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

Study Overview
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Brief Summary
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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: 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. 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
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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.

Official Title
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Effects of Intravenous Acetaminophen on Body Temperature and Hemodynamic Responses in Febrile Critically Ill Adults: a Randomized Controlled Trial

Conditions
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Fever, Critical Illness

Intervention / Treatment
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* Drug: Acetaminophen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Normal saline placebo<br>Normal saline 100 mLs intravenous, administered over 15 minutes | Drug: Placebo<br>* Normal saline placebo Normal saline 100 mLs intravenous, administered over 15 minutes<br>* Other names: 0.9% sodium chloride;|
| Experimental: Acetaminophen<br>Acetaminophen 1 gram/100 mLs intravenous, single dose administered over 15 minutes | Drug: Acetaminophen<br>* acetaminophen 1 gram/100mLs intravenously administered over 15 minutes<br>* Other names: Ofirmev;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 4 hours post study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 4 hours post study drug administration | 
| 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. | Baseline to 4 hours post study drug administration | 
| 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. | Baseline to 4 hours post study drug administration | 
| 2-hour Change Over Time Core Temperature | change over time core temperature after study drug administration (adjusted to baseline core temperature) | 2 hours | 
| 2-hour Change Over Time Systolic Blood Pressure | 2-hour change over time SBP from study drug administration (means adjusted to baseline SBP) | Baseline to 2 hours | 
| 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) | Baseline to 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fever, Acetaminophen, Critical Care, ICU, Febrile