Aggressive Fever Control With Intravenous Ibuprofen After Non-traumatic Brain Hemorrhage

Fever, defined as temperature higher than 38.3C (100.9 F), is common in patients with head injuries and is associated with poor recovery after injury. The current standard of care is to use oral acetaminophen (Tylenol) followed by a body cooling device. This method can effectively reduce fever but results in a high rate of shivering. Shivering is stressful to the heart and can further worsen brain injury. Methods to combat shivering have been developed and are successful in limiting the stress in the majority of patients that use a body cooling device. However, the drugs used to control shivering are sedating and may also interfere with brain recovery.

The purpose of this study is to assess whether ibuprofen given intravenously is more effective in combating fever than the current standard of care. Should results from this study demonstrate that ibuprofen infusion is effective, a larger study will be conducted to determine whether this aggressive fever control regimen leads to improved recovery after brain injury.

Study Overview

• Status: Terminated
• Conditions: Fever
• Intervention / Treatment: Drug: Intravenous Ibuprofen; Drug: Acetaminophen (Standard of Care)

Detailed Description

This is an open-label, investigator initiated single center, randomized, prospective study. Subjects meeting enrollment criteria will be randomly assigned 1:1 to one of two groups:

1. Standard Care: Acetaminophen 650 mg via oral/nasogastric tube every 6 hours as needed for T>=38.3 C (100.9 F) for up to post bleed day 14 or discharge from the Neuro ICU, whichever comes first.
2. Ibuprofen 400 mg/100 mL NS IV over 30 minutes, followed by a continuous infusion of 2000 mg/500 mL NS at 85 mg/hour (21 mL/hour) for up to post bleed day 14 or discharge from the Neuro ICU, whichever comes first.

Patients/surrogates will be approached for consent and randomized upon admission. Therapy will only be initiated once a patient becomes febrile (>=38.3 C, 100.9 F). The use of temperature modulating devices will be permitted as per institutionally approved guidelines in those patients continuing to demonstrate a fever (T>38.3 C, 100.9 F) with either therapy.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 years of age or older
• Aneurysmal subarachnoid hemorrhage (SAH), Hunt Hess grade >= 3, 24 hours after admission.
• Intracerebral hemorrhage (ICH), Glasgow Coma Scale (GCS) < 10
• Presence of intraventricular hemorrhage on initial brain computerized tomography (CT) scan

Exclusion Criteria:

• Imminent death within 72 hours of admission.
• Plan for discharge from the Neuro intensive care unit (ICU) within 72 hours of admission.
• Diagnosis with sepsis (Systemic inflammatory response syndrome (SIRS) criteria plus the presence of known or suspected infection)
• Presence of coagulopathy (international normalized ratio (INR) > 1.7)
• Thrombocytopenia (platelet count < 100,000)
• History of gastrointestinal bleed
• Abnormal liver function tests (aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/alkaline phosphatase (AP)/Gamma-glutamyl transferase (GGT) 2x normal)
• Hypersensitivity to ibuprofen
• Pregnancy as determined by urine beta human chorionic gonadotropin (hCG), or lactating postpartum women
• Renal impairment (Creatinine > 1.5 mg/dL)
• Measured body weight < 50 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous Ibuprofen; Patients assigned to the ibuprofen treatment group will receive a 400 mg IV ibuprofen bolus over 30 minutes followed by an infusion of ibuprofen at 85 mg/hr.	Drug: Intravenous Ibuprofen; Ibuprofen 400 mg/100 mL intravenous (IV) over 30 minutes, followed by a continuous infusion of 2000 mg/500 mL at 85 mg/hour (21 mL/hour) for up to post bleed day 14 or discharge from the Neuro ICU, whichever comes first; Other Names: Caldolor
Other: Standard of Care; Patients assigned to the standard of care group will be given 650 mg of oral acetaminophen and continue to receive 650 mg of oral acetaminophen every 6 hours as needed to maintain temperature < 38.3 C (100.9 F).	Drug: Acetaminophen (Standard of Care); Acetaminophen 650 mg via oral/nasogastric tube every 6 hours as needed for T>=38.3 C (100.9 F) for up to post bleed day 14 or discharge from the Neuro ICU, whichever comes first.; Other Names: Tylenol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of Fever Burden	Reduction in fever burden (degrees C x hours) with intravenous ibuprofen infusion as compared to oral acetaminophen over duration of treatment. Fever burden is calculated hourly by subtracting each patient's recorded temperature (from either a bladder or esophageal temperature probe) from 37 degrees C.	Up to14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Difference in Inflammatory Markers	Mean difference in markers of inflammation between IV ibuprofen and standard of care groups	Up to 14 days
Difference in Cost Between Ibuprofen and Acetaminophen	Cost analysis of aggressive fever control (AFC) between patients randomized to either intravenous ibuprofen infusion or standard of care (oral acetaminophen).	Up to 14 days
Bleeding Incidence	Incidence of bleeding (defined by a priori criteria)	Up to 14 days

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Cumberland Pharmaceuticals
• Investigators: Principal Investigator: J. Michael Schmidt, MD, Columbia University

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): March 17, 2016
• Study Completion (Actual): March 17, 2016

Study Registration Dates

• First Submitted: February 8, 2012
• First Submitted That Met QC Criteria: February 8, 2012
• First Posted (Estimate): February 10, 2012

Study Record Updates

• Last Update Posted (Actual): August 28, 2017
• Last Update Submitted That Met QC Criteria: August 15, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: intravenous ibuprofen; Fever reduction; Fever burden
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Body Temperature Changes; Heat Stress Disorders; Hemorrhage; Hyperthermia; Fever; Intracranial Hemorrhages; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Acetaminophen; Ibuprofen
• Other Study ID Numbers: AAAI1788