Article Identification

Article Title: Preparation/Administration of Push-Dose versus Continuous Infusion Epinephrine and Phenylephrine: A Simulation

Authors (Top 5): Hannah Morley, PharmD; Robert Seabury, PharmD; Katie Parsels, PharmD; Christopher Miller, PharmD; William Darko, BPharm, PharmD

Journal Name, Year, Volume, Issue: American Journal of Emergency Medicine, 2023, Volume 74, Pages 135–139

Type of Study: Crossover Simulation Study

DOI/PMID: 10.1016/j.ajem.2023.10.002

Quick Reference Summary

Key Findings: Push-dose (PD) administration of epinephrine and phenylephrine significantly reduces total preparation and administration time by approximately 70 seconds compared to continuous infusion (CI). However, PD is associated with a higher incidence of major preparation and administration errors (18.8% in PD vs. 0% in CI).

Primary Outcomes: PD demonstrated a median total time of 206.5 seconds versus CI's 275.8 seconds (P=0.003). Major errors leading to five-fold or greater overdose occurred in 18.8% of PD administrations and 0% in CI (P=0.020).

Core Clinical Question

Research Question: In emergency department (ED) and intensive care unit (ICU) settings, does push-dose (PD) administration of epinephrine and phenylephrine reduce preparation and administration time compared to continuous infusion (CI) without increasing major errors?

Background

Disease/Condition Overview:

• Hypotension is a prevalent issue in the ED and ICU, elevating the risk of adverse patient outcomes.

Prior Data on the Topic:

• PD vasopressors are administered as intermittent intravenous pushes (IVPs) and may expedite treatment due to fewer required materials.
• Limited comparative data exist on the preparation time and error rates between PD and CI administration of vasopressors.

Current Standard of Care:

• Epinephrine and phenylephrine are primarily administered as continuous infusions (CI) in EDs and ICUs, necessitating additional administration materials and setup time.

Knowledge Gaps Addressed by Study:

• The study aims to quantify the preparation and administration times and identify preparation and administration errors associated with PD versus CI administration of epinephrine and phenylephrine.

Study Rationale:

• Understanding the balance between efficiency and safety in vasopressor administration can inform best practices and improve patient outcomes in acute care settings.

Methods Summary

Study Design:

• Crossover simulation study conducted in a simulation center at an academic medical center.

Setting and Time Period:

• Simulation center at SUNY Upstate Medical University; received June 30, 2023, revised September 18, 2023, accepted October 1, 2023.

Population Characteristics:

• Participants: 16 pharmacists (9 ED, 7 ICU)
• Experience: All had advanced cardiac life support training and prior experience with CI epinephrine or phenylephrine (100%). 68.8% had experience preparing PD epinephrine or phenylephrine.

Inclusion/Exclusion Criteria:

• Included: Pharmacists employed by SUNY Upstate University Hospital and SUNY Upstate Medical University.
• Excluded: Pharmacy residents and pharmacy students.
• Participation: Voluntary and uncompensated.

Intervention Details:

• Push-Dose (PD):
  • Epinephrine: 100 μg in 10 mL NS as an IVP.
  • Phenylephrine: 1000 μg in 10 mL NS as an IVP.
• Preparation: Pharmacists prepared PD syringes and coordinated administration with simulated nurses.

Control/Comparison Group Details:

• Continuous Infusion (CI):
  • Epinephrine: 8 mg in 250 mL NS administered at 20 g/min via Alaris® smart pump.
  • Phenylephrine: 100 mg in 250 mL NS administered at 100 μg/min via Alaris® smart pump.

Primary and Secondary Outcomes:

• Primary Outcome: Total preparation and administration time (seconds).
• Secondary Outcome: Major and moderate preparation and administration errors, with major errors defined as causing a five-fold or greater overdose.

Statistical Analysis Approach:

• Software: SPSS Version 28 (IBM Corp., Armonk, NY)
• Descriptive Statistics: Minimum, maximum, mean with SD, median with IQR, number with percentage (%).
• Comparisons:
  • Continuous paired data: Paired t-test or Wilcoxon signed rank test.
  • Categorical paired data: McNemar test.
• Significance Level: P < 0.05.

Sample Size Calculations:

• Estimate: 16 pharmacists to detect a 15-second difference with 95% power and 5% alpha, assuming a 15-second standard deviation (SD).

Ethics and Funding Information:

• Ethics: Approved by Institutional Review Board (review exemption).
• Funding: None received.
• Conflicts of Interest: None disclosed.

Detailed Results

Participant Flow and Demographics:

• Total Participants: 16 pharmacists (9 ED, 7 ICU).
• Training: All completed advanced cardiac life support training.
• Experience with PD: 68.8% (11/16) had prior experience preparing PD vasopressors.

Primary Outcome Results:

• Total Preparation and Administration Time:
  • PD: Median 206.5 seconds (IQR 166.4–290.4)
  • CI: Median 275.8 seconds (IQR 247.4–303.9)
  • Difference: ≈70 seconds decrease with PD.
  • Statistical Significance: P=0.003
• Preparation Time:
  • PD: Median 188.5 seconds (IQR 147.6–261)
  • CI: Median 166 seconds (IQR 133.4–205.1)
  • Statistical Significance: P=0.067 (Not significant)
• Administration Time:
  • PD: Median 20.5 seconds (IQR 15.6–25.9)
  • CI: Median 104.3 seconds (IQR 95.5–117.4)
  • Statistical Significance: P<0.001

Secondary Outcome Results:

• Major Preparation and Administration Errors:
  • PD: 6 out of 32 administrations (18.8%) had at least one major error.
  • CI: 0 out of 32 administrations (0%) had major errors.
  • Statistical Significance: P=0.020
• Error Details:
  • Epinephrine PD: 4 major errors vs. 0 in CI (P=0.180)
  • Phenylephrine PD: Median 0 (0–2.3) major errors vs. 0 in CI (P=0.046)
• Types of Errors:
  • Dilutional Errors: Caused 83.3% (5/6) of overdoses, including:
    • Two 10-fold epinephrine overdoses (200 μg)
    • Four 10-fold phenylephrine overdoses (1000 μg)
  • Administration Error: One 5-fold overdose (100 μg) from a correctly prepared epinephrine syringe.

Confidence Intervals:

Not explicitly provided for error rates, but P-values indicate statistical significance where applicable.

Effect Sizes:

• PD reduced total time by approximately 70 seconds compared to CI.

Subgroup Analyses:

• Epinephrine vs. Phenylephrine PD:
  • Epinephrine PD: Faster total and administration times, no significant increase in major errors.
  • Phenylephrine PD: Faster administration time and higher major error rate.

Results Tables

Outcome	Push-Dose Group	Continuous Infusion Group	Difference (95% CI)	P-value
Total Time (seconds), median (IQR)	206.5 (166.4–290.4)	275.8 (247.4–303.9)	−70s	0.003
Preparation Time (seconds), median (IQR)	188.5 (147.6–261)	166 (133.4–205.1)	+22.5s	0.067
Administration Time (seconds), median (IQR)	20.5 (15.6–25.9)	104.3 (95.5–117.4)	+83.8s	<0.001

Table 1: Preparation and Administration Instructions Provided to ED/ICU Pharmacist.

Vasopressor Type	Preparation Instructions
PD Epinephrine	Prepare 100 μg in 10 mL NS syringe and administer as an IVP.
PD Phenylephrine	Prepare 1000 μg in 10 mL NS syringe and administer as an IVP.
CI Epinephrine	Prepare 8 mg in 250 mL NS bag; administer at 20 g/min CI.
CI Phenylephrine	Prepare 100 mg in 250 mL NS bag; administer at 100 μg/min CI.

Table 2: Preparation and Administration Times for Push-Dose versus Continuous Infusion Epinephrine and Phenylephrine.

Vasopressor	Total Time (seconds), median (IQR)	Preparation Time (seconds), median (IQR)	Administration Time (seconds), median (IQR)	P-value
Epinephrine PD	205 (70.9)	155.3 (121.3–235.6)	23.8 (16.3–25.9)	0.002
Epinephrine CI	269.2 (54.5)	154.3 (121–200.7)	102.3 (95.8–112.8)
Phenylephrine PD	257.8 (100.7)	223.3 (157.6–286.5)	20.3 (6.7)
Phenylephrine CI	296 (43.6)	174.8 (158.5–206.3)	108.5 (17.9)

Table 3: Major Preparation and Administration Errors for Push-Dose versus Continuous Infusion Epinephrine and Phenylephrine.

Vasopressor	Push-Dose Group	Continuous Infusion Group	P-value
Epinephrine & Phenylephrine	0 (0–0)	0 (0–0)	0.020
Epinephrine	0 (0–0)	0 (0–0)	0.180
Phenylephrine	0 (0–2.3)	0 (0–0)	0.046

*Abbreviations: IQR = interquartile range, n = number, SD = standard deviation.*

Authors' Conclusions

• Primary Conclusions:
  • ED/ICU pharmacists achieved faster median total preparation and administration times for PD epinephrine and phenylephrine compared to CI.
  • PD was associated with a higher rate of major preparation and administration errors.
• Interpretation of Results:
  • While PD administration can expedite vasopressor delivery, it increases the risk of significant dosing errors, primarily due to dilutional mistakes.
• Clinical Implications Stated by Authors:
  • The clinical benefit of PD over CI is unclear due to the increased error rate.
  • Cautious preparation and administration of PD vasopressors are recommended until further research clarifies the clinical impact of these errors.
• Future Research Recommendations:
  • Investigate the clinical outcomes associated with PD-related errors.
  • Explore the use of premade formulations to reduce preparation errors.
  • Assess the effect of standardized education and protocols on improving PD preparation and administration accuracy.

Literature Review

• Comparative Findings:
  • Brindley et al. (2017): Similar simulation found PD epinephrine reduced time without increasing major errors.
  • Cole et al. (2019): Retrospective review showed 3% errors leading to overdoses.
  • Rotando et al. (2019): Identified a 10.3% error rate in phenylephrine PD administrations.
• Guideline References:
  • ISMP Safe Practice Guidelines (2017): Recommend the use of premade formulations for PD vasopressors to minimize errors.
• Study Contributions:
  • Contrasts with Brindley et al. by identifying increased errors with PD.
  • Highlights the need for premade formulations and standardized preparation protocols to enhance safety.

Critical Analysis

A. Strengths:

• Methodological Strengths:
  • Crossover Design: Each pharmacist acted as their own control, reducing inter-individual variability.
  • Direct Observation: Errors were directly observed by trained investigators, enhancing accuracy over self-reported data.
• Internal Validity Considerations:
  • Standardized Protocols: Ensured consistency across all simulations.
  • Block Randomization: Minimized potential ordering effects in preparation sequences.
• External Validity Considerations:
  • Diverse Pharmacist Pool: Inclusion of both ED and ICU pharmacists enhances generalizability to various critical care settings.
  • Realistic Simulation Environment: Utilization of actual clinical equipment (e.g., Alaris® smart pump) increases applicability of findings to real-world scenarios.

B. Limitations:

• Study Design Limitations:
  • Simulation-Based: May not fully capture the complexities and stresses of actual clinical environments, potentially affecting performance.
• Potential Biases:
  • Hawthorne Effect: Pharmacists might alter behavior due to awareness of being observed.
• Generalizability Issues:
  • Single-Center Study: Conducted at an academic medical center, which may limit applicability to other settings like community hospitals.
• Statistical Limitations:
  • Small Sample Size: Involving only 16 pharmacists may limit the power to detect smaller effect sizes and affect the reliability of error rates.
• Missing Data Handling:
  • Not Explicitly Addressed: The study utilized dual data collection and consensus methods, but specifics on handling missing data were not detailed.

Clinical Application

• Change in Current Practice:
  • Efficiency vs. Safety: While PD administration can save valuable time, the increased risk of major errors necessitates a cautious approach.
• Applicable Patient Populations/Scenarios:
  • Critical Care Settings: Particularly in EDs and ICUs where rapid vasopressor administration is crucial.
• Implementation Considerations:
  • Premade Formulations: Adoption of premade PD and CI vasopressor formulations can reduce preparation errors.
  • Standardized Protocols: Implementing uniform preparation and administration protocols can enhance safety.
  • Education and Training: Ongoing training for pharmacists on PD preparation to minimize errors.
• Integration with Existing Evidence:
  • Complementary Findings: Aligns with existing guidelines advocating for premade formulations and highlights the potential risks associated with PD administration.

How To Use This Info In Practice

Recommendation: Use push-dose vasopressors with caution, ensuring standardized preparation protocols and considering premade formulations to minimize the risk of major dosing errors.

Notes for Clarity

• Bullet Points: Utilized throughout for easy scanning.
• Bolded Statistical Significance: Key P-values (P=0.003, P<0.001, P=0.020, P=0.046) have been bolded to highlight significance.
• Confidence Intervals: Included where available.
• Conflicts of Interest: None disclosed.
• Areas of Uncertainty: Highlighted the unclear clinical benefit of PD due to increased error rates.
• Funding Sources: No financial support was received for the project.
• Areas of Uncertainty: The clinical impact of increased errors remains uninvestigated.
• Limitations Highlighted: Emphasized simulation-based limitations and small sample size.