Ketamine was first developed in 1962 as a safer anesthetic and alternative to phencyclidine (PCP), which had numerous problematic side effects.1 It was then used on the battlefields of Vietnam and was approved by the FDA in 1970 for civilian use since it proved to be a safe and effective anesthetic for both human and veterinary applications.2 However, in the 1980s, concerns over misuse and the psychodysleptic effects eventually led to ketamine being classified as a schedule III controlled substance.3 In addition, concerns for adverse effects led to markedly reduced medical use in humans.
Interestingly, in the late 1990s and early 2000s, a resurgence of interest in ketamine developed within the United States, resulting in its slow adoption by the prehospital and ED settings as a sedative and analgesic.
Subsequent research has disproved some of the widely held misconceptions surrounding ketamine. It’s proven to be an effective sedative and analgesic, and extensive ongoing research is demonstrating it to be a promising option for the treatment of depression and other neuropsychiatric conditions.3 Foremost, though, ketamine has caught our attention with the three main prehospital applications it has staked a claim to: sedation, pain and, perhaps most importantly, behavioral control.
Ketamine is a PCP-derivative and therefore unique when compared to other sedative/anesthetic agents because it produces a distinct dissociative effect. Subjectively, it creates a sense of disconnection between the mind and body (known as “the K-hole”) whereas other agents drive one toward a loss of consciousness. Ketamine also separates itself from other prehospital agents by serving as an anesthetic, sedative, amnesiac and analgesic all in one.1,4
The exact mechanism of ketamine isn’t fully understood. It’s been theorized that the drug causes inhibition of N-methyl-D-aspartate (NMDA) receptors in the central nervous system, which, in turn, gives rise to ketamine’s dissociative effect.1,5 This dissociation is typified by a patient who’s awake yet distant from pain or most any external stimulus. A unique property of ketamine is that the patient’s airway reflexes and ability to breathe remain intact.
Ketamine can provide rapid sedation without the loss of a patient’s airway reflexes, hypoventilation or unwanted hypotension. Photo A.J. Heightman
You’re called to a shopping center by law enforcement for a man with bizarre behavior. He reportedly attacked his reflection in a storefront window, and has actively bleeding hand injuries. On arrival, you find a wildly combative 180-lb. man fighting with multiple police officers with seemingly superhuman strength.
Paramedics administer ketamine intramuscularly, in a single dose delivered in the anterolateral thigh. Within one minute, the patient is no longer actively fighting, and officers are able to quickly place him on a stretcher. He’s sedated but his respiratory effort is intact. He’s placed on the monitor, including waveform capnography; an IV line of lactated Ringer’s is established and fluid is infused.
Discussion: Patients with excited delirium syndrome (ExDS) require rapid-acting pharmacologic restraint to ensure the safety of responders, law enforcement and the patient themselves. Many EMS systems use benzodiazepines for sedation of agitated patients, but relatively large doses can be required to reliably gain behavioral control. However, these higher doses of benzodiazepines can commonly cause unwanted effects such as respiratory depression and hypotension. It’s often impossible to safely establish IV access in a patient with severe agitation, but an intramuscular (IM) delivery of a single dose of medication can usually be accomplished quickly and safely.
Antipsychotic agents don’t typically produce behavioral control quickly enough when given IM and the anticholinergic effects could potentially impair heat dissipation or cause prolongation of the QT interval, leading to lethal arrhythmias.6 In contrast, ketamine can provide rapid sedation without the loss of airway reflexes, hypoventilation or un-wanted hypotension.7–10
A dose given IM should generally be expected to produce sedation within a minute with a duration of at least 20–30 minutes.
Preservation of compensatory hyperventilation is critical in patients with severe metabolic acidosis—a common finding in ExDS. Benzodiazepine-related reductions in minute ventilation, which may not necessarily manifest as frank respiratory depression, can result in worsening acidosis with development of hemodynamic instability and acidosis-related arrhythmias.11 Such deterioration may be an important cause of cardiac arrest in patients with ExDS, underscoring the importance of using an agent that typically spares ventilatory effort, as seen with ketamine.
A 34-year-old man is entrapped in his heavily damaged vehicle, with limited rescuer access. He has multiple severe orthopedic injuries, a heart rate of 130 and blood pressure of 88/40.
The patient is in severe pain. He’s placed on oxygen and an intraosseous line is established in the proximal humerus. After anesthesia of the cannulated humerus with lidocaine, ketamine is administered. Within a few minutes, the patient reports marked reduction in pain, but has no change in mental status, behavior, respiratory effort or hemodynamic status.
Discussion: Ketamine’s cardiorespiratory safety profile makes it an ideal analgesic for patients with severe pain in the prehospital environment. Patients in whom the analgesic (otherwise known as sub-dissociative) dose of ketamine should be considered include:
- Patients in whom opioid analgesics have failed to provide adequate pain control, including opioid-tolerant patients;
- Patients in whom hemodymamic instability, such as hypotensive trauma patients, prevents the safe use of opioid analgesics; and
- Patients with opioid addiction who are in recovery and want to avoid re-exposure to opioid analgesics.12–14
For ease of administration, ketamine can be diluted in normal saline solution (e.g., 100 mg of ketamine can be diluted to a total volume of 10 mL to yield an easy-to-administer 10 mg/mL concentration).
One potential problem with ketamine is a short duration of effect, requiring a re-bolus at regular intervals to maintain effect. If an infusion pump is available, one recommended strategy for ketamine delivery is to begin with a bolus dose followed by a drip.
In some patients, particularly with repeated bolus administration, it’s possible to develop some neuropsychiatric effects—notably, euphoria and occasionally benign hallucinations. Succinctly, the patient may get high, which is described afterward as a distinctly different experience from the dysphoria and legendary hallucinations that can occur with partial dissociation or on recovery (emergence) from full dissociative sedation.15 When this euphoria occurs, it’s generally not distressing for the patient; they’re capable of interacting with care providers, and they can be directed.
Additionally, ketamine can be administered via the intranasal route and can rapidly achieve analgesia in situations where attempts at vascular access prove disadvantageous or difficult.16
Rapid or Delayed Sequence Airway
You’re called to the residence of a 62-year-old male who has pneumonia and is in septic shock. Despite high-flow oxygen with a partial non-rebreather, his SpO2 remains in the mid-70s. He’s sitting up straight with substantially increased work of breathing. His heart rate is in in the 130s and blood pressure is 77/36.
You’re aware that an attempt to intubate the patient at present will likely result in further desaturation and cardiac arrest. Consequently, you preoxygenate the patient with a nasal cannula running at 15 Lpm, placed beneath a bag-valve mask (BVM) with a positive end-expiratory pressure valve, which is also set to 15 Lpm at 10 cm/H2O.
Due to the patient’s anxiety and lack of cooperation, maintaining a mask seal is nearly impossible. The decision is made to administer ketamine at a full dissociative dose. The patient almost immediately relaxes. A seal is made with the BVM and his SpO2 increases to 96% with assisted bagging. His positioning is optimized for the intubation and a paralytic is pushed. The patient is successfully intubated without any hypoxic events, after which he’s placed on a ventilator and transported.
Discussion: Ketamine is probably best known and most widely accepted for its role in rapid sequence intubation (RSI). The properties of ketamine make it suitable for RSI under many different circumstances.17–20 Its quick onset is particularly beneficial when combined with rapid-acting neuromuscular blocking agents like rocuronium to ensure adequate induction prior to paralysis.
Ketamine’s duration of effect is much longer than that of the commonly used induction alternative etomidate. This allows providers more time to address the post-intubation sedation package along with other points of care, lessening any concerns of the induction agent wearing off in a patient who’s paralyzed and without sedation.
Managing an airway can also be very uncomfortable for the patient. Ketamine, as discussed earlier, has analgesic properties that none of the other induction agents have.
In the setting of delayed sequence intubation (DSI), ketamine is particularly advantageous. By leaving airway and breathing reflexes intact, ketamine becomes a tool to achieve better preoxygenation prior to airway management.
Lastly, ketamine has a hemodynamic profile that’s beneficial for many situations requiring emergency intubation. We don’t see the significant drop in blood pressure that we’ve become accustomed to with other induction agents, such as midazolam and propofol.21,22 In fact, ketamine has even been observed to increase the blood pressure and heart rate in some patient types.22
It’s this characteristic that gives benefit to patients with early-stage septic or hemorrhagic shock in need of RSI. It should be noted, however, that a recent prehospital study demonstrated a blunted hypertensive response in 26% of patients with a high shock index, whereas patients with a low shock index had an increase in both pulse rate and systolic blood pressure.23 A suggested approach to these patients with the highest shock index is to aggressively resuscitate and reduce the dose of ketamine.
You’re called for a critical care transport of a 47-year-old male patient with pneumonia. He has a history of asthma and was just intubated prior to your arrival at a small rural hospital. You find him still paralyzed from the vecuronium he received, tachycardic but regular in the 130s, with a blood pressure of 160/85, and with noted tears streaming from his eyes. He’s received multiple albuterol nebulizer treatments as well as magnesium. The facility tells you that they continue to get high peak inspiratory pressures on their ventilator and have had difficulty getting the patient’s oxygen saturation out of the 80s, and you notice the characteristic shark fin appearance of the capnograph after hooking up your waveform capnography. Your patient needs some form of sedation for comfort as well as help with bronchodilation.
You and your partner discuss management strategies for this patient for the 45-minute transport; you decide ketamine is the ideal agent that will provide both sedation and bronchodilation. After disconnecting the patient from the facility’s ventilator, you let him exhale fully before reattaching him to your ventilator.
Ketamine’s support of blood pressure has been shown to set the stage for an ideal role in RSI of the head-injured patient. Photo Ryan Hodnick
You give a bolus dose of ketamine followed by a continuous drip. The patient’s heart rate decreases to 105 and his blood pressure drops to 125/75, all the while his oxygen saturation climbs to 97%. After 10 minutes you notice the peak inspiratory pressures drop down as well, and the shark fin appearance of the capnograph begins to normalize into a square waveform.
Discussion: Ketamine can be used for continuous sedation infusions. This is a relatively new arena of ketamine use, and is still being explored.24,25 Ketamine has a wide therapeutic range with the lower end of clinical toxicity recorded between 5–10 times the therapeutic dosing.26,27
Bronchodilation is an added benefit of ketamine.5,28,29 This serves as a great adjunct to other standard therapy in the treatment of severe obstructive lung disorders such as asthma or chronic obstructive pulmonary disease (COPD). As a beta-2 agonist, ketamine steps forward as the ideal induction agent for intubation in these patients as well as the ideal agent for continued sedation.
Safety & Mythbusting
Ketamine has an excellent safety profile when given appropriately. It’s been advocated as one of the safest and most versatile anesthetic agents for battlefield medicine; for emergencies in space exploration missions; and even for emergency surgeries, including cesarean deliveries, when no anesthetist is available.30–33
One patient population to use caution with ketamine in, however, is the diagnosed schizophrenic. Administration of ketamine in patients with schizophrenia, especially at sub-dissociative doses, may worsen symptoms of psychosis.1,34,35
Emesis can occur with ketamine use, primarily associated with recovery from the dissociated state. Risk of this, however, can be easily minimized with administration of an antiemetic before recovery.
Laryngospasm has been reported approximately 0.3% of the time ketamine is administered.36 This is associated with unusually high IV doses and can be avoided by using proper dosing. Although patients typically have respirations supported through this brief period, intubation is rarely necessary.
Respiratory depression and apnea have also been reported less than 1% of the time.36 This can happen when ketamine is pushed too rapidly via the IV route. The depression or apnea is often transient in such cases.
Hypersalivation can be observed with ketamine, though is also reported as rare. It can be mitigated prior to ketamine administration by use of atropine—a drug that’s been moved to the back of most of our med boxes but still available to us.
Some patients recovering from ketamine administration have exhibited an emergence reaction, which is reported to be mild in 6.3% of cases and clinically important in 1.4% of cases.36
The more severe cases present with extremes of confusion and hallucinations accompanied by thrashing behavior or even combativeness.37 This phenomenon can often be mitigated by working to keep the patient calm or, if that fails, administration of benzodiazepines.
Moving from fact to fiction, though, one of the biggest myths with ketamine is the danger it supposedly presents to head-injured patients. Of chief concern is the perpetuated belief that ketamine administration elevates intracranial pressures in patients with closed head injuries, leading to poor outcomes.
This myth has since been debunked. In fact, ketamine’s support of blood pressure has been shown to set the stage for an ideal role in RSI of the head-injured patient.17,38,39
There are better agents to be utilized for induction, sedation and analgesia in situations where a patient’s blood pressure needs to be reduced to prevent further morbidity and mortality (such as aortic dissections or hypertensive strokes). Keep in mind, however, that hypertension and tachycardia aren’t contraindications outright: Take the case of excited delirium where, once the patient is dissociated, heart rate and blood pressure are often reduced as the agitation disappears.
Finally, ketamine is also safe for use in pediatric patients. It’s often times the drug of choice for procedural sedation of pediatric patients in the ED setting, with the incidence of adverse effects reported as low.40,41
Ketamine is one of the most versatile yet simultaneously most misunderstood drugs in our modern-day medication box. Its uses span the realm of care from analgesia to bronchodilation and it has a profile for sedation that no other agent can match.
Ketamine preserves airway reflexes and respiratory drive in a way no other sedative can. Ketamine, in many patients, is pressure supportive. Ketamine has shown synergistic effects with other commonly used opiates and sedatives.42–44 And, at a time when the price of many medications is skyrocketing, ketamine presents itself as an inexpensive alternative to many of the analgesics and sedatives we’ve spent years using and paying heavily.
As the word of ketamine and the understanding of its benefits spreads through the hardline halls of emergency medicine in the U.S., this acceptance of a new paradigm has us optimistic.
We look forward to the day when our question is no longer, “Are there any patients we could give ketamine to?,” but rather, “In what patients should we consider giving anything else?”
- Domino EF. Taming the ketamine tiger. 1965. Anesthesiology. 2010;113(3):678–684.
- Mercer SJ. “The drug of war”-A historical review of the use of ketamine in military conflicts. J R Nav Med Serv. 2009;95(3):145–150.
- Wolfson PE. Ketamine-Its history, uses, pharmacology, therapeutic practice, and an exploration of its potential as a novel treatment for depression. International Journal of Transpersonal Studies. 2014;33(2):33–39.
- Reboso Morales JA, González Miranda F. Ketamine. Rev Esp Anestesiol Reanim. 1999;46(3):111–122.
- Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;(182):313–333.
- Hermes H, Shiloh R, Epstein Y, et al. Heat intolerance in patients with chronic schizophrenia maintained with antipsychotic drugs. Am J Psychiatry. 2000;157(8):1327–1329.
- Isbister GK, Calver LA, Downes MA, et al. Ketamine as rescue treatment for difficult-to-sedate severe acute behavioral disturbance in the emergency department. Ann Emerg Med. 2016;67(5):581–587.
- Cole JB, Moore JC, Nystrom PC, et al. A prospective study of ketamine versus haloperidol for severe prehospital agitation. Clin Toxicol (Phila). 2016;54(7):556–562.
- Scaggs TR, Glass DM, Hutchcraft MG, et al. Prehospital ketamine is a safe and effective treatment for excited delirium in a community hospital based EMS system. Prehosp Disaster Med. 2016;31(5):563–569.
- Olives TD, Nystrom PC, Cole JB, et al. Intubation of profoundly agitated patients treated with prehospital ketamine. Prehosp Disaster Med. 2016;31(6):593–602.
- Ayres SM, Grace WJ, Pinkernell BH, et al. Inappropriate ventilation and hypoxemia as causes of cardiac arrhythmias: The control of arrhythmias without antiarrhythmic drugs. Am J Med. 1969;46(4):495–505.
- Barrett TW, Schriger DL. Annals of Emergency Medicine Journal Club. Move over morphine: Is ketamine an effective and safe alternative for treating acute pain? Answers to the September 2015 Journal Club. Ann Emerg Med. 2016;67(2):289–294.
- 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(3):222–229.
- Jouguelet-lacoste J, La Colla L, Schilling D, et al. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: A review of the current literature. Pain Med. 2015;16(2):383–403.
- Green SM, Roback MG, Kennedy RM, et al. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57(5):449–461.
- Shrestha R, Pant S, Shrestha A, et al. Intranasal ketamine for the treatment of patients with acute pain in the emergency department. World J Emerg Med. 2016;7(1):19–24.
- Hughes S. Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 3: is ketamine a viable induction agent for the trauma patient with potential brain injury. Emerg Med J. 2011;28(12):1076–1077.
- Lyon RM, Perkins ZB, Chatterjee D, et al. Significant modification of traditional rapid sequence induction improves safety and effectiveness of pre-hospital trauma anaesthesia. Crit Care. 2015;19:134.
- Patanwala AE, Mckinney CB, Erstad BL, et al. Retrospective analysis of etomidate versus ketamine for first-pass intubation success in an academic emergency department. Acad Emerg Med. 2014;21(1):87–91.
- Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: A multicentre randomised controlled trial. Lancet. 2009;374(9686):293–300.
- Farhan M, Hoda MQ, Ullah H. Prevention of hypotension associated with the induction dose of propofol: A randomized controlled trial comparing equipotent doses of phenylephrine and ephedrine. J Anaestesiol Clin Pharmacol. 2015;31(4):526–530.
- Choi YF, Wong TW, Lau CC. Midazolam is more likely to cause hypotension than etomidate in emergency department rapid sequence intubation. Emerg Med J. 2004;21(6):700–702.
- Miller M, Kruit N, Heldreich C, et al. Hemodynamic response after rapid sequence induction with ketamine in out-of-hospital patients at risk of shock as defined by the shock index. Ann Emerg Med. 2016;68(2):181–188.
- Benken ST, Goncharenko A. The future of intensive care unit sedation: A report of continuous infusion ketamine as an alternative sedative agent. J Pharm Pract. May 2, 2016. [Epub ahead of print.]
- Umunna BP, Tekwani K, Barounis D, et al. Ketamine for continuous sedation of mechanically ventilated patients. J Emerg Trauma Shock. 2015;8(1):11–15.
- Long H. Case report: Ketamine medication error resulting in death. Int J Med Toxicol. 2003;6(1):2.
- Green SM, Clark R, Hostetler MA, et al. Inadvertent ketamine overdose in children: Clinical manifestations and outcome. Ann Emerg Med. 1999;34(4 Pt 1):492–497.
- Goyal S, Agrawal A. Ketamine in status asthmaticus: A review. Indian J Crit Care Med. 2013;17(3):154–161.
- Hendaus MA, Jomha FA, Alhammadi AH. Is ketamine a lifesaving agent in childhood acute severe asthma? Ther Clin Risk Manag. 2016;12:273–279.
- Fisher AD, Rippee B, Shehan H, et al. Prehospital analgesia with ketamine for combat wounds: A case series. J Spec Oper Med. 2014;14(4):11–17.
- Komorowski M, Watkins SD, Lebuffe G, et al. Potential anesthesia protocols for space exploration missions. Aviat Space Environ Med. 2013;84(3):226–233.
- Burke TF, Nelson BD, Kandler T, et al. Evaluation of a ketamine-based anesthesia package for use in emergency cesarean delivery or emergency laparotomy when no anesthetist is available. Int J Gynaecol Obstet. 2016;135(3):295–293.
- Burke T, Manglani Y, Altawil Z, et al. A safe-anesthesia innovation for emergency and life-improving surgeries when no anesthetist is available: A descriptive review of 193 consecutive surgeries. World J Surg. 2015;39(9):2147–2152.
- Lahti AC, Koffel B, Laporte D, et al. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13(1):9–19.
- Lahti AC, Holcomb HH, Medoff DR, et al. Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport. 1995;6(6):869–872.
- Donaldson R, Ostermayer D, Holtz M, et al. Ketamine. WikEM. Retrieved Dec. 16, 2016, from www.wikem.org/wiki/Ketamine.
- Viswanath O, Kerner B, Jean Y, et al. Emergence delirium: A narrative review. J of Anesth & Clin Sci. 2015;4(2):2049–9752.
- Himmelseher S, Durieux ME. Revising a dogma: Ketamine for patients with neurological injury? Anesth Analg. 2005;101(2):524–534.
- Filanovsky Y, Miller P, Kao J. Myth: Ketamine should not be used as an induction agent for intubation in patients with head injury. CJEM. 2010;12(2):154–157.
- Hartling L, Milne A, Foisy M, et al. What works and what’s safe in pediatric emergency procedural sedation: An overview of reviews. Acad Emerg Med. 2016;23(5):519–530.
- Grunwell JR, Travers C, Mccracken CE, et al. Procedural sedation outside of the operating room using ketamine in 22,645 children: A report from the Pediatric Sedation Research Consortium. Pediatr Crit Care Med. 2016;17(2):1109–1116.
- Tucker AP, Kim YI, Nadeson R, et al. Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: A double-blinded, randomised, placebo controlled, crossover study of experimental pain. BMC Anesthesiol. 2005;5(1):2.
- Adriaenssens G, Vermeyen KM, Hoffman VLH, et al. Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: A double-blinded, randomised, placebo controlled, crossover study of experimental pain. British J of Anesth. 1999;83(3):393–396.
- David H, Shipp J. A randomized controlled trial of ketamine/propofol versus propofol alone for emergency department procedural sedation. Ann Emerg Med. 2011;57(5):435–441.
>> Recognize symptoms in patients that indicate the use of ketamine.
>> Learn contraindications of ketamine and how to use it safely.
>> Understand when ketamine is the best tool to use in managing the airway.
Dissociative: A distortion of perceptions of sight and sound and that produces feelings of detachment—dissociation—from the environment and self.
Metabolic acidosis: Acidosis in which excess acid is added to the body fluids or bicarbonate is lost from them.
Neuropsychiatric: Relating mental or emotional disturbance to disordered brain function.
Psychodysleptic: To bring on a dream-like state.