Rapid Tranquilization of the Violently Agitated Patient: Ketamine and an Update on Haloperidol

Roberts, James R. MD

doi: 10.1097/01.EEM.0000302947.67291.68
In Focus

Author Credentials and Financial Disclosure: James R. Roberts, MD, is the Chairman of the Department of Emergency Medicine and the Director of the Division of Toxicology at Mercy Health Systems, and a Professor of Emergency Medicine and Toxicology at the Drexel University College of Medicine, both in Philadelphia. Dr. Roberts has disclosed that he has no significant relationships with or financial interests in any commercial companies that pertain to this educational activity.

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Learning Objectives: After reading this article, the physician should be able to:

1. Discuss the rationale for using ketamine and haloperidol to treat acute delirium.

2. Describe the clinical use of ketamine and haloperidol for treating acute delirium.

3. Summarize the potential risks and benefits of these medications in the ED for the rapid tranquilization of violent patients.

Release Date: December 2007

The destructive pathophysiology and medical complications associated with acute violent agitation in ED patients are legend: metabolic acidosis, rhabdomyolysis, hyperthermia, sudden death, and multisystem failure all can result in an agitated delirious patient who is toxic on cocaine. The principles that apply are pertinent to any acutely agitated state, however.

Sudden unexpected cardiac arrest also has been well documented in previously healthy individuals who have experienced acute delirium secondary to psychosis or drug intoxication, particularly if they continue to struggle and have been physically restrained without the benefit of tranquilization. Although the natural inclination of any clinician or even the best-trained police officer is to subdue the wildly agitated patient physically until he is ready to cooperate or sensible enough to participate in his own care, this approach is potentially dangerous and counterproductive. Police and EMS personnel have become well aware of sudden unexpected death in the prehospital arena, particularly when uncontrollable individuals are restrained by the hobble technique, and the clinical approach has changed.

Patients in the throws of acute delirium cannot be talked down or cajoled into cooperating, and frequently the application of physical restraints only exacerbates the agitated state, causing the encephalopathic patient to struggle even more violently. Within a few surprisingly short minutes, the metabolic acidosis from lactate production can be quite severe, and the core temperature can quickly rise to a life-threatening hyperthermic range. Because any sudden unexpected death in a previously healthy individual is always a high-profile case and often flavored by claims of police brutality, lack of caring, and excessive violence on the part of law enforcement individuals, EPs must recognize the danger of a nonchalant attitude or eschew a leisurely medical response to the violently delirious individual.

Regardless of the etiology of the acute delirium, the clinical approach should be expeditious and aggressive. The physician has to gain the upper hand and quickly control the patient so a medical evaluation can begin, the safety net can be placed (IV, pulse oximetry, O2, monitor), and basic treatment initiated. Vital signs must be taken, IVs must be maintained, radiographs taken, basic blood tests performed (especially serum glucose), and a focused physical examination initiated. All these mandates are impossible when the patient is thrashing wildly. Be it cocaine toxicity, PCP, acute psychosis, or just out-of-control rage, the aim should be to get the security guards and restraints off the patient and the proper sedatives into the patient's veins. Last month's column discussed the most commonly used interventions, benzodiazepines and haldoperidol. This month's discussion will address ketamine, a drug that I believe is totally underused by EPs and an ideal one for the issues at hand. Also, I will also pass along important new and likely discouraging information on haldoperidol.

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The Combative Multi-Trauma Patient: A Protocol for Prehospital Management

Melamed E, et al, Euro J Emerg Med 2007;14(5):265

This fascinating Israeli study describes using ketamine for pharmacologically managing combative trauma patients in the prehospital setting. Many of the issues for EMS are similar to the ED for controlling agitated patients. In the U.S., paramedics rarely sedate patients en route, and often resort to police rather than ambulance transport. This retrospective study has data analysis on only 11 patients, but it focuses on the benefit of ketamine for prehospital management of combative trauma patients who were subject to long transport times. After analysis of the data on 11 patients, an expert panel was developed to discuss a standard protocol that included ketamine as the initial prehospital intervention. The inquisitive EP with an EMS interest might consider a similar study or protocol evaluation in the U.S.

Like emergency physicians, prehospital providers are confronted with combative, violent, and uncooperative patients, many of whom have suffered traumatic although often undifferentiated injuries. Venous access is problematic, as are the administration of oxygen, rapid assessment, and monitoring vital signs. Trauma is often complicated by painful conditions and head injury and drug or alcohol intoxication. As in the ED, the exact diagnosis and underlying comorbidities are often unknown, but one must still provide evaluation and care. Military EMS in Israel has had ketamine and benzodiazepines available to them for the sedation of combative patients, but this study looks specifically at prolonged transport issues.

Eleven young combative males were evaluated, average age 22.6 years. Injuries included traumatic brain injury (TBI) and nonspecific hypoxia and hypovolemia following penetrating, blunt, and blast injuries. The mean transit time was 114 minutes. Five patients received IV ketamine, three received ketamine and midazolam, and two received ketamine plus morphine. Sedation with ketamine, with or without midazolam, was effective in all cases. Although data and details are sparse in this report, the authors conclude that no adverse events occurred from the pharmacologic interventions.

The authors state that combative trauma patients present many challenges and few alternatives to medical personnel. Essentially, only physical restraint, sedation, or paralysis and intubation are practical. Physical restraints have an obvious impracticality in trauma scenarios. Although haloperidol and droperidol have been commonly used, the authors believe that hypotension precludes widespread use in trauma patients. There is also the potential for QTC prolongation. Obviously, one would like to avoid paralysis and intubation because of its technical difficulty in the prehospital scenario and because it masks important physical signs.

Ketamine prevents the body from perceiving visual, auditory, or painful stimuli. It has a very rapid onset of action and a short duration, produces profound sedation and analgesia, and does not produce hypotension or depress respirations. Trauma victims in the Israeli army have been administered ketamine for many years, but marshaling its use for the prehospital care is a relatively new intervention.

The protocol that was developed allowed the use of IM ketamine (5 mg/kg) or IV ketamine (1 mg/kg). If sedation was not completely accomplished within minutes, midazolam (10 mg IV/5 mg IM) was added.

The wide safety profile of ketamine, including its potent anesthetic effects, rapid onset, absence of cardiac or respiratory depression, and short duration of action make this an ideal intervention. It is especially useful for the immediate control of the undifferentiated combative patient who may have life-threatening injuries or comorbid conditions. Midazolam may reduce emergence reactions, although it does not necessarily augment the sedative effectives of ketamine. The combination is supported by the authors as a routine protocol.

Comment: Problems with this report are a very small sample size and retrospective analysis. One would hope that a prospective version will appear soon. Using ketamine to gain control of the undifferentiated and violently agitated patient rapidly and completely seems like a no-brainer to me. I don't know why it is not used more often in the ED for this purpose. I have used ketamine a handful of times, but I don't use it routinely because it is foreign to the nurses and consultants and difficult to stock in the ED. It has not, therefore, become a common practice for this indication. I particularly like this article because prehospital personnel have limited resources and know even less about the patient than do emergency physicians; we at least have a bevy of nurses, monitors, and security personnel.

I have used ketamine numerous times for asthmatic patients who are just about to be intubated, when you can't keep them on the stretcher or keep the oxygen/albuterol mask on their face. If you try ketamine someday for a crashing asthmatic, you will be amazed that this about-to-arrest, acutely agitated, hypoxic patient suddenly lies back and continues to breath deeply at a rapid rate while the pulse oximeter rises and you make leisurely plans for an elective intubation. Minimal changes in blood pressure and pulse rate occur but usually for the better. For asthma, the additional bronchodilation effect of ketamine is theoretically helpful and may forestall intubation. I have even put intubated asthma patients on a ketamine drip, although it's always immediately discontinued in the ICU or in the ED by some nervous non-emergency physician.

These authors offer 11 ketamine references, mostly case reports that address the use, safety, and benefits of ketamine. I know of one fascinating report (I wrote it) that describes the successful use of ketamine in an undifferentiated delirious patient with cocaine toxicity. (J Trauma 2001;51:108.) I urge everyone to read the article by Hick and Ho (Prehosp Emerg Care 2005;9:85) where ketamine was used to rescue a combative delirious patient bent on jumping to his death. That report is quite informative and very innovative. I am unaware of any negative articles in the sparse literature, and any reader's personal experience would be welcome.

Ketamine appears to be the perfect solution to a 400-pound patient who is hell-bent on killing you or himself. Although police are now increasingly using the taser, perhaps they should use a ketamine dart instead. It works better, is just about as fast, and doesn't have the negative connotations of electrically shocking a troubled individual in front of a slew of onlookers, many of whom have cameras and are not particularly sympathetic to the police officer's plight.

Ketamine is one of the most commonly used anesthetics in the entire world, and it's often given with minimal to no monitoring, aside from clinical appearance. Its use in the ED for childhood procedural sedation is now routine. Emergency physicians should read the article by Reich (Can J Anaesth 1989;36:186) where the authors report 25 years of surgical experience with ketamine in the Pacific Islands. Surgery was performed on 886 patients without monitoring, essentially without complications. Of course, ketamine's most laudable characteristic is that it has no cardiovascular or respiratory depression, and it does not decrease airway protective reflexes. Ketamine also does not lower the seizure threshold.

Many clinicians discuss the concomitant use of atropine or glycopyrrolate (Robinul) to combat potential bronchorrhea and benzodiazepines to thwart emergent reactions. Both complications are overrated in my experience and according to the medical literature. Neither adjunctive medication appears to be routinely required or particularly beneficial. There seems, however, to be no standard of care regarding co-administration of either atropine/glycopyrrolate or a benzodiazepine. A separate syringe/injection is suggested, and ketamine is incompatible with diazepam in the same syringe. Concerns about ketamine increasing intracranial pressure are still extant, and head injury is a touted yet unproven relative contraindication. This Israeli study would certainly put that myth in question because many patients had traumatic brain injuries. Other studies have suggested no significant effect of ketamine on intracranial pressure. (Crit Care Med 2003;31:711.) My colleagues are hesitant to use it if PCP was the culprit for the craziness, but I don't see how that's a contraindication either.

Although benzodiazepines are probably the safest and most familiar method of rapid tranquilization, sometimes they just doesn't work. Some people get a paradoxical response, and others need nearly to be put into respiratory arrest before they will stop flailing, biting, or spitting. I have been disappointed with lorazepam but more enthralled with diazepam. Giving a benzodiazepine plus ketamine sounds fine to me, although benzodiazepines merely have a theoretical benefit for emergent reactions and do not affect the anesthetic action of ketamine.

Ketamine probably acts by interrupting the limbic and thalamic system, impairing consciousness while maintaining blood pressure and respiratory drive. This drug has been around since 1966, and it is especially popular as a surgical anesthetic in developing countries where minimal monitoring is available. Many an appendix has been removed under ketamine anesthesia in an operating room in some developing country. IM ketamine has its maximum effect in about three to four minutes, although you can usually see some sedative activity in the first 60 seconds. Intravenously, the drug works in less than a minute. When used for pediatric sedation, even the IM injection wears off in about 30 to 40 minutes. Ketamine is one cool drug that should be familiar to any EP.

The value or need of midazolam to reduce recovery agitation (aka emergence) following ketamine sedation, particularly for children, has been questioned, but many still use it. (Ann Emerg Med 2000;35:229.) So-called ketamine flashbacks are actually quite rare; I have never actually seen a patient with them. Our neurologists are obtaining great results for chronic pain (such as reflex sympathetic dystrophy) when they infuse ketamine for days. In short, there is no standard of care that requires benzodiazepines be given with ketamine, although ketamine's short duration of action lends credence to routinely using other IV medications once the situation is under control.

Ketamine candidates need not be NPO. Many children will vomit following ketamine, occasionally after they are sent home, so this should be conveyed to the parents. In hospitalized patients, vomiting is not an issue, and aspiration is not a complication of ketamine use. Many ED patients will, however, be intubated once the situation is stablized.

Laryngospasm and subsequent airway obstruction are the most worrisome side effects. I have not encountered either. They are usually mild, transient, and respond well to repositioning and oxygen, or occasionally to a brief period of positive pressure ventilation. Intubation is rarely required for this side effect. (Ann Emerg Med 1998;31:688.)

Monitoring, except for pulse oximetry, is not routine for procedural sedation with ketamine. Everyone will likely place patients on full monitoring following the use of ketamine for the undifferentiated delirious patient. Oxygen should be available, and suction, definitive airway equipment, and additional sedatives should be at the bedside. One should not panic if minimal laryngospasm occurs; just take a few minutes, and provide oxygen, a jaw thrust, and perhaps a bag/mask puff or two. Of course, one should have a low threshold for intubating these patients, but much more so for the underlying problems than for the complications of ketamine.

I see no reason why ketamine should not be a frequent flyer in the ED. If I were 10 years younger, I would do the study myself; perhaps a reader will take on that project.

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FDA Weighs In on Haloperidol

In previous columns, I have supported using IV haloperidol, usually in combination with a benzodiazepine, to treat acute agitation in the undifferentiated violently delirious ED patient. Such intervention has been used for years, is considered standard of care, and is administered on an almost-daily basis in most busy EDs. I personally have seen no problems from the dose of IV haldoperidol used for ED sedation, usually 5 mg to 20 mg, except perhaps for a mild dystonic reaction. Even those are very rare.

Physicians are, however, well aware of the droperidol issue in which the FDA, based on a few case reports that described scenarios generally irrelevant to emergency physicians, essentially doomed the use of droperidol because of associated sudden death and ventricular arrhythmias, usually QTC prolongation or Torsades de Pointes. A black-box warning ensued, causing many hospitals to ban droperidol altogether. The FDA has recently issued a warning on haloperidol, and I thought it useful to pass it along to readers.

The off-label use of any medication is common, and probably half of what we do with drugs in the ED does not have FDA approval. The IV use of haldoperidol is a perfect example. The FDA though it was wise to essentially halt the use of this very safe and effective medication based on a few case reports, and also highlight the fact that the IV administration is not FDA-approved. While one can debate the basic common sense of such actions, haldoperidol now joins the ranks of droperidol as pharma non grata.

I am sure there is a malpractice web site for this drug already established. This is indeed discouraging, and some would say overkill, but that's life in the big city. By the way, anyone can register for free at MedWatch.com: Sign up for automatic emails, and get a slew of daily warnings about recent drug-related issues. Your patients can access this information, and so should you.

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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. Dr. Roberts requests feedback on this month's column, especially personal experiences with successes, failures, and technique.

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FDA Recommendations for Using Haloperidol

The FDA noted that although injectable haloperidol is approved by the FDA only for intramuscular injection, intravenous administration of haloperidol is a relatively common off-label clinical practice, primarily for treating severe agitation in intensive care units. Due to a number of case reports of sudden death, Torsades de Pointes (TdP), and QT prolongation in patients treated with haloperidol (especially when the drug is given intravenously or at doses higher than recommended), the drug manufacturer updated the labeling for haloperidol. The updated warnings note that:

▪ Higher doses and intravenous administration of haloperidol appear to be associated with a higher risk of QT prolongation and TdP.

▪ Although cases of sudden death from TdP and QT prolongation have been reported even in the absence of predisposing factors, particular caution is advised in treating patients using any formulation of haloperidol who have other QT-prolonging conditions, including electrolyte imbalance (particularly hypokalemia and hypomagnesemia); who have underlying cardiac abnormalities, hypothyroidism, or familial long QT syndrome; or who are taking drugs known to prolong the QT interval.

▪ Because of this risk of TdP and QT prolongation, ECG monitoring is recommended if haloperidol is given intravenously.

▪ Haloperidol is not approved for intravenous administration.

The FDA noted at least 28 case reports of QT prolongation and TdP in the medical literature, some with fatal outcomes from the off-label intravenous use of haloperidol. The agency said these case-control studies demonstrated a dose-response relationship between intravenous haloperidol dose and subsequent TdP: “Based on this information, as well as the biologic plausibility of QT prolongation with intravenous haloperidol, [the] FDA has strengthened warnings in the haloperidol labeling with regard to the risk of TdP and QT prolongation with intravenous haloperidol use.”

At the request of the Pharmacovigilance Department of the Italian Drug Agency (AIFA), Johnson & Johnson performed two post-marketing analyses of QT interval prolongation and TdP with haloperidol administration (oral or injectable). In one analysis, a search of J&J's worldwide safety database for QT prolongation-related adverse event reports through June 30, 2005, identified 229 reports, many of which the drug company said had concomitant QT-prolonging drugs or medical conditions.

“The reports included 73 cases of TdP, 11 of which were fatal,” the FDA noted. “Eight of the eleven fatal cases involved intravenous administration of various doses of haloperidol.”

In March 2007, Johnson & Johnson submitted to the FDA the results of a second investigation that examined cardiac adverse events with haloperidol decanoate. It found 13 reports of TdP, QT prolongation, ventricular arrhythmias and/or sudden death. The FDA noted: “Based on case reports alone, we are unable to estimate the frequency with which QT prolongation or TdP occur following administration of these drugs.”

Source: www.fda.gov/medwatch/safety/2007/safety07.htm#Haloperidol.

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FDA Alert: Haloperidol

The Food and Drug Administration issued this alert in September 2007.

This alert highlights revisions to the labeling for haloperidol (marketed as Haldol, Haldol Decanoate, and Haldol Lactate). The updated labeling includes WARNINGS stating that Torsades de Pointes and QT prolongation have been observed in patients receiving haloperidol, especially when the drug is administered intravenously or in higher doses than recommended. Haloperidol is not approved for intravenous use.

To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program, and complete a form online at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided online, or by telephone to 1-800-FDA-1088.

© 2007 Lippincott Williams & Wilkins, Inc.