The Reemergence of Ketamine for Treatment in Critically Ill Adults
Kimberly P. Hurth, Kristen B. Thomas, Michael A. Rudoni
Critical Care Medicine, 2020,1-13.
Doi : 10.1097/CCM.0000000000004335
Objectives : To assess the evidence and discuss the risks and clinical relevance of ketamine for the treatment of various disease states impacting the adult critically ill population.
Data Sources : A literature review was performed using PubMed evaluating primary literature published until August 2018.
Study Selection : Case reports, observational studies (cohort, case-control), and randomized controlled trials involving patients 18 years and older in a nonperioperative setting using either IV or intramuscular ketamine were included for analysis. Uses of ketamine discussed focused on critically ill patients in the ICU and emergency department settings.
Data Extraction : Included studies were evaluated for dosing, outcomes, and adverse effects of ketamine. For each study, the design, population, intervention, investigated outcomes, and results were assessed.
Data Synthesis : The evidence was organized according to use of ketamine, which included pain, sedation, status asthmaticus, alcohol withdrawal syndrome, status epilepticus, and acute behavioral psychologic disturbances. Evaluation of the evidence was based on the included primary literature along with any related guideline recommendations.
Conclusions : Ketamine has suggested potential benefit in several disease states impacting critically ill patients including pain, alcohol withdrawal syndrome, status epilepticus, and acute agitation. Further supporting evidence is needed to validate its use in the setting of critical illness. (Crit Care Med 2020; XX:00–00)
Key Words : alcohol withdrawal; ketamine; mechanical ventilation; pain; status asthmaticus; status epilepticus
Ketamine is a well-known anesthetic with sedative and analgesic properties historically used during medical procedures and in the postoperative setting. Clinical experience in humans began in the 1960s when ketamine was used during surgical interventions at the University of Michigan. It attained U.S. Food and Drug Administration approval in 1970, gaining popularity for its profound analgesia and preservation of airway reflexes (1).
A short-acting derivative of phencyclidine, ketamine is onetenth the potency of its parent compound and exhibits dissociative effects by perpetuating a dream-like detachment from the environment (1, 2). Despite potential for abuse and adverse neuropsychiatric reactions, recent literature has expanded our understanding of ketamine’s unique pharmacology and explores utilizing its analgesic, sedative, anti inflammatory, and antidepressant effects for many off-label indications (3). This review aims to summarize several of the emerging off-label indications for ketamine in the critically ill. The more familiar uses of rapid sequence intubation and procedural sedation are beyond the scope of this review and will not be discussed. Utilization of the Strength of Recommendation Taxonomy criteria will be applied for ketamine use in each disease state discussed (Appendix, Supplemental Digital Content 1, http://links.lww. com/CCM/F375) (4).
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.
Its pharmacokinetic properties make ketamine an attractive agent for use in the critical care setting (Table 1). Depending on the route of administration, ketamine typically exhibits a rapid onset of action (1, 5, 10). It undergoes clearance via cytochrome P450-mediated mechanisms (CYP 2B6, 2C9, 3A4),
which can be altered in the setting of hepatic impairment and interacting medications. In the general population, the elimination half-life is approximately 2–3 hours. Once metabolized hepatically via N-dealkylation, norketamine can be 33% as potent as the parent compound, leading to potential prolonged clinical effects. Ketamine is lipophilic with limited protein binding, allowing for easier distribution into the CNS (5).
POTENTIAL USES FOR KETAMINE
Evidence for each off-label use is displayed within Table 2.
Acute Pain Management
Rationale. Many studies investigating ketamine for pain management include patients presenting to the emergency department (ED). There are limited pain management recommendations for ketamine in nonoperative settings in the ICU, outside of those resulting from a randomized, double-blind study, which demonstrated a reduction in morphine consumption (p < 0.05) without a significant difference in pain score at 24 or 48 hours compared with morphine (11–13). Additionally, there was lower mean morphine equivalent use (p = 0.015) in a retrospective, case-control cohort involving 30 ICU patients (14). Due to ketamine’s effects on delta-, kappa-, and mu-opioid receptors in addition to NMDA inhibition, there is increasing interest in its utilization for acute pain.