Effect of Phenylephrine Versus Norepinephrine on Venous Return

Comparison of the Hemodynamic Effects of Phenylephrine and Norepinephrine in Patients Undergoing Deep Inferior Epigastric Perforator (DIEP) Flap Surgery.

Induction of general anesthesia often induces a decrease in the mean arterial blood pressure (MAP) caused by arterial and venous dilatation. Fluid administration is conventionally used to increase the patient's total blood volume, but is often associated with multiple adverse events such as postoperative edema.

Arterial hypotension can also be treated by vasopressor agents such as norepinephrine and phenylephrine which mainly increase the blood pressure by arterial vasoconstriction.

Compared to phenylephrine, norepinephrine has a shorter half-life (2 - 3 minutes) and improves the MAP by increase in cardiac contractility. In a recent study at our department it was demonstrated that besides arterial vasoconstriction, phenylephrine also improves venous return and cardiac output by venous vasoconstriction.

The aim of this study is to compare the hemodynamic effects of both vasopressor agents in patients undergoing deep inferior epigastric perforators (DIEP) flap surgery. If significant differences between both agents are demonstrated, these findings can provide an important basis for future recommendations.

Study Overview

• Status: Unknown
• Conditions: Arterial Hypotension
• Intervention / Treatment: Drug: Phenylephrine; Drug: Norepinephrine

Detailed Description

In consecutive patients scheduled for DIEP flap surgery, all hemodynamic and respiratory variables are recorded electronically for subsequent off line analysis.

A systolic blood pressure of minimal 100 mmHg will be maintained during surgery by optimization of the cardiac preload and titrated norepinephrine (1.5 µg/kg/h) or phenylephrine (15 µg/kg/h) administration. Cardiac preload optimization will be based on pulse pressure variation (PPV) measurement, which is calculated by pulse contour analysis of the radial arterial pressure curve. Following the international goal-directed fluid therapy guidelines, plasmalyte will be administrated if the PPV>11%.

The tricuspid annular plane systolic excursion (TAPSE) will be measured by transthoracic echocardiography (TTE) to evaluate the inotropic effect of norepinephrine and phenylephrine. In addition, TTE will be used to measure the cardiac output to calibrate the PPV measurements.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alain F Kalmar, MD, PhD; Phone Number: +32 246 17 29; Email: alain.kalmar@gmail.com
• Study Contact Backup: Name: Silvie Allaert, MD, PhD; Phone Number: +32 246 17 28; Email: silvie.allaert@azmmsj.be

Study Locations

• Belgium
  • Oost-Vlaanderen
    • Ghent, Oost-Vlaanderen, Belgium, 9000
      • Recruiting
      • General Hospital Maria Middelares
      • Contact: Alain F Kalmar, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Adult
• patients scheduled for DIEP flap surgery

Exclusion Criteria:

• unwilling or unable to grant written informed consent
• contra-indications for phenylephrine or norepinephrine
• cardiac arrhythmia
• no necessity for pharmacological blood pressure management

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: phenylephrine; starts at 15 µg/kg/h phenylephrine and titrated to main a minimal systolic blood pressure of 100 mmHg	Drug: Phenylephrine; intravenous administration
Active Comparator: norepinephrine; starts at 1.5 µg/kg/h phenylephrine and titrated to main a minimal systolic blood pressure of 100 mmHg	Drug: Norepinephrine; intravenous administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pulse pressure variation	the evolution of the pulse pressure variation in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean arterial blood pressure	the evolution of the mean arterial blood pressure in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative
cardiac output	the evolution of the cardiac output in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative
stroke volume (variation)	the evolution of the stroke volume (variation) in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative
heart rate	the evolution of the heart rate in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative
ventilation frequency	the evolution of the ventilation frequency in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative
end-tidal CO2	the evolution of the end-tidal CO2 in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative
tidal volume	the evolution of the tidal volume in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative
TAPSE	the evolution of the tricuspid annular plane systolic excursion in a time course of 20 minutes after the start of phenylephrine/norepinephrine administration	perioperative

Collaborators and Investigators

• Sponsor: Algemeen Ziekenhuis Maria Middelares
• Investigators: Principal Investigator: Alain F Kalmar, MD, PhD, Maria Middelares Hospital

Publications and helpful links

General Publications

• Kalmar AF, Allaert S, Pletinckx P, Maes JW, Heerman J, Vos JJ, Struys MMRF, Scheeren TWL. Phenylephrine increases cardiac output by raising cardiac preload in patients with anesthesia induced hypotension. J Clin Monit Comput. 2018 Dec;32(6):969-976. doi: 10.1007/s10877-018-0126-3. Epub 2018 Mar 22.
• O'Connell TD, Jensen BC, Baker AJ, Simpson PC. Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev. 2013 Dec 24;66(1):308-33. doi: 10.1124/pr.112.007203. Print 2014.
• Beloeil H, Mazoit JX, Benhamou D, Duranteau J. Norepinephrine kinetics and dynamics in septic shock and trauma patients. Br J Anaesth. 2005 Dec;95(6):782-8. doi: 10.1093/bja/aei259. Epub 2005 Oct 14.
• Hengstmann JH, Goronzy J. Pharmacokinetics of 3H-phenylephrine in man. Eur J Clin Pharmacol. 1982;21(4):335-41. doi: 10.1007/BF00637623.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2019
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): June 15, 2020

Study Registration Dates

• First Submitted: March 11, 2019
• First Submitted That Met QC Criteria: March 11, 2019
• First Posted (Actual): March 13, 2019

Study Record Updates

• Last Update Posted (Actual): October 11, 2019
• Last Update Submitted That Met QC Criteria: October 9, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: pulse pressure variation; fluid responsiveness; cardiac output; hemodynamic monitoring
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypotension; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Respiratory System Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Norepinephrine; Phenylephrine; Oxymetazoline
• Other Study ID Numbers: MMS.2019.008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No