Dusting off Ketamine
Gianluca Bini, DVM MRCVS DACVAA
Pharmacology
Ketamine is a phencyclidine derivative and was first approved for human use in 1970. Ketamine is a racemic mixture of R and S isomers with an acidic Ph (3.5 – 5.5) and benzethonium chloride as a preservative. Ketamine has a high therapeutic index, the clinical doses of ketamine described in small animals vary wildly, from 1 mg/kg to 35 mg/kg in cats and 1mg/kg to 20 mg/kg in dogs. It’s method of action is different than other injectable general anesthetics like propofol or alfaxalone as it does not activate the GABA A receptor. Ketamine acts mainly as a NMDA receptor antagonist. But it also works on some other receptors like opioid receptors, muscarinic receptors, as well as calcium-gated channels.
Although the most common routes of administration are intravenous and intramuscular, ketamine has also been administered, intraocularly, intranasally, rectally, orally as well as epidurally, with different degrees of success.
The onset of action of ketamine when administered IV is about 45 to 90 seconds, which makes it slower than propofol or alfaxalone; on the other hand, it takes about 2 to 3 minutes to have an effect when administered IM. Peak plasma levels are achieved in about 60 seconds when administered IV while it takes about 10 minutes if administered IM. It is important to point out that compared to propofol and alfaxalone which provide no analgesia, ketamine provides good analgesia especially for chronic pain.
Ketamine lasts between 40 and 90 minutes which is longer than propofol or alfaxalone, this could be beneficial in some cases. One of the advantages of a long-lasting induction agent allows for more stability at the beginning of the anesthetic event by reducing the minimum alveolar concentration of inhalant anesthetic needed to maintain anesthesia in our patients as well as providing good analgesia during that time. On the other hand, if the procedure is really short, some emergency delirium could occur in the recovery phase.
Ketamine is highly lipophilic and has limited protein binding, this has the theoretical advantage of being less impacted by a change in albumin concentration. The metabolism is carried out by the liver, and one notable particularity is that cats metabolize more of it to norketamine (an active metabolite of ketamine) which could prolong its effects in this specie.
Ketamine is available in different concentrations around the world, but in the United States it is available as 100mg/ml. There is a more concentrated version, which could be ordered compounded, usually used for zoo animals.
Although ketamine is available as a racemic mixture in the United States, it is also available as a pure S-isomer (S-ketamine) in other countries. There is some evidence that this has more intense analgesia, is more rapidly metabolized, is more potent with similar induction quality and causes less emergency delirium in recovery. One of the most notable papers in veterinary medicine has been published by Casoni and others 1 from the University of Bern, Switzerland; they actually found that S-ketamine is probably as potent as the racemic mixture in dogs, so probably that’s not an advantage in this specie. Moreover, reports of seizures occurring at induction with S-ketamine have been published in the past.
Interestingly ketamine is labeled for humans, primates, and cats, but not dogs for example.
NMDA receptors
The main mechanism of action of ketamine occurs by antagonizing the NMDA, or N-methyl-D-aspartate receptor, which is a glutamate-gated cation channel with a high calcium permeability, and glycine as co-agonist. The channel has a magnesium ion occluding the channel in the middle. An action potential with enough amplitude and duration is required in order to dislodge the magnesium and activate the receptor, opening the channel.
The result is an increased calcium influx leading to an increased neuronal excitability, wind-up, central sensitization and eventually causing excitotoxicity 2 . Excitotoxicity refers to an excessive or prolonged activation of NMDA receptors which causes neurotoxicity leading to loss of function and neuronal death, this phenomenon has been linked to Alzheimer, Parkinson, and Huntington diseases in humans 2 . There is also evidence that activation of the NMDA receptors decreases the neuron’s sensitivity to opioids, making pain treatments more challenging 3 .
Many mechanisms are responsible for the cascade of events triggered by the NMDA receptors activation, but in the last few decades researchers found an increasingly important link between NDMA receptors activation and nerve growth factor release, which in turn mediates inflammatory mediators release and nociceptive receptors as well as altering gene expression and sprouting of nociceptive neurons 4,5 . Therefore, activation of NMDA receptors can also lead to synaptic plasticity leading to long-term potentiation and therefore further worsening of chronic pain.
The clinical effects of ketamine
When ketamine is administered at anesthetic doses it induces thalamocortical and limbic
system dissociation, and the patient appears dissociated, the palpebral reflex is still present and the eyes may still be open (it is good practice to use eye lube in all anesthetized patient, but this is especially true if ketamine is being used).
Ketamine has some neuroprotective and anticonvulsant properties and does not alter the seizure threshold, although it is important to recognize that it could increase intracranial pressure which then may lead to seizure activity in patients that are already seizing due to some intracranial diseases (e.g. a tumor, traumatic brain injury). Moreover, ketamine also increases intraocular pressure, hence is contraindicated for some ophthalmic patients (e.g. a patient with a corneal ulcer and fragile eye).
Ketamine stimulates the sympathetic nervous system and cause an increase in heart rate which masks the cardiovascular depression (negative inotropic effect and hypotension) induced by the drug itself, although this is an advantageous side effect, when ketamine is administered to a very ill patient with depleted catecholamines reserves, cardiovascular depression will occur.
The heart rate increase caused by ketamine is also contraindicated in patients with hypertension, cardiomyopathy, congestive heart failure, or tachydysrhythmias.
Ketamine induces minimal respiratory depression, making it ideal in battleground scenarios or field work, where the equipment available is limited. This is also associated with bronchodilation, which is beneficial in patients with asthma.
Laryngeal and pharyngeal reflexes are maintained with ketamine, although those are uncoordinated and therefore offer inappropriate airway protection. Ketamine also increases salivation and respiratory secretion, potentially increasing the amount of liquids in the patient mouth. This could increase the risk of aspiration pneumonia.
Combinations
Ketamine can be paired with a variety of drugs, although the most common ones are benzodiazepines and propofol.
The combination of ketamine and midazolam (or diazepam) has been a staple of veterinary anesthesia for decades. The reported doses of ketamine have been consistently decreasing over the years, doses up to 20 mg/kg in dogs and 35 mg/kg in cats which were not uncommon, are now replaced by doses around 5 to 10 mg/kg.
When looking at doses, we also need to consider whether ketamine is used as the main induction agent or just a co-inductor to decrease the dose of the main induction agent (either propofol or alfaxalone).
If ketamine is the main induction agent, 5-10 mg/kg of ketamine IV are usually paired with 0.2-0.5 mg/kg of midazolam or diazepam. The role of the benzodiazepine here is to provide a sparing effect and muscle relaxation. Propofol can be used instead of the benzodiazepine, with similar results.
If propofol or alfaxalone are the main induction agents, these can be administered at a dose of 2-4 mg/kg, and the dose of ketamine is reduced to 1-2 mg/kg IV. In this case the role of ketamine is to have a sparing effect and thus reduce the incidence of side effect associated with propofol and alfaxalone (e.g., respiratory depression, hypotension).
Propofol still takes 60 seconds to have an effect, and a “sandwich” (or priming) technique is often used, in this case the anesthetist administers 1 mg/kg of propofol IV, followed by 1-2 mg/k of ketamine IV and lastly more IV propofol is administered to effect if needed. The syringe switch allows for the first bolus of propofol to take effect before more propofol is administered, and this may help decrease dose and side effects.
Analgesia
Ketamine is an excellent analgesic and can decrease central sensitization and wind-up pain at subanesthetic doses.
In this case it can be administered intraoperatively as a constant rate infusion at 10 – 30 mcg/kg/min, paying attention to stop the infusion about 30 minutes before the end of the anesthetic event, in order to minimize the chances of emergency delirium. In the post- operative period, ketamine can be used at a rate of 1 – 10 mcg/kg/min to provide effective analgesia. In either case a ketamine constant rate infusion can be combined with opioids, lidocaine (only in dogs) or dexmedetomidine, administered either as boluses or constant rate infusions as deemed appropriate. Due to the high concentration of ketamine (100mg/ml), this should be ideally diluted when administered as an infusion to improve accuracy.
Ketamine has also been administered epidurally at doses up to 3 mg/kg, it is as effective as lidocaine and with minimal cardiovascular side effects in dogs 6,7 . A few studies found toxic damage in the spinal cord in both rabbits and humans after repeated spinal administration 8,9 . Therefore, it is hard to make a recommendation as to whether this route of administration should be considered in everyday clinical practice.
Different routes of administration
Intranasal administration has been investigated, a study found that the bioavailability of 2mg/kg intranasal ketamine is similar to that of intravenous administration, when ketamine is administered this way, it has a quick onset and reaches peak plasma concentration in about 5-15 minutes, which is similar to what happens with intramuscular administration 10 .
Recently the use of subcutaneous ketamine for chronic pain relief has been on the rise, unfortunately there is no evidence in our patient population to support this use at the moment.
References
1. Casoni, D., Spadavecchia, C., & Adami, C. (2015). S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents. Veterinary anaesthesia and analgesia, 42(3), 250–259.
2. Armada-Moreira, A., Gomes, J. I., Pina, C. C., Savchak, O. K., Gonçalves-Ribeiro, J., Rei, N., Pinto, S., Morais, T. P., Martins, R. S., Ribeiro, F. F., Sebastião, A. M., Crunelli, V., & Vaz, S. H. (2020). Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases. Frontiers in cellular neuroscience, 14, 90.
3. Bennett G. J. (2000). Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. Journal of pain and symptom management, 19(1 Suppl), S2–S6
4. Barker, P. A., Mantyh, P., Arendt-Nielsen, L., Viktrup, L., & Tive, L. (2020). Nerve Growth Factor Signaling and Its Contribution to Pain. Journal of pain research, 13, 1223–1241.
5. Kumar, V., & Mahal, B. A. (2012). NGF - the TrkA to successful pain treatment. Journal of pain research, 5, 279–287.
6. Martin, D. D., Tranquilli, W. J., Olson, W. A., Thurmon, J. C., & Benson, G. J. (1997). Hemodynamic effects of epidural ketamine in isoflurane-anesthetized dogs. Veterinary surgery : VS, 26(6), 505–509.
7. Miranda-Cortés, A. E., Ruiz-García, A. G., Olivera-Ayub, A. E., Garza-Malacara, G., Ruiz- Cervantes, J. G., Toscano-Zapien, J. A., & Hernández-Avalos, I. (2020). Cardiorespiratory effects of epidurally administered ketamine or lidocaine in dogs undergoing ovariohysterectomy surgery: a comparative study. Iranian journal of veterinary research, 21(2), 92–96.
8. Vranken, J. H., Troost, D., Wegener, J. T., Kruis, M. R., & Van der Vegt, M. H. (2005). Neuropathological findings after continuous intrathecal administration of S (+)-ketamine for the management of neuropathic cancer pain. Pain, 117(1-2), 231-235.
9. Vranken, J. H., Troost, D., De Haan, P., Pennings, F. A., van der Vegt, M. H., Dijkgraaf, M. G., & Hollmann, M. W. (2006). Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S (+)-ketamine. The Journal of the American Society of Anesthesiologists, 105(4), 813-818.
10. Vlerick, L., Devreese, M., Peremans, K., Dockx, R., Croubels, S., Duchateau, L., & Polis, I. (2020). Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs. PloS one, 15(1), e0227762.
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