TITLE: The impact of patient-ventilator asynchrony in adult mechanically ventilated patients on outcomes：A systematic review and meta-analysis
AUTHORS: Michihito Kyo, Tatsutoshi Shimatani, Koji Hosokawa, Shunsuke Taito, Yuki Kataoka, Shinichiro Ohshimo, Nobuaki Shime

[DESCRIPTION]
<div class = "text-blocks"><div class = "text-block"><span style = "font-weight:bold;">1.Background</span></div><div class = "text-block">Patients-ventilator asynchrony (PVA) is defined as a mismatch between the patient breathing efforts with a ventilator’s breath delivery. (1) PVA is a common problem in mechanically ventilated patients, (2, 3) which could potentially induce the exhaustion of diaphragm and respiratory muscles and deliver high tidal volume to the lung leading to ventilator-induced lung injury (VILI). (4, 5)</div><div class = "text-block">The impact of PVA including an acute phase of mechanical ventilation on clinical outcomes was not similar across studies. Thille AW et al. reported that higher incidence of PVA was associated with longer duration of mechanical ventilation, while this was not associated with mortality. (2) Conversely, Blanch L et al. showed that ICU mortality of the patients with higher incidence of PVA was significantly higher than that with lower incidence of PVA. (6) Furthermore, to date, there is no systematic review regarding PVA in the acute phase of mechanical ventilation.</div><div class = "text-block">Furthermore, although adjustment of sedatives or ventilator settings were thought to be effective for improving PVA, there is no definitive intervention for improving PVA without closed-loop-ventilation such as Neurally Adjusted Ventilatory Assist (NAVA) and Proportional Assist Ventilation (PAV) in the weaning phase of mechanical ventilation. (7, 8, 9) </div><div class = "text-block">Therefore, we will conduct this systematic review and meta-analysis to clarify the impact of PVA on specific clinical outcomes and the effect of interventions in order to improve PVA for mechanically ventilated patients in the acute phase of mechanical ventilation.</div><div class = "text-block"><span style = "font-weight:bold;">2.Review question</span></div><div class = "text-block">Part A. The impact of PVA on clinical outcomes</div><div class = "text-block">To clarify the impact of patient-ventilator asynchrony in adult mechanically ventilated patients in acute phase of mechanical ventilation on outcomes.</div><div class = "text-block">Part B. The impact of interventions for mechanically ventilated patients on PVA</div><div class = "text-block">To clarify the impact of interventions for adult mechanically ventilated patients in acute phase of mechanical ventilation on PVA.</div><div class = "text-block"><span style = "font-weight:bold;">3.Method</span></div><div class = "text-block"><span style = "font-weight:bold;">3.1.1 Types of study to be included</span></div><div class = "text-block">Part A. The impact of PVA on clinical outcomes</div><div class = "text-block">We will include published and unpublished observational studies and secondary analysis of randomized controlled trials (RCTs) including crossover trials, cluster-randomized trials, quasi-randomized trials.</div><div class = "text-block">We will include studies presented only in abstract or letter form, in any language, from any country and with any length of follow-up.</div><div class = "text-block">Part B. The impact of interventions for mechanically ventilated patients on PVA</div><div class = "text-block">We will include published and unpublished observational studies and randomized controlled trials (RCTs) including crossover trials, cluster-randomized trials, quasi-randomized trials.</div><div class = "text-block">We will include studies presented only in abstract or letter form, in any language, from any country and with any length of follow-up.</div><div class = "text-block"><span style = "font-weight:bold;">3.1.2 Participants</span></div><div class = "text-block"><span style = "font-weight:bold;">Inclusion criteria</span></div><div class = "text-block">Adults aged 18 years and older</div><div class = "text-block">We define “acute phase” as within 72 hrs of initiation of mechanical ventilation, as soon as patients were not able to trigger all ventilator breaths or using assist-control ventilation mode.</div><div class = "text-block">Patients who have received mechanical ventilation including acute phase of mechanical ventilation.</div><div class = "text-block"><span style = "font-weight:bold;">Exclusion criteria</span></div><div class = "text-block">We will exclude the studies which assess the effects of interventions of NAVA and PAV. We will also exclude patients with weaning phase of mechanical ventilation, post-operation, do-not-resuscitate orders, suspected bronchopleural fistula or air leaks, those admitted for organ donation, less than 18 years old, pregnant patients.</div><div class = "text-block"><span style = "font-weight:bold;">3.1.3 Exposure(s)/Intervention(s)</span></div><div class = "text-block">Part A. The impact of PVA on clinical outcomes</div><div class = "text-block"><span>We will include studies that have evaluated whether the incidence of PVA defined as asynchrony index (AI) </span><span style = ":UNDERLINE;">></span><span> 10% or ineffective trigger index (ITI) </span><span style = ":UNDERLINE;">></span><span> 10% or higher index defined by the trialists is associated with clinical outcomes in the acute phase of mechanical ventilation.</span></div><div class = "text-block">AI is defined as the number of asynchronous breaths, according to each study, divided by the total number of breaths (both requested and delivered) multiplied by 100. (2)</div><div class = "text-block">ITI is defined as the number of ineffective triggered breaths divided by the total number of triggered and ineffectively triggered breaths multiplied by 100. (3)</div><div class = "text-block">Part B. The impact of interventions for mechanically ventilated patients on PVA</div><div class = "text-block">We will include studies that have evaluated the impact of interventions that possibly affect PVA including acute phase of mechanical ventilation.</div><div class = "text-block"><span style = "font-weight:bold;">3.1.4 Control(s)</span></div><div class = "text-block">Part A. The impact of PVA on clinical outcomes</div><div class = "text-block">asynchrony index (AI) < 10%, ineffective trigger index (ITI) < 10% or lower index defined by the study authors</div><div class = "text-block">Part B. The impact of interventions for mechanically ventilated patients on PVA</div><div class = "text-block">Patients who have been defined as a control by the study authors</div><div class = "text-block"><span style = "font-weight:bold;">3.2 Outcomes</span></div><div class = "text-block"><span style = "font-weight:bold;">Part A. The impact of PVA on clinical outcomes</span></div><div class = "text-block"><span style = "font-weight:bold;">3.2.1 Primary outcomes</span></div><div class = "text-block">We will assess the association between PVA as AI, ITI or index defined by the study authors, respectively, with the following outcomes. </div><div class = "text-block">1. Duration of mechanical ventilation</div><div class = "text-block">2. ICU mortality</div><div class = "text-block">3. Hospital mortality</div><div class = "text-block"><span style = "font-weight:bold;">3.2.2 Secondary outcomes </span></div><div class = "text-block">4. Rate of reintubation</div><div class = "text-block">5. Rate of tracheostomy</div><div class = "text-block">6. All adverse events (as defined by the study authors).</div><div class = "text-block"><span style = "font-weight:bold;">3.2.3 summary of PVA defined by the study authors</span></div><div class = "text-block">We will summarize the results as the same type of PVA such as breathe stacking, auto-triggering or double triggering, etc.</div><div class = "text-block"><span style = "font-weight:bold;">Part B. Interventions for improving PVA</span></div><div class = "text-block"><span style = "font-weight:bold;">3.2.1 Primary outcomes</span></div><div class = "text-block">1. Incidence of PVA</div><div class = "text-block">2. Duration of mechanical ventilation</div><div class = "text-block"><span style = "font-weight:bold;">3.2.2 Secondary outcomes</span></div><div class = "text-block">3. ICU mortality</div><div class = "text-block">4. Hospital mortality</div><div class = "text-block">5. Rate of reintubation</div><div class = "text-block">6. Rate of tracheostomy</div><div class = "text-block">7. All adverse events (as defined by the study authors).</div><div class = "text-block"><span style = "font-weight:bold;">3.3 Searches</span></div><div class = "text-block"><span style = "font-weight:bold;">3.3.1 Electronic searches </span></div><div class = "text-block">1.the Cochrane Central Register of Controlled Trials(CENTRAL) ;</div><div class = "text-block">2.MEDLINE via Ovid;</div><div class = "text-block">3.EMBASE;</div><div class = "text-block">See Appendix 1, 2, and 3 for the search strategies.</div><div class = "text-block">No restriction in languages.</div><div class = "text-block"><span style = "font-weight:bold;">3.3.2 Other resources  </span></div><div class = "text-block">1.the World Health Organization International Clinical Trials Platform Search Portal ( ICTRP)</div><div class = "text-block">See Appendix 4 for the search strategies.</div><div class = "text-block">2.ClinicalTrials.gov</div><div class = "text-block">See Appendix 5 for the search strategies.</div><div class = "text-block">We will also inspect the references of extracted studies and the international guideline “mechanical ventilation in adult patients with acute respiratory distress syndrome” from American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine. (10)</div><div class = "text-block"><span style = "font-weight:bold;">3.4 Strategy for data synthesis</span></div><div class = "text-block"><span style = "font-weight:bold;">3.4.1 Search strategy</span></div><div class = "text-block">The search strategy described above will be used to obtain the titles and abstracts of studies that may be of relevance to the review. These titles and abstracts will be screened independently by two authors who will discard any studies which are not applicable, although any studies and reviews which might include relevant data or information on trials will be retained initially. We will contact the authors of these studies in order to assist in the screening of these studies if necessary. Two authors will then independently assess the remaining abstracts and, if necessary, their full texts, to determine whether they satisfy the inclusion criteria or not. The two authors will then compare their lists, and any differences in opinion between them will be resolved by discussion and, if this fails, through arbitration by a third author.</div><div class = "text-block"><span style = "font-weight:bold;">3.4.2 Data extraction</span></div><div class = "text-block">Data extraction will then be carried out independently on the studies selected for inclusion by two authors using standard data extraction forms. Again, we will contact authors of these studies if necessary during this process, and any differences in opinion regarding data collection between the authors will be resolved by discussion, or through arbitration by a third author if required. If more than one publication of a given study exists, the reports will be grouped together and the publication with the most complete data used in the analyses. If relevant outcomes have only been published in earlier versions of studies, these data will be used, and any discrepancies between the published versions will be highlighted.</div><div class = "text-block"><span style = "font-weight:bold;">3.5 Risk of bias assessment</span></div><div class = "text-block"><span style = "font-weight:bold;">Part A. The impact of PVA on clinical outcomes</span></div><div class = "text-block">Two researchers independently will assess the risk of bias for each study using QUIPS tool (Hyden 2013) (11). We will assess the following domains:</div><div class = "text-block">1. Study Participation</div><div class = "text-block">2. Study Attrition</div><div class = "text-block">3. Prognostic Factor Measurement</div><div class = "text-block">4. Outcome Measurement</div><div class = "text-block">5. Study Confounding (Age, Severity score, Duration of mechanical ventilation)</div><div class = "text-block">6. Statistical Analysis and Reporting</div><div class = "text-block">Agreement between the two review researchers with regard to the primary outcomes. Disagreement will be resolved by discussion and if necessary a third review researcher.</div><div class = "text-block"><span style = "font-weight:bold;">Part B. Interventions for improving PVA</span></div><div class = "text-block">Two researchers independently will assess the risk of bias for each randomized control study using risk of bias 2 tool (12).</div><div class = "text-block">Two researchers independently will assess the risk of bias for each observational study using ROBINS-I tool (13).</div><div class = "text-block"><span style = "font-weight:bold;">3.6 Assessment of effects of prognostic factor and interventions</span></div><div class = "text-block">For the dichotomous variables of mortality and prevalence of reintubation and tracheostomy, pooled odds ratios (ORs) with 95% CIs are provided.</div><div class = "text-block">For the continuous outcomes including duration of mechanical ventilation (expressed in days) and incidence of PVA (expressed in percentage), the standardised mean differences or the mean differences with 95% CIs were calculated, as recommended by the Cochrane Handbook. (14)</div><div class = "text-block">Adverse events were narratively summarised because their definition often varies across studies.</div><div class = "text-block"><span style = "font-weight:bold;">3.8Missing values</span></div><div class = "text-block"><span style = "font-weight:bold;">3.8.1 Discrete variables</span></div><div class = "text-block">For discrete variables, we will analyze all the data following the concept of intention-to-treat (ITT). For continuous variables, we will not perform imputation of missing values, in accordance with the recommendations set out in the Cochrane handbook (14). We will perform meta-analyses using original data.</div><div class = "text-block"><span style = "font-weight:bold;">3.8.2Missing values</span></div><div class = "text-block">We will contact the study authors about missing values.</div><div class = "text-block"><span style = "font-weight:bold;">3.8.3Statistical measurement for missing values</span></div><div class = "text-block">If only standard errors or p-values are reported, the Altman method(15) is used to calculate the standard deviation. If the author is not known, the standard deviation is calculated from the confidence intervals and t-values using the method described in the Cochrane handbook(16) or supplemented by a validated method(17). Alternatively, the standard deviations are complemented by the validated method(17). The validity of these methods will be verified by a sensitivity analysis.</div><div class = "text-block"><span style = "font-weight:bold;">3.9 Assessment of heterogeneity</span></div><div class = "text-block">We will calculate I2 as a measure of variation across studies that is due to heterogeneity rather than chance, and interpreted the values as follows: 0%–40%, negligible heterogeneity; 30%–60%, mild-to-moderate heterogeneity; 50%–90%, moderate-to-substantial heterogeneity; 75%–100%, considerable heterogeneity. If heterogeneity is identified for an outcome (I2 >50%), we will investigate the underlying reasons and conduct the χ2 test, with a p value of <0.10 being considered to indicate statistical significance. </div><div class = "text-block"><span style = "font-weight:bold;">3.10 Assessment of publication bias</span></div><div class = "text-block">We will search trial registers (the World Health Organization International Clinical Trials Platform Search Portal, ClinicalTrials.gov) to identify completed but unpublished trials. If more than 10 studies are included in this review, we will perform a funnel plot analysis and will use Egger's test (a p value of < 0.05 being considered to be statistically significant for a two-sided test) to assess reporting bias.</div><div class = "text-block"><span style = "font-weight:bold;">3.11 Meta-analysis </span></div><div class = "text-block">We will conduct all analyses using the STATA version 16 (StataCorp, College Station, Texas, USA).</div><div class = "text-block">We will use the random-effects models for all analyses.</div><div class = "text-block"><span style = "font-weight:bold;">3.12 Subgroup analysis</span></div><div class = "text-block">We will also carry out prespecified subgroup analyses according to the following variables.</div><div class = "text-block">1. Causes of admission to ICU: Internal diseases vs. Traumatic diseases</div><div class = "text-block">2. Coexisting ARDS: ARDS vs. not ARDS</div><div class = "text-block">3. Ventilator mode: Assist control or pressure support ventilation vs. other ventilator mode</div><div class = "text-block">4. Timing: Acute phase (within 72 hrs of initiation of mechanical ventilation or as soon as patients were not able to trigger all ventilator breaths) vs Whole period of mechanical ventilation</div><div class = "text-block">5. Ways of evaluating PVA: Human vs Software</div><div class = "text-block"><span style = "font-weight:bold;">3.13 Sensitivity analysis </span></div><div class = "text-block">We plan the following prespecified sensitivity analyses for the primary outcomes: exclusion of studies (i) using imputed statistics, (ii) including timing when assessing the PVA is not only acute phase but without acute phase, (iii) including post-operative patients and (iv) with high or moderate risk of bias. Statistical significance was also set at p<0.05.</div><div class = "text-block"><span style = "font-weight:bold;">4. Summary of findings</span></div><div class = "text-block">We will create a summary-of-findings table that included an overall grading of the certainty of evidence for each of the main outcomes, which was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. (18)</div><div class = "text-block"><span style = "font-weight:bold;">Part A. The impact of PVA on clinical outcomes</span></div><div class = "text-block">1. Duration of mechanical ventilation</div><div class = "text-block">2. ICU mortality</div><div class = "text-block">3. Hospital mortality</div><div class = "text-block">4. Reintubation</div><div class = "text-block">5. Tracheostomy</div><div class = "text-block">6. All adverse events (as defined by the study authors)</div><div class = "text-block"><span style = "font-weight:bold;">Part B. Interventions for improving PVA</span></div><div class = "text-block">1. Incidence of PVA</div><div class = "text-block">2. Duration of mechanical ventilation</div><div class = "text-block">3. ICU mortality</div><div class = "text-block">4. Hospital mortality</div><div class = "text-block">5. Reintubation</div><div class = "text-block">6. Tracheostomy</div><div class = "text-block">7. All adverse events (as defined by the study authors)</div><div class = "text-block"><span style = "font-weight:bold;">5. Conflict of Interest</span></div><div class = "text-block">We have no conflict of interest.</div><div class = "text-block"><span style = "font-weight:bold;">6. References</span></div><div class = "text-block"><span>1. Gilstrap D, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=MacIntyre+N&cauthor_id=24070493" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">MacIntyre</span></a><span>N. Patient-ventilator interactions. Implications for clinical management. Am J Respir Crit Care Med 2013;188:1058–1068.</span></div><div class = "text-block"><span>2. Thille AW, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Rodriguez+P&cauthor_id=16896854" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Rodriguez</span></a><span> P, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Cabello+B&cauthor_id=16896854" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Cabello</span></a><span>B, et al. Patient-ventilator asynchrony during assisted mechanical ventilation. Intensive Care Med 2006;32:1515–22.</span></div><div class = "text-block"><span>3. de Wit M, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Miller+KB&cauthor_id=19886000" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Miller</span></a><span> KB, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Green+DA&cauthor_id=19886000" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Green</span></a><span>DA, et al. Ineffective triggering predicts increased duration of mechanical ventilation. Crit Care Med 2009;37:2740–5.</span></div><div class = "text-block">4. Beitler JR, Sands SA, Loring SH, et al. Quantifying unintended exposure to high tidal volumes from breath stacking dyssynchrony in ARDS: the BREATHE criteria. Intensive Care Med 2016;42:1427–1436.</div><div class = "text-block"><span>5. Pohlman MC, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=McCallister+KE&cauthor_id=18824913" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">McCallister</span></a><span> KE, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Schweickert+WD&cauthor_id=18824913" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Schweickert</span></a><span>WD, et al. Excessive tidal volume from breath stacking during lung-protective ventilation for acute lung injury. Crit Care Med 2008;36:3019 –3023.</span></div><div class = "text-block"><span>6. Blanch L, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Villagra+A&cauthor_id=25693449" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Villagra</span></a><span> A, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Sales+B&cauthor_id=25693449" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Sales</span></a><span>B, et al. Asynchronies during mechanical ventilation are associated with mortality. Intensive Care Med 2015;41:633–641.</span></div><div class = "text-block">7. Chanques G, Kress JP, Pohlman A, et al. Impact of ventilator adjustment and sedation-analgesia practices on severe asynchrony in patients ventilated in assist-control mode. Crit Care Med. 2013;41:2177–2187.</div><div class = "text-block">8. Pettenuzzo T, Aoyama H, Englesakis M, et al. Effect of Neurally Adjusted Ventilatory Assist on Patient-Ventilator Interaction in Mechanically Ventilated Adults: A Systematic Review and Meta-Analysis. Crit Care Med 2019;47:e602–609.</div><div class = "text-block">9. Kataoka J, Kuriyama A, Norisue Y, et al. Proportional modes versus pressure support ventilation: a systematic review and meta-analysis. Ann Intensive Care 2018;8:123.</div><div class = "text-block">10.FanE, Del SorboL, GoligherEC, et al; American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine.An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195:1253-1263.</div><div class = "text-block">11. Hayden JA, van der Windt DA, Cartwright JL, et al. Assessing Bias in Studies of Prognostic Factors. Ann Intern Med. 2013;158:280.</div><div class = "text-block"><span>12. Sterne JAC, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Savovi%C4%87+J&cauthor_id=31462531" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Savović</span></a><span>J, Pageet MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.</span></div><div class = "text-block"><span>13. Sterne JAC, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Hern%C3%A1n+MA&cauthor_id=27733354" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Hernán</span></a><span> MA, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Reeves+BC&cauthor_id=27733354" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">Reeves</span></a><span>et BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919.</span></div><div class = "text-block"><span>14. Higgins JPT, Green S E. </span><span style = "font-style:italic;">Cochrane Handbook for Systematic Reviews of Interventions Version 6</span><span>. updated Ma. The Cochrane Collaboration; 2019. Available at: </span><a href="http://www.cochrane-handbook.org" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">www.cochrane-handbook.org</span></a><span style = ":;">.</span></div><div class = "text-block">15.Altman DG, Bland JM. Statistics Notes Detecting skewness from summary information Lesson of the Week. 1996;313(November):1996.</div><div class = "text-block">16. Higgins JPT, Green S E. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. updated Ma. The Cochrane Collaboration; 2011. Available at: www.cochrane-handbook.org.</div><div class = "text-block">17. Furukawa TA, Barbui C, Cipriani A, et al. Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol. 2006;59:7–10.</div><div class = "text-block">18. Foroutan F, Guyatt G, Zuk V, et al. GRADE Guidelines 28: Use of GRADE for the assessment of evidence about prognostic factors: rating certainty in identification of groups of patients with different absolute risks.J Clin Epidemiol. 2020;121:62-70.</div></div>

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