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Heparin-binding protein and organ failure in critical illness
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: For patients severely ill enough to require care in an intensive care unit (ICU), both the disease itself (e.g. bacteria in the blood in sepsis or fractures after trauma) and effects of the immune system can cause circulatory, pulmonary, or renal dysfunction. Leukocytes play a dominant role in the immune system.  When activated they release a range of small proteins with different properties Heparin-binding protein (HBP) being one of these proteins, has many functions, including to increase vascular permeability. Heparin-binding protein causes plasma leakage from blood vessels into surrounding tissue (oedema), which can lead to  organ dysfunction depending on the site and degree of oedema formation. Increased concentration of HBP in plasma is associated with failing circulation and lung function in subgroups of critically ill patients.

Aims: We investigated the possibility of using concentration of HBP in plasma for predicting circulatory, respiratory or renal failure in an ICU population with mixed diagnosis. We assessed concentration of HBP in alveoli in ventilator induced lung injury (VILI), and finally assessed elimination of HBP in urine and effluent fluid from continuous dialysis.

Methods: In Papers I and II, HBP concentration in plasma was measured in 278 patients on admission to ICU. Sequential organ failure assessment (SOFA) scores and acute kidney injury (AKI) stage were recorded daily. In Paper III HBP concentration in bronco-alveolar fluid was measured in a pig model of ventilatory induced lung injury, in 16 healthy volunteers and in 10 intubated ICU patients. In Paper IV plasma and urine concentration of HBP was measured in 8 healthy volunteers and 20 burn ICU patients. In addition, HBP was sampled in plasma and effluent fluid in 32 ICU patients on continuous renal replacement therapy (CRRT).

Results: In Paper I, patients developing circulatory failure (circulatory sub-score of SOFA = 4) had higher plasma concentration of HBP compared to those who did not (median(IQR)ng/ml) (63.5(32–105) vs 36.4(24–59)) p<0.01), and patients developing respiratory failure (P:F ratio < 27) had higher HBP concentration than those who did not (44.4(30-109) vs 35.2(23-57) p<0.01). Discriminatory capacity was (ROC AUC (95%CI)) (0.65 (0.54–0.76)) for circulatory failure and (0.61(0.54–0.69)) for respiratory failure. In Paper II, patients developing renal failure (AKI stage 2-3) had higher plasma concentration of HBP compared to those who did not (72.1 (13.0–131.2) vs 34.5 (19.7–49.3) p<0.01). Discriminatory capacity for AKI stage 3 was 0.68(0.54-0.83) (ROC AUC (95%CI)). In the subgroup with severe sepsis, it was  0.93 (0.85–1.00). In Paper III, HBP concentration in bronchoalveolar lavage was higher in pigs subjected to injurious ventilation over 6 hours ventilation compared to controls (1144(359–1636) vs 89(33–191) p=0.02) (median(IQR)ng/ml). The median HBP concentration in bronchoalveolar lavage from healthy volunteers was 0.90(0.79– 1.01) compared to 1959(612–3306) from intubated ICU patients (p < 0.01).In Paper IV, renal clearance of HBP was 0.19 (0.08-0.33) in healthy individuals and 0.30 (0.01-1.04)  (median, IQR, ml/min)  in burn ICU patients. Clearance of HBP was higher in burn patients with increased cystatin C (0.45(0.15-2.81) vs. 0.28(0.14-0.55) p=0.04). Starting CRRT did not alter plasma concentration of HBP (p=0.14). Median HBP concentration in effluent fluid on CRRT was 9.1 ng/ml (7.8-14.4).

Conclusions: Papers I and II:There is an association between high concentration of HBP in plasma on ICU admission and circulatory, respiratory and renal failure. For the individual patient, the predictive value of a high HBP concentration is low, with the possible exception of renal failure in septic patients. Paper III:HBP concentration in alveoli increases in pigs subjected to injurious ventilation. HBP concentration in alveoli of intubated ICU patients ventilated protectively is elevated to similar levels, a factor of approximately 1000 times higher than the concentration seen in healthy controls. Paper IV:In healthy study participants, renal clearance of HBP is low. In critically ill burn patients with impaired renal function, clearance of HBP is increased. Starting CRRT in critically ill patients does not alter plasma concentration of HBP. Still, HBP is found in the CRRT effluent fluid, and concentration does not appear to be dependent on plasma concentration.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2019. , p. 50
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2039
Keywords [en]
Heparin-binding protein, Critical care, Shock, Acute respiratory distress syndrome, Acute kidney injury, Ventilator induced lung injury, Renal clearance
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
URN: urn:nbn:se:umu:diva-162915ISBN: 978-91-7855-083-8 (print)OAI: oai:DiVA.org:umu-162915DiVA, id: diva2:1347674
Public defence
2019-10-11, Hörsalen Snäckan, Östersunds sjukhus, Östersund, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-09-20 Created: 2019-09-02 Last updated: 2019-09-18Bibliographically approved
List of papers
1. Increased Plasma Levels of Heparin-Binding Protein on Admission to Intensive Care Are Associated with Respiratory and Circulatory Failure
Open this publication in new window or tab >>Increased Plasma Levels of Heparin-Binding Protein on Admission to Intensive Care Are Associated with Respiratory and Circulatory Failure
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0152035Article in journal (Refereed) Published
Abstract [en]

Purpose: Heparin-binding protein (HBP) is released by granulocytes and has been shown to increase vascular permeability in experimental investigations. Increased vascular permeability in the lungs can lead to fluid accumulation in alveoli and respiratory failure. A generalized increase in vascular permeability leads to loss of circulating blood volume and circulatory failure. We hypothesized that plasma concentrations of HBP on admission to the intensive care unit (ICU) would be associated with decreased oxygenation or circulatory failure.

Methods: This is a prospective, observational study in a mixed 8-bed ICU. We investigated concentrations of HBP in plasma at admission to the ICU from 278 patients. Simplified acute physiology score (SAPS) 3 was recorded on admission. Sequential organ failure assessment (SOFA) scores were recorded daily for three days.

Results: Median SAPS 3 was 58.8 (48-70) and 30-day mortality 64/278 (23%). There was an association between high plasma concentrations of HBP on admission with decreased oxygenation (p<0.001) as well as with circulatory failure (p<0.001), after 48-72 hours in the ICU. There was an association between concentrations of HBP on admission and 30-day mortality (p = 0.002). ROC curves showed areas under the curve of 0,62 for decreased oxygenation, 0,65 for circulatory failure and 0,64 for mortality.

Conclusions: A high concentration of HBP in plasma on admission to the ICU is associated with respiratory and circulatory failure later during the ICU care period. It is also associated with increased 30-day mortality. Despite being an interesting biomarker for the composite ICU population it's predictive value at the individual patient level is low.

Keywords
Biomarkers, Blood Proteins, Organ Dysfunction Scores
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-120365 (URN)10.1371/journal.pone.0152035 (DOI)000372701200089 ()27007333 (PubMedID)
Available from: 2016-05-16 Created: 2016-05-16 Last updated: 2019-09-12Bibliographically approved
2. Heparin-binding protein as a biomarker of acute kidney injury in critical illness
Open this publication in new window or tab >>Heparin-binding protein as a biomarker of acute kidney injury in critical illness
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2017 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 7, p. 797-803Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: There is no biomarker with high sensitivity and specificity for the development of acute kidney injury (AKI) in a mixed intensive care unit (ICU) population. Heparin-binding protein (HBP) is released from granulocytes and causes increased vascular permeability which plays a role in the development of AKI in sepsis and ischemia. The aim of this study was to investigate whether plasma levels of HBP on admission can predict the development of AKI in a mixed ICU population and in the subgroup with sepsis. METHODS: Longitudinal observational study with plasma HBP levels from 245 patients taken on admission to ICU. Presence and severity of AKI was scored daily for 1 week. RESULTS: Mean (95% CI) plasma concentrations of log HBP (ng/ml) in the groups developing different stages of AKI were: stage 0 (n = 175), 3.5 (3.4-3.7); stage 1 (n = 33), 3.7 (3.5-4.0), stage 2 (n = 20), 4.4 (3.5-4.8); and stage 3 (n = 17), 4.6 (3.8-5.2). HBP levels were significantly higher in patients developing AKI stage 3 (P < 0.01) compared to AKI stage 0 and 1. The area under the curve (AUC) for HBP to discriminate the group developing AKI stage 2-3 was 0.70 (CI: 0.58-0.82) and in the subgroup with severe sepsis 0.88 (CI: 0.77-0.99). CONCLUSION: Heparin-binding protein levels on admission to ICU are associated with the development of severe kidney injury. The relationship between HBP and AKI needs to be further validated in larger studies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-136671 (URN)10.1111/aas.12913 (DOI)000404981100012 ()28585315 (PubMedID)1399-6576 (Electronic) 0001-5172 (Linking) (ISBN)
Available from: 2017-06-21 Created: 2017-06-21 Last updated: 2019-09-02Bibliographically approved
3. Heparin-binding protein in ventilator-induced lung injury.
Open this publication in new window or tab >>Heparin-binding protein in ventilator-induced lung injury.
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2018 (English)In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 6, no 1, article id 33Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Although mechanical ventilation is often lifesaving, it can also cause injury to the lungs. The lung injury is caused by not only high pressure and mechanical forces but also by inflammatory processes that are not fully understood. Heparin-binding protein (HBP), released by activated granulocytes, has been indicated as a possible mediator of increased vascular permeability in the lung injury associated with trauma and sepsis. We investigated if HBP levels were increased in the bronchoalveolar lavage fluid (BALF) or plasma in a pig model of ventilator-induced lung injury (VILI). We also investigated if HBP was present in BALF from healthy volunteers and in intubated patients in the intensive care unit (ICU).

METHODS: Anaesthetized pigs were randomized to receive ventilation with either tidal volumes of 8 ml/kg (controls, n = 6) or 20 ml/kg (VILI group, n = 6). Plasma and BALF samples were taken at 0, 1, 2, 4, and 6 h. In humans, HBP levels in BALF were sampled from 16 healthy volunteers and from 10 intubated patients being cared for in the ICU.

RESULTS: Plasma levels of HBP did not differ between pigs in the control and VILI groups. The median HBP levels in BALF were higher in the VILI group after 6 h of ventilation compared to those in the controls (1144 ng/ml (IQR 359-1636 ng/ml) versus 89 ng/ml (IQR 33-191 ng/ml) ng/ml, respectively, p = 0.02). The median HBP level in BALF from healthy volunteers was 0.90 ng/ml (IQR 0.79-1.01 ng/ml) as compared to 1959 ng/ml (IQR 612-3306 ng/ml) from intubated ICU patients (p < 0.001).

CONCLUSIONS: In a model of VILI in pigs, levels of HBP in BALF increased over time compared to controls, while plasma levels did not differ between the two groups. HBP in BALF was high in intubated ICU patients in spite of the seemingly non-harmful ventilation, suggesting that inflammation from other causes might increase HBP levels.

Place, publisher, year, edition, pages
SpringerOpen, 2018
Keywords
HBP, Neutrophils, Pigs, Ventilator-induced lung injury
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-151814 (URN)10.1186/s40635-018-0198-x (DOI)000445485300001 ()30203380 (PubMedID)
Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2019-09-02Bibliographically approved
4. Renal clearance of heparin-binding protein and elimination during renal replacement therapy: Studies in ICU patients and healthy volunteers
Open this publication in new window or tab >>Renal clearance of heparin-binding protein and elimination during renal replacement therapy: Studies in ICU patients and healthy volunteers
Show others...
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 8, article id e0221813Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Public Library of Science, 2019
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-162913 (URN)10.1371/journal.pone.0221813 (DOI)000485058200055 ()31465432 (PubMedID)2-s2.0-85071497875 (Scopus ID)
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-11-14Bibliographically approved

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