Pulmonary edema is characterized by the abnormal accumulation of fluid in the extravascular space of the lungs and is a common finding in critically ill patients. This pathological condition may develop due to an increase in the pulmonary capillary permeability (acute lung injury (ALI), acute respiratory distress syndrome (ARDS)), an increase in the pulmonary capillary hydrostatic pressure (hydrostatic or cardiogenic pulmonary edema), or both. Pulmonary edema can be detected by clinical evaluation of factors such as patients' history, physical findings, and routine laboratory examinations, and is confirmed by the presence of bilateral pulmonary infiltration on chest radiography.
However, interpretation of these factors is often limited by a certain degree of subjectivity that might cause inter-observer variation even among experts, particularly in critically ill patients. Moreover, intensive care physicians may find it difficult to determine the cause of the extravascular lung water increase . Increased pulmonary vascular permeability is the crucial pathophysiological feature of ALI/ARDS and has been considered a quantitative diagnostic criterion for ALI/ARDS. PVPI has been evaluated to enable one to differentiate ALI/ARDS from hydrostatic edema. PVPI was shown to be useful for determining the mechanism of pulmonary edema in ALI/ARDS, and PVPI ≥ 3 allowed the diagnosis of ALI/ARDS with a sensitivity of 85% and a specificity of 100%. However, that study was a single-center retrospective review of only 48 patients.
Materials and methods
This prospective, observational, multi-institutional study was approved by the ethics committee of each of the 23 institutions, and written informed consent was provided by all patients' next of kin. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry: UMIN-CTR ID UMIN000003627.
Between March 2009 and August 2011, 301 patients from 23 critical care centers at tertiary care hospitals were enrolled in this study. In all of 23 participating institutions, the single transpulmonary thermodilution technique is one of the standard monitoring methods for circulatory and respiratory management of critically ill patients. The median (interquartile range) number of included patients per each institution was 10.
Data are presented as mean ± standard error or as median (interquartile range) depending on the distribution normality of the variables. Spearman's rank correlation was used for determining the correlation between two variables, and Mann-Whitney's U test was used for assessing the differences between two groups. For multiple-group comparison, analysis of variance on ranks with a Tukey honestly significant difference test was used. Receiver operating characteristic curves were generated for PVPI and ITBV by varying the discriminating threshold of each parameter.
The most frequent condition leading to exclusion of patients was respiratory insufficiency (P/F ratio ≤ 300 mmHg and slight bilateral infiltration) secondary to sepsis suggesting ALI but not accompanied by EVLWI ≥ 10 ml/kg - the predefined value for pulmonary edema, due to hypovolemia. Consensus on inclusion of such patients was not obtained from all attending experts. For this analysis, 266 patients were included and divided into the following three categories on the basis of the pathophysiological diagnostic differentiation of the respiratory insufficiency.
Relationship between extravascular lung water index and PaO2/FiO2 ratio
For this analysis, patients with pleural effusion with atelectasis were excluded because the increased EVLW is not the pathogenetic mechanism of this condition, and EVLWI in these patients was not high as in those patients with ALI/ARDS and cardiogenic edema.
In this prospective multi-institutional observational study, EVLW and pulmonary vascular permeability were assessed by transpulmonary thermodilution in patients requiring mechanical ventilation with P/F ratio ≤ 300 mmHg and bilateral pulmonary infiltration on chest X-ray scan. The results showed that EVLW was greater in patients with ALI/ARDS and cardiogenic edema than in those with pleural effusion with atelectasis; that pulmonary vascular permeability was increased in patients with ALI/ARDS compared with cardiogenic edema and pleural effusion with atelectasis patients; and that EVLW, the crucial pathogenetic factor of pulmonary edema, was weakly correlated with the P/F ratio in patients with ALI/ARDS and cardiogenic edema. ARDS is associated with a high incidence of morbidity and mortality despite the development of improved management techniques over the past two decades.
Difficulties in selecting appropriate patient populations that would benefit from specific treatments occur largely because of the lack of homogeneity in the disease definition. The AECC criteria, which have been exclusively used as the inclusion criteria in clinical trials for ALI/ARDS, were designed to identify patients with ALI/ARDS. These criteria are inclusive, so that the population selected on the basis of these criteria can be very heterogeneous in disease severity and clinical outcomes.
Although pulmonary capillary hydrostatic pressure elevation and pulmonary vascular permeability increase are known to induce pulmonary edema, discrimination of these pathogeneses is important because of the difference in treatments. At present, the differential diagnosis is made on the basis of the assessment of left atrial pressure, which is assumed to be normal in ALI/ARDS. However this hemodynamic definition of ALI/ARDS is controversial, as suggested previously. The pulmonary artery occlusion pressure might not reflect the hydrostatic pressure in the pulmonary micro-vessels and cannot be accurately measured.
Moreover, left ventricular preload might be elevated in ALI/ARDS patients, especially in those who have already received volume resuscitation and/or pre-existing or sepsis-related cardiac dysfunction, as described in the Berlin definition. The pulmonary artery occlusion pressure was recently found to be elevated in 30% of ARDS patients. The definition of ALI/ARDS should thus include the functional features of the pathophysiology of this syndrome; that is, increased pulmonary microvascular permeability. The PVPI has been suggested to be an important parameter in ALI/ARDS pathogenesis.
This study showed that EVLW was greater in patients with ALI/ARDS and cardiogenic edema than patients with pleural effusion with atelectasis; that pulmonary vascular permeability was increased in patients with ALI/ARDS compared with cardiogenic edema and pleural effusion with atelectasis patients; and that the cutoff value of PVPI for the quantitative diagnosis of ALI/ARDS was between 2.6 and 2.85, with a specificity of 0.9 to 0.95, and that PVPI < 1.7 ruled out an ALI/ARDS diagnosis.