Propofol Shortage Q&A with Dr. Alicia Karas

Clinician's Brief recently interviewed Alicia Z. Karas, DVM, MS, BA (Tufts Cummings School of Veterinary Medicine, Assistant Professor, Department of Clinical Sciences, Anesthesia) about the propofol shortage. Read on to learn more about the advantages and disadvantages of propofol and what products can be used as a substitute in the meantime.

1. What propofol substitutes would you suggest? Dosage/use recommendations?

AK:

Barbiturates: Thiopental is not available in the US currently and is unlikely to become available.

Dissociative-benzodiazepine techniques:

In dogs and cats: premed with opioid +/- sedative/tranquilizer of your choice, induce with ketamine-midazolam (OK to mix) IV, dose is about 1cc of a 50:50 mix per 9 kg. This is approximately 5.5 mg/kg ketamine and 0.25 mg/kg benzodiazepine. If you don't have any midazolam, it is OK to substitute diazepam at the same volume. If your patient is very sedated from the premedication, you may need only part of this dose. If your patient isn't sedated enough, you may need a bit more than what I have indicated. Our technique is to give 1/4 to 1/3 of the dose, wait 15 to 30 seconds, then give another increment, wait for effect, etc. (A colleague has indicated that they give each increment even longer to take effect, because it isn’t as rapid in onset as propofol). You should expect patients to have more jaw tone, and the eyes don't roll ventrally, and palpebral isn’t lost as it is in propofol or thiopental inductions.

Other techniques have been mentioned using various techniques, from a 2:1 ratio volume to volume of benzodiazepine to ketamine, and giving the entire dose at once. We prefer to use a “to effect” dosing method, because patients will vary in their individual needs, depending on sedation and condition. There is precedent for “titrating” ketamine doses in the human literature, in terms of minimizing pulmonary effects, and in a 2008 AJVR study, the authors found that dogs who were premedicated with hydromorphone and medetomidine could generally be induced with 1.25 mg/kg of ketamine + 0.0625 mg/kg of diazepam. (Enouri SS et al. Cardiopulmonary effects of anesthetic induction with thiopental, propofol, or a combination of ketamine hydrochloride and diazepam in dogs sedated with a combination of medetomidine and hydromorphone. AJVR 2008, 69: 586-595). They report:

"Of additional clinical importance is the low dose of all of the induction agents that was needed to achieve an anesthetic depth suitable to achieve orotracheal intubation in dogs after administration of medetomidine and hydromorphone, compared with the doses reported after sedation with other more traditionally used premedication regimens, such as acepromazine and butorphanol. Specifically, approximately a fourth of the recommended dose was used in all dogs. Had we adhered to the standard dosage recommendations, it is possible that there would have been additional cardiovascular changes with substantial risk to each dog. However, such dosages clearly were not needed for the induction of anesthesia and intubation after preanesthetic administration of medetomidine and hydromorphone, and they should be avoided unless the needs of a patient dictate otherwise."

Ketamine – benzodiazepine techniques can also be used for sedation for minor procedures, but the duration of a single injection depends on the dose.

Another dissociative- benzodiazepine technique that is used is to give IV Telazol ™ at 1 – 2 mg/kg “to effect”. Its actions may be considered very similar to those using ketamine, with perhaps a slightly longer duration and if patients are not well sedated, rougher recovery. If the amount of Telazol ™ is tiny, practitioners may dilute it 1:1 by volume so that it can be titrated to effect.

We do not use ketamine inductions (and Telazol ™ is similar) in animals w brain disease, hypertension, VPCs, and in cats with renal insufficiency (dogs with renal disease are able to metabolize ketamine and so it can be used safely if you use general rules for maintaining good cardiac output). We should probably not use them in those patients with epilepsy or for Caesarian section. We also avoid them in cats (but not in dogs) with murmurs, because of the potential for increasing left atrial pressures and heart failure. "Geriatric" isn’t a contraindication per se. They are also not advisable for use in animals with hepatic failure, but fortunately we see fewer of those than in human medicine, note that elevated liver enzymes do not = hepatic insufficiency.

Etomidate:

A drug with marvelously low cardiovascular depressant profile, etomidate is rather expensive and when inducing small animal patients with this drug, a good to profound degree of sedation is recommended because this lowers the dose required and also helps mitigate some of the unfortunate but not serious side effects, such as myoclonus, retching, etc. The dose is 1 – 2 mg/kg given IV with 0.5 mg/kg bolus and then titrated to effect. Its onset is rapid and only lasts for a few minutes. A dose of IV midazolam or diazepam, 0.2 mg/kg prior to induction is strongly recommended to smooth things. There are two potential problems with etomidate – one is that for critical patients (particularly those with sepsis), it causes acute adrenocortical suppression, which has been proposed to contribute to mortality in human ICU patients. Also, the standard form of etomidate has a large amount of propylene glycol, making pain on injection, hepatotoxicity, and possibly anemia in cats a problem. It should be avoided for patients with hepatic insufficiency and there is no data to support its use in Caesarian section.

Inhalant inductions:

While the use of these techniques is strongly discouraged for routine use because of the amount of personnel exposure to waste anesthetic gases, inhalant inductions may be necessary in patients who cannot tolerate ketamine, telazol or etomidate. The advantage is that there is no drug that must be metabolized, or to have adverse organ effects, other than those of being too deeply anesthetized. For now, I might only advocate that you use them when absolutely no other good options exist for that patient. Patients should be very sedate prior to masking as mask inductions can be stressful. This is a problem for C section patients, obviously. Inhalant inductions are contraindicated in any patient with upper respiratory obstruction (think English Bulldog, laryngeal paralysis), serious pulmonary disease/ pneumothorax, significant aspiration/regurgitation risk, and cardiovascular insufficiency, the latter because inhalant induction usually requires that patients be much deeper for intubation than they can tolerate safely.

2. What advantages does propofol have that makes it so popular in the veterinary profession (as opposed to other drugs that could be used in its place)?

AK: I’m going to discuss this issue with respect to issues in small companion animals; mainly dogs and cats. Propofol is a sedative-hypnotic drug that can be used for induction and maintenance of anesthesia.

It has another important use that distinguishes it from many other anesthesia induction agents, in that it can be used for “conscious sedation.” In other words, unlike pentothal, one of the most common drugs used to induce anesthesia by practitioners in veterinary medicine, propofol can be given intravenously in smaller “sedation” doses to permit minor non painful procedures or even as an infusion in critical care patients to sedate patients to permit mechanical ventilation. People should note that any patient who is sedated or anesthetized in any way, must be carefully monitored with respect to cardiovascular and respiratory function.

Prior to the introduction of propofol to veterinary practice, we induced general anesthesia with barbiturates (such as pentothal or methohexital) or with ketamine plus a benzodiazepine, or combinations of ketamine plus xylazine or acepromazine, or Telazol ™, and in rare cases, with etomidate or opioid-benzodiazepine combinations. Inhalation “mask” induction might also be used. As propofol gained popularity and became less costly, we veterinarians began to reach for propofol to induce anesthesia for several reasons.

First is that it generally provides predictable smooth induction and if the dose is given slowly “to effect” depending on the level of preanesthetic sedation, the potential for side effects (apnea, cyanosis, cardiovascular depression) can be minimized. Secondly, propofol is easy to use, it isn’t a controlled substance, no mixing of powder form, etc. Thirdly, we learned that propofol’s effect was terminated by metabolism that did not depend on healthy liver function, and this contrasted with what we perceived for other injectable drugs. (I say perceived as termination of the effect of barbiturates or ketamine inductions probably relies mainly on re-distribution of the drug within the body tissues, when used properly). But unlike pentothal, we could give repeated doses or infusions of propofol to dogs with little accumulation, and so if a dog required several boluses of propofol in one day, recovery was generally uneventful. (Note – in cats we recognize that the effects of propofol on hemoglobin and red blood cells limits the amount of propofol that they can be given).

So, many in the profession began to use propofol as their main injectable induction technique.

Propofol has some disadvantages, mainly that it can support the growth of microorganisms if not used properly. It must be used aseptically and within the time specified by the manufacturer. There is a tendency to not take this seriously in veterinary medicine – people don’t want to “waste” drug, they want to economize also.

The “unseen” danger of injecting a drug that has been demonstrated to cause infection in patients is difficult for people to keep in mind and we have to continually remind people to charge for sedation so that the bottle is paid for, and to discard unused drug when appropriate. Propofol is like many anesthetics, capable of causing both cardiovascular and respiratory depression. No drug is safe if used improperly, and some patients have critical disease problems that would make other induction techniques more suitable.

Also, some patients develop transient twitching after propofol injection, which seems to only subside as the drug wears off. There are other minor disadvantages, and I would recommend a great textbook chapter or review.

3. Do you think that the propofol shortage will encourage practitioners to adopt these new other drugs permanently?

AK: I think that several of the techniques will become more popular, and there is a potential for beneficial analgesic adjunctive effects with ketamine techniques. I would advise practitioners to take an individualized approach to anesthesia protocols in patients, because one size does not fit all. I would like my anesthesiologist to take into account my medical and physical status prior to anesthetizing me, and so I recommend that we do the same for our patients.

4. Do you have any general advice or strategies to offer to practices affected by the shortage?

AK:

a) Don’t use or store your existing stock of propofol improperly to stretch it out. It is not worth the risk.

b) Assess your patients individually, and choose a protocol that is safe for them. Consult a specialist for advice on special patients, or refer them, rather than trying to use risky techniques.

c) Using any new technique is something to do with caution. Work together as a team to introduce new protocols, observe and monitor your patient's heart rate and blood pressure. Use only as much inhalant anesthesia as absolutely necessary.

d) Get familiar with good, safe premedication techniques that employ sedatives or tranquilizers and opioids so that you can use less induction agent and less inhalant agent.

e) Get a good current anesthesia textbook and read away.

f) Some good online resources to consult include: www.vetanesthesiaspecialists.com, www.vasg.org/index.htm