Injectable Anesthesia: Pharmacology and Clinical Use of Contemporary Agents
Khursheed R. Mama(1), DVM, and Eugene P. Steffey(2), VMD, PhD
1 Associate Professor, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University
Fort Collins, Colorado, USA
2 Professor and Chief, Anesthesia/Critical Patient Care, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California
Davis, CA, USA
Many drugs are administered via injection for induction and maintenance of anesthesia. Anesthesia may be maintained, especially for short time periods, exclusively with injectable drugs or, more commonly, for prolonged periods by combining injectable drugs with inhalation agents. While a variety of administration routes are broadly applied to veterinary patients the intravenous (IV) injection is preferred and the focus of this discussion. Injectable anesthetic drugs in current use and reviewed below are classified as hypnotic-sedatives, dissociatives, and opioids. Thiopental is historically the standard to which most injectable anesthetic drugs are compared. There are also a variety of anesthetic adjuvant drugs that are important to contemporary discussion of injectable anesthesia such as benzodiazepine and alpha-2 adrenergic agents. Unfortunately, space limitations do not permit review of these supplemental drugs at this time.
By virtue of a sulfur group substitution at position 2 of the barbituric acid ring, thiopental is classified as a thiobarbiturate. Alkalinization (pH 10-11), which is necessary to render the compound water soluble, imparts a bacteriostatic nature to the solution, but also causes the drug to precipitate if re-constituted with an acidic fluid solution (e.g., lactated Ringers). Further in part due to the alkaline nature of the solution, peri-vascular administration can result in sloughing of the skin especially at drug concentrations greater than 2%.
The IV administration of thiopental results in a rapid, smooth onset of action and an associated ultra-short duration of action. This weak acid (pKa ~ 7.6) is approximately 61 % unionized (available and highly lipid soluble portion) at body pH; acidemia will increase the free portion of the drug and may result in a relative patient overdose. Hence, the recommended clinical dose (6-20 mg/kg) range is intentionally broad so as to allow for these, and other, individual animal considerations and interactions with other drugs. For example, the dose necessary for intubation is reduced approximately 50% following premedication. The onset of action is 15-30 seconds following IV administration and the anesthetic duration (10-15) minutes after a single dose is determined primarily by redistribution. Excitement is seen with slow administration (especially in unsedated animals) and hence an initial bolus of approximately one-third of the calculated dose is suggested. Clearance from body is dependent almost exclusively on hepatic metabolism and due to the limited ability of Greyhounds to metabolize this drug, its use in these animals is not recommended.
Thiopental provides dose dependent hypnosis and central nervous system depression without compromise to cerebral perfusion. Both intracranial and intraocular pressures are decreased following administration. The drug has anticonvulsant properties, but may increase sensitivity to somatic pain. An increase in heart rate and an immediate transient decrease in myocardial contractility are observed following administration. Changes in blood pressure, stroke volume and cardiac output are more variable. Ventricular dysrhythmias (e.g., ventricular bigeminy) are more likely to be observed following administration in unsedated and/or hypoxemic patients. Respiratory rate may be decreased following administration, but the response varies with dose and speed of administration of the drug and PaO2. A decrease in the packed cell volume is commonly noted following administration and is, in part, likely due to splenic sequestration of red blood cells.
Propofol is an alkyl phenol with sedative/hypnotic effects similar to those of thiopental. It is available as a 1% preparation with 10% soybean oil, 2.25 % glycerol and 1.2 % egg-lecithin. The pH is adjusted to approximately 7.5 with sodium hydroxide. Due to the lack of preservative and the nature of the medium used to solubilize propofol, microbial and fungal contamination is an important consideration. As a result, any drug remaining 6-12 hours after initially opening a vial should be discarded.
Propofol provides a useful alternative to thiopental for induction of anesthesia and has very similar clinical actions (e.g., decreased intracranial pressure, anti-convulsant, etc.). An IV dose of 5-8 mg/kg is recommended in unsedated animals. Both sedation and the addition of benzodiazepines to the anesthetic induction protocol will reduce the dose requirement and potentially reduce the costs associated with propofol administration. Excitement is uncommon even with slow IV administration of propofol and allows for titration of propofol to the appropriate level of sedation. While some animals may withdraw their limb in response to propofol administration (a burning sensation has been noted by some human patients), perivascular injection does not cause a local inflammatory reaction.
The onset of action following IV administration is about 20-30 seconds with rapid redistribution and clearance from both hepatic and extra-hepatic sites. The effective clinical duration of action is frequently less than 10 minutes and hence propofol is used primarily to induce anesthesia. Additional bolus doses or infusions may be administered to prolong anesthetic duration without significant effect on recovery time in the dog. The cat responds a little less predictably presumably due to hepatic enzyme saturation. Heinz-body anemia, general malaise, anorexia, and diarrhea have been reported with sequential daily administration of propofol in cats.
Cardiovascular depression is of a magnitude similar to that of thiopental when propofol is administered as an IV bolus. Arterial hypotension is the most common effect reported and is primarily a result of a decrease in systemic vascular resistance although negative inotropic effects have also been reported. This may be minimized by slow administration of the drug and the prior administration of fluids. Respiratory depression, which is commonly reported after propofol administration, is also minimized by slow administration.
Etomidate, is a hypnotic sedative that has been used as an anesthetic agent in humans since the 1960s. It is a weak base (pKa 4.24) and in the United States is available as a 2 mg/ml solution (pH 8.1) in 35 % propylene glycol which renders it hyperosmolar (4640 mosm/l). It is 75% protein bound and undergoes ester hydrolysis and glucuronide conjugation in the liver.
Pain and hemolysis of red blood cells following administration are attributed to the hyperosmolar nature of the compound. These effects can be minimized by administration of IV fluids with etomidate. The induction dose ranges from 0.5-2.0 mg/kg, IV. Premedication is highly recommended prior to etomidate administration to reduce the incidence of side effects (e.g., myoclonus, vomiting). Alternatively or additionally, etomidate may be administered with a benzodiazepine. As etomidate interferes with cortisol synthesis, administration of a physiologic dose of dexamethasone, or other short-acting glucocorticoid prior to etomidate use is suggested.
Because of etomidate's expense and the fact that many veterinarians are not familiar with its use, the drug is not extensively used in veterinary medicine. However it does offer significant advantage in the critically ill patient, especially the cat where other drug choices may be limited. This is due to minimal cardiopulmonary effects which include a transient decrease in heart rate and respiratory rate following administration.
Ketamine hydrochloride, a weak base (pKa of 7.5), is a raecemic mixture of two isomers. It has been administered via IV, intramuscular (IM), oral and rectal transmucosal routes at a wide dose range which varies with species, route of administration, premedication, etc. A dose of 5-10 mg/kg IV is commonly utilized in premedicated small animal patients. The onset of action following IV administration is 30-45 sec. About 93% of the drug is absorbed within 20 min following IM administration whereas only 16 % is available 30 min after oral administration. Recovery from a single dose is determined by redistribution and cumulative effects are seen with repeated dosing or high dose administration. In dogs ketamine undergoes N-demethylation to norketamine (10-20 % activity) and hydroxynorketamine which is then conjugated and excreted. In cats, only norketamine is formed due to their limited ability to conjugate with glucuronyl transferase. Hence ketamine may have a prolonged effect in patients with the inability to excrete ketamine and its metabolite.
Its dissociative classification is due to its central effects which include thalamocortical depression and hippocampal and limbic activation. Clinically these manifest as rigidity, muscle hypertonicity, seizure like behavior and, in humans, hallucinations in face of apparent lack of awareness, i.e., a dissociative state. Benzodiazepines are frequently administered with ketamine to improve muscle relaxation and facilitate intubation. Increases in intracranial and intraocular pressures are reported and ketamine may have seizurogenic properties. Recently ketamine has been reevaluated for its analgesic properties, specifically in preventing "wind-up." The NMDA receptor is purported to be a key mediator of exaggerated and chronic pain states. Reports indicate the effectiveness of NMDA antagonist drugs (e.g., ketamine) in decreasing pain in morphine-tolerant human cancer patients. There exists the possibility that morphine tolerance is mediated, in part, through the excitatory neurotransmitter glutamate. Short-term infusions of ketamine, designed to block the actions of glutamate at the NMDA receptor in the central nervous system, appear to return the pain pathways to a more normal function.
An increase in sympathetic tone which is clinically manifested as an increase in heart rate, myocardial contractility and blood pressure is usually seen following ketamine administration. Due to this and a resulting increase in myocardial work and oxygen consumption, ketamine is best avoided in patients with restrictive or hypertrophic cardiac disease. It should also be avoided in the hemodynamically compromised patient or one in which sympathetic tone is reduced because myocardial contractility may be depressed following drug administration in patients with depleted sympathetic reserve. Respiratory effects include mild transient hypoventilation and hypoxemia unless excitement is observed during induction in which case an increase in respiratory rate is observed. Pharyngeal and laryngeal responses may be maintained following drug administration. This coupled with increases in tracheobronchial and salivary secretions can make intubation more challenging especially in cats when ketamine is used as the sole anesthetic drug.
Tiletamine (Telazol®) is available in powder form as a 1:1 mixture with the benzodiazepine, zolazepam; the reconstituted solution contains 50 mg/ml of each compound or 100 mg/ml of the combination and should be refrigerated. The recommended dose based on the combination of drugs ranges from 3 to 10 mg/kg for IM or subcutaneous administration and 2 to 5 mg/kg for IV administration. Zolazepam reduces the incidence of muscle rigidity, excitement, and occasional seizure-like activity that can occur with tiletamine immobilization and the combination results in dose-dependent central nervous system depression. Unlike ketamine which stings on IM injection, the response to injection following tiletamine/zolazepam is generally little or none. Recumbency is usually observed within 5 to 10 minutes of intramuscular administration. Prolonged sedation and/or residual ataxia may last 2 to 4 hours following administration of doses greater than 5 to 7.5 mg/kg. Hypothermia, hepatic or renal insufficiency and hypoxemia may contribute to residual effects. Cardiovascular and respiratory considerations are similar to those listed for ketamine.
While opioids are usually considered for their analgesic benefits, they are useful as anesthetic induction agents in specific circumstances. Many opioids, including fentanyl, oxymorphone and hydromorphone have been used IV for induction of anesthesia in the dog and while each individual drug is associated with a different pharmacokinetic profile, all the aforementioned opioids offer the benefit of cardiovascular safety. While they do cause anticholinergic responsive bradycardia, they have minimal other cardiovascular effects. However, they do have the potential to cause excitement and hypersensitivity to sound and are not recommended for routine use for induction in cats or normal, healthy dogs. Rather they are typically used in combination with a benzodiazepine for induction of debilitated and/or cardiac patients.
The dose for intravenous induction using fentanyl is 10-20 µg/kg and for oxymorphone and hydromorphone is 0.1-0.2 mg/kg. Onset of action of fentanyl tends to be quicker than for the other two drugs and most patients can be intubated within one minute following administration. As laryngeal tone is well maintained, topical application of a local anesthetic may be used to facilitate intubation. Due to the long induction time and as a result of drug induced respiratory depression, hypoxemia is likely and pre-oxygenation is highly recommended prior to opioid inductions and mechanical ventilation following intubation is suggested. When using a balanced anesthetic technique for maintenance of anesthesia, the induction dose also serves as the loading dose prior to the maintenance infusion and provides a major portion of the analgesic component of the balanced technique of general anesthesia.
Khursheed R. Mama, DVM
Eugene Steffey, VMD, PhD