Injectable Anesthesia in Dogs - Part 2: Comparative Pharmacology

Introduction

This chapter compares the pharmacological properties of the injectable anesthetic agents, thiopental, etomidate, propofol and ketamine, in order to guide the veterinary practitioner in their appropriate use in the dog.

Central Nervous System Effects

All of the injectable anesthetic agents are classified as rapidly acting agents, although propofol and ketamine appear to be slower in onset than thiopental and etomidate. Some of these differences may be due to the recommended method of administration (ketamine), whereas others are due to properties of the drug itself (propofol). Intravenous injection of thiopental results in unconsciousness, which is often preceded by one or more deep breaths. Because of its lipid solubility, penetration of the brain is rapid with first effects visible in 15 - 30 seconds and a blood:brain equilibrium half-life of approximately 1 minute [1]. Induction with etomidate results in unconsciousness in less than 20 seconds [2] and with both etomidate and thiopental, the time between top-up doses during induction should be about 30 seconds. The brain/plasma concentration ratio following ketamine becomes constant in less than one minute [3], however, several studies in dogs have reported a slower time to intubation with ketamine. In each case, this was due to a slow induction technique where one to two minutes were allowed between top-up doses [4,5]. This slow technique is commonly used with ketamine and, unlike agents such as thiopental, results in a smooth induction. Propofol has the slowest blood-brain equilibration time of the four agents (3 minutes). Studies in sheep have demonstrated that at equi-anesthetic doses, propofol is not able to induce onset of anesthesia as rapidly as thiopental despite rapid injection of the former [1,6]. Clinically, this means that propofol should be administered slowly so as to avoid relative overdose.

Thiopental, etomidate and propofol all induce a dose-related depression of cerebral metabolic oxygen consumption rate and, presumably, because of preserved cerebral autoregulation reduces cerebral blood flow [7-9]. As a result of the reduced cerebral blood flow and accompanying fall in cerebral blood volume, cerebrospinal fluid pressure is reduced. With thiopental and etomidate, cerebral perfusion pressure is not compromised because intracranial pressure decreases more than mean arterial pressure. With propofol, cerebral perfusion pressure may decrease as a result of a fall in arterial blood pressure and care is required to minimize the fall so that cerebral perfusion is not compromised. With all three agents, intracranial tension in patients with acute or chronically elevated intracranial pressure is lowered and cerebral vascular reactivity to carbon dioxide is maintained, so further reductions can be induced with hyperventilation [10-14]. Ketamine, on the other hand, increases cerebral blood flow and intracranial pressure, principally by cerebral vasodilation and elevated systemic arterial pressure [15,16]. Part of the vasodilation is due to increased arterial carbon dioxide tensions when ventilation is not controlled [17], while the other is most likely from stimulation of cerebral metabolic rate. In patients with raised intracranial pressure, ketamine should be avoided, and although thiopental, propofol and etomidate are all suitable induction agents, care must be taken with propofol such that hypotension is prevented. Although ketamine has differential effects throughout the brain with inhibition in some areas and stimulation in others, an increase in overall cerebral metabolic rate occurs [18]. More recently, other anesthetic agents (inhalants, propofol) have been shown to blunt or eliminate the intracranial pressure or cerebral blood flow increases associated with ketamine [19,20].

Both propofol and thiopental demonstrated similar effects on cerebrospinal fluid pressure in eucapnic dogs, indicating that either would be suitable agents for measurement of cerebrospinal fluid pressure [21]. Ketamine, however, increases cerebrospinal fluid pressure [22].

Barbiturates are effective anticonvulsants that are employed in the emergency treatment of convulsions such as occur in tetanus, status epilepticus, and poisoning by convulsant drugs. Phenobarbital has greater efficacy as an anticonvulsant, however, 15 minutes or more are required following IV administration for peak concentrations in the brain. In veterinary medicine, thiopental or more commonly pentobarbital are administered, however, their hypnotic and anticonvulsant properties occur at similar doses. Etomidate possesses anticonvulsant properties and has been administered in people to terminate status epilepticus [23,24]. However, etomidate may activate seizure foci and for this reason, caution is advised in its use in dogs with focal epilepsy [25]. Ketamine is known to induce seizures in dogs when administered alone or in combination with xylazine, diazepam, acepromazine or thiamylal [26,27]. The reported frequency varies from occasional to 11%. While some of the patients were known epileptics, others had no prior history of seizures. Although ketamine has been shown to prevent the behavioral manifestations of seizures, electroencephalogram (EEG) seizure discharges may persist, suggesting that ketamine is a poor anticonvulsive drug [28]. Propofol suppresses seizures and possesses anticonvulsant properties similar to thiopental [29,30]. However, because of seizure-like activity associated with propofol anesthesia, the use of propofolin known epileptic patients is controversial. In people, convulsions [31,32] and myoclonic movements with opisthotonos [33,34] have been reported. However, a number of studies have demonstrated the absence of seizure-like activity during these movements and have suggested that these events result from preferential depression of subcortical areas [35-37]. Of the four agents, only thiopental is not associated with controversy concerning its use in patients with epilepsy or for procedures, such as myelography, where seizures may result.

Intraoperative monitoring of the central nervous system has become more common in human anesthesia. All of the injectable anesthetic agents affect the EEG and evoked potentials. Thiopental, etomidate and propofol induce a dose-related depression of the EEG after initial activation and dose-related depression of evoked responses to a lesser extent than do inhaled agents. Etomidate is associated with amplitude enhancement of the EEG and cortically generated sensory evoked potentials (SEP). While etomidate increases both amplitude and latency of somatosensory evoked potentials (SSEP), thiopental and propofol decrease amplitude and increase latency [38]. Ketamine has less marked changes on the EEG and evoked responses, with some increases in amplitude of cortically generated SEP [39].

Analgesia

Thiopental, etomidate and propofol do not block autonomic responses to noxious stimuli and thus painful procedures should not be carried out under these agents alone. Small doses (0.6 - 1.5 mg/kg) of thiopental have been reported to cause an increased sensitivity to somatic pain [40]. Following induction with thiopental, anti-analgesia was present for up to 5 hours in the recovery period. The hyperalgesic properties of sub-hypnotic concentrations of anesthetics have also been reported for propofol [41]. Only ketamine has been reported to possess analgesic properties. Induction with ketamine or addition of ketamine to general anesthesia before surgical stimulation decreases postoperative pain and leads to better pain control [42,43]. It appears that ketamine’s analgesic properties reduce sensitization of pain pathways and extend into the postoperative period. This may be mediated through the antagonistic effect of ketamine at N-methyl-D-asparate receptors, which appear to be responsible for pain memory [44]. Recently, low dose infusion of ketamine has been advocated to provide postoperative analgesia [213].

Cardiovascular Effects

All of the injectable anesthetic agents, except etomidate, induce significant changes in the cardiovascular system. In healthy dogs, heart rate, aortic blood pressure, left ventricular peak pressure, left ventricular end diastolic pressure, left ventricular contractile force, and myocardial oxygen consumption were unchanged after administration of 1.5 or 3.0 mg/kg of etomidate [45]. Similarly, etomidate 1.0 mg/kg induced minimal changes in hypovolemic dogs [46]. Although, a decrease in stroke volume and an increase in indices of arterial resistance and myocardial relaxation were reported in dogs with pacing-induced cardiomyopathy, the doses were high compared to clinical doses [47]. In vitro studies showed that etomidate had only slight effects on the intrinsic mechanical properties of cardiac papillary muscle from normal and cardiomyopathic hamsters [48]. In vitro studies, using muscle taken from human failing hearts, demonstrated changes in contractility only at doses above the clinical range [49]. This is in contrast to most other anesthetics that depress myocardial function within the clinical dose range. The hemodynamic stability seen with etomidate may be due in part to its unique preservation of both sympathetic outflow and autonomic reflexes [50,51].

Thiopental administered to healthy dogs caused an initial increase in heart rate, a decrease in stroke volume and no change in arterial blood pressure and cardiac output. Arterial blood pressure becomes elevated for several minutes and then returns to normal. Heart rate may stay elevated for up to 10 minutes [45,52-55]. Although careful dose response studies have not been carried out, thiopental infusions and lower doses tend to be accompanied by smaller hemodynamic changes than rapid bolus injections. Mechanisms for these cardiovascular effects include a direct negative inotropic effect, decreased ventricular filling from increased capacitance, and a transient decrease in sympathetic outflow from the central nervous system.

In healthy dogs, 8 mg/kg of propofol did not cause changes in cardiovascular parameters [55]. However, in hypovolemic dogs, 6 mg/kg of propofol caused a rapid decrease in mean arterial blood pressure, an increase in oxygen utilization ratio and no change in heart rate [56]. Generally, propofol is thought to be more depressant than thiopental [57,58]. Caution is advised on its use in patients with impaired cardiac function, as cardiac index and arterial blood pressure decrease [59]. In dogs with pacing-induced dilated cardiomyopathy, propofol was found to have negative inotropic effects and impaired left ventricular filling dynamics [60]. Mechanisms by which propofol induces hemodynamic changes include decreases in preload [59,61], afterload [61] and contractility [62,63]. When propofol is administered by infusion for maintenance of anesthesia, cardiovascular effects are less than when it is used to induce anesthesia. This is not surprising, since the myocardial depressant effect and the vasodilation appear to be dose-dependent and plasma-concentration dependent [64]. Compared with thiopental or etomidate, propofol appears to possess greater direct negative inotropic effects on papillary muscle [65]. Induction of anesthesia with propofol is not usually associated with a change in heart rate. Propofol does not change sympathetic activity nor does it change baroreflex sensitivity. However, it does reset the baroreflex set point, which allows a slower heart rate despite a fall in arterial pressure [66].

In healthy dogs, ketamine 10 mg/kg intravenously caused an increase in heart rate, cardiac output, arterial blood pressure, and oxygen transport and consumption [67]. When diazepam was administered prior to ketamine, less cardiovascular stimulation occurred with smaller increases in arterial blood pressure and cardiac output. [68]. When ketamine was administered to hypovolemic dogs, the increase in heart rate and arterial blood pressure was maintained, although cardiac output did not increase [69]. The increase in heart rate is attributed to a centrally mediated, generalized increase in sympathetic tone [70,71]. The increase in cardiac output is attributed to the increase in heart rate and the increase in arterial blood pressure is attributed to the increase in cardiac output. [67]. In dogs, a transient decrease in arterial blood pressure occurred immediately after administration of ketamine and this was attributed to direct myocardial depressant effects [67]. In vitro studies have documented a direct dose-dependent negative inotropic effect of ketamine in heart muscle [72]. In healthy patients, the depressant effects of ketamine are obscured by stimulation of cardiac sympathetic nerves [73]. In the failing heart, the ability to increase contractility was reduced even in the presence of β-adrenergic stimulation [72] and ketamine should not be used, even for sedation, in patients with impaired left ventricular function [74].

When considering the anesthetic management of dogs with cardiovascular disease or diseases accompanied by hemodynamic instability, etomidate is the injectable anesthetic agent of choice. In these situations, both thiopental and propofol are likely to induce profound hypotension, unless they are titrated in very small doses. Even then, in patients with myocardial failure, death may ensue. While ketamine has stimulatory properties, the increase in left ventricular work may be undesirable in situations where myocardial oxygen delivery is critical. This may occur in patients with myocardial failure, hypertrophic cardiomyopathy, hyperthyroidism and subaortic and pulmonic stenosis. Alternatively in patients with impaired left ventricular function or those incapable of increasing sympathetic output, administration of ketamine will result in cardiovascular depression. This may be severe resulting in death, as in the study where ketamine-midazolam were administered to isoflurane-anesthetized dogs [75].

Cardiac arrhythmias follow administration of the thiobarbiturates, with an incidence of 40% reported following thiopental 16 mg/kg [76]. The most frequent arrhythmia observed is ventricular premature depolarizations occurring alternately with, and usually coupled to, beats of sinus origin (bigeminy). Ventricular bigeminy seemed to originate in the ventricle, distal to the Bundle of His, and coincided with an increase in arterial blood pressure and an increase in atrial rate [77]. In the healthy dog, this arrhythmia does not result in hemodynamic instability, is non-progressive, and is short-lived. A normal rhythm is established when either heart rate or blood pressure returns towards baseline. The mechanism for the arrhythmic effect of thiobarbiturates is unknown but may be mediated by decreased K+ permeability since thiopental has been found to preferentially suppress inward rectifying K+ current in isolated myocytes [78]. The ability of injectable anesthetic agents to induce arrhythmias is often evaluated under inhalant anesthesia by determining the dose of epinephrine required to induce premature ventricular contractions. In this model, thiopental, ketamine and propofol all decreased arrhythmic threshold [79-81], while etomidate had little effect [81]. Whereas the arrhythmogenic effects of ketamine had disappeared by 40 to 60 minutes, those associated with thiopental persisted for 3 to 5 hours [82,83].

Propofol is more likely to be associated with bradycardia than other injectable anesthetic agents [84]. When propofol is administered with other agents that increase vagal tone or for procedures where vagal tone may be increased, anticholinergics should be administered prophylactically [84,85]. In people, the risk of bradycardia despite prophylactic anticholinergics may still be considerable and several reports suggest an inadequate response of propofol-induced bradycardia to atropine [84]. For this reason, propofol should be avoided in patients with conduction abnormalities such as sick sinus syndrome or in patients taking beta-blockers.

Respiratory Effects

While thiopental and propofol induce centrally mediated respiratory depression, ketamine and etomidate have minimal effects. Apnea is common following bolus administration of thiopental or propofol and increasing the dose or speed of injection will increase the incidence and duration of apnea [86,87]. Induction doses of propofol > 9 mg/kg induced transient cyanosis in healthy dogs whereas, at doses >14 mg/kg, the duration of apnea increased in a dose-dependent manner [87]. Despite slow injection, cyanosis is often observed and mask oxygenation during induction is recommended. As with cardiovascular effects, maintenance with infusion of propofol appears to be less depressant than induction. In people, a maintenance dose of 0.1 mg/kg/min resulted in a decrease in tidal volume, an increase in respiratory frequency and variable changes in minute respiratory volume. Doubling the infusion rate caused a further decrease in tidal volume but no change in respiratory rate [88]. With etomidate and ketamine, low doses induce few changes, but respiratory depression may follow higher doses or administration following premedication [2,68,89].

All injectable anesthetic agents depress the ventilatory response to carbon dioxide, although the degree is less with ketamine and etomidate [90,91]. Ketamine reduces the ventilatory responses to low oxygen to a lesser extent than thiopental and, while thiopental reduces hypercapnic-induced augmentation of hypoxic drive, ketamine preserves it [92]. Administration of oxygen under thiopental anesthesia in dogs induced an immediate and persistent decrease in ventilation, principally from a decrease in ventilatory rate and changes in ventilatory times [93].

Hypoxemic pulmonary vasoconstriction is preserved by thiopental, etomidate, and ketamine and potentiated by propofol [94]. This is important in one-lung ventilation where maintenance techniques using propofol resulted in improved oxygenation and shunt fraction compared to inhalant techniques [95].

Ketamine and propofol, but not thiopental or etomidate, have bronchodilating properties [96]. After tracheal intubation, respiratory resistance is lower after propofol than thiopental or etomidate, indicating that propofol is a superior drug in patients with reactive airways.

Responses to respiratory tract irritation (such as coughing, laryngospasm and breath-holding) are maintained under thiopental anesthesia [97,98], and in people, laryngeal reflexes are more active after induction with thiopental than with equivalent doses of propofol [99]. Swallow, cough and gag reflexes are relatively intact after ketamine and in cats, but not people, competent laryngeal protective reflexes are maintained, such that material that reaches the trachea is coughed up and swallowed [100,101]. In cats, contrast radiography has been suggested as a diagnostic aid in ketamine-anesthetized cats suspected of laryngeal reflex abnormalities [100]. Studies in dogs documenting laryngeal competency following ketamine are lacking and thiopental appears to be a better drug for assessing vocal cord function in patients suspected of vocal cord paralysis.

Barbiturates depress mucociliary clearance as much as inhalant anesthesia [102]. Propofol, on the other hand, does not affect respiratory ciliary function [103], making it the ideal restraining agent for radionucleotide studies to assess mucociliary function, as in dogs suspected of ciliary dyskinesia.

Hepatic Effects

The effects of injectable anesthetic agents on the liver have not been thoroughly studied. In general, however, if anesthetics decrease cardiac output, proportional decreases in total hepatic blood flow will follow. In the greyhound, low infusion rates of thiopental and etomidate produced decreases in hepatic arterial flow without changes in the systemic circulation [104]. At high infusion rates, hepatic arterial and mesenteric vascular resistances returned to baseline and decreases in liver blood flow were a result of general cardiovascular depression. With both agents, hepatic oxygen supply was maintained by an increase in extraction [104]. Similarly, ketamine induced vasoconstriction of the hepatic arterial vasculature when added to the perfusate of isolated perfused rat livers [105].

Liver enzymes were not changed in patients after minor surgery with etomidate, propofol, and thiopental whereas similar surgery under ketamine anesthesia was associated with a moderate increase in the serum concentration of some enzymes [106-108]. However, it is unlikely that induction doses of any of the agents would induce significant changes in liver function tests.

With all of the injectable agents, return of consciousness is primarily through redistribution of the drug from the vessel rich group to the muscle group. Uptake into fat and the vessel poor group occur over time and the liver metabolizes all drugs extensively. Propofol, etomidate and ketamine are drugs with high extraction ratios (rapidly metabolized) and thus their duration of action is more likely affected by changes in liver blood flow than changes in liver function. Thiopental, on the other hand, is a drug that is slowly metabolized and, although redistribution is mainly responsible for wake-up, severe changes in liver function do appear to prolong recovery [109,110]. Patients with severe liver disease also require smaller induction doses because of increased cerebral sensitivity and decreased plasma protein concentrations causing a higher fraction of free drug [111]. Etomidate is highly bound to plasma proteins (76%), extensively redistributed and rapidly metabolized. In people with cirrhosis, the volume of distribution and elimination half-life are increased whereas clearance is unchanged [112]. Ketamine is not highly protein bound, but is extensively redistributed and rapidly metabolized. In patients with liver insufficiency, no differences were reported in the dose required for anesthesia, the duration of ketamine-induced anesthesia or the clearance of the drug [113]. Propofol is extensively redistributed and rapidly metabolized [114]. In people with cirrhosis, after a bolus dose of propofol, no differences were found in clearance, the apparent volume of distribution at steady state and the elimination half-life [115].

In dogs with severe liver disease, such as portosystemic shunts, very prolonged recoveries sometimes occur following thiopental administration and this drug is best avoided. Etomidate appears to be a suitable induction agent, however, recovery may be a little longer. Prior to the introduction of propofol, ketamine was used extensively in veterinary practice to enable ultrasound guided liver biopsy. Sometimes, in patients with portosystemic shunts, recoveries were longer than expected. Propofol is now considered the agent of choice for ultrasound guided liver biopsies and for induction of anesthesia in patients with severe liver disease.

Gastrointestinal Effects

In fasted greyhounds, neither thiopental nor ketamine altered the basal electrical rhythm of the intestine [116]. Thiopental increased duodenal and jejunal activity while stomach and ileal activity was unchanged. Both propofol and ketamine have little effect on gastrointestinal motility [116-118]. In people, no differences in gastrointestinal propulsion were found between anesthetic techniques that included continuous infusion of propofol, propofol and ketamine or isoflurane alone suggesting that these techniques would be unlikely to induce postoperative ileus [119]. In the Intensive Care Unit, the best agents for maintenance of gastrointestinal function in people are considered to be ketamine for analgesia and propofol for sedation [120].

Gastroesophageal reflux during anesthesia may result in post-anesthetic esophagitis and stricture formation or, in the case of regurgitation, life-threatening aspiration. Differences in the incidence of gastroesophageal reflux have been reported between the injectable agents, with a reported incidence of 50.0% following propofol and 17.6% following thiopental [121]. Lower esophageal sphincter pressure and barrier pressure were also better maintained in dogs induced with thiopental compared to dogs induced with propofol [122]. The effect of ketamine or etomidate on gastroesophageal sphincter pressure and barrier pressure has not been reported in dogs although in cats, sphincter tone was better maintained with ketamine than with propofol and thiopental [123]. Upper esophageal sphincter pressure is also important as it can prevent movement of esophageal contents into the pharynx following gastroesophageal reflux. In people, a rapid decrease in upper esophageal sphincter pressure was reported with thiopental, whereas ketamine did not alter mean esophageal sphincter pressure from awake values [124].

Postoperative nausea and vomiting is a common side effect of anesthesia in people, with a reported incidence of 21.3%. Propofol is the only injectable anesthetic agent that is reported to lower this incidence (18%) [125]. Even in surgeries associated with an increased risk, sub-hypnotic doses of propofol administered at the end of surgery prevented retching and vomiting for 6 hours postoperatively compared to thiopental where an incidence of 46% was reported [126]. In animals, the incidence of vomiting postoperatively seems to be lower than in people. Vomiting, however, has been reported during induction with etomidate in 27% of non-premedicated dogs, with a reduced incidence of 10% after premedication with acepromazine [2]. Diazepam administered with etomidate did not change the incidence of vomiting [2], whereas diazepam added to ketamine increased the incidence of vomiting [68]. Vomiting following propofol is variable, with a low incidence as an induction agent [127] but a higher incidence (16%) as a maintenance agent [128].

Renal Effects

In healthy dogs, thiopental has minimal effects on renal blood flow, while ketamine may increase it [129,130]. Renal blood flow was better maintained in a hypovolemic shock model following thiopental than ketamine or diazepam [131]. In sheep, continuous infusion of propofol decreased both hepatic (17%) and renal (7%) blood flows [132].

Glomerular disease is often associated with a decrease in plasma protein levels and a lower dose is required to induce anesthesia with drugs such as thiopental and etomidate, which are highly protein bound [133-135]. Ketamine is not highly protein bound and undergoes metabolism in the liver to non-active metabolites. Studies documenting the pharmacokinetic effects of ketamine in renal disease are lacking, however, because it increases arterial blood pressure it may aggravate pre-existing hypertension or decreased left ventricular function. The pharmacokinetic profile of propofol in patients with renal dysfunction (uremia and renal failure) was not altered [136] and propofol is considered a safe anesthetic in dogs with renal failure, as long as hypotension is prevented.

Urinary Effects

Urodynamic studies, undertaken to better understand distal urinary tract dysfunction, necessitate administration of sedatives or injectable anesthetic agents to prevent artifacts caused by movement. Ketamine-diazepam and thiamylal (and presumably thiopental) are not considered suitable agents as ketamine abolished reflex detrusor contraction in all dogs whereas thiamylal abolished it in 46% of dogs [137]. Although propofol decreased urodynamic variables in female dogs, the values were closer to values in unsedated dogs, making propofol the drug of choice for studying urethral pressure profile in dogs [138].

Hematologic Effects

The hematologic effects of thiopental are well documented, whereas those of the other injectable agents are not. Thiopental decreases packed cell volume (PCV) and leukocyte numbers, whereas the change in total protein is variable. The fall in PCV is thought to be due to splenic sequestration of red blood cells [139]. Plasma volume may increase or not change, with an increase probably reflective of changes in systemic arterial pressure, with a decrease in arterial pressure causing an increase in capillary hydrostatic pressure and movement of fluid into the circulation [140]. The hematologic effects following ketamine have not been reported in dogs; however, in cats the decrease in PCV was smaller following ketamine than thiopental [141]. Long-term administration of thiopental may promote reversible antibiotic induced bone marrow suppression, and reversible leukopenia and an increased infection rate following long term barbiturate administration. The mechanism by which thiopental and antibiotics induce bone marrow suppression is not known [142].

Since injectable anesthetic agents may affect platelet aggregation, choice of an appropriate agent may be important in dogs with compromised hemostasis and co-existing bleeding disorders. Propofol and ketamine have been found to significantly inhibit intraoperative and early postoperative platelet aggregation [143,144], whereas the significant platelet inhibitory properties of etomidate, compared with thiopental, led to prolonged operative time and increased transfusion needs [145].

Metabolic, Endocrine and Immune Effects

Only etomidate has important effects on adrenocortical function. With thiopental and propofol, plasma cortisol concentrations decrease below baseline as a result of general anesthesia, however, neither prevents adrenocortical secretion of cortisol or aldosterone in response to surgical stress and ACTH stimulation [146,147]. Adrenocortical suppression, with increased mortality, was first reported in intensive care patients sedated with etomidate [148]. Adrenocortical suppression has been investigated in dogs and does occur after induction doses of etomidate [149,150]. Dogs are still capable of increasing cortisol levels in response to surgical stimulation, although not to the same degree as following induction with thiopental [150]. Etomidate causes a dose–dependent reversible inhibition of the enzyme 11-β-hydroxylase and, to a minor extent, 17-α-hydroxylase. Use of etomidate as an induction agent is considered safe, however, administration by continuous infusion is not recommended [151]. Glucocorticoid supplementation is only necessary in situations where it would normally be considered, such as dogs with hypoadrenocorticism or dogs receiving supplemental glucocorticoids for longer than 2 weeks.

Propofol is more effective than other injectable anesthetics at reducing abnormalities in ion fluxes produced during cerebral ischemia [152,153]. This neuroprotective effect of propofol is likely related to its potent antioxidant properties.

None of the newer injectable anesthetic agents cause histamine release [154]. Increased levels of histamine (up to 350% of normal levels) have been reported following clinical doses of thiopental in people with levels dropping to normal within 10 minutes [155]. All agents, except thiopental, are considered safe in allergic or atopic patients or in those with mast cell tumors or systemic mastocytosis.

Intradermal skin testing often necessitates administration of sedative or anesthetic agents because of poor patient compliance. Drugs that affect mast cell membranes or smooth muscle vasculature could interfere with skin test results and several studies have determined the effect of injectable anesthetic agents on intradermal skin test reactions. Using subjective and objective scores, ketamine was reported to be suitable in one study [156] and unsuitable in another [157]. Thiamylal did not affect subjective or objective scores, while propofol affected objective scores and subjective scores were not recorded [158].

Anesthesia, in general, as well as specific drugs, is reported to affect the immune system. In general, the humoral aspects of the stress of anesthesia and surgery are clearly more important with regard to immunosuppression, than specific anesthetic regimes. However, since postoperative infections, as well as nosocomial infections in critically ill patients still represent serious problems, a number of studies have focused on the effect of anesthetic agents on host defense mechanisms. Head trauma victims treated with thiopental, have been found to have a greater risk for development of nosocomial pneumonia independent of mechanical ventilation [159]. This could be due to effects such as impaired phagocytosis, which are induced by thiopental [160]. In fact, it appears that many anesthetic agents have wide ranging immunomodulatory properties. There is evidence that injectable drugs influence cellular functions such as intracellular ion changes and nitric oxide release, as well as leukocyte transmigration through endothelial cell monolayers [161]. These changes provide evidence that injectable anesthetic agents affect the immune system and, in an effort to decrease mortality and morbidity, attention is being directed at understanding the immune response and its relationship to anesthesia [162].

Ophthalmological Effects

Intraocular pressure decreases after induction with thiopental, etomidate and propofol [163,164]. Etomidate may induce a greater decrease than thiopental [165]. The decrease in intraocular pressure is due to relaxation of extra-ocular muscle tone, central nervous system depression, improved outflow of aqueous and lower venous and arterial pressures [166]. In people, a slight but significant increase in intraocular pressure occurs with ketamine [167,168]. The increase is thought to be due to increases in extra-ocular muscle tone induced by ketamine. All of the injectable agents, except ketamine, are considered suitable for induction of anesthesia in patients where increases in intraocular pressure should be avoided.

The oculocardiac reflex is a frequent problem in strabismus surgery in children and is occasionally encountered in ocular surgery in dogs. In children, ketamine anesthesia was associated with the least hemodynamic changes induced by the oculocardiac reflex [169]. Propofolanesthesia, on the other hand, substantially increased the incidence of oculocardiac reflex, despite the use of prophylactic anticholinergics [170].

Both thiopental and propofol were reported to be suitable induction agents in dogs undergoing surgery for cataract removal [171]. Although anesthesia was maintained with halothane and nitrous oxide in oxygen, recovery was faster in those induced with propofol. The use of muscle relaxants significantly improved the eye position and reduced the vaporizer setting needed during maintenance.

Propofol is reported to preserve the photoreceptor response better than thiopental and therefore may be considered a more suitable drug for electroretinogram (ERG) recordings than thiopental [172]. Ketamine, in combination with medetomidine, was also found to have little influence on electroretinographic examination [173].

Obstetric Effects

Pregnant patients may require anesthesia for procedures other than cesarean sections. While there is very little written specifically concerning the injectable anesthetic drugs, the anesthetic technique should ensure maternal and fetal safety by not using drugs that may be teratogenic, avoiding intrauterine fetal asphyxia and preventing preterm labor. Documented anesthetic agent-induced teratogenicity is lacking in pregnant women, however, the FDA categorize diazepam as a pregnancy category D drug and etomidate and thiopental as pregnancy category C drugs. Pregnancy category C means that the drug has been shown to be teratogenic (or to have an embryocidal effect or other adverse effect) while pregnancy category D means the drug can cause harm to the fetus when administered to pregnant women. Uterine contraction frequency is reported to be unaffected by thiopental, depressed by propofol [174] and depressed [174], unaffected [175] or increased with ketamine [176]. Uterine blood flow is well preserved in pregnant ewes with all injectable anesthetic agents [177,178] and provided hypoxemia, hypoventilation and hypotension are avoided, any of the agents are satisfactory. Pregnant patients may require a lower induction dose as, in people, the thiopental dose for anesthesia was reported to be 18% less in pregnant women than in non-pregnant women [179]. The reason for this is unclear; it could be due to pregnancy-induced changes in cardiac output and regional blood flow or to changes in progesterone, endorphins and dynorphins. In people, first trimester miscarriage [180] and preterm labor [181] are both increased with surgery, although no one agent or technique have been implicated. Based on these statistics, it is recommended in people that elective surgery be postponed until after delivery [182] and this recommendation should probably apply to valuable breeding bitches as well.

In people, low doses of any of the injectable agents are suitable to induce anesthesia for cesarean section, although thiopental and propofol would be more commonly used in the healthy adult. All drugs rapidly cross the placenta and higher doses (ketamine > 2mg/kg, thiopental > 7 mg/kg) are considered to induce neonatal depression. Ketamine is usually reserved for women that are asthmatic or hypovolemic, while etomidate is best suited for patients that are hypovolemic or where myocardial depression should be avoided [182]. In dogs, early literature reported higher puppy mortality rates from bitches anesthetized with techniques that included a barbiturate compared with techniques other than a barbiturate [183]. Several recent studies have documented induction techniques and neonatal survival following cesarean section. In the first study, undertaken in Europe, induction with thiopental resulted in a lower puppy survival rate compared with induction with propofol or epidural local anesthesia [184]. There was no difference in puppy survival rates between propofol induction and isoflurane maintenance compared with epidural local anesthesia. In another study using information received from veterinary practice in North America and Canada, the most common anesthetic techniques were induction and maintenance with isoflurane (34%) and induction with propofol followed by maintenance with isoflurane (30%). Ketamine or thiopental each were used to induce anesthesia in about 5% of dogs, while no dog received etomidate [185]. In that study, propofol and isoflurane were associated with a positive effect on neonatal survival at seven days, while ketamine was possibly associated with a negative effect on puppy survival at birth [186]. A negative effect was also associated with xylazine, and ketamine and xylazine when administered together in about half the cases. Whether the effect is due to ketamine itself or xylazine or the combination, is not known. In another study in dogs, xylazine was found not to depress the pups whereas addition of ketamine to xylazine was associated with depression [187].

Musculoskeletal Effects

While thiopental, propofol and etomidate decrease muscle tone, ketamine alone causes hypertonus. Tranquilizers administered prior to or in combination with ketamine, modify muscle tone [68]. In dogs, myoclonus (spontaneous involuntary muscle movement or tremor) may occur following etomidate, propofol and ketamine administration, but is rare following thiopental administration. In one study, the incidence of myoclonus following etomidate in non-premedicated dogs was 33% [2], whereas in another study 7.5% of dogs receiving propofol showed excitatory movements compared to 0% receiving thiopental [188]. While life-threatening sequelae associated with these movements have not been reported in veterinary patients, difficulty in completing the induction or in performing surgery have been reported. Myoclonus is also described in people following administration of either etomidate or propofol. With etomidate, the incidence and intensity were found to be dose related and inhibited by pretreatment with small doses of etomidate [189]. With both drugs, myoclonus is not associated with seizure-like EEG activity [36,189,190]. Rather, it is thought to result from activity either in the brain stem or in deep cerebral structures (due to either loss of inhibition or direct stimulation) [191].

Malignant hyperthermia, a fatal disease triggered by certain anesthetic agents, features acute uncontrolled increases in skeletal muscle metabolism due to loss of control of intracellular calcium. None of the injectable anesthetic agents are considered triggering agents and are therefore safe to administer to known or suspected patients [192].

Greyhounds

Prolonged recoveries following administration of thiopental to greyhounds were reported as early as 1970 [193]. More recent studies also support longer recovery times compared to mixed breed dogs [194]. These recoveries are characterized by quiet periods interspersed with periods of delirium, vocalization and violent struggling. Although part of the slow recovery can be attributed to the lean body conformation, recent evidence suggests that greyhounds have significantly lower hepatic clearance of thiobarbiturates [195]. In addition, the rate of elimination of thiobarbiturates is non-linear, suggesting that the enzymes responsible for metabolism have become saturated. This is further supported by evidence that prior induction of hepatic enzymes with phenobarbital results in recovery times and pharmacokinetic profiles for thiopental that were similar to those of mixed breed dogs [196]. Recoveries following administration of propofol are longer in greyhounds than in mixed breed dogs, although they are not prolonged to the same extent as thiobarbiturates [197,198]. Recent in vitro and in vivo studies confirm that the slow metabolism is related to reduced activity of a specific hepatic P450 enzyme [199,200].

Ketamine-diazepam and ketamine-midazolam were found to be suitable drugs for induction of anesthesia in greyhounds [5]. More rapid intubation was the only advantage of the ketamine-midazolam combination, whereas recoveries tended to be better with the ketamine-diazepam combination.

Based on this evidence, thiobarbiturates should not be used to induce anesthesia in greyhounds. Ketamine, etomidate and propofol are all suitable induction agents, but if used for maintenance of anesthesia, prolonged recoveries might ensue.

Geriatric Dogs

In people, dose requirements for thiopental, etomidate and propofol decrease with increasing age [201-203], whereas information on ketamine is lacking. No age-related changes in brain responsiveness have been found to explain this. For etomidate and propofol, but not for thiopental, an age-related decrease in clearance has been reported. The most likely cause is a reduction in hepatic blood flow that occurs with age. With all three agents, the volume of the central compartment is also reduced in the elderly [204]. This could be due to a reduction in the volume of highly perfused tissues relative to body mass or to a reduced perfusion of these tissues due to a lowered cardiac output. Many of the differences in dosage requirements of injectable anesthetic agents in different situations can, in fact, be explained by differences in cardiac output [205].

The pharmacokinetic properties of propofol have been investigated in geriatric dogs [206]. The dose necessary for intubation was lower than the published dose and clearance was lower for mixed breed dogs after bolus administration [207] or for beagles after an intravenous infusion [208]. In dogs, compared with people, a smaller central compartment was not reported. The decreased clearance in elderly dogs should result in a smaller total propofol dose for maintenance of anesthesia, either with increments or by continuous infusion.

Pediatric Dogs

Age has been found to influence the dose of both thiopental and propofol in dogs, with puppies requiring higher doses than adults [209,210]. In beagles, thiopental dose increased in a sigmoid manner from 1 week of age up to the age of 10 weeks, where it reached adult levels. With propofol, the increased dose is apparent for both induction and maintenance of anesthesia. Similar increased dosage requirements have been reported for thiopental and propofol in children. This may be related to a larger central volume and more rapid hepatic clearance in pediatric patients [211,212].

Summary

By understanding the pharmacology of the individual injectable anesthetic agents, the veterinary practitioner is able to make more informed choices when confronted with dogs with various diseases or that require sedation for specific purposes.