A systematic review of diagnostic methods to differentiate acute lung injury/acute respiratory distress syndrome from cardiogenic pulmonary edema

Differentiating between cardiogenic pulmonary edema (CPE) and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is challenging in the early stages of illness [1]. The most widely accepted definition of ALI/ARDS had been based on the American-European Consensus Conference (AECC) definition, of acute onset respiratory failure with bilateral infiltrates on chest radiograph, and pulmonary capillary wedge pressure (PCWP) <18 mmHg, or absence of elevated left atrial pressure [2]. However, pulmonary artery catheterization is rarely used in clinical practice because clinical estimation of PCWP is invasive, costly, and does not aid in the diagnosis of ALI/ARDS [3‐7]. There were potential inconsistencies in this definition, including a lack of explicit criteria for defining acute respiratory failure, the sensitivity of the PaO2/FiO2 (P/F) ratio to ventilator settings, poor reliability of the chest radiograph criteria, and difficulties distinguishing ARDS from CPE including that these diagnoses can coexist [8, 9]. Based on these limitations, the Berlin definition for ARDS was published in 2012 and is reported to have better predictive validity for mortality, than this earlier definition [8]. Pulmonary capillary wedge pressure measurement was removed from this definition. Patients were presumed to have ARDS if they had respiratory failure not fully explained by cardiac failure or fluid overload as judged by the treating physician using all available data.

In current practice and most clinical studies, ALI/ARDS is usually differentiated from CPE by the clinical circumstances and by physical findings, but this distinction is often made only by post hoc review after patient’ discharge or death, and is often based on the response to therapy [10, 11]. The ARDS Clinical Trial Network reported that fluid management to decrease cardiogenic fluid retention and the effects of lung permeability and edema, will shorten the duration of mechanical ventilation and intensive care without increasing nonpulmonary organ failure [12]. The differentiation between ALI/ARDS and CPE is important in order to avoid delaying treatment of fluid retention and avoiding unnecessary testing [13]. Several biomarkers to distinguish ALI/ARDS from CPE have been reported. The aim of this systematic review was to review published studies of potential biomarkers to distinguish ALI/ARDS from CPE.

This systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [14].

We systematically reviewed serum and pulmonary biomarkers, and imaging used to differentiate ALI/ARDS from CPE. BNP, released from ventricular cardiomyocytes in response to both ventricle volume expansion and pressure overload, was the most commonly evaluated biomarker; but the predictive ability was variable. While two studies measured BNP levels early in the clinical presentation, and these showed a good discriminatory ability [18, 19], other studies allowed BNP to be tested up to 3 hours (IQR 0.5–14) [10] or 48 hours after presentation and these were less able to distinguish ARDS/ALI from CPE [21]. BNP is known to decrease after treatment for heart failure [42] and this could explain the higher discriminatory ability before starting treatment. Replicate and prospective studies with consistent timing of measurements are required in order to improve the quality of evidence.

As well, the subjects in the study by Levitt [21] were younger than in the other studies [10, 18, 19] and in the younger subjects BNP was a less sensitive biomarker. Because elderly patients may respond less well to diuretics, ACE inhibitors, and inotropic agents compared to younger patients [43], the younger patients may also respond to treatment more rapidly. Renal failure often accompanies severe sepsis and ARDS and this can increase BNP despite normal cardiac function [44]. Due to these different patient characteristics in each study, we did not collect these raw data to combine for a meta-analysis.

CRP is widely used as a marker of systemic inflammation, and in one study by the authors of this review; AUC when CRP was used to differentiate ALI/ARDS from CPE was as good as when BNP was used [18]. While BNP levels can increase in some conditions such as renal failure or sepsis despite normal cardiac function [44], CRP is not directly influenced by cardiac function. CRP combined with BNP may have greater discriminatory ability than either BNP or CRP alone [18].

Plasma soluble suppression of tumorigenicity-2, an IL-1 receptor family member which is a mediator of inflammation and immunity, showed excellent discrimination [20]. Heparin-binding protein is an antimicrobial protein stored in neutrophil granules, and it induces cytoskeletal rearrangement of endothelial cells, which leads to breakdown of cell barriers and an increase in macromolecular efflux [39]. Copeptin, the C-terminal portion of the arginine vasopressin precursor, is secreted together with arginine vasopressin precursor from the neurohypophysis. This secretion is thought to reflect the inflammatory cytokine response and the presence of hemodynamic and osmoregulatory disturbances [45, 46]. These biomarkers appeared to be robust in discriminating ALI/ARDS from CPE in single studies; so validation in replicate studies will be necessary.

Sample size in each study for lung-specific biomarkers was small compared with studies of serum biomarkers, and airway sampling by BAL may be difficult in the emergency department setting. When pulmonary edema is present, pulmonary edema fluid can be obtained by inserting a suction catheter into an endotracheal tube until frothy fluid is obtained by suctioning [25]. The pulmonary edema fluid-to-plasma protein ratio has been studied for decades as a tool to differentiate pulmonary permeability edema from hydrostatic edema [47].

Combining cardiac and thoracic ultrasonography could help to determine the cause of acute pulmonary edema [36]. However, these techniques are operator-skill dependent. Chest CT may be better at discriminating ALI/ARDS from CPE than chest radiography; although CT is rarely performed for acute respiratory failure in the emergency department setting. Milne and colleagues performed an independent two-observer study of chest radiographs from 61 subjects with cardiac disease, and 28 with capillary permeability edema, not described as ALI or ARDS [48]. The overall accuracy for distinguishing capillary permeability edema from cardiac edema was 91%. Another study reported that 87% of subjects with hydrostatic edema but only 60% of those with increased permeability edema were correctly identified in critical ill patients [49]. It is controversial if chest radiography can be recommended to differentiate the type of pulmonary edema.

A limitation of studies focusing on biomarkers or images for discriminating ALI/ARDS from CPE is that these can coexist [8]. Some degree of hydrostatic edema is present in many cases of ALI/ARDS, in fact the pulmonary capillary wedge pressure is reported to be elevated in 30% of ARDS patients [12]. Schmickl and colleagues developed a decision support algorithm to distinguish CPE from ARDS based on clinical data [11]. However, while all studies included in this systematic review specifically excluded mixed cases of ALI/ARDS with CPE, these authors included these cases in the ALI/ARDS group. Protein biomarkers such as BNP showed no statistically significant difference when comparing “pure” CPE with serum from subjects with ALI/ARDS both with and without CPE. BNP levels were elevated for both ALI/ARDS with and without CPE and pure CPE (708 pg/mL vs 749 pg/mL; p = 0.18). Strict fluid management that addresses cardiogenic pulmonary edema and pulmonary permeability edema increases ventilator-free days [12]. This suggests that biomarkers like BNP could be useful for differentiating CPE from ALI/ARDS and for initiating fluid restriction and diuretics early to decrease the risk of CPE.

We identified that some biomarkers, e.g., soluble suppression of tumorigencity-2, BNP plus CRP, heparin-binding protein, and plasma transferrin had high AUCs for differentiating ALI/ARDS from CPE, but these were each only assessed in a single study. All studies compared the biomarker measurement to the clinical diagnosis, but no study compared accuracy of the clinical diagnosis alone to that of clinical diagnosis plus biomarkers. Since ALI/ARDS and CPE can certainly co-exist, biomarkers need to be considered to evaluate the relative role of CPE in contributing to the morbidity of ALI/ARDS.

Because there are no accepted criteria for differentiating CPE from ALI/ARDS at the time of clinical presentation, for these studies, the decision to classify as ALI/ARDS versus CPE was made by clinical expert(s) reviewing clinical information and response to therapy including diuretics. The fundamental questions are: are biomarkers measured at clinical presentation more reliable (and accessible) than post hoc experts’ opinion in differentiating these conditions and can biomarkers identify patients who should have therapy for both conditions (coexisting). Neither question was answered by this systematic review, largely because there is no true gold standard for distinguishing ARDS/ALI from CPE. Given this limitation we understood that the purpose of this review was to identify potential biomarkers that would most closely correlate with expert clinical judgement, which was often post hoc – after the diagnosis became clear. If these biomarkers could be then used for earlier detection and intervention, as suggested by the studies showing that BNP appeared to be most useful when measured at the time of presentation in the emergency department and before initiating therapy, this may allow guidance of appropriate intervention before such time that the clinical differentiation is clear.

We found that there were no identified biomarkers or tools with high-quality evidence for differentiating ALI/ARDS from CPE. Because there is no objective “gold standard” for diagnosing ALI/ARDS or CPE, a clear distinction between ALI/ARDS and CPE may not have been possible in any of these reported studies. The eventual diagnosis was determined by post hoc expert review, blinded to target marker. These limitations pose an obstacle to developing a reliable method to differentiate these disorders. However, differentiating the cause of pulmonary edema is important because the therapy of ALI/ARDS and CPE are fundamentally different. Although fluid restriction might be used to treat both CPE and ARDS/ALI, early recognition of ALI/ARDS allows an emphasis on lung-protective ventilation and in the treatment of the underlying cause of the ARDS whilst recognition of CPE may lead to the appropriate use of diuretics, inotropic therapy, and afterload reduction. Combining clinical criteria with validated biomarkers may improve the predictive accuracy and improve the outcomes of ALI/ARDS even it co-exists with CPE.