CE Article: Excited Delirium—A Case Review

Objectives

Upon conclusion of this course, students will be able to:

• Define the hallmarks of excited delirium syndrome;
• Understand the IMCRASS scoring system of agitation;
• Differentiate sedation options and their applications;
• Articulate the symptoms and signs of toxic encephalopathy.

Pittsburgh Medic 3 was dispatched to a residence for a woman who had reportedly overdosed and was possibly seizing. Upon arrival the crew found a 36-year-old woman sitting on the floor in an upstairs bedroom. The patient was conscious and alert but disoriented and appeared postictal. 

A friend on scene said the patient had been sitting down when she suddenly experienced full-body tonic-clonic seizurelike activity that lasted 3–5 minutes. The friend further stated that when the seizure activity stopped, the patient became unresponsive, stopped breathing, and developed cyanosis. At that time the friend administered two 4-mg doses of intranasal naloxone and called 9-1-1. There was no immediately visible evidence to suggest an opioid overdose, but the friend said she suspected it. 

Initial assessment of the patient revealed the following vital signs: pulse 124, respirations 20 and nonlabored, SpO₂ 98%, blood pressure 130/palp., and blood glucose 80 mg/dL. The patient’s skin was flushed and diaphoretic, and her temperature was 97.3ºF temporally. The patient appeared confused but adamantly denied ingesting illicit drugs or alcohol. The crew noted the patient had been incontinent of urine. The patient was slightly agitated and refused to don the surgical mask the crew provided to her. The patient’s initial Improved Montgomery County Richmond Agitation Sedation Scale (IMCRASS) score was +1. She was able to stand and ambulate with minimal assistance, and the crew assisted her to the unit, where she was placed on the stretcher. 

The crew attempted to administer supplemental oxygen via nasal cannula for comfort, and the patient suddenly became extremely agitated and violent. She was incoherent, punching, kicking, and attempting to bite the crew. The crew was unable to deescalate the situation, and the patient’s IMCRASS score was now +4. The crew was no longer able to safely continue to treat or transport the patient. They administered 5 mg midazolam to no effect. They followed five minutes later with a second 5-mg IM dose, but the patient continued to be extremely agitated. A third dose was administered five minutes after that. The patient’s IMCRASS score remained +4, and it took four crew members to secure her on the stretcher with straps and soft restraints. The crew noted tachycardia and tachypnea but was still unable to assess further due to the patient’s ongoing agitation. 

Transport and Hospital

After the patient was secured, the crew established IV access with a 20-g angiocatheter in her right forearm and initiated a normal saline bolus. They contacted online medical command and requested orders for additional sedation using ketamine. After discussing the case the MD agreed to the crew’s request. The crew administered 50 mg of IV ketamine. Her condition didn’t change, and after five minutes the MD approved another 50 mg. 

After that the patient became less combative. Her postsedation IMCRASS score was +2. The crew was able to administer supplemental oxygen and monitor the patient. They placed her on the cardiac monitor, and she exhibited a sinus tachycardia at a rate of 104 bpm, blood pressure of 98/54 mmHg, SpO₂ of 98%, EtCO₂ of 23 mmHg, and respiratory rate of 33. They continued the fluid infusion wide open and transported the patient to the hospital. Throughout the approximately 10-minute transport, the patient required ongoing physical restraint.

Upon arrival at the emergency department, the patient was transferred to a bed and her care to the staff. The patient remained agitated, and the ED staff administered multiple doses of a variety of sedatives, including midazolam, haloperidol, diazepam, and ketamine. She received a total of 10 mg Haldol, 10 mg Versed, 140 mg Valium, and 100 mg ketamine in divided doses. Her urine drug screen was positive for opiates, cocaine, amphetamines, and methadone. She was diagnosed with toxic encephalopathy, likely related to the precipitated opioid withdrawal from naloxone exacerbated by concomitant sympathomimetic drug toxicity, and rhabdomyolysis. She was admitted to the hospital and underwent aggressive IV fluid therapy. The patient’s acute toxicity resolved with supportive care without evidence of deleterious long-term impact. Acute kidney injury secondary to rhabdomyolysis resolved, and renal function stabilized. The patient remained amnestic to all the events.

Discussion

The rapid escalation of this patient’s agitation and delirium was sudden and unexpected. My partner and I were caught off guard, and that surprise informed our response for the duration of the incident. In retrospect it appears the patient was suffering from excited delirium syndrome (ExDS) related to sympathomimetic drug toxicity and possibly acute opioid withdrawal. 

According to the American College of Emergency Physicians’ 2009 white paper on the topic, excited delirium syndrome is defined by psychomotor agitation, hyperthermia, and acidosis.¹ The characteristic behaviors associated with ExDS include pressured, loud, and/or incoherent speech; disorientation; rapid onset over a short period of time; labile emotions; inappropriate thought content for the circumstances; hallucinations; and flight of ideas/tangential thinking. 

While ExDS has been recognized for more than 100 years, it remains poorly understood.² It is a rare syndrome and typically occurs in the presence of psychiatric illness with concomitant stimulant drug ingestion. The mortality rate for ExDS is high, with some patients dying while in custody and being physically restrained. These deaths are frequently attributed to acidosis and or positional asphyxiation. In most cases where cardiac arrest occurs secondary to ExDS, it is irreversible even when emergency providers are immediately available. 

The IMCRASS Scale

While ExDS is not well described, extreme agitation is relatively easy to identify when it occurs in front of you. This identification can be a subjective process, but the IMCRASS system (Figure 1) is a useful tool for categorizing the patient’s agitation. 

This scoring system categorizes agitation on a scale of 0 (alert and calm) to +4 (extremely combative). It also is used to score sedation, and that goes from 0 to -5 (unarousable and potentially needing airway management and ventilatory support). This standardized approach for quantifying the patient’s level of agitation and sedation is useful for communicating with medical command and receiving facility staff as well as documentation. 

Additionally, the patient’s IMCRASS score can be used to drive clinical decision-making in the field. According to the Pennsylvania ALS protocol for excited delirium, patients with IMCRASS scores of +1 or +2 can be given midazolam for sedation, and those with IMCRASS scores of +3 or +4 can receive ketamine.³ For sedation it is recommended to use 0.1 mg/kg of IM midazolam and/or 4 mg/kg of IM ketamine. Midazolam is a strong benzodiazepine and when given in high doses may cause respiratory depression and hypotension. Ketamine is a dissociative anesthetic and causes few hemodynamic changes even when given to ExDS patients. 

In this case I chose midazolam as the initial sedative because it is the primary treatment modality for seizure patients in our system. We could have used ketamine based upon the patient’s +4 IMCRASS score, and it is possible a single higher dose of ketamine given first would have achieved a more adequate level of sedation. If we had used ketamine first, the patient would have been dosed with 400 mg IM. Two 50-mg doses of ketamine were administered because it was given IV and the patient had already received three doses of midazolam. The decision to administer ketamine after Versed was made with input from online medical command and done cautiously, with acute awareness of potential adverse reactions such as respiratory depression and airway compromise. 

Judicious Use

Once sedation was achieved, the patient was watched closely, and her EKG, SpO₂, waveform EtCO₂, and blood pressure monitored. This is important for all patients who have been sedated, especially those who have received large doses of multiple agents, because if respiratory depression and/or airway compromise occurs, it must be recognized immediately. The necessary interventions, including supplemental oxygenation, airway management, and positive-pressure ventilation, must be rapidly deployed to prevent hypoxemia, hypercapnia, and cardiopulmonary collapse. 

Toxic encephalopathy is characterized by changes in cognitive function, level of consciousness, and vigilance secondary to a toxic exposure. Toxic encephalopathy can be associated with agitation, seizures, and tremor as well as potential underlying long-term neurologic injury from cerebral hypoperfusion. The incidence of toxic encephalopathy after administration of naloxone is extremely rare.⁴ Opioid withdrawal is not independently associated with delirium or seizures. If delirium and toxic encephalopathy occur following administration of naloxone, it is typically associated with rapid administration of high doses of naloxone and/or co-occurring stimulant toxicity. Additionally, rare incidences of adverse pulmonary outcomes following prehospital reversal of opioid toxicity with naloxone are also associated with higher doses.⁵ 

This experience highlights the need for EMS to use naloxone judiciously and administer only the doses needed to restore the patient’s respiratory drive. In most overdose cases, even those involving fentanyl and its analogs, 0.4 mg of IV naloxone will be sufficient to achieve this. Overdose victims given excessive doses of naloxone by well-intentioned lay rescuers should be monitored closely following initial reversal, with a low threshold to transport them to an ED for evaluation. 

Rhabdomyolysis is caused by the breakdown of skeletal muscle. This breakdown leads to the release of myoglobin and other toxins, including potassium from the injured cells, which damages the kidneys and contributes to systemic acidosis. Among ExDS patients rhabdomyolysis is common. In the setting of significant agitation, it is thought to be caused by psychomotor hyperactivity and struggling against physical restraint. The metabolic acidosis and hyperkalemia associated with extended motor agitation and muscular cellular injury likely contribute to the cardiac arrest so often seen among this cohort. Once sedation is achieved, IV access must be prioritized. Large boluses of isotonic solution will help prevent the most deleterious effects of rhabdomyolysis. If significant metabolic acidosis is suspected, sodium bicarbonate can be considered. 

Conclusion

ExDS can occur in unexpected situations. Today the use of illicit opioids, especially fentanyl and its analogs, is increasing. Synthetic opioids may be produced with little to no regulation or quality control mechanisms. This creates a situation where the drugs being used on the street can have great variability in potency and effect. People may not even be aware they are using drugs adulterated with fentanyl or one of its analogs. 

It is incredibly uncommon for a patient who has overdosed solely on opioids to become agitated and combative after receiving naloxone. However, when patients who have used opioids like fentanyl as well as sympathomimetic agents such as amphetamines or cocaine are then given naloxone, the sedative effects of the opioids are blocked, and it is possible the stimulating effects of the other drugs are potentiated. While this appears to be the etiology of this case, it is anecdotal and needs to be validated by further research. 

While it is often unclear, it appears that in most cases opioids and sympathomimetic drugs are used separately. In rare instances they have been combined, and the people using them may not even be aware. In September 2019 a group at a party in Pittsburgh used what they thought was cocaine. It had been adulterated with fentanyl. Seven overdosed, three died.⁶ 

Additionally, the process of sedation is not binary, and in cases like this standard treatment paradigms may not be effective. EMS providers must approach these incidents with a patientcentric mentality. This can be extremely difficult when the patient is agitated and combative, but unnecessary physical restraint and positional asphyxiation must be avoided at all costs. 

The sedation of patients with ExDS and extreme agitation is necessary and can be done safely in the field. Agencies must have robust and validated training programs that teach providers to identify the appropriate situations for the use of sedative medications using tools like the IMCRASS score. There must also be well defined standards for physical restraint, medication administration, postsedation monitoring, documentation, follow-up, and case review.  

References

1. DeBard ML, Adler J, Bozeman W, Chan T, et al.; ACEP Excited Delirium Task Force. White Paper Report on Excited Delirium Syndrome. ACEP, 2009; www.acep.org/globalassets/uploads/uploaded-files/acep/clinical-and-practice-management/ems-and-disaster-preparedness/ems-resources/acep-excited-delirium-white-paper-final-form.pdf.

2. Mash D. Excited Delirium and Sudden Death: A Syndromal Disorder at the Extreme End of the Neuropsychiatric Continuum. Front Physiol, 2016; 7: 435.

3. Pennsylvania Department of Health. Excited Delirium Statewide ALS Protocol (Optional), www.stems.us/wp-content/uploads/2018/08/PA_ALS_8002.pdf.

4. Clark AK, Wilder CM, Winstanley EL. A systematic review of community opioid overdose prevention and naloxone distribution programs. J Addict Med, 2014 May–Jun; 8(3): 153–63.

5. Farkas A, Lynch MJ, Westover R, et al. Pulmonary Complications of Opioid Overdose Treated With Naloxone. Ann Emerg Med, 2020 Jan; 75(1): 39–48. 

6. Associated Press. Pittsburgh authorities identify 3 who died in suspected mass overdose. NBC News, www.nbcnews.com/news/us-news/pittsburgh-authorities-identify-3-who-died-suspected-mass-overdose-n1057526.

7. American College of Medical Toxicology. Ketamine statement, 2020 Sep 28; www.acmt.net/_Library/Positions/Ketamine_sedation_and_law_enforcement.pdf.

Simon Taxel, BA, NRP, is a crew chief and public safety diver with the Pittsburgh Bureau of EMS and a contributing author to multiple EMS platforms.