Effects of Diazepam or Lidocaine Premedication on Propofol Induction and Cardiovascular Parameters in Dogs

Introduction

Propofol is a commonly used anesthetic induction agent in small animals.^1–3 Although the mechanism of action of propofol has not been clearly elucidated, it may enhance the function of γ-aminobutyric acid (GABA) receptors.^1,4 Propofol has a rapid onset, produces a smooth induction, is rapidly metabolized, and causes moderate cardiovascular and dose-dependent respiratory depression.^1–7 In order to decrease the amount of propofol required to induce anesthesia (especially in cardio-vascularly compromised animals), it is advantageous to use premedications that cause less cardiac depression.

The effects of various agents on the induction dose of propofol have been investigated in dogs.^8–16 Diazepam is a benzodiazepine that produces sedation and anxiolysis, has anticonvulsant actions, induces spinal cord-mediated skeletal muscle relaxation, causes retrograde amnesia from its effect at the GABA_A receptor in the central nervous system (CNS), and may be able to potentiate the effects of propofol.^4,8,17,18 Diazepam has minimal negative cardiovascular consequences, owing to the anatomical distribution of GABA_A receptors on the postsynaptic nerve endings almost exclusively within the CNS.^4,17

Lidocaine is a local anesthetic and a Class IB antiarrhythmic drug that can produce sedation and analgesia with minimal cardiovascular depression in dogs. Lidocaine has been shown to have sparing effects on the minimum alveolar concentration of isoflurane.^19,20 The possibility of decreasing the propofol dose and possible associated cardiovascular depression could make either of these drugs potentially effective pre-medications.

The purpose of this study was to investigate the effects of premedication with diazepam or lidocaine on propofol induction dose, heart rate, and direct arterial blood pressure in normal dogs.

Materials and Methods

The experimental design for this study was approved by the University of Georgia Animal Care and Use Committee, and husbandry of the animals was provided according to established institutional guidelines. Twenty-five random-source research dogs were used in the study. The dogs were deemed healthy if physical examination findings, packed cell volume (reference range 35.0% to 57.0%), and total protein values (reference range 5.2 to 7.3 g/dL) were normal. Dogs estimated to be <6 months or >5 years of age were excluded from the study. A definitive age could not be established because of the dogs’ unknown origin. Gender was not recorded. Body weights were determined and body condition scores were assessed using a previously published scoring system.²¹ The breeds of the dogs were estimated by the authors.

A 20-gauge, 1-inch catheter^a was placed in a cephalic vein, and a 22-gauge, 1-inch catheter^a was placed in the dorsal pedal artery after subcutaneous infiltration of 2% lidocaine^b (0.1 to 0.2 mL). The dogs were allowed at least 20 minutes of cage rest after placement of catheters. Dogs were randomly assigned to one of three treatment groups. Nine dogs received 0.9% saline (0.1 mL/kg intravenously [IV]); eight dogs were given lidocaine^b (2 mg/kg IV); and eight dogs received diazepam^c (0.25 mg/kg IV). Arterial blood pressures and heart rates were monitored continuously using a calibrated pressure transducer connected to a physiological monitor.^d Measurements were started before administration of drugs.

All dogs were given oxygen by mask for ≥5 minutes before the first measurements were recorded. Saline, lidocaine, or diazepam was injected in a covered syringe by a blinded investigator. Two minutes later, anesthesia was induced by incremental IV injections of propofol^e (0.8 mg/kg) delivered every 6 seconds up to a maximum dose of 8 mg/kg, or until jaw tone was sufficiently relaxed to accomplish endotracheal intubation. The investigator injecting the propofol and assessing the jaw tone was blinded to the premedication administered. Atracurium^f (0.3 mg/kg IV) was administered (as a component of an unrelated study), and the dogs were then intubated. The total amount of propofol given was recorded and is reported for each treatment group as mean ± standard deviation (SD). Systolic, diastolic, and mean arterial blood pressures (MAPs) and heart rates (HRs) were recorded immediately before administration of the premedications, immediately before induction with propofol, and after administration of atracurium but before intubation. Behavioral changes were recorded. Onset of apnea was not recorded, as atracurium was given immediately after induction.

Results

Body weights for all dogs ranged from 10.5 to 27 kg (mean ± SD was 21.4±7.5 kg). Body condition scores for all dogs ranged from 2 to 7 out of 9 (mean 4.8±1.2). No statistically significant differences were found in body weights or body condition scores among the three treatment groups [Table 1]. All dogs were mixed breeds and could not be clearly classified into one breed type.

Dogs in the saline group needed an average propofol dose of 5.8±1.1 mg/kg (range 4.6 to 7.7 mg/kg) to develop loss of jaw tone. Dogs receiving lidocaine required 5.5±1.0 mg/kg of propofol (range 4.0 to 7.2 mg/kg), and those that received diazepam required 4.8±1.0 mg/kg of propofol (range 3.1 to 6.2 mg/kg). No statistically significant differences were detected for the propofol doses used in the three groups [see Figure; Table 1]. The statistical power (1−β) for a 30% reduction effect on the propofol dose by the premedications was 0.87 as evaluated by the posthoc power analysis. This value implied that the number of animals in this study was sufficient to document statistically significant changes in the propofol induction doses between the groups.

Systolic, diastolic, and MAPs decreased after propofol administration in comparison to baseline in all groups, and HRs increased [Table 2]. No statistically significant differences were detected in these cardiovascular parameters between groups at any time point. No direct relationship between propofol dose and cardiovascular variables was noted. No adverse reactions were observed from the induction dose of propofol.

Discussion

The mean propofol dose (5.8±1.1 mg/kg) required for induction of anesthesia by the unmedicated dogs (saline group) in this study was within the range of previously published data (4.7±1.3 to 6.9±0.9 mg/kg).^9,22 The mean induction dose of propofol (4.8±0.96 mg/kg) used after 0.25 mg/kg diazepam IV in the present study correlated well with published data where premedication with diazepam (0.2 mg/kg IV) resulted in a propofol induction dose of 4.7±1.6 mg/kg.⁸ The current study did not reveal any statistically significant decrease in the propofol dosage after administration of diazepam. Significant decreases in propofol dosage have been described, however, after administration of a higher dose of diazepam (0.4 mg/kg) and also after midazolam (0.1 mg/kg), another benzodiazepine.^8,14 The dose rate published in veterinary textbooks for diazepam in dogs varies from 0.1 to 1 mg/kg, and a dosage of 0.25 mg/kg is frequently used in anesthetic protocols.^18,23

In the study reported here, the administration of lidocaine (2 mg/kg) did not significantly decrease the dosage of propofol required for induction of anesthesia. To the authors’ knowledge, there are no published data concerning the concurrent administration of lidocaine with propofol for comparison with these results.

A 30% treatment effect (i.e., a 30% reduction of the propofol dose rate associated with the premedication in comparison to the saline group) was considered clinically significant. In the current study, this meant a reduction of propofol from 5.8 mg/kg to 4.1 mg/kg was needed to indicate a clinically significant level of dosage reduction, which was not achieved by diazepam or by lidocaine. The retrospective power analysis of 0.87 suggested that the statistical significance (of the decrease in the induction dose considered clinically relevant) was not missed because of the small sample size.

The subjective assessment of the endpoint for propofol administration may influence results. Published assessments include loss of palpebral reflex, relaxation of jaw muscle tone, or the dose required for a smooth transition to inhalation anesthesia, even including propofol supplements administered after intubation.^10,15,22 In the current study, loss of jaw tone was the established endpoint and was assessed by a single, blinded, experienced anesthesiologist.

Speed of injection has been shown to influence the induction dose of propofol.^1,9,24–26 Recommended injection rates vary from 2 to 5 seconds (rapid) up to >90 seconds (slow).^1,3,7–9 Slower titration rates are purported to decrease apnea and hypotension but allow greater redistribution of the propofol, thereby resulting in more drug needed to induce anesthesia.^1,9,24–26 The injection rate of 30 to 60 seconds used in this study was neither rapid nor slow.

The physiological status of an animal, its body weight, and age can alter its response to anesthetic agents.²⁷ In this research study, all dogs were considered to be healthy and not excessively young or old. A small decrease in MAP was measured in these dogs following administration of propofol. Whereas none of the cardiovascular changes seen in this study were considered to be of clinical significance, debilitated, pediatric, or geriatric dogs may have decreased anesthetic requirements, and effects might be more prominent and of clinical importance.²⁷ A decreased dosage for propofol and increased incidence of apnea were reported in a series of geriatric dogs.²⁸ A dramatic decrease in blood pressure was recorded following administration of propofol in hypovolemic research dogs.²⁹ The influence of gender on the propofol induction dose is controversial and was not independently evaluated in the present study.¹

Atracurium is reported to occasionally decrease blood pressure as a result of histamine or prostacyclin release.^4,27 Other studies in dogs have not shown significant changes in cardiovascular parameters associated with the administration of atracurium. The study reported here did not differentiate between the effects of propofol and atracurium on blood pressures and HRs, but neither variable was statistically changed after induction of anesthesia, thus eliminating a significant contribution by atracurium.^30–32

Conclusion

This study did not show a significant decrease in the propofol dose needed for loss of jaw tone in healthy dogs pre-medicated with either diazepam (0.25 mg/kg IV) or lidocaine (2 mg/kg IV). No clinically significant changes in blood pressures or HRs were observed. Further investigations of these drug combinations in sick or geriatric animals would be of interest.