ToxCard: Dexmedetomidine & Ketamine in Toxicologic Causes of Agitation
Authors: Jacob Leedekerken, MD (Emergency Medicine Resident, Carolinas Medical Center, Charlotte, NC); Kathryn T Kopec, DO (Emergency Medicine Attending, Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: Cynthia Santos, MD, (@CynthiaSantosMD), Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)
A 22-year-old male presents to the emergency department (ED) via EMS acutely agitated following an unknown ingestion. He is currently yelling at staff and swinging wildly at security officers. Patient has not been responsive to verbal de-escalation. Vitals are unable to be obtained secondary to his agitation.
- Is ketamine or dexmedetomidine safe to use in acutely agitated patients secondary to toxicologic causes?
- What is the evidence on using ketamine or dexmedetomidine successfully in the toxicologic agitated patient?
The ideal pharmacologic agent for controlling agitated patients is often debated. Ketamine and dexmedetomidine are two newer drugs that are starting to be used more frequently in the management of agitation in the emergency department.
Dexmedetomidine is a highly selective alpha-2 adrenoreceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic properties . Sedative effects are secondary to the alpha-2 agonism in the locus coeruleus, whereas the analgesic effects stem from alpha-2 receptors in the central nervous system and spinal cord . It was originally approved for less than 24-hour sedation of mechanically ventilated patients in the ICU and then subsequently for sedation of non-intubated patients prior to and/or during procedures . However, off-label uses continue to expand given its advantageous properties.
- Sedative Effects:
- Found to be non-inferior to midazolam and propofol for light/moderate sedation in mechanically ventilated patients in MIDEX and PRODEX trials .
- Has demonstrated to have decreased the need for ventilation support by 20% and decreased ICU stay by roughly 14% .
- Has ability to facilitate sedation without neurologic depression allowing for serial neurological exams if needed .
- Cardiovascular Effects:
- Bolus dose may induce hypertension
- Often causes hypotension and bradycardia, however, with minimal clinical effects
- Secondary to decreased catecholamine release and unopposed vagal activity 
- The potential hypotension and bradycardia associated with dexmedetomidine has made it the agent of choice in cases with hypertension and tachycardia secondary to toxicological causes [6,7,8,9,10].
- Respiratory Effects:
- Minimal to no respiratory depression .
Ketamine is an NMDA receptor antagonist. It also causes nitric oxide synthase inhibition, limits reuptake of various neurotransmitters and binds to a variety of receptors including opioid receptors and muscarinic receptors . Ketamine’s NMDA antagonism decreases glutamate excitatory transmission. This main mechanism of action along with its’ effects on other pathways has been shown to have promising clinical effects such as: producing a “dissociative” state, sedation, and analgesia. These effects occur without clinically significant effects regarding respiratory depression or hypotension.
- Sedative Effects:
- Demonstrated successful use of acute agitation secondary to psychiatric disease or drug intoxication .
- Has demonstrated a shorter time to sedation in comparison with midazolam, haloperidol, lorazepam, or a combination of benzodiazepine and haloperidol [13,14].
- Cardiovascular Effects:
- Increases in blood pressure and heart rate are frequently seen but rarely clinically significant [15,16].
- Respiratory Effects: 
- Not associated with respiratory depression
- Potential use for bronchodilation/anxiolysis in asthma exacerbation
- Low incidence of laryngospasm
Given the aforementioned effects of both ketamine and dexmedetomidine, it is understandable why they are both being used in the treatment of the agitated patient. Ketamine has been gaining popularity as a chemical sedative for acute, undifferentiated agitation and dexmedetomidine as an adjunct sedative. These agents have the potential to be ideal agents for agitation control in patient populations that have a high incidence of mental health disorders or overdose on respiratory depressants, such as opiates or benzodiazepines.
What research has been published on the use of ketamine or dexmedetomidine in regard to their benefit or safety in agitated patients from toxicological causes?
Dexmedetomidine has demonstrated safety and agitation control in cases of cocaine , methamphetamines , dextromethorphan , MDMA , methylphenidate , serotonin toxicity [6,19,20], anticholinergic toxicity [8,21] and alcohol/opioid withdrawal [22,23,24]. Dexmedetomidine was used as a sedative adjunct in these cases and assisted with resolution of hypertension, tachycardia, and hyperthermia. No adverse effects, such as respiratory depression, were noted.
There are limited studies specifically looking at the use of ketamine for toxicologic emergencies, however, there are multiple studies of its successful use in the acute undifferentiated agitated patient. It has also been documented as an adjunct for the treatment of alcohol withdrawal syndrome (AWS).
- A 2018 systematic review of ketamine’s use in agitated patients found that 40.4% of patients had a discharge diagnosis of substance use .
- Multiple studies in adolescents and adults have demonstrated effectiveness and faster control of agitation with ketamine [12,13,14].
- Associated with reduced GABA agonist requirements, shorter ICU stays, and lower incidence of intubation in ICU patients diagnosed with delirium tremens .
- Selective alpha-2 adrenoreceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic properties.
- Potential adjunctive therapy for control of agitation from toxicological syndromes secondary to its respiratory sparring sedation and sympatholytic properties.
- Major adverse effects are bradycardia and hypotension, which can be actually be beneficial in severe agitation.
- NMDA receptor antagonist
- Use in AWS has potential advantages including reduction of GABA agonists, ICU length of stay, and decreased intubations.
- Beneficial for acute agitation given its quick onset of sedation compared to commonly used sedatives such as: midazolam, haloperidol, and lorazepam.
- Adverse effects: hypersalivation, emergence delirium/hallucinations, and nausea/vomiting.
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