Control of Fever in Septic Patients

Study Overview
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Brief Summary
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The benefits of fever treatment in critically ill patients remains unclear. The aim of the prospective, randomized clinical trial was to verify the hypothesis that the administration of ibuprofen in order to decrease the fever in septic patients without limited cardiorespiratory reserve leads to decreasing their prognosis.

Detailed Description
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Fever is a frequently observed part of the organism's response to infection, and it is a well-known fact that it has positive effects, as it inhibits the growth of microorganisms, and potentiates the activity of anti-microbial agents. On the other hand, fever increases the demand of tissues for oxygen and increases the production of carbon dioxide in tissues. Adapting to these metabolic changes requires an efficient cardiorespiratory apparatus. In other words, in patients with a limited cardiorespiratory reserve (typically patients of higher age or patients with a serious disease of the heart or lungs), the beneficial anti-microbial effect of fever may be masked with cardiorespiratory maladaptation to fever-induced metabolic changes. Indeed, one of the randomized clinical trials investigating the effect of aggressive antipyretic strategy used in practice (administration of acetaminophen at the temperature > 38.5 degrees Celsius, and addition of physical cooling should the temperature exceed 39.5 degrees Celsius upon the prognosis of critically ill patients showed that the aggressive treatment of fever may result in higher mortality when compared with a permissive approach, i.e. an approach when the treatment of fever is initiated only after the body temperature has exceeded 40 degrees Celsius. The study differs remarkably from other studies performed among the population of critically ill patients, and also from studies, which did not manifest the effect of fever treatment upon the mortality of patients, with the age of patients. The average age of patients in both arms of the study was only 47 years of age, whereas the average age of patients in other studies was usually around 60 years of age. It is thus possible to presume that, due to the lower age, the patients in this study possessed a sufficient cardiorespiratory reserve for adaptation to metabolic changes induced with fever, which may have enabled a full manifestation of its anti-microbial effect, and may have led to better patient prognosis. The mortality rate in the group of patients with the permissive approach to fever treatment was only 2.6 percent, whereas, in the group of patients with the aggressive treatment, the mortality rate was 15.9 percent (p=0.06); due to this fact, the study was prematurely terminated by the Ethics Committee. Based on this study, we decided to test the hypothesis that the administration of ibuprofen in order to decrease the fever would lead to a worsening of the patient prognosis. Ibuprofen was selected due to its potent antipyretic effect, and also due to the fact that the favorable effect of its anti-inflammatory effect upon the prognosis of patients with sepsis has not been fully demonstrated.

Official Title
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Control of Fever in Septic Patients

Conditions
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Sepsis, Severe Sepsis, Septic Shock

Intervention / Treatment
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* Drug: Ibuprofen administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age >18 years of age body temperature >38.3°C within 2 consecutive hours anti-microbial therapy for a known or suspected infection Exclusion Criteria: patients admitted after successful cardiopulmonary resuscitation (CPR) acute myocardial infarction brain injury (traumatic and non-traumatic) transfer from another ICU after 72 hours pregnancy antipyretic medication prior to randomization non-obtaining the informed consent moribund condition high risk of hemodynamic or respiratory maladaptation on the metabolic effect of fever

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
Interventional Model Description: The study subjects were enrolled in two parallel groups.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aggressive treatment strategy<br>The antipyretic strategy was initiated immediately upon increase of the temperature above 38.3°C. The antipyretic strategy consisted of administration of ibuprofen (per-orally or into the nasogastric tube, or rectal administration in the form of a suppository) in therapeutical dose, alway supplemented with physical cooling in cases when the temperature exceeded 39.5°C. The body temperature was measured in the urinary bladder. | Drug: Ibuprofen administration<br>* Administration of ibuprofen, according to treatment recommendations - per orally, into the nasogastric tube, or in the form of a suppository<br>|
| Experimental: Conservative treatment strategy<br>The antipyretic strategy was initiated only after the body temperature exceeded 39.5°C. The antipyretic strategy consisted of administration of ibuprofen (per-orally or into the nasogastric tube, or rectal administration in the form of a suppository) in therapeutical dose, alway supplemented with physical cooling in cases when the temperature exceeded 39.5°C. The body temperature was measured in the urinary bladder. | Drug: Ibuprofen administration<br>* Administration of ibuprofen, according to treatment recommendations - per orally, into the nasogastric tube, or in the form of a suppository<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SOFA score value | The SOFA score (Sequential Organ Failure Assessment) was measured on Day 3 and Day 7 | up to 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum interleukin-6 level | The serum interleukin-6 level was measured on Day 3 and Day 7 | up to 7 days | 
| Serum procalcitonine level | The serum procalcitonine level was measured on Day 3 and Day 7 | up to 7 days | 
| Serum lactate level | The serum lactate level was measured on Day 3 and Day 7 | up to 7 days | 
| Central venous oxygen saturation | The central venous oxygen saturation was measured on Day 3 and Day 7 | up to 7 days | 
| Duration of artificial ventilation | The duration of artificial ventilation in days was observed | 1 month | 
| Duration of vasopressor support | The duration of vasopressor support in days was observed | 1 month | 
| Length of ICU stay | The length of ICU stay in days was observed | 1 month | 
| Length of hospital stay | The length of hospital stay in days was observed | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, severe sepsis, septic shock, fever, ibuprofen, physiological reserves