Continuing Education Activity

Ketamine hydrochloride, commonly known as ketamine, is a medication approved by the United States Food and Drug Administration (FDA) for use as a general anesthetic either on its own or in combination with other medications. The medication is highly effective for brief medical procedures that do not necessitate skeletal muscle relaxation and can be utilized as a pre-anesthetic for the induction of general anesthesia when combined with other general anesthetic agents. Furthermore, ketamine is FDA-approved for enhancing the effects of low-potency substances such as nitrous oxide.

In addition to its anesthetic applications, ketamine proves invaluable in pain management, addressing treatment-resistant depression, managing suicidal ideation, and treating refractory status epilepticus, with specific indications awaiting FDA approval. The dosage determines the application and resulting effects of the drug, leading to variations in the prescribing protocol. This versatility renders ketamine valuable in both anesthesia and pain management. Ongoing research explores the potential applications of ketamine in psychiatry across all isomeric forms. At elevated doses, ketamine operates primarily as a sedative rather than an analgesic agent. This activity reviews ketamine's indications, mechanism of action, pharmacokinetics, adverse drug reactions, monitoring strategies, drug-drug interactions, and clinical toxicology for healthcare professionals to facilitate the enhancement of clinical best practice guidelines.

Objectives:

• Identify appropriate indications for ketamine use, recognizing its role in general anesthesia, pain management, and potential applications in psychiatry.
• Screen patients thoroughly, assessing their medical history and contraindications to determine suitability for ketamine administration.
• Assess patients' responses to ketamine, adapting dosages and treatment plans based on individual needs and clinical outcomes.
• Collaborate with interdisciplinary teams, sharing expertise on ketamine's diverse applications and contributing to comprehensive patient care plans.

Indications

Ketamine hydrochloride, commonly known as ketamine, is a medication approved by the United States Food and Drug Administration (FDA) for use as a general anesthetic either on its own or in combination with other medications.

FDA-Approved Indications

Ketamine is highly effective for brief medical procedures that do not necessitate skeletal muscle relaxation and can be utilized as a pre-anesthetic for the induction of general anesthesia when combined with other general anesthetic agents. Furthermore, ketamine is FDA-approved for enhancing the effects of low-potency substances such as nitrous oxide.

Off-Label Uses

Ketamine is used in emergencies to provide short-term procedural sedation and rapid sequence intubation. The Society of Critical Care Medicine guidelines recognize ketamine as an effective medication for rapid sequence intubation. The medication is preferred for patients with bronchospasm because of its bronchodilatory properties. Ketamine is used for procedures that require short-term sedation or anesthesia and can be safely used in a wide age range, starting from 3 months. Children metabolize ketamine faster than adults, so higher dosing is required. However, older patients are slow metabolizers and need lower dosing.

A wealth of evidence indicates the value of ketamine in treating severe pain, including conditions such as trauma, fractures, abdominal and flank pain, low back pain, and extremity pain. In addition to its anesthetic applications, ketamine proves invaluable in pain management, addressing treatment-resistant depression, managing suicidal ideation, and treating refractory status epilepticus, with specific indications awaiting FDA approval. When used for pain management, sub-dissociative dosing, otherwise known as low-dose ketamine (LDK), is used either alone or as an adjunct to other pain relief medications. It is safe and effective to use in combination with injectable nonsteroidal pain medications as well as opioids. As concerns about opioid use have grown, it has become more widely accepted.[1][2] The dosage determines the application and resulting effects of the drug, leading to variations in the prescribing protocol. This versatility renders ketamine valuable in both anesthesia and pain management.

Ongoing research explores the potential applications of ketamine in psychiatry across all isomeric forms. At elevated doses, ketamine operates primarily as a sedative rather than an analgesic agent. Ketamine is also used successfully for treatment-resistant depression and suicidal ideation, although it is not yet FDA-approved.[3] 

Ketamine is a racemic mixture of both (R)- and (S)-enantiomers, whereas esketamine consists solely of the (S)-enantiomer. The FDA has approved the esketamine for treatment-resistant depression in conjunction with another oral antidepressant.[4] Ketamine is also used in refractory status epilepticus.[5][6]

At doses below a certain threshold, ketamine produces analgesia and sedation. However, once the critical threshold of roughly 1 to 1.5 mg/kg intravenously (IV) or 3 to 4 mg/kg intramuscularly (IM) is reached, the characteristic dissociative state abruptly appears. The dissociative state is inconsistent 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 as described in the American Society of Anesthesiologists guidelines.[7]

Mechanism of Action

Ketamine hydrochloride is a nonbarbiturate dissociative anesthetic. As a cyclohexanone derivative, the drug rapidly acts and produces profound anesthesia and analgesia. Its chemical name is ±)-2-(o-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride; the structural formula is CHClNO. Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) and glutamate receptor antagonist that blocks HCN1 receptors. The unique dissociative action and partial agonism of opiate mu-receptors permit painful procedures in a consistent state of sedation and comfort.[8][9][10]  

Ketamine's efficacy in chronic pain as an antidepressant far outlast the actual drug concentrations and is possibly mediated by a secondary increase in structural synaptic connectivity mediated by a neuronal response to the ketamine-induced "hyper-glutamatergic state." The N-methyl-D-aspartate (NMDA) receptor has a significant role in the etiology of depression. Ketamine, through its NMDA antagonistic action, works rapidly in controlling symptoms of depression and acute suicidal ideation. Ketamine can elevate the levels of glutamate in the brain, stimulating synaptogenesis and elevated levels of brain-derived neurotrophic factor (BDNF).[11] Ketamine may interact with the sigma receptors.[12] It works by decreasing central sensitization, wind-up phenomenon (development of ongoing, worsening, or chronic pain), and pain memory. Cholinergic, monoaminergic, and opioid systems seem to play both a positive and negative modulatory function in both analgesia and sedation. Ketamine reverses tolerance to opioids.[13][14]

Ketamine generally maintains normal pharyngeal and laryngeal reflexes and permits spontaneous respiration. It enhances or maintains normal skeletal muscle tone and is associated with cardiovascular and respiratory stimulation.[15] These characteristics make it particularly useful in the emergency department for short-term procedures, especially if a patient is unprepared for an emergency procedure. Since no guarantee of maintenance of the pharyngeal and laryngeal reflexes is apparent, no assumption of airway protection can exist. Additionally, transient minimal respiratory depression may exist if the medication is administered too rapidly or at too high a dose. Therefore, the clinician should be ready to perform emergency intubation.

Pharmacokinetics

Absorption: Ketamine administered IV exhibits a rapid onset of action, achieving peak plasma concentrations quickly. The IM route of administration provides a high bioavailability of 93% and results in peak plasma levels within 5 to 30 minutes. However, oral ketamine has a significantly lower bioavailability of around 16% to 29% due to extensive first-pass hepatic metabolism. In contrast, intranasal and intrarectal administration of ketamine has demonstrated better bioavailability at 45% to 50% and 25% to 30%, respectively.[16]

Metabolism: Ketamine is primarily metabolized by the enzymes CYP3A4 and, secondarily, the enzymes CYP2B6 and CYP2C9.[17][18] It undergoes N-dealkylation, hydroxylation, conjugation, and dehydration.

Distribution: Ketamine quickly enters the brain. It has a plasma protein binding from 10% to 50%. The steady-state volume of distribution is 3 to 5 L/kg.

Elimination: Following IV administration, ketamine redistributes from the CNS to peripheral tissues. Its elimination half-life is typically 2 to 4 hours. After administration, most ketamine and metabolites are excreted through urine, with 91% of administered radioactivity appearing over 5 days. Only about 20% occur as the parent drug or major metabolites. Additionally, hydroxylated metabolites of ketamine and nor-ketamine are eliminated in urine and bile.[19]

Administration

Available Dosage Forms and Strengths

Ketamine is usually administered either IV or IM. The available strengths include 200 mg/20 mL (10 mg/mL), 500 mg/5 mL (100 mg/mL), and 500 mg/10 mL (50 mg/mL). It is essential to dilute ketamine with an equal volume of normal saline, sterile water, or 5% dextrose. 

Adult Dosage

Dosing varies according to the desired effect, the patient's age, and underlying conditions. When using larger total doses of ketamine, administering it more rapidly than normal, or using ketamine with sedatives, barbiturates, or narcotics, exaggerated responses may occur, and prolonged recovery times should be expected.[20][21] The recommended initial IV dosage of ketamine falls within the range of 1 to 4.5 mg/kg (0.5 to 2 mg/lb) administered over 60 seconds for individuals aged 16 years and above. An average dose of 2 mg/kg (1 mg/lb) is typically needed to induce around 5 to 10 minutes of anesthesia or dissociative effects. The onset of action occurs within approximately 10 to 30 seconds, while the duration of action lasts about 5 to 15 minutes.

Additional doses can be administered IV or IM to maintain anesthesia without producing cumulative effects for more prolonged anesthesia. Either one-half or additional doses may be repeated as needed. Dosing adjustments will be required if used in combination with other drugs, such as IV benzodiazepines or narcotics. When using diazepam in adults, maintenance should be via slow infusion at 0.1 to 0.5 mg/minute of ketamine. Additional doses of diazepam in the amount of 2 to 5 mg are an option. Tonic-clonic movements may present during the emergence of ketamine. These movements do not indicate additional doses of the anesthetic are required.[22] 

An alternative induction dose in adults is 1 to 2 mg/kg IV at a 0.5 mg/kg/min rate. 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 10 mg/kg (5 mg/lb) dose usually produces 12 to 30 minutes of surgical anesthesia with an onset of action in 3 to 5 minutes. Sub-dissociative dosing (low-dose ketamine) is administered at 0.1 to 0.4 mg/kg IV.[23]

Specific Patient Populations

Hepatic impairment: No dosage adjustments are provided in the FDA recommendations; use caution.

Renal impairment: No dosage adjustments are provided in the FDA recommendations; use caution.

Pregnancy considerations: The FDA does not recommend ketamine use during pregnancy due to a lack of established safety. Animal data show that ketorolac may cause harm to the fetus; avoid use during pregnancy, labor, and delivery. The American College of Obstetricians and Gynecologists (ACOG) states that general anesthesia is rarely used during vaginal or cesarean delivery in current obstetrics except in emergencies or when neuraxial anesthesia is not feasible. However, ketamine or propofol can be used as an inducing agent when required.[24]

Breastfeeding considerations: Use is not recommended according to the FDA. However, limited clinical data suggest that ketamine and its metabolites are present in low concentrations in breast milk, and its low oral bioavailability implies a minimal risk to infants. The use of ketamine in nursing mothers does not affect lactation. Ketamine should be used with clinical monitoring of the infant.[25]

Pediatric patients: Children metabolize the ketamine more rapidly than adults and may require higher or additional dosing. 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 minutes to 4 minutes following injection.

Older patients: Older patients metabolize ketamine slowly and may need lower dosing. A recent randomized controlled trial demonstrated promising results of ketamine for treatment-resistant depression.[26]

Adverse Effects

The most common adverse drug reactions associated with ketamine are nausea, vomiting, dizziness, diplopia, drowsiness, dysphoria, and confusion. Reports of the emergence phenomenon exist for approximately 6% to 12% of patients. The common adverse drug reactions of ketamine are listed below.

• Allergic: anaphylaxis and angioedema.[27][28]

• Cardiovascular: Transient increases in blood pressure, bradycardia, left ventricular dysfunction in patients with heart failure, respiratory and cardiac arrest, and arrhythmias.[29][30]

• Gastrointestinal: Anorexia, nausea, and vomiting.

• Muscular: Muscle stiffness and spasms or tonic-clonic movements resembling seizures, and enhanced skeletal muscle tone

• Ophthalmologic: Diplopia, nystagmus, and increased intraocular pressure.[31]

• Psychiatric: Amnesia, anxiety, confusion, depression, disorientation, dysphoria, dissociative state, hallucinations, flashbacks, unusual thoughts, extreme fear, excitement, irrational behavior, and insomnia. 

• Respiratory: Apnea, increased laryngeal and tracheal secretions, laryngospasm, airway obstruction in infants (may not be drug-related), and respiratory depression.

• Skin: Injection site reactions (infrequent), local pain, erythema, and morbilliform rash.[32]

• Neurologic: Confusion, emergence, delirium, seizures, and hallucinations.[33]

Drug-Drug Interactions

• Central nervous system (CNS) depressants: Coadministration of ketamine with opioid analgesics, benzodiazepines, or CNS depressants, including alcohol, may induce profound sedation, respiratory depression, coma, and potentially fatal outcomes. Careful monitoring of neurological status and respiratory parameters, such as respiratory rate and pulse oximetry, is essential when combining ketamine with these agents. Consider personalized dose adjustments based on the patient's clinical condition.[34]

• Sympathomimetic medications: Vasopressin and sympathomimetic medications may increase ketamine's sympathomimetic effects. Simultaneous use of MAO inhibitors with ketamine is contraindicated.[35] Monitoring of vital signs is recommended when administering ketamine with sympathomimetics or vasopressin, with dose adjustments tailored to the patient's individual clinical needs.

• Theophylline: Concurrent use of ketamine with theophylline or aminophylline could potentially reduce the seizure threshold. Alternative medications should be considered for patients prescribed theophylline or aminophylline with ketamine.[36]

Contraindications

Ketamine is contraindicated in patients with 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; anaphylaxis and angioedema have been reported.[27][28]

Warning and Precautions

Pregnancy and lactation: Ketamine is not recommended for use during obstetrics, pregnancy, or breastfeeding, according to the FDA.

Schizophrenia: Use should be avoided in patients with schizophrenia due to the potential for exacerbating the underlying condition.[37]

Hemodynamic instability: Increased blood pressure, heart rate, and cardiac index have been observed. Hypotension and bradycardia, arrhythmias, and cardiac decompensation have also been observed. During the administration of ketamine, it is important to monitor the patient's vital signs and cardiac function closely. Ketamine is contraindicated in patients at risk of significant hypertension.[38]

Intracranial hypertension: Ketamine can increase cerebrospinal fluid pressure. In patients with cerebrospinal fluid (CSF) elevations, the use of ketamine is controversial due to questionable elevations of intracranial pressure 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. New research suggests ketamine may improve cerebral perfusion pressure and have neuroprotective properties.[39][40]

Pediatric neurotoxicity: Extended use of ketamine for over 3 hours in children ≤3 years can lead to pediatric neurotoxicity, resulting in cognitive deficits. One of the possible mechanisms is neuronal apoptosis by the blockade of NMDA receptors.[41][42]

Emergence delirium: Emergence delirium may be reduced by decreasing the recommended dose of ketamine, using it in conjunction with benzodiazepines, and reducing verbal and tactile stimulation during the drug administration. If "emergence" occurs, a small hypnotic dose of a short-acting barbiturate or benzodiazepine is recommended to terminate the reaction.[43] Diazepam, 2 to 5 mg IV push given over 1 minute (15 mg or less in most cases), can reduce emergence phenomena. In a randomized controlled study of adult emergency department patients, Sener et al found a significant reduction in the incidence of agitation when coadministering midazolam with ketamine for procedural sedation.[44]

Hepatotoxicity: The FDA has recently issued a warning regarding drug-induced liver injury associated with ketamine. Chronic ketamine administration is associated with hepatoxicity (cholestatic pattern). Biliary duct dilatation with or without biliary obstruction has also been reported with recurrent use (eg, misuse or supervised unapproved indications). Clinicians should obtain baseline liver function tests, such as alkaline phosphatase and gamma-glutamyl transferase, and monitor liver function tests at periodic intervals.[45]

Monitoring

The following vital signs should be monitored: blood pressure, pulse, breathing, and oxygen saturation. Clinicians should be prepared for intubation. Neuropsychiatric function requires monitoring, and a patient must be at baseline before discharge from care. After a patient's return to baseline, another responsible adult should supervise the patient's discharge. Patients should not drive, use heavy machinery, or perform potentially hazardous activities for up to 24 hours following ketamine administration.

Ketamine is a DEA Schedule III controlled substance.[46] Clinicians need to be vigilant for physical and psychological dependence and addiction when ketamine is used recreationally. Drug dependence and tolerance to ketamine may develop after prolonged use. Withdrawal symptoms may also occur if ketamine is stopped suddenly.[47][48]

Toxicity

Ketamine is potentially fatal in alcohol-intoxicated patients. It has been used recreationally as a drug of abuse. The street name for ketamine is "K" or "Special K." Illicit use of ketamine includes snorting or inhalation, and it is ingestable in food or drinks. The recreational use of ketamine can lead to toxicity.[49] Ketamine overdose induces varying dose-dependent symptoms, notably altering consciousness and manifesting as sedation, impaired mental status, mydriasis, and hemodynamic compromise. Accidental ingestion up to 10 times higher than the standard induction dose of ketamine has been reported. Overdose of ketamine did not result in systemic effects such as hemodynamic or central nervous system perturbations, except for prolonged awakening.[50]

No antidote for ketamine is recognized. Treatment primarily involves supportive care and maintaining the airway, breathing, and circulation. Gastrointestinal decontamination with activated charcoal may be considered, while medications such as benzodiazepines, alpha-2 agonists, and anticholinergics assist in symptom management. Hydration with crystalloids can aid in managing hyperthermia and dehydration. Observation periods and continuous monitoring of post-symptom resolution are vital components of treatment. Ketamine misuse in recreational settings, with multiple substances, is a significant health concern. A study has revealed that ketamine, when combined with other drugs, is a significant contributor to overdoses and fatalities. Specifically, ketamine was found to be involved in 79% of overdose cases and 89.1% of deaths related to co-ingestants. This suggests a strong correlation between ketamine use and adverse outcomes when combined with other substances.[51]

Enhancing Healthcare Team Outcomes

Ketamine's primary use is by anesthesiologists, certified registered nurse anesthetists, dentists, emergency physicians, pain specialists, psychiatrists, and paramedics; these disciplines need to function as an interprofessional team to optimize the drug's effectiveness while minimizing the potential for adverse events. All clinicians who administer ketamine should understand the indications and contraindications.

Nurses and pharmacists can play a crucial role during ordering and administration, guarding against improper dosing and checking for adverse events and drug interactions. [52] Resuscitative equipment is imperative if intubation is required. Before discharge, the clinical team must record the patient's vitals. Important discharge education includes informing patients not to drive, use heavy machinery, or perform potentially hazardous activities for 24 hours after the administration of ketamine. Critical care supervision is necessary for patients under mechanical ventilation. An interprofessional team approach is necessary to improve patient outcomes related to ketamine and minimize adverse drug reactions.

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Disclosure: Steven Rosenbaum declares no relevant financial relationships with ineligible companies.

Disclosure: Vikas Gupta declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Jorge Palacios declares no relevant financial relationships with ineligible companies.