ONLINE DATA SUPPLEMENT. A Multicenter Randomized Trial of Computer-driven Protocolized Weaning from

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1 ONLINE DATA SUPPLEMENT A Multicenter Randomized Trial of Computer-driven Protocolized Weaning from Mechanical Ventilation François Lellouche, Jordi Mancebo, Philippe Jolliet, Jean Roeseler, Frédérique Schortgen, Michel Dojat, Belen Cabello, Lila Bouadma, Pablo Rodriguez, Salvatore Maggiore, Marc Reynaert, Stefan Mersmann, and Laurent Brochard Contents: Complete Methods Supplementary results Information on the computer-driven ventilation References Figure legend Tables Figure Appendix: Weaning guidelines (control group)

2 Complete Methods Protocol Patients This study was conducted in five university medico-surgical intensive care units: Créteil (France), Barcelona (Spain), Geneva (Switzerland), Brussels (Belgium), and Paris (France). Two ventilators equipped with the computer-driven weaning system (Evita Weaning system, Dräger Evita 4, Lübeck, Germany) were available at each center. These ventilators were well known to the nurses and healthcare workers. Each center could include 40 patients at the most, to homogenize the distribution of inclusions. Each center obtained approval of the study from the ethics committee. Signed informed consent was obtained from each patient or next of kin. Patients on mechanical ventilation for at least 24 hours and ventilated with an assisted mode (assist-control, intermittent mandatory ventilation with pressure support, or pressure-support ventilation) were considered for enrolment in the study. Enrolment criteria required age younger than 18 or older than 85 years, and absence of the following: do-not-resuscitate order, expected poor short-term prognosis, tracheostomy, and cardiac arrest with a poor neurological prognosis, and pregnancy. Patients could be enrolled at an early stage, before usual criteria for weaning readiness were present, when they reached the following criteria: plateau pressure below 30 cm of water with a tidal volume of 8 ml per kilogram of body weight on assist-control ventilation, positive end-expiratory pressure level lower than or equal to 8 cm of water, a ratio of partial pressure of arterial oxygen over the fraction of inspired oxygen of 150 or higher or arterial oxygen saturation higher than 90 percent with a fraction of inspired oxygen lower than or equal to 50 percent, epinephrine or norepinephrine requirement no greater than 1 mg per hour, body temperature above 36 C and below 39 C, and stable neurological status with a Glasgow Coma Scale above 4 with little or no sedation.

3 Study protocol Data on all ventilated patients in the study centers were recorded daily. As shown in figure E1, as soon as the inclusion criteria were met and after informed consent was obtained, a pre-inclusion test with a level of pressure support of 15 cm of water or higher, but an inspiratory pressure no greater than 30 cm of water (pressure-support level plus positive end-expiratory pressure) was performed to evaluate patient tolerance of this ventilation mode; the test was repeated daily until positive. The test could be stopped before 30 minutes if the patient showed evidence of hemodynamic or respiratory distress (heart rate increase by more than 30 beats per minute as compared to baseline, systolic arterial pressure lower than 80 mm Hg or higher than 160 mm Hg, or respiratory rate higher than 40 breaths per minute). The test was considered positive when, after 30 minutes, the patient remained clinically stable with a respiratory rate lower than 35 breaths per minute and an expiratory tidal volume of at least 6 ml per kilogram of body weight within the authorized pressure-support range, and with an arterial oxygen saturation no lower than 90 percent when the fraction of inspired oxygen was no greater than 50 percent. When the pressure-support test was positive, the patient was assigned at random either to the computer-driven weaning group or to the control group. Patients assigned to the computer-driven weaning were connected to an Evita 4 equipped with the system. In the usual care arm, ventilation and weaning was conducted according to the usual practice introduced several years ago in each unit. Written guidelines were available in four of the five units, and educational sessions were performed on a regular basis. In the control group, the patients were returned to the ventilation mode used before randomization. Every effort was made to minimize potential study-induced changes in usual ventilation and weaning procedures in the control arm. We choose not to assess the protocol compliance in order not to influence practice.

4 A random allocation sequence was generated by a computer by blocks of six. Randomization was concealed and generated by an electronic-mail system. Randomization was also stratified by center, and also on presence of a central neurological disorder, a chronic obstructive pulmonary disease, or absence of both factors. When both factors were present, the neurological disorder was given priority. This stratification was designed to ensure even distribution of patients with these three factors between the two treatment groups. The randomization process was centralized. For subsequent changes in ventilation mode, the same criteria were used in the two groups. Thus, controlled or assist-control ventilation could be used when a procedure requiring sedation was performed (surgery or invasive diagnostic or therapeutic procedure) or when the clinical status deteriorated, with a respiratory rate higher than 40 breaths per minutes, clinical discomfort, and hypoxemia (need for a fraction of inspired oxygen higher than 60 percent and need for positive end-expiratory pressure higher than 8 cm of water to obtain an arterial oxygen saturation higher than 90 percent). In both groups, patients who were switched to controlled ventilation were evaluated daily with pressure-support tests. When the pressure support test became positive again, the patient was again ventilated with mode assigned by the randomization process throughout the rest of the time on ventilation. In the control arm, the following weaning principles were used in the participating centers (see specific guidelines used by each center) - At least daily screening for criteria to perform a SBT (at least twice daily in two centers) - SBT performed with T-piece or minimal PS support (between 7 and 12 cmh 2 O, the latter if HME was used), with criteria of success or failure. The duration of SBT was 30 to 120 minutes

5 - Standardized extubation criteria were used in all study patients: after succeeding a spontaneous breathing trial, the following criteria had to be present in both groups: 1. Ratio of partial pressure of arterial oxygen over fraction of inspired oxygen higher than 200 mm Hg 2. Positive end-expiratory no greater than 5 cm of water 3. In patients with abundant airway secretions, efficient cough as assessed with specific scores recommended 4. Epinephrine or norepinephrine infusion rate no greater than 0.5 mg per hour 5. Glasgow Coma Scale score greater than 8 6. Little or no sedation Clinical criteria required for extubation (in all centers) The following recommendations about clinical criteria for extubation were used by all study centers: 1-Respiratory requirements - PaO 2 /FiO 2 >200 and with PEEP < 5cmH 2 O - In the computer-driven weaning group: extubation when recommended by the computer-driven system. - In the control group: extubation when a spontaneous breathing test is successful. In both groups, in case of abundant secretions, preserved coughing that is clearly audible (spontaneously or during suctioning) is required (E1, E2). 2-Hemodynamic requirements: - In both groups, hemodynamic stability with epinephrine and norepinephrine requirements no greater than 0.5 mg/h 3-Neurological requirements:

6 - in both groups, the Glasgow Coma Scale must be > 8 - sedation must be stopped or minimal; analgesics can be maintained as needed to keep the patient comfortable 4-Other No procedure necessitating sedation (transesophageal echocardiography, gastrointestinal endoscopy) or surgery is planned. Dialysis, body temperature between 36 C and 39 C, and anemia in the absence of active bleeding do not contraindicate extubation. In case of respiratory failure after extubation, noninvasive ventilation could be used if deemed appropriate by the physician. In patients who required reintubation, the usual weaning protocol was used subsequently. In the control group, ventilatory settings were chosen by the physician in charge of the patient, and no recommendations were made regarding the type of ventilator nor the ventilatory mode except that closed-loop modalities were not allowed. Tracheostomy was possible when required but in both groups was to be performed no sooner than 10 days after admission to the intensive care unit. In both groups, sedation was at the discretion of the physician. No changes in usual sedation procedures were introduced during this study.

7 Follow-up The patients were followed until discharged home from the hospital. Patient characteristics recorded for the study included the Simplified Acute Physiologic Score II (E3), the Logistic Organ Dysfunction score (E4), and the McCabe score (E5). At inclusion, the following data were recorded: ventilatory parameters and arterial blood gases, duration of invasive mechanical ventilation before inclusion, presence of comorbidities, hemodynamic parameters, body temperature. The following were recorded every day: ventilatory mode; maximal and minimal level of pressure support, positive end-expiratory pressure, and oxygen fraction; date of extubation; and intensive care unit complications including infections and pneumonia, thromboembolic disease, gastro-intestinal tract diseases, ischemic heart disease, and weaning complications (failure being defined as reintubation within 72 hours, self-extubation, and laryngeal dyspnea with stridor). Use of noninvasive ventilation after extubation and tracheostomy were also noted. Amounts of sedative agents, neuromuscular blockers, and corticosteroids used in each patient were recorded before and after inclusion until the first extubation. Drugs used for sedation and analgesia were midazolam, fentanyl, propofol, and morphine. The daily dosage of each drug was collected from the intubation day to the day of first extubation, and the mean daily dosages of each drug in each patient before and after inclusion were calculated. For the statistical analysis we converted mean propofol and morphine daily dosages to midazolam and fentanyl equivalents. We considered that 1 mg of midazolam was equivalent to 42 mg of propofol (according to Higgings et al. who achieved similar degrees of sedation with 0.3±0.002 µg/kg/min of midazolam and 12.6±1.45 µg/kg/min in patients recovering from scheduled cardiac surgery (E6)). For opioids, 20 µg of fentanyl was considered equivalent to 1 mg of morphine (E7). All interruptions of the computer-driven weaning system were recorded, as well as technical problems.

8 End-points The primary end-points were the time to successful extubation, defined as the time from inclusion until successful extubation (followed by 72 hours without ventilator support) and the total duration of mechanical ventilation. In patients with tracheostomy, the first day of full separation from the ventilator followed by 72 hours of spontaneous unassisted breathing was taken as the day of successful separation (i.e., the time of decannulation was not considered). Secondary end-points were the time to first extubation, the total duration of ventilatory support, length of intensive care unit and hospital length of stay, number of intensive care unit complications, number of nosocomial pneumonia episodes, complications of extubation, intensive care unit mortality, and hospital mortality. Principles of the computer-driven ventilation The working principles of the computer-driven ventilation have been explained elsewhere (E8- E12). In brief, a knowledge-based system is embedded into a ventilator set on pressure-support ventilation and adapts the level of pressure support based on a continuous evaluation of the patient s respiratory needs, in order to keep the patient within a so-called comfort zone. Comfort was defined primarily as a respiratory rate between 15 and 30 breaths per minute (up to 34 in patients with neurological disease), a tidal volume above a minimum threshold (250 ml if weight is less than 55 kilograms and 300 ml otherwise), and end-tidal CO 2 level below a maximum threshold (55 mm Hg, and 65 mm Hg in patients with chronic obstructive pulmonary disease). To reach these targets, the level of inspiratory assistance in pressure-support ventilation is intermittently adapted by the system (E8, E11) by steps of 2 to 4 cm of water, taking into account the previous

9 breathing-pattern history since the patient was connected to the system. In addition, the system automatically tries to reduce the pressure support down to a minimal level. At this point, tolerance to spontaneous breathing with a low pressure support level is assessed. If the patient successfully passes this test, a message recommending separation from the ventilator is displayed on the screen. Several complementary rules allow the system to manage transient instabilities, suctioning, or hazardous situations. The fraction of inspired oxygen and the level of positive end-expiratory pressure are not managed by the system. The physician in charge of the patient had to set these parameters and could also modify the level of pressure support at any time by changing the ventilator settings. Statistical analysis To calculate the number of patients to be included, we reviewed previous studies looking at weaning from mechanical ventilation. The median duration of weaning varied across studies from 3.5 to 3.9 days (E13), 3 to 4 days (E14), and 5.7, 3.7 to 9.3 days (E15). The present study aimed at enrolling patients at an early stage, before they met usual criteria for weaning initiation, and at excluding patients who needed ventilation for less than 24 hours. Therefore, the duration of the socalled weaning time was expected to range from 5 to 8 days. To show a reduction in the weaning time by two days (from 7 to 5 days, 30 percent) with an expected standard deviation of 5 days, a power of 0.80, and an α risk of 0.05, 75 patients were needed in each arm. No interim analysis was planned. The analysis was performed in the two groups as treated. Results are given as medians (25 th -75 th interquartile ranges). Proportions and rates were compared using the chi-square test or the Fisher exact test when required. The Mann-Whitney U test was used to analyze mechanical ventilation durations or length of stay. The cumulative probability of remaining on mechanical

10 ventilation was analysed by the Kaplan-Meier method and a log-rank test was used to assess differences between groups. For this purpose, we considered that patients were successfully extubated if they were able to remain on spontaneous breathing for at least 72 hours without being reintubated. P values smaller than 0.05 were considered significant. All the P values were twosided. Statistical analysis was performed with SPSS software, version

11 Supplementary results Results of the main end point expressed as mean ± SD (Computer-driven weaning vs Usual weaning): Weaning time: 4.4 ± 4.7 vs 8.3 ± 15.4 days Duration of mechanical ventilation: 8.7 ± 7.6 vs 14.0 ± 18.9 days ICU length of stay: 17.5 ± 18.6 vs 24.3 ± 21.2 days Results concerning the compliance to the weaning guidelines in the control group: The compliance to weaning guidelines can be estimated indirectly from: - The high compliance to the modes of ventilation recommended during weaning (Table E2) - We also tried to estimate the proportion of SBTs conducted divided by SBT Eligible Days as follows: Performed SBT: 121 episodes of SBTs performed on T-piece were performed in the control group; unfortunately this does not include other SBT techniques (PSV+/-CPAP...) SBT eligible days: We hypothesized that an indication to perform SBT existed in patients ventilated with a weaning mode (PSV or SIMV), apart from day 1 (where patients were supposed to be included at an early stage) and except when FiO2 was at or above 50%. In the control group, weaning modes (PSV and SIMV) were used during 414 days (392+22). Subtracting day 1 and days at or above 50% or FiO2, we could estimate that T-piece trials were performed 51% of the days of ventilation with PSV or SIMV at FiO2 below 50%.This could indicate that weaning was suboptimal if one assumes that other screening criteria were present. However, because only the SBTs performed with T-piece were recorded, this ratio may be underestimated.

12 Results concerning tracheostomy: Tracheostomy was delayed in both groups as recommended by protocol: the median time of tracheostomy (intubation to tracheostomy) was 16 (25-75 percentiles: 10-21) in the automatic weaning group and 23 (25-75 percentiles: 18-43) in the control group.

13 Information on the computer-driven ventilation The computer-driven ventilation (E8-E12, E16-E19) This is a closed-loop knowledge-based system used for ventilator management in the intensive care unit and specifically designed to improve the weaning process. It is dedicated at managing pressure-support ventilation (PSV), with or without positive end-expiratory pressure (PEEP). The knowledge corpus used to develop this computer-driven ventilation came mainly from the scientific literature and from a group of intensivists, physiologists, and scientists at the Henri Mondor Teaching Hospital (Créteil, France) (E8-E11). In the present study, the system was used to drive an Evita 4 ventilator (Dräger, Lübeck, Germany). The knowledge-based system interprets clinical data in real-time and controls the mechanical assistance provided to the patient with a 24-hour per day management,. The system develops a therapeutic strategy that gradually reduces the level of assistance, at a pace depending on the patient s tolerance, and evaluates the patient s ability to breathe without mechanical assistance. The system uses three main parameters acquired from the ventilator: respiratory rate (RR), which is the main driver of the ventilation, tidal volume (Vt), and end-tidal partial pressure of CO 2 (PETCO 2 ). It controls the level of pressure above PEEP during ventilation in PSV mode. The knowledge-based system has two main functions: 1) automatic adaptation of the assistance and 2) development and application of a weaning strategy. The system implemented on a commercial ventilator works through the same principles and rules than in the most recent studies (E9-E11). The new rules introduced in the system are based on recent published data concerning the effect of humidification devices during assisted mechanical ventilation and the results of a pilot study (E19):

14 - Rules concerning the lower pressure support level according to the humidification device (20-24): to compensate for HME dead space the level of pressure support has to be increased in comparison with heated humidifiers. The estimated increased need varied among the studies from 5 to 10 cmh 2 O. - Another rule was introduced following clinical evaluation: the possibility for the system to decrease the level of minimum pressure support below the predefined value, down to 5 cmh 2 O. In some cases (patients with near normal respiratory mechanics), the predefined minimum PS was too high, leading to overassistance of the patient and a ventilatory diagnosis of hyperventilation (respiratory rate below 15/min and ETCO2 below 55 mmhg) which prevented the system from doing the automatic spontaneous breathing test. Indeed, this test can be performed only if the patient has a ventilatory diagnosis of normal ventilation. 1) Automatic adaptation of assistance The general strategy used is as follows: 1) The knowledge-based system tries to keep the patient in a situation of comfort defined as follows. The system allows the patient breathing freely with a respiratory rate between 15 (RRmin) and 30 breaths per minute (34 in case of neurological disease) (RRmax), a tidal volume above a minimum threshold (VtMin=250 ml if weight is less than 55 kg and VtMin=300 ml otherwise) and a PETCO 2 below a maximum threshold (max PETCO 2 =55 mmhg, or max PETCO 2 =65 mmhg in patients with chronic obstructive pulmonary disease). When these criteria are met, the knowledge-based system diagnoses Normal ventilation; 2) To reach the above-defined targets, the level of pressure in PSV is periodically adapted by the computer-driven ventilation, being increased in case of RR above RRmax and lowered in case of RR below RRmin and below PETCO 2 thresholds.

15 The algorithm is based on a ventilatory diagnosis defined from values of respiratory rate, tidal volume and end-tidal CO 2 averaged every 2 to 5 minutes. The pace of display for this ventilatory diagnosis (2 to 5 minutes), the magnitude of the pressure changes and the duration of the spontaneous breathing trial depends on previous breathing pattern history since the patient was connected to the system: contingent on the first level of pressure support used (higher or lower than 15 cmh 2 O) at the time of connection, the duration of the spontaneous breathing trials lasts from 30 minutes to 2 hours. The magnitude of the pressure decrement (2 or 4 cmh 2 O) is also based on the previous breathing-pattern history. The required duration of stability before assistance is decreased depends on the level of pressure delivered to the patient, which reflects disease severity. The system tolerates transient instabilities. 2) Automatic weaning strategy In addition to the above-mentioned strategy designed to maintain the patient in a situation of comfort, the system tries to reduce the pressure level automatically by steps of 2 to 4 cm H 2 O, taking into account the breathing pattern history. When a minimal level of PSV is reached, an observation period is carried out: if tolerance is good, a recommendation for separation from the ventilator is displayed on the computer screen. This process is equivalent to a spontaneous breathing trial with results given to the clinician. When the computer-driven ventilation recommends separation (the patient is ready for separation ), extubation can be envisaged. If extubation is delayed for any reason, however, there are several options, the ventilator will continue monitoring and ventilatory adaptation according on pre-defined rules. The minimum level of pressure support to be used during the spontaneous breathing trial has been determined from previous physiological studies (E23, E25). Moreover, to compensate for

16 Heat and Moisture Exchanger (HME) dead space the level of pressure support has to be increased again for 5 to 10 cmh 2 O in comparison with Heated Humidifier (HH). This was based on recent studies comparing effects of humidification device use on breathing pattern and work of breathing (E20-E24). The minimum levels threshold also depends on the tracheal access (tracheostomy versus oral or nasal intubation). These conditions must be entered in the system by the clinician before starting a session. Other pieces of information are necessary to start the session: presence of specific clinical condition (chronic obstructive pulmonary disease, central neurological disease), weight of the patient. The minimal levels used for the test are as follows: Tracheostomy + HH =5 cmh 2 O Tracheostomy + HME =9 cmh 2 O Endotracheal intubation + HH =7 cmh 2 O Endotracheal intubation + HME =12 cmh 2 O To avoid overassistance, the level of pressure support could be decreased down to a minimum of 5 cmh 2 O in case of hyperventilation with such levels of pressure support. As soon as the patient reaches the minimum level of pressure support with a ventilatory diagnosis of normal ventilation, the spontaneous breathing trial begins automatically and is called by the system observation period : its duration varies from 30 minutes to 2 hours according to previous breathing pattern history. If the patient remains stable (i.e., if the level of pressure support remains stable at the minimum level, with a normal ventilation ) during all the observational period, the following message is displayed on the screen: the patient does not need ventilatory support, and the clinician has to check other weaning and extubation criteria (haemodynamic, neurology, ability to protect upper airway ).

17 If the patient is not stable, the pressure support increased according to the ventilatory diagnosis (example: increase of the level of pressure support of 2 cmh 2 O in case of diagnosis of tachypnea, or of 4 cmh 2 O in case of severe tachypnea with thresholds defining upon patient category: COPD, neurological disorder or none of these factors). If the pressure support is increased by the system, the observation period (spontaneous breathing trial) ends. Then, if the pressure support goes back to the minimal value, an observational period occurs again, till the patient complete this period with normal ventilation. The level of PEEP must be lower or equal to 5 cmh 2 O to start the observational period (the spontaneous breathing trial). This rule avoids weaning patients needing high levels of PEEP. 3) What is needed before starting? To ventilate the patient correctly, the computer needs information, which must be entered by the user before starting ventilation with the computer-driven ventilation. This information includes body weight, whether the patient has chronic CO 2 retention and/or COPD, the route of tracheal intubation (endotracheal intubation or tracheotomy) and whether a heat-and-moisture exchanger ( artificial nose ) is used for humidification. The first two questions are used to set the limits for Vt and PETCO 2, whereas the other two serve to determine the minimal level of pressure used in the final step of the weaning strategy (spontaneous breathing trial). 4) What can be modified during the ventilation phase? At any time and for any reason, the user can take control of the ventilator by switching back to a conventional mode. This erases the ventilation history recorded by the system. During ventilation with the computer-driven ventilation, all settings are available to the user (FiO 2, trigger, PEEP and alarm limits). All ventilator alarms remain available throughout the

18 period of automatic control. Specific knowledge is introduced to manage alarming situations such as apnea and disconnection. Endotracheal suctioning can be performed as often as required without any special maneuver on the computer. Several rules allow the system to recognize disconnection and suctioning. This recognition induces several actions. Last, the clinician can modify the level of pressure support during ventilation by the system but this resets ventilation with this new level. Examples of rules used to manage the level of pressure: When the respiratory rate is above 30 breaths/min (RRMax) (34 in case of neurological disease) and PETCO 2 and tidal volume are acceptable, the knowledge-based system diagnoses Tachypnea and increases the assistance by 2 cm H 2 O. When the respiratory rate exceeds 36 breaths/min, the knowledge-based system diagnoses Severe Tachypnea and increases the pressure support by 4 cm H 2 O. When the respiratory rate is less than 15 breaths/min (RRMin), with no increase in PETCO 2, Hyperventilation is diagnosed and pressure support is decreased by 4 cm H 2 O. When tidal volume or PETCO 2 are outside the defined range (Insufficient Ventilation), pressure support is increased by 2 cm H 2 O. Examples of special actions: Often, suctioning is performed in response to the presence of secretions that may have increased the pressure needs. If assistance was increased prior to disconnection, the system recognizing disconnection replaces the low level of assistance immediately after reconnection.

19 REFERENCES E1. Coplin, W. M., Pierson, D. J., Cooley, K. D., Newell, D. W., and Rubenfeld, G. D. Implications of extubation delay in brain-injured patients meeting standard weaning criteria. Am J Respir Crit Care Med : E2. Khamiees, M., Raju, P., DeGirolamo, A., Amoateng-Adjepong, Y., and Manthous, C. A. Predictors of extubation outcome in patients who have successfully completed a spontaneous breathing trial. Chest : E3. Le Gall, J. R., Lemeshow, S., and Saulnier, F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. Jama : E4. Le Gall, J. R., Klar, J., Lemeshow, S., Saulnier, F., Alberti, C., Artigas, A., and Teres, D. The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. Jama : E5. McCabe, W. R., and Jackson, G. G. Gram-negative bacteriemia: I.Etiology and ecology. Archives of Internal Medicine : E6. Higgins, T. L., Yared, J. P., Estafanous, F. G., Coyle, J. P., Ko, H. K., and Goodale, D. B. Propofol versus midazolam for intensive care unit sedation after coronary artery bypass grafting. Crit Care Med : E7. Jacobi, J., Fraser, G. L., Coursin, D. B., Riker, R. R., Fontaine, D., Wittbrodt, E. T., Chalfin, D. B., Masica, M. F., Bjerke, H. S., Coplin, W. M., et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med : E8. Dojat, M., Brochard, L., Lemaire, F., and Harf, A. A knowledge-based system for assisted ventilation of patients in intensive care units. Int J Clin Monit Comput :

20 E9. Dojat, M., Harf, A., Touchard, D., Laforest, M., Lemaire, F., and Brochard, L. Evaluation of a knowledge-based system providing ventilatory management and decision for extubation. Am J Respir Crit Care Med : E10. Dojat, M., Pachet, F., Guessoum, Z., Touchard, D., Harf, A., and Brochard, L. NeoGanesh: a working system for the automated control of assisted ventilation in ICUs. Artif Intell Med : E11. Dojat, M., Harf, A., Touchard, D., Lemaire, F., and Brochard, L. Clinical evaluation of a computer-controlled pressure support mode. Am J Respir Crit Care Med : E12. Dojat, M., and Brochard, L. Knowledge-based systems for automatic ventilatory management. Respir Care Clin N Am :379-96, viii. E13. Saura, P., Blanch, L., Mestre, J., Valles, J., Artigas, A., and Fernandez, R. Clinical consequences of the implementation of a weaning protocol. Intensive Care Med : E14. Esteban, A., Frutos, F., Tobin, M. J., Alia, I., Solsona, J. F., Valverdu, I., Fernandez, R., de la Cal, M. A., Benito, S., Tomas, R., et al. A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. N Engl J Med : E15. Brochard, L., Rauss, A., Benito, S., Conti, G., Mancebo, J., Rekik, N., Gasparetto, A., and Lemaire, F. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med : E16. Dojat, M., and Pachet, F. Effective domain-dependent reuse in medical knowledge bases. Computer and Biomedical Research : E17. Dojat, M., and Sayettat, C. A realistic model for temporal reasoning in real-time patient monitoring. Applied Artificial Intelligence 1996:

21 E18. Chittaro, L., and Dojat, M. Using a general theory of time and change in patient monitoring: experiment and evaluation. Comput Biol Med : E19. Bouadma, L., Lellouche, F., Cabello, B., Porta, V., Deye, N., Levy, S., Mancebo, J., and Brochard, L. Use of an automated control system to adapt the level of pressure support and manage weaning. Intensive Care Med :S23. E20. Pelosi, P., Solca, M., Ravagnan, I., Tubiolo, D., Ferrario, L., and Gattinoni, L. Effects of heat and moisture exchangers on minute ventilation, ventilatory drive, and work of breathing during pressure-support ventilation in acute respiratory failure. Crit Care Med : E21. Iotti, G. A., Olivei, M. C., and Braschi, A. Mechanical effects of heat-moisture exchangers in ventilated patients. Crit Care :R E22. Campbell, R. S., Davis, K., Jr., Johannigman, J. A., and Branson, R. D. The effects of passive humidifier dead space on respiratory variables in paralyzed and spontaneously breathing patients. Respir Care : E23. Brochard, L., Rua, F., Lorino, H., Lemaire, F., and Harf, A. Inspiratory pressure support compensates for the additional work of breathing caused by the endotracheal tube. Anesthesiology : E24. Girault, C., Breton, L., Richard, J. C., Tamion, F., Vandelet, P., Aboab, J., Leroy, J., and Bonmarchand, G. Mechanical effects of airway humidification devices in difficult to wean patients. Crit Care Med : E25. Diehl, J. L., El Atrous, S., Touchard, D., Lemaire, F., and Brochard, L. Changes in the work of breathing induced by tracheotomy in ventilator-dependent patients. Am J Respir Crit Care Med :383-8.

22 FIGURE LEGEND: Figure E1: This schema shows the phases that preceded and followed study inclusion. In patients who met the inclusion criteria, informed consent was sought from the patient or family. Daily preinclusion tests were performed ( pressure-support test ), and randomization occurred when the test was positive. Patients were then weaned from mechanical ventilation either with the computerdriven weaning (CDW) or according to local protocols. In patients with clinical deterioration, the patients were ventilated in assist-control mode and reassessed daily with a pressure support test. When the pressure support test was again positive, the patient was returned to the ventilation mode assigned by randomization, which was continued throughout the rest of the time on ventilation.

23 Figure E1: Daily evaluation after 24 h of mechanical ventilation INCLUSION CRITERIA = PRE-INCLUSION PHASE Daily Pressure-support test _ Informed consent signed + Clinical worsening, sedation >24h Assist-Control Ventilation = INCLUSION PHASE RANDOMIZATION + + CDW Usual Weaning Weaning Time EXTUBATION (or SB in case of tracheostomy) +/- NIV Ventilatory support stopped for 72 h

24 Table E1 Comparisons of outcomes for ICU survivors in the two groups Table E1 COMPARISON OF OUTCOMES FOR ICU SURVIVORS IN THE TWO GROUPS OUTCOME median no. of days (interquartile ranges) CDW group Survived (N=58) Usual weaning group Survived (N=54) P Value Time to first extubation 2.00 ( ) First period of mechanical ventilation duration 5.00 ( ) 3.00 ( ) ( ) 0.01 Time to successful extubation * 2.00 ( ) 4.00 ( ) Duration of mechanical ventilation * 6.00 ( ) ( ) CDW denotes computer-driven weaning. The time to first extubation is the time from study inclusion (first positive pressure-support test) to first extubation. * The time to successful extubation is the time from study inclusion (first positive pressure-support test) to last successful extubation. Duration of mechanical ventilation is the time from intubation to first or last successful extubation (total). Data are expressed as medians (25 th -75 th interquartile range).

25 Table E2. This table shows the modes of ventilation (expressed in days of ventilation and in percentage of the total days of ventilation after inclusion) used after study inclusion in each study group. The number of T-piece trials performed in each group is also displayed. TABLE E2 VENTILATION MODES USED.* VENTILATION MODES USED AFTER INCLUSION CDW group (N = 74) Usual weaning group (N = 70) P Value Days on PSV (%) 293 (75.5) 398 (71.5) Days on ACV (%) 64 (16.5) 134 (24.5) Days on SIMV (%) 31 (8.0) 22 (4.0) number of T-tube trials CDW denotes computer-driven weaning, PSV pressure support ventilation, ACV assist controlled ventilation, SIMV synchronized intermittent mandatory ventilation

26 Table E3 This table shows the average daily doses of sedatives and opioids according to prescription preferences in each centers. Only Brussels used propofol as main sedative, the other centers used midazolam. Creteil, Geneva and Paris used fentanyl as opioid, Barcelona used morphine and Brussels used sufentanyl. TABLE E3: AVERAGE DAILY DOSE OF SEDATIVES AND OPIOIDS SEDATIVES CDW group Usual weaning group P value Creteil, Barcelona, Geneva and Paris (n=45) (n=45) Midazolam (mg/day) Before inclusion After inclusion Propofol (mg/day) Before inclusion After inclusion 31 (0-61) 0 (0-3) 0 (0-95) 0 (0-2) 34 (5-55) 0 (0-0) 0 (0-341) 0 (0-5) Brussels (n=22) (n=18) Midazolam (mg/day) Before inclusion After inclusion Propofol (mg/day) Before inclusion After inclusion Drug not used 1804 ( ) 0 (0-65) Drug not used 1583 ( ) 121 (0-363) OPIOIDS Barcelona (n=18) (n=14) Morphine (mg/day) Before inclusion After inclusion Fentanyl (µg/day) Before inclusion After inclusion Sufentanyl (µg/day) Before inclusion After inclusion 12 (2-19) 1 (0-6) Drug not used Drug not used 6.5 (1-15) 2 (0-5) Drug not used Drug not used Creteil, Geneva and Paris (n=27) (n=31) Morphine (mg/day) Before inclusion After inclusion Fentanyl (µg/day) Before inclusion After inclusion Sufentanyl (µg/day) Before inclusion After inclusion Drug not used 530 (0-1080) 0 (0-150) Drug not used Drug not used 961 ( ) 0 (0-400) Drug not used Brussels (n=22) (n=18) Morphine (mg/day) Before inclusion Drug not used Drug not used

27 After inclusion Fentanyl (µg/day) Before inclusion After inclusion Sufentanyl (µg/day) Before inclusion After inclusion Drug not used 0 (0-0) 0 (0-0) Drug not used 0 (0-185) 0 (0-0) CDW denotes computer-driven weaning Drug not used means that in the specific center the sedative/analgesic is not used or very unfrequently used.

28 APPENDIX 1 Weaning guidelines (control group) Usual weaning guidelines used in the participating centers. No change was made for the study. 1) Créteil, Henri Mondor Teaching Hospital Steps Criteria Action 1) Daily screening test PEEP 5cmH 2 O, FiO 2 50% No vasopressor Sepsis under control No sedation or Ramsay score 2-3 Cough 2) Spontaneous breathing test if PSV 7 (No HME) or 12 cm Daily screening criteria met H 2 O (With HME) To be repeated when The followings are not contraindication to or T-piece negative: the spontaneous breathing :anemia, T < 30 minutes to 2 hours Extubation if well 39 C, dobutamine, need for dialysis, (depending on pre-test tolerated (RR< 35/min, etc. probability) hemodynamics and SpO 2 no PEEP satisfactory and stable, consciousness satisfactory, ph>7.35). ABG when doubtful 3) Ventilation during the weaning Pressure-support ventilation Never use SIMV period RR 25-35/min and comfortable The PSV level is also a guide If 15 cm H 2 O=> SB test 4) Weaning tests: No routine tests (maximal inspiratory If probability uncertain or patient failed the SB test

29 or expiratory pressure, f/vt) FAILURE: (I) Search for a cause Heart failure / Fluid overload Diaphragm dysfunction, ICU-acquired paresis Sepsis GI tract disorders Psychological factors Avoid hypokalemia or major hypophosphoremia (II) Continue weaning Other PSV + daily SB tests PSV or T-piece Tracheostomy

30 2) Geneva: Weaning possible if all criteria below present: - Improvement of condition that led to intubation - No uncontrolled severe infection - Metabolic disorders corrected - Hemoglobin level adequate - No hemodynamic instability - PaO 2 > 8.5 kpa with FIO and PEEP 5 cmh 2O Mechanical ventilation Question asked at least twice a day: Weaning possible? YES Initiation of weaning Stop or decrease sedation Level of Pressure Support: 20 cmh 2 O NO NO PS level 20 cmh 2 O above PEEP > 60 minutes? Spontaneous breathing test feasible if after 60' with PS 20 cmh 2O, PEEP 5 cmh 2O (all must be present): - Respiratory rate 30/' - Tidal volume 6 ml/kg - No hemodynamic instability - SpO 2 90% and FIO No other contraindication Extubation criteria (all must be present) - Respiratory rate 30/' - Pulse < 120/' - Syst. ABP < 180 and > 90 mmhg - No hemodynamic instability - PaO kpa and FIO ph > 7.30 YES Question asked at least twice a day: Spontaneous breathing test feasible? YES Spontaneous breathing test during 30' First choice: Pressure support 10 cmh 2 O, ± PEEP 5 cmh 2 O Other choices: - T-piece trial - CPAP, flow 30 l/min. PEEP 5 cmh 2 O Extubation criteria present? YES Extubation possible? Adaptation of PS NO and/or PEEP level NO - Level of consciousness good - Efficient swallowing - Efficient cough NO YES Patient weaned but extubation not possible EXTUBATION 30

31 3) Sant Pau Hospital Weaning process can begin if: The cause of the respiratory failure is partially or completely controlled, including SpO 2 90% with FiO and PEEP 5 cm H 2 O Hemodynamic stability (systolic blood pressure between 90 and 160 mm Hg + heart rate between 60 and 125 beats per minute + absence of uncontrolled arrhythmias) Temperature < 39 C Hemoglobin 8 g/dl Absence of significant water or electrolyte abnormalities Patients can follow simple orders and there is no need for high-dose sedatives For patients with neurological disorders: Glasgow Coma Scale > 8, intracranial pressure < 20 mm Hg, cerebral perfusion pressure > 60 mmhg Patients who meet these criteria undergo a spontaneous breathing test (2 hours on a T-tube or pressure support ventilation with 7 cm H 2 O of pressure support and PEEP 5 cm H 2 O). The following indicate an inability to tolerate spontaneous breathing: Respiratory rate >35 per minute + clinical manifestations* Hypoxemia (PaO 2 <60 mmhg under O 2 flow 4 L/min) Acidosis (ph 7.3) * Clinical manifestations: systolic blood pressure 160 mmhg or 90 mmhg, heart rate 140 bpm or increase by 25% or more over baseline, new arrhythmia, worse level of consciousness, sweating, or agitation. 1. Patients are extubated if they successfully complete the 2-hour spontaneous breathing trial and can cough effectively. 2. For patients who cannot tolerate the spontaneous breathing test, weaning is continued on pressure-support ventilation. Pressure support is adjusted to achieve a respiratory frequency of per minute and good clinical adaptation. Pressure support is diminished as soon as possible according to tolerance by the patient. Extubation is performed when the patient can tolerate low pressure support levels (near 10 cm H 2 O) 31

32 with low PEEP levels ( 5 cm H 2 O), provided clinical tolerance and cough are adequate. 3. Daily spontaneous breathing trials are performed in patients who are not weaned in pressure support mode (Item 1). 32

33 4) Brussels - Pressure-support ventilation is used as soon as it is tolerated, with a pressure-support level between 15 and 20 cmh 2 O. - The weaning process can begin if: The cause of respiratory failure is partially or completely controlled, with SpO 2 90% under FIO and PEEP 5 cm H 2 O and with no aggravation of infiltrates by chest X-ray Hemodynamic stability No uncontrolled sepsis Absence of significant water or electrolyte abnormalities, Hemoglobin > 8 g/dl Patients can follow simple orders, Glasgow > 8, sedation stopped These criteria are evaluated two or three times per 24 hours. When they are met, a spontaneous breathing test is performed (20 minutes on a T-piece) Failure of the spontaneous breathing test is defined as: Modification of the respiratory pattern, with signs of respiratory distress Hypoxemia (PaO 2 <60 mmhg under O 2 flow 4 L/min) or acidosis (ph 7.3) Decreased level of consciousness, agitation, Glasgow < 8 no extubation Systolic Blood Pressure 160 mmhg or 90 mmhg, heart rate 140 bpm or 25% increase over baseline, arrhythmia Sweating 1. Patients are extubated if they successfully complete the spontaneous breathing trial and they have adequate coughing and swallowing. 2. Repeated daily spontaneous breathing trials (2 to 3 times a day) are performed in patients who fail the first trial. 33