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Etomidate and Telazol
CLINICAL ANESTHESIA
0195-5616/99 $8.00 + .00
ETOMIDATE AND TELAZOL Luisito S. Pablo, DVM, MS, and James E. Bailey, DVM, MS
The choice of anesthetic agents in veterinary practice is influenced by many factors that may not be related to the patient's condition. Factors that influence drug choice include cost, familiarity with a specific anesthetic regimen, personnel, record keeping, training of the veterinarian, and caseload of the practice. These factors have often limited the anesthetic options of the veterinary practitioner. If we consider the number of injectable anesthetic agents available now, practitioners should consider themselves fortunate at how many choices they have and try to choose the best anesthetic regimen for a specific patient. This article provides a discussion of the pharmacology and clinical use of two less commonly used drugs, Telazol and etomidate (Amidate). These two drugs have relatively specific purposes in veterinary anesthetic practice.
ETOMIDATE
Etomidate is a carboxylated imidazole derivative (nonbarbiturate) intravenous anesthetid5 Chemically, it is not related to other drugs commonly used for anesthesia. It is water soluble in an acidic solution and becomes .lipid soluble at a physiological pH. 47 The commercial preparation contains 35% propylene glycol (vol/vol), resulting in a clear but extremely hyperosmolar solution. 3 The solution is not known to support microbial growth, but unused portion should be discarded.
From the Department of Large Animal Clinical Sciences, University of Florida, College of Veterinary Medicine, Gainesville, Florida
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 29 • NUMBER 3 • MAY 1999
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Central Nervous System Effects
The primary central nervous system (CNS) effect of etomidate is hypnosis, 42 and it preferentially suppresses the neocortex. 9 The mechanism of this effect of etomidate is not fully understood; however, it is known to penetrate the blood-brain barrier rapidly, and a peak brain level is reached within 1 minute following intravenous administration. 47 It is postulated that its hypnotic effect can be attributed partly to its action on the GABAminergic systemP Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS of mammalsY It appears that etomidate increases the number of available GABA receptors. 18 Etomidate does not possess analgesic propertiesY Etomidate decreases intracranial pressure in a dose-dependent manner. 36• 41 A study in dogs showed that etomidate caused direct cerebral vasoconstriction. 32 Etomidate decreased both cerebral oxygen metabolism (CMRo2 ) and cerebral blood flow. The reduction in cerebral blood flow was independent of CMRo2 , however. The CMRo2 decreased as a result of the depression of the neuronal function action of etomidate.32 Etomidate maintained cerebral perfusion pressure better than thiopental and propofol as a result of its minimal effect on the systemic arterial pressure. 16 Cardiovascular System
Etomidate produces minimal changes in cardiovascular function. Dogs that received 1.5 and 3.0 mg/kg of etomidate intravenously (IV) had stable hemodynamic variables. Heart rate, aortic blood pressure, left ventricular peak pressure, left ventricular end diastolic pressure, left ventricular contractile force, and myocardial oxygen consumption did not change. 39 In another study, a dose of 0.3 mg/kg IV over 30 seconds in dogs produced no significant changes in systemic arterial pressure, heart rate, cardiac output, or systemic vascular resistance. 4 Doses of 0.25 and 1.0 mg/kg of etomidate did not change the heart rate in dogs; however, a high dose of 4.0 mg/kg resulted in a significant reduction in heart rate. 38 When etomidate was administered for induction and maintenance of anesthesia in Beagles premedicated with medetomidine, the cardiac index .and cardiac output remained lower than baseline values. This reduction was most likely due to medetomidine. During etomidate infusion, the cardiac index and cardiac output did not differ from the values obtained after medetomidine injection. 28 In another study in dogs, infusion rates from 0.02 to 0.3 mg/kg/min resulted in minimal changes in mean arterial blood pressure (MAP). Only when the infusion rate was increased to 0.4 mg/kg/min did the MAP decrease. 32 The MAP then decreased to clinically acceptable levels. In experimental hemorrhagic shock in dogs, the MAP increased and heart rate decreased following a bolus injection of 1.0 mg/kg of etomidate. 56 Infusion of 0.1 mg/kg/min in the same dogs resulted in a
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further increase in the MAP, which reached 94 mm Hg at the end. 5 6 These results are further supported by another study that showed the minimal cardiopulmonary effect of etomidate in hypovolemic dogs. 40 Detailed studies of etomidate's effect on the cardiovascular system in cats are lacking. In one study, etomidate given intravenously at 0.8 mg/kg did not cause consistent changes in heart rate, except for a transient increase immediately after the injection. In general, there was no change in heart rate. 27 In another study, bolus injection of 0.8 mg/kg of etomidate in cats resulted in a slight reduction in the MAP. However, the MAP returned to baseline values 1 minute after injection. 46 Heart rates of the cats increased significantly, but returned to baseline values within 2 minutes. 46 We have used etomidate clinically in cats with compromised cardiovascular function based on our understanding of the lack of depressant cardiovascular effects of etomidate in other species. Respiratory System Effects
Etomidate produces minimal respiratory depression. A dose of 1.5 mg/kg in dogs produced an increased respiratory rate and reduced tidal volume, resulting in unchanged minute volume. The arterial pH and partial pressure of C02 did not change from baseline values; however, at 2 minutes after etomidate injection, mild hypoxemia developed. The partial pressure of 0 2, arterial (Pao 2) returned to baseline values shortly thereafter. When a higher dose of 3.0 mg/kg was used, mild respiratory acidosis occurred, but the values were clinically acceptable. Moderate hypoxemia developed 2 and 5 minutes after injection. The Pao2 returned to baseline values at 10 minutes. 39 From this study, it appears that the respiratory depressant effect of etomidate is dose dependent. The rate of injection also influences the development of respiratory depression. Similar to thiopental and propofol, a slower injection rate should result in less respiratory depression. Endocrine Effects
A noted side effect of etomidate administration is the inhibition of adrenal synthesis. 7• 19• 54 The significance of this effect was realized when a high mortality was reported in an intensive care unit, where human patients were sedated with etomidate infusion for many hours. 29 Etomidate decreases cortisol, aldosterone, and corticosterone by inhibiting 11a- and 11-(3-hydroxylase as well as the cholesterol side chain cleavage enzyme. 16 A study in dogs showed that anesthetic induction using etomidate at 2.0 mg/kg reduced the adrenocortical response to anesthesia and surgery from 2 to 6 hours after injection. 8 This is further supported by a study in cats showing cortisol suppression for 3.5 to 5.5 hours following a single bolus injection of etomidate at 2.0 mg/kg. 34 The clinical significance and impact of these findings are still unclear. Evi-
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dence showing that etomidate increases morbidity or mortality in clinical cases when used as an induction agent or given in the form of an infusion for short period times is nonexistent. Cardiopulmonary responses to experimentally induced hypoxia of anesthetized dogs did not change after a reduction in cortisol production induced by etomidate.25 Still, caution should be exercised when using etomidate in patients with known adrenal insufficiency. Corticosteroid (prednisolone, dexamethasone) supplementation is warranted if etomidate is used in these cases. Clinical Uses
Etomidate can be used as an agent for the induction and maintenance of anesthesia in small animals . We do not use etomidate routinely, but there are clinical conditions in small animals that make the use of etomidate a rational option. Etomidate is good choice for the hypovolemic patient that requires general anesthesia as it causes minimal cardiovascular changes. It has also been shown to have a cerebral protective effect in patients with hypovolemic ischemia. 56 Etomidate is an optimal anesthetic agent for dogs and cats with preexisting cardiovascular disease resulting in a poor hemodynamic state. Patients with dilated cardiomyopathy or other cardiovascular diseases that result in a low-output state tolerate etomidate anesthesia. Etomidate can also be used in patients with cardiac rhythm disturbances as it is not arrhythmogenic. 16, 30 Pregnant bitches and queens with moderate to severe systemic disturbance needing a cesarean section require an induction agent with minimal cardiorespiratory depressant effects. In pregnant women, it was shown that the transfer of etomidate to the fetus was incomplete and that its concentration in the plasma of the fetus decreased rapidly. 21 The umbilical/maternal venous blood ratio was 1:24 for etomidate 5 minutes after delivery compared to 1:1.3 for thiopentalP It has also been shown that women who received etomidate for induction of anesthesia had babies with a better clinical status compared to those whose mothers were given thiopental. 11 We have reserved the use of etomidate for cesarean section in bitches and queens with severe systemic disturbances. Etomidate can also be used in small animal patients with neurological disorders, especially if there are concomitant cardiovascular problems. In some instances, patients need to be anesthetized for diagnostic procedures such as cerebrospinal tap. These diagnostic aids may be critical for treatment and prognosis. Despite efforts to optimize the condition of these patients, they are often in a deteriorating condition. Etomidate, with its high margin of safety and brain protective effect, is a good choice for these cases. 55 We have also used etomidate as an induction agent in traumatized small animal patients. Following resuscitative efforts, some patients may require general anesthesia for emergency trauma surgery. The minimal
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hemodynamic changes and rapid onset of action of etomidate make it a suitable choice of drug for the acutely traumatized patient.5 Etomidate is also not arrhythmogenic and may not exacerbate ventricular dysrhythmias induced by trauma (e.g., traumatic myocarditis). With a hepatic extraction ratio of 0.5, the decreased hepatic blood flow in shock states is likely to result in moderate effects on the inactivation of etomidate. 52 Etomidate has been recommended for small animal patients with hepatic dysfunction. 20• 37 It is rapidly hydrolyzed by the liver to inactive metabolites, and it is also acted on by plasma esterases. Even in small animal patients with cirrhosis, etomidate has been regarded as a suitable agent. 43 The clearance rates of etomidate in human patients with severe cirrhosis were similar to those in patients with normal hepatic function, despite its longer elimination half-life in patients with cirrhosis. 51 In this study, it was concluded that etomidate was a safe agent for cirrhotic patients. Despite this finding, caution should be used when infusing etomidate in patients with hepatic problems. It has been shown that etomidate infusion as low as 80 f.Lg/kg/min in dogs decreased liver blood flow. This can be attributed to vasoconstriction in the hepatic arterial bed. 48 There are instances when rapid sequence induction in small animal patients is necessary. Etomidate can be used as an induction agent to allow rapid control of the airway. This becomes more important if these patients have concomitant heart disease or hemodynamic instability. For example, etomidate would be a good choice when anesthetizing a dog or cat with heart disease that needs a surgical correction of traumatic diaphragmatic rupture. When using etomidate, premedication with a tranquilizer, sedative, or analgesic is recommended to minimize the side effects (excitement, myoclonus, pain on injection, and vomiting) seen during induction. 38 The premedicants that we recommend are those with minimal cardiopulmonary depressant effect. A combination of a benzodiazepine and an opiate has been routine in our practice. Diazepam or midazolam at 0.05 to 0.2 mg/kg given IV or intramuscularly (IM) has been used with oxymorphone {0.05-0.1 mg/kg IM), butorphanol {0.1-0.2 mg/kg IM), or morphine (0.25-0.5 mg/kg IM). After premedication, a calculated dose of 2.0 mg/kg of etomidate is drawn up. One fourth of the calculated dose is given as .a slow IV injection. For rapid sequence induction, one half of the calculated dose can be administered initially. If the patient cannot be intubated, additional etomidate is administered until endotracheal intubation can be accomplished. In most cases, intubation can be performed without delivering the entire calculated dose. Anesthesia can be maintained using etomidate at a rate of 50 to 150 f.Lg/kg/min in premedicated dogs and cats. The infusion rate should be adjusted based on the subjective signs of anesthesia shown by the patient and the degree of pain involved with the procedure. Although the clinical impact of the adrenal suppression using a short-term infusion of etomidate has not been established, caution should be taken when using the propylene glycol formulation of etomidate for short-term infusion.
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Marked hemoglobinuria and intravascular hemolysis were reported in dogs given infusions of etomidate in a propylene glycol formulation. 33 This may be critical in patients with renal insufficiency because of the pigment load brought about by hemolysis. The single induction dose of etomidate also causes hemolysis in dogs and cats,33• 57 but the clinical significance of this is unknown. It appears that hemoglobinuria may be more severe in animals receiving a higher dose of the etomidate/propylene glycol formulation. 33 Until further studies are performed to establish the dose dependency of the hemoglobinuria, the use of etomidate as a maintenance agent in critically ill patients should be avoided. Limitations, Side Effects, Contraindications, and Precautions
There are reasons for the limited use of etomidate in practice, despite its positive pharmacodynamic actions. It is one of most expensive anesthetic agents available commercially. It is packaged in glass ampules, which limits its repeated use after opening. A cost comparison of induction agents used for dogs is presented in Table 1. Etomidate has been approved for human use; however, approval for veterinary use has not been sought by the manufacturer. The side effects reported in dogs following etomidate administration include excitement, myoclonic activity, vomiting, apnea, and pain on injection. Rough recovery characterized by excitement and purposeless muscle movements was also observed in these dogs. 38 These side effects were either eliminated or reduced by using premedicants. 38 Intravascular hemolysis has been observed following induction and maintenance doses.2s, 33 Etomidate should not be used in patients with adrenal insufficiency. Patients on prolonged steroid therapy that did not receive steroid days
Table 1. COST COMPARISON OF INDUCTION AGENTS IN A 20-kg DOG
Induction Agents
Doses Used (mg/kg)
Cost* ($)
Thiopental Ketamine-diazepam Xylazine-ketamine Telazol (intravenous) Medetomidine-ketamine Propofol Methohexital Ketamine-midazolam Etomidate
10.0 5.5-0.25 1.0-10.0 4.0 0.040-5.0 4.0 6.0 5.5-0.25 2.0
0.29 0.81 1.83 2.44 3.39 3.60 4.40 14.78 38.60
Relative Costt
1.0 2.8 6.3 8.4
11.7 12.4 15.0 51.0 133.0
*Prices are based on university contract. tThe relative cost was calculated by dividing the cost of a specific drug with the cost of thiopental.
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before anesthesia should receive steroid when etomidate is used as an anesthetic. Caution should also be taken when administering etomidate in patients with renal insufficiency. The pigment load associated with hemolysis compromises the filtering ability of the kidneys, and fluid therapy should be instituted to maintain renal perfusion. We prefer not to use etomidate in cases of renal failure. Better anesthetic alternatives are available for these cases. TELAZOL
Telazol is a combination of zolazepam and tiletamine at a ratio of 1:1 (zolazepam 50 mg/mL and tiletamine 50 mg/mL). The commercial preparation is a lyophilized powder which needs saline, 5% dextrose, or water for reconstitution. The solution is clear with a pH of 2.0 to 3.5. The reconstituted preparation should be discarded after 4 days if kept at room temperature and after 14 days if refrigerated. 1 It is a schedule III controlled substance. It is approved for use in dogs and cats as an IM injectable agent/ although IV injection has been employed. 10' 23, 24, 26 General Pharmacology
The pharmacological effects of Telazol are those of its component parts. Zolazepam belongs to the benzodiazepine group, which collectively produces sedation, hypnosis, and muscle relaxation. It also has anticonvulsant and anxiolytic properties. By itself, it does not cause profound sedation in healthy dogs and cats. Tiletamine, an arylaminocycloalkanone, is a cataleptic or dissociative agent similar to ketamine. It causes unconsciousness in cats using a relatively high dose. 22 The combination of tiletamine and zolazepam can produce sedation or general anesthesia in dogs and cats depending on the dose used. Anesthesia produced by Telazol is still considered to be dissociative, accompanied by better muscle relaxation and less clonic muscular movement and convulsive seizures than tiletamine alone. The animal maintains ocular, laryngeal, pharyngeal, and pedal reflexes. The analgesia produced by Telazol is sufficient for procedures associated with mild to moderate pain. 1 Cardiovascular Effects
The cardiovascular depressant effects of Telazol in dogs and cats are dose dependent. Telazol at 10.0 mg/kg given IM in dogs produced sinus tachycardia and a proportionate stroke volume reduction, resulting in minimal changes in cardiac output. At a higher dose of 20.0 mg/ kg IM, the cardiac output decreased significantly, despite the sinus tachycardia. 44 The systolic blood pressure increased initially following a
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dose of 10.0 mg/kg IM and then decreased slightly within 5 minutes. The systolic blood pressure stayed at this lower level throughout the anesthetic period, although the diastolic blood pressure increased. At 20.0 mg/kg IM, the blood pressure and myocardial contractility decreased.1 Using three IV doses of Telazol (6.6, 13.2, and 19.8 mg/kg) in dogs, the hemodynamic changes found include increases in cardiac output and heart rate and decreases in peripheral vascular resistance, contractility, and arterial blood pressure. The arterial blood pressure returned to baseline and then increased above baseline.24 In cats, IM and IV injections of Telazol did not produce any change in heart rate. 1• 23 Recommended IM doses in cats (9.7-15.8 mg/kg) resulted in a 10% reduction in blood pressure for 1 hour after administration. Thereafter, the systemic blood pressure returned to baseline values.44 Using IV doses of Telazol (9.7, 15.8, and 23.7 mg/kg) in cats, the blood pressure, peripheral vascular resistance, and contractility increased above baseline values after a brief decrease. There was also a brief reduction in cardiac output using the two higher doses. 23 Overall, Telazol produces a stable hemodynamic state, particularly at lower doses. Respiratory Effect
Telazol can cause respiratory depression, especially when high doses are used. Hypoventilation occurred following the administration of 23.7 mg/kg in cats and 19.8 mg/kg in dogs. 23• 24 An IM dose of 20 mg/kg in dogs resulted in hypoventilation, and cyanosis and hypoxemia were observed in some dogs. The hypoxemia spontaneously resolved in about 35 minutes after injection. 44 Nonpremedicated dogs that received 2.0 or 4.0 mg/kg of Telazol IV had normocapnia and mild hypoxemia (Pao2, 80-82 mm Hg). 10 Hypoxemia was also reported in cats after IM doses of 10 and 20 mg/kg. Cats recovered from this episode by 15 or 35 minutes postinjection.44 Cyanosis was not observed following IM and IV administration of Telazol at 9.9 mg/kg in dogs and 12.8 mg/kg in cats. 49 Unfortunately, blood gas analysis was not performed in this study. Clinical Use
In clinical practice, Telazol can be used for immobilization, induction, and maintenance of general anesthesia in dogs and cats. One distinct advantage of Telazol over other injectable agents (thiopental, propofol, and etomidate) is that it produces its effect either by the IV or IM route. The IM route becomes useful in anesthetizing aggressive or fractious dogs and cats. We have used doses of 8 to 15 mg/kg and 6 to 12 mg/kg in nonpremedicated cats and dogs, respectively. In most cases, we start with the lower end of the dose. In the majority of cases, the animal attains recumbency when using these doses, although we had
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one aggressive dog that received an IM dose of 8.0 mg/kg and did not attain recumbency. If the immobilization is inadequate 5 minutes after the initial dose, a second dose of 2 to 4 mg/kg is given IM. By doing this, the minimal amount of the drug is given for a desired effect. Two main side effects have been observed following the use of Telazol: prolonged and rough recoveries that are related to the higher doses of Telazol used. 24• 31 By giving Telazol to effect, the total dose can be reduced. If an aggressive patient requires general anesthesia, the anesthetic induction is completed by using halothane or isoflurane in oxygen using a face mask. Endotracheal intubation is then accomplished, and anesthesia is maintained using an inhalant agent. The quality of recovery improves markedly when recovery is maintained with an inhalant agent, particularly in long surgical procedures. The improved recovery can be attributed to the redistribution, metabolism, and clearance of tiletamine while the animal is under anesthesia. Minimal residual tiletamine appears to lead to a quiet and smooth recovery. This observation applies more in dogs than in cats. Generally, cats have a better quality of recovery than dogs. This has been attributed to the difference in the pharmacokinetics of tiletamine and zolazepam in dogs and cats. The effect of zolazepam, a tranquilizer, is longer than that of tiletamine in cats. In dogs, tiletamine's effect appears to outlast the tranquilizing effect of zolazepam. 31 Telazol can be used as an IV induction agent administered at 2 to 4 mg/kg without premedication. Induction with this technique is smooth, and its effect should be seen within 1 to 2 minutes. Anesthesia is then maintained using halothane or isoflurane following endotracheal intubation. We prefer to premedicate our patients with an opioid (butorphanol, morphine, or oxymorphone) for analgesia and a low dose of acepromazine (0.025-0.05 mg/kg IM). Premedication minimizes the stress and anxiety of the patient and allows for easier placement of an IV catheter. Premedication also reduces the required dose of Telazol, and induction and recovery quality are better. For this technique, a calculated dose of 4.0 mg/kg of Telazol is drawn up. If premedication has produced profound sedation, 25% of this dose is given IV and the effect is monitored over 60 seconds. Increments of 1.0 mg/kg are given every 60 seconds until the patient can be intubated. We do not recommend using Telazol as a maintenance agent because of the side effects associated with its repeated dosing. Repeated dosing in cats has been associated with prolonged recovery/ and the quality of recovery in dogs worsens. In general, Telazol alone can be used for diagnostic and minor surgical procedures in patients with no or minor systemic disturbance (American Society of Anesthesiologists [ASA] physical status I and II). We recommend that the lower end of the recommended dose or an even lower than recommended dose be used (Table 2). The decision on the dose to be administered should be based on the age, physical status, and behavior of the patient. For example, in a quiet middle-aged dog, Telazol can be given at 5.0 mg/kg IM for diagnostic procedures. It is
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Table 2. SUGGESTED AND MAXIMUM SAFE INTRAMUSCULAR DOSES OF TELAZOL* IN NONPREMEDICATED DOGS AND CATS
Cats Dogs
Diagnostic Purpose (mg/kg)
Minor Surgical Procedure (mg/kg)
Maximum Safe Dose (mg/kg)
9.7-11.9 6.6-9.9
10.6-12.5 9.9-13.2
29.92 72.0
*Doses are based on manufacturer's recommendations.
prudent that additional analgesic be administered for painful procedures, or anesthesia can be supplemented with an inhalant agent using a face mask or endotracheal tube. In studies that involved neutering of 6- to 14-week-old pups and kittens, Telazol (11.0 mg/kg IM) provided effective anesthesia and analgesia for castration in kittens. Nevertheless, a higher dose of 12.3 mg/kg IM in pups did not provide adequate anesthesia for castration. Analgesia was inadequate for ovariohysterectomy in pups and kittens using the same doses.H· 15 In another study in cats undergoing ovariectomy only, a dose of 15 mg/kg IM of Telazol was judged to produce satisfactory anesthesia and analgesia. Good muscle relaxation was present only in 60% of the subjects, however. 53 Telazol has been used as a preanesthetic medication in dogs and cats. Doses of 2.5 to 3.0 mg/kg IM or subcutaneously resulted in mild to moderate sedation. 6 • 26 The sedation produced in dogs was followed during recovery by involuntary muscle movement. 6 If the dog is manageable, we believe that Telazol should be avoided as a premedicant, because much better alternatives are available. Side Effects, Contraindications, and Precautions
Telazol can cause hypersalivation in dogs and cats. The use of atropine or glycopyrrolate to control salivation has been recommended1· 45; however, we do not use an anticholinergic routinely. Atropine or glycopyrrolate may further increase the heart rate and oxygen consumption by the heart. Salivation has not been a major problem as long as the airway has been secured using an endotracheal tube. Controlled and clinical studies showing the safety of Telazol in compromised patients are not available. Judicious use of Telazol in sick and debilitated patients should be exercised. The cardiostimulatory effects of tiletamine and the minimal cardiorespiratory depressant actiqn of zolazepam appear to be logical reasons for its use in compromised patients. Nevertheless, these effects should be weighed against the major side effects of Telazol, namely, prolonged recovery, rough recovery, and the possibility of convulsions. Telazol should be avoided in patients with CNS signs and in those patients with head trauma. Tiletamine, a dissociative agent like keta-
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mine, increases the cerebral blood flow and metabolic oxygen requirement of the brain. The cardiostimulatory effects of Telazol may be contraindicated in cats with hypertrophic cardiomyopathy or hyperthyroidism. In theory, Telazol should also be avoided in patients with preexisting dysrhythmias because it indirectly increases sympathetic tone. 23 This is further supported by the appearance of premature ventricular complexes in patients following Telazol injection. 45 Patients without preexisting cardiac disease develop premature ventricular complexes as a result of the increased sympathetic tone produced by the combination of surgical pain and Telazol. It is interesting to note that Telazol did not change the arrhythmogenic dose of epinephrine in dogs and cats under halothane anesthesia, however. 2 Other contraindications for Telazollisted include pancreatic disease, renal insufficiency or failure, severe cardiopulmonary disease, pregnancy, cesarean section, penetrating eye injury, and glaucoma.1 The most common adverse reactions to Telazol reported in cats are death (42%), prolonged recovery (19%), dyspnea (16%), ataxia (16%), pulmonary edema (12%), and apnea (9%).* In dogs, the adverse reactions are death (31%), hyperthermia (25%), turbulent recovery (19%), prolonged recovery (9%), and convulsions (9%).* These figures are based on the adverse drug reaction information provided by US Food and Drug Administration's Center for Veterinary Medicine for the period from 1989 through 1996.50 It is interesting to note that the most common adverse reactions reported to the US Food and Drug Administration are included in the drug information provided by the manufacturer. 1 *Numbers represent the percentage of a certain complication in relation to all reported complications for a specific drug.
Table 3. SUGGESTED USES FOR ETOMIDATE AND TELAZOL Etomidate
Induction agent for Hypovolemic patients Patients with cardiovascular disease with low-output state Patients with dysrhythmias Cesarean section in patients with severe systemic disturbance Patients with neurological disorders Trauma patients Rapid sequence induction in patients with concomitant heart disease Maintenance agent (infusion or intermittent boluses) for short-term anesthesia in cases in which inhalant anesthesia cannot be used
Telazol
Induction agent for Aggressive dogs and fractious cats (intramuscular route) Patients classified as ASA 1 and 2 (intravenous route) before inhalant anesthesia Sole anesthetic agent for diagnostic and minor surgical procedures
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SUMMARY
These two drugs, etomidate and Telazol, have different pharmacological properties. The good properties of these drugs should be employed in specific patients and procedures to be performed (Table 3). There is no ideal injectable agent available yet for clinical practice. This in itself makes practice quite interesting because of the continuous process of rationalizing and determining the best drug for a specific condition and patient. References 1. Arrioja-Dechert A: Compendium of Veterinary Products, ed 4. Port Huron, MI, North
American Compendiums, 1997 2. Bednarski RM, Muir WW: Ventricular arrhythmogenic dose of epinephrine in dogs and cats anesthetized with tiletamine/zolazepam and halothane. Am J Vet Res 51:1468, 1990 3. Bretschneider H: Osmolalities of commercially supplied drugs often used in anesthesia. Anesth Analg 66:361, 1987 4. Brussel T, Theissen JL, Vigfusson G, et a!: Hemodynamic and cardiodynamic effects of propofol and etomidate: Negative inotropic properties of propofol. Anesth Analg 69:35, 1989 5. Capan LM, Gottlieb G, Rosenberg A: General principles of anesthesia for major acute trauma. In Capan LM, Miller SM, Turndorf H (eds): Trauma Anesthesia and Intensive Care, New York, JB Lippincott, 1991, p 284 6. Cullen LK, Reynoldson JA: Effects of tiletarnine/zolazepam premedication on propofol anaesthesia in dogs. Vet Rec 140:363, 1997 7. DeJong FH, Mallios C, Jansen C, et a!: Etomidate suppresses adrenocortical function by inhibition of 11 {beta}-hydroxylation. J Clin Endocrinol Metab 59:1143, 1984 8. Dodam JR, Kruse-Elliott KT, Aucoin DP, eta!: Duration of etomidate-induced adrenocortical suppression during surgery in dogs. Am J Vet Res 51:786, 1990 9. Doenicke A, Kugler J, Penzel G, eta!: Him funktion und toleranzbreite nach etomidate, einem neuen barbituratfrer en i.v. applizierbaren hypnoticum. Anaesthetist 22:357, 1973 10. Donaldson LL, McGrath CJ, Tracy CH: Testing low doses of intravenous Telazol in canine practice. Vet Med (Praha) 84:1202, 1989 11. Downing J, Buley RJR, Brock-Utne JG, et al: Etomidate for induction of anaesthesia at caesarean section: Comparison with thiopentone. Br J Anaesth 51:135, 1979 12. Esener Z, Sarihasan B, Guven H, et a!: Thiopentone and etomidate concentrations in maternal and umbilical plasma, and in colostrum. Br J Anaesth 69:586, 1992 13. Evans R, Hill R: GABA-mimetic action of etomidate. Br J Pharmacal 61:484, 1977 14. Faggella AM, Aronsohn MG: Anesthetic techniques for neutering 6- to 14-week-old kittens. JAVMA 202:56, 1993 15. Faggella AM, Aronsohn MG: Evaluation of anesthetic protocols for neutering 6- to 14week-old pups. JAVMA 205:308, 1994 16. Fragen RJ: Clinical pharmacology and applications of intravenous anesthetic induction agents. In Bowdle TA, Horita A, Kharasch ED (eds): The Pharmacologic Basis of Anesthesiology. New York, Churchill Livingstone, 1994, p 319 17. Fragen RJ, Avram MJ: Barbiturates. In Miller RD (ed): Anesthesia, ed 3. New York, Churchill Livingstone, 1990, p 227 . 18. Fragen RJ, Avram MJ: Nonopioid intravenous anesthetics. In Barash PC, Cullen BF, Stoelting RK (eds): Clinical Anesthesia, ed 2. Philadelphia, JB Lippincott, 1992, p 388 19. Fry DE, Griffiths H: The inhibition by etomidate of the 11 {beta}-hydroxylation of cortisol. Clin Endocrinol 20:625, 1984 20. Greene SA: Hepatic disease. In Thurmon JC, Tranquilli WJ, Benson GJ (eds): Veterinary Anesthesia, ed 3. Baltimore, Williams & Wilkins, 1996, p 793
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21. Gregory MA, Davidson DG: Plasma etomidate levels in mother and fetus. Anaesthesia 46:716, 1991 22. Hall LW, Clarke KW: Veterinary Anaesthesia, ed 9. London, Bailliere Tindall, 1991, p 92 23. Hellyer P, Muir WW, Hubbell JAE, et a!: Cardiorespiratory effects of the intravenous administration of tiletamine-zolazepam to cats. Vet Surg 17:105, 1988 24. Hellyer P, Muir WW, Hubbell JAE, et a!: Cardiorespiratory effects of the intravenous administration of tiletamine-zolazepam to dogs. Vet Surg 18:160, 1989 25. Hirschman LJ: The cardiopulmonary and metabolic effects of hypoxia during acute adrenocortical suppression by etomidate in the dog. Journal of the American Association of Nurse Anesthetists 59:281, 1991 26. Ilkiw JE: Other potentially useful new injectable anesthetic agents. Vet Clin North Am Small Anim Pract 22:281, 1992 27. Inoue K, Arndt JO: Efferent vagal discharge and heart rate in response to methohexitone, althesin, ketamine and etomidate in cats. Br J Anaesth 54:1105, 1982 28. Ko JCH, Thurmon JC, Benson GJ, et a!: Hemodynamic and anesthetic effects of etomidate infusion in medetomidine-premedicated dogs. Am J Vet Res 55:842, 1994 29. Ledingham lA, Watt 1: Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1:1270, 1973 30. Lemke KA, Tranquilli WJ: Anesthetics, arrhythmias, and myocardial sensitization to epinephrine. JAVMA 205:1679, 1994 31. Lin HC, Thurmon JC, Benson GJ, et a!: Telazol-a review of its pharmacology and use in veterinary medicine. J Vet Pharmacal Ther 16:383, 1993 32. Milde LN, Milde JH, Michenfelder JD: Cerebral functional, metabolic, and hemodynamic effects of etomidate in dogs. Anesthesiology 63:371, 1985 33. Moon PF: Acute toxicosis in two dogs associated with etomidate-propylene glycol infusion. Lab Anim Sci 44:590, 1994 34. Moon PF: Cortisol suppression in cats after induction of anesthesia with etomidate, compared with ketamine-diazepam combination. Am J Vet Res 58:868, 1997 35. Morgan M, Lumley J, Whitwam JG: Etomidate, a new water-soluble nonbarbiturate intravenous induction agent. Lancet 1:955, 1975 36. Moss E, Powell D, Gibson RM, et a!: Effect of etomidate on intracranial pressure and cerebral perfusion pressure. Br J Anaesth 51:347, 1979 37. Muir WW: Small animal anesthesia. In Veterinary Proceedings of the the North American Veterinary Conference, Orlando, 1994, p 19 38. Muir WW, Mason DE: Side effects of etomidate in dogs. JAVMA 194:1430, 1989 39. Nagel ML, Muir WW, Nguyen K: Comparison of the cardiopulmonary effects of etomidate and thiamylal in dogs. Am J Vet Res 40:193, 1979 40. Pascoe PJ, Ilkiw JE, Haskins SC, et a!: Cardiopulmonary effects of etomidate in hypovolemic dogs. Am J Vet Res 53:2178, 1992 41. Renou AM, Vernheit J, Macrez P, et a!: Cerebral blood flow and metabolism during etomidate anesthesia in man. Br J Anaesth 50:1047, 1978 42. Reves JG, Glass PSA: Nonbarbiturate intravenous anesthetics. In Miller RD (ed): Anesthesia. New York, Churchill Livingstone, 1990, p 259 43. Robertson S: Advantages of etomidate use as an anesthetic agent. Vet Clin North Am Small Anim Pract 22:277, 1992 44. Short CE: Dissociative anesthesia. In Principles and Practice of Veterinary Anesthesia. Baltimore, Williams & Wilkins, 1987, p 158 45. Short CE: Talking about Telazol: Roundtable. Vet Med (Praha) 84:1, 1989 46. Skovsted P, Sapthavichaikul S: The effects of etomidate on arterial pressure, pulse rate and preganglionic sympathetic activity in cats. Can Anaesth Soc J 24:565, 1977 47. Stoelting RK: Pharmacology and Physiology in Anesthetic Practice. Philadelphia; JB Lippincott, 1987, p 141 48. Thomson lA, Fitch W, Hughes RL, et a!: Effects of certain IV anaesthetics on liver blood flow and hepatic oxygen consumption in the Greyhound. Br J Anaesth 58:69, 1986 49. Tracy CH, Short CE, Clark BC: Comparing the effects of intravenous and intramuscular administration of Telazol. Vet Med (Praha) 83:104, 1988 50. United States Food and Drug Administration Center for Veterinary Medicine: Adverse drug reaction information. http:/ /www.fda.gov I cvm (updated June 24, 1998)
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51. Van Beem H, Manger FW, Van Boxtel C, et a!: Etomidate anesthesia in patients with cirrhosis of the liver: Pharmacokinetic data. Anaesthesia 38:61, 1983 52. Van Hamee M, Ghoneim MM, Ambre J: Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology 49:274, 1978 53. Verstegen J, Fargetton X, Donnay I, et a!: An evaluation of medetomidine/ketamine and other drug combinations for anaesthesia in cats. Vet Rec 128:32, 1991 54. Wagner RL, White PF, Kan PB, et a!: Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Eng! J Med 310:1415, 1984 55. Wauquier A: Profile of etomidate. Anaesthesia 38:26, 1983 56. Wauquier A, Clincke G, Broeck WAEVD, eta!: Global incomplete ischemia in dogs assessed by quantitative EEG analysis. Effects of hypnotics and flunarizine. Prog Brain Res 62:217, 1984 57. Wertz E: Does etomidate cause hemolysis? Br J Anaesth 70:490, 1993
Address reprint requests to Luisito S. Pablo, DVM, MS University of Florida College of Veterinary Medicine Department of Large Animal Clinical Sciences PO Box 100136 Gainesville, FL 32610-0136
0195-5616/99 $8.00 + .00
ETOMIDATE AND TELAZOL Luisito S. Pablo, DVM, MS, and James E. Bailey, DVM, MS
The choice of anesthetic agents in veterinary practice is influenced by many factors that may not be related to the patient's condition. Factors that influence drug choice include cost, familiarity with a specific anesthetic regimen, personnel, record keeping, training of the veterinarian, and caseload of the practice. These factors have often limited the anesthetic options of the veterinary practitioner. If we consider the number of injectable anesthetic agents available now, practitioners should consider themselves fortunate at how many choices they have and try to choose the best anesthetic regimen for a specific patient. This article provides a discussion of the pharmacology and clinical use of two less commonly used drugs, Telazol and etomidate (Amidate). These two drugs have relatively specific purposes in veterinary anesthetic practice.
ETOMIDATE
Etomidate is a carboxylated imidazole derivative (nonbarbiturate) intravenous anesthetid5 Chemically, it is not related to other drugs commonly used for anesthesia. It is water soluble in an acidic solution and becomes .lipid soluble at a physiological pH. 47 The commercial preparation contains 35% propylene glycol (vol/vol), resulting in a clear but extremely hyperosmolar solution. 3 The solution is not known to support microbial growth, but unused portion should be discarded.
From the Department of Large Animal Clinical Sciences, University of Florida, College of Veterinary Medicine, Gainesville, Florida
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 29 • NUMBER 3 • MAY 1999
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Central Nervous System Effects
The primary central nervous system (CNS) effect of etomidate is hypnosis, 42 and it preferentially suppresses the neocortex. 9 The mechanism of this effect of etomidate is not fully understood; however, it is known to penetrate the blood-brain barrier rapidly, and a peak brain level is reached within 1 minute following intravenous administration. 47 It is postulated that its hypnotic effect can be attributed partly to its action on the GABAminergic systemP Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS of mammalsY It appears that etomidate increases the number of available GABA receptors. 18 Etomidate does not possess analgesic propertiesY Etomidate decreases intracranial pressure in a dose-dependent manner. 36• 41 A study in dogs showed that etomidate caused direct cerebral vasoconstriction. 32 Etomidate decreased both cerebral oxygen metabolism (CMRo2 ) and cerebral blood flow. The reduction in cerebral blood flow was independent of CMRo2 , however. The CMRo2 decreased as a result of the depression of the neuronal function action of etomidate.32 Etomidate maintained cerebral perfusion pressure better than thiopental and propofol as a result of its minimal effect on the systemic arterial pressure. 16 Cardiovascular System
Etomidate produces minimal changes in cardiovascular function. Dogs that received 1.5 and 3.0 mg/kg of etomidate intravenously (IV) had stable hemodynamic variables. Heart rate, aortic blood pressure, left ventricular peak pressure, left ventricular end diastolic pressure, left ventricular contractile force, and myocardial oxygen consumption did not change. 39 In another study, a dose of 0.3 mg/kg IV over 30 seconds in dogs produced no significant changes in systemic arterial pressure, heart rate, cardiac output, or systemic vascular resistance. 4 Doses of 0.25 and 1.0 mg/kg of etomidate did not change the heart rate in dogs; however, a high dose of 4.0 mg/kg resulted in a significant reduction in heart rate. 38 When etomidate was administered for induction and maintenance of anesthesia in Beagles premedicated with medetomidine, the cardiac index .and cardiac output remained lower than baseline values. This reduction was most likely due to medetomidine. During etomidate infusion, the cardiac index and cardiac output did not differ from the values obtained after medetomidine injection. 28 In another study in dogs, infusion rates from 0.02 to 0.3 mg/kg/min resulted in minimal changes in mean arterial blood pressure (MAP). Only when the infusion rate was increased to 0.4 mg/kg/min did the MAP decrease. 32 The MAP then decreased to clinically acceptable levels. In experimental hemorrhagic shock in dogs, the MAP increased and heart rate decreased following a bolus injection of 1.0 mg/kg of etomidate. 56 Infusion of 0.1 mg/kg/min in the same dogs resulted in a
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further increase in the MAP, which reached 94 mm Hg at the end. 5 6 These results are further supported by another study that showed the minimal cardiopulmonary effect of etomidate in hypovolemic dogs. 40 Detailed studies of etomidate's effect on the cardiovascular system in cats are lacking. In one study, etomidate given intravenously at 0.8 mg/kg did not cause consistent changes in heart rate, except for a transient increase immediately after the injection. In general, there was no change in heart rate. 27 In another study, bolus injection of 0.8 mg/kg of etomidate in cats resulted in a slight reduction in the MAP. However, the MAP returned to baseline values 1 minute after injection. 46 Heart rates of the cats increased significantly, but returned to baseline values within 2 minutes. 46 We have used etomidate clinically in cats with compromised cardiovascular function based on our understanding of the lack of depressant cardiovascular effects of etomidate in other species. Respiratory System Effects
Etomidate produces minimal respiratory depression. A dose of 1.5 mg/kg in dogs produced an increased respiratory rate and reduced tidal volume, resulting in unchanged minute volume. The arterial pH and partial pressure of C02 did not change from baseline values; however, at 2 minutes after etomidate injection, mild hypoxemia developed. The partial pressure of 0 2, arterial (Pao 2) returned to baseline values shortly thereafter. When a higher dose of 3.0 mg/kg was used, mild respiratory acidosis occurred, but the values were clinically acceptable. Moderate hypoxemia developed 2 and 5 minutes after injection. The Pao2 returned to baseline values at 10 minutes. 39 From this study, it appears that the respiratory depressant effect of etomidate is dose dependent. The rate of injection also influences the development of respiratory depression. Similar to thiopental and propofol, a slower injection rate should result in less respiratory depression. Endocrine Effects
A noted side effect of etomidate administration is the inhibition of adrenal synthesis. 7• 19• 54 The significance of this effect was realized when a high mortality was reported in an intensive care unit, where human patients were sedated with etomidate infusion for many hours. 29 Etomidate decreases cortisol, aldosterone, and corticosterone by inhibiting 11a- and 11-(3-hydroxylase as well as the cholesterol side chain cleavage enzyme. 16 A study in dogs showed that anesthetic induction using etomidate at 2.0 mg/kg reduced the adrenocortical response to anesthesia and surgery from 2 to 6 hours after injection. 8 This is further supported by a study in cats showing cortisol suppression for 3.5 to 5.5 hours following a single bolus injection of etomidate at 2.0 mg/kg. 34 The clinical significance and impact of these findings are still unclear. Evi-
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dence showing that etomidate increases morbidity or mortality in clinical cases when used as an induction agent or given in the form of an infusion for short period times is nonexistent. Cardiopulmonary responses to experimentally induced hypoxia of anesthetized dogs did not change after a reduction in cortisol production induced by etomidate.25 Still, caution should be exercised when using etomidate in patients with known adrenal insufficiency. Corticosteroid (prednisolone, dexamethasone) supplementation is warranted if etomidate is used in these cases. Clinical Uses
Etomidate can be used as an agent for the induction and maintenance of anesthesia in small animals . We do not use etomidate routinely, but there are clinical conditions in small animals that make the use of etomidate a rational option. Etomidate is good choice for the hypovolemic patient that requires general anesthesia as it causes minimal cardiovascular changes. It has also been shown to have a cerebral protective effect in patients with hypovolemic ischemia. 56 Etomidate is an optimal anesthetic agent for dogs and cats with preexisting cardiovascular disease resulting in a poor hemodynamic state. Patients with dilated cardiomyopathy or other cardiovascular diseases that result in a low-output state tolerate etomidate anesthesia. Etomidate can also be used in patients with cardiac rhythm disturbances as it is not arrhythmogenic. 16, 30 Pregnant bitches and queens with moderate to severe systemic disturbance needing a cesarean section require an induction agent with minimal cardiorespiratory depressant effects. In pregnant women, it was shown that the transfer of etomidate to the fetus was incomplete and that its concentration in the plasma of the fetus decreased rapidly. 21 The umbilical/maternal venous blood ratio was 1:24 for etomidate 5 minutes after delivery compared to 1:1.3 for thiopentalP It has also been shown that women who received etomidate for induction of anesthesia had babies with a better clinical status compared to those whose mothers were given thiopental. 11 We have reserved the use of etomidate for cesarean section in bitches and queens with severe systemic disturbances. Etomidate can also be used in small animal patients with neurological disorders, especially if there are concomitant cardiovascular problems. In some instances, patients need to be anesthetized for diagnostic procedures such as cerebrospinal tap. These diagnostic aids may be critical for treatment and prognosis. Despite efforts to optimize the condition of these patients, they are often in a deteriorating condition. Etomidate, with its high margin of safety and brain protective effect, is a good choice for these cases. 55 We have also used etomidate as an induction agent in traumatized small animal patients. Following resuscitative efforts, some patients may require general anesthesia for emergency trauma surgery. The minimal
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hemodynamic changes and rapid onset of action of etomidate make it a suitable choice of drug for the acutely traumatized patient.5 Etomidate is also not arrhythmogenic and may not exacerbate ventricular dysrhythmias induced by trauma (e.g., traumatic myocarditis). With a hepatic extraction ratio of 0.5, the decreased hepatic blood flow in shock states is likely to result in moderate effects on the inactivation of etomidate. 52 Etomidate has been recommended for small animal patients with hepatic dysfunction. 20• 37 It is rapidly hydrolyzed by the liver to inactive metabolites, and it is also acted on by plasma esterases. Even in small animal patients with cirrhosis, etomidate has been regarded as a suitable agent. 43 The clearance rates of etomidate in human patients with severe cirrhosis were similar to those in patients with normal hepatic function, despite its longer elimination half-life in patients with cirrhosis. 51 In this study, it was concluded that etomidate was a safe agent for cirrhotic patients. Despite this finding, caution should be used when infusing etomidate in patients with hepatic problems. It has been shown that etomidate infusion as low as 80 f.Lg/kg/min in dogs decreased liver blood flow. This can be attributed to vasoconstriction in the hepatic arterial bed. 48 There are instances when rapid sequence induction in small animal patients is necessary. Etomidate can be used as an induction agent to allow rapid control of the airway. This becomes more important if these patients have concomitant heart disease or hemodynamic instability. For example, etomidate would be a good choice when anesthetizing a dog or cat with heart disease that needs a surgical correction of traumatic diaphragmatic rupture. When using etomidate, premedication with a tranquilizer, sedative, or analgesic is recommended to minimize the side effects (excitement, myoclonus, pain on injection, and vomiting) seen during induction. 38 The premedicants that we recommend are those with minimal cardiopulmonary depressant effect. A combination of a benzodiazepine and an opiate has been routine in our practice. Diazepam or midazolam at 0.05 to 0.2 mg/kg given IV or intramuscularly (IM) has been used with oxymorphone {0.05-0.1 mg/kg IM), butorphanol {0.1-0.2 mg/kg IM), or morphine (0.25-0.5 mg/kg IM). After premedication, a calculated dose of 2.0 mg/kg of etomidate is drawn up. One fourth of the calculated dose is given as .a slow IV injection. For rapid sequence induction, one half of the calculated dose can be administered initially. If the patient cannot be intubated, additional etomidate is administered until endotracheal intubation can be accomplished. In most cases, intubation can be performed without delivering the entire calculated dose. Anesthesia can be maintained using etomidate at a rate of 50 to 150 f.Lg/kg/min in premedicated dogs and cats. The infusion rate should be adjusted based on the subjective signs of anesthesia shown by the patient and the degree of pain involved with the procedure. Although the clinical impact of the adrenal suppression using a short-term infusion of etomidate has not been established, caution should be taken when using the propylene glycol formulation of etomidate for short-term infusion.
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Marked hemoglobinuria and intravascular hemolysis were reported in dogs given infusions of etomidate in a propylene glycol formulation. 33 This may be critical in patients with renal insufficiency because of the pigment load brought about by hemolysis. The single induction dose of etomidate also causes hemolysis in dogs and cats,33• 57 but the clinical significance of this is unknown. It appears that hemoglobinuria may be more severe in animals receiving a higher dose of the etomidate/propylene glycol formulation. 33 Until further studies are performed to establish the dose dependency of the hemoglobinuria, the use of etomidate as a maintenance agent in critically ill patients should be avoided. Limitations, Side Effects, Contraindications, and Precautions
There are reasons for the limited use of etomidate in practice, despite its positive pharmacodynamic actions. It is one of most expensive anesthetic agents available commercially. It is packaged in glass ampules, which limits its repeated use after opening. A cost comparison of induction agents used for dogs is presented in Table 1. Etomidate has been approved for human use; however, approval for veterinary use has not been sought by the manufacturer. The side effects reported in dogs following etomidate administration include excitement, myoclonic activity, vomiting, apnea, and pain on injection. Rough recovery characterized by excitement and purposeless muscle movements was also observed in these dogs. 38 These side effects were either eliminated or reduced by using premedicants. 38 Intravascular hemolysis has been observed following induction and maintenance doses.2s, 33 Etomidate should not be used in patients with adrenal insufficiency. Patients on prolonged steroid therapy that did not receive steroid days
Table 1. COST COMPARISON OF INDUCTION AGENTS IN A 20-kg DOG
Induction Agents
Doses Used (mg/kg)
Cost* ($)
Thiopental Ketamine-diazepam Xylazine-ketamine Telazol (intravenous) Medetomidine-ketamine Propofol Methohexital Ketamine-midazolam Etomidate
10.0 5.5-0.25 1.0-10.0 4.0 0.040-5.0 4.0 6.0 5.5-0.25 2.0
0.29 0.81 1.83 2.44 3.39 3.60 4.40 14.78 38.60
Relative Costt
1.0 2.8 6.3 8.4
11.7 12.4 15.0 51.0 133.0
*Prices are based on university contract. tThe relative cost was calculated by dividing the cost of a specific drug with the cost of thiopental.
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before anesthesia should receive steroid when etomidate is used as an anesthetic. Caution should also be taken when administering etomidate in patients with renal insufficiency. The pigment load associated with hemolysis compromises the filtering ability of the kidneys, and fluid therapy should be instituted to maintain renal perfusion. We prefer not to use etomidate in cases of renal failure. Better anesthetic alternatives are available for these cases. TELAZOL
Telazol is a combination of zolazepam and tiletamine at a ratio of 1:1 (zolazepam 50 mg/mL and tiletamine 50 mg/mL). The commercial preparation is a lyophilized powder which needs saline, 5% dextrose, or water for reconstitution. The solution is clear with a pH of 2.0 to 3.5. The reconstituted preparation should be discarded after 4 days if kept at room temperature and after 14 days if refrigerated. 1 It is a schedule III controlled substance. It is approved for use in dogs and cats as an IM injectable agent/ although IV injection has been employed. 10' 23, 24, 26 General Pharmacology
The pharmacological effects of Telazol are those of its component parts. Zolazepam belongs to the benzodiazepine group, which collectively produces sedation, hypnosis, and muscle relaxation. It also has anticonvulsant and anxiolytic properties. By itself, it does not cause profound sedation in healthy dogs and cats. Tiletamine, an arylaminocycloalkanone, is a cataleptic or dissociative agent similar to ketamine. It causes unconsciousness in cats using a relatively high dose. 22 The combination of tiletamine and zolazepam can produce sedation or general anesthesia in dogs and cats depending on the dose used. Anesthesia produced by Telazol is still considered to be dissociative, accompanied by better muscle relaxation and less clonic muscular movement and convulsive seizures than tiletamine alone. The animal maintains ocular, laryngeal, pharyngeal, and pedal reflexes. The analgesia produced by Telazol is sufficient for procedures associated with mild to moderate pain. 1 Cardiovascular Effects
The cardiovascular depressant effects of Telazol in dogs and cats are dose dependent. Telazol at 10.0 mg/kg given IM in dogs produced sinus tachycardia and a proportionate stroke volume reduction, resulting in minimal changes in cardiac output. At a higher dose of 20.0 mg/ kg IM, the cardiac output decreased significantly, despite the sinus tachycardia. 44 The systolic blood pressure increased initially following a
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dose of 10.0 mg/kg IM and then decreased slightly within 5 minutes. The systolic blood pressure stayed at this lower level throughout the anesthetic period, although the diastolic blood pressure increased. At 20.0 mg/kg IM, the blood pressure and myocardial contractility decreased.1 Using three IV doses of Telazol (6.6, 13.2, and 19.8 mg/kg) in dogs, the hemodynamic changes found include increases in cardiac output and heart rate and decreases in peripheral vascular resistance, contractility, and arterial blood pressure. The arterial blood pressure returned to baseline and then increased above baseline.24 In cats, IM and IV injections of Telazol did not produce any change in heart rate. 1• 23 Recommended IM doses in cats (9.7-15.8 mg/kg) resulted in a 10% reduction in blood pressure for 1 hour after administration. Thereafter, the systemic blood pressure returned to baseline values.44 Using IV doses of Telazol (9.7, 15.8, and 23.7 mg/kg) in cats, the blood pressure, peripheral vascular resistance, and contractility increased above baseline values after a brief decrease. There was also a brief reduction in cardiac output using the two higher doses. 23 Overall, Telazol produces a stable hemodynamic state, particularly at lower doses. Respiratory Effect
Telazol can cause respiratory depression, especially when high doses are used. Hypoventilation occurred following the administration of 23.7 mg/kg in cats and 19.8 mg/kg in dogs. 23• 24 An IM dose of 20 mg/kg in dogs resulted in hypoventilation, and cyanosis and hypoxemia were observed in some dogs. The hypoxemia spontaneously resolved in about 35 minutes after injection. 44 Nonpremedicated dogs that received 2.0 or 4.0 mg/kg of Telazol IV had normocapnia and mild hypoxemia (Pao2, 80-82 mm Hg). 10 Hypoxemia was also reported in cats after IM doses of 10 and 20 mg/kg. Cats recovered from this episode by 15 or 35 minutes postinjection.44 Cyanosis was not observed following IM and IV administration of Telazol at 9.9 mg/kg in dogs and 12.8 mg/kg in cats. 49 Unfortunately, blood gas analysis was not performed in this study. Clinical Use
In clinical practice, Telazol can be used for immobilization, induction, and maintenance of general anesthesia in dogs and cats. One distinct advantage of Telazol over other injectable agents (thiopental, propofol, and etomidate) is that it produces its effect either by the IV or IM route. The IM route becomes useful in anesthetizing aggressive or fractious dogs and cats. We have used doses of 8 to 15 mg/kg and 6 to 12 mg/kg in nonpremedicated cats and dogs, respectively. In most cases, we start with the lower end of the dose. In the majority of cases, the animal attains recumbency when using these doses, although we had
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one aggressive dog that received an IM dose of 8.0 mg/kg and did not attain recumbency. If the immobilization is inadequate 5 minutes after the initial dose, a second dose of 2 to 4 mg/kg is given IM. By doing this, the minimal amount of the drug is given for a desired effect. Two main side effects have been observed following the use of Telazol: prolonged and rough recoveries that are related to the higher doses of Telazol used. 24• 31 By giving Telazol to effect, the total dose can be reduced. If an aggressive patient requires general anesthesia, the anesthetic induction is completed by using halothane or isoflurane in oxygen using a face mask. Endotracheal intubation is then accomplished, and anesthesia is maintained using an inhalant agent. The quality of recovery improves markedly when recovery is maintained with an inhalant agent, particularly in long surgical procedures. The improved recovery can be attributed to the redistribution, metabolism, and clearance of tiletamine while the animal is under anesthesia. Minimal residual tiletamine appears to lead to a quiet and smooth recovery. This observation applies more in dogs than in cats. Generally, cats have a better quality of recovery than dogs. This has been attributed to the difference in the pharmacokinetics of tiletamine and zolazepam in dogs and cats. The effect of zolazepam, a tranquilizer, is longer than that of tiletamine in cats. In dogs, tiletamine's effect appears to outlast the tranquilizing effect of zolazepam. 31 Telazol can be used as an IV induction agent administered at 2 to 4 mg/kg without premedication. Induction with this technique is smooth, and its effect should be seen within 1 to 2 minutes. Anesthesia is then maintained using halothane or isoflurane following endotracheal intubation. We prefer to premedicate our patients with an opioid (butorphanol, morphine, or oxymorphone) for analgesia and a low dose of acepromazine (0.025-0.05 mg/kg IM). Premedication minimizes the stress and anxiety of the patient and allows for easier placement of an IV catheter. Premedication also reduces the required dose of Telazol, and induction and recovery quality are better. For this technique, a calculated dose of 4.0 mg/kg of Telazol is drawn up. If premedication has produced profound sedation, 25% of this dose is given IV and the effect is monitored over 60 seconds. Increments of 1.0 mg/kg are given every 60 seconds until the patient can be intubated. We do not recommend using Telazol as a maintenance agent because of the side effects associated with its repeated dosing. Repeated dosing in cats has been associated with prolonged recovery/ and the quality of recovery in dogs worsens. In general, Telazol alone can be used for diagnostic and minor surgical procedures in patients with no or minor systemic disturbance (American Society of Anesthesiologists [ASA] physical status I and II). We recommend that the lower end of the recommended dose or an even lower than recommended dose be used (Table 2). The decision on the dose to be administered should be based on the age, physical status, and behavior of the patient. For example, in a quiet middle-aged dog, Telazol can be given at 5.0 mg/kg IM for diagnostic procedures. It is
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Table 2. SUGGESTED AND MAXIMUM SAFE INTRAMUSCULAR DOSES OF TELAZOL* IN NONPREMEDICATED DOGS AND CATS
Cats Dogs
Diagnostic Purpose (mg/kg)
Minor Surgical Procedure (mg/kg)
Maximum Safe Dose (mg/kg)
9.7-11.9 6.6-9.9
10.6-12.5 9.9-13.2
29.92 72.0
*Doses are based on manufacturer's recommendations.
prudent that additional analgesic be administered for painful procedures, or anesthesia can be supplemented with an inhalant agent using a face mask or endotracheal tube. In studies that involved neutering of 6- to 14-week-old pups and kittens, Telazol (11.0 mg/kg IM) provided effective anesthesia and analgesia for castration in kittens. Nevertheless, a higher dose of 12.3 mg/kg IM in pups did not provide adequate anesthesia for castration. Analgesia was inadequate for ovariohysterectomy in pups and kittens using the same doses.H· 15 In another study in cats undergoing ovariectomy only, a dose of 15 mg/kg IM of Telazol was judged to produce satisfactory anesthesia and analgesia. Good muscle relaxation was present only in 60% of the subjects, however. 53 Telazol has been used as a preanesthetic medication in dogs and cats. Doses of 2.5 to 3.0 mg/kg IM or subcutaneously resulted in mild to moderate sedation. 6 • 26 The sedation produced in dogs was followed during recovery by involuntary muscle movement. 6 If the dog is manageable, we believe that Telazol should be avoided as a premedicant, because much better alternatives are available. Side Effects, Contraindications, and Precautions
Telazol can cause hypersalivation in dogs and cats. The use of atropine or glycopyrrolate to control salivation has been recommended1· 45; however, we do not use an anticholinergic routinely. Atropine or glycopyrrolate may further increase the heart rate and oxygen consumption by the heart. Salivation has not been a major problem as long as the airway has been secured using an endotracheal tube. Controlled and clinical studies showing the safety of Telazol in compromised patients are not available. Judicious use of Telazol in sick and debilitated patients should be exercised. The cardiostimulatory effects of tiletamine and the minimal cardiorespiratory depressant actiqn of zolazepam appear to be logical reasons for its use in compromised patients. Nevertheless, these effects should be weighed against the major side effects of Telazol, namely, prolonged recovery, rough recovery, and the possibility of convulsions. Telazol should be avoided in patients with CNS signs and in those patients with head trauma. Tiletamine, a dissociative agent like keta-
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mine, increases the cerebral blood flow and metabolic oxygen requirement of the brain. The cardiostimulatory effects of Telazol may be contraindicated in cats with hypertrophic cardiomyopathy or hyperthyroidism. In theory, Telazol should also be avoided in patients with preexisting dysrhythmias because it indirectly increases sympathetic tone. 23 This is further supported by the appearance of premature ventricular complexes in patients following Telazol injection. 45 Patients without preexisting cardiac disease develop premature ventricular complexes as a result of the increased sympathetic tone produced by the combination of surgical pain and Telazol. It is interesting to note that Telazol did not change the arrhythmogenic dose of epinephrine in dogs and cats under halothane anesthesia, however. 2 Other contraindications for Telazollisted include pancreatic disease, renal insufficiency or failure, severe cardiopulmonary disease, pregnancy, cesarean section, penetrating eye injury, and glaucoma.1 The most common adverse reactions to Telazol reported in cats are death (42%), prolonged recovery (19%), dyspnea (16%), ataxia (16%), pulmonary edema (12%), and apnea (9%).* In dogs, the adverse reactions are death (31%), hyperthermia (25%), turbulent recovery (19%), prolonged recovery (9%), and convulsions (9%).* These figures are based on the adverse drug reaction information provided by US Food and Drug Administration's Center for Veterinary Medicine for the period from 1989 through 1996.50 It is interesting to note that the most common adverse reactions reported to the US Food and Drug Administration are included in the drug information provided by the manufacturer. 1 *Numbers represent the percentage of a certain complication in relation to all reported complications for a specific drug.
Table 3. SUGGESTED USES FOR ETOMIDATE AND TELAZOL Etomidate
Induction agent for Hypovolemic patients Patients with cardiovascular disease with low-output state Patients with dysrhythmias Cesarean section in patients with severe systemic disturbance Patients with neurological disorders Trauma patients Rapid sequence induction in patients with concomitant heart disease Maintenance agent (infusion or intermittent boluses) for short-term anesthesia in cases in which inhalant anesthesia cannot be used
Telazol
Induction agent for Aggressive dogs and fractious cats (intramuscular route) Patients classified as ASA 1 and 2 (intravenous route) before inhalant anesthesia Sole anesthetic agent for diagnostic and minor surgical procedures
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These two drugs, etomidate and Telazol, have different pharmacological properties. The good properties of these drugs should be employed in specific patients and procedures to be performed (Table 3). There is no ideal injectable agent available yet for clinical practice. This in itself makes practice quite interesting because of the continuous process of rationalizing and determining the best drug for a specific condition and patient. References 1. Arrioja-Dechert A: Compendium of Veterinary Products, ed 4. Port Huron, MI, North
American Compendiums, 1997 2. Bednarski RM, Muir WW: Ventricular arrhythmogenic dose of epinephrine in dogs and cats anesthetized with tiletamine/zolazepam and halothane. Am J Vet Res 51:1468, 1990 3. Bretschneider H: Osmolalities of commercially supplied drugs often used in anesthesia. Anesth Analg 66:361, 1987 4. Brussel T, Theissen JL, Vigfusson G, et a!: Hemodynamic and cardiodynamic effects of propofol and etomidate: Negative inotropic properties of propofol. Anesth Analg 69:35, 1989 5. Capan LM, Gottlieb G, Rosenberg A: General principles of anesthesia for major acute trauma. In Capan LM, Miller SM, Turndorf H (eds): Trauma Anesthesia and Intensive Care, New York, JB Lippincott, 1991, p 284 6. Cullen LK, Reynoldson JA: Effects of tiletarnine/zolazepam premedication on propofol anaesthesia in dogs. Vet Rec 140:363, 1997 7. DeJong FH, Mallios C, Jansen C, et a!: Etomidate suppresses adrenocortical function by inhibition of 11 {beta}-hydroxylation. J Clin Endocrinol Metab 59:1143, 1984 8. Dodam JR, Kruse-Elliott KT, Aucoin DP, eta!: Duration of etomidate-induced adrenocortical suppression during surgery in dogs. Am J Vet Res 51:786, 1990 9. Doenicke A, Kugler J, Penzel G, eta!: Him funktion und toleranzbreite nach etomidate, einem neuen barbituratfrer en i.v. applizierbaren hypnoticum. Anaesthetist 22:357, 1973 10. Donaldson LL, McGrath CJ, Tracy CH: Testing low doses of intravenous Telazol in canine practice. Vet Med (Praha) 84:1202, 1989 11. Downing J, Buley RJR, Brock-Utne JG, et al: Etomidate for induction of anaesthesia at caesarean section: Comparison with thiopentone. Br J Anaesth 51:135, 1979 12. Esener Z, Sarihasan B, Guven H, et a!: Thiopentone and etomidate concentrations in maternal and umbilical plasma, and in colostrum. Br J Anaesth 69:586, 1992 13. Evans R, Hill R: GABA-mimetic action of etomidate. Br J Pharmacal 61:484, 1977 14. Faggella AM, Aronsohn MG: Anesthetic techniques for neutering 6- to 14-week-old kittens. JAVMA 202:56, 1993 15. Faggella AM, Aronsohn MG: Evaluation of anesthetic protocols for neutering 6- to 14week-old pups. JAVMA 205:308, 1994 16. Fragen RJ: Clinical pharmacology and applications of intravenous anesthetic induction agents. In Bowdle TA, Horita A, Kharasch ED (eds): The Pharmacologic Basis of Anesthesiology. New York, Churchill Livingstone, 1994, p 319 17. Fragen RJ, Avram MJ: Barbiturates. In Miller RD (ed): Anesthesia, ed 3. New York, Churchill Livingstone, 1990, p 227 . 18. Fragen RJ, Avram MJ: Nonopioid intravenous anesthetics. In Barash PC, Cullen BF, Stoelting RK (eds): Clinical Anesthesia, ed 2. Philadelphia, JB Lippincott, 1992, p 388 19. Fry DE, Griffiths H: The inhibition by etomidate of the 11 {beta}-hydroxylation of cortisol. Clin Endocrinol 20:625, 1984 20. Greene SA: Hepatic disease. In Thurmon JC, Tranquilli WJ, Benson GJ (eds): Veterinary Anesthesia, ed 3. Baltimore, Williams & Wilkins, 1996, p 793
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21. Gregory MA, Davidson DG: Plasma etomidate levels in mother and fetus. Anaesthesia 46:716, 1991 22. Hall LW, Clarke KW: Veterinary Anaesthesia, ed 9. London, Bailliere Tindall, 1991, p 92 23. Hellyer P, Muir WW, Hubbell JAE, et a!: Cardiorespiratory effects of the intravenous administration of tiletamine-zolazepam to cats. Vet Surg 17:105, 1988 24. Hellyer P, Muir WW, Hubbell JAE, et a!: Cardiorespiratory effects of the intravenous administration of tiletamine-zolazepam to dogs. Vet Surg 18:160, 1989 25. Hirschman LJ: The cardiopulmonary and metabolic effects of hypoxia during acute adrenocortical suppression by etomidate in the dog. Journal of the American Association of Nurse Anesthetists 59:281, 1991 26. Ilkiw JE: Other potentially useful new injectable anesthetic agents. Vet Clin North Am Small Anim Pract 22:281, 1992 27. Inoue K, Arndt JO: Efferent vagal discharge and heart rate in response to methohexitone, althesin, ketamine and etomidate in cats. Br J Anaesth 54:1105, 1982 28. Ko JCH, Thurmon JC, Benson GJ, et a!: Hemodynamic and anesthetic effects of etomidate infusion in medetomidine-premedicated dogs. Am J Vet Res 55:842, 1994 29. Ledingham lA, Watt 1: Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1:1270, 1973 30. Lemke KA, Tranquilli WJ: Anesthetics, arrhythmias, and myocardial sensitization to epinephrine. JAVMA 205:1679, 1994 31. Lin HC, Thurmon JC, Benson GJ, et a!: Telazol-a review of its pharmacology and use in veterinary medicine. J Vet Pharmacal Ther 16:383, 1993 32. Milde LN, Milde JH, Michenfelder JD: Cerebral functional, metabolic, and hemodynamic effects of etomidate in dogs. Anesthesiology 63:371, 1985 33. Moon PF: Acute toxicosis in two dogs associated with etomidate-propylene glycol infusion. Lab Anim Sci 44:590, 1994 34. Moon PF: Cortisol suppression in cats after induction of anesthesia with etomidate, compared with ketamine-diazepam combination. Am J Vet Res 58:868, 1997 35. Morgan M, Lumley J, Whitwam JG: Etomidate, a new water-soluble nonbarbiturate intravenous induction agent. Lancet 1:955, 1975 36. Moss E, Powell D, Gibson RM, et a!: Effect of etomidate on intracranial pressure and cerebral perfusion pressure. Br J Anaesth 51:347, 1979 37. Muir WW: Small animal anesthesia. In Veterinary Proceedings of the the North American Veterinary Conference, Orlando, 1994, p 19 38. Muir WW, Mason DE: Side effects of etomidate in dogs. JAVMA 194:1430, 1989 39. Nagel ML, Muir WW, Nguyen K: Comparison of the cardiopulmonary effects of etomidate and thiamylal in dogs. Am J Vet Res 40:193, 1979 40. Pascoe PJ, Ilkiw JE, Haskins SC, et a!: Cardiopulmonary effects of etomidate in hypovolemic dogs. Am J Vet Res 53:2178, 1992 41. Renou AM, Vernheit J, Macrez P, et a!: Cerebral blood flow and metabolism during etomidate anesthesia in man. Br J Anaesth 50:1047, 1978 42. Reves JG, Glass PSA: Nonbarbiturate intravenous anesthetics. In Miller RD (ed): Anesthesia. New York, Churchill Livingstone, 1990, p 259 43. Robertson S: Advantages of etomidate use as an anesthetic agent. Vet Clin North Am Small Anim Pract 22:277, 1992 44. Short CE: Dissociative anesthesia. In Principles and Practice of Veterinary Anesthesia. Baltimore, Williams & Wilkins, 1987, p 158 45. Short CE: Talking about Telazol: Roundtable. Vet Med (Praha) 84:1, 1989 46. Skovsted P, Sapthavichaikul S: The effects of etomidate on arterial pressure, pulse rate and preganglionic sympathetic activity in cats. Can Anaesth Soc J 24:565, 1977 47. Stoelting RK: Pharmacology and Physiology in Anesthetic Practice. Philadelphia; JB Lippincott, 1987, p 141 48. Thomson lA, Fitch W, Hughes RL, et a!: Effects of certain IV anaesthetics on liver blood flow and hepatic oxygen consumption in the Greyhound. Br J Anaesth 58:69, 1986 49. Tracy CH, Short CE, Clark BC: Comparing the effects of intravenous and intramuscular administration of Telazol. Vet Med (Praha) 83:104, 1988 50. United States Food and Drug Administration Center for Veterinary Medicine: Adverse drug reaction information. http:/ /www.fda.gov I cvm (updated June 24, 1998)
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51. Van Beem H, Manger FW, Van Boxtel C, et a!: Etomidate anesthesia in patients with cirrhosis of the liver: Pharmacokinetic data. Anaesthesia 38:61, 1983 52. Van Hamee M, Ghoneim MM, Ambre J: Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology 49:274, 1978 53. Verstegen J, Fargetton X, Donnay I, et a!: An evaluation of medetomidine/ketamine and other drug combinations for anaesthesia in cats. Vet Rec 128:32, 1991 54. Wagner RL, White PF, Kan PB, et a!: Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Eng! J Med 310:1415, 1984 55. Wauquier A: Profile of etomidate. Anaesthesia 38:26, 1983 56. Wauquier A, Clincke G, Broeck WAEVD, eta!: Global incomplete ischemia in dogs assessed by quantitative EEG analysis. Effects of hypnotics and flunarizine. Prog Brain Res 62:217, 1984 57. Wertz E: Does etomidate cause hemolysis? Br J Anaesth 70:490, 1993
Address reprint requests to Luisito S. Pablo, DVM, MS University of Florida College of Veterinary Medicine Department of Large Animal Clinical Sciences PO Box 100136 Gainesville, FL 32610-0136