Push Th(d)ose Vasopressors

Push Th(d)ose Vasopressors

Background

Since Scott Weingart first advocated for using push-dose pressors in the Emergency Department (ED) over a decade ago(1), push-dose vasopressors, also known as bolus-dose vasopressors have seemingly found their way into many EDs. However, recent studies have sought to ask more questions regarding its use and safety in the Emergency Department.

Vasopressors such as epinephrine and norepinephrine are commonly used for regulating and maintaining adequate blood pressure or mean arterial pressure (MAP). While these are usually administered as a continuous infusion via central access, administering them as a small bolus through peripheral access came to be known as push-dose vasopressor in practice.

Traditionally, this small bolus strategy was used in the operating room (OR) by anesthetists to treat transient hypotension due to sedating agents or spinal anesthesia. Multiple studies have supported the safety and efficacy of push-dose vasopressors in this clinical setting/patient population (2).

Swensen, et al. (3) studied the safety of bolus-dose phenylephrine for hypotension in the Emergency Department, however, data on the efficacy and safety of push-dose pressors remains sparse in ED and in-patient settings. Studies published in the past few years have questioned the lack of evidence regarding the safety and efficacy of push-dose pressor use in ED settings and highlighted some negative consequences of its use (4). To understand the concerns, it’s important we first understand the vasopressors, indications for use, and preparation in the ED.

Push-dose pressors in the Emergency Department

The two common vasopressors used as push-dose pressors in the Emergency Department are Epinephrine and Phenylephrine. Patients needing emergency airway, traumatic brain injury, and post-cardiac arrest with the return of spontaneous circulation may all experience hypotension which could lead to adverse outcomes. Push-does pressors have been proposed as a temporary measure to limit the hypotension while a vasopressor infusion/definitive treatment is being set up (5).

phenilephrine vs epinephrine
push dose epinephrine
push dose phenilephrine

Clinical settings in the ED where the use of push-dose pressor is proposed:

  1. Airway management: Hypotension prior, during, and post-intubation could be treated with bolus-dose vasopressors. Panchal et al. (6) did a retrospective chart review of intubated hypotensive patients in which phenylephrine was used. Bolus-dose phenylephrine demonstrated an increase in systolic blood pressure and the authors recommended further studies to understand the best use of phenylephrine for post-intubation hypotension.
  2. Return of spontaneous circulation (ROSC): In patients with ROSC, bolus-dose pressors may aid in the maintenance of end-organ perfusion, which is often impaired after ROSC (7).
  3. Traumatic brain injury: By rapidly increasing mean arterial pressure and thus cerebral perfusion pressure, bolus-dose vasopressors may help to prevent secondary brain injury.

What are the concerns regarding the use of push-dose pressors in the ED?

Acquisto and Bodkin (8) cited a few dosing errors while using push-dose pressors and highlighted that emergency physicians are less familiar with the practice of medication preparation/manipulation and hence dosing errors are expected, inadvertently causing patients more harm than benefit. They also emphasized on the lack of evidence in the literature regarding the efficacy and safety of push-dose pressors in a stressful environment like the ED.

Rotando and Picard et al. (9) in their prospective observational study of 146 patients receiving push-dose pressors in the ICU had thirteen (11.2%) patients have a dose-related medication error and seventeen (11.6%) adverse events. They concluded while push-dose pressors where efficacious, they were associated with adverse drug events and medication errors.

Cole et al (10). performed a retrospective analysis of 249 patients receiving push-dose pressors and found a higher incidence of adverse hemodynamic effects (39%) and human errors (19%). They emphasized the need for further studies to question whether push-dose pressors improve outcomes, and if so, how to safely implement them in practice.

Another concern raised is whether physicians may bypass standard resuscitation practices of fluid boluses in favor of using push-dose pressors. Schwartz et al. (11) found that only 34% of patients received an appropriate fluid challenge before using push-dose pressors in a retrospective chart review of 73 patients receiving push-dose pressors for acute hypotension in the ED. Furthermore, it appeared that patients who did not receive an appropriate fluid bolus needed more doses of bolus-dose pressors followed by the need for continuous vasopressor infusion within 30 minutes of bolus-dose pressor use.

Emergency physicians work in stressful environments which raises concerns on the ability of the physician to perform accurate dose calculations under duress (4). The prepared syringe also contains multiple individual doses, and using more concentrated solutions potentially increases the risk of overdose and extravasation injury (12).

Conclusion

While the practice of using push-dose pressors has found its way into the Emergency Department, it is crucial to acknowledge that evidence regarding its safety and benefits is limited. However, rather than disregarding the practice, high-quality research should be encouraged, which could potentially be practice-changing. Holden et al. (12) offer a framework of operational and safety considerations for the use of push-dose pressors in the ED and is a must-read for all using push-dose pressors in their current practice.

References

  1. Scott Weingart. EMCrit Podcast 6 – Push-Dose Pressors. EMCrit Blog. Published on July 10, 2009. Accessed on September 25th 2020. Available at [https://emcrit.org/emcrit/bolus-dose-pressors/ ].
  2. Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg. 2002 Apr;94(4):920-6, table of contents. doi: 10.1097/00000539-200204000-00028. PMID: 11916798.
  3. Swenson K, Rankin S, Daconti L, Villarreal T, Langsjoen J, Braude D. Safety of bolus-dose phenylephrine for hypotensive emergency department patients. Am J Emerg Med. 2018 Oct;36(10):1802-1806. doi: 10.1016/j.ajem.2018.01.095. Epub 2018 Feb 19. PMID: 29472039.
  4. Cole JB. Bolus-Dose Vasopressors in the Emergency Department: First, Do No Harm; Second, More Evidence Is Needed. Ann Emerg Med. 2018 Jan;71(1):93-95. doi: 10.1016/j.annemergmed.2017.05.039. Epub 2017 Jul 26. PMID: 28754354.
  5. Weingart S. Push-dose pressors for immediate blood pressure control. Clin Exp Emerg Med. 2015;2(2):131-132. Published 2015 Jun 30. doi:10.15441/ceem.15.010
  6. Panchal AR, Satyanarayan A, Bahadir JD, Hays D, Mosier J. Efficacy of Bolus-dose Phenylephrine for Peri-intubation Hypotension. J Emerg Med. 2015 Oct;49(4):488-94. doi: 10.1016/j.jemermed.2015.04.033. Epub 2015 Jun 20. PMID: 26104846.
  7. Gottlieb M. Bolus dose of epinephrine for refractory post-arrest hypotension. CJEM. 2018 Oct;20(S2):S9-S13. doi: 10.1017/cem.2016.409. Epub 2017 Jan 10. PMID: 28069098.
  8. Acquisto NM, Bodkin RP, Johnstone C. Medication errors with push dose pressors in the emergency department and intensive care units. Am J Emerg Med. 2017 Dec;35(12):1964-1965. doi: 10.1016/j.ajem.2017.06.013. Epub 2017 Jun 7. PMID: 28625533.
  9. Rotando A, Picard L, Delibert S, Chase K, Jones CMC, Acquisto NM. Push dose pressors: Experience in critically ill patients outside of the operating room. Am J Emerg Med. 2019 Mar;37(3):494-498. doi: 10.1016/j.ajem.2018.12.001. Epub 2018 Dec 3. PMID: 30553634.
  10. Cole JB, Knack SK, Karl ER, Horton GB, Satpathy R, Driver BE. Human Errors and Adverse Hemodynamic Events Related to “Push Dose Pressors” in the Emergency Department. J Med Toxicol. 2019 Oct;15(4):276-286. doi: 10.1007/s13181-019-00716-z. Epub 2019 Jul 3. PMID: 31270748; PMCID: PMC6825064.
  11. Schwartz MB, Ferreira JA, Aaronson PM. The impact of push-dose phenylephrine use on subsequent preload expansion in the ED setting. Am J Emerg Med. 2016 Dec;34(12):2419-2422. doi: 10.1016/j.ajem.2016.09.041. Epub 2016 Sep 22. PMID: 27720568.
  12. Holden D, Ramich J, Timm E, Pauze D, Lesar T. Safety Considerations and Guideline-Based Safe Use Recommendations for “Bolus-Dose” Vasopressors in the Emergency Department. Ann Emerg Med. 2018 Jan;71(1):83-92. doi: 10.1016/j.annemergmed.2017.04.021. PMID: 28601272.
Cite this article as: Neha Hudlikar, UAE, "Push Th(d)ose Vasopressors," in International Emergency Medicine Education Project, November 11, 2020, https://iem-student.org/2020/11/11/push-thdose-vasopressors/, date accessed: December 2, 2022

More Posts From Dr. Hudlikar

COVID-19 and Hydroxychloroquine

Authors: Nardos Makkonen, MD and Amita Sudhir, MD
University of Virginia, USA

Life does not choose the logically best design to meet a new situation. It adapts what already exists...The result, unlike the clean straight lines of logic, is often irregular, messy.

John Barry

In The Great Influenza, The story of the Deadliest Pandemic in History, the author John Barry states, “Life does not choose the logically best design to meet a new situation. It adapts what already exists…The result, unlike the clean straight lines of logic, is often irregular, messy.” This has never been more evident than now as the way we practice medicine changes fundamentally in the face of a new pandemic. While the news of a novel coronavirus spread, many in the scientific community found themselves struggling to find answers. In the wake of the pandemic, multiple studies were published aiming to identify risk factors, disease progression, and most importantly, therapeutic options.

As the number of positive cases grew exponentially, so did the urgency to find an effective therapy. Scientists and medical professionals were tasked with finding a swift solution. In addition to vaccine development, trials looking at the effectiveness of previously existing antiviral medications against SARS-CoV-2 were underway. A number of in-vitro models showed promising results – existing antiviral and antimalarial medications, including Hydroxychloroquine and Remdesivir, were noted to have cytotoxic properties against the novel coronavirus (1, 2). At first, it was difficult to tell how this could shape the management of affected patients. Then came a study that would change the global conversation on COVID therapies.

covid19

An article published on March 20th in the International Journal of Antimicrobial Agents looked at the effect of hydroxychloroquine and azithromycin on COVID positive patients. The study was an open-label, non-randomized clinical trial of thirty-six patients; twenty patients were treated with hydroxychloroquine, while sixteen were in the control group. The article looked at SARS–CoV-2 clearance from the nasopharynx after six days. Higher frequency of viral clearance was reported in the treatment group, hydroxychloroquine (plus azithromycin if deemed necessary) versus an untreated control group [14 out of 20 (70%) vs. 2 out of 16 (13%); P < 0.001]. The authors concluded that the addition of azithromycin to hydroxychloroquine was significantly more efficient for virus elimination (3). Multiple articles were published that questioned various aspects of the original article. Nonetheless, the original excitement surrounding the medication led to its widespread use for treatment of COVID positive patients in various hospitals across the world. However, in the ensuing months, multiple additional studies have been published that have informed our understanding of hydroxychloroquine as a treatment option for SARS–CoV-2, suggesting that it may not be the panacea that the initial study suggested it is.

One of the first randomized control trials on the topic was a multicenter, open-label, randomized control trial looking at 150 patients. Seventy-five patients were assigned to hydroxychloroquine plus standard of care, while the other 75 were assigned to standard of care alone. The primary endpoint of this study was looking at viral clearance by 28 days. The results suggested hydroxychloroquine was not associated with a significantly higher probability of negative conversion than the standard of care alone (4). In another retrospective cohort study of 1438 patients hospitalized in metropolitan New York, treatment with hydroxychloroquine, azithromycin, or both did not result in a significantly lower in-hospital mortality (5). A meta-analysis looked at eleven studies, including three randomized controlled trials and eight observational studies. Here, 2354 patients received hydroxychloroquine alone or in combination, while 1952 did not. The study found no significant difference in clinical progression, mortality, or viral clearance by RT-PCR among patients with COVID-19 infection who are treated with hydroxychloroquine compared with control groups (6). In addition, a significantly higher incidence of adverse events associated with hydroxychloroquine use across a number of studies was noted.

Adverse effects were also noted in a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. The findings show no confirmed benefit of hydroxychloroquine or chloroquine when used alone or with a macrolide on in-hospital outcomes for COVID-19. Notably, each of these drugs was found to be associated with decreased in-hospital survival and increased frequency of ventricular arrhythmias (7). Importantly, the Lancet has since released a letter of concern on 6/2/20 regarding its publication of this multinational registry analysis (8).

Beyond its potential therapeutic use for known COVID positive patients, hydroxychloroquine was touted as beneficial for prophylactic use. Prior to the publication of significant studies on the prophylactic efficacy of the medication, the Indian Council of Medical Research, under the Ministry of Health and Family Welfare, recommended chemoprophylaxis with hydroxychloroquine for asymptomatic health-care workers treating patients with suspected or confirmed COVID-19, and for asymptomatic household contacts of confirmed cases. The announcement led some in the scientific community to express concern, stating “the drug is untested, the benefits unknown, and the risks not negligible” (9). This concern was substantiated in subsequent studies. A recent randomized, double-blind, placebo-controlled trial analyzed the effect of hydroxychloroquine in postexposure prophylaxis. The study included 821 asymptomatic participants. 87.6% of the participants (719 of 821) had a high-risk exposure to a confirmed COVID contact. The primary outcome was symptomatic illness confirmed by a positive molecular assay or, if testing is not available, COVID-related symptoms. The results noted no significant difference in the primary outcome between participants receiving hydroxychloroquine (49 out of 414 [11.8%]) and those receiving placebo (58 out of 407 [14.3%]) (10). Additionally, side effects were noted to be more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%).

On May 27th, Dr. Anthony Fauci, the director of National Institute of Allergy and Infectious Diseases, when asked about hydroxychloroquine, stated that “The scientific data is really quite evident now about the lack of efficacy.” As of now, the World Health Organization is planning on resuming Hydroxychloroquine clinical trials after previously halting studies due to safety concerns (11). One adage often repeated in medicine is that what we learn now may not apply in 10 years. In the age of COVID, what we learn now may not apply in the next few months or even weeks. Seeing images of ventilated patients, and at times dead bodies across hospital hallways have filled us all with a deep desire for a quick fix. As physicians, we are likely to grasp at any straws that might help us fight this disease; we have to be careful to look critically at the evidence. Hope springs for a cure with each new study, but we should apply the same rigorous scientific methodology to COVID that we have developed for other diseases. As we move towards alleviating the suffering of this pandemic, it is essential to avoid falling into pitfalls and causing more harm along the way.

References and Further Reading

  1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.
  2. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.
  3. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;:105949.
  4. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.
  5. Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020;
  6. Chacko J, Brar G, Premkumar R. Hydroxychloroquine in COVID-19: A systematic review and meta-analysis. 2020. doi:10.1101/2020.05.14.20101774
  7. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020. doi:10.1016/s0140-6736(20)31180-6.
  8. Editors TL. Expression of concern: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020. doi:10.1016/s0140-6736(20)31290-3.
  9. Rathi S, Ish P, Kalantri A, Kalantri S. Hydroxychloroquine prophylaxis for COVID-19 contacts in India. Lancet Infect Dis. 2020;
  10. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;
  11. BerkeleyJr. World Health Organization resumes coronavirus trial on malaria drug hydroxychloroquine after examining safety concerns. CNBC. https://www.cnbc.com/2020/06/03/world-health-organization-resumes-coronavirus-trial-on-malaria-drug-hydroxychloroquine-after-safety-concerns.html. Published
Cite this article as: Amita Sudhir, USA, "COVID-19 and Hydroxychloroquine," in International Emergency Medicine Education Project, June 15, 2020, https://iem-student.org/2020/06/15/covid-19-and-hydroxychloroquine/, date accessed: December 2, 2022