Protocolised reduction of non-resuscitation fluids versus usual care in patients with septic shock (REDUSE): a protocol for a multicentre feasibility trial.

INTRODUCTION: Administration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care. METHODS AND ANALYSIS: The design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation. ETHICS AND DISSEMINATION: Ethics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05249088.

TNFR1, TNFR2, neutrophil gelatinase-associated lipocalin and heparin binding protein in identifying sepsis and predicting outcome in an intensive care cohort.

To date no biomarkers can aid diagnosing sepsis with adequate accuracy. We set out to assess the ability of Tumor necrosis factor receptor (TNFR) 1 and 2, Neutrophil gelatinase-associated lipocalin (NGAL) and Heparin binding protein (HBP) to discriminate sepsis from non-infected critically ill patients in a large ICU cohort, and to evaluate their value to predict mortality at 30 days. Adult patients admitted to the ICU with an arterial catheter were included. Clinical data and blood samples were prospectively recorded daily. Diagnoses were set retrospectively. Descriptive statistics and logistic regression models were used. NGAL, TNFR1 and TNFR2 were higher in sepsis patients compared to other diagnoses, as well as in non-survivors compared to survivors. In addition, these biomarkers increased with increasing stages of acute kidney injury. TNFR1 and TNFR2 performed similarly to NGAL and CRP in identifying sepsis patients, but they performed better than CRP in predicting 30-day mortality in this ICU cohort. Thus, TNFR1 and TNFR2 may be particularly useful in identifying high risk sepsis patients and facilitate relevant health care actions in this group of sepsis patients.

Renal clearance of heparin-binding protein and elimination during renal replacement therapy: Studies in ICU patients and healthy volunteers.

BACKGROUND: Heparin-binding protein (HBP) is released by neutrophils upon activation, and elevated plasma levels are seen in inflammatory states like sepsis, shock, cardiac arrest, and burns. However, little is known about the elimination of HBP. We wanted to study renal clearance of HBP in healthy individuals and in burn patients in intensive care units (ICUs). We also wished to examine the levels of HBP in the effluent of renal replacement circuits in ICU patients undergoing continuous renal replacement therapy (CRRT). METHODS: We measured plasma and urine levels of HBP and urine flow rate in 8 healthy individuals and 20 patients in a burn ICU. In 32 patients on CRRT, we measured levels of HBP in plasma and in the effluent of the CRRT circuit. RESULTS: Renal clearance of HBP (median (IQR) ml/min) was 0.19 (0.08-0.33) in healthy individuals and 0.30 (0.01-1.04) in burn ICU patients. In ICU patients with cystatin C levels exceeding 1.44 mg/l, clearance was 0.45 (0.15-2.81), and in patients with cystatin C below 1.44 mg/l clearance was lower 0.28 (0.14-0.55) (p = 0.04). Starting CRRT did not significantly alter plasma levels of HBP (p = 0.14), and the median HBP level in the effluent on CRRT was 9.1 ng/ml (IQR 7.8-14.4 ng/ml). CONCLUSION: In healthy individuals and critically ill burn patients, renal clearance of HBP is low. It is increased when renal function is impaired. Starting CRRT in critically ill patients does not alter plasma levels of HBP significantly, but HBP can be found in the effluent. It seems unlikely that impaired kidney function needs to be considered when interpreting concentrations of HBP in previous studies. Starting CRRT does not appear to be an effective way of reducing HBP concentrations.