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, wikipedia.org

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.       1^st 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.       2^nd gen antipsychotics include:

a.       Olanzapine (Zyprexa), ziprasidone (Geodon), aripiprazole (Abilify) – IM and PO

b.      Risperidone (Risperdal), and quetiapine (Seroquel) – PO only

7.       2^nd gen antipsychotics also antagonize dopamine, but also serotonin as well

8.       There have been very few head to head trials of 2^nd 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 2^nd generation

b.      Oral 1^st generation

c.       IM 2^nd generation – olanzapine 10 mg or ziprasidone 10- 20 mg

d.      IM or IV 1^st 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 2^nd 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

References:

1) http://www.currentpsychiatry.com/specialty-focus/schizophrenia-other-psychotic-disorders/article/haloperidol-clearly-is-neurotoxic-should-it-be-banned/194f71df8139c102e153b6839a066424.html

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 cynthiaturner.com)

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.

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.

Brought in By Ambulance #5: Chemical Takedown - IM Ketamine for Prehospital Restraint

Clinical scenario: You are working the overnight shift in the Emergency Department (ED) when a pre-arrival for "agitation" pops up on the board.  You see EMS roll by with several police officers and decide that you should follow.  On the stretcher lies a partially clothed, basically unresponsive patient who is maintaining a respiratory rate of 10 and oxygen saturation of 88% on room air.  As you quickly slap on the oxygen, check the patient's response to pain with a sternal rub, see an end-tidal CO2 reading of 35, and contemplate intubation, EMS starts to provide their signout.  The paramedics responded to a call for "altered behavior" and were confronted with a psychotic, agitated, diaphoretic patient who would likely fit the description of Excited Delirium Syndrome (ExDS).  The patient quickly ran at and jumped on a paramedic.  The paramedics, fire department, and police restrained the patient who required multiple doses of Haldol and Ativan to facilitate transport.  As you further assess the patient, you wonder, "is there a better way to chemically restrain a patient that maximizes the safety of EMS providers and patients?".  As the patient's sats improve to 98%, you realize that you have some time to think. You have recently heard about prehospital use of IM ketamine for just this purpose and decide to review the evidence.

Practical exercise:  Calculate the IM Ketamine dose to takedown the Incredible Hulk.

Literature Review:
In 2011, the term "Excited Delirium Syndrome (ExDS)" was coined to describe the clinical syndrome referred to in different venues as "agitated delirium", "excited delirium", or "Sudden Death in Custody Syndrome".   The American College of Emergency Physicians (ACEP) convened a task force to define the spectrum of the syndrome which has the following clinical features [1,2]:

                   - hyper-aggressive or bizarre behavior, including lack of clothing
                   - lack of sensitivity to pain
                   - hyperthermia
                   - diaphoresis
                   - attraction to light or shiny objects

The exact etiology of ExDS is unknown, but there is a strong association with pre-existing psychiatric disease (in particular, schizophrenia) and drugs of abuse (cocaine, methamphetamine, and PCP) [2].

Most importantly,  ExDS conveys a high risk of mortality, in the realm of 10% [1,2].  The exact cause of death is not completely clear, but is thought to arise from severe acidosis or hyperkalemia, and is usually the end result of physical struggle or restraint.  Agitated, combative patients also pose a risk to prehospital providers.  Follow this link to watch a video of ExDS from presentation to death. 

Multiple pharmacologic therapies for chemical restraint of patients with ExDS have been suggested, from anti-psychotics, to benzodiazepines to the dissociative drug, ketamine:

Table 2 from Vilke et. al (Ref 3).

Anti-psychotics and benzodiazepines have long delays to peak effect when given via the IM route, in the realm of 15-30 minutes.  Because of its relatively rapid onset,  there has more widespread  prehospital of IM ketamine for chemical restraint of ExDS.

Several studies have attempted to examine the efficacy of ketamine for prehospital management of ExDS.  Anecdotal evidence for the effectiveness of prehospital ketamine came from initial case series and has been adopted into EMS protocols for extreme agitation [4,5].  These initial case series also highlighted the potential adverse effects of the drug, including hypersalivation, laryngospasm, and hypoxia (at least in the doses used ~ 5 mg/kg IM).

After the initial case series were reported, a pilot, retrospective study of prehospital ketamine for ExDS was published in the Western Journal of Emergency Medicine [6].  In this study, the authors reviewed the paramedic run sheets for 52 violent and agitated patients who were given a single 4 mg/kg dose of IM ketamine  The average time to sedation and medical control was approximately 2 minutes. At the 4 mg/kg IM dosage,  3/52 patients developed respiratory depression, two of whom were intubated.  In each of these cases, the patients had received IV midazolam in conjunction ketamine to prevent emergence reaction.  The authors concluded that "ketamine may be safely and effectively used by trained paramedics following a specific protocol."  A major caveat to this study is that the authors did not examine what happened later in the emergency department.  Interestingly, a previously published case series of 13 patients found that of the three patients who developed respiratory distress, two did so only after arrival to the ED while one patient arrived with ventilation being assisted by EMS [5].  In none of these cases was the impending respiratory distress documented in the prearrival note, suggesting that 6% may be a gross underestimation of the true incidence of respiratory complications. 

Another outcome measure for respiratory complication is by examining incidence of intubation after the patients arrive in the emergency department.  A recent retrospective study published in the American Journal of Emergency Medicine examined the correlation between ketamine dosage and need for intubation [7].  They reviewed the prehospital and emergency department records for 51 consecutive patients who were administered ketamine for prehospital chemical restraint.  Fourteen (29%) of patients required intubation.  Of note, none of these patients were intubated in the field.  Patients who were intubated were administered a significantly higher ketamine dose (6.16 +/- 1.62 mg/kg) than those who were not (4.90 +/- 1.54 mg/kg).  It is not clear what proportion of patients were intubated as a side-effect of the ketamine as opposed to facilitation of  medical care in the emergency department.  It was specifically noted that two of the patients were intubated because of "recurrent agitation and need for additional sedation" and one patient was intubated to facilitate medical workup (a lumbar puncture).  The mortality rate for these patients was not documented, but 71% of the patients were admitted to the hospital, primarily on medical (55%) rather than psychiatric (14%) services.

A final consideration is whether ketamine interacts at all with the psychiatric disorders that underlie some cases of ExDS.  Ketamine acts as an NMDA-receptor antagonist, thereby causing a deficiency in glutamate-mediated

Ketamine chemical structure (wiki)

neurotransmission [8] .   Because PCP and ketamine-abuse can model some aspects of schizophrenia, some have postulated that some aspects of schizophrenia are due to defects in glutamate-mediated neurotransmission.  Indeed, in one study they found that CSF from schizophrenic patients had lower glutamate content when compared with controls [9].  While the "glutamate hypothesis of schizophrenia" remains controversial, because a subset of ExDS syndrome patients have psychotic disorders, one might be concerned that ketamine could have an adverse effect on the underlying psychiatric disease, although this does not appear to have been directly studied anywhere and there are no reports in the limited literature regarding ketamine administration for chemical restraint.

Take Home Points:  ExDS is a syndrome with a high rate of mortality. IM Ketamine is a promising treatment for the prehospital realm because of its rapid time of onset (~2-5 min).  Providers administering ketamine need to have heightened awareness and ability to handle potential respiratory complications, including respiratory depression and laryngospasm.  The long-term effects of single dose ketamine administration in patients with underlying psychiatric diagnoses is unclear.

Submitted by Maia Dorsett (@maiadorsett), PGY-3
Faculty Reviewed by H. Phil Moy

References:
1. Vilke, G. M., DeBard, M. L., Chan, T. C., Ho, J. D., Dawes, D. M., Hall, C., ... & Bozeman, W. P. (2012). Excited delirium syndrome (ExDS): defining based on a review of the literature. The Journal of emergency medicine, 43(5), 897-905.
2. Vilke, G. M., Payne-James, J., & Karch, S. B. (2012). Excited delirium syndrome (ExDS): redefining an old diagnosis. Journal of forensic and legal medicine, 19(1), 7-11.
3. Vilke, G. M., Bozeman, W. P., Dawes, D. M., DeMers, G., & Wilson, M. P. (2012). Excited delirium syndrome (ExDS): treatment options and considerations. Journal of forensic and legal medicine, 19(3), 117-121.
4. Ho, J. D., Smith, S. W., Nystrom, P. C., Dawes, D. M., Orozco, B. S., Cole, J. B., & Heegaard, W. G. (2013). Successful management of excited delirium syndrome with prehospital ketamine: two case examples. Prehospital Emergency Care, 17(2), 274-279.
5.Burnett, A. M., Salzman, J. G., Griffith, K. R., Kroeger, B., & Frascone, R. J. (2012). The emergency department experience with prehospital ketamine: a case series of 13 patients. Prehospital Emergency Care, 16(4), 553-559.
6. Scheppke, K. A., Braghiroli, J., Shalaby, M., & Chait, R. (2014). Prehospital use of IM ketamine for sedation of violent and agitated patients. Western Journal of Emergency Medicine, 15(7), 736.
7. Burnett, A. M., Peterson, B. K., Stellpflug, S. J., Engebretsen, K. M., Glasrud, K. J., Marks, J., & Frascone, R. J. (2014). The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. The American journal of emergency medicine.
8. Murray, R. M., Paparelli, A., Morrison, P. D., Marconi, A., & Di Forti, M. (2013). What can we learn about schizophrenia from studying the human model, drug‐induced psychosis?. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 162(7), 661-670.
9.  Kim, J. S., Kornhuber, H. H., Schmid-Burgk, W., & Holzmüller, B. (1980). Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neuroscience letters, 20(3), 379-382.