Safety and Efficacy of Acetaminophen in the Intensive Care Unit. (SEA-ICU)

November 3, 2022 updated by: Vininder K. Bains, University of British Columbia

Safety and Antipyretic Efficacy of Acetaminophen in the Febrile Intensive Care Unit Patient.

The intensive care unit (ICU) team needs to know what effects acetaminophen has in critically ill patients. Acetaminophen is better known as Tylenol. It is the drug given to reduce fever. Most research that has looked at how safe and effective this drug is, has been done with healthy people. Those studies tell us it is safe and works well to bring down fever.

This may not be true for the ICU patient. Some research found acetaminophen was not as good at reducing fever as expected in the ICU. Fever helps to fight infection so it may help patients get better, but it is also stressful. When you have fever, you to need more oxygen, and your heart beats faster. If you have a fever after brain injury, you are less likely to make a full recovery. In patients with brain injury, a weak heart or trouble breathing we should treat fever. If we can predict how well acetaminophen will reduce fever, we can decide if this drug is enough, or other treatments are also needed.

If you do not have problems with your brain, heart, or lungs, it is safe to not treat fever. When you give this drug to treat fever, the body cools itself by sweating, and bringing hot blood to the skin's surface. These changes do not affect healthy people. Research suggests ICU patients may be at risk for sudden drop in blood pressure.

Our study will answer 2 questions: 1) When acetaminophen is given to treat fever in ICU patients, are they more likely to have a drop in blood pressure? 2) How much will acetaminophen reduce fever in ICU patients? We will study ICU patients with a fever who can safely get, or not get this drug. This information will help us decide when and how to treat fever in the ICU.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

In the ICU, fever is commonly treated with 650 mg acetaminophen every 4 hours with the hopes of reducing fever burden, thereby also reducing metabolic demand. Acetaminophen is thought to be a safe and effective antipyretic. This assumption has not been tested in the critically ill despite its widespread use. Observational studies report critically ill patients experience hypotension, sometimes severe enough to require treatment; other studies indicate acetaminophen may not be as effective at reducing fever burden in the critically ill.

OBJECTIVES:

  • To see if 650mg acetaminophen, given to febrile critically ill patients affects blood pressure; by comparing the incidence of hypotension severe enough to require treatment in the way of a fluid bolus (500cc or greater) or increase in vasoactive drugs (increase in norepinephrine by 5mcg or greater); by assessing for changes in mean arterial pressure and systolic blood pressure.
  • To quantify the degree of fever suppression achieved by 650mg acetaminophen in the febrile critically ill population.

RESEARCH PROPOSAL:

Patients admitted into Vancouver Hospital's ICU are eligible for this study if they have a new fever and meet the inclusion/exclusion criteria. Study participants will be randomly assigned into one of 2 study arms, the control group and the 650mg group. Study participants in the control group will receive 2 capsules of placebo and the 650mg group will receive 2 capsules of 325mg acetaminophen. Data (continuous measures of temperature, heart rate and blood pressure) will be collected from the time of the study drug administration until 6 hours post. All patients, health care workers, and researchers will be blinded to which arm the patient is enrolled in until the end of the study. The incidence of fluid bolus administration, increases in vasoactive drug use, will be recorded and compared. We will also compare blood pressure data, and fever burden between the 2 groups.

INCLUSION/EXCLUSION CRITERIA To be included the subject must be admitted to the ICU; have an arterial line as standard of care; have at least 2 hours of a temperature greater than 38.3°C; within 24 hours of fever onset or ICU admission; be hemodynamically stable, and not received any drugs with known antipyretic effects at least 6 hours prior to initiating the study. Patients are excluded if they have an acute brain injury, liver dysfunction, cardiac dysfunction, requiring greater than 50% fraction of inspired oxygen (FiO); mechanical ventilation is permitted, any extracorporeal blood treatments (dialysis, plasmapheresis, etc.), injury to more than 20% of the skin (i.e. burn patient), or the responsible physician is opposed to enrolment.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 1M9
        • Vancouver Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Generally to be considered for this study one must be critically ill, febrile, and can safely either receive acetaminophen or have acetaminophen withheld. Also one must not have conditions that would alter normal drug absorption or normal thermoregulation. Specifically the eligibility criteria are:

INCLUSION CRITERIA:

  • Adult patients (> 18 years) admitted to Intensive Care Unit at Vancouver Hospital with a core temperature > 38.3 °C for 2 or more consecutive hours, but not longer than 48 hours*
  • Continuous arterial pressure monitor in place at the time of intervention and data collection
  • Patients may only participate in the study once
  • To remain in the ICU for the entire study period (2 hours prior to drug administration to 4 hours post drug administration)

EXCLUSION CRITERIA:

  • Significant liver dysfunction
  • Acute neurological injury
  • Seizure disorder
  • Cardiomyopathy, elevated cardiac enzymes indicative of an acute cardiac injury, electrocardiogram (ECG) changes indicative of cardiac ischemia (i.e., ST segment elevation/depression)
  • Hemodynamic instability (requiring fluid boluses, or change/initiation of vasopressors. Patients receiving steady doses of vasopressor support may be included)
  • Severe hypoxemia, (fraction of inspired oxygen (FiO2) requirements of more than 60% to maintain hemoglobin oxygen saturation (SaO2) > 90% or partial pressure of oxygen in the blood (PaO2) > 70)
  • Temperature > 40.0 °C
  • Receiving external cooling
  • Haemodialysis, plasma exchange, or any treatment where the blood is taken out of the body and processed
  • Acute thermal injury to skin (i.e., burn)
  • Gut malabsorption (i.e., receiving < 40% required calories enterally)
  • Receiving medications that have known antipyretic effects (acetaminophen, ibuprofen, steroids, etc.)
  • Physician opposed to enrolment in the study

NOTE: in response to very low enrollment 2 exclusion criteria were changed on Nov 5, 2015. These were:

  1. patients no longer needed to recieve 40% of required calories enterally, instead patients who were not receiving any caloric intake via the gut could be enrolled as long as they were still permitted to receive oral medications.
  2. patients no longer had to have acetaminophen discontinued upon enrollment. They could not be receiving it regularly but could still receive acetaminophen on an as needed (PRN) basis as long as it could be safely withheld for up to 12 hours if they developed a fever.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Control Group
This group consists of stable but febrile ICU patients (temp >38.3°C). Participants in this group will receive a one-time dose of placebo via the enteral route (via the gut), after which vital signs (including continuous measures of core temperature, heart rate, and blood pressure) will be monitored for 4 hours.
Drug: Placebo
one-time dose of placebo (identical capsule) given via the enteral route (via the gut)
Other Names:
  • Pharmacy compounded look alike capsule to the study drug
Experimental: Acetaminophen Group
This group consists of stable but febrile ICU patients (temp >38.3°C). Participants in this group will receive a one-time does of acetaminophen 650mg via the enteral route (via the gut), after which vital signs (including continuous measures of core temperature, heart rate, and blood pressure) will be monitored for 4 hours.
Drug: Acetaminophen
one-time dose of acetaminophen 650mg given via the enteral route (via the gut)
Other Names:
  • Tylenol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinically Significant Hypotension
Time Frame: 4 hours post acetaminophen administration
Clinically significant hypotension is defined as an acute drop in mean arterial pressure requiring treatment. Treatment is defined as either a 500 cc (or greater) fluid bolus and/or an increase in inotrope support of greater than 5 mcg/min over baseline.
4 hours post acetaminophen administration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Pressure
Time Frame: 4 hours post intervention
systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressures (MAP) will be monitored for 4 hours post intervention
4 hours post intervention
Equivalent-dose of Vasoactive Medication Post Intervention
Time Frame: 4 hours post intervention

Total dose of all vasoactive medications will be converted to total Equidose value (with the formula 10 mcg/min norepinephrine ≈ 5 mcg/kg/min dopamine ≈ 10 mcg/min epinephrine ≈ 1 mcg/min phenylephrine ≈ 0.02 u/min vasopressin as per Russell et al. (2008)) before comparing the treatment and control groups

Only 2 of the 6 participants were on low-dose vasoactive medications, (i.e., one was on norepinephrine and the other was on milrinone) therefore the pre-planned conversion calculation was not done.
4 hours post intervention
Equivalent-volume Fluid Administered Post Intervention
Time Frame: 4 hours post intervention
Total crystalloid and colloid fluid will be converted the the equi-volume dose (with the ratio 1.4:1 (as per Finfer et al.(2004) & Vincent and Weil (2006) before making comparisons between the treatment and control groups.
4 hours post intervention
Fever Burden
Time Frame: 6 hours post intervention

Continuous measurements of core body temperature will be recorded for 6 hours. Fever burden (FB) is defined as area between the 6 hour temperature curve and 38.3°C cut-off and it is reported in °C-hour.

PRE-INTERVENTION FB: is reported for a 2 hour period. POST-INTERVENTION FB: post-intervention fever burden is reported for a 6 hour period and average hourly fever burden.

Peak Temperature: is the highest recorded temperature for the study period in °C Minimum Temperature: is the lowest recorded temperature for the study period in °C
6 hours post intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of British Columbia

Collaborators

Vancouver Coastal Health Research Institute

Investigators

  • Study Chair: William Henderson, PhD, University of British Columbia
  • Principal Investigator: Vininder K Bains, BSN, Vancouver Coastal Health
  • Study Chair: Martha Mackay, PhD, University of British Columbia
  • Study Chair: Leanne Currie, PhD, University of British Columbia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2015

Primary Completion (Actual)

February 1, 2016

Study Completion (Actual)

February 1, 2016

Study Registration Dates

First Submitted

October 29, 2014

First Submitted That Met QC Criteria

October 30, 2014

First Posted (Estimate)

October 31, 2014

Study Record Updates

Last Update Posted (Actual)

November 4, 2022

Last Update Submitted That Met QC Criteria

November 3, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H13-01160

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

IPD Plan Description

Under review with the research team.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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