The Reemergence of Ketamine for Treatment in Critically Ill Adults

Kimberly P. Hurth, PharmD, BCCCP; Anthony Jaworski, PharmD, BCCCP; Kristen B. Thomas, PharmD, BCPS; William B. Kirsch, PharmD, BCPS; Michael A. Rudoni, PharmD, BCPS, BCCCP; Kevin M. Wohlfarth, PharmD, BCPS, BCCCP, BCCP


Crit Care Med. 2020;48(6):899-911. 

In This Article


Commonly marketed as a racemic mixture, the S(+) and R(–) enantiomers of the parent compound, as well as its primary metabolites ([R,S]-norketamine and [2R,6R;2S,6S]-hydroxynorketamine), play important roles in ketamine's pharmacology. Although incompletely understood, ketamine's versatility may be owed to its numerous sites of activity with most of its known therapeutic properties—particularly anesthesia and analgesia—largely the result of noncompetitive inhibition of N-methyl-D-aspartate (NMDA) receptors (NMDARs).[1,2] S(+)-ketamine is twice as potent as the racemic mixture and exhibits four times the affinity for the phencyclidine binding site of NMDAR compared with R(–)-ketamine. The result is dissociation manifesting as catatonia and amnesia while preserving laryngeal reflexes at subanesthetic IV doses. Antagonism of NMDAR also results in analgesic and antidepressant effects, the latter influenced more by R (–)-ketamine and the hydroxynorketamine metabolites. Analgesia may also be mediated through serotonin and norepinephrine activation and opioid-receptor agonism by ketamine (S[+] > R) and norketamine, and is useful in opioid-induced hyperalgesia by decreasing the so-called "wind-up" phenomenon associated with repeated stimuli.[5] Gamma-aminobutyric acid (GABA) activity may be either enhanced or antagonized by ketamine through augmentation of GABAA receptors and decreasing GABA uptake or by disinhibition of GABA release via NMDAR blockade, respectively.[2,5] The relevance of GABAergic effects is uncertain since doses larger than those used clinically are needed; however, premedication with benzodiazepines may attenuate ketamine-associated delirium suggesting an antagonistic effect on GABA. Ketamine binds both nicotinic and muscarinic acetylcholine receptors (AChRs). Blockade of the α7 nicotinic AChR, as well as direct and indirect effects on monoamines (dopamine, serotonin, norepinephrine), are proposed to be involved in its role as an antidepressant.[2]

Blockade of catecholamine reuptake makes ketamine a favorable alternative to anesthetics with negative hemodynamic profiles; however, hypertension and tachycardia can also occur. As such, providers should exercise caution in patients with coronary artery disease, preexisting hypertension, and certain neurologic conditions where elevations in intracranial pressure (ICP) would be harmful.[6–8] Despite the sympathomimetic potential, ketamine's myocardial depressant effects can be unmasked in states of catecholamine depletion (e.g., acute heart failure) resulting in hypotension and bradycardia.[1,9] Furthermore, neurologic effects (e.g., delirium, hallucinations, nightmares) are common and associated with well-described emergence reactions.