Ketamine: Drug Whys

A comprehensive examination of ketamine treatment uses, pharmacology, pharmacokinetics, administration routes and dosing


Generic Name: ketamine (multiple generics available)
Common Brand Name: Ketalar® (Par Pharmaceutical Companies – U.S.)
Class: general anesthetic

Treatment uses of Ketamine

The only labeled indication for ketamine is induction and maintenance of general anesthesia, which is a state of insensitivity to pain, usually achieved by the inhalation of gases or injection of drugs before surgical operations. General anesthesia implies a deep level of sedation during which the patient has virtually no level of awareness. 

Ketamine has a variety of off-label uses.
Ketamine has a variety of off-label uses.

Ketamine has a variety of off-label uses (i.e., without approval by the U.S. Food and Drug Administration). The primary off-label use has been analgesia for complex regional pain syndrome (CRPS), a condition previously referred to as "reflex sympathetic dystrophy," which describes a pain condition most often occurring as a complication of either trauma or surgery. CRPS pain occurs distal from an injury or surgical site and is significantly more severe than expected. 

Analgesia is the reduction of pain sensation without complete removal of all pain sensation. Analgesics may suppress awareness, but not deeply enough that a patient cannot be aroused. 

More recently, another off-label use, analgesia and procedural sedation, has gained considerable popularity. Sedation refers to suppressing the level of awareness. Low dose ketamine is also used in treatment of refractory bronchospasm and has been studied as a treatment for severe depression.

Compared to other general anesthetics the value of ketamine lies in its pharmacology. Ketamine is rapid acting, produces a profound anesthetic state but causes little to no respiratory or cardiovascular depression. This makes it an ideal anesthetic agent for short diagnostic or surgical procedures since a patent airway can be maintained without intubation or the need for manual ventilation. 

Anesthesia providers sometimes use ketamine in concert with propofol, another general anesthetic, which at low doses also allows anesthesia without intubation. The mixture of ketamine and propofol is nicknamed, "ketafol" and is commonly prepared in a syringe using a 2:1, 3:1 or 4:1 ratio of ketamine to propofol. 

Propofol by itself is particularly painful when injected into a peripheral IV and propofol frequently causes hypotension. Ketamine has opposite hemodyamic effects, is not painful when injected and provides analgesic effects against the painful propofol injection.

In the anesthesia and analgesia healthcare settings, ketamine is often used postoperatively to manage intractable pain (pain not well controlled with narcotic analgesics) and for treatment of post-operative pain in patients whose preoperative use of narcotic analgesics (either prescribed or abused) require narcotic doses so high that significant respiratory suppression creates an extremely unsafe condition. 

EMS patients are significant recipients of ketamine for analgesia and procedural sedation, owing to some significant advantages of this drug over other available analgesics and sedatives. Most recently, in the prehospital world, ketamine has shown promise in rapid and safe sedation of patients with excited delirium syndrome (ExDS), a complex but poorly understood condition marked by acute onset of extreme hyperactivity with bizarre and aggressive behavior often exhibiting superhuman strength. Law enforcement officers who make early recognition of ExDS should promptly call for EMS recognizing that rapid chemical sedation often provides the only window of opportunity to promptly manage physical manifestations of ExDS, which is often fatal, even when promptly and judiciously managed.

It needs to be reinforced that ketamine is a general anesthetic. Health care providers, state licensing boards, and professional associations disagree on who should be permitted to use anesthetic drugs. Some believe that only licensed anesthesia providers (anesthesiologists and nurse anesthetists) should administer general anesthetics. Many state medical and nursing licensing boards restrict or limit ketamine use by licensed providers. While EMS has been authorized to carry and administer ketamine by drug enforcement authorities in many states, providers would be wise to understand that such practice falls under a very bright spotlight by their medical colleagues. 

Ketamine dosing administration 

The recommended dose of ketamine for induction of general anesthesia is 1 to 4.5 milligrams per kilogram intravenously or 6.5 to 13 milligrams per kilogram when given intramuscularly. When adjuvant drugs (drugs with indications other than for pain that have analgesic properties) are administered, significantly less ketamine may be required to induce general anesthesia. Adjuvant drugs include agents such as midazolam (Versed®) or nitrous oxide. In such situations, the doses of ketamine needed to induce general anesthesia may be lowered to 0.5 to 2 milligrams per kilogram or 4 to 10 milligrams for kilogram intramuscularly. To maintain general anesthesia, the manufacturer recommends administering one-half to the full induction dose OR a continuous infusion of 0.1 to 0.5 milligrams per minute of ketamine. Clinical studies suggest this may actually need to in the 1 to 2 milligram per minute range or 15 to 90 micrograms per kilogram per minute. 

For procedural sedation, which in the EMS setting could include extrication, transcutaneous pacing, fracture management or control of a patient with excited delirium syndrome (ExDS), the recommended dosing is 0.2 to 0.8 milligrams per kilogram when administered intravenously or intraosseous and 2 to 4 milligrams per kilogram when given intramuscularly. Interestingly, the American College of Emergency Physicians (ACEP) recommends 1 milligram per kilogram intravenously over 30 to 60 seconds for sedation, followed by incremental doses of 0.5 milligrams per kilogram every 5 to 15 minutes as needed if sedation is inadequate or if repeated doses are needed for longer periods of sedation. 

When continuous IV infusions are needed for sedation, 2 to 7 micrograms per kilogram per minute is the recommended dosing. The Society of Critical Care Medicine (SCCM) recommends a bolus of 0.1 to 0.5 milligrams per kilogram of ketamine as an adjunct to opioids in critically ill patients, followed by an infusion of 0.83 to 6.7 micrograms per kilogram per minute (equivalent to 0.05 to 0.4 milligrams per kilogram per hour). 

In the limited studies using ketamine in management of ExDS, 29 percent of patients required intubation after receiving ketamine and those receiving higher doses of ketamine required intubation more frequently. Experts suggest an initial ceiling of 3 milligrams per kilogram when given intramuscularly (or 250 milligrams for an average sized patient) as appropriate to reduce the need for intubation in ExDS patients.

Intravenous ketamine doses should be administered over at least 60 seconds or at a rate no faster than 0.5 milligrams per kilogram per minute. Several references recommend intravenous administration over 2 to 3 minutes. More rapid administration is associated with respiratory depression, apnea and higher than usual increases in blood pressure. 

Data on intranasal ketamine dosing varies widely, making it impossible to publish consensus recommendations. When given intranasally the bioavailability is 50 percent, suggesting that higher than intravenous doses are necessary to achieve like effects. Typically, intranasal ketamine is dosed at the higher end of IV dose recommendations into the mid-range intramuscular dosing recommendations, depending on indication.

Ketamine is not recommended for use in patients under 16 years of age, but is nonetheless often used for procedural sedation in the pediatric population. Ketamine solution can be given orally (usually mixed by a compounding pharmacy into solution, lollipops, or gummy candies to achieve sedation in children) but because it is rapidly broken down by bile acids, orally ingested ketamine only has a bioavailability of 16 to 20 percent. This requires considerably higher doses to achieve desired effects.

ACEP recommends 1.5 to 2 milligrams per kilogram intravenously over 30 to 60 seconds for conscious or procedural sedation in children under 16 years of age with incremental doses of 0.5 to 1 milligrams per kilogram every 5 to 15 minutes as needed if initial sedation is inadequate or repeated doses are needed for longer sedation. For intramuscular administration in children under 16, ACEP recommends 4 to 5 milligrams per kilogram as a single dose with a repeat dose of 2 to 4 milligrams per kilogram if sedation is inadequate after 5 to 10 minutes or if additional doses are required. Numerous intranasal ketamine studies in children have achieved procedural sedative effects at 4 to 6 milligram per kilogram dosing.

Dose reductions are not provided in the manufacturers recommendations for ketamine administration in patients with renal or hepatic (liver) impairment. While the manufacturer recommends geriatric (elderly) patients be given adult doses of ketamine, virtually every pharmacology reference suggests starting at the lowest recommended adult doses when treating older patients. 

Overdoses of ketamine have been reported. Symptoms associated with overdose are typically limited to respiratory depression. Supportive ventilation is the preferred treatment. In reports of significant overdoses of 10 to 100 times recommended dosing, prolonged sedation has been the most frequently observed complication.

Ketamine pharmacology, pharmacokinetics, and stability 

Following intravenous administration, ketamine produces anesthetic effect rapidly (within 30 seconds following a 2 milligram per kilogram dose) and lasts for about 5 to 10 minutes. Intramuscular administration produces anesthetic effects in 3 to 4 minutes, lasting 12 to 25 minutes. The sedative effects of ketamine can last for 45 minutes to 2.5 hours, which explains why sub-anesthetic doses can be used for analgesia alone. The larger the total dose of ketamine, the longer the time until complete recovery. 

Besides profound anesthesia, ketamine leaves near normal pharyngeal and laryngeal reflexes (hence, the airway remains patent and protected), normal to slightly enhanced skeletal muscle tone, and occasionally transient respiratory depression. Ketamine produces an elevation in heart rate and blood pressure that begins shortly after injection and typically returns to pre-administration values within 15 minutes. The usual systolic and diastolic blood pressure increases range from 10 percent to 50 percent above baseline values, but can be higher or last longer in individual patients. Ketamine also results in bronchodilation, increased cerebral blood flow and metabolism, lowering of the seizure threshold and increased salivary secretions. Anesthesia providers commonly premedicate the patient with atropine (0.4 to 0.6 milligrams IV 30 to 60 minutes before induction) to reduce salivary secretions. Emergence from a ketamine induced anesthetic state is heralded by tachycardia, a rise in blood pressure, nystagmus and attempts at swallowing. Return to consciousness is usually gradual. 

Ketamine is rapidly absorbed following intravenous or intramuscular administration. Ninety-one percent of ketamine is excreted in the urine and 3 percent in feces with smaller amounts found in bile. Ketamine was found to pass through the placenta in dogs and monkeys. It is not known whether ketamine is excreted in human breast milk.

Ketamine produces a dissociative state (one in which the patient is dissociated from their surrounding environment) by direct action on the cerebral cortex and limbic system. Patients often appear catatonic. Chemically, ketamine is an analog of phencyclidine (PCP) and as a consequence, can have some of the psychological effects often seen with PCP hallucinogens, especially in adult patients between the ages of 15 and 65. The effects of ketamine have made it a drug of abuse.

Ketamine concentrations 

Ketamine has multiple generic forms in the U.S. Available forms are 20 mL vials of 10 milligrams per mL, 10 mL vials of 50 milligrams per mL, and 5 mL vials of 100 milligrams per mL. Vials should be stored between 68 to 77F (room temperature) and protected from light. The 50 mg/mL and 100 mg/mL vials can be further diluted with NS or D5W to mix an infusion. Ketamine may precipitate when mixed with diazepam. The manufacturer recommends that the 10 mg/mL vials not be further diluted. 

Intranasal administration invariably requires a 100 mg/mL strength (in order to administer a therapeutic dose in a concentrated enough form to be absorbed). This creates a conundrum of sorts for EMS services as attempts to use this concentrated form of ketamine intravenous or intramuscular can easily lead to dosing errors in the austere, dimly lit, difficult environments where ketamine is often required. The 100 mg/mL strength of ketamine should never be administered intravenously without proper dilution.

Ketamine cautions and warnings 

Ketamine has a wide margin of safety owing to its lack of effect on airway and respirations even at higher than recommended doses. Respiratory depression or apnea can occur with too rapid administration. In such cases, supportive ventilation should be provided and if persistent, intubation may be required. Laryngospasm has been reported with administration of ketamine, particularly at higher doses. 

Extra caution should be exercised if narcotics or barbiturates are used concurrently with ketamine; lower doses of ketamine may be required and respiratory depression is more commonly reported. This is particularly relevant to EMS providers because opioid naïve patients given ketamine after failing to have their pain controlled with narcotics are at very high risk for apnea or respiratory depression. Likewise, ExDS patients may well have multiple pharmaceuticals onboard, leaving them at greater likelihood of needing airway management and mechanical ventilation following ketamine administration. Additional ketamine can always be administered but ketamine given cannot be taken back.

Ketamine contains a Black Box Warning from the US Food and Drug Administration (FDA) on emergence reactions, which are symptoms that appear as the patient emerges from the effects of ketamine sedation. Emergence reactions occur in 12 percent of patients and are psychologic manifestations that vary from pleasant dream-like states to vivid images, hallucinations, or full-blown delirium. They may be associated with confusion, excitement or irrational behavior and usually last for only a few hours. Rarely, these may recur up to 24 hours later. As mentioned earlier there is considerably lower incidence of emergence reactions in patients under 15 and over 65 years of age. Emergence reactions are also less with intramuscular ketamine, prior exposure to ketamine and lower doses. Administration of a benzodiazepine, such as midazolam, diazepam or lorazepam, in conjunction with ketamine also reduces emergence reactions. Acute emergence reactions should be treated with benzodiazepines and most published literature recommends diazepam. The author and his colleagues have found midazolam equally effective. 

Clinicians experienced with using ketamine for conscious sedation suggest that emergence reactions can be directly influenced by environment and thought trains present at the time sedation is induced and at the time of awakening. Assuring as calm and quiet environment as possible and asking the patient to imagine a placid, peaceful scene prior to induction is reported to be associated with more calm and peaceful awakenings. 

Because of the risk of emergence reactions ketamine may have unpredictable effects in patients with schizophrenia and is not recommended for routine use. 

Monitoring of oxygenation and ventilation is mandatory when using any general anesthetic. Pulse oximetry and end-tidal carbon dioxide (capnography) monitors should be applied as early as practical and monitored continuously. In spontaneously breathing patients, nasal capnography, in conjunction with astute clinical assessment, provides quick and reliable warning of hypoventilation and apneic episodes. 

Supplemental oxygen administration has been standard practice by anesthesia providers during conscious sedation, but its use has recently been questioned as desaturations are more likely related to hypoventilation and supplemental oxygen may do nothing more than mask respiratory depression. The current best practice is to administer supplemental oxygen when saturations fall below 94 percent. If desaturation results from apnea or hypoventilation, manual ventilation is the preferred treatment. 

Important ketamine side effects and interactions 

Besides increases in blood pressure and heart rate previously mentioned, hypotension and bradycardia are occasionally seen. Diplopia and nystagmus are often seen following ketamine administration. Concerns about ketamine related increases in intraocular pressure (IOP) have been largely disproven although higher doses of ketamine (6 milligrams per kilogram or greater) can result in slightly increased IOP. 

Enhanced skeletal muscle tone in some patients given ketamine can appear as tonic-clonic movements and may be mistaken for seizures. Of note, these movements do not imply an emergence from anesthesia or a need for additional ketamine. The effects of ketamine on intracranial pressure (ICP) were examined in a 2014 literature review that found no evidence to support ketamine increases ICP in sedated and mechanically ventilated severe traumatic brain injury (TBI) patients and some evidence to suggest ketamine may lower ICP in selected TBI patients. Ketamine is less likely than other anesthetic agents to induce vomiting.

Currently, there are no drug interactions of concern to EMS providers. Ketamine may interfere with urine drug screen testing for phencyclidine (PCP), resulting in false-positives. 

Ketamine average costs (U.S.)

  • 10 mg/mL (20 mL vial) generic ketamine
  • EMS Service cost: $17.78 each
  • Large Hospital cost: $11.11
  • 100 mg/mL (5 mL vial) generic ketamine
  • EMS Service cost: $9.78 each
  • Large Hospital cost: $6.08

References

1. Lexicomp: Wolters Kluwer Health, Hudson, Ohio (accessed July, 2015).
2. Albany Medical Center Pharmacy, Albany, New York. 
3. Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on ICP in traumatic brain injury. Neurocrit Care. 2014;21:163-173.

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