Clinical trial NCT00271752: The Procalcitonin and Survival Study
Official title: The Procalcitonin and Survival Study - A Multicentre Single Blinded Randomized Controlled Trial to Investigate if Treatment Guided by Daily Procalcitonin Measurements Can Reduce Mortality in the Intensive Care Unit
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Localized Infection
Sepsis
Multiple Organ Failure
Keywords: Procalcitonin
Sepsis
Intensive Care Unit
Sepsis and Complications
Organ Failure
Lead sponsor: Danish Procalcitonin Study Group
Sponsor class: OTHER
Collaborators: name: Copenhagen HIV Programme
name: Danish Research Agency
name: Hvidovre University Hospital
First posted: 2006-01-04
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomised, single blinded, multicentre trial to evaluate whether daily procalcitonin (PCT) measurements and immediate diagnostic and therapeutic responses to abnormal values and day-to-day changes can reduce the mortality of critically ill patients in the Intensive Care Unit (ICU).

Detailed description: Sepsis and complications to sepsis are major causes of mortality in critically ill patients. Rapid treatment of sepsis is of crucial importance for survival of patients. In the ICU, the infectious status of the patient is often difficult to assess because symptoms cannot be expressed (unconscious or sedated patients) and signs may present atypically because of immunologic incompetence and masking by the drugs given and thermo-therapy. Biological and biochemical markers of inflammation (White Blood Cells (WBC), C-reactive protein) may often be influenced by other parameters than infection, such as: trauma, surgery, other types of inflammation such as rheumatoid diseases (C-reactive protein) and gluco-corticosteroid treatment (WBC), and may be unacceptably slowly released after progression of an infection. At the same time, lack of a relevant antimicrobial therapy in an early course of infection may be fatal for the patient.

For these reasons, in the clinical setting, it is often necessary to initiate or adjust antimicrobial therapy on an unsure ground and the relevant therapy may in some situations be delayed for important hours or even days. Specific and rapid markers of bacterial infection have been sought for use in the ICU. Mortality in critically ill patients increases gravely when Procalcitonin levels increase from day to day (own submitted, though yet unpublished data). Low PCT levels have been shown to effectively rule out sepsis.

However, no randomised controlled trials have been conducted to show if mortality in critically ill patients can be reduced by using a strategy of daily standardised Procalcitonin measurements as an early detector of serious bacterial infection. Therefore evidence is presently not sufficient to introduce daily consecutive Procalcitonin measurements to guide the diagnostic and therapeutic management of patients admitted to the ICU .

The rationale for this trial is to assess the ability of daily Procalcitonin measurements to reduce the mortality of critically ill patients.

Eligibility criteria: Inclusion Criteria:

Fulfilment of all of the following three criteria:

1. Male or female, aged \> 18 years of age.
2. Admitted to the participating Intensive Care Units (ICUs) at the following hospitals: Hvidovre Hospital, Bispebjerg Hospital, Amager Hospital, Herlev Hospital, Glostrup Hospital, and Gentofte Hospital
3. Ability to understand and provide written informed consent to participate in this trial; or ability to understand and provide oral informed consent in the presence of at least one impartial witness who should sign and personally date the consent form; or the subject's legally acceptable representative can understand and provide written informed consent if the subject is not capable of this because of the present mental or physical condition of the subject.

Exclusion Criteria:

A subject will NOT be eligible for inclusion in this trial if any of the following criteria apply:

1. Subjects with known hyperbilirubinaemia (\> 0.4 mg/ml) or hypertriglyceridaemia (\> 10 g/l) since this can interfere with measurements. If subjects with unknown status on these points are included and have PCT measurements, the measuring equipment will detect these conditions.
2. Subjects suffering from a blood disorder, where daily sampling of 7 ml of blood for a maximum of 28 days (210 ml distributed on 28 days) will be an inconvenience or a potential risk, which could compromise the safety of the subject.
3. Subjects who are pregnant or breast feeding

The a priori probability of surviving with the normal recommended diagnostics and treatment with the presently available means to detect infections and, on the other hand, the normal diagnostics and treatment together with daily procalcitonin measurements and prompt clinical reaction should be equal.

Primary outcomes:
measure: mortality/survival
timeFrame: 28 day
Secondary outcomes:
measure: mortality/survival
timeFrame: 60 day
measure: mortality/survival
timeFrame: 90 day
measure: mortality/survival
timeFrame: 120 day
measure: mortality/survival
timeFrame: 180 day
measure: Consumption of antimicrobial chemotherapy
timeFrame: 28 day
measure: Prevalence of complications to infection: sepsis
timeFrame: 28 day
measure: severe sepsis
timeFrame: 28 day
measure: septic shock
timeFrame: 28 day
measure: Multi Organ Dysfunction Syndrome
timeFrame: 28 day
measure: Disseminated Intravascular Coagulation
timeFrame: 28 day
measure: use of diagnostic imaging during admission to the ICU
timeFrame: 28 day
measure: Quality of life post-ICU
timeFrame: 180 day
Other outcomes:
Locations:
city: Copenhagen NV
country: Denmark
facility: Intensive Care Unit, Bispebjerg Hospital
state: Copenhagen
city: Gentofte
country: Denmark
facility: Intensive Care Unit, KAS Gentofte
state: Copenhagen
city: Glostrup
country: Denmark
facility: Intensive Care Unit, KAS Glostrup, Copenhagen University Hospital
state: Copenhagen
city: Herlev
country: Denmark
facility: Intensive Care Unit, Herlev Hospital
state: Copenhagen
city: Hvidovre
country: Denmark
facility: Intensive Care Unit 542, Hvidovre Hospital, Copenhagen University Hospital
state: Copenhagen
city: Hilleroed
country: Denmark
facility: Intensive Care Unit, Hilleroed Sygehus
state: Frederiksborg County
city: Skejby, Århus
country: Denmark
facility: Skejby Sygehus
state: Midtjylland
city: Århus
country: Denmark
facility: Intensive Care Unit, Århus Sygehus, Nørrebrogade
state: Midtjylland
city: Roskilde
country: Denmark
facility: Roskilde Sygehus
state: Sjælland
Study officials:
affiliation: Dept. of Clinical Microbiology, Hvidovre University Hospital & Copenhagen HIV Programme (CHIP), Faculty of Health Sciences, University of Copenhagen
name: Jens-Ulrik S Jensen, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Holm FS, Sivapalan P, Seersholm N, Itenov TS, Christensen PH, Jensen JS. Acute Lung Injury in Critically Ill Patients: Actin-Scavenger Gelsolin Signals Prolonged Respiratory Failure. Shock. 2019 Sep;52(3):370-377. doi: 10.1097/SHK.0000000000001279.
citation: Jensen JS, Itenov TS, Thormar KM, Hein L, Mohr TT, Andersen MH, Loken J, Tousi H, Lundgren B, Boesen HC, Johansen ME, Ostrowski SR, Johansson PI, Grarup J, Vestbo J, Lundgren JD; Procalcitonin And Survival Study (PASS) Group. Prediction of non-recovery from ventilator-demanding acute respiratory failure, ARDS and death using lung damage biomarkers: data from a 1200-patient critical care randomized trial. Ann Intensive Care. 2016 Dec;6(1):114. doi: 10.1186/s13613-016-0212-y. Epub 2016 Nov 21.
citation: Johansen ME, Johansson PI, Ostrowski SR, Bestle MH, Hein L, Jensen AL, Soe-Jensen P, Andersen MH, Steensen M, Mohr T, Thormar K, Lundgren B, Cozzi-Lepri A, Lundgren JD, Jensen JU. Profound endothelial damage predicts impending organ failure and death in sepsis. Semin Thromb Hemost. 2015 Feb;41(1):16-25. doi: 10.1055/s-0034-1398377. Epub 2015 Jan 15.
citation: Johansen ME, Jensen JU, Bestle MH, Hein L, Lauritsen AO, Tousi H, Larsen KM, Loken J, Mohr T, Thormar K, Johansson PI, Cozzi-Lepri A, Lundgren JD. The potential of antimicrobials to induce thrombocytopenia in critically ill patients: data from a randomized controlled trial. PLoS One. 2013 Nov 28;8(11):e81477. doi: 10.1371/journal.pone.0081477. eCollection 2013.
citation: Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr T, Andersen MH, Thornberg KJ, Loken J, Steensen M, Fox Z, Tousi H, Soe-Jensen P, Lauritsen AO, Strange DG, Reiter N, Thormar K, Fjeldborg PC, Larsen KM, Drenck NE, Johansen ME, Nielsen LR, Ostergaard C, Kjaer J, Grarup J, Lundgren JD; Procalcitonin And Survival Study (PASS) Group. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. BMJ Open. 2012 Mar 11;2(2):e000635. doi: 10.1136/bmjopen-2011-000635. Print 2012.
citation: Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr TT, Andersen MH, Thornberg KJ, Loken J, Steensen M, Fox Z, Tousi H, Soe-Jensen P, Lauritsen AO, Strange D, Petersen PL, Reiter N, Hestad S, Thormar K, Fjeldborg P, Larsen KM, Drenck NE, Ostergaard C, Kjaer J, Grarup J, Lundgren JD; Procalcitonin And Survival Study (PASS) Group. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011 Sep;39(9):2048-58. doi: 10.1097/CCM.0b013e31821e8791.
citation: Jensen JU, Lundgren B, Hein L, Mohr T, Petersen PL, Andersen LH, Lauritsen AO, Hougaard S, Mantoni T, Bomler B, Thornberg KJ, Thormar K, Loken J, Steensen M, Carl P, Petersen JA, Tousi H, Soe-Jensen P, Bestle M, Hestad S, Andersen MH, Fjeldborg P, Larsen KM, Rossau C, Thomsen CB, Ostergaard C, Kjaer J, Grarup J, Lundgren JD. The Procalcitonin And Survival Study (PASS) - a randomised multi-center investigator-initiated trial to investigate whether daily measurements biomarker Procalcitonin and pro-active diagnostic and therapeutic responses to abnormal Procalcitonin levels, can improve survival in intensive care unit patients. Calculated sample size (target population): 1000 patients. BMC Infect Dis. 2008 Jul 13;8:91. doi: 10.1186/1471-2334-8-91.