Efficacy of Physiotherapy Interventions on Weaning in Mechanically Ventilated Critically Ill Patients: A Systematic Review and Meta-Analysis

Mechanical ventilation (MV) is currently considered a life-saving intervention. However, growing evidence highlighted that prolonged MV significantly affects functional outcomes and length of stay. In this scenario, controversies are still open about the optimal rehabilitation strategies for improving MV duration in ICU patients. In addition, the efficacy of physiotherapy interventions in critical ill patients without positive history of chronic respiratory conditions is still debated. Therefore, this systematic review of randomized controlled trials (RCTs) with meta-analysis aimed at characterizing the efficacy of a comprehensive physiotherapy intervention in critically ill patients. PubMed, Scopus, and Web of Science databases were systematically searched up to October 22, 2021 to identify RCTs assessing acute patients mechanical ventilated in ICU setting undergoing a rehabilitative intervention. The primary outcomes were MV duration, extubation, and weaning time. The secondary outcomes were weaning successful rate, respiratory function, ICU discharge rate and length of stay. Out of 2503 records, 12 studies were included in the present work. The meta-analysis performed in 6 RCTs showed a significant improvement in terms of MV duration (overall effect size: −3.23 days; 95% CI = −5.79, −0.67, p = 0.01; Z = 2.47) in patients treated with a comprehensive physiotherapy intervention including early mobilization, positioning, airway clearance techniques, lung expansion and respiratory muscle training. The quality assessment underlined 9 studies (75%) of good quality and 3 studies of fair quality according to the PEDro scale. In conclusion, our results provided previously unavailable data about the role of comprehensive physiotherapy intervention in improving MV duration in critical ill patients without chronic respiratory conditions. Further studies are needed to better characterize the optimal combination of rehabilitation strategies enhancing the improvements in critical ill patients without chronic respiratory disorders.

Mechanical ventilation (MV) is currently considered a life-saving intervention. However, growing evidence highlighted that prolonged MV significantly affects functional outcomes and length of stay. In this scenario, controversies are still open about the optimal rehabilitation strategies for improving MV duration in ICU patients. In addition, the efficacy of physiotherapy interventions in critical ill patients without positive history of chronic respiratory conditions is still debated. Therefore, this systematic review of randomized controlled trials (RCTs) with meta-analysis aimed at characterizing the efficacy of a comprehensive physiotherapy intervention in critically ill patients. PubMed, Scopus, and Web of Science databases were systematically searched up to October 22, 2021 to identify RCTs assessing acute patients mechanical ventilated in ICU setting undergoing a rehabilitative intervention. The primary outcomes were MV duration, extubation, and weaning time. The secondary outcomes were weaning successful rate, respiratory function, ICU discharge rate and length of stay. Out of 2503 records, 12 studies were included in the present work. The meta-analysis performed in 6 RCTs showed a significant improvement in terms of MV duration (overall effect size:  (1). It has been estimated that approximately 30% of patients admitted to the Intensive Care Unit (ICU) might require MV to support the patients' breathing during critical illness (2)(3)(4). However, growing evidence highlighted that prolonged MV significantly affects functional outcomes and length of stay, with detrimental consequences in terms of residual disability and social and sanitary costs (3,(5)(6)(7)(8). More in detail, prolonged MV has been related to physical and functional impairment, secretion clearance dysfunctions, respiratory, and skeletal muscles weakness, together with malnutrition, chronic cardiac and respiratory disease, depression, anxiety, and delirium (9).
Besides the above-mentioned physical sequelae, patients admitted to ICU requiring prolonged MV may consume more than 37% of ICU resources (10). Moreover, from 4 to 13% of ICU MV patients require more than 21 days of MV for at least 6 h/day, consuming 60% more healthcare resources than non-ventilated patients (11). Albeit MV might be considered mandatory in patients with acute respiratory failure, prolonged MV could cause several complications, including ventilatorassociated pneumonia (VAP), lung infections and atelectasis (12). Furthermore, prolonged MV has been related to a higher risk of death in patients admitted to ICU (13).
Taken into consideration these aspects, a patient-tailored rehabilitation program aimed at optimizing weaning from MV should be considered as a cornerstone in the management of critically ICU patients to improve their physical and psychosocial outcomes (14).
Recent findings suggest that about 70% of ICU patients can be weaned successfully within the first day, while in 30% of cases the initial attempts fail with relevant negative implications in the weaning process (15). "Difficult-to-wean patients" requiring prolonged MV, account for up to 15% of those requiring MV in the ICU and weaning centers (16) and about 25% of them develop early muscle weakness (2).
To date, benefits from early mobilization, respiratory and physical therapy interventions have been supported in several conditions (17)(18)(19)(20)(21). Recently, a network meta-analysis (NMA), performed by Worraphan et al. (22), assessed the effectiveness of currently available physiotherapy interventions in facilitating weaning from MV. However, the authors focused only on inspiratory muscle training (IMT) and early mobilization (EM) interventions, while other rehabilitative strategies were not assessed (22). Similarly, the systematic review by Vorona et al. (23) assessed the effects of inspiratory muscle rehabilitation in critically ill adults reporting intriguing results in terms of safety and tolerability. However, the authors did not report specific indications about the precise rehabilitation program performed (23).
Despite the effects of physiotherapy interventions in weaning from MV have been deeply studied, to date, evidence in literature about the effects of different strategies is still lacking. Furthermore, to the best of our knowledge, no previous systematic review assessed the effects of different training programs in critical ill patients without chronic respiratory issues before the ICU admission.
In light of these considerations, strong evidence is needed to provide clinically relevant data to guide physicians in prescribing effective and safe physiotherapy interventions in order to improve the tailored rehabilitative management of prolonged MV critically ill patients.
Therefore, this systematic review of randomized controlled trials (RCTs) with meta-analysis aimed at summarizing the current evidence on the efficacy of targeted physiotherapy and/or comprehensive physiotherapy interventions to reduce MV duration and implement the weaning process in critically ill patients.

Registration
This systematic review of RCTs has been performed ethically in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (24). A protocol was developed before study initiation and submitted to PROSPERO 1 (registration number CRD42022299537 2 ).

Search Strategy
We

Selection Criteria
In accordance with the PICO model (25), we considered eligible RCTs satisfying the following criteria: -(P) Participants: acute patients admitted to ICU facilities and mechanical ventilated, age > 18 years, without preexistent chronic respiratory conditions.
-(I) Intervention: we considered all rehabilitation and/or physiotherapy interventions identified by the search if they were protocolized (therapies were systematically provided to patients according to pre-defined algorithm or plan).
More in detail, the rehabilitation treatments considered were: -Positioning, including all the changes in body positioning different from routine monotonic delivery of MV aiming at promoting the clearance of respiratory secretions, improving lung volume and oxygenation (26). -Early mobilization techniques, including active exercises or assisted exercises performed with patient's own muscle strength occurred while the patient receive MV (27). -ACTs and lung expansion, including mechanical insufflation-exsufflation, percussion and vibrations, hyperinflation, and positive-expiratory-pressure devices (28).
-Respiratory muscle training, including specific exercises aiming at improving respiratory muscle strength and function (29). -Automatic Systems, including mechanical support systems that automatically drive the level of pressure to promote and facilitate the discontinuation of MV through the early recognition of the patient's ability to breathe spontaneously (30).
-(C) Comparator: any comparator; -(O) Outcome: the primary outcomes were MV duration, extubation, and weaning time (defined as time between first assessment and the absence of MV for 48 h). The secondary outcomes were: (i) weaning successful rate (express as percentage of patients weaned per whole sample); (ii) changes in respiratory muscle or function (maximal inspiratory pressure, Tidal volume, respiratory muscle thickness); (iii) ICU discharge rate; (iv) ICU length of stay.
Only RCTs that were peer-reviewed and published in an International journal in English language were included.
The exclusion criteria were: (i) studies involving animals; (ii) participants with pregnancy, clinical instability, or palliation; (iii) Masters or doctorate theses and conference proceedings. No publication date restriction was applied.
After duplication removal, the remaining articles were screened by two investigators that independently reviewed the title and abstracts to choose relevant ones. Those that met all the inclusion criteria or that were ambiguous were kept for the second screening phase, which consisted of a full-text review. Any disagreements were discussed with a third reviewer to reach consensus. No automation tool was used in this process.

Data Extraction and Synthesis
All the records screened in full-text were assessed for eligibility by two independent reviewers and relevant data were extracted through Excel. Any disagreement was solved by discussion between the two reviewers or consulting a third reviewer. No automation tool was used in the process.
A descriptive approach was used to synthesize both study characteristics and data extracted. The studies were grouped for the syntheses basing on the outcomes assessed.
Subgroup analysis has been performed based on the type of intervention proposed.

Meta-Analysis
The meta-analysis was performed on Revman 5.4.0 (The Cochrane Collaboration, 2020, United States). The heterogeneity among comparisons was estimated by the chi-squared and I2 statistic tests. An I2 > 75% determined significant heterogeneity across the articles. In the event of considerable heterogeneity, a random-effects model was adopted to determine the pooled estimates with the effect size (ES) and 95% CIs. Missing means and SDs were estimated from medians, ranges, and interquartile ranges (IQRs) using the method introduced by Hozo et al. (31).

Quality Assessment and Risk of Bias
The quality assessment was performed through PEDro scale by two independent reviewers. A third reviewer was involved in case of disagreement to achieve consensus. According to PEDro scale, the studies were rated as excellent (9-10 points), good (6-8 points), fair (4-5 points), or poor (<4 points).
The risk of bias was assessed through Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) (32) by two reviewers independently. In case of disagreement, the consensus was achieved by discussion of consulting a third reviewer. Bias was reported by each domain of RoB 2 [(i) random sequence generation; (ii) allocation concealment; (iii) blinding of participants and personnel; (iv) blinding of outcome assessment; (v) incomplete outcome data; (vi) selective outcome reporting; (vii) other bias] and a rating (low, high, unclear) was assigned to each domain.

Study Characteristics
Altogether, a total of 2503 records were identified from the 5 databases assessed. After duplication removal of 868 records, 1635 studies were assessed for eligibility and screened for title and abstract. As a result, 1543 records were excluded, and 92 studies were subsequently screened in full-text.
Therefore, the following RCTs were included in the present systematic review: Berti (33)  The sample size of the RCTs included ranged from 20 (38) to 126 (40), for a total of 413 patients in the intervention groups (219 males and 194 females) and 378 in comparators (224 males and 154 females).
The subject assessed in the different studies were characterized by a mean age ranging from 47.8 ± 14.72 (39) to 83 ± 3 (34) in the intervention group, while mean age ranged between 47.85 (43) and 82 ± 7 (34) in the comparator group.
Interestingly, respiratory muscle training has been the physiotherapy intervention most studied in the RCTs included in the present systematic review (34,37,38,40,42,43). On the other hand, three studies (36,39,40) assessed early mobilization/positioning, two studies (33,35) assessed airway clearance techniques (ACTs) and lung expansion, and one study (41) assessed automatic systems for MV weaning.

Intervention Characteristics
Rehabilitation treatments have been classified as early mobilization, positioning, ACTs/lung expansion, respiratory muscle training and automatic weaning systems.
-Positioning and early mobilization: three studies (36,39,44) assessed the effects of different positioning and early mobilization programs. In particular, Dong et al. (36) assessed a progressive rehabilitation program composed of six levels of intensity, from positioning and rotational This study reports about ICU patients on MV (mean age IG: 83 ± 3; CG: 82 ± 7; 43% male in IG, 50% male in CG; mean weight IG: 66 ± 5; CG: 65 ± 6). They were assessed for all days of the protocol duration. The main finding is represented by the reduction of the weaning period by 1.7 days (95% CI 0.4 to 3.0) in ICU patients exposed to IMT (3.6 ± 1.5 days), as compared to usual care (5.3 ± 1.9 days). Maximal inspiratory pressure increased significantly in the IG than in the CG (MD 7.6 cmH20, 95% CI 5.8 to 9.4). The Tobin index decreased in both groups over the weaning period, with significant differences between groups (MD 8.3 br/min/L, 95% CI 2.9 to 13.7). Cader et al. (  Differently, Pattanshetty and Gaude (39) assessed the effects of a comprehensive rehabilitation intervention including positioning, in addition to chest wall vibrations, manual hyperinflation (MH), and suctioning. The rehabilitation program was proposed for 20 min twice a day.
Lastly, Pinkaew et al. (44) assessed the effects of two different groups compared to conventional treatment. More in detail, one interventional arm received traditional therapy, early mobilization, and exercises with elastic band for 3 sets of 10 repetitions once a day, 5 times a week. On the other hand, the second interventional group was treated only with conventional therapy and early mobilization. Lastly, Liu and Zhang (43) assessed the effects of a comprehensive rehabilitation treatment including positioning and active or passive joint movement, combined with neuromuscular electrical stimulation and respiratory muscle training with a suitable sandbag positioned on the belly area.
-Automatic Systems: only one study (41) assessed the role of an automated weaning program SmartCare TM included in a mechanical ventilator that automatically adjusted the pressure support at the minimum level, while keeping the patient within a comfort zone.
All the rehabilitation programs of the RCTs assessed in the present systematic review have been summarized in Table 1.
Interestingly, Chen et al. (35) that assessed ACTs and lung expansion, underlined significant differences of MV days between IPPB alone and combined with PEEP when compared to control group (11.7 ± 3.7 days vs. 15.8 ± 9.1 days vs. 27.2 ± 16.1 days respectively; p < 0.05).
On the other hand, respiratory muscle training was assessed by Cader et al. (34) that reported a significant reduction of the weaning period by 1.7 days (95% Confidence Interval (CI): 0.4 to 3.0) in ICU patients treated with IMT (3.6 ± 1.5 days) compared to usual care (5.3 ± 1.9 days). Accordingly, the same authors in 2012 (42) (43) assessed a comprehensive rehabilitation treatment reporting significant differences between groups in terms of MV duration (6.14 ± 2.07 vs. 13.54 ± 4.75 days; p < 0.05). In contrast, Sandoval Moreno et al. (40) when assessing the effects of respiratory muscle training found no statistically significant differences in median weaning time between groups (8.78 ± 11.41 h vs. 9.36 ± 12.51 h; p = NS).
Lastly, Taniguchi et al. (41) in assessing the automated system for MV weaning reported a shorter weaning duration in the respiratory physiotherapy-driven weaning control group (60   Weaning successful rate after respiratory muscle training intervention was assessed by Martin et al. (37), reporting that 25 of 35 of patients undergoing respiratory muscle training are successfully weaned from MV (71, 95% CI = 55 to 84%), in contrast with 16 of 34 subjects of the CG (47, 95% CI = 31 to 63%). Accordingly, Liu and Zhang (43) reported a weaning success rate of 92.0% after a comprehensive rehabilitation program, underlining significant differences between groups (p < 0.05).
On the contrary, Cader et al. (42) highlighted no significant differences in extubation success between the groups (p = 0.20). Similarly, Sandoval Moreno et al. (40) showed that weaning successful rate was 75.81% in the rehabilitation group while it was 75% in the control group, with no significant differences between groups (p = NS).
Finally, Taniguchi et al. (41) reported that extubation failure (2 vs. 2; p = 1.00) was similar between the automated system weaning group and physiotherapy-driven weaning group. Table 1 summarizes the main findings of the RCTs included in the present systematic review.

Main Findings -Respiratory Function
Maximum inspiratory pressure (MIP) represented the most common respiratory function parameter assessed by the RCTs included in the present review (34,35,37,38,40,41) Differently, Tobin index has been assessed by 2 studies. In particular, Cader et al. (34) in 2010 assessed showed significant differences between groups in Tobin index after the respiratory muscle training program (8.3 br/min/L, 95% CI 2.9 to 13.7). Accordingly, in 2012 the same working group (42) reported a significant reduction in Tobin index (95% CI −26.23 to −6.05; p = 0.001).
Instead, Taniguchi et al. (41) assessed tidal volume without underlining significant differences between groups comparing automated system weaning group to physiotherapy-driven weaning protocol.

Main Findings -Intensive Care Unit Discharge Rate and Length of Stay
Only one study (33) assessed discharge rate, reporting that ICU discharge rate was significantly higher in IG group (p < 0.05) after the rehabilitation treatment including ACTs and lung expansion.
In contrast, McCaughey et al. (38) reported a significant improvement in length of stay in ICU (median 11 vs. not estimable days; p = 0.011) after active abdominal FES training compared to the control group. Liu and Zhang (43) reported an average length of stay of 18.84 ± 5.37 days stay in the CG, while in the IG treated with a comprehensive rehabilitation program was 10.47 ± 2.55 days (p < 0.05). Table 1 shows the main findings of the studies included in detail.

Meta-Analysis
A meta-analysis was performed to highlight the efficacy of rehabilitative interventions on weaning duration in mechanically ventilated critically ill patients, showing an overall ES of −3.23 days (95% CI = −5.79, −0.67, p = 0.01; Z = 2.47) in decreasing MV time. Given the low number of RCTs, and the high heterogeneity a random-effects model was adopted (for further details see Figure 2).

DISCUSSION
Rehabilitation is widely considered a cornerstone in the complex process of weaning from MV (45,46). However, to date, specific rehabilitative indications and precise strategies are still lacking, despite current research is now focusing on tailored rehabilitative programs aimed at reducing weaning duration and improving weaning successful rate (47). In this scenario, this systematic review of RCTs summarized the available evidence in literature targeting specific rehabilitative strategies that could represent a valid therapeutical approach to improve the weaning process and reduce MV duration in critically ill patients.
To date, growing attention has been placed on a combined rehabilitative approach for weaning in MV patients in order to improve the synergism between different therapeutic interventions (22,48).
Noticeably, the results of our meta-analysis underlined the efficacy of a comprehensive rehabilitation intervention in reducing MV duration [ES: −3.23 days (95% CI = −5.79, −0.67, p = 0.01; Z = 2.47)]. These results suggest the key role of a specific pulmonary physiotherapy intervention in the ICU setting in order to minimize MV complications and optimize the functional recovery in critically ill patients. Similarly, the recent systematic review by Worraphan et al. (22) underlined significant improvement in weaning duration after EM and IMT combined with conventional physiotherapy. On the other hand, the authors assessed RCTs including patients suffering from chronic respiratory diseases with potential muscle impairment related to other pathological conditions that might significantly affect the treatment outcomes (22).
Concurrently, physical rehabilitation interventions have been otherwise defined in literature as 'conventional physiotherapy, ' 'usual therapy, ' 'rehabilitation activity, 'early mobilization, ' 'respiratory physiotherapy, ' without deeply characterizing rehabilitative protocol or omitting the description of single interventions (33-44, 49, 50). In this scenario, activities such as passive and active limbs exercises, positioning, change of postures in bed, sitting on the edge of the bed, neuromuscular electrical stimulation (NMES) of peripheral muscles, secretion management and lung recruitment strategies can be integrated into the above definitions (33-44, 49, 50). As a result, a large gap of knowledge has been identified in the current literature, highlighting that only few articles (36,43,44) deeply characterized the components of EM protocols. Therefore, we focused on a specific characterization of four main rehabilitative strategies that were categorized as early mobilization, ACTs including lung recruitment/expansion components, respiratory muscle training, and automated systems (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Interestingly, positioning and early mobilization proved to be safe interventions for critically ill patients during weaning from MV, with recent evidence suggesting positive effects on weaning time and ICU length of stay (51,52). Although evidence is still debated, ER protocols are recommended and widely employed to prevent or mitigate the ICU-acquired weakness and to improve clinical outcomes in acutely hospitalized adults who have been mechanically ventilated for more than 24 h (53).
On the other hand, albeit rehabilitation interventions in critical ill MV patients have been focused mainly on positioning and peripheral muscle training (23,54), a growing interest has been raising in IMT in recent years (14). To date, IMT is a well-known effect of prolonged MV, and there is growing evidence that specific IMT can improve strength and endurance or reduce ventilator-induced diaphragm weakness (55). The systematic review and meta-analysis by Vorona et al. (23), underlined that IMT is a feasible and safe intervention in MV patients, suggesting IMT as a potential key component of an integrated rehabilitation program in difficult-to-wean patients with diaphragmatic weakness (23). However, the authors included only chronic patients in this review, with significant implications in terms of study results, given the chronic muscle alterations induced by respiratory conditions and the modifications in secretion production (23). On the other hand, a precise patient's stratification is the cornerstone of specific physiotherapy interventions tailored to patient's characteristics (56). Accordingly, the present systematic review and meta-analysis includes acute critical patients with no previous chronic respiratory conditions that might have affected respiratory mechanics or the potential respiratory muscles response to training (57)(58)(59). Our findings emphasize the positive contribution of specific IMT strategies using a threshold load that deeply characterizes the rehabilitation strategies inducing specific results on lung function (34,37,42). Despite conflicting results were reported by the RCTs included in the present work (40), IMT might represent a suitable option in ICU patients during weaning period, especially in patients with a proven IM weakness. In particular, Martin et al. (37) reported a significant improvement of MIP and less weaning time for patients trained with IMT and observed that successfully weaned patients had a significantly greater change in MIP than those in fail-to-wean group, even if trained with the IMT protocol (37). This interesting information suggests that the rehabilitative effort should be targeted to patients with a proven IM weakness. Therefore, it is important to monitor daily changes to identify the optimal responders to better focus on then rehabilitation efforts. On the other hand, although IMT has proven to be a safe treatment, it should be noted that the risk for exercise-induced muscle damage should be considered in severely debilitated patients (60). Interestingly, the systematic review from Elkins et al. (14) previously assessed the role of IMT in facilitating weaning from MV among patients in ICU. The authors reported positive results of IMT in selected patients (14). However, no previous systematic review assessed the role of IMT in a comprehensive rehabilitative approach. Moreover, to the best of our knowledge, the present work is the first systematic review and meta-analysis assessing acute ICU patients without chronic respiratory conditions, targeting a specific population in order to promote a specific therapeutical approach. Interestingly, the results of our quantitative synthesis have shown the efficacy of a comprehensive rehabilitation intervention including IMT in patients in ICU.
Despite these findings, the optimal parameters for IMT are yet to be established. However, it has been proposed that treatment intensity should be prescribed based on maximum inspiratory pressure and, if conditions do not allow to measure MIP, could be titrated via a trial-and-error method, starting from a low resistance, and gradually increasing intensity based on tolerance, symptoms and changes in vital parameters (61).
Moreover, expiratory muscle strength is currently considered an independent predictor of weaning success (62) and transversus abdominis, internal and external obliques muscle plays a crucial role in protecting airways with cough (63). Unfortunately, abdominal FES assessed by McCaughey et al. (38) did not show significant changes in terms of muscle strength. However, abdominal FES might be considered as a feasible rehabilitative option in patients with low compliance levels to other rehabilitation strategies.
On the other hand, ACTs and lung expansion strategies have been suggested as key components of rehabilitation interventions aimed at keeping the airways patency and reducing the work of breathing (64). While most of the studies included in the present review assessed different strategies (including suctioning, posture changes, percussion, and vibration), only two studies (33,35) investigated the effects of different techniques on the weaning process. Our findings suggested positive effects of ACTs intervention on weaning duration. However, it should be noted that ACTs are prone to many confounding factors and the effects of this specific rehabilitation intervention alone have not been widely investigated. On the other hand, it has been reported that the use of PEEP can increase the functional residual capacity, keeping the alveoli and airways open during the expiratory phase, with positive implications in work of breathing and clearance of secretion (65).
Interestingly, while IPPB alone had the best weaning rate, IPPB + PEEP seems to have better effects on sputum production in the first session and better inspiratory muscle strength at the end of the study (35). However, further investigations are needed to clarify the promising contribution of these two strategies to success of first spontaneous breathing trials. In this scenario, Pattanshetty et al. (39) investigated the impact of positioning and chest wall vibrations over manual hyperinflation and suctioning to manage secretions and prevent ventilatorassociated pneumonia. While the effects of manual chest vibration on mucus clearance are strongly controversial (66), positioning can help lung recruitment, promote weaning and, in this case, could have enhanced the efficacy of MH.
In recent years, there has been a growing interest in automatic systems aiming at promoting standardized weaning strategies (30,67). Such automated systems included in ventilators software has been shown to significantly reduce the weaning time in critically ill patients (68). However, different authors showed that respiratory physiotherapy-driven weaning protocols can further decrease weaning time, probably due to a more efficient assessment and management of intercurrent situations and individual variability during the process. These results emphasized the need for personalized therapeutic interventions combined with continuous monitoring of the patient response to guarantee a rapid and precise support in the complex rehabilitation framework of MV patients (68). In this scenario, a specific patient's stratification might be crucial to better standardize the optimal therapeutic strategies in acute patients admitted to ICU (41).
Our findings highlighted the lack of data about the long-term outcomes of post-weaned patients and the eventual long-term advantages of rehabilitative interventions are far from being fully understood. Therefore, it is mandatory to emphasize the role of physiotherapy in weaning optimization, reducing MV complications and immobilization consequences in terms of functional outcomes, residual disability and increased social and health care costs (3,(5)(6)(7)(8).
Taken together, the findings of the present systematic review of RCTs and meta-analysis highlight the efficacy of pulmonary rehabilitation strategies including early mobilization, ACTs and respiratory muscle training. However, our data underline a gap of knowledge about the optimal components of tailored pulmonary physiotherapy interventions in MV patients admitted to ICU. Future research should focus on precise patient stratifications to better characterize the synergism between different rehabilitative interventions, focusing resources and improving outcomes of MV patients admitted to ICU.
We are aware that the present systematic review is not free from limitations. First, several therapeutic approaches have been assessed with significant implications in terms of specificity of the study results. Second, due to the heterogeneity of the study included, it was not possible to assess the efficacy of single rehabilitation modality. Therefore, the optimal rehabilitation program is still uncertain given the lack of quantitative data about each single intervention. On the other hand, it should be noted that in clinical setting the pulmonary rehabilitation programs were composed by the integration of different rehabilitation strategies including a early mobilization, positioning, ACTs/lung expansion, respiratory muscle training and automatic weaning systems. Moreover, the aim of the study was to assess the role of comprehensive physiotherapy intervention; therefore, to the best of our knowledge, the present work represents the first systematic review of RCTs assessing an integrated rehabilitation intervention in line with the current clinical practice performed in patients in ICU setting without pulmonary chronic conditions.
In conclusions, the results of this systematic review of RCTs with meta-analysis supported the efficacy of a comprehensive physiotherapy intervention in reducing MV duration in critical ill patients without chronic respiratory conditions. The development of specific rehabilitation strategies, that could represent a valid therapeutic approach to improve the weaning process and reduce MV duration, is an urgent need not only to prevent the onset of severe complications, but also to ensure sustainability in terms of health care costs reduction.
In this scenario, the present work provided promising results about the role of early mobilization, positioning, airway clearance techniques, lung expansion and respiratory muscle training in the complex framework of mechanically ventilated critical ill patients.
Further studies are needed to better characterize the effects of specific rehabilitation strategies to reduce MV duration and optimize the weaning process in order to improve the best rehabilitative intervention in critical ill patients without chronic respiratory conditions.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AUTHOR CONTRIBUTIONS
LL, AS, FD'A, and MI contributed to study design and conceptualization. LL and FD'A contributed to databases searching. LL, FD'A, and MI contributed to data screening and data extraction. LL, AS, and FD'A contributed to data synthesis, interpretation, and manuscript drafting. NM contributed to statistical analysis. CM and MI contributed to critical revision. BP, NM, LC, and AA contributed to visualization. AS, AA, CM, and MI contributed to study supervision. LL contributed to study submission. All authors read and approved the final version of the manuscript.