Hydrostatic Edema Research Articles

Pulmonary Edema Due to Oral Gavage in a Toxicological Study Related to Aquaporin-1, -4 and -5 Expression

A one-time oral gavage can be enough to cause of alveologenic edema with higher expression of AQP-1 and -4 than that with repeated-dose oral gavage, which caused both profound perivascular edema and hydrostatic pressure edema, while AQP-5 was similarly expressed. The alteration of AQPs expression was probably related to alveolar fluid clearance across the alveolar and bronchiolar epithelium in different stages of lung injury. The results clarified the type of lung edema in acute and sub-chronic toxicity studies without treatment related effect of tested material. The pathogenesis of pulmonary edema due to oral gavage toxicological study is associated with the cellular immune response to the reflux materials. Mast cell and leukocyte accumulation may contribute to increase vascular permeability leading to permeability edema. The increase in alveolar septum epithelium, perivascular and peribronchial cuffing, accumulation alveolar lipid containing macrophage and medial hyperplasia of the pulmonary artery might have been caused to increase airway resistance, which resulted in hydrostatic pressure edema.

Extravascular lung water in acute respiratory distress syndrome and the Berlin definition: time for real change

See related Editorial by Phillips, http://ccforum.com/content/17/4/174 I echo the call for a real change in the diagnosis of acute respiratory distress syndrome (ARDS), as put forward in the recent editorial by Phillips [1]. Whilst there are real limitations regarding availability, feasibility and interpretation of extravascular lung water (EVLW), it remains one of the few clinically available quantitative parameters for assessment of the severity of lung injury. We and others have shown the relationship between different EVLW indices and lung injury [2]. Moreover, our previously published results in this journal support the results of Jozwiak and colleagues showing a twofold increase in the odds ratio for ICU mortality when the pulmonary vascular permeability index was increased [3]. In our study, the area under the curve for the pulmonary vascular permeability index as a predictor for mortality was 0.682 (95% confidence interval 0.505 to 0.859), which is higher than that reported for the Berlin definition of ARDS. The case for EVLW as a criterion for ARDS definition has been challenged on the grounds of its lack of predictive value and feasibility. Whether EVLW reflects increased hydrostatic or inflammatory edema has been investigated recently, and the pulmonary vascular permeability index appears to be a useful indicator [4,5]. In my opinion, a clear pathophysiological and prognostic relationship exists between EVLW and lung injury [2-6]. Current data support the need for larger, multicenter trials identifying which EVLW index and cutoff values should be applied for diagnoses, and whether EVLW-driven management protocols can improve outcomes in ARDS.

The Berlin definition: real change or the emperor's new clothes?

Th e Berlin consensus group met recently after 18 years of defi ning acute respiratory distress syndrome (ARDS) using the American European Consensus Committee (AECC) criteria because, in their words, ‘a number of issues regarding various criteria of the AECC defi nition have emerged, including a lack of explicit criteria for defi ning acute, sensitivity of PaO 2 /FiO 2 to diff erent ventilator settings, poor reliability of the chest radiograph (CXR) criterion, and diffi culties distinguishing hydrostatic edema’ [1]. Save for defi ning acute, they arrived at a new defi nition using nearly these exact same criteria and thus did not answer their original concerns. When defi ning ARDS, as the late Daniel Schuster championed for years, the defi nition should include some direct measure of lung injury, at once eliminating much of what confounds the AECC and now the Berlin criteria – atelectasis, aspiration, eff usion, pneumonia, left ventricular dysfunction, and the eff ects of ventilator settings on the PaO 2 /FiO 2 ratio and CXR. Th is idea has been dismissed for years on grounds of feasibility – and dismissed yet again in Berlin – but given the very poor predictive value of the Berlin criteria for outcome and poor correlation with postmortem fi ndings as regards severity classifi cation and proper identifi cation [2], I would argue it is indeed time to take another look. If we are to progress in our research eff orts, it becomes imperative to identify homogeneous treatment groups – specifi c to a treatment strategy. Berlin criteria do not have the reliability, sensitivity or specifi city to do so or even to properly prognosticate. An area under the receiver operating charac teristic curve of 0.577 (95% confi dence interval, 0.561 to 0.593) regarding the predictive validity for mortality found for the Berlin defi nition is abysmal, and should not be pointed to as progress. Quite the contrary, it is a rallying call for change. Th e idea that hydrostatic and permeability causes of edema and hypoxemia are mutually exclusive, as implied by the AECC and now by the Berlin group, should be abandoned. Cardiomyopathy of sepsis and acute heart failure are common in ARDS – occurring in upwards of 60% of patients with severe sepsis – the number one cause of ARDS [3]. Considering that left ventricular dysfunction and cardiomyopathy of severe systemic infl am matory response syndrome/sepsis have better prognoses than diff use alveolar injury, some measure of the relative contribution to CXR and PaO 2 /FiO 2 ratio changes of hydrostatic versus pulmonary injury causes in ARDS then becomes important for identifi cation, severity classifi cation, prognostication and treatment. Increased extravascular lung water is at the center of the pathophysiologic changes in ARDS. Indexing extravascular lung water to pulmonary blood volume – the

The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material

Our objective was to revise the definition of acute respiratory distress syndrome (ARDS) using a conceptual model incorporating reliability and validity, and a novel iterative approach with formal evaluation of the definition. The European Society of Intensive Care Medicine identified three chairs with broad expertise in ARDS who selected the participants and created the agenda. After 2 days of consensus discussions a draft definition was developed, which then underwent empiric evaluation followed by consensus revision. The Berlin Definition of ARDS maintains a link to prior definitions with diagnostic criteria of timing, chest imaging, origin of edema, and hypoxemia. Patients may have ARDS if the onset is within 1 week of a known clinical insult or new/worsening respiratory symptoms. For the bilateral opacities on chest radiograph criterion, a reference set of chest radiographs has been developed to enhance inter-observer reliability. The pulmonary artery wedge pressure criterion for hydrostatic edema was removed, and illustrative vignettes were created to guide judgments about the primary cause of respiratory failure. If no risk factor for ARDS is apparent, however, objective evaluation (e.g., echocardiography) is required to help rule out hydrostatic edema. A minimum level of positive end-expiratory pressure and mutually exclusive PaO(2)/FiO(2) thresholds were chosen for the different levels of ARDS severity (mild, moderate, severe) to better categorize patients with different outcomes and potential responses to therapy. This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice.

Serial Measurement of Extravascular Lung Water and Blood Volume During the Course of Neurogenic Pulmonary Edema after Subarachnoid Hemorrhage

Neurogenic pulmonary edema (NPE) as a systemic consequence early after aneurysmal subarachnoid hemorrhage (SAH) sometimes complicates perioperative and postoperative fluid management and increases the risk of a poor outcome. This is the first report to demonstrate the ability of a bedside transpulmonary thermodilution device to trace physiological patterns consistent with current theories regarding the mechanism and course of post-SAH NPE. Three SAH patients admitted within 4 hours of ictus and diagnosed as having NPE were studied. Cardiac output, global end-diastolic volume (GEDV), extravascular lung water, and pulmonary vascular permeability index (PVPI) were measured by the transpulmonary thermodilution immediately after the diagnosis. Biochemical makers relating to stress and fluid regulation were also sampled. In all cases, extravascular lung water was abnormally high on initial measurement, in which an elevation of plasma catecholamine and B-type natriuretic peptide was detected. The fluid distribution of each patient was characterized by either (1) high PVPI and low GEDV without cardiac dysfunction (permeability edema); or (2) low cardiac output and high GEDV accompanied by transient cardiac dysfunction without PVPI elevation (hydrostatic edema). Although the volume status of 2 patients normalized by day 4 and was successfully managed with routine fluid therapy, a patient categorized initially with permeability edema complicated with hydrostatic edema due to heart failure and pneumonia showed a poor outcome. Our clinical experience suggests that the present monitoring system is capable of distinguishing different etiologies for pulmonary edema complicating SAH that may assist with fluid management decisions.

Active transepithelial Cl−‐secretion promotes hydrostatic lung edema

Hydrostatic lung edema evolves from increased fluid filtration and inhibition of epithelial Na+ channels (ENaC) that facilitate alveolar fluid clearance. Recently, we identified alveolar fluid secretion (AFS) as new key component in edema formation. Here, we tested whether Cl− secretion via cystic fibrosis transmemberane conductance regulator (CFTR) and Na+‐K+‐Cl− cotransporter 1 (NKCC1) may mediate AFS at elevated left atrial pressure (PLA) and may be induced by inhibition of ENaC.In isolated lungs, we quantified AFS by a double indicator dilution technique, and transepithelial Cl− flux by radionuclide tracing and alveolar Cl− imaging. PLA elevation induced lung edema and AFS that coincided with transepithelial Cl− secretion and alveolar Cl− influx. These effects were blocked by inhibitors of CFTR, NKCC or Na+‐K+‐ATPase, and CFTR−/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride at physiologicalPLA induced AFS and Cl− secretion that were again CFTR‐, NKCC‐ and Na+‐K+‐ ATPase dependent.We conclude that transepithelial Cl− and fluid flux reverse from absorptive to secretory mode at hydrostatic stress as a result of ENaC inhibition, and are mediated by NKCC and CFTR.

Cardiovascular Agents Affect the Tone of Pulmonary Arteries and Veins in Precision-Cut Lung Slices

IntroductionCardiovascular agents are pivotal in the therapy of heart failure. Apart from their action on ventricular contractility and systemic afterload, they affect pulmonary arteries and veins. Although these effects are crucial in heart failure with coexisting pulmonary hypertension or lung oedema, they are poorly defined, especially in pulmonary veins. Therefore, we investigated the pulmonary vascular effects of adrenoceptor agonists, vasopressin and angiotensin II in the model of precision-cut lung slices that allows simultaneous studies of pulmonary arteries and veins.Materials and MethodsPrecision-cut lung slices were prepared from guinea pigs and imaged by videomicroscopy. Concentration-response curves of cardiovascular drugs were analysed in pulmonary arteries and veins.ResultsPulmonary veins responded stronger than arteries to α1-agonists (contraction) and β2-agonists (relaxation). Notably, inhibition of β2-adrenoceptors unmasked the α1-mimetic effect of norepinephrine and epinephrine in pulmonary veins. Vasopressin and angiotensin II contracted pulmonary veins via V1a and AT1 receptors, respectively, without affecting pulmonary arteries.DiscussionVasopressin and (nor)epinephrine in combination with β2-inhibition caused pulmonary venoconstriction. If applicable in humans, these treatments would enhance capillary hydrostatic pressures and lung oedema, suggesting their cautious use in left heart failure. Vice versa, the prevention of pulmonary venoconstriction by AT1 receptor antagonists might contribute to their beneficial effects seen in left heart failure. Further, α1-mimetic agents might exacerbate pulmonary hypertension and right ventricular failure by contracting pulmonary arteries, whereas vasopressin might not.

Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with high-altitude pulmonary oedema: a meta-analysis

High-altitude pulmonary oedema (HAPE) is a non-cardiogenic hydrostatic oedema involving a genetic component. Considering the low incidence of HAPE, sample sizes in current reports are relatively limited. We aimed to assess the association between the angiotensin-converting enzyme (ACE) I/D polymorphism and HAPE via a meta-analysis of published and unpublished data. We searched PubMed, CBM, CNKI, and Cochrane Library Database before 20 November 2010. A random-effects model was applied (STATA) and study quality was assessed in duplicate. A total of five studies including 305 cases and 662 controls were meta-analysed. The summary odds ratio (OR) indicated that no significant differences in risk of developing HAPE were found between carriers of ACE D and I alleles (OR = 1.20; 95% confidence interval (CI), 0.98-1.48; p = 0.084). Lack of association persisted for genotypes under the recessive mode. However, genotype association under the dominant mode showed D allele carriers significantly conferred a 1.55-fold increased HAPE risk compared with II genotype carriers (95% CI, 1.15-2.08; p = 0.004). Funnel plot and Egger's test suggested no evidence of publication bias. Our results supported the notion that ACE D allele carriers were at significant increased risk of developing HAPE.

Posterior Reversible Encephalopathy Syndrome with Obstructive Hydrocephalus

We describe an unusual presentation of posterior reversible encephalopathy syndrome (PRES) with predominant posterior fossa edema, causing ascending transtentorial herniation, tonsillar herniation, and obstructive hydrocephalus. MR imaging with additional MR spectroscopy and MR perfusion helped discriminate PRES from infiltrative tumor, and supported the pathogenesis of hydrostatic edema. Infusion of an antihypertensive drug was promptly administered. Diversion of cerebrospinal fluid by ventriculostomy was subsequently performed. However, the patient developed thalamic hemorrhage and secondary intraventricular hemorrhage with contralateral hemiparesis. Awareness of this rare cause of obstructive hydrocephalus with aggressive treatment of high blood pressure may help obviate the need of ventriculostomy and may prevent the hemorrhagic complication.

A murine model for the study of edema induced intestinal contractile dysfunction

We have published extensively regarding the effects of edema on intestinal contractile function. However, we have found the need to expand our model to mice to take advantage of the much larger arsenal of research support, especially in terms of transgenic mouse availability and development. To that end, we have developed and validated a hydrostatic intestinal edema model in mice. Male C57 Black 6 mice were subjected to a combination of high volume crystalloid resuscitation and mesenteric venous hypertension in an effort to induce hydrostatic intestinal edema. Wet to dry ratios, myeloperoxidase activity, mucosal injury scoring, STAT-3 nuclear activation, phosphorylated STAT-3 levels, NF-κB nuclear activation, myosin light chain phosphorylation, intestinal contractile activity, and intestinal transit were measured to evaluate the effects of the model. High volume crystalloid resuscitation and mesenteric venous hypertension resulted in the development of significant intestinal edema without an increase in myeloperoxidase activity or mucosal injury. Edema development was associated with increases in STAT-3 and NF-κB nuclear activation as well as phosphorylated STAT-3. There was a decrease in myosin light chain phosphorylation, basal and maximally stimulated intestinal contractile activity, and intestinal transit. Hydrostatic edema in mice results in activation of a signal transduction profile that culminates in intestinal contractile dysfunction. This novel model allows for advanced studies into the pathogenesis of hydrostatic edema induced intestinal contractile dysfunction.

Sodium hydrogen exchanger as a mediator of hydrostatic edema-induced intestinal contractile dysfunction

Resuscitation-induced intestinal edema is associated with early and profound mechanical changes in intestinal tissue. We hypothesize that the sodium hydrogen exchanger (NHE), a mechanoresponsive ion channel, is a mediator of edema-induced intestinal contractile dysfunction. An animal model of hydrostatic intestinal edema was used for all experiments. NHE isoforms 1-3 mRNA and protein were evaluated. Subsequently, the effects of NHE inhibition (with 5-(N-ethyl-N-isopropyl) amiloride [EIPA]) on wet-to-dry ratios, signal transduction and activator of transcription (STAT)-3, intestinal smooth muscle myosin light chain (MLC) phosphorylation, intestinal contractile activity, and intestinal transit were measured. NHE1-3 mRNA and protein levels were increased significantly in the small intestinal mucosa with the induction of intestinal edema. The administration of EIPA, an NHE inhibitor, attenuated validated markers of intestinal contractile dysfunction induced by edema as measured by decreased STAT-3 activation, increased MLC phosphorylation, improved intestinal contractile activity, and enhanced intestinal transit. The mechanoresponsive ion channel NHE may mediate edema-induced intestinal contractile dysfunction, possibly via a STAT-3 related mechanism.

Evaluating the Potential Role of Nitric Oxide as a Mediator of Hydrostatic Edema Mediated Intestinal Contractile Dysfunction

Administration of L-nil, a selective inhibitor of inducible nitric oxide synthase (iNOS), improves ileus in an animal model of resuscitation induced intestinal edema. The purpose of this study was to elucidate the iNOS/nitric oxide (NO) signal transduction pathway in intestinal edema. Male Sprague Dawley rats were divided into two groups; CONTROL and RESUS+VH (edema, 80 cc/kg normal saline (resuscitation) with mesenteric venous hypertension). iNOS mRNA and protein, iNOS activity, NO tissue levels, soluble guanylyl cyclase (sGC) expression, and cyclic guanosine monophosphate (cGMP) levels were measured. As a functional endpoint, we evaluated intestinal contractile strength and frequency in L-nil treated animals. Edema was associated with increased iNOS mRNA and protein expression without subsequent increases in iNOS activity or tissue NO levels. There was no significant change in sGC expression or increase in cGMP induced by edema. Administration of L-nil did not decrease edema development or preserve contractile strength, but increased contractile frequency. Hydrostatic intestinal edema is not associated with increased iNOS activity or tissue NO levels. Administration of L-nil in edema increases intestinal contractile frequency. This may represent a potential mechanism for the amelioration of ileus seen with the administration of L-nil.

A Pressing Headache

A Pressing Headache

Hydrostatic intestinal edema induced signaling pathways: Potential role of mechanical forces

Hydrostatic intestinal edema initiates a signal transduction cascade that results in smooth muscle contractile dysfunction. Given the rapid and concurrent alterations in the mechanical properties of edematous intestine observed with the development of edema, we hypothesize that mechanical forces may serve as a stimulus for the activation of certain signaling cascades. We sought to examine whether isolated similar magnitude mechanical forces induced the same signal transduction cascades associated with edema. The distal intestine from adult male Sprague Dawley rats was stretched longitudinally for 2 h to 123% its original length, which correlates with the interstitial stress found with edema. We compared wet-to-dry ratios, myeloperoxidase activity, nuclear signal transduction and activator of transcription (STAT)-3 and nuclear factor (NF)-kappa B DNA binding, STAT-3 phosphorylation, myosin light chain phosphorylation, baseline and maximally stimulated intestinal contractile strength, and inducible nitric oxide synthase (iNOS) and sodium hydrogen exchanger 1-3 messenger RNA (mRNA) in stretched and adjacent control segments of intestine. Mechanical stretch did not induce intestinal edema or an increase in myeloperoxidase activity. Nuclear STAT-3 DNA binding, STAT-3 phosphorylation, and nuclear NF-kappa B DNA binding were significantly increased in stretched seromuscular samples. Increased expression of sodium hydrogen exchanger 1 was found but not an increase in iNOS expression. Myosin light chain phosphorylation was significantly decreased in stretched intestine as was baseline and maximally stimulated intestinal contractile strength. Intestinal stretch, in the absence of edema/inflammatory/ischemic changes, leads to the activation of signaling pathways known to be altered in intestinal edema. Edema may initiate a mechanotransductive cascade that is responsible for the subsequent activation of various signaling cascades known to induce contractile dysfunction.

Procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome

Coagulation and fibrinolysis abnormalities are observed in acute lung injury (ALI) in both human disease and animal models and may contribute to ongoing inflammation in the lung. Tissue factor (TF), the main initiator of the coagulation cascade, is upregulated in the lungs of patients with ALI/acute respiratory distress syndrome (ARDS) and likely contributes to fibrin deposition in the air space. The mechanisms that govern TF upregulation and activation in the lung are not well understood. In the vascular space, TF-bearing microparticles (MPs) are central to clot formation and propagation. We hypothesized that TF-bearing MPs in the lungs of patients with ARDS contribute to the procoagulant phenotype in the air space during acute injury and that the alveolar epithelium is one potential source of TF MPs. We studied pulmonary edema fluid collected from patients with ARDS compared with a control group of patients with hydrostatic pulmonary edema. Patients with ARDS have higher concentrations of MPs in the lung compared with patients with hydrostatic edema (25.5 IQR 21.3-46.9 vs. 7.8 IQR 2.3-27.5 micromol/l, P = 0.009 by Mann-Whitney U-test). These MPs are enriched for TF, have procoagulant activity, and likely originate from the alveolar epithelium [as measured by elevated levels of RAGE (receptor for advanced glycation end products) in ARDS MPs compared with hydrostatic MPs]. Furthermore, alveolar epithelial cells in culture release procoagulant TF MPs in response to a proinflammatory stimulus. These findings suggest that alveolar epithelial-derived MPs are one potential source of TF procoagulant activity in the air space in ARDS and that epithelial MP formation and release may represent a unique therapeutic target in ARDS.

Yin and Yang of cGMP signalling in hydrostatic lung edema

Background Hydrostatic lung edema is a characteristic complication of acute left-sided ventricular or valvular heart failure that if untreated has a high mortality due to the resulting respiratory failure. Traditionally, formation of hydrostatic lung edema has been attributed to an imbalance of Starling forces, i.e. transcapillary hydrostatic and oncotic pressure in the pulmonary circulation resulting in interstitial and finally, alveolar edema. Yet, mechanosensitive cell responses may play a critical regulatory role in this scenario.

Trauma and Acute Respiratory Distress Syndrome

Trauma and Acute Respiratory Distress Syndrome

Comparison of two non-bronchoscopic methods for evaluating inflammation in patients with acute hypoxaemic respiratory failure

IntroductionThe simple bedside method for sampling undiluted distal pulmonary edema fluid through a normal suction catheter (s-Cath) has been experimentally and clinically validated. However, there are no data comparing non-bronchoscopic bronchoalveolar lavage (mini-BAL) and s-Cath for assessing lung inflammation in acute hypoxaemic respiratory failure. We designed a prospective study in two groups of patients, those with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and those with acute cardiogenic lung edema (ACLE), designed to investigate the clinical feasibility of these techniques and to evaluate inflammation in both groups using undiluted sampling obtained by s-Cath. To test the interchangeability of the two methods in the same patient for studying the inflammation response, we further compared mini-BAL and s-Cath for agreement of protein concentration and percentage of polymorphonuclear cells (PMNs).MethodsMini-BAL and s-Cath sampling was assessed in 30 mechanically ventilated patients, 21 with ALI/ARDS and 9 with ACLE. To analyse agreement between the two sampling techniques, we considered only simultaneously collected mini-BAL and s-Cath paired samples. The protein concentration and polymorphonuclear cell (PMN) count comparisons were performed using undiluted sampling. Bland-Altman plots were used for assessing the mean bias and the limits of agreement between the two sampling techniques; comparison between groups was performed by using the non-parametric Mann-Whitney-U test; continuous variables were compared by using the Student t-test, Wilcoxon signed rank test, analysis of variance or Student-Newman-Keuls test; and categorical variables were compared by using chi-square analysis or Fisher exact test.ResultsUsing protein content and PMN percentage as parameters, we identified substantial variations between the two sampling techniques. When the protein concentration in the lung was high, the s-Cath was a more sensitive method; by contrast, as inflammation increased, both methods provided similar estimates of neutrophil percentages in the lung. The patients with ACLE showed an increased PMN count, suggesting that hydrostatic lung edema can be associated with a concomitant inflammatory process.ConclusionsThere are significant differences between the s-Cath and mini-BAL sampling techniques, indicating that these procedures cannot be used interchangeably for studying the lung inflammatory response in patients with acute hypoxaemic lung injury.

Use of US in the Evaluation of Patients with Symptoms of Deep Venous Thrombosis of the Lower Extremities

Deep venous thrombosis (DVT) is a major health problem and is estimated to have an incidence of 600,000 cases per year. Clinical signs and symptoms of DVT are unreliable. If clinical signs alone were used to diagnose DVT, 42% of patients would receive unnecessary anticoagulation therapy. Most patients evaluated with ultrasonography (US) do not have DVT. The key to making a precise diagnosis is recognizing the characteristics of various diseases on US images. The anatomic approach is the most useful strategy for characterizing the spectrum of pathologic conditions seen in patients with symptoms that simulate DVT. The inferior extremity can be divided into four regions-inguinal, thigh, popliteal, and lower leg-with the rough limits defined for each as they are examined at US. The differential diagnoses affecting the lower extremities include infectious, neoplastic, traumatic, inflammatory, vascular, and miscellaneous entities. Some pathologic conditions seen in the inguinal region are adenopathies, lymphangitis, soft-tissue tumors, hematomas, adductor tendonitis, and hernias. In the thigh, cellulitis, myositis, abscess, benign and malignant tumors, and sports-related lesions are seen. In the popliteal region, cellulitis, arthritis, benign and malignant masses, muscle contusions, ruptured popliteal cysts, and thrombophlebitis are seen. And in the lower leg, cellulitis, lipomas, tennis leg, superficial thrombophlebitis, tendonitis, and soft-tissue hydrostatic edema secondary to cardiac and renal failure can simulate DVT.

Soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury.

To determine if levels of soluble intercellular adhesion molecule-1 (sICAM-1), a marker of alveolar epithelial and endothelial injury, differ in patients with hydrostatic pulmonary edema and acute lung injury (ALI) and are associated with clinical outcomes in patients with ALI. Measurement of sICAM-1 levels in (1) plasma and edema fluid from 67 patients with either hydrostatic pulmonary edema or ALI enrolled in an observational, prospective single center study, and (2) in plasma from 778 patients with ALI enrolled in a large multi-center randomized controlled trial of ventilator strategy. In the single-center study, levels of sICAM-1 were significantly higher in both edema fluid and plasma (median 938 and 545 ng/ml, respectively) from ALI patients compared to hydrostatic edema patients (median 384 and 177 ng/ml, P < 0.03 for both comparisons). In the multi-center study, higher plasma sICAM-1 levels were associated with poor clinical outcomes in both unadjusted and multivariable models. Subjects with ALI whose plasma sICAM-1 levels increased over the first 3 days of the study had a higher risk of death, after adjusting for other important predictors of outcome (odds ratio 1.48; 95% CI 1.03-2.12, P = 0.03). Both plasma and edema fluid levels of sICAM-1 are higher in patients with ALI than in patients with hydrostatic pulmonary edema. Higher plasma sICAM-1 levels and increasing sICAM-1 levels over time are associated with poor clinical outcomes in ALI. Measurement of sICAM-1 levels may be useful for identifying patients at highest risk of poor outcomes from ALI.