In this article, we break down the most important ketamine clinical pearls. Ketamine (ketamine hydrochloride) is FDA approved for general anesthesia in diagnostic and surgical procedures that do not require skeletal muscle relaxation. It has been used on its own or as a pre-anesthetic adjunct to other anesthetic agents. Advantages of ketamine include its short duration of action and it can be utilized in children as young as three months. However, the FDA classifies ketamine as a Schedule III (3) non-narcotic drug and it has been identified as a drug of abuse due to its hallucinogenic and sedative properties. Ketamine works through non-competitive reversible N-methyl-D-aspartate (NMDA) receptor inhibition. By inhibiting NMDA receptors, glutamate production (an excitatory neurotransmitter) in the central nervous system is decreased, producing dissociative anesthetic and analgesic effects in the patient. 

Ketamine Clinical Pearls – Therapeutic Uses

The primary use of ketamine in clinical practice is to induce general anesthesia most often with other general anesthetics for short-term procedures in an emergency setting. Ketamine is less likely to cause hypotension or respiratory depression compared to opioids. When administered via IV route, onset of action is within 30 seconds and its duration is 5 to 30 minutes. It is also the medication of choice for patients with bronchospasm because of its bronchodilatory effects. 

Treating Pain – At low doses, ketamine can be used as an adjunct to opioid therapy in opioid-tolerant patients to treat both acute and chronic pain. Combining ketamine with opioids has been shown to block opioid-induced hyperalgesia and acute opioid tolerance. The 2018 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU (PADIS) mentions low-dose ketamine when seeking to reduce opioid consumption in postsurgical adults in the ICU (conditional recommendation, low quality of evidence). Additional guidelines published in 2018 by the American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Academy of Pain Medicine (AAPM), and the American Society of Anesthesiologists (ASA) discuss the role of ketamine in the management of acute and chronic pain. Both guidelines suggest limiting the use of subanesthetic ketamine for acute pain in patients undergoing surgeries where severe postoperative pain is expected or in opioid-tolerant or -dependent patients needing surgery. The evidence for long-term effectiveness of ketamine use in chronic pain remains mixed.

Treating Delirium – Per the 2018 PADIS guidelines, ketamine should not be used to prevent delirium in critically ill adults (conditional recommendation, low quality of evidence).

Treating Depression – Clinical use of ketamine in treating depression and suicidal ideation is considered off-label by the FDA. However, several studies have shown the effectiveness of ketamine in treating depression. Its mechanism of action is thought to help regulate emotion and cognition, which can be especially beneficial in patients with mood disorders who have elevated glutamate levels in the brain. In 2019, the FDA approved Spravato (esketamine), the S-enantiomer of ketamine, for its use in treatment-resistant depression in conjunction with another oral antidepressant.

Rapid Sequence Intubation – Ketamine may be used as an induction agent in rapid sequence intubation so be prepared for intubation when administering ketamine. Its role may be emphasized in trauma patients presenting with hypotension.

Status Epilepticus – Ketamine has limited data available for its use in refractory status epilepticus. Its use is considered off-label and can be given as an alternative or adjunct agent after conventional antiseizure therapies have failed. Continuous EEG monitoring is recommended. It is important to note that the data regarding ketamine use in refractory and super-refractory status epilepticus are currently limited to case series and studies.

Monitoring

It is recommended to monitor heart rate, blood pressure, cardiac output, respiratory rate, oxygen levels, and emergence reactions. 

Risks, Effects, and Clinical Limitations – Ketamine Clinical Pearls

Nausea, delirium, hallucinations, hypoventilation, pruritus, and sedation are the most commonly reported side effects. Ketamine may also cause emergence delirium which is an acute state of confusion that occurs during recovery from anesthesia and may present as disorientation, hallucinations, restlessness, and hyperactivity. Decreasing the ketamine dose or pretreating with benzodiazepines may reduce the incidence of emergence reactions. However, benzodiazepines should only be used to treat an emergence reaction if the patient is a danger to themselves or staff and should not be given routinely as prophylaxis to prevent emergence reactions. Suboptimal sedation requiring additional ketamine versus a true emergence reaction should be considered prior to benzodiazepine administration.

Drug-Drug Interactions – Ketamine potentiates the sedative effects of alcohol, opioids, benzodiazepines, and other CNS depressants. This is the primary concern when it comes to drug interactions with ketamine. CYP enzymes are not considered a primary pathway of breakdown so we typically do not need to worry about drug interactions via this pathway.

Contraindications and Precautions – Ketamine is relatively contraindicated in patients with poorly controlled hypertension, stroke, severe cardiovascular disease, elevated intracranial or intraocular pressure, severe liver disease, and active psychosis. It should not be used in newborns or patients who have shown prior hypersensitivity. Ketamine may be considered in trauma patients with schizophrenia as there does not appear to be an associated increase in psychosis incidence; however, additional precautions in this patient population should be exercised regardless. It is not recommended for use during obstetrics, pregnancy or breastfeeding. Exercise additional care if used in patients intoxicated with alcohol. 

Hopefully, this helps get you up to speed with some of the most common ketamine clinical pearls!

This article was written by Sarah Zahirudin, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP

Study Materials and Resources For Healthcare Professionals and Students – Amazon Books

References:

1. Rosenbaum S, Gupta V, Patel P, and Palacios J. Ketamine. National Library of Medicine. StatPearls [Internet]. Updated Nov 2022. Available at https://www.ncbi.nlm.nih.gov/books/NBK470357/.
2. Gao, M, Rejaei D, and Liu H. Ketamine use in current clinical practice: a review. Acta Pharmacologica Sinica. 2016: 1-8. DOI: 10.1038/aps.2016.5
3. Devlin J, Skrobik Y, Gelinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Critical Care Medicine. 2018; 46(9): 825-873. Available at https://journals.lww.com/ccmjournal/Fulltext/2018/09000/Clinical_Practice_Guidelines_for_the_Prevention.29.aspx.
4. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5): 521-546. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023575/. 
5. Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5): 456-466. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023582/.
6. (2019). FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. FDA. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. 
7. Alkhachroum A, Der-Nigoghossian C, Mathews E, et al. Ketamine to treat super-refractory status epilepticus. Neurology. 2020;95(16): 2286-2294. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713785/.