NOrepinephrine and VasoprEssin Versus Norepinephrine aLone in Critically Ill Patients With Septic Shock (NOVEL)

NOrepinephrine and VasoprEssin Versus Norepinephrine aLone in Critically Ill Patients With Septic Shock (NOVEL Trial)

Sepsis, a systemic host response to the invasion of a pathogenic microorganism, may progress to severe sepsis, wherein the patient experiences acute dysfunction in at least one organ system, and further develop into septic shock if the patient cannot regain adequate systemic blood pressure and perfusion after adequate and appropriate fluid resuscitation. Further prospective study of the potential mortality benefit with combination norepinephrine and vasopressin in critically ill patients with septic shock needs to be performed. Our research will resolve this essential question and improve the scientific knowledge surrounding vasoactive medications in patients with septic shock.

Study Overview

• Status: Withdrawn
• Conditions: Shock, Septic
• Intervention / Treatment: Drug: Vasopressin; Drug: Norepinephrine

Detailed Description

Sepsis, a systemic host response to the invasion of a pathogenic microorganism, may progress to severe sepsis, wherein the patient experiences acute dysfunction in at least one organ system, and further develop into septic shock if the patient cannot regain adequate systemic blood pressure and perfusion after adequate and appropriate fluid resuscitation. The exact societal burden from severe sepsis and septic shock in difficult to quantify: millions of individuals in both industrialized and developing nations experience these syndromes each year, the best medical centers in the world have only achieved a 22% mortality rate for severe sepsis, and caregivers as well as patients endure a long-lasting impact from caring from loved ones who have survived severe sepsis. Recently, the impactful work performed by Rivers and colleagues that established early goal-directed therapy (EGDT) as the standard of care for patients with severe sepsis or septic shock has been compared to usual care in three international trials. The results of these trials suggest that usual care is as effective as EGDT, which necessitates new research be conducted into each component of EGDT to determine how and to what extent specific therapies are safe and effective. One key aspect of the provision of care to patients with septic shock is the time to initiation and choice of vasoactive agents. This study will investigate the use of norepinephrine and vasopressin versus norepinephrine alone as the initial vasoactive regimen in critically ill adult patients with septic shock.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18 years (no maximum age)

• At least 2 of 4 systemic inflammatory response syndrome criteria:

  1. Fever (>38°C) or hypothermia (<36°C),
  2. Tachycardia (heart rate >90 bpm),
  3. Tachypnea (respiratory rate >20 breaths/min or partial pressure of carbon dioxide <4.3 kPa) or need for mechanical ventilation,
  4. Abnormal leucocyte count (>12000 cells/mm3, <4000 cells/mm3 or >10% immature (band) forms).
• Hypotension despite adequate intravenous fluid resuscitation (minimum 20 mL/kg within the previous 4 hours)
• Clinical suspicion for or confirmation of an infection
• Admitted or being admitted to the medical intensive care unit

Exclusion Criteria:

• End-stage renal disease requiring long-term dialysis
• Pregnant
• Not expected to be alive within 48 hours of enrollment
• Receipt of a continuous infusion of vasoactive medication(s) other than use for emergency stabilization of blood pressure (for less than 4 hours)
• Enrollment in another clinical trial within 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Norepinephrine and vasopressin; Norepinephrine (0.05 to 0.5 mcg/kg/min) and vasopressin (0.04 units/min) will be given by continuous infusion to achieve and maintain a target mean arterial pressure (65-75 mm Hg).	Drug: Vasopressin; Subjects will receive vasopressin (0.04 units/min) by continuous infusion to achieve and maintain a target mean arterial pressure (65-75 mm Hg). The treating physician may choose the initial dosage of norepinephrine within the initial range of 0.05-0.5 mcg/kg/min. The treating physician may alter the target mean arterial pressure if clinically indicated.; Drug: Norepinephrine; Subjects will receive norepinephrine (0.05 to 0.5 mcg/kg/min) by continuous infusion with titration by bedside nurse to achieve and maintain a target mean arterial pressure (65-75 mm Hg). The treating physician may choose the initial dosage of norepinephrine within the initial range of 0.05-0.5 mcg/kg/min. The treating physician may alter the target mean arterial pressure if clinically indicated.
Active Comparator: Norepinephrine; Norepinephrine (0.05 to 0.5 mcg/kg/min) will be given by continuous infusion to achieve and maintain a target mean arterial pressure (65-75 mm Hg).	Drug: Norepinephrine; Subjects will receive norepinephrine (0.05 to 0.5 mcg/kg/min) by continuous infusion with titration by bedside nurse to achieve and maintain a target mean arterial pressure (65-75 mm Hg). The treating physician may choose the initial dosage of norepinephrine within the initial range of 0.05-0.5 mcg/kg/min. The treating physician may alter the target mean arterial pressure if clinically indicated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to goal MAP	Within 28 days of therapy initiation

Collaborators and Investigators

• Sponsor: University of Arkansas
• Investigators: Principal Investigator: Drayton Hammond, Pharm.D., University of Arkansas

Publications and helpful links

General Publications

• Hammond DA, Ficek OA, Painter JT, McCain K, Cullen J, Brotherton AL, Kakkera K, Chopra D, Meena N. Prospective Open-label Trial of Early Concomitant Vasopressin and Norepinephrine Therapy versus Initial Norepinephrine Monotherapy in Septic Shock. Pharmacotherapy. 2018 May;38(5):531-538. doi: 10.1002/phar.2105. Epub 2018 Apr 30.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): November 27, 2017
• Study Completion (Actual): November 27, 2017

Study Registration Dates

• First Submitted: May 22, 2015
• First Submitted That Met QC Criteria: May 22, 2015
• First Posted (Estimate): May 27, 2015

Study Record Updates

• Last Update Posted (Actual): November 29, 2017
• Last Update Submitted That Met QC Criteria: November 27, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: septic shock; norepinephrine; vasopressin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Natriuretic Agents; Hemostatics; Coagulants; Sympathomimetics; Vasoconstrictor Agents; Antidiuretic Agents; Norepinephrine; Vasopressins; Arginine Vasopressin
• Other Study ID Numbers: 204265

Plan for Individual participant data (IPD)

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