Association between trajectory of heparin-binding protein and extubation in ARDS patients: A longitudinal study
Introduction
Acute respiratory distress syndrome (ARDS) is a critical condition in intensive care units (ICUs), characterized by severe hypoxemia and bilateral chest radiographical opacities due to non-cardiogenic pulmonary edema. It has high mortality rates, and mechanical ventilation is a crucial intervention. However, extubation, the process of removing the ventilator, can be challenging, with 10-20% of patients experiencing extubation failure, which is strongly associated with adverse clinical outcomes. Accurate prediction of extubation success is essential for ARDS patients.
The pathophysiology of ARDS involves injury to pulmonary vascular endothelial cells and alveolar epithelia, leading to increased capillary permeability and fluid leakage into the alveolar and interstitial spaces, impairing pulmonary function. Pulmonary vascular permeability is a critical determinant of disease progression and clinical prognosis in ARDS.
Heparin-binding protein (HBP), a neutrophil-derived protein, plays a significant role in ARDS by mediating proinflammatory cytokine release, immune cell chemotaxis, and endothelial damage. HBP levels are elevated in ARDS patients, correlating with the development and severity of the disorder. However, research on the relationship between HBP dynamics and extubation outcomes in ARDS patients is limited.
This study aims to monitor HBP levels longitudinally and use group-based trajectory modeling (GBTM) to investigate the association between different HBP trajectories and extubation outcomes in ARDS patients. The findings will help establish a predictive tool for ventilator weaning strategies and optimize clinical decision-making.
Methods
Study Design and Participants
ARDS patients admitted to the ICU of Ningbo Medical Center Lihuli Hospital between September 2023 and March 2025 were enrolled. The diagnosis of ARDS was based on global criteria. Informed consent was waived due to the retrospective nature of the study. The inclusion criteria were: staying in the ICU for more than six days, complete clinical data, and age > 18 years. Exclusion criteria included extubation within six days, tracheostomy, and patients requesting discharge during treatment.
Data Collection
Data were extracted from the critical care electronic database, including baseline characteristics such as age, gender, body mass index (BMI), chronic diseases, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, PaO2/FiO2 at enrollment, and primary ARDS disease. HBP levels were measured daily from 1-6 days after enrollment.
Clinical Outcomes
The primary outcome was extubation success, defined as sustained spontaneous breathing for more than 48 hours without mechanical ventilation. Secondary outcomes included ventilator-free days, length of ICU and hospital stays, and ICU mortality.
Statistical Analysis
The Kolmogorov-Smirnov test assessed the normality of continuous variables. Normally distributed data were expressed as means ± SD and compared using the t-test. Non-normally distributed data were presented as [M (P25, P75)] medians and compared using the Mann-Whitney U-test. Categorical variables were expressed as numbers (%) and compared using the Chi-square test.
HBP trajectories were categorized using GBTM, implemented in R with the 'gbmt' package. The optimal number of trajectory classes was determined using Bayesian Information Criterion (BIC) and Akaike Information Criterion (AIC) values, average posterior probability of assignment (AvePP > 70%), odds of correct classification (OCC > 5), minimal class sizes (> 5% of sample size), and clinical experience.
A two-step regression analysis was conducted to identify factors associated with extubation success. Univariate logistic regression was performed for different HBP patterns and clinical variables. Multivariate logistic regression was then used to assess the relationship between HBP trajectories and extubation success, adjusting for potential confounders.
Results
Characteristics of the Study Population
267 patients were included, with 156 successfully extubated. The cohort was predominantly male (73.78%), with a median age of 72 years (IQR: 63-80) and a median APACHE II score of 21 (IQR: 16.00-24.00). The primary ARDS disease was pulmonary disease. Baseline characteristics are summarized in Table 1, and the flowchart is shown in Figure 1.
HBP levels on the first day were lower in successfully extubated patients compared to those with extubation failure (P < 0.05). No significant differences were observed in other indicators between the groups.
Group-Based Trajectory Modeling
Using a polynomial order of three, we explored group-based trajectory models with 1-6 subgroups. BIC and AIC values decreased with increasing subgroup numbers. A 5-subgroup trajectory configuration was determined to be optimal, considering clinical relevance and model parsimony.
Characteristics and Clinical Outcomes of Various HBP Trajectories
ARDS patients were classified into five distinct HBP trajectory groups: traj1 (persistently extremely low HBP, n = 51), traj2 (persistently low HBP, n = 63), traj3 (high-to-low transitional HBP, n = 18), traj4 (persistently moderate HBP, n = 74), and traj5 (persistently high HBP, n = 61). All trajectories are shown in Figure 2, and daily HBP levels are detailed in Table S3.
The extubation success rate progressively decreased from traj1 to traj5, with statistically significant differences (P < 0.001). Ventilator-free days and ICU mortality also showed significant differences among the groups (P < 0.05).
Association Between HBP Trajectories and Extubation Success
Logistic regression analysis revealed significant differences in extubation success among the five groups. Traj2, traj3, traj4, and traj5 were associated with decreased extubation success rates compared to traj1 (OR = 0.239, 0.195, 0.143, 0.081, respectively). These associations persisted after adjusting for potential confounders.
Subgroup Analysis
Subgroup analysis by age and SOFA score showed non-significant interaction effects (P > 0.05). However, robust associations between distinct HBP trajectories and extubation outcomes were observed in patients aged ≥ 72 years and with SOFA scores < 7 or ≥ 7.
Discussion
This study identified five distinct HBP trajectories in ARDS patients, with higher HBP levels associated with a higher risk of extubation failure. This association remained significant after adjusting for confounding factors. These findings may help identify high-risk populations for extubation failure and provide clinical guidelines for extubation decision-making.
ARDS is a severe pulmonary manifestation of systemic inflammatory response syndrome (SIRS), with inflammatory cell activation and mediators driving its progression. HBP, a key component of neutrophil granules, plays a pivotal role in initiating inflammation and enhancing vascular permeability. It binds to endothelial cell surfaces, activating pathways that lead to increased vascular permeability and chemoattractant activity, promoting inflammatory cell recruitment.
Elevated plasma HBP levels are observed in ARDS patients, correlating with lung injury severity. HBP is a predictive biomarker for clinical deterioration in respiratory failure. This study's findings support HBP's role as a robust indicator of pulmonary microvascular permeability alteration and lung injury severity.
In this study, five HBP trajectory groups were identified using GBTM. Patients with persistent moderate or high HBP levels exhibited lower extubation success rates compared to those with persistently extremely low HBP. Logistic regression confirmed this inverse association, suggesting that sustained moderate or high HBP may perpetuate alveolar-capillary barrier dysfunction, driving pulmonary edema and inflammation, and leading to more severe lung injury.
Clinically, this persistence correlates with prolonged mechanical ventilation, higher extubation failure and ICU mortality risks, and critical disease progression requiring vigilant monitoring. Descending HBP trajectories showed superior extubation outcomes and lower ICU mortality, highlighting the importance of dynamic HBP monitoring over static measurements for guiding extubation decisions.
Subgroup analyses by age and SOFA scores demonstrated persistent associations between HBP trajectory patterns and extubation outcomes, with robust correlations in patients aged ≥ 72 years and across SOFA score subpopulations. These findings align with studies showing extreme HBP elevation in advanced age, compromised immunity, and elevated mortality risk.
HBP trajectories can help clinicians identify high-risk patients for extubation failure, enabling closer monitoring and timely interventions. Future research should focus on establishing specific HBP cut-off values for clinical decision-making.
Limitations
The study had a moderate sample size and was conducted at a single center. As a retrospective study, it cannot verify a causal relationship between HBP trajectories and extubation outcomes. Larger, multi-center studies are needed to validate the findings.
Conclusion
This study identifies distinct HBP trajectories strongly associated with extubation success in ARDS, providing a potential tool for risk stratification. Monitoring HBP dynamics can help clinicians identify high-risk patients for extubation failure, who may benefit from vigilant monitoring and tailored weaning protocols. Future research should focus on validating these trajectories and establishing specific HBP cut-off values for clinical decision-making.
