The Safety and Efficacy of Push Dose Vasopressors in Critically Ill Adults

Background Information:

Acute Hypotension is associated with increased morbidity and mortality. Continuous vasopressor infusions have previously been the mainstay of treatment. However, peripherally dosed push dose pressors, (PDPs), are beginning to be administered more frequently for management of acute hypotension.^1-4 The PDPs, phenylephrine and epinephrine, result in vasoconstriction and increased cardiac contractility. They can be associated with side effects such as reflex bradycardia, decreased stroke volume in phenylephrine, tachycardia and hypertension associated with epinephrine. The authors of this trial sought out to describe PDP and assess the efficacy and safety of PDP use in the management of hypotension. Prior literature primarily focused on safety and medication errors, and while this study did the same, they also assessed variables associated with PDP response.

Paper: Singer S, et al. The safety and efficacy of push dose vasopressors in critically ill adults. Am J Emerg Med. 2022 Sep 5. PMID: 36108346

Clinical Question:

What is the efficacy and safety of peripherally administered push dose pressors for the treatment of acute hypotension?

What They Did:

• Single-center, retrospective cohort study performed at a single academic medical center
• Cohorts were analyzed according to PDP response (responders vs non-responders)
• Performed a logistic regression analysis to assess predictors of response to PDPs
• Patients were identified using a pharmacy informatics database query
• Analyzed PDP administration in the setting of acute hypotension. Assessed clinical practice, outcome, length of stay, safety, and efficacy of both phenylephrine and epinephrine peripherally administered through a push dose.
  • Epinephrine – 10ug/mL, 10mL syringe
  • Phenylephrine – 100ug/mL, 10mL syringe
  • Phenylephrine bolus doses from 100-200ug and epinephrine 10-20ug administered every 2-5 minutes pursuant to provider order

Inclusion Criteria:

• Adults age >18 years old
• Received at least one bolus dose of phenylephrine or epinephrine pre-filled syringes

Exclusion Criteria:

• Operating room patients
• Patients with any of the following:
  • Priapism
  • Epistaxis
• Missing vital signs within 1 hour of PDP dose
• Received both Epinephrine (Epi), and Phenylephrine (PE) were excluded

Outcomes:

Primary

• Efficacy, defined as a systolic BP increase of 25% post PDP administration
• Responder – Episodes that achieved a > 25% increase in SBP were classified as responders
• Nonresponder – Episodes that achieved a < 25% increase in SBP were classified as responders

Safety

• HTN (BP>180/110) within 1 hour PDP
• Bradycardia within 1 hour of Phenylephrine
• Tachycardia (>30% increase in HR from baseline within 1 hr of epi)

Additional Outcomes

• Delta of SBP/DBP 1 hour pre/post
• Requirement of a dose increase of continuous vasopressor support within 4 hours of PDP administration
• Cardiac arrest within 1 hour of PDP
• ICU/Hospital length of stay
• In hospital mortality
• Extravasation
• Severe adverse events such as:
  • Administration of atropine for bradycardia within 1 hr of phenylephrine
  • Hypertension requiring an anti-hypertensive within 1 hr of epinephrine

Results:

• 1727 patients (n=2183 PDP episodes) were included in the final analysis.
• 3175 patients evaluated for inclusion however 1348 excluded due to PDP being given in OR as the main reason for exclusion
• Median dose of phenylephrine = 400mcg (Range 200 to 888mcg) and Epinephrine = 50mcg (Range 20 to 100mcg)
• Primary outcome achieved in 71.8% (102) pts in the epi group and 55.9% (1140) pts in the phenylephrine group

Critical Results:

• The odds ratios in the chart above apply to phenylepinephrine responders, the following values apply to non-responders
  • Receipt of crystalloid boluses: OR 0.0639; 95% CI 0.432 to 0.946
  • Receipt of PRBCs: OR 0.303; 95% CI 0.099 to 0.935
• Phenylepinephrine responders more frequently received pRBC, crystalloid boluses and sedation

• No serious adverse events occurred in the epinephrine cohort
• History of CHF associated with response to epinephrine (OR 11.889, 95% CI 1.030 – 137.257)
• Neither cohort had any adverse extravasation requiring phentolamine or terbutaline

Strengths:

• Largest study assessing PDP use in ED patients and those admitted to multiple ICUs
• All study definitions were chosen priori
• Assessed more than just safety and medication errors by also assessing Variables predicting PDP response
• Utilized a variety of statistical testing such as Chi Squared for categorical variables and Mann-Whitney U or Wilcoxin Rank test for continuous variables
• PDP use was assessed in a variety of settings outside of the OR
• Presence of cardiac dysfunction was assessed and known to affect hemodynamics was collected
• Well defined primary outcomes, adverse effects and “episode” of PDP administration
• Utilized well accepted and validated clinical decision tools (ie. APACHE II and Charlson Comorbidity)

Limitations:

• Initially evaluated 3175 patients for inclusion but 1348 excluded due to PDP being given in OR
• Retrospective design – unable to control for many potential confounding factors
• They found an association between fluid boluses and lack of phenylephrine response, they could not evaluate patient’s fluid status due to documentation limitations in the EHR
• Lack of available documentation due to patient’s tenuous hemodynamic status
• Inability to ascertain occurrence of ventricular dysrhythmias related to PDP administration
• Small sample size of epinephrine cohort
• At this institution, the preparation/ dilution of PDPs at the bedside is not allowed. In other words these were pre-made syringes and not mixed at the bedside. From a safety standpoint this is a great thing, but also could be the reason we see such few adverse events

Discussion:

• There is a recent “push” to utilize “Push dose pressors” as the correction of acute hypotension in a variety of clinical scenarios. This study chose a relevant topic to analyze that could influence acute management in the ED and has a fairly larger sample size of patients to do so.
• Phenylephrine and epinephrine are two of the most common vasopressors and more studies need to be done to analyze long term effects of the two.
• The retrospective design of this study omitted assessment of ventricular dysrhythmias related to push dose pressor administration, as they were reliant on information in the EMR. Adrenergic agonists certainly have the potential to affect sympathetic sequelae, and adverse events. Further studies are needed to assess the prevalence of cardiac dysrhythmia.
• Overall, 56% of patients that received phenylephrine and 70% of patients that received epinephrine achieved a 25% increase in SBP. Both agents improved SBP, DBP, and MAP. The increase in metrics was expected, however, it is worth noting that epinephrine seems more effective……..
• Not so fast…15.5% in phenylephrine group and 27.5% in the epi group received continuous vasopressor infusions within 50 min prior to PDP and 46.3% in the phenylephrine group and 74.6% in the epi group received continuous vasopressor infusions within the 60min after PDP administration….both would favor epi seeming more effective
• Administration of crystalloid boluses and PRBCs were associated with a lack of response to phenylephrine. This could indicate that hypotension may have been adequately managed with preload expansion. Another study showed similar results, >30mL/kg of fluids prior to phenylephrine administration received fewer and lower cumulative phenylephrine dose.^{5, 6} These findings highlight the importance of adequate preload expansion in the treatment of acute hypotension.
• Administration of any sedative was predictive of phenylephrine response. This could be useful in RSI, where sedatives are frequently used before intubation. The mechanism of peri intubation hypotension is multifactorial including vasoplegia, loss of adrenergic tone, worsening acidosis due to apnea, and reduced venous return after initiation of positive pressure ventilation
• Epinephrine concentrations diluted at bedside showed less hemodynamic events. This highlights the importance of pre-made PDP syringes and
• proper labeling, storage, and staff education for PDPs.
• The low adverse event rate that occurred in this study should emphasize the importance of premade PDP syringes, proper labeling, storage, and staff education when using PDPs
• The low adverse event rate that occurred in this study should emphasize the importance of premade PDP syringes, proper labeling, storage, and staff education when using PDPs
• Caution should be taken when utilizing PDPs in patients with cardiac dysfunction or congestive heart failure. Lastly, bedside dilutions of epinephrine had less efficacy thus highlighting the importance of pre-made syringes, proper labeling, storage, and staff education regarding PDPs.
• In regards to the role of PDP in patients with cardiac dysfunction and CHF, this study found no differences in response to either agent in patients with cardiac dysfunction. Interestingly, CHF history was associated with a positive response to epinephrine. Unfortunately, due to the small sample size of the epinephrine cohort, further studies are warranted to determine the effects of cardiac dysfunction on PDP response.
• Caution should be taken when utilizing PDPs in patients with cardiac dysfunction or congestive heart failure. Lastly, bedside dilutions of epinephrine had less efficacy thus highlighting the importance of pre-made syringes, proper labeling, storage, and staff education regarding PDPs.
• In regards to the role of PDP in patients with cardiac dysfunction and CHF, this study found no differences in response to either agent in patients with cardiac dysfunction. Interestingly, CHF history was associated with a positive response to epinephrine. Unfortunately, due to the small sample size of the epinephrine cohort, further studies are warranted to determine the effects of cardiac dysfunction on PDP response.

Author’s Conclusions:

This study demonstrates that PDP phenylephrine and epinephrine are safe and efficacious in treating the acute hypotensive period

Our Conclusion:

Although conclusions on mortality and clinical outcomes cannot be definitively made, this retrospective study demonstrates the safe and efficacious use of PDP in the acute hypotension period with no severe adverse effects.

Potential to Impact Current Practice:

Initiatives should be made at the institution level to develop in-service education sessions, policies and procedures for the safe administration of PDPs in the acute hypotensive period. If pre-made syringes are not financially feasible then the creation of these medications should be done by a dedicated emergency department pharmacist.

Clinical Bottom Line:

Acute hypotension must be treated emergently in order to decrease morbidity and mortality. Push dose pressors are a valid choice in bridging the patient to continuous vasopressors. Furthermore this study emphasizes the importance of pre-made syringes, proper labeling, storage, and staff education for PDPs.

References:

1. Singer S, et al. The safety and efficacy of push dose vasopressors in critically ill adults. Am J Emerg Med. 2022 2022 Sep 5. PMID: 36108346
2. Cole JB, et al. Human Errors and Adverse Hemodynamic Events Related to “Push Dose Pressors” in the Emergency Department. J Med Toxicol. Epub 2019 Jul 3. PMID: 31270748
3. Maheshwari K, et al. The relationship between ICU hypotension and in-hospital mortality and morbidity in septic patients. Intensive Care Med. 2018;44(6):857–67. PMID: 29872882
4. Jones AE, et al. Emergency department hypotension predicts sudden unexpected in-hospital mortality: a prospective cohort study. Chest. 2006;130(4):941–6. PMID: 17035422
5. Holler JG, et al. Nontraumatic hypotension and shock in the emergency department and the prehospital setting, prevalence, etiology, and mortality: a systematic review. PLoS One. 2015;10(3):e0119331. PMID: 25789927
6. Schwartz MB, et al. The impact of push-dose phenylephrine use on subsequent preload expansion in the ED setting. Am J Emerg Med. 2016; PMID: 27720568

Guest Post By:

Courney Knieriem, MD
PGY-1, Emergency Medicine Resident
RWJBH Community Medical Center, Toms River, NJ
Courtneyknieriem.md@rutgers.edu

Mark Ramzy, DO
Emergency Medicine Attending and Critical Care Intensivist
Clinical Assistant Professor of Emergency Medicine
RWJBH Community Medical Center, Toms River, NJ
Twitter: @MRamzyDO

For More Thoughts on This Topic Checkout:

• EMCrit: Push-Dose Pressures Update
• EMDOCS: Push-Dose Pressures – An Update for 2019
• Alabama Chapter of the American College of Emergency Physicians (alacep.org)

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)

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