Brault et al. Critical Care (2022) 26:188 https://doi.org/10.1186/s13054-022-04063-4 RESEARCH Open Access The PROMIZING trial enrollment algorithm for early identification of patients ready for unassisted breathing Clement Brault1,2,3*, Jordi Mancebo4, Juan‑Carlos Suarez Montero4, Tracey Bentall2, Karen E. A. Burns2,6,7, Thomas Piraino6, François Lellouche8,9, Pierre‑Alexandre Bouchard9, Emmanuel Charbonney10,11, Guillaume Carteaux12,13,14, Tommaso Maraffi15, Gaëtan Beduneau16, Alain Mercat17, Yoanna Skrobik18, Fei Zuo6, Myriam Lafreniere‑Roula19, Kevin Thorpe20, Laurent Brochard1,2† and Karen J. Bosma5† Abstract Background: Liberating patients from mechanical ventilation (MV) requires a systematic approach. In the context of a clinical trial, we developed a simple algorithm to identify patients who tolerate assisted ventilation but still require ongoing MV to be randomized. We report on the use of this algorithm to screen potential trial participants for enroll‑ ment and subsequent randomization in the Proportional Assist Ventilation for Minimizing the Duration of MV (PROM‑ IZING) study. Methods: The algorithm included five steps: enrollment criteria, pressure support ventilation (PSV) tolerance trial, weaning criteria, continuous positive airway pressure (CPAP) tolerance trial (0 ­cmH2O during 2 min) and spontaneous breathing trial (SBT): on fraction of inspired oxygen ­(FiO2) 40% for 30–120 min. Patients who failed the weaning crite‑ ria, CPAP Zero trial, or SBT were randomized. We describe the characteristics of patients who were initially enrolled, but passed all steps in the algorithm and consequently were not randomized. Results: Among the 374 enrolled patients, 93 (25%) patients passed all five steps. At time of enrollment, most patients were on PSV (87%) with a mean (± standard deviation) ­FiO2 of 34 (± 6) %, PSV of 8.7 (± 2.9) ­cmH2O, and positive end-expiratory pressure of 6.1 (± 1.6) ­cmH2O. Minute ventilation was 9.0 (± 3.1) L/min with a respiratory rate of 17.4 (± 4.4) breaths/min. Patients were liberated from MV with a median [interquartile range] delay between initial screening and extubation of 5 [1–49] hours. Only 7 (8%) patients required reintubation. Conclusion: The trial algorithm permitted identification of 93 (25%) patients who were ready to extubate, while their clinicians predicted a duration of ventilation higher than 24 h. Keywords: Ventilator weaning, Extubation, Mechanical ventilation, Respiratory mechanics, Critical care Background Liberating critically ill patients from invasive mechani- cal ventilation (MV) at the earliest opportunity is essen- † LaurentBrochard, Karen J. Bosma contributed equally as senior authors. tial to avoid the morbidity and mortality associated with prolonged ventilation [1, 2]. However, the process of *Correspondence: Clement.brault@unityhealth.to discontinuing MV is complex. In the “acute phase” of 1 Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge acute respiratory failure and/or uncontrolled critical ill- Institute, 209 Victoria St, Toronto, ON, Canada Full list of author information is available at the end of the article ness, patients generally receive full ventilator support © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Brault et al. Critical Care (2022) 26:188 Page 2 of 9 (i.e., controlled mode of ventilation) to allow the respira- We screened all critically ill patients who received inva- tory muscles to rest. In the subsequent “recovery phase,” sive MV for more than 24 h, and who were not expected patients are able to share in the work of breathing. Once to be extubated in the next 24 h. Major exclusion crite- patients have improved from the acute phase and meet ria were an underlying medical condition likely to result general “weaning criteria,” daily screening for readiness in prolonged or chronic ventilator dependence such as a to wean from MV marks the beginning of the “wean- severe chronic obstructive pulmonary disease or a pro- ing phase” and is recommended as the best practice to gressive neuromuscular disorder (the full lists of inclu- aid early liberation from MV [1]. Currently, there is no sion and exclusion criteria are provided in Additional consensus for determining when a patient in the acute file 1: Table E1). After enrollment, further screening tests phase of illness can move to the recovery phase, or even were done in a step-by-step algorithm to identify patients when the patient is able to share the work of breathing. who were eligible for randomization in the PROMIZING When clinicians switch from a controlled mode to an Study to receive either PSV or PAV + (Fig. 1). The goal of assisted mode of ventilation may be considered the first this process was to ensure that patients who proceeded step in suspecting readiness to wean. Several studies have to randomization still required continued MV using evaluated different approaches to managing patients dur- objective criteria, to ensure that they would not dilute ing the weaning phase over the past few decades [3–7]. treatment effect (including shortening duration of MV). Weaning typically incorporates spontaneous breathing trials (SBT) using various techniques (low levels of pres- Step 1—Enrollment criteria sure support ventilation (PSV) or continuous positive Patients satisfying all screening criteria were followed airway pressure (CPAP) or T-piece) of 30–120 min dura- daily until they met the enrollment criteria (see Addi- tion [8–10]. Finally, patients who pass an SBT move to tional file 2: Table E2). This step ensured (i) that patients the last “liberation phase,” and are assessed for extubation were able to trigger ventilator breaths with a reasonable (see Additional file 6: Fig. E1). level of assistance, (ii) did not have severe impairment in We created a standardized approach for assessing gas exchange, and (iii) were not hemodynamically unsta- patient’s readiness to move from the "acute phase" to ble. Patients who met enrollment criteria, or their substi- the "recovery phase" and then to the "weaning phase" of tute decision makers, were approached for consent. Upon MV for identifying potential clinical research partici- obtaining consent, patients were considered enrolled in pants for a randomized controlled trial (RCT) comparing the PROMIZING study and ready to undergo further two spontaneous modes of MV. Our purpose here is to screening tests to determine eligibility for randomization. describe how the application of this algorithm led to the identification of patients who, previously unsuspected by Step 2—Pressure support ventilation tolerance trial their clinical team, were actually ready for extubation. Patients meeting all enrollment criteria were immedi- ately placed on PSV, if they were not already. The PSV tolerance trial (PSVTT) consisted in a pressure of 5–20 Methods ­cmH2O (the total pressure did not exceed 30 ­cmH2O) for Study protocol at least 30 min [11]. The positive end-expiratory pressure This is an analysis of the enrollment algorithm of the (PEEP) and the fraction of inspired oxygen (­ FiO2) settings Proportional Assist Ventilation for Minimizing the Dura- were similar to that before the PSVTT. If patients were tion of Mechanical Ventilation study (PROMIZING, unable to tolerate the PSV because of respiratory distress NCT02447692). The PROMIZING study is an ongoing or clinical instability (see Additional file 3: Table E3), they multi-centre randomized controlled trial comparing PSV were immediately returned to the prior ventilation mode. and proportional assist ventilation with load-adjusta- A new PSVTT was attempted at least once daily until ble gain factors (PAV +) to facilitate weaning from MV. patients passed the trial. Informed consent was obtained from the patient or the substitute decision maker at time of enrollment. This Step 3 – General weaning criteria early consent allowed the investigators to conduct fur- Patients who passed the PSVTT were immedi- ther tests to determine eligibility for randomization in ately evaluated for general weaning criteria includ- the PROMIZING Study and to collect minimal infor- ing (i) a peripheral oxygen saturation (­SpO2) ≥ 90% mation for the screened and non-randomized patients on ­FiO2 ≤ 40% and a PEEP ≤ 8 ­cmH2O, (ii) an arterial described here. We report here the effects of the enroll- pH ≥ 7.32, and (iii) vasopressor requirement ≤ 0.1 µg/ ment protocol for patients screened between September kg/min of norepinephrine equivalents. Patients who 2016 and February 2020. We do not report any outcome did not meet these three weaning criteria were ran- of the randomized patients. domized in the PROMIZING study (Not ready for Brault et al. Critical Care (2022) 26:188 Page 3 of 9 STEP 1 Enrolment criteria n = 382 STEP 2 PSV tolerance trial n = 374 STEP 3 General weaning criteria n = 374 139 patients failed and were randomized in RECOVERY PHASE PROMIZING study: Not ready for weaning group STEP 4 ZERO CPAP tolerance trial n = 235 101 patients failed and were randomized in WEANING PHASE PROMIZING study: ZERO CPAP tolerance failure group STEP 5 SBT on T-piece or CPAP 0 cmH2O n = 134 41 patients failed and were randomized in WEANING PHASE PROMIZING study: SBT failure group LIBERATION PHASE 93 patients passed all steps and were not randomised in PROMIZING study: SNR group Fig. 1 PROMIZING stepwise algorithm and study flowchart. CPAP: continuous positive airway pressure, SNR: screened and non-randomized, PROMIZING: Proportional assist ventilation for minimizing the duration of mechanical ventilation study, PSV: pressure support ventilation, SBT: spontaneous breathing trials weaning group). Patients who met these three criteria Step 5 – Spontaneous breathing trial on T‑piece or CPAP 0 proceeded directly to a ZERO CPAP tolerance trial to Patients were monitored during a 30–120 min SBT on assess their rapid shallow breathing index (RSBI) and either T-piece or no assistance on the ventilator using capacity to undergo an SBT. CPAP with a pressure level of 0 ­cmH2O as previously described, with ­FiO2 40% [5, 12]. Failure criteria included respiratory distress and clinical instability as for the Step 4 – Zero CPAP tolerance trial PSVTT and the ZERO CPAP tolerance trial (see Addi- Patients were monitored during a two minute CPAP tional file 4: Table E4). Patients were randomized into tolerance trial on their ventilator using a pressure level the PROMIZING trial if they failed the SBT (SBT failure of 0 ­cmH2O. We assessed the RSBI (as the ratio of res- group). Conversely, patients who passed the SBT were piratory rate to tidal volume, RR/Vt). Patients who failed screened and non-randomized (SNR) because they were this ZERO CPAP tolerance trial due to either a RR/Vt considered ready for extubation (SNR group). ratio > 100, or respiratory distress or clinical instability (see Additional file 4: Table E4) were randomized into the Statistical analysis PROMIZING trial (ZERO CPAP tolerance failure group). Demographic, prognostic scores and respiratory param- Patients with a RR/Vt ratio ≤ 100 breaths/min/L and eters were collected before randomization. Continuous ­SpO2 ≥ 90% proceeded directly to a SBT. variables were expressed as the mean (± standard devia- tion, SD), or median [interquartile range, IQR]. Categori- cal variables were quoted as the frequency (percentage). Brault et al. Critical Care (2022) 26:188 Page 4 of 9 For comparing difference in groups’ characteristics, we Description of screened non‑randomized patients used Chi-square test or a one-way analysis of variance Of the 93 patients included in the SNR group, 59 (65%) (ANOVA) followed by a Tukey’s multiple comparisons were male and the mean (± SD) age was 65 (± 13) years. post-test when appropriate. All statistical analyses were The mean duration from intubation to enrollment was conducted using R Core Team software (version 4.1.1, R 4.5 (± 4.1) days. The mean Richmond agitation-sedation Foundation for Statistical Computing, Vienna, Austria. scale (RASS) was -1.01 (± 1.38) consistent with drowsy or URL https://​www.R-​proje​ct.​org/). Unadjusted p-values light sedation (Table 1). are provided to quantify the statistical evidence against At the time of enrollment, a large majority of patients equality among the groups in various baseline variables. were under PSV (85%) with a mean ­FiO2 of 34 (± 6) %, pressure support of 8.7 (± 2.9) ­cmH20, and PEEP of 6.1 (± 1.6) ­cmH2O. The mean minute ventilation (­VE) was Results 9.0 (± 3.1) L/min with a RR of 17.4 (± 4.4) breaths/min Study population (Table 1). Between September 2016 and February 2020, we enrolled All patients in the SNR group were extubated with a (before randomization) 382 patients in the PROMIZING median [IQR] duration between initial screening and study. Eight patients could not be classified into one of extubation of 5 [1–49] hours, and only 7 (8%) patients the four groups as they did not complete the pre-rand- required reintubation. Among the latter, two patients omization assessment or did not have complete data. The subsequently died in intensive care unit (ICU). An addi- mean (± SD) age was 63 (± 13) years and 65% were male. tional five patients died in ICU despite getting extubated. The mean delay between the first intubation and the enrollment was 5.9 (± 5.0) days (Table 1). Comparison of baseline characteristics between non‑randomized and randomized patients Effect of the study algorithm on the mechanical ventilation Compared to the other groups, the SNR group contained process a higher proportion of postoperative patients and had Of the 374 patients, 139 (37%) were randomized because a higher P ­ aO2/FiO2 ratio. The time from intubation to they did not meet general weaning criteria (Not ready enrollment was shorter in the SNR group. Conversely, for weaning group). Of the remaining 235 patients, 142 there was not strong evidence of differences among the patients moved to the next steps: 101 (27%) met general groups in age, sex, and RASS. The sequential organ fail- weaning criteria but failed the ZERO CPAP tolerance ure assessment (SOFA) on ICU admission was signifi- trial (ZERO CPAP tolerance failure group subsequently cantly higher in the SNR group, reflecting higher organ randomized); 41 (11%) passed the 2-min CPAP but failed dysfunction, but this was not confirmed with other prog- the SBT (SBT failure group subsequently randomized) nostic scores (Table 1). and 93 (25%) initially screened patients were not rand- Although the ventilation mode was similar between omized in the PROMIZING study, because they were groups (see Additional file 5: Table E5), the initial venti- considered already ready for the liberation phase (SNR lator settings slightly differed with a lower level of ­FiO2, group) (Fig. 1). pressure support and PEEP in the SNR group. These dif- ferences were significant when compared with the Not Distribution of patients in the mechanical ventilation ready for weaning and ZERO CPAP tolerance failure process according to the mode of ventilation groups, while they disappeared when compared with the At enrollment, 41 (11%) of the 374 patients analyzed SBT failure group. Likewise, the RR was lower in the SNR were under assist-control ventilation (ACV). Among group compared to the Not ready for weaning group, them, 19 (46%) progressed to the recovery phase (Not leading to a significant decrease in V ­ E (Table 1 and Fig. 2). ready for weaning group), 11 (27%) progressed to the weaning phase (ZERO CPAP tolerance and SBT fail- Discussion ure groups), and 11 (27%) progressed to the liberation The major findings of this study are as follow: first, the phase (SNR group). Compared with patients with PSV at stepwise algorithm developed for screening and rand- enrollment (325, 87%), there was no significant difference omizing patients in the PROMIZING trial was helpful concerning the percentage of patients in the recovery in identifying patients who were ready to be separated (118, 36%), weaning (128, 40%) or liberation phase (79, from the ventilator. Second, a surprisingly large propor- 24%) (p = 0.211, p = 0.119, and p = 0.724; respectively) tion of patients (25% in the present study) for whom cli- (Table 2). nicians predicted a duration of ventilation higher than 24 h were ultimately determined by the algorithm to be Brault et al. Critical Care (2022) 26:188 Page 5 of 9 Table 1 Baseline (pre-randomization) characteristics comparisons Parameters All patients Not ready for weaning ZERO CPAP SBT failure SNR Group p value n = 374 group tolerance failure Group (Recovery phase) (Recovery phase) group (Weaning phase) n = 93 n = 139 (Weaning phase) n = 41 n = 101 Age, years 63 ± 13 62 ± 13 63 ± 14 63 ± 13 65 ± 13 0.326 Male – n (%) 242 (65) 95 (69) 58 (59) 30 (75) 59 (65) 0.212 BMI, Kg/m2 – median [IQR] 27.8 [24.2–32.1] 28.9 [25.1–34.5] 27.0 [23.5–30.2] 25.9 [23.3–31.2] 28.1 [24.9–32.0] 0.010 RASS −1.37 ± 1.65 −1.59 ± 1.78 −1.44 ± 1.67 −1.22 ± 1.60 −1.01 ± 1.38 0.062 Postoperative – n (%) 74 (20) 17 (12) 19 (19) 7 (17) 31 (33) 0.001 Prognostic scores Day 0 SOFA score 6.50 ± 3.35 6.60 ± 3.19 5.73 ± 3.06 5.42 ± 2.70 7.55 ± 3.80 < 0.001†§ Charlson Comorbidity Index 4.41 ± 3.13 4.11 ± 3.16 4.31 ± 2.87 5.24 ± 3.74 4.64 ± 3.02 0.216 APACHE III score 77 ± 30 83 ± 27 74 ± 28 71 ± 30 73 ± 35 0.023* Mode of ventilation at enrollment Pressure ACV – n (%) 19 (5) 10 (7) 3 (3) 0 (0) 6 (7) 0.189 Volume ACV – n (%) 22 (6) 9 (7) 8 (8) 0 (0) 5 (5) 0.327 PSV – n (%) 325 (87) 118 (85) 88 (85) 40 (98) 79 (85) 0.179 Other (including PAV +) – n 10 (3) 2 (1) 4 (4) 1 (2) 3 (3) 0.665 (%) First intubation to enrollment, 5.9 ± 5.0 6.6 ± 4.8 6.8 ± 5.9 5.2 ± 4.6 4.5 ± 4.1 NA days Gas exchange PaO2/FiO2 236 ± 81 218 ± 103 260 ± 101 242 ± 70 286 ± 102 < 0.001* PaCO2 41.2 ± 8.0 42.3 ± 8.1 41.1 ± 8.9 40.4 ± 6.7 39.8 ± 7.1 0.132 Respiratory parameters FiO2, % 38 ± 8 43 ± 9 36 ± 6 37 ± 6 34 ± 6 < 0.001* Pressure support, ­cmH2O 10.3 ± 3.4 11.1 ± 3.5 10.9 ± 3.2 9.7 ± 3.0 8.7 ± 2.9 < 0.001*† PEEP, ­cmH2O 7.8 ± 2.5 9.7 ± 2.3 7.0 ± 1.7 6.6 ± 1.4 6.1 ± 1.6 < 0.001*† Vt, mL 516 ± 155 547 ± 171 461 ± 130 514 ± 128 528 ± 151 < 0.001† RR, breaths/min 20.9 ± 6.8 21.7 ± 7.2 23.1 ± 7.3 21.0 ± 6.1 17.4 ± 4.4 < 0.001*†§ VE, L/min 10.3 ± 3.3 11.2 ± 3.3 10.1 ± 3.2 10.4 ± 3.2 9.0 ± 3.1 < 0.001* Data presented as mean ± standard deviation unless otherwise stated Pairwise comparisons between groups by Tukey Honest Significant Difference Test where p = 0.05 was taken as a threshold for these post-hoc comparisons: ACV: assist control ventilation, APACHE: acute physiology and chronic health evaluation, BMI: body mass index, CPAP: continuous positive airway pressure, SNR: screened and non-randomized, ­FiO2: fraction of inspired oxygen, IQR: interquartile range, MV: mechanical ventilation, NA: not available, PAV + : proportional assist ventilation, PEEP: positive end-expiratory pressure, PSV: pressure support ventilation, RASS: Richmond agitation and sedation scale, RR: respiratory rate, SBT: spontaneous breathing trial, SOFA: sequential organ failure assessment, ­VE: minute ventilation, ­Vt: tidal volume *Difference (p < 0.05) between Not ready for weaning group vs. SNR group † Difference (p < 0.05) between ZERO CPAP tolerance failure group vs. SNR group § Difference (p < 0.05) between SBT failure group vs. SNR group Table 2 Distribution of patients in the mechanical ventilation process according to the mode of ventilation at enrollment Study algorithm Group Mechanical ventilation Patients with ACV Patients with PSV p value phase n (%) n (%) Not ready for weaning group Recovery 19 (46) 118 (36) 0.211 ZERO CPAP tolerance and SBT failure Weaning 11 (27) 128 (40) 0.119 groups SNR Group Liberation 11 (27) 79 (24) 0.724 ACV: assist control ventilation, CPAP: continuous positive airway pressure, PSV: pressure support ventilation, SBT: spontaneous breathing trial, SNR: screened and non- randomized Brault et al. Critical Care (2022) 26:188 Page 6 of 9 Fig. 2 Ventilator settings and respiratory parameters at baseline (pre-randomization) according groups. Data presented as mean ± standard deviation. Pairwise comparisons between groups by Tukey Honest Significant Difference Test where p = 0.05 was taken as a threshold for these post-hoc comparisons: * Difference (p < 0.05) between Not ready for weaning group vs. SNR group. † Difference (p < 0.05) between ZERO CPAP tolerance failure group vs. SNR group. § Difference (p < 0.05) between SBT failure group vs. SNR group. SNR: screened and non-randomized, F­ iO2: fraction of inspired oxygen, CPAP: continuous positive airway pressure, PEEP: positive end-expiratory pressure, SBT: spontaneous breathing trial ready for liberation from MV. These patients were extu- of a ventilator liberation protocol to identify patients bated within a median delay of 5 h from time of enroll- ready for extubation [3, 15, 16]. To date, guidelines have ment, and only 7 (8%) required reintubation. This low focused on the weaning phase of MV by proposing a daily reintubation rate confirmed that the algorithm was safe interruption of sedation and performing a SBT (PSV with [13]. Compared to patients not ready for extubation, they low support pressure, CPAP or T-piece trial) as soon as had a slightly lower PSV, PEEP and V ­ E. In contrast, the possible [17]. Because the absence of clear guidance con- mode of ventilation at enrollment and the level of seda- cerning the recovery phase (i.e., when to switch the ven- tion were similar. tilator from a controlled mode to an assisted mode, and It is difficult for clinicians to determine when a patient perform these tests) and a lack of objective criteria for is ready to advance from the acute phase of critical illness deciding if a patient is ready for extubation, our algo- (requiring full ventilatory support) to the recovery phase rithm might add substantial improvements to the current (partial ventilatory support) and ultimately, the wean- recommendations. ing phase. Several factors could explain this observation We developed a step-by-step algorithm for patient such as the absence of simple bedside parameters (e.g., recruitment in the PROMIZING trial, which could accel- ­PaO2/FiO2 ratio or respiratory system compliance) to pre- erate the weaning from MV. By different ways, it allowed dict with certainty the safety and tolerability of allowing to easily select patients potentially ready to be extubated. patients to share the work of breathing and subsequently First, our algorithm screened early in the MV process, start SBTs. Furthermore, the risk of post-extubation res- from the acute phase of their illness, when some patients piratory failure requiring reintubation (occurring in up to were still in ACV. We proposed simple criteria to switch 15% of cases) is associated with a high mortality rate [13, from ACV to PSV such as adequate gas exchange (with 14]. Consequently, clinicians frequently tend to underes- ­FiO2 ≤ 60% and PEEP ≤ 15 ­cmH2O) and no hemodynamic timate the capacity of patients to be successfully weaned instability. Thus, we encouraged a PSVTT as soon as the and breathe without assistance, leading to a risk of patient’s condition shows early signs of improvement, but delayed extubation and exposing patients to unnecessary even before patients were seen to trigger the ventilator or discomfort and complications (e.g., ventilation-acquired before sedatives were weaned or vasopressors were dis- pneumonia) [1]. To avoid delays in the weaning process, continued. Among our 41 patients with ACV at enroll- international guidelines suggested the implementation ment, our algorithm detected that 19 patients were ready Brault et al. Critical Care (2022) 26:188 Page 7 of 9 to progress to the recovery (i.e., switch on PSV) phase, weaning criteria including a 2-min CPAP trial to assess and 11 to the weaning phase (i.e., SBT). Moreover, 11 the RSBI (conducted on zero PEEP) followed by a SBT if patients successively passed all phases of our algorithm the ZERO CPAP tolerance trial was successful. Recently, and were ready for extubation. Of note, patients with Burns et al. showed a large heterogeneity of SBT tech- ACV and PSV at enrollment had a similar extubation niques across the world [8]. Our protocol proposed rate (27 vs. 24%; p = 0.724). This strategy to transfer the to perform an 30–120 min SBT on T-piece or CPAP at breathing workload as soon as possible might limit the zero PEEP on the ventilator rather than a PSV using low development of diaphragm weakness and atrophy, which level of pressure support in order to better simulate the can occur during the first days of MV [18]. Several stud- physiologic conditions after extubation [5]. Because usual ies found a relationship between the diaphragm thickness criteria of successful SBT were subjective and depended and weaning failure, delays in liberation of MV or risk of on the clinician’s interpretation, we provided easy to use reintubation [19–22]. criteria to define failure of each PSV, CPAP and T-piece Second, our protocol might shorten the length of MV, trials [27]. because we used pragmatic criteria to progress from Several limitations of this study need to be discussed. the recovery phase to the weaning phase. Currently, the We did not record data regarding the cumulative dose list of weaning criteria proposed by Boles et al. includes and duration of sedative drugs received or the patient’s clinical assessment (e.g., adequate cough and no exces- fluid balance, which may influence the weaning process sive tracheobronchial secretion) and hemodynamic and [28, 29]. Moreover, our algorithm did not include addi- respiratory measurements [1]. However, some patients tional physiologic measurements, such as the airway who do not meet all the criteria could successfully pass occlusion pressure (­P0.1). Finally, in spite of broad and the SBT. In contrast, we moved patients to the weaning easy-to-assess enrollment criteria (especially concern- phase if they met only three simple criteria: adequate ing oxygenation: ­ PaO2 ≥ 60 mmHg on ­ FiO2 ≤ 60% and oxygenation ­(SpO2 ≥ 90% on F ­iO2 ≤ 40% and PEEP ≤ 8 PEEP ≤ 15 ­cmH2O), the delay between intubation and ­cmH2O), no severe acidosis (pH ≥ 7.32), and low-dose of the enrollment remained long (around 6 days). This find- vasopressors. Although the discontinuation of vasopres- ing may also represent an opportunity for improvement sors has been a precondition for SBT in clinical trials and as patients could be enrolled earlier in the acute phase. guidelines, other studies have not found significant differ- Because a criterion to enroll patients in PROMIZING ences between patients extubated on and off vasopressors was an expected need of ventilation of at least 24 h, it is concerning the success of extubation, at least with low unlikely that clinicians would have conducted a weaning doses [23, 24]. In addition, previous studies have shown trial independent from the study screening protocol on that patients extubated on vasopressors had a significant the same day, suggesting that application of the screening decrease in the ICU length of stay [24, 25]. Finally, we algorithm assisted in identifying patients ready for wean- conducted the SBT regardless of the PSV or PEEP level ing earlier than the clinicians suspected. (i.e., a gradual withdrawal of assistance was not neces- sary as long as the pressure support was between 5 and Conclusion 20 ­cmH2O). Thereby, the duration of the recovery phase The process to liberate patients from MV accounts for could be very short in some of our patients, because they a significant duration of the ventilation time. Finding met the general weaning criteria immediately after pass- strategies to minimize this duration is desirable. We ing the 30 min PSVTT. developed a comprehensive step-by-step algorithm for Third, our algorithm defined and separated the differ- enrollment and randomization of patients in the PROM- ent phases of the MV process (i.e., acute, recovery, wean- IZING study, which compares two spontaneous modes ing and liberation phases), and proposed criteria for of MV. Surprisingly, our algorithm allowed an easy and identifying patients in each phase (see Additional file 6: early identification of patients ready to extubate, and Fig. E1). In this way, the diagnosis of a possible liberation might decrease the duration of MV. In our study, 25% of from MV could be assessed over a few hours. Currently, our patients, who were in need of ventilator assistance there is no consensus in the definition of the different for at least 24 h according to their clinicians in charge, phases, often leading to confusion [26]. Using our algo- passed the whole process (recovery, weaning, and libera- rithm, the acute phase corresponded to a non-controlled tion) and were safely removed from the ventilator and underlying disease, when patients may need full ventila- extubated. tor support (i.e., ACV). The recovery phase began with the switch to PSV (or proportional ventilation mode), Abbreviations allowing the patient to share the work of breathing. Mov- ACV: Assist-control ventilation; ANOVA: Analysis of variance; CPAP: Continuous ing to the weaning phase required meeting the general positive airway pressure; SNR: Screened and non-randomized; FiO2: Fraction Brault et al. Critical Care (2022) 26:188 Page 8 of 9 of inspired oxygen; ICU: Intensive care unit; IQR: Interquartile range; MV: Availability of data and materials Mechanical ventilation; P0.1: Airway occlusion pressure; PaO2: Partial pressure The raw data supporting the conclusions of this article will be made available of oxygen; PAV + : Proportional assist ventilation with load-adjustable gain by the authors, on reasonable request. factors; PEEP: Positive end-expiratory pressure; PROMIZING: Proportional assist ventilation for minimizing the duration of mechanical ventilation study; PSVTT: Pressure support ventilation tolerance trial; PSV: Pressure support ventilation; Declarations RASS: Richmond agitation-sedation scale; RR/Vt: Ratio of respiratory rate to tidal volume; SBT: Spontaneous breathing trials; SD: Standard deviation; SOFA: Ethics approval and consent to participate: Sequential organ failure assessment; SpO2: Peripheral oxygen saturation; VE: No animal studies are presented in this manuscript. Minute ventilation. No potentially identifiable human images or data are presented in this study. This study was reviewed and approved by the Western University Research Ethics Board and the Clinical Trials Ontario (project identifier: 0733). Supplementary Information The online version contains supplementary material available at https://​doi.​ Consent for publication org/​10.​1186/​s13054-​022-​04063-4. Informed consent was obtained from the patient or the substitute decision maker at time of enrollment. This early consent allowed to collect minimal information for the screened and non-randomized patients described here. Additional file 1 Screening inclusion and exclusion criteria of the PROM‑ We do not report any outcome of the randomized patients. IZING study. FEV1: forced expiratory volume in the first second, GOLD: global initiative for chronic obstructive lung disease, ICU: intensive care Competing interests unit, MRC: medical research council, pCO2: partial pressure of carbon Not applicable. dioxyde, PROMIZING: Proportional assist ventilation for minimizing the duration of mechanical ventilation study. Author details 1 Additional file 2 Enrollment inclusion, deferral and exclusion criteria of Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge the PROMIZING study.CPAP: continuous positive airway pressure, ECMO: Institute, 209 Victoria St, Toronto, ON, Canada. 2 Interdepartmental Divi‑ extracorporeal membrane oxygenation,PaO2: Arterial partial pressure of sion of Critical Care, University of Toronto, Toronto, Canada. 3 Intensive Care oxygen PAV: proportional assist ventilation, PEEP: positive end-expiratory Department, Amiens-Picardie University Hospital, Amiens, France. 4 Intensive pressure, PROMIZING: Proportional assist ventilation for minimizing Care Department, Hospital Universitari de La Santa Creu I Sant Pau, Barcelona, the duration of mechanical ventilation study, SpO2: peripheral oxygen Spain. 5 London Health Sciences Centre, University of Western Ontario, London, saturation. ON, Canada. 6 Unity Health Toronto - St. Michael’s Hospital, Toronto, ON, Canada. 7 Applied Health Research Institute, St. Michael’s Hospital, Toronto, Additional file 3 Pressure support ventilation tolerance trial inclusion, ON, Canada. 8 Département de Médecine Québec, Université Laval, Québec deferral and exclusion criteria of the PROMIZING study.PROMIZING: City, QC, Canada. 9 Institut Universitaire de Cardiologie Et de Pneumologie de Proportional assist ventilation for minimizing the duration of mechanical Québec, Québec City, QC, Canada. 10 Centre de Recherche du Centre Hospital‑ ventilation study. ier de L’Université de Montréal, Montréal, QC, Canada. 11 Centre de Recherche Additional file 4 Definition of respiratory distress and clinical instability. du CIUSSS NIM, Montréal, QC, Canada. 12 Medical Intensive Care Department, RASS: Richmond agitation sedation scale, SBP: systolic blood pressure, AP-HP, Henri Mondor University Hospital, Créteil, France. 13 Faculté de Santé, SpO2: peripheral oxygen saturation. Groupe de Recherche Clinique CARMAS, Université Paris Est-Créteil, 94010 Cré‑ teil, France. 14 INSERM U955, Institut Mondor de Recherche Biomédicale, Additional file 5 Mode of ventilation at baseline (pre-randomization). 94010 Créteil, France. 15 Service de Réanimation, Centre Hospitalier Intercom‑ CPAP: continuous positive airway pressure, SBT: spontaneous breathing munal de Créteil, 40 Avenue de Verdun, 94000 Créteil, France. 16 UNIROUEN, trial, SNR: screened and non-randomized. EA 3830, Medical Intensive Care Unit, Rouen University Hospital, Normandie Additional file 6 Principles and objectives of each phases of the University, 76000 Rouen, France. 17 Medical Intensive Care Unit, Angers Univer‑ mechanical ventilation process in the PROMIZING study.Step 1 to 5 refer sity Hospital, Angers, France. 18 Opus Clinic, Montreal, QC, Canada. 19 Applied to the algorithm for enrollment of patients in the PROMIZING study.ACV: Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s assist-control ventilation, CPAP: continuous positive airway pressure, PAV: Hospital, Toronto, ON, Canada. 20 Dalla Lana School of Public Health, University proportional assist ventilation, PROMIZING: Proportional assist ventilation of Toronto and Applied Health Research Centre, Toronto, ON, Canada. for minimizing the duration of mechanical ventilation study, PSV: pressure support ventilation, SBT: spontaneous breathing trials. Received: 24 March 2022 Accepted: 9 May 2022 Acknowledgements We are very grateful for the work done by Sorcha Mulligan and Joyce Deng as research managers for the study. References 1. Boles J-M, Bion J, Connors A, Herridge M, Marsh B, Melot C, et al. Weaning Author contributions from mechanical ventilation. Eur Respir J Eur Respir Soc. 2007;29:1033–56. LB and KJB designed the work. JM, JSM, TB, KB, TP, FL, PAB, EC, GC, TM, GB, 2. Béduneau G, Pham T, Schortgen F, Piquilloud L, Zogheib E, Jonas M, et al. AM, YS, FZ, LB, and KJB collected the data. CB, MLR, and KT analyzed the data. Epidemiology of weaning outcome according to a new definition. The CB, JM, LB, and KJB wrote the manuscript. JM, LB, and KJB critically reviewed WIND study. Am J Respir Crit Care Med. 2017;195:772–83. the manuscript. All authors approved the final version of the manuscript. All 3. Girard TD, Alhazzani W, Kress JP, Ouellette DR, Schmidt GA, Truwit JD, et al. authors are agreed to be accountable for all aspects of the work in ensuring An official American Thoracic Society/American College of Chest Physi‑ that questions related to the accuracy or integrity of any part of the work are cians clinical practice guideline: liberation from mechanical ventilation in appropriately investigated and resolved. critically ill adults. Rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. Am J Respir Crit Care Med. 2017;195:120–33. Funding 4. Subirà C, Hernández G, Vázquez A, Rodríguez-García R, González-Castro A, This study is funded by a Canadian Institutes of Health Research (CIHR) Oper‑ García C, et al. 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Libera‑ tion from mechanical ventilation in critically ill adults. An official ATS/ ACCP clinical practice guideline. Ann Am Thorac Soc. 2017;14:441–3. 18. Goligher EC, Dres M, Patel BK, Sahetya SK, Beitler JR, Telias I, et al. Lung- and diaphragm-protective ventilation. Am J Respir Crit Care Med. 2020;202:950–61. 19. Goligher EC, Dres M, Fan E, Rubenfeld GD, Scales DC, Herridge MS, et al. Mechanical ventilation-induced diaphragm atrophy strongly impacts clinical outcomes. Am J Respir Crit Care Med. 2018;197:204–13. 20. Jung B, Moury PH, Mahul M, de Jong A, Galia F, Prades A, et al. Diaphrag‑ matic dysfunction in patients with ICU-acquired weakness and its impact on extubation failure. Intensive Care Med. 2016;42:853–61. 21. Demoule A, Molinari N, Jung B, Prodanovic H, Chanques G, Matecki S, et al. Patterns of diaphragm function in critically ill patients receiving Ready to submit your research ? Choose BMC and benefit from: prolonged mechanical ventilation: a prospective longitudinal study. Ann Intensive Care. 2016;6:75. • fast, convenient online submission 22. Dres M, Dubé B-P, Mayaux J, Delemazure J, Reuter D, Brochard L, et al. Coexistence and impact of limb muscle and diaphragm weakness at • thorough peer review by experienced researchers in your field time of liberation from mechanical ventilation in medical intensive care • rapid publication on acceptance unit patients. Am J Respir Crit Care Med. 2017;195:57–66. • support for research data, including large and complex data types 23. Teixeira C, Tonietto TF, Gonçalves SC, Cremonese RV, De Oliveira RP, Savi A, et al. Noradrenaline use is not associated with extubation failure in septic • gold Open Access which fosters wider collaboration and increased citations patients. Anaesth Intensive Care. 2008;36(3):385–90. • maximum visibility for your research: over 100M website views per year 24. Quasim T, Shaw M, McPeake J, Hughes M, Iwashyna TJ. Safety of extubat‑ ing mechanically ventilated patients receiving vasoactive infusions: a At BMC, research is always in progress. retrospective cohort study. Am J Respir Crit Care Med. 2018;198:1093–6. Learn more biomedcentral.com/submissions