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Critical IllnessPhase 4SEA-ICUNCT02280239

Safety and Efficacy of Acetaminophen in the Intensive Care Unit.

A Phase 4 study testing Acetaminophen in people with Critical Illness and Fever, run by University of British Columbia at 1 site in Canada.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Critical Illness, Fever
What is being tested?
Acetaminophen
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
10 participants
Where
1 siteCanada
Study dates
May 2015to Feb 2016
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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)
Show all 16Show fewer
  • 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:
  • 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.
  • 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.

Trial locations and contacts

1 site in 1 country.

Canada1 site
  • Vancouver Hospital

    Vancouver, British Columbia, V5Z 1M9

Other trials in Canada

About this study

Official title: 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.

Read more

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.

Read the 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.

Being tested
Acetaminophen, Placebo
Keywords
Fever, Acetaminophen, Body Temperature Regulation, Critical Illness, Hypotension
Medical subject headings
Critical Illness, Fever, Hypotension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AcetaminophenDrug

    Also called Tylenol

    one-time dose of acetaminophen 650mg given via the enteral route (via the gut)

  • PlaceboDrug

    Also called Pharmacy compounded look alike capsule to the study drug

    one-time dose of placebo (identical capsule) given via the enteral route (via the gut)

Study groups in NCT02280239
Study groupRoleWhat they receive
Control GroupPlacebo comparatorThis 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.
Receives: Drug: Placebo
Acetaminophen GroupExperimentalThis 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.
Receives: Drug: Acetaminophen

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinically Significant Hypotension

    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.

    Measured: 4 hours post acetaminophen administration

Secondary outcomes (4)
  1. Blood Pressure

    systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressures (MAP) will be monitored for 4 hours post intervention

    Measured: 4 hours post intervention

  2. Equivalent-dose of Vasoactive Medication 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.

    Measured: 4 hours post intervention

  3. Equivalent-volume Fluid Administered 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.

    Measured: 4 hours post intervention

  4. Fever Burden

    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

    Measured: 6 hours post intervention

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Oct 2014 (estimated)
  2. Study startMay 2015
  3. Primary completionFeb 2016
  4. Study completionFeb 2016

Why it stopped: Only enrolled 10 participants over 9 months which is less then anticipated (75).

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02280239
Sponsor's protocol ID
H13-01160
Acronym
SEA-ICU
Status last verified
Nov 2022
First submitted
29 Oct 2014
Last updated
4 Nov 2022
Data monitoring committee
No
Individual data sharing
Undecided: Under review with the research team.

Publications

  • Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373.

    PubMed 18305265
  • Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247-56. doi: 10.1056/NEJMoa040232.

    PubMed 15163774
  • Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med. 2006 May;34(5):1333-7. doi: 10.1097/01.CCM.0000214677.76535.A5.

    PubMed 16557164
  • Boyle M, Nicholson L, O'Brien M, Flynn GM, Collins DW, Walsh WR, Bihari D. Paracetamol induced skin blood flow and blood pressure changes in febrile intensive care patients: An observational study. Aust Crit Care. 2010 Nov;23(4):208-14. doi: 10.1016/j.aucc.2010.06.004. Epub 2010 Jul 22.

    PubMed 20655241
  • Boyle M, Hundy S, Torda TA. Paracetamol administration is associated with hypotension in the critically ill. Aust Crit Care. 1997 Dec;10(4):120-2. doi: 10.1016/s1036-7314(97)70414-4.

    PubMed 9708071
  • Krajcova A, Matousek V, Duska F. Mechanism of paracetamol-induced hypotension in critically ill patients: a prospective observational cross-over study. Aust Crit Care. 2013 Aug;26(3):136-41. doi: 10.1016/j.aucc.2012.02.002. Epub 2012 Mar 14.

    PubMed 22424816
  • Allegaert K, Naulaers G. Haemodynamics of intravenous paracetamol in neonates. Eur J Clin Pharmacol. 2010 Sep;66(9):855-8. doi: 10.1007/s00228-010-0860-z. Epub 2010 Jul 4.

    PubMed 20607221
  • de Maat MM, Tijssen TA, Bruggemann RJ, Ponssen HH. Paracetamol for intravenous use in medium--and intensive care patients: pharmacokinetics and tolerance. Eur J Clin Pharmacol. 2010 Jul;66(7):713-9. doi: 10.1007/s00228-010-0806-5. Epub 2010 Mar 19.

    PubMed 20300741
  • Danguy des Deserts M, Nguyen BV, Giacardi C, Commandeur D, Paleiron N. [Acetaminophen-induced hypotension after intravenous and oral administration]. Ann Fr Anesth Reanim. 2010 Apr;29(4):313-4. doi: 10.1016/j.annfar.2010.02.006. Epub 2010 Mar 12. No abstract available. French.

    PubMed 20227233
  • Mrozek S, Constantin JM, Futier E, Zenut M, Ghardes G, Cayot-Constantin S, Bonnard M, Ait-Bensaid N, Eschalier A, Bazin JE. [Acetaminophene-induced hypotension in intensive care unit: a prospective study]. Ann Fr Anesth Reanim. 2009 May;28(5):448-53. doi: 10.1016/j.annfar.2009.01.018. Epub 2009 Mar 21. French.

    PubMed 19304444
  • Hersch M, Raveh D, Izbicki G. Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Pharmacotherapy. 2008 Oct;28(10):1205-10. doi: 10.1592/phco.28.10.1205.

    PubMed 18823215
  • Cruz P, Garutti I, Diaz S, Fernandez-Quero L. [Metamizol versus propacetamol: comparative study of the hemodynamic and antipyretic effects in critically ill patients]. Rev Esp Anestesiol Reanim. 2002 Oct;49(8):391-6. Spanish.

    PubMed 12455318
  • Mackenzie I, Forrest K, Thompson F, Marsh R. Effects of acetaminophen administration to patients in intensive care. Intensive Care Med. 2000 Sep;26(9):1408. doi: 10.1007/s001340000614. No abstract available.

    PubMed 11089781
  • Bendjelid K, Soubirou JL, Bohe J. [Systemic arterial hypotension induced by paracetamol administration: nurse's anecdotes or facts from the intensive care unit?]. Ann Fr Anesth Reanim. 2000 Jun;19(6):499. doi: 10.1016/s0750-7658(00)00230-6. No abstract available. French.

    PubMed 10941454
  • Gozzoli V, Treggiari MM, Kleger GR, Roux-Lombard P, Fathi M, Pichard C, Romand JA. Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive Care Med. 2004 Mar;30(3):401-7. doi: 10.1007/s00134-003-2087-2. Epub 2004 Jan 13.

    PubMed 14722642

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Acetaminophen in people with Critical Illness and Fever, run by University of British Columbia at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 4 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 4 Nov 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinically Significant Hypotension (time frame: 4 hours post acetaminophen administration). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02280239, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2022.

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