Liberation from mechanical ventilation involves three steps: weaning, readiness assessment, and extubation. Readiness is determined using clinical criteria such as improvement of the underlying condition, hemodynamic stability, and adequate respiratory effort. Successful extubation is defined as not requiring invasive support within 48 hours. Due to the complexity of ICU patients, various clinical parameters and multi-component scores have been developed to predict extubation success. This study aims to develop and evaluate a multi-component score, the Readiness for EXtubation score (REXs), to predict extubation readiness in ICU patients under invasive mechanical ventilation.

Background: Liberation from mechanical ventilation (MV) involves a three-step process; weaning, readiness testing, and extubation. Readiness testing uses objective clinical criteria to determine whether a patient is ready to begin weaning from MV. These criteria include improvement of the underlying indication for MV, hemodynamic stability, and the ability to initiate and sustain both adequate inspiration and expiration. Successfully extubation from invasive MV is a critical milestone in the recovery from severe respiratory failure and and is a clinical challenge for clinicians.

Spontaneous breathing trials (SBT) are conducted to evaluate a patient's readiness for ventilator liberation in the intensive care unit (ICU). Extubation is considered successful if invasive mechanical support is not required within 48 hours after the removal of the endotracheal tube. As the final step of the weaning process, the decision to extubate is typically guided by objective criteria demonstrating the patient's ability to sustain respiratory function without mechanical assistance. Considering the complex pathologies of intensive care patients, besides SBT many clinical parameters have been used as predictors of weaning and extubation. For this reason, different multi-component scales and scores have been developed.

The study protocol is designed and will be reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.

The aim of this study is to develop a multi-component Readiness for EXtubation score (REXs) that can predict extubation readiness and to analyze this score that can be applied to patients under invasive MV in the ICU.

Sample Size: The sample size was calculated as 427 using the Area Under ROC Curve in the ExPreS study. The total targeted sample size was accepted 470 patients with estimating that there would be a 10% dropout.

Screening and Admission: The daily screen will be performed between 8:00 and 10:00 a.m. by the clinician assigned to the unit each morning that the patient was on invasive mechanical ventilation. Patients meeting the criteria will be included in the study.

Data Collection and Anonymization: The data collected are part of routine clinical care, and the data will be anonymized. Clinicians will add anonymously the data they obtain to a created electronic case report form (e-CRF). Clinicians will be allowed to assign numbers to patients so that they can be distinguished by the clinicians who add them.

The dataset that constitute the e-CRF for each patient are; demographics (country, age, sex, BMI), ICU type, cause of ICU admission, number of comorbidities, weaning/extubation type, SBT duration, arterial blood gases (ABG: pH, PaCO2, PaO2), ventilation parameters (brand/model, FiO2, PEEP, ventilation index, RSBI, MVspont/MVtotal, PCF, P0.1, vital capacity, NIF, Cdyn), secretion type, agitation and sedation score (RASS), heart rate, hemoglobin, nutrition target percentage, ventilatory support after extubation, extubation failure (24,48 and 72 hrs), duration of invasive MV, ICU and hospital length of stay and mortality.

pH: It measures the acidity or alkalinity of blood and is crucial for assessing acid-base balance. Normal arterial pH is 7.35-7.45. A pH lower than 7.35 indicates acidosis, while a pH higher than 7.45 indicates alkalosis. Abnormal pH can indicate metabolic or respiratory disorders. The pH of the blood is crucial when assessing the success of weaning. The pH outside the normal range can indicate an imbalance in acid-base homeostasis, which may suggest inadequate respiratory function or metabolic disturbances that would make weaning unsafe. Maintaining a normal pH ensures that the patient's respiratory and metabolic systems can function without requiring excessive ventilatory support.

PaCO2: PaCO2 is a direct measure of ventilation. During weaning, a PaCO2 level within normal limits is needed for extubation success. Persistent hypercapnia during weaning suggests that the patient may be unable to sustain adequate ventilation on their own, leading to potential failure.

PaO2/FiO2: This ratio is a measure of the severity of hypoxemia. During weaning, a higher PaO2/FiO2 ratio suggests that the lungs are functioning well enough to support breathing without mechanical assistance. A low ratio suggests the need for continued mechanical ventilation.

PEEP: PEEP is used to prevent alveolar collapse and improve oxygenation. When weaning, reducing PEEP gradually helps assess whether the patient can maintain oxygenation without it. High levels of PEEP might be detrimental when reducing ventilatory support, as it can affect weaning success.

Ventilation Index (VI): The ventilation index (VI) combines respiratory rate and tidal volume, giving an overall assessment of ventilation efficiency. A low VI is favorable during weaning because it indicates that the patient is able to achieve adequate ventilation with minimal support. VI is calculated as VI="(PIP* PaCO2*RR)/1000".

Rapid Shallow Breathing Index (RSBI): The rapid shallow breathing index (RSBI), also known as the ratio of respiratory rate to tidal volume (RR/VT), is the most commonly used predictor of weaning success due to its simplicity and ease of interpretation. The clinical utility of the RSBI is emphasized in the 2007 international consensus guidelines for weaning from mechanical ventilation, the 2007 Brazilian consensus guidelines, and the 2013 Brazilian guidelines for mechanical ventilation, all of which recommend its use.

MVspont/MVtotal: This ratio reflects the proportion of ventilation that is spontaneous versus mechanical in one minute. A higher spontaneous ventilation (MVspont) relative to total ventilation (MVtotal) indicates that the patient is relying less on mechanical support, which may be reflect favorable for weaning.

Peak Cough Flow (PCF): PCF is an indicator of a patient's ability to clear secretions. Secretion retention is a key factor in weaning failure, as it increases respiratory load and is often linked to an ineffective cough. Evaluating cough strength in ICU patients can help predict weaning outcomes, as insufficient cough strength appears to be associated with higher in-hospital mortality. Consequently, assessing cough strength in intubated patients is increasingly being integrated into ICU extubation protocols. The subject is instructed to take a deep breath and cough as forcefully as possible. The clinician then freezes the ventilator screen and measures the maximal expiratory flow (L/min) from the flow curve. Clinicians can use the mechanical ventilator's algorithm if available. The average of three successful measurements will be taken.

P0.1: In a study on healthy subjects, Whitelaw et al. conducted random, brief end-expiratory occlusions using a specialized circuit during both resting and CO2 rebreathing. They observed that the decrease in airway pressure (Paw) within the first 100 milliseconds (0.1 s) of an occluded breath remained relatively constant, was consistent for each subject under different conditions, and correlated more strongly with end-tidal CO2 than with minute ventilation. They introduced this parameter as airway occlusion pressure Pocc, or P0.1. P0.1 reflects the inspiratory effort of the patient. It is used to assess the respiratory drive. Normal P0.1 suggests that the patient has adequate respiratory drive to maintain spontaneous breathing. Clinicians can use the mechanical ventilator's algorithm if available. The average of three successful measurements will be taken.

Vital Capacity (VC): Vital capacity (VC) reflects the total volume of air a person can exhale after a maximal inhalation. During weaning, a VC of at least 10-15 mL/kg is generally considered adequate for successful extubation. Vital capacity is measured by instructing patients to inhale deeply to their maximum capacity, followed by a forceful exhalation. The clinician then freezes the ventilator screen and measures maximal volume (mL) from the volume curve. Clinicians can use the mechanical ventilator's algorithm if available. The maximum of three successful measurements will be taken.

Negative Inspiratory Force (NIF): Negative inspiratory force (NIF), also referred to as maximum inspiratory pressure, reflects the maximal effort of the inspiratory muscles during inhalation against an obstructed airway. This index is used to evaluate respiratory muscle strength, with a value greater than - 30 cm H2O serving as a criterion for initiating the mechanical ventilator weaning process. After exhaling, the patient is given the command to take a deep breath. The clinician freezes the screen when the patient perform the fastest inhalation during expiratory hold maneuver. The clinician measures the minimum pressure from the pressure curve. Clinicians can use the mechanical ventilator's algorithm if available. The minimum of three successful measurements will be taken.

Cdyn: Dynamic compliance is a measure of lung and chest wall compliance during mechanical ventilation. High compliance typically indicates less stiff lungs, which is favorable during weaning. It is obtained by dividing the VT by the difference between PIP and PEEP.

Secretion: In mechanically ventilated patients, the primary mechanisms of secretion clearance-mucociliary transport and cough-are impaired. Major contributing factors to pulmonary secretion retention include the presence of an artificial airway, insufficient humidification of inspired gases, and limited mobility. Ineffective secretion clearance increases the risk of ventilator dependency and reintubation due to airway obstruction, aspiration, or infection.

Agitation/Sedation: Effective management of agitation and sedation is essential for successful weaning in mechanically ventilated patients, as both excessive sedation and agitation can impede the process. Over-sedation reduces respiratory drive, weakens respiratory muscles, prolongs ventilation, and increases the risk of ventilator-associated pneumonia. In contrast, agitation can heighten the work of breathing, increase the risk of self-extubation, and cause cardiovascular strain. The Richmond Agitation-Sedation Scale (RASS) is a 10-point tool that categorizes patient states, ranging from severe agitation (+4, combative) to deep sedation and unresponsiveness (-5), with 0 indicating a calm and alert state.

Heart rate: Heart rate is an important indicator of cardiovascular stability during weaning. A significant increase in heart rate during mechanical ventilation or SBTs can signal distress, leading to the suspension of the weaning attempt.

Hemoglobin: The impact of hemoglobin levels on weaning outcomes in mechanically ventilated patients remains controversial, with limited data, particularly for those experiencing difficult weaning. Patients with weaning difficulties may benefit more from higher hemoglobin levels than those in the early stages of respiratory failure, as sufficient hemoglobin is essential for adequate oxygen delivery during the weaning process. Lower hemoglobin levels reduce arterial oxygen content, impair oxygen delivery, and increase respiratory muscle workload, potentially hindering successful weaning.

%Nutrition Target: Adequate nutrition is essential for survival and reducing hospital stay in critically ill patients, as it supports muscle strength, including respiratory muscles, which is crucial for successful weaning from mechanical ventilation. Malnutrition can impair weaning by weakening respiratory function. To guide evidence-based nutritional therapy, several global guidelines have been published. The American Society for Parenteral and Enteral Nutrition (ASPEN) and the Society of Critical Care Medicine (SCCM) recommend energy intake of 25-30 kcal/kg/day and protein intake of 1.2-2.0 g/kg/day, while the European Society for Parenteral and Enteral Nutrition (ESPEN) suggests 20-25 kcal/kg/day with 1.3 g/kg of protein equivalents per day.

Statistical Analysis: Statistical analysis will be performed using IBM SPSS Statistics 26 (IBM Corp., Armonk, NY, USA). Categorical variables will be summarized as numbers (n) and frequencies (%). The Fisher's exact test will be applied for 2×2 contingency tables, and the Chi-square test will be used for all other contingencies to evaluate associations between clinical/demographic characteristics and extubation success or failure. For continuous variables, the Shapiro-Wilk test will be used to assess normality of distribution. Normally distributed variables will be summarized as means (± standard deviation), while non-normally distributed variables will be expressed as medians (with interquartile range). The independent samples Student's t-test will be employed to compare groups for normally distributed variables, and the Mann-Whitney U test will be used for non-normally distributed variables. All parameters with a p-value < 0.4 in group comparisons (extubation success vs. failure) will be further investigated using univariable logistic regression analysis to assess their association with extubation outcome; odds ratios (OR) and 95% confidence intervals (CI) will be calculated. Receiver operating characteristic (ROC) analysis will be performed to evaluate the predictive value of each parameter. The cutoff values optimizing sensitivity and specificity will be determined using the Youden Index. The REXs cutoffs used in comparisons will be established based on the Youden Index. Finally, REXs cutoff values indicating low, moderate, and high probability of extubation risk will be determined.

Inclusion Criteria:

- Patients who are in the weaning process from mechanical ventilation after being connected to invasive mechanical ventilation in the intensive care unit.

Exclusion Criteria:

• Patients without legal guardian consent.
• Tracheostomized patients.
• Patients enrolled in other studies.
• Individuals with diaphragmatic pacers.
• Pregnant patients.

Patients on mechanical ventilation admitted to the Intensive Care Unit

During the publication phase of the study, all data will be anonymized and made available as supplementary material accompanying the published article.