This study complies with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement. It was conducted in a medical intensive care unit over a 14-month period between April 2018 and June 2019. The study was approved by the Comité de Protection des Personnes du Sud Ouest et Outre Mer 4 (RCB ID: 2018-A00176-49). Written and oral information about the study was given to patients or their families prior enrolment. Informed consent was obtained from all patients or their relatives.
Patients older than 18 years, ventilated via an endotracheal tube for more than 48 h and who had already failed a first spontaneous breathing trial were eligible. We sought to enrol patients early during the weaning process as soon as the readiness-to-wean criteria (see below) were present. Patients undergoing spontaneous breathing trial during holidays and weekends were not considered for inclusion. Patients had to meet predefined readiness-to-wean criteria on daily screening: SpO2 > 90% or PaO2/FiO2 ≥ 150 mmHg with a fraction of inspired oxygen (FiO2) ≤ 40% and a positive end-expiratory pressure ≤ 8 cmH2O] . In our practice, readiness-to-wean criteria are sought for to conduct a spontaneous breathing trial regardless of the presence of readiness to extubate criteria which are the following: cough strength, neurological status and abundance of secretions. Therefore, In case of successful spontaneous breathing trial, extubation may not be considered. Pregnant women, patients with contraindications to magnetic phrenic nerve stimulation (chest tube, cardiac pacemaker or implanted defibrillator, cervical implants), and patients in whom weaning was impossible (pre-existing neuromuscular disorders, cervical cord injury) were not considered for inclusion.
Measurements and data collection
Upon inclusion, demographic data were prospectively collected: age, gender, comorbidities (chronic hypertension, chronic obstructive pulmonary disease, chronic left ventricle failure), sequential organ failure assessment and simplified acute physiology score, date of intensive care unit admission, date of intubation, main reason for intubation, weight and height upon admission and fluid balance over the last 24 h. In addition, the following clinical variables were prospectively collected before and at the end of the spontaneous breathing trial: systolic and diastolic arterial pressure, heart rate, respiratory rate, SpO2. Arterial blood gases, lactate, plasma protein concentration and haemoglobin were sampled before and at the end of the spontaneous breathing trial. Haemoglobin concentration was measured from the arterial blood sample by the ABL 800flex device (Radiometer, Copenhagen, Denmark). The repeatability of the haemoglobin concentration measurements with the ABL 800flex is reported by the manufacturer to be 0.6% ± 1.4%. The plasma protein concentration was measured with the Cobas 7000 c501 device (Roche Diagnostics, Basel, Switzerland). The repeatability of plasma protein concentration measurements with this device is reported by the manufacturer to be 0.6% ± 0.9%.
Diaphragm function evaluation
Before conducting the spontaneous breathing trial, diaphragm function was assessed in terms of the changes in endotracheal tube pressure induced by bilateral phrenic nerve magnetic stimulation during airway occlusion (Ptr, stim), as described in other reports . Briefly, two figure-of-eight coils connected to a pair of Magstim® 200 stimulators (The Magstim Company, Dyfed, UK) were positioned immediately posterior to the sternomastoid muscles at the level of the cricoid cartilage. Bilateral phrenic nerve stimulation was performed while the endotracheal tube was manually occluded and stimulations were delivered at the maximum intensity allowed by the stimulator (100%) known to result in supramaximal diaphragm contraction [3, 17]. The patients were studied in a standardized semi-recumbent position during a brief disconnection of the endotracheal tube from the ventilator. While the endotracheal tube was manually occluded, bilateral anterolateral magnetic stimulation was performed. The absence of active respiratory efforts was verified by checking the absence of drop in airway pressure signal on the laptop’s screen. Two operators (MD, ER) were required to achieve both stimulation and measurements. After positioning the coils, at least three stimulations were performed at 100% of maximal output allowed by the stimulator. Stimulations were separated by at least 60-s to avoid superposition. The average of three measures was taken into account for analysis. Ptr,stim was defined as the amplitude of the negative pressure wave following stimulation, taken from baseline to peak. It was measured at the proximal external end of the endotracheal tube, using a linear differential pressure transducer (MP45 ± 100 cmH2O, Validyne, Northridge, Calif., USA). The pressure signal was sampled and digitized at 100 Hz (MP30, Biopac Systems, Santa Barbara, Calif., USA or Powerlab, AD Instruments, Bella Vista, Australia) for subsequent data analysis. Diaphragm function assessment was repeated at the end of the spontaneous breathing trial in the absence of sustained respiratory distress at the end of the spontaneous breathing trial (SpO2 < 90%, respiratory rate > 30/min for a least 5 min).
Cardiac function evaluation
Cardiac function was evaluated before conducting the spontaneous breathing trial by transthoracic echocardiography equipped with a cardiac probe (Sparq, Philips) performed by a fully trained and experienced operator (ER) and reviewed off-line by a second operator (MD). The following variables were obtained from the apical four-chamber view: left ventricular ejection fraction (visual estimation), early (E) and late (A) diastolic wave velocities at the mitral valve, tissue Doppler early (e’) wave velocity at the lateral mitral valve annulus, the deceleration time of the E wave, cardiac output as estimated by the stroke volume measured using the Doppler method applied at the left ventricular outflow tract, tricuspid annular plane systolic excursion in M-mode, peak systolic velocity at the lateral tricuspid annulus and systolic pulmonary arterial pressure estimated by the tricuspid regurgitation maximal velocity pressure gradient. Finally, colour Doppler mapping was used to detect the presence of significant mitral regurgitation and semiquantitatively assess its severity. The cardiac assessment was completed by a 12-lead electrocardiogram.
Lung ultrasound (Philips Sparq) was performed by a trained investigator, who acquired all images of the study. As previously described , a 2–4 MHz convex probe was used to scan the whole lung on both sides. The number of B-lines was counted on a rib short-axis scan between two ribs at each intercostal space of the upper and lower parts of the anterior, lateral, and posterior regions of the left and right chest wall (total of 12 areas). For a given region of interest, points were allocated according to the worst ultrasound pattern observed: presence of lung sliding with A lines or fewer than two isolated B lines = 0, moderate loss of lung aeration: multiple, well-defined B lines = 1, severe loss of lung aeration: multiple coalescent B lines = 2, lung consolidation = 3 . Skin was marked to apply the probe at precisely the same area before and after the spontaneous breathing trial. In addition to lung ultrasound, the presence of pleural effusion was also investigated and evaluated, as previously described (small, moderate, large) .
Patients eligible to the study underwent a spontaneous breathing trial. The spontaneous breathing trial was performed for 30 min (or less in case of clinical intolerance) with the pressure support level and positive end-expiratory pressure set to zero (so called 0–0 test), while FiO2 remained unchanged. This spontaneous breathing trial modality is similar to the “T-tube” and reflects equally the work of breathing after extubation . Spontaneous breathing trial failure was defined by the following criteria: respiratory rate ≥ 35 breaths/min or increase ≥ 50%, SpO2 ≤ 90% or PaO2 ≤ 50 mmHg (with FiO2 ≥ 50%), heart rate ≥ 140 bpm, de novo supraventricular or ventricular arrhythmia, systolic arterial pressure > 180 or < 90 mmHg, alteration of consciousness, and diaphoresis or any signs of respiratory distress . In the event of spontaneous breathing trial failure, the pre-spontaneous breathing trial settings were resumed.
After obtaining consent and before starting the spontaneous breathing trial, clinical and laboratory variables were collected. Electrocardiogram, echocardiography, lung ultrasound and diaphragm evaluation were performed. The spontaneous breathing trial was then started. At the end of the spontaneous breathing trial or sooner in case of clinical intolerance, electrocardiogram, echocardiography and lung ultrasound were repeated before resuming the initial ventilator settings.
Diaphragm dysfunction was defined by a Ptr,stim below 7 cmH2O [21,22,23]. Weaning-induced pulmonary oedema was defined in case of spontaneous breathing trial failure associated with at least one of the following two features:(1) echocardiographic diagnosis of pulmonary artery occlusion pressure elevation (E/A ratio above 0.95 and E/e’ ratio above 8.5 during the spontaneous breathing trial ) and/or (2) plasma protein concentration (5% increase in haemoglobin and/or plasma protein concentration) during the spontaneous breathing trial [25, 26].
Data were expressed as median (interquartile range) or number (%). Comparisons between spontaneous breathing trial success and spontaneous breathing trial failure were assessed with a Mann–Whitney U test. Baseline Ptr,stim were compared between patients with spontaneous breathing trial success and patients with spontaneous breathing trial failure associated with or without weaning-induced pulmonary oedema with a Kruskal–Wallis test. Baseline lung ultrasound score was compared between patients with spontaneous breathing trial success and patients with spontaneous breathing trial failure and the presence or absence of diaphragm dysfunction with a Kruskal–Wallis test. The correlation between Ptr,stim and lung ultrasound score was assessed with the non-parametric Spearman correlation. The proportion of patients with weaning-induced pulmonary oedema and with spontaneous breathing trial failure for another reason was compared with a Fisher’s exact test. A convenient sample size was defined on the basis of previous similar physiological investigations [25, 27, 28]. Regarding the characteristics of the population included, we assumed a spontaneous breathing trial success/failure rate of 50%/50% [1, 25] and planned to include a minimum of 25 patients per group. We also expected a dropout rate of approximately 10% due to technical problems, and therefore planned to enrol 55 patients. For all final comparisons, a p value less than or equal to 0.05 was considered to be statistically significant. Analyses were performed using Prism 8.3.0 software (GraphPad Software, USA).