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.

Hot bullet, dirty wound?

Clinical scenario:  You are working in the emergency department when a car pulls up, dropping off an otherwise healthy male who has suffered a gun shot wound (GSW) to left shoulder.  He says that he was in the rear passenger seat driving around with friends and "minding his own business" when he heard multiple gun shots.  He felt immediate pain in his left shoulder.  A full exam reveals two wounds to the left shoulder and nowhere else.  The patient has bilateral breath sounds and his left arm is neurovascularly intact.  X-rays demonstrate no pneumothorax, but the patient has a comminuted left scapular fracture:

You update the patient's tetanus,  administer pain control, and call Orthopedics.  The orthopedist on call asks that the patient receive prophylactic antibiotics. An ardent defender of antibiotic stewardship, you wonder if antibiotics are necessary.  Is it possible that the heat exposure that comes with firearm discharge sterilizes a contaminated bullet?  Do prophylactic antibiotics decrease the chance of infection?

Literature Review:
Question 1:  Does the heat of firearm discharge sterilize a contaminated bullet?

Image source: http://pixshark.com/

A study by Thoresby and Darlow from 1967 simulated GSWs  using a series of gelatin models, contaminated bullets, and contaminated overlying “clothes”[1].   There were 3 “series” of testing. The first fired bullets contaminated with Serratia marcescens into a gelatin block. The second fired sterile bullets shot through pieces of military fatigues inoculated with Serratia overlying the entrance or exits side of the gelatin (with a piece of foil in between the cloth and gelatin to avoid direct transmission). The third fired bullets through an aerosolized cloud of Serratia in front of the gelatin block.  Significantly, there was bacterial growth along the bullet track in the gelatin in all three series (except for their respective controls). This suggests that bullets are not sterilized by heat upon discharge of the gun. Furthermore, it demonstrates that bacteria were drawn into the cavitation space via vaccum forces in series in which inoculated cloth was placed on the exit site.

EKG Challenge No. 10 Case Conclusion: Heartbreaker

You are working in the emergency department when you get a pre-arrival for "abdominal pain, hypotensive".  You follow EMS into the room when they arrive and are confronted with an elderly female who appears very pale and quite sick.  Per the paramedics and the patient,  she has had upper abdominal pain, nausea and weakness for the last two days.  Her initial blood pressure is 80/60 with a heart rate of 112, and you start working her up for all the badness that causes hypotension and abdominal pain in the elderly.  Everyone gets cracking on some IV access,  and you head for the ultrasound to help you better evaluate the cause of this patient's hypotension.  You start with the cardiac views of your RUSH exam, and see this:

 

Given these findings, you order an EKG:

On review of the EKG you note ST elevation that is most prominent in V2 and V3 (although it can also be seen in I, II, V4, V5) without significant reciprocal ST depression:

Given the apical akinesis and ST elevation in the precordial leads, the patient is sent for an emergent cardiac catheterization, which identifies no coronary artery disease.  

Normal Coronary arteries

                                        
The cardiologist notes apical akinesis of the patient's left ventricle, which during systole resembles a Japanese pot for catching an octopus.   He diagnoses the patient with Takatsubo's Cardiomyopathy.

EKG Challenge No. 10: This one looks sick ...

You are working in the department when you get a pre-arrival for "abdominal pain".  You follow EMS into the room and are confronted with a middle-aged to elderly female who appears very pale and quite sick.  As she is placed on the monitor, you speak with her and she endorses some diffuse abdominal pain and nausea for the last two days.  Her initial blood pressure is 80/60 with a heart rate of 112, and you start working her up for all the badness that causes hypotension and abdominal pain in the elderly.  Everyone gets cracking on some IV access,  and you head for the ultrasound to help you better evaluate the cause of this patient's hypotension.  You start with the cardiac views of your RUSH exam, and see this:

 Given these findings, you order an EKG:

What is your differential?  What do you do next?  Please leave your comments.  Click here to read the case conclusion.

Thank you to Dr. Chris Holthaus for the echo video.

Is it in? Well, flush the line

Clinical Scenario: 

You are working in the TCC when an ESRD patient presents with fever and hypotension, RN’s are able to attain a small IV, but knowing the patient will need abx and IVF, you prepare to place a central venous catheter (CVC). Under ultrasound guidance you place a triple lumen catheter.  You aspirate dark red blood and are confident it is venous. The follow up chest xray shows a cvc with an awkward course to the heart. You send off a blood gas, and are setting up to tranduce the line.  While waiting, you wonder is there another method to confirm CVC placement?

Literature Review:
Approximately three million CVC’s are placed every year in the US. Complication rates vary by source but the most commonly cited rate is around 10%, including arterial puncture, hematoma, pneumothorax, chylothorax, arrhythmia and air embolus . The use of ultrasound during CVC placement has reduced the complication rate to around 3%.  (1) In 2010 Liu et al described the novel use of bedside ultrasound (2D) and a saline flush,to confirm catheter placement in the SVC. The method involves flushing 10ml saline throught the most distal CVC port, while performing a cardiac ultrasound either in the subxiphoid or parasternal view. 

Horowitz et al 

Flushing of the saline causes immediate turbulence in the right atrium and ventricle, that is easily viewable on ultrasound.(1) Prekker et al also reported on using this technique with success, adding that saline can be flushed immediately after venous puncture but before the guide wire or CVC is placed. (2) In 2014 Horowitz et al performed a prospective blinded study testing whether flushed saline under cardiac US could accurately confirm femoral line placement.  In their study, all patients had an arterial line and a femoral CVC placed, then a blinded EM physician performed subxyphoid cardiac ultrasound while a provider flushed either the arterial line or venous CVC. The EM physician would either say "venous" or "arterial" based on the presence of a + flush sign (See image) . The study results showed 100% sensitivity and 90.3% specificity. (3) In other words, the presence of +flush test was always associated with venous CVC. There were zero incidences of an arterial flush being identified as venous. However, approx 10% of venous CVC's were incorrectly identified by negative flush test (specificity 90.3%). 

Take home points:
Rapid assessment of CVC placement can be achieved by saline flush and cardiac ultrasound. A +flush sign has been shown to be 100% sensitive for a venous CVC. However more studies are needed at this time as most literature is focused on case series, with only one prospective randomized study. 

Submitted by Louis Jamtgaard, PGY-3 @Lgaard
Faculty Reviewed by Deb Kane

References

1) Liu et al. Evaluation of proper above-the-diaphragm central venous catheter placement: the saline flush test. Am J Emerg Med. 2011 Sep;29(7):842.e1-3. doi: 10.1016/j.ajem.2010.06.025. Epub 2010 Sep 25.

2) Prekker ME Rapid confirmation of central venous catheter placement using an ultrasonographic "Bubble Test".Acad Emerg Med. 2010 Jul;17(7):e85-6. doi: 10.1111/j.1553-2712.2010.00785.x.

3) Horowitz R¹The FLUSH study--flush the line and ultrasound the heart: ultrasonographic confirmation of central femoral venous line placement. Ann Emerg Med. 2014 Jun;63(6):678-83. doi: 10.1016/j.annemergmed.2013.12.020. Epub 2014 Jan 15.

Hippocratic Medicine No. 2: Between a Rock and a Hard Place

Clinical Scenario:
You are working in the emergency department on a typical busy day. There are fifteen boarding patients waiting for their bed upstairs, another thirty-plus in the waiting room.  You walk into a room to assess a 75 yo female with confusion. Family says that she has been confused: forgetting to put on one shoe, unable to finish her crossword puzzles, and no longer able to bowl without throwing a gutter ball. Amazingly, the urinalysis is negative. Concerned that she may have had a subacute stroke, you order a head CT without contrast which shows “a large amount of vasogenic edema concerning for neoplasm.” The radiologist recommends a follow up MRI for further evaluation. The consulting neurologist instead asks for a Head CT (HCT) with contrast, reasoning they would not be the admitting service if the patient is found to have a mass. Neurosurgery recommends an MRI to evaluate for a suspected mass, and you learn that it will be 8 hours before the patient can go to MRI. With the pressure of the waiting room, the full rooms, and the boarding patients in the ED, you reluctantly order the HCT with contrast, which shows a right parietal neoplasm. Having rarely, if ever, ordered HCT with contrast, you ask- What are the indications for HCT with contrast in a patient with subacute onset of focal neurological deficits?

Literature Review:
The American College of Radiology (ACR) publishes evidence-based guidelines to help direct the efficacious use of radiologic studies. Their 2012 Appropriateness Criteria for Focal Neurologic deficits discusses the use of HCT vs. MRI. HCT without contrast is recommended for initial evaluation in this case. While contrast can provide additional information, “some pathology is difficult to visualize with CT under any circumstances,” and “MRI is more sensitive than CT for detecting primary and secondary brain lesions and for defining extent of disease.” Additionally, MRI spares the patient exposure to ionizing radiation and “provides information that…approaches the accuracy of a neuropathologic diagnosis” [1].  Specifically, for our patient with subacute onset of neurological deficits, the ACR recommends a HCT without contrast for acute screening. The highest rated imaging for further evaluation is an MRI head with and without contrast, rated an 8/9 for “usually appropriate.” A HCT with contrast was rated a 4/9, for “may be appropriate,” with the typical indication being inability to get an MRI. This patient had no contraindications to MRI and should not have had the contrasted HCT. Eight hours later she had a MRI to more appropriately plan her operative course. 

Orolingual Angioedema follow r-tPA administration: Pathophysiology and Risk Assessment

Clinical Scenario:  You are working a typical shift in the emergency department when a right-handed middle aged female with a history of hypertension presents with right sided hemiparesis which had an acute onset 45 minutes prior to arrival in the emergency department.  Her head CT is negative for acute ICH, her FSBS is normal, and after running through the contraindications to tPA administration, she is deemed a tPA candidate.  When discussing the risks and benefits of tPA, you include the risk of life-threatening, including intracranial, hemorrhage.  The patient and her husband express understanding and opt for tPA administration.   Approximately 40 minutes into the infusion, the patient begins to develop lip swelling.  She has no wheezing and no urticaria. Steroids and diphenhydramine are administered without effect.  You review her medications and see that she takes lisinopril. After she develops significant tongue swelling and airway compromise, you decide rapidly that this patient needs her airway secured.  Fortunately, the airway is secured smoothly.

As your heart rate makes its way from 220 to resting, you search on google scholar for "angioedema" and "alteplase".  (Honestly) having never heard of alteplase-induced angioedema until the Neurology resident murmured it over the phone as you update him on the patient's status, you have lots of questions about this sphincter-tightening syndrome. What is the incidence of this potential dramatic complication?  Are there any risk factors for developing it?  Should you be counseling patients about this risk as part of your shared decision making regarding alteplase administration?

Literature Review:
Most emergency physicians are well-aware of the potential complications of ACE-inhibitor induced angioedema.  ACE-inhibitors can lead to angioedema by inhibiting the break down of bradykinins, which are potent vasodilators.  Interestingly, alteplase plays into this pathway as well:

Image source: Hill et. al. (Reference 1)

As per its name "Tissue Plasminogen Activator", tPA is a serine protease that cleaves plasminogen into plasmin.  Plasmin then cleaves thrombus-bound fibrin, leading to the fibrinolytic effect desired in acute ischemic stroke.   However, plasmin also can activate the complement cascade and kinin pathway leading to increased bradykinin levels, and therefore vasodilation and risk of angioedema [1].  If angioedema develops, it tends to do so within an hour of receiving r-tPA and resolves within 3-24 hrs [2].

So what is the overall incidence of this complication?  Several retrospective and prospective studies have examined this question in predominantly the Caucasian and Asian populations.  A recent retrospective study and systematic review calculated an overall incidence of 1.9% (95% CI 1.3 - 2.6) with a relative risk of 12.9 if a patient is already taking an ACE inhibitor (95% CI 4.5 - 37) [3].

Image Source: Lin et. al. (Reference 3)

It is important to note that the majority of these patients did not require intubation for airway protection (for example, out of 5 patients developing angioedema in a retrospective review of 559 patients, only one required intubation) [3].  No deaths from airway compromise were reported in any of the studies.

In our own institution (Barnes Jewish Hospital), we took care of approximately 240 patients who received r-tPA for stroke in 2014  (110 administered IV tPA in the emergency department + 130 "drip and ship" patients admitted directly to the inpatient wards).  Among these 240 patients, there were no reported cases of angioedema.

Clinical Takehome:  Orolingual angioedema is a rare complication of r-tPA administration.  However, patients who take ACE inhibitors are at significantly increased risk.  It is therefore important to specifically ask about ACE inhibitors in patients who are tPA candidates and include this in your discussion of potential rare complications of tPA administration in this subset of patients.  Patients who receive r-tPA should have close monitoring for this complication during and in the first hour following the infusion.  Finally, secure the airway as soon as the angioedema begins to progress from lips to tongue, because no one wants to perform a surgical airway in a patient who just received r-tPA.

Submitted by Maia Dorsett (@maiadorsett), PGY-3
Faculty Reviewed by Peter Panagos

References:
1.  Hill, M. D., Barber, P. A., Takahashi, J., Demchuk, A. M., Feasby, T. E., & Buchan, A. M. (2000). Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. Canadian Medical Association Journal, 162(9), 1281-1284.
2.  Lekoubou, A., Philippeau, F., Derex, L., Olaru, A., Gouttard, M., Vieillart, A., & Kengne, A. P. (2014). Audit report and systematic review of orolingual angioedema in post-acute stroke thrombolysis. Neurological research, 36(7), 687-694.
3.Lin, S. Y., Tang, S. C., Tsai, L. K., Yeh, S. J., Hsiao, Y. J., Chen, Y. W., ... & Jeng, J. S. (2014). Orolingual angioedema after alteplase therapy of acute ischaemic stroke: incidence and risk of prior
angiotensin‐converting enzyme inhibitor use. European Journal of Neurology, 21(10), 1285-1291.
4. Correia, A. S., Matias, G., Calado, S., Lourenço, A., & Viana-Baptista, M. (2015). Orolingual Angiodema Associated with Alteplase Treatment of Acute Stroke: A Reappraisal. Journal of Stroke and Cerebrovascular Diseases, 24(1), 31-40.