The goal of this single center observational cohort study is to investigate the relationship between physiological measures of lung oedema, and the biomarker Heparin-binding Protein (HBP).

The main questions it aims to answer are:

• Does the concentration of HBP in plasma correlate with measures of lung vascular permeability and extravascular water in the lungs?
• Does the concentration of HBP in plasma correlate with the patient's total accumulated fluid balance?

Researchers will collect blood samples and gather information on lung vascular permeability and extravascular lung water in Intensive care patients who are provided with a hemodynamic surveillance system called PiCCO. The study will include 25 patients.

Abbreviations used:

HBP - Heparin-Binding Protein

PiCCO - Pulse Index Contour Continuous Cardiac Output

TPDT - Transpulmonary Thermodilution Technique

ICU - Intensive Care Unit

PVPI - Pulmonary Vascular Permeability Index

EVLW - Extra Vascular Lung water

PBV - Pulmonary Blood Volume

GEDV - Global End Diastolic Volume

This study aims to map the relationship between the pulmonary vascular permeability index (PVPI) and Heparin-binding Protein (HBP), a protein released from leukocytes in states of acute inflammation.

All ICU patients monitored with a Pulse Index Contour Continuous Cardiac Output (PiCCO) device are eligible. The PiCCO device is based on a transpulmonary thermodilution technique (TPDT) in combination with a pulse contour analysis.

Background:

Patients with acute organ failure requiring intensive care often experience lung oedema. Commonly, lung oedema is due either to cardiac failure or increased vascular permeability in the lung vessels. The transpulmonary thermodilution technique (TPDT) has been shown to be useful for quantifying the amount of fluid in the lungs and provides measures of extravascular lung water (EVLW) and total pulmonary blood volume (PBV). The ratio between EVLW and PBV is the Pulmonary Vascular Permeability Index (PVPI), an indicator of the integrity of the alveolocapillary membrane. When the integrity of this barrier is disrupted, the EVLW increases relative to the blood volume in the lungs, and PVPI increases. An increase in EVLW in the presence of a normal PVPI is due to increased hydrostatic pressure, as in cardiac failure, whereas an increase in both EVLW and PVPI is indicative of non-cardiac lung oedema. PVPI and EVLW are measured bedside with a Pulse Index Contour Continuous Cardiac Output (PiCCO) device based on a combination of transpulmonary thermodilution technique (TPDT) and pulse contour analysis. The system requires a central venous line and an arterial catheter with a thermistor and needs regular calibrations.

Increased vascular leakage is a pathophysiological hallmark of ARDS in the lungs and of acute inflammation in general. The research in this field has been vast, and researchers have presented many new biomarkers of interest. One such biomarker is Heparin binding Protein (HBP), also called azurocidin or CAP137. HBP is a protein released by activated granulocytes in states of acute inflammation. Elevated levels of HBP has been demonstrated in sepsis, pneumonia, cardiac arrest, and acute kidney injury. HBP is a mediator of vascular permeability by acting on endothelial cells.

In experimental data, an association between HBP in plasma and pulmonary vascular permeability has been demonstrated. A study of burn patients found a correlation between leukocytosis and PVPI. To our knowledge, no studies have investigated the relation between HBP and PVPI in vivo.

Our hypothesis is that there is a positive correlation between HBP and PVPI and between total accumulated fluid balance and high concentrations of HBP.

Methods:

Blood samples are collected three times daily during calibration of the PiCCO device. Calibrations are done by injecting a bolus of cold saline into the central venous line. The temperature change is sensed by the thermistor, allowing for the calculation of several hemodynamic measurements. Each calibration will update measures of cardiac function and volume status. The study is conducted for three consecutive days for each patient and terminated earlier if the PICCO is removed for any reason. Timepoints for sampling and PiCCO measurements are all registered in a study protocol .

No additional drugs or other treatments will be administered during the study. As such, the study is without intervention.

Any abnormalities revealed by the PICCO monitoring device will be followed up by the doctor responsible for the ICU as in standard care and there is no change due to the study. HBP values will be analysed once recruitment is complete, and hence will not influence treatment.

Possible Risks and Side Effects of Participation

Blood samples are frequently drawn in ICU patients, and the additional samples collected in the study are considered without consequences for the participants. Only patients with an indication for PiCCO monitoring are eligible, so inclusion in the study doesn't imply any risk or pain associated with additional punctures of veins or arteries. Complications related to intensive care and PICCO monitoring exist regardless of study participation.

Consent

Oral and written consent will be obtained as soon as feasible. In the meantime relatives are informed and given the opportunity to refuse inclusion on behalf of the patient.

What Happens to Collected Data?

The project will collect health information from medical records and observational charts in the ICU. All data will be pseudoanonymized (coded) and only accessible to authorized researchers. The key to decoding is a subject enrolment and identification list which will be stored securely in the intensive care unit. All information will be protected in accordance with the General Data Protection Regulation (GDPR).

Inclusion Criteria:

• Patients >18 years
• Monitored with a PiCCO system

Exclusion Criteria:

• Patients transferred from another ICU

All ICU adult patients admitted to the ICU in Östersund fulfilling the inclusion criterias above.

Data will be available upon reasonable request to the main author.