Handgrip strength association with weaning outcome in mechanically ventilated ICU patients: a systematic review and meta-analysis.

Background: It is unclear whether other cardiac biomarkers than NT-proBNP can be useful in the risk stratification of patients weaning from mechanical ventilation. The aim of this study is to summarize the role of ischemic cardiac biomarkers in predicting spontaneous breathing trial (SBT) or extubation failure. Methods: We systematically searched Embase, MEDLINE, Web of Science, and Cochrane Central for studies published before January 2024 that reported the association between ischemic cardiac biomarkers and SBT or extubation failure. Data were extracted using a standardized form and methodological assessment was performed using the QUIPS tool. Results: Seven observational studies investigating four ischemic cardiac biomarkers (Troponin-T, Troponin-I, CK-MB, Myoglobin) were included. One study reported a higher peak Troponin-I in patients with extubation failure compared to extubation success (50 ng/L [IQR, 20-215] versus 30 ng/L [IQR, 10-86], p = 0.01). A second study found that Troponin-I measured before the SBT was higher in patients with SBT failure in comparison to patients with SBT success (100 ± 80 ng/L versus 70 ± 130 ng/L, p = 0.03). A third study reported a higher CK-MB measured at the end of the SBT in patients with weaning failure (SBT or extubation failure) in comparison to weaning success (8.77 ± 20.5 ng/mL versus 1.52 ± 1.42 ng/mL, p = 0.047). Troponin-T and Myoglobin as well as Troponin-I and CK-MB measured at other time points were not found to be related to SBT or extubation failure. However, most studies were underpowered and with high risk of bias. Conclusions: The association with SBT or extubation failure is limited for Troponin-I and CK-MB and appears absent for Troponin-T and Myoglobin, but available studies are hampered by significant methodological drawbacks. To more definitively determine the role of ischemic cardiac biomarkers, future studies should prioritize larger sample sizes, including patients at risk of cardiac disease, using stringent SBTs and structured timing of laboratory measurements before and after SBT.

BackgroundThis study aims to assess the changes in lung aeration and ventilation during the first spontaneous breathing trial (SBT) and after extubation in a population of patients at risk of extubation failure.MethodsWe included 78 invasively ventilated patients eligible for their first SBT, conducted with low positive end-expiratory pressure (2 cm H2O) for 30 min. We acquired three 5-min electrical impedance tomography (EIT) records at baseline, soon after the beginning (SBT_0) and at the end (SBT_30) of SBT. In the case of SBT failure, ventilation was reinstituted; otherwise, the patient was extubated and two additional records were acquired soon after extubation (SB_0) and 30 min later (SB_30) during spontaneous breathing. Extubation failure was defined by the onset of post-extubation respiratory failure within 48 h after extubation. We computed the changes from baseline of end-expiratory lung impedance (∆EELI), tidal volume (∆Vt%), and the inhomogeneity index. Arterial blood was sampled for gas analysis. Data were compared between sub-groups stratified for SBT and extubation success/failure.ResultsCompared to SBT success (n = 61), SBT failure (n = 17) showed a greater reduction in ∆EELI at SBT_0 (p < 0.001) and SBT_30 (p = 0.001) and a higher inhomogeneity index at baseline (p = 0.002), SBT_0 (p = 0.003) and SBT_30 (p = 0.005). RR/Vt was not different between groups at baseline but was significantly greater at SBT_0 and SBT_30 in SBT failures, compared to SBT successes (p < 0.001 for both). No differences in ∆Vt% and arterial blood gases were observed between SBT success and failure. The ∆Vt%, ∆EELI, inhomogeneity index and arterial blood gases were not different between patients with extubation success (n = 39) and failure (n = 22) (p > 0.05 for all comparisons).ConclusionsCompared to SBT success, SBT failure was characterized by more lung de-recruitment and inhomogeneity. Whether EIT may be useful to monitor SBT remains to be determined. No significant changes in lung ventilation, aeration or homogeneity related to extubation outcome occurred up to 30 min after extubation.Trial registration Retrospectively registered on clinicaltrials.gov (Identifier: NCT03894332; release date 27th March 2019).

Handgrip strength is an alternative measure to assess peripheral muscle strength and is correlated with the Medical Research Council (MRC) scale, with promising values for diagnosing ICU-acquired weakness (ICUAW). Because ICUAW has been associated with delayed weaning from mechanical ventilation, we hypothesized that ICUAW evaluated with both the MRC scale score and handgrip strength are associated with failure of a spontaneous breathing trial (SBT) and duration of mechanical ventilation weaning. We conducted a prospective observational study in 3 general ICUs with a total of 54 beds at 2 academic hospitals. Adult subjects with > 48 h of mechanical ventilation who were eligible for weaning were included in the study. In the evaluation before the first SBT, the MRC score (P < .001) and handgrip strength (P < .001) were significantly different between subjects extubated after a successful first SBT (simple weaning) and those extubated any time after a failed first SBT (difficult weaning). Only the MRC score discriminated between first SBT success or failure (P < .001); in multivariate analysis, the MRC score was significantly associated with first SBT failure (odds ratio 0.91, 95% CI 0.88-0.97, P < .001) and difficult weaning (odds ratio 0.91, 95% CI 0.87-0.96, P < .001). Handgrip strength exhibited good accuracy in identifying ICUAW. MRC score was independently associated with SBT failure and difficult or prolonged weaning.

Handgrip Measurement Method Affects Asymmetry but Not Weakness Identification in Community-Dwelling Older Adults.

Both premature and delayed liberation from mechanical ventilation are associated with increased morbidity and mortality, and fluid balance could negatively influence extubation outcomes. We sought to determine the impact of fluid balance in the 48 h before a spontaneous breathing trial (SBT) on weaning outcomes in a mixed ICU population. This was a prospective observational study in 2 adult medical-surgical ICUs. All enrolled subjects met eligibility criteria for weaning from mechanical ventilation. SBT failure was defined as inability to tolerate a T-piece trial for 30-120 min. Data on demographics, physiology, fluid balance in the 48 h preceding SBT (fluid input minus output over the 48-h period), lung ultrasound findings, and outcomes were collected. Of a total of 250 SBTs, SBT failure eventuated in 51 (20.4%). Twenty-nine subjects (11.6%) had COPD, and 40 subjects (16%) were intubated due to respiratory sepsis. One-hundred eighty-nine subjects (75.6%) were extubated on the first attempt. Compared with subjects with SBT success, SBT failure subjects were younger (median of 66 vs. 75 y, P = .001) and had a higher duration of mechanical ventilation (median of 7 vs. 4 d, P < .001) and a higher prevalence of COPD (19.6 vs. 9.5%, P = .04). There were no statistically significant differences in 48-h fluid balance before SBT between groups (SBT failure, 1,201.65 ± 2,801.68 mL; SBT success, 1,324.39 ± 2,915.95 mL). However, in the COPD subgroup, we found a significant association between positive fluid balance in the 48 h before SBT and SBT failure (odds ratio of 1.77 [1.24-2.53], P = .04). Fluid balance should not delay SBT indication because it does not predict greater probability of SBT failure in the medical-surgical critically ill population. Notwithstanding, avoiding positive fluid balance in patients with COPD might improve weaning outcomes. (ClinicalTrials.gov registration NCT02022839.).

To evaluate the value of lung ultrasound score (LUS) on predicting weaning outcome in patients with intro-abdominal infection (IAI) undergoing mechanical ventilation. Patients with IAI undergoing mechanical ventilation admitted to Research Institute of General Surgery of East War Zone Hospital and intensive care unit (ICU) of the First People's Hospital of Lianyungang from January to December in 2018 were included. The patients who satisfied weaning criteria were enrolled in the weaning process, which included spontaneous breathing trial (SBT) and extubation. They were divided into SBT success group and SBT failure group according to whether passed 120-minute SBT or not. LUS scores before and after SBT were compared between the two groups. The patients in the SBT success group were extubated, and they were divided into successful extubation group and failed extubation group for sub-group analysis according to whether re-intubation was needed in 48 hours after extubation. LUS score before extubation (at the end of SBT) and 48 hours after extubation (48 hours after extubation in the successful extubation group or before re-intubation in the failed extubation group) were compared. The receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of LUS score before SBT for SBT failure and LUS score before extubation for the failure. A total of 76 patients with IAI undergoing mechanical ventilation were included. Twenty-three patients had duration of mechanical ventilation less than 48 hours, severe chronic obstructive pulmonary disease (COPD), tracheotomy or automatic discharge were excluded, and 53 patients were enrolled. SBT was failed in 9 patients, and successfully performed in 44 patients, of whom 23 patients with successful extubation, and 21 with failed extubation. The LUS scores before and after SBT in the SBT failure group were significantly higher than those in the SBT success group (before SBT: 13.22±1.99 vs. 10.79±1.64, t = -3.911, P = 0.000; after SBT: 19.00±1.12 vs. 13.41±1.86, t = -8.665, P = 0.000). ROC curve analysis showed that the area under ROC curve (AUC) of LUS score before SBT for predicting SBT failure was 0.82 [95% confidence interval (95%CI) was 0.67-0.98, P = 0.002]. When the optimum cut-off value was 12.5, the sensitivity was 66.7%, and the specificity was 84.1%. Sub-group analysis showed that the LUS scores before and after extubation in the failed extubation group were significantly higher than those in the successful extubation group (before extubation: 14.19±1.60 vs. 12.69±1.81, t = -2.881, P = 0.006; after extubation: 16.42±1.59 vs. 12.78±1.54, t = -7.710, P = 0.000). ROC curve analysis showed that the AUC of LUS score before extubation for predicting the failure was 0.81 (95%CI was 0.69-0.92, P = 0.000). When the optimum cut-off value was 13.5, the sensitivity was 80.0%, and the specificity was 65.2%. LUS score can effectively predict SBT outcome, risk of re-intubation after extubation in patients with IAI undergoing mechanical ventilation.

RationaleDyspnea, a key symptom of acute respiratory failure, is not among the criteria for spontaneous breathing trial (SBT) failure. Here, we sought (1) to determine whether dyspnea is a reliable failure criterion for SBT failure; (2) to quantify the relationship between dyspnea and the respective electromyographic activity of the diaphragm (EMGdi), the parasternal (EMGpa) and the Alae nasi (EMGan).MethodsMechanically ventilated patients undergoing an SBT were included. Dyspnea intensity was measured by the Dyspnea-Visual Analogic Scale (Dyspnea-VAS) at the initiation and end of the SBT. During the 30-min SBT or until SBT failure, the EMGdi was continuously measured with a multi-electrode nasogastric catheter and the EMGan and EMGpa with surface electrodes.ResultsThirty-one patients were included, SAPS 2 (median [interquartile range]) 53 (37‒74), mechanically ventilated for 6 (3‒10) days. Seventeen patients (45%) failed the SBT. The increase in Dyspnea-VAS along the SBT was higher in patients who failed (6 [4‒8] cm) than in those who passed (0 [0‒1] cm, p = 0.01). The area under the receiver operating characteristics curve for Dyspnea-VAS was 0.909 (0.786–1.032). The increase in Dyspnea-VAS was significantly correlated to the increase in EMGan (Rho = 0.42 [0.04‒0.70], p < 0.05), but not to the increase in EMGpa (Rho = − 0.121 [− 0.495 to − 0.290], p = 0.555) and EMGdi (Rho = − 0.26 [− 0.68 to 0.28], p = 0.289).ConclusionDyspnea is a reliable criterion of SBT failure, suggesting that Dyspnea-VAS could be used as a monitoring tool of the SBT. In addition, dyspnea seems to be more closely related to the electromyographic activity of the Alae nasi than of the diaphragm.

IntroductionThe process of weaning may impose cardiopulmonary stress on ventilated patients. Heart-rate variability (HRV), a noninvasive tool to characterize autonomic function and cardiorespiratory interaction, may be a promising modality to assess patient capability during the weaning process. We aimed to evaluate the association between HRV change and weaning outcomes in critically ill patients.MethodsThis study included 101 consecutive patients recovering from acute respiratory failure. Frequency-domain analysis, including very low frequency, low frequency, high frequency, and total power of HRV was assessed during a 1-hour spontaneous breathing trial (SBT) through a T-piece and after extubation after successful SBT.ResultsOf 101 patients, 24 (24%) had SBT failure, and HRV analysis in these patients showed a significant decrease in total power (P = 0.003); 77 patients passed SBT and were extubated, but 13 (17%) of them required reintubation within 72 hours. In successfully extubated patients, very low frequency and total power from SBT to postextubation significantly increased (P = 0.003 and P = 0.004, respectively). Instead, patients with extubation failure were unable to increase HRV after extubation.ConclusionsHRV responses differ between patients with different weaning outcomes. Measuring HRV change during the weaning process may help clinicians to predict weaning results and, in the end, to improve patient care and outcome.

BackgroundAlterations in perfusion to the brain during the transition from mechanical ventilation (MV) to a spontaneous breathing trial (SBT) remain poorly understood. The aim of the study was to determine whether changes in cerebral cortex perfusion, oxygen delivery (DO2), and oxygen saturation (%StiO2) during the transition from MV to an SBT differ between patients who succeed or fail an SBT.MethodsThis was a single-center prospective observational study conducted in a 16-bed medical intensive care unit of the University Hospital Leuven, Belgium. Measurements were performed in 24 patients receiving MV immediately before and at the end of a 30-min SBT. Blood flow index (BFI), DO2, and %StiO2 in the prefrontal cortex, scalene, rectus abdominis, and thenar muscle were simultaneously assessed by near-infrared spectroscopy using the tracer indocyanine green dye. Cardiac output, arterial blood gases, and systemic oxygenation were also recorded.ResultsDuring the SBT, prefrontal cortex BFI and DO2 responses did not differ between SBT-failure and SBT-success groups (p > 0.05). However, prefrontal cortex %StiO2 decreased in six of eight patients (75%) in the SBT-failure group (median [interquartile range 25–75%]: MV = 57.2% [49.1–61.7] vs. SBT = 51.0% [41.5–62.5]) compared to 3 of 16 patients (19%) in the SBT-success group (median [interquartile range 25–75%]: MV = 65.0% [58.6–68.5] vs. SBT = 65.1% [59.5–71.1]), resulting in a significant differential %StiO2 response between groups (p = 0.031). Similarly, a significant differential response in thenar muscle %StiO2 (p = 0.018) was observed between groups. A receiver operating characteristic analysis identified a decrease in prefrontal cortex %StiO2 > 1.6% during the SBT as an optimal cutoff, with a sensitivity of 94% and a specificity of 75% to predict SBT failure and an area under the curve of 0.79 (95% CI: 0.55–1.00). Cardiac output, systemic oxygenation, scalene, and rectus abdominis BFI, DO2, and %StiO2 responses did not differ between groups (p > 0.05); however, during the SBT, a significant positive association in prefrontal cortex BFI and partial pressure of arterial carbon dioxide was observed only in the SBT-success group (SBT success: Spearman’s ρ = 0.728, p = 0.002 vs. SBT failure: ρ = 0.048, p = 0.934).ConclusionsThis study demonstrated a reduced differential response in prefrontal cortex %StiO2 in the SBT-failure group compared with the SBT-success group possibly due to the insufficient increase in prefrontal cortex perfusion in SBT-failure patients. A > 1.6% drop in prefrontal cortex %StiO2 during SBT was sensitive in predicting SBT failure. Further research is needed to validate these findings in a larger population and to evaluate whether cerebral cortex %StiO2 measurements by near-infrared spectroscopy can assist in the decision-making process on liberation from MV.

Spontaneous breathing trial (SBT) is recommended during weaning from mechanical ventilation (MV), but objective and easy tools lack to identify pediatric weaning failure. We aimed to assess whether changes in estimated arterial CO₂ (PaCO₂) derived from transcutaneous measurements (PTCCO₂) were associated with pediatric weaning failure. Children (age 72 h -18 years) with MV > 12 h were continuously monitored using a transcutaneous sensor to estimate PaCO₂ from skin CO₂ tension (PTCCO₂). Values were recorded during SBT (30 min on positive end-expiratory pressure (PEEP) +5 cmH2O, with pressure support of +5 cmH2O for endotracheal tubes with internal diameter ≤ 3.5 mm), then up to 6 h after extubation. Mean PTCCO2 and PTCCO2 changes during SBT, and after extubation, were retrospectively collected to evaluate their association with SBT failure and extubation failure (reintubation within 48 h). Eighty children (median [IQR] age 1.1 [0.3; 8.7] years) were included, with 89 SBT (14 failures, 75 successes). Sixty-four patients were extubated following their first SBT, with 10 (16%) extubation failures. PTCCO2 changes were not associated with SBT and extubation failures. Patients who failed extubation had a higher mean PTCCO2 value after extubation as compared to those who were successfully extubated (mean PTCCO2 of 51.8 [46.2; 55.4] vs. 42.3 [37.5; 47.2] mmHg, p = 0.02). The difference between the maximal PTCCO2 value within the 2 h following extubation and the value at extubationwerehigher in patients who failed extubation (ΔPTCCO2 of 20 [9.1; 26] vs. 6.8 [2.9; 9.7] mmHg, p < 10-2). Early post-extubation increase in estimated PaCO₂ was associated with extubation failure, whereas PTCCO₂ changes during SBT were not.

The evolution of diaphragm activity and function determined by ultrasound during spontaneous breathing trials

Maximum hand-grip (HG) strength, body composition and main anthropometric variables were evaluated in 278 children with normal weight and growth, aged 5-15 yr divided into 3 age groups: group 1, age+/-SD: 7.6+/-0.9 yr 7.6+/-0.9 SD (Tanner stage 1); group 2, age: 10.8+/-0.7 yr (Tanner stage: 2-3); group 3, age: 13.2+/-0.9 yr (Tanner stage: 4-5). Weight, height, body surface area (BSA), BMI, percent body fat (BF) and fat free mass (FFM) increased progressively and significantly from the younger to the older age group. A significant difference between genders was detected only for BF and FFM, females having a higher fat mass and a lower FFM compared to males. Most children were right-handed (91%). In either genders, a curvilinear relation was detected between HG strength and age, with best fit for the dominant (d) hand given by the equations: dHG=5.891 *10(0.051) age, r2=0.986, p<0.001 in males and dHG=6.163 *10(0.045) age r2=0.973, p<0.001 in females. The increase in HG strength after 11 yr appears to be steeper in males as compared with that found in females. In both d and non-dominant (nd) hand, a significant difference in HG strength was detected between males and females, the average difference being about 10% at all ages. For both genders, nd hand was significantly weaker than d hand in the older age groups (2 and 3), but not in the younger group 1. Age and gender-dependent differences in HG strength (but not differences between d and nd hand) disappear if HG strength is normalized for FFM. Thus, in general, dHG strength normalized for FFM resulted on average to be 0.67+/-0.11 kg/kg. A multiple linear regression analysis indicated that HG was positively correlated with BMI, BSA, stature, stature2 and FFM (p<0.001 for all correlations) without differences between genders, while a negative correlation was found between HG strength and %BF. The most significant correlation was found between HG strength and FFM, without any significant difference between genders, so that the overall equation describing the line for the d hand was: dHG strength= 2.32+0.63 FFM, r2=0.72, p<0.001. In conclusion, the present study indicates that the age-dependent increase of HG strength as well as the between-gender differences are strongly related to changes of FFM values occurring during childhood. Moreover, the study provides a standard normative value of maximal HG strength for the healthy children population in Northern Italy.

Muscle weakness, defined by the Medical Research Council scale, has been associated with delay in mechanical ventilation weaning. In this study, we evaluated handgrip strength as a prediction tool in weaning outcome. This was a 1-y prospective study in 2 ICUs in 2 university hospitals. Adult patients who were on mechanical ventilation for at least 48 h and eligible for mechanical ventilation weaning were screened for inclusion. Handgrip strength was evaluated using a handheld dynamometer before each spontaneous breathing trial (SBT). Attending physicians were unaware of handgrip strength and decided on extubation according to guidelines. Eighty-four subjects were included (median age 66 [53-79] y, with a median Simplified Acute Physiology Score II of 49 [37-63]). At the first evaluation, median handgrip strength was significantly associated with weaning outcome as defined by international guidelines: simple (20 [12-26] kg), difficult (12 [6-21] kg), or prolonged (6 [3-11] kg) weaning (P = .008). Time to liberation from mechanical ventilation and ICU stay were significantly longer for subjects classified as having muscle weakness according to the handgrip strength-derived definition (P = .02 and P = .03, respectively). In multivariate analysis, known history of COPD (odds ratio [OR] 5.48, 95% CI 1.44-20.86, P = .01), sex (OR 6.16, 95% CI 1.64-23.16, P = .007), and handgrip strength at the first SBT (OR 0.89, 95% CI 0.85-0.97, P = .004) were significantly associated with difficult or prolonged weaning. Extubation failure, as defined by re-intubation or unscheduled noninvasive ventilation within 48 h after extubation, occurred 14 times after 92 attempts, leading to an extubation failure rate of 15%. No association was found between handgrip strength and extubation outcome. Muscle weakness, assessed by handgrip strength, is associated with difficult or prolonged mechanical ventilation weaning and ICU stay, but not with extubation outcome.

ObjectivesWe aimed to assess combined predictive ability of ultrasound lung, diaphragm and echocardiography variables, to anticipate failure of spontaneous breathing trial (SBT) and extubation.MethodsWe conducted a prospective observational study in 73 consecutive mechanically ventilated children aged (1month-18years) eligible for SBT as per protocol. Comprehensive USG lung, diaphragm and echocardiography was performed by single trained paediatric intensivist 30 minutes before initiating SBT to measure lung aeration score (LAS), diaphragmatic thickening fraction (DTF-R) preferred right due to ease of access and left ventricular (LV) systolic and diastolic function. Children succeeded SBT were given extubation trial. Outcome variables were analysed individually between success and failure groups of SBT and extubation trial respectively.ResultsAmong 73 subjects enrolled pre SBT, SBT success group(n=65) had significantly high mean DTF-R (%) (34.66 ± 12.70) in comparison to SBT failure group(n=8) (18.95 ± 11.56) (p, 0.004). Children who passed SBT as per clinical protocol and successfully extubated (n=57) had mean DTF-R (%)(35.09 ± 13.17) comparable to (31.59 ± 8.64) extubation failure group(n=8) (p, 0.63). Extubation success group had significantly low LAS (15.98 ± 4.49) in contrast to extubation failure group (21.75 ± 6.30) (p,0.012). LV diastolic dysfunction (LVDD) defined by E/ E’ cutoff (≥10)1 had diagnostic accuracy of 86.2% to predict extubation failure individually. Whereas, combined predictive ability of DTF(R)+LAS+LVDD to predict extubation failure was superior to individual variables (AUROC, 0.82) (p=0.004).Predictor VariableCut-offAUROC95% CIP valueSensitivitySpecificityPPVNPVDiagnostic accuracyDTF-Right (%)<43%0.5540.352–0.7560.632100%26%16%100%35%DTF-Left (%)<24%0.5950.328–0.8630.39062%75%26%94%74%LAS (x/50)>220.7770.604–0.9510.01262%84%36%94%82%DTF (Right)+ LAS+LVDD_0.8200.65–0.990.00475%86%43%96%85%ConclusionThe combined ultrasound evaluation of heart, lung and diaphragm in comparison to individual variables, significantly enhanced prediction accuracy of extubation failure before SBT in children. DTF alone is a non-reliable marker for prediction of extubation failure.

ABSTRACTObjective:Inspiratory fall in intrathoracic pressure during a spontaneous breathing trial (SBT) may precipitate cardiac dysfunction and acute pulmonary edema. We aimed to determine the relationship between radiological signs of pulmonary congestion prior to an SBT and weaning outcomes. Methods:This was a post hoc analysis of a prospective cohort study involving patients in an adult medical-surgical ICU. All enrolled individuals met the eligibility criteria for liberation from mechanical ventilation. Tracheostomized subjects were excluded. The primary endpoint was SBT failure, defined as the inability to tolerate a T-piece trial for 30-120 min. An attending radiologist applied a radiological score on interpretation of digital chest X-rays performed before the SBT. Results:A total of 170 T-piece trials were carried out; SBT failure occurred in 28 trials (16.4%), and 133 subjects (78.3%) were extubated at first attempt. Radiological scores were similar between SBT-failure and SBT-success groups (median [interquartile range] = 3 [2-4] points vs. 3 [2-4] points; p = 0.15), which, according to the score criteria, represented interstitial lung congestion. The analysis of ROC curves demonstrated poor accuracy (area under the curve = 0.58) of chest x-rays findings of congestion prior to the SBT for discriminating between SBT failure and SBT success. No correlation was found between fluid balance in the 48 h preceding the SBT and radiological score results (ρ = −0.13). Conclusions:Radiological findings of pulmonary congestion should not delay SBT indication, given that they did not predict weaning failure in the medical-surgical critically ill population. (ClinicalTrials.gov identifier: NCT02022839 [http://www.clinicaltrials.gov/])