Ketamine Injection

Ketamine is a general anesthetic indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation, for the induction of anesthesia before the administration of other anesthetic agents, and as a supplement to other anesthetic agents.^[1] It is also used for acute agitation and treatment of acute or chronic pain.^{[2][3][4][5][6][7]} Ketamine is unique sedative-hypnotic that produces dissociative anesthesia characterized by potent sedation, amnesia, and analgesia while maintaining cardiovascular stability and preserving spontaneous respiration and protective airway reflexes.^[1][2] It is similar in structure, mechanism of action, and activity to phencyclidine (PCP), but ketamine is much less potent and has a shorter duration of action.^[8] Ketamine has bronchodilatory properties and, in comparison to other sedatives (e.g., opioids, benzodiazepines), offers the advantage of fewer adverse reactions. Hence, ketamine may be an effective alternative to conventional intensive care sedation in certain clinical scenarios (e.g., patients who develop adverse cardiovascular effects with opioids or benzodiazepines, sedation with preservation of spontaneous ventilation, patients with refractory bronchospasm or status asthmaticus).^[9][10] Ketamine is a sympathomimetic; elevations in heart rate and blood pressure are often mild-to-moderate, but it should not be used in patients in whom significant elevations would be deleterious.^[11][1] Ketamine anesthesia is notorious for producing a cataleptic state where the eyes remain open with nystagmus; this “disconnected” state may be disconcerting to caregivers and warrants proper caregiver preparation. Other prominent effects of ketamine include excessive airway secretion and emergence reactions. The latter can be managed with short-acting benzodiazepines or barbiturates.^{[11][12][13][2]}

Ketamine is contraindicated in patients with a hypersensitivity to ketamine or any excipients.^[1]

Obtain baseline and periodic liver function tests, including alkaline phosphatase and gamma-glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing. Recurrent ketamine use is associated with hepatobiliary dysfunction (most often a cholestasis pattern).^[1]

Ketamine is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard, such as those with uncontrolled hypertension, aneurysm, thyrotoxicosis, or a history of stroke.^[11][1] Monitor patients with increased intracranial pressure in a setting with frequent neurologic assessments.^[1] Use ketamine with great caution in any patient with the potential for increased intracranial pressure, including those with head trauma, intracranial mass lesions or abnormalities, intracranial bleeding, and hydrocephalus. Alternative agents may be preferable in patients with known structural barriers to normal cerebrospinal fluid flow. Similarly, use ketamine with caution in patients with increased intraocular pressure (e.g., glaucoma), ocular trauma, or those undergoing ocular surgery.^{[11][14][13][2]} Ketamine can have direct negative inotropic properties and should be titrated cautiously in patients with poor ventricular function.^[15] The sympathomimetic effect of ketamine can produce elevations in blood pressure, heart rate, and cardiac output, which are typically mild-to-moderate. Ketamine increases coronary perfusion, enhancing myocardial contraction and increasing myocardial oxygen consumption. Hence, ketamine should also be used with caution in patients with cardiac disease, especially coronary artery disease (e.g., angina). Ketamine raises pulmonary arterial pressures somewhat more than systemic pressures and may exacerbate preexisting pulmonary hypertension or congestive heart failure.^[11] Monitor vital signs and cardiac function during ketamine administration.^[1] In addition, cardiac monitoring may be prudent in patients with thyroid disease requiring thyroid replacement therapy.^[11][14][2] Ketamine-induced hypertension and tachycardia can be attenuated with the administration of a benzodiazepine, a barbiturate, or a synthetic opioid.^[13]

Advise patients to avoid driving or operating machinery within 24 hours of receiving ketamine due to the residual anesthetic effects and potential for drowsiness.^[1]

Ketamine administration requires an experienced clinician trained in the use of general anesthetics, airway maintenance, and assisted ventilation as well as requires a specialized care setting where resuscitation equipment is readily available. Continuously monitor vital signs in patients receiving ketamine.^[1]

Emergence reactions (e.g., dream-like states, vivid imagery, hallucinations, delirium), sometimes accompanied by confusion, excitement, and irrational behavior may occur during ketamine recovery. Emergence reactions typically last no more than a few hours; however, adverse psychiatric events have occurred and/or persisted days to weeks after ketamine exposure. Incidence can be reduced by using lower recommended doses of ketamine in conjunction with an intravenous benzodiazepine during anesthesia, as well as minimizing verbal, tactile, and visual patient stimulation during recovery. Emergence reactions appear to be less common with intramuscular administration.^[1] Reported risk factors include age older than 10 years, females, rapid intravenous administration, preexisting psychosis (e.g., schizophrenia), or patients who normally dream frequently.^[11][16] The use of alternative agents is recommended for procedural sedation in patients with a history of psychosis.^[2] Strong psychological factors appear to influence the severity; avoid ketamine in hallucination-prone individuals.^[11][16] Upsetting reactions are much less common in children 10 to 15 years compared to adults and are rare in children younger than 10 years, presumably because a naive child with few life experiences is less likely to interpret unusual dreams or hallucinations as unpleasant.^[11] For older children and adults, advanced planning of a pleasant topic to dream about may decrease the incidence of a distressing reaction.^[13]

Ketamine has the potential for substance abuse, psychological dependence, and/or criminal diversion. Illicit use of ketamine for its psychological effects (i.e., similar to PCP) and ‘date rape’ use due to its amnestic effects have been reported. Physical dependence, tolerance, and a withdrawal syndrome may occur with long-term use.^[1][17]

The use of ketamine in patients with porphyria is controversial due to contradictory evidence. Many experts consider ketamine anesthesia safe in porphyria patients; safe use in dormant acute intermittent porphyria and hereditary coproporphyria crisis have been reported.^[18][19][20] Most animal and cell culture models suggest it is non-inducing at clinical concentrations.^[21][22] However, increases in delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and other porphyrins after ketamine anesthesia have been reported and some experts consider porphyria a relative contraindication to its use.^{[11][14][23][2]}

Avoid ketamine as a sole agent for head and neck anesthesia during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx; muscle relaxants may be required. Ketamine does not suppress pharyngeal and laryngeal reflexes.^[1] Clinicians using ketamine for procedures involving the pharynx (e.g., endoscopy) should make every effort to avoid vigorous stimulation of the posterior pharynx while still preventing accumulation of secretions or blood in the area.^[2] Neonates and infants younger than 3 months have a higher incidence of ketamine-induced respiratory complications (e.g., laryngospasm, apnea, coughing spells, aspiration), most likely attributable to differences in airway anatomy and age-associated laryngeal excitability. Because of these age-related differences, avoid ketamine in non-intubated patients younger than 3 months and use with caution in those younger than 1 year. Ketamine use is relatively contraindicated in patients with an unsupported airway who have a history of airway instability, tracheal surgery, tracheal stenosis, tracheomalacia, laryngomalacia, pulmonary disease, or an acute pulmonary infection including upper respiratory infection.^{[11][14][13][2]} Ketamine can increase oral secretions, influencing airway patency and further compromising respiratory function, particularly in unsupported patients. Administration of an anticholinergic prior to or concurrently with ketamine may help limit secretions; however, prophylaxis is not routinely recommended during procedural sedation.^{[11][1][14][13][2]} Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in pediatric patients younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in a young child against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.^[24]

Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.^[24] Animal data has suggested ketamine can induce apoptosis when administered in high doses or for prolonged periods. Neurotoxicity in the developing brain may correlate to learning and behavioral abnormalities later in life. Concern about potential human neurotoxicity has prompted investigation, but current evidence is lacking.^[2][25] Results from a small prospective study conducted in 49 young pediatric patients (3 to 22 months, ASA I) undergoing outpatient laser surgery have suggested that repeated exposure to anesthetic ketamine has the potential to negatively impact neurodevelopment. In the study, Bayley Scales of Infant Development-Second Edition scores, a tool used to predict neurodevelopmental outcomes after surgery, were significantly lower after the third exposure to ketamine (each dose = 8 mg/kg IM) compared to baseline in the group with 3 total exposures. In addition, concentrations of the S100B protein were significantly higher after the last procedure compared to baseline in groups with 1, 2, and 3 exposures; elevation of this protein in blood reliably occurs in clinical scenarios associated with central nervous system (CNS) injury.^[26] Although the study designs were much different, these results conflict with those from a study evaluating 24 infant patients treated randomly with either a single dose of ketamine 2 mg/kg IV or placebo prior to cardiopulmonary bypass surgery for ventricular septal defect repair, where no significant differences in markers of CNS injury (including S100B expression and Bayley scores) were noted after ketamine exposure.^[27]

In general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.^[1]

Ketamine administration is not recommended during pregnancy, labor, or obstetric delivery because safe use has not been established.^[1] Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.^[24]

Use ketamine with careful monitoring in breast-feeding mothers; alternate agents are preferred. Minimal data indicate that ketamine use in breast-feeding mothers may not affect the breast-fed infant or lactation.^[28]

Ketamine-induced hypertension and sinus tachycardia are dose-dependent and mediated through the sympathetic nervous system with the release of endogenous catecholamines.^[13] Elevation of blood pressure begins shortly after ketamine injection, reaches maximum levels within a few minutes, and usually returns to preanesthetic levels within 15 minutes of injection. In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above baseline shortly after induction, but the elevation can be higher and longer in some patients.^[1] Ketamine-induced hypertension and tachycardia can be attenuated with the administration of a benzodiazepine, a barbiturate, or a synthetic opioid.^[13] In general, ketamine’s indirect sympathomimetic effects compensate for its direct negative inotropic properties; however, hypotension, bradycardia, and even cardiac arrest may occur in patients with diminished myocardial contractility.^[29][13] Arrhythmia (arrhythmia exacerbation) has also been reported in patients receiving ketamine.^[13]

Respiratory depression and apnea are rare with ketamine use and more likely to occur after rapid administration of high doses, when central nervous system injuries or abnormalities are present, or in neonates.^[11] Administer intravenous doses over at least 60 seconds.^[11] Most patients do not require assisted ventilation with ketamine anesthesia; however, laryngospasm and other forms of airway obstruction have occurred and may require airway intervention.^[11][1][30] In addition, ketamine can increase bronchial secretions, influencing airway patency and compromising respiratory function, particularly in unsupported patients. Administration of an anticholinergic prior to or concurrently with ketamine may help limit secretions.^[11][14][13]

Hypersalivation is a well-known effect of ketamine mediated via cholinergic stimulation. Ketamine stimulates both salivary and tracheobronchial secretions which may influence airway patency and compromise respiratory function, particularly in unsupported patients. To lessen such problems, administration of an anticholinergic prior to or concurrently with ketamine is recommended in most clinical situations.^{[11][1][14][13]} Anorexia, nausea, and vomiting have also been observed with ketamine use.^[1] Prophylactic ondansetron may slightly reduce the rate of vomiting (number needed to benefit: 9 or more).^[2] Emesis appears to be more frequent late in the recovery phase.^[11]  Emesis was reported in 3.8% (6/156 patients; 1 while sedated and 5 well into recovery) and 6.7% (69/1,022 patients; 8 while sedated and 60 during recovery) of pediatric patients receiving intravenous and intramuscular ketamine, respectively, for procedural sedation in the emergency department with no evidence of aspiration. Drug-induced emesis was responsible for the onset of laryngospasm in 1 patient.^[31][32] Because protective airway reflexes are maintained during ketamine anesthesia, the risk of clinical aspiration when ketamine is used as a sole agent is minimal.^[32] However, protective reflexes may be diminished by supplementary anesthetics and muscle relaxants. Therefore, it is prudent to administer ketamine on an empty stomach to forgo the risk of aspiration. Ketamine may be administered in patients without an empty stomach when, in the judgment of the practitioner, the benefits of the drug outweigh the risks. Ketamine-induced nausea and vomiting are not usually severe and most patients are able to take liquids by mouth shortly after regaining consciousness.^[1]

Increased intracranial pressure has been reported after the administration of ketamine. Monitor patients with elevated intracranial pressure closely with frequent neurological assessments.^[1]

Diplopia, nystagmus, and increased intraocular pressure (ocular hypertension) have been noted with ketamine administration.^[1] Dissociative anesthesia results in a state of catalepsy in which the eyes may remain open with slow nystagmus and intact corneal reflexes. This “disconnected” stare may be disconcerting to caregivers who are present before full anesthesia recovery; hence, education and proper preparation are recommended prior to anesthesia. Limiting verbal, tactile, and visual stimulation in patients who appear awake but are still recovering may reduce the incidence of emergence reactions.^[11][12][13]

Emergence reactions are common during ketamine recovery, occurring in approximately 12% of adult patients. Psychological manifestations may vary in severity, presenting as pleasant dream-like states, vivid imagery, nightmares, hallucinations, or emergence delirium. In some cases, these states are accompanied by confusion, excitability, and irrational behaviors which may be recalled as unpleasant. Emergence reactions typically last no more than a few hours; however, adverse psychiatric events have occurred and/or persisted days to weeks after ketamine exposure.^[1] Upsetting reactions are much less common in children 10 to 15 years compared to adults and are rare in children younger than 10 years, presumably because a naive child with few life experiences is less likely to interpret unusual dreams or hallucinations as unpleasant.^[11] For older children or adults, advanced planning of a pleasant topic to dream about may decrease the incidence of a distressing reaction.^[13] Incidence can be reduced by using lower recommended doses of ketamine in conjunction with an intravenous benzodiazepine during anesthesia, as well as minimizing verbal, tactile, and visual patient stimulation during recovery.^[1] Severe reactions may require a small hypnotic dose of a short- or ultra short-acting benzodiazepine or barbiturate.^[1][2]

Physiological dependence and tolerance are possible with prolonged administration of ketamine.^[1] Psychological dependence has been reported with illicit use.^[33] Symptoms of illicit ketamine use include anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychosis. Users of ketamine describe sensations of floating to being separated from their bodies.^[1] A withdrawal syndrome associated with daily intake of large doses may present as craving, fatigue, poor appetite, and anxiety.^[1] Ketamine causes amnesia and abrupt loss of consciousness and is odorless and tasteless, which allows it to be added beverages without being detected. These properties have led it to be used as a “date rape” drug.^[34]

Involuntary movements of the head and extremities, often described as tonic-clonic, are frequent with ketamine use; these movements are unrelated to painful stimuli and are not indicative of the need for additional anesthetic.^[11][1] Movements are usually not intense enough to interfere with the performance of the procedure. Brief and sometimes intense myoclonia and twitching may be confused with seizure activity; however, these movements are benign and not associated with EEG changes. Skeletal muscle hypertonia and rigidity may also occur with ketamine use. Severe hypertonia is more frequent at high doses.^[11] A report describes generalized extensor spasm with opisthotonus in 2 infants receiving high doses of ketamine (total dose: 14 to 19 mg/kg within approximately 1 hour); in both cases, muscular hyperactivity ceased approximately 5 minutes after the administration of a small dose of pentobarbital.^[35]

Anaphylaxis/anaphylactoid reactions, transient erythema, maculopapular rash, and an injection site reaction including localized pain and rash have been reported with ketamine use.^[1]

There have been case reports of genitourinary pain in patients with a history of chronic ketamine use for off-label indications. Lower urinary tract and bladder symptoms including dysuria, increased urinary frequency, urinary urgency, urinary incontinence, and hematuria have been reported in individuals with a history of chronic ketamine use or abuse. Cystitis (including noninfective, interstitial, ulcerative, erosive, and hemorrhagic cystitis), hydronephrosis, and reduced bladder capacity have been reported upon diagnostic assessment. Consider ketamine cessation if genitourinary pain continues in the setting of other genitourinary symptoms.^[1]

Transient central diabetes insipidus (DI) has been associated with continuously infused ketamine in 2 case reports.^[36][37] A 2-year-old female with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) and stable hypertrophic cardiomyopathy was admitted to the hospital for pneumonia. She subsequently developed respiratory failure requiring mechanical ventilation. At 10 hours after initiation of a continuous ketamine infusion, the patient developed polyuria (urine output 8 mL/kg/hour), hypernatremia, elevated serum osmolality, and decreased urine osmolality. A vasopressin infusion was started, and the patient responded appropriately. Medications administered before ketamine infusion included continuous infusions of lorazepam, fentanyl, and dexmedetomidine, as well as vancomycin and cefotaxime for the pneumonia; only the antibiotics were continued after ketamine initiation. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score 7) between the development of DI and ketamine.^[36] The other case describes transient DI in a 28-year-old male who received ketamine for pain management after spinal cord injury. Similar to the pediatric case, the patient experienced DI within hours after receiving ketamine, and responded well to desmopressin.^[37] The exact mechanism of ketamine-induced DI is unclear; it may involve ketamine’s N-methyl-D-aspartate receptor antagonism and inhibition of glutamate-stimulated arginine vasopressin release from the neurohypophysis.^[36]

Recurrent ketamine use is associated with hepatobiliary dysfunction (most often a cholestasis pattern). Obtain baseline and periodic liver function tests, including alkaline phosphatase and gamma-glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing.^[1]

Ketamine administration is not recommended during pregnancy, labor, or obstetric delivery because safe use has not been established.^[1] Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.^[24]

Use ketamine with careful monitoring in breastfeeding mothers; alternate agents are preferred. Minimal data indicate that ketamine use in breastfeeding mothers may not affect the breastfed infant or lactation.^[28]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

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