assess changes in renal function with this CRI. Diltiazem was diluted with D5W to a concentration of 1 mg/mL according to the manufacturer’s instructions. Baseline indirect blood pressure was measured immediately before (time 0 minutes) the assigned loading dose. Since hypotension can be seen with a diltiazem IV bolus,17 the loading dose was given slowly over 10 minutes with blood pressure monitored every other minute. Subsequently, blood pressure was monitored every 15 minutes until the completion of the infusion of diltiazem. In this study, hypotension was defined as a systolic blood pressure < 90 mmHg.18 When receiving D5W, blood pressure was monitored immediately before the bolus, immediately after the bolus, and then hourly until completion of the infusion. Echocardiograms and electrocardiograms were performed on all dogs again during the last hour of the infusion.

Dogs returned 7 days later for a second infusion, which was D5W for those dogs that originally received diltiazem and vice versa. This timeframe allowed for the elimination of diltiazem19 if given as the first infusion. Other than receiving the opposite treatment, the same protocol was followed.

Statistical analysis

Based on echocardiographic parameters of left heart size and systolic function in a population of healthy dogs, a total of 10 dogs with each serving as their own control should provide 90% power to detect, as significant, a 20% change in fractional shortening.20 Commercially available software was used to compute sample size calculation (G*Power version 3.1; Heinrich-Heine-Universität Düsseldorf) and statistical analyses (Prism version 9.0; GraphPad Software, Inc). The normality of all echocardiographic and electrocardiographic outcomes was evaluated using the Shapiro-Wilk test. A Wilcoxon matched-pairs signed-rank test was used to compare prediltiazem infusion and pre-D5W infusion echocardiographic parameters to those recorded postdiltiazem infusion and post-D5W infusion, respectively. Prediltiazem infusion parameters were also compared to pre-D5W parameters as well as postdiltiazem infusion parameters compared to their respective post-D5W infusion parameters with a Wilcoxon matched-pairs signed-rank test. Change in systolic blood pressure was assessed in each group with a Friedman test. Outcomes are presented as median and range. Statistical significance was set P < .05.

Results

Population demographics

The final study population consisted of 10 dogs with a median age of 3 years (range, 1 to 6 years). Nine dogs were castrated males and 1 dog was a spayed female. Dogs were reported as Border Collie (n = 2), Goldendoodle (2), retriever mix (2), Golden Retriever (1), Gordon Setter (1), Pembroke Welsh Corgi (1), and terrier mix (1). Median body weight was 24.8 kg (range, 13.9 to 31.6 kg). All dogs were deemed healthy based on history, physical examination, and screening diagnostics. Five dogs were randomized to receive diltiazem first resulting in the other 5 receiving D5W first. The order of assessment was also randomized based on the time of presentation to the hospital.

Echocardiography

None of the outcomes met the normality assumption. Most parameters of left ventricular systolic function did not change with either treatment (Table 1). Baseline FS was significantly higher before receiving diltiazem (median, 36.3%; range, 23.8 to 53.8%) compared to FS measured before receiving D5W (median, 28.7%; range, 24.0 to 55.0%; P = .037) (Table 2). All other baseline parameters were not significantly different between the treatment groups. Postdiltiazem STI (median, 0.30; range, 0.16 to 0.34) was significantly lower than post-D5W STI (median, 0.32; range, 0.22 to 0.40; P = .046). All other echocardiographic parameters did not differ significantly between each of the groups after receiving diltiazem or D5W. All pretreatment echocardiographic parameters were not significantly different from their respective posttreatment values.

Table 1

Median (range) echocardiographic determinants of left ventricular systolic function for 10 healthy client-owned dogs immediately before (pre) or during the last hour (post) of treatment with either diltiazem (240 µg/kg, IV bolus over 10 min followed by a constant rate infusion [CRI] of 6 µg/kg/min for 300 min) or the same volume of 5% dextrose in water (D5W; administered similarly over the same duration) during a prospective, masked, crossover study conducted between May 27 and August 22, 2021.

Diltiazem D5W
Parameter Pre Post Pre Post
FS (%) 36.3 (23.8–53.8) 36.0 (27.0–53.4) 28.7 (24.0–55.0) 33.1 (24.9–51.1)
EF (%) 52.5 (39.2–64.1) 58.3 (39.1–71.4) 56.5 (38.2–61.9) 54.5 (38.5–70.0)
EPSS (cm) 0.29 (0.15–0.42) 0.21 (.15–.42) 0.29 (0.15–0.46) 0.23 (0.08–0.51)
ESV (mL) 20.4 (6.7–34.3) 14.7 (5.6–36.5) 19.8 (6.9–26.8) 18.8 (6.8–36.3)
ESVI 26.9 (10.3–38.3) 19.0 (8.7–37.4) 24.3 (10.6–33.7) 24.9 (10.4–37.6)
STI 0.32 (0.23–0.43) 0.30 (0.16–0.34) 0.37 (0.20–0.77) 0.32 (0.22–0.40)

EF = Ejection fraction. EPSS = E-point septal separation. ESV = End-systolic volume. ESVI = End-systolic volume index. FS = Fractional shortening. STI = Systolic time interval.

Table 2

Comparison using the Wilcoxon matched-pairs signed-rank test of outcomes from the study described in Table 1.

Parameter Comparison P value
FS Pre- vs postdiltiazem .333
Pre- vs post-D5W .285
Prediltiazem vs pre-D5W .037
Postdiltiazem vs post-D5W .093
EF Pre- vs postdiltiazem .114
Pre- vs post-D5W .445
Prediltiazem vs pre-D5W .799
Postdiltiazem vs post-D5W .074
EPSS Pre- vs postdiltiazem .052
Pre- vs post-D5W .386
Prediltiazem vs pre-D5W .475
Postdiltiazem vs post-D5W .540
ESV Pre- vs postdiltiazem .139
Pre- vs post-D5W .647
Prediltiazem vs pre-D5W .284
Postdiltiazem vs post-D5W .139
ESVI Pre- vs postdiltiazem .169
Pre- vs post-D5W .721
Prediltiazem vs pre-D5W .284
Postdiltiazem vs post-D5W .169
STI Pre- vs postdiltiazem .125
Pre- vs post-D5W .059
Prediltiazem vs pre-D5W .092
Postdiltiazem vs post-DW .046

EF = Ejection fraction. EPSS = E-point septal separation. ESV = End-systolic volume. ESVI = End-systolic volume index. FS = Fractional shortening. STI = Systolic time interval.

Systemic blood pressure

The systolic blood pressure assessed at hourly time points (Figure 1) after starting the infusions did not change significantly with either diltiazem (P = .450) or D5W (P = .940). Systolic blood pressure stayed above 100 mmHg for all dogs throughout the study except for 1 dog. The lowest recorded blood pressure for that dog was 98 mmHg while receiving diltiazem and 96 mmHg while receiving D5W.

Figure 1
Figure 1

Median indirect systolic blood pressure for 10 healthy client-owned dogs immediately before (time 0 minutes) and at 60-minute intervals while receiving diltiazem (240 µg/kg, IV bolus over 10 min followed by a constant rate infusion [CRI] of 6 µg/kg/min for 300 min) or the same volume of 5% dextrose in water (D5W; administered similarly over the same duration) during a prospective, masked, crossover study conducted between May 27 and August 22, 2021. For each time point, the circle represents the median and the error bars represent the range. Note that indirect systolic blood pressure did not change over time with diltiazem (P = .450) or D5W (P = .940).

Citation: American Journal of Veterinary Research 84, 2; 10.2460/ajvr.22.09.0158

Electrocardiography

Diltiazem significantly increased the PR interval from baseline (pre, 0.11 s; range, 0.07 to 0.13 s; and post, 0.13 s; range, 0.08 to 0.17 s; P = .005), and the PR interval was higher after receiving diltiazem compared to after receiving D5W (median, 0.11 s; range, 0.08 to 0.13 s; P = .013) (Tables 3 and 4). Unexpectedly, heart rate was significantly higher after receiving diltiazem (median, 100 beats per minute (bpm); range, 60 to 140 bpm) compared to heart rate after receiving D5W (median, 80 bpm; range, 60 to 140 bpm; P = .047) Additionally, R-wave amplitude significantly increased from baseline (pre, 1.6 mV; range, 0.5 to 3.4 mV; and post, 1.6 mV; range, 0.7 to 3.9 mV; P = .027) and QRS duration increased from baseline (pre, 0.055 s; range, 0.046 to 0.076 s; and post, 0.058 s, range, 0.048 to 0.080 s; P = .017) with diltiazem but not D5W.

Table 3

Median (range) electrocardiographic parameters assessed in dogs described in Table 1.

Diltiazem D5W
Parameter Pre Post Pre Post
HR (bpm) 80 (40–160) 100 (60–140) 100 (60–160) 80 (60–140)
P-wave amp (mv) 0.20 (0.12–0.37) 0.20 (0.16–0.40) 0.21 (0.15–0.38) 0.21 (0.14–0.34)
P-wave dur (s) 0.05 (0.04–0.06) 0.04 (0.04–0.06) 0.05 (0.03–0.06) 0.05 (0.04–0.06)
PR interval (s) 0.11 (0.07–0.13) 0.13 (0.08–0.17) 0.10 (0.08–0.14) 0.11 (0.08–0.13)
R-wave amp (mV) 1.6 (0.5–3.4) 1.6 (0.7–3.9) 1.7 (0.5–3.6) 1.6 (.06–3.5)
R-wave dur (s) 0.03 (0.02–0.04) 0.03 (0.02–0.04) 0.02 (0.02–0.04) 0.02 (0.02–0.5)
QRS dur (s) 0.055 (0.046–0.076) 0.058 (0.048–0.080) 0.059 (0.040–0.080) 0.058 (0.046–0.076)
T-wave amp (mV) 0.32 (0.10–0.60) 0.26 (0.10–0.46) 0.29 (0.11–0.48) 0.32 (0.11–0.50)
MEA (degrees) 60 (60–90) 60 (60–90) 75 (60–90) 60 (60–90)

amp = Amplitude. BPM = Beats per minute. Dur = Duration. HR = Heart rate. MEA = Mean electrical axis.

Table 4

Comparison using the Wilcoxon matched-pairs signed-rank test of electrocardiographic changes from dogs described in Table 1.

Parameter Comparison P value
HR Pre- vs postdiltiazem .158
Pre- vs post-D5W .166
Prediltiazem vs pre-D5W .179
Postdiltiazem vs post-D5W .047
P-wave amplitude Pre- vs postdiltiazem .358
Pre- vs post-D5W .758
Prediltiazem vs pre-D5W .720
Postdiltiazem vs post-D5W .603
P-wave duration Pre- vs postdiltiazem .347
Pre- vs post-D5W .502
Prediltiazem vs pre-D5W .537
Postdiltiazem vs post-D5W .567
PR interval Pre- vs postdiltiazem .005
Pre- vs post-D5W .505
Prediltiazem vs pre-D5W .838
Postdiltiazem vs post-D5W .013
R-wave amplitude Pre- vs postdiltiazem .027
Pre- vs post-D5W .153
Prediltiazem vs pre-D5W .647
Postdiltiazem vs post-D5W .202
R-wave duration Pre- vs postdiltiazem .297
Pre- vs post-D5W .403
Prediltiazem vs pre-D5W .533
Postdiltiazem vs post-DW .915
QRS duration Pre- vs postdiltiazem .017
Pre- vs post-D5W .758
Prediltiazem vs pre-D5W .506
Postdiltiazem vs post-DW .376
T-wave amplitude Pre- vs postdiltiazem .540
Pre- vs post-D5W .445
Prediltiazem vs pre-D5W .919
Postdiltiazem vs post-DW .128
MEA Pre- vs postdiltiazem .317
Pre- vs post-D5W .083
Prediltiazem vs pre-D5W .157
Postdiltiazem vs post-DW > .999

HR = heart rate. MEA = mean electrical axis.

Discussion

Diltiazem is a benzothiazepine CCB which is more commonly categorized as a nondihydropyridine CCB. Due to its effects on slowing heart rate, it is a commonly used antiarrhythmic medication for the treatment of supraventricular tachyarrhythmias; however, inhibition of calcium entry into cardiac myocytes decreases release of additional calcium from the sarcoplasmic reticulum thus decreasing the strength of muscle contraction.6 The negative inotropic effects of diltiazem are of concern in clinical patients, especially in those with dilated cardiomyopathy phenotype, due to the potential for decompensation and development of congestive heart failure. Prior studies812,17 evaluating diltiazem given intravenously in dogs did not use protocols that would be relevant to clinical patients hospitalized for treatment of a supraventricular tachyarrhythmia. This study evaluated the effects of an intravenous infusion of diltiazem at a commonly used dose and for a longer duration on systolic function assessed by echocardiogram in a prospective, masked, placebo-controlled manner.

The dose and duration of diltiazem in this study did not exhibit any significant influence on echocardiographic markers of systolic function except for a decrease in STI. STI was calculated from the ratio of preejection period to left ventricular ejection time assessed using M-mode echocardiography. The preejection period is the interval beginning at the start of ventricular depolarization and ending at the start of left ventricular ejection. Left ventricular ejection time is the interval between opening and closure of the aortic valve. STI is an index of global left ventricular function and is expected to increase with decreased left ventricular performance; however, it may be nonspecific due to variables that can affect left ventricular performance such as heart rate, preload, and afterload.21,22 Some of these parameters may be affected by respiration.23 Consequently, an average of 3 cardiac cycles were recorded in order to account for the variation that may be seen. Left ventricular ejection time is significantly correlated to heart rate in dogs,21 leading to a reduction in STI. In this study, median heart rate was significantly higher in the dogs after receiving diltiazem compared to their heart rate after receiving D5W. Since an increase in heart rate may lower left ventricular ejection time, we suspect that this may one explanation for the decrease in STI with diltiazem in our population of dogs. Additionally, the decrease in STI and increase in heart rate could be related to vasodilation from diltiazem.24

Diltiazem is a negative chronotrope; consequently, an increase in heart rate with diltiazem compared to D5W was an unexpected finding in this study. Compared to the atrioventricular node, the sinoatrial node may be less reliant on L-type calcium channels to reach threshold depolarization and/or an increase in sympathetic tone during the time of the postdiltiazem cardiac studies may have contributed to the increased heart rate when compared to the heart rate at the time of the post-D5W cardiac studies and the study dose of diltiazem was unable to overcome the increase in sympathetic drive. Although there were no objective measurements in place to assess anxiety and sympathetic tone in this study, more procedures were performed (increased frequency of Doppler blood pressure measurement) on the dogs when they received the diltiazem infusion compared to the D5W infusion. It is possible that there may have been positive inotropic effects on other echocardiographic markers of left ventricular function including FS due to activation of the sympathetic nervous system.

Baseline echocardiographic parameters were obtained prior to each infusion. Baseline FS was higher prior to receiving diltiazem compared to the baseline prior to receiving D5W. The cause of this difference is unknown. There were no attributable differences in the study population at those 2 timepoints since each dog served as its own negative control, and none of the dogs had any structural cardiac abnormalities. There was no difference in FS after receiving diltiazem versus after receiving D5W. We cannot exclude the possibility that the higher baseline FS before receiving diltiazem may have contributed to the not observed differences between the 2 groups at follow up; however, there was no difference in FS from baseline after receiving diltiazem or D5W.

None of the dogs in this study developed systemic hypotension at the current rate of diltiazem infusion. Systemic blood pressure, measured indirectly by Doppler sphygmomanometry, did not significantly change throughout the study with either of the infusions of diltiazem or D5W. A decrease in systemic blood pressure can be seen with the administration of IV diltiazem,11,17 and systemic hypotension may develop at higher infusion rates (60 to 90 μg/kg/min).11 The loading dose of diltiazem given as an IV bolus may pose a risk for a significant reduction in systemic blood pressure. Administering the bolus slowly is generally recommended1,7,17 and may have helped minimize the risk of development of this complication. In the absence of decreased systolic function, a decrease in blood pressure from diltiazem-induced vasodilation could have been offset by an increase in aortic flow.

Negative dromotropy is an anticipated result of diltiazem administration. Expectedly, the PR interval significantly increased from baseline in dogs after receiving diltiazem, and the postdiltiazem PR interval was higher compared to the post-D5W PR interval. There was no change in P-wave amplitude or duration from diltiazem administration, meaning the negative dromotropic effects seen in this study were primarily through the calcium channel blockade in the atrioventricular node. Diltiazem is also expected to slow pacemaker activity through inhibiting L-type calcium channels in the sinoatrial node; however, there should be a limited effect on T-type calcium channels with this medication.6,25 In this study, an increase in heart rate was found after administration of diltiazem compared to after administration of D5W. We speculate that this increase in heart rate was due to activation of the sympathetic nervous system. Sympathetic neural effects on chronotropy and dromotropy are through agonism of β1-adrenoreceptors, which leads to phosphorylation of L-type calcium channels as well as many other proteins.26 Consequently, there are several mechanisms for the increased sympathetic drive to overcome the negative chronotropic effects of diltiazem. The influence of sympathetic tone on atrioventricular nodal conduction is much less pronounced,27 leading to the prolongation of the PR interval with diltiazem.

R-wave amplitude was increased from baseline with diltiazem but not D5W. Diltiazem is not expected to cause a change in ventricular mass or size. Normal variation and type I error or alterations in patient positioning are suspected as the cause of this finding. Slight prolongation in QRS duration was also found compared to baseline with diltiazem but not D5W. The cause of this is unknown as it is not an expected consequence of diltiazem administration, and none of the dogs had any electrolyte disturbances or were administered a sodium channel blocker. Prolongation in QRS duration in people can be associated with left ventricular dysfunction,28 but we did not find significant clinically relevant echocardiographic evidence of decreased left ventricular systolic function in this study. However, the change in QRS duration with diltiazem is thought to be clinically insignificant since it remained ≤ 0.08 seconds for all dogs.28

This study has several limitations. Only 1 clinically applicable infusion rate was used to evaluate the cardiovascular effects of diltiazem. Although comparing the effects of multiple rates may have provided additional information, the objectives of this study were not to evaluate the efficacy of various doses on heart rate management but instead to investigate the potential for negative inotropy using an infusion rate at the higher end of the dose range in a prospective, masked, placebo-controlled manner.7,14,15 Since a significant decrease in left ventricular systolic function was not found, assessment of lower infusion rates is not thought to be clinically relevant since left ventricular systolic function is inversely related to diltiazem dose.13 Plasma diltiazem concentrations were not monitored, which could be considered another limitation of the study. However, the rationale for the selected dose of diltiazem used was also based on previous pharmacokinetic data in dogs with a diltiazem CRI of 6 μg/kg/min expected to maintain a plasma concentration of approximately 120 ng/mL and an IV loading dose of 240 μg/kg expected to quickly achieve steady-state concentrations of 120 ng/mL based on the volume of distribution of diltiazem in dogs.19 Additionally, this targeted plasma concentration achieves heart rates similar to what is seen with a normal sinus rhythm.7,13 An additional limitation is that the assessment of left ventricular systolic function and inferences on CO were made through standard 2-D echocardiography. The thermodilution technique is considered to be the gold standard modality to evaluate CO, but it is an invasive procedure with the potential for risks including the development of arrhythmias.29,30 Transthoracic echocardiography is a commonly used, noninvasive technique and is an acceptable method in the evaluation of CO in dogs.31,32 The use of Doppler sphygmomanometry as a method of noninvasive blood pressure measurement has been shown to be a poor predictor of direct arterial pressure.3335 Its use was primarily dictated by what resources were readily available for our study. In awake, normotensive dogs, Doppler typically underestimates direct systolic arterial blood pressure;33,34 however, its sensitivity for detecting hypotension is diminished35 so our findings must be interpreted with caution. Furthermore, there was an unexpected increase in heart rate after the administration of diltiazem. Consequently, it may be difficult to make definitive deductions based on these conflicting results. For instance, STI is the ratio of 2 time intervals which could be affected differently by the changes in heart rate.

Supraventricular tachyarrhythmias are common in veterinary medicine, yet some clinicians might not utilize injectable diltiazem due to concern for a reduction in cardiac contractility. There was no substantial evidence that negative inotropy occurs with the dosing regimen that we utilized; however, the results of this study cannot be directly applied to clinical patients with a supraventricular tachyarrhythmia since our population consisted of healthy dogs without evidence of cardiac disease. Dogs treated with injectable diltiazem in the inpatient setting likely have underlying structural cardiac disease and may already have developed congestive heart failure by the time of presentation.1 However, an intravenous diltiazem CRI may also be utilized for non-cardiac disease such as treatment of acute kidney injury in dogs.36 Consequently, the information gained from this study cohort is still clinically useful since a significant decrease in cardiac output would be detrimental to renal function in dogs with acute kidney injury.

The present study, which was performed in healthy adult dogs, does not support the concern that a clinically used IV CRI of diltiazem causes negative inotropy. These results help to establish the framework for future investigations of diltiazem’s effect on cardiac contractility in dogs with structural cardiac disease. Additionally, an increase in sympathetic tone may be able to overcome the negative chronotropic effects of this infusion rate of diltiazem.

Acknowledgments

Funding for this study was provided by the American College of Veterinary Internal Medicine Resident Research Grant Program and the Kansas State University Department of Clinical Sciences Mark Derrick Canine Research Fund. Student funding support was provided by the Morris Animal Foundation Veterinary Student Scholars Program and the Kansas State University College of Veterinary Medicine Office of Research. The authors declare that there were no conflicts of interest.

The authors also thank Shannon Nicholson for her help in facilitating the echocardiographic and electrocardiographic studies.

References

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    DeFrancesco TC. Management of cardiac emergencies in small animals. Vet Clin North Am Small Anim Pract. 2013;43(4):817842. doi:10.1016/j.cvsm.2013.03.012

    • PubMed
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    Noszczyk-Nowak A, Michalek M, Kaluza E, Cepiel A, Paslawska U. Prevalence of arrhythmias in dogs examined between 2008 and 2014. J Vet Res. 2017;61(1):103110. doi:10.1515/jvetres-2017-0013

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    Keene BW, Atkins CE, Bonagura JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2019;33(3):11271140. doi:10.1111/jvim.15488

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    Knight DH. Efficacy of inotropic support of the failing heart. Vet Clin North Am Small Anim Pract. 1991;21(5):879904. doi:10.1016/s0195-5616(91)50101-7

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    Nagashima Y, Hirao H, Furukawa S, et al. Plasma digoxin concentration in dogs with mitral regurgitation. J Vet Med Sci. 2001;63(11):11991202. doi:10.1292/jvms.63.1199

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Cooke KL, Snyder PS. Calcium channel blockers in veterinary medicine. J Vet Intern Med. 1998;12(3):123131. doi:10.1111/j.1939-1676.1998.tb02107.x

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    Papich MG. Diltiazem hydrochloride. In: Saunders Handbook of Veterinary Drugs. Elsevier; 2016:244246.

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    Bourassa MG, Cote P, Theroux P, Tubau JF, Genain C, Waters DD. Hemodynamics and coronary flow following diltiazem administration in anesthetized dogs and in humans. Chest. 1980;78(1 suppl):224230. doi:10.1378/chest.78.1_supplement.224

    • PubMed
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    Walsh RA, O’Rourke RA. Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs. J Clin Invest. 1985;75(5):14261434. doi:10.1172/JCI111844

    • PubMed
    • Search Google Scholar
    • Export Citation
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    Urquhart J, Patterson RE, Bacharach SL, et al. Comparative effects of verapamil, diltiazem, and nifedipine on hemodynamics and left ventricular function during acute myocardial ischemia in dogs. Circulation. 1984;69(2):382390. doi:10.1161/01.cir.69.2.382

    • PubMed
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    Griffin RM, Dimich I, Jurado R, Kaplan JA. Haemodynamic effects of diltiazem during fentanyl-nitrous oxide anaesthesia. An in vivo study in the dog. Br J Anaesth. 1988;60(6):655659. doi:10.1093/bja/60.6.655

    • Search Google Scholar
    • Export Citation
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    Kapur PA, Campos JH, Tippit SE. Influence of diltiazem on cardiovascular function and coronary hemodynamics during isoflurane anesthesia in the dog: correlation with plasma diltiazem levels. Anesth Analg. 1986;65(1):8187.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Miyamoto M, Nishijima Y, Nakayama T, Hamlin RL. Cardiovascular effects of intravenous diltiazem in dogs with iatrogenic atrial fibrillation. J Vet Intern Med. 2000;14(4):445451. doi:10.1892/0891-6640(2000)014<0445:ceoidi>2.3.co;2

    • PubMed
    • Search Google Scholar
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    Gelzer AR, Kraus MS. Management of atrial fibrillation. Vet Clin North Am Small Anim Pract. 2004;34(5):11271144, vi. doi:10.1016/j.cvsm.2004.05.001

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    Pedro B, Fontes-Sousa AP, Gelzer AR. Diagnosis and management of canine atrial fibrillation. Vet J. 2020;265:105549. doi:10.1016/j.tvjl.2020.105549

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    Acierno MJ, Brown S, Coleman AE, et al. ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med. 2018;32(6):18031822. doi:10.1111/jvim.15331

    • PubMed
    • Search Google Scholar
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    Skarvan K, Priebe HJ. Cardiovascular effects of diltiazem in the dog. Br J Anaesth. 1988;60(6):660670. doi:10.1093/bja/60.6.660

  • 18.

    Ruffato M, Novello L, Clark L. What is the definition of intraoperative hypotension in dogs? Results from a survey of diplomates of the ACVAA and ECVAA. Vet Anaesth Analg. 2015;42(1):5564. doi:10.1111/vaa.12169

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Han S-H, Chung M-H, Cha I-J. Pharmacokinetics and pharmacodynamics of intravenous diltiazem in dogs. Seoul J Med. 1990;1:110.

  • 20.

    Visser LC, Ciccozzi MM, Sintov DJ, Sharpe AN. Echocardiographic quantitation of left heart size and function in 122 healthy dogs: a prospective study proposing reference intervals and assessing repeatability. J Vet Intern Med. 2019;33(5):19091920. doi:10.1111/jvim.15562

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Atkins CE, Snyder PS. Systolic-time intervals and their derivatives for evaluation of cardiac-function. J Vet Int Med. 1992;6(2):5563. doi:10.1111/j.1939-1676.1992.tb03152.x

    • Search Google Scholar
    • Export Citation
  • 22.

    Lewis RP, Rittgers SE, Forester WF, Boudoulas H. Critical-review of systolic-time intervals. Circulation. 1977;56(2):146158. doi:10.1161/01.Cir.56.2.146

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Van Leeuwen P, Kuemmell HC. Respiratory modulation of cardiac time intervals. Br Heart J. 1987;58(2):129135. doi:10.1136/hrt.58.2.129

  • 24.

    Kawai C, Konishi T, Matsuyama E, Okazaki H. Comparative effects of three calcium antagonists, diltiazem, verapamil and nifedipine, on the sinoatrial and atrioventricular nodes. Experimental and clinical studies. Circulation. 1981;63(5):10351042. doi:10.1161/01.cir.63.5.1035

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    De Paoli P, Cerbai E, Koidl B, Kirchengast M, Sartiani L, Mugelli A. Selectivity of different calcium antagonists on T- and L-type calcium currents in guinea-pig ventricular myocytes. Pharmacol Res. 2002;46(6):491497. doi:10.1016/s1043661802002360

    • Search Google Scholar
    • Export Citation
  • 26.

    Gordan R, Gwathmey JK, Xie LH. Autonomic and endocrine control of cardiovascular function. World J Cardiol. 2015;7(4):204214. doi:10.4330/wjc.v7.i4.204

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Loeb JM, deTarnowsky JM. Integration of heart rate and sympathetic neural effects on AV conduction. Am J Physiol Heart Circ Physiol. 1988;254(4):H651H657. doi:10.1152/ajpheart.1988.254.4.H651

    • Search Google Scholar
    • Export Citation
  • 28.

    Murkofsky RL, Dangas G, Diamond JA, Mehta D, Schaffer A, Ambrose JA. A prolonged QRS duration on surface electrocardiogram is a specific indicator of left ventricular dysfunction. J Am Coll Cardiol. 1998;32(2):476482. doi:10.1016/s0735-1097(98)00242-3

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Shih A, Maisenbacher HW, Bandt C, et al. Assessment of cardiac output measurement in dogs by transpulmonary pulse contour analysis. J Vet Emerg Crit Care (San Antonio). 2011;21(4):321327. doi:10.1111/j.1476-4431.2011.00651.x

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Mantovani MM, Fantoni DT, Gimenes AM, et al. Clinical monitoring of cardiac output assessed by transoesophageal echocardiography in anaesthetised dogs: a comparison with the thermodilution technique. BMC Vet Res. 2017;13(1):325. doi:10.1186/s12917-017-1227-9

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Lopes PC, Sousa MG, Camacho AA, et al. Comparison between two methods for cardiac output measurement in propofol-anesthetized dogs: thermodilution and Doppler. Vet Anaesth Analg. 2010;37(5):401408. doi:10.1111/j.1467-2995.2010.00552.x

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    LeBlanc NL, Scollan KF, Stieger-Vanegas SM. Cardiac output measured by use of electrocardiogram-gated 64-slice multidector computed tomography, echocardiography, and thermodilution in healthy dogs. Am J Vet Res. 2017;78(7):818827. doi:10.2460/ajvr.78.7.818

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Stepien RL, Rapoport GS. Clinical comparison of three methods to measure blood pressure in nonsedated dogs. J Am Vet Med Assoc. 1999;215(11):16231628.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Vachon C, Belanger MC, Burns PM. Evaluation of oscillometric and Doppler ultrasonic devices for blood pressure measurements in anesthetized and conscious dogs. Res Vet Sci. 2014;97(1):111117. doi:10.1016/j.rvsc.2014.05.003

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Bourazak LA, Hofmeister EH. Bias, sensitivity, and specificity of Doppler ultrasonic flow detector measurement of blood pressure for detecting and monitoring hypotension in anesthetized dogs. J Am Vet Med Assoc. 2018;253(11):14331438. doi:10.2460/javma.253.11.1433

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Mathews KA, Monteith G. Evaluation of adding diltiazem therapy to standard treatment of acute renal failure caused by leptospirosis: 18 dogs (1998–2001). J Vet Emerg Crit Care. 2007;17(2):149158. doi:10.1111/j.1476-4431.2007.00232.x

    • Search Google Scholar
    • Export Citation

Contributor Notes

Corresponding author: Dr. Whitehouse (wwhitehouse@vet.k-state.edu)
  • Figure 1

    Median indirect systolic blood pressure for 10 healthy client-owned dogs immediately before (time 0 minutes) and at 60-minute intervals while receiving diltiazem (240 µg/kg, IV bolus over 10 min followed by a constant rate infusion [CRI] of 6 µg/kg/min for 300 min) or the same volume of 5% dextrose in water (D5W; administered similarly over the same duration) during a prospective, masked, crossover study conducted between May 27 and August 22, 2021. For each time point, the circle represents the median and the error bars represent the range. Note that indirect systolic blood pressure did not change over time with diltiazem (P = .450) or D5W (P = .940).

  • 1.

    DeFrancesco TC. Management of cardiac emergencies in small animals. Vet Clin North Am Small Anim Pract. 2013;43(4):817842. doi:10.1016/j.cvsm.2013.03.012

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Noszczyk-Nowak A, Michalek M, Kaluza E, Cepiel A, Paslawska U. Prevalence of arrhythmias in dogs examined between 2008 and 2014. J Vet Res. 2017;61(1):103110. doi:10.1515/jvetres-2017-0013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Keene BW, Atkins CE, Bonagura JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2019;33(3):11271140. doi:10.1111/jvim.15488

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Knight DH. Efficacy of inotropic support of the failing heart. Vet Clin North Am Small Anim Pract. 1991;21(5):879904. doi:10.1016/s0195-5616(91)50101-7

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Nagashima Y, Hirao H, Furukawa S, et al. Plasma digoxin concentration in dogs with mitral regurgitation. J Vet Med Sci. 2001;63(11):11991202. doi:10.1292/jvms.63.1199

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Cooke KL, Snyder PS. Calcium channel blockers in veterinary medicine. J Vet Intern Med. 1998;12(3):123131. doi:10.1111/j.1939-1676.1998.tb02107.x

  • 7.

    Papich MG. Diltiazem hydrochloride. In: Saunders Handbook of Veterinary Drugs. Elsevier; 2016:244246.

  • 8.

    Bourassa MG, Cote P, Theroux P, Tubau JF, Genain C, Waters DD. Hemodynamics and coronary flow following diltiazem administration in anesthetized dogs and in humans. Chest. 1980;78(1 suppl):224230. doi:10.1378/chest.78.1_supplement.224

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Walsh RA, O’Rourke RA. Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs. J Clin Invest. 1985;75(5):14261434. doi:10.1172/JCI111844

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Urquhart J, Patterson RE, Bacharach SL, et al. Comparative effects of verapamil, diltiazem, and nifedipine on hemodynamics and left ventricular function during acute myocardial ischemia in dogs. Circulation. 1984;69(2):382390. doi:10.1161/01.cir.69.2.382

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Griffin RM, Dimich I, Jurado R, Kaplan JA. Haemodynamic effects of diltiazem during fentanyl-nitrous oxide anaesthesia. An in vivo study in the dog. Br J Anaesth. 1988;60(6):655659. doi:10.1093/bja/60.6.655

    • Search Google Scholar
    • Export Citation
  • 12.

    Kapur PA, Campos JH, Tippit SE. Influence of diltiazem on cardiovascular function and coronary hemodynamics during isoflurane anesthesia in the dog: correlation with plasma diltiazem levels. Anesth Analg. 1986;65(1):8187.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Miyamoto M, Nishijima Y, Nakayama T, Hamlin RL. Cardiovascular effects of intravenous diltiazem in dogs with iatrogenic atrial fibrillation. J Vet Intern Med. 2000;14(4):445451. doi:10.1892/0891-6640(2000)014<0445:ceoidi>2.3.co;2

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Gelzer AR, Kraus MS. Management of atrial fibrillation. Vet Clin North Am Small Anim Pract. 2004;34(5):11271144, vi. doi:10.1016/j.cvsm.2004.05.001

  • 15.

    Pedro B, Fontes-Sousa AP, Gelzer AR. Diagnosis and management of canine atrial fibrillation. Vet J. 2020;265:105549. doi:10.1016/j.tvjl.2020.105549

  • 16.

    Acierno MJ, Brown S, Coleman AE, et al. ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med. 2018;32(6):18031822. doi:10.1111/jvim.15331

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Skarvan K, Priebe HJ. Cardiovascular effects of diltiazem in the dog. Br J Anaesth. 1988;60(6):660670. doi:10.1093/bja/60.6.660

  • 18.

    Ruffato M, Novello L, Clark L. What is the definition of intraoperative hypotension in dogs? Results from a survey of diplomates of the ACVAA and ECVAA. Vet Anaesth Analg. 2015;42(1):5564. doi:10.1111/vaa.12169

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Han S-H, Chung M-H, Cha I-J. Pharmacokinetics and pharmacodynamics of intravenous diltiazem in dogs. Seoul J Med. 1990;1:110.

  • 20.

    Visser LC, Ciccozzi MM, Sintov DJ, Sharpe AN. Echocardiographic quantitation of left heart size and function in 122 healthy dogs: a prospective study proposing reference intervals and assessing repeatability. J Vet Intern Med. 2019;33(5):19091920. doi:10.1111/jvim.15562

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Atkins CE, Snyder PS. Systolic-time intervals and their derivatives for evaluation of cardiac-function. J Vet Int Med. 1992;6(2):5563. doi:10.1111/j.1939-1676.1992.tb03152.x

    • Search Google Scholar
    • Export Citation
  • 22.

    Lewis RP, Rittgers SE, Forester WF, Boudoulas H. Critical-review of systolic-time intervals. Circulation. 1977;56(2):146158. doi:10.1161/01.Cir.56.2.146

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Van Leeuwen P, Kuemmell HC. Respiratory modulation of cardiac time intervals. Br Heart J. 1987;58(2):129135. doi:10.1136/hrt.58.2.129

  • 24.

    Kawai C, Konishi T, Matsuyama E, Okazaki H. Comparative effects of three calcium antagonists, diltiazem, verapamil and nifedipine, on the sinoatrial and atrioventricular nodes. Experimental and clinical studies. Circulation. 1981;63(5):10351042. doi:10.1161/01.cir.63.5.1035

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    De Paoli P, Cerbai E, Koidl B, Kirchengast M, Sartiani L, Mugelli A. Selectivity of different calcium antagonists on T- and L-type calcium currents in guinea-pig ventricular myocytes. Pharmacol Res. 2002;46(6):491497. doi:10.1016/s1043661802002360

    • Search Google Scholar
    • Export Citation
  • 26.

    Gordan R, Gwathmey JK, Xie LH. Autonomic and endocrine control of cardiovascular function. World J Cardiol. 2015;7(4):204214. doi:10.4330/wjc.v7.i4.204

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Loeb JM, deTarnowsky JM. Integration of heart rate and sympathetic neural effects on AV conduction. Am J Physiol Heart Circ Physiol. 1988;254(4):H651H657. doi:10.1152/ajpheart.1988.254.4.H651

    • Search Google Scholar
    • Export Citation
  • 28.

    Murkofsky RL, Dangas G, Diamond JA, Mehta D, Schaffer A, Ambrose JA. A prolonged QRS duration on surface electrocardiogram is a specific indicator of left ventricular dysfunction. J Am Coll Cardiol. 1998;32(2):476482. doi:10.1016/s0735-1097(98)00242-3

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Shih A, Maisenbacher HW, Bandt C, et al. Assessment of cardiac output measurement in dogs by transpulmonary pulse contour analysis. J Vet Emerg Crit Care (San Antonio). 2011;21(4):321327. doi:10.1111/j.1476-4431.2011.00651.x

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Mantovani MM, Fantoni DT, Gimenes AM, et al. Clinical monitoring of cardiac output assessed by transoesophageal echocardiography in anaesthetised dogs: a comparison with the thermodilution technique. BMC Vet Res. 2017;13(1):325. doi:10.1186/s12917-017-1227-9

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Lopes PC, Sousa MG, Camacho AA, et al. Comparison between two methods for cardiac output measurement in propofol-anesthetized dogs: thermodilution and Doppler. Vet Anaesth Analg. 2010;37(5):401408. doi:10.1111/j.1467-2995.2010.00552.x

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    LeBlanc NL, Scollan KF, Stieger-Vanegas SM. Cardiac output measured by use of electrocardiogram-gated 64-slice multidector computed tomography, echocardiography, and thermodilution in healthy dogs. Am J Vet Res. 2017;78(7):818827. doi:10.2460/ajvr.78.7.818

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Stepien RL, Rapoport GS. Clinical comparison of three methods to measure blood pressure in nonsedated dogs. J Am Vet Med Assoc. 1999;215(11):16231628.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Vachon C, Belanger MC, Burns PM. Evaluation of oscillometric and Doppler ultrasonic devices for blood pressure measurements in anesthetized and conscious dogs. Res Vet Sci. 2014;97(1):111117. doi:10.1016/j.rvsc.2014.05.003

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Bourazak LA, Hofmeister EH. Bias, sensitivity, and specificity of Doppler ultrasonic flow detector measurement of blood pressure for detecting and monitoring hypotension in anesthetized dogs. J Am Vet Med Assoc. 2018;253(11):14331438. doi:10.2460/javma.253.11.1433

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Mathews KA, Monteith G. Evaluation of adding diltiazem therapy to standard treatment of acute renal failure caused by leptospirosis: 18 dogs (1998–2001). J Vet Emerg Crit Care. 2007;17(2):149158. doi:10.1111/j.1476-4431.2007.00232.x

    • Search Google Scholar
    • Export Citation

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