Study Design
Data analysis was performed on the ReaSTOC database, which is an ongoing prospective physiological and biomedical signal data warehousing project including all consecutive patients admitted to our adult medical ICU (ClinicalTrials.gov identifier NCT02893462). A previous publication has described the design and conduct of the ReaSTOC study (37). The protocol #29BRC18.0080 was approved on November the 5th 2019 by the local ethics committee of our institution (Comité d’Ethique du CHRU de Brest IRB #2018CE.27). Written informed consent was waived according to French legislation (Law n°2012 − 300 March 5th 2012 also called “Loi Jardé” https://www.legifrance.gouv.fr/eli/jo/2012/3/6), in accordance with the ethical standards of our local human experimentation review board and with the Helsinki Declaration of 1975.
Population
All patients included within the database and under MV for more than 24 hours were considered eligible for weaning, according to a standardized protocol. A patient could be analyzed for several SBT during his ICU stay, if he had not experienced prior extubation; thus, only the first period of invasive MV was considered if endotracheal intubation was deemed necessary after an extubation failure.
Exclusion criteria were pregnancy, discontinuation of treatment (terminal extubation), participation decline by the patient or relatives, time of MV < 24 hours, self-extubation, patients under legal protection or without social security, or patients with missing cardiac variability data.
Patients were classified in three groups according to their ventilation weaning difficulty, as proposed by the 6th international consensus conference (3).
Group 1 – “simple weaning” included patients who successfully completed the first weaning test, followed immediately by extubation. In the literature, this group represents 69% of weaned patients and the prognosis is rather favorable with a 5% ICU mortality and a 12% in-hospital mortality.
Group 2 – “difficult weaning” included patients who achieved one to three SBT before extubation, within less than 7 days after the first attempt.
Group 3 – “prolonged weaning” included patients requiring more than 3 SBT, or less than 3 tests but within more than 7 days after the first attempt, before extubation. Within groups 2 and 3, ICU mortality is equal or higher than 25% (6,27).
Weaning protocol
According to a standardized protocol, established for years within our ICU (16), the ability of a patient to perform a SBT (Pre-Test) was assessed daily by the nursing team while considering the above criteria: no sedation, no or low dose of inotropic or vasopressor treatment, adapted response to simple orders, FiO2 < 50% and PEEP ≤ 5cmH2O. If these conditions are met, the SBT is initiated by a ventilator disconnection and the use of a T-piece, for a maximal 30 minutes duration, using an oxygen flow rate adjusted to a predetermined SpO2 target.
Failure of the SBT was defined by signs of poor clinical tolerance including : respiratory rate (RR) > 35 cycles/min, SpO2 < 90%, change of > 20% in heart rate (HR) or blood pressure, sweating, agitation or consciousness disorders. If any of these conditions occurred, SBT was immediately stopped and the patient was re-placed under mechanical ventilation. If none of these conditions were observed and if the patient had an effective cough, the SBT was considered successful and the patient was extubated.
Successful MV weaning was defined as extubation after a successful SBT, without reintubation within 72 hours.
Data collection
Demographic and physiological parameters, medical condition prior to ICU admission, length-of-stay and MV, as well as hemodynamic and respiratory data before, during and after the weaning test were collected for each patient. At the end of the weaning test, the decision whether or not to extubate was recorded and justified in the case of non-extubation or reintubation. Decisions to limit treatment or terminally extubate were specified and documented.
Weight balance was assessed at the time of SBT and considered as either negative (decrease in body weight since admission), neutral (same body weight as admission), or positive (increase in body weight since admission).
Body-Mass Index (BMI) was assessed on admission according to the actual patient’s height and weight. It was subsequently divided into 5 classes: low-weight-denutrition (BMI < 18.5 kg/m2), normal (BMI = 18.5–24.9 kg/m2), overweight (BMI = 25-29.9 kg/m2), obesity (BMI = 30-39.9 kg/m2), or morbid obesity (BMI > 40 kg/m2).
Continuous photoplethysmography (PPG) data were recorded 30-min prior to SBT, during SBT, and 30-min after extubation, at a 75 Hz frequency (Phillips Intellivue MP70 monitor) via the SYNaPSE extraction software (System for Nonintrusive Physiological Signal Exploration LTSI INSERM UMR 1099). Recording of PPG curves was used to perform HRV analysis, in the temporal (RMSSD, triangular index), frequency (VLF, LF, HF, LF/HF), and non-linear domains (SD1, SD2, SD2/SD1, Approximate - Sample and Shanon entropies). Such approach using plethysmogram has been validated within a prior study (37,38).
The respiratory parameter called Early-Warning Score Oxygen (EWSO2) was defined in the observational study by Viglino et al. (39) and its variations during the weaning test were collected.
Statistical analysis
In the absence of an a priori hypothesis, no number of subjects was calculated and all available data were used for analysis. Results are presented as mean and standard deviation, unless specified otherwise. The comparison of quantitative variables in each group was performed using Student or Wilcoxon tests according to distribution’s normality, and qualitative variables were compared using Khi-2 or Fischer tests. Outcome independent predictors were identified by logistic regression; performance of these predictors for a specific cut-off value was determined while calculating the area under the receiving operating characteristics curve (AUC for ROC). Youden's J statistic (also called Youden's index) is a single statistic that captures the performance of a dichotomous diagnostic test. Its value ranges from − 1 through 1 (inclusive), and has a zero value when a diagnostic test gives the same proportion of positive results for groups with and without the disease, i.e the test is useless. A value of 1 indicates that there are no false positives or false negatives, i.e. the test is perfect.
Probability of an event for MV weaning was determined using Kaplan-Meier analysis.
All analysis were performed using R++ (v1.5.03; Zebrys, Toulouse, France). A p-value equal or less than 0.05 was considered statistically significant.
Predictive models were developed by artificial intelligence and machine learning using the ZGPD model (TADA, MyDataModels, Biot, France), that uses evolutionary and genetic algorithms and symbolic regression. A model was obtained by search for associations between the variables among 40% of the iterations performed on the database. These associations of variables defining the model were subsequently tested on 30% of the data, and finally validated on the remaining 30% of the data.
The selection of the most relevant models among all those created was based on the global performance score of the model and its relevance to clinical practice. The global performance score reflects the strength of the model and is based on three statistical components: accuracy (ACC), Matthews correlation coefficient (MCC) and the area under the curve (AUC).