Extravascular Lung Water Content Research Articles

Combined treatment with vitamin C, hydrocortisone and thiamine does not attenuate morbidity and mortality of septic sheep

BackgroundSepsis is associated with a highest mortality rate in the ICU. Present study tests the efficacy of combined therapy with vitamin C, hydrocortisone and thiamine (combined therapy) in the ovine model of sepsis induced by Pseudomonas aeruginosa. In this study, sepsis was induced in sheep by instillation of Pseudomonas aeruginosa (1 × 1011 CFU) into the lungs via bronchoscope, under anesthesia. Nine hours after injury, intravenous infusion of vitamin C (0.75 g every 6 h), hydrocortisone (25 mg every 6 h), and thiamine (100 mg every 12 h) or saline was given to the treatment and control groups. Cardiopulmonary variables were recorded.ResultsThe survival rate was 16.7% in control and 33.3% in treatment groups. In the control group, mean arterial pressure dropped from 93.6 ± 8.6 to 75.5 ± 9.7 mmHg by 9 h, which was not affected by the combined therapy. Pulmonary dysfunction was not attenuated by the combined therapy either. The combined therapy had no effect on increased extravascular lung water content and fluid effusion into thoracic cavity. The bacterial number in the bronchoalveolar lavage fluid was significantly increased in the treatment group than the control group. The blood bacterial number remained comparable between groups.ConclusionsCombined vitamin C, hydrocortisone, and thiamine did not attenuate severity of ovine sepsis.

High molecular weight sodium hyaluronate improves survival of syndecan-1-deficient septic mice by inhibiting neutrophil migration.

We investigated the role of endothelial glycocalyx and its component syndecan-1 protein in the pathophysiology of sepsis-induced vascular hyper-permeability and examined the therapeutic effects of high-molecular-weight sodium hyaluronate (HMW-SH).MethodsSepsis was induced by cotton smoke inhalation followed by intranasal administration of Pseudomonas aeruginosa in female (> 6 months) Balb/c and syndecan-1 knockout mice. Survival of mice, lung capillary endothelial glycocalyx integrity, lung water content, and vascular hyper-permeability were determined with or without HMW-SH treatment in these mice. Effects of HMW-SH on endothelial permeability and neutrophil migration were tested in in vitro setting.ResultsIn septic wildtype mice, we found a severely damaged pulmonary microvascular endothelial glycocalyx and elevated levels of shed syndecan-1 in the circulation. These changes were associated with significantly increased pulmonary vascular permeability. In septic syndecan-1 knockout mice, extravascular lung water content was higher, and early death was observed. The administration of HMW-SH significantly reduced mortality and lung water content in septic syndecan-1 knockout mice, but not in septic wildtype mice. In in vitro setting, HMW-SH inhibited neutrophil migration and reduced cultured endothelial cell permeability increases. However, these effects were reversed by the addition of recombinant syndecan-1 ectodomain.ConclusionsHMW-SH reduced lung tissue damage and mortality in the absence of syndecan-1 protein, possibly by reducing vascular hyper-permeability and neutrophil migration. Our results further suggest that increased shed syndecan-1 protein levels are linked with the inefficiency of HMW-SH in septic wildtype mice.

Lung ultrasound to quantitatively evaluate extravascular lung water content and its clinical significance

Background As we all know, pulmonary edema can be diagnosed by lung ultrasound (LUS), but how to accurately and quantitatively evaluate lung water content by ultrasound is a difficult problem that needs to be solved urgently. B-line assessment with LUS has recently been proposed as a reliable, noninvasive semiquantitative tool for evaluating extravascular lung water (EVLW). To date, however, there has been no easy quantitative method to evaluate EVLW by LUS. Objective (1) To explore the feasibility of establishing a rabbit model with increased EVLW by injecting warm normal saline (NS) into the lungs via the endotracheal tube. (2) To establish a simple, accurate and clinically operable method for quantitative assessment of EVLW using LUS. (3) To develop LUS into a resource for guiding the clinical treatment of patients with increased EVLW. Methods Forty-five New Zealand rabbits were randomized into nine groups (n = 5). After anesthesia, each group of rabbits was injected with different amounts of warm sterile NS (0 ml/kg, 2 ml/kg, 4 ml/kg, 6 ml/kg, 8 ml/kg, 10 ml/kg, 15 ml/kg, 20 ml/kg, 30 ml/kg) via the endotracheal tube. Each rabbit was examined by LUS before and after NS injection. At the same time, the spontaneous respiratory rate (RR, breaths per minute), heart rate (HR, bpm) and arterial blood gas (ABG) of the rabbits were recorded. Then, both lungs were dissected to obtain the wet and dry weight and conduct a complete histological examination. Results Injecting NS into the lungs through a tracheal tube can successfully establish a rabbit model with increased EVLW. The extent of EVLW increase is related to the volume of NS injected into the lungs. As the EVLW increases, three different types of B-lines can be seen in the LUS. When the NS injection volume is 2–6 ml/kg, comet-tail artifacts and B-lines are the main patterns found on LUS; as additional NS is injected into the lungs, the rabbits' RR gradually increases, while their HR gradually decreases, ABG remains normal or shows mild metabolic acidosis (MA). Confluent B-lines grow gradually but significantly, reaching a dominant position when the NS injection volume reaches 6–8 ml/kg and predominating almost entirely when the NS injection volume is 8–15 ml/kg; at that time, rabbits' RRs and HRs decrease sharply, and the ABG indicated type I respiratory failure (RF).Compact B-lines occur and predominate almost entirely when the NS injection volume reaches 10 ml/kg and 15–20 ml/kg, respectively. At that time, rabbits begin to enter cardiac and respiratory arrest, and ABG shows type II RF and MA. Conclusion In this study, the establishment of an animal model with increased EVLW confirmed that different lung water content had corresponding manifestations in ultrasound and was associated with different degrees of clinical symptoms, and the study results can be used to guide clinical practice.

Extravascular Lung Water and Effect on Oxygenation Assessed by Lung Ultrasound in Adult Cardiac Surgery.

IntroductionThe extravascular lung water content is determined by the use of lung ultrasound (LUS) which is represented as B-lines. The aim of this study was to investigate whether the LUS measurement of extravascular lung water was correlated to changes in oxygenation.MethodsThis prospective cohort study was comprised of 73 patients with an average age of 56 (range: 18 to 87 years) who underwent elective cardiac surgery using cardiopulmonary bypass. The LUS score was performed preoperatively, time zero (T0), at one hour (T1), and at 24 hours (T2) post-surgery. Additionally, arterial oxygen partial pressure and fraction of inspired oxygen (PaO2/FiO2) ratio were measured at each time and the time-to-extubation.ResultsA negative correlation was found between the LUS score and PaO2/FiO2 at T1 (p < 0.004). Extubation time and changes in the lung ultrasound score at T0 - T2 were positively correlated (p < 0.03). Plus, there was a positive correlation between fluid balance and lung ultrasound score at T2 (p < 0.03).ConclusionWe found three significant correlations that support the use of LUS in cardiac surgery: 1) the more B-lines, the lower the oxygenation; 2) the more B-lines, the longer the period of ventilation; 3) the more B-lines, the more positive the fluid balance. LUS is a non-invasive bedside investigation that can be used to judge extravascular lung water, providing useful information in the management of patient oxygenation, fluid balance, and extubation.

Lung Ultrasound Score Predicts the Extravascular Lung Water Content in Low-Birth-Weight Neonates with Patent Ductus Arteriosus.

BackgroundPatent ductus arteriosus (PDA) is a common congenital cardiac abnormality in premature infants. In low-birth-weight infants weighing less than 2500 g, if the PDA continues to open, abnormal circulation hemodynamics and pulmonary edema may occur. This study aimed to investigate the role of lung ultrasound score in the assessment of pulmonary edema in low-weight neonates with PDA.Material/MethodsTwo hundred and twenty-one neonates with low birth weight were selected as the subjects, children with PDA as the observation group, and children with closed ductus arteriosus as the control group. On the fourth postnatal day, lung ultrasound examination and 6-segment lung ultrasound scoring were performed.ResultsAll 221 infants (94 in the observation group, 127 controls) underwent ultrasound examinations of the lungs. Intergroup differences in gestational age, birth weight, length of hospital stay, and left ventricular ejection fraction were not statistically significant. There was a significant difference in lung ultrasound score (t=0.005, P=0.000) and aortic root ratio to left atrial (t=0.085, P=0.000), which was negatively correlated with gestational age (r=−0.235, P=0.000) and positively correlated with PDA diameter (r=0.261, P=0.011).ConclusionsLow-birth-weight children often have PDA. Its continued opening changes the circulation hemodynamics in children. Lung ultrasound score can semi-quantitatively evaluate the extravascular lung water content, identifying the need to intervene and follow up the hemodynamic significance of PDA over time.

Using lung ultrasound to quantitatively evaluate pulmonary water content.

Increases in extravascular lung water (EVLW) can lead to respiratory failure. This study aimed to investigate whether the B-line score (BLS) was correlated with the EVLW content determined by the lung wet/dry ratio in a rabbit model. A total of 45 New Zealand rabbits were randomly assigned to nine groups. Among the animals, models of various lung water content levels were induced by the infusion of different volumes of warm sterile normal saline (NS) via the endotracheal tube. The arterial blood gas, spontaneous respiratory rate, and PaO2 /FiO2 ratio were detected before and after infusion. In addition, the B-lines were determined before and immediately after infusion in each group. Finally, both lungs were resected to determine the wet/dry ratio. In addition, all lung specimens were analyzed histologically, and EVLW was quantified using the BLS based on the number and confluence of B-lines in the intercostal space. The BLS increased with increasing infusion volume. The BLS was statistically correlated with the wet/dry ratio (r2 = .946) and with the PaO2 /FiO2 ratio (r2 = .916). Furthermore, a repeatability study was performed for the lung ultrasound (LUS) technology (Bland-Altman plots), and the results suggest that LUS had favorable intraobserver and interobserver reproducibility. This study is the first to suggest that the BLS can serve as a sensitive, quantitative, noninvasive, and real-time indicator of EVLW in a rabbit model of lung water accumulation. Notably, the BLS displayed an obvious correlation with the experimental gravimetry results and could also be used to predict the pulmonary oxygenation status.

Quantitative estimation of extravascular lung water volume and preload by dynamic 15O-water positron emission tomography.

Left ventricular filling pressure (preload) can be assessed by pulmonary capillary wedge pressure (PCWP) during pulmonary arterial catheterization (PAC). An emerging method [pulse indexed contour cardiac output (PICCO)] can estimate preload by global end-diastolic volume (GEDV) and congestion as extravascular lung water (EVLW) content. However, no reliable quantitative non-invasive methods are available. Hence, in a porcine model of pulmonary congestion, we evaluated EVLW and GEDV by positron emission tomography (PET). The method was applied in 35 heart failure (HF) patients and 9 healthy volunteers. Eight pigs were studied. Pulmonary congestion was induced by a combination of beta-blockers, angiotensin-2 agonist and saline infusion. PAC, PICCO, computerized tomography, and 15O-H2O-PET were performed. EVLW increased from 521 ± 76 to 973 ± 325 mL (P < 0.001) and GEDV from 1068 ± 170 to 1254 ± 85 mL (P < 0.001). 15O-H2O-PET measures of EVLW increased from 566 ± 151 to 797 ± 231 mL (P < 0.001) and GEDV from 364 ± 60 to 524 ± 92 mL (P < 0.001). Both EVLW and GEDV measured with PICCO and 15O-H2O-PET correlated (r2 = 0.40, P < 0.001; r2 = 0.40, P < 0.001, respectively). EVLW correlated with Hounsfield units (HU; PICCO: r2 = 0.36, P < 0.001, PET: r2 = 0.46, P < 0.001) and GEDV with PCWP (PICCO: r2 = 0.20, P = 0.01, PET: r2 = 0.29, P = 0.002). In human subjects, measurements were indexed (I) for body surface area. Neither EVLWI nor HU differed between chronic stable HF patients and healthy volunteers (P = 0.11, P = 0.29) whereas GEDVI was increased in HF patients (336 ± 66 mL/m2 vs. 276 ± 44 mL/m2, P = 0.01). The present study demonstrates that 15O-H2O-PET can assess pulmonary congestion and preload quantitatively. Hence, prognostic information from 15O-H2O-PET examinations should be evaluated in clinical trials.

Phosgene-induced lung edema: Comparison of clinical criteria for increased extravascular lung water content with postmortem lung gravimetry and lavage-protein in rats and dogs

Phosgene-induced acute lung injury (ALI) is characterized by a concentration x time (Cxt)-dependent increased pulmonary vascular permeability, phenotypically manifested as potentially life-threatening acute lung edema. In contemporary animal bioassays, the quantification of protein in bronchoalveolar lavage fluid (BAL) is taken as an unequivocal endpoint suggestive of disruption of alveolar barrier function. However, extravasated protein can only be a surrogate endpoint for assessing the extravascular fluid dynamics of the lung. This pathophysiological hallmark of ALI is diagnosed and quantified in vivo in humans by assessing the accumulation of excess extravascular lung water (EVLW). The Point of Departure (POD) of the Cxt relationship of this adverse outcome pathway should also constitute the basis for setting safe occupational and emergency response values. Unlike the EVLW approach, toxicology-based animal models utilize postmortem analyses of total protein in BAL and lung weights as the basis for human risk assessment. With either approach, it remains difficult to unequivocally evaluate pulmonary edema in terms of etiopathology and specificity, i.e., cardiogenic and hydrostatic versus increased permeability edema. The objective of this paper is to retrospectively analyze the clinical scoring of the severity grades of in vivo EVLWs from humans with the respective postmortem biomarkers BAL protein and collagen versus wet lung weights in rats and dogs exposed by inhalation to phosgene gas. Despite the different methodological approaches taken in humans and animals, the EVLW-based predicted thresholds for the onset of pulmonary edema and potentially life-threatening severe pulmonary edema were in remarkable agreement. Data from dogs appear to more aptly reflect the human etiopathology and should be given preference over data from rodents. Especially in rats, elevations in BAL protein may lead to a marked overestimation of the edematous potency of phosgene due to secreted protein into airways. In summary, increased lung weight in rats and dogs scaled favorably with the human-EVLW and was shown to be the biomarker of choice for the scaling lung edema. Caution is advised when using BAL protein in isolation as a surrogate endpoint of pulmonary edema.

Adipose-derived stem cells attenuate pulmonary microvascular hyperpermeability after smoke inhalation.

BackgroundPulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS). Smoke inhalation causes ARDS, thus significantly increasing the mortality of burn patients. Adipose-derived stem cells (ASCs) exert potent anti-inflammatory properties. The goal of the present study was to test the safety and ecfficacy of ASCs, in a well-characterized clinically relevant ovine model of ARDS.MethodsFemale sheep were surgically prepared. ARDS was induced by cooled cotton smoke inhalation. Following injury, sheep were ventilated, resuscitated with lactated Ringer’s solution, and cardiopulmonary hemodynamics were monitored for 48 hours in a conscious state. Pulmonary microvascular hyper-permeability was assessed by measuring lung lymph flow, extravascular lung water content, protein content in plasma and lung lymph fluid. Sheep were randomly allocated to two groups: 1) ASCs: infused with 200 million of ASCs in 200mL of PlasmaLyteA starting 1 hours post-injury, n = 5; 2) control, treated with 200mL of PlasmaLyteA in a similar pattern, n = 5.ResultsLung lymph flow increased 9-fold in control sheep as compared to baseline. Protein in the plasma was significantly decreased, while it was increased in the lung lymph. The treatment with ASCs significantly attenuated these changes. Treatment with ASCs almost led to the reversal of increased pulmonary vascular permeability and lung water content. Pulmonary gas exchange was significantly improved by ASCs. Infusion of the ASCs did not negatively affect pulmonary artery pressure and other hemodynamic variables.ConclusionsASCs infusion was well tolerated. The results suggest that intravenous ASCs modulate pulmonary microvascular hyper-permeability and prevent the onset of ARDS in our experimental model.

Cannabidiol reduces lung injury induced by hypoxic-ischemic brain damage in newborn piglets.

BackgroundBrain hypoxic-ischemic (HI) damage induces distant inflammatory lung damage in newborn pigs. We aimed to investigate the effects of cannabidiol (CBD) on lung damage in this scenario.MethodsNewborn piglets received intravenous vehicle, CBD, or CBD+WAY100635 (5-HT1A receptor antagonist) after HI brain damage (carotid flow interruption and FiO2 0.10 for 30 min). Total lung compliance (TLC), oxygenation index (OI), and extravascular lung water content (EVLW) were monitored for 6 h. Histological damage, interleukin (IL)-1β concentration, and oxidative stress were assessed in brain and lung tissue. Total protein content was determined in bronchoalveolar lavage fluid (BALF).ResultsCBD prevented HI-induced deleterious effects on TLC and OI and reduced lung histological damage, modulating inflammation (decreased leukocyte infiltration and IL-1 concentration) and reducing protein content in BALF and EVLW. These effects were related to CBD-induced anti-inflammatory changes in the brain. HI did not increase oxidative stress in the lungs. In the lungs, WAY100635 blunted the beneficial effects of CBD on histological damage, IL-1 concentration, and EVLW.ConclusionsCBD reduced brain HI-induced distant lung damage, with 5-HT1A receptor involvement in these effects. Whether the effects of CBD on the lungs were due to the anti-inflammatory effects on the brain or due to the direct effects on the lungs remains to be elucidated.

Abstract 19670: Adipose-derived Mesenchymal Stem Cells Attenuate Pulmonary Microvascular Hyperpermeability After Smoke Inhalation

Pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS). Smoke inhalation causes ARDS, significantly increasing the mortality of burn patients. Mesenchymal stem cells (MSCs) exert potent anti-inflammatory properties. The goal of the present study was to test the safety and efficacy of MSCs in a well-characterized clinically relevant ovine model of ARDS. Methods: Female sheep (30-40 kg) were surgically prepared 5-7 days prior the study. ARDS was induced by cooled cotton smoke inhalation. Following the injury, sheep were ventilated, resuscitated with lactated Ringer’s solution and cardiopulmonary hemodynamics was monitored for 48 h in a conscious state. Pulmonary microvascular hyper-permeability was assessed by measuring lung lymph flow, extravascular lung water content, protein in plasma and lung lymph. Sheep were randomly allocated to two groups: 1) MSCs: infused with 5 million/kg of intravenous MSCs over 30min starting 1 h post-injury, n=5; 2) control, treated with a vehicle in a similar pattern (200ml of PlasmaLyte A), n=5. Results: Lung lymph flow, an index of pulmonary transvascular fluid flux was ~7-fold increased in control sheep compared to baseline. This was associated with a significant protein decrease in plasma and its increase in lung lymph. The treatment with MSCs significantly attenuated these changes (Table). Moreover, the treatment with MSCs almost reversed increased pulmonary vascular permeability index {(lung lymph proteinхlung lymph flow)/plasma protein} and reduced lung water content (Lung wet-to-dry weight ratio). Pulmonary gas exchange was significantly improved by MSCs (PaO2/FiO2 was 406±101 in MSCs and 262±127 in control at 24 hrs, p&lt;0.05). Infusion of the MSCs did not affect pulmonary artery pressure and other hemodynamic variables. Conclusions: MSCs infusion was well tolerated. The results suggest that intravenous MSCs modulate pulmonary microvascular hyper-permeability and prevent onset of ARDS.

Comparative analysis of fluid therapy in coronary artery bypass grafting surgery

Our prospective, randomized, simple-blinded, pilot study investigates the influence of fluid therapy by using balanced crystalloid solution, 4% solution of gelatin polysuccinate, and 6% hydroxyethyl starch 130/0.42 on the extravascular lung water content in patients with coronary artery bypass grafting surgery. The aim of fluid therapy was to maintain a global end diastolic volume index within 680-850 ml/m &lt;sup&gt;2&lt;/sup&gt;. Transpulmonary thermodilution was used to determine an extravascular lung water index. Saturation of mixed venous blood, lactate, fluid balance, and hemodynamics were also investigated. It was shown that fluid therapy with the use of balanced crystalloid solution does not enhance the extravascular lung water content as compared with the use of colloid solutions. To achieve appropriate oxygen delivery, the effective infused volume of crystalloid solution was the double of that of colloid solutions.

Effects of colloids and crystalloids on extravascular lung water content in cardiac surgery patients: randomized controlled equivalence trial

Effects of colloids and crystalloids on extravascular lung water content in cardiac surgery patients: randomized controlled equivalence trial

Postperfusion lung syndrome: Respiratory mechanics, respiratory indices and biomarkers.

Postperfusion lung syndrome is rare but lethal. Secondary inflammatory response was the popularly accepted theory for the underlying etiology. Respiratory index (RI) and arterial oxygen tension/fractional inspired oxygen can be reliable indices for the diagnosis of this syndrome as X-ray appearance is always insignificant at the early stage of the onset. Evaluations of extravascular lung water content and pulmonary compliance are also helpful in the definite diagnosis. Multiorgan failure and triple acid-base disturbances that might develop secondary to postperfusion lung syndrome are responsible for the poor prognosis and increased mortality rather than postperfusion lung syndrome itself. Mechanical ventilation with low tidal volume (TV) and proper positive end-expiratory pressure can be an effective treatment strategy. Use of ulinastatin and propofol may benefit the patients through different mechanisms.

Effect of tidal volume on extravascular lung water content during one-lung ventilation for video-assisted thoracoscopic surgery: a randomised, controlled trial.

The use of low tidal volume during one-lung ventilation (OLV) has been shown to attenuate the incidence of acute lung injury after thoracic surgery. To test the effect of tidal volume during OLV for video-assisted thoracoscopic surgery on the extravascular lung water content index (EVLWI). A randomised, double-blind, controlled study. Single university hospital. Thirty-nine patients scheduled for elective video-assisted thoracoscopic surgery. Patients were randomly assigned to one of three groups (n = 13 per group) to ventilate the dependent lung with a tidal volume of 4, 6 or 8 ml kg(-1) predicted body weight with I:E ratio of 1:2.5 and PEEP of 5 cm H2O. The primary outcomes were perioperative changes in EVLWI and EVLWI to intrathoracic blood volume index (ITBVI) ratio. Secondary outcomes included haemodynamics, oxygenation indices, incidences of postoperative acute lung injury, atelectasis, pneumonia, morbidity and 30-day mortality. A tidal volume of 4 compared with 6 and 8 ml kg(-1) after 45 min of OLV resulted in an EVLWI of 4.1 [95% confidence interval (CI) 3.5 to 4.7] compared with 7.7 (95% CI 6.7 to 8.6) and 8.6 (95% CI 7.5 to 9.7) ml kg(-1), respectively (P < 0.003). EVLWI/ITBVI ratios were 0.57 (95% CI 0.46 to 0.68) compared with 0.90 (95% CI 0.75 to 1.05) and 1.00 (95% CI 0.80 to 1.21), respectively (P < 0.05). The incidences of postoperative acute lung injury, atelectasis, pneumonia, morbidity, hospitalisation and 30-day mortality were similar in the three groups. The use of a tidal volume of 4 ml kg during OLV was associated with less lung water content than with larger tidal volumes of 6 to 8 ml kg(-1), although no patient developed acute lung injury. Further studies are required to address the usefulness of EVLWI as a marker for the development of postoperative acute lung injury after the use of a low tidal volume during OLV in patients undergoing pulmonary resection. Clinicaltrials.gov identifier: NCT01762709.

Correlation of thermodilution-derived extravascular lung water and ventilation/perfusion-compartments in a porcine model

This study examines the correlation between the transpulmonary thermodilution derived extravascular lung water content (EVLW) and the ventilation/perfusion-distribution ([Formula: see text]) measured by multiple inert gas elimination (MIGET) in a porcine model. [Formula: see text] measured by micropore membrane inlet mass spectrometry-MIGET (MMIMS-MIGET) and EVLW were simultaneously measured in twelve pigs in the heathy state, with impaired gas exchange from repetitive lung lavage and after 3h of ventilation. The relationship between [Formula: see text] compartments and EVLW was analysed by linear correlation and regression. Considerable increases in EVLW and [Formula: see text] mismatching were induced through the lavage procedure. Significant correlations between the EVLW and the [Formula: see text] fractions representing pulmonary shunt and low [Formula: see text] were found. Perfusion to the normal [Formula: see text] regions was inversely correlated to the EVLW. Increased EVLW is associated with increased low [Formula: see text] and shunt, but not equal to pulmonary shunt alone. Beneath true shunt EVLW can also be associated with low [Formula: see text] regions.

Relationship between extravascular lung water and severity categories of acute respiratory distress syndrome by the Berlin definition.

IntroductionThe Berlin definition divides acute respiratory distress syndrome (ARDS) into three severity categories. The relationship between these categories and pulmonary microvascular permeability as well as extravascular lung water content, which is the hallmark of lung pathophysiology, remains to be elucidated. The aim of this study was to evaluate the relationship between extravascular lung water, pulmonary vascular permeability, and the severity categories as defined by the Berlin definition, and to confirm the associated predictive validity for severity.MethodsThe extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) were measured using a transpulmonary thermodilution method for three consecutive days in 195 patients with an EVLWi of ≥10 mL/kg and who fulfilled the Berlin definition of ARDS. Collectively, these patients were seen at 23 ICUs. Using the Berlin definition, patients were classified into three categories: mild, moderate, and severe.ResultsCompared to patients with mild ARDS, patients with moderate and severe ARDS had higher acute physiology and chronic health evaluation II and sequential organ failure assessment scores on the day of enrollment. Patients with severe ARDS had higher EVLWi (mild, 16.1; moderate, 17.2; severe, 19.1; P <0.05) and PVPI (2.7; 3.0; 3.2; P <0.05). When categories were defined by the minimum PaO2/FIO2 ratio observed during the study period, the 28-day mortality rate increased with severity categories: moderate, odds ratio: 3.125 relative to mild; and severe, odds ratio: 4.167 relative to mild. On independent evaluation of 495 measurements from 195 patients over three days, negative and moderate correlations were observed between EVLWi and the PaO2/FIO2 ratio (r = -0.355, P<0.001) as well as between PVPI and the PaO2/FIO2 ratio (r = -0.345, P <0.001). ARDS severity was associated with an increase in EVLWi with the categories (mild, 14.7; moderate, 16.2; severe, 20.0; P <0.001) in all data sets. The value of PVPI followed the same pattern (2.6; 2.7; 3.5; P <0.001).ConclusionsSeverity categories of ARDS described by the Berlin definition have good predictive validity and may be associated with increased extravascular lung water and pulmonary vascular permeability.Trial registrationUMIN-CTR ID UMIN000003627

Hyperoxia disrupts pulmonary epithelial barrier in newborn rats via the deterioration of occludin and ZO-1

BackgroundProlonged exposure to hyperoxia in neonates can cause hyperoxic acute lung injury (HALI), which is characterized by increased pulmonary permeability and diffuse infiltration of various inflammatory cells. Disruption of the epithelial barrier may lead to altered pulmonary permeability and maintenance of barrier properties requires intact epithelial tight junctions (TJs). However, in neonatal animals, relatively little is known about how the TJ proteins are expressed in the pulmonary epithelium, including whether expression of TJ proteins is regulated in response to hyperoxia exposure. This study determines whether changes in tight junctions play an important role in disruption of the pulmonary epithelial barrier during hyperoxic acute lung injury.MethodsNewborn rats, randomly divided into two groups, were exposed to hyperoxia (95% oxygen) or normoxia for 1–7 days, and the severity of lung injury was assessed; location and expression of key tight junction protein occludin and ZO-1 were examined by immunofluorescence staining and immunobloting; messenger RNA in lung tissue was studied by RT-PCR; transmission electron microscopy study was performed for the detection of tight junction morphology.ResultsWe found that different durations of hyperoxia exposure caused different degrees of lung injury in newborn rats. Treatment with hyperoxia for prolonged duration contributed to more serious lung injury, which was characterized by increased wet-to-dry ratio, extravascular lung water content, and bronchoalveolar lavage fluid (BALF):serum FD4 ratio. Transmission electron microscopy study demonstrated that hyperoxia destroyed the structure of tight junctions and prolonged hyperoxia exposure, enhancing the structure destruction. The results were compatible with pathohistologic findings. We found that hyperoxia markedly disrupted the membrane localization and downregulated the cytoplasm expression of the key tight junction proteins occludin and ZO-1 in the alveolar epithelium by immunofluorescence. The changes of messenger RNA and protein expression of occludin and ZO-1 in lung tissue detected by RT-PCR and immunoblotting were consistent with the degree of lung injury.ConclusionsThese data suggest that the disruption of the pulmonary epithelial barrier induced by hyperoxia is, at least in part, due to massive deterioration in the expression and localization of key TJ proteins.

The clinical usefulness of extravascular lung water and pulmonary vascular permeability index to diagnose and characterize pulmonary edema: a prospective multicenter study on the quantitative differential diagnostic definition for acute lung injury/acute respiratory distress syndrome

IntroductionAcute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by features other than increased pulmonary vascular permeability. Pulmonary vascular permeability combined with increased extravascular lung water content has been considered a quantitative diagnostic criterion of ALI/ARDS. This prospective, multi-institutional, observational study aimed to clarify the clinical pathophysiological features of ALI/ARDS and establish its quantitative diagnostic criteria.MethodsThe extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI) were measured using the transpulmonary thermodilution method in 266 patients with PaO2/FiO2 ratio ≤ 300 mmHg and bilateral infiltration on chest radiography, in 23 ICUs of academic tertiary referral hospitals. Pulmonary edema was defined as EVLWI ≥ 10 ml/kg. Three experts retrospectively determined the pathophysiological features of respiratory insufficiency by considering the patients' history, clinical presentation, chest computed tomography and radiography, echocardiography, EVLWI and brain natriuretic peptide level, and the time course of all preceding findings under systemic and respiratory therapy.ResultsPatients were divided into the following three categories on the basis of the pathophysiological diagnostic differentiation of respiratory insufficiency: ALI/ARDS, cardiogenic edema, and pleural effusion with atelectasis, which were noted in 207 patients, 26 patients, and 33 patients, respectively. EVLWI was greater in ALI/ARDS and cardiogenic edema patients than in patients with pleural effusion with atelectasis (18.5 ± 6.8, 14.4 ± 4.0, and 8.3 ± 2.1, respectively; P < 0.01). PVPI was higher in ALI/ARDS patients than in cardiogenic edema or pleural effusion with atelectasis patients (3.2 ± 1.4, 2.0 ± 0.8, and 1.6 ± 0.5; P < 0.01). In ALI/ARDS patients, EVLWI increased with increasing pulmonary vascular permeability (r = 0.729, P < 0.01) and was weakly correlated with intrathoracic blood volume (r = 0.236, P < 0.01). EVLWI was weakly correlated with the PaO2/FiO2 ratio in the ALI/ARDS and cardiogenic edema patients. A PVPI value of 2.6 to 2.85 provided a definitive diagnosis of ALI/ARDS (specificity, 0.90 to 0.95), and a value < 1.7 ruled out an ALI/ARDS diagnosis (specificity, 0.95).ConclusionPVPI may be a useful quantitative diagnostic tool for ARDS in patients with hypoxemic respiratory failure and radiographic infiltrates.Trial registrationUMIN-CTR ID UMIN000003627

Effect of Dahuang Fuzi decoction on alveolaur epithelial barrier in rats with lung injury with severe acute pancreatitis

Objective To investigate effect of Dahuang Fuzi decoction on alveolaur epithelial barrier in rats with lung injury with severe acute pancreatitis. Method Ninty-six health SD rats were randomly divided into three groups: sham operation group, SAP-ALI group, Dahuang Fuzi decoction group, and then according to the time point of sacrifice after operation, each group was subdivided into 3,6,12,24 hour subsets ( each, n = 8). After the belly of a rat in the sham operation group was cut open, the pancreas was flipped several times,and then a stoma was made in the jejunum to form its fistula. In the SAP-ALl group,1 mL/kg sodium taurocholate was reversely injected into the pancreatobile duct to establish the model of SAP, and then the jejimum fistula was performed. The SAP-ALI model in Dahuang Fuzi decoction group was treated by injection of 10ml of Dahuang Fuzi decoctionon into the fistula respectively. Blood was collected from heart to detect serum amvlase and endotoxin (ET) levels before the rat being executed. The lung histopathologic changes, pulmonary injury scores and wet/dry weight(W/D) ratios were observed after the rats were executed. The alveolar liquid clearance rate(ALCR), total lung water content (TLW), extravascular lung water content(EVLW) and alveolar epithelial permeability (AEP) were examined in 3,6, 12,24 h after injury.Results There was continuous increase of AEP,TLW and EVLW,as well as progressive reduction of ALCR compared with sham operation group at 3,6,12,24 h after operation. Compared with SAP-ALI group, there was continuous decrease of AEP,TLW and EVLW, and elevated of ALCR at 3,6,12,24 h after operation.Conclusions Dahuang Fuzi decoction can significantly reduce alveolaur epithelial barrier and degree of lung tissue of SAP-ALI rats by inhibiting the elevation of LPS and inflammation reaction. Key words: Severe acute pancreatitis; Acute lung injury; Alveolaur epithelial barrier; Dahuang fuzi decoction; Lung epithelial permeability; Alveolar liquid clearance rate; Total lung water content; Extravascular lung water content