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Ketamine an Ideal Treatment for Excited Delirium

Roberts, James R. MD

doi: 10.1097/01.EEM.0000475570.76943.ce
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Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, CEN, athttp://bit.ly/ProceduralPause, and read his past columns athttp://bit.ly/RobertsInFocus.

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All emergency clinicians have encountered violent and combative patients with no medical history available, and it is impossible to reason with them or initiate an evaluation. Such patients have been given the specific diagnosis of excited delirium. Regardless of the etiology, excited delirium is a well-accepted term describing predominantly young or middle-aged men, many with underlying psychiatric illness and often with concomitant drug and alcohol use.

Many teenagers take street drugs such as MDMA, PCP, and cocaine that also produce a similar scenario. Their rantings often buy them a visit to the ED, usually in police custody. The delirium must be dealt with quickly; these are the types of patients who die after physical restraint by police or after TASERing in the field. Those affected are widely adrenergic, remarkably stimulated, strong, and combative, and often get the better of three or four people trying to restrain them. Often they are hyperthermic and acidotic. Once they arrive in the ED, it's time to get the restraints off and drugs into their system so they can at least have their vital signs taken, glucose checked, and evaluations initiated.

Clinicians have used a variety of sedatives, often given in small standard doses, many of them effective. Failure to use enough of the correct sedative prolongs the hypermetabolic state. Intravenous sedatives are always best, but often everyone's favorite benzodiazepine is simply not adequate. The IM use of haloperidol (Haldol), ziprasidone (Geodon), or olanzapine (Zyprexa) is also relatively common, but these drugs take 15 to 30 minutes to become effective, often requiring a second dose. Also they provide prolonged sedation for eight to 10 hours.

On the scene now is ketamine, a remarkable drug with very few side effects that is effective within seconds. Ketamine quickly quells even the widely agitated 300-pound man. Now vital signs and glucose can be checked, and medical evaluation can commence.

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Ketamine Use for Acute Agitation in the Emergency Department

Hopper AB, Vilke GM, et al.

J Emerg Med

2015;48(6):712

These authors from the University of California at San Diego and Maricopa Medical Center in Arizona begin by reviewing a well-known axiom in emergency medicine: Extremely agitated and violent patients often respond slowly and inadequately to traditional sedatives. Verbal de-escalation is not effective, though first-line treatments can be if one administers large doses of potent medications. Ineffective empiric doses for the acutely agitated patient are often inadequate, and much larger doses are required, although they are not used often because of clinician inexperience or concern with megadoses. Ketamine is a dissociative agent that acts through antagonism of glutamate receptors, resulting in a rapid but transient state of analgesia and amnesia. Ketamine is commonly used in the ED for procedural sedation, even in children, as well as an induction agent for intubation. These authors have only recently proposed it as an initial ED treatment for agitation.

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They note that ketamine is effective in producing dissociative anesthesia within one to three minutes after IV or intramuscular administration. Ketamine has been proposed as an alternative to traditional antipsychotic medications for first-line intervention in severe undifferentiated acute agitation. Ketamine has even been used successfully prehospital.

Like any medication, ketamine has potential downsides. Many adverse effects are rare and overstated. Ketamine can worsen tachycardia and hypertension, and has been reported to depress respiratory drive when taken in high doses. A post-administration emergence phenomenon has been reported to occur in 10-20 percent of adult patients, but it's often mild and easily treated with low doses of midazolam.

The authors retrospectively identified patients who were given ketamine for acute undifferentiated agitation over an eight-year period (2004-2012). The American Association of Emergency Psychiatry guidelines define acute agitation as “an extreme form of arousal that is associated with increased verbal and motor activity.” All patients were also noted to be physically aggressive with staff, to require restraints, and to have increased verbal and motor activity that prevented initial treatment. Included in the analysis were vital signs and the route and dose of ketamine. The use of additional sedatives following the initial use of ketamine was also detailed. To be included in the study, three reviewing emergency physicians had to reach full consensus on chart data. The researchers also noted vital sign changes within four hours of administration of ketamine as well as post-ketamine hypoxia.

The authors identified 32 cases that met the inclusion criteria. The various diagnoses upon discharge are noted in the table. Interestingly, one autistic nonverbal patient who was uncooperative with treatment received ketamine on five separate visits. About half of the patients received medication for agitation prior to ketamine, most often an antipsychotic or a benzodiazepine. About half received ketamine IV, and the other half were administered ketamine IM. Additional calming medication was required in 62 percent of the cases, and often additional ketamine was used. About 40 percent of the patients were intoxicated with alcohol or other substances requiring additional calming medication. The medications that were administered after the initial dose of ketamine were varied, including haloperidol, midazolam, diazepam, lorazepam, diphenhydramine, and droperidol.

Not a single case of a dysphoric emergence reaction was reported in the series, and no patients returned to the ED for exacerbation of a psychiatric condition because of ketamine use. Pre-administration systolic blood pressure was 131 ± 20 mm Hg, with an average post-administration increase of 17 ± 25 mm Hg. The average baseline heart rate was 98 ± 23 beats/min, with an average increase of 8 ± 17 beats/min. The lowest recorded blood pressure showed an average drop of 14 ± 24 mm Hg. The average decrease in heart rate was 10 beats per minute. No patients became hypoxic, and the lowest oxygen saturation after ketamine administration was 94%.

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The authors highlight the advantages of ketamine, citing its rapid onset, preservation of reflexes, and ability to be given IM. Its half-life is relatively short, potentially allowing for more rapid disposition. They also note the lack of significant tachycardia or hypoxia previously reported by other authors. They did find, however, that more than half of the patients required additional medication for agitation after receiving ketamine, but said it lacks serious side effects and successfully treats agitation related to psychiatric illness and alcohol and drug intoxication. The authors said this study demonstrates ketamine's usefulness for multiple causes of severe agitation, its potential alternative first-line medication, and for those unresponsive to traditional pharmacological interventions.

Comment: Ketamine is emerging as a drug with many uses in the ED. I wrote last month about its benefit for sedation during procedures and as a nifty drug for intubating patients with asthma. (http://emn.online/InFocusArchive.) Our group also reported on IM ketamine for rapidly tranquilizing an uncontrollable, violent, and dangerous patient back in 2001. (J Trauma 2001;51[5]:1008.) Ketamine was considered a drug only to be used by anesthesiologists for many years, and our anesthesia colleagues have been reluctant to bless this drug for use in the ED.

Ketamine appears to be an ideal drug for the patient with unknown pathology who presents in an uncontrollable and violent state. This is probably its greatest benefit. Quelling undifferentiated excited delirium in a patient with no history and even no measured blood pressure is a huge plus. Prior articles have cautioned its use in patients with psychiatric illness or those with sympathomimetic delirium, noting that an increase in blood pressure and pulse could be detrimental. This article puts that those concerns to rest. Aside from its great benefit of producing rapid sedation without hypoxia, severe tachycardia, hypertension, or hypotension, the intramuscular use of ketamine is a sought-after benefit. The dose is 1.5-2 mg/kg if the drug can be given intravenously, and 5-6 mg/kg dose is standard intramuscularly. It's probably best to limit the first dose to 300 mg IV/600 mg IM. Those who have not used it before will be amazed by its rapid onset by the IM route. The patient can have his vital signs and glucose checked, an IV started, blood drawn, and a physical exam commenced within a couple minutes.

One has about only 30-40 minutes to complete the initial steps before the ketamine begins to wear off so many clinicians will empirically administer benzodiazepines before this occurs or as the ketamine effect starts to wane. It is quite safe to administer IV benzodiazepines to such patients. Additional doses are often required, and one can now rely on more traditional sedatives and IM antipsychotics, often haloperidol, but this is often an individual decision. One downside of antipsychotic use is that adequate doses produce a patient with whom you cannot interact for eight to 10 hours. Ketamine has also been used by the military for treating patients with head or battlefield injuries who require helicopter transport.

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The authors of this study have significant experience with excited delirium in the ED, and have published widely on the subject. Emergency physicians for some reason are still hesitant to give a drug that is predominantly an anesthetic. This study is, admittedly, relatively small and retrospective, not an ideal way to ferret out all the details. Patients were not prospectively randomized or enrolled in different treatment arms, so it is difficult to generalize to all populations. Just the fact that pretreatment vital signs could be taken speaks to less-than-severe cases.

Those who use ketamine will agree that significant post-ketamine tachycardia and hypertension are not uncommon; the highest systolic blood pressure in this series was 185 mm Hg. Hypertension and tachycardia are often ameliorated by IV benzodiazepines while the ketamine is still active. The highest and lowest post-dose heart rate does not make this drug a great concern for heart rate. Of paramount interest is the use of ketamine before the diagnosis is known. But that is common with many ED interventions. It is used for a variety of conditions, including severe autism, head trauma, alcohol intoxication, substance abuse, and acute psychiatric illness. One last caveat: Be sure to start supplemental oxygen and cardiac monitoring once ketamine is given.

Reader Feedback: Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to emn@lww.com.

Stop Giving into Beta Blocker Dogma

Dr. Roberts: I enjoyed your article, but I must take issue with your comment that “it is generally stated that beta blockers, which will decrease heart rate, can cause unopposed alpha-adrenergic stimulation because of beta blockade, leading to severe hypertension. It is generally advised that the hypertension associated with MDMA use not be treated with beta blockers.” (“MDMA/Ecstasy: Out of Sight, Not Out of Mind,” EMN 2015;37[9]:23; http://emn.online/Sept15Roberts.)

We recently published a large systematic review on this topic, and found that beta blockers were safe and effective for treating hypertension and tachycardia induced by MDMA, methamphetamine, and other amphetamine derivatives. (Drug Alcohol Depend 2015;150:1.) We found no cases of unopposed alpha-stimulation in our literature search.

The dogma of unopposed alpha-stimulation with beta blockers for stimulant toxicity has persisted in medical literature for decades, and is based on two case reports and a study of 10 cocaine-positive patients receiving intra-coronary propranolol. I routinely treat methamphetamine- and cocaine-toxic patients whose hypertension and tachycardia do not respond to benzodiazepines with beta blockers. I have never experienced a case of unopposed alpha-stimulation in more than 20 years of practicing emergency medicine.

Given the millions of doses of beta blockers administered each year for myriad indications, one would expect this to be a common phenomenon. I believe it is time to stop perpetuating this dogma and acknowledge the large volume of evidence showing that beta blockers are an excellent treatment option for patients with stimulant toxicity.

— John Richards, MD, Sacramento, CA

Dr. Roberts responds: I thank Dr. Richards for his insightful, and likely correct, comments. I tend to agree with his conclusions about beta blocker safety from his review of nine studies of beta blockers for treating amphetamine and related hypertension, but there is still controversy. The September 2015 UptoDate reference states the following about beta blockers for cocaine and methamphetamine hypertension and other sympathomemetic effects: “We recommend that beta blockersnotbe used in the treatment of cocaine-related cardiovascular complications because they may create unopposed alpha-adrenergic stimulation and are associated with coronary vasoconstriction and end-organ ischemia.”

And: “We suggest against the use of all beta-blocking agents, including labetalol, in the treatment of hypertension associated with sympathomimetic poisoning. ... We avoid beta-blocking agents, including labetalol, in the treatment of sympathomimetic poisoning because they may lead to unopposed alpha-adrenergic stimulation and a paradoxical increase in blood pressure.”

Hence, my cautions based on commonly trusted literature are supported, although they may not, in fact, actually be correct or true. Probably they are not scientifically correct. I also have used beta blockers in these situations with safety and efficacy. Very unfortunately, in Philadelphia, the capital of medical malpractice litigation, one would have a hard time defending an MI or hypertensive CNS hemorrhage after beta blocker use. That is a sad and disheartening comment on medicine today. Obviously, you would be an ideal defense witness. Although I have 20 more years of similar beta blocker experience than you, it looks like I took myself out of the medical expert pool with my comments.

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Discharge Diagnoses in Patients Given Ketamine

  • Autism
  • Head trauma
  • Alcohol intoxication
  • Substance abuse (amphetamines, cocaine)
  • Anticholinergic delirium
  • Suicide attempt
  • AIDS encephalitis
  • Primary psychiatric illness

Source: J Emerg Med 2015;48(6):712.

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