Angela Cirilli, MD, Ultrasound Director, Emergency Medicine, St. John’s Riverside Hospital, Yonkers NY; Assistant Professor of Emergency Medicine/Internal Medicine, Lake Erie College of Osteopathic Medicine
Brian Wiener, MD, Chief Resident, Emergency Medicine Residency, St. John’s Riverside Hospital, Yonkers, NY
Brian Patrick Murray, DO, Emergency Medicine and Medical Toxicology Physician, Assistant Professor, Emergency Medicine, Wright Patterson Air Force Base, OH
- Ketamine is a safe drug for procedural sedation and other uses. However, no drug is entirely safe, and adverse events, such as laryngospasm, should be anticipated.
- Low-dose ketamine appears to be effective with or without other analgesics for relief of acute and, in some cases, chronic pain.
- Excited delirium is seen in patients due to drug use and other factors. Ketamine is a reasonable choice for treatment and sedation of these patients to protect them, reduce catecholamines, and prevent adverse events. However, ketamine has been associated with rare adverse events and, therefore, it should be used under physician order (medical command) and the patient should be taken to the hospital for further care.
- Delayed sequence intubation allows a patient to be sedated, pre-oxygenated, and then paralyzed before intubation.
Ketamine is a medication traditionally used by emergency physicians for intubation and procedural sedation. From the time of its initial clinical use in 1970, few would have imagined the widespread clinical utility of ketamine. The focus of this article will be to discuss many common and accepted uses of ketamine, primarily for agitation, rapid sequence intubation (RSI), sedation, and pain management. The article will also explore other areas where it is clinically useful, including chronic pain, depression, and asthma. Lastly, more recent and evolving uses of ketamine, such as a treatment for alcohol withdrawal and status epilepticus, will be discussed.
History and Development
Ketamine was developed in 1962 at Parke-Davis Laboratories in Detroit, MI, by Calvin Stevens.1 The original use of ketamine was as a veterinary anesthetic agent.2 The U.S. Food and Drug Administration (FDA) approved ketamine for human use in 1970. The U.S. military administered ketamine as a field anesthetic to soldiers during the Vietnam War. In the following years, ketamine was used for brief surgical procedures as a sedative agent for both induction and maintenance of general anesthesia. By the mid 1970s, ketamine gained popularity as a recreational street drug known by multiple names, including Special K, Vitamin K, Super K, and others.3 Today, ketamine is included in the World Health Organization’s “Essential Drugs List” as one of the safest and most effective drugs needed in a modern health system.4
Ketamine has two broader categories for use: a relatively low dose for sub-dissociative analgesic pain and a high dissociative dose for sedation. Exact cutoffs for what is considered low vs. high doses are difficult to pinpoint and are likely variable among different recipients depending on their tolerance to narcotics and substances. Between these two large categories of low, subdissociative doses, and high, dissociative doses is a dosing category colloquially referred to as the notorious “K-hole.” The “K-hole” is an unpleasant, semi-trance-like state that has been described as feeling like an out-of-body or near-death experience, and should be avoided.
Ketamine is metabolized primarily by liver enzymes through demethylation, hydroxylation, and glucuronidation, and then it is excreted in the urine. Multiple cytochrome P450 systems are involved in this process, including CYP2B6, CYP3A4, as well as others.5,6 This is important to keep in mind because many drugs that modulate the activity of the P450 system through inhibition or stimulation might interfere with ketamine metabolism.7,8 (See Table 1.)
One of the many attractive aspects of ketamine is that it can be administered through multiple routes, including intravenous (IV), intramuscular (IM), subcutaneous (SQ), oral (PO), intranasal (IN), epidural, rectal (PR), and topical routes.9 Ketamine is given most commonly as an IV medication, with a time of onset of about 15 to 30 seconds after administration.10 Following IM administration, onset is approximately four minutes and lasts 15 to 30 minutes. When given IM, the dosing often is increased compared to IV. However, dosing recommendations depend on the application, age, and comorbidities of the patient, as well as any co-administered medications.11 When using ketamine orally, higher doses are required because of significant first-pass metabolism in the liver.12
Intranasal (IN) administration of ketamine is particularly attractive because it is less invasive, rapidly absorbed, and not subject to first-pass metabolism. Therefore, it can be used easily in pediatric patients, often obviating the need for difficult and painful IV access.10
When administering ketamine via the IM route, it is important to be cognizant of the concentration being used because it comes in one of three forms: 10 mg/mL, 50 mg/mL, and 100 mg/mL. For example, when giving dissociative dose ketamine for agitated delirium, the IM dose may be as high as 3 mg/kg to 5 mg/kg, which equates to 400 mg in a standard 80-kg adult patient.13 If using a 10 mg/mL solution, this would require a 40 mL dose, too large to be given in a single IM injection. However, 400 mg of a 100 mg/mL solution would require only 4 mL, a volume much more suitable for an IM injection. Additionally, given a 10-fold increase in concentration between the different formulations, it is important to be aware of the concentration to prevent a medication dosing error, particularly in pediatric patients. Of note is that ketamine dosing should be based on ideal body weight and not actual weight.
Bioavailability also depends on the route of administration. The bioavailability of IV ketamine is close to 100%. Bioavailability is between 75% and 95% for IM and SQ administration, 25% to 50% for IN, 10% to 30% for PO, and 25% to 30% for PR.14 (See Table 2.) Elimination of ketamine is primarily renal.12 Ketamine usually is undetectable in a patient’s blood 24 hours after IV administration, but the drug and its metabolites can be detected in the urine for close to 14 days.15
Historically, the most recognized pharmacological receptor which ketamine acts upon is the N-methyl-D-aspartate (NMDA) receptor where it acts as a noncompetitive NMDA receptor antagonist that blocks glutamate.20 However, ketamine has a very complex pharmacodynamic profile and actually acts on several different receptors in the body, explaining why ketamine has such extensive clinical utility in various medical conditions.10 The actions of ketamine at the opioid receptors are hypothesized by many to explain its analgesic effects. The full extent of exactly how ketamine interacts with these various receptors is incompletely understood.
Severe Agitation/Excited Delirium
The extremely agitated patient with excited delirium represents a wide array of patients who may be affected by drugs of abuse, psychiatric disturbances, and organic causes, and may represent a serious threat to their care providers and themselves. Therefore, an agent is needed to gain rapid control of these patients to eliminate harm to themselves and others. Traditionally, acute agitation in the emergency department (ED) often is treated with antipsychotics, benzodiazepines, or a combination, sometimes with the addition of an anticholinergic such as diphenhydramine. This combination is effective at inducing anxiolysis in an agitated patient; however, they have many undesirable properties, including slow onset, variability in clinical response, and QT prolongation.20,21 In addition, these patients may have other medications or substances in their system that could augment any cardiovascular or respiratory effects of these drugs.
Ketamine is a medication that has been studied recently to treat acute agitated delirium. Characteristics that make it desirable for this patient population are its rapid onset, its ability to be given via several routes, little effect on respiratory drive, and overall low side effect profile, as demonstrated in the sedation literature.22
A prospective, nonrandomized trial by Riddell et al analyzed 106 agitated ED patients who received either ketamine or benzodiazepines and haloperidol, alone or in combination. The researchers found that fewer patients in the ketamine group were agitated at 5, 10, and 15 minutes following medication administration than in the other medication groups.23 This study concluded that in highly agitated and violent ED patients, ketamine is faster at controlling agitation than standard ED medications. However, the dosing in that study was not standardized. A meta-analysis by Sullivan et al in 2019 evaluating both prehospital and ED use of ketamine for agitation found that more than 85% of agitated patients treated with ketamine achieved appropriate sedation.24
Dosing. Ketamine in acutely agitated patients is usually given either IV or IM. The majority of dosing regimens published have been predominantly IM for this purpose, with only a few discussing IV dosing. Ketamine for agitated delirium has been studied in both the prehospital and ED setting.13,20,25-38 (See Table 3.)
The standard IM dose of ketamine given to acutely agitated patients is 4 mg/kg to 6 mg/kg; however, when patient weight is not available, the average-size adult can be given up to a maximum bolus dose of 500 mg IM safely.39 If a patient has an IV, standard acute agitation dosing follows dissociative dosing guidelines and is typically 1 mg/kg to 2 mg/kg IV, with a maximum administration of 200 mg. This dosing regimen should be based on ideal body weight and not actual body weight. It is also important to note that many of the prior studies using ketamine for agitation did not standardize the doses or route of administration, since much of the data to support the dosing regimen is retrospective.
A recent meta-analysis by Gonin et al looked at prehospital data and found that the average dose given to the acutely agitated or excited delirium patient was 4 mg/kg to 6 mg/kg IM, or 1 mg/kg to 2 mg/kg IV when weight-based dosing was used, with ranges of 40 mg to 400 mg IM/IV total when weight was not reported or known.40 The aeromedical literature dosing was lower, from 0.5 mg/kg to 1 mg/kg IV, followed by an infusion of 1 mg/kg/hour to 1.5 mg/kg/hour, titrated to effect.35 A protocol for standardizing IM dosing of ketamine in the acutely agitated ED patient was recently studied by Mo et al recommending 4 mg/kg IM and found that the mean dose given was 3.2 mg/kg.13 In that study, the authors stated that lower doses were given due to concerns by the administering physicians of oversedation. However, when looking at lower doses given in the ED setting, Isbister et al found unsuccessfully sedated patients (only 10% in this particular study) received less than 4 mg/kg to 5 mg/kg, or < 200 mg IM total.35 This study was confounded by the fact that the patients had already failed other sedatives, and ketamine was being used as a rescue medication. Another study by Hopper et al found the failure-to-sedate rates of ketamine to be 65%; however, lower doses were used in this paper, with a median dose of 200 mg IM. Authors in this study noted that it was confounded by a high rate of intoxication with ethanol as well as other substances, possibly making this a more resistant group to sedate.36
Interestingly, there may be a ceiling effect to ketamine sedation once dissociation is achieved, and increased doses are not associated with oversedation or increased adverse effects unlike other sedatives.35 However, more research is needed to differentiate the clear difference between IV and IM dosing, and the ideal minimal mg/kg dosing to achieve maximal dissociation with minimal adverse effects.
Adverse Reactions of Ketamine Used for Acute Agitation. While ketamine has been shown to be effective at controlling agitation, particularly in the combative excited delirium patients, there are many adverse reactions to be aware of. Adverse reactions reported with the use of ketamine are nausea and vomiting, increased oropharyngeal secretions, laryngospasm, emergence phenomenon, associated intubation, and cardiac arrest following ketamine administration.24
The recent meta-analysis by Sullivan et al analyzing ketamine use in acutely agitated patients noted a total of four deaths reported, two of which were not likely related to ketamine (one where ketamine was given after cardiac arrest, and another patient who died of sepsis on hospital day 29).24 However, another study by Olives et al reported two cases of cardiac arrest after ketamine. One was a patient who experienced several seizures, and the other was in a patient with a lethal citalopram and clonidine overdose with underlying amphetamine toxicity.28
One of the most significant concerns with ketamine use in the acutely agitated patient has been the high rate of reported airway intervention. In the prehospital data, intubation rates associated with ketamine use in the agitated patient range from 15% to 63%, with the highest intubation rates reported by Olives et al.28,40 However, recent studies analyzing the use of ketamine in the ED for agitation have reported as low as zero intubations.35,36 As stated, when looking at a recent meta-analysis of pooled data by Mankowitz et al, the overall average intubation rate was 20% associated with ketamine when used for agitation.20 When further analyzing subgroups of prehospital vs. hospital patients in this study, they found a prehospital pooled intubation rate of 25%, compared to the ED pooled intubation rate of only 8%. It has been suggested by Mankowitz et al that this difference is seen possibly because the prehospital agitated or excited delirium patients are, at baseline, a different group than ED patients who have already successfully made it to the ED, allowed for IV establishment, and often tolerated other sedatives. Prehospital patients may have a high rate of co-ingestants and other toxins that put them at greater risk from sedatives. In addition, it has been noted that many patients who received prehospital ketamine for agitation were not intubated until arriving to the ED, and therefore, it is possible that ED physicians are less likely to intubate someone when they have seen the patient prior to the dissociated state.
Thus, when giving ketamine for acute agitation, it is prudent to monitor the patient closely for adverse events, such as nausea, vomiting, laryngospasm, aspiration from increased secretions, respiratory depression and need for airway intervention, and cardiac arrest. It is recommended that if giving ketamine for agitation, providers should always have a bag mask ventilation device, advanced airway equipment, and adequate monitoring capabilities, including end tidal capnometry when available and pulse oximetry, at the bedside.
Dosing of Common Induction Agents Used for Rapid Sequence Intubation
Four of the most commonly used sedatives for ED RSI are etomidate, ketamine, propofol, and midazolam.
Ketamine has a unique and favorable hemodynamic profile compared to other sedation agents. Unlike other agents, the sympathetic effects of ketamine elevate the systolic and diastolic blood pressure (BP), whereas propofol or midazolam may decrease the blood pressure.41,42 This hemodynamic effect makes ketamine a great choice for the hypotensive patient. However, in severely catecholamine-depleted patients, ketamine actually can induce transient hypotension similar to other sedatives.43 It is believed that in these patients, the negative ionotropic effects override the sympathomimetic effects, leading to myocardial suppression. In addition, there have been a few reported cases of cardiac arrest following RSI with ketamine.44,45 Therefore, in patients with shock or suspected catecholamine depletion who need to be intubated, it has been recommended to decrease the amount of ketamine, similar to other sedatives, in half (from 1 mg/kg to 2 mg/kg to 0.5 mg/kg to 1 mg/kg IV push).46
Another benefit to using ketamine as an induction agent is that it provides analgesia, possibly through opioid receptor agonism, in addition to its sedative effects. Additionally, ketamine also is suggested to be a better agent for use when intubating a patient with asthma because of its ability to cause bronchodilation. (See Table 4.)
Ketamine for Treatment of Acute Pain
Ketamine for Acute Pain Control in the ED
Acute pain is a common complaint in the ED. Ketamine has analgesic properties, likely mediated through its effect on opioid receptors as well as modulation of several other less defined receptors. Because of its analgesic properties, ketamine is a considered a third-line medication for pain control when standard analgesics have failed. Ketamine can be given through multiple routes, including IV, IM, IN, and even transdermally, as is done in the treatment of intractable neuropathic pain.47
Ketamine has been studied for use in musculoskeletal pain, sickle cell disease, migraines, long bone fractures, perioperative pain, pain associated with painful procedures such as incision and drainage, and in chronic refractory pain in opiate-tolerant patients.48 Additionally, ketamine has been well established as a means to treat cancer-related pain when patients are not relieved by opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), amitriptyline, and drugs similar to gabapentin.49
A well-studied analgesic application of low-dose ketamine (LDK) is the treatment of vaso-occlusive and acute pain crisis in adult and pediatric patients with sickle cell disease. A common practice is to give ketamine as a low-dose continuous infusion, and it has been shown to decrease pain in patients who are unresponsive to opioid analgesics.50,51 Other studies have shown that the addition of a low-dose infusion of ketamine to opioids in the treatment of sickle cell vaso-occlusive episodes results in significantly decreased opioid requirements.52,53
Another well-studied application of LDK for analgesia is in the setting of renal colic. When comparing LDK in addition to ketorolac for the treatment of pain related to suspected renal colic, subdissociative doses of ketamine at 0.3 mg/kg infused over 10 minutes given 30 minutes following 30 mg of ketorolac to patients who still had pain provided a statistically significant pain reduction.54 Another study compared the use of 0.6 mg/kg of IV ketamine to 30 mg of IV ketorolac. This study concluded that LDK is as effective as ketorolac for pain management in ED patients with renal colic, but ketamine was associated with a higher rate of adverse drug reactions, including nausea, dizziness, elevated blood pressure, and agitation.55
In light of the opioid pandemic, many studies have focused on ketamine in addition to, or in place of, opioids to treat renal colic patients to decrease overall opioid use. It has been shown that when using a combination of low-dose (0.15 mg/kg to 0.2 mg/kg) IV ketamine with 0.1 mg/kg IV morphine, compared to morphine plus placebo, patients with renal colic had decreased pain scores and fewer rescue doses of morphine.56,57
In a randomized, double-blinded trial, initial treatment of suspected renal colic with ketamine at 0.3 mg/kg IV push (IVP) compared to morphine 0.1 mg/kg demonstrated more rapid pain relief and fewer doses of rescue analgesia in the ketamine group compared to morphine.58
LDK Dosing for Analgesia. When looking at the dosing of LDK for analgesia, the average dosing recommendations are 0.1 mg/kg to 0.4 mg/kg.59 However, the dosing range reported in the literature is up to 0.6 mg/kg given IVP in some studies.48,55 Because dissociative effects can be seen at the upper end of these lower dose ranges, the American College of Emergency Physicians’ policy on ketamine use supports a lower dosing regimen around the 0.1-0.3 mg/kg over 10-15 minutes IV, with an option for following infusion at 0.15-0.2 mg/kg/hour and states that IM dosing is less predictable and less studied or specified in the literature.60 Studies have suggested to put the bolus dose of ketamine in 100 mL of normal saline and slowly infuse it over 15 minutes instead of rapid IV push to minimize adverse effects.61 (See Table 5.)
Administration of ketamine intranasally has shown promise in the prehospital setting for acute pain management due to the ability to be administered quickly and without the need for IV access and can be given at 1 mg/kg. When using IN ketamine, the best and most efficient method of administration is through an atomizer, which maximizes the amount of drug that can be delivered to the vascularized surface area of each nostril. This results in rapid absorption into the blood.
A recent, randomized double-blind trial demonstrated that 0.75 mg/kg prehospital IN ketamine resulted in clinically significant reductions in pain and an increase in comfort compared to placebo (76% vs. 41%).62 When comparing IN ketamine 1 mg/kg vs. IV morphine 0.1 mg/kg in suspected renal colic patients, IN ketamine has been shown to be similar in efficacy to IV morphine.63 However, another study comparing IN ketamine (1 mg/kg) to IV fentanyl (1 mcg/kg) for analgesia showed that although ketamine had greater effect in first 15 minutes, at 30 minutes the fentanyl group had better pain scores.64 Additionally, there was a higher prevalence of side effects seen in the ketamine group in this study.
Adverse Effects of LDK When Used for Analgesia. While the use of LDK for analgesia generally has proven effective at alleviating many types of pain and pain resistant to other treatment options, it is critical that the ED practitioner remember ketamine is considered an anesthetic. Although most studies show analgesic benefit, they also have shown ketamine to have many side effects, including nausea, vomiting, dizziness, delirium, systolic and diastolic hypertension, and some concern for emergence reactions. Although some studies have reported a higher occurrence of adverse events with IN ketamine compared to narcotics,64 other studies have shown IV LDK to have an equal occurrence of adverse events compared to narcotics.65 Emergence reactions are a concern with LDK, but overall these have been shown to be not that common and often self-limited.66
Exacerbation of Chronic Pain
Chronic pain can be treated with either outpatient intermittent IV ketamine infusions or continuous inpatient ketamine infusions.67,68 There are more than 1,000 “ketamine clinics” in the United States that offer outpatient infusions of LDK for a variety of conditions, including chronic pain, depression, and other mood disorders.69 Some of these report long-term analgesic effects up to three months.70,71,72
Ketamine Use for Procedural Sedation in the ED
Ketamine is an excellent choice for procedural sedation because it provides patients with sedation, analgesia, and amnesia when given for painful procedures. A systematic review involving more than 70,000 patients showed that significant adverse reactions are rare when using ketamine for procedural sedation in adults.73 Although emergence reactions are less common in pediatric patients, there is a concern for a higher occurrence among adults. One systematic review found a pooled occurrence rate of 10% to 20%, stating that the reactions were treated easily with low doses of midazolam (0.03 mg/kg to 0.05 mg/kg). Strayer et al further concluded that ketamine has been shown to be a safe medication for procedural sedation despite often being used in poorly monitored settings.73 (See Table 6.)
When comparing etomidate to ketamine for procedural sedation, etomidate was found to have more adverse effects, including myoclonus, airway assistance, and hypoxia, compared to ketamine.74 Ketamine is popular for pediatric procedural sedation.
Use of Ketamine in Acute Asthma or Bronchospasm
Ketamine has a number of proposed and proven beneficial pharmacologic properties when used to treat acute asthma in children and adults.75-79
The use of ketamine for pediatric patients with severe asthma exacerbations is mixed, with observational studies and case reports showing benefit, and a few other studies concluding there is no benefit.80 There have been multiple favorable case reports supporting the use of a ketamine IV bolus followed by a short infusion to treat refractory status asthmaticus unresponsive to other medications, using high dissociative or sedation doses of 1.5 mg/kg to 2 mg/kg IVP or 4.8 mg/kg IM.81-83 However, there have been no controlled studies using dissociative doses this high in non-intubated or non-mechanically ventilated patients. Therefore, caution should be taken. There is even a case report in which nebulized ketamine was given at 1 mg/kg in the ED to avoid mechanical ventilation in a pediatric patient with a severe asthma exacerbation who failed to respond to albuterol, steroids, and magnesium.84 In this case, the patient had relief of breathing and improved oxygen saturation and blood gas shortly after receiving ketamine.
An observational study of 10 pediatric patients by Petrillo et al showed positive results with improvement in overall asthma severity scores and improved respiratory rates using ketamine doses of 1 mg/kg followed by an eight-hour infusion at 2.4 mg/kg/hour.85 Another study looking at LDK boluses of 0.3 mg/kg, 0.4 mg/kg, and 0.5 mg/kg IVP followed by a short 30-minute infusion compared to placebo concluded no benefit was seen at the lower dose of 0.3 mg/kg, but a statistically significant improvement in peak expiratory flow rates were noted in the 0.4 mg/kg to 0.5 mg/kg IVP groups for severe asthma exacerbations.86 Another separate, randomized controlled trial on both pediatric and adult nonintubated patients with severe asthma exacerbations showed no statistically significant improvement using LDK of 0.2 mg/kg IVP followed by infusions of 0.5 mg/kg/hour.87,88
In a review, Goyal et al concluded that ketamine use may avoid the need for mechanical ventilation and may be considered to be a rescue medication and potent bronchodilator in refractory asthma exacerbations. However, several authors agree that more randomized controlled trials are warranted before a conclusive role of ketamine in asthma is established, and the ideal ED dosing for a nonintubated patient with severe asthma exacerbation is unclear.80,89
While ketamine appears to have significant utility for emergency medicine physicians, the medication can have multiple undesired side effects. One of the biggest criticisms against ketamine is that the drug-related airway effects are under-recognized and the medication possibly has a large incidence of psychiatric-related issues. (See Table 7.)
Ketamine has been shown to cause hypoventilation requiring close airway monitoring and occasional airway intervention, such as bag mask oxygenation or supplemental oxygenation via nasal cannula.90 Although airway intervention such as intubation seems a rarity when using ketamine for procedural sedation,91 it has been described more commonly as an adverse outcome when ketamine is used for acute agitation.20 It has been suggested that giving the medication slowly over one minute when using ketamine as an IV push dose during sedation can help prevent hypoventilation.91 Although physicians often say “ketamine does not cause respiratory depression,” the statement has been called into question by multiple systematic reviews and meta-analyses that have demonstrated that moderate to high doses (greater than initial dosing of 2.5 mg/kg IV or total dose > 5 mg/kg IV or 2 mg/kg to 3 mg/kg IM) may result in desaturation and an increase in end tidal CO2, suggesting hypoventilation. Therefore, it is important to have a nasal cannula, a bag valve mask (BVM), and airway equipment set up at the bedside when using ketamine for procedural sedation or acute agitation.
Laryngospasm occurs when the muscles of the vocal cord spasm, narrowing the airway patency and subsequently making it difficult to move air through the larynx. Patients often manifest laryngospasm by intense coughing episodes. This is a feared side effect of ketamine. Ketamine-associated laryngospasm is relatively uncommon and thought to have an incidence of approximately 0.3% in children93 and appears to occur most frequently in infants.94
Laryngospasm usually is self-limited, lasting only one to two minutes, and it usually responds quickly to assisted ventilation and oxygenation. Supplemental oxygen should be administered and manual ventilation with a bag-valve mask should be considered until it resolves while continuously monitoring pulse ox and end tidal CO2. If the laryngospasm persists beyond one to two minutes, then consider paralyzing the patient to immobilize and relax the vocal cords, and then intubate the patient for airway protection. The exception would be when using ketamine for delayed sequence intubation where sedation is given with a time delay prior to neuromuscular blockade for a few minutes of preoxygenation with plans to intubate. In this scenario, it may be prudent to proceed with intubation as soon as laryngospasm is identified.
Risk factors predictive of ketamine-associated airway and respiratory adverse events are high intravenous doses, rapid IV pushes, administration to children younger than 2 years of age or older than 13 years of age, and the use of co-administered anticholinergics or benzodiazepines.91
Because of the higher incidence of laryngospasm in infants, the American College of Emergency Physicians (ACEP) lists age less than 3 months as a contraindication for ketamine use. In addition, ACEP also lists a history of airway instability, tracheal surgery, or tracheal stenosis as relative contraindications given the potential side effect of laryngospasm.22
Another known side effect of ketamine is emergence reactions or recovery agitation, which typically occurs as ketamine is wearing off. Emergence reactions manifest as hallucinations, vivid dreams, severe confusion, and fear. There have been numerous studies and debate regarding the frequency with which emergence reactions occur in adults and children. More important is awareness that the phenomenon is temporary and will resolve as the drug is metabolized and eliminated. It has been suggested that premedication with midazolam or other benzodiazepines prior to sedation can prevent or moderate the effect of emergence reactions. Benzodiazepines also often are given at the time of recognition when patients are waking up to mitigate the agitation. In adults, premedication with a benzodiazepine or haloperidol may help prevent recovery agitation seen with ketamine but may delay overall post-sedation recovery.95 However, a pediatric systematic review concluded there was not enough evidence to strongly recommend prophylactic midazolam to prevent emergence phenomena in children undergoing ketamine sedation.96
Because ketamine can cause psychosis and delirium in select patients, ACEP has determined that known or suspected pre-existing schizophrenia, even if currently stable and controlled with medications, is a contraindication to using ketamine, since ketamine may exacerbate psychosis.22
Sympathomimetic Stimulation Hemodynamic Effects
Ketamine affects hemodynamics by increasing the heart rate and blood pressure. It is thought that this is a result in part of direct stimulation of the sympathetic ganglions in the central nervous system.97,98 In addition, ketamine has been shown to have negative ionotropic effects on the heart, which is usually outweighed by the increased sympathetic response.96 Ketamine can increase myocardial oxygen demand and may increase the risk for acute coronary syndrome (ACS) in patients with cardiovascular disease. Therefore, ACEP gives the relative contraindication against using ketamine for patients who have known or suspected cardiovascular disease, including angina, heart failure, and hypertension.40 In this recommendation, ACEP also relatively advises against ketamine use in patients who are already hypertensive or are elderly with risk factors for coronary artery disease (CAD).
Neurotoxicity in Children
There have been concerns with neurotoxic side effects from ketamine use in children.99
Although neurotoxic effects are rare after a single dose, research has shown that there may be long-lasting cognitive effects on memory, specifically on source memory or the ability to recall where a memory came from, in chronic ketamine abusers similar to the cognitive memory defect pattern seen in schizophrenia.100 In addition, animal studies have shown high doses of ketamine use may be associated with learning disabilities and brain neuronal dysfunction.101-103 Human evidence is lacking, however. Animal studies demonstrate that this ketamine-induced neuronal apoptosis seems to be more significant in younger developing brains.104,105
Additional Cholinergic Adverse Effects of Ketamine
In addition to binding to NMDA receptors, which explains the majority of the anesthetic effects of ketamine, it also binds to various other receptors, including both nicotinic and muscarinic acetylcholine receptors, causing some unwanted cholinergic side effects.106 This causes increased oral salivation, tracheal and bronchial mucous secretion, nausea, and vomiting.97 Increased salivary and tracheal secretions are of concern when sedating because of the possibility of aspiration and adverse respiratory events.
Therefore, premedication with an anticholinergic agent, such as glycopyrrolate or atropine, has been recommended to mitigate the salivary effects of ketamine and lower the risk for aspiration or adverse airway events.107 Previously, there was concern that because atropine crosses the blood-brain barrier, it may contribute to central anticholinergic psychotomimetic side effects such as emergence reactions and hallucinations when used with ketamine. However, atropine was compared to glycopyrrolate, which does not cross the blood-brain barrier, and shown to have no statistically significant difference when given with ketamine with regard to the occurrence of psychotomimetic side effects.107 Incidentally, atropine was slightly better than glycopyrrolate for eliminating oral secretions, but not to a significant degree.107
In a large meta-analysis comparing atropine to glycopyrrolate during pediatric sedation with ketamine, Green et al found that atropine had a superior adverse event profile and was associated with less vomiting than glycopyrrolate or no anticholinergic agent, and glycopyrrolate paradoxically had an increased risk of adverse airway events compared to atropine or no anticholinergic agent.108 A prior analysis by Green et al on the same database showed that use of either anticholinergic had a paradoxical increase in the number of adverse airway events and, therefore, was not recommended.109 In practice, there is not enough evidence to recommend using either anticholinergic agent prior to ketamine.
Ketamine and Associated Cardiac Arrest
Ketamine has the potential to cause transient hypotension in severely catecholamine-depleted individuals. In case reports of extremely sick, hemodynamically unstable, and catecholamine-depleted individuals, ketamine has been suggested to lead to cardiac arrest following RSI.110 Dewhirst et al concluded that in patients with an exhausted endogenous catecholamine reserve, the unopposed direct negative inotropic effects of ketamine may lead to cardiovascular compromise during ketamine use for RSI.
A case series of ketamine use for status epilepticus in 10 patients described another single patient who went into cardiac arrest minutes after receiving ketamine and was found to have a subarachnoid hemorrhage.111 The author cautioned that ketamine should be used with caution in patients with a subarachnoid hemorrhage, since there may be an increased risk of life-threatening arrhythmias and cardiac arrest.
In addition, two cases of cardiac arrest have been reported after dissociative dosing of IM ketamine was used for severe agitation in the prehospital setting.28 In the first case, a male was given IM ketamine for severe agitation and shortly after went into arrest. He was later found on autopsy to have high doses of citalopram and clonidine in his system in addition to amphetamines. The second case was a patient who was in refractory status epilepticus who became apneic and pulseless shortly after receiving ketamine. He was later found to have severe electrolyte dysfunction on autopsy. The authors concluded that in the severely agitated patients, there are many organic causes and physiological derangements possible that may make them susceptible to cardiac arrest with or without ketamine.
As previously stated, ACEP gives a relative contraindication, based on inconclusive evidence, for ketamine use to be avoided in patients with known or suspected cardiovascular disease, including angina, heart failure, or hypertension.22 In their clinical guidelines for ketamine dissociative sedation, they report that exacerbations of cardiac disease may be caused by the sympathomimetic properties of ketamine.
Although cardiac arrest is not a common side effect documented with ketamine use, it is important for practitioners to be aware of these reports and the possibility of ketamine-induced cardiac arrest.
Special Considerations: Does Ketamine Cause Increased Intracranial Pressure?
There has been an ongoing debate for many years as to whether ketamine causes increased intracranial pressure (ICP) and/or intraocular pressure (IOP). In the 1990s, ketamine was generally abandoned as an induction agent in patients with traumatic brain injury (TBI) based on prior papers suggesting a direct connection between ketamine leading to an increase in intracranial pressures.112,113
However, more recent studies have found no overall difference in ICP in TBI patients receiving ketamine vs. controls.114 Some studies even suggest that patients with a TBI may benefit from ketamine sedation.115 There have been many studies that refute the notion that ketamine increases ICP and/or IOP and claim that ketamine is a safe and effective drug for patients with TBI and intracranial hypertension.116,117 To date, the overall evidence on whether ketamine causes brain injury in TBI patients, or patients in whom there is a concern for increased ICP or IOP, is very low.118
During status epilepticus (SE), there are brain neuronal changes that make the neurons less responsive to benzodiazepines. The longer SE goes on, the harder it becomes to stop.
This resistance is due in part to the fact that during prolonged SE, GABA brain receptors begin to involute into brain neurons, leading to an overall decrease in the number of GABA receptors available for interaction with benzodiazepines.119 At the same time, NMDA receptor expression increases in excitatory cells, leaving more available for interaction with an NMDA receptor antagonist such as ketamine. This involution of GABA receptors is ongoing as the seizing continues, making benzodiazepines increasingly ineffective the longer SE lasts.120
There are two separately studied applications of ketamine for seizure control, low dose IV and PO ketamine for control of drug-resistant epilepsy, and the use of high dissociative dose ketamine for benzodiazepine-refractory SE.121 In a recent systematic review of case reports, case series, and retrospective studies, ketamine was concluded to be an emerging third-line medication for refractory SE and an effective alternative when treating refractory SE.122
Alcohol abuse is a prevalent condition affecting 20% of men and 10% of women, with as many as 50% of them suffering from alcohol withdrawal, which is associated with significant morbidity and mortality.123 Acute management of these patients can range from simple withdrawal to life-threatening delirium tremens (DTs) that may be resistant to monotherapy. Traditionally, benzodiazepines (BZDs) have been the first-line drug of choice for alcohol withdrawal.124 When additional agents are required, phenobarbital is a common second choice.125 In severe BZD-refractory alcohol withdrawal, phenobarbital and/or propofol may be used. Multiple recent retrospective studies have suggested that ketamine may be a useful adjunct in treating alcohol withdrawal.
Alcohol activates GABA channels and inhibits glutamate channels. With continued alcohol abuse, there is a down regulation in the total number of GABA receptors and an upregulation in excitatory glutamate receptors. Therefore, in alcohol withdrawal, the central nervous system is left in an over-excitatory state. The first-line agents for alcohol withdrawal are BZDs. BZDs are used because they interact with the major inhibitory GABA receptors in the central nervous system, depressing the over-excitatory state left from ethanol’s absence. In severe alcoholics, however, the overall decreased number of inhibitory GABA receptors renders BZDs less effective. In addition, BZDs are unable to interact with the upregulated glutamate channels seen in severe alcoholics.126 Phenobarbital, which is considered as a second-line agent in BZD-refractory alcohol withdrawal, is a GABA agonist and a glutamate antagonist.127 Ketamine is another potential adjunct to BZD-refractory alcohol withdrawal because of its inhibition of NMDA receptors, which are a type of glutamate receptor. However, ketamine does not affect GABA receptors.128,129
A few features that make ketamine an enticing option for treating alcohol withdrawal include its evidence-based ability to get rapid control of the patient with severe agitated delirium with a relatively low but potential risk of respiratory depression, in addition to its anti-epileptic properties. There are no large prospective studies that confidently indicate ketamine is a useful adjunct in alcohol withdrawal. However, there are three retrospective studies worth discussing.
In ICU patients with severe alcohol withdrawal, ketamine reduced overall BZD requirements and was well tolerated at low infusion doses of 0.2 mg/kg/hour.130 A second study demonstrated that a ketamine infusion (at 0.15 mg/kg/hour to 0.3 mg/kg/hour with additional 0.3 mg/kg as needed based on severity) was associated with reduced BZD requirements, shorter ICU length of stay, lower likelihood of intubation, and a trend toward overall shorter hospitalizations in ICU patients with delirium tremens.131
A third study by Shah et al in 2018 assessed the effect of much higher doses of continuous ketamine infusion on symptom control and BZD requirements in severe alcohol withdrawal ICU patients. In this study, the median initial ketamine infusion rate was 0.75 mg/kg/hour, with a range of 0.5 mg/kg/hour to 4.5 mg/kg/hour, and an average maximum daily rate of 1.6 mg/kg/hour. This study found that all patients achieved symptom control within one hour of ketamine initiation, and the use of ketamine significantly decreased lorazepam infusion rates during the first 24 hours. In addition, within 48 hours of starting ketamine, 43% of patients in the study were completely weaned off all infusions.132 It should be noted that 73.3% of patients in this study were intubated, with 72% of them intubated prior to the initiation of ketamine.
Although these studies demonstrate that ketamine may be a promising new therapy for patients with severe alcohol withdrawal, more prospective studies are needed to confirm these results and evaluate the optimal dosing.
Dosing. As stated, the optimal ketamine dosing for acute alcohol withdrawal is unclear, with widely reported ranges in literature. Animal studies have shown that ethanol dependence upregulates NMDA receptors over time and contributes to cross tolerance with selective NMDA receptor antagonists such as ketamine.133 For this reason, patients may have a wide range of dose response depending on their alcohol abuse history. It is theorized that severe alcoholics may require higher doses of ketamine because of these upregulated NMDA receptors.
Although there is more research supporting the use of phenobarbital for BZD-resistant alcohol withdrawal, ketamine also may prove to be useful in a niche role when withdrawal patients are agitated and need a push dose of 1 mg/kg to 2 mg/kg or higher to obtain rapid control of the acutely agitated delirium patient with withdrawal symptoms.20
There are more than 1,000 “ketamine clinics” in the United States that offer outpatient infusions of LDK for a variety of conditions, including intractable migraines. A frequent practice pattern at these clinics includes administering 0.1 mg/kg/hour of IV ketamine and increasing the dose by increments of 0.1 mg/kg/hour every few hours until patients achieve a desirable pain score. This infusion protocol often is repeated until the patient endorses relief for up to eight hours.134 Off-label use of ketamine has been adopted by some ED physicians in the treatment of refractory migraines not responsive to first-line abortive therapies including NSAIDs, triptans, and dopamine antagonists such as metoclopramide and prochlorperazine. There is a sparsity of large, well-controlled trials that support this off-label use of ketamine.
The proposed mechanism for why ketamine relieves migraine headaches is centered around the hypothesis that NMDA receptors are responsible for the body’s ability to process pain signals in the central nervous system (CNS). There are neurologists who argue that over-activation of the NMDA receptor results in excitotoxicity and causes a myriad of pain disorders.
Ketamine antagonizes this over-activation of the NMDA receptor.135 It is suggested further that the therapeutic effects of ketamine last longer in the body than the actual drug levels themselves because of secondary changes in the neuronal system through NMDA modulation that produce long-lasting therapeutic effects for migraines and other disease states.136
The evidence supporting ketamine use in status migrainosus is controversial. A case series by Lauritsen et al concluded ketamine was associated with short-term improvement in pain severity when used to treat chronic refractory migraines.134 A separate retrospective review by Pomeroy et al concluded that low-dose subdissociative ketamine infusions may be beneficial for treating chronic migraines when other aggressive treatment modalities have failed.137
Turner et al assessed the efficacy of IN ketamine (0.1 mg/kg/dose to 0.2 mg/kg/dose to a max of 10 mg on initial dose, 25 mg maximum dose on subsequent doses given every 15 minutes up to five doses) to abort migraines in pediatric patients and found a significant reduction in pain scores in 73.5% of patients with a very low incidence of therapy-limiting side effects.138
Despite these positive studies, a randomized placebo-controlled trial concluded that low-dose ketamine did not improve migraine pain scores compared to placebo, and overall discomfort was significantly greater in the ketamine group at 30 minutes post-administration.139 Therefore, the authors in this particular study stated that the current data do not suggest ketamine can provide relief to patients with migraine headaches.
More evidence is warranted before ketamine is incorporated into routine treatment of migraines. Many additional questions remain regarding the use of ketamine for migraines, including overall efficacy, place in therapy, ideal dosage, and associated risk of undesirable side effects.140
Ketamine for Treatment-Resistant Depression
There is literature supporting the use of IN and/or IV ketamine infusions for treatment of refractory depression, but literature supporting the use of ketamine in the ED for this purpose is limited.
Standard medications for the treatment of depression take weeks to months to achieve efficacy. IN ketamine may be effective within two hours at alleviating depressive symptoms.141 A single IN administration of ketamine has been suggested to alleviate the effects of depression for seven days, and in some cases, longer.142 Another small, randomized, double-blind, placebo-controlled trial evaluated ED use of ketamine 0.2 mg/kg IVP in patients with suicidal ideation requiring admission and found remission of suicidal ideation at 90 minutes post ketamine in 88% compared 33% of placebo patients.143
Delayed Sequence Intubation
In contrast to RSI where sedation and paralytics are given almost simultaneously, delayed sequence intubation (DSI) is a technique used by physicians to better facilitate preoxygenation of the agitated patient prior to intubation. Agitated or delirious patients may be suffering from hypoxia, ingestions, hemodynamic instability, or acid base disturbances, and often are at risk from adverse events during intubation. Additionally, these patients may not tolerate preoxygenation, putting them further at risk during intubation.
By delaying the administration of a paralytic but sedating the agitated patient, the provider then can apply a non-rebreather facemask or even a noninvasive ventilation device such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP) and perform any other stabilizing peri-intubation procedures, such as procuring adequate vascular access, establishing fluid resuscitation, placing NG tubes, and gathering personnel and adequate equipment.142
Ketamine is ideal for DSI because when given without a muscle paralytic, it puts patients in a sedated, dissociative state while breathing reflexes remain intact. Although the use of ketamine in obtunded patients requiring noninvasive positive pressure ventilation was previously contraindicated because of the risk of secretions, vomiting, and inability to properly protect their airway, DSI is performed in a controlled setting, with the patient monitored by the physician at the bedside the entire time so that any issues may be addressed immediately. When attempting to perform ketamine DSI, the dosing usually is either 1 mg/kg to 2 mg/kg IV or 4 mg/kg to 6 mg/kg IM.144 (See Table 8.)
There have been only a few studies and case reports looking at the use of DSI with ketamine.145-149 Weingart et al completed an observational, prospective, multicenter study of both ICU and ED patients with delirium and hypoxia requiring intubation and found the mean oxygen saturation of 89.9% pre-sedation improved to 98.8% post sedation and pre-intubation using this technique.145 In addition, they reported no adverse events with this technique. Patients were given ketamine, and then either a non-rebreather oxygen mask was applied or noninvasive positive pressure ventilation (NIPPV) was given in addition to performing any necessary peri-intubation procedures (e.g., central lines, peri-intubation resuscitation, nasogastric tubes). The temporal delay between sedative and neuromuscular blocker was three to four minutes. In addition, Weingart et al commented that two patients with asthma receiving ketamine improved so drastically they no longer required intubation and tolerated NIPPV.
Jarvis et al examined the effects of a prehospital oxygenation bundle in non-cardiac arrest patients requiring intubation that included patient positioning, apneic oxygenation, DSI, and goal-directed oxygenation with bag mask positive pressure ventilation for three minutes post ketamine to a goal pulse ox of 94%. They found a reduction in the number of patients with peri-intubation hypoxia from 44.2% prior, compared to 3.5% post initiation of the oxygenation bundle.146
This was a small sample size and, therefore, rare but serious side effects may not be observed. In addition, there was no comparison to RSI in this study, and more randomized, controlled trials are needed to determine the safety and efficacy of DSI.150 In addition, DSI delays time to securing a definitive airway.151
In conclusion, DSI will require more research and controlled studies before it is fully accepted as safe and effective. If attempted by the ED physician in a combative or agitated patient who is resistant to preoxygenation, all equipment to carry through with a routine RSI, including neuromuscular blockers, should be ready at the bedside at the time the ketamine is given. Should laryngospasm, apnea, hypoventilation, inability to oxygenate, or airway compromise occur during the dissociative sedated state post ketamine, it is advised to proceed with a neuromuscular blockade and immediate intubation.144 This is in contrast to the management of laryngospasm seen during routine procedural sedation, where it is recommended to apply oxygenation, bag mask until it usually resolves in one to two minutes, only proceeding with intubation for laryngospasm lasting longer than two minutes.
Ketamine as a Drug of Abuse
Ketamine is taken as a “club drug” at nightclubs, music festivals, raves, concerts, and dance parties to enhance social intimacy and sensory stimulation. On the streets, ketamine frequently is referred to by names including “special K,” “vitamin K,” “super K,” “Ket,” “K,” “KitKat,” and “Kitty.”3 It is also sometimes referred to as horse/dog/cat tranquilizer, referencing its use in veterinary medicine. Ketamine is extremely hard to produce and manufacture illegally. Therefore, most of the illicit drug supply that is taken as abuse on the streets is diverted from pharmacy and veterinarian supply.3
The most common routes of administration include oral, sublingual, insufflation, and, less commonly, IM and IV injections. Recreational doses typically range from 100 mg to 300 mg orally, 30 mg to 200 mg IN, 75 mg to 125 mg IM or SQ, and 50 mg to 100 mg IV.152 Ketamine often is distributed in a liquid form that can be ingested or injected. In clubs or at raves, it is frequently dried into a powder and is smoked in a joint with a mixture of marijuana or cigarettes.153 This same powder also is frequently insufflated nasally. The more knowledgeable street users try to maximize its efficacy by using a medical nasal inhaler, which is called a “bullet” or a “bumper.” Taking one inhalation, or hit, can be referred to as a “bump.” Ketamine often is abused in combinations with multiple other drugs, referred to as a “trail mix,” including cocaine, methamphetamine, sildenafil, or heroin.150
Ketamine has many uses for emergency physicians, including management of acute agitated delirium, rapid sequence intubation, procedural sedation, and pain control. Consider using ketamine for other refractory conditions, including resistant migraines, severe status asthmaticus, and status epilepticus. There may be unrecognized airway and psychiatric effects.