Critical Illness, Fever
Conditions
Keywords
Fever, Acetaminophen, Critical Care, ICU, Febrile
Brief summary
The purpose of this study is to compare the effects of intravenous acetaminophen to placebo on body temperature and hemodynamic (heart rate and blood pressure) responses in febrile critically ill adult patients. There are limited data to explain the variable and unpredictable antipyretic and hemodynamic response to acetaminophen in febrile ICU patients. The complex pathophysiology of critically ill patients, co-morbid conditions, the effect of multiple pharmacologic and non-pharmacologic care interventions, and/or the potential interferences with absorption of enteral or rectal formulations may be related to variations in the antipyretic response to acetaminophen. It is necessary for clinicians to have a better understanding of the therapy response and potential adverse effects of this commonly administered medication, especially the recently available IV formulation, in critically ill patients. Further research of the antipyretic response to acetaminophen in critically ill patients is warranted to inform evidence-based practice guidelines for fever management. Further randomized, placebo-controlled studies of hemodynamic responses to IV acetaminophen are also warranted. Primary Hypothesis: There is a significant reduction in time-weighted average core body temperature over 4 hours after administration of IV acetaminophen compared to placebo in febrile critically ill patients. Secondary Hypotheses: 1. There is a significant reduction in time-weighted average heart rate over 4 hours after administration of IV acetaminophen compared to placebo in febrile critically ill patients. 2. There is a significant reduction in time-weighted mean arterial pressure over 4 hours after administration of IV acetaminophen compared to placebo in febrile critically ill patients. Adult patients with fever (≥ 38.3ºCentigrade/101ºFarenheit) in the intensive care unit will be screened for eligibility and enrolled after informed consent. Patients will be randomized to receive IV acetaminophen 1 gram or normal saline 100 mLs. Body temperature, heart rate, and blood pressure will be measured at baseline and during the 4 hours post study drug administration.
Detailed description
Adult patients with fever (≥ 38.3ºCentigrade (C)/101ºFarenheit(F)) in the intensive care unit will be screened for eligibility and approached for informed consent. Enrolled patients will be stratified based on the leading etiology of their fever: either neurologic injury or infection and then randomized to receive IV acetaminophen 1 gram or normal saline 100 milliliters (mLs). Core body temperature will be measured using a zero-heat flow thermometry system (non-invasive, small disk on forehead). Patients will be monitored and data collected during the 4-hour post study drug administration period. A rescue protocol will be implemented if the temperature reaches ≥ 40 ºC during the study period and includes notification of primary team provider by the nurse and the pharmacist will contact them to inform the provider of study group (acetaminophen or placebo). The provider can decide whether to order antipyretic medication or physical cooling interventions at that time.
Interventions
DRUGAcetaminophen
acetaminophen 1 gram/100mLs intravenously administered over 15 minutes
DRUGPlacebo
Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age and older * Patient in an intensive care unit * Weight greater or equal to 50 kgs * Fever: core body temperature greater than or equal to 38.3 degrees Celsius * Clinically stable: no active resuscitation with fluids, blood products, or dose increases of vasoactive medications within 1 hour of study drug administration
Exclusion criteria
* Acetaminophen hypersensitivity * Acute liver failure or acute liver injury * Heat stroke, malignant hyperthermia, neuroleptic malignant syndrome * Therapeutic cooling, physical cooling, extracorporeal blood circuit therapies * Administration of acetaminophen-containing medications, non-steroidal anti-inflammatory drugs, or aspirin greater than 81 mg within specified times per drug prior to fever presentation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Core Body Temperature | Baseline to 4 hours post study drug administration | time-weighted average core body temperature over 4 hours. Core temperature was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the core temperature values was divided by time in minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure | Baseline to 4 hours post study drug administration | time-weighted average systolic blood pressure over 4 hours. Systolic blood pressure was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the systolic blood pressure values was divided by time in minutes. |
| Respiratory Rate | Baseline to 4 hours post study drug administration | time weighted average for respiratory rate over 4 hours. Respiratory rate was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the respiratory rate values was divided by time in minutes. |
| Heart Rate | Baseline to 4 hours post study drug administration | time-weighted average heart rate over 4 hours. Heart rate was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the heart rate values was divided by time in minutes. |
| 2-hour Change Over Time Systolic Blood Pressure | Baseline to 2 hours | 2-hour change over time SBP from study drug administration (means adjusted to baseline SBP) |
| 2-hour Change Over Time Heart Rate | Baseline to 2 hours | 2-hour change over time heart rate from time of study drug administration (means adjusted to baseline HR) |
| 2-hour Change Over Time Core Temperature | 2 hours | change over time core temperature after study drug administration (adjusted to baseline core temperature) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Normal Saline Placebo Normal saline 100 mLs intravenous, administered over 15 minutes
Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes | 20 |
| Acetaminophen Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes
Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Acetaminophen | Normal Saline Placebo | Total |
|---|---|---|---|
| Acute Physiologic and Chronic Health Evaluation (APACHE) II score | 24 scores on a scale STANDARD_DEVIATION 6 | 24 scores on a scale STANDARD_DEVIATION 6 | 24 scores on a scale STANDARD_DEVIATION 6 |
| Age, Continuous | 58 years STANDARD_DEVIATION 15 | 57 years STANDARD_DEVIATION 13 | 57.5 years STANDARD_DEVIATION 14 |
| Body Mass Index (BMI) | 29 kilograms per meter squared STANDARD_DEVIATION 5 | 31 kilograms per meter squared STANDARD_DEVIATION 7 | 30 kilograms per meter squared STANDARD_DEVIATION 6 |
| Core body temperature | 38.4 degrees Celsius STANDARD_DEVIATION 0.3 | 38.6 degrees Celsius STANDARD_DEVIATION 0.5 | 38.5 degrees Celsius STANDARD_DEVIATION 0.4 |
| diastolic blood pressure | 73 mm Hg STANDARD_DEVIATION 15 | 64 mm Hg STANDARD_DEVIATION 13 | 67.5 mm Hg STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 17 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heart Rate | 90 beats per minute STANDARD_DEVIATION 14 | 93 beats per minute STANDARD_DEVIATION 15 | 91.5 beats per minute STANDARD_DEVIATION 14.5 |
| mean arterial pressure | 100 mm Hg STANDARD_DEVIATION 20 | 89 mm Hg STANDARD_DEVIATION 16 | 94.5 mm Hg STANDARD_DEVIATION 18 |
| Mode of ventilation Number of patients NOT on mechanical ventilation | 8 Participants | 5 Participants | 13 Participants |
| Mode of ventilation Number of patients on Assist Control | 2 Participants | 4 Participants | 6 Participants |
| Mode of ventilation Number of patients on Pressure Support | 10 Participants | 11 Participants | 21 Participants |
| Number of patients receiving Mechanical Ventilation | 12 Participants | 15 Participants | 27 Participants |
| Number of patients receiving types of medication infusions Number of patients on analgesic infusions | 1 Participants | 3 Participants | 4 Participants |
| Number of patients receiving types of medication infusions Number of patients on no medication infusions | 5 Participants | 0 Participants | 5 Participants |
| Number of patients receiving types of medication infusions Number of patients on sedative infusions | 8 Participants | 9 Participants | 17 Participants |
| Number of patients receiving types of medication infusions Number of patients on vasodilator infusions | 2 Participants | 2 Participants | 4 Participants |
| Number of patients receiving types of medication infusions Number of patients on vasopressor infusions | 4 Participants | 6 Participants | 10 Participants |
| Number of patients with infectious and noninfectious etiology of fever Number of patients with Infectious etiology | 15 Participants | 15 Participants | 30 Participants |
| Number of patients with infectious and noninfectious etiology of fever Number of patients with Noninfectious etiology | 5 Participants | 5 Participants | 10 Participants |
| Number of patients with sepsis | 13 Participants | 14 Participants | 27 Participants |
| Primary ICU diagnosis Number of patients iwth Neurologic diagnoses | 12 Participants | 10 Participants | 22 Participants |
| Primary ICU diagnosis Number of patients with Medical diagnoses | 6 Participants | 6 Participants | 12 Participants |
| Primary ICU diagnosis Number of patients with Surgical diagnoses | 2 Participants | 4 Participants | 6 Participants |
| respiratory rate | 20 breaths per minute STANDARD_DEVIATION 6 | 24 breaths per minute STANDARD_DEVIATION 5 | 22 breaths per minute STANDARD_DEVIATION 5.5 |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 23 Participants |
| systolic blood pressure | 151 mm Hg STANDARD_DEVIATION 26 | 135 mm Hg STANDARD_DEVIATION 26 | 143 mm Hg STANDARD_DEVIATION 26 |
| Temperature of room | 21.4 degrees Celsius STANDARD_DEVIATION 1.2 | 21.5 degrees Celsius STANDARD_DEVIATION 1.4 | 21.4 degrees Celsius STANDARD_DEVIATION 1.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Core Body Temperature
time-weighted average core body temperature over 4 hours. Core temperature was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the core temperature values was divided by time in minutes.
Time frame: Baseline to 4 hours post study drug administration
Population: Patients in an ICU with fever, weighed \> 50kg and did not meet any exclusion criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Placebo | Core Body Temperature | 38.4 degrees Celsius | Standard Error 0.1 |
| Acetaminophen | Core Body Temperature | 37.9 degrees Celsius | Standard Error 0.1 |
Comparison: We estimated that 20 patients per group would provide 80% power for detecting a difference in means of 0.6 degrees Celsius, with a pooled SD of 0.67 degrees, using a two group t test and a two sided alpha level of 0.05. A previous RCT of IV acetaminophen in healthy male volunteers with induced fever found a core temperature difference of 0.60 degrees with a common SD of 0.67 degrees Celsius.p-value: 0.00295% CI: [-0.76, -0.18]ANCOVA
Secondary
2-hour Change Over Time Core Temperature
change over time core temperature after study drug administration (adjusted to baseline core temperature)
Time frame: 2 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Placebo | 2-hour Change Over Time Core Temperature | -0.01 degrees Celsius | Standard Error 1.3 |
| Acetaminophen | 2-hour Change Over Time Core Temperature | -0.8 degrees Celsius | Standard Error 1.3 |
p-value: 0.00295% CI: [-1, -0.3]ANCOVA
Secondary
2-hour Change Over Time Heart Rate
2-hour change over time heart rate from time of study drug administration (means adjusted to baseline HR)
Time frame: Baseline to 2 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Placebo | 2-hour Change Over Time Heart Rate | 2 BPM | Standard Error 2 |
| Acetaminophen | 2-hour Change Over Time Heart Rate | -6 BPM | Standard Error 2 |
p-value: 0.0295% CI: [-15, -1]ANCOVA
Secondary
2-hour Change Over Time Systolic Blood Pressure
2-hour change over time SBP from study drug administration (means adjusted to baseline SBP)
Time frame: Baseline to 2 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Placebo | 2-hour Change Over Time Systolic Blood Pressure | -0.1 mm Hg | Standard Error 5 |
| Acetaminophen | 2-hour Change Over Time Systolic Blood Pressure | -24 mm Hg | Standard Error 5 |
p-value: 0.00195% CI: [-38, -10]ANCOVA
Secondary
Heart Rate
time-weighted average heart rate over 4 hours. Heart rate was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the heart rate values was divided by time in minutes.
Time frame: Baseline to 4 hours post study drug administration
Population: Patients in the ICU with fever, weight of \> 50kg and no exclusion criteria met.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Placebo | Heart Rate | 92 beats per minute | Standard Error 2 |
| Acetaminophen | Heart Rate | 87 beats per minute | Standard Error 2 |
p-value: 0.0395% CI: [-10, -1]ANCOVA
Secondary
Respiratory Rate
time weighted average for respiratory rate over 4 hours. Respiratory rate was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the respiratory rate values was divided by time in minutes.
Time frame: Baseline to 4 hours post study drug administration
Population: Patients in the ICU with fever, weight of \> 50kg and no exclusion criteria met.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Placebo | Respiratory Rate | 22 breaths per minute | Standard Error 1 |
| Acetaminophen | Respiratory Rate | 21 breaths per minute | Standard Error 1 |
p-value: 0.4295% CI: [-4, 12]ANCOVA
Secondary
Systolic Blood Pressure
time-weighted average systolic blood pressure over 4 hours. Systolic blood pressure was measured every 5 minutes times 4, and then every 15 minutes over the following 4 hours from the time of study drug administration. The sum of the systolic blood pressure values was divided by time in minutes.
Time frame: Baseline to 4 hours post study drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Placebo | Systolic Blood Pressure | 143 mm Hg | Standard Error 3 |
| Acetaminophen | Systolic Blood Pressure | 127 mm Hg | Standard Error 3 |
p-value: <0.00195% CI: [-25, -8]ANCOVA