Early and mid-term outcomes of aortic annular enlargement: a systematic review and meta-analysis.

Background: There is mounting evidence at experienced centers that aortic annular enlargement (AAE) procedures are safe adjuncts to surgical aortic valve replacement (SAVR) that do not increase perioperative morbidity and mortality. This systematic review and meta-analysis aims to assess the impact of AAE procedures on mid-term outcomes after SAVR. Methods: OVID MEDLINE, OVID Embase, and Cochrane Library were searched comprehensively. Comparative studies examining adult patients undergoing SAVR with and without AAE were eligible for inclusion. Studies involving aortic root replacement, Ross procedures, and Ozaki procedures were excluded. The risk of bias was assessed according to Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I), and the quality of evidence was evaluated according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). Random effects meta-analysis facilitated the quantitative synthesis. Results: A total of 2,765 records were retrieved. After full-text review, 15 eligible studies were identified for data extraction and synthesis. The dataset included a total of 216,654 patients (AAE: 7,967; no AAE: 208,687). Only mid-term outcomes were available. In unmatched and unadjusted studies, perioperative mortality was noted to be higher in the AAE group. However, this difference was not observed in studies with matching or adjusted outcomes. In both the unmatched and unadjusted studies, and the matched and adjusted studies, there were no statistically significant differences identified regarding perioperative stroke, myocardial infarction, or permanent pacemaker implantation. Similarly, there were no statistically significant differences identified in mid-term mortality [hazard ratio (HR), 1.03; 95% confidence interval (CI): 0.95 to 1.11; P=0.49; I2=20% (matched/adjusted studies)], aortic valve reintervention [HR, 0.98; 95% CI: 0.75 to 1.27; P=0.86; I2=0% (matched/adjusted studies)], or heart failure [HR, 1.06; 95% CI: 0.86 to 1.30; P=0.58; I2=25% (matched/adjusted studies)]. Conclusions: SAVR with AAE does not appear to be associated with increased perioperative morbidity or mortality. There is no conclusive indication that AAE enhances mid-term survival, freedom from reoperation, or freedom from heart failure after SAVR.

Comparative effectiveness of alternative spontaneous breathing trial techniques: a systematic review and network meta-analysis of randomized trials.

BACKGROUND: The spontaneous breathing trial (SBT) technique that best balance successful extubation with the risk for reintubation is unknown. We sought to determine the comparative efficacy and safety of alternative SBT techniques. METHODS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to February 2023 for randomized or quasi-randomized trials comparing SBT techniques in critically ill adults and children and reported initial SBT success, successful extubation, reintubation (primary outcomes) and mortality (ICU, hospital, most protracted; secondary outcome) rates. Two reviewers screened, reviewed full-texts, and abstracted data. We performed frequentist random-effects network meta-analysis. RESULTS: We included 40 RCTs (6716 patients). Pressure Support (PS) versus T-piece SBTs was the most common comparison. Initial successful SBT rates were increased with PS [risk ratio (RR) 1.08, 95% confidence interval (CI) (1.05-1.11)], PS/automatic tube compensation (ATC) [1.12 (1.01 -1.25), high flow nasal cannulae (HFNC) [1.07 (1.00-1.13) (all moderate certainty), and ATC [RR 1.11, (1.03-1.20); low certainty] SBTs compared to T-piece SBTs. Similarly, initial successful SBT rates were increased with PS, ATC, and PS/ATC SBTs compared to continuous positive airway pressure (CPAP) SBTs. Successful extubation rates were increased with PS [RR 1.06, (1.03-1.09); high certainty], ATC [RR 1.13, (1.05-1.21); moderate certainty], and HFNC [RR 1.06, (1.02-1.11); high certainty] SBTs, compared to T-piece SBTs. There was little to no difference in reintubation rates with PS (vs. T-piece) SBTs [RR 1.05, (0.91-1.21); low certainty], but increased reintubation rates with PS [RR 2.84, (1.61-5.03); moderate certainty] and ATC [RR 2.95 (1.57-5.56); moderate certainty] SBTs compared to HFNC SBTs. CONCLUSIONS: SBTs conducted with pressure augmentation (PS, ATC, PS/ATC) versus without (T-piece, CPAP) increased initial successful SBT and successful extubation rates. Although SBTs conducted with PS or ATC versus HFNC increased reintubation rates, this was not the case for PS versus T-piece SBTs.

Comparison of venovenous extracorporeal membrane oxygenation, prone position and supine mechanical ventilation for severely hypoxemic acute respiratory distress syndrome: a network meta-analysis.

PURPOSE: Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 < 80 mmHg is a life-threatening condition. The optimal management strategy is unclear. The aim of this meta-analysis was to compare the effects of low tidal volumes (Vt), moderate Vt, prone ventilation, and venovenous extracorporeal membrane oxygenation (VV-ECMO) on mortality in severe ARDS. METHODS: We performed a frequentist network meta-analysis of randomised controlled trials (RCTs) with participants who had severe ARDS and met eligibility criteria for VV-ECMO or had PaO2/FiO2 < 80 mmHg. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to discern the relative effect of interventions on mortality and the certainty of the evidence. RESULTS: Ten RCTs including 812 participants with severe ARDS were eligible. VV-ECMO reduces mortality compared to low Vt (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.59-0.99, moderate certainty) and compared to moderate Vt (RR 0.75, 95% CI 0.57-0.98, low certainty). Prone ventilation reduces mortality compared to moderate Vt (RR 0.78, 95% CI 0.66-0.93, high certainty) and compared to low Vt (RR 0.81, 95% CI 0.63-1.02, moderate certainty). We found no difference in the network comparison of VV-ECMO compared to prone ventilation (RR 0.95, 95% CI 0.72-1.26), but inferences were based solely on indirect comparisons with very low certainty due to very wide confidence intervals. CONCLUSIONS: In adults with ARDS and severe hypoxia, both VV-ECMO (low to moderate certainty evidence) and prone ventilation (moderate to high certainty evidence) improve mortality relative to low and moderate Vt strategies. The impact of VV-ECMO versus prone ventilation remains uncertain.

Sex and gender-based analysis and diversity metric reporting in acute care trials published in high-impact journals: a systematic review.

OBJECTIVE: To characterise sex and gender-based analysis (SGBA) and diversity metric reporting, representation of female/women participants in acute care trials and temporal changes in reporting before and after publication of the 2016 Sex and Gender Equity in Research guideline. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE for trials published in five leading medical journals in 2014, 2018 and 2020. STUDY SELECTION: Trials that enrolled acutely ill adults, compared two or more interventions and reported at least one clinical outcome. DATA ABSTRACTION AND SYNTHESIS: 4 reviewers screened citations and 22 reviewers abstracted data, in duplicate. We compared reporting differences between intensive care unit (ICU) and cardiology trials. RESULTS: We included 88 trials (75 (85.2%) ICU and 13 (14.8%) cardiology) (n=111 428; 38 140 (34.2%) females/women). Of 23 (26.1%) trials that reported an SGBA, most used a forest plot (22 (95.7%)), were prespecified (21 (91.3%)) and reported a sex-by-intervention interaction with a significance test (19 (82.6%)). Discordant sex and gender terminology were found between headings and subheadings within baseline characteristics tables (17/32 (53.1%)) and between baseline characteristics tables and SGBA (4/23 (17.4%)). Only 25 acute care trials (28.4%) reported race or ethnicity. Participants were predominantly white (78.8%) and male/men (65.8%). No trial reported gendered-social factors. SGBA reporting and female/women representation did not improve temporally. Compared with ICU trials, cardiology trials reported significantly more SGBA (15/75 (20%) vs 8/13 (61.5%) p=0.005). CONCLUSIONS: Acute care trials in leading medical journals infrequently included SGBA, female/women and non-white trial participants, reported race or ethnicity and never reported gender-related factors. Substantial opportunity exists to improve SGBA and diversity metric reporting and recruitment of female/women participants in acute care trials. PROSPERO REGISTRATION NUMBER: CRD42022282565.

Reverse triggering ? a novel or previously missed phenomenon?

BACKGROUND: Reverse triggering (RT) was described in 2013 as a form of patient-ventilator asynchrony, where patient's respiratory effort follows mechanical insufflation. Diagnosis requires esophageal pressure (Pes) or diaphragmatic electrical activity (EAdi), but RT can also be diagnosed using standard ventilator waveforms. HYPOTHESIS: We wondered (1) how frequently RT would be present but undetected in the figures from literature, especially before 2013; (2) whether it would be more prevalent in the era of small tidal volumes after 2000. METHODS: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, from 1950 to 2017, with key words related to asynchrony to identify papers with figures including ventilator waveforms expected to display RT if present. Experts labelled waveforms. 'Definite' RT was identified when Pes or EAdi were in the tracing, and 'possible' RT when only flow and pressure waveforms were present. Expert assessment was compared to the author's descriptions of waveforms. RESULTS: We found 65 appropriate papers published from 1977 to now, containing 181 ventilator waveforms. 21 cases of 'possible' RT and 25 cases of 'definite' RT were identified by the experts. 18.8% of waveforms prior to 2013 had evidence of RT. Most cases were published after 2000 (1 before vs. 45 after, p = 0.03). 54% of RT cases were attributed to different phenomena. A few cases of identified RT were already described prior to 2013 using different terminology (earliest in 1997). While RT cases attributed to different phenomena decreased after 2013, 60% of 'possible' RT remained missed. CONCLUSION: RT has been present in the literature as early as 1997, but most cases were found after the introduction of low tidal volume ventilation in 2000. Following 2013, the number of undetected cases decreased, but RT are still commonly missed. Reverse Triggering, A Missed Phenomenon in the Literature. Critical Care Canada Forum 2019 Abstracts. Can J Anesth/J Can Anesth 67 (Suppl 1), 1-162 (2020). https://doi-org.myaccess.library.utoronto.ca/ https://doi.org/10.1007/s12630-019-01552-z .

Spontaneous Breathing Trial Techniques for Extubating Adults and Children Who Are Critically Ill: A Systematic Review and Meta-Analysis.

Importance: Considerable controversy exists regarding the best spontaneous breathing trial (SBT) technique to use. Objective: To summarize trials comparing alternative SBTs. Data Sources: Several databases (MEDLINE [from inception to February 2023], the Cochrane Central Register of Controlled Trials [in February 2023], and Embase [from inception to February 2023] and 5 conference proceedings (from January 1990 to April 2023) were searched in this systematic review and meta-analysis. Study Selection: Randomized trials directly comparing SBT techniques in critically ill adults or children and reporting at least 1 clinical outcome were selected. Data Extraction and Synthesis: Paired reviewers independently screened citations, abstracted data, and assessed quality for the systematic review and meta-analysis using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA guidelines). Data were pooled using random-effects models. Main Outcomes and Measures: Primary outcomes included SBT success, extubation success, and reintubation. Results: The systematic review and meta-analysis identified 40 trials that included 6716 patients. Low-quality evidence (14 trials [n = 4459]) suggested that patients were not more likely to pass a pressure support (PS) compared with a T-piece SBT (risk ratio [RR], 1.04; 95% CI, 0.97-1.11; P = .31; I2 = 73%), unless 1 outlier trial accounting for all heterogeneity was excluded (RR, 1.09; 95% CI, 1.06-1.12; P < .001; I2 = 0% [13 trials; n = 3939]; moderate-quality evidence), but were significantly more likely to be successfully extubated (RR, 1.07; 95% CI, 1.04-1.10; P < .001; I2 = 0%; 16 trials [n = 4462]; moderate-quality evidence). Limited data (5 trials [n = 502]) revealed that patients who underwent automatic tube compensation/continuous positive airway pressure compared with PS SBTs had a significantly higher successful extubation rate (RR, 1.10; 95% CI, 1.00-1.21; P = .04; I2 = 0% [low-quality evidence]). Compared with T-piece SBTs, high-flow oxygen SBTs (3 trials [n = 386]) had significantly higher successful extubation (RR, 1.06; 95% CI, 1.00-1.11; P = .04; I2 = 0%) and lower reintubation (RR, 0.37; 95% CI, 0.21-0.65; P = <.001; I2 = 0% [both low-quality evidence]) rates. Credible subgroup effects were not found. Conclusions and Relevance: In this systematic review and meta-analysis, the findings suggest that patients undergoing PS compared with T-piece SBTs were more likely to be extubated successfully and more likely to pass an SBT, after exclusion of an outlier trial. Pressure support SBTs were not associated with increased risk of reintubation. Future trials should compare SBT techniques that maximize differences in inspiratory support.

Inter-limb kinetic asymmetries during sit-to-stand performance persist following unilateral total knee arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Kinetic asymmetries during sit-to-stand have been consistently observed early after total knee arthroplasty; however, the longer-term outcomes are less clear. The purpose of this systematic review and meta-analysis was to analyze the results of studies examining inter-limb kinetic symmetry during sit-to-stand performance among individuals who were at least one-year post unilateral total knee arthroplasty. METHODS: PubMed, SPORTDiscus, CINAHL, and Health Source databases were searched. Studies were included if they were published in a peer-reviewed journal, included subjects who had undergone unilateral total knee arthroplasty at least one-year prior, and examined vertical ground reaction forces and/or knee extension moments for the involved and uninvolved limbs during sit-to-stand performance. Data were transformed into a limb symmetry index, which expressed the ratio of the peak forces/moments for the involved limb, relative to the uninvolved limb (1.0 reflects perfect symmetry). These ratios were meta-analyzed using the ratio of means method. FINDINGS: Seven studies were deemed eligible for inclusion. Ground reaction force data was pooled from seven studies and knee extension moment data was pooled from two studies. For the peak vertical ground reaction forces, the pooled limb symmetry index was 0.96 (CI95% = [0.93, 0.99]). For the peak knee extension moments, the pooled limb symmetry index was 0.91 (CI95% = [0.84, 0.98]). In both cases this reflects greater limb/knee loading for the uninvolved limb, relative to the involved limb. INTERPRETATION: Asymmetries in limb/knee loading persist beyond the one-year post-operative period following total knee arthroplasty, potentially contributing to degenerative changes for the uninvolved limb.

Developing and Validating a Prediction Model For Death or Critical Illness in Hospitalized Adults, an Opportunity for Human-Computer Collaboration.

Hospital early warning systems that use machine learning (ML) to predict clinical deterioration are increasingly being used to aid clinical decision-making. However, it is not known how ML predictions complement physician and nurse judgment. Our objective was to train and validate a ML model to predict patient deterioration and compare model predictions with real-world physician and nurse predictions. DESIGN: Retrospective and prospective cohort study. SETTING: Academic tertiary care hospital. PATIENTS: Adult general internal medicine hospitalizations. MEASUREMENTS AND MAIN RESULTS: We developed and validated a neural network model to predict in-hospital death and ICU admission in 23,528 hospitalizations between April 2011 and April 2019. We then compared model predictions with 3,374 prospectively collected predictions from nurses, residents, and attending physicians about their own patients in 960 hospitalizations between April 30, and August 28, 2019. ML model predictions achieved clinician-level accuracy for predicting ICU admission or death (ML median F1 score 0.32 [interquartile range (IQR) 0.30-0.34], AUC 0.77 [IQ 0.76-0.78]; clinicians median F1-score 0.33 [IQR 0.30-0.35], AUC 0.64 [IQR 0.63-0.66]). ML predictions were more accurate than clinicians for ICU admission. Of all ICU admissions and deaths, 36% occurred in hospitalizations where the model and clinicians disagreed. Combining human and model predictions detected 49% of clinical deterioration events, improving sensitivity by 16% compared with clinicians alone and 24% compared with the model alone while maintaining a positive predictive value of 33%, thus keeping false alarms at a clinically acceptable level. CONCLUSIONS: ML models can complement clinician judgment to predict clinical deterioration in hospital. These findings demonstrate important opportunities for human-computer collaboration to improve prognostication and personalized medicine in hospital.

Mortality As a Measure of Treatment Effect in Clinical Trials Recruiting Critically Ill Patients.

OBJECTIVES: All-cause mortality is a common measure of treatment effect in ICU-based randomized clinical trials (RCTs). We sought to understand the performance characteristics of a mortality endpoint by evaluating its temporal course, responsiveness to differential treatment effects, and impact when used as an outcome measure in trials of acute illness. DATA SOURCES: We searched OVID Medline for RCTs published from 1990 to 2018. STUDY SELECTION: We reviewed RCTs that had randomized greater than or equal to 100 patients, were published in one of five high-impact general medical or eight critical care journals, and reported mortality at two or more distinct time points. We excluded trials recruiting pediatric or neonatal patients and cluster RCTs. DATA EXTRACTION: Mortality by randomization group was recorded from the article or estimated from survival curves. Trial impact was assessed by inclusion of results in clinical practice guidelines. DATA SYNTHESIS: From 2,592 potentially eligible trials, we included 343 RCTs (228,784 adult patients). While one third of all deaths by 180 days had occurred by day 7, the risk difference between study arms continued to increase until day 60 (p = 0.01) and possibly day 90 (p = 0.07) and remained stable thereafter. The number of deaths at ICU discharge approximated those at 28-30 days (95% [interquartile range [IQR], 86-106%]), and deaths at hospital discharge approximated those at 60 days (99% [IQR, 94-104%]). Only 13 of 43 interventions (30.2%) showing a mortality benefit have been adopted into widespread clinical practice. CONCLUSIONS: Our findings provide a conceptual framework for choosing a time horizon and interpreting mortality outcome in trials of acute illness. Differential mortality effects persist for 60 to 90 days following recruitment. Location-based measures approximate time-based measures for trials conducted outside the United States. The documentation of a mortality reduction has had a modest impact on practice.

Reducing unnecessary diagnostic phlebotomy in intensive care: a prospective quality improvement intervention.

BACKGROUND: Critically ill patients receive frequent routine and recurring blood tests, some of which are unnecessary. AIM: To reduce unnecessary routine phlebotomy in a 30-bed tertiary medical-surgical intensive care unit (ICU) in Toronto, Ontario. METHODS: This prospective quality improvement study included a 7-month preintervention baseline, 5-month intervention and 11-month postintervention period. Change strategies included education, ICU rounds checklists, electronic order set modifications, an electronic test add-on tool and audit and feedback. The primary outcome was mean volume of blood collected per patient-day. Secondary outcomes included the number blood tubes used and red cell transfusions. Balancing measures included the timing and types of blood tests, ICU length of stay and mortality. Outcomes were evaluated using process control charts and segmented regression. RESULTS: Patient demographics did not differ between time periods; total number of patients: 2096, median age: 61 years, 60% male. Mean phlebotomy volume±SD decreased from 41.1±4.0 to 34.1±4.7 mL/patient-day. Special cause variation was met at 13 weeks. Segmental regression demonstrated an immediate postintervention decrease of 6.6 mL/patient-day (95% CI 1.8 to 11.4 p=0.009), which was sustained. Blood tube consumption decreased by 1.4 tubes/patient-day (95% CI 0.4 to 2.4, p=0.005) amounting to 13 276 tubes (95% CI 4602 to 22 127 tubes) saved over 11 months. Red blood cell transfusions decreased from 10.5±5.2 to 8.3±4.4 transfusions/100 patient-days (incident rate ratio 0.56, 95% CI 0.35 to 0.88, p=0.01). There was no impact on length of stay (2 days, IQR 1-5) and mortality (18.1%±2.0%). CONCLUSION: Iterative improvement interventions targeting clinician test ordering behaviour can reduce ICU phlebotomy and may impact red cell transfusions. Frequent stakeholder consultation, incorporating stewardship into daily workflow, and audit and feedback are effective strategies.

Association Between Tracheostomy and Functional, Neuropsychological, and Healthcare Utilization Outcomes in the RECOVER Cohort.

Tracheostomy is commonly performed in critically ill patients requiring prolonged mechanical ventilation (MV). We evaluated the outcomes of tracheostomy in patients who received greater than or equal to 1 week MV and were followed for 1 year. DESIGN: In this secondary analysis of a prospective observational study, we compared outcomes in tracheostomy versus nontracheostomy patients. Outcomes post ICU included Functional Independence Measure (FIM) subscales, 6-Minute Walk Test (6MWT), Short Form 36 (SF36), Medical Research Council (MRC) Scale, pulmonary function tests (PFTs), Impact of Event Scale (IES), Beck Depression Inventory-II (BDI-II), and vital status and disposition. SETTING: Nine University affiliated ICUs in Canada. PATIENTS: Medical/surgical patients requiring MV for 7 or more days who were enrolled in the Towards RECOVER Study. MEASUREMENTS AND MAIN RESULTS: Of 398 ICU survivors, 193 (48.5%) received tracheostomy, on median ICU day 14 (interquartile range [IQR], 8-0 d). Patients with tracheostomy were older, had similar severity of illness, had longer MV duration and ICU and hospital stays, and had higher risk of ICU readmission (odds ratio [OR], 1.9; 95% CI, 1.0-3.2) and hospital mortality (OR, 2.6; 95% CI, 1.1-6.1), but not 1-year mortality (hazard ratio, 1.41; 95% CI, 0.88-1.2). Over 1 year, tracheostomy patients had lower FIM-Total (7.7 points; 95% CI, 2.2-13.2); SF36, IES, and BDI-II were similar. From 3 months, tracheostomy patients had 12% lower 6MWT (p = 0.0008) and lower MRC score (3.4 points; p = 0.006). Most PFTs were 5-8% lower in the tracheostomy group. Tracheostomy patients had similar specialist visits (rate ratio, 0.63; 95% CI, 0.28-2.4) and hospital readmissions (OR, 0.82; 95% CI, 0.54-1.3) but were less likely to be at home at hospital discharge and 1 year. CONCLUSIONS: Patients who received tracheostomy had more ICU and hospital care and higher hospital mortality compared with patients who did not receive a tracheostomy. In 1 year follow-up, tracheostomy patients required a higher daily burden of care, expressed by FIM.

Left ventricular assist device implantation via lateral thoracotomy: A systematic review and meta-analysis.

BACKGROUND: Left ventricular assist device (LVAD) implantation via lateral thoracotomy can offer similar effectiveness to conventional approaches with less perioperative adverse events. We performed a systematic review and meta-analysis to determine the potential benefits of lateral thoracotomy (LT) for LVAD implantation compared to median sternotomy. METHODS: We searched MEDLINE and Embase databases for studies comparing continuous-flow LVAD implantation using LT with conventional sternotomy. Main outcomes were perioperative mortality and complications. RESULTS: Twenty-five observational studies enrolling 3072 patients were included with a median follow-up of 10 months. Perioperative mortality (30 day or in-hospital) was 7% (LT) and 14% (sternotomy); however, mortality differences were no longer statistically significant in matched/adjusted studies (RR:0.86; 95%CI:0.52-1.44; p = 0.58). LT was associated with decreased need for blood product transfusions (mean difference[MD]: -4.7; 95%CI: -7.2 to -2.3 units; p < 0.001), reoperation for bleeding (RR:0.34; 95%CI:0.22-0.54; p < 0.001), postoperative RVAD implantation (RR:0.53; 95%CI:0.36-0.77; p < 0.001), days requiring inotropes (MD: -1.1; 95%CI: -2.1 to -0.03 inotrope days; p = 0.04), ICU (MD: -3.3; 95%CI: -6.0 to -0.7 ICU days; p = 0.01), and hospital length of stay (MD: -5.1; 95%CI: -10.1 to -0.1 hospital days; p = 0.04) in matched/adjusted studies. Overall mortality during follow-up was significantly lower for LT in unmatched/unadjusted studies but not statistically significantly lower in matched/adjusted studies (Hazard Ratio:0.82; 95%CI:0.59-1.14; p = 0.24). CONCLUSION: LVAD implantation via LT was associated with significantly decreased need for blood products, reoperation for bleeding, and postoperative RVAD implantation. Furthermore, days on inotropic support were also lower, likely contributing to the shorter length of stay. These findings support greater use of a LT approach for carefully selected patients.

Interpolating Strange Attractors via Fractional Brownian Bridges.

We present a novel method for interpolating univariate time series data. The proposed method combines multi-point fractional Brownian bridges, a genetic algorithm, and Takens' theorem for reconstructing a phase space from univariate time series data. The basic idea is to first generate a population of different stochastically-interpolated time series data, and secondly, to use a genetic algorithm to find the pieces in the population which generate the smoothest reconstructed phase space trajectory. A smooth trajectory curve is hereby found to have a low variance of second derivatives along the curve. For simplicity, we refer to the developed method as PhaSpaSto-interpolation, which is an abbreviation for phase-space-trajectory-smoothing stochastic interpolation. The proposed approach is tested and validated with a univariate time series of the Lorenz system, five non-model data sets and compared to a cubic spline interpolation and a linear interpolation. We find that the criterion for smoothness guarantees low errors on known model and non-model data. Finally, we interpolate the discussed non-model data sets, and show the corresponding improved phase space portraits. The proposed method is useful for interpolating low-sampled time series data sets for, e.g., machine learning, regression analysis, or time series prediction approaches. Further, the results suggest that the variance of second derivatives along a given phase space trajectory is a valuable tool for phase space analysis of non-model time series data, and we expect it to be useful for future research.

Non-invasive ventilation versus invasive weaning in critically ill adults: a systematic review and meta-analysis.

BACKGROUND: Extubation to non-invasive ventilation (NIV) has been investigated as a strategy to wean critically ill adults from invasive ventilation and reduce ventilator-related complications. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, proceedings of four conferences and bibliographies (to June 2020) for randomised and quasi-randomised trials that compared extubation with immediate application of NIV to continued invasive weaning in intubated adults and reported mortality (primary outcome) or other outcomes. Two reviewers independently screened citations, assessed trial quality and abstracted data. RESULTS: We identified 28 trials, of moderate-to-good quality, involving 2066 patients, 44.6% with chronic obstructive pulmonary disease (COPD). Non-invasive weaning significantly reduced mortality (risk ratio (RR) 0.57, 95% CI 0.44 to 0.74; high quality), weaning failures (RR 0.59, 95% CI 0.43 to 0.81; high quality), pneumonia (RR 0.30, 95% CI 0.22 to 0.41; high quality), intensive care unit (ICU) (mean difference (MD) -4.62 days, 95% CI -5.91 to -3.34) and hospital stay (MD -6.29 days, 95% CI -8.90 to -3.68). Non-invasive weaning also significantly reduced the total duration of ventilation, duration of invasive ventilation and duration of ventilation related to weaning (MD -0.57, 95% CI -1.08 to -0.07) and tracheostomy rate. Mortality, pneumonia, reintubation and ICU stay were significantly lower in trials enrolling COPD (vs mixed) populations. CONCLUSION: Non-invasive weaning significantly reduced mortality, pneumonia and the duration of ventilation related to weaning, particularly in patients with COPD. Beneficial effects are less clear (or more careful patient selection is required) in non-COPD patients. PROSPERO REGISTRATION NUMBER: CRD42020201402.

The Usefulness of the Rapid Shallow Breathing Index in Predicting Successful Extubation: A Systematic Review and Meta-analysis.

BACKGROUND: Clinicians use several measures to ascertain whether individual patients will tolerate liberation from mechanical ventilation, including the rapid shallow breathing index (RSBI). RESEARCH QUESTION: Given varied use of different thresholds, patient populations, and measurement characteristics, how well does RSBI predict successful extubation? STUDY DESIGN AND METHODS: We searched six databases from inception through September 2019 and selected studies reporting the accuracy of RSBI in the prediction of successful extubation. We extracted study data and assessed quality independently and in duplicate. RESULTS: We included 48 studies involving RSBI measurements of 10,946 patients. Pooled sensitivity for RSBI of < 105 in predicting extubation success was moderate (0.83 [95% CI, 0.78-0.87], moderate certainty), whereas specificity was poor (0.58 [95% CI, 0.49-0.66], moderate certainty) with diagnostic ORs (DORs) of 5.91 (95% CI, 4.09-8.52). RSBI thresholds of < 80 or 80 to 105 yielded similar sensitivity, specificity, and DOR. These findings were consistent across multiple subgroup analyses reflecting different patient characteristics and operational differences in RSBI measurement. INTERPRETATION: As a stand-alone test, the RSBI has moderate sensitivity and poor specificity for predicting extubation success. Future research should evaluate its role as a permissive criterion to undergo a spontaneous breathing trial (SBT) for patients who are at intermediate pretest probability of passing an SBT. TRIAL REGISTRY: PROSPERO; No.: CRD42020149196; URL: www.crd.york.ac.uk/prospero/.

Adherence of Clinical Practice Guidelines for Pharmacologic Treatments of Hospitalized Patients With COVID-19 to Trustworthy Standards: A Systematic Review.

Importance: The COVID-19 pandemic created the need for rapid and urgent guidance for clinicians to manage COVID-19 among patients and prevent transmission. Objective: To appraise the quality of clinical practice guidelines (CPGs) using the National Academy of Medicine (NAM) criteria. Evidence Review: A search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials to December 14, 2020, and a search of related articles to February 28, 2021, that included CPGs developed by societies or by government or nongovernment organizations that reported pharmacologic treatments of hospitalized patients with COVID-19. Teams of 2 reviewers independently abstracted data and assessed CPG quality using the 15-item National Guideline Clearinghouse Extent of Adherence to Trustworthy Standards (NEATS) instrument. Findings: Thirty-two CPGs were included in the review. Of these, 25 (78.1%) were developed by professional societies and emanated from a single World Health Organization (WHO) region. Overall, the CPGs were of low quality. Only 7 CPGs (21.9%) reported funding sources, and 12 (37.5%) reported conflicts of interest. Only 5 CPGs (15.6%) included a methodologist, described a search strategy or study selection process, or synthesized the evidence. Although 14 CPGs (43.8%) made recommendations or suggestions for or against treatments, they infrequently rated confidence in the quality of the evidence (6 of 32 [18.8%]), described potential benefits and harms (6 of 32 [18.8%]), or graded the strength of the recommendations (5 of 32 [15.6%]). External review, patient or public perspectives, or a process for updating were rare. High-quality CPGs included a methodologist and multidisciplinary collaborations involving investigators from 2 or more WHO regions. Conclusions and Relevance: In this review, few COVID-19 CPGs met NAM standards for trustworthy guidelines. Approaches that prioritize engagement of a methodologist and multidisciplinary collaborators from at least 2 WHO regions may lead to the production of fewer, high-quality CPGs that are poised for updates as new evidence emerges. Trial Registration: PROSPERO Identifier: CRD42021245239.

Separation from mechanical ventilation and survival after spinal cord injury: a systematic review and meta-analysis.

BACKGROUND: Prolonged need for mechanical ventilation greatly impacts life expectancy of patients after spinal cord injury (SCI). Weaning outcomes have never been systematically assessed. In this systematic review and meta-analysis, we aimed to investigate the probability of weaning success, duration of mechanical ventilation, mortality, and their predictors in mechanically ventilated patients with SCI. METHODS: We searched six databases from inception until August 2021 for randomized-controlled trials and observational studies enrolling adult patients (≥ 16 years) with SCI from any cause requiring mechanical ventilation. Titles and abstracts were screened independently by two reviewers. Full texts of the identified articles were then assessed for eligibility. Data were extracted independently and in duplicate by pairs of authors, using a standardized data collection form. Synthetic results are reported as meta-analytic means and proportions, based on random effects models. RESULTS: Thirty-nine studies (14,637 patients, mean age 43) were selected. Cervical lesions were predominant (12,717 patients had cervical lesions only, 1843 in association with other levels' lesions). Twenty-five studies were conducted in intensive care units (ICUs), 14 in rehabilitative settings. In ICU, the mean time from injury to hospitalization was 8 h [95% CI 7-9], mean duration of mechanical ventilation 27 days [20-34], probability of weaning success 63% [45-78] and mortality 8% [5-11]. Patients hospitalized in rehabilitation centres had a greater number of high-level lesions (C3 or above), were at 40 days [29-51] from injury and were ventilated for a mean of 97 days [65-128]; 82% [70-90] of them were successfully weaned, while mortality was 1% [0-19]. CONCLUSIONS: Although our study highlights the lack of uniform definition of weaning success, of clear factors associated with weaning outcomes, and of high-level evidence to guide optimal weaning in patients with SCI, it shows that around two-thirds of mechanically ventilated patients can be weaned in ICU after SCI. A substantial gain in weaning success can be obtained during rehabilitation, with additional duration of stay but minimal increase in mortality. The study is registered with PROSPERO (CRD42020156788).

Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.