Continuing Education Activity

Ketamine is a structural analog of the dissociative anesthetic and recreational drug phencyclidine (PCP). Similar to phencyclidine, ketamine causes analgesia and amnesia without the cardiovascular and respiratory depression associated with common anesthetics. Originally called CI-581, ketamine has one-tenth the potency of PCP and causes less severe dysphoria and hallucinations. Intramuscular and intravenous forms of ketamine are commonly used to provide pediatric anesthesia, especially for high-risk children or patients in limited-resource settings. In surgical settings, ketamine is typically combined with benzodiazepines, which can reduce the adverse psychological symptoms that occur during emergence. Off-label, subanesthetic doses of ketamine also have a use for acute and chronic pain management, sedation, and treatment of severe depression. Like its chemical cousin phencyclidine, ketamine’s psychomimetic effects have made it a popular recreational drug. In low doses, its euphoric and dissociative effects are sometimes referred to as “k-land,” whereas at high doses, the immobilizing and hallucinogenic effects are referred to as being in a “k-hole.” In the context of an illegal, recreational drug, ketamine goes by the street names “K,” “vitamin K,” “super K,” “special K,” “super C,” “special LA coke,” “jet,” “superacid,” and “green.” Ketamine toxicity can cause a variety of neurological, cardiovascular, psychiatric, urogenital, and abdominal symptoms, which are dose-dependent, and whether ketamine administration was in an iatrogenic or illicit context. For example, some experts have attributed the higher incidence of ulcerative cystitis in recreational users to the adulterants with which the drug is mixed. Providers using ketamine should be aware of the various mechanisms to treat ketamine toxicity and to prevent acute complications such as rhabdomyolysis and seizures, and chronic complications such as psychiatric disturbances and ulcerative cystitis. This activity reviews the evaluation of ketamine toxicity and the role of the interprofessional team in managing this condition.

Objectives:

• Describe the chemical basis of ketamine.
• Discuss the expected side effects of ketamine.
• Explain the symptoms and signs of ketamine toxicity.
• Outline medical team evaluation and management of a patient with ketamine toxicity.

Introduction

Ketamine is a structural analog of the dissociative anesthetic and recreational drug phencyclidine (PCP).[1] Similar to phencyclidine, ketamine causes analgesia and amnesia without the cardiovascular and respiratory depression associated with common anesthetics.[1] Originally called CI-581, ketamine has one-tenth the potency of PCP and causes less severe dysphoria and hallucinations.[1]

After the chemist Calvin Stevens first synthesized ketamine in 1962, ketamine was tested in clinical trials performed in pediatric and adult surgical patients, and the Food and Drug Administration approved it for human use in 1970.[1][2] Ketamine was the most common battlefield anesthetic used during the Vietnam War (fact file on ketamine). Intramuscular and intravenous forms of ketamine are commonly used to provide pediatric anesthesia, especially for high-risk children or patients in limited-resource settings.[3] In surgical settings, ketamine is typically combined with benzodiazepines, which can reduce the adverse psychological symptoms that occur during emergence.[4] Off-label, subanesthetic doses of ketamine also have a use for acute and chronic pain management, sedation, and treatment of severe depression.[5][6][7]

Like its chemical cousin phencyclidine, ketamine’s psychomimetic effects have made it a popular recreational drug. In low doses, it’s euphoric and dissociative effects are sometimes referred to as “k-land,” whereas at high doses, the immobilizing and hallucinogenic effects are referred to as being in a “k-hole.”[1][8] In the context of an illegal, recreational drug, ketamine goes by the street names “K,” “vitamin K,” “super K,” “special K,” “super C,” “special LA coke,” “jet,” “superacid,” and “green.”[8][9]

Ketamine toxicity can cause a variety of neurological, cardiovascular, psychiatric, urogenital, and abdominal symptoms, which are dose-dependent, and depend on whether ketamine administration was in an iatrogenic or illicit context. For example, some experts have attributed the higher incidence of ulcerative cystitis in recreational users to the adulterants with which the drug is mixed. Emergency medicine providers should be aware of the various mechanisms to treat ketamine toxicity and to prevent acute complications such as rhabdomyolysis, seizures, and chronic complications such as psychiatric disturbances and ulcerative cystitis.

Etiology

Ketamine toxicity can result from the medical use of parenteral or intranasal ketamine or the recreational misuse of ketamine, commonly through intravenous or intramuscular injection, insufflation (snorting), oral consumption, or smoking.[8]

Epidemiology

The World Drug Report in 2015 categorized ketamine as a worldwide recreational drug, with 58 countries reporting illicit use. However, ketamine misuse occurs on a relatively small scale, and PCP derivatives constituted only 1% of “new psychoactive substances” reported to the United Nations Office of Drugs and Crime in 2014 (fact file on ketamine). Ketamine misuse often occurs in combination with other substances, including alcohol, amphetamines, MDMA, cocaine, and caffeine.

In the United States, where ketamine classifies as a C-III controlled substance since 1999, ketamine misuse has increased since the 1980s.[9] However, compared to the surges in opioid and illicit cannabis misuse, ketamine misuse has occurred on a relatively small scale. Ketamine was involved in 0.033% of the United States Emergency Department visits involving illicit drugs in 2005, with this proportion increasing slightly to 0.12% in 2011 (Drug Abuse Warning Network, 2011). Ketamine-related emergency department visits often involved other drugs, with 71.5% of ketamine-related visits in the United States in 2011 involving alcohol (Drug Abuse Warning Network, 2011). The national survey-based ‘Monitoring the Future Study’ in the United States reported that ketamine use decreased between 2012 and 2002, from 2.5% to 1.5%, and from 1.3% to 0.4%, among 12th graders and college students, respectively. In the United Kingdom, where ketamine has been classified as a Class C drug since 2006,[9] ketamine misuse has also decreased during the 21st century. According to the World Health Organization fact file on ketamine, the percentage of adults and young adults in the United Kingdom who used ketamine decreased from 0.6% to 0.4% and from 1.8% to 0.8%, respectively, between 2011 and 2013.

Ketamine use is becoming increasingly popular as a recreational drug in Southeast Asian countries such as Taiwan, Malaysia, and China.[9] In Hong Kong, where ketamine classifies as a Schedule I drug since 2000, ketamine became the most commonly misused drug in the early 2000s.[9] Between 1996 and 2000, an epidemiological study involving drug-related motor vehicle collision fatalities found 9% involved ketamine use, representing a disproportionate number of fatalities compared to alcohol and opioid misuse, which are drugs in which tolerance develops more rapidly.[10] Surveys demonstrate that ketamine misuse is more common in southeast China than in other regions of the country.[10]

Pathophysiology

Ketamine's main site action is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, though it exhibits effects on a myriad of other receptors. It acts as an antagonist at muscarinic and nicotinic acetylcholine receptors, blocks sodium and potassium channels, activates high-affinity D2 dopamine receptors and L-type voltage-gated calcium channels, and facilitates gamma-aminobutyric acid (GABA) inhibition. Ketamine may also increase neurotransmitters such as norepinephrine, dopamine, and serotonin in the brain.[11][12] As a drug that stimulates the sympathetic nervous system, tachycardia and hypertension are common with ketamine use, which masks its direct cardiac depressant effects. However, in patients in the intensive care unit who are catecholamine-depleted, the use of ketamine may result in hypotension. Although ketamine binds to mu and other opioid receptors, naloxone does not block its analgesic effects.[13]

Toxicokinetics

To date, there remains sparse information about the toxicokinetics of ketamine in the human population.

In animal studies, however, the safety ratio (defined as the proportion of the usual recreational dose to a fetal or lethal dose) has been used to evaluate the acute risk observed with ketamine.

The definition of the lethal dose (LD50) is the amount of drug that results in death in 50% of experimental animals tested. Gable et al. determined the oral ketamine safety ratio for rodents as 25 and estimated that the median lethal dose averaged at 11.3 mg/kg IV or 678 mg for a 70 kg human.[14][15]

Ketamine has been used to provide analgesia in refractory chronic pain conditions and even anesthesia for short surgeries. However, the safety data is mixed regarding its toxicity when administered neuraxial in animals, with some authors suggesting that its neurotoxicity derives from preservatives. According to the latest Polyanalgesic Consensus Conference for intrathecal drug delivery, the designation for the administration of spinal ketamine was as a 6-line adjuvant used in conjunction with other neuraxial analgesics in individuals with refractory cancer or other terminal chronic pain conditions. There is a current ban on the publication on the study of intrathecal analgesics that lacks adequate safety data in several of the top pain and anesthesia journals.[16]

History and Physical

Ketamine overdose symptoms are similar to those of PCP overdose, although the effects of ketamine tend to resolve more quickly. Physical signs and symptoms are dose-dependent through the loss of consciousness.  Patients may be unable to provide a relevant history, and clinicians should seek pertinent clinical information from witnesses. Clinicians should also maintain familiarity with street names for ketamine.

The following symptoms may be present during ketamine use and intoxication: 

• General – sedation, impaired consciousness
• Head, Ear, Eyes, Nose, Throat – horizontal, vertical or rotary nystagmus, mydriasis, excessive salivation 
• Cardiovascular – hypertension, tachycardia, palpitations, arrhythmias, chest pain 
• Abdominal – abdominal pain, abdominal tenderness, nausea, vomiting 
• Neurological – altered mental status (disorientation), paranoia, dysphoria, anxiety, confusion, slurred speech, dizziness, ataxia, dysarthria, trismus, muscular rigidity, psychomotor, psychomimetic, or acute dystonic reactions
• Genitourinary – lower urinary tract symptoms
• Trauma – a thorough examination for evidence of trauma is needed as injuries secondary to ketamine intoxication can occur due to the diminished perception of pain.

Symptoms mostly unique to overdose, overly rapid infusion, or combined with other drugs include: 

• Respiratory – respiratory depression, apnea
• Cardiovascular – hypotension, bradycardia, myocardial infarction 
• Neurological – seizure, stupor, coma 

Symptoms mostly unique to iatrogenic, intravenous delivery include[17]:

• Respiratory – respiratory depression, laryngospasm

Evaluation

Several laboratory tests could be obtained to evaluate the degree of metabolic or cellular derangements.

• Serum PCP, acetaminophen, salicylate levels, to rule out common co-ingestions
• ECG, to rule out conduction abnormalities and arrhythmias
• Urine myoglobin and serum creatine kinase, to rule out the complication of rhabdomyolysis
• Imaging, to rule out other causes of altered mental status such as hemorrhage or secondary trauma
• CSF, to rule out central nervous system infection such as meningitis as a cause of neuropsychiatric symptoms
• CBC, to evaluate for leukocytosis
• CMP, to evaluate for blood urea nitrogen and creatinine elevation (renal compromise) or elevation in the liver function tests (hepatotoxicity)
• Fingerstick blood glucose, which can suggest hypoglycemia as a primary cause of mental status changes, or hypoglycemia secondary to ketamine toxicity

Treatment / Management

Typically, only supportive care is necessary for patients with ketamine toxicity. The effects of ketamine intoxication typically last between 15 minutes to several hours depending on the dose, route of administration (e.g., oral more than intravenous), metabolic capacity, and intrinsic sensitivity to the effects of the drug, which depends on genetics and several other factors.[18] Patients who are asymptomatic at presentation but report recent ketamine use should undergo observation for six hours. Patients who experience symptom relief after intoxication should have continuous monitoring for 1 to 2 hours after their last symptom resolves.

Monitoring includes the patient’s airway, breathing, and circulation, as ketamine can potentially cause cardiopulmonary compromise, especially when taken in combination with other drugs. If the patient vomits, the patient should be positioned to lean forward or lie on the left side with the head facing down to avoid airway compromise and aspiration. Ketamine has been shown to cause bronchodilation and maintain a protective airway better than other anesthetic agents used for sedation, although there have been reports of aspiration.[19] If airway compromise occurs, intubation can provide respiratory support. The patient’s vital signs, especially temperature, should also be monitored for other symptoms, especially hyperthermia. If the patient develops severe symptoms or complications, the patient should be placed on a monitor and admitted for observation.

If ketamine was ingested, especially in large quantities or with other drugs, activated charcoal could be used for gastrointestinal decontamination. Activated charcoal is typically given in a 1 g/kg dose, with a maximum oral dose of 50 g/ng.[20] Activated charcoal should be avoided in patients with unprotected airways or absent bowel sounds.[20] Activated charcoal administration within a sufficiently brief amount of time may obviate the need for gastric lavage. Hemoperfusion and dialysis tend to be ineffective due to ketamine’s large volume of distribution.

According to the toxicology data network, there are no medications approved by the U.S. Food and Drug Administration to treat a ketamine overdose, but medications can provide management of agitation and psychosis. Benzodiazepines such as lorazepam and diazepam can alleviate agitation, psychomimetic effects, hypertension, hyperthermia, and seizures. Lorazepam is typically given 2 to 4 mg intravenously or intramuscularly, and diazepam dosing generally is 5 mg to 10 mg IV. Butyrophenones, including haloperidol, have been used to treat psychotic episodes and agitation.[8] Haloperidol is typically given in doses of 5 mg to 10 mg IM and can be administered every 10 to 15 minutes until adequate sedation is achieved. However, providers should exercise caution when using haloperidol, as lowered seizure thresholds, QT prolongation, and torsades de pointes correlate with the prolonged use of haloperidol. Unnecessary stimulation should be avoided, and the patient’s room should be dim and quiet. If necessary, the health care team may provide physical restraints to initiate IV access and secure the patient’s safety. If sedation does not adequately manage hyperthermia, evaporative cooling can decrease heat production.

Other medications can manage other symptoms. Alpha-2 agonists such as clonidine can treat or prevent ketamine’s psychomimetic side effects, increase hemodynamic stability by decreasing blood pressure, and provide synergism with ketamine’s analgesic effects.[6][21][22] Clonidine is typically given at 2.5-5 mcg/kg in oral form, though patches are an option for long-duration inpatient infusions, and intravenous clonidine can be used to address acute symptoms. Atropine or glycopyrrolate can prevent and treat the excess salivation associated with ketamine use, while physostigmine can address nystagmus and blurred vision. Hydration with crystalloids can improve dehydration.

Differential Diagnosis

Ketamine intoxication can present similarly to PCP, methoxetamine, and dextromethorphan intoxication, all of which bind to the N-methyl-D-aspartate receptor. Also, providers should consider intoxication with alcohol, amphetamine, cocaine, LSD, MDMA, and salicylate, as well as delirium tremens from alcohol withdrawal. Malignant hyperthermia that develops after succinylcholine or volatile anesthetics such as halothane, and side effects from antihistamines like diphenhydramine and anticholinergics such as benztropine, can also mimic signs of ketamine intoxication.

Psychiatric conditions such as bipolar disorder and schizophrenia and complications from psychiatric treatments such as serotonin syndrome from SSRIs, neuroleptic malignant syndrome from antipsychotics, and side effects from tricyclic and tetracyclic antidepressants, can present similarly to ketamine intoxication.

Especially in the presence of altered mental status, CNS infections such as meningitis and encephalitis, and CNS malignancies also merit consideration. Acute conditions affecting the central nervous system, such as head trauma and intracerebral hemorrhage, can cause mental status and vital sign changes that simulate ketamine toxicity. Acute systemic conditions such as hypoxia, hypoglycemia, sepsis, hyperthyroidism, and electrolyte abnormalities such as hyponatremia should be differentials.

Prognosis

Because ketamine overdose is a relatively uncommon condition and co-ingestions often complicate severe cases, limited information is available with regards to survival rates. Cases of addiction to ketamine are relatively infrequent, and there are scant statistics on relapse rates and prognosis. Nonetheless, ketamine remains one of the few psychoactive drugs with serious complication rates of less than 1%.[23][24]

The risk of death from accidents when intoxicated with ketamine is associated with the highest mortality rate, according to several studies.[24][25] In a longitudinal study, two ketamine users died within one year, one from drowning in a bath and the second from hypothermia.[25]

Ketamine in the setting of other cardiovascular comorbidities can lead to catastrophic outcomes. Ketamine stimulates the sympathetic nervous system resulting in increased heart rate, cardiac output, and blood pressure. Hence, intoxicated patients with severe cardiovascular disease or hypertension may be at increased risk for stroke, myocardial ischemia, or increased intracranial pressure. The chronic pain ketamine guidelines note several case reports of ketamine precipitating unstable angina and arrhythmias.[6]

Acute use of ketamine may rarely cause encephalopathy, seizures, or coma. Acute kidney injury, electrolyte abnormalities, liver failure, and rhabdomyolysis may also occur.

Chronic ketamine misuse is associated with ulcerative cystitis [26], which may diminish bladder capacity and ureteral size and contribute to hydronephrosis. Symptomatically, the urologic complications of chronic ketamine misuse may cause abdominal pain, pelvic pain, hematuria, dysuria, frequency, urgency, and urge incontinence. Chronic ketamine use may also be associated with hepatic anomalies, as suggested by LFT abnormalities, or biliary anomalies, or diagnosed by imaging studies including CT and ERCP.[3] The urogenital and hepatic effects of ketamine appear to be dose-dependent. 

Some psychiatric effects of ketamine, including hallucinations and vivid dreams, may recur days or weeks following ketamine use, although these effects are usually transitory.[27] However, chronic use of ketamine causes more lasting psychiatric effects such as depression and memory and concentration impairment. Ketamine dependence may occur, as chronic PCP or ketamine users have reported psychiatric symptoms, including anxiety, irritability, depression, and changes in sleep and energy patterns within a day after cessation of ketamine use.[28] However, there is no definitive evidence of physical dependence in the form of withdrawal symptoms. Ironically, an intranasal ketamine formulation was recently approved to treat depression [29] and received attention as a treatment for a recalcitrant posttraumatic stress disorder. The drug is also actively being investigated as an agent to reduce alcohol, cocaine, or opioid dependence.[30] 

Complications

The adverse effects of ketamine use include:

• Psychosis
• Addiction
• Amnesia
• High blood pressure
• Impaired motor function
• Seizures
• Respiratory complications
• Impaired coordination and judgment
• Risk of depression
• Ketamine induced ulcerative cystitis

Deterrence and Patient Education

Patients require education about the dissociative effect associated with ketamine, which can result in a significant alteration in consciousness, thereby resulting in accidental injury to oneself or others. Ketamine can impair psychomotor performance, such as coordination, balance, and hand-eye movements. This lack of coordination can result in an increase in mortality from motor vehicle collisions if patients choose to drive while intoxicated. Since ketamine is subject to misuse and is classified by the U.S. Drug Enforcement Agency as a schedule-III controlled substance, patients given access to ketamine for chronic pain or depression should receive education on the risk of addiction and risk-stratified similar to those under consideration for chronic opioid therapy.

Ketamine misuse can result in chronic health problems that can be costly to manage. Ulcerative cystitis, a common effect associated with ketamine, is often refractory to conventional management. A diagnosis of ketamine-induced ulcerative cystitis often leads to repetitive cystoscopies and palliative bladder catheterization. These patients may require life-long treatments.

Enhancing Healthcare Team Outcomes

Ketamine use continues both medically and recreationally. Practitioners use it in anesthesiology, acute and chronic pain medicine, psychiatry, and veterinary medicine. In patients who misuse ketamine, the likelihood of serious sequelae, including end-stage organ damage, increases significantly. It is incumbent upon healthcare practitioners, including nurse practitioners, nurses, and pharmacists, to prevent acute complications from ketamine use and monitor and treat cognitive impairment, psychomimetic effects, and other associated adverse events associated with ketamine intoxication. Working with the clinicians, it is essential to educate patients and, in some cases, the families on the safe use of this medication.

In conclusion, ketamine toxicity and addiction pose significant risks to a small segment of the population, and given increasing utilization, the prevalence of these phenomena is expected to increase. As a schedule III controlled substance, the various formulations of ketamine are not as tightly regulated as most opioids, which, along with the low risk for fatal overdose, warrants increased attention by both regulatory bodies and practitioners on the front-line combating pain and depression.  

Patients who need ketamine medically or who misuse the drug are best managed by an interprofessional team that can provide monitoring, counsel, and information regarding the drug. This team includes physicians, mid-level practitioners (i.e., NPs, PAs), pharmacists, and nurses. This interprofessional approach increases the chances of optimal patient care and outcomes. [Level 5]