section name header

Introduction ⬇

AHFS Class:

Notice: On October 10, 2023, FDA issued a warning to patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. Ketamine is not FDA approved for the treatment of any psychiatric disorder. In addition, compounded drugs, including compounded ketamine products, are not FDA approved and have not been evaluated for safety, effectiveness, or quality prior to marketing. Home use of compounded ketamine products presents additional risk because onsite monitoring by a health care provider is not available. FDA has identified potential safety concerns associated with the use of compounded ketamine products from compounders and telemedicine platforms, including abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression, and lower urinary tract and bladder symptoms. For additional information see [Web].825

Generic Name(s):

Ketamine hydrochloride, an N -methyl-d-aspartate (NMDA) receptor antagonist, is a nonbarbiturate general anesthetic that also has analgesic and antidepressant properties.1,3,4,5,9,10,26,35

Uses ⬆ ⬇

[Section Outline]

Ketamine hydrochloride was initially developed as an anesthetic agent; however, the drug can also produce profound analgesia and other pharmacologic effects, and is therefore used for a variety of other indications such as procedural sedation, pain management†, sedation and analgesia in the intensive care setting†,3,9,10,11,12,25,26,31,44,84,89,214,821,823 and some psychiatric indications, including treatment-resistant depression and suicidality†.300,301,302,303,304,305,306,307,309,311,312,313,314,315,317,320,326,327

Induction and Maintenance of Anesthesia !!navigator!!

Ketamine is used IV or IM for induction of anesthesia prior to administration of other general anesthetic agents.1,3 Ketamine also may be used as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation or as a supplement to other general anesthetic agents.1 While the manufacturer states that safety and effectiveness of ketamine in patients younger than 16 years of age have not been established,1 the drug has been used widely in pediatric patients†.3,9,23

Induction of anesthesia with ketamine is rapid and results in a trance-like cataleptic state characterized by profound analgesia and amnesia, with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability.1,2,4,5,11,35 The anesthetic state produced by ketamine is distinct from that of other general anesthetic drugs (e.g., barbiturates, propofol, benzodiazepines, inhalation anesthetics).5,11 Dissociated patients are nonresponsive and unable to respond to external stimuli (including pain).11 Unlike other anesthetic or sedative drugs, increasing the dose of ketamine beyond the dissociative threshold does not enhance or deepen sedation.11

Efficacy of ketamine as an anesthetic agent has been evaluated in over 12,000 operative and diagnostic procedures involving over 10,000 patients from 105 studies.1 Procedures for which ketamine has been used include debridement, dressing changes, and skin grafting in burn patients; neurodiagnostic procedures (e.g., myelograms, lumbar punctures); diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions; sigmoidoscopy and minor surgery of the anus and rectum; circumcision; short gynecologic procedures (e.g., dilatation and curettage); orthopedic procedures (e.g., closed reductions, manipulations, femoral pinning, amputations, biopsies); and cardiac catheterization.1,3,9,10

Due to the risk of emergence reactions and the availability of other anesthetic agents, current use of ketamine is generally limited to certain patient populations (e.g., those with hemodynamic instability) or settings (e.g., prehospital environments that lack appropriate monitoring and respiratory support) where the drug's unique pharmacologic properties may be advantageous.3,9,44,51 Because ketamine produces sympathomimetic effects, the drug may be particularly useful for induction of anesthesia in hemodynamically unstable patients (e.g., those with traumatic injury or septic shock).3,9,10 Because of its bronchodilating effects, ketamine is generally considered the induction agent of choice in patients with reactive airway disease (e.g., asthma) or active bronchospasm.3,9,10

Ketamine is commonly used as an induction agent for rapid sequence intubation, particularly in patients with reactive airway disease or hemodynamic compromise; studies have shown that ketamine may produce similar outcomes to etomidate and may be used as an alternative.9,80,81,88

Procedural Sedation !!navigator!!

Ketamine is used as a procedural sedation agent to facilitate short painful or emotionally disturbing procedures (e.g., fracture reduction, laceration repair, abscess drainage, emergency cardioversion, chest tube insertion, central line placement) in the emergency department and other clinical settings (e.g., radiology suite, dental office, cardiac catheterization laboratories).1,3,4,9,10,11,14,79,89,106,109,214,821,823

Procedural sedation is a technique in which sedative or dissociative agents are administered with or without analgesics to allow patients to tolerate painful or unpleasant medical procedures; a depressed state of consciousness is intentionally induced while cardiorespiratory function is maintained.89,214,821,823 In contrast to other procedural sedation agents, ketamine produces dissociative sedation and does not follow the usual sedation continuum where the more drug that is given, the deeper the patient will progress in their level of sedation; once the dissociative threshold has been reached, additional administration of ketamine will not enhance or deepen sedation.11,824 Administration of a single IV or IM dose of ketamine can effectively produce a dissociative state for approximately 5-10 or 20-30 minutes, respectively, while maintaining cardiovascular stability, spontaneous respiration, and protective airway reflexes.1,11

Ketamine is widely used for procedural sedation in pediatric patients† and is particularly useful for facilitating painful procedures as well as procedures requiring immobilization of uncooperative patients.3,9,11,78,79,89,106,821,823 A benefit of the drug is that it can be administered via the IM route in patients in whom IV administration may be difficult (e.g., severely agitated or combative patients, young children, patients with extensive burns).3,9,11,23,821 Although ketamine is used less frequently in adults due to an increased risk of emergence delirium, the current evidence also suggests that the drug can be used safely and effectively in the adult population.3,9,11,89,214 Ketamine has a well-established role in the care of burn patients undergoing painful procedures (e.g., dressing changes, debridement, grafts).3,9,10,23

Ketamine is commonly administered in combination with propofol to provide deep sedation for painful procedures; the combination regimen is given to potentiate the advantages of each drug while decreasing the risks (e.g., propofol-associated hypotension and respiratory depression; ketamine-associated vomiting and recovery agitation).9,10,89,107,108

Studies comparing the use of ketamine with other sedative/analgesic agents (e.g., propofol, benzodiazepines, etomidate, opiate analgesics) have reported various findings, and outcomes have differed based on whether the drug was used alone or in combination with other agents.823

Pain !!navigator!!

Ketamine exhibits potent analgesic properties in low (i.e., subanesthetic or subdissociative) doses and has been used for a variety of acute and chronic pain conditions†.3,4,9,10,25,26 Such conditions include acute pain† in the emergency department and prehospital settings,3,9,10,14,15,19,20,21 postoperative pain†,3,9,10,25 and chronic pain† of various etiologies.3,9,10,26,43,44,45,47 In addition to its analgesic effects, ketamine also can prevent the development of central sensitization, hyperalgesia, and opiate tolerance, which may be particularly useful in patients who are opiate tolerant or opiate dependent.10,19,25,26,52,82

Postoperative Pain

Ketamine in low (i.e., subanesthetic or subdissociative) doses has been used for the management of postoperative pain† following a variety of surgical procedures in both adults and pediatric patients.3,10,25,27,28,29,30,34,75,76,82 97,98,99,100,101,102,103 The drug should be used as part of a multimodal regimen consisting of a combination of pharmacologic and nonpharmacologic methods targeting different pain mechanisms in the peripheral and central nervous systems.82

Efficacy of low-dose ketamine in the postoperative setting is well established and supported by numerous studies demonstrating reduced opiate requirements and, in some cases, additional reductions in postoperative pain when the drug was used as a component of multimodal analgesia; although some studies reported discrepant results, the inconsistency may be due to differences in patient populations, dosage regimens, and concomitant analgesics used.3,10,27,29,33,34,75,76,82 Because ketamine appears to be most beneficial for procedures associated with severe pain,25,27,31,32,76,82 some experts state that subanesthetic ketamine infusions should be reserved for patients undergoing surgeries in which the postoperative pain is expected to be severe; such procedures include thoracic, abdominal (upper, lower, and intra-abdominal), and orthopedic (limb and spinal) surgeries.25,82 These experts state that patients undergoing procedures associated with only mild postoperative pain (e.g., tonsillectomy, head and neck surgery) have not been shown to benefit from perioperative ketamine.25 For these procedures, standard analgesia with low dosages of opiates, nonsteroidal anti-inflammatory agents (NSAIAs), and local anesthetics usually can provide adequate pain relief.27,76 However, management of post-tonsillectomy pain in children can be difficult and several studies have demonstrated that administration of a single IV dose of ketamine 0.5 mg/kg (alone or in combination with other analgesics) can provide effective postoperative pain control.9,97,98,100,102,103

Ketamine may be particularly useful in the management of opiate-tolerant or opiate-dependent patients undergoing surgery.25,82 In a randomized controlled study in opiate-dependent patients undergoing spinal surgery, intraoperative use of ketamine was associated with reduced opiate consumption at 48 hours and reduced opiate usage at 6 weeks.25 Ketamine also may be considered as an adjunct to reduce postoperative opiate consumption in patients who have an increased risk of opiate-related respiratory depression (e.g., those with obstructive sleep apnea).25

Acute Pain

Ketamine (in subanesthetic doses) has been used alone or as an adjunct to other analgesics (e.g., opiates) for relief of acute pain† in the emergency department and prehospital settings (e.g., ambulance).3,9,10,14,15,16,17,18,19,20,21,22,24,25,83,84 Studies evaluating subanesthetic ketamine for analgesia in these settings have been conducted principally in the adult population.16,17,18,19,20,21,22,24 However, low or subanesthetic doses of ketamine also have been used for analgesia in pediatric patients 3 months of age or older presenting to the emergency department.11,84 When used as an adjunct to opiate analgesics in the emergency department or prehospital setting, ketamine has resulted in greater reduction in pain scores compared with opiate therapy alone,14,16,17,20,84 and/or decreased opiate requirements.14,16,17,18,19,20,84 When given as a single agent for acute pain in the emergency department, IV ketamine has been reported to provide comparable reductions in pain scores to IV morphine.14,21,22

Although evidence is limited, ketamine may be useful in opiate-dependent patients with acute exacerbations of chronic pain conditions (e.g., sickle cell disease)†.25

Chronic Pain

Ketamine has been used as an adjunct analgesic for the management of chronic pain of various etiologies, including complex regional pain syndrome (CRPS)†, neuropathic pain associated with spinal cord injury†, phantom limb pain†, fibromyalgia†, ischemic pain†, cancer pain†, and migraine pain†, in adults and pediatric patients.3,9,10,26,42,43,44,45,46,47,48,52,53,54,86,87 Evidence of efficacy varies depending on the specific pain condition treated and generally is limited to small randomized controlled studies, observational studies, and case reports demonstrating short-term benefits of ketamine infusions during and for a short time following the infusion; however, ketamine dosages and administration protocols varied widely in these studies.3,10,26,42,43,44,46,48,49,50,86,87

Ketamine has been evaluated most extensively in chronic pain conditions associated with a neuropathic component.26,31,43 With regard to specific conditions, some experts state that there is weak to moderate evidence that ketamine infusions are effective for reducing pain related to CRPS in adults and pediatric patients; the evidence to date includes mostly systematic reviews, case reports, and observational studies with only a few small randomized controlled studies.26,42,45,47,50 In one study in 19 patients with CRPS, reductions in pain were reported for up to 12 weeks with continuous IV infusion of ketamine (maximum rate of 0.35 mg/kg per hour over 4 hours daily for 10 days).26,47,85 There also is weak evidence supporting ketamine infusions for short-term improvements in neuropathic pain associated with spinal cord injury.26,49,86,87 Other chronic pain syndromes that have been investigated generally have not responded to or only minimally responded to ketamine therapy; experts state that the available evidence remains inconclusive for the efficacy of ketamine infusions for mixed neuropathic pain, phantom limb pain, postherpetic neuralgia, fibromyalgia, ischemic pain, migraine, and low-back pain.3,4,26,46

Although data are limited regarding the use of ketamine as an adjuvant treatment of cancer pain, some experts state that oral or IV ketamine may be considered for the management of refractory cancer pain in adults.52 Evidence to date remains inconclusive for the efficacy of ketamine in chronic cancer pain and is mostly based on case reports and uncontrolled studies.3,4,26,54 While a few randomized controlled studies indicate that the drug may have some benefit as an adjunct analgesic in cancer-related pain, these studies generally were small and had short durations of follow-up relative to the chronic nature of the pain being treated.3,4,26,42,53 In a larger controlled clinical trial in 214 adults with cancer-related neuropathic pain inadequately treated with adjuvant analgesics, the addition of oral ketamine (up to 400 mg daily for 16 days) was no more effective than placebo in improving pain scores.55 In another controlled clinical trial in 185 adults in palliative care settings who had refractory cancer-related pain, adjunctive therapy with ketamine (administered as a subcutaneous infusion in escalating doses up to 500 mg every 24 hours over 5 days) also was no more effective than placebo in improving pain scores.53,54,56 Studies of IV and oral ketamine have been conducted in children with cancer pain; although these studies were mostly retrospective, there is some evidence suggesting that pain control can be achieved with ketamine in these patients.53

Additional study is needed to establish the role of ketamine in patients with chronic pain and to determine optimum dosages, durability of response, and long-term benefits and risks of the drug.10,26,31,43,48,52,53,54 Some clinicians recommend that use of ketamine be restricted to patients with refractory pain who have failed to obtain adequate relief from standard analgesics and nonpharmacologic treatments.4,44

Treatment-resistant Depression and Suicidality !!navigator!!

Ketamine has been used in low (i.e., subanesthetic) doses for the treatment of severe and treatment-resistant depression associated with major depressive disorder or bipolar disorder†.300,301,302,303,304,305,306,307,309,311,312,313,314,315,317,320,326,327 Although there are various definitions for treatment-resistant depression, the condition often has been defined as the failure of at least 2 trials of first-line antidepressants given in an adequate dosage for an adequate duration of therapy.301,307,309,315 In patients with refractory forms of depression, ketamine usually has been given in subanesthetic doses as an IV infusion.300,301,303,304,307,312,327

Ketamine has demonstrated rapid and potent antidepressant effects when administered to depressed patients in controlled studies and case series, with improvement in depression reported within several hours to a day following a single IV infusion of the drug.300,301,303,304,307,314 In controlled studies, single, low-dose IV infusions of the drug have resulted in response rates of approximately 37-71% in patients with treatment-resistant depression.300,317

Most depressed patients who respond to a single IV infusion of ketamine experience a relapse of depression within several days to a week or two following the initial infusion.307,314,317 Therefore, multiple-infusion regimens of ketamine (i.e., weekly, biweekly, 3 times weekly) have been studied in depressed patients in open-label as well as blinded studies with encouraging results suggesting that repeated infusions are more effective than a single infusion and can extend the duration of depressive symptom remission.303,306,307,312,313,314,315 However, the long-term efficacy and safety of repeated infusions of ketamine have not been fully determined to date and further studies are needed to evaluate relapse prevention therapy with the drug.300,306,307,312,314 There is some concern that multiple-infusion regimens of ketamine may cause long-term cognitive impairment or neurotoxicity, although no evidence of such impairment has been seen in preliminary studies.307,312,314 Some clinicians have suggested that the optimal use of ketamine infusions may be short-term to produce rapid antidepressant and antisuicidal effects until a less invasive relapse prevention strategy for a patient can be implemented.312

In addition to its antidepressant effects, randomized controlled studies suggest that ketamine may be helpful in the short-term treatment of suicidal ideation†.304,307,310,314,317,323,324,325,326 In a systematic review and individual participant data meta-analysis, suicidal ideation rapidly decreased (within 1 day) following a single IV infusion of ketamine and the effect lasted for up to 1 week even among patients whose depression did not fully respond to ketamine therapy, suggesting that the drug may have a partially independent antisuicidal effect.307,310

Despite the increasingly widespread use of IV ketamine to treat patients with treatment-resistant depression and suicidality, including in outpatient ketamine infusion centers and psychiatric clinics, some clinicians currently recommend that the drug's use for these psychiatric indications be limited to controlled settings under the care of skilled clinicians.302,308 Clinicians and patients should consider enrollment in clinical studies evaluating ketamine's efficacy and safety so that further data can be collected and analyzed to improve clinical practice.302,314

When considering the use of ketamine for treating mood disorders, the American Psychiatric Association's (APA's) Council of Research Task Force on Novel Biomarkers and Treatments recommends balancing the potential benefits of ketamine infusion therapy with the potential risks of long-term exposure to the drug, including neurotoxicity, cystitis, and abuse potential.302,314,320 A thorough pretreatment evaluation process to determine the appropriateness of ketamine therapy is recommended in such cases.302 If ketamine is prescribed outside of a controlled setting, careful screening, monitoring during treatment, and follow-up of patients are necessary.302,314,316

Since conventional oral antidepressants generally require several weeks or months to be effective, the addition of ketamine to oral antidepressant therapy has been suggested as one possible method to produce a more rapid antidepressant response in patients with depression.309,311,314,315 In a randomized, double-blind, placebo-controlled study, the efficacy and safety of single-infusion ketamine augmentation of oral escitalopram therapy (10 mg daily) were evaluated in 30 outpatients with severe major depressive disorder.309 Ketamine was given as a single IV infusion (0.5 mg/kg over 40 minutes) on day 1 of escitalopram therapy.309 At 4 weeks, response occurred in significantly more escitalopram plus ketamine-treated patients than in the escitalopram plus placebo-treated patients (approximately 92 and 57% of patients, respectively).309 In addition, the escitalopram plus ketamine-treated patients had a shorter mean time to response than the escitalopram plus placebo-treated patients (6 days compared with 27 days).309

Some clinicians state that electroconvulsive therapy (ECT) should still be considered as a first-line therapy for patients with refractory depression, and have expressed concern that a trial of single- or multiple-dose ketamine therapy might delay patients from being referred for an ECT consultation.308 Preliminary experience with the adjunctive use of ketamine in the course of ECT for depression does not suggest improved efficacy or tolerability.314

Preliminary evidence suggests that intranasal† ketamine given in 50-mg doses is effective in rapidly improving depressive symptoms in patients with major depressive disorder and generally is well tolerated; however, further study is needed to more clearly determine the efficacy, tolerability, and optimal dosing of this alternative route of administration.305,314,317 The APA's Council of Research Task Force on Novel Biomarkers and Treatments currently advises against the prescription of self-administration of ketamine at home and recommends medical supervision whenever the drug is used pending further accumulation of safety data from controlled settings.302

For information on the intranasal use of esketamine hydrochloride, the S -enantiomer of racemic ketamine, for treatment-resistant depression, see Esketamine Hydrochloride 28:16.04.92.329

Sedation and Analgesia in Critical Care Settings !!navigator!!

Ketamine has been used by continuous IV infusion to provide sedation in critically ill patients† in the intensive care unit (ICU) setting.9,12,800 Sedative agents are administered in ICU patients to reduce pain, agitation, and anxiety, and increase tolerance to invasive procedures (e.g., mechanical ventilation).800 The provision of adequate analgesia and other measures to ensure patient comfort is recommended before sedatives are administered.800 Common drugs used for ICU sedation include benzodiazepines (e.g., midazolam, lorazepam), propofol, and dexmedetomidine.800 Although ketamine also has been used for this indication, there is limited, but increasing, experience describing such use; available data evaluating ketamine in the ICU from randomized controlled trials and observational studies are heterogenous in terms of therapeutic indications, dosages used, concomitant drugs, and target levels of sedation.12,116,117,800

Ketamine also has been used for pain management in critically ill patients†.12,25,800 Although opiate analgesics generally are considered the first-line drugs for management of non-neuropathic pain in this setting, some experts suggest the use of low-dose ketamine (e.g., 0.5 mg/kg by IV injection followed by 0.06-0.12 mg/kg per hour as an IV infusion) as an adjunct to opiates when attempting to reduce opiate requirements in postsurgical ICU patients.800 This recommendation is based principally on indirect evidence from non-ICU patients and limited data from a randomized controlled study in postsurgical patients in the ICU.800

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Dispensing and Administration Precautions

Other General Considerations

Administration !!navigator!!

Ketamine hydrochloride usually is administered by slow (e.g., over 60 seconds) IV injection, IV infusion, or IM injection.1,3,4,5,10,35,51 Ketamine also has been used in IV patient-controlled analgesia (PCA), either as the sole analgesic or in combination with opioids to improve pain control and reduce opioid-related adverse effects.25 Ketamine also has been administered by oral†,3,5,23,25,35 52 intranasal†,3,5,10,23,25,35,302,305,314,317 rectal†,3,5,23,35 subcutaneous†,3,53,54,56 and intraosseous (IO)† routes.3,5,10 Because of extensive first-pass metabolism, the bioavailability of ketamine following oral or rectal administration is limited (approximately 20-30%).3,4 Although ketamine has been administered epidurally† or intrathecally†,3,5,35 there have been concerns about potential neurotoxicity with these routes, and some experts state it may be prudent to avoid neuraxial administration of the drug.9,23,26,27,51,82

Some experts state that IV administration of ketamine is preferred to IM administration when access can be obtained readily.11 IM administration is associated with a higher rate of vomiting and longer recovery times compared with IV administration.11 In addition, IV access can permit convenient administration of additional doses for longer procedures and allow for rapid treatment of adverse effects (e.g., IV benzodiazepines for emergence reactions).11 In certain patients (e.g., severely agitated or uncooperative patients, young children), IM administration may be preferred.3,9,11,35

Store ketamine hydrochloride injection at controlled room temperature between 20-25°C (excursions permitted between 15-30°C) and protect from light.1

Ketamine has been reported to be compatible with several drugs when administered as additives, simultaneously in the same syringe, or when a Y-type administration set is used; specialized references should be consulted for more specific information.90

Dilution

Ketamine hydrochloride is commercially available as an injection containing 10, 50, or 100 mg/mL of ketamine for IV or IM use.1 The 100-mg/mL concentration should not be administered IV without proper dilution; the commercially available injection concentrate must be diluted with an equal volume of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection prior to IV injection.1

For IV infusion, a diluted solution containing 1 mg of ketamine per mL (1 mg/mL) may be prepared by adding 500 mg of ketamine (10 mL from a vial labeled as containing 50 mg/mL of ketamine or 5 mL from a vial labeled as containing 100 mg/mL of ketamine) to an infusion bag containing 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 In patients requiring fluid restriction, a 2-mg/mL solution may be prepared by adding 500 mg of ketamine (10 mL from a vial labeled as containing 50 mg/mL of ketamine or 5 mL from a vial labeled as containing 100 mg/mL of ketamine) to an infusion bag containing 250 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 The manufacturer states that the 10-mg/mL vial of ketamine hydrochloride is not recommended for dilution;1 however, some stability studies have used ketamine hydrochloride solutions prepared by diluting a 10-mg/mL solution of the drug with 0.9% sodium chloride injection.104,105

Use immediately after dilution.1

Rate of Administration

For induction of anesthesia, administer ketamine slowly (e.g., over 60 seconds); rapid IV administration can cause respiratory depression and enhanced vasopressor response.1,11,12 Induction dose may be administered by IV infusion at rate of 0.5 mg/kg per minute.1

For maintenance of anesthesia, repeat one-half to full induction dosages as needed; may be given by slow microdrip infusion technique at a dosage of 0.1-0.5 mg/minute.1

For dissociative sedation in emergency department settings, IV administration over 30-60 seconds has been recommended.11

When ketamine is used in subanesthetic doses for acute pain†, some clinicians have recommended that the drug be administered as a short IV infusion over 15 minutes.15

When ketamine is administered in subanesthetic doses for the treatment of severe and treatment-resistant depression and/or suicidality†, the drug is usually given as an IV infusion over 40 minutes.300,301,302,303,304,306,307,312,315,326,327 Although shorter and longer infusion rates have been used in some patients,302,322 clinical experience is too limited to recommend an alternative infusion rate at this time.302

Standardize 4 Safety

Standardized concentrations for ketamine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web]. 249,250

Table 1: Standardize 4 Safety Continuous Infusion Standards for Ketaminea249

Patient Population

Concentration standard

Dosing units

Pediatric patients (<50 kg)

2 mg/mL

10 mg/mL

mg/kg/hr or mcg/kg/min based on indication

aKetamine is not included in the adult continuous infusion standards250

Table 2: Standardize 4 Safety PCA Standard Concentrations for Ketamine251

Patient Population

Concentration standard

Dosing units

Pediatric patients (<50 kg)

2 mg/mL

mg/kg/hr

10 mg/mL

Adults

5 mg/mL

mg/kg/hr

10 mg/mL

Dosage !!navigator!!

Dosage of ketamine hydrochloride is expressed in terms of ketamine.1

Dose-dependency of Effects

Dosage of ketamine depends on the intended use and desired pharmacologic effect.10,37 At low doses, ketamine produces analgesia and sedation, and at higher doses, the drug produces a state of dissociative anesthesia.23,26,37 Ketamine has a dosing threshold at which dissociation occurs; doses at or above the threshold are referred to as “dissociative” or “anesthetic,” and doses below this threshold are referred to as “subdissociative” or “subanesthetic.”11,35 Although specific dosing ranges have not been established,14,25,31 dissociation generally appears at an IV dose of approximately 1-1.5 mg/kg or an IM dose of approximately 3-5 mg/kg.11,14,25,34,37 Once the dissociative threshold has been reached, additional administration of ketamine will not enhance or deepen sedation.11,37

Induction and Maintenance of Anesthesia

As with other general anesthetics, individual response to ketamine is variable and can depend on factors such as dosage, route of administration, patient age, or concomitant drugs.1 Dosage should be individualized based on therapeutic response and the patient's anesthetic needs.1,10 In general, higher doses of ketamine correspond with longer times to complete recovery from anesthesia.1

Adult Dosage

For induction of anesthesia in adults, the manufacturer recommends an initial IV ketamine dose of 1-4.5 mg/kg or an initial IM dose of 6.5-13 mg/kg.1 Administer IV ketamine doses by slow IV injection over 60 seconds or as an IV infusion at a rate of 0.5 mg/kg per minute.1 On average, an IV dose of 2 mg/kg will produce surgical anesthesia for 5-10 minutes within 30 seconds of administration, and an IM dose of 9-13 mg/kg will produce surgical anesthesia for 12-25 minutes within 3-4 minutes following administration.1,51

For maintenance of anesthesia in adults, additional IV doses of 0.5-4.5 mg/kg or IM doses of 3.25-13 mg/kg may be administered as needed.1 The manufacturer additionally states that a slow microdrip IV infusion, using a dosage of 0.1-0.5 mg/minute will maintain general anesthesia after induction with ketamine.1 A continuous IV infusion of 1-6 mg/kg per hour also has been recommended for maintenance of anesthesia.26 The maintenance dosage should be adjusted based on the patient's anesthetic requirements and concomitant use of other anesthetic agents.1

The manufacturer states that the incidence of psychologic manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using lower recommended dosages of ketamine in conjunction with an IV benzodiazepine during induction and maintenance of anesthesia.1

Pediatric Dosage

In general, pediatric patients require higher doses of ketamine compared with adults, although there is considerable interpatient variability in dosing requirements.23

Some experts recommend an initial IV ketamine dose of 1-3 mg/kg for induction of anesthesia in pediatric patients†; supplemental IV doses of 0.5-1 mg/kg may be given if clinically indicated.23 The recommended IM dose of ketamine for induction of anesthesia in pediatric patients is 5-10 mg/kg.23 Because of possible airway complications, some experts state that ketamine is contraindicated in infants younger than 3 months of age.11

Procedural Sedation

Adult Dosage

For dissociative sedation in adults undergoing short painful or emotionally disturbing procedures in the emergency department, the usual IV dose of ketamine is 1 mg/kg administered by IV injection over 30-60 seconds.11 Dissociative sedation is usually achieved with a single IV loading dose; however, if sedation is inadequate or a prolonged period of sedation is needed for longer procedures, additional IV doses of 0.5-1 mg/kg may be administered every 5-15 minutes as needed.11 Lower IV doses of ketamine (e.g., 0.2-0.75 mg/kg) also have been used to produce analgesia, particularly if a dissociative effect is not required for the procedure.11,26

Although the IM route is not preferred in adults, some experts state that an IM dose of 4-5 mg/kg may be administered; additional doses of 2-5 mg/kg may be given after 5-10 minutes if initial sedation is inadequate or additional doses are needed for longer procedures.11 Lower IM doses of ketamine (e.g., 0.4-2 mg/kg) also have been used, particularly if a dissociative effect is not required for the procedure.11,26

Pediatric Dosage

For dissociative sedation in pediatric patients† 3 months of age or older undergoing short painful or emotionally disturbing procedures in the emergency department, some experts state that the usual IV dose of ketamine is 1.5-2 mg/kg administered by IV injection over 30-60 seconds.11 Dissociative sedation is usually achieved with a single IV loading dose; however, if initial sedation is inadequate or prolonged sedation is necessary for longer procedures, additional incremental IV doses of 0.5-1 mg/kg may be administered every 5-15 minutes as needed.11 These experts state that the minimum IV dose that will reliably elicit the dissociative state in children is 1.5 mg/kg;11 however, lower IV doses (e.g., 0.25-1 mg/kg) also have been used successfully to provide adequate procedural sedation in pediatric patients, particularly if a dissociative effect is not required for the procedure.11,23,78

The recommended IM dose of ketamine for dissociative sedation in pediatric patients† 3 months of age or older undergoing short painful or emotionally disturbing procedures in the emergency department is 4-5 mg/kg.11,37 Although dissociative sedation is usually achieved with a single IM dose, additional doses of 2-5 mg/kg may be administered after 5-10 minutes if initial sedation is inadequate or additional doses are needed for longer procedures.11 Although some experts state that the minimum IM dose that will reliably elicit the dissociative state in children is 4-5 mg/kg,11 lower IM doses (e.g., 1-2 mg/kg) also have been used successfully, particularly if a dissociative effect is not required for the procedure.11,23

Sedation and Analgesia in Critical Care Settings

There is increasing experience with the use of ketamine for ICU sedation, but dosages described in the literature are highly variable.12,116,117,800 Available data evaluating ketamine in the ICU from randomized controlled trials and observational studies are heterogenous in terms of therapeutic indications, dosages used, concomitant drugs, and target levels of sedation.12,116,117,800 Although adult and pediatric dosages of continuous IV ketamine have varied in these published studies, they generally fall within the broad range associated with analgosedative effects; the desired target level of sedation and concomitant use of other sedative/analgesic agents are some factors that may influence dose variability.116,117 Continuous infusion dosages have ranged between 0.02-3 mg/kg per hour; lower dosages have been more commonly used when ketamine is used as part of patient-controlled analgesia.116,117 Use of initial bolus IV injections (range 0.3-0.5 mg/kg) and continuous infusion titration based on sedation or pain scores have also been reported.116,117

For pain management in postsurgical patients in the ICU, some experts have suggested the use of low-dose ketamine (e.g., 0.5 mg/kg by IV injection followed by IV infusion of 0.06-0.12 mg/kg per hour as an adjunct to opioid therapy); other dosage regimens also have been used.12,116,800

Pain

Ketamine is used in low (i.e., subanesthetic or subdissociative) dosages for the management of pain; however, a dosage range that is considered subanesthetic has not been consistently defined.25,27,31,32,34 Most acute pain studies used IV bolus doses less than 0.5 mg/kg and infusion rates of 0.5 mg/kg per hour or less; however, there is wide variability in the dosage ranges and routes of administration used.25

Postoperative Pain

For the management of postoperative pain† in pediatric patients and adults, IV ketamine bolus doses ranging from 0.1-0.5 mg/kg with or without continuous IV infusion (at rates usually ranging from 0.1-0.6 mg/kg per hour) have been commonly used in clinical studies; however, dosages and timing of administration in relation to the surgical procedure varied widely in these studies and the optimum dosage regimen is not known.9,10,25,27,30,31,33,34,82,97,98,99,100,101,102,103 Some experts state that there is moderate evidence supporting the use of IV ketamine bolus doses up to 0.35 mg/kg and IV infusions up to 1 mg/kg per hour as an adjunct to opiates for perioperative analgesia.25 In several studies, administration of a single IV ketamine dose of 0.5 mg/kg (alone or in combination with other analgesics) was effective in achieving postoperative pain control in children undergoing tonsillectomy.9,97,98,100,102,103 Because of possible airway complications, some experts state that ketamine is contraindicated in infants younger than 3 months of age.11

IM administration of analgesic agents for postoperative pain is not recommended because of unreliable absorption and substantial pain at the site of injection.82

Acute Pain

For the management of acute pain† in the emergency department and prehospital settings, the usual IV dose of ketamine is 0.1-0.3 mg/kg administered as a slow IV injection or short IV infusion over 10-15 minutes based on studies conducted principally in adults; although longer infusions of ketamine are rare in this setting, continuous IV infusions of 0.1-0.3 mg/kg per hour have been used.9,10,14,16,18,20,21,22,84 Non-weight-based IV ketamine doses ranging from 10-20 mg also have been used in clinical studies of ketamine for the treatment of acute pain in adults.17,19 When ketamine is used for acute pain in settings without intensive monitoring, some experts state that IV bolus doses should not exceed 0.35 mg/kg and infusion rates generally should not exceed 1 mg/kg per hour, but also acknowledge that higher or lower doses may be necessary due to interindividual differences in response.25

Because of possible airway complications, some experts state that ketamine is contraindicated in infants younger than 3 months of age.11

Ketamine may be administered IM for acute pain in the emergency department or prehospital settings; however, experts state that a dosage range has not been definitively established and analgesic effects are less predictable when the drug is administered by IM injection.84

Chronic Pain

Although there is no consensus on dosages or administration protocols for ketamine in patients with chronic pain†, the drug generally is administered in subanesthetic doses by IV infusion.26,35,42,43,44,45,48 There is some evidence suggesting that administration of higher dosages over longer periods and more frequent infusions may provide more benefit.26,43,44 Some experts state that it is reasonable to initiate a single outpatient infusion of ketamine at a minimum dose of 80 mg for at least 2 hours and then reassess before initiating further treatments.26 In a study in children and adolescents 12-17 years of age with chronic pain conditions (e.g., chronic headache, fibromyalgia, complex regional pain syndrome), ketamine was administered by continuous IV infusion at a rate of 0.1-0.3 mg/kg per hour for 4-8 hours each day up to a maximum of 16 hours (in total, up to a maximum of 3 consecutive days).45 Children with severe cancer-related pain have been treated with IV infusions of ketamine at 0.1-1 mg/kg per hour.53 Based on limited evidence, IV ketamine bolus doses up to 0.35 mg/kg followed by IV infusions of 0.5-2 mg/kg per hour have been recommended by some experts for the management of chronic pain; however, higher (e.g., up to 7 mg/kg per hour for the treatment of refractory pain) or lower (e.g., 0.1-0.5 mg/kg per hour) infusion rates also have been used.26,43,50

Treatment-resistant Depression and Suicidality

For severe and treatment-resistant depression and suicidality† in adults, ketamine usually is given as a low-dose (i.e., subanesthetic dose) IV infusion of 0.5 mg/kg over 40 minutes.300,301,302,303,304,306,307,312,315,326 Obese patients (i.e., body mass index [BMI] of 30 or higher) appear to be at increased risk for ketamine-associated hypertension and other adverse hemodynamic effects and potentially may benefit from adjusting the ketamine dosage to their calculated ideal body weight rather than actual body weight; further clinical experience to determine optimal dosing in such patients is needed.300,302,315,327 There is limited evidence that higher ketamine infusion dosages (e.g., 0.75 mg/kg) may be necessary in certain chronically ill and/or severely treatment-resistant patients, but further study is needed to determine the efficacy and safety of such higher-dosage regimens.322

There currently is limited clinical experience with longer-term (multiple-dose) ketamine infusion therapy for treatment-resistant depression and suicidality; however, IV infusions of ketamine have been given once, twice, or 3 times weekly for the first 2 weeks during the acute treatment phase in some patients300,302,303,306,307,312,313,315 and sometimes have been continued once or twice weekly for another 2-4 weeks during the continuation phase for a total of 4-6 weeks of therapy or gradually tapered.302,313,315 Patients who do not initially respond to several infusions of ketamine appear unlikely to respond to subsequent infusions.302 Discontinuance of ketamine therapy is recommended by some experts if the interval between infusions cannot be extended to one week or longer by the second month of treatment; these experts state that the goal should be to eventually taper and discontinue ketamine treatment until additional long-term safety data with the drug become available.302

Special Populations !!navigator!!

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

The manufacturer recommends that dosages in geriatric patients should generally be started on the lower end of the dosing range to accommodate any underlying hepatic, renal, or cardiac dysfunction and any comorbidities or other drug therapy.1

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Cardiovascular Effects

Ketamine inhibits the reuptake of catecholamines and has other direct and indirect sympathomimetic effects at subanesthetic and anesthetic doses.3,11,26,40 Typical cardiovascular effects include increases in heart rate, blood pressure, cardiac output, and myocardial oxygen consumption; hypotension, bradycardia, arrhythmias, and cardiac decompensation also have been observed.1,3,9,11,40 Ketamine also causes direct relaxation of vascular smooth muscle; however, systemic vascular resistance usually is unaffected.3 The sympathomimetic effects of ketamine often are used to therapeutic advantage (e.g., in patients with severe hypotension, sepsis, or other hemodynamically compromised states).3,9,10

Transient increases in blood pressure, heart rate, and cardiac output can occur following administration of ketamine at anesthetic or subanesthetic doses.1,3,11,26,40 When ketamine is administered IV in anesthetic doses, increased blood pressure usually occurs shortly after the IV injection, reaches a maximum within a few minutes, and returns to preanesthetic levels within 15 minutes.1 Systolic and diastolic blood pressure usually peaks at 10-50% over baseline values, but increases can be higher or last longer in some individuals.1 In healthy individuals receiving subanesthetic doses of ketamine (0.5 mg/kg by IV infusion over 40 minutes), increases in blood pressure were observed 10 minutes after the start of infusion; mean maximum increases in systolic and diastolic blood pressure of 13.38 and 12.65 mm Hg, respectively, occurred approximately 28 minutes after initiation of the infusion and returned to baseline levels within 2 hours.40 The mean maximum increase in heart rate in these individuals was 10.69 beats per minute.40

Elevated blood pressure and/or heart rate may occur during IV infusions of ketamine for treatment-resistant depression and suicidality; these hemodynamic effects usually are transient and subside following completion of the IV infusion.300,302,307,312,313,326 Transient but significantly elevated blood pressure occurred in nearly one-third of ketamine-treated patients in one study.300 Short-term antihypertensive therapy sometimes has been used to treat ketamine infusion-associated blood pressure elevations in this and other studies.300,315

Monitor vital signs and cardiac function during ketamine administration.1 Ketamine should be used with caution or avoided in patients with known or suspected cardiac conditions that may be exacerbated by the sympathomimetic effects of the drug (e.g., unstable angina, coronary artery disease, myocardial infarction [MI], congestive heart failure, hypertension).11,25,26 The manufacturer states that ketamine is contraindicated in patients in whom a substantial elevation of blood pressure would constitute a serious hazard.1

Emergence Reactions

Emergence reactions have been reported during the recovery period in patients receiving ketamine; the manufacturer reports an incidence of approximately 12% in patients receiving ketamine for anesthesia, although higher rates have been reported in the published literature.1,11,12,12,51 The duration of such reactions is generally a few hours.1 Emergence reactions occur more frequently in adults (approximately 30-50%) than in pediatric patients (approximately 5-15%).11,51

Emergence manifestations vary in severity from pleasant to unpleasant dream-like states, vivid imagery, hallucinations, alterations in mood and body image, floating sensations, extracorporeal (out-of-body) experiences, and emergence delirium; in some cases, these states have been accompanied by confusion, excitement, and irrational behavior, which some patients recall as an unpleasant experience.1,5,10,11,51 The manufacturer states that no residual psychologic effects have been reported from ketamine use during induction and maintenance of anesthesia.1

Emergence reactions may be less frequent when ketamine is given IM.1 The incidence of emergence reactions may be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period; however, this should not preclude appropriate monitoring of vital signs.1 Prophylactic administration of benzodiazepines (e.g., diazepam, midazolam) may reduce the incidence of ketamine-induced psychological manifestations during emergence, and the manufacturer suggests a regimen using a decreased dosage of ketamine in conjunction with an IV benzodiazepine during induction and maintenance of anesthesia.1,11,26 Benzodiazepines also may be used to terminate severe or unpleasant emergence reactions.11,26

Respiratory Effects

Adverse respiratory effects are rare with ketamine;11 however, respiratory depression may occur following rapid IV administration or overdosage of the drug.1 When given in anesthetic doses, clinically important respiratory depression usually does not occur.1 Respiration is frequently stimulated, but ketamine may occasionally cause a transient and minimal respiratory depression 1

When used in subanesthetic doses for the treatment of depression in otherwise healthy individuals, ketamine usually does not cause clinically important adverse respiratory effects.302

Ketamine also produces bronchodilation, likely through vagolytic and other centrally mediated mechanisms.3,26

Airway or respiratory complications have been reported in about 3.9% of pediatric patients receiving ketamine for dissociative sedation in the emergency department; transient apnea and respiratory depression have been reported in about 0.8% and transient laryngospasm has been reported in about 0.3% of pediatric patients in this setting.11,60

Maintain adequate oxygenation and ventilation during administration of ketamine.1 IV injections of ketamine should be administered slowly (e.g., over 60 seconds).1

Risks with Pharynx, Larynx, or Bronchial Tree Procedures

Ketamine does not suppress pharyngeal or laryngeal reflexes.1 Therefore, ketamine as a sole anesthetic should be avoided during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx.1 Muscle relaxants may be required for successful completion of these procedures.1

Pediatric Neurotoxicity

Prolonged use of general anesthetics and sedation drugs, including ketamine, in children younger than 3 years of age or during the third trimester of pregnancy may affect brain development.1,750,753 Animal studies in multiple species, including nonhuman primates, have demonstrated that use for longer than 3 hours of anesthetic and sedation drugs that block N -methyl-d-aspartic acid (NMDA) receptors and/or potentiate γ-aminobutyric acid (GABA) activity leads to widespread neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the developing brain, resulting in long-term deficits in cognition and behavior.1,750,751,752,753 Across animal species, vulnerability to these neurodevelopmental changes occurs during the period of rapid brain growth or synaptogenesis; this period is thought to correlate with the third trimester of pregnancy through the first year of life in humans, but may extend to approximately 3 years of age.1,750 The clinical relevance of these animal findings to humans is not known.1,750

While some published evidence suggests that similar deficits in cognition and behavior may occur in children following repeated or prolonged exposure to anesthesia early in life, other studies have found no association between pediatric anesthesia exposure and long-term adverse neurodevelopmental outcomes.1,750,752 Most studies to date have had substantial limitations, and it is not clear whether the adverse neurodevelopmental outcomes observed in children were related to the drug or to other factors (e.g., surgery, underlying illness).1,750 There is some clinical evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders;750,751,752 however, further research is needed to fully characterize the effects of exposure to general anesthetics in early life, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).750

Results from an observational study (the Pediatric Anesthesia Neurodevelopment Assessment [PANDA] study) and from a multicenter, randomized trial (the General Anesthesia Compared to Spinal Anesthesia [GAS] trial) provide some evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders.750,751,752,754 The PANDA study compared global cognitive function (as measured by intelligence quotient [IQ] score) of children 8-15 years of age who had a single anesthesia exposure for elective inguinal hernia surgery before the age of 3 years with that of a biologically related sibling who had no anesthesia exposure before the age of 3 years.750,752 All of the children had a gestational age at birth of at least 36 weeks, and sibling pairs were within 3 years of being the same age.750,752 Children who underwent the elective procedure were mostly males (90%) and generally healthy.750,752 The mean duration of anesthesia was 84 minutes; 16% of those receiving anesthesia had exposures exceeding 2 hours.750 The study found no substantial difference in IQ score between children who had a single anesthesia exposure before the age of 3 years and their siblings who had not.750,752 The GAS trial was designed to compare neurodevelopmental outcomes in children who received general anesthesia in infancy with those in children who received awake regional (caudal and/or spinal) anesthesia in infancy for inguinal herniorrhaphy before they reached a postmenstrual age of 60 weeks (with a gestational age at birth of more than 26 weeks); the primary outcome was the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale IQ at 5 years of age.750,751 In an interim analysis at the age of 2 years, no difference in composite cognitive score (as measured by the Bayley Scales of Infant and Toddler Development III) was detected between children who had received sevoflurane anesthesia of less than 1 hour's duration (median duration: 54 minutes) compared with those who had received awake regional anesthesia.750,751 This result was confirmed in a subsequent analysis of the GAS trial of neurodevelopmental outcomes at 5 years of age.754

Anesthetic and sedation drugs are an essential component of care for children and pregnant women who require surgery or other procedures that cannot be delayed;750,753 no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug.1,750 Pending further accumulation of data in humans from well-designed studies, decisions regarding the timing of elective procedures requiring anesthesia should take into consideration both the benefits of the procedure and the potential risks.1,750 When procedures requiring the use of general anesthetics or sedation drugs are considered for young children or pregnant women, clinicians should discuss with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.750,753 FDA states that procedures that are considered medically necessary should not be delayed or avoided.750,753

Hepatic Injury

Recurrent use of ketamine (e.g., misuse/abuse or medically supervised unapproved indications) is associated with hepatobiliary dysfunction, most often a cholestatic pattern.1 For patients who receive recurrent doses of ketamine as part of a treatment plan, obtain baseline liver function tests, including alkaline phosphatase and gamma glutamyl transferase.1 Monitor patients receiving recurrent therapy at periodic intervals during treatment.1

Elevated hepatic enzyme concentrations may occur26 with anesthetic and subanesthetic doses of ketamine, particularly following prolonged infusion and/or repeated doses within a short time frame.27,44 Hepatotoxicity has been reported following longer-term use (e.g., more than 3-4 days).3,4,26,38,44 Increased hepatic enzyme concentrations have been reported in approximately 10% of patients receiving repetitive low doses or continuous high doses of ketamine infusions clinically.44 In a small study in patients receiving IV infusions of S -ketamine for chronic pain, hepatic enzyme elevations up to 3 times the upper limit of normal occurred following a second exposure to the drug.26,44 Hepatic enzyme concentrations generally return to baseline over several months.26,44

Increased Intracranial Pressure

Ketamine increases cerebral metabolism and cerebral blood flow, and can also potentially increase intracranial pressure.1,3 Monitor patients with elevated intracranial pressure with frequent neurologic assessments.1

Some experts state that the drug should be avoided in patients with elevated intracranial pressure.25 However, there is some controversy regarding the use of ketamine in patients with head trauma.3,14 Despite concerns of increased intracranial pressure, cerebral perfusion is maintained and there is evidence that ketamine can be safely and effectively used in patients with head injuries or risk of intracranial hypertension.3,4,12,14,67

Studies suggest that intracranial pressure increases are minimal in patients with normal ventilation11,12 and are associated with concomitant elevations in cerebral perfusion.12 In a systematic review of data from studies using ketamine in mechanically ventilated patients with traumatic brain injury, ketamine was not associated with increased intracranial pressure; in some cases, intracranial pressure was decreased.67

Because of concerns about increased intracranial pressure, some experts state that ketamine should be used with caution or avoided in patients with CNS masses, abnormalities, or hydrocephalus.11

Other Warnings and Precautions

Laryngospasm

Laryngospasm and airway obstruction may occur during ketamine administration.1,11 Although the risk of laryngospasm is low with minor oropharyngeal procedures typically performed in the emergency department, efforts should be made to avoid vigorous stimulation of the posterior pharynx and accumulation of secretions or blood during these procedures.11

Ocular Effects

Elevation of intraocular pressure (IOP) may occur.1,23 Blurred vision26 and pupillary dilation have been reported with subanesthetic doses of ketamine.35 Transient blindness also has been reported.11

Use with caution or avoid use in patients with elevated IOP (e.g., glaucoma, acute globe injury).11,25,26

Genitourinary Effects

Urinary tract complications, including dysuria, urinary frequency, urgency, urge incontinence, cystitis, hematuria, postmicturition pain, and secondary renal failure, reported, generally in association with chronic ketamine use or abuse.1,3,4,26,27,35,38,44,51,57,302

In patients experiencing urinary symptoms without evidence of infection, consider interruption of ketamine therapy and evaluation by a specialist.4 The manufacturer states to consider discontinuance of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms.1 Some experts advise that patients receiving long-term ketamine therapy for mood disorders be assessed for urinary symptoms (e.g., discomfort) during therapy.302

Schizophrenia/Psychosis

Ketamine can exacerbate schizophrenia,11,35 and generally should be avoided in patients with schizophrenia or active psychosis.11,25,26 Although data are limited, caution is advised when ketamine is used for procedural sedation or acute pain in patients with other psychiatric disorders,11 including substance abuse-induced psychosis.15

Long-term use of ketamine can cause persistent neuropsychiatric symptoms, cognitive impairment, and psychologic abnormalities.3

When used for treatment-resistant depression and suicidality, acute dissociative and psychotomimetic effects (e.g., psychotic symptoms) have been reported with IV infusions of ketamine.300,307,312,313,315,317,320 Such effects generally occur only during and immediately following ketamine infusion and resolve within 2-4 hours following the end of the infusion, are generally mild in severity, and are well tolerated.307,313,315,317,320 Clinical experience to date suggests that dissociative symptoms occur more commonly than psychotomimetic effects when ketamine is used in patients with treatment-resistant depression.300,307,312

Overdosage

Changes in heart rate and blood pressure, respiratory depression, and apnea may occur with overdosage or by a rapid rate of administration of ketamine.1 Monitor patients for clinically relevant changes in heart rate and blood pressure.1 Assisted ventilation, including mechanical ventilation, may be required.1

Several cases of accidental ketamine overdosage (with doses up to 10 or 100 times the intended dose in adults or children, respectively) resulted in prolonged sedation, but no other clinically important adverse effects or complications;1,36,51 ventilator support was required rarely.36 Death secondary to acute ketamine overdosage in the absence of multidrug intoxication is rare, although accidental deaths have been reported.35,36,51 A lethal dose of ketamine in humans has not been identified.35

Abuse, Tolerance, and Dependence

Ketamine is a known drug of abuse1,3,4,35,41,44,51 and is subject to control under the Federal Controlled Substances Act of 1970 as a schedule III drug.1,41 Although cases of abuse and dependence have been reported with ketamine, the abuse potential with the drug has not been clearly defined.35 The pharmacologic and behavioral effects of ketamine are similar to, but somewhat less intense and shorter in duration than those of phencyclidine (PCP).41 Ketamine is most commonly abused by nasal insufflation (i.e., snorting) of the powder (evaporated from the injectable liquid), although IV, IM, and oral routes also have been used.35,41 Reported desired effects of ketamine include feelings of dissociation and unreality, altered state of consciousness, enhanced sensory perception, hallucinations, intoxication, mild euphoria, and a sensation of floating.3,35,44,51 Most cases of ketamine abuse have been reported in the context of multidrug or polysubstance abuse.51 Surveys and studies examining the use pattern of ketamine indicate that abuse of the drug may be more prevalent in certain geographic regions (e.g., Hong Kong).51 The annual prevalence rate for ketamine use in adolescents (17-18 years of age) in the US was 1.5% in 2012.51

Although brief exposure to ketamine in a hospital setting is not likely to cause addiction, the possibility of addiction exists and patients should be individually assessed for their risk.25 Abuse of ketamine can result in adverse urinary, CNS, and hepatobiliary effects.1,4,35,41,51 The manufacturer states that ketamine should be prescribed and administered with caution because of the risk of abuse.1

Tolerance to the drug's effects may develop following prolonged administration of ketamine.1,35,51 A sevenfold increase in the dose required for a desired “high” has been reported after 2 months of continuous use in recreational users of ketamine.4

Although reported rarely, dependence on ketamine is possible.1,35,51 Cases of ketamine abuse resulting in physical or psychologic dependence have been reported.41 Withdrawal symptoms have been reported following discontinuation of frequent (more than weekly) use of large doses of ketamine for long periods of time.1 Reported symptoms of withdrawal associated with daily administration of large doses of ketamine include craving, fatigue, poor appetite, and anxiety.1

Chronic Toxicity

Long-term abuse of ketamine has been associated with urinary tract complications, hepatobiliary toxicity, neuropsychiatric effects (e.g., hallucinatory flashbacks, inability to concentrate, memory impairment), and MRI abnormalities.1,2,3,4,26,27,35,38,39,41,44,51,57

Urinary tract complications have been reported in association with long-term ketamine use, generally in the setting of chronic drug abuse, but also with clinical use of the drug.1,2,3,4,27,35,51,57,302 Reported lower urinary tract and bladder symptoms include cystitis, hematuria, dysuria, increased urinary frequency, urgency, incontinence, and postmicturition pain; secondary renal damage also can occur in severe cases.1,4,26,27,44,51,57,302 The exact mechanism of urinary tract damage is not clear, but ketamine and/or its metabolites are thought to have a direct irritant effect on the urothelium or interstitial cells of the bladder.4,35,38,57 Decreased bladder capacity and compliance, bladder wall thickening, transmural inflammation, detrusor muscle dysfunction, vesicoureteric reflux, hydronephrosis, and papillary necrosis have been observed.1,4,35,38,44,57

Hepatobiliary toxicity also has been associated with long-term use of ketamine for therapeutic purposes or in the setting of chronic drug abuse.2,3,4,26,38,44 Epigastric pain, bile duct dilatation, and abnormal liver function tests consistent with posthepatic obstruction have been observed in chronic ketamine abusers.4,38,44

Long-term use of ketamine has been reported to cause neuropsychiatric effects including hallucinatory flashbacks, inability to concentrate, and other cognitive deficits, possibly resulting from long-term effects of N -methyl-d-aspartic acid (NMDA)-receptor blockade.4,35,41,51 Both short-term and long-term memory impairment have been reported in chronic ketamine users.4,35,38,44,51

MRI studies in chronic ketamine abusers have found areas of degeneration in the superficial white matter as early as 1 year of ketamine abuse; cortical atrophy and substantially decreased thalamocortical connectivity in the brain also have been observed.4,38,39

Specific Populations

Pregnancy

There are no adequate and well-controlled studies of ketamine in pregnant women.1 Although ketamine has been used for induction of anesthesia during vaginal delivery and caesarean sections,2,10 the manufacturer states that the drug is not recommended for use during pregnancy or delivery because safety has not been established.1 Some neonates exposed to ketamine at maternal IV doses of 1.5 mg/kg or higher during delivery have experienced respiratory depression and low Apgar scores requiring resuscitation.2 Marked increases in maternal blood pressure and uterine tone have been observed following administration of IV ketamine doses greater than 2 mg/kg.2

In animal reproduction studies using IM ketamine doses approximately 0.3-0.6 times the usual human IM dose of 10 mg/kg (based on body surface area), developmental delays, skeletal hypoplasia, and increased fetal resorptions were observed.1

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including ketamine, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.750,753 The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.750

Lactation

It is not known whether ketamine is distributed into milk.69,70 Because the drug should be undetectable in plasma approximately 11 hours after administration, nursing after this time period should not expose the infant to clinically relevant amounts of ketamine.70

Pediatric Use

Although the manufacturer states that safety and efficacy of ketamine have not been established in patients younger than 16 years of age,1 the drug has been used widely in pediatric patients† in a variety of clinical settings for anesthesia, procedural sedation and analgesia, postoperative analgesia, and chronic pain management.3,9,11,23,25,45 Ketamine frequently is used in children to facilitate painful procedures in the emergency department and is considered a drug of choice for this use.3,11,14 Ketamine may be particularly useful in pediatric patients because the drug may be administered IM.3

Repeated or prolonged use of general anesthetics and sedation drugs, including ketamine, in children <3 years of age or during the third trimester of pregnancy may adversely affect neurodevelopment.750,753 In animals, use of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity leads to widespread neuronal apoptosis in the brain and long-term deficits in cognition and behavior when used for longer than 3 hours;750,751,752,753 however, the clinical relevance to humans is unknown.750

Ketamine may be preferred for induction of anesthesia in children with congenital heart disease with right-to-left shunt† because of its sympathomimetic effects and hemodynamic stability.3,9,10,23

Ketamine generally should not be used in infants younger than 3 months of age because of the potential increased risk of airway complications (e.g., airway obstruction, laryngospasm, apnea) thought to be due to age-specific differences in airway reactivity and anatomy.3,11,14

Geriatric Use

While reported clinical experience to date has not revealed age-related differences in response to ketamine when used as an anesthetic agent, clinical studies have not included sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 When ketamine is used as an anesthetic agent in geriatric patients, the dosage should be selected carefully, usually starting at the low end of the dosing range, because of the greater frequency of age-related decreases in hepatic, renal, and/or cardiac function, and of concomitant disease or other drug therapy.1

Hepatic Impairment

Prolonged effects of ketamine may occur in patients with hepatic impairment.2 Some experts recommend that use of ketamine be avoided or limited in patients with severe hepatic disease or cirrhosis, and that the drug be used with caution (e.g., with monitoring of liver function tests) in patients with moderate hepatic disease.25 Discontinuance of ketamine therapy is recommended if hepatotoxicity occurs.44

Renal Impairment

Ketamine concentrations have been reported to be 20% higher in individuals with acute renal failure than in those with normal renal function.5,68

Common Adverse Effects !!navigator!!

The most common adverse reactions with ketamine are emergence reactions and elevated blood pressure and pulse.1

Drug Interactions ⬆ ⬇

[Section Outline]

Ketamine principally undergoes N -demethylation to the active metabolite norketamine.1 N -Demethylation of ketamine to norketamine is mediated principally by cytochrome P-450 (CYP) isoenzyme 2B6 and 3A4 and, to a lesser extent, by other CYP enzymes.1

Ketamine, and its active norketamine metabolite, are principally metabolized by CYP3A4 with lesser involvement by CYP2B6 and CYP2C9.1,2,3,5,6

Drugs and Foods Affecting Hepatic Microsomal Enzymes !!navigator!!

Drugs that inhibit or induce CYP3A4 and CYP2B6 may increase or decrease, respectively, the systemic exposure of ketamine or norketamine.2,3,5,6

Grapefruit Juice

In healthy individuals, concomitant administration of the CYP3A4 inhibitor grapefruit juice (200 mL 3 times daily for 5 days) and S -ketamine (single oral dose of 0.2 mg/kg) increased peak plasma concentrations and AUC of ketamine by twofold and threefold, respectively.6 This interaction may be clinically important if ketamine is taken orally.6

Itraconazole

Concomitant administration of the CYP3A inhibitor itraconazole (200 mg orally once daily) and S -ketamine (single oral dose of 0.2 mg/kg) in healthy individuals had no effect on the AUC of ketamine.6,65

Macrolide Antibiotics

Concomitant administration of the CYP3A4 inhibitor clarithromycin and S -ketamine (single oral dose of 0.2 mg/kg) in healthy individuals increased peak plasma concentration and AUC of ketamine by 3.6- and 2.6-fold, respectively, and decreased the ratio of norketamine to ketamine by 54%.6,66 In addition, self-reported pharmacologic effects of ketamine were increased when S -ketamine was administered following pretreatment with clarithromycin.6,66 Erythromycin, but not azithromycin, is expected to have similar effects on the pharmacokinetics of S -ketamine.6

Rifampin

Concomitant use of the potent CYP3A4 and CYP2B6 inducer rifampin (600 mg orally daily for 5 days) and S -ketamine (0.57-1.14 mg/kg by IV infusion over 2 hours) in healthy individuals decreased the AUC of S -ketamine and S -norketamine by 10 and 50%, respectively.6,7

St. John's Wort

In healthy individuals, concomitant administration of the CYP3A4 inducer St. John's wort ( Hypericum perforatum ) and S -ketamine (single oral dose of 0.3 mg/kg) decreased peak plasma concentration and AUC of S -ketamine by 66 and 58%, respectively, and of S -norketamine by 18 and 23%, respectively.6

Ticlopidine

Concomitant use of the CYP2B6 inhibitor ticlopidine (250 mg orally twice daily) and S -ketamine (single oral dose of 0.2 mg/kg) in healthy individuals increased the AUC of S -ketamine by 2.4-fold6,65 and decreased the ratio of norketamine to ketamine.65

CNS Depressants !!navigator!!

Concomitant use of ketamine with CNS depressants (e.g., alcohol, benzodiazepines, opiate agonists, skeletal muscle relaxants) may result in additive CNS depression and increased risk of profound sedation, respiratory depression, coma, or death.1,2,3,51 Concomitant use of opiate agonists with ketamine during anesthesia may prolong recovery time.1

Closely monitor the patient's neurological status and respiratory parameters, including respiratory rate and pulse oximetry; consider dosage adjustment based on the individual clinical situation.1

Barbiturates

Decreased half-life and plasma concentrations of ketamine have been observed in patients receiving long-term therapy with barbiturates, likely due to hepatic enzyme induction.62,68

Benzodiazepines

Increased half-life of ketamine has been reported in patients who were premedicated with diazepam rectally (as a single dose) prior to anesthesia; these patients required lower doses of ketamine.62Decreased ketamine half-life was observed in patients who had been receiving long-term therapy with oral diazepam.62

Ketamine metabolism was not substantially altered in patients who received IV clorazepate prior to anesthesia.62

Administration of lorazepam has been reported to diminish the antidepressant response to repeated ketamine infusions in a patient with severe depression associated with bipolar disorder.318 Based on limited clinical evidence and theoretic concerns based on proposed mechanisms of action that benzodiazepines may diminish the antidepressant effects of ketamine,318,327,328 some clinicians recommend avoiding benzodiazepine administration for 8-12 hours prior to ketamine infusions.327

Ergonovine !!navigator!!

Concomitant use of ketamine and ergonovine may result in increased blood pressure.2,92

Lamotrigine !!navigator!!

Limited data suggest that lamotrigine, which inhibits the release of glutamate, may antagonize some of the effects of ketamine.6 Attenuated effects of ketamine, including perceptual abnormalities, schizophrenia-like symptoms, and learning and memory impairment, have been observed in healthy individuals who were pretreated with lamotrigine (300 mg) prior to receiving ketamine (0.26 mg/kg by IV injection or 0.65 mg/kg per hour by IV infusion).6 Failure of ketamine anesthesia following administration of IV doses totaling approximately 3.125 mg/kg has been reported in a patient with lamotrigine overdosage.6,8

Lamotrigine has been reported to reduce ketamine cravings in a patient with ketamine abuse disorder.6

Neuromuscular Blocking Agents !!navigator!!

Ketamine may potentiate the neuromuscular blocking effects of atracurium, resulting in respiratory depression and apnea.2,63 It is not known whether ketamine affects the duration of neuromuscular blockade of other neuromuscular blocking agents.63

Sympathomimetics and Vasopressin !!navigator!!

Concomitant use with sympathomimetics or vasopressin may result in an enhanced sympathomimetic effect of ketamine.1 If these drugs are used concomitantly, closely monitor vital signs and consider dosage adjustments based on the individual clinical situation.1

Theophyllines !!navigator!!

Concomitant use of ketamine and aminophylline or theophylline may result in a clinically important reduction in the seizure threshold.1,2 Tonic seizures have been reported during ketamine anesthesia in patients receiving aminophylline or theophylline.2,64 Consider use of an alternative to ketamine in patients receiving theophylline or aminophylline.1

Thyroid Agents !!navigator!!

Patients receiving thyroid replacement therapy may have an increased risk of ketamine-induced hypertension and tachycardia.2,91

Other Information ⬆ ⬇

Description

Ketamine is a nonbarbiturate general anesthetic that also has analgesic, amnestic, anti-inflammatory, and antidepressant properties.1,3,4,5,9,10,26,35,303,304,317,320,321 The drug is an arylcycloalkylamine derived from phencyclidine (PCP).1,3,4,5,9,35 Ketamine is commercially available in the US as a racemic mixture containing equal amounts of the R - and S -enantiomers.3,4,5,9,12,35,319 S -Ketamine, which is commercially available as esketamine in the US and some other countries, has a higher binding affinity for N -methyl-d-aspartate (NMDA) receptors and has approximately 3-4 times greater anesthetic potency than R -ketamine.3,4,5,12,35,319 S -Ketamine also appears to be associated with more frequent psychotomimetic adverse effects compared with R -ketamine.319

The pharmacologic effects of ketamine are dose dependent and mediated principally by its actions on the N -methyl-d-aspartate (NMDA) receptor, with contributory effects from other receptor interactions.3,4,5,26,35 The anesthetic, amnestic, analgesic, and psychotomimetic effects of ketamine have been attributed to the drug's noncompetitive antagonism of the NMDA receptor.1,3,4,5,9,10,25,26,27,35 The NMDA receptor is a ligand-gated channel complex that plays an important role in excitatory glutamate-mediated neurotransmission, which can affect cognition, chronic pain, opiate tolerance, and mood regulation.26 The receptor is blocked at resting state by extracellular magnesium.4,5,35 Upon neuronal depolarization, magnesium is released, resulting in ligand-induced channel opening and calcium influx.4,5,35 Ketamine binds to the phencyclidine (PCP) site of the NMDA receptor channel, decreasing the frequency of channel opening and duration of time in the open active state, thereby inhibiting receptor activation and excitatory glutamatergic neurotransmission.3,4,5,26,35

The NMDA receptor is closely involved in the development of opiate tolerance, opiate-induced hyperalgesia, and central sensitization (a condition closely related to the development of chronic pain).4,44 Activation of the NMDA receptor enhances neuronal excitability that can lead to hyperalgesia and allodynia.4 In the development of opiate tolerance and opiate-induced hyperalgesia, repeated activation of opiate receptors causes phosphorylation and opening of the NMDA receptor channel, leading to downregulation of opiate receptors and a reduction in opiate responsiveness.4,5 In chronic pain states, prolonged nociceptive stimulation causes activation and upregulation of NMDA receptors at dorsal horn synapses, resulting in enhanced and amplified trafficking of pain signals to the brain (central sensitization).44 Therefore, antagonism of NMDA receptors by ketamine decreases amplification of the response to repeated opiate receptor stimulation and can also prevent or reduce central sensitization.5,26

In addition to its effects on the NMDA receptor, ketamine also acts on a wide range of other targets, including opiate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid A (GABAA), cholinergic, nicotinic, and muscarinic receptors; L-type voltage-dependent calcium channels, hyperpolarization-activated cyclic nucleotide (HCN) channels, voltage-gated sodium channels, and large-conductance potassium (BK) channels; and the monoaminergic system.3,4,5,26,35

Ketamine produces dissociative anesthesia as a result of a functional and electrophysiologic dissociation between the thalamocortical and limbic systems.5,11,51 The drug appears to selectively depress sensory association areas in the cortex, limbic systems, and thalamus without substantially obtunding the more primitive pathways (reticular-activating and limbic systems).1 At anesthetic doses, ketamine disrupts frontal-to-posterior corticocortical connectivity while maintaining thalamocortical somatosensory pathways.3 Thus, sensory input may reach cortical receiving areas but fail to be observed in some of the association areas,5 effectively dissociating the CNS from outside stimuli.11 At subanesthetic doses, ketamine has been shown to alter functional connectivity between the subgenual anterior cingulate cortex and a network cluster involving the thalamus, hippocampus, and the retrosplenial cortex, without reported loss of consciousness.3

At anesthetic doses, ketamine produces a dissociative, cataleptic state characterized by profound analgesia, sedation, and amnesia.1,2,4,5,11,35 Although there is some variability, ketamine dissociation usually occurs at a dosing threshold of approximately 1-1.5 mg/kg when given IV or 3-4 mg/kg when given IM.11 Plasma ketamine concentrations associated with dissociative anesthesia have been reported to range from approximately 1.2-3 mcg/mL; concentrations associated with hypnosis and amnesia during surgery range from 0.8-4 mcg/mL and awakening usually occurs at plasma concentrations of 0.5-1.1 mcg/mL.23,35,51

At doses and plasma concentrations lower than those used for anesthesia, ketamine produces analgesia and sedation.4,11,25,26 Although there is some variability, doses less than 1 mg/kg generally have been considered subanesthetic.11,14,25,34 Following IV or IM administration, analgesic effects are associated with plasma ketamine concentrations ranging from 0.07-0.2 mcg/mL.23,25,35,51 Analgesic effects following oral administration occur at plasma ketamine concentrations of 0.04 mcg/mL, possibly due to a higher ratio of norketamine.51

The precise mechanism(s) of ketamine's antidepressant activity has not been clearly established.303,304,317,320,321 Considerable preclinical research suggests that the NMDA class of glutamate receptors plays a role in the pathophysiology of depression as well as in the mechanism of action of antidepressant treatments.304,320,321 In addition, NMDA receptor antagonists, including ketamine, have been shown to be effective in animal models of depression and in models that predict antidepressant activity in many studies.304,320,321 Preclinical and clinical data suggest that the antidepressant effects of ketamine may be mediated by an increase in glutamate, which leads to a cascade of events that results in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly in the prefrontal cortex.320,321 Following IV infusion of 0.5 mg/kg of ketamine over 40 minutes in patients with treatment-resistant major depressive disorder, peak plasma ketamine concentrations of 0.07-0.2 mcg/mL are achieved.35,302 These concentrations usually are associated with antidepressant effects but not general anesthetic effects.35,302

Like PCP, ketamine may cause psychotomimetic effects as a result of NMDA-receptor antagonism; such effects can occur following anesthetic or subanesthetic doses.26,35 At higher ketamine doses used for anesthesia, psychotomimetic effects appear to be dose related; however, a dose-related effect has not been clearly established at subanesthetic doses.26 The analgesic properties of ketamine are closely related to its psychotomimetic effects.25 Psychotomimetic effects of ketamine may occur at IV doses in the range of 0.1-1 mg/kg or IM doses in the range of 25-200 mg.51

Ketamine has a rapid onset of anesthetic action when given IV or IM.1 Following IV administration of the usual induction dose of 2 mg/kg, onset of surgical anesthesia occurs within 30 seconds and the duration of anesthetic effect is 5-10 minutes.1 Following IM administration of doses ranging from 9-13 mg/kg, onset of surgical anesthesia occurs within 3-4 minutes and the duration of anesthetic effect is usually 12-25 minutes.1 Following IV administration of a 2.5-mg/kg dose, ketamine has an initial distribution phase (α) lasting about 45 minutes and a half-life of 10-15 minutes, which is associated with the duration of anesthetic effect (about 20 minutes).1,2 Norketamine, the main active metabolite of ketamine, appears in the blood 2-3 minutes following IV administration of the drug and reaches peak plasma concentration in approximately 30 minutes.5

Peak plasma concentrations following oral administration of ketamine occur within 20-120 minutes.35 Bioavailability of ketamine following IM administration is 93% in adults;3,5,23,35 lower IM bioavailability has been reported in children.35 Due to extensive first-pass metabolism, bioavailability following oral or rectal administration is low (16-30 or 11-30%, respectively), with relatively higher concentrations of norketamine.3,4,14,35 Bioavailability of ketamine following intranasal administration has been reported to be up to 45-50%,3,4,35 but can vary substantially.3,14 In children 4-10 years of age, plasma ketamine concentrations are similar to those observed in adults.5 Plasma concentrations of norketamine are higher in children than adults following equivalent weight-adjusted doses.5

Ketamine is rapidly and widely distributed into highly perfused tissues, including the CNS, with a distribution half-life of 10-15 minutes.2,3,5,14 Animal studies have shown ketamine to be highly concentrated in body fat, liver, and lung.2 Because ketamine is lipophilic, it has a large volume of distribution.12 Termination of the anesthetic effect of ketamine occurs partly via redistribution from the CNS to peripheral tissues and partly by hepatic biotransformation.1,2

Ketamine crosses the placenta.2 Following an IM dose of 250 mg (approximately 4.2 mg/kg) in parturient patients, placental transfer rate of ketamine from maternal artery to umbilical vein was 47% at the time of delivery (average of 12 minutes from the time of injection to vaginal delivery).2 It is not known whether ketamine is distributed into milk.69 Ketamine is less than 50% bound to plasma proteins (α1-acid glycoprotein or albumin).5,12 Ketamine is metabolized extensively in the liver,2,4,9,35 principally undergoing N -demethylation to the active metabolite norketamine, which has approximately one-third the anesthetic activity of the parent drug.3,4,5,6,12 N -demethylation of ketamine to norketamine is mediated principally by cytochrome P-450 (CYP) isoenzyme 2B6 and 3A4 and, to a lesser extent, by other CYP enzymes.1 Norketamine is further metabolized to hydroxynorketamines and dehydronorketamine.35 Other biotransformation pathways of ketamine include hydroxylation of the cyclohexone ring,1,9 conjugation with glucuronic acid, and dehydration of the hydroxylated metabolites to form a cyclohexene derivative.1 About 90% of a parenteral dose of ketamine is excreted in the urine, mostly as conjugates of hydroxylated metabolites.2,3,4,10 Less than 5% of a dose is excreted unchanged in feces and urine.4 Because ketamine is extensively metabolized prior to excretion, the effect of renal function on the pharmacokinetics of ketamine and norketamine is minimal.5 Plasma concentrations of ketamine have been reported to be 20% higher in individuals with acute renal failure than in those with normal renal function.5,68

Ketamine is not appreciably removed by hemodialysis or hemofiltration (10 or 4%, respectively).68 The elimination half-life of ketamine is approximately 2-4 hours1,2,3,5,35 and is shorter in children (approximately 100 minutes) than in adults.5 The half-life of norketamine is 12 hours.4

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ketamine is subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.1,41

Ketamine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

10 mg (of ketamine) per mL*

Ketalar® (C-III)

Par

Ketamine Hydrochloride Injection (C-III)

50 mg (of ketamine) per mL*

Ketalar® (C-III)

Par

Ketamine Hydrochloride Injection (C-III)

100 mg (of ketamine) per mL*

Ketalar® (C-III)

Par

Ketamine Hydrochloride Injection (C-III)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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