A Phase 4 interventional study of Acetaminophen and Placebo in Critical Illness and Fever, sponsored by University of British Columbia. Terminated at 1 site in Canada. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-11-04.
Sponsored by University of British Columbia · Phase 4, Interventional, and Treatment
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.
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:
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.
1,881 studies on the registry are indexed under Critical Illness; 462 are open to participants now.
This study's enrollment of 10 is below the median of 90 across 979 interventional studies indexed under Critical Illness.
Browse Critical Illness studies →University of British Columbia is the lead sponsor of 1,309 studies on the registry; 253 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 1 (17%) have results posted.
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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:
EXCLUSION CRITERIA:
NOTE: in response to very low enrollment 2 exclusion criteria were changed on Nov 5, 2015. These were:
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
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)
Also known as: Tylenol
one-time dose of placebo (identical capsule) given via the enteral route (via the gut)
Also known as: Pharmacy compounded look alike capsule to the study drug
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.
Time frame: 4 hours post acetaminophen administration
Blood Pressure
systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressures (MAP) will be monitored for 4 hours post intervention
Time frame: 4 hours post intervention
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.
Time frame: 4 hours post intervention
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.
Time frame: 4 hours post intervention
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
Time frame: 6 hours post intervention
SCREENING: Of the 950 patients who were admitted between May 28, 2015 and Jan. 20, 2016, 790 were screened, at least once. A few were screened a second time if their status had changed. ELIGIBILITY: 100 patients were eligible. RECRUITMENT: 27/100 were successfully contacted to be invited to this study. 10 consented to participate.
| Milestone | Control Group | Acetaminophen Group |
|---|---|---|
| Started | 1 | 5 |
| Completed | 1 | 5 |
| Not completed | 0 | 0 |
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.
| Participants | Control Group | Acetaminophen Group |
|---|---|---|
| Clinically Significant Hypotension | 0 | 0 |
systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressures (MAP) will be monitored for 4 hours post intervention
| mmHg | Control Group | Acetaminophen Group |
|---|---|---|
| SBP: Pre-Intervention (2 hours) | 141.6 (102 to 159) | 122.6 (80 to 170) |
| SBP: Post-Intervention (4 hours) | 141.5 (127 to 157) | 119.5 (86 to 158) |
| DBP: Pre-Intervention (2 hours) | 57.4 (46 to 63) | 66.2 (45 to 91) |
| DBP: Post-Intervention (4 hours) | 51.0 (47 to 55) | 65.4 (45 to 83) |
| MAP: Pre-Intervention (2 hours) | 80.8 (61 to 90) | 84.1 (56 to 114) |
| MAP: Post-Intervention (4 hours) | 75.5 (68 to 83) | 82.4 (61 to 107) |
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.
| mcg | Control Group | Acetaminophen Group |
|---|---|---|
| Pre-Intervention (2 hours) TOTAL Norepinephrine | 167.0 | NA |
| Pre-Intervention (2 hours) TOTAL Milrinone | NA | 6000.0 |
| Post-Intervention (4 hours) TOTAL Norepinephrine | 576.0 | NA |
| Post-Intervention (4 hours) TOTAL Milrinone | NA | 7000.0 |
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.
| mL | Control Group | Acetaminophen Group |
|---|---|---|
| Pre-Intervention (2 hours) Total fluid INTAKE | 235 (235 to 235) | 298 (30 to 736) |
| Pre-Intervention (2 hours) Total fluid OUTPUT | 80 (80 to 80) | 370 (140 to 790) |
| Post-Intervention (4 hours) Total Fluid INTAKE | 734 (734 to 734) | 612 (353 to 856) |
| Post-Intervention (4 hours) Total Fluid OUTPUT | 245 (245 to 245) | 852 (230 to 1400) |
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
| °C*hours | Control Group | Acetaminophen Group |
|---|---|---|
| Pre-Intervention FB (2 hours) | 0.97 (0.97 to 0.97) | 2.16 (1.07 to 3.78) |
| Post-Intervention FB (6 hours) | 0.74 (0.74 to 0.74) | 5.65 (1.60 to 10.24) |
Collected over Until ICU discharge (max 28 days). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Control Group | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| Acetaminophen Group | 1/5 (20%) | 0/5 (0%) | 0/5 (0%) |
| Age, Categorical(Participants) | Control Group | Acetaminophen Group | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 0 | 5 | 5 |
| >=65 years | 1 | 0 | 1 |
| Age, Continuous(years) | Control Group | Acetaminophen Group | Total |
|---|---|---|---|
| Median | 76 (76 to 76) | 35 (29 to 59) | 43.5 (29 to 76) |
| Sex: Female, Male(Participants) | Control Group | Acetaminophen Group | Total |
|---|---|---|---|
| Female | 0 | 2 | 2 |
| Male | 1 | 3 | 4 |
| Region of Enrollment(participants) | Control Group | Acetaminophen Group | Total |
|---|---|---|---|
| Canada | 1 | 5 | 6 |
Plan to share: Undecided — Under review with the research team.
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