What can I use for induction if propofol and thiopental are not available? (Proceedings)

The practice of veterinary anesthesia has been impacted by the short supply of propofol and discontinued production of thiopental. Thiopental is officially in the "Discontinued Drug" list of the FDA. The company that used to make thiopental decided to stop production because of its stand against the use of this drug for lethal injections. On the other hand, propofol shortage was first experienced by human and veterinary practitioners as a result of a recall due to the presence of particulate matter in the propofol vials in the fall of 2009. This was followed by another recall of propofol due to microbial contamination found in another manufacturer's supply. Ultimately, the latter company stopped their production of propofol. It appears that there is still a short supply of propofol for practitioners. As a result of these events, veterinary practitioners have to find alternatives to propofol and thiopental for inducing anesthesia in dogs and cats. There are still injectable drugs on the market that can be utilized for this purpose. Hopefully, another injectable agent, alfaxalone, will be introduced to the US in the near future that will lessen the impact of the shortage problem of injectable agents. The objective of this presentation is to discuss the available injectable drugs and their methods of administration including dosages, expected effects and side effects.

Ketamine combinations

Ketamine is a dissociative agent approved by the FDA for use in cats but not in dogs. It is not used alone in dogs because of the high incidence of seizure, muscle rigidity, and violent and excessive movement. Even though it is not approved in dogs, it is used as an induction agent in dogs and cats in combination with a sedative. The sedatives that have been used include diazepam, midazolam, acepromazine, xylazine, medetomidine, dexmedetomidine, and Telazol.

Ketamine can be given simultaneously with a benzodiazepine. With the other sedatives (acepromazine and alpha-2 agonists), profound sedation must be achieved in dogs before it is administered. Ketamine is recommended as an induction agent in dogs and cats that received an alpha-2 agonist as premedicant. In cats, it can be used as a sole induction agent but the quality of induction is not as smooth compared when it is used with a sedative.

Ketamine will increase heart rate, blood pressure, and cardiac output by indirectly stimulating the sympathetic system; however, it has a direct negative effect on myocardial contractility. The respiratory depressant effect of ketamine is less compared with propofol and thiopental. Apneustic breathing is common following ketamine induction. Airway reflexes are usually present with ketamine. Some animals will swallow during endotracheal intubation but they can be intubated.

Ketamine should not be given to patients with brain disease, hypertension, severe liver disease, and cats in renal failure. Ketamine will also increase intraocular pressure (IOP). Profound sedation mitigates this increase in IOP.

Table 1 shows the different ketamine combinations

Telazol

Telazol is a compound product made up of tiletamine and zolazepam. Tiletamine is a dissociative agent similar to ketamine while zolazepam is classified as a benzodiazepine. The preparation is a lyophilized powder and needs to be reconstituted with 5 ml of saline, 5% dextrose, or water resulting in a concentration of 50 mg/ml of each drug. It is approved for used in dogs and cats as an IM injection; however, it has been used clinically as an IV induction agent using lower dosages and can be used as an alternative to propofol and thiopental.

As an IV induction agent the dose range for dogs and cats are 2.0-4.0 mg/kg and 2.0-5.0 mg/kg, respectively. It can be administered without premedication. Without sedation the ocular, laryngeal, pharyngeal, and pedal reflexes are less depressed. The eyes of the animal may remain open. Sedation improves the quality of induction with Telazol. It also leads to lower doses needed for endotracheal intubation. The induction is smooth and the effect is seen within 1 to 2 minutes. After tracheal intubation, anesthesia is then maintained with inhalant agent.

Telazol causes minimal respiratory depression. With the IV dose, normocapnia is observed. For its cardiovascular effects in dogs, IV doses of 6.6, 13.2, and 19.8 mg/kg resulted in increases in cardiac output and heart rate and reduction in peripheral vascular resistance, contractility, and arterial blood pressure. After the initial decrease in blood pressure, it returned to baseline and then increased above baseline. In cats, IV doses of 9.7, 15.8, and 23.7 mg/kg resulted in a brief reduction in blood pressure, peripheral vascular resistance, and contractility and then followed by an increase. Despite the use of high doses in these studies, Telazol still produced stable hemodynamic states in healthy animals. The doses of Telazol we use clinically are lower and should result in a much better hemodynamic state.

The quality of recovery in dogs following Telazol administration is poor while recoveries in cats are smoother. This observation is due to the difference in the handling of Telazol by dogs and cats. Dogs metabolize zolazepam faster than tiletamine resulting in more residual dissociative effect. Zolazepam's effect lasts longer than tiletamine in cats and this leads to longer tranquilizing effect. To minimize the rough recoveries in dogs, it is advisable to maintain anesthesia with inhalant following Telazol induction to allow time for the tiletamine effect to wear off. Telazol should not be used as a maintenance agent. Repeated administration of Telazol results in worse recoveries in dogs and a more prolonged recovery in cats.

The contraindications and precautions for Telazol are similar to ketamine.

Etomidate

Etomidate is a nonbarbiturate intravenous anesthetic. The commercial preparation of etomidate that we use has 35% propylene glycol which makes it hyperosmolar. It is not a controlled substance. It is another alternative to propofol and thiopental. The main advantage of etomidate is its minimal effect on the cardiovascular function. Using clinically acceptable dosages of etomidate, heart rate, systemic blood pressure, cardiac output, and systemic vascular resistance are not expected to change significantly. It also produces minimal and transient respiratory depression, and the depression is further reduced by administering it slowly.

During induction, the animal may exhibit the following signs: excitement, myoclonic activity, vomiting, pain on injection, retching, and gagging. These side effects can be eliminated or reduced by using a sedative before induction. Hemolysis will also develop because the solution is hyperosmolar. Although recovery will be acceptable after using etomidate as maintenance agent, the animal will develop more hemolysis that will compromise the patient's condition. Another side effect of etomidate that may have clinical impact is its inhibition of adrenal synthesis. Etomidate lowers cortisol, aldosterone, and corticosterone blood levels. If used in patients with adrenal insufficiency (Addisonian), steroids should be administered.

The usual calculated dose for etomidate is 2.0 mg/kg. One-fourth of this dose is given initially, and the rest of the dose is given to effect. With premedication, the total dose used for induction will be reduced. The author does not use etomidate to maintain anesthesia.

Etomidate is relatively expensive. The quality of induction is not as smooth as with propofol. The author does not recommend its use for routine inductions. For neurological cases, etomidate is indicated because it decreases intracranial pressure, cerebral oxygen metabolism and cerebral blood flow. Since ketamine and tiletamine are poor choices for patients with intracranial pressure concerns, etomidate will be the best alternative to thiopental and propofol.

Neuroleptanalgesic combinations

The most common neuroleptanalgesic combination used in veterinary anesthesia is composed of a benzodiazepine and an opioid. Midazolam and diazepam are the choices for benzodiazepine; in our practice, hydromorphone, fentanyl, and remifentanil are the options for an opioid. These combinations can be used for inducing anesthesia in sick and depressed animals. In healthy, bright and alert patients, the induction of anesthesia is generally not smooth. The animals also become very sensitive to noise.

Midazolam or diazepam is given at 0.25 mg/kg IV. Hydromorphone is given at 0.2 mg/kg IV while fentanyl and remifentanil are given at 10.0 ug/kg IV. The combination can be given simultaneously especially with midazolam. Diazepam will precipitate when mixed with the opioids. It is best given with a fluid being administered to allow continuous flushing thereby preventing the mixing of the diazepam and an opioid in the IV line. Another way to prevent the mixing of the drugs is to flush the IV catheter with heparinized saline between the administration of the two drugs. The induction time is longer compared with thiopental and propofol.

As a result of the poor quality of induction, the author cannot recommend the routine use of neuroleptanalgesic combination as an alternative to thiopental and propofol. This combination should be reserved for the sick and depressed animals.

Methohexital

Methohexital is an oxybarbiturate and classified as ultrashort-acting barbiturate. It is a controlled substance similar to thiopental. It is available as an IV induction agent for humans. In the early 90s, the author used this drug for induction mostly for Greyhounds. With the advent of propofol, its use in the clinic was discontinued. It is two or three times more potent than thiopental. When used for anesthetic induction, its action is rapid. It is given more rapidly than thiopental to minimize the muscle tremors. Recovery is quick due to redistribution and the rapid rate of breakdown in the liver; however, recovery may be accompanied by excitement and violent movement. Premedication with a sedative will reduce the occurrence of excitement in recovery. It is also recommended to maintain the animal on inhalant anesthesia for at least 30-45 minutes to improve the quality of recovery following methohexital induction.

It is known to be more cardiovascular depressant than thiopental. It can cause transient arterial hypotension following induction, however the blood pressure will return to normal levels especially in healthy animals. It is also known to cause apnea and ventilation should be supported after induction. Apnea may occur for more than five minutes.

Methohexital (Brevital) vials are in crystalline form and should be diluted using sterile water, 5.0% dextrose in water, or 0.9% saline to a 1.0%. The reconstituted solution can be stored at room temperature.

For anesthetic induction, one half of the calculated dose (3.0-5.0 mg/kg) should be administered over about 10 seconds, and the remaining dose should be titrated in bolus increments until the animal can be intubated.

Alfaxalone

Alfaxalone is an injectable steroid anesthetic that can replace propofol and thiopental as an induction agent prior to inhalant anesthesia. It is marketed in Australia, New Zealand, South Africa, France, and the United Kingdom for use as an induction agent in dogs and cats. It can also be administered as an IM injection in cats to facilitate handling and restraint.

The solubilizing agent for alfaxalone in the commercial preparation is 2 alpha- hydroxypropyl beta cyclodextrin. Cyclodextrins are complex polysaccharides with a hydrophobic center for alfaxalone, a lipophilic agent. This is of clinical significance because the original preparation came with a solubilizing agent causing histamine release. The commercial preparation is known as alfaxalone-CD RTU (Alfaxan) and available in 10 mg/ml concentration. CD stands for cyclodextrin while RTU indicates "ready to use."

For induction of anesthesia, alfaxalone is given as a slow IV injection similar to propofol. It usually results in smooth induction with or without premedication. Once induced, the animal can be intubated and maintained using an inhalant agent. If given rapidly, apnea may occur right after induction. Overall, the respiratory function is maintained during anesthesia. Arterial blood pressure may also decrease right after induction. The anesthesia produced by alfaxalone is characterized by good muscle relaxation. It does not possess any analgesic property. If the patient is not maintained with inhalant, recovery is usually smooth and uneventful. The recovery is considered rapid after giving the recommended dose rate for surgical anesthesia. The animal will assume sternal recumbency within 60 to 80 minutes after alfaxalone administration.

When giving as an IM injection in cats, the injection should be deep to ensure absorption and produce the desired effect. Tissue irritation is not produced following perivascular or IM injection.

Similar to other induction agents, administration of premedicant(s) will reduce the induction dose of alfaxalone; however, premedicants may prolong the duration of anesthesia and the recovery time. It can be used in combination with any of the following premedicants: acepromazine, atropine, glycopyrrolate, morphine, methadone, butorphanol, diazepam, dexmedetomidine, and xylazine. Anesthesia can also be maintained by administering alfaxalone as a CRI or intertermittent boluses. Recovery is not prolonged following anesthetic maintenance using alfaxalone.

The IV doses of alfaxalone for inducing anesthesia in dogs and cats are 1.0-2.0 mg/kg and 2.0-5.0 mg/kg, respectively. The IM dose for cats is 5.0-10.0 mg/kg. At the higher IM dose, deep sedation or light anesthesia is expected. Some minor surgical procedures can be performed at this dose. The CRI doses for dogs and cats are 6.0-7.0 mg/kg/hour and 7.0-8.0 mg/kg/hour, respectively. Intermittent boluses to maintain anesthesia can be given at 1.0-2.0 mg/kg in dogs and 1.1-1.3 mg/kg in cats. According to the manufacturer, these boluses can be given every 10 minutes.

Animals should be kept in a quiet environment during recovery. Gentle handling is advisable. Noise and any source of stimulation may lead to paddling and minor muscle twitching.

The preparation of alfaxalone does not have preservative. It is advisable to remove the solution from the vial using aseptic technique. Provided aseptic technique is used for drug withdrawal, it may be stored at 4 deg. C for up to seven days.

The future release of alfaxalone in the U.S. will lessen the reliance of veterinary practices on propofol. The exact date for its release is still unknown.