SurvMaximin: Robust federated approach to transporting survival risk prediction models.

OBJECTIVE: For multi-center heterogeneous Real-World Data (RWD) with time-to-event outcomes and high-dimensional features, we propose the SurvMaximin algorithm to estimate Cox model feature coefficients for a target population by borrowing summary information from a set of health care centers without sharing patient-level information. MATERIALS AND METHODS: For each of the centers from which we want to borrow information to improve the prediction performance for the target population, a penalized Cox model is fitted to estimate feature coefficients for the center. Using estimated feature coefficients and the covariance matrix of the target population, we then obtain a SurvMaximin estimated set of feature coefficients for the target population. The target population can be an entire cohort comprised of all centers, corresponding to federated learning, or a single center, corresponding to transfer learning. RESULTS: Simulation studies and a real-world international electronic health records application study, with 15 participating health care centers across three countries (France, Germany, and the U.S.), show that the proposed SurvMaximin algorithm achieves comparable or higher accuracy compared with the estimator using only the information of the target site and other existing methods. The SurvMaximin estimator is robust to variations in sample sizes and estimated feature coefficients between centers, which amounts to significantly improved estimates for target sites with fewer observations. CONCLUSIONS: The SurvMaximin method is well suited for both federated and transfer learning in the high-dimensional survival analysis setting. SurvMaximin only requires a one-time summary information exchange from participating centers. Estimated regression vectors can be very heterogeneous. SurvMaximin provides robust Cox feature coefficient estimates without outcome information in the target population and is privacy-preserving.

International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: Retrospective Cohort Study.

BACKGROUND: Many countries have experienced 2 predominant waves of COVID-19-related hospitalizations. Comparing the clinical trajectories of patients hospitalized in separate waves of the pandemic enables further understanding of the evolving epidemiology, pathophysiology, and health care dynamics of the COVID-19 pandemic. OBJECTIVE: In this retrospective cohort study, we analyzed electronic health record (EHR) data from patients with SARS-CoV-2 infections hospitalized in participating health care systems representing 315 hospitals across 6 countries. We compared hospitalization rates, severe COVID-19 risk, and mean laboratory values between patients hospitalized during the first and second waves of the pandemic. METHODS: Using a federated approach, each participating health care system extracted patient-level clinical data on their first and second wave cohorts and submitted aggregated data to the central site. Data quality control steps were adopted at the central site to correct for implausible values and harmonize units. Statistical analyses were performed by computing individual health care system effect sizes and synthesizing these using random effect meta-analyses to account for heterogeneity. We focused the laboratory analysis on C-reactive protein (CRP), ferritin, fibrinogen, procalcitonin, D-dimer, and creatinine based on their reported associations with severe COVID-19. RESULTS: Data were available for 79,613 patients, of which 32,467 were hospitalized in the first wave and 47,146 in the second wave. The prevalence of male patients and patients aged 50 to 69 years decreased significantly between the first and second waves. Patients hospitalized in the second wave had a 9.9% reduction in the risk of severe COVID-19 compared to patients hospitalized in the first wave (95% CI 8.5%-11.3%). Demographic subgroup analyses indicated that patients aged 26 to 49 years and 50 to 69 years; male and female patients; and black patients had significantly lower risk for severe disease in the second wave than in the first wave. At admission, the mean values of CRP were significantly lower in the second wave than in the first wave. On the seventh hospital day, the mean values of CRP, ferritin, fibrinogen, and procalcitonin were significantly lower in the second wave than in the first wave. In general, countries exhibited variable changes in laboratory testing rates from the first to the second wave. At admission, there was a significantly higher testing rate for D-dimer in France, Germany, and Spain. CONCLUSIONS: Patients hospitalized in the second wave were at significantly lower risk for severe COVID-19. This corresponded to mean laboratory values in the second wave that were more likely to be in typical physiological ranges on the seventh hospital day compared to the first wave. Our federated approach demonstrated the feasibility and power of harmonizing heterogeneous EHR data from multiple international health care systems to rapidly conduct large-scale studies to characterize how COVID-19 clinical trajectories evolve.

Authorship Correction: International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: Retrospective Cohort Study.

[This corrects the article DOI: 10.2196/31400.].

Effect of individualized PEEP titration guided by intratidal compliance profile analysis on regional ventilation assessed by electrical impedance tomography - a randomized controlled trial.

BACKGROUND: The application of positive end-expiratory pressure (PEEP) may reduce dynamic strain during mechanical ventilation. Although numerous approaches for PEEP titration have been proposed, there is no accepted strategy for titrating optimal PEEP. By analyzing intratidal compliance profiles, PEEP may be individually titrated for patients. METHODS: After obtaining informed consent, 60 consecutive patients undergoing general anesthesia were randomly allocated to mechanical ventilation with PEEP 5 cmH2O (control group) or PEEP individually titrated, guided by an analysis of the intratidal compliance profile (intervention group). The primary endpoint was the frequency of each nonlinear intratidal compliance (CRS) profile of the respiratory system (horizontal, increasing, decreasing, and mixed). The secondary endpoints measured were respiratory mechanics, hemodynamic variables, and regional ventilation, which was assessed via electrical impedance tomography. RESULTS: The frequencies of the CRS profiles were comparable between the groups. Besides PEEP [control: 5.0 (0.0), intervention: 5.8 (1.1) cmH2O, p < 0.001], the respiratory and hemodynamic variables were comparable between the two groups. The compliance profile analysis showed no significant differences between the two groups. The loss of ventral and dorsal regional ventilation was higher in the control [ventral: 41.0 (16.3)%; dorsal: 25.9 (13.8)%] than in the intervention group [ventral: 29.3 (17.6)%; dorsal: 16.4 (12.7)%; p (ventral) = 0.039, p (dorsal) = 0.028]. CONCLUSIONS: Unfavorable compliance profiles indicating tidal derecruitment were found less often than in earlier studies. Individualized PEEP titration resulted in slightly higher PEEP. A slight global increase in aeration associated with this was indicated by regional gain and loss analysis. Differences in dorsal to ventral ventilation distribution were not found. TRIAL REGISTRATION: This clinical trial was registered at the German Register for Clinical Trials (DRKS00008924) on August 10, 2015.

The Equilibration of PCO2 in Pigs Is Independent of Lung Injury and Hemodynamics.

OBJECTIVES: In mechanical ventilation, normoventilation in terms of PCO2 can be achieved by titration of the respiratory rate and/or tidal volume. Although a linear relationship has been found between changes in respiratory rate and resulting changes in end-tidal cO2 (△PetCO2) as well as between changes in respiratory rate and equilibration time (teq) for mechanically ventilated patients without lung injury, it is unclear whether a similar relationship holds for acute lung injury or altered hemodynamics. DESIGN: We performed a prospective randomized controlled animal study of the change in PetCO2 with changes in respiratory rate in a lung-healthy, lung-injury, lung-healthy + altered hemodynamics, and lung-injury + altered hemodynamics pig model. SETTING: University research laboratory. SUBJECTS: Twenty mechanically ventilated pigs. INTERVENTIONS: Moderate lung injury was induced by injection of oleic acid in 10 randomly assigned pigs, and after the first round of measurements, cardiac output was increased by approximately 30% by constant administration of noradrenalin in both groups. MEASUREMENTS AND MAIN RESULTS: We systematically increased and decreased changes in respiratory rate according to a set protocol: +2, -4, +6, -8, +10, -12, +14 breaths/min and awaited equilibration of Petco2. We found a linear relationship between changes in respiratory rate and △PetCO2 as well as between changes in respiratory rate and teq. A two-sample t test resulted in no significant differences between the lung injury and healthy control group before or after hemodynamic intervention. Furthermore, exponential extrapolation allowed prediction of the new PetCO2 equilibrium and teq after 5.7 ± 5.6 min. CONCLUSIONS: The transition between PetCO2 equilibria after changes in respiratory rate might not be dependent on moderate lung injury or cardiac output but on the metabolic production or capacity of cO2 stores. Linear relationships previously found for lung-healthy patients and early prediction of PetCO2 equilibration could therefore also be used for the titration of respiratory rate on the PetCO2 for a wider range of pathologies by the physician or an automated ventilation system.

Biosensor-Enabled Multiplexed On-Site Therapeutic Drug Monitoring of Antibiotics.

Personalized antibiotherapy ensures that the antibiotic concentration remains in the optimal therapeutic window to maximize efficacy, minimize side effects, and avoid the emergence of drug resistance due to insufficient dosing. However, such individualized schemes need frequent sampling to tailor the blood antibiotic concentrations. To optimally integrate therapeutic drug monitoring (TDM) into the clinical workflow, antibiotic levels can either be measured in blood using point-of-care testing (POCT), or can rely on noninvasive sampling. Here, a versatile biosensor with an antibody-free assay for on-site TDM is presented. The platform is evaluated with an animal study, where antibiotic concentrations are quantified in different matrices including whole blood, plasma, urine, saliva, and exhaled breath condensate (EBC). The clearance and the temporal evaluation of antibiotic levels in EBC and plasma are demonstrated. Influence of matrix effects on measured drug concentrations is determined by comparing the plasma levels with those in noninvasive samples. The system's potential for blood-based POCT is further illustrated by tracking ß-lactam concentrations in untreated blood samples. Finally, multiplexing capabilities are explored successfully for multianalyte/sample analysis. By enabling a rapid, low-cost, sample-independent, and multiplexed on-site TDM, this system can shift the paradigm of "one-size-fits-all" strategy.

International electronic health record-derived post-acute sequelae profiles of COVID-19 patients.

The risk profiles of post-acute sequelae of COVID-19 (PASC) have not been well characterized in multi-national settings with appropriate controls. We leveraged electronic health record (EHR) data from 277 international hospitals representing 414,602 patients with COVID-19, 2.3 million control patients without COVID-19 in the inpatient and outpatient settings, and over 221 million diagnosis codes to systematically identify new-onset conditions enriched among patients with COVID-19 during the post-acute period. Compared to inpatient controls, inpatient COVID-19 cases were at significant risk for angina pectoris (RR 1.30, 95% CI 1.09-1.55), heart failure (RR 1.22, 95% CI 1.10-1.35), cognitive dysfunctions (RR 1.18, 95% CI 1.07-1.31), and fatigue (RR 1.18, 95% CI 1.07-1.30). Relative to outpatient controls, outpatient COVID-19 cases were at risk for pulmonary embolism (RR 2.10, 95% CI 1.58-2.76), venous embolism (RR 1.34, 95% CI 1.17-1.54), atrial fibrillation (RR 1.30, 95% CI 1.13-1.50), type 2 diabetes (RR 1.26, 95% CI 1.16-1.36) and vitamin D deficiency (RR 1.19, 95% CI 1.09-1.30). Outpatient COVID-19 cases were also at risk for loss of smell and taste (RR 2.42, 95% CI 1.90-3.06), inflammatory neuropathy (RR 1.66, 95% CI 1.21-2.27), and cognitive dysfunction (RR 1.18, 95% CI 1.04-1.33). The incidence of post-acute cardiovascular and pulmonary conditions decreased across time among inpatient cases while the incidence of cardiovascular, digestive, and metabolic conditions increased among outpatient cases. Our study, based on a federated international network, systematically identified robust conditions associated with PASC compared to control groups, underscoring the multifaceted cardiovascular and neurological phenotype profiles of PASC.

Changes in laboratory value improvement and mortality rates over the course of the pandemic: an international retrospective cohort study of hospitalised patients infected with SARS-CoV-2.

OBJECTIVE: To assess changes in international mortality rates and laboratory recovery rates during hospitalisation for patients hospitalised with SARS-CoV-2 between the first wave (1 March to 30 June 2020) and the second wave (1 July 2020 to 31 January 2021) of the COVID-19 pandemic. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective cohort study of 83 178 hospitalised patients admitted between 7 days before or 14 days after PCR-confirmed SARS-CoV-2 infection within the Consortium for Clinical Characterization of COVID-19 by Electronic Health Record, an international multihealthcare system collaborative of 288 hospitals in the USA and Europe. The laboratory recovery rates and mortality rates over time were compared between the two waves of the pandemic. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was all-cause mortality rate within 28 days after hospitalisation stratified by predicted low, medium and high mortality risk at baseline. The secondary outcome was the average rate of change in laboratory values during the first week of hospitalisation. RESULTS: Baseline Charlson Comorbidity Index and laboratory values at admission were not significantly different between the first and second waves. The improvement in laboratory values over time was faster in the second wave compared with the first. The average C reactive protein rate of change was -4.72 mg/dL vs -4.14 mg/dL per day (p=0.05). The mortality rates within each risk category significantly decreased over time, with the most substantial decrease in the high-risk group (42.3% in March-April 2020 vs 30.8% in November 2020 to January 2021, p<0.001) and a moderate decrease in the intermediate-risk group (21.5% in March-April 2020 vs 14.3% in November 2020 to January 2021, p<0.001). CONCLUSIONS: Admission profiles of patients hospitalised with SARS-CoV-2 infection did not differ greatly between the first and second waves of the pandemic, but there were notable differences in laboratory improvement rates during hospitalisation. Mortality risks among patients with similar risk profiles decreased over the course of the pandemic. The improvement in laboratory values and mortality risk was consistent across multiple countries.

A novel mechanical ventilator providing flow-controlled expiration for small animals.

For investigating the effects of mechanical ventilation on the respiratory system, experiments in small mammal models are used. However, conventional ventilators for small animals are usually limited to a specific ventilation mode, and in particular to passive expiration. Here, we present a computer-controlled research ventilator for small animals which provides conventional mechanical ventilation as well as new type ventilation profiles. Typical profiles of conventional mechanical ventilation, as well as flow-controlled expiration and sinusoidal ventilation profiles can be generated with our new ventilator. Flow control during expiration reduced the expiratory peak flow rate by 73% and increased the mean airway pressure by up to 1 mbar compared with conventional ventilation without increasing peak pressure and end-expiratory pressure. Our new ventilator for small animals allows for the application of various ventilation profiles. We could analyse the effects of applying conventional ventilation profiles, pressure-controlled ventilation and volume-controlled ventilation, as well as the novel flow-controlled ventilation profile. This new approach enables studying the mechanical properties of the respiratory system with an increased freedom for choosing independent ventilation parameters.

Flow controlled expiration does not impair pedal power during physical exercise on a bicycle ergometer.

Flow Controlled Expiration (FLEX) has been demonstrated to be lungprotective in models of ARDS during controlled mechanical ventilation. However, modern ventilation strategies in critical care include spontaneous breathing. Therefore, we investigated breathing discomfort and potential performance constraints of FLEX in 24 healthy test persons under increased ventilation demand. The subjects generated 20, 50 or 100 W pedal power on a bicycle ergometer while breathing with and without FLEX and rated breathing discomfort on a scale ranging from 0 (comfortable) to 10 (not tolerable). Then the subjects were asked to indicate the power they could maintain for 30 min with and without FLEX. With FLEX, tidal volume was higher and respiratory rate lower than without. Breathing discomfort was slightly increased by FLEX (on average from 2.2 to 3.2, p = 0.002). The estimated maintainable power was similar with and without FLEX (p = 0.986). We conclude that FLEX does not intolerably increase breathing discomfort and does not impair physical performance.

A linearized expiration flow homogenizes the compartmental pressure distribution in a physical model of the inhomogeneous respiratory system.

OBJECTIVE: Flow-controlled expiration (FLEX) and flow-controlled ventilation (FCV) imply a linearized expiration, and were suggested as new approaches for lung-protective ventilation, especially in the case of an inhomogeneous lung. We hypothesized that a linearized expiration homogenizes the pressure distribution between compartments during expiration, compared to volume-controlled (VCV) and pressure-controlled (PCV) ventilation. APPROACH: We investigated the expiratory pressure decays in a physical model of an inhomogeneous respiratory system. The model contained four compartments of which two had a high (25 ml cmH2O-1) and two a low compliance (10 ml cmH2O-1). These were combined with either a high (6.5 cmH2O s l-1) or low resistance (2.8 cmH2O s l-1), respectively. The model was ventilated in all modes at various tidal volumes and peak pressures, and we determined in each compartment the expiratory time at which the pressure declined to 50% (t50) of the end-inspiratory pressure, and the maximal differences of t50 (Δt50) and pressure (Δpmax) between all compartments. MAIN RESULTS: During FLEX and FCV, t50 was 6- to 7-fold higher compared to VCV and PCV (all P < 0.001). During VCV and PCV, Δt50 was higher (128 ± 18 ms) compared to FLEX and FCV (49 ± 19 ms; all P < 0.001). Δpmax reached up to 3.8 ± 0.2 cmH2O during VCV and PCV, but only 0.6 ± 0.1 cmH2O during FLEX and FCV (P < 0.001). SIGNIFICANCE: FLEX and FCV provide a more homogeneous expiratory pressure distribution between compartments with different mechanical properties compared with VCV and PCV. This may reduce shear stress within inhomogeneous lung tissue.

Sine ventilation in lung injury models: a new perspective for lung protective ventilation.

Mechanical ventilation is associated with the risk of ventilator induced lung injury. For reducing lung injury in mechanically ventilated patients, the application of small tidal volumes and positive end-expiratory pressures has become clinical standard. Recently, an approach based on linear airway pressure decline and decelerated expiratory flow during expiration implied lung protective capacities. We assumed that ventilation with a smoothed, i.e. sinusoidal airway pressure profile may further improve ventilation efficiency and lung protection. We compared the effects of mechanical ventilation with sinusoidal airway pressure profile (SINE) regarding gas exchange, respiratory system compliance and histology to conventional volume and pressure controlled ventilation (VCV and PCV) and to VCV with flow-controlled expiration (FLEX) in two rat models of lung injury, tween induced surfactant depletion and high tidal volume mechanical ventilation. In both lung injury models ventilation with SINE showed more efficient CO2 elimination and blood oxygenation, improved respiratory system compliance and resulted in lower alveolar wall thickness, compared to VCV, PCV and FLEX. Optimization of the airway pressure profile may provide a novel means of lung protective mechanical ventilation.

Intratidal recruitment/derecruitment persists at low and moderate positive end-expiratory pressure in paediatric patients.

In paediatric patients positive end-expiratory pressure (PEEP) is traditionally set lower than in adults. We investigated whether moderately higher PEEP improves respiratory mechanics and regional ventilation. Therefore, 40 children were mechanically ventilated with PEEP 2 and 5cmH2O. Volume-dependent compliance profiles were analysed as a measure of intratidal recruitment/derecruitment. Regional ventilation was assessed using electrical impedance tomography. Mean compliance was 17.9±9.9mLcmH2O-1 (PEEP 2cmH2O), and 19.0±10.9mLcmH2O-1 (PEEP 5 cmH2O, p<0.001). Strong intratidal recruitment/derecruitment occurred in 40% of children at PEEP 2 cmH2O, and 36% at PEEP 5 cmH2O. Children showing strong recruitment/derecruitment were 33 (PEEP 2 cmH20) and 20 (PEEP 5 cmH20) months younger than children showing moderate recruitment/derecruitment. A higher PEEP improved peripheral ventilation. In conclusion, mechanically ventilated paediatric patients undergo intratidal recruitment/derecruitment which occurs more prominently in younger than in older children. A PEEP of 5cmH2O does not fully prevent intratidal recruitment/derecruitment but homogenizes regional ventilation in comparison to 2cmH2O.

Breathing-phase selective filtering of respiratory data improves analysis of dynamic respiratory mechanics.

BACKGROUND: The analysis of non-linear respiratory system mechanics under the dynamic conditions of controlled mechanical ventilation is affected by systemic disturbances of the respiratory signals. Cardio-pulmonary coupling induces cardiogenic oscillations to the respiratory signals, which appear prominently in the second half of expiration. OBJECTIVE: We hypothesized that breathing phase-selective filtering of expiratory data improves the analysis of respiratory system mechanics. METHODS: We retrospectively analyzed data from a multicenter-study (28 patients with injured lungs, under volume-controlled ventilation) and from two additional studies (3 lung healthy patients and 3 with injured lungs, under pressure-controlled ventilation). Data streams were recorded at different levels of positive end-expiratory pressure. Using the gliding-SLICE method, intratidal dynamic respiratory mechanics were analyzed with and without low-pass filtering of expiratory or inspiratory data separately. The quality of data analysis was derived from the coefficient of determination R^2. RESULTS: Without filtering, R^2 lay below 0.995 for 87 of 280 investigated data streams. In 68 cases expiration-selective low-pass filtering improved the quality of analysis to R^2 ⩾ 0.995. In contrast, inspiration-selective filtering did not improve R^2. CONCLUSIONS: The selective filtering of expiration data eliminates negative side-effects of cardiogenic oscillations thus leading to a significant improvement of the analysis of dynamic respiratory system mechanics.

The dynamics of carbon dioxide equilibration after alterations in the respiratory rate.

Manual or automated control of mechanical ventilation can be realized as an open or closed-loop system for which the regulation of the ventilation parameters ideally is tuned to the dynamics and equilibration time of the biological system. We investigated the dynamic, transient state and equilibration time (teq) of the CO2 partial pressure (PCO2) after changes in the respiratory rate (RR). In 17 anaesthetized patients without known history of lung disease, respiratory rate was alternately increased and decreased and end-tidal CO2 partial pressures (PetCO2) were measured. Linear relations were found between ΔRR and PetCO2 changes (ΔPetCO2 = 0.3 − 1.1 ΔRR) and between ΔRR and teq for increasing and decreasing RR (teq(hypervent) = 0.5 |ΔRR|, teq(hypovent) = 0.7 |ΔRR|). Extrapolation of the transition between two PCO2 steady-states allowed for the prediction of the new PCO2 steady-state as early as 0.5 teq with an error <4 mmHg. At bedside or in automated ventilation systems, the linear dependencies between ΔRR and ΔPCO2 and between ΔRR and teq as well as early steady-state prediction of PCO2 could be used as a guidance towards a timing and step size regulation of RR that is well adapted to the biological system.