More than haldol

Clinical Scenario:
You are working in the ED when you see EMS roll in with the all too common "SNF" patient. An 83 yo M with the alphabet soup of co-morbid conditions. HTN, dCHF, OSA, COPD, V-tach s/p AICD, non IDDM, CKD stage III who presents the the ever ubiquitous chief complaint of altered mental status.   The patient was reported to be "off" by staff at the nursing facility, he was seen by a psychiatrist who was concerned about delirium and advised the patient be reevaluated in the ED.  Upon arrival the patient is AOx3, conversant, and pleasant.  He gets a delirium workup that is fairly unremarkable with the exception of a UA showing weak evidence of UTI. The patient is admitted to the medicine but boards in the busy ER overnight.  During his stay he becomes agitated and uncooperative.  He is now AOx1 (person) and cannot be redirected.  His thoughts are incoherent and the patient will not return to his gurney.  You make the decision to administer IV haloperidol.  The patient relaxes, is able to be redirected. 

A few hours later several family member approach you about the decision to use Haldol. They are educated, with a large amount of experience in the psychiatric field.  They ask if you are aware of the neurotoxic effects of haloperidol and emphasize the use of newer atypical antipsychotics which are neuroprotective.  You admittedly aren't that up to date on this topic, but assure them that haloperidol is used frequently at our institution for acute delirium.  You perform a brief literature review. 

Limited literature review:
You read the reference provided by the family member, which is an editorial from an online psychiatry journal citing that 28 different studies have shown neurotoxic effects of older antipsychotics based on animal models, cell culture, and post-mortem human tissue.  The author instead calls for the use of the 9 atypical antipsychotics to be used as they have reported neuroprotective properties such as neurogenesis. (1) The main difference you note is that the author comes from the perspective of using antipsychotics for long term care, while in the ED we want safe and rapid control for delirium or agitation in the short term. 

Haldol structure,

In your review you find the American Association of Emergency Psychiatry released a consensus statement/guidelines on the treatment of acute agitation in the ED.  

Here are some highlights:
1.       Prior to giving meds consider verbal redirection and nicotine replacement
2.       1st gen antipsychotics inhibit dopamine and is structurally similar to GABA
3.       When using haloperidol remember it can prolong QT (rare), cause extrapyramidal side effects (possibly as high as 20%,why it is often given with lorazepam which reduces to 6% incidence).
4.       Haloperidol is not FDA approved for IV administration (PO, IM only), although it is commonly administered this way.
5.       Second generation antipsychotics have long been preferred by outpatient psychiatrist for long term management of various psychiatric conditions. 
6.       2nd gen antipsychotics include:
a.       Olanzapine (Zyprexa), ziprasidone (Geodon), aripiprazole (Abilify) – IM and PO
b.      Risperidone (Risperdal), and quetiapine (Seroquel) – PO only
7.       2nd gen antipsychotics also antagonize dopamine, but also serotonin as well
8.       There have been very few head to head trials of 2nd generations versus Haldol.  
a.      However one double blind, placebo study compared both IM olanzapine and IM Haldol for agitation and showed that IM olanzapine reduced agitation significantly more than IM Haldol 15, 30, and 45 minutes following the first injection (2)
10.   Two studies have been conducted comparing PO risperidone and lorazepam versus IM haloperidol and lorazepam.  Data showed similar benefits to both regimens.  However, both were conducted at Psychiatric emergency centers and not typical EDs. (3)
11.   Their final recommendation for agitation associated with delirium:
a.       Oral 2nd generation
b.      Oral 1st generation
c.       IM 2nd generation – olanzapine 10 mg or ziprasidone 10- 20 mg
d.      IM or IV 1st generation
12.   Peak concentration for PO meds is fairly similar to IM with exception of olanzapine (6h for PO)
13.   IM meds peak concentration is approx. 15-45 minutes for both classes

The consensus statement does not discuss the “neurotoxic” effects of haloperidol previously mentioned in the editorial citing non-living human studies. 

Take home points:
So which agent do you use? The theoretical neurotoxic effects of haloperidol seems to be more of a potential issue for long term psychiatric disease.  ED concerns should focus on causing extrapyramidal side effects or excess sedation.  The data for 2nd generation antipsychotics use in the ED  is limited, however there is some data to show their efficacy in controlling of acute agitation. 

Expert Commentary:
Dr. Holthaus Comments: Nice summary Dr. Miller!  The one additional consideration I wanted to share about carte blanche 5/2 (Haldol/Ativan) for all comers is the potential clinical “down time” (ranging anywhere from 3-6+ hours depending on comorbidities/age/habitus/co-ingestants) and its impact on prolonging ED LOS while “waiting” for the patient to recover enough to allow a formal psychiatric interview and then to make the final disposition decision (all compounding time in series). 
     Potential alternate ways around this in my opinion are to 1) Ask psychiatry to evaluate them while acutely psychotic (if available/present and safe) then administer the 5/2 and get labs/etc. allowing an earlier psychiatric disposition to be made as medical etiologies are ruled out in parallel.  2) If psychiatry is unavailable or it's unsafe then consider giving something else that has less back side down time but can achieve a similar up front clinical effect: adequate onset time/calming-sedating enough to allow restraints/seclusion/redirection and at least 1-2 hours for lab-imaging acquisition/results, is safe (and titratable if more is needed), and allows a potentially earlier metabolic window for mental clarity/off set that is amenable to a formal psychiatric interview.  This is in my mind, preferably midazolam (or diazepam if no midazolam) with an IV onset less than 5min, can be quickly/safely titrated to effect, and can also be given IM.  Granted bezodiazepines can potentially worsen delirium but generally if they’re shorter acting and less likely to be hanging around this makes this less likely to persist.  I agree benzos do not directly address their psychosis like the anti-psychotics but my counter-argument would be that these could be administered later if still needed.  Don’t get me wrong, I have no problem with 5/2 but I like it best after a disposition is made (and it also carries the added advantage of making the nurses happier in regards to behavior management and puts people out of their misery while waiting forever for a bed).  However, I will think twice now after Dr. Miller’s analysis and consider more second generation use if using antipsychotics for acute agitation management.

Submitted by Christopher Miller,  PGY-2
Edited by Louis Jamtgaard, PGY-3 @Lgaard
Faculty Reviewed by Chris Holthaus


2) Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158:1149-1151.

3) Wilson et al. The psychopharmacology of agitation: consensus statement of the american association for emergency psychiatry project Beta psychopharmacology workgroup. West J Emerg Med. 2012, 13(1), 26-34.

Additional References:
Currier et al. J Clin Psychiatry. 2004, 65(3), 386-94.

Wilson et al.  Despite expert recommendations, second-generation antipsychotics are not often prescribed in the emergency department.  J Emerg Med. 2014, 46(6), 808-13.

Hitting the bottle hard, beyond benzos for AWS.

Clinical Scenario:
It’s the age old story, chronic alcoholic evaluated for an unrelated issue, cleared from that issue only to now have developed alcohol withdrawal. The patient in question is a middle aged male with heavy alcohol use history who was transferred from another center for specialist evaluation. After being cleared by the consultant, he is now 24 hours from his last drink and looks decidedly not well. He is tremulous, tachycardic, anxious, and vomiting. You recognize his alcohol withdrawal, but despite treatment, he rapidly worsens requiring very high doses of benzodiazepines and an ICU admission. What adjunct therapies are available for severe alcohol withdrawal?

Synapse in AWS (© 2015 Cynthia Turner
Alcohol abuse is an exceedingly common problem and alcohol-related ED visits are encountered daily across the country.  Annually, around 500,000 episodes of acute alcohol withdrawal require treatment. The symptoms typically begin to manifest within hours to days after cessation of alcohol and typically peak at 2 – 3 days.  The clinical course of alcohol withdrawal varies widely among patients.  Chronic alcohol use leads to down-regulation of GABA receptors and up-regulation of NMDA glutamate receptors. Additionally, GABA receptor expression is suppressed. In the active drinker, this allows patients to maintain a normal level of consciousness despite blood alcohol levels that would incapacitate a nondrinker. Withdrawal is therefore, associated with a decrease in GABAergic activity and an increase in glutaminergic activity. The increase in excitatory activity and loss of inhibitory activity results in the symptom complex of alcohol withdrawal. Symptoms include autonomic hyperactivity, tremor, insomnia, nausea/vomiting, hallucinations (commonly visual or tactile in addition to auditory), psychomotor agitation, anxiety, generalized tonic-clonic seizures. Benzodiazepines are the standard of care for alcohol withdrawal. Adjunct therapies of old have targeted adrenergic symptoms, not so much the underlying disease. These include beta-blockers and calcium channel blockers. Other more targeted therapies like gabapentin are hindered by prolonged onset of action. Adjuncts that make a bit more sense pharmacologically and are gaining popularity include barbiturates, ketamine, and dexmedotomidine.  Let’s look at some of that data.

Literature Review:

Phenobarbital?! What is this the dark ages? Phenobarbital has a rapid onset and long duration of action, with a half-life of 80 – 120 hours. Barbiturates stimulate the GABA receptor and may augment the efficacy of benzodiazepines – so it makes sense.  A retrospective cohort study by J. Gold et al at Bellevue described success with an alcohol withdrawal treatment protocol that used phenobarbital as the primary adjunct. In this protocol, increasing bolus doses of benzodiazepines (in their case primarily diazepam) were given in a symptom-based manner. If symptoms were not controlled with these measures, phenobarbital was added to the mix. All of their patients were admitted to the ICU specifically for alcohol withdrawal. They found that their 24hour diazepam dose, maximum individual dose and use of phenobarbital increased after protocol initiation. With these increases, they also observed a reduction in the need for mechanical ventilation and non-significant trends towards improved ICU length of stay and nosocomial infections.

What about everyone’s favorite drug of the moment, ketamine? Well, it might be good for this too! (Is there anything it can’t do?) Ketamine is an NMDA antagonist. Remember that this is the other system that has been screwed up by chronic alcohol use. A pharm paper by Wong et al out of UPMC describes a retrospective review of patients treated in their ICU for alcohol withdrawal with ketamine. In their 23 cases, they found that after initiation of ketamine infusions, patients’ benzodiazepine requirement at 12 and 24 hours decreased. Sedation scores and alcohol withdrawal scores were stable despite the decrease in benzodiazepine administration. Their median infusion dose was 0.2mg/kg/hr and on average, was continued for just over 2 days. They do note that ketamine does increase heart rate and blood pressure, which can pose challenges in treatment titration.

Dexmedetomidine, a cousin to clonidine, has anesthetic, anxiolytic, analgesic and sympatholytic effects. A case series of 10 patients with severe alcohol withdrawal treated in the ICU with dexmedetomidine (J DeMuro et al) described improvements in vital signs but these improvements did not reach statistical significance. They noted no change in the rate of adverse events despite addition of dexmedetomidine to multiple other agents including bolus dose benzodiazepines, beta-blockers, antipyschotics and propofol. They also noted that dexmedetomidine allowed lower doses of other agents, thereby reducing the risk of respiratory depression with large doses of benzodiazepines, argue their authors. Additionally, they add to the literature that documents safe use of dexmedetomidine far past the FDA approved 24 hour window. The decreased need for benzodiazepines with dexmedetomidine use was echoed by S. Mueller et al. They performed a randomized, double-blind placebo controll trial comparing high dose dexmedetomidine, low dose dexmedetomidine, and placebo. They noted no difference in sedation scores despite greater reduction in benzodiazepine requirements in the dexemedetomidine group.

An important eye in the sky point to take away from a lot of this literature is don’t be stingy with the benzos. These folks have seriously mucked up their brain chemistry and may need an alarming amount of medication. Just taking the literature we’ve reviewed here, DeMuro describes benzodiazepine dosing in the 10 cases used in his series as 2mg lorazepam Q6hrs or 1mg midazolam Q4 hours and reports an average ICU LOS of 9.3 days. Compare that to the 24 hour totals in the Gold paper of over 500mg diazepam (around 50mg lorazepam) with their average ICU LOS of 3.21 days. Far from an apples to apples comparison, but a striking point.

Take home points:
So we end with another age old story. This time we answered the question we asked in the beginning only to find ourselves with more. Yes there are adjuncts to benzodiazepines that may improve clinically important outcomes like intubation, ICU length of stay, and complication rate. However, each of these has it’s own appeal and downsides, and there is no clear winner. So the next time you approach that patient with severe alcohol withdrawal, think back to some of this literature. Use strategies that have been shown to improve outcomes – symptom based and aggressive early benzodiazepine dosing. Beyond that, use of adjuncts looks like a good idea. Choosing a particular adjunct will likely be a multifactorial decision and include factors like availability, cost, and your own comfort with a particular agent. Plus, if your alcohol withdrawal patient is this sick, it might be time to call your friendly, neighborhood toxicologist.

Submitted by Sara Manning, PGY-3@EM_SaraM
Edited by Louis Jamtgaard, PGY-3 @Lgaard
Faculty reviewed by Evan Schwarz @TheSchwarziee 

DeMuro, JP et al, “Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: a retrospective case series” 2012. Journal of Anesthesia. Vol. 26(4); pp. 601-605.
Gold, JA et al, “A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens.” 2007. Critical Care Medicine. Vol. 35(3); pp. 724 – 730.
Goldfrank et al, Goldfranks Toxicologic Emergencies, 8ed. 2006. McGraw-Hill.
Mueller, SW et al, “A Randomized, Double-Blind, Placebo-Controlled Dose Range Study of Dexmedetomidine as Adjunctive Therapy for Alcohol Withdrawal.” 2014. Vol. 42; pp – 1131 – 1139.
Wong, A et al, “Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome.” 2015, Vol. 49(1)pp 14 – 19.

Droperidol the psycho dropper or heart stopper?

Clinical Scenario:
You are working a typical EM-1 shift loaded full of psychiatric patients, EMS brings you another agitated male with a history of schizophrenia. He is shouting absurdities and threatening staff members.  The RN glances over at you, 5/2 doc? You're feeling a little different today and order 10mg of droperidol IM. The drug is administered and the patient calms down. With pride you present the patient to your attending. Your attending is alarmed and immediately requests an EKG and places the patient on a cardiac monitor and tells you the patient is in imminent danger of converting into torsades de pointes (TdP) secondary to prolonged QT.  You perform a rapid review of the literature.

Literature Review:
Droperidol is a butyrophenone that has been used since the mid 1970's primarily for acute agitation but it has also found a role in treating nausea, headaches, and abdominal pain. In 2001, droperidol received a black box warning by the FDA because of its association with QT prolongation and potential fatal arrhythmias.
FDA Black Box warning

There is no consensus as to what degree of QT prolongation is clinically significant, but several papers have cited QT longer than 500ms or delta QT of 60ms as at risk for TdP. (1) Mechanistically, in animal models Droperidol has been shown to both block efflux of myocardial potassium and induce early depolarization in cardiac fibers. Human studies have shown varied results, but lean towards droperidol causing some degree of prolonged QT without clinically significant arrhythmias. (2) 

 Lischke et al performed a randomized, double blind study on 40 patients undergoing cardiac surgery that were given either 7 mg,12.5 mg, or 17.5 mg of droperidol prior to surgery. Serial ECGs were obtained and QT prolongation ranged from 37 to 59ms in all groups in a dose dependent manner, however there were no recorded dysrhythmias or fatal events. (3) Again, Guy et al performed a prospective study in 55 patients who received 0.25mg/kg of droperidol prior to surgery, mean QT increased by 24ms, however no arrhythmias were noted. A 2014 prospective study by Calver involved continuous Holter monitoring for 24hrs in patients who had received 10-30mg IM of droperidol for acute agitation. Four out of 46 patients had abnormal QT greater than 480ms, but only one case was temporally associated with droperidol administration.  No arrhythmias were recorded. (4)  Kao et al reviewed decades of published literature including multiple systematic reviews and randomized controlled trials with outcome measures specifically observing for adverse effects of droperidol, and none cited any cases of fatal arrythmias. (1)

 Kao et al reviewed the FDA surveillance data cited by the FDA as cardiac events related to droperidol administrations, and found that the case reports were plagued by confounders and failed to show causation between droperidol administration and fatal arrhythmias.   Many of the European studies cited by FDA used doses of 50 -100mg IM, significantly higher than doses typically used in the US.  
Kao et al FDA surveillance data

Furthermore, similar case studies are described with haloperidol another commonly used antipsychotic.  

Take home points:
Bottom line is there are no randomized trials that demonstrate that droperidol causes fatal arrhythmias, there is data to show the droperidol prolongs QT in a likely clinically insignificant manner. There are rare case reports that suggest cardiac events might be associated with droperidol administration, but most cases involve confounders and cannot demonstrate causation.  Therefore it is likely reasonable to administer droperidol in most cases without any type of cardiac monitoring. However use of droperidol in this manner falls outside of FDA approval, therefore it is likely reasonable to take some precations (EKG or cardiac monitoring) in high risk groups (ESRD, severe cardiac disease) or consider alternative agents.  

Submitted by Louis Jamtgaard PGY-3 @Lgaard
Faculty reviewed by Evan Schwarz @TheSchwarziee

  1. Kao LW Droperidol, QT prolongation, and sudden death: what is the evidence? Ann Emerg Med. 2003 Apr;41(4):546-58.

  1. JM Guy, X Andre-Fouet, J Porte, et al. Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol [in French] Ann Cardiol Angeiol (Paris), 40 (1991), pp. 541–545

  1. V Lischke, M Behne, P Doelken, et al. Droperidol causes a dose-dependent prolongation of the QT interval Anesth Analg, 79 (1994), pp. 983–986

  1. Calver LBr J Clin Pharmacol. 2014 May;77(5):880-6. doi: 10.1111/bcp.12272. High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings.