CE Article: Excited Delirium

Objectives

• Recognize excited delirium syndrome (ExDS);
• Describe the pathophysiology of ExDS;
• Know potential causes of ExDS;
• Describe the treatment of ExDS.

 "Medic 10 and Engine 201, respond to assist the police with a behavioral emergency."

You are midway through an otherwise-uneventful shift when the call comes in. As you respond the dispatcher confirms the scene has been secured by police. As you pull into the parking lot of an apartment complex, you are surprised to see a swarm of officers struggling to restrain a naked 26-year-old male. A police officer approaches and explains they were called about a man harassing people. "I saw him punch out the window of a parked car when I was pulling up," the officer explains. "I tried to talk to him and get him to calm down, but he didn't even seem to hear me. He started fighting us when we approached. I used my Taser to subdue him."

As you approach you notice the officers have cuffed the patient's arms behind his back and have him in a left lateral recumbent position. Two officers are trying to restrain his legs, while another is holding his upper body in place. The patient is screaming incoherently, attempting to fight against the restraints, and does not respond when you try to talk to him. You are unable to assess vitals but notice he is breathing rapidly and has hot, diaphoretic skin. There is a laceration on his right hand and arm. You direct the arriving firefighter/EMTs to place the patient on high-flow oxygen via nonrebreather mask.

"I think this is a case of excited delirium," you say to your partner.

"I agree," she replies. "Do you think we should sedate him?"

History and Controversy

Excited delirium syndrome (ExDS) is characterized by extreme agitation and aggression in a patient with altered mental status. Patients with ExDS display violent behavior, increased pain tolerance and superhuman strength. These patients are difficult to physically restrain and continue to struggle even once restrained. Because ExDS produces hyperthermia, patients are often found naked or inappropriately clothed with hot and diaphoretic skin. The sympathetic overdrive seen in ExDS also causes tachycardia and tachypnea. EMS providers must be able to recognize ExDS and initiate treatment because the syndrome progresses to cardiac arrest in an estimated 10% of cases.¹

Some definitions are helpful when thinking about excited delirium. Delirium is an acute and temporary change in cognition and mental status, during which patients exhibit disorientation, hallucinations, disorganized thinking, paranoia and delusions. It's a psychiatric condition seen in a variety of settings, not only excited delirium. For example, many patients in the ICU experience delirium. Delirium can be contrasted with dementia, which is a more long-term, chronic change in cognition.

Excited is a less well-defined term that is used to describe patients with uncontrollable and violent behavior.² Finally, a syndrome is a cluster of signs and symptoms that are commonly seen together and believed to have the same underlying cause. A syndrome is different from a disease because while the pathophysiology of a disease is known, the underlying cause of a syndrome is not understood. Putting these terms together provides a definition of excited delirium: a group of signs and symptoms that includes a transient change in mental status and cognition associated with uncontrollable and violent behavior.

Although EMS providers and emergency physicians have recognized and treated acutely agitated patients for decades, ExDS has only recently been recognized as a clinical entity. The syndrome was first acknowledged by medical examiners, who used ExDS as a diagnosis of exclusion to explain the deaths of severely agitated patients, often in police custody. The American College of Emergency Physicians officially recognized ExDs in 2009.³ Since then the syndrome has been integrated into EMS protocols and training. Currently the National EMS Education Standards include agitated delirium, an older term for ExDS, within the curriculum for EMS providers at the EMT, advanced EMT (AEMT) and paramedic levels.⁴

Some degree of controversy surrounds the diagnosis of ExDS. Because many patients with ExDS die while in police custody, civil liberties groups have raised concern that the diagnosis is used to conceal excessive use of force.⁵ The syndrome is not included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and the American Psychological Association has not yet decided whether to officially recognize it.⁵ Much about excited delirium remains unknown, and research into the syndrome's pathogenesis and optimal treatment is ongoing.

Pathophysiology and Triggers

The triggers for ExDS include drug use and psychiatric illness. In general the drugs that can cause excited delirium are stimulants or hallucinogens. Cocaine, methamphetamine, PCP and LSD are the traditional triggers.¹ New designer drugs, including "bath salts," a group of chemical compounds that can activate the sympathetic nervous system and produce psychotic behavior, and synthetic marijuana (often called "K2" or "spice") can also produce an agitated state.^6,7 A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, increase the risk of ExDS. Noncompliance with psychiatric medications, particularly abruptly ceasing antipsychotic medications, is thought to be a trigger too.

Cocaine is the prototypical drug associated with excited delirium. Cocaine-induced excited delirium became recognized during the cocaine epidemic of the 1980s, when there was a spike in cases of ExDS.⁸ Cocaine elicits its effect by increasing the amount of the neurotransmitter dopamine in the synapses between neurons in the central nervous system. Dopamine is the primary neurotransmitter in reward pathways, which is why taking cocaine produces euphoria. Cocaine is also a sympathomimetic drug, so it activates the sympathetic nervous system, producing tachycardia, tachypnea, hypertension, dilated pupils and increased alertness. Much of the research into the pathophysiology of ExDS has focused on the role of cocaine in triggering the syndrome.

The triggers for ExDS provide a framework for understanding the syndrome's pathophysiology. Patients with ExDS have excessive dopamine signaling in the central nervous system. Dopamine can affect the brain's temperature regulation system, so increased dopamine signaling could explain the hyperthermia seen in ExDS. Because both schizophrenia and cocaine are associated with alterations in central dopamine signaling, the dopamine explanation for excited delirium unifies these two causes.¹ More recent research has suggested that reactive oxygen species, which are highly reactive molecules of oxygen that cause tissue damage, might be generated in ExDS.⁹ Damage caused by these reactive oxygen species could be responsible for producing ExDS.

Cardiac Arrest, Acidosis and Other Sequelae

Excited delirium can cause acidosis, rhabdomyolysis and secondary trauma. In 10% of patients the syndrome results in cardiac arrest.¹ It is important for EMS providers to know the complications of ExDS in order to provide appropriate treatment and prevent patients from entering cardiac arrest.

Metabolic acidosis is a concern in ExDS. The precise mechanism for the acidosis is unknown, but exertion beyond normal physiological limits and the resulting lactic acidosis may be a cause.¹⁰ The body's compensatory response to metabolic acidosis is to increase the respiratory rate to "blow off" carbon dioxide. Therefore, restraining patients in positions that hinder ventilation could worsen the acidosis. In addition, the very act of restraining the patient, even in a position that does not compromise respiration, could trigger a worsening acidosis by provoking a fight-or-flight response and causing the patient to exert further energy struggling against restraints.

Rhabdomyolysis, the breakdown of muscles, is seen in ExDS.¹¹ The combination of hyperthermia, agitation and extreme exertion during ExDS is responsible. Fighting against restraints is another possible precipitating factor. As muscles are broken down and become necrotic, potassium is released into the circulation and can produce hyperkalemia. Additionally, acute kidney injury can occur from direct damage to nephrons caused by myoglobin released into the bloodstream. Hypovolemia is also common in rhabdomyolysis and results from the extravasation of fluid into the injured muscle.

When cardiac arrest occurs in ExDS, it is often preceded by a brief period of tranquility, where the previously agitated and violent patient suddenly becomes calm and lethargic. The cause of the cardiac arrest is not well understood and likely involves several factors. Positional asphyxiation, when patients are held in positions that restrict respirations during the restraint process, has been cited as one possible cause for sudden death in ExDS.¹² Positional asphyxiation is thought to occur when patients are placed in the prone position, hog-tied or have pressure applied to the chest or neck. Although research in healthy volunteers demonstrated that restrictive restraint positions did not produce hypoxia or hypercapnia, it did show that these restraint positions restrict pulmonary function.¹³ Patients with ExDS are different from healthy volunteers, and any restriction of ventilation in these already-acidotic patients might precipitate cardiac arrest. In patients with cocaine-induced excited delirium, the cocaine might have toxic effects on the heart and produce cardiac arrest via cardiotoxicity.¹² Long QT syndrome has been observed in some cases of excited delirium, and QT prolongation may be another possible cause of cardiac arrest in ExDS.¹⁴

Recognition and Differential Diagnosis

Signs and symptoms of ExDS are summarized in Figure 1. The hallmark of ExDS is agitation and violent behavior in a patient with altered mental status. Patients with ExDS often have superhuman strength, do not respond to physical compliance techniques due to increased tolerance to pain, and are highly resistant to physical restraint. On physical exam, patients will present with hyperthermia, tachycardia and tachypnea.

A variety of other medical conditions can produce symptoms similar to those seen in ExDS. The first step is to rule out alternative causes for altered mental status, including hypoxia, hypoglycemia, head trauma, infection and epilepsy. Consider heatstroke if it is a warm day. The anticholinergic toxidrome, which can occur after overdose on a variety of different over-the-counter and prescription medications, can produce agitation and hot skin and might mimic ExDS. Another important differential diagnosis is neuroleptic malignant syndrome (NMS), a neurologic emergency associated with antipsychotic (neuroleptic) medications that causes altered mental status, hyperthermia, tachycardia, tachypnea and muscle rigidity. Serotonin syndrome, caused by elevated serotonin levels in the central nervous system, produces similar symptoms to NMS and is another possible differential diagnosis. Infectious conditions such as meningitis and encephalitis should be considered. Finally, thyroid storm, a severe form of hyperthyroidism, can produce delirium, tachycardia and hyperthermia that could mimic ExDS.

Treatment

Scene Safety and Initial Approach

Scene safety is paramount when approaching patients with ExDS, and EMS must work with law enforcement to treat them safely. The combined effort of EMS and law enforcement to provide effective care to those with ExDS has been termed the "dual response."¹⁵ Law enforcement is essential for securing the scene and physically controlling the patient, reducing the risk to EMS as it initiates treatment.

When approaching a patient with suspected ExDS, law enforcement and EMS should attempt to verbally deescalate the situation. Verbal deescalation should be performed by one person to avoid confusing the agitated patient. During verbal deescalation, the responder should attempt to reassure the patient by using a calm tone of voice, short sentences and simple vocabulary.¹⁶ Sirens and other environmental factors that could further agitate or provoke fear should be minimized.

However, patients with ExDS do not typically respond to verbal deescalation and will usually require physical control by law enforcement. While EMS should stage until the scene is secured, it is important for EMS to access the patient expeditiously once the patient has been physically controlled to reduce the time the patient spends fighting against restraints. If feasible, EMS providers should coordinate with law enforcement before initiation of physical restraint and consider entering the scene as law enforcement begins the process of restraining the patient. Police departments and EMS agencies should preplan their response to patients with ExDS and consider performing interagency drills to hone their responses.

Physical Restraint

Although law enforcement has the primary responsibility for physically restraining patients with ExDS, there are several important considerations for EMS. Restraints should not be applied in a manner that restricts the patient's ability to breathe. The "hog-tie" position should never be used, and prone positioning should be avoided, as both of these restrict pulmonary function and hinder monitoring of airway and breathing. Responders must avoid compressing the neck or chest while restraining patients. Remember that restraints should never punitive, and no more force should be applied than is required to safely restrain the patient.

An effective method of physical restraint is applying four-point restraints in the "one-hand-up, one-hand-down" position. Place the patient supine on the cot with soft restraints applied to all four extremities. Use the "one-arm-up, one-arm-down" position while restraining the upper extremities. Secure one arm to the head of the cot and the other to the side. This positioning reduces the patient's ability to struggle against the restraints. Raise the head of the cot to lessen the risk of aspiration.

Sedation

Sedation is the primary treatment for ExDS. There are a variety of options for it, including benzodiazepines and ketamine. Antipsychotics can also be administered. In general select agents that act rapidly and can be administered intramuscularly or intranasally. Paramedics should have a low threshold for treating ExDS with sedatives, which should be administered early into the encounter.

There are several considerations when choosing the route for administering sedatives. Intravenous access should not be attempted on patients when they are acutely agitated because the risk of needle stick to EMS providers is high and the IV will likely become dislodged as the patient struggles. The risk of needle stick for intramuscular injection is likely lower than for initiating an IV. IM injections can be administered in many different sites and performed through clothing in an emergency. Benzodiazepines, ketamine and antipsychotics can all be administered IM. Midazolam can also be administered intranasally, which has the benefit of being needleless but involves placing the provider's fingers near the agitated patient's mouth. Therefore, the risk of a bite injury with IN injection should be weighed against the risk of needle stick with IM injection if both routes are permissible.

Benzodiazepines, including midazolam and lorazepam, are the mainstay of treatment for ExDS. These drugs are familiar to EMS providers because they are frequently used for controlling seizures and for sedation during painful procedures like cardioversion. While benzodiazepines are effective for sedating agitated patients, their use comes with several disadvantages. The onset of action of IM benzodiazepines can take up to 15 minutes, which is a long time to be struggling with an aggressive patient. In addition benzodiazepines can cause respiratory depression, so providers must carefully monitor respirations and be prepared to manage the patient's airway and breathing. Finally benzodiazepines have a long half-life, and administering multiple doses of midazolam in a short period of time could lead to a dose-stacking effect, where excessive sedation could occur many minutes after the doses are initially administered.

Ketamine is a dissociative anesthetic that provides analgesia, amnesia and sedation while preserving airway reflexes and blood pressure. Its medical uses include induction for intubation, procedural sedation and analgesia, and pain control. Given its wide therapeutic index and minimal side effect profile, it has been increasingly used for sedation of violent or agitated patients in the emergency department.¹⁷ For the violent or agitated patient, the recommended dose is 1–2 mg/kg IV or 4–5 mg/kg IM. Onset of action is roughly one minute for IV and 3–5 minutes IM. Duration of action is 10–15 minutes IV and 20–30 minutes IM. Side effects include transient tachycardia and hypertension, hypersalivation, laryngospasm and vomiting. Ketamine should not be used in patients with schizophrenia, as it can exacerbate psychotic symptoms.

As with any sedative agent, providers should be prepared for advanced airway control and treatment of hypoxia. In a prehospital study of 52 patients receiving IM ketamine for ExDS, three experienced significant respiratory depression, two of whom were intubated; notably all three had also received midazolam.¹⁸ Another study of 49 ExDS patients treated with IM ketamine in the field showed that 29% were intubated on ED arrival.¹⁹ While ketamine appears promising for prehospital ExDS treatment, the current evidence suggests caution be used, given the relatively high rate of intubation. Ketamine has repeatedly been shown to be among the safest of sedation agents with regard to apnea, hypoxia and hypotension when used in the emergency department for procedural sedation,²⁰ but more research is needed before it can become the clear treatment standard for ExDS in the field.

Antipsychotic medications are traditionally divided into first-generation (typical) and second-generation (atypical). These medications generally work by blocking dopamine receptors in the brain, the major difference being that second-generation antipsychotics also affect serotonin receptors and produce fewer extrapyramidal symptoms. Either Benadryl or Cogentin is frequently coadministered with these medications to reduce these symptoms. Haloperidol (Haldol) is the most commonly used typical antipsychotic and can be given IM at a dose of 5–10 mg. Droperidol is another first-generation antipsychotic, but its use has become limited after a controversial FDA black box warning regarding QT prolongation in 2001. Second-generation antipsychotics include olanzapine (Zyprexa) and ziprasidone (Geodon). Zyprexa can be given at 10 mg IM, but its prolonged time of onset of 15–45 minutes renders it less effective for the immediate sedation of the ExDS patient.²¹ Geodon is given at 10–20 mg IM and also has a longer onset of action. These medications may cause QT prolongation, and both carry an FDA black box warning against use in elderly patients with dementia-related psychosis.

Hyperthermia, Acidosis and Rhabdomyolysis

After achieving adequate sedation, the goals of treatment shift to providing care for the sequelae of the syndrome. As discussed above, these sequelae include hyperthermia, acidosis and rhabdomyolysis.

Fluid resuscitation is a key supportive treatment for ExDS. Because patients with ExDS are in a state of extreme exertion and hyperthermia, they are often dehydrated from diaphoresis.²² Administering IV fluids can help correct dehydration and treat rhabdomyolysis if present. Either Ringer's lactate or normal saline is an appropriate IV fluid. A 20-mL/kg fluid bolus is a suitable initial volume, but EMS providers should have a low threshold for administering additional boluses.

All patients with ExDS should be monitored for hyperthermia. If hyperthermia is suspected based on estimation from skin temperature or measurement with a thermometer, administer cooling. There are many possible approaches for cooling, including placing icepacks in the groin and axillae and administering cooled IV fluids.

If acidosis is suspected, sodium bicarbonate can be administered IV. Because acidosis is common in patients with ExDS, some EMS services advocate routinely administer 50 mEq (1 ampule) of sodium bicarbonate to all patients with excited delirium.²³ Sodium bicarbonate is also effective for treating rhabdomyolysis by limiting the toxicity of the products of muscle breakdown. Because patients compensate for metabolic acidosis by increasing their respiratory rate, EMS providers should be careful to ensure they are breathing adequately and be prepared to assist ventilations.

Monitoring and Ongoing Patient Care

Once the patient has been sedated and is safe to approach, they should be carefully monitored. Evaluate the airway, breathing and circulation. Perform a careful rapid trauma assessment and identify any possible secondary injuries the patient could have received either prior to EMS arrival or during the restraint process. Carefully monitor vital signs, including pulse oximetry and capnography. Obtain a 12-lead EKG and evaluate blood glucose levels.

Notify the receiving facility so they can prepare for the patient, including notifying security. Police should accompany the patient in the back of the unit, particularly if the patient is handcuffed.

Case Conclusion

You and your partner wisely recognize that the patient is suffering from excited delirium based on his altered mental status, agitation, violent behavior, extreme physical exertion, hot skin and tachypnea. Since the patient does not respond to attempts at verbal deescalation and continues to fight against restraints, you elect to sedate him.

You choose ketamine because of its faster onset of action than midazolam. Estimating the patient's weight, you draw up a 4 mg/kg dose and administer it intramuscularly into the lateral thigh. Within three minutes the patient is fully sedated. You place him on the cardiac monitor, obtain a 12-lead EKG and monitor SpO₂, and respirations with waveform capnography via nasal prongs. You continue the patient on 15 lpm oxygen via nonrebreather mask and have suction, appropriately sized airway adjuncts and a BVM at the ready in case he requires airway management or assistance with ventilations. You move the patient to your stretcher and, with the help of police, remove his handcuffs and replace them with four-point soft restraints in the one-arm-up, one-arm-down position.

With the patient sedated, his airway monitored and his extremities safely restrained in a position that does not compromise respirations, you move on to treating the potential sequelae of ExDS. Your partner initiates an 18g IV in the left antecubital fossa and administers IV fluid wide open. Meanwhile, you place icepacks in the groin and axilla to correct the patient's marked hyperthermia and perform a careful physical exam to identify any injuries. Finding only the laceration on the hand and arm, you bandage it and prepare for transport. Two police officers accompany you in the back of the unit, and you continue to carefully monitor the patient en route to a local hospital.

References

1. Vilke GM, DeBard ML, Chan TC, et al. Excited Delirium Syndrome (ExDS): defining based on a review of the literature. J Emerg Med, 2012 Nov; 43(5): 897-905.

2. Lipsedge M. Excited delirium: A psychiatric review. Med Sci Law, 2016; 56(2): 121-7.

3. ACEP Excited Delirium Task Force. White Paper Report on Excited Delirium Syndrome, https://www.fmhac.net/assets/documents/2012/presentations/krelsteinexciteddelirium.pdf.

4. National Highway Traffic Safety Administration. National Emergency Medical Services Education Standards, https://www.ems.gov/pdf/education/EMS-Education-for-the-Future-A-Systems-Approach/National_EMS_Education_Standards.pdf.

5. Jouvenal J. 'Excited delirium' cited in dozens of deaths in police custody. Is it real or a cover for brutality? Washington Post, 2015 May 6; https://www.washingtonpost.com/local/crime/existence-of-excited-delirium-ruling-in-va-womans-death-has-experts-split/2015/05/06/b1cc9499-ddaa-474c-9e8a-9ae89a9ae679_story.html?utm_term=.0ee72d43a05c.

6. Benzer TI, Nejad SH, Flood JG. Case records of the Massachusetts General Hospital. Case 40-2013. A 36-year-old man with agitation and paranoia. N Engl J Med, 2013 Dec 26; 369(26): 2,536-45.

7. Kesha K, Boggs CL, Ripple MG, et al. Methylenedioxypyrovalerone ("bath salts"), related death: case report and review of the literature. J Forensic Sci, 2013 Nov; 58(6): 1,654-9.

8. Ruttenber AJ, Lawler-Heavner J, Yin M, et al. Fatal excited delirium following cocaine use: epidemiologic findings provide new evidence for mechanisms of cocaine toxicity. J Forensic Sci, 1997 Jan; 42(1): 25-31.

9. Schiavone S, Neri M, Mhillaj E, et al. The role of the NADPH oxidase derived brain oxidative stress in the cocaine-related death associated with excited delirium: A literature review. Toxicol Lett, 2016 Sep 6; 258: 29-35.

10. Hick JL, Smith SW, Lynch MT. Metabolic acidosis in restraint-associated cardiac arrest: a case series. Acad Emerg Med, 1999 Mar; 6(3): 239-43.

11. Ruttenber AJ, McAnally HB, Wetli CV. Cocaine-associated rhabdomyolysis and excited delirium: different stages of the same syndrome. Am J Forensic Med Pathol, 1999 Jun; 20(2): 120-7.

12. Takeuchi A, Ahem TL, Henderson SO. Excited Delirium. West J Emerg Med, 2011 Feb; 12(1): 77-83.

13. Chan TC, Vilke GM, Neuman T, Clausen JL. Restraint position and positional asphyxia. Ann Emerg Med, 1997 Nov; 30(5): 578-86.

14. Bozeman WP, Ali K, Winslow JE. Long QT syndrome unmasked in an adult subject presenting with excited delirium. J Emerg Med, 2013 Feb; 44(2): e207-10.

15. Roach B, Echols K, Burnett A. Excited Delirium and the Dual Response: Preventing In-Custody Deaths. FBI, https://leb.fbi.gov/2014/july/excited-delirium-and-the-dual-response-preventing-in-custody-deaths.

16. Richmond JS, Berlin JS, Fishkind AB, et al. Verbal De-escalation of the Agitated Patient: Consensus Statement of the American Association for Emergency Psychiatry Project BETA De-escalation Workgroup. West J Emerg Med, 2012 Feb; 13(1): 17-25.

17. Hayes BD. Ketamine for Excited Delirium Syndrome. Academic Life in Emergency Medicine, https://www.aliem.com/2015/ketamine-for-excited-delirium-syndrome/.

18. Scheppke KA, Braghiroli J, Shalaby M, Chait R. Prehospital Use of IM Ketamine for Sedation of Violent and Agitated Patients. West J Emerg Med, 2014 Nov; 15(7): 736-41.

19. Burnett AM, Peterson BK, Stellpflug SJ, et al. The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. Am J Emerg Med, 2015 Jan; 33(1): 76-9.

20. Bellolio MF, Gilani WI, Barrionuevo P, et al. Incidence of Adverse Events in Adults Undergoing Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis. Acad Emerg Med, 2016 Feb; 23(2): 119-34.

21. Lulla A, Singh M. The Art of the ED Takedown. emDocs, https://www.emdocs.net/the-art-of-the-ed-takedown/.

22. Vilke GM, Bozeman WP, Dawes DM, Demers G, Wilson MP. Excited delirium syndrome (ExDS): treatment options and considerations. J Forensic Leg Med, 2012 Apr; 19(3): 117-21.

23. Miami-Dade Fire Rescue. Medical Operations Manual, https://mdsceh.miamidade.gov/mobi/moms/Protocol%2039.pdf.

Alexander Ordoobadi is a medical student at Harvard Medical School. He also volunteers as a medic with the Bethesda-Chevy Chase Rescue Squad in Montgomery County, MD. Contact him at Alexander_Ordoobadi@hms.harvard.edu.

Sean M. Kivlehan, MD, MPH, NREMT-P, is the associate director of the International Emergency Medicine Fellowship at Brigham and Women's Hospital and faculty at Harvard Medical School. He was also a New York City paramedic for 10 years. E-mail him at SMKivlehan@bwh.harvard.edu.