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Effects of Intravenous Acetaminophen on Body Temperature and Hemodynamic Responses in Febrile Critically Ill Adults (ICUFeverAPAP)

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ClinicalTrials.gov Identifier: NCT01869699
Recruitment Status : Completed
First Posted : June 5, 2013
Results First Posted : August 9, 2017
Last Update Posted : August 9, 2017
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Conditions Fever
Critical Illness
Interventions Drug: Acetaminophen
Drug: Placebo
Enrollment 41
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Period Title: Overall Study
Started 21 20
Completed 20 20
Not Completed 1 0
Reason Not Completed
Withdrawal by Subject             1             0
Arm/Group Title Normal Saline Placebo Acetaminophen Total
Hide Arm/Group Description

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Total of all reporting groups
Overall Number of Baseline Participants 20 20 40
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 20 participants 20 participants 40 participants
57  (13) 58  (15) 57.5  (14)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Female
9
  45.0%
8
  40.0%
17
  42.5%
Male
11
  55.0%
12
  60.0%
23
  57.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Hispanic or Latino
3
  15.0%
6
  30.0%
9
  22.5%
Not Hispanic or Latino
17
  85.0%
14
  70.0%
31
  77.5%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kilograms per meter squared
Number Analyzed 20 participants 20 participants 40 participants
31  (7) 29  (5) 30  (6)
[1]
Measure Description: Body Mass Index (BMI) units of measure are kilograms per meter squared
Primary ICU diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Number of patients with Medical diagnoses
6
  30.0%
6
  30.0%
12
  30.0%
Number of patients with Surgical diagnoses
4
  20.0%
2
  10.0%
6
  15.0%
Number of patients iwth Neurologic diagnoses
10
  50.0%
12
  60.0%
22
  55.0%
Acute Physiologic and Chronic Health Evaluation (APACHE) II score   [1] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 20 participants 20 participants 40 participants
24  (6) 24  (6) 24  (6)
[1]
Measure Description: Acute Physiologic and Chronic Health Evaluation (APACHE) II is a severity-of-disease classification system (Knaus et al., 1985), one of several ICU scoring systems. It is applied within 24 hours of admission of a patient to an intensive care unit (ICU): an integer score from 0 to 71 is computed based on several measurements; higher scores correspond to more severe disease.
Number of patients with infectious and noninfectious etiology of fever  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Number of patients with Infectious etiology
15
  75.0%
15
  75.0%
30
  75.0%
Number of patients with Noninfectious etiology
5
  25.0%
5
  25.0%
10
  25.0%
Number of patients receiving types of medication infusions  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Number of patients on vasopressor infusions
6
  30.0%
4
  20.0%
10
  25.0%
Number of patients on vasodilator infusions
2
  10.0%
2
  10.0%
4
  10.0%
Number of patients on sedative infusions
9
  45.0%
8
  40.0%
17
  42.5%
Number of patients on analgesic infusions
3
  15.0%
1
   5.0%
4
  10.0%
Number of patients on no medication infusions
0
   0.0%
5
  25.0%
5
  12.5%
Number of patients with sepsis   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
14
  70.0%
13
  65.0%
27
  67.5%
[1]
Measure Description: Sepsis was defined as new confirmed or suspected infection and 2 or more systemic inflammatory response syndrome (SIRS) criteria. (Dellinger RP, Levy MM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Medicine 2013; 39: 165-228.)
Number of patients receiving Mechanical Ventilation  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
15
  75.0%
12
  60.0%
27
  67.5%
Mode of ventilation  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Number of patients on Pressure Support
11
  55.0%
10
  50.0%
21
  52.5%
Number of patients on Assist Control
4
  20.0%
2
  10.0%
6
  15.0%
Number of patients NOT on mechanical ventilation
5
  25.0%
8
  40.0%
13
  32.5%
Temperature of room  
Mean (Standard Deviation)
Unit of measure:  Degrees Celsius
Number Analyzed 20 participants 20 participants 40 participants
21.5  (1.4) 21.4  (1.2) 21.4  (1.3)
Core body temperature  
Mean (Standard Deviation)
Unit of measure:  Degrees Celsius
Number Analyzed 20 participants 20 participants 40 participants
38.6  (0.5) 38.4  (0.3) 38.5  (0.4)
Heart Rate  
Mean (Standard Deviation)
Unit of measure:  Beats per minute
Number Analyzed 20 participants 20 participants 40 participants
93  (15) 90  (14) 91.5  (14.5)
systolic blood pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 20 participants 20 participants 40 participants
135  (26) 151  (26) 143  (26)
diastolic blood pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 20 participants 20 participants 40 participants
64  (13) 73  (15) 67.5  (14)
mean arterial pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 20 participants 20 participants 40 participants
89  (16) 100  (20) 94.5  (18)
respiratory rate  
Mean (Standard Deviation)
Unit of measure:  Breaths per minute
Number Analyzed 20 participants 20 participants 40 participants
24  (5) 20  (6) 22  (5.5)
1.Primary Outcome
Title Core Body Temperature
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Patients in an ICU with fever, weighed > 50kg and did not meet any exclusion criteria.
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description:

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Overall Number of Participants Analyzed 20 20
Mean (Standard Error)
Unit of Measure: degrees Celsius
38.4  (0.1) 37.9  (0.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Saline Placebo, Acetaminophen
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.47
Confidence Interval (2-Sided) 95%
-0.76 to -0.18
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Heart Rate
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Patients in the ICU with fever, weight of > 50kg and no exclusion criteria met.
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description:

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Overall Number of Participants Analyzed 20 20
Mean (Standard Error)
Unit of Measure: beats per minute
92  (2) 87  (2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Saline Placebo, Acetaminophen
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -6
Confidence Interval (2-Sided) 95%
-10 to -1
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Systolic Blood Pressure
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description:

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Overall Number of Participants Analyzed 20 20
Mean (Standard Error)
Unit of Measure: mm Hg
143  (3) 127  (3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Saline Placebo, Acetaminophen
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -17
Confidence Interval (2-Sided) 95%
-25 to -8
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Respiratory Rate
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Patients in the ICU with fever, weight of > 50kg and no exclusion criteria met.
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description:

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Overall Number of Participants Analyzed 20 20
Mean (Standard Error)
Unit of Measure: breaths per minute
22  (1) 21  (1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Saline Placebo, Acetaminophen
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.42
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1
Confidence Interval (2-Sided) 95%
-4 to 12
Estimation Comments [Not Specified]
5.Secondary Outcome
Title 2-hour Change Over Time Core Temperature
Hide Description change over time core temperature after study drug administration (adjusted to baseline core temperature)
Time Frame 2 hours
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description:

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Overall Number of Participants Analyzed 20 20
Mean (Standard Error)
Unit of Measure: degrees Celsius
-0.01  (1.3) -0.8  (1.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Saline Placebo, Acetaminophen
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-1 to -0.3
Estimation Comments [Not Specified]
6.Secondary Outcome
Title 2-hour Change Over Time Systolic Blood Pressure
Hide Description 2-hour change over time SBP from study drug administration (means adjusted to baseline SBP)
Time Frame Baseline to 2 hours
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description:

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Overall Number of Participants Analyzed 20 20
Mean (Standard Error)
Unit of Measure: mm Hg
-0.1  (5) -24  (5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Saline Placebo, Acetaminophen
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -24
Confidence Interval (2-Sided) 95%
-38 to -10
Estimation Comments [Not Specified]
7.Secondary Outcome
Title 2-hour Change Over Time Heart Rate
Hide Description 2-hour change over time heart rate from time of study drug administration (means adjusted to baseline HR)
Time Frame Baseline to 2 hours
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description:

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

Overall Number of Participants Analyzed 20 20
Mean (Standard Error)
Unit of Measure: BPM
2  (2) -6  (2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Saline Placebo, Acetaminophen
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -8
Confidence Interval (2-Sided) 95%
-15 to -1
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Normal Saline Placebo Acetaminophen
Hide Arm/Group Description

Normal saline 100 mLs intravenous, administered over 15 minutes

Placebo: Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes

Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes

Acetaminophen: acetaminophen 1 gram/100mLs intravenously administered over 15 minutes

All-Cause Mortality
Normal Saline Placebo Acetaminophen
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Normal Saline Placebo Acetaminophen
Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/20 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Normal Saline Placebo Acetaminophen
Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/20 (0.00%) 
The generalizability of our findings is limited due to the use of a single site and our sample size was modest. Also, patients in this study had baseline stable and normal or high BP, so unclear if same results in patients with unstable or low BP.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Hildy Schell-Chaple
Organization: University of California, San Francisco
Phone: 415-353-1039
EMail: hildegarde.schell-chaple@ucsf.edu
Publications:
Layout table for additonal information
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01869699     History of Changes
Other Study ID Numbers: UCSF-ICUFever
First Submitted: May 31, 2013
First Posted: June 5, 2013
Results First Submitted: June 9, 2017
Results First Posted: August 9, 2017
Last Update Posted: August 9, 2017