By Bryan Jarrett/Ian deSouza
(Presented in conference by Raul Hernandez)
The Case
A 49 year-old man was found laying on bedroom floor by his family, covered in his own feces and urine. He was verbal but also confused and combative and had to be restrained by 2 emergency response teams after he attempted to punch a medical technician. His family reported a past medical history seizures.
Pre-hospital Course: 10mg midazolam IM was administered
Initial ED assessment and interventions: Very agitated, persistent tachycardia
| 5 min | 21 min | 22 min | 35 min | 90 min | Shortly after |
| 70mg IM Ketamine | 4mg IV Lorazepam | 4mg IV Lorazepam | 4mg IV Lorazepam | 140mg IV Ketamine | Rocuronium, intubated,
Propofol drip |
Further history: Pacemaker (unknown reason), R MCA stroke, seizures (nonadherent with meds), recent hospitalization for similar presentation 1 month prior
Exam:
HR 119, RR 26, BP 83/38, T 100.3, FS 121
No signs of trauma, pinpoint pupils, no nystagmus
No clonus or spasticity, moving all extremities before sedation
Workup:
ECG: Sinus tachycardia
VBG with pH 7.03, lactate 4.5
CBC: WBC 16.9
HCT: No acute findings, old R MCA stroke
CSF: 8 WBCs, high glucose and low protein
CXR: Bibasilar atelectasis and small L pleural effusion
ED and Hospital Course:
Patient was presumed to have been post-ictal and loaded with fosphenytoin. He was given empiric antibiotics for healthcare-related pneumonia (after purulent sputum was suctioned) and meningitis (vancomycin + ceftriaxone + pipercillin/tazobactam + acylclovir). The patient was admitted to the MICU and then extubated on HD2. He completed antibiotic course for healthcare-related pneumonia and was discharged at his baseline on HD8.
The Discussion
Agitated Delirium
Agitation may be defined as “a temporary disruption of the typical physician-patient collaboration, which interferes with assessment and treatment, during a period when immediate assessment and treatment are needed”. Agitated patients need to be calmed or restrained for adequate evaluation and treatment.
What are the medical causes of agitation?- Head Injury
- Intoxication/Adverse drug reaction
- Hypoxia
- Hypoglycemia
- Infection
- Hyper/Hypothermia
- Seizure/Post-ictus
- Stroke/Intracranial Hemorrhage
What is the initial approach to the agitated patient?
- Assess what you can from the patient, EMS, and family
- Appearance
- Mental status/orientation
- Psychiatric history
- Medications/intoxicants
- Look for signs of agitation
- Motor restlessness
- Heightened response to internal or external stimuli
- Irritability/hostility/anger
- Inappropriate or purposeless verbal or motor activity
- Rage/property damage
- Attempt to de-escalate the situation
- ALWAYS keep staff safety in mind
- Use a quiet, secure area
- Let the person talk
Physical and chemical restraints should be employed to:
- Prevent harm to the patient
- Prevent harm to other patients
- Prevent harm to caregivers or staff
- Prevent serious disruption of environment
- Assist in assessment or management of patient (NOT for convenience for staff)
Physical restraints (should always used in conjunction with chemical restraints)
Use 1 person for each limb and the shortest period of time possible. Perform frequent re-assessment for neurovascular events and assess the continued need for restraint.
What is the evidence for the chemical sedation of agitated patients?
Benzodiazepines & Antipsychotics
Benzodiazepines and antipsychotics are currently the most commonly used agents either alone or in combination. A Cochrane review of 21 RCTs has examined the efficacy of different drugs used for agitation in the setting of psychosis:[i]
- Benzodiazepine vs Antipsychotic: No difference other than increased extrapyramidal side effects with antipsychotics alone
- Benzodiazepine PLUS Antipsychotics vs one agent alone: No difference other than increased sedation with combination
- Benzodiazepine PLUS haloperidol was inferior to olanzapine or ziprasidone alone → if known psychosis, 2nd generation antipsychotics may be superior
There were very little good data, as the trials small and of varying quality. But, there are subtleties that can be gleaned from these RCTs.[ii],[iii],[iv] Midazolam generally provided more rapid sedation but also resulted in more respiratory depression and oversedation. However, the need for intubation was rare.
Ketamine
There are few studies examining ketamine as a primary agent.
Ketamine’s benefit is its rapid onset (~2 min vs. ~10-15 min for benzodiazepines or antipsychotics). This is particularly important in patients with severe excited delirium who are at risk for respiratory failure or sudden cardiac death[v]. The only prospective trial was a recent pre-hospital study of 146 patients:[vi]
- Compared 5mg/kg IM ketamine vs 10mg IM Haldol
- Ketamine provided a faster onset but higher complication rate (49% vs 5%, see below)
Ketamine is effective for initial control of agitation, but many (up to 60%) may require additional dose/medications[vii]. On the contrary, it may be useful as a rescue drug for agitation that is refractory to other traditional sedatives.
- In previously mentioned study,[vii] there were 8 cases where multiple doses of benzodiazepines and antipsychotics did not resolve agitation; however, only one dose of ketamine then provided sedation for 3 hours
- In 49 patients given 10-30mg droperidol who then had residual agitation, 90% were adequately sedated with 4-6mg/kg IM ketamine[viii]
What are the adverse effects associated with ketamine?
Reports vary widely, and pre-hospital studies show significantly more complications than studies from the ED. The determination of need for intubation seems to have been very subjective, and this complication rate is likely subject to bias. In one study, the intubation rate was 39% with ketamine vs 4% with haloperidol. The indications for intubation were:
- “not protecting airway” (32%)
- hypersalivation (16%)
- agitation/apnea/aspiration (12% each)
- laryngospasm/seizure/trauma
Another pre-hospital study[ix] with same ketamine dose reported a 29% intubation rate. The indications were:
- “not protecting airway” (50%)
- continued agitation (14%)
- laryngospasm/hypoxia (2% each)
In this second study, in-hospital intubation was associated with higher doses (mean of 6.1mg/kg vs 4.9mg/kg)
In contrast to these pre-hospital trials, most data from procedural sedation or anesthesia literature has reported very few serious complications:
- A systematic review of >600 procedural sedations with ketamine alone reported 1 case laryngospasm, no intubations, 14% agitation, 1% apnea (compared with 4% apnea with midazolam alone)[x]
- Another meta-analysis of 87 studies – mostly anesthesia-based – reported: 1 significant cardiorespiratory event (hypoxic arrest) out of 70,000 patients induced with 4-6mg/kg IM of ketamine. They did note that there were transient episodes of apnea within first 5 min of administration[xi]
- The rates of emergence reaction vary widely.
- The most complications are actually reported in children. A study of 8282 children reported 0.26% laryngospasm, 3.9% adverse respiratory events with no intubations, 1.4% clinically relevant agitation (higher rate with sub-dissociative doses), and 8.4% emesis[xii]
So…….in summary, for the undifferentiated, agitated patient:
- Attempt verbal de-escalation first and physical restraint if necessary with particular attention to safety of staff and patient
- Some basic information may be helpful when selecting an agent for chemical sedation
- Psych history
- EtOH intoxication suspected
- If there is a psych history, then an antipsychotic is likely the best choice, with the available evidence supporting PO olanzapine and ziprasidone first and IM droperidol or haloperidol as secondary options
- If EtOH intox is suspected, be cautious using benzodiazepines as the combined GABA receptor agonism may lead to respiratory depression
- For now, first-line therapy is still IM antipsychotics (mostly droperidol) +/- benzodiazepine; however, large studies and meta-analyses do not demonstrate a significant benefit of using them in combination
- Ketamine has two specific roles:
- Refractory to alternative sedation techniques
- Need for rapid sedation (can then add longer-acting agents)
- Ketamine is safe for use in the ED with the following adverse events:
- Laryngospasm – uncommon (<1%) and usually does not require intubation
- Emergence reaction – common (~15%), but easily treated before or during agitation with subsequent long-acting benzos
- Emesis – common (~15%), almost always after emergence and there is low aspiration risk
And finally, ALWAYS monitor and frequently reassess the patient after initiating physical restraints and/or administering chemical sedation!
References
[i] Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013 Apr 30;(4):CD003079.
[ii] Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010 Oct;56(4):392-401.e1.
[iii] Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Ann Emerg Med. 2006 Jan;47(1):61-7.
[iv] Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med. 2005 Dec;12(12):1167-72.
[v] Takeuchi A, Ahern TL, Henderson SO. Excited Delirium. Western Journal of Emergency Medicine. 2011;12(1):77-83.
[vi] Cole JB, Moore JC, Nystrom PC, Orozco BS, Stellpflug SJ, Kornas RL, Fryza BJ, Steinberg LW, O’Brien-Lambert A, Bache-Wiig P, Engebretsen KM, Ho JD. A prospective study of ketamine versus haloperidol for severe prehospital agitation. Clin Toxicol (Phila). 2016 Apr 22:1-7.
[vii] Hopper AB, Vilke GM, Castillo EM, Campillo A, Davie T, Wilson MP. Ketamine use for acute agitation in the emergency department. J Emerg Med. 2015 Jun;48(6):712-9
[viii] Isbister GK, Calver LA, Downes MA, Page CB. Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2016 May;67(5):581-587.e1.
http://lifeinthefastlane.com/behavioural-emergencies/
[ix] Burnett AM, Peterson BK, Stellpflug SJ, Engebretsen KM, Glasrud KJ, Marks J, Frascone RJ. The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. Am J Emerg Med. 2015 Jan;33(1):76-9.
[x] Bellolio MF, Gilani WI, Barrionuevo P, Murad MH, Erwin PJ, Anderson JR, Miner JR, Hess EP. 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.
[xi] Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med. 2008 Nov;26(9):985-1028.
[xii] Green SM, Roback MG, Krauss B, Brown L, McGlone RG, Agrawal D, McKee M, Weiss M, Pitetti RD, Hostetler MA, Wathen JE, Treston G, Garcia Pena BM, Gerber AC, Losek JD; Emergency Department Ketamine Meta-Analysis Study Group. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009 Aug;54(2):158-68.e1-4.
And
Green SM, Roback MG, Krauss B, Brown L, McGlone RG, Agrawal D, McKee M, Weiss M, Pitetti RD, Hostetler MA, Wathen JE, Treston G, Garcia Pena BM, Gerber AC, Losek JD; Emergency Department Ketamine Meta-Analysis Study Group. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009 Aug;54(2):171-80.e1-4.
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