Nobre 2008

Methods	Randomised clinical trial, single centre, medical ICU in Switzerland
Participants	Inclusion criteria: suspected severe sepsis or septic shock in the ICU Exclusion criteria: 1. microbiologically documented infections caused by Pseudomonas aeruginosa, Acinetobacter baumanni, Listeria spp., Legionella pneumophila, Pneumocystis jiroveci or Mycobacterium tuberculosis, for which a prolonged duration of antibiotic therapy is standard of care (17); 2. severe infections due to viruses or parasites (e.g. haemorrhagic fever, malaria); 3. infectious conditions requiring prolonged antibiotic therapy (e.g. bacterial endocarditis, brain abscess, deep abscesses); 4. antibiotic therapy started 48 hours or more before enrolment; 5. chronic, localised infections (e.g. chronic osteomyelitis); 6. severely immunocompromised patients, such as patients infected with human immunodeficiency virus and with a CD4 count of less than 200 cells/mm³, neutropenic patients (.500 neutrophils/mm³) or patients on immunosuppressive therapy after solid organ transplantation; 7. withholding of life support; or 8. absence of antimicrobial treatment despite clinical suspicion of sepsis Included in this analysis: 52 out of 79 randomised patients: 27 not considered for this analysis due to a diagnosis other than RTI
Interventions	Guiding antibiotic decisions in ICU patients with repeated measurements Algorithm used in this study: procalcitonin levels measured at baseline and daily. Patients that presenting a favourable clinical course, investigators used pre‐defined “stopping rules” based on circulating procalcitonin levels to encourage caregivers to discontinue ABs. Patients with baseline procalcitonin level greater or equal to 1 µg/L were re‐evaluated at day 5. Investigators encouraged treating physicians to discontinue ABs when: 1. procalcitonin dropped more than 90% from the baseline peak level; or 2. an absolute value below 0.25 µg/L was reached Patients with procalcitonin level below 1 µg/L at baseline were re‐evaluated at day 3 and treating physicians were encouraged to discontinue ABs when procalcitonin level was below 0.1 µg/L and careful clinical evaluation ruled out severe infection
Outcomes	All‐cause mortality at day 28 Clinical cure defined as clinical signs and symptoms present at baseline that had resolved by the final clinical assessment Re‐occurrence of the initial infection Length of ICU stay
Notes	Funding: BRAHMS AG Follow‐up: fixed follow‐up period of 28 days Registration: NCT00250666
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐based random number generation
Allocation concealment (selection bias)	Low risk	Sequentially numbered, opaque, sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Open‐label trial where physicians knew in which group patients were and where procalcitonin levels were only communicated in the intervention arm
Blinding of outcome assessment (detection bias) All outcomes	High risk	Non‐blinded study members
Incomplete outcome data (attrition bias) All outcomes	Low risk	Follow‐up for mortality: 52/52 (100%)
Selective reporting (reporting bias)	Low risk	Outcomes correspond to study protocol
Other bias	Unclear risk	81% adherence to procalcitonin algorithm in procalcitonin group