Control of Fever in Septic Patients

Sepsis Clinical Trial

— COVERSEP  

Official title:

Control of Fever in Septic Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04227652
• Other study ID #: FNO-KARIM-13-COVERSEP
• Secondary ID: RVO-FNOs/2013-2
• Status: Completed
• Phase: N/A
• Start date: September 3, 2013
• Est. completion date: March 31, 2019

Study information

• Verified date: January 2020
• Source: University Hospital Ostrava
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: March 31, 2019
• Est. primary completion date: February 28, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Severe Sepsis
• Shock, Septic
• Toxemia

Intervention

Drug:
• Ibuprofen administration
Administration of ibuprofen, according to treatment recommendations - per orally, into the nasogastric tube, or in the form of a suppository

Locations

Country	Name	City	State
Czechia	University Hospital Ostrava	Ostrava	Moravian-Silesian Region

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Ostrava

Country where clinical trial is conducted

Czechia, 

References & Publications (4)

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. — View 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. Erratum in: Surg Infect (Larchmt). 2010 Oct;11(5):495. Li, Pam [corrected to Li, Pamela]; Alhaddad, Ahmed [corrected to Elhaddad, Ahmed]. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	SOFA score value	The SOFA score (Sequential Organ Failure Assessment) was measured on Day 3 and Day 7	up to 7 days
Secondary	Serum interleukin-6 level	The serum interleukin-6 level was measured on Day 3 and Day 7	up to 7 days
Secondary	Serum procalcitonine level	The serum procalcitonine level was measured on Day 3 and Day 7	up to 7 days
Secondary	Serum lactate level	The serum lactate level was measured on Day 3 and Day 7	up to 7 days
Secondary	Central venous oxygen saturation	The central venous oxygen saturation was measured on Day 3 and Day 7	up to 7 days
Secondary	Duration of artificial ventilation	The duration of artificial ventilation in days was observed	1 month
Secondary	Duration of vasopressor support	The duration of vasopressor support in days was observed	1 month
Secondary	Length of ICU stay	The length of ICU stay in days was observed	1 month
Secondary	Length of hospital stay	The length of hospital stay in days was observed	3 months