This meta-analysis supports the validity of the relative change of BNP (DBNP%) during a SBT to add incremental value and inform the likelihood of successful liberation from MV in adults. This meta-analysis also demonstrated high accuracy using a pooled AUROC of DBNP% for studies that excluded patients who failed a SBT. Combining methods of absolute and relative change in BNP measures, irrespective of inclusion or exclusion of patients who failed their SBT showed high sensitivity and specificity for predicting successful liberation. The data from pediatric studies and studies describing other BNP measures, such as DBNP, BNP-pre SBT and BNP-post SBT, were insufficient to suggest incremental value and for clinical decision support about likelihood of liberation success.
There findings are noteworthy given the limited predictive ability of SBT alone, which is generally regarded as the best available assessment. In studies, SBT misclassified patients in 10-20% of patients who subsequently failred to successfully liberation from MV(14,24). While reintubation was described as occurring without immediate difficulty, these patients had greater risk of morbidity and mortality following a failed attempt at liberation from MV(1). Better prediction by use of alternative tests that add incremental value, such as BNP, may lead to greater confidence in clinical decision-making to extubate, reduced reintubation, and improved outcomes. This possibility has been recognized as early as 2008 in two methods of analysis: as an incremental “value-added” test during SBT(3), and as a “stand-alone” alternative test(25). These two approaches were well represented in the studies included in this meta-analysis. A subset of studies (group 1, n=8) included patients failing their SBT in the analysis of the group that failed MV liberation; this in effect assessed BNP as an alternative test to conventional SBT. This method may have decreased accuracy compared to evaluation of pooled analysis where patients who failed their SBT were excluded. A second subset of studies (group 2, n=9) excluded patients with a failed SBT in the analysis of the MV liberation failure group. This in effect assesses BNP as an incremental test to a successful SBT. The major benefit in this case is the potential reclassification of patients for whom liberation may have been attempted, but may have failed. This distinction is important to determine the optimal use of BNP in assessment for MV liberation. In our view, the two ways in which SBT failure is incorporated in the analysis should ideally be pooled and analysed separately. However; we expected limited data and pooled them for further analysis as planned in the protocol. Similarly, the different methods of BNP measures (DBNP, DeltaBNP%, BNP-pre and BNP-post) should not be pooled, as some address a change in BNP values, whereas others only address a single value at a specific time. The only exception in which BNP measures could be pooled would be be DBNP and DBNP% given the possibility that baseline BNP level may not be relevant in the case of substantial change occurring during a SBT.
Most of the data that could be pooled related to absolute and relative changes in BNP during a SBT (DBNP and DBNP%). In order to increase the breadth of our analyses, we pooled studies of either method of measures (DBNP and DBNP%) for studies that excluded patients who failed their SBT. The Moses-Littenberg summary ROC analysis showed high accuracy (Additional File 5). However, this analysis requires the availability of true positive, true negative, false positive and false negative data to perform, limiting its applicability to certain subgroups. This summary ROC analysis was mostly driven by DBNP% (3 out of 4 studies, 148 out of 178 patients). We were able to perform a pooled AUROC of DBNP% for studies that excluded SBT failure from the analysis of the liberation failure (Figure 5). This AUROC analysis further supports the initial findings and provides evidence of high accuracy (0.92 [0.88-0.97], I2 0%). This represents the most robust combination of BNP measures in pooled analysis obtained from the data.
Unfortunately, the data was insufficient to perform sensitivity and specificity estimates for this specific combination of BNP measures. The closest approximation was obtained by a bi-variate analysis using pooled data of studies of either DBNP and DBNP% measures, regardless of inclusion or exclusion of the SBT failure group. The sensitivity and specificity obtained were high [0.889 (0.831-0.929) and 0.828 (0.730-0.896), respectively]. It is important to note that these results were mostly driven by studies where patients with SBT failure were excluded (4 out of 5 studies; 248 out of 278 patient s), and DBNP% (4 out of 5 studies; 178 out of 278 patients). This closely approximates the prior analysis performed on DBNP% for studies that excluded patients with SBT failure from the analysis.
There were insufficient studies to analyse DBNP, BNP-pre and BNP-post separately as an incremental test (i.e., excluding SBT failure from the liberation failure analysis) or an alternate “stand-alone” test (i.e., including SBT failure from the liberation failure analysis). Pooling studies of both methods of analysis for each BNP measure appears to support a high accuracy in these cases (Figure 4). The main limitation is the inability to determine if it is of better use as an incremental or alternate test. Additionally, for BNP-pre and BNP-post, the studies were not described with as much detail as those for studies on DBNP and DBNP%. Furthermore, it is difficult to determine a superior measure or method, as only two studies directly compared various BNP measures. Both Cheng et al(26) and Martini et al(21) compared DBNP and DBNP%, and both studies suggested DBNP% was superior.
From a clinical standpoint, using these measures requires using a specific threshold for dichotomization between likelihood of liberation success versus failure (Table 1). This was determined through analysis of the AUC curve of best sensitivity, specificity, positive and negative predictive values and diagnostic accuracy. No pre-specified threshold was studied prospectively across any of the studies. Studies of DBNP% suggested a threshold above 13.4-20% (n=4) optimally predicted liberation failure, if both BNP types (BNP and NT-ProBNP) were pooled. The other BNP measures had three or fewer studies for each measure or combination (Table 1). As such, this systematic review cannot recommend a specific threshold for any of the BNP measures to optimally discriminate liberation success and failure that could be adopted in clinical practice.
Our study would suggest that BNP performs best if used as a relative change BNP during a SBT among those studies that only included adult patients who successfully passed an initial SBT by other clinical criteria. There is a potential role to the use of either DBNP% or DBNP irrespective of whether patients have successfully or unsuccessfully passed an SBT, but the data is less robust and requires further investigation.
As described above, the heterogeneity of BNP measures and varying analytic approaches limited our ability to perform pooled analysis; acknowledging this limits the inferences that can be made. Similarly, due to limitation in the reporting across studies, we were unable to perform stratified analysis by potentially important subgroups, such as case-mixe and type of ICU admission. We opted to combine both general ICU populations and specific ICU subgroups to capture enough data to perform the AUROC analyses. The bi-variate analysis and Moses-Littenberg analyses were unaffected, as all studies included were of a mixed ICU population. We believe that this makes our results more generalizable to mixed medical/surgical ICU practice; however, we cannot provide strong inferences on the value of BNP for MV liberation in selected ICU subgroups, as each population was represented by a single study. There are several confounders to the accuracy of BNP testing. Heart disease (and specifically depressed left ventricular ejection fraction) and kidney failure can significantly alter BNP kinetics. Unfortunately, these patient characteristics were inconsistently included or excluded across studies. In the case of kidney failure, the distinction between acute and chronic renal failure was also poor. In balance, renal function was normal in most studies, and at most mildly impaired in the rest. As for heart disease, the definitions were variable. The etiology of respiratory failure has an impact on the accuracy of BNP: delirium, traumatic brain injury, inability to clear secretions or stridor, amongst others, limit the accuracy of BNP as they may not lead to a change in BNP measurements. A low number of studies that were included in this review attempted to limit this impact by excluding stridor and TBI from the analysis. Unfortunately, capturing clearance of secretions or delirium as the cause of respiratory failure is understanbly difficult and was not done in any study. Another limitation is the lack of studies that directly compared the accuracy of a successful SBT by clinical indices and by BNP measure. In this instance, a patient that has passed a SBT by clinical indices may fail by BNP measure, leading to a delay in extubating a patient that would have succeded. Unfortunately, the relative accuracies were not directly assessed in any study.
Finally, the quality of studies (as defined by QUADAS-2) uniformally ranked as at risk of bias, except for one(27). The main issue was lack of transparency regarding blinding of physicians to the BNP test. In our opinion, this is not a critical flaw, as the decision to extubate patients was most often based on clinical SBT criteria in all studies.
Implications for Clinical, Policy and Research
Research on mechanical ventilation liberation is complex and would benefit from greater standardization. Successful liberation from mechanical ventilation appears well-defined and this is reflected in the studies collected. Liberation failure, on the other hand, has a variable definition amongst studies, mostly relating to the inclusion or exclusion of SBT failure. Regardless of its importance for applicability of alternative or incremental testing, the terms used require standardization to facilitate research.
Additional data is needed to strengthen BNP as a liberation tool. We consider that this should take the form of a comparative study of BNP as an alternative or an incremental tool to the clinical indices after an SBT. This study would ideally take the form of an assessment of DBNP and DBNP%, and compare inclusion versus exclusion of SBT in the analysed subgroups. This would allow determination of whether BNP is superior to SBT on its own or simply incremental.
The potential benefits of improved tools to inform greater likelihood of success or failure of liberation from MV have far-reaching implications. On top of reclassifying individuals after initial assessment with clinical indices, this may allow stratification of the risk of failure. Such a stratification may help better determine targets for optimization (such as further volume de-escalation), better identification of the need for post-extubation therapies (such as high-flow oxygen therapy and BiPAP), and need for prolonged ICU observation. Clinical risk scores on this basis could be developed to aid in management of these patients after extubation.