Direct-acting oral anticoagulants (DOACs), including apixaban, rivaroxaban, edoxaban, and dabigatran, are widely used for various indications and considered first-line therapy for prevention of acute ischemic stroke in patients with nonvalvular atrial fibrillation . The management of acute ischemic stroke in patients on DOACs presents a difficult clinical scenario in the emergency department due to concern for increased risk of hemorrhage. IV thrombolytics (e.g., alteplase, tenecteplase), a mainstay in acute ischemic stroke management, are not recommended in current guidelines for patients whose last DOAC dose was within the last 48 hours [2, 3]. Therefore, patients with an acute ischemic stroke who are compliant with their DOACs are often excluded from guideline recommended therapy. Additionally, as covered in a previous ALiEM post, it is not recommended to reverse anticoagulation status in order to administer a thrombolytic.
The use of IV thrombolytics in patients on DOACs was evaluated by Kam et al in a 2022 study published in JAMA . This retrospective analysis included 163,038 patients from the AHA/ASA Get With The Guidelines-Stroke registry with acute ischemic stroke who received IV alteplase within 4.5 hours of symptom onset. Of the total number of patients, only 2207 had documented use of a DOAC within the last 7 days, with 25 of these patients reporting DOAC use within 48 hours. Patients on warfarin or other anticoagulants were excluded. The primary outcome was symptomatic intracranial hemorrhage (ICH) within 36 hours of IV alteplase administration. After adjusting for clinical factors, the rate of symptomatic ICH was not significantly different between patients taking DOACs and those not on anticoagulation (3.7% vs. 3.2%, adjusted OR 0.88, 95% CI 0.70 to 1.10). However, when stratified based on time from last DOAC dose, patients who took their DOAC 0-48 hours prior had an 8% rate of symptomatic ICH compared to 3.2% among those not on DOACs. Furthermore, the rate of any alteplase complication was 12% vs. 6% in those taking DOACs within 48 hours vs. no DOAC.
- The population at highest risk for bleeding is patients who took a DOAC within the last 48 hours, and this study only included 25 such patients.
- A similar study tried to answer the same question for warfarin patients with an INR between 1.5-1.7. They also failed to include enough patients to make any definitive conclusions. 
- Timing from the last DOAC dose was given as a range, with the majority of patients reporting use sometime within the last 7 days. It has been established in current AHA/ASA guidelines that receipt of DOACs past 48 hours prior is considered safe for thrombolytic administration, and if the included institutions were following current recommendations, thrombolytics were likely administered mostly to patients outside the 48-hour window.
- Large potential for selection bias, since it was reported that almost 23,000 patients on DOACs from the original registry (who were otherwise eligible) did not receive thrombolytics.
- Not clear how patients were determined to be on DOACs or if the authors were able to confirm this in unresponsive/intubated/deceased patients retrospectively. This could have resulted in DOAC patients being included in the non-DOAC group, which could have falsely evened-out the bleeding rates.
- The management of acute ischemic stroke in patients receiving prior anticoagulation presents a challenging clinical scenario.
- Studies to date fail to include enough patients to evaluate the true risk of bleeding.
- This study supports the current guideline recommendation to avoid alteplase in patients receiving a DOAC within 0-48 hours due to the increased risk of intracranial hemorrhage.
Want to learn more about EM Pharmacology?
- January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Published correction appears in Circulation. 2019;140(6):e285. Circulation. 2019;140(2):e125-e151. doi: 10.1161/CIR.0000000000000665. PMID: 30686041.
- Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. PMID: 31662037.
- Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. 2021;6(1):I-LXII. doi: 10.1177/2396987321989865. PMID: 33817340.
- Kam W, Holmes DN, Hernandez AF, et al. Association of Recent Use of Non-Vitamin K Antagonist Oral Anticoagulants With Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Treated With Alteplase. JAMA. 2022;327(8):760-771. doi:10.1001/jama.2022.0948. doi: 10.1001/jama.2022.0948. PMID: 35143601.
- Xian Y, Liang L, Smith EE, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA. 2012;307(24):2600-2608. doi:10.1001/jama.2012.6756. doi: 10.1001/jama.2012.6756. PMID: 22735429.
Jessica Mason, PharmD
PGY-2 Emergency Medicine Pharmacy Resident
Massachusetts General Hospital
Bupropion ingestions are one of the scarier poisonings due to a relatively narrow therapeutic index and the numerous adverse effects that may occur. Medical toxicologist Dr. Dan Rusyniak details his hatred of this drug in overdose in a Tox & Hound blog post aptly-titled Illbutrin. When bupropion was first approved in the 1980s, the max dose was 600 mg/day . However, reports of seizures, particularly in patients with bulimia, caused its temporary removal from the market . It was reintroduced a few years later with a max dose of 450 mg/day . Common signs and symptoms noted in overdose include seizures, agitation, sinus tachycardia, and QRS/QTc prolongation. Seizures occur in up to 40% of overdose cases, are often refractory to initial therapy, and can happen as long as 24 hours after an overdose with extended release formulations [4, 5].
A study of 256 patients from the Toxicology Investigators Consortium (ToxIC) Registry identified three factors associated with seizure development after bupropion overdose [6, 7].
- QTc prolongation > 500 msec (OR = 3.4, 95% CI: 1.3-8.8)
- Tachycardia (heart rate > 140) (OR = 1.9, 95% CI: 1-3.6)
- Age 13–18 years (OR = 2.4, 95% CI: 1.3-4.3)
Agitation and tremors are more common in patients who develop seizures with bupropion compared to those who do not . Additionally, presence of tachycardia (heart rate >100 bpm) has a sensitivity of 91% and a negative predictive value of 93% for development of seizures .
- Seizures are common following bupropion overdose and patients who seize are generally tachycardic.
- Patients should be observed at least 24 hours after a extended release bupropion overdose, as seizures can be significantly delayed.
Want to learn more about EM Pharmacology?
- Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50(7):256-261. PMID: 2500425.
- Horne RL, Ferguson JM, Pope HG, et al. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 1988;49(7):262-266. PMID: 3134343.
- Huecker MR, Smiley A, Saadabadi A. Bupropion. In: StatPearls. StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470212/.
- Starr P, Klein-Schwartz W, Spiller H, Kern P, Ekleberry SE, Kunkel S. Incidence and onset of delayed seizures after overdoses of extended-release bupropion. Am J Emerg Med. 2009;27(8):911-915. doi: 10.1016/j.ajem.2008.07.004. PMID: 19857406.
- Al-Abri SA, Orengo JP, Hayashi S, Thoren KL, Benowitz NL, Olson KR. Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion. Clin Toxicol (Phila). 2013;51(10):1230-1234. doi: 10.3109/15563650.2013.849349. PMID: 24131328.
- Wax PM, Kleinschmidt KC, Brent J, ACMT ToxIC Case Registry Investigators. The toxicology investigators consortium (Toxic) registry. J Med Toxicol. 2011;7(4):259-265. doi: 10.1007/s13181-011-0177-z. PMID: 21956161.
- Rianprakaisang TN, Prather CT, Lin AL, Murray BP, Hendrickson RG, Toxicology Investigators Consortium (ToxIC). Factors associated with seizure development after bupropion overdose: a review of the toxicology investigators consortium. Clin Toxicol (Phila). Published online April 21, 2021:1-5. doi: 10.1080/15563650.2021.1913180. PMID: 33878992.
Rapid and precise control of blood pressure is vital for patients with a hypertensive emergency or an acute stroke. Commonly, nicardipine is utilized in these situations, with nitroprusside being a less appealing alternative. The most recent AHA/ASA Acute Ischemic Stroke Guidelines, updated in 2019, also recommend clevidipine as a first-line antihypertensive option . Clevidipine is a dihydropyridine calcium channel blockers, similar in mechanism to nicardipine and amlodipine. The main advantage of clevidipine over nicardipine is related to its pharmacokinetics (Table 1). Given its shorter half-life of elimination, clevidipine can be titrated every 1-2 minutes. Additionally, if hypotension does occur, stopping the clevidipine infusion allows blood pressure to rebound quickly.
|Clevidipine||2-4 mins||5-15 mins||1-15 mins|
|Nicardipine||10-20 mins||1-2 hours||2-4 hours|
|Nitroprusside||1-2 mins||1-10 mins||2 mins|
Table 1: Pharmacokinetics of Common Antihypertensive Infusions [Micromedex; Lexicomp]
Most studies demonstrate equivalent outcomes between clevidipine and other agents (e.g., nicardipine, nitroprusside, nitroglycerin) [2-5]. The ECLIPSE trial is the largest to assess the safety and efficacy of clevidipine . The authors randomized cardiac surgery patients to clevidipine, nicardipine, nitroprusside, or nitroglycerin and found no difference in the incidence of myocardial infarction, stroke, or renal dysfunction. They noted that mortality was higher in patients receiving nitroprusside vs clevidipine, but equivalent compared to the the other medications. Additionally, clevidipine treated patients had significantly fewer excursions outside the prespecified blood pressure range than patients treated with any of the other agents.
Clevidipine is formulated in a 20% lipid emulsion and packaged in a glass vial. This causes clevidipine to appear similar to propofol, which could lead to safety issues. Also, care should be taken when using both clevidipine and propofol concomitantly, especially at high doses, as both provide clinically significant amounts of lipids, so triglycerides should be monitored.
Clevidipine is a safe and effective antihypertensive to use in patients that require rapid and strict blood pressure control, specifically in patients with an aortic dissection or an acute ischemic/hemorrhagic stroke.
Want to learn more about EM Pharmacology?
- Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. PMID: 31662037.
- Allison TA, Bowman S, Gulbis B, Hartman H, Schepcoff S, Lee K. Comparison of clevidipine and nicardipine for acute blood pressure reduction in patients with stroke. J Intensive Care Med. 2019;34(11-12):990-995. doi: 10.1177/0885066617724340. PMID: 28820038.
- Rosenfeldt Z, Conklen K, Jones B, Ferrill D, Deshpande M, Siddiqui FM. Comparison of nicardipine with clevidipine in the management of hypertension in acute cerebrovascular diseases. J Stroke Cerebrovasc Dis. 2018;27(8):2067-2073. doi: 10.1016/j.jstrokecerebrovasdis.2018.03.001. PMID: 29627171.
- Ulici A, Jancik J, Lam TS, Reidt S, Calcaterra D, Cole JB. Clevidipine versus sodium nitroprusside in acute aortic dissection: A retrospective chart review. Am J Emerg Med. 2017;35(10):1514-1518. doi: 10.1016/j.ajem.2017.06.030. PMID: 28669696.
- Brehaut SS, Roche AM. Abstract W P65: Clevidipine Outperforms Other Agents in Emergent Acute Hypertension Treatment in Ischemic Stroke Pre-rt-PA. 2015;46:AWP65. doi: 10.1161/str.46.suppl_1.wp65.
- Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg. 2008;107(4):1110-1121. doi:10.1213/ane.0b013e31818240db. PMID: 18806012.
A 63-year old female presents to your ED with positional dizziness since rising out of bed from a nap this afternoon. She says she had a similar episode in the past and reports, “they took the stones out of my ear by making me lay down and move my head a few times.” Based on your assessment of the patient’s history and physical exam you determine she has peripheral vertigo, likely BPPV. However, despite multiple attempts with the Epley Maneuver, the patient is still symptomatic. What next steps could you consider?
Benign paroxysmal positional vertigo: The basics
Benign paroxysmal positional vertigo (BPPV) is a type of peripheral vertigo caused by a cluster of otoconial fragments that are displaced into the involved semicircular canal. The classic presentation is brief episodes of dizziness reported with position changes, commonly with rolling or arising from bed. The condition is more common in females and with advanced age (>40). BPPV should be differentiated from central vertigo and other types of peripheral vertigo including Meniere’s disease, vestibular schwannoma, vestibular neuritis, and labyrinthitis among others. Displaced otoliths are most commonly located in the posterior or horizontal semicircular canals. The strongest positive predictors of BPPV include dizziness lasting <15 seconds and onset with turning over in bed . Episodes occur more frequently in the ear that is habitually dependent while sleeping , most commonly the right ear . Regarding canal involvement, a retrospective review of 253 patients demonstrated the following :
- 83% Unilateral posterior canal
- 7% Unilateral horizontal canal
- 6% Bilateral posterior canals
- 0% Anterior canal
There exist many different diagnostics and therapeutic positional techniques for addressing BPPV. Below we discuss the commonly taught techniques and several viable alternatives to consider when initial evaluation and/or treatment are unsuccessful.
1. Diagnostic: Loaded Dix-Hallpike Test
A Dix-Hallpike test is the most commonly taught and used diagnostic technique. However, providers may consider the “loaded” Dix-Hallpike.
Technique: Flex the patient’s head forward 30° in the same plane as the affected posterior canal for 30 seconds before placing supine with traditional technique. The loaded Dix-Hallpike has increased sensitivity, duration of nystagmus, and severity of symptoms compared to the traditional techniques . Consider using pillow/blankets under the thoracic spine to allow adequate cervical extension as an alternative to hanging the patient’s head over the end of the bed (trick of the trade). Elderly patients with severe kyphosis may need to be tested with the head of the bed tilted downward (Trendelenburg).
2. Diagnostic: Sidelying Test
This is an alternative to Dix-Hallpike in patients who cannot lie flat, such as with back pain, limited mobility, obesity, or orthopnea. It can be performed on the edge of the bed (often logistically easier in crowded ED rooms than Dix-Hallpike).
Technique: Rotate the head 45° contralateral to the posterior canal being tested. The patient descends to their side which is ipsilateral to the posterior canal being tested. This position is held for 30 seconds. If the patient experiences vertigo and the provider notices nystagmus, the test is positive. A negative test should prompt testing on the other side.
3. Therapeutic: Epley Maneuver
This is the most commonly taught and performed repositioning maneuver. The American Academy of Neurology and American Academy of Otolaryngology has given this technique a Level A Recommendation and clinical benefit demonstrated in a systematic review . Consider using a “chin tuck”, similar to the loaded Dix-Hallpike, for additional success.
4. Therapeutic: Semont Maneuver
Much like the Epley Maneuver is a continuation of the Dix-Hallpike Test, this therapeutic maneuver is a continuation of the Sidelying Test. The technique for left-sided posterior canalithiasis involves having a seated patient turn their head 45° to the left. The patient then drops their trunk to the right side, with the head turned 45° to the left (facing “up”). This position is held for 30-60 seconds. The patient then quickly sits up and lies down on the left side without stopping in the seated position. The head should still be kept 45° to the left so that the head now faces “down” and into the bed. This position is held for 30-60 seconds. Return the patient to the upright position.
1. Diagnostic: Roll Test
The Roll Test should be considered in patients displaying symptoms consistent with BPPV but posterior canal tests (Dix-Hallpike, Sidelying) are negative or appear to demonstrate horizontal nystagmus.
Technique: Have the patient begin by lying supine with the head flexed forward 30°. The provider then rotates the patient’s head rapidly 90° to one side followed by the other side, after re-centering the head. A positive test will involve bursts of nystagmus beating towards the affected ear which are stronger when the affected ear is dependent.
2. Therapeutic: BBQ or Lempert Roll
This repositioning maneuver can be performed as a continuation of the Roll Test and has shown success rates over 90% .
Technique: This involves stepwise rotations of the non-tilted head starting in the supine position and ultimately rolling a full 360°, holding each incremental 90° rotation for 30 seconds, starting from the affected to the unaffected side. This can be repeated 2-4 times until symptoms improve or nystagmus disappears.
3. Therapeutic: Appiani/Gufoni Maneuver
The Appiani/Gufoni Maneuver repositioning maneuver has shown success rates comparable to other techniques in a meta-analysis .
Technique: Have the sitting patient descend to their unaffected side, hold this position for one minute or until symptoms subside. Then turning the head 45° towards the bed, holding this position for 1-2 minutes before sitting back up. Repeat until nystagmus is absent.
The same maneuvers can be used to treat both posterior and anterior BPPV (i.e., Epley, Semont). However, there is a paucity of literature given the rarity of this condition. One small study reports success using a “reverse Epley” in 2 of 4 patients .
- If your initial therapeutic approach does not work, consider treating the other side as the side of dysfunction can be easily misidentified at first. Serial examinations are often required to confirm BPPV.
- Providers should be aware of any underlying spinal or carotid disorders when performing many of the rapid head movements in these patients.
- Patients should be observed for a short time immediately after repositioning for signs of possible worsening symptoms and risk of fall .
- In cases of bilateral BPPV, consider treating the less involved side initially, followed by the more involved side 10-15 minutes later.
- Recurrence is common unfortunately despite successful therapeutic intervention. Up to 44% of patients had recurrent symptoms at 2-year follow-up in one study .
- Patient education: After successful treatment, sleeping slightly elevated or on the uninvolved side may prevent recurrences [10, 11].
Realizing that you may have mis-identified the side and location of the dysfunction, you perform maneuvers assuming alternative locations for the provoking otoliths. To test for horizontal canal (instead of the more common posterior canal) dysfunction, you perform the roll test and notice nystagmus and worsening symptoms when facing the right side. Consequently, you have the patient perform the Lempert Roll technique, which causes her symptoms to resolve.
While you observe her for 10 minutes, there is no recurrence of her symptoms and she can ambulate without issues. You advise her to sleep on her left side. Outpatient follow-up with a physical therapist, specializing in vestibular disorders, should be strongly considered, especially if the patient is at risk for falls or if responsiveness to treatment was unclear.
The authors would like to extend a special thanks to Jeff Walter PT, DPT, NCS whose in-depth knowledge, experience, and research in the area of vestibular disorders were essential to this post. He is the creator of a FOAM blog: Vestibular Today on vestibular disorders that include many useful resources, diagrams, and videos.
- Noda K, Ikusaka M, Ohira Y, Takada T, Tsukamoto T. Predictors for benign paroxysmal positional vertigo with positive Dix–Hallpike test. Int J Gen Med. 2011;4: 809. PMID 22162937
- Çakir BÖ, Ercan İ, Çakir ZA, Civelek Ş, Sayin İ, Turgut S. What is the true incidence of horizontal semicircular canal benign paroxysmal positional vertigo? Otolaryngology. 2006 Mar; 134(3):451-4. PMID 16500443
- Von Brevern M, Seelig T, Neuhauser H, Lempert T. Benign paroxysmal positional vertigo predominantly affects the right labyrinth. J Neurol Neurosurg Psych Res. 2004 Oct 1; 75(10):1487-8. PMID 15377705
- Walters J. Geisinger Vestibular & Balance Center. Unpublished data. 2011.
- Andera L, Azeredo WJ, Greene JS, Sun H, Walter J. Optimizing Testing for BPPV–The Loaded Dix-Hallpike. J Int Adv Otol. 2020 Aug; 16(2):171. PMID 32784153
- Helminski JO, Zee DS, Janssen I, Hain TC. Effectiveness of particle repositioning maneuvers in the treatment of benign paroxysmal positional vertigo: a systematic review. Physical therapy. 2010 May 1; 90(5):663-78. PMID 20338918
- Li J, Guo P, Tian S, Li K, Zhang H. Quick repositioning maneuver for horizontal semicircular canal benign paroxysmal vertigo. J Otol. 2015 Sep; 10(3): 115–117. PMID 29937793
- Fu W, Han J, Chang N, et al. Immediate efficacy of Gufoni maneuver for horizontal canal benign paroxysmal positional vertigo: a meta-analysis. Auris Nasus Larynx. 2020 Feb 1; 47(1): 48-54. PMID 31151785
- Honrubia V, Baloh RW, Harris MR, Jacobson KM. Paroxysmal positional vertigo syndrome. Am J Otol 1999; 20: 465. PMID 10431888
- Shigeno K, Ogita H, Funabiki K. Benign paroxysmal positional vertigo and head position during sleep. J Vestib Res. 2012 Jan 1; 22(4):197-203. PMID 23142834
- Li S, Tian L, Han Z, Wang J. Impact of postmaneuver sleep position on recurrence of benign paroxysmal positional vertigo. PloS one. 2013 Dec 18; 8(12):e83566. PMID 24367602
- Uneri A. Falling sensation in patients who undergo the Epley maneuver: a retrospective study. Ear Nose Throat J. 2005 Feb; 84(2):82-5. PMID 15794543
Blood pressure control in the setting of ischemic stroke has a clearly recognized benefit in patient outcomes. The impact of blood pressure control in hemorrhagic stroke is not as well understood. The ACEP E-QUAL Network podcast, a partnership with ALiEM to promote clinical practice improvements, reviewed this topic with Dr. Latha Ganti (University of Central Florida College of Medicine). Dr. Ganti addressed the evidence behind recommended blood pressure targets and the available medications to achieve control. We present highlights from this discussion with Dr. Jason Woods.
What is the goal of blood pressure control in hemorrhagic stroke?
Management of blood pressure in intracranial hemorrhage (ICH) raises questions about the benefit of limiting hematoma expansion while maintaining cerebral perfusion. While it seems intuitive that hypertension should be controlled to limit hematoma expansion, patients with hemorrhagic stroke may be dependent on higher blood pressures for adequate perfusion.
Does lowering blood pressure lead to perihematomal ischemia?
ICH Adapt studies did not show evidence of decreased cerebral blood flow in perihematomal tissue and demonstrated that there is likely preservation of autoregulation which prevents ischemia .
Does lowering BP help prevent hematoma expansion and improve outcomes?
The risk of hematoma expansion is highest within the first couple of hours following initial bleeding. Hematoma expansion is clearly associated with worse outcomes. Scoring tools exist to estimate the risk of hematoma expansion. The “spot sign,” seen on source images from a computed tomography angiogram of the brain, suggests an area of dynamic bleeding.
- ICH ADAPT: no difference in hematoma expansion or clinical outcome with acute blood pressure lowering .
- INTERACT 2: intensive lowering of blood pressure did not result in a significant reduction in mortality or severe disability .
- ATACH 2: intensive lowering of blood pressure did not improve functional outcomes but was associated with increased renal dysfunction .
What is the optimal systolic blood pressure (SBP) target?
AHA Guidelines 2015
- ICH patients with SBP 150-220 mmHg, lower to 14 mmHg is safe
- ICH patients with SBP > 220 mmHg, aggressive reduction with continuous infusion may be reasonable
So what’s the right thing to do? If data suggests that lowering may not be as beneficial, what should the target blood pressure be?
- Target SBP 140-160 mmHg is a reasonable target
What medications are preferred for blood pressure control in ICH?
The ideal agent for blood pressure management in ICH would have a quick onset, but short duration, to allow titration.
- Onset < 5 min
- Duration of effect 2-4 hr
- IV bolus dose: 20 mg, followed by 20-80 mg every 10 min to a total dose of 300 mg.
- Infusion dose: 0.5 mg-2 mg/min
- Avoid in: asthma, COPD, heart failure, AV block
- Onset 1-2 min
- Half-life ~ 40 min
- Infusion dose: 0.5-1 mcg/kg/min, max 3 mcg/kg/min
- Onset 1-4 min
- Duration of effect 5-15 min
- Infusion dose: 1 mg/hr, up to 21 mg/hr, titrate by 2.5 mg/hr every 5-10 min
- Avoid in: severe aortic stenosis, and lipid metabolism dysfunction or known allergy to eggs or soy (delivered as lipid emulsion)
Available second-line (mostly off-label, not preferred)
When it comes to blood pressure: keep it simple.
- Target SBP 140-160 mmHg
- Top three drugs: Labetalol, Nicardipine, Clevidipine
Although labetalol has common contraindications, it is available as a bolus dose. In a clinical setting where drips may not be readily available, Labetalol can be easier to get.
Interested in more ACEP-EQUAL podcasts?
Listen to the other ACEP E-QUAL podcasts on our Soundcloud account.
- Butcher K, Jeerakathil T, Emery D, et al. The Intracerebral Haemorrhage Acutely Decreasing Arterial Pressure Trial: ICH ADAPT. Int J Stroke. 2010;5(3):227-233. PMID: 20536619
- Butcher KS, Jeerakathil T, Hill M, et al. The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial. Stroke. 2013;44(3):620-626. PMID: 23391776
- Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368(25):2355-2365. PMID: 23713578
- Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016;375(11):1033-1043. PMID: 27276234
Acute management of cerebrovascular accidents can be challenging enough, but questions about anticoagulant reversal in the setting of hemorrhagic stroke add another layer of complexity. The ACEP E-QUAL Network podcast, a partnership with ALiEM to promote clinical practice improvements, reviewed this topic with Dr. Joshua Goldstein (Massachusetts General Hospital, Harvard Medical School). Dr. Goldstein addressed common anticoagulants and their reversal agents, summarizing available literature to inform clinical practice. We present highlights from this discussion with Dr. Jason Woods.
What is the goal of anticoagulant reversal?
Since it is impossible to go back in time to prevent intracranial hemorrhage (ICH), the focus of management for hemorrhagic stroke should be to prevent further bleeding and allow brain tissue an opportunity to recover. The goal of anticoagulant reversal in patients with ICH is to decrease ongoing bleeding.
Warfarin is a vitamin K antagonist. Since vitamin K is required for the processing of coagulation factors II, VII, IX, and X, patients on warfarin have decreased amounts of these factors in circulation. To increase the availability of these factors, countering the effect of warfarin therapy can be two-fold:
- Replenish vitamin K to allow the production of new factors.
- Provide replacement of these factors directly.
Vitamin K supplementation will not provide immediate effect, and it may take up to 24 hours for the production of new coagulation factors. While it should be given early, patients also require factor replacement acutely.
Fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) can be given to supplement coagulation factors.
- FFP carries each of the 4 needed factors in addition to other clotting factors.
- The cost of FFP is low.
- Transfusion will take some time as it will require ~ 1 L volume.
- PCC, marketed as Kaycentra in the US, consists of concentrated Factor II, VII, IX, X, and proteins C and S.
- The cost of PCC is higher.
- Transfusion is quick, ~70 mL, and leads to rapid correction of INR.
Studies have shown PCC to be associated with faster INR reversal, less ICH expansion, and a non-statistical trend toward decreased mortality . PCC does carry a theoretical risk of thromboembolism given the rapid correction, but no evidence exists to suggest that this is the case.
Direct Oral Anticoagulants (DOACs)
There are 2 categories of DOACs:
- Factor II inhibitors (e.g., dabigatran)
- Factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban)
Approach to reversal: remove the inhibitor to allow normal function of already existent Factor II or Xa
- Time can be thought of as a reversal agent. Most DOACs have a half-life ~12 hours. If the timing of the last dose is known and it was hours ago, there may not be much medication left to reverse.
- Monoclonal antibodies
- Reversal of dabigatran can be achieved with the use of a monoclonal antibody, idarucizumab, to bind up circulating inhibitor.
- Reversal of Factor Xa inhibitors can similarly be attempted with the use of monoclonal antibody andexanet. Andexanet is notably more expensive than idarucizumab.
- PCC can be used off-label to outcompete circulating inhibitor with extra coagulation factors and increase the number of functional factors.
It should be noted that there are no reliable tests for measuring DOAC activity.
Dual Antiplatelet Therapy (DAPT)
The most common agents are aspirin and Plavix (clopidogrel). The issue with patients on these antiplatelet agents is not a lack of platelets, but the presence of medication that suppresses normal platelet function. Theoretically, if one could provide extra platelets, the inhibiting agent could be saturated and the remaining platelets provide some functional activity.
The PATCH trial demonstrated, however, that platelet transfusion led to significantly worse outcomes . While there is no readily available reversal agent for DAPT, platelet transfusion should be avoided. In fact, observational data suggest that patients on single antiplatelet therapy don’t fare worse and may not need reversal like those with DAPT .
- IV vitamin K + PCC (or FFP)
- Specific agent: Idarucizumab
- Non-specific agent: PCC
Factor Xa inhibitor reversal
- Specific agent: Andexanet
- Non-specific agent: PCC
- No available agent
- Transfusion of platelets associated with worse outcomes.
Interested in more ACEP-EQUAL podcasts?
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- Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15(6):566-573. [PMID: 27302126]
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