Ketamine (Systemic)


VA CLASSIFICATION
Primary: CN203
Secondary: CN206

Commonly used brand name(s): Ketalar.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthetic (general)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anesthesia, general—Ketamine is indicated to provide anesthesia for short diagnostic and surgical procedures that do not require skeletal muscle relaxation{51}. It is also indicated to induce anesthesia prior to administration of other general anesthetics{51}. [ Ketamine may be used for the induction and/or maintenance of anesthesia in pediatric patients.{57}{64} {65}{66}{67}{68}{69}{70}{71}{72}{73}{74}{75}{76}{77}{78}{79}{80}{81}{82}{83}{84}{85}{86}{87}{88}{89} {90}{91}{92}{93}{94}{95}{96}{97}{98}{99}{100}{101}{102}{103}{104}{105}{106}However, in many cases, other anesthetic agents may be more appropriate for the maintenance of anesthesia in pediatric patients.{58}]1

Anesthesia, general, adjunct—Ketamine is indicated to supplement low-potency anesthetics such as nitrous oxide {51}.

[Anesthesia, local, adjunct]1—Ketamine is indicated as a supplement to local and regional anesthesia.

[Sedation and analgesia {19} {20}]1—Ketamine is indicated to provide sedation and analgesia for painful procedures, including labor and vaginal delivery

[Sedation]1—Ketamine is indicated for sedation during painful procedures in the emergency department in pediatric patients.{59}{64} {65}{66}{67}{68}{69}{70}{71}{99}{100}{101}{102}{105}{106}{107} {108} {109}{110}{111}{112}{113}{114}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124}{125}{126}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic phencyclidine derivative {27}.
Molecular weight—
    Ketamine hydrochloride: 274.19 {01}

Mechanism of action/Effect:

The precise mechanism of action is unknown. Ketamine has been shown to block afferent impulses associated with the affective-emotional component of pain perception within the medial medullary reticular formation {11}, to suppress spinal cord activity, and to interact with several central nervous system (CNS) transmitter systems {12}. Ketamine blocks the N-methyl-D-aspartate (NMDA) glutamate receptor by a dual mechanism, blocking both the closed channel from the aqueous phase and the closed channel from the membrane phase {30} {31}.


Other actions/effects:


Cerebrovascular:

Ketamine increases intracranial cerebrospinal fluid pressure{13}{51}.



Cardiovascular:

Ketamine may transiently increase blood pressure and heart rate . The increase in blood pressure may be up to 50% over the preanesthesia values, but usually decreases to preanesthesia values within 15 minutes of initial administration . However, ketamine has been associated with cardiovascular depression{51}, especially with doses administered subsequent to the initial dose of ketamine{14}.



Respiratory:

Ketamine does not decrease the respiratory response to hypercapnia {15}. Ketamine relaxes bronchial smooth muscle{16} {17} {29}. Despite the usual lack of respiratory depressant effects, apnea can occur, especially with rapid injection of ketamine . Additionally, laryngospasm and other forms of airway obstruction have occurred during anesthesia with ketamine {51}.

In a study in pediatric patients 6 to 10 years of age, ketamine decreased the minute ventilation throughout a 30-minute ketamine infusion {18}.


Absorption:

Rapid.{51}

Distribution:

Initially distributed rapidly into highly perfused tissues, such as the brain, heart, and lungs, with levels achieved being 4 to 5 times higher than corresponding plasma concentrations. Ketamine is then redistributed to muscle and peripheral tissues, and eventually fat tissue.{04}{52}{53}{54}

Biotransformation:

Hepatic—Primary metabolic pathway involves hepatic N- demethylation via the cytochrome P450 system to form norketamine; this metabolite is subsequently hydroxylated and conjugated to water soluble compounds.{52}{54} Other hydroxylated metabolites have also been reported.{53}{54}

Termination of anesthetic effects may be caused by redistribution from the brain to other tissues {04}.

Half-life:


Distribution:

Approximately 10–17 minutes. {09}{51}



Elimination:

Approximately 2.5–3 hours. {09}{51}

Approximately 1–2 hours in children, suggesting more rapid metabolism or elimination in this population.{55}


Time to induction of anesthesia


Intravenous (following a dose of 1 to 2 mg per kg of body weight [mg/kg]) :

Sensation of dissociation: 15 seconds.

Anesthesia: 30 seconds. {51}



Intramuscular (following a dose of 9 to 13 mg/kg):

Anesthesia: 3 to 4 minutes. {51}


Duration of action:


Intravenous (following a dose of 2 mg/kg):

5 to 10 minutes.{51}



Intramuscular (following a dose of 9 to 13 mg/kg):

12 to 25 minutes.{51}


Time to recovery

Rapid.

Elimination:
    Renal, 90% as hydroxylated and conjugated metabolites{54}{56}; about 4% as unchanged ketamine or as norketamine.{54}{56}
    Fecal, up to 5%.{54}


Precautions to Consider

Pregnancy/Reproduction

Studies in humans have not been done. Studies in animals have not shown that ketamine causes birth defects; however, it crosses the placenta {51}. Also, in one study in rats, ketamine produced histologic changes in the heart, liver, and kidneys of the offspring, including focal nuclear hypochromatosis, interfibrillary edema, parenchymal cell degeneration, proximal convoluted tubule degeneration, and diffuse hematopoietic cell infiltration. The degenerative effects were dependent on both dosage and duration of administration {05}. Ketamine is used in low doses to provide obstetrical anesthesia. It has not been shown to cause adverse effects when used in low doses {19} {20}.

Breast-feeding

It is not known whether ketamine is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of ketamine in children. However, neonates and infants less than four months of age may be at an increased risk for respiratory complications with the use of ketamine.{55}

See General Dosing Information for additional information on the use of ketamine in pediatric patients.


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the use of ketamine in the elderly.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, halogenated hydrocarbon inhalation    (halogen hydrocarbon inhalation anesthetics may prolong the elimination half-life of ketamine; recovery from anesthesia may be prolonged following concurrent use {10})

    (combined administration of halothane and ketamine has resulted in clinically significant decreases in blood pressure, heart rate, and cardiac output {06} {07})


Barbiturates or
Narcotics    (concurrent use with ketamine may prolong recovery time{51})


Thyroid hormones {21} {22}    (ketamine should be administered with caution to patients receiving thyroid hormones because of the increased risk of hypertension and tachycardia)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Cerebrospinal fluid (CSF) pressure, or
Intraocular pressure    (may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Any condition in which a significant elevation of blood pressure would be hazardous {51} , such as:
» Cardiovascular disease, severe
» Hypertension, severe or poorly controlled
» Myocardial infarction, recent
» Stroke, history of
» Cerebral trauma
» Intracerebral mass or hemorrhage
Risk-benefit should be considered when the following medical problems exist
Alcohol or drug abuse or addiction (or history of) {23}{51}    (nonmedical use of ketamine has been reported)


Alcohol intoxication, acute {51}
Congestive heart failure or
Hypertension, mild, uncomplicated or
Myocardial ischemia or
Tachyarrhythmias    (may be exacerbated {04})


» Eye injury, open globe
» Increased cerebrospinal fluid (CSF) pressure     (ketamine may further elevate CSF pressure {51})


» Increased intraocular pressure {51}    (ketamine may further elevate intraocular pressure)


» Psychiatric disorders such as schizophrenia or acute psychosis     (ketamine can cause anxiety, disorientation, dysphoria, and hallucinations {51})


Sensitivity to ketamine
» Thyrotoxic states    (increased risk of hypertension and tachycardia {21} {22})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Cardiac function {51}    (monitoring throughout the procedure is recommended, especially in patients with congestive heart failure, hypertension, myocardial ischemia, or tachyarrhythmias )


Note: Various organizations, including the American Society of Anesthesiologists (ASA) and the American Academy of Pediatrics (AAP), have established guidelines for pre-, intra-, and post-procedural care, evaluation, and monitoring of patients receiving sedation for diagnostic and therapeutic procedures {47} {48} {49}. The level of monitoring should be appropriate to the level of sedation and the procedure being performed. When ketamine is used for light sedation (i.e., the patient is able to tolerate unpleasant procedures without cardiorespiratory compromise and is able to respond purposefully to verbal commands) by non-anesthesiologists, the American Society of Anesthesiologists recommends that a designated individual, other than the person performing the procedure, be present to monitor the patient {49}. That designated person would be permitted to assist with other minor, interruptible tasks {49}. However, when ketamine is used to produce deep sedation, the patient should be monitored continuously by someone not involved in conducting the surgical or diagnostic procedure {49}. For deeply sedated patients, the person monitoring the patient should not assist with other tasks, even if the tasks are minor and interruptible {49}.




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Increased blood pressure {02} {03} —may reach hypertensive levels
    
tachycardia {51}
    
tonic and clonic muscle movements — may resemble seizures {04}{51}
    
tremor {04}
    
vocalization {04}

Incidence less frequent
    
Bradycardia {51}
    
hypotension {51}
    
respiratory depression — may lead to apnea {51}
    
vomiting {51}

Incidence rare
    
Cardiac arrhythmias {51}
    
laryngospasm or other forms of airway obstruction {51}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent in patients between 15 and 45 years of age; less frequent in other age groups {02} {03}
    
Emergence reaction {51} (alterations in mood or body image; delirium; dissociative or floating sensations)
    
visual hallucinations {51}
    
vivid dreams or illusions {51}

Note: Although vivid dreams and/or hallucinations usually disappear upon wakening, some patients may experience flashbacks several weeks postoperatively. {51}


Incidence less frequent or rare
    
Double vision
    
loss of appetite
    
nausea with or without vomiting
    
nystagmus (wandering or back-and-forth eye movements)
    
pain at injection site
    
reddened skin or skin rash
{51}




Overdose
For specific information on the agents used in the management of ketamine overdose, see:    • Anesthetics, Barbiturate (Systemic) monograph;
   • Anticholinergics/Antispasmodics (Systemic) monograph; and/or
   • Benzodiazepines (Systemic)monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Respiratory depression {03} (slowed or difficult breathing)
    
tracheobronchial secretions, increased {03} (increased salivation)


Treatment of overdose


To decrease absorption:
If ketamine was ingested, gastric decontamination may be attempted. {28}



To enhance elimination:
There are no means to enhance elimination because ketamine is lipid-soluble and has a large volume of distribution. {28}



Specific treatment:
Increased tracheobronchial secretions may be treated with an anticholinergic agent such as atropine or scopolamine. {51}



Monitoring:
Monitoring of vital signs and mental status is recommended.{51}



Supportive care:
If respiratory depression is present, the patient"s airway should be protected and ventilation should be supported. {51}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anesthetics, General (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Sensitivity to ketamine

Pregnancy—Ketamine crosses the placenta
Any other medication, including use of “street” drugs
Other medical problems, especially brain tumor or injury, severe cardiovascular disease, eye injury, glaucoma, hypertension, hyperthyroidism, psychiatric disorders, recent myocardial infarction, and stroke

Proper use of this medication

» Proper dosing

Precautions after receiving this medication
» Possibility of psychomotor impairment following anesthesia; using caution in driving or performing other tasks requiring alertness for about 24 hours postanesthesia

» Avoiding alcohol or other CNS depressants within 24 hours following anesthesia unless prescribed or otherwise approved by physician or dentist

» Possibility of experiencing emergence reaction after procedure


Side/adverse effects
Signs of potential delayed side effects, especially mood or mental changes, nightmares or unusual dreams, and blurred vision


General Dosing Information
The usual adult dosages are intended as a guideline. Actual dosage must be individualized to meet the needs of each patient.{51}

Ketamine may cause vomiting following administration . To prevent possible aspiration of vomitus, ketamine should be administered to the patient on an empty stomach{51}.

Because ketamine increases salivary and tracheal-bronchial mucous gland secretions, use of atropine, scopolamine, or another anticholinergic agent is recommended prior to induction of anesthesia. The fact that atropine has been shown to increase the frequency of unpleasant dreams should be kept in mind{51}.

Ketamine may be administered intramuscularly or intravenously. Intravenous administration produces anesthesia more rapidly than intramuscular administration{51}.

Administration of an overdose, or administering ketamine at too rapid a rate, may produce respiratory depression, apnea, and hypertension. Intravenous ketamine should be administered over a period of 60 seconds unless a rapid-sequence induction technique is indicated{51}.

Tolerance to the effects of ketamine has been reported following repeated administration.

A state of confusion (emergence delirium) may occur during recovery. Although it has been suggested that minimizing verbal, tactile, and visual stimulation during recovery may reduce the incidence of emergence reactions, the efficacy of such measures has not been documented. Administration of a benzodiazepine prior to or concurrently with ketamine, or just prior to termination of surgery, may decrease the incidence of emergence delirium{51}. However, increased CNS depression may result from combined use of ketamine and a benzodiazepine.

Although ketamine is approved by regulatory agencies in the U.S. and Canada only for intramuscular and intravenous administration, ketamine has been used orally and intranasally in pediatric patients{25}{26}{36}{40}{44}{45}. The literature supporting oral and intranasal use is sparse, and the studies are not sufficient to support a finding of safety or efficacy{50}. Some investigators have reported success using ketamine 3 to 10 mg per kg of body weight alone or combined with other agents (e.g., a benzodiazepine) mixed in a small quantity of a beverage (0.2 to 0.3 mL per kg of body weight) and administered orally 20 minutes to 1 hour before the beginning of a painful procedure or administration of general anesthesia{25}{36}{40}{42}{44}{45}. Doses at the high end of this range can result in deep sedation or general anesthesia. Additionally, when ketamine is administered with a benzodiazepine, increased sedation can result. It should be anticipated that patients receiving ketamine at the high end of this range, and patients receiving ketamine concurrently with other CNS depressants may achieve a level of sedation requiring very close monitoring; patients should be monitored closely as warranted by the level of sedation achieved (see Patient monitoring ) {47}{48}{49}.

Some clinicians have reported an unacceptable incidence of adverse events in pediatric patients, especially increased salivation and emergence phenomena, following administration of oral ketamine as a premedication{39}{43}. This may be reduced by administering atropine and a benzodiazepine concurrently{51}.

When ketamine is used to provide sedation for painful emergency department (ED) procedures in pediatric patients, appropriate monitoring is essential. Ketamine doses used for this indication are similar to those used for inducing general anesthesia. The unique state of "dissociative anesthesia" produced by ketamine at these doses are similar to that observed with inhalational agents. Respiratory complications such as airway obstruction, apnea, hypoventilation and layrngospasm may occur.{63} Physicians who sedate children with ketamine must have the skills and monitoring in place so as to provide early recognition and rescue of patients who become deeply sedated or enter a state of general anesthesia.{63} The American Academy of Pediatrics (AAP) guidelines{47} for the monitoring of pediatric patients undergoing sedation should also be observed.{62} Additionally, when other sedating medications (e.g., midazolam) are used in combination with ketamine, a reduction in the ketamine dose is advisable.{61} Many pediatric patients will not have an empty stomach when presenting to the ED. Although the risk of aspiration due to vomitus appears quite low in this population, even when patients are not fasted, a few cases of this complication have been reported, primarily in patients with other recognized risk factors.{55} Therefore, in pediatric patients not having empty stomachs and requiring painful ED procedures, some experts recommend delaying the procedure, if possible, or else titrating the dose to effect beginning with an initial dose lower than that usually used.{61}

Caution is recommended when ketamine is considered for use in surgical procedures of the pharynx, larynx, or trachea because it increases salivary and tracheobronchial secretions and does not reliably suppress pharyngeal and laryngeal reflexes{51}.

In subhypnotic doses, ketamine produces a dissociative state{04}. The patient does not appear to be asleep and experiences a feeling of being dissociated from the environment.

For treatment of adverse effects
Recommended treatment may include

   • For respiratory depression or apnea—Assisting respiration mechanically may be preferred over administration of analeptics{51}
   • For severe emergence reaction—Administering a short- or ultrashort-acting barbiturate or a benzodiazepine{51}
   • For hypertension—Administering clonidine{24}
   • For increased salivation—Administering an anticholinergic agent such as atropine or scopolamine; an anticholinergic agent is usually administered before ketamine is administered{51}


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

Note: The dosing and strengths are expressed in terms of ketamine base (not the hydrochloride salt).


KETAMINE HYDROCHLORIDE INJECTION USP

Usual adult and adolescent dose
Anesthetic (general)


Induction:
Intravenous, 1 to 4.5 mg (base) per kg of body weight, administered as a single dose. Alternatively, 1 to 2 mg per kg of body weight may be given as an intravenous infusion at a rate of 500 mcg (0.5 mg) (base) per kg of body weight per minute {51}; or

Intramuscular, 6.5 to 13 mg (base) per kg of body weight{51}.

Note: For induction of surgical anesthesia, most patients require a dose of about 2 mg per kg of body weight administered intravenously over sixty seconds to provide anesthesia within thirty seconds that lasts for five to ten minutes {51}.




Maintenance:
Intravenous infusion, 100 to 500 mcg (0.1 to 0.5 mg) (base) per kg of body weight.

Note: Maintenance dosage must be adjusted as determined by the patients anesthetic requirements and concurrent use of an additional anesthetic agent {51}.
Tonic-clonic movements that may appear during anesthesia are not indicative of the need for additional ketamine {51}.



[Anesthesia, local, adjunct]1
Intravenous, 5 to 30 mg (base), prior to administration of the local anesthetic. The dose may be repeated if necessary {08}.

[Sedation and analgesia]1
Intravenous: 200 to 750 mcg (0.2 to 0.75 mg) (base) per kg of body weight administered over 2 to 3 minutes initially, followed by 5 to 20 mcg (0.005 to 0.02 mg) (base) per kg of body weight per minute as a continuous intravenous infusion.

Intramuscular: 2 to 4 mg (base) per kg of body weight initially, followed by 5 to 20 mcg (0.005 to 0.02 mg) (base) per kg of body weight per minute as a continuous intravenous infusion.


Usual adult prescribing limits
[Anesthesia, local, adjunct]1
Intravenous: 30 mg (base).


Usual pediatric dose
[Anesthetic (general)]1
Neonates through children 16 years of age:


Induction:
Intravenous, 2 mg (base) per kg of body weight,{57} and titrated to individual response as necessary.{60}

Intramuscular, 4 to 12 mg (base) per kg of body weight.{57}



Maintenance:
Intravenous, 1 mg (base) per kg of body weight as needed, or 0.05 mg (base) per kg of body weight per minute initially as a continuous infusion and titrated to effect.{57}


[Sedation for procedures in pediatric patients]1
Infants 4 months of age through children 15 years of age:

Intravenous, 1 to 2 mg (base) per kg of body weight.{59} Dose may be titrated to the individual response of the patient.{61}

Intramuscular, 4 to 5 mg (base) per kg of body weight.{59} Dose may be titrated to the individual response of the patient.{61}

Note: A lower dose of 0.25 to 0.5 mg (base) per kg of body weight may be administered intravenously for patients in need of sedation rather than a state of general anesthesia, and further small increments added as indicated.{63} For intramuscular use, doses as low as 2 mg (base) per kg of body weight combined with midazolam 0.05 mg per kg of body weight and atropine 0.02 mg per kg of body weight allow sufficient sedation/analgesia so as to allow injection of local anesthetic.{63}



Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


10 mg (base) per mL (Rx) [Ketalar (benzethonium chloride )][Generic](benzethonium chloride)


50 mg (base) per mL (Rx) [Ketalar (benzethonium chloride )][Generic](benzethonium chloride)


100 mg (base) per mL (Rx) [Ketalar (benzethonium chloride)][Generic](benzethonium chloride)

Canada—


10 mg (base) per mL (Rx) [Ketalar (benzethonium chloride )]


50 mg (base) per mL (Rx) [Ketalar (benzethonium chloride )]

U.K.—


10 mg (base) per mL (Rx) [Ketalar]


50 mg (base) per mL (Rx) [Ketalar]


100 mg (base) per mL (Rx) [Ketalar]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {51}. Protect from light and heat. Protect from freezing.

Preparation of dosage form:
For direct intravenous administration—The 100-mg-per-mL concentration of ketamine must be diluted with an equal volume of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection prior to injection {51}.

For intravenous infusion—Add 10 mL of the 50-mg-per-mL concentration, or 5 mL of the 100-mg-per-mL concentration, of ketamine (base) to 500 mL of 5% dextrose injection or 0.9% sodium chloride injection and mix well. The resultant solution will contain 1 mg of ketamine (base) per mL. If fluid restriction is necessary, 250 mL of the diluent may be used to provide a solution containing 2 mg of ketamine (base) per mL {51}.

Incompatibilities:
Ketamine and barbiturates should not be injected from the same syringe because they will form a precipitate {51}.

If diazepam is administered concurrently with ketamine, the two medications should be given separately. The two medications should not be mixed together in a syringe or added to the same intravenous infusion solution {51}.



Revised: 12/04/2001



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