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Anti-pyretic Therapy in Critically Ill Adults

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ClinicalTrials.gov Identifier: NCT01173367
Recruitment Status : Completed
First Posted : August 2, 2010
Last Update Posted : February 23, 2012
Sponsor:
Collaborator:
Canadian Intensive Care Foundation
Information provided by (Responsible Party):
Daniel Niven, University of Calgary

Tracking Information
First Submitted Date  ICMJE July 28, 2010
First Posted Date  ICMJE August 2, 2010
Last Update Posted Date February 23, 2012
Study Start Date  ICMJE August 2010
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 29, 2010)
28-day survival [ Time Frame: 28-day ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 29, 2010)
  • Feasibility of randomizing critically ill patients to different fever management strategies [ Time Frame: 12 months ]
  • Consumption of anti-microbials [ Time Frame: Maximum 28-days from enrollment ]
  • Incidence of nosocomial infection [ Time Frame: Maximum 28-days from enrollment ]
  • The effect of anti-pyretic treatment of fever on markers of inflammation [ Time Frame: 48 hours ]
  • Incidence of myocardial infarction during treatment of fever [ Time Frame: Maximum 28-days from enrollment ]
  • Incidence of hepatocellular inflammation related to acetaminophen use [ Time Frame: Maximum 28-days from enrollment ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Anti-pyretic Therapy in Critically Ill Adults
Official Title  ICMJE Assessment of the Safety of Anti-pyretic Therapy in Critically Ill Adults
Brief Summary The impact of fever and its management in different medical and surgical populations of critically ill patients has not been explained to date. The current study aims to assess the safety and efficacy of treatment of critically ill patients with a permissive versus aggressive fever treatment strategy.
Detailed Description

The impact of fever and its management in different medical and surgical populations of critically ill patients has not been explained to date. Clinical trials in critically ill surgical patients have demonstrated null or potentially harmful effects of treatment of moderate degrees of fever. However, the pathophysiological effects of fever treatment are not well defined according to different patient populations, and clinical trial results are questionably generalized to medical ICU patients. This may relate to different mechanisms of fever in these populations and merits further investigation. There is also very little known about the exact timing of expression of the diverse pro and anti-inflammatory mediators involved in inducing, maintaining and eventually abrogating the fever response. Treating on the sole basis of an elevated temperature may lead to detrimental effects if the anti-inflammatory cascade naturally regulating this response is active, demonstrating the importance of understanding the normal pattern of regulation of these diverse mediators. The current study aims to assess the safety and efficacy of treatment of critically ill patients with a permissive versus aggressive fever treatment strategy. In addition, the effect of anti-pyretic therapy on markers of inflammation in neurologically intact critically ill adults will be evaluated.

The study population will be neurologically intact febrile adults (≥18 years) admitted to the Peter Lougheed Center (PLC) or Foothills Medical Center (FMC) ICU over a 12-month period in Calgary, Alberta, Canada. Consenting patients that fulfill enrolment criteria will be randomly allocated to either the permissive or aggressive treatment group (see Interventions section for details). Randomization will be concealed using the consecutively numbered sealed opaque envelope technique. Samples of blood will be collected from study patients at enrolment and subsequently at 12, 24 and 48 hours for assessment of inflammatory mediators.

Markers of feasibility will include the rate of enrolment, adherence of patients to assigned treatment regimen/protocol violation, acceptance of the protocol by staff, and facility and maintenance of random allocation technique. Markers of safety will include potential adverse events such as 28-day survival, nosocomial infection rate, and evidence of myocardial ischemia, or hepatocellular inflammation during the febrile episode.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Fever
Intervention  ICMJE
  • Other: Aggressive Fever Treatment
    Patients assigned to the aggressive fever treatment protocol will receive acetaminophen 650 mg enterally every 6 hours for fever ≥ 38.3°C and external cooling will be initiated for temperatures ≥ 39.5°C. Acetaminophen and external cooling will be discontinued once core temperature is less than 38.3°C and 39.5°C respectively.
  • Other: Permissive Fever Treatment
    Patients assigned to the permissive treatment strategy will not receive anti-pyretic therapy until the temperature reaches 40.0°C at which point they will receive acetaminophen 650mg every 6 hours. External cooling will be initiated for temperatures ≥ 40.5°C. Acetaminophen and external cooling will be discontinued once core temperature is less than 40.0°C and 40.5°C respectively.
Study Arms  ICMJE
  • Active Comparator: Aggressive Fever Treatment
    Intervention: Other: Aggressive Fever Treatment
  • Active Comparator: Permissive Fever Treatment
    Intervention: Other: Permissive Fever Treatment
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 21, 2012)
26
Original Estimated Enrollment  ICMJE
 (submitted: July 29, 2010)
75
Actual Study Completion Date  ICMJE January 2012
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥18 years old
  • Fever (two consecutive measurements ≥ 38.3°C at least 2 hours apart or a single temperature measurement ≥ 39.5°C)
  • Admitted to ICU with an expected length of stay at least 48 hours related to critical illness
  • Attending physician approval

Exclusion Criteria:

  • Admission to ICU for support for specific procedure (e.g. endoscopy, acute dialysis, bronchoscopy)
  • Acute brain injury due to any etiology
  • Acute myocardial ischemia
  • Documented hepatitis with elevated alanine aminotransferase (ALT) more than twice the upper limit of normal, or chronic hepatic failure (defined by evidence of cirrhosis on available imaging or known varices, ascites, hepatic encephalopathy, hepatorenal syndrome, and/or hepatocellular carcinoma)
  • Hyperthermia syndromes (malignant hyperthermia, heat stroke, neuroleptic malignant syndrome, serotonin syndrome, or endocrine causes including thyrotoxicosis, pheochromocytoma, and adrenal crisis)
  • Refractory shock with lactic acidosis >4 mmol/L (at the time of screening for study enrollment) despite supportive therapy or need for paralytic treatment to reduce metabolic demand
  • Requirement for use of anti-pyretic agents (acetaminophen or NSAIDs) for indications other than treatment of fever
  • Receipt of anti-pyretic pharmacotherapy within 6-hours of expected study enrollment (650mg acetaminophen, 800mg ibuprofen, or 325mg acetylsalicylic acid)
  • Contraindications to esophageal temperature monitoring
  • Pregnancy (all women of child-bearing potential need to have a pregnancy test performed prior to enrollment)
  • Time from onset of fever in the ICU to consideration for study enrollment is > 12 hours
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01173367
Other Study ID Numbers  ICMJE E-23090
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Daniel Niven, University of Calgary
Study Sponsor  ICMJE University of Calgary
Collaborators  ICMJE Canadian Intensive Care Foundation
Investigators  ICMJE
Principal Investigator: Kevin Laupland, MD MSc FRCPC Faculty of Medicine, University of Calgary
Principal Investigator: Henry T Stelfox, MD PhD FRCPC Faculty of Medicine, University of Calgary
PRS Account University of Calgary
Verification Date February 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP