Ketamine: Old Drug, New Uses

EXECUTIVE SUMMARY

• Ketamine is a dissociative medication, the only one in its class. Most commonly used as a general anesthetic, it permits patients to tolerate acutely uncomfortable procedures while maintaining most brainstem function, such as breathing and perfusion.
• Ketamine is useful in the treatment of acute pain. The dosage is significantly lower than when used for anesthesia, and, therefore, patients generally do not have significant side effects. It also has been used in the treatment of chronic pain.
• More recently, ketamine has shown promise in the treatment of depression. Patients treated with low-dose ketamine can experience improvement in their mental outlook and relief of suicidality within 24 hours. An isomer of ketamine is now approved for severe, refractory depression.
• However, ketamine is now used (abused) to create an acute, short-lived psychosis and has become a popular street drug.

Introduction

Is there anything ketamine cannot do — control pain, provide sedation, treat depression, or control seizures? Ketamine is a versatile medication well positioned for emergency medicine and prehospital applications alike. First described in the literature in 1966 by Corssen and Domino, ketamine was introduced as a dissociative anesthetic for surgical procedures.¹ Ketamine’s beginnings started as an alternative to a failed medication called phencyclidine (PCP). Phencyclidine was first developed as a possible sedative agent in 1956; despite initial promising tests, it quickly became apparent that it was ineffective because of its multiple adverse reactions, including hypertension, excess salivation, and severe psychological effects.^2,3

Ketamine was developed as an alternative anesthetic in 1962 by Calvin Stevens at what would become Pfizer Pharmaceuticals, with the first human administration in 1964.⁴ The drug’s unique “dissociative anesthesia” quickly became apparent to the initial researchers, as well as its significantly improved safety profile.² Ultimately, it was approved for human use by the U.S. Food and Drug Administration (FDA) in 1970.²

Ketamine’s sympathomimetic properties, wide safety margin, short recovery time, long shelf-life, low cost, and ease of use in austere environments made its prehospital and military applications immediately evident.^2,3,5 By September 1970, military physicians were already using ketamine to treat burn patients in the conflict between the Palestine Liberation Army and the Jordanian Armed Forces.³ Ketamine was further used by the British Army in counterinsurgency operations in Oman (1972) and in the 1975 Yom Kippur War, and by American forces during the Vietnam War.^2,3 It remains an effective drug for acute pain control in combat prehospital settings, such as the recent conflicts by American forces in Afghanistan and Iraq.⁶ Over the past decade, ketamine has been used significantly more frequently on the battlefield for treatment of combat injuries, typically in doses of 50 mg at intramuscular (IM) or intranasal (IN) routes.⁵ It is possible that this trend will continue in the conflicts of the future.⁵

While ketamine was approved by the FDA in 1970, its popularity in the civilian world soon began to decrease as other medications, such as propofol, entered the market. Concern over ketamine abuse grew, due in large part to books such as Journeys into the Bright World and The Scientist, which described the authors’ psychedelic experiences with ketamine. As a response to this, the 1999 U.S. Controlled Substances Act classified ketamine as a Schedule III controlled substance. With the simultaneous development of high-dose opioids, it briefly seemed that ketamine’s usefulness as a medication was waning.⁷

The American Pain Society’s “pain as the fifth vital sign” campaign in 1995, as well as a subsequent push for strict pain management and the rampant overprescription of opioids (a complex topic outside the topic of this article) contributed to the current opioid epidemic.⁸ In the ongoing public health crisis, it is strongly encouraged civilian healthcare providers take a second look at the myriad uses of ketamine.

Pharmacology

Ketamine consists of (S) and (R)-ketamine, two optical enantiomers.⁹ The two primary formulations of ketamine are the racemic mixture (also called Ketalar), and the S-enantiomer, which will be discussed later.¹⁰ For the purposes of this article, racemic ketamine will simply be referred to as “ketamine.” The drug is metabolized primarily by the cytochrome P450 enzymes of the liver, and, thus, patients with hepatic impairment should have any doses of ketamine adjusted.^9,11 Research is ongoing into ketamine’s main metabolites, dronorketamine and hydroxynorketamine, which appear to have significant pharmacologic activity of their own.¹²

As a derivative of PCP, ketamine’s primary function occurs via antagonizing the N-methyl-D-aspartate (NMDA) receptor.¹⁰ This action produces ketamine’s primary anesthesia, analgesia, and psychokinetic effects.¹² However, new research is showing that ketamine affects a significant range of cellular processes, including opioid agonists, the cyclic guanosine-monophosphate system, non-NMDA glutamate receptors, calcium ion channels, and many others, perhaps further explaining the extremely diverse range of this drug.¹²

Ketamine is both water and lipid soluble, granting it a wide variety of routes of administration, including oral, intravenous (IV), IM, IN, epidural, and intrarectal.^4,9 The IV and IM administrations of the drug are far more efficient than the oral route because of extensive first-pass hepatic metabolism.⁹ While the IN pathway has significantly less bioavailability than the IV and IM routes, its ease of use, rapid absorption, and avoidance of hepatic metabolism make it a useful alternative.⁹

In adults, ketamine is cleared primarily by the kidneys, and it has a short half-life of approximately two to four hours. Children eliminate the drug approximately twice as fast as adults do.⁹

Acute Pain Management

Since 2014, ketamine has been included in the U.S. Army’s Tactical Combat Casualty Care Guidelines as one of the primary three options for battlefield analgesia, next to meloxicam/acetaminophen for minor pain and oral transmucosal fentanyl citrate for moderate/severe pain without hemorrhagic shock.⁵ In austere environments other than the battlefield, low-dose ketamine remains an effective means of managing acute pain, even in challenging clinical situations such as high-altitude mountain rescue.^13,14 A 2020 meta-analysis found that ketamine monotherapy in the prehospital setting is an effective and safe medication for managing acute pain in trauma patients.¹⁵ Given this, the American College of Surgeons Committee on Trauma (ACS-COT), the American College of Emergency Physicians (ACEP), and multiple emergency medical services organizations recommend the use of ketamine for acute pain control in trauma patients in both the prehospital and hospital setting.¹⁶ In austere environments where weight-based dosing is not readily available, patients may receive 50 mg IM ketamine every 30-60 minutes until adequate analgesia is achieved, or until they begin to develop visible nystagmus. Other options include administration of 20 mg IV/intraosseous (IO) ketamine over one minute, given every 20 minutes until adequate analgesia is achieved or until the patient begins to develop nystagmus.¹⁶

Outside of extreme environments and the prehospital setting, ketamine is a valuable tool for the treatment of acute pain in the emergency department (ED). More than half of all ED visits are associated with acute pain.¹⁷ In the current opioid epidemic gripping the United States, it is imperative that emergency medicine physicians deploy safe and effective alternatives for providing analgesia.¹⁸ Although not yet in widespread use, low-dose ketamine (LDK) is a promising new treatment for both acute and chronic pain in the ED, particularly when treating patients with a history of chronic opioid use.¹⁷

LDK provides analgesia at subdissociative doses of < 0.5 mg/kg IV.¹⁷ A 2020 meta-analysis of eight randomized controlled trials with more than 1,000 patients demonstrated that LDK was as effective at reducing subjective pain within 60 minutes as IV morphine.¹⁷ However, multiple studies also have demonstrated that LDK is effective at IV bolus doses ranging from 0.1 mg/kg to 0.6 mg/kg.¹⁸ Even in postoperative cesarean delivery patients, a single bolus of LDK at 0.25 mg/kg IV is enough to significantly reduce pain.¹⁹ Other possible means of delivery include a bolus dose followed by IV infusions ranging between 0.1 mg/kg/hr to 0.2 mg/kg/hr.¹⁸ Other studies show a wide range of LDK doses for acute pain, including IV boluses of 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg.²⁰ Ketamine also may be administered intraosseously, subcutaneously, intranasally, orally, and through both epidural/intrathecal routes of administration.^4,20 Given the high degree of neurotoxicity associated with direct spinal administration, this route is not recommended in the ED setting.²⁰

Ketamine has a low oral bioavailability, limiting its potential uses in the ED.²⁰ However, daily oral LDK, in doses up to 64 mg/day, has been shown to be effective in the treatment of chronic pain.¹⁹ There are early promising results in the treatment of complex regional pain syndrome via the application of 10% ketamine cream three times per day.¹⁹

IN administration of LDK also appears to be an effective means of administration, possibly through an ability to cross the olfactory mucosa to the cerebrospinal fluid (CSF), and is non-inferior compared to IV analgesics for up to 60 minutes.^21-24 It is recommended that IN LDK be considered for the large segment of ED patients who have difficult IV access, particularly in resource- and provider-limited EDs.²⁴ IN starting doses for analgesia range from 0.25 mg/kg to 4 mg/kg in the literature; however, 0.7 mg/kg appears to be an effective initial dose. One study found significant relief of pain in 80% of patients administered this dose.^4,23 Side effects appear to be minimal and clinically insignificant, with no significant changes in vital signs.²¹ One study suggested that patients did not have to be monitored following IN LDK administration, a great asset to any resource-limited or understaffed EDs.²³

While LDK alone appears to be equally effective to opioids, LDK given in conjunction with opioids for complex presentations, such as sickle cell pain crisis and chronic opioid dependence, also shows a significant reduction in pain.^17,18 LDK at 0.2 mg/kg IV reduces concurrent opioid requirement by up to 25%; LDK at a dose of 0.1 mg/kg IV also reduces the amount of adjunct opioid required for effective analgesia.^25,26

LDK appears to be a particularly effective means of treatment in several patient populations. It may be used in patients for whom other non-opioid analgesics have failed, in acute pain flares in the setting of hemodynamic instability, in patients taking chronic opioid regimens due to malignancy, in opioid-tolerant patients, and in patients using medications for alcohol dependency.^17,18 Patients with renal insufficiency often have an increased risk for adverse effects secondary to opioid use, something that is not a concern with LDK.¹⁷ LDK may be used safely and effectively in orthopedic fractures, incision and drainage procedures, musculoskeletal pain, soft tissue infections, and even sickle cell pain crises.¹⁸

LDK currently is limited by a number of factors in the ED. Its novelty often leads to a lack of expertise in both physician and nursing teams, often making EDs hesitant to use it.¹⁸ While it has been officially endorsed by organizations such as ACEP, a significant level of unfamiliarity with the drug in emergency medicine circles persists.¹¹ Providers also may be concerned about the possibility of side effects, given the relative unfamiliarity of the drug. However, a meta-analysis of 1,187 patients who received LDK found the most common adverse effects to be transient dizziness, nausea, vomiting, and mild hallucinations/agitation, concluding that the side effects of LDK not to be a significant deterrent to its use.¹⁸ Further meta-analyses have concluded that LDK’s side effects are not clinically significant, and it has been noted that the patients do not require any increased clinical resources, an important asset in the ED.^11,26 It is worth emphasizing that opioids have adverse side effects as well, including apnea, vomiting, and hypotension; LDK displays no significant evidence of hypoxia or apnea.¹⁷ The tachycardia, hypertension, and mild hallucinations associated with LDK have been suggested to be much lower risk than the bradycardia, hypotension, apnea, and sedation associated with opioid use.²⁷ The extremely wide therapeutic window of ketamine also provides a protective measure against medication errors; overdoses up to 100 times the therapeutic dose have been reported in the medical literature without significant adverse outcomes.²⁷ In contrast, medication errors of opioid analgesics given in the ED often are associated with severe adverse events.²⁸ Indeed, opioid analgesics are one of the most common drug classes associated with adverse drug events.²⁷

Overall, LDK appears to be comparable to opioids for analgesia of acute pain in some cases.²⁹ Although this novel means of treating acute pain may be unfamiliar to many EDs, it is encouraged that providers explore the use of this medication in their practice. The wide variety of available means to administer LDK, as well as the effectiveness of LDK monotherapy or as an adjunct to other analgesics, holds great promise for the future.

Migraine Treatment

Migraines are responsible for the majority of the 5 million visits to American EDs for headache each year, at an estimated cost of $700 million annually. Migraines often are difficult to treat in the typical ED environment.³⁰ While current evidence is limited, several preliminary studies indicate that ketamine may be effective in the treatment of chronic migraines, particularly through an IV infusion rate of 0.1 mg/kg/hr that is increased steadily until pain control is achieved.^19,31 Doses of 25 mg IN ketamine appear to be effective in the treatment of migraine with aura.¹⁹ However, further research in this possible mode of treatment is necessary, and controversy remains regarding the effectiveness of LDK for migraine in the ED.^32,33

Ketamine as an Induction Agent

Rapid sequence induction (RSI) is a crucial aspect of emergency medicine, but no uniform approach or guidelines currently exist.³⁴ Ketamine often is used as an RSI medication, typically at an IV dose of 1 mg/kg to 2 mg/kg, capable of producing dissociative anesthesia anywhere from 30 seconds to one to two minutes.³⁵ This state of anesthesia can be maintained through intermittent boluses dosed at 0.5 mg/kg, or through a continuous infusion at 10 mcg/kg/min to 30 mcg/kg/min.³⁶

Ketamine has a longer duration of action than propofol and etomidate, as well as relative hemodynamic stability compared to other RSI drugs, making it an effective RSI agent.³⁷ Although etomidate appears to have a similar effect on hemodynamic stability, it also has a significantly higher likelihood of adrenal insufficiency in critically ill patients than ketamine; however, the clinical relevance of this remains in doubt.^38,39 Meanwhile, the psychiatric side effects of ketamine also are not frequently observed in RSI, since patients will remain sedated for several hours at a minimum.³⁸

The drug’s unique dissociative properties — allowing the brainstem to continue to function while the patient is unaware of unpleasant external stimuli — also allow it to be effectively employed in unconventional procedures.³⁷ In agitated or uncooperative patients, preoxygenation for intubation may be extremely difficult. Given the importance of proper preoxygenation for these patients, ketamine may be used in delayed sequence intubation (DSI). In this technique, an agitated patient is given a dissociative dose of ketamine at 1 mg/kg to 2 mg/kg IV or 4 mg/kg to 6 mg/kg IM. Once the patient is dissociated, preoxygenation can be commenced, and plans for definitive airway management can proceed safely. Any periods of apnea associated with a ketamine bolus are self-limited within 60 seconds, although emergent means to proceed with RSI should be easily accessible if necessary.³⁷ It is important to note that ketamine should be used carefully with suspected alcohol intoxication, given the potential to worsen the sedative effects of alcohol, and should be used with caution in suspected cocaine toxicity, given the theoretical possibility for worsening of the overdose’s sympathomimetic effects.¹⁶

Ketamine monotherapy also may be used in spontaneously breathing patients. This procedure is recommended only in austere environments or with a topical anesthetic. In the ketamine-only breathing intubation technique, a dissociative dose of ketamine is used to facilitate intubation in a patient while brainstem functions remain intact.³⁷ While the medical literature is limited, this technique has been suggested to be effective in patients who “may not tolerate even a brief period of apnea,” such as severe pneumonia, acute respiratory distress syndrome, severe alcohol withdrawal, thyroid storm, or severely acidotic patients.³⁷ However, ketamine monotherapy should be used sparingly; it has been noted to have a lower rate of success and an increased rate of adverse events when compared to traditional RSI.⁴⁰ The addition of topical anesthesia to the upper airway and glottis significantly improved outcomes in these cases and should be strongly considered if available.⁴⁰

Because of ketamine’s analgesic and sedative properties, ketamine monotherapy may be continued in the intubated patient in the ED, through either 1 mg/kg to 2 mg/kg boluses or an infusion rate of 1 mg/kg/hr to 5 mg/kg/hr. This also may be employed effectively with benzodiazepines or propofol to minimize the risks of emotional/psychiatric distress.³⁷ Of note, the ACS-COT and ACEP organizations do not recommend dosages of ketamine between 0.5 mg/kg to 0.9 mg/kg IV; under their official guidelines, they note that dosages in this range are not effective for sedation and produce a “feeling of unreality” that can make patients difficult to manage.¹⁶

For RSI, ketamine may be administered at 1 mg/kg to 2 mg/kg IV or 2 mg/kg IV for a maximum of 200 mg.^16,41 A 2017 study of 968 trauma patients found no significant difference between the use of ketamine and etomidate as induction agents in terms of hospital stay, transfusion requirements, or mortality.⁴² ACEP and ACS-COT recommend ketamine as an RSI agent because of its hemodynamic, sedative, and analgesic properties, noting that it is particularly effective in hypotensive trauma patients.¹⁶ RSI ketamine also may be dosed at 4 mg/kg to 11 mg/kg in the IM form, 500 mg maximum in the oral form, and 3 mg/kg to 9 mg/kg IN for (S)-ketamine.⁹ (See Table 2.)

Hypotension at RSI is strongly linked to increases in mortality and morbidity in the hospital setting.³⁴ In most cases, ketamine maintains tissue perfusion more effectively compared to propofol, fentanyl, midazolam, and other RSI agents.³⁷ However, ketamine should not be used in patients with severe heart failure because of the potential for a negative cardiac inotropic effect.⁴¹

Clinicians should be aware of the potential for ketamine-induced hypotension. While ketamine typically is remembered for its catecholamine-mediated increase of blood pressure and heart rate, evidence shows that in some cases it may induce hypotension in shock patients. A 2016 prospective observational study of 112 shock patients found that patients with a high shock index (defined as pulse rate/systolic blood pressure) ≥ 0.9 had a significantly greater rate of postinduction hypotension following ketamine administration than patients with a shock index < 0.9.⁴³ The rates of postinduction hypotension in these two groups were 26% and 2%, respectively.⁴³ The researchers concluded that ketamine still was a useful induction drug for managing hemodynamics; however, they warned that it may be less effective in especially severe presentations.⁴³

Of note, both propofol and etomidate display similar effects of postinduction hypotension, suggesting that this is not purely pharmacological but, rather, multifactorial in the setting of critical illness.⁴³ Other studies indicate an age older than 60 years and a shock index above 1.0 are associated with an increased need for vasopressors in the immediate period post-RSI, regardless of whether ketamine or propofol is used.⁴⁴ Even with the hypotension that ketamine may induce in high shock index patients, some studies argue that it still is associated with less post-RSI hypotension than other RSI agents.³⁷

The risk of post-RSI hypotension following ketamine administration also has been noted in septic patients.⁴⁵ A study of 531 intubated sepsis patients observed that ketamine was associated with higher rates of post-RSI hypotension than etomidate.⁴⁵

Other studies have noted that ED physicians are more likely to use ketamine in hypotensive or hypovolemic patients with a high shock index, perhaps somewhat explaining the post-RSI hypotension seen in these patients.^34,44 However, the same study found that ketamine may have a post-intubation reduction in blood pressure in excess of 20%.³⁴ It may be that ketamine’s catecholamine-releasing effects are inherently limited in catecholamine-depleted, severely ill patients.⁴⁵ Existing research is limited, but the possibility of post-ketamine RSI hypotension in patients with a severe shock index should not be discounted.³⁴

It is recommended that hypovolemic patients with high shock indexes be monitored closely for any indication of hypotension following induction and a strong focus placed on resuscitation prior to intubation. Older adult patients and patients with higher shock indexes on presentation are more likely to require post-RSI vasopressors to maintain adequate perfusion.⁴⁴ In these patients, resuscitation prior to intubation should be prioritized, and that the induction dose of ketamine be halved to 0.5 mg/kg to 1 mg/kg IV.³⁷ The most severely hypoperfused patients should be administered the minimal dose of an induction agent needed to achieve adequate sedation.³⁷

Asthma Exacerbation

Despite ketamine’s bronchodilatory properties, there is no strong evidence to indicate that it is an effective treatment for refractory status asthmaticus. Only a handful of studies have been conducted on this subject, and they are limited by the wide range of ketamine dosages used and the extremely variable results.⁴⁶ Given this, it is not recommended that ketamine be used in combination with corticosteroids, anticholinergics, and short-acting beta agonists in the first-line treatment of asthma.⁴⁶

However, ketamine is an effective RSI agent when intubating status asthmaticus with respiratory failure, due to dilating the bronchial smooth muscle. Although it may increase oral secretions within several minutes, this rarely is an issue during the time frame that RSI requires.⁴¹ When paired with preoxygenation via bilevel positive airway pressure (BiPAP), it has a nearly 100% success rate of intubation.⁴⁷

Trauma

As discussed earlier, ketamine monotherapy is an effective analgesic in prehospital management in trauma patients and has been shown as an effective means of improving prehospital physiologic severity indicators in low-resource, austere environments.^15,48 Ketamine also may be given safely to trauma patients who have opioid use disorder.⁴⁹ Ketamine’s wide safety profile works to its advantage in such settings. A review of children who were given 5, 10, and 100 times the intended ketamine dose found that none experienced long-term sequelae, although several experienced brief respiratory depression and required assisted ventilation.⁵⁰ While ketamine is a safe drug and is associated with very low rates of prehospital mortality, it should be administered only when providers can closely monitor patients for respiratory depression and intervene with definitive airways if necessary, due to the transient apnea that it can induce.^16,51 Particular attention should be paid when ketamine is infused via a rapid IV injection; apnea secondary to IM administration appears to be rarer.⁴⁹

Similarly, ketamine is an effective RSI medication for trauma patients, with no significant differences in mortality, length of hospital stay, or blood transfusion requirements compared to other common RSI agents, such as etomidate, propofol, thiopental, or midazolam.³⁵ In theory, ketamine given to trauma patients post-operatively may modulate the inflammatory response, reducing the severity of any chronic postoperative pain.⁹

The early dogma of the 1970s claimed that ketamine dangerously elevated intracranial pressure (ICP).⁵² However, this theory has been disproven in recent years. The initial studies that suggested ketamine elevated ICP do not appear to have adequately accounted for the effects of ventilation in the small number of cases analyzed; it appears that the reported elevation in ICP was due to hypercarbia.¹⁹ In reality, ketamine demonstrates a number of neuroprotective effects, reducing adverse events such as focal ischemia, hemorrhagic necrosis, and chronic cerebral hypoperfusion.¹⁹ Ketamine stimulates cerebral perfusion and demonstrates improved outcomes in traumatic brain injury (TBI) and hemorrhagic strokes.¹⁹

Infarct volume in focal ischemia and volume of hemorrhagic necrosis both are reduced in the presence of ketamine.⁵³ Ketamine potentially may even be used in the treatment of delayed ischemia following subarachnoid hemorrhage and vasospasm.⁵³

In animal models, ketamine has even been shown to reduce neuronal damage in status epilepticus. In a review of 58 cases of refractory status epilepticus, researchers noted that one-third of cases completely resolved in response to ketamine.⁵³

These myriad neuroprotective effects likely are the result of several factors, including noncompetitive antagonism of the NMDA receptor, thus reducing excitotoxicity, interference of glutamate release from neurons, stimulation of cerebral blood flow, a reduction of apoptosis and cell death, reduction in neuroinflammation, and mitigation of microthrombosis.^19,53

Ketamine’s neuroprotective effects are most pronounced for ED physicians in cases of head trauma. In life-threatening cases displaying hypotension secondary to shock, it is crucial that ED physicians minimize any secondary injuries to the brain through hypoperfusion. This is especially crucial in hypovolemic patients.⁵⁴ In these cases, ketamine’s hypertensive and neuroprotective properties make it an ideal induction agent.⁵⁴

This has been borne out by recent data. A 2019 review of 555 pediatric patients who experienced head trauma found that there was no significant difference in mortality between those who received prehospital ketamine therapy and those who did not.⁵⁵ Ketamine may be used safely as an induction agent for intubation in patients with head injury, including in children.^56,57 Even in the inpatient setting, the administration of ketamine to sedated and ventilated patients does not demonstrate any significant increase in ICP, across both adult and pediatric populations.^58,59

Likewise, ketamine is safe to use in known or suspected open globe injuries, since the changes that it produces in intraocular pressure are not clinically significant.¹⁶ Of note, ketamine is contraindicated for procedural sedation or analgesia to obtain an eye examination because of the nystagmus that it may induce.¹⁶

Status Epilepticus

A 2017 meta-analysis of 25 articles published between 1996 and 2017 found that ketamine is an effective treatment for status epilepticus (SE), with a success rate of 74% in adults and 73% in children.⁶⁰ However, medication doses ranged widely. The adult cases required a bolus dose of ketamine ranging from 0.5 mg/kg to
5 mg/kg, followed by a continuous infusion between 0.6 mg/kg/hr to 10 mg/kg/hr.⁶⁰ The pediatric dosages varied even more considerably, with one study administering oral ketamine at 1.5 mg/kg/day in two doses per day for five days.⁶⁰ Further research is needed to determine the proper dosages and timing of ketamine in SE.⁶⁰ Fortunately, ketamine has an extremely wide safety profile.⁵⁰

As already discussed, there is no evidence to suggest that ketamine significantly increases ICP in either traumatic or nontraumatic brain injury.⁶¹ Given this, there is promising research that ketamine may be used to treat refractory status epilepticus (RSE) resistant to typical antiepileptic drugs, or even super-refractory status epilepticus (SRSE) resistant to anesthetic agents.⁶¹

In a study of 68 patients with SRSE monitored by scalp electroencephalogram, researchers found that ketamine infusion decreased seizure burden by at least 50% in 81% of patients within 24 hours of starting the infusion.⁶¹ The average dose required was relatively high, at 2.2 mg/kg/hr of ketamine. Of note, treatment with ketamine was more effective when it was initiated early, suggesting that ketamine may be used effectively as a first-line treatment for RSE.⁶¹ A 2018 meta-analysis has corroborated this finding, noting that ketamine is roughly twice as effective when administered early, with an average seizure cessation rate of 64% if used within a mean of three days, and a cessation rate of 32% if used within a mean of 26.5 days.⁶²

Although further research is required, ketamine also appears to be an effective second-line antiepileptic medication in pediatric seizures resistant to benzodiazepines.⁶³ A 2023 retrospective single-center study corroborated this, finding that ketamine bolus, followed by an infusion of 1 mg/kg/hr, terminated seizures in 46% of neonatal and pediatric patients. However, the administration of other drugs, such as pentobarbital, which all the patients received in addition to ketamine, may limit the generalizability of this study.⁶⁴ Nevertheless, early data in this field are promising.

Pediatric Patients

Ketamine has been shown to be both safe and effective in pediatric patients. It is recommended that ketamine be dosed by weight or length-based weight estimate consistent with ACEP recommendations.¹⁶ Ketamine should not be given to patients younger than the age of 3 months, in large part because of the immature functioning of the liver.^16,65

Airway and respiratory adverse events have been described in 3.9% of ketamine-induced pediatric sedations, with vomiting being the most common complication, ranging from 8% to as high as 26%.⁶⁶ A meta-analysis of 8,282 pediatric sedations found that vomiting is most common in early adolescents and is associated with IM administration of ketamine, as well as high IV dosages (defined as initial dose ≥ 2.5 mg/kg or total dose ≥ 5.0 mg/kg).⁶⁶ Although ketamine is well known for its psychomimetic side effects, these appear to be rare, brief, and are not disturbing in children, with severe agitation during recovery at an incidence of approximately 1.4%.⁶⁵ In the past, midazolam has been given as an adjunct to reduce the incidence of ketamine’s psychomimetic properties, but this treatment appears to be ineffective.⁶⁶ Additionally, ketamine may potentiate the sedative effects of benzodiazepines when the medications are given concurrently.⁴⁹ Because of its proven ineffectiveness as well as increased sedative effects, the routine use of benzodiazepines to prophylactically prevent emergence reactions is not recommended.⁴⁹

Ketamine has been shown to be an effective medication for pediatric procedural sedation in the ED across more than 50 studies encompassing nearly 10,000 patients.⁶⁶ It is now one of the key Pediatric Non-Operating Room Anesthesia agents available, which includes other agents, such as midazolam, fentanyl, and propofol.⁶⁵ There are data to suggest that lower doses of ketamine can be used for pediatric procedural sedation in the ED; a 2007 retrospective study of 72 pediatric patients found that ketamine given at 0.5 mg/kg to 1.0 mg/kg IV usually is sufficient.⁶⁷ Other studies have shown that a median loading dose of 1.00 mg/kg IV can be used for more complex gastroenterological procedures in pediatric patients.⁶⁸ IN ketamine also may be used effectively for sedation in several procedures, including laceration repair, dental procedures, and gastric aspiration, although the onset of sedation typically takes 11 minutes, as compared to one minute for IV ketamine.⁶⁹ Providers may find it particularly useful in uncooperative patients or in patients with difficult IV access.⁶⁵

Ketamine also may be used for analgesia and anxiolysis as a premedication for children about to undergo anesthesia. Oral ketamine, dosed at 4 mg/kg to 6 mg/kg, when combined with midazolam 0.1 mg/kg to 0.5 mg/kg (up to 10 mg to 15 mg total) and atropine, can produce deep sedation, with IM ketamine at 2 mg/kg to 4 mg/kg used with children who refuse oral medication.⁶⁵ IN ketamine in children has a low rate of complications and is associated with both high levels of provider satisfaction and patient comfort.⁷⁰ Much like in adults, IN ketamine is an effective alternative to opioids for acute pain control.^21,71 IN ketamine for pediatric patients typically is administered between 1 mg/kg to 1.5 mg/kg.⁷¹

Ketamine is an effective RSI medication for pediatric patients, largely because of its rapid and brief duration of action, and maintenance of respiratory function.⁶⁵ A retrospective analysis of 10,750 tracheal intubations from 40 pediatric intensive care units found that ketamine is associated with fewer hemodynamic adverse events.⁷² Ketamine also is useful in securing difficult pediatric airways, particularly in conditions such as Pierre Robin and Goldenhar syndrome, where fiberoptic intubations may be required.⁶⁵ In these cases, combining ketamine with a sympatholytic drug such as dexmedetomidine may help manage excess secretions and keep the airway patent.⁶⁵ Anesthetics such as a lidocaine spray also should be used during these procedures, since ketamine does not inhibit the cough and swallow reflexes of the patient.⁶⁵

Psychiatric Uses

Approximately 1 million people each year will attempt suicide in the United States, making it the 10th leading cause of death in the country.⁷³ A significant portion of these patients who died by suicide were seen in the ED shortly before their death.⁷³ Unfortunately, acute treatments for suicidal ideation are limited, particularly in the ED.⁷⁴

However, a growing body of evidence suggests that ketamine is an effective medication to stabilize patients at imminent risk of suicide.⁷⁴ A 2018 meta-analysis of 10 different studies found that a single dose of subanesthetic IV ketamine significantly reduced suicidal ideation within one day, with effects lasting up to one week afterward. Of the patients, 54.9% were completely free of suicidal ideation 24 hours after the ketamine dose, and 60.0% denied any suicidal ideation one week after the dose. For comparison, electroconvulsive therapy, the gold standard of treatment, takes six treatments over two weeks to achieve similar results.⁷⁴ This finding has been replicated in a subsequent meta-analysis, which found that a single dose of IV ketamine at 0.5 mg/kg infused over 30-45 minutes may reduce suicidal thoughts for up to 72 hours.⁷⁵ However, further research is needed on the long-term effects this has on suicidal thoughts, if it significantly affects suicidal behavior, and on optimal dosing strategy.^74,76

Ketamine also appears to be a promising treatment for major depression, and able to produce a rapid improvement of symptoms.⁷⁷ While the effects of this treatment appear to be transient, other available antidepressants are limited by a prolonged onset of action.⁷⁷ Recent studies have suggested that repeated doses of ketamine can extend its duration of action.⁷⁸ In 2019, the FDA approved the (S)-ketamine (esketamine) enantiomer as the nasal spray Spravato for treatment-resistant depression. Spravato is significantly more effective than placebo at reducing depression symptoms, often as soon as 24 hours, but it requires continuous use.⁷⁹

A single dose of IV ketamine may reduce the symptoms of post-traumatic stress disorder (PTSD) for 24 hours, although symptoms appear to recur approximately 48 hours after the infusion.⁸⁰ Repeated infusions of ketamine are even more effective at reducing symptom severity in patients with chronic PTSD.⁸¹ Long-term oral ketamine is an effective treatment for PTSD, reducing hospital admissions in these patients by up to 65%, with no subsequent evidence of tolerance-building or adverse effects.⁷⁹ There is debate over whether ketamine administered soon after trauma may prevent the development of PTSD, but following a 2020 retrospective study of 1,158 injured U.S. soldiers, ketamine given in the peri-trauma setting does not appear to significantly affect the development of PTSD at all.⁸⁰

Ketamine also may be used to reduce relapses in cocaine use disorder and heroin use disorder, possibly due to disrupting the maladaptive reward memory pathway.⁷⁹ The literature on this topic currently is limited, but preliminary evidence for ketamine in the treatment of addiction is promising.⁸²

While ketamine’s treatment of acute suicidal ideation and other psychiatric conditions holds great promise, the psychotic effects of ketamine use remain controversial.⁷⁴ ACEP and ACS-COT officially state that ketamine does not appear to cause an increased incidence of psychosis.¹⁶ However, a 2020 meta-analysis of 36 studies found that bolus doses of ketamine, in both the racemic and esketamine enantiomers, appear to be associated with transient positive psychotic symptoms, defined as three or more of the following: “conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness.” Of note, the researchers estimated the effective dose of this to be approximately 0.5 mg/kg IV, similar to the dosage used to treat depression, and recommended that dosing of ketamine be performed in slower infusions lasting 40-60 minutes.⁸³ The 2018 meta-analysis that recommended using ketamine to treat acute suicidal ideation specifically excluded patients with diagnoses such as substance use disorder and schizophrenia/schizoaffective disorder for this reason.⁷⁴ However, the recent literature has suggested that these side effects are rare and self-limiting, and that ketamine can be administered safely to patients with a history of psychosis or currently psychotic features.⁸⁴

Several studies have suggested that subanesthetic administration of ketamine may decrease concentration, recall and recognition, memory, and overall mental sharpness. While these effects appear to be largely confined to either during or immediately after the infusion of the drug, long-term ketamine abuse outside the hospital setting appears to be associated with cognitive impairment. However, this association has not been proven conclusively and may be due to a number of confounding environmental or comorbid factors.⁹

Esketamine

Although the racemic form of ketamine, also known as Ketalar, has been available for decades, the S-enantiomer of the drug has been growing in popularity in recent years.¹²

The S-ketamine enantiomer, better known as esketamine, has a number of unique properties when compared to the racemic mixture. As an anesthetic, it is approximately twice as potent as the racemic mixture, typically requiring approximately 140 mg to induce anesthesia, as compared to approximately 275 mg for racemic ketamine.⁹ Esketamine also appears to be a significantly more potent analgesic than the racemic mixture, although it is associated with increased side effects, including sensory alteration and acute psychotic reactions.⁹

Esketamine also is four times more potent for the NMDA receptor than ketamine, and initially appeared to be a more effective antidepressant than IV racemic ketamine.^79,85 Despite this, IV racemic ketamine appears to be significantly more effective at treating depression than IN esketamine, even though the latter is FDA approved. Further research is needed on this topic.⁸⁵

Esketamine’s impact on a patient’s hemodynamic status does not differ significantly from that of ketamine.⁹ Early research suggests that low-dose esketamine, when added on to anesthesia, may improve hemodynamic stability and postoperative recovery in older adults, but more data are required.⁸⁶ Esketamine also appears to be a safe RSI induction agent when paired with propofol, both improving hemodynamics, postoperative cognitive function in older adult patients, and decreasing anesthesia time.⁸⁷ Likewise, IN esketamine appears to be an effective means of sedation in pediatric patients when paired with IN dexmedetomidine.⁸⁸

However, despite its growing popularity, the current literature regarding esketamine is largely limited to its potential as an antidepressant agent.⁷⁹ Further research is required before the potential of this enantiomer can be fully discovered.

Ketamine Abuse

Ketamine’s fame as a recreational drug is growing. Known by names such as “K,” “Ket,” “Special K,” and “the horse tranquilizer” (a reference to its applications in veterinary medicine), ketamine has been used as a psychosis-inducing drug since the late 1970s.⁸⁹

Ketamine is an extraordinarily safe drug, and deaths due to ketamine overdose are so rare that they are practically nonexistent in the literature.⁹ However, poisonings have increased in recent years, and they sometimes can be seen in concurrent cases of polysubstance abuse.⁹⁰ Prolonged and heavy recreational use of ketamine, often as a party drug that usually is snorted or inhaled, is associated with bladder wall thickening and perivesical inflammation that manifests as unpleasant urinary symptoms, including frequency, incontinence, hematuria, and ulcerative cystitis.^9,90 Chronic users also may display abnormal liver function tests, as well as a dilated common bile duct and choledochal cysts on exam.⁹¹ In addition to this, chronic users may experience memory deficits, as well as persistent depressive, dissociative, and delusional thinking.^9,91 In the most severe cases, these side effects may significantly affect the user’s quality of life and further compound other addiction problems.⁸⁹ Abstinence from the drug may improve these symptoms and remains the gold standard of treatment for chronic abuse.⁹¹

Ketamine’s Adverse Reactions

Although ketamine is a promising medication, it is not without potential adverse reactions. A 2024 multicenter center of 234,170 patients who underwent procedural sedation found that 5.6% of patients who received ketamine underwent desaturation, defined as oxygen saturation < 90% for two or more consecutive minutes, compared to 5.2% of patients who did not receive ketamine. Notably, this effect was dose-dependent and magnified in vulnerable subgroups, including older adults, those with a history of smoking, or a recent intensive care unit admission.⁹²

In addition to this, ketamine may be associated with laryngospasm during sedation, which subsequently increases the risk for hypoxemia, bradycardia, aspiration, and cardiac arrest.⁹³ While laryngospasm may occur with multiple medications, this rare complication appears to occur most commonly when propofol and ketamine are used in combination.⁹³ IV ketamine has a similar prevalence compared to IV propofol alone, with a recent 2022 article demonstrating a laryngospasm prevalence of 1.4/1,000 pediatric procedural sedations. However, even this low prevalence shows that ED physicians should be properly trained in airway management for any adverse airway events.⁹³

“Emergence delirium” is a side effect of ketamine that has been noted since the 1970s, with initial reports of an incidence rate as high as 21%. However, emergence delirium is far less common than initially reported, due to early confusion in classification. A 2009 study found that emergence delirium, defined as “combative, disoriented, and agitated behavior, not amenable to comforting or calming,” occurs in only 2.1% of cases. In eight of the nine cases of emergence delirium they described, the researchers found that these pediatric patients became calm and cooperative within 20 minutes.⁹⁴ While up to 39% of pediatric patients may experience altered perceptions on awakening from procedural sedation, this experience is pleasant and not distressing.⁹⁴ Similarly, recovery reactions in adults are uncommon and mild. The rare cases of physical combativeness or excitation may be treated effectively with titrated benzodiazepines.⁹⁵

Similarly, repeated use of ketamine for the treatment of depression may lead to patients developing urinary tract symptoms, liver toxicity, headache, dizziness, hypertension, and blurred vision. Clinical tools such as the Ketamine Side Effect Tool are growing in popularity, allowing clinicians to have a specific, systematic way to monitor and report the side effects of repeated ketamine use.⁹⁶ Long-term use of ketamine also may be associated with sexual dysfunction and cystitis.⁹⁷

In extremely rare cases, ketamine may cause anaphylactic shock.⁹⁸ Clinicians should be aware of the potential for this severe complication and prepared for intervention if necessary.

Conclusion

Ketamine’s safety profile; unique combination of analgesic, anesthetic, and psychokinetic properties; and extremely wide range of potential uses, with promising research into its antiepileptic and psychiatric mechanisms, make it a valuable tool in the ED physician’s arsenal. ED physicians will find many day-to-day uses of this remarkable medication.

Summary

• Ketamine is an extremely versatile medication with anesthetic, analgesic, and psychokinetic effects that often is administered orally, intramuscularly, and intranasally.

• Low-dose ketamine is an effective treatment for acute pain in the ED setting.

• Ketamine is an effective RSI agent due to its hemodynamic, sedative, and analgesic properties.

• Ketamine does not elevate ICP and may be neuroprotective in some cases.

• Ketamine is an effective medication for pediatric patients.

• Ketamine’s psychiatric properties are a promising, rapidly growing field for the treatment of acute suicidal ideation, depression, and other mental illnesses.

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