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Ketamine Hydrochloride

Class: General Anesthetics
- NMDA Receptor Antagonists
- N-Methyl-d-aspartate Receptor Antagonists
Chemical Name: 2-(2-Chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride
Molecular Formula: C13H16ClNO•HCl
CAS Number: 1867-66-9

Medically reviewed by Drugs.com. Last updated on Oct 21, 2019.

Warning

    Emergence Reactions
  • Emergence reactions may occur during recovery from ketamine anesthesia.1 11 12 51 Manifestations vary in severity from pleasant to unpleasant dream-like states, vivid imagery, hallucinations, and emergence delirium.1 51 (See Neuropsychiatric Effects under Cautions.) These states may be accompanied by confusion, excitement, and irrational behavior, which some patients recall as an unpleasant experience.1

  • Duration of such reactions is generally no more than a few hours; however, recurrences have rarely occurred up to 24 hours later.1 Residual psychologic effects not reported.1

  • Incidence of emergence reactions may be reduced if verbal and tactile stimulation is minimized during recovery period; however, this should not preclude appropriate monitoring of vital signs.1

  • Benzodiazepines (e.g., midazolam, diazepam) may be administered to prevent or terminate emergence reactions.11 26

  • When ketamine is used on an outpatient basis, patients should not be released until complete recovery from anesthesia; patients should then be accompanied by a responsible adult.1

  • Risk of emergence reactions appears to be reduced in geriatric patients and in patients who have previously received the drug.1

Introduction

General anesthetic that also has analgesic and antidepressant properties;1 3 4 5 an N-methyl-d-aspartate (NMDA) receptor antagonist.1 3 4 5 9 10 26 35

Uses for Ketamine Hydrochloride

Induction and Maintenance of Anesthesia

Used IV or IM for induction of anesthesia prior to administration of other general anesthetic agents.1 3 9 10

Used as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation; although best suited for brief procedures, may be used for longer procedures with additional (i.e, maintenance) dosing.1

Also may be used to supplement low-potency agents (e.g., nitrous oxide).1

Produces dissociative anesthesia (i.e., a trance-like cataleptic state characterized by profound analgesia and amnesia, with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability), which differs markedly from the anesthetic state produced by other general anesthetics (e.g., barbiturates, benzodiazepines, propofol, inhalation anesthetics).1 5 11 35

Due to risk of emergence reactions (see Boxed Warning) and availability of other anesthetic agents, current use generally limited to certain patient populations (e.g., hemodynamically compromised patients) and settings (e.g., prehospital environments that lack appropriate monitoring and respiratory support) where the drug's unique pharmacologic properties may be particularly advantageous.3 9 44 51

Produces sympathomimetic effects and may be particularly useful in hemodynamically unstable patients (e.g., those with traumatic injury or septic shock)3 9 10 or in poor-risk patients with depressed vital functions.1

Because of its bronchodilating effects, generally considered the induction agent of choice in patients with reactive airway disease (e.g., asthma) or active bronchospasm.3 9 10

Although currently FDA-labeled for use in adults only,1 has been used widely in pediatric patients.3 9 23

Procedural Sedation

Used to produce dissociative sedation for 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.1 3 4 9 10 11 14 79 89

Commonly used for procedural sedation in pediatric patients; used less frequently in adults because of increased risk of emergence delirium.3 9 11 78 79 89

Administration of a single IV or IM dose can effectively provide dissociation for approximately 5–10 or 20–30 minutes, respectively, while maintaining cardiovascular stability, spontaneous respiration, and protective airway reflexes.1 11

Has a well-established role in burn patients undergoing painful procedures (e.g., dressing changes, debridement, grafts).3 9 10 23

Availability of the IM route is advantageous 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

Has been used in combination with propofol (commonly referred to as “ketofol”) to counteract adverse effects of the drugs (i.e., ketamine mitigating propofol-induced hypotension and propofol mitigating ketamine-induced vomiting and recovery agitation).9 10 89

Postoperative Pain

Has been used in low (i.e., subanesthetic or subdissociative) doses as part of a multimodal regimen for postoperative pain in adults and pediatric patients.3 10 25 27 28 29 30 34 75 76 82 97 98 99 100 101 102 103

Efficacy of low-dose ketamine in the postoperative setting is well established; clinical studies have demonstrated reduced opiate requirements and, in some cases, additional reductions in pain.3 10 27 29 33 34 75 76 82

Appears to provide most benefit for patients undergoing procedures associated with severe postoperative pain (e.g., thoracic, abdominal, orthopedic surgeries).25 27 31 32 76 82 Some experts state that benefit not demonstrated in patients undergoing procedures associated with mild postoperative pain (e.g., tonsillectomy, head and neck surgery);25 for such procedures, standard analgesia with low dosages of opiates, NSAIAs, and local anesthetics can usually provide adequate pain relief.27 76

May be particularly useful in the management of opiate-tolerant or opiate-dependent patients undergoing surgery.25 82 Also may be considered as an adjunct to reduce postoperative opiate requirements in patients with increased risk of opiate-related respiratory depression (e.g., those with obstructive sleep apnea).25

Acute Pain

Has been used (in subanesthetic doses) alone or as an adjunct to other analgesics (e.g., opiates) for relief of acute pain in emergency department or prehospital settings.3 9 10 14 15 16 17 18 19 20 21 22 24 25 83 84 Reported to provide comparable reduction in pain scores to IV morphine.14 21 22

When used as an adjunct to opiate analgesics, ketamine may reduce pain scores and/or decrease opiate requirements.14 16 17 18 19 20 84

Studies evaluating subanesthetic ketamine for acute pain generally conducted 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 presenting to the emergency department.11 84

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

Has been used as an adjunct analgesic for 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.3 9 10 26 42 43 44 45 46 47 48 52 53 54 86 87

Evidence of efficacy varies depending on specific chronic pain condition; some evidence supports short-term benefits of ketamine infusions for certain conditions associated with a neuropathic component.3 10 26 31 42 43 44 46 48 49 50 86 87

There is weak to moderate evidence supporting use for CRPS.26 47 85 There is weak evidence supporting use for neuropathic pain associated with spinal cord injury.26 49 86 87 Evidence remains inconclusive for cancer-related pain, mixed neuropathic pain, phantom limb pain, postherpetic neuralgia, fibromyalgia, ischemic pain, migraine, and low-back pain.3 4 26 46 54

Additional study needed to establish role of ketamine in patients with chronic pain, and to determine optimum dosages, durability of response, and long-term benefits and risks.10 26 31 43 48 52 53 54

Treatment-resistant Depression and Suicidality

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

In controlled studies, single, low-dose IV infusions of ketamine resulted in approximately 37–71% response rates in patients with treatment-resistant depression.300 317 Limited clinical experience in patients with bipolar disorder; not known if such patients respond differently to ketamine than patients with major depressive disorder.314

Multiple-infusion regimens of ketamine (i.e., weekly, biweekly, 3 times weekly) appear to be more effective in depressed patients than single infusions and can prolong remission.303 306 307 312 313 314 315 However, long-term efficacy and safety of repeated doses not fully determined.300 306 307 312 314 Although not observed to date, multiple-infusion regimens potentially may cause long-term cognitive impairment and/or neurotoxicity.307 312 314 Some clinicians suggest that short-term use of ketamine to produce rapid antidepressant and antisuicidal effects until a less invasive relapse prevention strategy can be implemented may be optimal.312

Has been used in the short-term treatment of suicidal ideation.304 307 310 314 317 323 324 325 326 In a systematic review and meta-analysis, suicidal ideation rapidly decreased following IV infusions of ketamine even among patients whose depression did not fully respond to ketamine therapy, suggesting the drug may have a partially independent antisuicidal effect.307 310

Preliminary evidence suggests that intranasal ketamine can rapidly improve depressive symptoms in patients with major depressive disorder and is generally well tolerated; however, further studies are needed to more clearly determine the efficacy, tolerability, and optimal dosing of this alternative route of administration.305 314 317 Pending further accumulation of safety data from controlled settings, 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.302

Despite the increasing use of ketamine to treat patients with treatment-resistant depression and suicidality and the rapid increase in the number of facilities offering ketamine therapy (e.g., ketamine infusion centers and psychiatric clinics), some clinicians currently recommend limiting ketamine's use to controlled settings under the care of skilled clinicians.302 308 316 If ketamine is used outside of a controlled setting, careful screening, monitoring during treatment, and follow-up of patients are necessary.302 314 316

When considering the use of ketamine for mood disorders, the 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 (e.g., neurotoxicity, cystitis, abuse potential).302 314 320 (See Cautions.)

Some clinicians consider electroconvulsive therapy (ECT) to be first-line therapy for patients with refractory depression and are concerned that a trial of ketamine 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

Sedation and Analgesia in Critical Care Settings

Has been used by continuous IV infusion to provide short-term (i.e., < 24 hours) sedation in critically ill patients in the ICU setting; however, evidence supporting this use is generally lacking, and other agents (e.g., propofol, midazolam, dexmedetomidine) are more commonly used.9 12 13 77

Also has been used for pain management in critically ill patients.12 13 25

Misuse and Abuse

A known drug of abuse; prescribe and administer with caution.1 3 35 41 51 Subject to control under the Federal Controlled Substances Act of 1970 as a schedule III drug.1 41

Most commonly abused by nasal insufflation (i.e., snorting) of the evaporated powder, although IV, IM, and oral routes also used.35 41 Most cases of ketamine abuse reported in the context of multidrug or polysubstance abuse.51

Pharmacologic and behavioral effects of ketamine are similar to, but somewhat less intense and shorter in duration than those of phencyclidine (PCP).41

Reported desired effects include feelings of dissociation and unreality, altered state of consciousness, enhanced sensory perception, hallucinations, intoxication, mild euphoria, and sensation of floating.3 35 44 51

Although brief exposure in a hospital setting is not likely to cause addiction, the possibility exists and patients should be assessed for their risk.25

Ketamine Hydrochloride Dosage and Administration

General

  • When used for general anesthesia, administer by or under supervision of clinicians experienced in the use and complications of general anesthetics.1 23 26 Appropriate monitoring and resuscitative equipment should be readily available.1 26

  • When used for procedural sedation in the emergency department, administer by appropriately trained individuals who can safely administer and manage complications of the drug.11 Experts recommend the presence of 2 individuals during procedure (one to perform procedure and one to monitor patient).11 Patients should be continuously observed by a dedicated healthcare professional until recovery is well established.11

  • May administer benzodiazepines (e.g., diazepam, midazolam) concomitantly to reduce risk of psychotomimetic effects during emergence in adults receiving ketamine anesthesia.1 11 26 Routine benzodiazepine prophylaxis not recommended in pediatric patients because of uncertain benefit.11

  • May administer anticholinergic agents (e.g., atropine, glycopyrrolate) prior to or concomitantly to reduce hypersalivation and risk of laryngospasm.1 10 11 Because of uncertain benefit, some experts state that such prophylaxis should be reserved for patients with clinically important hypersalivation or impaired ability to mobilize secretions.11

  • Because nausea and vomiting may occur following administration,1 11 14 16 25 prophylactic use of antiemetics (e.g., ondansetron) may be beneficial, particularly in patients at higher risk (e.g., early adolescents receiving ketamine for procedural sedation).11 14 93 94 95

  • When used by IV infusion for mood disorders (e.g., treatment-resistant depression, suicidality), administer by experienced clinicians in a facility where adequate monitoring for and management of possible adverse reactions (e.g., altered cardiovascular and respiratory function, acute dissociative and psychotomimetic effects) are possible.302

Administration

Usually administered by slow (e.g., over 60 seconds) IV injection, IV infusion, or IM injection.1 3 4 5 10 35 51 Also has been administered by oral,3 5 25 35 52 intranasal,3 5 10 25 35 302 305 314 317 rectal,3 5 35 sub-Q,3 53 54 56 intraosseous (IO),3 5 10 epidural, and intrathecal routes.3 5 35 Because of concerns about potential neurotoxicity, some experts recommend that neuraxial administration be avoided.9 23 26 27 51 82

IV administration is preferred when access can be obtained readily;11 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

IM administration is associated with a higher rate of vomiting and longer recovery times compared with IV administration, but may be useful in certain patients (e.g., severely agitated or uncooperative patients, young children).3 9 11 35

May be administered in a patient whose stomach is not empty if benefits outweigh potential risks.1 11 Because vomiting may occur, consider risk of aspiration when used concomitantly with other anesthetics and muscle relaxants that may impair protective airway reflexes.1 11

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Dilution

Do not administer ketamine 100 mg/mL IV without proper dilution; must dilute the commercially available injection concentrate with an equal volume of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection prior to IV injection.1

To prepare a solution containing 1 mg/mL for IV infusion, add 500 mg of ketamine (10 mL from a vial containing 50 mg/mL or 5 mL from a vial containing 100 mg/mL) to an infusion bag containing 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 In patients requiring fluid restriction, may prepare a solution containing 2 mg/mL for IV infusion by adding 500 mg of ketamine (10 mL from a vial containing 50 mg/mL or 5 mL from a vial containing 100 mg/mL) to an infusion bag containing 250 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 Manufacturer states that dilutions using the 10-mg/mL concentration of ketamine not recommended.1

Rate of Administration

Because rapid IV administration can cause respiratory depression, administer IV injections slowly over 60 seconds.1 11 12 For dissociative sedation in emergency department settings, IV administration over 30–60 seconds has been recommended.11

When ketamine is administered with diazepam for anesthesia, manufacturer recommends IV injection at a rate of 0.5 mg/kg per minute for induction of anesthesia and IV infusion at a rate of 0.1–0.5 mg/minute for maintenance of anesthesia.1

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

When ketamine is used for 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 Clinical experience with shorter and longer infusion rates is too limited302 322 to recommend their use at this time.302

Dosage

Available as ketamine hydrochloride; dosage expressed in terms of ketamine.1

Dosage depends on intended use and desired pharmacologic effect.10 37 Ketamine produces analgesia and sedation at low doses and a state of dissociative anesthesia at higher doses.23 26 37

Doses at or above the dissociative threshold are referred to as “dissociative” or “anesthetic,” and doses below the 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 is reached, additional administration of ketamine will not enhance or deepen sedation.11

Pediatric Patients

Anesthesia

When used for anesthesia, individual response is variable and can depend on factors such as dosage, route of administration, patient age, or concomitant drugs; individualize dosage based on therapeutic response and patient's anesthetic requirements.1 10

Higher doses generally correspond with longer anesthesia recovery times.1

Purposeless and tonic-clonic movements of extremities may occur during the course of anesthesia; such movements do not imply a light plane of consciousness and are not indicative of the need for additional doses or anesthesia.1

Rapid induction of anesthesia occurs following IV injection; the patient should be in a supported position during administration.1

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

Induction and Maintenance of Anesthesia
IV

Some experts recommend an initial dose of 1–3 mg/kg for induction of anesthesia in pediatric patients; may give supplemental IV doses of 0.5–1 mg/kg if clinically indicated.23

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

IM

Some experts recommend a dose of 5–10 mg/kg for induction of anesthesia in pediatric patients.23 11

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

Procedural Sedation

Because dissociation occurs rapidly, administer ketamine just prior to initiating procedure.11

IV

Dissociative sedation in pediatric patients ≥3 months3 11 of age undergoing short painful or emotionally disturbing procedures in the emergency department: 1.5–2 mg/kg administered by IV injection over 30–60 seconds.11 Although single dose usually sufficient, may administer additional incremental doses of 0.5–1 mg/kg every 5–15 minutes as needed if initial sedation is inadequate or additional doses are needed for longer procedures.11

Although some experts state that minimum IV dose that will reliably elicit the dissociative state is 1.5 mg/kg,11 lower doses (e.g., 0.25–1 mg/kg) also have been used, particularly if a dissociative effect is not required for the procedure.11 23 78

IM

Dissociative sedation in pediatric patients ≥3 months3 11 of age undergoing short painful or emotionally disturbing procedures in the emergency department: 4–5 mg/kg.11 37 Although single dose usually sufficient, may administer additional IM doses of 2–5 mg/kg after 5–10 minutes if initial sedation is inadequate or additional doses are needed for longer procedures.11

Although some experts state that minimum IM dose that will reliably elicit the dissociative state is 4–5 mg/kg,11 lower doses (e.g., 1–2 mg/kg) also have been used, particularly if a dissociative effect is not required for the procedure.11 23

Postoperative Pain
IV

Bolus doses of 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 [1.67–10 mcg/kg per minute]) commonly used in clinical studies in adults and pediatric patients; however, dosages and timing of administration in relation to surgical procedure varied widely and optimum dosage regimen not known.9 10 25 25 27 30 31 33 34 82 97 98 99 100 101 102 103

Some experts state there is moderate evidence supporting use of IV bolus doses up to 0.35 mg/kg and IV infusions up to 1 mg/kg per hour (16.67 mcg/kg per minute) as an adjunct to opiates for perioperative analgesia.25

In several studies, administration of a single IV dose of ketamine 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 <3 months of age.11

IM

IM administration of analgesic agents for postoperative pain not recommended because of substantial pain and unreliable absorption.82

Acute Pain
IV

Acute pain in emergency department or prehospital settings: Usually, 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 are rare in this setting, continuous IV infusions of 0.1–0.3 mg/kg per hour (1.67–5 mcg/kg per minute) have been given.9 10 14 16 18 20 21 22 84

Acute pain in settings without intensive monitoring: Some experts state that IV bolus doses generally should not exceed 0.35 mg/kg and infusion rates generally should not exceed 1 mg/kg per hour (16.67 mcg/kg per minute).25

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

IM

Dosage range not definitively established; analgesic effects are less predictable when administered IM.84

Chronic Pain
IV

There is no consensus on dosages or administration protocols; the drug generally is administered in subanesthetic doses by IV infusion.26 35 42 43 44 45 48

Some evidence suggests that administration of higher dosages over longer periods and more frequent infusions may provide more benefit.26 43 44

In a study in children and adolescents 12–17 years of age with chronic pain conditions (e.g., chronic headache, fibromyalgia, CRPS), 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 received IV infusions of ketamine at 0.1–1 mg/kg per hour.53

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

Adults

Anesthesia

When used for anesthesia, individual response is variable and can depend on factors such as dosage, route of administration, patient age, or concomitant drugs; individualize dosage based on therapeutic response and patient's anesthetic requirements.1 10

Higher doses generally correspond with longer anesthesia recovery times.1

Purposeless and tonic-clonic movements of extremities may occur during the course of anesthesia; such movements do not imply a light plane of consciousness and are not indicative of the need for additional doses or anesthesia.1

Rapid induction of anesthesia occurs following IV injection; the patient should be in a supported position during administration.1

Induction and Maintenance of Anesthesia
IV

Initially, 1–4.5 mg/kg by slow IV injection over 60 seconds.1 On average, a dose of 2 mg/kg will produce 5–10 minutes of surgical anesthesia.1 51

May administer additional IV doses of 0.5–4.5 mg/kg as needed.1 A continuous IV infusion of 1–6 mg/kg per hour also has been recommended for maintenance of anesthesia.26 Adjust dosage based on patient's anesthetic requirements and concomitant use of other anesthetic agents.1

Diazepam-augmented regimen (to reduce incidence of emergence reactions): Ketamine (1–2 mg/kg administered IV at a rate of 0.5 mg/kg per minute) with diazepam (doses of 2–5 mg administered by IV injection in a separate syringe over 60 seconds).1 To maintain anesthesia, may administer IV infusion of ketamine at a rate of 0.1–0.5 mg/minute with diazepam (2–5 mg by IV injection in a separate syringe as needed).1 A total diazepam dosage ≤15 mg usually is sufficient for induction, and a total diazepam dosage ≤20 mg usually is sufficient for combined induction and maintenance.1

IM

Initially, 6.5–13 mg/kg.1 A dose of 10 mg/kg will usually produce 12–25 minutes of surgical anesthesia.1 51

May administer additional IM doses of 3.25–13 mg/kg as needed.1 Adjust dosage based on patient's anesthetic requirements and concomitant use of other anesthetic agents.1

Procedural Sedation

Because dissociation occurs rapidly, administer ketamine just prior to initiating procedure.11

IV

Dissociative sedation in adults undergoing short painful or emotionally disturbing procedures in the emergency department: 1 mg/kg administered by IV injection over 30–60 seconds.11 Although single dose usually sufficient, may administer additional doses of 0.5–1 mg/kg every 5–15 minutes if initial sedation is inadequate or additional doses are needed for longer procedures.11

Lower IV doses (e.g., 0.2–0.75 mg/kg) have been used, particularly if a dissociative effect is not required for the procedure.11 26

IM

Although IM route not preferred in adults, may administer 4–5 mg/kg.11 Single dose usually sufficient; however, may administer additional IM doses of 2–5 mg/kg after 5–10 minutes if initial sedation is inadequate or additional doses are needed for longer procedures.11

Lower IM doses (e.g., 0.4–2 mg/kg) have been used, particularly if a dissociative effect is not required for the procedure.11 26

Sedation and Analgesia in Critical Care Settings
IV

Critically ill adults with severe pain unresponsive to conventional therapies: Initial IV doses of 0.1–0.5 mg/kg followed by IV infusion of 0.05–0.4 mg/kg per hour (0.83–6.67 mcg/kg per minute) recommended by some experts; other dosage regimens also have been used.12 13 77

If additional pain control needed, may administer additional IV doses up to a maximum of 0.5 mg/kg; alternatively, may titrate infusion in increments of 0.06 mg/kg per hour (1 mcg/kg per minute) every 15 minutes up to a maximum of 1.2 mg/kg per hour (20 mcg/kg per minute) as tolerated.12

Postoperative Pain
IV

Bolus doses of 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 [1.67–10 mcg/kg per minute]) commonly used in clinical studies; however, dosages and timing of administration in relation to surgical procedure varied widely and optimum dosage regimen not known.9 25 27 30 31 33 34 82

Some experts state there is moderate evidence supporting use of IV bolus doses up to 0.35 mg/kg and IV infusions up to 1 mg/kg per hour (16.67 mcg/kg per minute) as an adjunct to opiates for perioperative analgesia.25

IM

IM administration of analgesic agents for postoperative pain not recommended because of substantial pain and unreliable absorption.82

Acute Pain
IV

Acute pain in emergency department or prehospital settings: Usually, 0.1–0.3 mg/kg administered as a slow IV injection or short IV infusion over 10–15 minutes; although longer infusions are rare in this setting, continuous IV infusions of 0.1–0.3 mg/kg per hour (1.67–5 mcg/kg per minute) have been given.9 10 16 18 20 21 22 84

Acute pain in settings without intensive monitoring: Some experts state that IV bolus doses generally should not exceed 0.35 mg/kg and infusion rates generally should not exceed 1 mg/kg per hour (16.67 mcg/kg per minute).25

IM

Dosage range not definitively established; analgesic effects are less predictable when administered IM.84

Chronic Pain
IV

There is no consensus on dosages or administration protocols; the drug generally is administered in subanesthetic doses by IV infusion.26 35 42 43 44 48

Some evidence suggests 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 with a single outpatient infusion at a minimum dose of 80 mg for at least 2 hours and then reassess before initiating further treatments.26 IV bolus doses up to 0.35 mg/kg or infusions of 0.5–2 mg/kg per hour have been recommended; however, higher (e.g., up to 7 mg/kg per hour for refractory pain) or lower (e.g., 0.1–0.5 mg/kg per hour) infusion rates also have been used successfully.26 43 50

Treatment-resistant Depression and Suicidality
IV

Usually given in subanesthetic doses of 0.5 mg/kg by IV infusion over 40 minutes.300 301 302 303 304 306 307 312 315 326 Although a higher infusion dosage (e.g., 0.75 mg/kg) has been used in a limited number of chronically ill and/or severely treatment-resistant patients, further studies are needed to determine efficacy and safety of higher-dosage regimens.322

Obese patients (i.e., body mass index [BMI] ≥30) may be at increased risk for adverse hemodynamic effects and may benefit from adjusting dosage to calculated ideal body weight rather than actual body weight; further clinical experience to determine optimal dosing in such patients is needed.300 302 315

Limited experience with longer-term (multiple-dose) ketamine infusion therapy; however, IV infusions have been given once, twice, or 3 times weekly for 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 not responding to several initial infusions appear unlikely to respond to subsequent infusions.302 Some experts recommend discontinuing therapy if the interval between infusions cannot be extended to 1 week or longer by the second month of treatment; these experts state that the goal should be to eventually taper and discontinue treatment until additional long-term safety data are available.302

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1

Geriatric Patients

Select dosage with caution because of greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease or other drug therapy in geriatric patients.1

Cautions for Ketamine Hydrochloride

Contraindications

  • Patients in whom substantial BP elevation would constitute a serious hazard.1

  • Known hypersensitivity to ketamine.1

  • Some experts state that relative contraindications may include history of airway instability, tracheal surgery, or tracheal stenosis; active pulmonary infection or disease; known or suspected cardiovascular disease (e.g., angina, CHF, hypertension); CNS masses, abnormalities, or hydrocephalus; elevated IOP (e.g., glaucoma, acute globe injury); and porphyria, hyperthyroidism, or concomitant thyroid replacement therapy.11

Warnings/Precautions

Warnings

Neuropsychiatric Effects

Like PCP, ketamine, a PCP derivative, can cause psychotomimetic effects.3 11 13 19 26 27 35 41 46 (See Actions.)

Emergence reactions may occur during the recovery period in patients receiving ketamine anesthesia.1 Such reactions occur more frequently in adults than pediatric patients.11 51 (See Boxed Warning.)

When given in low (subanesthetic) doses, ketamine can produce mild cognitive, psychotic, and mood disturbances that are usually transient and limited to time of administration.3 13 19 27 41 46 At higher doses, ketamine can produce more severe, schizophrenic-like symptoms, vivid hallucinations, psychosis, feelings of an “out of body” experience, mental confusion, hyperexcitability, and catalepsy.11 41 Serious emergence reactions are extremely rare with low-dose ketamine.19

When used for treatment-resistant depression and suicidality, acute dissociative and psychotomimetic effects (e.g., psychotic symptoms) reported with IV infusions of ketamine.300 307 312 313 315 317 320 Such effects generally occur only during and immediately following ketamine infusions and resolve within 2–4 hours post-infusion, are mild in severity, and are well tolerated.307 313 315 317 320

Long-term use can cause persistent neuropsychiatric symptoms, cognitive impairment, and psychologic abnormalities.3 When repeated administration of ketamine is used in patients with mood disorders, some experts recommend considering assessment of cognitive function.302

Other Warnings and Precautions

Cardiovascular Effects

Mild to moderate increases in BP, heart rate, and cardiac output may occur as a result of ketamine's sympathomimetic effects.1 3 11 26 40

When used for treatment-resistant depression and suicidality, elevated BP and/or heart rate may occur during IV infusions of ketamine; these hemodynamic effects usually are transient and subside following completion of the infusion.300 302 307 312 313 326 Short-term antihypertensive therapy sometimes has been used to treat ketamine infusion-associated BP elevations in some patients.300 315

Generally avoid use in patients with known or suspected cardiac conditions (e.g., unstable angina, CAD, MI, CHF, hypertension) that may be exacerbated by sympathomimetic effects of the drug.11 25 26

Contraindicated in patients in whom a substantial elevation of BP would constitute a serious hazard; monitor cardiac function continuously in patients who experience hypertension or cardiac decompensation during ketamine anesthesia.1

Because sympathomimetic effects may be increased, use with caution or avoid use in patients with porphyria, hyperthyroidism, or in those receiving thyroid replacement therapy.11

Laryngospasm or other Airway Obstruction

Laryngospasm and other forms of airway obstruction may occur.1 Prepare to rapidly identify and manage such complications (e.g., with assisted ventilation, oxygen, or possible intubation).1 11

Major stimulation of posterior pharynx may increase risk of laryngospasm.11 Do not use as sole agent during surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree.1 If ketamine is used alone, avoid mechanical stimulation of the pharynx (e.g., endoscopy) whenever possible; muscle relaxants, with proper maintenance of respiration, may be required.1

Risk of laryngospasm is low with minor oropharyngeal procedures typically performed in the emergency department; avoid vigorous stimulation of posterior pharynx and accumulation of secretions or blood during these procedures.11

Use with caution or avoid use in patients with history of airway instability, tracheal surgery, or tracheal stenosis; risk of laryngospasm may be increased in such patients.11

Respiratory Effects

Severe respiratory depression or apnea may occur following rapid IV administration or overdosage.1 If respiratory depression occurs, provide respiratory support (e.g., mechanical ventilation).1

Administer IV injections slowly (e.g., over 60 seconds).1

When used in subanesthetic doses for the treatment of depression in otherwise healthy individuals, ketamine is unlikely to cause clinically important adverse respiratory effects.302

Use with caution or avoid use in patients with active pulmonary infection or disease (e.g., upper respiratory infection, asthma).11

Administration Precautions

Administer only by or under supervision of individuals experienced with the use and potential complications of ketamine.1 11 26 82 (See General under Dosage and Administration.)

When used in anesthetic doses, administer in a monitored setting in the presence of personnel trained in advanced airway management and cardiovascular life support; resuscitative equipment should be readily available.1 11 23 26

When used in subanesthetic doses in the emergency department, adverse effects generally are mild and self-limiting; therefore, some experts state that ketamine administration may follow same procedures and policies used for other analgesics in this setting.83 84 Consult local protocols since expectations may differ.84

When used in subanesthetic doses as an IV infusion for the treatment of mood disorders (e.g., treatment-resistant depression, suicidality), some experts recommend administration by experienced clinicians in a facility where adequate monitoring for and management of possible adverse reactions (e.g., altered cardiovascular and respiratory function, acute dissociative and psychotomimetic effects) are possible.302

Visceral Pain

If used in patients undergoing surgical procedures involving visceral pain pathways, add a supplemental agent that obtunds visceral pain.1

Intracranial Pressure

Increased intracranial pressure may occur;1 11 however, 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

Manufacturer states to use with extreme caution in patients with elevated intracranial pressure;1 some experts state that ketamine should be avoided in such patients.25 Use with caution or avoid use in patients with CNS masses, abnormalities, or hydrocephalus.11

Intraocular Pressure

Elevation of IOP may occur.1 23 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 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

Hepatobiliary Effects

Elevated hepatic enzyme concentrations may occur, particularly following prolonged infusion and/or repeated doses within a short time frame.26 27 44 Enzyme abnormalities generally return to normal following drug discontinuance.26 (See Hepatic Impairment under Cautions.)

Hepatotoxicity reported following longer-term use (e.g., >3–4 days).3 4 26 38 44 Epigastric pain, bile duct dilatation, and abnormal liver function tests consistent with posthepatic obstruction observed in chronic ketamine abusers.4 38 44

Discontinue therapy if hepatotoxicity occurs.44

Use with caution or avoid in patients with chronic alcoholism or with acute alcohol intoxication.1 26

Schizophrenia/Psychosis

May exacerbate schizophrenia;11 35 generally avoid use in patients with schizophrenia or active psychosis.11 25 26 Caution advised when used for procedural sedation or acute pain in patients with other psychiatric disorders,11 including substance abuse-induced psychosis.15

Dependence, Tolerance, and Abuse

Tolerance and dependence may develop following prolonged administration.1 35 51 Abuse or diversion also may occur.3 4 35 41 44 51 Although cases of abuse and dependence reported, abuse potential not clearly defined.35

Long-term abuse 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

Use caution when prescribing and administering the drug.1

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.1 Not recommended for use during pregnancy or delivery; safety not established.1

Respiratory depression and low Apgar scores requiring resuscitation reported in some neonates exposed to ketamine at maternal IV doses of ≥1.5 mg/kg during delivery.2 Marked increases in maternal BP and uterine tone observed at IV doses >2 mg/kg.2

Based on animal data, repeated or prolonged use of general anesthetics and sedative drugs, including ketamine, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.750 753 (See Pediatric Use under Cautions and also see Advice to Patients.)

Lactation

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 infant to clinically relevant amounts of ketamine.70

Pediatric Use

Manufacturer states that safety and efficacy not established in patients <16 years of age;1 however, ketamine has been used widely in pediatric patients in a variety of settings for anesthesia, procedural sedation, postoperative pain, and chronic pain management.3 9 11 23 25 45

Frequently used in children to facilitate painful procedures in the emergency department and is considered a drug of choice for this use.3 11 14 May be particularly useful in pediatric patients because the drug may be administered IM.3

Generally should not be used in infants <3 months of age because of potential increased risk of airway complications, including airway obstruction, laryngospasm, and apnea.3 11 14

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 for >3 hours 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;750 751 752 753 clinical relevance to humans is unknown.750 Some evidence suggests similar deficits may occur in children following repeated or prolonged exposure to anesthesia early in life.750 752 Some evidence also indicates 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 Most studies to date have substantial limitations; further research needed to fully characterize effects, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).750 Consider benefits and potential risks when determining the timing of elective procedures requiring anesthesia.750 FDA states that medically necessary procedures should not be delayed or avoided.750 753 (See Advice to Patients.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients; other reported clinical experience has not identified any age-related differences in response.1 A reduced risk of emergence reactions has been observed in geriatric patients >65 years of age relative to younger adults.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Prolonged effects of ketamine may occur in patients with cirrhosis or hepatic impairment.2

Some experts state to avoid or limit use in patients with severe hepatic disease or cirrhosis, and to use caution (with monitoring of liver function tests) in patients with moderate hepatic disease.25 (See Hepatobiliary Effects under Cautions.)

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

Emergence reactions (e.g., dream-like states, vivid imagery, hallucinations, delirium, confusion, agitation, irrational behavior),1 4 11 12 51 diplopia,1 nystagmus,1 hypertonia,1 11 tonic-clonic or other involuntary movements,1 11 increased BP,1 3 11 26 40 increased heart rate,1 3 11 26 40 increased respiratory rate,1 nausea,1 11 14 16 25 vomiting.1 11 14 16 23 25 59

Treatment-resistant depression and suicidality: Transient increases in BP and/or heart rate,300 306 307 312 313 transient dissociative and psychotomimetic effects (e.g., psychotic symptoms).300 307 312 313 315 317 320

Interactions for Ketamine Hydrochloride

Metabolized mainly by CYP3A4, and to a lesser extent by CYP2B6 and CYP2C9.2 3 5 6 35

Drugs and Foods Affecting Hepatic Microsomal Enzymes

CYP inhibitors (particularly CYP3A4): Potential increased systemic exposure of ketamine and norketamine.3 5 6

CYP inducers (particularly CYP3A4): Potential decreased systemic exposure of ketamine and norketamine.3 5 6

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anesthetic agents

Ketamine is clinically compatible with commonly used general and local anesthetic agents when adequate respiration is maintained1

Barbiturates

Possible prolonged recovery time from anesthesia1

Long-term treatment: Decreased half-life and plasma concentrations of ketamine observed in patients receiving long-term therapy with barbiturates, likely due to hepatic enzyme induction62 68

Benzodiazepines (e.g., clorazepate, diazepam, lorazepam)

Possible additive CNS depression and increased risk of respiratory depression2 51

Possible antagonism of antidepressant effect of ketamine based on limited evidence and mechanisms of action318 327 328

Clorazepate: Ketamine metabolism not substantially altered in patients who received IV clorazepate prior to anesthesia62

Diazepam: Increased half-life of ketamine reported in patients receiving diazepam rectally (as a single dose) prior to anesthesia; however, half-life of ketamine was decreased in patients receiving long-term oral diazepam2 62

When used to treat mood disorders, consider avoiding benzodiazepines within 8–12 hours prior to ketamine infusion327

CNS depressants (e.g., alcohol, benzodiazepines, opiate agonists, skeletal muscle relaxants)

Possible additive CNS depression and increased risk of respiratory depression2 51

Opiate agonists: Possible prolonged recovery time from anesthesia1

Ergonovine

Possible increased BP2 92

Grapefruit juice

Increased peak plasma concentration and AUC of orally administered S-ketamine by twofold and threefold, respectively6

May be clinically important if ketamine is administered orally6

Itraconazole

AUC of orally administered S-ketamine not affected6 65

Lamotrigine

Possible reduced effects of ketamine, including reduced anesthetic efficacy6 8

Macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)

Clarithromycin: Increased peak plasma concentration and AUC of orally administered S-ketamine by 3.6- and 2.6-fold, respectively, and decreased ratio of norketamine to ketamine by 54%;6 66 increased pharmacologic effects of ketamine reported6 66

Erythromycin, but not azithromycin, expected to have similar effects6

Neuromuscular blocking agents (e.g., atracurium)

Atracurium: May potentiate neuromuscular blocking effects and result in respiratory depression and apnea2 63

Not known whether ketamine affects duration of other neuromuscular blocking agents63

Rifampin

Decreased AUC of orally administered S-ketamine and S-norketamine by 10 and 50%, respectively6 7

St. John's wort (Hypericum perforatum)

Decreased peak plasma concentration and AUC of orally administered S-ketamine by 66 and 58%, respectively, and of S-norketamine by 18 and 23%, respectively6

Theophyllines (e.g., aminophylline, theophylline)

Possible lowering of seizure threshold and increased risk of tonic seizures2 64

Thyroid agents

Possible increased risk of hypertension and tachycardia2 91

Ticlopidine

Increased AUC of orally administered S-ketamine by 2.4-fold6 65 and decreased ratio of norketamine to ketamine65

Ketamine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

IM: 93% in adults.3 5 23 35

Oral: 16–30%; higher relative concentrations of norketamine due to extensive first-pass metabolism.3 4 14 35

Rectal: 11–30%; higher relative concentrations of norketamine due to extensive first-pass metabolism.3 4 14 35

Intranasal: Reported up to 45–50%3 4 35 but can vary substantially.3 14

Onset

Following IV injection of 2 mg/kg, anesthesia occurs within 30 seconds.1

Following IM injection of 9–13 mg/kg, anesthesia occurs within 3–4 minutes.1

Following a single IV infusion, improvement in depression usually occurs within several hours to a day post-infusion.300 301 303 304 307

Duration

Following IV injection of 2 mg/kg, duration of anesthesia is 5–10 minutes.1

Following IM injection of 9–13 mg/kg, duration of anesthesia is usually 12–25 minutes.1

Plasma Concentrations

Following IV injection of 2 mg/kg, plasma ketamine concentrations are about 1.8–2 mcg/mL at 5 minutes.2

Following IM injection of 6 mg/kg, plasma ketamine concentrations are about 1.7–2.2 mcg/mL at 15 minutes.2

Major active metabolite, norketamine, appears in blood 2–3 minutes following IV administration of ketamine and reaches peak plasma concentration around 30 minutes.5

Following oral administration, peak plasma ketamine concentrations occur within 20–120 minutes.35

Plasma ketamine concentrations associated with dissociative anesthesia range from approximately 1.2–3 mcg/mL23 35 and are typically around 0.5–1.1 mcg/mL during awakening.23 35 51

Plasma ketamine concentrations associated with analgesia range from 0.07–0.2 mcg/mL.23 25 35 51 Following oral administration, analgesia occurs at plasma ketamine concentrations of 0.04 mcg/mL, possibly due to higher ratio of norketamine.51

Psychotomimetic effects may occur at plasma concentrations as low as 0.05 mcg/mL; more severe effects (e.g., anxiety, paranoid feelings) occur around plasma concentrations of 0.5 mcg/mL.5 51

Following IV infusion of 0.5 mg/kg over 40 minutes, peak plasma ketamine concentrations of 0.07–0.2 mcg/mL are achieved; these concentrations are usually associated with antidepressant effects but not general anesthetic effects.35 302

Special Populations

Lower IM bioavailability reported in children.35

In children 4–10 years of age, plasma ketamine concentrations are similar to those observed in adults.5 Plasma norketamine concentrations are higher in children than adults following equivalent weight-adjusted doses.5

Distribution

Extent

Rapidly and widely distributed into highly perfused tissues, including the CNS, with a distribution half-life of 10–15 minutes.2 3 5 14 Highly concentrated in body fat, liver, and lung in animal studies.2

Termination of anesthetic effect occurs partly via redistribution from CNS to peripheral tissues and partly by hepatic biotransformation.1 2

Crosses placenta.2 Following IM injection of 250 mg (approximately 4.2 mg/kg) in parturient patients, placental transfer rate from maternal artery to umbilical vein was 47% at an average of 12 minutes from the time of injection to vaginal delivery.2

Plasma Protein Binding

<50% (to α1-acid glycoprotein or albumin).5 12

Elimination

Metabolism

Metabolized extensively in the liver,2 4 9 35 principally undergoing N-demethylation by CYP3A4 and to a lesser extent by CYP2B6 and CYP2C9 to norketamine (active metabolite).2 6 35 Norketamine demonstrates approximately one-third the anesthetic activity of the parent drug.3 4 5 6 12

Also undergoes hydroxylation of the cyclohexone ring,1 9 conjugation with glucuronic acid, and dehydration of the hydroxylated metabolites to form a cyclohexene derivative.1

Norketamine is further metabolized to hydroxynorketamines and dehydronorketamine.35

Elimination Route

About 90% of a parenteral dose is excreted in the urine, mostly as conjugates of hydroxylated metabolites;2 3 4 10 <5% of a dose is excreted unchanged in feces and urine.4

Half-life

Ketamine: Approximately 2–4 hours.2 3 5 35

Norketamine: 12 hours.4

Special Populations

Half-life of ketamine is shorter in children (approximately 100 minutes) than in adults.5

In individuals with acute renal failure, 20% higher ketamine concentrations reported compared with those with normal renal function.5 68

Not appreciably removed by hemodialysis or hemofiltration (10 or 4%, respectively).68

Stability

Storage

Parenteral

Injection

20–25°C; protect from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1 HID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Acetaminophen

Butorphanol tartrate

Droperidol with fentanyl citrate

Hydromorphone HCl

Morphine sulfate

Incompatible

Barbiturates1

Diazepam1

Y-Site CompatibilityHID

Compatible

Cefepime HCl

Ceftazidime

Cloxacillin sodium

Propofol

Actions

  • Nonbarbiturate general anesthetic that produces analgesia and sedation at low doses and a state of dissociative anesthesia at higher doses.1 3 4 5 23 26 37

  • Structurally and pharmacologically related to PCP.1 3 4 5 9 35

  • Pharmacologic effects are principally a result of the drug's action as a noncompetitive NMDA receptor antagonist.1 3 4 5 9 10 26 35 NMDA receptor plays an important role in excitatory glutamate-mediated neurotransmission, which can affect cognition, chronic pain, opiate tolerance, and mood regulation.26 NMDA receptor also is closely involved in the development of opiate tolerance, opiate-induced hyperalgesia, and central sensitization.4

  • Binds to the PCP binding site of the NMDA receptor channel, decreasing frequency of channel opening and duration of time in the open active state.3 4 5 26 35

  • Also acts on a wide range of other targets, including opiate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), GABAA, cholinergic, nicotinic, and muscarinic receptors; hyperpolarization-activated cyclic nucleotide (HCN), calcium, sodium, and potassium channels; and the monoaminergic system.3 4 5 26 35

  • Produces dissociative anesthesia as a result of a functional and electrophysiologic dissociation between the thalamocortical and limbic systems.5 11 35 Anesthetic state is characterized by profound analgesia and amnesia, with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability.1 5 11 35 Appears to disrupt frontal-to-posterior corticocortical connectivity while maintaining thalamocortical somatosensory pathways at anesthetic doses.3

  • Produces analgesia and sedation at doses and plasma concentrations lower than those used for anesthesia.4 11 25 26 At subanesthetic doses, alters 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

  • Precise mechanism(s) of ketamine's antidepressant activity not 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 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 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

  • Inhibits reuptake of catecholamines and has other direct and indirect sympathomimetic effects (e.g., increased heart rate, BP, myocardial and cerebral oxygen consumption, cerebral blood flow, intracranial and intraocular pressure).3 9 11 40

Advice to Patients

  • May cause sedation and potentially impair cognitive function.1 Importance of advising patients not to operate hazardous machinery, including driving a motor vehicle, or engage in potentially dangerous activities for ≥24 hours after anesthesia, depending upon the dosage of ketamine administered and consideration of other drugs used during the procedure.1

  • Possibility of emergence reactions.1 Importance of informing patients that they may experience psychologic manifestations as the effects of ketamine wear off; these effects may vary in severity and range from pleasant dream-like states to hallucinations, confusion, and unpleasant experiences.1 11 Such effects generally do not last more than a few hours and do not produce residual psychologic effects; however, recurrences may occur up to 24 hours later.1

  • When procedures requiring general anesthetics or sedation drugs, including ketamine, are considered for young children or pregnant women, importance of discussing 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

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

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

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

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)

AHFS DI Essentials™. © Copyright 2020, Selected Revisions October 21, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

1. Par Pharmaceutical, Inc. Ketalar (ketamine hydrochloride) injection prescribing information. Chestnut Ridge, NY; 2018 Jul.

2. Pfizer Limited. Ketalar 100 mg/mL injection summary of product characteristics. Sandwich, Kent, United Kingdom; 2018 Mar. https://www.medicines.org.uk/emc/product/2231/smpc

3. Li L, Vlisides PE. Ketamine: 50 Years of Modulating the Mind. Front Hum Neurosci. 2016; 10:612. http://www.ncbi.nlm.nih.gov/pubmed/27965560?dopt=AbstractPlus

4. Quibell R, Fallon M, Mihalyo M et al. Ketamine. J Pain Symptom Manage. 2015; 50:268-78. http://www.ncbi.nlm.nih.gov/pubmed/26096492?dopt=AbstractPlus

5. Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013; 19:370-80. http://www.ncbi.nlm.nih.gov/pubmed/23575437?dopt=AbstractPlus

6. Andrade C. Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions. J Clin Psychiatry. 2017; 78:e858-e861. http://www.ncbi.nlm.nih.gov/pubmed/28858450?dopt=AbstractPlus

7. Noppers I, Olofsen E, Niesters M et al. Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration. Anesthesiology. 2011; 114:1435-45. http://www.ncbi.nlm.nih.gov/pubmed/21508826?dopt=AbstractPlus

8. Kornhall D, Nielsen EW. Failure of ketamine anesthesia in a patient with lamotrigine overdose. Case Rep Crit Care. 2014; 2014:916360. http://www.ncbi.nlm.nih.gov/pubmed/25114807?dopt=AbstractPlus

9. Kurdi MS, Theerth KA, Deva RS. Ketamine: Current applications in anesthesia, pain, and critical care. Anesth Essays Res. 2014 Sep-Dec; 8:283-90. http://www.ncbi.nlm.nih.gov/pubmed/25886322?dopt=AbstractPlus

10. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016; 37:865-72. http://www.ncbi.nlm.nih.gov/pubmed/27018176?dopt=AbstractPlus

11. Green SM, Roback MG, Kennedy RM et al. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011; 57:449-61. http://www.ncbi.nlm.nih.gov/pubmed/21256625?dopt=AbstractPlus

12. Erstad BL, Patanwala AE. Ketamine for analgosedation in critically ill patients. J Crit Care. 2016; 35:145-9. http://www.ncbi.nlm.nih.gov/pubmed/27481750?dopt=AbstractPlus

13. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013; 41:263-306. http://www.ncbi.nlm.nih.gov/pubmed/23269131?dopt=AbstractPlus

14. Sheikh S, Hendry P. The Expanding Role of Ketamine in the Emergency Department. Drugs. 2018; 78:727-735. http://www.ncbi.nlm.nih.gov/pubmed/29651740?dopt=AbstractPlus

15. Todd KH. A Review of Current and Emerging Approaches to Pain Management in the Emergency Department. Pain Ther. 2017; 6:193-202. http://www.ncbi.nlm.nih.gov/pubmed/29127600?dopt=AbstractPlus

16. Johansson P, Kongstad P, Johansson A. The effect of combined treatment with morphine sulphate and low-dose ketamine in a prehospital setting. Scand J Trauma Resusc Emerg Med. 2009; 17:61. http://www.ncbi.nlm.nih.gov/pubmed/19943920?dopt=AbstractPlus

17. Jennings PA, Cameron P, Bernard S et al. Morphine and ketamine is superior to morphine alone for out-of-hospital trauma analgesia: a randomized controlled trial. Ann Emerg Med. 2012; 59:497-503. http://www.ncbi.nlm.nih.gov/pubmed/22243959?dopt=AbstractPlus

18. Galinski M, Dolveck F, Combes X et al. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med. 2007; 25:385-90. http://www.ncbi.nlm.nih.gov/pubmed/17499654?dopt=AbstractPlus

19. Ahern TL, Herring AA, Stone MB et al. Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. Am J Emerg Med. 2013; 31:847-51. http://www.ncbi.nlm.nih.gov/pubmed/23602757?dopt=AbstractPlus

20. Beaudoin FL, Lin C, Guan W et al. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014; 21:1193-202. http://www.ncbi.nlm.nih.gov/pubmed/25377395?dopt=AbstractPlus

21. Miller JP, Schauer SG, Ganem VJ et al. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015; 33:402-8. http://www.ncbi.nlm.nih.gov/pubmed/25624076?dopt=AbstractPlus

22. Motov S, Rockoff B, Cohen V et al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2015; 66:222-229.e1. http://www.ncbi.nlm.nih.gov/pubmed/25817884?dopt=AbstractPlus

23. Coté CJ, Lerman J, Anderson BJ, eds. A Practice of anesthesia for infants and children. 6th ed. Philadelphia, PA: Elsevier, Inc; 2019: 140-2.

24. Ahern TL, Herring AA, Miller S et al. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015; 16:1402-9. http://www.ncbi.nlm.nih.gov/pubmed/25643741?dopt=AbstractPlus

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28. Wang L, Johnston B, Kaushal A et al. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials. Can J Anaesth. 2016; 63:311-25. http://www.ncbi.nlm.nih.gov/pubmed/26659198?dopt=AbstractPlus

29. Ye F, Wu Y, Zhou C. Effect of intravenous ketamine for postoperative analgesia in patients undergoing laparoscopic cholecystectomy: A meta-analysis. Medicine (Baltimore). 2017; 96:e9147. http://www.ncbi.nlm.nih.gov/pubmed/29390443?dopt=AbstractPlus

30. Guillou N, Tanguy M, Seguin P et al. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003; 97:843-7. http://www.ncbi.nlm.nih.gov/pubmed/12933413?dopt=AbstractPlus

31. Persson J. Ketamine in pain management. CNS Neurosci Ther. 2013; 19:396-402. http://www.ncbi.nlm.nih.gov/pubmed/23663314?dopt=AbstractPlus

32. Laskowski K, Stirling A, McKay WP et al. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011; 58:911-23. http://www.ncbi.nlm.nih.gov/pubmed/21773855?dopt=AbstractPlus

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