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. 2023 Dec 1;102(48):e36200. doi: 10.1097/MD.0000000000036200

Thrombin worsens extravascular lung water and outcomes of septic patients with acute respiratory distress syndrome: A case control study

Fu-Tsai Chung a,b,c,d,e,*, Chih-Hsi Kuo b, Chun-Hua Wang b, Shu-Min Lin b
PMCID: PMC10695594  PMID: 38050307

Abstract

Endothelial cell (EC) activation may increase systemic vascular permeability, causing extravascular lung water (EVLW) in sepsis with acute respiratory distress syndrome (ARDS). However, the correlation between thrombin and EVLW in sepsis and ARDS has not yet been addressed. Patients with sepsis and ARDS were prospectively enrolled between 2014 and 2016, and EVLW and serum thrombin levels on days 1 and 3 were measured and compared between surviving and non-surviving patients. Additionally, morphological changes in human umbilical vein endothelial cells (HUVECs) in the serum of patients with high and low EVLW were evaluated. The levels of EVLW, endothelial cells, and thrombin may positively correlate with the survival of patients with severe sepsis and ARDS. Twenty-seven patients were enrolled, and baseline characteristics, including age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II, prior 24-h fluid balance, body mass index, and shock status, were similar between survivors and non-survivors; however, day 1 EVLW was higher in non-survivors (27.5 ± 8.4 vs 22 ± 6.5 mL/kg, P = .047). EVLW of survivors improved from day 1 to day 3 (22 ± 6.5 vs 11 ± 3.8 mL/kg, P < .001), but did not improve in non-survivors (27.5 ± 8.4 vs 28 ± 6.7 mL/kg, P = .086), which means that patients had significantly lower EVLW on day 3 than on day 1. Thrombin levels of survivors significantly improved (1.03 ± 0.55 vs 0.87 ± 0.25 U/mL, P = .04) but did not improve in non-survivors (1.97 ± 0.75 vs 2.2 ± 0.75 U/mL, P = .08) from day 1 to day 3. EVLW and thrombin levels were positively correlated (r2 = 0.71, P < .0001). In vitro, the morphology and junctions of HUVECs changed when the serum from patients with high EVLW was added. The intercellular distances among the control, high EVLW, and low EVLW groups were 5.25 ± 1.22, 21.33 ± 2.15, and 11.17 ± 1.64 µm, respectively (P < .05).

Keywords: sepsis, acute respiratory distress syndrome, extravascular lung water, thrombin, endothelial cells

1. Introduction

Sepsis remains one of the leading causes of in-hospital death. Despite advances in intensive care for patients with sepsis, the mortality rate of patients with severe sepsis remains high, up to 30% to 50%,[1–3] and even up to 70% in septic patients with disseminated intravascular coagulation.[4] The prevalence of sepsis and deaths due to sepsis also remain high.[5]

The major pathogenesis of sepsis involves structural and functional changes in the microvascular systems. Extensive damage and apoptosis of endothelial cells (ECs) have been observed in sepsis, and further activation of ECs has been observed before damage to ECs in sepsis.[6,7] From ECs activation, biomarkers of sepsis have been identified. Many EC-related molecules have been demonstrated to be biomarkers for sepsis, especially for diagnosis, outcome prediction, and development of novel treatments.[8,9]

One severe complication of sepsis is acute respiratory distress syndrome (ARDS), which is characterized by endothelial barrier dysfunction leading to fluid accumulation in the lungs, reflecting the hyperpermeability of pulmonary capillaries in severe sepsis.[10] With increasing pulmonary vascular permeability, the extravasation of water in the lungs (extravascular lung water [EVLW]) increases and causes interstitial lung edema. Hyperpermeability and interstitial lung edema lead to hypoxemia and ischemia of the tissues and organs in patients with sepsis and ARDS. Our previous studies also reported high mortality in patients with elevated EVLW.[11,12] In ARDS, fluid accumulation in the lungs is related to the injury of alveolar epithelial cells and pulmonary capillary endothelial cells, which may cause the release of inflammatory cytokines, neutrophil infiltration, and deposition of the extracellular matrix. Finally, the respiratory system fails to provide adequate oxygenation and ventilation.[13,14]

Some clinical trials with anti-inflammatory agents, corticosteroids, and pulmonary vasodilators have been conducted but have failed to reduce mortality.[15] In addition, the host response to sepsis is characterized by a systemic inflammatory response. In sepsis, the expression of tissue factors in the damaged endothelium can be caused by bacterial toxins and cytokines. Tissue factors also increases thrombin formation.[16] Ongoing inflammatory reactions and microvascular thrombi can lead to organ dysfunction. The measurement of thrombin generation may be helpful in understanding the hemostatic potential of an organism.[17] The generation of thrombin can be used to identify the coagulation in sepsis.[18–20]

Based on these observations, this study aimed to investigate the course of thrombin generation in patients with severe sepsis and ARDS and the correlation between thrombin and EVLW in these subjects. We also hypothesized that thrombin formation may play a role in the pathogenesis of ARDS through further activation and permeability changes in endothelial cells. To test this hypothesis, we compared morphological changes in endothelial cells when high- and low-EVLW patient serum was added. Furthermore, the possible signals from these endothelial cells were investigated in vitro.

2. Methods

2.1. Ethics

The institutional review boards of the study hospitals approved this study (IRB No.: 99-3957B and SPH-10406-02), and written informed consent was obtained from all patients. The study was registered on ClinicalTrials. gov (NCT01694147).

2.2. Patients

Between 2014 and 2016, patients who met the standard published criteria for sepsis and ARDS were enrolled and consecutively recruited. The study population was recruited from patients admitted to the medical intensive care unit (ICU) of a university-affiliated medical center and a local hospital. Written informed consent was obtained from all patients or their surrogates. Patients for whom informed consent was not required because the patient had been anonymized; a statement affirming that the patient gave permission. Moreover, the included patients meet standard published criteria for severe sepsis[11] with acute respiratory distress diseases (ARDS)[21] by the Berlin definition upon initial enrollment. All enrolled cases were of pulmonary origin and recruited consecutively. The patients were followed up until death or discharge from the hospital. Patients receiving endotracheal mechanical ventilation for hypoxemic acute respiratory failure were eligible if the following criteria were met for no more than 48 hours before enrollment: ratio of partial pressure of arterial oxygen over fraction of inspired oxygen (PaO2:FIO2) no >300 mm Hg at time of enrollment, recent appearance of bilateral pulmonary infiltrates consistent with edema, and no clinical evidence of left atrial hypertension. Exclusion criteria were age < 18 years, known pregnancy, participation in another trial within 30 days before meeting the eligibility criteria, expected duration of mechanical ventilation shorter than 48 hours, and decision to withhold life-sustaining treatment.

2.3. Baseline assessments and definition of survivors

All eligible patients were enrolled within 48 hours of meeting the ARDS criteria[21] by the Berlin definition upon initial enrollment. Patient-specific data were obtained upon enrollment, including demographic data, medical history, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. Survivors were defined as patients who survived during their ICU stay and were transferred out of the ICU. In addition, relevant medical history was collected, including chronic airway diseases (asthma, chronic airway obstructive disease, and bronchiectasis), cardiovascular disease (hypertension, cerebral stroke, coronary disease, heart failure, and arrhythmia), and chronic renal failure. Physiological parameters, including the previous 24-hour net input/output fluid balance and shock status, were assessed. Shock was defined as systolic blood pressure < 90 mm Hg or mean arterial pressure < 60 mm Hg and requiring vasopressor use. Patient management decisions, including the type and amount of volume resuscitation, were based on the discretion of the primary intensive care physician. Laboratory serologic data (albumin, white blood cell counts, and platelet counts) and oxygenation parameters (PaO2/FiO2, lung injury score, and chest X-ray score) were listed simultaneously as EVLW was made available by the pulse contour continuous cardiac output system.

2.4. Measurement of extravascular lung water and hemodynamic parameter

EVLW measurements were based on the transpulmonary thermodilution method, the details of which are reported in our previous study.[22–24] This method used a single indicator (cold saline solution) and demonstrated a satisfactory correlation with the gravimetric method.[24] In summary, a 4-F arterial catheter (PulsiocathPV2014L16; Pulsion Medical Systems, Munich, Germany) was positioned in the descending aorta via the femoral artery using the Seldinger technique. The femoral arterial catheter and a standard central venous catheter were connected to pressure transducers and an integrated bedside monitor (pulse contour continuous cardiac output; Pulsion Medical Systems). Following 3 consecutive central venous injections of 10 mL iced 0.9% saline solution, continuous cardiac output (CO) calibration and EVLW measurements were obtained. CO calibrations and EVLW determinations were performed immediately following catheter insertion and were employed as the hemodynamic parameters for managing patients in the medical ICU with ARDS.

2.5. The primary and secondary outcome measures

The primary outcome measures were EVLW between survivors and non-survivors on day 1 and 3, clinically. The secondary outcome measures were thrombin level between survivor and non-survivors on day 1 and 3, and the relation between EVLW and thrombin level. In vitro, the morphology and distance among Human umbilical vein endothelial cells (HUVECs) with serum of patients with high and low EVLW were observed and measured.

2.6. Determination of thrombin levels

Plasma thrombin level was assayed using a commercial enzyme-linked immunosorbent assay kit provided by Medgenix (BioSource International, Camarillo, CA) (David., 2002).

2.7. Cell culture

Human umbilical vein endothelial cells (HUVECs) were obtained from the America Type Culture Collection. HUVECs were routinely grown on gelatin-coated plastic in M199 medium (Biochrom KG) containing 5% fetal calf serum (PAA Laboratories GmbH) and in EGM containing 2% fetal bovine serum and 0.4% bovine brain extract, respectively. Prior to stimulation, HUVECs were starved for 16 hours in serum-free M199 containing 5% lactalbumin hydrolysate (Gibco Life Technologies), 10 mg/mL transferrin (Sigma) and in EGM without supplements, respectively. The following concentrations of phorbol myristate acetate, tumor necrosis factor-alpha, and growth factors were used for stimulation: phorbol myristate acetate 50 nM, tumor necrosis factor-alpha 25 ng/mL, Acidic fibroblast growth factor 5 ng/mL, basic fibroblast growth factor 5 ng/mL, Vascular endothelial growth factor 50 ng/mL, EGF 10 ng/mL, Platelet-Derived Growth Factor AA 10 ng/mL, and Platelet-Derived Growth Factor BB 10 ng/mL. For further analysis, conditioned media and cellular proteins were collected 24 hours after stimulation.[25]

2.8. Immunocytochemistry and confocal laser scanning microscopy

After treatment of HUVECs, immunocytochemistry and confocal laser scanning microscopy were performed as previous reference.[26] Primary antibodies: see Western blot analysis. Secondary antibodies: Alexa Fluor 488 goat anti-mouse/rabbit and Alexa Fluor 633 goat anti-rabbit (Invitrogen, Karlsruhe, Germany). F-actin was stained with rhodamine/phalloidin (Invitrogen, Karlsruhe, Germany).

2.9. Statistical analysis

All data are expressed as the mean ± standard deviation or 95% confidence interval (CI) and number (%). Because the sample size was small, nonparametric tests were used in this study. Quantitative variables between the 2 groups were then compared using the Mann–Whitney U test for continuous and ordinal variables and Fisher exact test for nominal variables. Data at different time points were compared using one-way analysis of variance. A 2-sided P value < 0.05 was considered statistically significant. All analyses were conducted using the Statistical Package for the Social Sciences software (version 17.0, SPSS, Chicago, IL) and Prism 5 for Windows (version 5.03, GraphPad Software, Inc., San Diego, CA).

3. Results

During the study period, 27 patients with sepsis and ARDS who required ventilator support at our institution were recruited. The baseline characteristics, including patient age, sex, APACHE II score, and body mass index, are listed in Table 1. The mean age of all patients was 63.9 ± 15.2 years. There were 18 men and 9 women. Baseline characteristics, including age, sex, APACHE and Chronic Health Evaluation II, prior 24-h fluid balance, body mass index, and shock status, were similar in both groups. But EVLWI level was significantly higher in the non-survivor group than in the survivor group (27.5 ± 8.4 vs 22 ± 6.5 mL/kg, P = .047).

Table 1.

Baseline characteristics of all enrolled patients on d 1.

Variable All Survivor Non-survivor P value
Patients, n 27 13 14
Baseline characteristics
Age (yr) 63.9 ± 15.2 63.7 ± 17.3 66.8 ± 13.1 .78
Female, n (%) 9 (33.3) 5 (38.5) 4 (28.6) .59
APACHE II score 27.2 ± 7.1 28.1 ± 6.2 33.1 ± 6.0 .26
BMI 21.2 ± 4.1 22.1 ± 5.0 20.0 ± 3.0 .69
Physiology at enrollment
prior 24 h fluid balance (mL) 2875 ± 1235 2498 ± 897 3257 ± 1376 .39
Shock (vasopressor requirement), n (%) 22 (81.5) 10 (76.9) 12 (85.7) .56
EVLW (mL/kg) 24.0 ± 7.9 22 ± 6.5 27.5 ± 8.4 .047
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Values are expressed as Mean ± SD, or numbers (%), unless otherwise noted.

APACHE = acute physiology and chronic health evaluation; BMI = body mass index, EVLW = extravascular lung water.

During ICU stay, patients in the survivor group had a better EVLWI (22 ± 6.5 vs 11 ± 3.8 mL/kg, P = .0001) from day 1 to day 3, but patients in the non-survivor group did not (27.5 ± 8.4 vs 28 ± 6.7 mL/kg, P = .86), meaning that patients had significantly lower EVLWI on Day 3 compared to Day 1 (Fig. 1). Similarly, thrombin levels of survivor patients significantly improved (1.03 ± 0.55 vs 0.87 ± 0.25 U/mL, P = .04) but did not improve in the non-survivor group (1.97 ± 0.75 vs 2.2 ± 0.75 U/mL, P = .08) from day 1 to day 3 (Fig. 2). The correlation between EVLWI and thrombin was positive (r2 = 0.71, P < .0001) (Fig. 3).

Figure 1.

Figure 1.

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During ICU stay, patients in the survivor group had a better EVLWI (22 ± 6.5 vs 11 ± 3.8 mL/kg, P = .0001) from d 1 to d 3, but patients in the non-survivor group did not (27.5 ± 8.4 vs 28 ± 6.7 mL/kg, P = .86), meaning that patients had significantly lower EVLWI on D 3 compared to D 1. ICU = intensive care unit.

Figure 2.

Figure 2.

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Thrombin levels of survivor patients significantly improved (1.03 ± 0.55 vs 0.87 ± 0.25 U/mL, P = .04) but did not improve in the non-survivor group (1.97 ± 0.75 vs 2.2 ± 0.75 U/mL, P = .08) from d 1 to d 3.

Figure 3.

Figure 3.

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The correlation between EVLWI and thrombin was positive (r2 = 0.71, P < .0001).

In the in vitro study, we found that HUVEC showed morphological changes when the serum from patients with high EVLW was added; however, the morphology of HUVEC was almost normal when the serum from patients with low EVLW was added (Fig. 4). As shown in the representative figure, the distance between cells was randomly collected from 6 sites by 2 research assistants. We analyzed the data using one-way analysis of variance. The mean and standard deviation among control, high EVLW and low EVLW group were 5.25 ± 1.22, 21.33 ± 2.15, 11.17 ± 1.64 µm (micrometers) and P value < 0.05.

Figure 4.

Figure 4.

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As shown in the representative figure, the distance between cells was randomly collected from 6 sites by 2 research assistants. We analyzed the data using one-way analysis of variance (ANOVA). The mean and standard deviation among control, high EVLW and low EVLW group were 5.25 ± 1.22, 21.33 ± 2.15, 11.17 ± 1.64 µm (micrometers) and P value < .05.

4. Discussion

The results of our study indicated that EVLW decreased in survivors from day 1 to day 3 when severe sepsis and ARDS were present (Fig. 1). Thrombin levels also significantly decreased in surviving patients with severe sepsis and ARDS from days 1 to 3 (Fig. 2). However, the levels of both EVLW and thrombin in non-survivors did not decrease (Figs. 1 and 2). In addition, EVLW was positively correlated with thrombin levels (Fig. 3). Based on these clinical studies, thrombin may play a critical role in elevating EVLW levels in patients with severe sepsis and ARDS. In an in vitro study, we found that the serum of patients with sepsis with high EVLW affected adhesion junction stability (Fig. 4).

Endothelial cells and thrombin play critical roles in the pathophysiology of sepsis, a life-threatening condition characterized by dysregulated immune response, systemic inflammation, and coagulation abnormalities.[27] Endothelial dysfunction is characterized by impaired vasomotor regulation and increased vascular permeability. This dysfunction is mediated by intracellular signaling pathways such as Rho Guanosine triphosphate hydrolases and protein kinase C, as well as the disruption of endothelial junctions.[28] Thrombin, traditionally known for its role in coagulation, plays a pivotal role in the pathophysiology of sepsis. Increased thrombin generation results in a procoagulant state and the formation of microthrombi, exacerbating endothelial dysfunction and tissue hypoxia.[29] Thrombin activates protease-activated receptors on endothelial cells, triggering inflammation and increasing vascular permeability.[29,30] Furthermore, thrombin-mediated endothelial activation leads to the production of von Willebrand factor, contributing to microvascular thrombosis and impaired blood flow.[31] Thrombin also influences immune cell behavior by amplifying the coagulation and inflammatory responses in sepsis.[29] Understanding the intricate interactions between endothelial cells and thrombin is crucial for elucidating the pathogenesis of sepsis and identifying potential therapeutic targets.

As shown in Figures 3 and 4, thrombin may influence endothelial cells to regulate endothelial barrier function.[32] Our study showed that serum from patients with high EVLW-augmented could affect the junctions of endothelial cells, which is important for mediating the detrimental effects of thrombin on barrier function.[33]

Based on these observations, this study demonstrated thrombin generation in patients with severe sepsis and ARDS, and the correlation between thrombin and EVLW in these subjects. We also demonstrated that thrombin formation may play a role in the pathogenesis of ARDS by further activation and permeability change of endothelial cells in vitro. In patients with low EVLW, we found that the serum could partially reverse the permeability, which implies that the patients with low EVLW may contain some proteins to reverse endothelial cell permeability. To test this hypothesis, we compared the morphological changes in endothelial cells when high and low EVLW patient serum was added, and the results shown in Figure 4 confirm this hypothesis.

Some animal studies have reported the inhibition of thrombin via direct inhibition by thrombin inhibitors, binding of thrombin with antithrombin III, decreased thrombin generation, or thrombin degradation. These studies have demonstrated the effects on both coagulation and inflammatory pathways within the endothelium.[34,35] This study provides a potential therapeutic strategy for thrombin inhibition in sepsis. Further studies are required to clarify their role in the management of patients with sepsis.

The present study had some limitations. The sample size in our study was not large despite the statistical significance, which may have increased the rates of type I and type II errors and precluded the identification of discrete subpopulations. It is also important to highlight that a multivariate analysis was not possible. The small sample size means that no significant differences were found between the 2 groups of patients in terms of their backgrounds; however, there may be potential differences in severity. Second, shock was diagnosed based on blood pressure measurements. This may have underestimated the true prevalence and introduced a bias in the results. There were some additional confounders, including mechanical ventilator settings, which may have affected the results of the study; however, in the small and observational study, we only provided an association between thrombin and ARDS, discussed the findings, and cited references for readers. Additionally, fluid balance can affect EVLW. However, we have limited data for fluid balance progression within hours despite the fact that the fluid balance of the 2 groups was not significantly different. Anticoagulants may have influenced the results; however, all included patients were of pulmonary origin, and therefore, none needed anticoagulants initially or within a few days. Serum was only collected initially when included in this manuscript. Therapeutic strategies may prevent pathologies associated with endothelial barrier dysfunction in patients with severe sepsis or ARDS. However, this study demonstrated an association between thrombin and ARDS. Further studies are required in the future.

In conclusion, EVLW could be a permeability indicator for septic patients with ARDS via vascular leakage biomarkers such as thrombin. The levels of EVLW and thrombin are positively correlated and may affect the survival of these patients. We showed that the serum of patients with high EVLW effectively caused endothelial barrier dysfunction in those with severe sepsis and ARDS with high EVLW levels.

Acknowledgments

We would like to thank the staff of medical ICUs of the hospitals. We would like to thank Editage (www.editage.com) for English language editing.

Author contributions

Conceptualization: Fu-Tsai Chung.

Data curation: Fu-Tsai Chung, Chih-Hsi Kuo, Chun-Hua Wang, Shu-Min Lin.

Formal analysis: Fu-Tsai Chung.

Funding acquisition: Fu-Tsai Chung.

Writing – original draft: Fu-Tsai Chung.

Writing – review & editing: Fu-Tsai Chung.

Abbreviations:

APACHE
acute physiology and chronic health evaluation
ARDS
acute respiratory distress syndrome
CI
confidence interval
CO
continuous cardiac output
EC
endothelial cell
EVLW
extravascular lung water
HUVECs
human umbilical vein endothelial cells
ICU
intensive care unit
PaO2:FIO2 =
ratio of partial pressure of arterial oxygen over fraction of inspired oxygen

Ethics approval and consent to participate: The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study has received ethics approval from the Institutional Review Board of study hospitals (IRB No.: 99-3957B of Chang Gung Memorial Hospital and SPH-10406-02 of Saint Paul Hospital) and written informed consent was obtained from all patients. Following the guidelines of the Chang Gung written informed consent was obtained from each participant.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

This study was supported by grants from Chang Gung Memorial Hospital (CMRPVVL0041, CMRPG3A0562, CMRPG3H0931, CMRPG3B0831, CMRPG3B0832, and CMRPG3B0833) and the National Science Council (NSC-100-2314-B-182A-054, 104-2314-B-182-049 and 105-2314-B-182-045). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have no conflicts of interest to disclose.

How to cite this article: Chung F-T, Kuo C-H, Wang C-H, Lin S-M. Thrombin worsens extravascular lung water and outcomes of septic patients with acute respiratory distress syndrome: A case control study. Medicine 2023;102:48(e36200).

Contributor Information

Chih-Hsi Kuo, Email: chihhsikuo@gmail.com.

Chun-Hua Wang, Email: wchunhua@ms7.hinet.net.

Shu-Min Lin, Email: smlin100@gmail.com.

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