Ketamine

Article Author:
Steven Rosenbaum
Article Editor:
Jorge Palacios
Updated:
10/27/2018 12:31:40 PM
PubMed Link:
Ketamine

Indications

Ketamine (ketamine hydrochloride) has been approved for use in general anesthesia either alone or in combination with other medications. It is a superb drug for use in short-term medical procedures that do not require skeletal muscle relaxation, and it is approved for the induction of general anesthesia as a pre-anesthetic to other general anesthetic agents.

Ketamine is indicated to supplement low-potency agents such as nitrous oxide. 

Ketamine is used for short-term procedural sedation and rapid sequence intubation and is very useful in the emergency department setting for these conditions. It is the medication of choice for patients with bronchospasm because of its bronchodilatory properties. It can be utilized for procedures requiring short-term sedation/anesthesia, such as the reduction of fractures and dislocations, as well as in wound repair in uncooperative patients, especially children. It can be safely used in a wide age range, beginning at 3 months. Because children metabolize ketamine faster than adults, higher dosing is required than in the adult population. Elderly patients, on the other hand, need lower dosing since they are slow metabolizers of this agent.  

There is a wealth of evidence indicating the value of ketamine in the treatment of severe pain including conditions such as trauma, fractures, abdominal and flank pain, low back pain, and extremity pain. When used for pain management, subdissociative dosing, otherwise known as low dose ketamine (LDK), of ketamine is used, either alone or as an adjunct to other medications for pain relief. It is safe and effective to use in combination with injectable nonsteroidal pain medications as well as opioids and has gained greater acceptance as concern has grown with regard to opioid use.

Ketamine is being used to treat patients with depression and suicidal ideation successfully.

Ketamine has been used recreationally as a drug of abuse. The street name for ketamine is "K" or "Special K."

Ketamine is FDA approved for use in anesthesia and procedural sedation. It has been used "off-label" and shown in numerous studies to be safe when used for pain management as discussed above. Ketamine is not, as of this writing, FDA approved for the treatment of depression and suicidal ideation.  Recreational use is not FDA approved.

At doses below a certain threshold, ketamine produces analgesia and sedation. However, once the critical dosage threshold of roughly 1 to 1.5 mg/kg when given intravenously (IV) or 3 to 4 mg/kg when given intramuscularly (IM) is reached, the characteristic dissociative state abruptly appears. Because of this, the dissociative state is not consistent with the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) definitions of moderate sedation or deep sedation; therefore, ketamine must be considered from a different perspective than drugs with the classical sedation continuum.

Mechanism of Action

Ketamine hydrochloride is a nonbarbiturate dissociative anesthetic. It is a cyclohexanone derivative that is rapidly acting and produces profound anesthesia and analgesia. Its chemical name is ±)-2-(o-Chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride; its structural formula is CHClNO. Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) and glutamate receptor antagonist. It blocks HCN1 receptors.   The unique dissociative action and partial agonism in opiate mu-receptors permit painful procedures to be performed in a consistent state of sedation and patient comfort.

Its mechanism of action is not well understood, but ketamine may interact with the sigma receptors. It tends to work by decreasing central sensitization, wind-up phenomenon (development of ongoing, worsening or chronic pain), and pain memory. Cholinergic, aminergic, and opioid systems appear to play both a positive and negative modulatory role in both sedation and analgesia.

Ketamine's effects in chronic pain, and as an antidepressant, far outlast the actual drug levels, and are probably mediated by a secondary increase in structural synaptic connectivity that is mediated by a neuronal response to the ketamine-induced hyper-glutamatergic state." (Sleigh 2014).

Ketamine reverses tolerance to opioids

It is metabolized via the hepatic system by way of N-dealkylation, hydroxylation, conjugation, and dehydration. The half-life of ketamine is approximately 45 minutes. An active metabolite has approximately third the activity of the parent compound.

Note:

Ketamine generally maintains normal pharyngeal and laryngeal reflexes and, therefore, permits spontaneous respiration. It slightly enhances or maintains normal skeletal muscle tone and is associated with cardiovascular and respiratory stimulation. These characteristics make it particularly useful in the emergency department setting for short-term procedures, especially, as is often the case, when a patient has not been "prepped" for an emergency procedure. Since maintenance of the pharyngeal and laryngeal reflexes is not guaranteed it cannot be assumed to be "protective" of the airway; additionally, there may be transient minimal respiratory depression if the medication is administered too rapidly or in too high a dose. Therefore, the physician must be prepared to perform an emergency intubation.

Administration

Ketamine can be administered either IV or IM. The onset of action, when given IV, is seconds. When administered IM, the onset of action is approximately 4 minutes with a duration of action from 15 to 30 minutes. Dosing needs to be varied according to the desired effect, patient's age, and underlying conditions. Children metabolize the drug more rapidly than adults and may require higher or additional dosing; elderly patients metabolize ketamine more slowly and may need lower dosing. When using larger total doses of ketamine, administering it more rapidly than normal, or when using ketamine with sedatives, barbiturates, or narcotics, exaggerated responses may be experienced and prolonged recovery times should be expected.

The initial IV dose of ketamine ranges from 1 to 4.5 mg/kg (0.5 to 2 mg/lb) administered over 60 seconds for those 16 years old or older. A dose of 2 mg/kg (1 mg/lb) is the average amount required to produce approximately 5 to 10 minutes of anesthesia/dissociation with the onset of action in about 10 to 30 seconds and a duration of action approximately 5 to 15 minutes. For more prolonged anesthesia, additional doses can be administered IV or IM  to maintain anesthesia without producing significant cumulative effects. One-half to full additional doses may be repeated as needed. Adjustments to dosing will be required if used in combination with other drugs such as IV benzodiazepines or narcotics. Maintenance when using diazepam in adults should be by slow infusion at 0.1 to 0.5 mg/minute of ketamine. Additional doses of diazepam in the amount of 2 to 5 mg may be given.

  • In adults, an alternative induction dose is 1 to 2 mg/kg IV at a rate of 0.5 mg/kg/min.  IV diazepam 2 to 5 mg can be given over 60 seconds to reduce emergence phenomena. In most cases, 15 mg IV or less will suffice.
  • The initial IM dose of ketamine ranges from 6.5 to 13 mg/kg (3 to 6 mg/lb). A dose of 10 mg/kg (5 mg/lb) usually produces 12 to 30 minutes of surgical anesthesia with an onset of action of about 3 to 5 minutes
  • In children, the IM dosing range is from 9 to 13 mg/kg (4 to 6 mg/lb) and usually produces surgical anesthesia within 3 to 4 minutes following injection.
  • Subdissociative dosing (low dose ketamine) is dosed at 0.1 to 0.4 mg/kg IV.

Illicit use of ketamine includes snorting or inhalation and can be ingested in food/drinks.

Note:

Tonic-clonic movements may be noted during the administration of ketamine.  These movements do not mean that additional doses of the anesthetic are required.

Adverse Effects

The most common side effects associated with ketamine are nausea, vomiting, dizziness, diplopia, drowsiness, dysphoria, and confusion.  Emergence phenomenon has been reported in from 6% to 12% of patients. Rarely, patients experience hallucinations.

A complete list of side effects follows:

  • Allergic: anaphylaxis, breathing difficulties, facial, lip, throat and tongue swelling, hives
  • Cardiovascular: arrhythmias, blood pressure frequently elevated, bradycardia, hypotension, left ventricular dysfunction in patients with heart failure, respiratory and cardiac arrest
  • Gastrointestinal: anorexia, nausea, and vomiting
  • Muscular: muscle stiffness and spasms/tonic-clonic movements resembling seizures, enhanced skeletal muscle tone
  • Neurologic: confusion, seizures
  • Ophthalmologic: diplopia, increased intraocular pressure, nystagmus
  • Psychiatric: amnesia, anxiety, confusion, depression, disorientation, dysphoria, dissociative state (patients may not be able to speak or respond purposefully to verbal commands), emergence phenomena/delirium (6% to 12% in different studies and can last for up to 3 hours) including hallucinations, flashbacks, unusual thoughts, extreme fear, excitement, and irrational behavior, insomnia, physical and psychological dependence, addiction when used recreationally. (Drug dependence and tolerance may develop after prolonged use. Withdrawal symptoms may occur if ketamine is stopped suddenly.)
  • Respiratory: apnea, increased laryngeal and tracheal secretions, laryngospasm, airway obstruction in infants (may not be drug related), respiratory depression 
  • Skin: (infrequently) at the site of injection, local pain, and erythema, morbilliform rash

Note:

Emergence delirium may be reduced by decreasing the recommended dose of ketamine, using it in conjunction with benzodiazepines, and/or reducing verbal and tactile stimulation during the administration of the drug. Should "emergence" occur, a small hypnotic dose of a short-acting barbiturate or benzodiazepine is recommended to terminate the reaction. Diazepam 2 to 5 mg IV push given over 1 minute (15 mg or less in most cases) can be used to reduce emergence phenomena.  "Emergence" is not typical in children younger than 15 years or elderly patients greater than 65 years. In a randomized controlled study of adult emergency department patients, Sener et al. found that the incidence of agitation was significantly reduced when midazolam was coadministered with ketamine for procedural sedation.

Contraindications

Ketamine is contraindicated in those patients who have underlying conditions in which increased blood pressure would pose a risk of complications such as aortic dissection, uncontrolled hypertension, myocardial infarction or aneurysms.

  • It is contraindicated in those who have shown prior hypersensitivity to the drug.
  • It is not recommended for use during obstetrics, pregnancy, or for women who are breastfeeding as it is unknown if this medication passes into breast milk. 
  • Use in chronic alcoholics and the acutely alcohol-intoxicated patient may cause death.  
  • It is contraindicated in patients with schizophrenia due to the potential for exacerbating the underlying condition.

In patients with cerebrospinal fluid (CSF) elevations, the use of ketamine is controversial due to questionable elevations of the CSF caused by ketamine. Some studies indicate that the concern for CSF elevation with ketamine has been overstated. Kropf et al. found similar hemodynamic properties compared with etomidate. Newer research suggests that ketamine may improve cerebral perfusion pressure and may, in fact, have neuroprotective properties.

Monitoring

Monitor vital signs and cardiac function. Blood pressure, pulse, breathing, and oxygen saturation always need to be monitored when using ketamine.

Be prepared for intubation when administering ketamine.

Neuropsychiatric function must always be monitored, and a patient must be at baseline prior to discharge from your care. Even after a patient's return to baseline, the patient should be discharged to the care of another responsible adult. Patients should not drive, use heavy machinery, or perform other potentially hazardous activities for 24 hours after ketamine has been administered.

Toxicity

Ketamine is potentially fatal in chronic alcoholics and acutely alcohol-intoxicated patients.

*May increase CSF pressure (controversial-see above/contraindications)