Effects of closed loop ventilation on ventilator settings, patient outcomes and ICU staff workloads – a systematic review

BACKGROUND Lung protective ventilation is considered standard of care in the intensive care unit. However, modifying the ventilator settings can be challenging and is time consuming. Closed loop modes of ventilation are increasingly attractive for use in critically ill patients. With closed loop ventilation, settings that are typically managed by the ICU professionals are under control of the ventilator's algorithms. OBJECTIVES To describe the effectiveness, safety, efficacy and workload with currently available closed loop ventilation modes. DESIGN Systematic review of randomised clinical trials. DATA SOURCES A comprehensive systematic search in PubMed, Embase and the Cochrane Central register of Controlled Trials search was performed in January 2023. ELIGIBILITY CRITERIA Randomised clinical trials that compared closed loop ventilation with conventional ventilation modes and reported on effectiveness, safety, efficacy or workload. RESULTS The search identified 51 studies that met the inclusion criteria. Closed loop ventilation, when compared with conventional ventilation, demonstrates enhanced management of crucial ventilator variables and parameters essential for lung protection across diverse patient cohorts. Adverse events were seldom reported. Several studies indicate potential improvements in patient outcomes with closed loop ventilation; however, it is worth noting that these studies might have been underpowered to conclusively demonstrate such benefits. Closed loop ventilation resulted in a reduction of various aspects associated with the workload of ICU professionals but there have been no studies that studied workload in sufficient detail. CONCLUSIONS Closed loop ventilation modes are at least as effective in choosing correct ventilator settings as ventilation performed by ICU professionals and have the potential to reduce the workload related to ventilation. Nevertheless, there is a lack of sufficient research to comprehensively assess the overall impact of these modes on patient outcomes, and on the workload of ICU staff.


Introduction
Mechanical ventilation is a key element of respiratory support in critically ill patients with respiratory failure.In the early years of critical care, the one-single goal of mechanical ventilation was to provide sufficient gas exchange, often targeting physiological levels of arterial partial pressures of oxygen ( paO 2 ) and carbon dioxide ( paCO 2 ). 1 In the last decades, the goals of ventilation shifted towards lung protection, even if this jeopardised the initial ventilatory targets (e.g. by applying permissive hypercapnia, to reduce tidal volume and plateau pressure). 2While so-called lung protective ventilation has become the standard of care, 3 its application in clinical practice can be challenging and time consuming; achieving the ventilatory targets requires complex titrations of ventilator settings according to the individual needs of patients, which change over time.There is clearly no 'one-size-fits-all', and constant individualisation and titration of ventilatory settings are required mandating the use of sometimes complex bedside calculations.Currently, lung protective ventilation includes a low tidal volume (V T ), to prevent volutrauma and barotraumas; low pressures and energy, to avoid energy trauma; and restricted oxygen, to minimise chemotrauma.Automated, or closed loop modes of ventilation, are increasingly attractive for use in the ICU. 4 Ventilator settings that are typically manually adjusted by the user during conventional ventilation can, once the targets are manually set, be controlled by the software during closed loop ventilation.Closed loop ventilation has the potential to optimise ventilator settings, to increase safety of ventilation, and even to improve patient outcomes. 5,6Closed loop ventilation might also reduce ICU nursing and medical staff workload, through immediate reaction to patients' changing demands. 7This is particularly interesting when faced with increasing challenges due to shortages in ICU nursing staff, 8 and especially in extreme situations as seen in the recent coronavirus disease 2019 (COVID-19) pandemic when large numbers of patients required invasive mechanical ventilation.
We present the results of a systematic search of the literature for publications on randomised clinical trials of closed loop ventilation that focused on effectiveness in providing lung protective ventilation and settings, safety, patient outcomes related efficacy and ICU staff workloads (Table 1).We hypothesised that currently available closed loop ventilation modes are effective, well tolerated and efficacious, while reducing the ICU staff workloads.

Search details
We conducted a literature search using various combinations of keywords and MeSH terms, including 'Interactive Ventilatory Support', 'Respiration, Artificial', 'Automation', 'closed loop ventilation', 'automated ventilation', 'mechanical ventilation' and 'explicit computerized protocols' in PubMed, Embase and the Cochrane Central register of Controlled Trials (CENTRAL).Inclusion criteria were randomised clinical trials that studied the effect of closed loop ventilation modes on ventilator settings, patient outcomes and ICU staff workload.We used no time or language restrictions, and included publications of studies in all patient categories, including paediatric and adult ICU cohorts.The reference lists of studies and systematic reviews identified by the search were used to find additional reports that may have been missed by the original search.The search was registered at PROSPERO with registration number CRD42023446174, and a final search was performed in January 2023.
Publications identified by the search were screened for eligibility by two independent investigators (RLG and LAB-K) by reading the titles and abstracts.If a study was considered potentially eligible, the full text was obtained, and reviewed for using the predefined inclusion and exclusion criteria.

Selection of studies
A publication was eligible if reporting on a randomised clinical trial of closed loop ventilation; in invasively ventilated paediatric or adult ICU patients; and reporting on aspects regarding effectiveness, safety, efficacy or workload.
We excluded reports on studies of noninvasive ventilation, and ventilation in another setting than the ICU, that is ventilation in an emergency department or in an operating room.
Effects of closed loop ventilation: a systematic review 439

Risk of bias and study quality
For each study, information was collected for the assessment of the risk of bias.The Cochrane Collaboration's tool for assessing risk of bias was used to assess the risk of bias for the included studies. 9 also calculated the fragility index for studies having a statistically significant dichotomous primary outcome, 10,11 and compared them with the number of patients lost to follow-up for that endpoint in order to assess the robustness of the study results; the fragility index calculates the number of patients required to lose statistical significance. 12porting Data were reported as medians with interquartile ranges or means with standard deviations.For each study that reported a dichotomous primary endpoint, the fragility index and the number of patients lost to follow-up were reported.We did not perform a meta-analysis of the studies identified by the search, because the studies used various outcome measures, and had different study designs and durations.
As blinding of personnel was not possible due to the nature of the intervention, risk of performance bias was high in all studies (eFigure S1, http://links.lww.com/EJA/A926).In most studies, it was unclear how detection bias was avoided.Allocation concealment was used in 24 studies to reduce the risk of selection bias.The fragility index could be calculated in five studies and varied between 0 and 18 (eTable S2, http://links.lww.com/EJA/A926,).

Effectiveness
With SmartCare, V T decreased in difficult to wean patients 32 but was not affected in critically ill patients 47 compared with conventional ventilation (Table 2, Fig. 3 and eTable S3, http://links.lww.com/EJA/A926).With ASV, V T increased in cardiac surgery patients 17 and in ARDS patients. 42ASV decreased V T in ARDS patients, 55 but did not affect V T in cardiac surgery 48,51 and COPD patients. 21,47INTELLiVENT-ASV led to a lower V T 22,25,34 in cardiac surgery and unselected ICU patients, but V T increased 24 or was unaffected in general ICU patients. 27,30,35With NAVA, V T decreased in ARDS patients. 37NAVA did not affect V T in abdominal surgery patients. 20PAVþ did not affect V T in a general ICU population. 16,29,31V did not affect DP and MP in ARDS patients, 42 but with INTELLiVENT-ASV, DP and MP were lower in cardiac surgery patients,.34 With NAVA, DP increased but MP decreased in hypoxemic respiratory failure patients.41 PAVþ did not affect DP in general ICU patients.29 Smartcare, ASV and NAVA did not affect FiO 2 in critically ill patients, 47 cardiac surgery patients 51 and paediatric patients, 62 respectively. INELLiVENT-ASV reduced FiO 2 in cardiac surgery patients 25,34 and in critically ill patients, 22,24,27,30 Avea-CLiO 2 and a closed loop FiO 2 controller available for use with ASV also increased time spent in preferred SpO 2 ranges in paediatric patients.[58][59][60][61] Safety SmartCare, ASV and INTELLiVENT-ASV resulted in a similar number of reported 'adverse events' 18,35,42,45,47,48,51 Eur J Anaesthesiol 2024; 41:438-446 (Table 2, Fig. 3 and eTable S4, http://links.lww.com/EJA/A926). AS was associated with lower peak pressures 47 and a lower incidence of atelectasis.50 INTELLiVENT-ASV was associated with less hypoxemic events, 34,35 and increased time spent in preferred SpO 2 ranges in medical ICU patients. 35AVA was associated with less extubation failure. 39Vþ did not affect reintubation rates 31 but had to be discontinued in a large proportion of patients.33 Avea-CLiO 2 as well as a closed loop FiO 2 controller available for use with ASV were associated with less hypoxemic events.[58][59][60][61] Efficacy SmartCare was associated with shorter 54,56,63 or similar weaning duration in various patient categories 14,15,18,23 (Table 2, Fig. 3 and eTable S5, http://links.lww.com/ EJ,43,45,46,48,49,57 and NAVA 40 were also associated with shorter duration of weaning and shorter duration of ventilation, and NAVA with more ventilator free days.38,39 PAVþ was associated with shorter duration of ventilation, ICU and hospital length of stay 29,44 and improved survival. 31 Wokload SmartCare, 18,19 ASV, 43,46,51 INTELLIVENT-ASV 25,27,28,30 and Avea-CLiO 2 were associated with fewer manual interventions at the ventilator [58][59][60][61] (Table 2, Fig. 3 and eTable S6, http://links.lww.com/EJA/A926). SmartCare ws associated with a lower number of blood gas analyses.14 ASV was associated with fewer alarms 13 and less time spent at or approaching the ventilator.51

Discussion
The findings of this systematic review can be summarised as follows: there are currently six commercially available closed loop ventilation modes for use in critically ill Effects of closed loop ventilation: a systematic review 441  patients; their effectiveness (in terms of ventilator settings) and efficacy (in terms of patient outcomes), have been studied in various cohorts of patients; and safety (in terms of adverse events) has seldom been reported.In addition, the effect of these closed loop modes on workload of ICU staff has not yet been sufficiently researched.
Our analysis has several strengths.We conducted a comprehensive and unrestricted search.By reviewing the reference lists of the identified articles, we searched for additional studies that may not have been identified by the search.We applied clear inclusion and exclusion criteria for the selection of articles of interest.We checked the robustness of the study findings by comparing the fragility index with the number of patients lost to follow-up for binary clinical endpoints.
To our knowledge, this systematic review is the first to focus on all commercially available closed loop ventilation modes for use in the ICU, addressing several aspects of care and outcomes related to ventilation.The findings extend those of a previous review that focused only on INTELLiVENT-ASV. 5Although effectiveness is important in our assessment, we believe that from the four endpoints investigated, efficacy and safety, and in particular ICU staff workload, should always be considered when evaluating the advantages and disadvantages of any mode of closed loop ventilation.
Each closed loop ventilation mode seemed to be effective with regard to one or more aspects of lung protective ventilation, and some were even associated with a higher efficacy.Unfortunately, however, each study used different effectiveness endpoints, therefore an interaction with other ventilation parameters in potentially nonlung protective ranges could not be determined.Moreover, this hampered meta-analysis of the studies.Some of the included articles also reported opposite results related to ventilation parameters.This is possibly due to the different patient groups included in the study, to the study design or to the local use of the reported ventilation modes.Software changes did not occur for the different ventilation modes in a way that algorithms changed ventilation strategies leading to opposite ventilation variables.It is important to mention that most, if not all, studies were performed in centres with experience in invasive ventilation, meaning that standard ventilation care was most likely at a high level.Even while this may reduce the chance of showing superiority of the tested 442 Goossen et al.Eur J Anaesthesiol 2024; 41:438-446 closed loop mode, with regard to effectiveness, most studies found the closed loop mode to be superior or at least as effective.On the contrary, with regard to efficacy endpoints, only some studies reported superiority.Herein, it should also be realised that most studies were small, and probably too small to have sufficient power to demonstrate superiority with respect to clinical outcomes.
Safety endpoints varied from adverse events that were predefined as a clinical endpoint, such as reintubation, to proportions of time spend outside of 'safe' zones of ventilation.In addition to effectiveness and efficacy, each study used other clinical safety endpoints.Severe adverse events, or adverse events, were never reported.Very probably, these were either not collected systematically, or simply not reported.The high failure rate of PAVþ (discontinuation of the automated mode) in one study was attributed to excessive sedation, high respiratory rate and high respiratory effort. 33Whereas this is an unfavourable event, it did not hamper patient safety.Future studies are needed to determine safety of closed loop ventilation, particularly in centres with less experience of invasive ventilation, and outside a research setting.In  Staff workload is difficult to capture, and thus far, there have been no studies of ICU staff workload related to ventilation.Our search identified only a small number of studies that reported on manual interventions, alarms, and the need for blood gas analysis.While these studies all showed a reduction of these three aspects, it remains uncertain if this truly reflects a reduction in ICU staff workload, during different phases of mechanical ventilation: for example, the weaning phase in particular, is seen as a labour-intensive phase of mechanical ventilation. 64We need better studies in the future that, for instance, capture nursing activities scores with metrics that encompass the majority of tasks of an ICU nurse, including those related to invasive ventilation. 65,66osed loop ventilation can facilitate rapid and precise adjustments to ventilator settings.8][69] In practice, it is difficult and time consuming for the ICU staff to achieve this.Closed loop ventilation could help to achieve strict and precise titration, while considerably reducing workload.
This systematic review has limitations.In coherence with the articles included, this review displays a large variety in the endpoints, effectiveness and efficacy, hampering meta-analysis and with that, limiting conclusions on effectiveness, safety, efficacy and workload.In particular, safety reporting was scarce, albeit we expected this to be one of the most important endpoints to report in studying available closed loop ventilation modes.We did not reach out to the researchers in order to collect individual patient data on seldom reported endpoints such as safety and workload.Moreover, the fragility index as a measure of robustness of study results was only applicable for the minority of included studies and, where assessed, high fragility was found.

Conclusion
The current commercially available closed loop ventilation modes are at least as effective compared with conventional ventilation.Safety is rarely reported, and efficacy has mostly been shown in small studies.The effect of closed loop ventilation on workload of ICU staff has not yet been sufficiently researched.

ventilation parameters & SAEs
Compared with conventional ventilation, V T ΔP, MP and FiO 2 decrease; more patients are within predefined target ranges for various ventilation variables and parameters; number of SAEs is similar.

ventilation parameters
Compared with conventional ventilation, V T increases but ΔP and MP are similar; with ASV high inspiratory pressures occur less often, number of reintubations is similar.

ventilation parameters & reintubations
Compared with conventional ventilation, despite changes in V T and ΔP, MP is similar; with NAVA number of AEs is similar, and number of reintubations is lower.

ventilation parameters & reintubations
Compared with conventional ventilation, V T decreases, FiO 2 is not affected; with SmartCare the number of reintubations is similar.
Effects of closed loop ventilation: a systematic review 443

Fig. 3
Fig.3Summary of primary and secondary endpoints with significant results, reported for effectiveness, safety, efficacy and workload with closed loop ventilation.See text for details.
efficacy & workload outcomes PAV+ shortens ICU length of stay and duration of ventilation; mortality is lower; [no data reported on workload].efficacy & workload outcomes ASV shortens duration of weaning, ventilation and ICU length of stay; number of manual interventions at the ventilator and number of alarms are lower.efficacy & workload outcomes NAVA shortens duration of weaning and increases VFD-28; ICU length of stay and duration of ventilation are not different; (no data reported on workload).efficacy & workload outcomes With Smart Care duration of weaning is similar; number of manual interventions at the ventilator, and number of ABG analyses are lower.Compared with conventional ventilation, SpO 2 is more often within target ranges.ventilation parameters & AEs Compared with conventional ventilation, V T and ΔP are similar; PAV+ has a high failure rate; number of AEs and number of reintubations are similar., Clockwise the icons represent the following modes: PAVþ, proportional assist ventilation; ASV, adaptive support ventilation; NAVA, neurally adjusted ventilatory assist; SmartCare; Avea-CLiO 2 ; INTELLiVENT-ASV, INTELLiVENT adaptive support ventilation.Abbreviations: DP, driving pressure; (S) AE, (serious) adverse event; ABG, arterial blood gas analysis; MP, mechanical power; SpO 2 , peripheral oxygen saturation; VFD, ventilator-free days; V T , tidal volume.Eur J Anaesthesiol 2024; 41:438-446

Table 1
Definitions used for Outcome parameters

Table 2
Effectiveness, safety, efficacy and workload with closed loop ventilation AHRF, acute hypoxemic respiratory failure; ARDS, acute respiratory distress syndrome; ARF, acute respiratory failure; ASV, adaptive support ventilation; COPD, chronic obstructive pulmonary disease; FiO 2 , fraction of inspired oxygen." improved, compared with conventional ventilation; ¼ no difference, compared with conventional ventilation; # worse, compared with conventional ventilation; -not reported