PHARMACOLOGY

Ketamine is a rapid-acting, nonbarbiturate general anesthetic. It produces an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes and normal or slightly enhanced skeletal muscle tone. Mild cardiac stimulation and occasionally respiratory depression occur.

The anesthetic state produced by ketamine has been termed "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing somatosensory blockade. Ketamine decreases the activity of the neocortex and subcortical structures (thalamus) and increases the activity in the limbic system and reticular substance.

Following administration of recommended doses of ketamine, blood pressure and pulse rate are usually moderately and temporarily increased. In 12 283 procedures, the median systolic rise was 24% and the median diastolic rise was 22%.

Respiration is usually unaffected. Mild stimulation occasionally occurs. However, transient respiratory depression (rate and tidal volume) may occur and is generally associated with rapid (less than 60 seconds) i.v. administration. Blood gas pressures (PO2 and PCO2) are relatively unaffected.

A patent airway is maintained partly by virtue of unimpaired pharyngeal and laryngeal reflexes.

Ketamine undergoes N-demethylation and hydroxylation of the cyclohexanone ring, with the formation of water-soluble conjugates which are excreted in the urine. Further oxidation also occurs with the formation of a cyclohexanone derivative. The unconjugated N-demethylated metabolite was found to be less than one sixth as potent as ketamine. The unconjugated demethyl cyclohexanone derivative was found to be less than one tenth as potent as ketamine.

Studies in human subjects resulted in the mean recovery of 91% of the dose in the urine and 3% in the feces. Peak plasma levels averaged about 0.75 µg/mL and CSF levels were about 0.2 µg/mL, 1 hour after dosing.

INDICATIONS

As the sole anesthetic agent for recommended diagnostic and surgical procedures. Although best suited to short procedures, ketamine can be used, with additional doses, for longer procedures.

Note: If skeletal muscle relaxation is desired, a muscle relaxant should be used. In surgical procedures involving visceral pain pathways, ketamine should be supplemented with an agent which obtunds visceral pain.

For the induction of anesthesia prior to the administration of other general anesthetic agents.

To supplement low potency agents such as nitrous oxide.

Specific areas of application or types of procedures have included: Neurodiagnostic procedures such as pneumoencephalograms, ventriculograms, myelograms, and lumbar punctures.

Diagnostic and operative procedures of the eye, ear, nose and mouth. Eye movements may persist during ophthalmological procedures. Before ketamine can be recommended for intraocular surgery, more data are required.

Diagnostic and operative procedures of the pharynx, larynx or bronchial tree.

Note: Adequate muscle relaxants must be used in such procedures (see Contraindications and Precautions).

Sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.

Extraperitoneal procedures used in gynecology such as dilation and curettage. More data are required before ketamine can be recommended for use in obstetrical delivery or cesarean section (see Warnings and Precautions).

Orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

Dental extractions.

Miscellaneous procedures of general surgery such as debridement, painful dressings, and skin grafting in burn patients.

Anesthesia in poor-risk patients where depression of vital functions precludes the use of other general anesthetics.

In procedures where i.m. administration is preferred.

CONTRAINDICATIONS

In persons with a history of cerebrovascular accident; in those in whom a significant elevation of blood pressure would constitute a serious hazard, such as patients with significant hypertension; in persons with severe cardiac decompensation; in surgery of the pharynx, larynx, or bronchial tree unless adequate muscle relaxants are used; in those showing hypersensitivity to the drug.

PRECAUTIONS

Ketamine is for use only by or under the direction of physicians experienced in administering general anesthetics and in maintenance of an airway and in the control of respiration.

Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation.

Barbiturates and ketamine, being chemically incompatible because of precipitate formation, should not be injected from the same syringe.

Barbiturates and narcotics, being CNS depressants, may prolong recovery time if used concurrently with ketamine.

Postoperative confusional states may occur during the recovery period.

Respiratory depression may occur with overdosage or excessively administration of ketamine, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics.

An increase in cerebrospinal fluid pressure has been reported following the administration of ketamine. Therefore, special caution should be exercised when using ketamine in cases with pre-existing elevated intracranial pressure, and in those cases with normal intracranial pressure in which, in the opinion of the physician, a rise in such pressure would entail special risks. Use with extreme caution in patients with preanesthetic elevated cerebrospinal pressure.

Although animal studies of teratogenicity, fertility, and reproduction indicated the safety of ketamine, its safe use in human pregnancy has not been established (see Precautions).

Because pharyngeal and laryngeal reflexes are usually active, ketamine should not be used alone in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree. Mechanical stimulation of the pharynx should be avoided, whenever possible if ketamine is used alone.
Administration of muscle relaxants with proper attention to respiration, may be required in both of these instances.

Precautions should be taken in patients with upper respiratory infections because of the increased danger of respiratory difficulties, such as laryngospasm.

Resuscitative equipment should be available and ready for use.

The i.v. loading dose should be administered over a period of 60 seconds. More rapid administration may result in respiratory depression and enhanced pressor response.

In surgical procedures involving visceral pain pathways, ketamine should be supplemented with an agent which obtunds visceral pain.

During recovery from anesthesia, the patient may go through a phase of emergence reaction characterized by vivid dreams, dream-like states, confusion (with or without psychomotor activity), excitement, delirium, irrational behavior and occasionally hallucinations. In some cases these states have been accompanied by confusion, excitement, and irrational behavior which a few patients recall as an unpleasant experience. The duration ordinarily is no more than a few hours; in a few cases, however, recurrences have taken place up to 24 hours postoperatively. No residual psychological effects are known to have resulted from the use of ketamine.

In 12 283 procedures, incidence of postanesthetic emergence responses was measured according to the following parameters: See Table 1.

Table I--Ketalar
Postanesthetic Emergence Responses

* Some procedures have multiple emergence reactions, therefore the overall rate is less than the sum of the reactions.

As Table I shows, that emergence reactions were more common in the 15 to 35 year old group.

The reactions tabled above occurred in the majority of instances in patients in whom droperidol or diazepam had not been used as premedications.

The incidence of these emergence phenomena is least in the young (15 years of age or less) and elderly (over 65 years of age) patient. Also, they are less frequent when the drug is given i.m. and when it is administered by a physician experienced in its use.

The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using lower recommended dosages of ketamine in conjunction with i.v. diazepam during induction and maintenance of anesthesia.

The incidence of emergence reactions may be reduced if verbal, tactile and visual stimulation of the patient is avoided during the recovery period and certainly until the patient is fully conscious. These precautions do not preclude postoperative monitoring of vital signs.

The use of hypnotic doses of ultrashort-acting thiobarbiturates (50 to 100 mg i.v.) can be used to terminate severe emergence reactions. Diazepam, 5 mg i.v. has also been used to terminate emergence reactions.

Long-term follow-up observations of 221 patients (140 with ketamine, 81 with other anesthetic agents) have not revealed any residual psychological effects.

During anesthesia, the eyelids may remain retracted. During recovery, they close. Premature stimulation during recovery in the presence of nystagmus and diplopia may precipitate retching, nausea, or frank vomiting.

Purposeless movements of extremities may occur during the course of anesthesia. These movements do not imply a light plane of anesthesia and are not indicative of the need for additional doses of the anesthetic.

When ketamine is used on an outpatient basis, the patient should not be released until recovery from anesthesia is completed and then should be accompanied by a responsible adult. Use with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient.

Pregnancy: In obstetrics, with the exception of administration during abdominal delivery or vaginal delivery, no controlled clinical studies have been conducted. The safe use in pregnancy has not been established, and such use is not recommended.

Drug Interactions: Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with ketamine.

Ketamine is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained.

Information to Be Provided to the Patient: Occupational Hazards: As appropriate, especially in cases where early discharge is possible, the duration of ketamine administration should be considered, in addition to that of the other drugs employed during anesthesia. Patients should be cautioned that driving an automobile, operating machinery or engaging in hazardous activities should not be undertaken for 24 hours or more, after anesthesia (depending upon the dosage of ketamine and the administration of other drugs).

ADVERSE EFFECTS

One of the most characteristic physiologic effects of ketamine is temporary augmentation of the pulse rate and blood pressure. Elevation of blood pressure begins shortly after injection, reaches a maximum within a few minutes and usually returns to preanesthetic values within 15 minutes of injection. The median peak rise has ranged from 20 to 25% of preanesthetic values for both systolic and diastolic readings. Depending on the condition of the patient, this elevation of blood pressure may be considered a beneficial effect, or in others, an adverse reaction. If elevation of blood pressure would be considered adverse to the patient, the benefit to risk ratio should be carefully determined (see Contraindications). Maintaining or moderately increasing blood pressure may be beneficial to some patients, as those in shock or those in whom reduction in blood pressure is contraindicated (see Warnings).

Hypotension, arrhythmias, and bradycardia have been occasionally observed.

Although respiration is frequently stimulated, severe depression of respiration or apnea may occur following rapid i.v. administration of high doses of ketamine. Respiratory depression, mild or moderate and transient, occurred in a small percentage of patients with normal doses. In the majority of these patients, it is not a serious problem. Laryngospasm and other forms of airway obstruction have occurred during ketamine anesthesia.

Increased salivation may occur unless an antisialagogue is used.

In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements, sometimes resembling seizures. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.

EEG recordings were made in 14 patients receiving ketamine. Although 1 of these patients exhibited slight twitching of the arms and legs, none showed EEG changes to suggest seizure reactions. Epileptiform attacks have been observed in a few patients following ketamine administration. However, ketamine has been used successfully in patients known to be suffering from epilepsy.

Blurred vision, nystagmus and diplopia are not uncommon findings during the recovery period.

Anorexia, nausea or vomiting are minimal, allowing the great majority of patients to take liquids orally shortly after regaining consciousness.

Except for occasional reports of local pain and exanthema at the injection site, ketamine is well tolerated by the patient when administered either by the i.v. or i.m. route. Transient erythema, morbilliform rash and anaphylaxis have been reported.

Ketamine causes a small transient increase in intraocular pressure. However, it has been used in patients with glaucoma without causing any deterioration in this condition.

Drug Abuse and Dependence: Ketamine abuse has been reported. Reports suggest that ketamine produces a variety of symptoms including, but not limited to, flashbacks, hallucinations, dysphoria, anxiety, insomnia, or disorientation. Ketamine dependence and tolerance may develop in individuals with a history of drug abuse or dependence. Therefore, ketamine should be prescribed and administered with caution.

OVERDOSAGE

Symptoms: Respiratory depression can result from an overdose of Ketalar, or when the rate of administration is too rapid. Ventilatory support should be employed. Mechanical ventilation to maintain adequate blood oxygen saturation and carbon dioxide elimination is preferred to administration of analeptics.

Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine (up to 10 times the usually required dose) have been followed by prolonged but complete recovery.

Treatment: See Symptoms.

DOSAGE

Preoperative Preparations: Ketamine has been safely used alone when the stomach was not empty. However, since the need to use supplementary anesthetic or muscle relaxant agents cannot always be predicted, it is preferable not to give anything by mouth for at least 6 hours before elective surgery. Ketamine is recommended for use in patients whose stomach is not empty when in the judgment of the physician the benefits of the drug outweigh the possible hazards.
Atropine, scopolamine, or other drying agents should be given at an appropriate interval prior to induction.

Certain drugs such as droperidol or diazepam i.m. have been used in an attempt to reduce the incidence of emergence reactions; sufficient data have not yet been accumulated to constitute thorough documentation. The incidence of emergence reactions is reduced as experience with the drug is gained.

Dosage: As with other general anesthetic agents, the individual response to ketamine is somewhat varied depending on the dose, route of administration, and age of patient, so that dosage recommendation cannot be absolutely fixed. The drug should be titrated to the patient's requirements.

Onset and Duration: Because of rapid induction following the initial i.v. injection, the patient should be in a supported position during administration.

The onset of action of ketamine is rapid; an i.v. dose of 2 mg/kg of body weight usually produces surgical anesthesia within 30 seconds after injection, with the anesthetic effect usually lasting 5 to 10 minutes. If a longer effect is desired, additional increments can be administered i.v. or i.m. to maintain anesthesia without producing significant cumulative effects.

I.M. doses, from experience primarily in children, in a range of 9 to 13 mg/kg usually produce surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

Use of Ketamine as the Sole Anesthetic Agent: Induction: I.V. Route: The initial dose of ketamine administered i.v. may range from 1 to 4.5 mg/kg. The average amount required to produce 5 to 10 minutes of surgical anesthesia has been 2 mg/kg.

Rate of Administration: It is recommended that ketamine be administered slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.

I.M. Route: The initial dose of ketamine administered i.m. may range from 6.5 to 13 mg/kg. A dose of 10 mg/kg will usually produce 12 to 25 minutes of surgical anesthesia.

Maintenance of Anesthesia: Increments of one half to the full induction dose, either i.v. or i.m., may be repeated as needed for maintenance of anesthesia. Nystagmus, movements in response to stimulation, and vocalization may indicate lightening of anesthesia.

Use of Ketamine Prior to the Administration of Other General Anesthetic Agents: Ketamine is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained. When ketamine is used as an induction agent, prior to the administration of other general anesthetic agents:

The full induction dose of ketamine should be given i.v. over 60 seconds.

At the completion of the induction dose of ketamine, the anesthetist should proceed immediately with the chosen general anesthetic procedure. A second dose of ketamine (half the original induction dose) may be required at 5 to 8 minutes following the initial induction dose when using an agent such as methoxyflurane where some considerable time is required for full surgical anesthesia to be established with the gaseous anesthetic. Otherwise, lightening in the depth of anesthesia may occur and the patient may enter the stage of excitement, associated with vocalization and purposeful movements.

Recovery: Postoperatively, the patient should be observed but left undisturbed. This does not preclude the monitoring of vital signs.

SUPPLIED

10 mg: Each mL contains: ketamine HCl equivalent to 10 mg ketamine base. Steri-Vials of 20 mL.
50 mg: Each mL contains: ketamine HCl equivalent to 50 mg ketamine base. Steri-Vials of 10 mL.
The solution for i.v. or i.m. use contains 1:10 000 benzethonium chloride as a preservative (pH 3.5 to 5.5). The 10 mg/mL solution has been made isotonic with sodium chloride (2.6 mg/5 mL).