Ketamine poisoning

INTRODUCTION — Ketamine was synthesized in 1962 by Parke-Davis and first used in humans in 1965 [1,2]. The United States military used ketamine as a field anesthetic during the Vietnam War, and it gradually gained popularity as an induction and maintenance agent for procedural sedation and general anesthesia. In addition to its misuse as a recreational drug, ketamine is used clinically for treatment of psychomotor agitation in the prehospital and emergency settings [3], depression and mood disorders [4], chronic migraine headache [5], status epilepticus [6], and pain [7].

This topic will review the presentation and treatment of ketamine intoxication as well as poisoning with ketamine analogues and novel psychoactive substances, including deschloroketamine, 2-fluoro-deschlorketamine, methoxketamine, methoxetamine, 2-oxo-PCE, tiletamine, and similar agents. A summary table to facilitate emergency management is provided (table 1).

Discussions of the use of ketamine for procedural sedation and induction for rapid sequence intubation (RSI) are found separately. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Ketamine' and "Pediatric procedural sedation: Pharmacologic agents", section on 'Ketamine' and "Procedural sedation in adults in the emergency department: Medication selection, dosing, and discharge criteria", section on 'Ketamine sedation'.)

EPIDEMIOLOGY — By the 1970s, ketamine had become a widely used recreational drug, with street names such as K, Special K, KitKat, Vitamin K, ket, and Super K. Ketamine abuse is closely associated worldwide with the use of other "club drugs" including "Molly" or "ecstasy" (3,4-methylenedioxymethamphetamine or MDMA), gamma hydroxybutyrate (GHB), and methamphetamine, often in the setting of large dance parties [8]. A large retrospective review of ketamine exposures reported to United States poison centers over a 16-year period noted that 49 percent of exposures were in patients 16 to 25 years of age, 49 percent were polypharmacy exposures, and 51 percent were ketamine-only exposures [9]. In this study, two deaths occurred in patients with ketamine-only exposures. (See "MDMA (ecstasy) intoxication" and "Gamma hydroxybutyrate (GHB) intoxication" and "Methamphetamine: Acute intoxication".)

PATHOPHYSIOLOGY — Ketamine is an arylcycloalkylamine that is structurally related to phencyclidine (PCP). Ketamine is a dissociative anesthetic and hallucinogen. It acts primarily as an antagonist of the N-methyl-D-aspartate (NMDA) receptor but also possesses some opioid receptor activity and sympathomimetic properties. The latter results in enhanced central and peripheral monoaminergic transmission and inhibition of central and peripheral cholinergic transmission [10]. The primary site of ketamine's central nervous system activity appears to be the thalamocortical projection system, where it causes depression of certain cortical and thalamic functions and stimulation of parts of the limbic system [11].

KINETICS AND METABOLISM — Two phases of ketamine distribution can be distinguished following intravenous (IV) administration. The first phase corresponds to the anesthetic effect of the drug and is characterized by rapid distribution (half-life of 10 to 16 minutes) and a large volume of distribution due to the drug's high lipid solubility. The second phase represents redistribution from the central nervous system to peripheral tissues, with an elimination half-life of two to three hours.

Ketamine undergoes significant first-pass metabolism. The drug is metabolized by hepatic enzymes through demethylation, hydroxylation, and glucuronidation, and then excreted in the urine [12].

DOSES AND FORMULATIONS — Common therapeutic dosages of ketamine are 3 to 8 mg/kg for intramuscular (IM) use and 0.5 to 4.5 mg/kg for intravenous (IV) use depending upon the procedure and the patient's age [2]. The usual induction dose is 1 to 2 mg/kg. Recreational doses typically range from 75 to 125 mg via the IM or subcutaneous route, 60 to 250 mg intranasally, 50 to 100 mg IV, and 200 to 300 mg orally [13].

Ketamine synthesis is a complex, multistep process that precludes easy, small-scale, clandestine drug production. However, illicit production does still occur. Sources of ketamine sold illicitly include diversion of legitimate veterinary and medical supplies as well as illicit manufacture.

The number of medications and designer drugs that are analogs of ketamine has increased and includes esketamine (approved by the US Food and Drug Administration [FDA] for treatment of depression) as well as deschloroketamine, 2-fluoro-2-deschlorketamine, methoxetamine, methoxyketamine, 2-oxo-PCE, and tiletamine. There is limited clinical experience with the toxicity of these analogs, but a spectrum of poisoning that includes fatality has been reported [14-18]. The increasing frequency of identification of novel ketamine analogs suggests increasing use and possibly an increase in the frequency of poisonings from these substances in the near future. In the absence of more definitive data, we suggest that clinicians manage poisoning from designer drug analogs of ketamine in a manner similar to that described below for ketamine poisoning. (See 'Management' below.)

CLINICAL PRESENTATION

Vital signs — At low or therapeutic doses (less than 5 mg/kg), ketamine may cause slight elevations in heart rate and blood pressure. Higher doses (over 5 mg/kg) have inconsistent cardiovascular effects and may result in hypertension, hypotension, tachycardia, or bradycardia [19]. Massive overdose or use with other sedatives may result in respiratory depression or apnea [20]. One case of malignant hyperthermia has been reported [21].

Central nervous system effects — Ketamine is capable of causing a spectrum of central nervous system effects, ranging from mild agitation to coma, depending on the dose and patient susceptibility. Agitation and other psychiatric disturbances caused by ketamine are much less common and less severe than those caused by phencyclidine (PCP).

The desired clinical effect of iatrogenic ketamine administration varies depending upon the clinical goal. Historically, ketamine has been used most often for sedation or anesthesia. This results from dissociation, or interruption of the patient's sensory perception. The inability to sense pain makes ketamine an effective anesthetic. Reflexes, including those involved in airway protection, are maintained.

Lower doses, sometimes referred to as subdissociative doses, have been used to treat pain and acute depression [22]. Subdissociative doses of ketamine result in altered perception but allow patients to maintain full or nearly full alertness.

In overdose, ketamine, like PCP, is capable of inducing coma and deep anesthesia. In smaller doses (ie, those preferred by most abusers), ketamine slightly alters sensory perception and acts as a hallucinogen. Effects include slight depression of mental status, diminished alertness, ataxia, and nystagmus. In abuse and with emergence reactions, patients may also experience extreme agitation, fear, and psychiatric disturbance [23-25]. The typical presentation of recreational ketamine users who present for medical evaluation is impaired consciousness [19].

Emergence reactions occur as the effects of therapeutic doses of ketamine dissipate following sedation. The phenomenon may involve vivid dreams, "out-of-body" experiences, and illusions. Reactions can be associated with excitement, confusion, euphoria, or fear. The incidence of emergence reactions may be lower than previously thought [26].

The following manifestations may also be seen with ketamine intoxication:

●Amnesia (not as prominent as with benzodiazepines)

●Ataxia

●Moderate dilatation of pupils

●Increased muscle tone

●Absence-like effect (patient appears awake but is unresponsive)

Respiratory and airway effects — Ketamine is a preferred anesthetic because, in therapeutic doses, it does not cause cardiopulmonary depression [27]. In massive doses or in combination with other sedative agents, however, respiratory depression and apnea can occur [28-30]. Independent idiosyncratic effects seen after iatrogenic administration include laryngospasm, hypersalivation, and bronchorrhea [20,31-33]. The cause of these phenomena is unclear.

Cardiovascular effects — In therapeutic doses, ketamine can exert a mild sympathomimetic effect on the cardiovascular system with slight increases in blood pressure and heart rate [34]. Hypotension and bradycardia have been reported but are rare. Ketamine increases myocardial oxygen demand and may increase the risk of acute coronary syndrome, particularly in patients with additional risk factors for cardiovascular disease.

Ocular effects — While less common with ketamine than phencyclidine (PCP) intoxication, nystagmus may be seen and may be rotatory, vertical, or horizontal [34].

Other effects from subacute and chronic exposure — Chronic ketamine abuse may lead to neuropsychiatric impairment, urologic injury, referred to as ketamine-induced ulcerative cystitis or ketamine-induced uropathy, or hepatic injury. The mechanism of ketamine-associated uropathy and hepatic injury remains unclear.

Urologic injury — First reported in 2007, ketamine-induced urologic injury is presumed to result from irritation of the urologic system and may include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, hematuria, and rarely hydronephrosis or papillary necrosis [35-37]. Ketamine-induced uropathy is being diagnosed and reported with increasing frequency, though it is unclear if this is due to an increase in incidence or clinician awareness. Ketamine-induced uropathy appears to be a permanent injury, though patients may have symptomatic improvement through medical or surgical treatment. In 2016 and 2018, studies of ketamine abusers in Malaysia and China using data compiled from questionnaires reported a high prevalence of erectile dysfunction, with long-term users more likely to experience the problem [38,39]. Renal injury, including hydronephrosis as well as renal failure and end-stage renal disease, has also been noted in chronic ketamine abusers [40,41]. Notably, worse outcomes were noted in patients with concomitant markers of hepatic injury including elevated gamma-glutamyl transpeptidase, AST, and ALT.

Hepatobiliary injury — Sclerosing cholangitis and hepatic injuries have been reported in patients who received a ketamine infusion to maintain sedation during mechanical ventilation. In the wake of the coronavirus disease 2019 (COVID-19) pandemic, numerous case reports and series have documented sclerosing cholangitis, jaundice, decompensated cirrhosis, and hepatic failure (sometimes fatal) in patients who received prolonged ketamine infusions [42]. Cholangiopathy and sclerosing cholangitis in association with ketamine infusion was previously noted in a large French case series of 293 patients who received ketamine infusion during management in a burn center [43]. The risk of sclerosing cholangitis and hepatic injury appears to be dose related, as lesser doses appear to result in this complication less frequently. Chronic abuse of ketamine has previously been described as a risk factor for sclerosing cholangitis. .  

Adverse effects following therapeutic adminstration — When administered correctly, ketamine is generally safe. Nevertheless, respiratory depression, apnea, hypotension, bradycardia, myocardial infarction, and death have all been reported after ketamine overdose or overly rapid infusion.

The most common adverse events after iatrogenic administration include:

●Vomiting

●Psychiatric disturbance/emergence phenomenon

●Respiratory depression

●Laryngospasm

●Salivation

These effects occur after intravenous (IV) use. Since most recreational users insufflate (ie, "snort") ketamine, the complications listed are rarely observed outside of the hospital.

Adverse effects after illicit use — Ketamine abusers are typically adolescents or young adults. However, according to one case series, the age of abusers ranges from 13 to 60 years [19]. Overwhelmingly, impaired consciousness is the presenting complaint. Patients may have white powder in or on their nose at time of presentation. Symptoms from ketamine abuse appear to resolve quickly in most instances. In another small case series, half of patients who abused ketamine were asymptomatic by the time a clinician evaluated them in the emergency department, while half complained of anxiety, chest pain, or palpitations [34]. Hallucinations usually resolved prior to evaluation. Tachycardia was the most common physical finding; hypertension was also noted.

Ketamine is frequently abused in combination with other illicit drugs, such as amphetamines, MDMA, and cocaine [44,45]. Toxicity from these other agents is common. In New York City between 1997 and 2000, 12 deaths occurred in people abusing ketamine, but in all cases, multiple drugs were involved. Death following IV injection of ketamine alone has been reported, but such events are likely rare [9,27]. Animal data suggest that combined use of caffeine and ketamine exacerbates toxicity [46]. This may be important in some cases, as use of caffeinated energy drinks is common in the settings where ketamine is often used recreationally.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for ketamine toxicity varies with the major presenting symptoms. (See "General approach to drug poisoning in adults".)

Coma can be caused by many toxins, including opioids, alcohols, and sedative hypnotic agents. The clinician must also consider neurologic injury, hypoglycemia, and hypoxia in any comatose patient (table 2 and table 3). (See "Stupor and coma in adults".)

The differential diagnosis for psychomotor agitation or hallucinosis includes intoxication with drugs such as phencyclidine (PCP), lysergic acid diethylamide (LSD), cocaine, amphetamines, and a variety of novel psychoactive substances. Withdrawal from ethanol or sedative hypnotic agents may also cause such symptoms. Psychiatric and other medical causes are far more common etiologies of psychomotor agitation than is ketamine toxicity. (See "Management of moderate and severe alcohol withdrawal syndromes".)

Focal neurologic findings, such as nystagmus and ataxia, can be caused by intoxication with such drugs as PCP, dextromethorphan, and anticonvulsants such as phenytoin and carbamazepine, and by injury to the central nervous system. (See "Overview of nystagmus".)

DIAGNOSIS — Diagnosis of ketamine intoxication is based on history and clinical evidence; no definitive laboratory test is routinely available. Although ketamine and phencyclidine are structurally similar, there is no reliable cross-reactivity between ketamine metabolites and available phencyclidine (PCP) detection assays.

LABORATORY EVALUATION — Routine laboratory evaluation of the poisoned patient should include the following:

●Fingerstick glucose to detect hypoglycemia as the cause of any alteration in mental status

●Acetaminophen and salicylate levels to rule out these common coingestions

●Electrocardiogram (ECG) to rule out conduction system poisoning by drugs that effect the QRS or QTc intervals

●Pregnancy test in women of childbearing age

Clinicians should obtain additional tests based on clinical findings. In patients experiencing chest pain, cardiac enzymes may be indicated. Muscle rigidity and severe agitation from ketamine overdose can cause rhabdomyolysis. If this is a concern, serum creatine kinase and urine myoglobin should be obtained.

MANAGEMENT — The management of problems commonly encountered with ketamine intoxication is described below. A summary table to facilitate emergency management is provided (table 1). A general approach to the poisoned patient is found elsewhere. (See "General approach to drug poisoning in adults".)

Airway and breathing support

Laryngospasm — Ketamine-induced laryngospasm is rare and most frequently occurs in infants [31]. It is typically self-limited, usually lasting less than one minute. Respiratory support should include administration of supplemental oxygen and positive-pressure ventilation by bag-valve mask. In circumstances when laryngospasm does not resolve with basic airway support, endotracheal intubation may be needed.

The management of laryngospasm in children, including laryngospasm notch pressure, is discussed separately. (See "Complications of pediatric airway management for anesthesia", section on 'Management of laryngospasm'.)

Pediatric airway management is otherwise reviewed in detail separately. (See "Basic airway management in children" and "Technique of emergency endotracheal intubation in children" and "Supraglottic airway devices in children with difficult airways".)

Respiratory depression — Hypoxia during administration of ketamine for procedural sedation most frequently occurs from positional airway compromise; respiratory depression or apnea is much less common. Clinicians should provide supplemental oxygen and ensure airway patency with basic maneuvers such as head-tilt chin-lift or jaw-thrust. For apnea or respiratory insufficiency, clinicians should provide assisted ventilation using a bag-valve mask. Rarely, endotracheal intubation may be needed, if apnea persists. (See "Basic airway management in adults" and "Technique of emergency endotracheal intubation in children".)

Excessive salivation — Extreme sialorrhea is a known complication of ketamine administration. Suction and proper positioning should be performed to prevent aspiration. Pharmacologic treatment is needed if respiratory compromise develops, continual suctioning is necessary, or excessive saliva interferes with a necessary procedure (eg, laceration repair). Such treatment involves use of an anticholinergic agent, usually glycopyrrolate (5 mcg/kg IV, may be repeated once every two to three minutes; maximum single dose is 0.2 mg; maximum total dose is 0.8 mg) or atropine (0.01 to 0.02 mg/kg IV; minimum dose 0.1 mg; maximum dose 1.2 mg). Glycopyrrolate may be more effective at reducing secretions than atropine, although this has not been well studied, and it is less likely to produce cardiac and central nervous system effects.

When providing procedural sedation, some clinicians coadminister atropine with ketamine to prevent salivation, but there is little evidence to support this practice. Coadministration is not a necessity, but atropine or glycopyrrolate should be readily available when ketamine is administered [47,48]. (See "Procedural sedation in children: Approach".)

Cardiovascular support — Significant cardiovascular complications are uncommon and may be managed using standard treatments. After securing the airway and breathing if necessary, clinicians should treat bradycardia with atropine (0.01 to 0.02 mg/kg intravenously [IV]; minimum dose 0.1 mg IV; may be repeated every five minutes to a maximum total dose of 3 mg). Tachycardia from psychomotor agitation is treated with benzodiazepines. (See "Advanced cardiac life support (ACLS) in adults", section on 'Bradycardia' and 'Psychomotor agitation, muscle rigidity, hallucination' below.)

Treatment of hypotension begins with IV boluses of crystalloid. Hypotension requiring treatment with vasopressors is uncommon, but sympathomimetic agents such as norepinephrine and dopamine may be used.

Supportive care — Once airway, breathing, and circulation are secured as necessary, supportive care is typically the only treatment needed for ketamine toxicity. The adverse effects of ketamine typically last between 15 minutes and several hours; prolonged care is rarely needed.

Psychomotor agitation, muscle rigidity, hallucination — Psychiatric disturbance from ketamine toxicity is generally short lived. Minimizing stimuli, such as light and noise, is helpful. When restraint is needed, physical restraints should only be used until adequate chemical sedation is provided. Benzodiazepines are the mainstay of such treatment. They are helpful in managing fear, panic, hallucinations, and emergence reactions. Lorazepam may be used in 1 to 2 mg IV doses until the desired level of sedation is achieved. Alternatively, diazepam in 5 to 10 mg IV doses may be used.

Muscle rigidity can occur with IV ketamine use but is generally without consequence. Lorazepam may be given in the doses above for muscle relaxation if needed.

Butyrophenones (such as haloperidol and droperidol) and other antipsychotic agents should not be used to treat agitation [49]. They interfere with heat dissipation, may prolong the QTc interval, and may reduce the seizure threshold.

Gastrointestinal decontamination — Gastrointestinal (GI) decontamination is almost never indicated. When used illicitly, ketamine is usually snorted, and occasionally injected IV or intramuscularly (IM). Toxicity from these routes of administration would not be affected by GI decontamination.

Enhanced elimination — No enhanced elimination technique is available for ketamine overdose. A risky and outmoded method of enhanced elimination of phencyclidine (PCP), urine acidification, has never been tested in ketamine and should not be used.

PEDIATRIC CONSIDERATIONS — Ketamine-induced laryngospasm occurs more commonly in infants or young children than adults. Management is discussed above (see 'Laryngospasm' above). Child protective services should be consulted for children too young to have abused ketamine intentionally.

DISPOSITION — In extraordinarily rare instances of end-organ toxicity, such as myocardial infarction, patients require admission to an intensive care unit. In most cases, patients may be discharged after symptoms have resolved, usually within six hours. No specific follow-up is needed for most of the adverse events previously mentioned. Drug abusers should be referred for drug counseling and rehabilitation.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS

●Emergency management of severe complications – A summary table to facilitate emergency management of severe complications from ketamine poisoning is provided (table 1).

●Clinical presentation after recreational use – Ketamine is a dissociative anesthetic and hallucinogen. Patients who use ketamine illicitly usually insufflate ("snort") or ingest the drug. They often have no medical complaints. Some describe anxiety, chest pain, palpitations, or hallucinations. Tachycardia is a common physical finding. Massive overdose or use with other sedatives may result in respiratory depression or apnea. Ketamine is capable of causing a spectrum of central nervous system effects, ranging from mild agitation to coma, depending upon the dose and patient susceptibility. It is frequently abused in combination with other illicit drugs, such as amphetamine, MDMA, and cocaine. (See 'Clinical presentation' above.)

●Possible iatrogenic effects from medical use – When administered correctly for medical treatment, ketamine is generally safe. Nevertheless, patients given ketamine intravenously (IV) can develop problems, including:

•Psychiatric disturbance/emergence phenomenon

•Respiratory depression

•Laryngospasm

•Salivation

Respiratory depression, apnea, hypotension, bradycardia, myocardial infarction, and death are rare but have been reported after iatrogenic overdose or overly rapid infusion of ketamine. (See 'Clinical presentation' above.)

●Diagnosis and diagnostic testing – Diagnosis of ketamine intoxication is based on history and clinical evidence; no definitive laboratory test is readily available. Tests obtained as part of the evaluation of a patient with suspected ketamine poisoning are determined based on clinical circumstances described. (See 'Diagnosis' above and 'Laboratory evaluation' above.)

●Laryngospasm and respiratory depression – Ketamine-induced laryngospasm is rare but most frequently occurs in infants. It is typically self-limited, lasting less than one minute. Assisted ventilation using a bag-valve mask should be provided. Should laryngospasm not resolve with basic airway support, endotracheal intubation may be needed. Hypoxia during procedural sedation with ketamine is caused most often by positional airway compromise, but true respiratory depression or apnea may occur, requiring airway intervention. A summary table to facilitate emergency management of ketamine poisoning is provided (table 1). (See 'Airway and breathing support' above.)

●Excessive salivation – Ketamine can cause extreme salivation (sialorrhea). Suction and positioning should be performed to prevent aspiration. We suggest pharmacologic treatment for sialorrhea if respiratory compromise develops, continual suctioning is necessary, or excessive saliva interferes with a necessary procedure (eg, laceration repair) (Grade 2C). Either glycopyrrolate (5 mcg/kg IV, may be repeated once every two to three minutes; maximum single dose is 0.2 mg; maximum total dose is 0.8 mg) or atropine (0.01 to 0.02 mg/kg IV; minimum dose 0.1 mg; maximum dose 1.2 mg) can be administered. (See 'Excessive salivation' above.)

●Cardiovascular complications not common – Significant cardiovascular complications are uncommon and are managed using standard treatments. (See 'Cardiovascular support' above.)

●Agitation – Psychomotor agitation can occur with overdose. When necessary, we suggest treatment with benzodiazepines (Grade 2C). In adults, lorazepam may be used in 1 to 2 mg IV doses until the desired level of sedation is achieved. Butyrophenones (such as haloperidol and droperidol) interfere with heat dissipation, may prolong the QTc, and may reduce the seizure threshold. We suggest that butyrophenones not be used to sedate patients with ketamine toxicity (Grade 2C). (See 'Psychomotor agitation, muscle rigidity, hallucination' above.)

●Disposition – In most cases, ketamine intoxication produces no significant adverse effects, and patients may be discharged after a period of asymptomatic observation, usually within six hours. (See 'Disposition' above.)