Ketamine - Intravenous Anesthetics

KETAMINE

Ketamine (Figure 25–6) is a partially water-soluble and highly lipid-soluble phencyclidine derivative differing from most other intrave-nous anesthetics in that it produces significant analgesia. The characteristic state observed after an induction dose of ketamine is known as “dissociative anesthesia,” wherein the patient’s eyes remain open with a slow nystagmic gaze (cataleptic state). Of the two ste-reoisomers the S (+) form is more potent than the R (–) isomer, but only the racemic mixture of ketamine is available in the USA.

Ketamine’s mechanism of action is complex, but the major effect is probably produced through inhibition of the NMDA receptor complex.

Pharmacokinetics

The high lipid solubility of ketamine ensures a rapid onset of its effect. As with other intravenous induction drugs, the effect of a single bolus injection is terminated by redistribution to inactivetissue sites. Metabolism occurs primarily in the liver and involves N-demethylation by the cytochrome P450 system. Norketamine,the primary active metabolite, is less potent (one third to one fifth the potency of ketamine) and is subsequently hydroxylated and conjugated into water-soluble inactive metabolites that are excreted in urine. Ketamine is the only intravenous anesthetic that has low protein binding (12%) (Table 25–2).

Organ System Effects

If ketamine is administered as the sole anesthetic, amnesia is not as complete as with the benzodiazepines. Reflexes are often preserved, but it cannot be assumed that patients are able to protect the upper airway. The eyes remain open and the pupils are moderately dilated with a nystagmic gaze. Frequently, lacrimation and salivation are increased, and pre-medication with an anticholinergic drug may be indicated to limit this effect.

A. CNS Effects

In contrast to other intravenous anesthetics, ketamine is considered to be a cerebral vasodilator that increases cerebral blood flow, as well as CMRO₂. For these reasons, ketamine has traditionally not been recommended for use in patients with intracranial pathology, especially increased ICP. Nevertheless, these perceived undesirable effects on cerebral blood flow may be blunted by the maintenance of normocapnia. Despite the potential to produce myoclonic activity, ketamine is considered an anticonvulsant and may be recommended for treatment of status epilepticus when more conventional drugs are ineffective.Unpleasant emergence reactions after administration are the main factor limiting ketamine’s use. Such reactions may include vivid colorful dreams, hallucinations, out-of-body experiences, and increased and distorted visual, tactile, and auditory sensitivity. These reactions can be associated with fear and confusion, but a euphoric state may also be induced, which explains the potential for abuse of the drug. Children usually have a lower incidence of and less severe emergence reactions. Combination with a benzodi-azepine may be indicated to limit the unpleasant emergence reac-tions and also increase amnesia.

B. Cardiovascular Effects

Ketamine can produce transient but significant increases in sys-temic blood pressure, heart rate, and cardiac output, presumably by centrally mediated sympathetic stimulation. These effects, which are associated with increased cardiac workload and myocar-dial oxygen consumption, are not always desirable and can be blunted by coadministration of benzodiazepines, opioids, or inhaled anesthetics. Though the effect is more controversial, ket-amine is considered to be a direct myocardial depressant. This property is usually masked by its stimulation of the sympathetic nervous system but may become apparent in critically ill patients with limited ability to increase their sympathetic nervous system activity.

C. Respiratory Effects

Ketamine is not thought to produce significant respiratory depres-sion. When it is used as a single drug, the respiratory response to hypercapnia is preserved and blood gases remain stable. Transient hypoventilation and, in rare cases, a short period of apnea can follow rapid administration of a large intravenous dose for induc-tion of anesthesia. The ability to protect the upper airway in the presence of ketamine cannot be assumed despite the presence of active airway reflexes. Especially in children, the risk for laryngo-spasm because of increased salivation must be considered; this risk can be reduced by premedication with an anticholinergic drug. Ketamine relaxes bronchial smooth muscles and may be helpful in patients with reactive airways and in the management of patients experiencing bronchoconstriction.

Clinical Uses & Dosage

Its unique properties, including profound analgesia, stimulation of the sympathetic nervous system, bronchodilation, and minimal respiratory depression, make ketamine an important alternative to the other intravenous anesthetics and a desirable adjunct in many cases despite the unpleasent psychotomimetic effects. Moreover, ketamine can be administered by multiple routes (intravenous, intramuscular, oral, rectal, epidural), thus making it a useful option for premedication in mentally challenged and uncoopera-tive pediatric patients.Induction of anesthesia can be achieved with ketamine, 1–2 mg/kg intravenously or 4–6 mg/kg intramuscularly. Though the drug is not commonly used for maintenance of anesthesia, its short con-text-sensitive half-time makes ketamine a candidate for this pur-pose. For example, general anesthesia can be achieved with the infusion of ketamine, 15–45 mcg/kg/min, plus 50–70% nitrous oxide or by ketamine alone, 30–90 mcg/kg/min.Small bolus doses of ketamine (0.2–0.8 mg/kg IV) may be useful during regional anesthesia when additional analgesia is needed (eg, cesarean delivery under neuraxial anesthesia with an insufficient regional block). Ketamine provides effective analgesia without compromise of the airway. An infusion of a subanalgesic dose of ketamine (3–5 mcg/kg/min) during general anesthesia and in the early postoperative period may be useful to produce analge-sia or reduce opioid tolerance and opioid-induced hyperalgesia. The use of ketamine has always been limited by its unpleasant psychotomimetic side effects, but its unique features make it a very valuable alternative in certain settings, mostly because of the potent analgesia with minimal respiratory depression. Most recently it has become popular as an adjunct administered at subanalgesic doses to limit or reverse opioid tolerance.