Dean Olsen, DO Director, Medical Education and Emergency Medicine Residency Nassau University Medical Center Faculty, New York City Poison Control Center Professor, Toxicology NYIT College of Osteopathic Medicine 1
Financial None Conflicts of interest None
Define and characterize agitated delirium Identify patients with agitated delirium Understand the complications of agitated delirium Review the data on pharmacologic management of excited delirium Develop a stepwise approach for treatment
Excited (or agitated) delirium is characterized by agitation, aggression, acute distress and sudden death Patients are unaware of their surroundings A transient disorder with impairment of attention and cognition. The patient has difficulty focusing, shifting, or sustaining attention. Confusion may fluctuate
Excited delirium first described in the mid 1800 s Bell s mania Lethal catatonia Acute exhaustive mania Agitated delirium Described first in psychiatric patients Mania Fever Death 75% mortality Sequence of events delirium with agitation (fear, panic, shouting, violence and hyperactivity), sudden cessation of struggle, respiratory arrest and death
ACEP Excited Delirium Task Force White. 2009
ACEP Excited Delirium Task Force White. 2009
Sudden unexpected death is the hallmark of fatal excited delirium. Multiple theories Increased catecholamine levels Increased serotonin levels Increased dopamine levels Hyperthermia Stress cardiomyopathy Arrhythmia / Long QT Positional asphyxia
Average Body Temperature 105.2F Forensic Sci Int. 2009 Sep 10;190(1-3):e13-9.
Sudden death Associated with multiple predictable but usually uncontrollable factors Many die at scene and probably can not be saved If they get to the ED alive, don t kill them Respiratory Depression Almost always the result of the treatment
Restriction of breathing due to improper positioning of restrained patient SIDS Contributory in sudden death of excited delirium
Psychiatric [Functional] Non-psychiatric [Organic] Medical Toxicologic Approximately 2/3 have organic etiology
The most common cause of agitation prehospital and in the ED is drug/alcohol use.
Stimulant and Psychostimulant use- drugs that alter dopamine processing, and temperature regulation Alcohol Alcohol withdrawal Cocaine Amphetamines Phencyclodine (PCP) Designer amphetamines Xtc Bath salts Synthetic cannabinoids LSD Anticholinergics
Intracranial bleeding Meningitis / encephalitis Stroke Thyroid Storm Hypoglycemia Hypoxia Shock
Marzuk P, et al. JAMA. 1998;279:1795-1800
20
21
Restraint (physical and chemical) Oxygen Dextrose Examinations (physical, Temperature, labs ECG) Observation Serial assessment Thanks Bob Hoffman, MD NYCPCC
Poorly studied Selection bias Most not representative of true excited delirium Unclear pharmacology Imperfect endpoints Safety monitoring less then perfect
Time to sedation? Or Time to rectal temperature Time to iv access Time to fingerstick glucose Time to ecg Time to proper monitoring
Largest blinded study to date (1997) on combination intramuscular Ativan / Haldol therapy in the emergency department Included all patients with psychosis Used multiple doses of both drugs alone and in combination Concluded that combination therapy is more effective than either alone
Problems Excluded all patients with ethanol Excluded patients with delirium!! No objective evaluation of agitated patients Authors used a psychiatric rating scale A minority of patients (10%) had stimulant abuse (not confirmed) Most patients had schizophrenia Long sedation times This was really a study of psychosis patients NOT excited / agitated delirium
Lorazepam (Ativan) is should be avoided in intoxicated patients Pharmacodynamics make this drug high risk for use in patients who are intoxicated 15 min peak effect 1-3 min peak effect with midazolam
Randomized blinded study of IM administration 5mg Droperidol vs 5mg Midazolam vs 20mg Ziprasidone Primary endpoint was time to sedation Secondary endpoints Disposition Need for rescue medication / additional sedation
Midazolam sedated patients faster Midazolam patients woke up faster Ziprasidone patients took longer to sedate and remained sedated longer
Conclusion more patients remained agitated at 15 minutes with ziprasidone relative to the other agents, and patients receiving midazolam more frequently required additional sedation Population all alcohol intoxication (90%) 1/3 with head injury No temperature Stimulant use underrepresented No QT monitoring No data on dose equivalency Not convinced authors have a clear focus on consequential factors
Ann Emerg Med 2006; 47: 61-67 Double blind trial Midazolam vs Droperidol 5mg intravenous Repeated q5min till sedation Primary outcome time to sedation Secondary outcomes Need for subsequent sedation QT
Conclusions Midazolam sedated more people at 5 min Drugs are equal at 10 min Midazolam produced a little more respiratory depression Problems No information on baseline agitation No baseline agitation score No temperature Not powered to determine safety
Ann Emerg Med. 2010; 56: 392-401 Randomized blinded study IM therapy 10mg of single agent or 5+5 combo Primary endpoint -time to sedation Secondary endpoints time to additional medication, oxygen desaturation [90%], airway obstruction requiring intervention tracheal intubation cardiac arrhythmias prolonged QT interval, hypotension, extrapyramidal side effects
No Adverse Event Adverse Event
Time to sedation similar for midazolam and Droperidol Drug related adverse events higher in Midazolam group and sedation times are shorter midazolam, particularly through the intramuscular route, has unpredictable effects and a high rate of adverse reactions in this setting. Basically they are telling us if you give benzos to people who are intoxicated they have airway related events
This is mostly a study of belligerent intoxicated patients (75% midaz group) Alcohol intoxicated vs alcohol related Stimulant abuse underrepresented No information on baseline agitation No baseline agitation score No temperature How well does this represent our population? Not powered to determine safety To study adverse event that occurs 1 in 50 would have to have sample size of several hundred
Ann Emerg Med 2013; 61: 72-80 Double blind study Midazolam (2.5-5mg) + droperidol (5mg) intravenous vs. Midazolam + Olanzapine (5mg) Intravenous vs. Midazolam (2.5-5mg) alone Primary outcome Time to sedation Proportion of patients sedated at 5 and 10 min Secondary outcome Need for additional drugs Need of re-sedation at and after 60 min Total midazolam dose Qt and adverse events
2 drugs worked faster than one drug of the same dose Droperidol and olanzapine equal at 5 and 10 min Midazolam alone and with droperidol produced slightly more adverse events ECG s were on only gotten on slightly more than half of the patients so we cant say much about qt Data on change of qt not provided
No information on baseline agitation No baseline agitation score No temperature Used a small dose of midazolam Many patients were triaged as non critical Long times between triage and when seen by provider No data on qt issue Safety can not be determined
[Ann Emerg Med. 2016;-:1-9.] Randomized controlled double blinded trial Combination therapy midazolam-droperidol (5mg/5mg) vs mono therapy of antipsychotics intravenous (10mg) Repeat doses were given Primary endpoint- proportion of patients sedated at 10 min Secondary endpoints Time to sedation Need for more sedation QT
Combination drug therapy more effective at rapid sedation and less need for repeat dosing Problems No information on baseline agitation No baseline agitation score No temperature EKG s only done on half the patients No dose equivalency data Long triage times
[Ann Emerg Med. 2015;66:230 238.] Prospective observational study looking at QT and efficacy of droperidol Over 1000 patients 13 abnormal QT s No torsades de pointes Sampling bias Underpowered to determine association between droperidol and TDP
Lower seizure threshold Interfere with the ability to dissipate heat QT prolongation Not good for head injuries Can worsen arrhythmias
This is difficult to study rigorously Data are lacking There is more than 1 way to skin a cat Haldol and Ativan has not been studied in agitated delirium Benzos and antipsychotics work either alone or when used together Midazolam works faster All agitated patients are not the same Belligerent alcoholic Psych patient who is haldolopenic Stimulant abuse / etoh withdrawal Newer antipsychotics have not been shown to offer any clear benefit over older ones Benzos + alcohol = respiratory depression
Dissociative medication No respiratory depression Problems: Causes catecholamine release Can worsen psychosis
Ketamine sedation is effective and safe in agitated patients with a psychiatric illness in the aeromedical setting and does not lead to worsening agitation in the subsequent 72-h period. (Emerg Med J 2012;29:335) Article didn t look at excited delirium Retrospective Has nothing to do with excited delirium
Case Report Review of Ref 4 Review Case Series Case Report Case Report
Unblinded retrospective chart review of paramedic runs where ketamine was used for sedation 53 patients given 4mg/kg IM No baseline characteristics of patients Little information on what happened in the ED with this population Very low quality data [West J Emerg Med. 2014;15(7):736 741.]
Clin Toxicol (Phila). 2016 Aug;54(7):556-62 Prospective observational study unblinded 5mg/kg ketamine IM vs Haldol 10mg IM Primary Outcome Time to sedation Secondary outcomes Need for repeat dosing Adverse effects Intubation
Mean time to sedation Ketamine 5 min Haldol 17 min Adverse Events Ketamine 49% Haldol 5% Intubations Ketamine 39% Haldol 4%
Ketamine worked faster Almost half of Ketamine patients had adverse events 40% wound up intubated Problems Doses were not equivalent Minority of patients had stimulant use Patients were not severely agitated
Data are insufficient to recommend ketamine alone or in combination with other agents at this time in undifferentiated excited delirium Be careful of people who try to suggest otherwise
Haloperidol / Lorazepam Haloperidol / Lorazepam / Diphenhydramine Never studied in severe agitation Make little pharmacological sense Admission of a lack of understanding
Can you tell the difference between: Psychiatric agitation Cocaine intoxication Alcohol intoxication Alcohol withdrawal
2/3 die at the scene or during transport by paramedics or police >80% involve alcohol Must direct treatment strategy
Restraint (physical and chemical) Oxygen Dextrose Examinations (physical, Temperature, labs ECG) Observation Serial assessment Thanks Bob Hoffman, MD NYCPCC
Supine positon Handcuffed Butterfly net or mesh bag Patient may then be rolled to the side facing away from provider to obtain IV Vein in forearm accessible in handcuffed patients
Ease and safety vs guaranteed absorption These patients all need IV access anyway Sometimes must start with IM
Rapid onset Rapid Peak Rapid offset No prerequisite Safe in undifferentiated cases
1. Stimulant or psychostimulant Intoxicated 2. Belligerent alcoholic patient 3. Noncompliant psychiatric patient 4. Agitated and none of the above
Psychotic or emotional Antipsychotic Cocaine / amphetamine / psychostimulant / ethanol withdrawal Benzodiazepine Alcohol Intoxication Antipsychotic or maybe ketamine Unknown- Keep it safe Benzodiazepine Dose Midazolam 10mg Haldol 5-10 mg Diazepam 20
Agitated delirium can be fatal Drugs and alcohol are a common cause complicating pharmacological management Hyperthermia is common Properly restrain patients Not all agitated patients are the same Tailor your drug therapy to the etiology When you don t know, benzos are probably safest to use
Questions Ecstasy causes SIADH Check serum sodium before hydrating these patients If you need help- call the poison center 84