Injectable Anesthesia in Dogs - Part 1: Solutions, Doses and Administration

Introduction

Injectable anesthesia is a state of unconsciousness induced by drugs that are administered by injection. The usual route of injection is intravenous (the focus of this chapter), however, depending on the drug, intramuscular or subcutaneous routes are sometimes used. The reasons for administration are many (Table 1).

This chapter will explore the use of these drugs in dogs, by comparing their pharmacological properties as a guide to appropriate use. The drugs discussed in this chapter include thiopental sodium, ketamine hydrochloride, etomidate and propofol (Table 2).

Therapeutic Index

Therapeutic margins determine the safety of a drug. Anesthetic drugs with high therapeutic indices tend to be safer in patients with systemic illness or when administered by inexperienced personnel. The therapeutic margins for the injectable anesthetic agents have been reported in different species with different end-points. In dogs, the therapeutic index (lethal dose/hypnotic dose, LD50/HD50) is reported as 16 for etomidate compared with 7 for thiopental [2]. A similar wide safety margin was reported in rats where etomidate had a therapeutic index (lethal dose/effective dose, LD50/ED50) of 26.0 compared with 4.6 for thiopental [3]. In mice, the therapeutic index (lethal dose/anesthetic dose, LD50/AD50) is reported as 6.9 for thiopental and 8.5 for ketamine [4], whereas in monkeys the therapeutic index (LD50/AD50) was 16.0 for ketamine compared with 6.5 for thiamylal [5].

Based on these published values, etomidate is a very safe anesthetic drug, whereas, depending on the species, ketamine is either safer or as safe as thiopental.

Solutions

Preparations of each of the injectable anesthetic agents are available in different forms. Thiopental is marketed as the sodium salt in powder form and is reconstituted with 0.9% sodium chloride or water for injection (1).

Figure 1. Thiopental sodium as powder with sterile diluent for reconstitution.

The usual concentration for clinical use is 2.5%. The drug is a weak acid and since the unionized form is poorly water-soluble, concentrated solutions for administration are alkalinized so that the drug is restricted almost entirely to the water-soluble ionized form. Reconstituted thiopental retains its alkalinity and resists bacterial contamination for up to four weeks [6]. Manufacturers recommend discarding unused portions of thiopental 24 hours after reconstitution, however, recent work has demonstrated that thiopental remained stable and sterile for 6 days at room temperature and beyond 7 days (the longest tested) at 3°C [7]. Etomidate, ketamine and propofol are commercially formulated, each in different diluents. Etomidate is soluble in water but not stable, so it is formulated as a 0.2% solution in propylene glycol (35% by volume) with a pH of 6.9 and an osmolality of 4,640 mOsm/L (Fig. 2).

Figure 2. Etomidate as Abboject ready for injection.

Propofol is insoluble in aqueous solution but highly lipid soluble. The available formulation is an oil-in-water emulsion containing 1% propofol (wt/vol), 10% soybean oil, 1.2% egg lecithin and 2.25% glycerol with sodium hydroxide to adjust the pH to 7.0 (Fig. 3 and Fig. 4).

Figure 3. Propofol, as marketed for human use.

Figure 4. Propofol as marketed for veterinary use.

Ketamine is partly water-soluble and is prepared in a slightly acidic (pH 3.5 - 5.5) solution. It is formulated for veterinary use as a 10% solution in sodium chloride with the preservative, benzethonium chloride (Fig. 5).

Figure 5.Ketamine as marketed by one company for veterinary use.

Diluent Side Effects

Patient infections related to the use of propofol have been reported. This is thought to be due to microbial contamination of propofol and has resulted in life-threatening sepsis and postoperative infections of clean wounds in both human and veterinary patients [8,9]. propofol, but not thiopental and etomidate, was found to be an excellent medium for rapid bacterial growth [10]. The high pH of thiopental was thought to inhibit bacterial growth [11]. Strict aseptic technique should be followed when opening and drawing up propofol from glass ampoules, vials or pre-filled syringes. Refrigeration is not recommended as a mechanism to prevent or retard microbial growth and, once an ampoule is opened, unused propofol should be drawn into a sterile syringe and capped (Fig. 6). Unused propofol from a vial or syringe should be discarded after 6 hours.

Figure 6.Propofol stored in a sterile vial, or if from an open ampoule, drawn into a sterile syringe and sealed.

Of the injectable anesthetic agents, only thiopental, because of its alkaline pH, induces tissue necrosis and sloughing if administered perivascularly (Fig. 7, Fig. 8 and Fig. 9).

Figure 7. Early slough from perivascular administration of thiopental.

Figure 8. Slough, with scab removed, from perivascular administration of thiopental.

Figure 9. Scar from perivascular administration of thiopental.

If perivascular injection is suspected the area should be infiltrated with a volume of normal saline. The infiltrated volume depends on the volume and concentration of thiopental administered perivascularly, as the perivascular concentration should be diluted to at least 1%. Some people advocate using lidocaine instead of saline because it neutralizes the pH and decreases vasospasm. However, saline alone will prevent tissue necrosis. Pain is associated with intravenous administration of etomidate and propofol and intramuscular administration of ketamine. In both people and dogs, etomidate causes pain on injection and phlebitis, possibly due to the osmolality of the solvent [12,13]. In people, pain on injection of propofol is a frequent side-effect, however, in dogs the incidence is low (1%) [14]. ketamine, because of its acid pH, causes pain and irritation after intramuscular injection.

Hemolysis has been reported following either bolus administration or infusion of etomidate for both induction and maintenance [15,16]. Following induction, the degree of hemolysis is not usually clinically significant in that free hemoglobin is not measurable although the plasma of centrifuged samples has a reddish color (Fig. 10) [17].

Figure 10. Free hemoglobin in plasma after induction using etomidate.

On the other hand, infusion of etomidate may cause clinically significant intravascular hemolysis with hemoglobinemia and bilirubinemia. Hemoglobin concentration and packed cell volume are usually maintained. The mechanism is presumed to be associated with the high osmolality due to the propylene glycol diluent [17]. High dose infusion of etomidate has also been reported to cause propylene glycol toxicity, a hyperosmolar state with lactic acidosis and an increased anion gap [16, 18]. Because of the hemoglobinemia, etomidate should be used with caution in patients with renal disease [19].

Disorders of lipid metabolism can be aggravated by the emulsion formulation of propofol. People have increased concentrations of free fatty acids and serum triglycerides after propofol administration (Fig. 11) [20] and the association between pancreatitis and hypertriglyceridemia is well documented [21]. Because of the number of reported cases of pancreatitis associated with propofol administration, the association is probable but causality remains to be proven [22]. Based on this evidence, propofol should be used with caution in patients with diabetic hyperlipidemia, pancreatitis or primary hyperlipoproteinemia.

Figure 11. White coloration, from triglycerides, visible in the plasma taken from a dog during maintenance of anesthesia by constant rate infusion of propofol.

Published Dose Requirements

For thiopental, the ED50 for intubation in healthy non-premedicated dogs is reported to be 19.4 mg/kg, whereas the ED95 is 25.9 mg/kg. [23].

The reported dose for induction of anesthesia with etomidate in healthy dogs with and without premedication varied from 0.5 to 2.2 mg/kg with the mean dose of 1.1 ± 0.4 mg/kg for all dogs [12]. The mean dose in the non-premedicated group was 1.3 mg/kg, whereas premedication decreased the mean dose to 1.0 mg/kg.

The reported calculated induction dose for ketamine is 10 mg/kg, in combination with diazepam 0.5 mg/kg [24,25] or midazolam 0.5 mg/kg [26]. When ketamine was combined with midazolam, sternal recumbency was assumed after an average dosage of 1.5 mg/kg of ketamine and 0.08 mg/kg of midazolam, while lateral recumbency required an average dosage of 2.9 mg/kg of ketamine and 0.15 mg/kg of midazolam [26].

The ED50 of propofol for induction of anesthesia was found to be 2.2 mg/kg in premedicated dogs and 3.8 mg/kg in non-premedicated dogs [27]. After premedication with 0.5 mg/kg of acepromazine, a dose of 2.6 mg/kg of propofol would be expected to provide satisfactory conditions for intubation in 90% of dogs, whereas a dose of 6.0 mg/kg would be expected to provide the same conditions in non-premedicated dogs [27].

Induction Characteristics

Induction of anesthesia with thiopental is usually rapid, smooth and excitement-free. Central nervous system activation occurs initially and this may translate into an excitement phase if insufficient thiopental is administered.

Etomidate inductions are associated with an increased frequency of excitement, myoclonus (spontaneous involuntary muscle movement, tremor or hypertonus), pain on injection and vomiting in dogs [12]. The frequency of side effects is dose-dependent and can be decreased by preanesthetic medication. Excitement, myoclonus and purposeless muscle movements have been reported during the induction phase in people [28] and inadequate dosage or slow rates of administration may predispose to these side effects by producing light planes of anesthesia and prolonging the induction period.

propofol inductions in dogs are usually quiet, smooth and excitement-free [29], even if a dose insufficient to induce anesthesia is administered [27]. Apnea is the most frequent adverse side effect [14], with respiratory depression reported in 85% of dogs and apnea lasting greater than 5 minutes in 38% of dogs. In several studies, the authors commented that the respiratory depression was comparable to that caused by thiopental, but greater than that induced by etomidate or ketamine [14]. Excitation, characterized by paddling, muscle twitching or opisthotonos was reported in 7.5% of dogs [30].

Induction of anesthesia with ketamine alone is unsatisfactory as muscle tone is extreme and spontaneous movement virtually continuous [31,32]. Tranquilizers are usually administered prior to, or in combination with, ketamine to eliminate or minimize the deleterious side effects. The benzodiazepines, diazepam or midazolam, are the drugs most commonly administered intravenously in combination with ketamine. When combined with ketamine, diazepam increased emesis, but decreased muscle hypertonus, seizure activity and salivation [24]. Recently, the anesthetic effects in dogs following induction with ketamine-diazepam, compared with thiopental, have been reported [25]. In part because of the induction technique, the time to intubation was significantly longer in the ketamine-diazepam group. Pharyngeal and laryngeal reflexes were present in the ketamine-diazepam group but did not preclude tracheal intubation. Induction quality was considered fair to good in both groups, although salivation was marked in all dogs receiving ketamine-diazepam.

Recovery Characteristics

After an induction dose of thiopental, dogs recover with a large amount of the drug still present in the body. Metabolism of thiopental is slow and animals may appear groggy for some time. Recovery from thiopental is not always smooth and unsuccessful attempts to stand and walk are not uncommon. Following a dose of 15 mg/kg, anesthesia lasted for 12 ± 6 minutes, while dogs were sternal in 52 ± 29 and walking in 77 ± 32 minutes [33].

One of the beneficial features of propofol is its rapid, excitement-free recovery in non-premedicated dogs, irrespective of the duration of anesthesia [29]. Following a single dose, recovery was complete in non-premedicated dogs in 18 ± 7 minutes and 22 ± 10 minutes in premedicated dogs. When additional top-up doses were given to maintain anesthesia, recovery was complete in non-premedicated dogs in 22 ± 11 minutes, and 25 ± 13 minutes in premedicated dogs [29. While postoperative vomiting is rare after induction of anesthesia with propofol, maintenance of anesthesia by continuous infusion of propofol resulted in a 16% incidence of vomiting in the postoperative period [34].

Recovery from etomidate is relatively rapid but excitement and purposeless muscle movements may occur [12]. These side effects can be abolished by premedication. Non-premedicated dogs administered etomidate at two doses (1.0 and 4.0 mg/kg) were sternal in 7 ± 2 and 33 ± 7 minutes and standing in 10 ± 3 and 42 ± 4 minutes, respectively. Dogs premedicated with acepromazine (0.04 mg/kg) and administered etomidate (1 mg/kg) were sternal in 13 ± 4 and standing in 18 ± 3 minutes [12].

As with induction of anesthesia, recovery following ketamine alone is unsatisfactory with violent emergence and occasional convulsions [31,32]. Following ketamine, dogs appear to have a lower threshold for seizure activity than cats [35]. Recovery is characterized by an initial 10 to 15 minute period in which the dog is disoriented and clumsy, followed by alertness and coordination [32]. The quality of recovery was considered good in dogs induced with either ketamine-diazepam or thiopental [25]. However, the dogs were maintained on inhalant anesthetics for periods exceeding 60 minutes, so recovery was unlikely to be due solely to the induction agents. Emergence excitement is commonly observed and hyperthermia from increased muscular activity and metabolic activity frequently occurs in non-premedicated dogs waking up from ketamine [31].

Thiopental/Propofol Mixture

Recently, a synergistic hypnotic interaction has been reported between and propofol so that a combination of the agents has a greater effects than either of the agents alone [36]. This could result from pharmacological interaction, probably at the GABA receptor complex. Generally, a 1:1 volume mixture of propofol (1%) and thiopental (2.5% solution) is used such that 1 ml of the mixture contains 5 mg of propofol and 12.5 mg of thiopental. In people, comparative studies have demonstrated a rapid recovery that is qualitatively similar to propofol and superior to thiopental [37]. Other studies have reported an additive hypnotic effect, a reduction in pain on injection and a reduced hypotensive effect compared to propofol injection alone [38]. In dogs, the 1:1 mixture induced anesthesia of similar quality to propofol or thiopental alone [39]. Recovery quality and recovery times were similar to those of propofol and superior to those of thiopental. Apnea and pain on injection were not reported. As well as pharmacological benefits, the solution has some advantages over propofol alone. The 1:1 volume mixture either did not support bacterial growth or was bactericidal [40], was chemically stable for 1 week at room temperature [41], and when mixed and stored in polypropylene syringes, both propofol and thiopental were stable for up to 312 hours at 4°C and for up to 120 hours at 23°C [42].

It would seem that this mixture offers some advantages over either thiopental or propofol alone especially in veterinary practices where propofol use is not high. In these situations, unused propofol is discarded and some veterinarians consider this practice cost prohibitive.

Recommendations for Dose and Administration

Thiopental 

Because the therapeutic index of thiopental is lower than that of some other injectable agents, more side effects are likely, especially in the hands of unskilled personnel or when the drug is administered to sick patients. In the latter case, greater care is needed to prevent a relative overdose.

Dose and Administration

The initial dose of thiopental is calculated on a body weight basis, however, it is important to titrate the drug to effect as individual patient dose requirements vary. The usual concentration is 2.5%, however, if the calculated volume is small (<6 mL), a more dilute solution will allow better titration. In non-premedicated healthy dogs, the calculated dose is 20 mg/kg. Premedication reduces the calculated dose to 12.5 mg/kg, while administration of adjuvant agents such as diazepam or midazolam, together with premedication, reduces the calculated dose to 10 mg/kg.

One quarter of the calculated dose (bolus dose) is usually administered over 20 - 30 seconds and the patient observed for drug effects. If more of the drug is required, another quarter of the calculated dose is administered over 20 - 30 seconds. In a dog with a normal circulation time, 30 seconds is the usual time between administrations of doses. If the end-point is intubation, the patient is usually at an adequate level of anesthesia when the palpebral reflex is absent, jaw tone is present but the patient does not chew or yawn when the jaw is opened. A sluggish pedal reflex may still be present. Respiration should be present and mucous membrane color should be pink with a normal capillary refill time. If a deeper level of anesthesia is required, the pedal reflex may be absent, but respiration should be present and regular and mucous membrane color should be pink. When administering a bolus dose, a deep breath often occurs immediately before peak effect. When administering thiopental to sick patients, a very small calculated dose (< 1.0 mg/kg) should be first administered and the onset time and effect determined. This will often guide the administrator to sensitivity of the patient for the drug as well as circulatory status of the patient.

Over-dosage

Over-dosage may occur as either a relative or absolute overdose. Apnea is one of the most common side effects following administration of thiopental; it is usually of short duration. If mucous membrane color is pink, capillary refill time normal, pulse is strong, and some jaw tone present, the patient can be observed until respiration starts or vital signs change. If mucous membrane color is cyanotic, the patient should be intubated and ventilated at 10 breathes per minute (bpm) with 100% oxygen. Heart rate and rhythm should be checked and pulse quality assessed or arterial blood pressure measured. If pulse quality is strong or systolic arterial blood pressure > 80 mmHg, ventilation should be continued until the anesthetic level lightens. Ventilation should then be decreased to about 4 bpm in anticipation of respiration starting. If pulse quality is weak or systolic arterial blood pressure is < 80 mmHg, a balanced replacement solution should be administered as a bolus of 20 ml/kg over 10 - 15 minutes and administration of an inotrope such as dopamine should be considered especially if systolic blood pressure is < 60 mmHg. If no pulse is present, full cardiopulmonary resuscitation should be instigated. Successful resuscitation following cardiac arrest induced by an over-dosage of thiopental is difficult.

Adjunct Drugs

A benzodiazepine (diazepam or midazolam) is often administered together with thiopental to facilitate induction and to decrease the dose requirement. One quarter to one half of the calculated dose (diazepam 0.2 - 0.5 mg/kg or midazolam 0.2 mg/kg) is administered following each thiopental bolus dose.

Lidocaine is also administered together with thiopental to decrease the incidence of arrhythmias and to decrease the dose requirement. One quarter of the calculated dose (Lidocaine 8.0 mg/kg) is administered following each bolus dose of thiopental. The two drugs are never mixed together in the same syringe as they have pH incompatibilities and a precipitate will develop.

Etomidate 

The relative safety and lack of cardiovascular and respiratory effects of etomidate compared with thiopental, ketamine and propofol make it the induction agent of choice in dogs that have cardiovascular disease or diseases that result in hemodynamic instability.

Dose and Administration

The initial dose of etomidate is calculated on a body weight basis, however, the drug is titrated to effect. A calculated dose of 2.0 mg/kg is suitable and should be administered with an adjuvant agent such as diazepam (calculated dose, 0.5 mg/kg) or midazolam (calculated dose, 0.2 mg/kg) to facilitate induction.

One quarter of the calculated dose of etomidate is usually administered over 20 - 30 seconds followed by one quarter to one half of the calculated dose of a benzodiazepine and the patient observed for drug effects. If more drug is required, another quarter of the calculated dose of etomidate followed by a quarter to half of the calculated dose of benzodiazepine are administered over 20 - 30 sec. In a dog with a normal circulatory time, 30 seconds is the usual time between dosage administrations. If the end-point is intubation, the patient is usually at an adequate level of anesthesia when the palpebral reflex is absent, jaw tone is present but the patient does not chew or yawn when the jaw is opened. A sluggish pedal reflex may still be present. Respiration should be present and mucous membrane color should be pink with a normal capillary refill time. If a deeper level of anesthesia is required, the pedal reflex may be absent, but respiration should be present and regular, and mucous membrane color should be pink. In order to minimize side effects associated with injection of a solution with a high osmolality into a small peripheral vein, the etomidate is injected at the injection port of a fluid administration set through which a balanced electrolyte solution is being administered.

Unlike thiopental or propofol, induction quality with etomidate, even with adjuvants drugs, can be poor. Some patients will become rigid while in others the myoclonus will appear almost seizure-like. Occasionally, induction is not achieved with the calculated dose and administration of other injectable drugs may be needed to reach an adequate level of anesthesia.

Propofol 

Propofol can be administered intravenously to induce a short period of sedation or anesthesia, or anesthesia can be maintained with propofol by either repeated bolus injections or continuous infusion. A potent opioid, such as fentanyl or sufentanil, can be administered by continuous infusion in combination with propofol for total intravenous anesthesia.

Dose and Administration

When propofol is used as an induction agent, the calculated dose in non-premedicated healthy dogs is 10 mg/kg. Premedication reduces the dose to 6 mg/kg, while administration of adjuvant agents such as diazepam or midazolam, together with premedication, reduces the calculated dose to 4.0 mg/kg.

Because of the high incidence of apnea and cyanosis associated with propofol induction, oxygen should be delivered by facemask throughout the induction. If the patient will not tolerate the facemask prior to propofol administration, it can usually be placed after administration of the first quarter dose.

One quarter of the calculated dose is usually administered over 1 minute and the patient observed for drug effects. If more of the drug is required another quarter of the calculated dose is administered over another minute. In a dog with a normal circulation time, 30 seconds is the usual time between administrations of doses. If the end-point is intubation, the patient is usually at an adequate level of anesthesia when the palpebral reflex is absent, jaw tone is present but the patient does not chew or yawn when the jaw is opened. A sluggish pedal reflex may still be present. Respiration should be present and mucous membrane color should be pink with a normal capillary refill time. If a deeper level of anesthesia is required, the pedal reflex may be absent, but respiration should be present and regular, and mucous membrane color should be pink. When administering propofol to sick patients, a very small calculated dose (< 0.5 mg/kg) should be first administered and the onset time and effect determined.

If anesthesia is to be maintained with propofol, small bolus doses (1 mg/kg) are administered when the patient shows signs of a light level of anesthesia. Alternatively, propofol can be administered by continuous rate infusion. The dose for maintenance is 0.1 - 0.4 mg/kg/min. Generally, for light anesthesia or combined with an opioid infusion for surgical anesthesia an infusion rate of 0.2 mg/kg/min should be tried. If anesthetic depth appears inadequate, a small bolus dose (approximately 1 mg/kg) should be administered intravenously, and the infusion rate increased (about 25%). If the patient appears too deep, the infusion should be stopped until a suitable anesthetic level is achieved, then the infusion should be restarted at a lower rate (25% decrease). Because of propofol-induced respiratory depression, an oxygen-enriched gas should always be administered.

Ketamine 

Because of hypertonus and purposeless movement on induction, a tranquilizer is usually administered prior to ketamine and/or an adjuvant drug, such as diazepam or midazolam, is administered with ketamine.

Dose and Administration

When ketamine is used as an induction agent, the calculated dose in non-premedicated healthy dogs is 10 mg/kg, together with diazepam 0.5 mg/kg. Premedication reduces the dose of ketamine to 5 mg/kg, while the dose of diazepam remains at 0.5 mg/kg.

One quarter of the calculated dose of ketamine, followed by one half of the calculated dose of diazepam is usually administered over 1 minute and the patient observed for drug effects. If more of the drug is required another quarter of the calculated dose of ketamine and the remainder of the diazepam is administered over another minute. In a dog with a normal circulation time, 1 minute is the usual time between administrations of doses. If the end-point is intubation, the patient is usually at an adequate level when placement of the laryngoscope in the pharynx does not induce coordinated chewing. Generally, the tongue will protrude from the mouth when a suitable level of anesthesia for intubation has been reached. Because ketamine is a dissociative anesthetic, the eyes will remain open, the palpebral reflex and jaw tone will be present and lacrimation and salivation can be pronounced.

Summary

A summative comparison of the more common pharmacological properties (Table 15) and the relative costs of each agent (Table 16) follows. For more details about the effects of the different drugs on various body systems and their use in dogs with various diseases or for certain procedures, the reader is referred to "Injectable Anesthesia in Dogs – Part 2: Comparative Pharmacology-".