What Is the Role of Ketaminein Perioperative Management?

INTRODUCTION

Over 40 years ago during the Vietnam War, ketamine, a nonbarbiturate phencyclidine derivative, was considered an ideal “battlefield anesthetic” because it did not alter hemodynamics and had sedative, hypnotic, analgesic, and amnestic properties. ^, Over time, its popularity waned because of an undesirable side effect profile: hallucinations, delirium, lacrimation, tachycardia, and the potential for an increase in intracranial pressure (ICP) and coronary ischemia. Nevertheless, reports suggest that with lower doses, ketamine may not be associated with untoward effects and may reduce perioperative pain, prevent opioid-induced hyperalgesia, decrease inflammation, reduce bronchoconstriction, and improve the quality of life in a palliative care setting.

Ketamine binds with the N-methyl-D-aspartate (NMDA) and sigma opioid receptors to produce intense analgesia and a state of “dissociated anesthesia” in which the patient appears calm, does not react to pain, and maintains airway reflexes. Ketamine also interacts with nicotinic and muscarinic acetylcholine receptors, reduces neuronal sodium permeability, and blocks L-type Ca ²⁺ channels in the muscle and myocardium. Ketamine possesses a chiral center and exists commonly as a mixture of S(+) and R(−) stereoisomers. S(+) ketamine has greater analgesic potency and a shorter duration of action compared with R(−) ketamine because it has a fourfold greater affinity for the NMDA receptor. The liver metabolizes ketamine (via the cytochrome CYP3A4 and CYP2B6 pathways) into norketamine, a weaker active metabolite that is excreted in the urine.

OPTIONS/THERAPIES

Intravenous (IV; patient-controlled analgesia [PCA]), intranasal, intramuscular, sublingual, rectal, and epidural administrations of ketamine achieve effective plasma levels. Ketamine is not currently approved for intrathecal administration because of the potential neural toxicity.

General Anesthesia

Ketamine crosses the blood-brain barrier rapidly and reaches maximal effect in 1 minute. A single dose of ketamine (2 mg/kg IV) lasts 10 to 15 minutes, with the elimination half-life being 2.5 to 3 hours. Ketamine is used in clinical anesthesia as an induction agent to preserve hemodynamic stability, as an adjunctive anesthetic to spare opioid use, and as a sole anesthetic for noninvasive painful procedures such as dressing changes.

Intensive Care

Concerns about ketamine’s psychotropic effects have limited its use as a sedative-analgesic in the intensive care unit (ICU). Nevertheless, there is some evidence that this may be unfounded; a recent study showed that a low-dose ketamine infusion (0.2 mg/kg/hr) reduced delirium incidence and duration in mechanically ventilated and sedated ICU patients, although there was no difference in opioid consumption during their ICU stay. Overall, ketamine’s potential advantages include preserved heart rate and blood pressure for patients with poor cardiopulmonary reserve, antagonism of the NMDA receptor in patients experiencing short-term and repetitive pain (e.g., suctioning and turning), potentially decreased opioid consumption, and bronchodilation for patients with status asthmaticus.

Palliative Care

Ketamine has been used as an analgesic and antidepressant in the palliative care setting. ^, Reports of “burst doses” of ketamine to relieve symptoms have been published. ^, A study evaluating the effectiveness of oral ketamine versus methadone in chronic neuropathic pain refractory to traditional treatment found oral ketamine to be more efficacious in reducing overall pain scores and allodynia than methadone. Nevertheless, despite ketamine’s potential to relieve refractory cancer pain, numerous systematic reviews have found insufficient evidence to evaluate ketamine’s effectiveness as an adjuvant to opioid treatment in this patient population. ^,

Ketamine at subanesthetic doses has significant antidepressant and antisuicidal properties with clinical use increasing in treatment-resistant depression, both via IV and intranasal route. ^, A recent meta-analysis assessing intranasal ketamine for major depressive disorder found a significant antidepressant effect starting at 2 hours and lasting for 28 days. Furthermore, intraoperative ketamine might even be beneficial as a mood stabilizer after elective surgery, with one study finding improvement in scores for depressed mood postoperatively in patients undergoing orthopedic surgery. Nevertheless, studies investigating this effect long term are needed.

Organ and Physiologic Responses to Ketamine

Cardiovascular Response

Ketamine acts on the heart via sympathetic-mediated stimulation and inhibition of catecholamine uptake. ^, At clinical concentrations, ketamine has a positive inotropic effect and induces vasoconstriction, probably by inhibiting endothelial nitric oxide production, which preserves hemodynamic stability even in septic shock. Nevertheless, ketamine may act as a myocardial depressant in patients who are catecholamine depleted. ^, Its sympathetic activity can be attenuated by concomitant administration of benzodiazepines or alpha-2 agonists. Ketamine has been proposed as an antiarrhythmic agent and an anti-inflammatory agent because it inactivates neutrophils and suppresses cytokines.

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