Automated weaning and SBT systems versus non‐automated weaning strategies for weaning time in invasively ventilated critically ill adults

Karen EA Burns; Francois Lellouche; Rosane Nisenbaum; Martin R Lessard; Jan O Friedrich

doi:10.1002/14651858.CD008638.pub2

. 2014 Sep 9;2014(9):CD008638. doi: 10.1002/14651858.CD008638.pub2

Automated weaning and SBT systems versus non‐automated weaning strategies for weaning time in invasively ventilated critically ill adults

Karen EA Burns ^1,^✉, Francois Lellouche ², Rosane Nisenbaum ³, Martin R Lessard ⁴, Jan O Friedrich ⁵

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6516852 PMID: 25203308

Abstract

Background

Automated systems use closed‐loop control to enable ventilators to perform basic and advanced functions while supporting respiration. SmartCare™ is a unique automated weaning system that measures selected respiratory variables, adapts ventilator output to individual patient needs by operationalizing predetermined algorithms and automatically conducts spontaneous breathing trials (SBTs) when predetermined thresholds are met.

Objectives

The primary objective of this review was to compare weaning time (time from randomization to extubation as defined by study authors) between invasively ventilated critically ill adults weaned by automated weaning and SBT systems versus non‐automated weaning strategies.

As secondary objectives, we ascertained differences between effects of alternative weaning strategies on clinical outcomes (time to successful extubation, time to first SBT and first successful SBT, mortality, ventilator‐associated pneumonia, total duration of ventilation, lengths of intensive care unit (ICU) and hospital stay, use of non‐invasive ventilation (NIV), adverse events and clinician acceptance).

The third objective of our review was to use subgroup analyses to explore variations in weaning time, length of ICU stay, mortality, ventilator‐associated pneumonia, use of NIV and reintubation according to (1) the type of clinician primarily involved in implementing the automated weaning and SBT strategy, (2) the ICU (as a reflection of the population involved) and (3) the non‐automated (control) weaning strategy utilized.

We conducted a sensitivity analysis to evaluate variations in weaning time based on (4) the methodological quality (low or unclear versus high risk of bias) of the included studies.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 5; MEDLINE (1966 to 31 May 2013); EMBASE (1988 to 31 May 2013); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 31 May 2013), Evidence‐Based Medicine Reviews and Ovid HealthSTAR (1999 to 31 May 2013), as well as conference proceedings and trial registration websites; we also contacted study authors and content experts to identify potentially eligible trials.

Selection criteria

Randomized and quasi‐randomized trials comparing automated weaning and SBT systems versus non‐automated weaning strategies in intubated adults.

Data collection and analysis

Two review authors independently assessed trial quality and abstracted data according to prespecified criteria. Sensitivity and subgroup analyses were planned to assess the impact on selected outcomes of the following: (1) the type of clinician primarily involved in implementing automated weaning and SBT systems, (2) the ICU (as a reflection of the population involved) and (3) the non‐automated (control) weaning strategy utilized.

Main results

We pooled summary estimates from 10 trials evaluating SmartCare™ involving 654 participants. Overall, eight trials were judged to be at low or unclear risk of bias, and two trials were judged to be at high risk of bias. Compared with non‐automated strategies, SmartCare™ decreased weaning time (mean difference (MD) ‐2.68 days, 95% confidence interval (CI) ‐3.99 to ‐1.37; P value < 0.0001, seven trials, 495 participants, moderate‐quality evidence), time to successful extubation (MD ‐0.99 days, 95% CI ‐1.89 to ‐0.09; P value 0.03, seven trials, 516 participants, low‐quality evidence), length of ICU stay (MD ‐5.70 days, 95% CI ‐10.54 to ‐0.85; P value 0.02, six trials, 499 participants, moderate‐quality evidence) and proportions of participants receiving ventilation for longer than seven and 21 days (risk ratio (RR) 0.44, 95% CI 0.23 to 0.85; P value 0.01 and RR 0.39, 95% CI 0.18 to 0.86; P value 0.02). SmartCare™ reduced the total duration of ventilation (MD ‐1.68 days, 95% CI ‐3.33 to ‐0.03; P value 0.05, seven trials, 521 participants, low‐quality evidence) and the number of participants receiving ventilation for longer than 14 days (RR 0.61, 95% CI 0.37 to 1.00; P value 0.05); however the estimated effects were imprecise. SmartCare™ had no effect on time to first successful SBT, mortality or adverse events, specifically reintubation. Subgroup analysis suggested that trials with protocolized (versus non‐protocolized) control weaning strategies reported significantly shorter ICU stays. Sensitivity analysis excluded two trials with high risk of bias and supported a trend toward significant reductions in weaning time favouring SmartCare™.

Authors' conclusions

Compared with non‐automated weaning strategies, weaning with SmartCare™ significantly decreased weaning time, time to successful extubation, ICU stay and proportions of patients receiving ventilation for longer than seven days and 21 days. It also showed a favourable trend toward fewer patients receiving ventilation for longer than 14 days; however the estimated effect was imprecise. Summary estimates from our review suggest that these benefits may be achieved without increasing the risk of adverse events, especially reintubation; however, the quality of the evidence ranged from low to moderate, and evidence was derived from 10 small randomized controlled trials.

Plain language summary

SmartCare™ versus non‐automated weaning strategies for weaning time in invasively ventilated critically ill adults

The process of discontinuing mechanical ventilation is known as weaning. During weaning, the work of breathing is transferred from the ventilator to the patient. Weaning is typically achieved by clinicians reducing ventilator support and/or conducting tests to determine whether a patient can breathe on his/her own. SmartCare™ is a unique system that automates this process by measuring selected respiratory variables, adapting ventilator output to meet individual patient needs and automatically conducting tests of spontaneous breathing to determine the earliest time when patients can breathe on their own.

We identified 10 trials of moderate quality involving 654 participants and comparing SmartCare™ versus non‐automated weaning strategies. Compared with non‐automated strategies, SmartCare™ significantly decreased weaning time, time to successful removal from breathing machines and time spent in the ICU, with fewer patients receiving breathing machine support for longer than seven days and 21 days, and no increase in adverse events. SmartCare™ also showed a favourable trend toward fewer patients receiving ventilation for longer than 14 days, with no increase in adverse events. Subgroup analyses suggested more beneficial effects on weaning time in trials comparing SmartCare™ to a protocolized weaning strategy versus a non‐protocolized control strategy. Sensitivity analyses, which excluded two trials with high risk of bias, supported significant reductions in weaning time with SmartCare™.

Summary of findings

Background

Invasive ventilation has enabled clinicians to support respiration until the factors precipitating respiratory compromise can be identified and addressed. However, invasive mechanical ventilation is associated with the development of important complications, including ventilator‐associated pneumonia (VAP), sinusitis, upper airway pathology, respiratory muscle weakness, prolonged lengths of intensive care unit (ICU) and hospital stay and mortality (Cook 1998; Dries 1997; Heyland 1999; Mancebo 1996; Niederman 1984; Papazian 1996; Pingleton 1988; Vincent 1995). Consequently, identifying the earliest time for liberation from mechanical ventilation and thereby limiting the duration of invasive ventilation are important goals in providing care to critically ill patients.

Description of the condition

The process of discontinuing mechanical ventilation is known as weaning. Weaning accounts for approximately 40% of the time spent on mechanical ventilation (Esteban 1994; Esteban 2002). Transferring the work of breathing from ventilator to patient may occur abruptly in some patients and gradually in others (Lessard 1996), with approximately 75% of patients resuming the work of breathing without difficulty (Brochard 1994; Esteban 1995). For other patients, however, liberation from invasive ventilation is challenging.

Identifying when patients are ready to be weaned is often arbitrary, with the clinician relying on subjective assessments (Sahn 1973) and objective measurements of various respiratory variables in an effort to identify the optimal time to discontinue mechanical ventilation. Clinicians often underestimate the chance of a patient successfully discontinuing mechanical ventilation (Afessa 1999; Stroetz 1995). Recent literature supports the use of strategies to facilitate timely discontinuation of mechanical support, including early identification of weaning candidates (Ely 1996; Kollef 1997; Marelich 2000), conduct of spontaneous breathing trials (SBTs) (Esteban 1997; Esteban 1999; Perren 2002) and use of specific modes to reduce support in patients who fail an SBT (Brochard 1994; Esen 1992; Esteban 1995). Despite large‐scale implementation, many barriers to implementing weaning protocols in clinical practice are known, including the requirement for broad, educational interventions and multi‐disciplinary compliance with them (Ely 1999; Vitacca 2000).

Description of the intervention

Several modes of mechanical ventilation are available. Selection of one of these as an initial mode of support or as a way to transition patients to extubation depends upon the patient's ability to breathe spontaneously, underlying co‐morbidities and clinical circumstances. With volume‐controlled ventilation (VCV), clinicians may set several parameters depending on the ventilator used: tidal volume, respiratory rate, peak flow rate, flow pattern (or inspiratory flow time), inspiratory‐to‐expiratory ratio (I:E), fractional concentration of oxygen (FiO₂) and positive end‐expiratory pressure (PEEP) delivered; inspiration terminates after delivery of the preset tidal volume. Synchronized intermittent mechanical ventilation (SIMV) and assist control (AC) are two commonly used modes of volume‐limited ventilation. With SIMV and AC, clinicians set the respiratory rate and the tidal volume. Patients can increase their minute ventilation by initiating spontaneous breaths with variable tidal volume (SIMV) or by triggering additional breaths delivered at a preset tidal volume in AC.

With pressure‐controlled ventilation (PCV), clinicians may set various parameters including I:E ratio, inspiratory time, inspiratory pressure level, respiratory rate, FiO₂ and PEEP. Inspiration ends after a set inspiratory pressure is delivered with pressure‐controlled ventilation for a set inspiratory time. With PCV, tidal volumes vary according to airway resistance, compliance, endotracheal tube resistance, inspiratory pressure and end‐expiratory alveolar pressure. Compared with VCV, PCV limits airway pressure during inspiration.

With pressure support (PS), patients trigger breaths that are supported up to a predetermined inspiratory pressure level. Unlike PCV, the ventilator cycles into expiration after inspiratory flow has decreased to a predetermined level. PS is thus a spontaneous mode of ventilation whereby all breaths are initiated by the patient and are supported by a preset pressure. This preset pressure can be titrated up or down by the clinician according to the respiratory status of the patient. Finally, PS can be used in combination with SIMV (SIMV + PS) such that triggered breaths during the spontaneous period are supported by a preselected PS level (Banner 1997). With SIMV + PS, the end of the inspiratory period may occur after a set time for an SIMV breath, or following a predetermined decrease in flow after a PS breath. SIMV can provide a range of ventilatory support. With SIMV, patients can trigger a mandatory volume breath (during the SIMV period) or a spontaneous breath (if triggering occurs earlier in a spontaneous period) before taking the next mandatory breath.

Weaning can be accomplished by several methods. Patients under controlled ventilation (VCV or PCV) can be taken abruptly off the ventilator to test whether they can breathe unassisted for a single testing period (spontaneous breathing trial (SBT) or T‐piece trial) or for periods of increasing duration (progressive T‐piece trials). With SIMV, the mandatory breath rate is reduced in a stepwise manner. Consequently, spontaneous breaths must increase if minute ventilation is to be maintained to the point where a patient can support his/her ventilation without assistance. In PS, the level of pressuresupporting breaths can be progressively decreased to the point where every inspiration is unassisted.

Early attempts were made to enable interaction between patients and ventilator‐adapted SIMV and PS (Strickland 1991; Strickland 1993). More recently, investigators have conducted pilot trials (Bouadma 2005) and retrospective studies (Kataoka 2007) of automated systems that adapt PS alone. Automated systems use closed‐loop control to perform basic and advanced functions while supporting respiration. Closed‐loop systems adapt ventilator output by comparing measured and targeted values of selected respiratory variables and either minimizing or equilibrating (negative feedback) or amplifying (positive feedback) the differences between these values (Burns 2008). Automated modes of mechanical ventilation use more sophisticated closed‐loop systems to enable interaction between patient and ventilator.

How the intervention might work

Several closed‐loop, automated systems are currently marketed. Mandatory minute ventilation (MMV) (Evita 4, Draeger Medical Inc., Luebeck, Germany) combines features of controlled ventilation with mandatory and spontaneous breaths as VCV + PS or SIMV + PS. Clinicians can set tidal volume (V_T), mandatory breath rate, level of PS provided during spontaneous breaths and a target minute ventilation (V_E). Based on the patient's spontaneous respiratory rate, MMV adapts the mandatory respiratory rate to achieve the target V_E. Adaptive support ventilation (ASV) (Galileo, Raphael and Hamilton—G5, Hamilton Medical AG, Rhaezuens, Switzerland) is an automated system that adapts inspiratory pressure in PCV or PS mode to achieve a target V_T . ASV targets a desired V_E, set as a percentage of normal ventilation, and seeks the optimal V_T and respiratory rate (least energy expenditure) to achieve this V_E using Otis' equation. Neither MMV nor ASV automates the conduct of SBTs. Conversely, SmartCare™ (Draeger Medical Inc.) measures selected respiratory variables, adapts ventilator output by operationalizing predetermined algorithms and automates the conduct of SBTs (Burns 2008). To initiate SmartCare™, end‐users enter the patient's weight, the presence or absence of chronic obstructive pulmonary disease (COPD) or a central neurological disorder, the type of airway prosthesis used (tracheostomy or oro/nasal endotracheal tube) and the type of humidification applied (heated humidification or heat and moisture exchanger). The first three variables establish limits for respiratory rate, V_T and partial pressure of end‐tidal carbon dioxide (PETCO₂), and the latter two items determine the threshold to cycle into an SBT (ranging from 5 to 12 cm H₂O). SmartCare™ categorizes patients into one of eight diagnostic categories based on average measurements of these variables that are made every two to five minutes. With SmartCare™, patients may breathe with a respiratory rate ranging from 15 to 30 breaths/min (RR min), alternatively 34 breaths/min for patients with neurological disease (RR max), a V_T above a minimum threshold (V_T min = 250 mL if weight < 55 kg, or V_T min = 300 mL if weight > 55 kg) and a PETCO₂ below a maximum threshold (max PETCO₂ = 55 mmHg, or max PETCO₂ = 65 mmHg for patients with COPD). SmartCare™ ascribes a state of normal ventilation when a patient's ventilatory measurements fall within these constraints. If the patient's measured values fall outside of these constraints, an alternate diagnosis is made, and the system adjusts the level of PS provided up or down to achieve these targets.

SmartCare™ automatically initiates an SBT (or 'observation period') when predetermined PS thresholds are reached, provided the patient is in a state of normal ventilation and PEEP is < 5 cm H₂O. SBTs are of 30 minutes' to two hours' duration. Upon successful completion of an SBT, the ventilator issues a directive, stating that the patient is 'ready for separation from ventilator.' Clinicians must ensure that patients meet specific criteria before proceeding with the extubation. With the SmartCare™ system, clinicians control titration of FiO₂ and PEEP. Consequently, if PEEP is not titrated to ≤ 5 cm H₂O, an SBT will not be conducted. Clinicians can specify whether the automated algorithms are applied during the day only or continuously.

Why it is important to do this review

Regardless of the mode of ventilation used for weaning, limiting the duration of invasive ventilation and development of intubation‐related complications is an important goal in providing care for critically ill patients. Systems that automate weaning and SBT conduct obviate the need for clinicians to recognize and manually adjust ventilator settings to wean and conduct SBTs. Consequently, with automated systems, ventilator weaning is unencumbered by limited clinician availability in the busy ICU setting. In this review, we will identify, critically appraise and synthesize the best current evidence comparing automated weaning and SBT systems versus non‐automated weaning strategies in liberating critically ill adult patients from invasive ventilation.

Objectives

As secondary objectives, we ascertained differences between effects of alternative weaning strategies on clinical outcomes (time to successful extubation, time to first SBT and first successful SBT, mortality, ventilator‐associated pneumonia, total duration of ventilation, length of intensive care unit (ICU) and hospital stay, use of non‐invasive ventilation (NIV), adverse events and clinician acceptance).

We conducted a sensitivity analysis to evaluate variations in weaning time based on (4) the methodological quality (low or unclear versus high risk of bias) of the included studies.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials (RCTs) and quasi‐randomized trials comparing automated weaning and SBT systems versus non‐automated weaning strategies. Whereas an RCT was defined as a study that generates an unpredictable sequence for allocating participants to study groups (e.g. a random number table, computer‐generated random numbers, shuffling of envelopes, throwing of dice) (Higgins 2011), quasi‐randomized trials were defined as trials in which participants were allocated to treatment arms by alternate or predictable assignment.

Types of participants

We included trials investigating predominantly critically ill adults requiring invasive mechanical ventilation. We used authors' definitions of adult, as criteria for admission to adult ICUs may vary internationally. We did not restrict studies to specific population characteristics, including sex, age, race or the presence of selected risk factors. We excluded trials that evaluated participants requiring planned short‐term ventilation (i.e. postoperative patients) or exclusively tracheostomized participants.

Types of interventions

We included RCTs and quasi‐randomized trials that compared automated weaning and SBT systems versus non‐automated weaning strategies. Non‐automated strategies included usual care, standard care, protocolized care and other strategies (as defined by the study authors) but did not involve use of a nearly fully automated system. Recognizing that AC, intermittent mechanical ventilation (IMV), SIMV and pressure support (PS) ventilation are the most frequently used modes of weaning, we excluded modes that were not usually used for weaning (e.g. AutoFlow, Draeger Medical Inc.) and pressure‐regulated volume control (Maquet‐Dynamed, Tyco, Canada); nearly fully automated systems (e.g. Adaptive Support Ventilation (ASV), Hamilton Medical AG, Bonaduz, Switzerland); modes that switch from pressure control (PC) to PS (i.e. Automode, Siemens Medical Solutions, Erlangen, Germany); and strategies in which modifications of PS were linked to inspiratory flow (automatic tube compensation). We excluded studies that (1) compared alternative weaning strategies in the postoperative setting (i.e. planned short‐term ventilation for most participants, for example, cardiac surgical patients); (2) explored the use of NIV in this regard (i.e. extubation to NIV); (3) evaluated exclusively tracheostomized participants; or (4) explored the use of a nearly fully automated closed‐loop system (invasively or non‐invasively applied) in the control arm. If ambiguity existed as to what constituted a simple mode (set point control) without full automation, we referenced the classification system proposed by Chatburn et al (Chatburn 2004).

Types of outcome measures

Primary outcomes

The primary outcome was weaning time (time from randomization to extubation) as defined by the study authors.

Secondary outcomes

Secondary outcomes included:

time to successful extubation (time from randomization to successful extubation as defined by study authors);
time to first SBT and first successful SBT (time from randomization to first SBT and first successful SBT as defined by study authors);
mortality (the most protracted duration at time points reported by study authors);
VAP as defined by study authors;
total duration of ventilation (time from initiation of invasive ventilation to discontinuation or extubation) as defined by study authors;
Length of ICU stay;
use of NIV following extubation;
adverse events (including but not limited to reintubation, self‐extubation, requirement for tracheostomy and prolonged ventilation as defined by study authors);
clinician acceptance of alternative weaning strategies; and
length of hospital stay.

To be included, studies had to report at least one of the aforementioned primary or secondary outcomes.

Search methods for identification of studies

Electronic searches

We used database‐specific search strategies to search the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 5; (Appendix 1); MEDLINE (1966 to 31 May 2013) (Appendix 2); EMBASE (1988 to 31 May 2013) (Appendix 3); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 31 May 2013) (Appendix 4), Evidence‐Based Medicine Reviews (Appendix 5) and Ovid HealthSTAR (1999 to 31 May 2013) (Appendix 6) to identify potentially eligible trials. We based our search strategies on the optimally sensitive search strategies of The Cochrane Collaboration to identify RCTs in MEDLINE and EMBASE (Dickersin 1994; Lefebvre 2001; Robinson 2002). We combined our subject search terms in MEDLINE with the Cochrane highly sensitive search strategy for identifying RCTs, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We adapted our MEDLINE search strategy to other databases. We did not limit our search by language or publication status.

Searching other resources

We contacted the first authors of all included studies and content experts to obtain additional information on unpublished trials or trials in progress. We searched the bibliographies of all retrieved trials and review papers for potentially relevant trials. Additionally, we handsearched conference proceedings from five scientific meetings (Annual Congress of the European Society of Intensive Care Medicine (2001‐2012), College of Chest Physicians (2003‐2012), American Thoracic Society (2004‐2013), International Symposia of Intensive Care and Emergency Medicine and Critical Care Medicine (2004‐2013) and Critical Care Medicine (2004‐2012)) to identify abstracts of RCTs that met our inclusion criteria. Finally, we searched for ongoing trials on the following websites: www.controlled‐trials.com and http://clinicaltrials.gov.

Data collection and analysis

We utilized the methods of the Cochrane Anaesthesia Review Group. Two review authors (KB, FL) independently screened titles and abstracts identified by electronic and manual searches, and one review author each screened conference proceedings (JF) and trial registration websites (KB).

Selection of studies

Two review authors (KB, JF) retrieved and evaluated the full‐text versions of potentially relevant trials. Two review authors (KB, JF) independently selected trials that met the study inclusion criteria by using a checklist developed for this purpose (Appendix 7). We resolved disagreements through discussion and, if agreement could not be reached, in consultation with a third review author (ML). We recorded reasons for study exclusion in the Characteristics of excluded studies table. One review author (JF) handsearched conference proceedings.

Data extraction and management

The same two review authors (KB, JF) independently extracted data using a standardized data collection form (Appendix 7) that included information regarding name of first author, year of publication, study design, study population and study setting. In addition to information pertaining to participant characteristics, study inclusion and exclusion criteria, details of compared interventions, clinicians involved in implementing weaning strategies and study outcomes, we extracted information regarding study methodology. This included method of randomization, allocation concealment, frequency and handling of withdrawals and adherence to the intention‐to‐treat principle. Most trials used median and interquartile ranges as summary statistics for continuous outcomes, suggesting that data were skewed. When mean and standard deviation were not provided, we approximated the mean from the median and estimated the standard deviation as the interquartile range divided by 1.33 (Higgins 2011) to pool outcomes. We attempted to contact the first authors of all included trials to obtain missing data or to clarify study design features, when necessary. We resolved disagreements through discussion and in consultation with a third review author (ML) as required. We did not blind review authors to the names of study authors, investigators or institutions, nor were they blinded to study results.

Assessment of risk of bias in included studies

The quality of all included trials was assessed by two review authors (KB, JF), independently and in duplicate. We judged study quality on the basis of the following (Higgins 2011).

1. Was sequence generation truly random?

Adequate sequence generation included reference to a random number table, use of a computer random number generator, coin tossing, shuffling of cards or envelopes, throwing of dice, drawing of lots or minimization.

2. Was allocation adequately concealed?  Adequate allocation concealment included central randomization (e.g. allocation by a central office unaware of participant characteristics unless based on stratification), such as an on‐site computer system combined with allocation kept in a locked unreadable computer file that could be accessed only after the characteristics of an enrolled participant had been entered; sequentially numbered, sealed, opaque envelopes; or another, similar approach, which ensured that the person generating the allocation sequence did not administer it.

3. Was knowledge of the allocated interventions adequately prevented during the study?  Blinding of study participants and personnel from study intervention allocation after inclusion of participants is not feasible; however, we judged whether outcome assessors were separate from the individuals administering or supervising assigned interventions.

4. Were withdrawals described, and did they occur with similar frequency between intervention and control groups?

5. Were participants analysed according to the intervention to which they were allocated, whether or not they received it? Within studies, we described what was reported for each domain and contacted study authors for further information.

6. Were reports of the study free of the suggestion of selective outcome reporting?

7. Did the trial stop early for benefit? What was the impact of early stopping of the trial, if applicable?

Following evaluation, we assigned a judgement related to the risk of bias for each domain as follows.  a) Low risk of bias: all criteria met.  b) Unclear risk of bias: one or more criteria unclear.  c) High risk of bias: one or more criteria not applied or met.

A judgement of 'Yes' indicated low risk of bias, 'No' indicated high risk of bias and 'Unclear' indicated an unknown or unclear risk of bias.

For example, low risk of bias was assigned when allocation concealment was adequate (including central randomization, such as allocation by a central office unaware of participant characteristics unless based on stratification; an on‐site computer system combined with allocation kept in a locked unreadable computer file that could be accessed only after the characteristics of an enrolled participant had been entered; sequentially numbered, sealed, opaque envelopes; or other, similar approaches that ensured that the person who generated the allocation sequence did not administer it). We assigned unclear risk of bias when allocation concealment was unclear or when study authors did not clearly report their approach, and high risk of bias when allocation concealment was not applied. We evaluated the impact of methodological quality (low or unclear versus high risk of bias) on weaning time. We constructed a 'Risk of bias' (RoB) table to depict the results.

We used the principles of the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system (Guyatt 2008) to assess the quality of the body of evidence in our review associated with specific outcomes (weaning time, time to successful extubation, time to first SBT and first successful SBT, mortality, total duration of mechanical ventilation, length of ICU stay and reintubation) and constructed a 'Summary of findings' (SoF) table using GRADE software. The GRADE approach is used to appraise the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Assessment of the quality of a body of evidence considered within‐study risk of bias (methodological quality), directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias.

Two review authors (KB, JF) entered data into Review Manager (RevMan 5.1) for statistical analysis.

Measures of treatment effect

We summarized treatment effects using risk ratio (RR) and mean difference (MD) for binary and continuous outcomes, respectively.

Unit of analysis issues

We used proportions for binary outcomes and preferentially used mean and standard deviation, when reported or available through correspondence with study authors, in pooled analyses. Summary estimates constitute the unit of analysis in this review.

Dealing with missing data

For published reports with insufficient or ambiguous information, we contacted investigators to inquire about study methods and missing data.

Assessment of heterogeneity

We assessed clinical heterogeneity by judging, qualitatively, differences between studies with regard to participant populations enrolled, weaning strategies implemented and study outcomes reported. We conducted statistical tests of heterogeneity and assessed the impact of heterogeneity for each outcome using the I² statistic. This statistic describes the percentage of total variance across studies that is attributable to heterogeneity rather than chance (Higgins 2003). We considered an I² statistical threshold of 0% to 40%, 30% to 60%, 50% to 90% and > 75% to represent between study heterogeneity that might not be important, moderate, substantial or considerable, respectively (Higgins 2011). To limit overlap and to operationalize these thresholds, we considered the mutually exclusive I² intervals of 0% to 30%, 31% to 50%, 51% to 74% and > 75% to represent unimportant, moderate, substantial and considerable heterogeneity, respectively. For outcomes that were qualitatively similar, and in the absence of important heterogeneity, we performed meta‐analysis using random‐effects (RE) models and reported summary estimates along with their associated 95% confidence intervals (CIs).

Assessment of reporting biases

Publication bias occurs when published trials are not fully representative of all completed trials, as positive trials (large and small) tend to be published more often than negative trials, especially small negative trials. We examined funnel plots (a graphical display) for asymmetry and size of the treatment effect for the primary outcome against trial precision (one/standard error) to assess for publication bias, if sufficient (at least 10) studies were identified (Egger 1997).

Data synthesis

We used RE models to pool data quantitatively using Review Manager 5.1 software (RevMan 5.1) when studies were clinically similar overall. We summarized the evidence in the SoF table.

Among the included studies, interventions were continuously applied and outcomes were reported at multiple time points. We recognized that performance of multiple analyses increases the chance of spurious positive findings. Although many statistical approaches have been developed to adjust for multiple testing, no consensus has been reached regarding when multiplicity should be taken into consideration. Further, adjustments for multiple testing are not routinely conducted in systematic reviews. We highlighted the primary outcome and the six secondary outcomes in this protocol as key outcomes featured in the SoF table. We emphasized estimation of intervention effects rather than testing to determine them and considered planned subgroup analyses as exploratory in nature.

Subgroup analysis and investigation of heterogeneity

A priori, we planned to perform subgroup analyses to assess the impact of the following study design features on weaning time, length of ICU stay, mortality, VAP, use of NIV and reintubation.

Type of clinician principally involved in implementing the automated weaning strategy (i.e. registered respiratory therapist (RRT) versus other. including mixed clinicians), as defined by the study authors.
Type of ICU (i.e. medical‐surgical and purely surgical versus purely medical, including coronary care units), as defined by the study authors.
Type of non‐automated weaning strategy (predominantly protocolized versus predominantly non‐protocolized care or other), as defined by the study authors.

A priori, we anticipated that subgroup analyses would be underpowered. We viewed subgroup analyses as exploratory, given their tendency to generate misleading conclusions (Oxman 1992; Yusuf 1991). For these outcomes, we tested the differences in RR between subcategories using a Chi² test (Borenstein 2008). We considered P value < 0.05 to be statistically significant.

Sensitivity analysis

A priori, we planned a sensitivity analysis to assess the impact on weaning time of excluding studies with high risk of bias.

Results

Description of studies

Results of the search

We screened 2636 unique citations to identify 20 articles potentially meeting our inclusion criteria (Figure 1). Among these, we identified 13 randomized trials (Beale 2007; Bifulco 2008; Burns 2013a; Jiang 2006; Lellouche 2006; Lim 2012; Liu 2013; Ma 2010; Papirov 2007; Reardon 2011; Rose 2008; Stahl 2009; Wong 2008) potentially meeting our study inclusion criteria, including one quasi‐randomized trial (Jiang 2006). Through correspondence, one study author confirmed that the trial never started (Beale 2007), another acknowledged that the trial was stopped because of slow recruitment after enrolment of three participants (Wong 2008) and a final study author confirmed that the trial included exclusively tracheostomized participants and stopped prematurely because of the need to return the study ventilators (Papirov 2007). Five trials (Beale 2007; Papirov 2007; Reardon 2011; Stahl 2009; Wong 2008) were identified on trial registration websites. We identified no weaning and SBT systems used for weaning, as opposed to short‐term ventilation (e.g. postoperative patients), other than SmartCare™.

Included studies

Ten trials (Bifulco 2008; Burns 2013a; Jiang 2006; Lellouche 2006; Lim 2012; Liu 2013; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009) provided summary estimates and were included in this review. Of these, two trials were published in abstract form (Bifulco 2008; Lim 2012) and two were published in Chinese (Jiang 2006; Ma 2010). Two included trials were identified on trial registration websites (Reardon 2011; Stahl 2009), of which one provided partial study results (Reardon 2011). One trial was published in full and was available as a dissertation (Stahl 2009). Full details of participants, interventions and outcomes for each trial are provided in the Characteristics of included studies table.

Excluded studies

We excluded seven studies (Chen 2008; Donglemans 2007; Jolliet 2006; Jouvet 2007; Kataoka 2007; Schadler 2012; Taniguchi 2009) (see Characteristics of excluded studies), in addition to three aborted trials (Beale 2007; Papirov 2007; Wong 2008). The two review authors (KB, JF) achieved complete agreement on study selection. All study authors (Bifulco 2008; Burns 2013a; Jiang 2006; Lellouche 2006; Lim 2012; Liu 2013; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009) provided additional information regarding study methods or results.

Of the included trials, eight were single‐centre studies (Bifulco 2008; Jiang 2006; Lim 2012; Liu 2013; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009) and two were multi‐centre trials (Burns 2013a; Lellouche 2006). Trials were conducted in Australia (Rose 2008), Canada (Burns 2013a), China (Jiang 2006; Liu 2013; Ma 2010), Europe (Bifulco 2008; Lellouche 2006; Stahl 2009), Singapore (Lim 2012) and the United States (Reardon 2011). Study populations included medical or critical care unit (CCU) (Jiang 2006; Lim 2012; Reardon 2011), surgical (Stahl 2009), medical‐surgical (Bifulco 2008; Lellouche 2006; Liu 2013; Ma 2010), medical‐surgical trauma (Rose 2008) and multi‐disciplinary (Burns 2013a) participant populations. One trial (Jiang 2006) was conducted at a military hospital and included exclusively male participants.

Weaning candidates were identified daily during multi‐disciplinary rounds (Reardon 2011) after at least 24 hours (Bifulco 2008; Burns 2013a; Lellouche 2006; Lim 2012; Rose 2008; Stahl 2009) or more than 48 hours of mechanical ventilation (Ma 2010; Reardon 2011), or when the illness causing respiratory failure had been controlled (Jiang 2006). One trial (Jiang 2006) included 23 participants nasotracheally intubated and 15 who had a tracheostomy. Ten trials were screened daily or daily when feasible to identify weaning (Bifulco 2008; Burns 2013a; Jiang 2006; Lellouche 2006; Lim 2012; Liu 2013; Reardon 2011; Rose 2008; Stahl 2009) and SBT (Burns 2013a; Ma 2010) candidates. Whereas five trials included tolerance of PS or a formal PS trial (Bifulco 2008; Burns 2013a; Lellouche 2006; Lim 2012; Rose 2008) among their inclusion criteria, three trials included participants who had failed a prerandomization SBT (Burns 2013a; Liu 2013; Ma 2010). Four trials specified PS thresholds of 15 cm H₂O (Burns 2013a; Lellouche 2006; Lim 2012) or higher (Bifulco 2008; Lim 2012) with IPV ≤ 30 cm H₂O (Lim 2012), and another trial specified maximum pressure support of 20 cm H₂O to achieve V_T > 200 mL (Rose 2008). Prerandomization SBTs were conducted using T‐piece (Burns 2013a; Ma 2010), PS (Burns 2013a; Liu 2013) or continuous positive airway pressure (CPAP) (Burns 2013a; Liu 2013) and were of 30 to 120 minutes' duration (Burns 2013a; Liu 2013; Ma 2010). One trial used a staged process and included participants who tolerated a PS trial and were too early to undergo an SBT or had failed an SBT (Burns 2013a). Other trials specified inclusion of participants capable of initiating breaths (Reardon 2011) or of performing spontaneous breathing (Jiang 2006; Liu 2013; Ma 2010; Stahl 2009). Inclusion criteria also specified threshold PEEP levels ≤ 5 cm H₂O (Bifulco 2008; Jiang 2006; Liu 2013; Ma 2010), ≤ 8 cm H₂O (Lellouche 2006; Rose 2008), < 8 cm H₂O (Reardon 2011) or ≤ 10 cm H₂O (Burns 2013a; Lim 2012; Stahl 2009), as well as FiO₂ levels (Burns 2013a; Jiang 2006; Lellouche 2006; Lim 2012; Liu 2013; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009) or partial pressure of oxygen in arterial blood (PaO₂)/FiO₂ ratios (Bifulco 2008; Jiang 2006;Lim 2012; Liu 2013; Ma 2010; Rose 2008). Two trials (Lim 2012; Rose 2008) specified a plateau pressure ≤ 30 cm H₂O, and another trial (Lellouche 2006) specified among its inclusion criteria use of inspiratory pressures not greater than 30 cm H₂O. One trial specified inclusion of a volume‐ or pressure‐targeted mandatory mode for > 24 hours (Rose 2008), and others specified use of assisted modes of ventilation (Lellouche 2006; Lim 2012).

Control ventilation strategies of included studies

Control group ventilation strategies varied amongst the included trials. Trials specified comparing SmartCare™ versus an evidence‐based standard of care (Reardon 2011), a paper‐based weaning protocol (Burns 2013a; Ma 2010), a written weaning guideline (Liu 2013) and a conventional weaning protocol typically based on usual or local practice (Bifulco 2008; Jiang 2006; Lellouche 2006; Lim 2012; Rose 2008; Stahl 2009). One trial (Lellouche 2006) affirmed the presence of paper‐based weaning and SBT guidelines at four of five participating centres. Two trials specified use of SIMV with PS (Jiang 2006; Ma 2010), and five trials used PS (Burns 2013a; Liu 2013; Reardon 2011; Rose 2008; Stahl 2009) in the control arm if tolerated. Other trials used a combination of modes, including PS (predominant mode), ACV, SIMV and SBTs (T‐piece, PS or CPAP trials) (Lellouche 2006), initial ACV (rarely PCV) transitioned to SIMV with/without PS or PS alone with SBTs conducted at the discretion of physicians/RRTs (Lim 2012) and PS with T‐piece trials (Reardon 2011).

Support was gradually reduced in some trials (Bifulco 2008; Jiang 2006; Ma 2010; Stahl 2009). One trial titrated to a respiratory zone of comfort with no constraints as to the size or frequency of PS adjustments (Rose 2008), and another specified gradual reduction of PS with single steps of not more than 10 cm H₂O (Stahl 2009). In another trial (Burns 2013a), the level of PS was reevaluated at least every four to six hours and was titrated to avoid respiratory distress or need for assistance. One trial (Bifulco 2008) reduced PS by 2 cm H₂O based on clinical response, with frequency of reductions determined by clinicians. Selected trials reduced support to an SIMV rate of 4 breaths/min and PS 7 to 8 cm H₂O for two hours (alternatively, PS 5 cm H₂O in tracheostomized participants) (Ma 2010), PS of 10 cm H₂O with ≤ 5 cm H₂O PEEP for 30 minutes to two hours (Reardon 2011) or PS 7 cm H₂O (intubated patients) or 5 cm H₂O (tracheostomized participants) (Rose 2008). One trial (Reardon 2011) adjusted PS to maintain V_T of 6 to 8 cc/kg ideal body weight. Another trial (Jiang 2006) conducted SBTs while endeavouring to reduce time on mechanical ventilation until participants were ventilator free and returned participants to mechanical ventilation when respiratory rate > 32 breaths/min, heart rate > 100 beats/min or pulse oximetry (SpO₂) < 90%. Participants on PS were screened at least daily for SBTs in one trial (Burns 2013a). Four centres in another study (Lellouche 2006) used a combination of PS and SBTs for weaning, with one centre using PS to wean participants who could not tolerate an initial SBT and conducting SBTs in participants who were not weaned in PS mode.

Post‐randomization SBTs in the control arm weaning strategy were conducted using a T‐piece for five minutes following two hours of observation on SIMV with PS (Ma 2010) and either a two‐hour T‐piece trial or periods of ventilator disconnection with spontaneous breathing (Jiang 2006). Although SBTs were conducted on minimal PS (7 cm H₂O) for 60 minutes in one trial (Rose 2008), they were performed using a T‐piece (or trach mask) or CPAP (≤ 5 cm H₂O) or PS 5 to 7 cm H₂O with PEEP ≤ 5 cm H₂O (with heated humidification (HH)) or 10 to 12 cm H₂O with PEEP ≤ 5 cm H₂O (with heat and moisture exchangers (HMEs)) for 30 to 120 minutes in another trial (Burns 2013a). A final trial used PS < 7 cm H₂O or T‐piece trials in intubated participants and trach mask trials in participants with a tracheostomy (Liu 2013). Of four centres in one study (Lellouche 2006) with a weaning protocol, one conducted 20‐minute T‐piece trials up to two to three times per day following an initial SBT failure, while others conducted two‐hour SBTs on T‐piece or PS 7 cm H₂O daily for participants not in PS mode, or preferentially performed 30‐minute SBTs using PS 10 cm H₂O (alternatively, T‐piece or CPAP 5 cm H₂O) following at least twice‐daily screening. The final centre conducted SBTs using PS 7 cm H₂O (without HME) and 12 cm H₂O (with HME) or T‐piece for 30 minutes to two hours with daily screening (Lellouche 2006). In another trial (Reardon 2011), control participants were weaned with SBTs using T‐piece or PS ≤ 10 cm H₂O with PEEP ≤ 5 cm H₂O for 30 minutes to two hours. A final trial (Liu 2013) specified daily screening with conduct of 30‐minute SBTs with CPAP 5 cm H₂O alone or with added PS 5 to 8 cm H₂O.

Five trials permitted return to controlled or assist‐control ventilation upon meeting selected criteria (Burns 2013a; Lellouche 2006; Liu 2013; Reardon 2011; Stahl 2009), with one trial specifying that a single return to controlled ventilation and two weaning trials were permitted for each participant (Stahl 2009). Other trials specified use of volume‐controlled ventilation (Reardon 2011) in participants who no longer met weaning criteria or returned participants to SIMV with PS in the event of SBT intolerance (Ma 2010).

Physicians titrated ventilator support in six trials (Bifulco 2008; Jiang 2006; Lellouche 2006; Liu 2013; Ma 2010; Stahl 2009), with one trial (Jiang 2006) specifying that attending clinicians were responsible for implementing SmartCare™, while physicians not involved with the study implemented the control strategy. One trial (Bifulco 2008) specified that SmartCare™ was managed by physicians, including residents in training, who did not participate in the care or weaning of participants in the conventional arm. Another trial (Ma 2010) specified that the main research physician managed participants in the control arm and selected SmartCare™ settings. Two trials (Lim 2012; Liu 2013) specified that RRTs implemented the SmartCare™ strategy, and both RRTs and physicians (Lim 2012) or physicians (Liu 2013) implemented the control weaning strategy. Different physicians provided care to participants assigned to alternative study groups in one trial (Bifulco 2008). In another trial (Rose 2008), ventilator titration was performed primarily by nurses, with physicians directing participant care during twice‐daily structured rounds. In two trials conducted in North America (Burns 2013a; Reardon 2011), weaning was conducted primarily by RRTs with physician support.

SmartCare™ strategies

Few studies provided additional details pertaining to modifiable settings on the SmartCare™ weaning system. One study reported setting trigger sensitivity at 2 L/min and FiO₂ between 30% and 45% (Jiang 2006). Three trials did not permit night rest (Burns 2013a; Lellouche 2006; Stahl 2009), and two trials (Bifulco 2008; Ma 2010) activated the night rest option. One trial (Ma 2010) set PS at 5 to 15 cm H₂O, FiO₂ at 40% and PEEP at 3 cm H₂O, while another trial (Burns 2013a) set maximum inspiratory pressure at 35 cm H₂O, maximum respiratory rate at 40 breaths/min and level of end tidal carbon dioxide (ETCO₂) limits of 15 mmHg and 70 mmHg. This trial used a PEEP/FiO₂ chart in both study groups and clustered humidification strategies (HH and HME) within participating ICUs (Burns 2013a). Two trials (Bifulco 2008; Lellouche 2006) used passive humidification (HME) to warm inspired air, and one trial (Stahl 2009) used active humidification (HH).

Both weaning strategies

Sedation was administered at the discretion of the attending physician in one trial (Lellouche 2006), managed according to written sedation protocols titrated by critical care nurses to Richmond Agitation‐Sedation Scale (RASS) or the Riker Sedation‐Agitation Scale (SAS) scores in another trial (Burns 2013a) and managed by a sedation protocol with daily awakening in another trial (Liu 2013); sedation was not reported in the remaining trials (Bifulco 2008; Jiang 2006; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009).

Risk of bias in included studies

See Figure 2 and Characteristics of included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Random sequence generation (selection bias)

In all trials, allocation to treatment group was done by random assignment, with one trial assigning weaning strategies based on odd or even numbers distributed at hospital admission (Jiang 2006). One trial each specified use of the minimum balance index for randomization (based on the sequence of ICU admission) (Ma 2010) and a random digit table (Liu 2013). Seven trials reported using computer‐generated randomization sequence burns (Bifulco 2008; Burns 2013a; Lellouche 2006; Lim 2012; Rose 2008; Reardon 2011; Stahl 2009); of these, two trials (Reardon 2011; Rose 2008) used on‐line random number generator systems (www.randomization.com and www. random.org). One trial (Liu 2013) reported using a random number table.

Allocation

Two trials each reported use of sequentially numbered, sealed, opaque envelopes (Rose 2008; Stahl 2009); one trial used sequentially numbered, sealed envelopes held by the trial co‐ordinator/RRT (Lim 2012), and one trial used opaque envelopes (Reardon 2011). Group allocation was communicated by telephone in one trial (Bifulco 2008) and by electronic mail messages from a central site in two trials (Burns 2013a; Lellouche 2006). In one trial, allocation was not concealed (Jiang 2006). In another trial (Ma 2010), the minimum balance index based on gender, age and Acute Physiology and Chronic Health Evaluation (APACHE) score, with points assigned for each category, was used for allocation by assigning participants to the strategy with the lowest number of cumulative points. In two trials, allocation was the responsibility of both the researcher implementing the study (Ma 2010) and an RRT (Liu 2013) who held the randomization list. Once participants had been randomly assigned, one investigator (Ma 2010) confirmed that the assigned treatment was initiated, and another (Liu 2013) confirmed that physicians did not know the assigned treatment until the ventilator was brought to the bedside.

Blinding

Blinding was not possible given the nature of the interventions being investigated, and blinded outcome assessment was not reported in any trial. Individuals assessing outcomes were not separate from individuals supervising or administering the study interventions in all 10 trials (Bifulco 2008; Burns 2013a; Jiang 2006; Lellouche 2006; Lim 2012; Liu 2013; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009).

Incomplete outcome data

One investigator affirmed that participants dropped out of the study as the result of infection (e.g. VAP) or self‐extubation, and the distribution of withdrawals between treatment groups was unknown (Jiang 2006). This trial (Jiang 2006) reported on 13 participants in the smartcare (SC) arm and 25 in the SBT (control) arm, suggesting the potential for an imbalance between groups in terms of randomization or withdrawals. In another trial reporting on similar numbers of participants in each study arm, study authors (Ma 2010) affirmed participant attrition due to consent withdrawals and VAP, which occurred equally between treatment groups. Two additional trials reported study withdrawals (Bifulco 2008; Burns 2013a) and specified the number of withdrawals by group assignment. The largest trial (Lellouche 2006) reported that post randomization, two participants were withdrawn because extubation preceded electronic assignment, and one participant was excluded after consent was withdrawn, but treatment assignment was not specified. Meanwhile, one thesis (Stahl 2009) reported that the first 10 participants who failed an initial attempt at weaning were discontinued from the study. The protocol was subsequently modified to permit a second weaning attempt. Additionally, postrandomization withdrawals occurred with similar frequency between treatment groups (four per group). Through correspondence, we clarified that these 10 participants were included in the final analysis, and outcomes were included in the analyses when possible. Two trials (Reardon 2011; Rose 2008) reported no study withdrawals or dropouts. Five participants in the SmartCare™ group (20.8%) and four participants in the physician‐controlled local protocol group (16.7%) who died were not included in the analyses in one trial (Liu 2013). Similarly, although no participants were withdrawn in one trial (Lim 2012), one participant died and did not contribute data to selected outcomes.

Selective reporting

Outcome reporting was complete in five trials (Burns 2013a; Lellouche 2006; Liu 2013; Rose 2008; Stahl 2009), and summary data were provided through correspondence for a fifth trial (Ma 2010). The authors of two trials (Bifulco 2008; Jiang 2006) affirmed that they intended to collect additional outcomes, but fewer data were collected because of early stopping and limited personnel availability (Bifulco 2008) and as a result of transfer of the principal investigator to another hospital (Jiang 2006). We anticipated that selected ICU outcomes (duration of mechanical ventilation, ICU mortality and length of ICU stay) could have been reported in at least two trials (Jiang 2006; Ma 2010). One trial (Reardon 2011) reported partial trial results on a trial registration website, and another in an abstract publication (Lim 2012).

Other potential sources of bias

Stopping early for benefit

Three trials reached full recruitment (Burns 2013a; Jiang 2006; Lellouche 2006). One trial stopped early for benefit following an interim statistical analysis, which suggested that 40 to 50 participants would be sufficient (Liu 2013). Six trials stopped early for futility (Bifulco 2008; Lim 2012; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009) due to funding and/or personnel constraints (Bifulco 2008), time constraints and the need to fulfil graduate degree requirements (Ma 2010; Rose 2008; Stahl 2009), slow or delayed recruitment (Reardon 2011; Stahl 2009) and sample size recalculation (Rose 2008; Stahl 2009).

Analysis according to allocated weaning strategy

Nine trials reported or affirmed analysis of participants by treatment group assignment (Bifulco 2008; Burns 2013a; Lellouche 2006; Lim 2012; Liu 2013; Ma 2010; Reardon 2011; Rose 2008; Stahl 2009) while adhering to the intention‐to‐treat principle or a modified intention‐to‐treat principle as the result of withdrawals or deaths. Analysis by intention‐to‐treat was uncertain in one trial (Jiang 2006), with important imbalances reported between the numbers of participants in the treatment arms.

Effects of interventions

See: Table 1; Table 2

Summary of findings for the main comparison. Continuous outcomes automated versus non‐automated weaning.

SmartCare™ versus non‐automated weaning for weaning time in invasively ventilated critically ill adults
Patient or population: patients with weaning time in invasively ventilated critically ill adults  Settings:  Intervention: SmartCare™ versus non‐automated weaning
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect MD  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Average duration	Estimated duration
	Control	SmartCare™ versus non‐automated weaning
Weaning time (from randomization to extubation) based on ICU type: purely medical	Mean weaning time (from randomization to extubation) based on ICU type—purely medical—in the control groups was 13 days	Mean weaning time (from randomization to extubation) based on ICU type—purely medical—in the intervention groups was  4.78 lower  (6.2 to 3.36 lower)		38  (1 study)	⊕⊕⊕⊝  moderate^a
Weaning time (from randomization to extubation) based on ICU type: medical‐surgical or surgical only	Mean weaning time (from randomization to extubation) based on ICU type—medical‐surgical or surgical only—in the control groups was 3 to 11 days	Mean weaning time (from randomization to extubation) based on ICU type—medical‐surgical or surgical only—in the intervention groups was  1.85 lower  (2.67 to 1.04 lower)		457  (6 studies)	⊕⊕⊝⊝  low^a,b
Time to successful extubation	Mean time to successful extubation in the control groups was 1 to 10 days	Mean time to successful extubation in the intervention groups was  0.99 lower  (1.89 to 0.09 lower)		516  (7 studies)	⊕⊕⊝⊝  low^a,c
Time to first successful spontaneous breathing trial	Mean time to first successful spontaneous breathing trial in the control groups was 0 to 6 days	Mean time to first successful spontaneous breathing trial in the intervention groups was  1.72 lower  (6.23 lower to 2.78 higher)		175  (2 studies)	⊕⊕⊕⊝  moderate^d
Total duration of mechanical ventilation	Mean total duration of mechanical ventilation in the control groups was 3 to 17 days	Mean total duration of mechanical ventilation in the intervention groups was  1.68 lower  (3.33 to 0.03 lower)		521  (7 studies)	⊕⊕⊝⊝  low^a,c
Intensive care unit length of stay (based on type of control arm): predominantly protocolized control strategy	Mean intensive care unit length of stay based on type of control arm—predominantly protocolized control strategy—in the control groups was 23 to 37 days	Mean length of intensive care unit stay based on type of control arm—predominantly protocolized control strategy—in the intervention groups was  9.84 lower  (17.02 to 2.66 lower)		337  (4 studies)	⊕⊕⊝⊝  low^a,c
Intensive care unit length of stay (based on type of control arm): predominantly non‐protocolized control strategy	Mean intensive care unit length of stay based on type of control arm—predominantly non‐protocolized control strategy—in the control groups was 10 to 20 days	Mean intensive care unit length of stay based on type of control arm—predominantly non‐protocolized control strategy—in the intervention groups was  1.26 lower  (4.1 lower to 1.59 higher)		162  (2 studies)	⊕⊕⊕⊝  moderate^c
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval.
GRADE Working Group grades of evidence.  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Criterion	SmartCare™ group (n= )	Control group 1 (n= )	Control group 2 (n= )
No. randomly assigned
No. analysed
Reasons for differences (if any)
Inclusion criteria	______________________________________________________________ ______________________________________________________________ ______________________________________________________________ ______________________________________________________________
Exclusion criteria	______________________________________________________________ ______________________________________________________________ ______________________________________________________________ ______________________________________________________________ ______________________________________________________________

Did the study include readiness to wean criteria? (If yes, please list) Did the study screen daily for these criteria?	□ Yes □ Unclear □ No _________________________________________________________ _________________________________________________________ _________________________________________________________ _________________________________________________________ _________________________________________________________ _________________________________________________________ _________________________________________________________ □ Yes □ Unclear □ No
Did the study include an SBT? If yes, what technique was used for the SBT? (e.g. PS, T‐tube, CPAP, other, not specified) If yes, what was the duration of SBT? If yes, criteria for SBT failure provided?	□ Yes □ Unclear □ No _________________________________________________________ _________________________________________________________ _________________________________________________________ □ Yes □ Unclear □ No If yes, please list criteria: _________________________________________________________ _________________________________________________________ _________________________________________________________ _________________________________________________________ _________________________________________________________
Control arm weaning strategy Control strategy described? If yes, how was weaning guided in the control arm? If yes, what mode or technique was used in the control arm? Type of clinician responsible for implementing the control strategy? (check ALL that apply)	□ Yes □ Unclear □ No □ Protocol □ Usual practice (clinician discretion) □ Other, please specify______________________________________ _________________________________________________________ _________________________________________________________ □ SIMV □ PS □ Daily T‐piece □ Intermittent (multiple daily) T‐piece □ Combination of the above, please specify ________________________________________________________ □ Other, please specify ________________________________________________________ □ Physician □ Nurse □ Respiratory therapist □ Kinesiotherapist □ Other, specify___________________________________________ □ Mixed, specify___________________________________________
SmartCare™ weaning arm Was SmartCare™ used in the intervention arm? Type of clinician responsible for implementing SmartCare™ strategy? (check ALL that apply)	□ Yes □ Unclear □ No □ Physician □ Nurse □ Respiratory therapist □ Kinesiotherapist □ Other, specify___________________________________________ □ Mixed, specify___________________________________________

Weaning time (time from randomization to extubation)	□ Yes □ Unclear □ No
Time to successful extubation	□ Yes □ Unclear □ No
Time to first SBT	□ Yes □ Unclear □ No
Time to first successful SBT	□ Yes □ Unclear □ No
Mortality time point #1 __________ time point #2__________ time point #3__________	□ Yes □ Unclear □ No □ Yes □ Unclear □ No
Ventilator‐associated pneumonia	□ Yes □ Unclear □ No
Total duration of mechanical ventilation (from initiation to extubation)	□ Yes □ Unclear □ No
Length of ICU stay	□ Yes □ Unclear □ No
Length of hospital stay	□ Yes □ Unclear □ No
Use of non‐invasive ventilation following extubation	□ Yes □ Unclear □ No
Adverse events: (please check) reintubation self‐extubation requirement for tracheostomy prolonged mechanical ventilation _________days other (specify) ____________________________	□ Yes □ Unclear □ No □ Yes □ Unclear □ No □ Yes □ Unclear □ No □ Yes □ Unclear □ No □ Yes □ Unclear □ No
Clinician acceptance of weaning strategies	□ Yes □ Unclear □ No

Outcomes	Unit of measurement	Intervention group			Control group				95% CI or additional information
		n	Mean (SD)	Median (IQR)	n	Mean (SD)	Median (IQR)	P value	95% CI or additional information
Weaning time (time from randomization to extubation)
Time to successful extubation
Time to first SBT
Time to first successful SBT
Total duration of mechanical ventilation (from initiation to extubation)
Length of ICU stay
Length of hospital stay
Clinician acceptance of weaning strategies
Other, please specify _____________________________

Outcomes	Intervention group (n = )	Control group (n = )	P value	Additional information
Mortality time point #1
Mortality time point #2
Mortality time point #3
Ventilator‐associated pneumonia
Use of non‐invasive ventilation following extubation
Adverse events: Reintubation Self‐extubation Requirement for tracheostomy Prolonged mechanical ventilation _________days Other (specify) _________________________
Other outcome, please specify

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Weaning time (randomization to extubation) based on type of control arm	7	495	Mean Difference (IV, Random, 95% CI)	‐2.68 [‐3.99, ‐1.37]
1.1 Predominantly protocolized control strategy	4	325	Mean Difference (IV, Random, 95% CI)	‐2.57 [‐4.26, ‐0.88]
1.2 Predominantly non‐protocolized control strategy	3	170	Mean Difference (IV, Random, 95% CI)	‐2.59 [‐4.75, ‐0.43]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Most protracted measure of mortality (based on type of control arm)	6	470	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.74, 1.79]
1.1 Predominantly protocolized control strategy	3	275	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.83, 1.75]
1.2 Predominantly non‐protocolized control strategy	3	195	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.20, 5.96]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Ventilator‐associated pneumonia (based on clinician type)	4	337	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.64, 1.21]
1.1 RRT clinicians	2	131	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.32, 1.28]
1.2 Other clinicians	2	206	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.67, 1.37]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Length of intensive care unit stay (based on type of control arm)	6	499	Mean Difference (IV, Random, 95% CI)	‐5.70 [‐10.54, ‐0.85]
1.1 Predominantly protocolized control strategy	4	337	Mean Difference (IV, Random, 95% CI)	‐9.84 [‐17.02, ‐2.66]
1.2 Predominantly non‐protocolized control strategy	2	162	Mean Difference (IV, Random, 95% CI)	‐1.26 [‐4.10, 1.59]
2 Total duration of mechanical ventilation	7	521	Mean Difference (IV, Random, 95% CI)	‐1.68 [‐3.33, ‐0.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Use of noninvasive ventilation following extubation (based on type of control arm)	4	377	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.44, 1.06]
1.1 Predominantly protocolized control strategy	3	275	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.35, 0.93]
1.2 Predominantly non‐protocolized control strategy	1	102	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.50, 3.57]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Use of non‐invasive ventilation following extubation (based on clinician type)	4	377	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.44, 1.06]
1.1 RRT clinicians	2	131	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.31, 2.09]
1.2 Other clinicians	2	246	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.30, 1.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse event: reintubation (based on type of control arm)	6	491	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.64, 1.22]
1.1 Predominantly protocolized control strategy	4	337	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.58, 1.19]
1.2 Predominantly non‐protocolized strategy	2	154	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.55, 2.24]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Weaning time (randomization to extubation) based on type of control arm	5	418	Mean Difference (IV, Random, 95% CI)	‐2.14 [‐3.20, ‐1.07]
1.1 Predominantly protocolized control strategy	3	286	Mean Difference (IV, Random, 95% CI)	‐3.94 [‐6.10, ‐1.78]
1.2 Predominantly non‐protocolized control strategy	2	132	Mean Difference (IV, Random, 95% CI)	‐1.67 [‐2.67, ‐0.66]

Methods
Participants	Ventilated for at least 24 hours Eligible for discontinuation of mechanical ventilation using usual criteria for weaning readiness Successful preinclusion test with PS > 15 cm H₂O
Interventions	SmartCare™ versus conventional weaning protocol (used in ICU)
Outcomes	Weaning time (time from randomization to extubation) Total duration of mechanical ventilation (from initiation to extubation)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐based central randomization (statistics department)
Allocation concealment (selection bias)	Low risk	Study arm communicated by telephone
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Individuals assessing outcomes were not separate from individuals supervising or administering the study interventions
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Two withdrawals from the SmartCare™ arm were reported, and one withdrawal from the control arm, representing 3 of 30 (10%) participants
Selective reporting (reporting bias)	Unclear risk	Minimal outcomes collected because of early stopping and limited availability of personnel. Study authors confirmed that they intended to collect data on VAP rate, duration of mechanical ventilation and mortality
Did the trial stop early for benefit?	Low risk	Stopped early because of limited funding and personnel
Participants analysed according to the group allocated to?	Low risk	All participants with data were included in the analysis on the basis of treatment assignment. A modified intention‐to‐treat analysis was conducted because of study withdrawals

Methods
Participants	Invasive mechanical ventilation > 24 hours At least partial reversal of condition precipitating invasive ventilation Stabilization of other organ system failures SpO₂ ≥ 90% with FiO₂ ≤ 0.7 with PEEP ≤ 12 cm H₂O Weight > 35 kg Successful completion of pressure support trial after 60 to 120 minutes and either too early for an SBT or for successful completion of an SBT Excluded: Patients younger than 16 years Declining intubation or with anticipated withdrawal of life support Prolonged cardiac arrest Prior ventilation > 24 hours during the same hospitalization Tracheostomy Known or suspected severe myopathy or neuropathy, quadriplegia Severe heart failure Pregnancy
Interventions	SmartCare™ versus paper‐based weaning protocol
Outcomes	Weaning time (time from randomization to extubation) Time to successful extubation Time to first SBT Time to first successful SBT Time from initiation to randomization Time to reintubation Length of ICU stay Length of hospital stay ICU mortality Hospital mortality Death on mechanical ventilation Ventilator‐associated pneumonia (nosocomial pneumonia) Use of non‐invasive ventilation following extubation Adverse event: reintubation Adverse event: self‐extubation Adverse event: tracheostomy Prolonged mechanical ventilation > 21 days Clinician acceptance
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, central randomization. Stratified by centre, COPD and central neurological disease. If both COPD and central neurological disease, the latter was prioritized
Allocation concealment (selection bias)	Low risk	Electronic mail system
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Research co‐ordinators and respiratory therapists assessed and recorded study outcomes; were not separate from individuals supervising or administering the study interventions
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Two protocolized weaning and 3 automated weaning participants were withdrawn immediately after randomization. In addition, 2 automated weaning participants were withdrawn while on protocol. Outcomes for the latter participants were included in the analysis
Selective reporting (reporting bias)	Low risk	Study authors reported all primary and secondary outcomes
Did the trial stop early for benefit?	Low risk	Target sample size was 90
Participants analysed according to the group allocated to?	Low risk	Participants were maintained in the group to which they were assigned for analysis. All participants with data were analysed according to treatment assignment. A modified intention‐to‐treat analysis was conducted because of study withdrawals

Methods
Participants	Underlying disease that caused respiratory failure had been controlled P/F ratio > 200 mmHg, PEEP ≤ 5 cm H₂O, FiO₂ ≤ 0.40 Stable haemodynamics with no acute pulmonary oedema or hypotension and no vasoconstrictive medications Capable of spontaneous breathing
Interventions	SmartCare™ versus spontaneous breathing trials/periods of spontaneous breathing
Outcomes	Weaning time (time from randomization to extubation) Time from initiation to randomization Clinician workload (blood gas sampling) Prolonged mechanical ventilation > 7 days Prolonged mechanical ventilation > 14 days
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Pseudorandomized
Allocation concealment (selection bias)	High risk	Based on number (odd/even) assigned at hospital admission
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Attending physicians were responsible for implementing SmartCare™ while physicians not involved with the study implemented the control strategy; study personnel were not blinded to treatment assignment
Incomplete outcome data (attrition bias)   All outcomes	High risk	Withdrawals occurred as the result of ventilator‐associated infection and self‐extubation. We are uncertain as to numbers and distribution of withdrawals between the 2 treatment groups. This trial reported on 13 participants in the SC arm and 25 in the SBT (control) arm, suggesting the potential for an imbalance between groups in randomization or withdrawals
Selective reporting (reporting bias)	Unclear risk	Did not report key outcomes including total duration of mechanical ventilation, ICU mortality, length of ICU stay and adverse events. Study author affirmed that he left the hospital; however, data on outcomes pertaining to ICU stay could have been reported
Did the trial stop early for benefit?	Low risk	Study authors intended to enrol in the trial 10 to 20 participants, presumably per arm
Participants analysed according to the group allocated to?	Unclear risk	Unsure whether participants were analysed according to treatment assignment, given discrepancy in number of participants included in each study arm. It is likely that not all randomly assigned participants were included, but we are uncertain as to whether participants were analysed by the group to which they were assigned

Methods
Participants	Mechanical ventilation for at least 24 hours and ventilated using an assisted mode 18 to 85 years old could be enrolled at an early stage when plateau pressure < 30 cm H₂O with tidal volume ≤ 8 cc/kg on assist‐control ventilation, PEEP ≤ 8 cm H₂O and P/F ratio > 150 or SaO₂ > 90% with FiO₂ ≤ 0.5 Epinephrine or norepinephrine ≤ 1000 mcg/h Body temperature > 36°C and < 39°C Stable neurological status with Glasgow Coma Scale > 4 on little or no sedation Excluded: Do not resuscitate order or expected poor short‐term prognosis Tracheostomy Cardiac arrest with poor neurological prognosis Pregnancy
Interventions	SmartCare™ versus usual care
Outcomes	Weaning time (time from randomization to extubation) Time to successful extubation Total duration of mechanical ventilation (from initiation to extubation) Time from initiation to randomization Length of ICU stay Length of hospital stay ICU mortality Hospital mortality Death on mechanical ventilation Ventilator‐associated pneumonia Use of non‐invasive ventilation following extubation Adverse event: reintubation Adverse event: self‐extubation Adverse event: tracheostomy Adverse event: pneumothorax Prolonged mechanical ventilation > 14 days Prolonged mechanical ventilation > 21 days
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomization system
Allocation concealment (selection bias)	Low risk	Electronic mail from central site
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Site investigators assessed and recorded study outcomes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Two participants were withdrawn because extubation preceded electronic assignment, and 1 participant was excluded after consent was withdrawn. Assigned treatment groups for these 3 participants were not provided
Selective reporting (reporting bias)	Low risk	All outcomes reported
Did the trial stop early for benefit?	Low risk	Intended to enrol 75 participants per group
Participants analysed according to the group allocated to?	Low risk	Analysed according to assigned strategy; however, 1 study withdrawal and 1 participant extubated before electronic assignment were reported

Methods
Participants	Single‐centre study involving a coronary care unit and including participants between 21 and 85 years of age, with stable neurological status, on an assisted mode of mechanical ventilation for > 24 hours Excluded: Poor short‐term prognosis Pregnant Haemodynamically unstable
Interventions	Participants were randomly assigned 1:1 to knowledge‐based weaning (SmartCare™) or usual care APACHE II score was used to stratify illness severity
Outcomes	Primary outcome: total weaning time (from inclusion to extubation without reintubation for 72 hours) Adjusted for APACHE II score Total duration of mechanical support
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomization
Allocation concealment (selection bias)	Low risk	Sequentially numbered, sealed envelopes held by trial co‐ordinator/RRT or designate
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Study co‐ordinators collected outcome data
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No participant withdrew from the study. Only one death prevented computation of time to extubation. Total of 5 deaths occurred during the study
Selective reporting (reporting bias)	Unclear risk	Yes, reported outcomes were limited in this abstract publication. Study author provided additional data for the 62 participants ultimately included in this trial (originally 54 participants) and reported time to successful extubation and total duration of mechanical ventilation
Did the trial stop early for benefit?	Low risk	Stopped early for futility. Investigators sought to recruit 75 participants per study arm
Participants analysed according to the group allocated to?	Low risk	Yes. No participant was withdrawn following randomization, and no cross‐overs occurred; however, 1 participant who died was excluded from the outcome analyses

Methods
Participants	48 participants who failed an initial SBT (identified using daily screening) were randomly assigned to computer‐driven weaning with SmartCare™ or physician‐controlled local practice Excluded: Age < 18 or > 85 years Informed consent unavailable Treatment abandonment or expected poor short‐term prognosis Tracheostomy (before enrolment)
Interventions	Participants were randomly assigned to SmartCare™ weaning or physician‐controlled local practice guided by a local, written weaning guideline
Outcomes	Weaning time (randomization to first extubation) with and without NIV Total duration of mechanical ventilation Length of ICU stay ICU mortality Ventilator‐associated pneumonia Use of non‐invasive ventilation following extubation Adverse event: self‐extubation Adverse event: reintubation (within 48 hours) Adverse event: tracheostomy Prolonged mechanical ventilation > 7 days Prolonged mechanical ventilation > 21 days
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random digit table developed by investigative team
Allocation concealment (selection bias)	High risk	Randomization list was held by RRT. Physicians involved in caring for participants did not know the enrolled group until they saw the ventilator at the bedside; however, the implementing RRT held the list of random digits
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	RRTs, not blinded to treatment assignment, assessed outcomes
Incomplete outcome data (attrition bias)   All outcomes	High risk	Data on 9 participants (5 intervention group; 4 control group) who died before extubation were not included in the final analysis
Selective reporting (reporting bias)	Low risk	No evidence of selective outcome reporting
Did the trial stop early for benefit?	High risk	Stopped early for benefit. Study authors intended to enrol 100 participants but stopped after an interim analysis, which suggested that 40 to 50 participants would be sufficient
Participants analysed according to the group allocated to?	Low risk	Yes. All participants with data were analysed according to treatment assignment. A modified intention‐to‐treat analysis was conducted because of study withdrawals

Methods
Participants	Age ≥ 18 years Not ventilated at time of ICU admission Ventilation time > 48 hours Improvement in condition after treatment Stable vital signs Participants meeting following criteria for weaning: Causes for respiratory failure and mechanical ventilation have been resolved or significantly improved P/F ratio > 200 ; PEEP ≤ 5 cm H₂O; FiO₂ ≤ 0.4; pH ≥ 7.25 (or for COPD, pH ≥ 7.30, PaO₂ > 50 mmHg, FiO₂ < 0.35) Haemodynamic stability, mean arterial pressure ≥ 65 mmHg without use of vasoactive drugs and no sedatives within 24 hours Ability to breathe independently Significantly improved pulmonary symptoms and chest x‐ray with no new infections Did not include participants who passed an SBT
Interventions	SmartCare™ (SC) versus synchronized intermittent mandatory ventilation, pressure ventilation (SP) group with T‐piece trials
Outcomes	Weaning time (time from randomization to extubation) Length of ICU stay Clinician workload (ventilator adjustments per participant) Ventilator‐associated pneumonia Adverse event: reintubation Adverse event: tracheostomy Adverse event: pneumothorax Adverse event: other—subcutaneous emphysema
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Minimum balance index based on ICU admission sequence
Allocation concealment (selection bias)	Unclear risk	Strategy for allocation was based on gender, age, APACHE score, with points assigned to each category (gender: M vs F, age 18 to 44, 45 to 64, ≥ 65 and APACHE < 10, 11 to 15, > 15). Theoretical permutations were run (if assigned to SC or SP weaning), and permutation with lowest cumulative number of points determined treatment assignment for the next participant. Allocation was the responsibility of the researcher implementing the study. Participant assignment was not changed or reconsidered following randomization (i.e. cross‐overs)
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	One investigator assessed and recorded study outcomes
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Study withdrawals were due to consent withdrawal and VAP. We are uncertain of the numbers, but study authors confirmed that they were equally distributed between treatment groups. This study reported on 30 participants in the SC arm and 32 in the SP (control) arm
Selective reporting (reporting bias)	Low risk	Study author did not report summary continuous outcomes but provided subgroup data to enable computation of weaning time and length of ICU stay. This trial followed participants in the ICU but did not report ICU mortality
Did the trial stop early for benefit?	Low risk	Stopped early for futility. Study authors intended to enrol 100 participants. However, because of time constraints and graduate degree requirements, the trial was stopped early
Participants analysed according to the group allocated to?	Low risk	Study author confirmed that participants were analysed according to treatment assignment at admission

PERMALINK

Automated weaning and SBT systems versus non‐automated weaning strategies for weaning time in invasively ventilated critically ill adults

Karen EA Burns

Francois Lellouche

Rosane Nisenbaum

Martin R Lessard

Jan O Friedrich

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Risk of bias in included studies

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Continuous outcomes automated versus non‐automated weaning.

Summary of findings 2. Binary outcomes: automated versus non‐automated weaning.

1.1. Analysis.

2.1. Analysis.

3.1. Analysis.

4.1. Analysis.

5.1. Analysis.

6.1. Analysis.

8.1. Analysis.

9.1. Analysis.

7.1. Analysis.

10.1. Analysis.

11.1. Analysis.

12.1. Analysis.

14.1. Analysis.

15.1. Analysis.

16.1. Analysis.

17.1. Analysis.

18.1. Analysis.

19.1. Analysis.

Methods
Participants	Age > 18 years Initiated on mechanical ventilation via endotracheal tube Admitted to medical intensive care unit and medical intensive care unit team Required mechanical ventilation for longer than 48 hours Meets specified weaning criteria Excluded: Do not resuscitate or do not intubate order Pregnancy Mechanical ventilation initiated at another hospital Cardiac arrest for longer than 5 minutes with poor neurological prognosis Tracheostomy
Interventions	SmartCare™ versus evidence‐based standard of care for mechanical ventilation discontinuation (weaned with T‐piece SBTs or with PS)
Outcomes	Time to successful extubation Mortality: 28 day Composite of death during weaning, ventilator‐associated pneumonia during weaning, self‐extubation and reintubation (not reported separately) Adverse event: other—serious adverse events Adverse event: other—other adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Used an on‐line random number generator (www.random.org) with permuted blocks of 4, stratified by cause of respiratory failure (neurological, obstructive lung disease or other)
Allocation concealment (selection bias)	Low risk	Opaque envelopes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Site investigators and study co‐ordinators ascertained and recorded outcomes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No withdrawals nor dropouts reported
Selective reporting (reporting bias)	Unclear risk	Results of this trial are not fully published. Study authors intended to collect data on (1) primary outcome: weaning duration and (2) secondary outcomes: ICU stay, total duration of mechanical ventilation, hospital stay, inpatient mortality, sedation requirements, number of SBTs before extubation and complications (including death during weaning, VAP, self‐extubation and reintubation as a composite outcome) Limited results reported on trial registration website (www.clinicaltrials.gov) include weaning duration, hospital deaths, complications (composite outcome) and serious adverse event rate and other adverse events
Did the trial stop early for benefit?	Low risk	Trial was stopped because of slow study recruitment (i.e. for futility)
Participants analysed according to the group allocated to?	Low risk	Study authors reported using an intention‐to‐treat analysis on www.clinicaltrials.gov

Methods
Participants	Mechanical ventilation with volume‐ or pressure‐targeted mandatory modes for > 24 hours Drager Evita XL ventilator with SmartCare™/PS (v 1.1) software available for use immediately before randomization PEEP ≤ 8 cm H₂O P/F ratio > 150 mmHg or SaO₂ ≥ 90% with FiO₂ ≤ 0.50 Plateau pressure ≤ 30 cm H₂O Haemodynamic stability (epinephrine or norepinephrine ≤ 16.5 mcg/min or dopamine ≤ 500 mcg/min) Body temperature 36°C to 39°C Stable neurological status with Glasgow Coma Scale > 4 No anticipated requirement for transport or surgery within 2 hours Successful completion of SBT using PS (max 20 cm H₂O) to achieve V_T > 200 mL
Interventions	SmartCare™ versus usual care
Outcomes	Time to successful extubation Time to first successful SBT Total duration of mechanical ventilation (from initiation to extubation) Time from meeting criteria for discontinuation to actual extubation Length of ICU stay Length of hospital stay Mortality before separation potential Mortality before successful extubation Use of non‐invasive ventilation following extubation Adverse event: reintubation Adverse event: tracheostomy Prolonged mechanical ventilation > 14 days
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Website‐based (www.randomization.com) computer‐generated randomization
Allocation concealment (selection bias)	Low risk	Sequentially numbered, sealed opaque envelopes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Principal study investigator assessed and recorded study outcomes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Data from all randomly assigned participants were included in the analyses
Selective reporting (reporting bias)	Low risk	All outcomes reported
Did the trial stop early for benefit?	Low risk	Target sample was 222, of which 102 participants were enrolled. Trial was stopped early for futility based on graduate degree requirements and sample size recalculation
Participants analysed according to the group allocated to?	Low risk	Analyses were performed on an intention‐to‐treat basis

Methods
Participants	Age 18 to 80 years Body weight between 35 kg and 200 kg Invasively mechanical ventilated via endotracheal tube or tracheostomy for ≥ 24 hours Ramsey Score ≤ 3 Spontaneous breathing mode with PEEP ≤ 10 Sufficient arterial oxygenation with PaO₂ > 55 mmHg/75 cm H₂O or SaO₂ > 90% on FiO₂ ≤ 0.50. Haemodynamically stable (dopamine < 5 mcg/kg/min) Rectal temperature ≤ 39°C Haemoglobin ≥ 70 g/L pH > 7.20
Interventions
Outcomes	Time to successful extubation Total duration of mechanical ventilation (from initiation to extubation) Time from initiation to randomization Time to reintubation Length of ICU stay Clinician workload (physician changes in ventilator settings, FiO₂, PEEP and nurses' cleaning of cuvette) ICU mortality Hospital mortality Adverse event: reintubation Proportion successfully extubated
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Study authors used a computer‐generated randomization system (Rita software (version 1.13a))
Allocation concealment (selection bias)	Low risk	Sealed, opaque, sequentially numbered envelopes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Individuals assessing outcomes were not separate from individuals supervising or administering study interventions
Incomplete outcome data (attrition bias)   All outcomes	Low risk	First 10 participants who failed an initial attempt at weaning were discontinued from the study. The protocol was subsequently modified to permit a second weaning attempt. Dropouts occurred with similar frequency between study groups (4 per group) post randomization (8/60 (13.3%)), and their outcomes were included in the analyses when possible. These 8 participants could not be extubated. The first 10 participants who failed an attempt at weaning were included in the final analyses
Selective reporting (reporting bias)	Low risk	All outcomes were reported
Did the trial stop early for benefit?	Low risk	Stopped early for futility after 60 of 108 planned participants were enrolled
Participants analysed according to the group allocated to?	Low risk	Yes, study authors adhered to the intention‐to‐treat principle

Study	Reason for exclusion
Beale 2007	This 500‐participant trial, identified on a trial registration website, proposed to compare the intensive care unit (ICU) standard ventilator weaning protocol versus the SmartCare™ automated weaning system in patients likely to need mechanical ventilation for a period of 48 hours, but it was never launched
Chen 2008	This non‐randomized trial compared 109 participants who were treated with adaptive support ventilation versus 110 participants whose condition was managed by a respiratory therapist–driven protocol
Donglemans 2007	This trial compared adaptive support ventilation versus pressure control/pressure support in 122 fast‐track coronary artery bypass surgery participants. The trial did not evaluate SmartCare™
Jolliet 2006	This feasibility study was non‐randomized and reported on the use of SmartCare™ during non‐invasive ventilation in participants with acute respiratory failure
Jouvet 2007	This randomized single‐centre trial evaluated SmartCare™ in a paediatric population
Kataoka 2007	This retrospective study reported on the experience of a single centre in using SmartCare™ after off‐pump coronary artery bypass surgery for early extubation
Papirov 2007	This 60‐participant pilot randomized controlled trial (RCT) was designed to compare computer‐driven weaning with SmartCare™ versus physician‐directed weaning in elderly patients at a geriatric rehabilitation hospital and regional weaning centre (non‐ICU setting). To be included, patients had to have stabilization of the acute health problems that prompted admission to the referral hospital. The study was terminated after an undisclosed number of participants had been enrolled because of a request to return the study ventilators. The trial was excluded, as it included exclusively tracheostomized participants (confirmed by study author)
Schadler 2012	This study evaluated SmartCare™ in a postoperative population
Taniguchi 2009	This trial compared manual versus automatic reduction in pressure support in a randomized trial of 106 postoperative participants. The automated system used mandatory rate ventilation with a Taema‐Horus Ventialtor (Air Liquid, France)
Wong 2008	This randomized trial, identified on a trial registration website, was stopped for futility after 3 participants were enrolled over 18 months despite attempts to modify study inclusion criteria