Clinical trial NCT04227652: Control of Fever in Septic Patients
Official title: Control of Fever in Septic Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sepsis
Severe Sepsis
Septic Shock
Keywords: sepsis
severe sepsis
septic shock
fever
ibuprofen
physiological reserves
Lead sponsor: University Hospital Ostrava
Sponsor class: OTHER
First posted: 2020-01-13
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study subjects were enrolled in two parallel groups.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: SOFA score value
timeFrame: up to 7 days
Secondary outcomes:
measure: Serum interleukin-6 level
timeFrame: up to 7 days
measure: Serum procalcitonine level
timeFrame: up to 7 days
measure: Serum lactate level
timeFrame: up to 7 days
measure: Central venous oxygen saturation
timeFrame: up to 7 days
measure: Duration of artificial ventilation
timeFrame: 1 month
measure: Duration of vasopressor support
timeFrame: 1 month
measure: Length of ICU stay
timeFrame: 1 month
measure: Length of hospital stay
timeFrame: 3 months
Other outcomes:
Locations:
city: Ostrava
country: Czechia
facility: University Hospital Ostrava
state: Moravian-Silesian Region
Study officials:
affiliation: University Hospital Ostrava
name: Roman Kula, MD,CSc.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005 Winter;6(4):369-75. doi: 10.1089/sur.2005.6.369.
citation: Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, Holliday M, Henderson S, Mackle D, McArthur C, McGuinness S, Myburgh J, Weatherall M, Webb S, Beasley R; HEAT Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015 Dec 3;373(23):2215-24. doi: 10.1056/NEJMoa1508375. Epub 2015 Oct 5.
citation: Ye S, Xu D, Zhang C, Li M, Zhang Y. Effect of Antipyretic Therapy on Mortality in Critically Ill Patients with Sepsis Receiving Mechanical Ventilation Treatment. Can Respir J. 2017;2017:3087505. doi: 10.1155/2017/3087505. Epub 2017 Mar 12.
citation: Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8. doi: 10.1056/NEJM199703273361303.