Pulmonary response prediction through personalized basis functions in a virtual patient model.

BACKGROUND AND OBJECTIVE: Recruitment maneuvers with subsequent positive-end-expiratory-pressure (PEEP) have proven effective in recruiting lung volume and preventing alveoli collapse. However, determining a safe, effective, and patient-specific PEEP is not standardized, and this more optimal PEEP level evolves with patient condition, requiring personalised monitoring and care approaches to maintain optimal ventilation settings. METHODS: This research examines 3 physiologically relevant basis function sets (exponential, parabolic, cumulative) to enable better prediction of elastance evolution for a virtual patient or digital twin model of MV lung mechanics, including novel elements to model and predict distension elastance. Prediction accuracy and robustness are validated against recruitment maneuver data from 18 volume-controlled ventilation (VCV) patients at 7 different baseline PEEP levels (0 to 12 cmH2O) and 14 pressure-controlled ventilation (PCV) patients at 4 different baseline PEEP levels (6 to 12 cmH2O), yielding 623 and 294 prediction cases, respectively. Predictions were made up to 12 cmH2O of added PEEP ahead, covering 6 × 2 cmH2O PEEP steps. RESULTS: The 3 basis function sets yield median absolute peak inspiratory pressure (PIP) prediction error of 1.63 cmH2O for VCV patients, and median peak inspiratory volume (PIV) prediction error of 0.028 L for PCV patients. The exponential basis function set yields a better trade-off of overall performance across VCV and PCV prediction than parabolic and cumulative basis function sets from other studies. Comparing predicted and clinically measured distension prediction in VCV demonstrated consistent, robust high accuracy with R2 = 0.90-0.95. CONCLUSIONS: The results demonstrate recruitment mechanics are best captured by an exponential basis function across different mechanical ventilation modes, matching physiological expectations, and accurately capture, for the first time, distension mechanics to within 5-10 % accuracy. Enabling the risk of lung injury to be predicted before changing ventilator settings. The overall outcomes significantly extend and more fully validate this digital twin or virtual mechanical ventilation patient model.

Non-invasive over-distension measurements: data driven vs model-based.

Clinical measurements offer bedside monitoring aiming to minimise unintended over-distension, but have limitations and cannot be predicted for changes in mechanical ventilation (MV) settings and are only available in certain MV modes. This study introduces a non-invasive, real-time over-distension measurement, which is robust, predictable, and more intuitive than current methods. The proposed over-distension measurement, denoted as OD, is compared with the clinically proven stress index (SI). Correlation is analysed via R2 and Spearman rs. The OD safe range corresponding to the unit-less SI safe range (0.95-1.05) is calibrated by sensitivity and specificity test. Validation is fulfilled with 19 acute respiratory distress syndrome (ARDS) patients data (196 cases), including assessment across ARDS severity. Overall correlation between OD and SI yielded R2 = 0.76 and Spearman rs = 0.89. Correlation is higher considering only moderate and severe ARDS patients. Calibration of OD to SI yields a safe range defined: 0 ≤ OD ≤ 0.8 cmH2O. The proposed OD offers an efficient, general, real-time measurement of patient-specific lung mechanics, which is more intuitive and robust than SI. OD eliminates the limitations of SI in MV mode and its less intuitive lung status value. Finally, OD can be accurately predicted for new ventilator settings via its foundation in a validated predictive personalized lung mechanics model. Therefore, OD offers potential clinical value over current clinical methods.

Modelling patient specific cardiopulmonary interactions.

Mechanical ventilation is well known for having detrimental effects on the cardiovascular system, particularly when using high positive end-expiratory pressure. High positive end-expiratory pressure levels cause a decrease in stroke volume, which, under normal conditions, usually bring about a decrease in stressed blood volume. Stressed blood volume, defined as the total pressure generating volume of the cardiovascular system, has been shown to be a potential index of fluid responsiveness, making it a potentially important diagnostic tool. Generally, respiratory and haemodynamic care are provided independently of one another. However, that positive end-expiratory pressure alters both stroke volume and stressed blood volume suggests both the pulmonary and cardiovascular state should be conjointly optimised and used to guide positive end-expiratory pressure. However, the complex and patient-specific nature of cardiopulmonary interactions which occur during mechanical ventilation presents a challenge for accurate modelling of respiratory and cardiovascular interactions required to better optimise care. Previous models attempting to incorporate cardiopulmonary interactions have suffered from poor reliability at higher PEEP levels, largely due to an exaggerated effect of intrathoracic pressure on the cardiovascular system. A new parameter, alpha, is added to a previously validated cardiopulmonary model, to modulate the percentage of intrathoracic pressure applied to the vena cava and left ventricle. The new parameter aims to increase reliability under high PEEP conditions as well as provide a patient specific solution to modelling cardiopulmonary interactions. The results from the identified optimal alpha are compared to the original model to investigate how this new parameter may be used to create a more patient-specific cardiopulmonary model, which would be better suited for guidance of care in the ICU.

Low cost circulatory pressure acquisition and fluid infusion rate measurement system for clinical research.

Acquiring patient physiological waveforms is useful for studying hemodynamic management and developing medical monitoring systems. A low cost, Arduino controlled data acquisition system acquires arterial pressure waveforms (Edwards Lifesciences TruWave compatible) and measures fluid infusion rate using hanging scales. This system can be used at the same time as a clinical monitor, enabling recording of patient arterial pressure and fluid delivery for clinical research. The system is powered via a USB connection, which additionally provides serial output, aiding compatibility and customisation. A simple software user interface, developed in Python, shows outputs. Each data acquisition system, including all necessary connection cables costs ~US$90 and is multiple-use.

Physiological trend analysis of a novel cardio-pulmonary model during a preload reduction manoeuvre.

BACKGROUND AND OBJECTIVE: Mechanical ventilation causes adverse effects on the cardiovascular system. However, the exact nature of the effects on haemodynamic parameters is not fully understood. A recently developed cardio-vascular system model which incorporates cardio-pulmonary interactions is compared to the original 3-chamber cardiovascular model to investigate the exact effects of mechanical ventilation on haemodynamic parameters and to assess the trade-off of model complexity and model reliability between the 2 models. METHODS: Both the cardio-pulmonary and three chamber models are used to identify cardiovascular system parameters from aortic pressure, left ventricular volume, airway flow and airway pressure measurements from 4 pigs during a preload reduction manoeuvre. Outputs and parameter estimations from both models are contrasted to assess the relative performance of each model and to further investigate the effects of mechanical ventilation on haemodynamic parameters. RESULTS: Both models tracked measurements accurately as expected. There was no identifiable increase in error from the added complexity of the cardio-pulmonary model, with both models having a mean average error below 0.5% for all pigs. Identified left ventricle and vena cava elastances of the 3-chamber model was found to diverge exponentially with PEEP from identified left ventricle and vena cava elastances of the cardio-pulmonary model. The r2 of the fit for each pig ranged from 0.888 to 0.998 for left ventricle elastance divergence and from 0.905 to 0.999 for vena cava elastance divergence. All other identified parameters showed no significant difference between models. CONCLUSIONS: Despite the increase in model complexity, there was no loss in the cardio-pulmonary model's ability to accurately estimate haemodynamic parameters and reproduce system dynamics. Furthermore, the cardio-pulmonary model was able to demonstrate how mechanical ventilation affected parameter estimations as PEEP was increased. The 3-chamber model was shown to produce parameter estimations which diverged exponentially with PEEP, while the cardiopulmonary model estimations remained more stable, suggesting its ability to produce more physiologically accurate parameter estimations under higher PEEP conditions.

Reconstructing asynchrony for mechanical ventilation using a hysteresis loop virtual patient model.

BACKGROUND: Patient-specific lung mechanics during mechanical ventilation (MV) can be identified from measured waveforms of fully ventilated, sedated patients. However, asynchrony due to spontaneous breathing (SB) effort can be common, altering these waveforms and reducing the accuracy of identified, model-based, and patient-specific lung mechanics. METHODS: Changes in patient-specific lung elastance over a pressure-volume (PV) loop, identified using hysteresis loop analysis (HLA), are used to detect the occurrence of asynchrony and identify its type and pattern. The identified HLA parameters are then combined with a nonlinear mechanics hysteresis loop model (HLM) to extract and reconstruct ventilated waveforms unaffected by asynchronous breaths. Asynchrony magnitude can then be quantified using an energy-dissipation metric, Easyn, comparing PV loop area between model-reconstructed and original, altered asynchronous breathing cycles. Performance is evaluated using both test-lung experimental data with a known ground truth and clinical data from four patients with varying levels of asynchrony. RESULTS: Root mean square errors for reconstructed PV loops are within 5% for test-lung experimental data, and 10% for over 90% of clinical data. Easyn clearly matches known asynchrony magnitude for experimental data with RMS errors < 4.1%. Clinical data performance shows 57% breaths having Easyn > 50% for Patient 1 and 13% for Patient 2. Patient 3 only presents 20% breaths with Easyn > 10%. Patient 4 has Easyn = 0 for 96% breaths showing accuracy in a case without asynchrony. CONCLUSIONS: Experimental test-lung validation demonstrates the method's reconstruction accuracy and generality in controlled scenarios. Clinical validation matches direct observations of asynchrony in incidence and quantifies magnitude, including cases without asynchrony, validating its robustness and potential efficacy as a clinical real-time asynchrony monitoring tool.

Quantifying ventilator unloading in CPAP ventilation.

BACKGROUND: The intrinsic (muscular) patient effort driving inspiration in non-invasive ventilation modes, such as continuous positive airway pressure (CPAP) therapy, has not been identified from non-invasive data. Current CPAP settings are based on clinical judgment and assessment of symptoms of respiratory distress. Non-optimal settings, including too much positive end expiratory pressure (PEEP) can cause unintended lung injury and ventilator unloading, where patient effort drops and the CPAP device enables too much work being imposed on the injured lung. Currently, there is no non-invasive means of quantifying or identifying these effects. METHODS: A novel model-based method of ascertaining intrinsic patient work of breathing (WOB) in CPAP is developed based on linear single compartment and 2nd order b-spline models previously used in invasive ventilation modes. Results are compared to current clinical indications, such as total Imposed WOB from the CPAP device and beak length, the latter of which is the clinical metric used to indicate alveolar overdistension. Intrinsic and Imposed WOB are compared. The hypothesis is that ventilator unloading can be assessed as a decrease in Intrinsic WOB relative to Imposed WOB, as PEEP and associated ventilator unloading rise. This hypothesis is tested using 14 subjects from a CPAP trial of several breathing rates at two PEEP levels. RESULTS: The ratio of Intrinsic to Imposed WOB, normalised per unit tidal volume, decreased with increasing PEEP (4-7 cm H2O), capturing the expected trend of ventilator unloading. Ventilator unloading was observed across all breathing rates. Beak length measurements showed no conclusive evidence of capturing overdistension at higher PEEP or ventilator unloading. CONCLUSIONS: Patient Intrinsic WOB in CPAP was non-invasively quantified using model-based methods, based on pressure and flow measurements. The ratio of Intrinsic to Imposed WOB per unit tidal volume clearly and consistently showed ventilator unloading across all patients and breathing rates, with Intrinsic WOB decreasing with increasing PEEP. This trend was not observed in the current clinical metric of beak length. Non-invasively quantifying Intrinsic WOB and ventilator unloading is the critical first step to objectively optimising clinical CPAP settings, patient care, and outcomes.

Over-distension prediction via hysteresis loop analysis and patient-specific basis functions in a virtual patient model.

BACKGROUND AND OBJECTIVE: Recruitment maneuvers (RMs) with subsequent positive-end-expiratory-pressure (PEEP) have proven effective in recruiting lung volume and preventing alveolar collapse. However, a suboptimal PEEP could induce undesired injury in lungs by insufficient or excessive breath support. Thus, a predictive model for patient response under PEEP changes could improve clinical care and lower risks. METHODS: This research adds novel elements to a virtual patient model to identify and predict patient-specific lung distension to optimise and personalise care. Model validity and accuracy are validated using data from 18 volume-controlled ventilation (VCV) patients at 7 different baseline PEEP levels (0-12cmH2O), yielding 623 prediction cases. Predictions were made up to ΔPEEP = 12cmH2O ahead covering 6x2cmH2O PEEP steps. RESULTS: Using the proposed lung distension model, 90% of absolute peak inspiratory pressure (PIP) prediction errors compared to clinical measurement are within 3.95cmH2O, compared with 4.76cmH2O without this distension term. Comparing model-predicted and clinically measured distension had high correlation increasing to R2 = 0.93-0.95 if maximum ΔPEEP ≤ 6cmH2O. Predicted dynamic functional residual capacity (Vfrc) changes as PEEP rises yield 0.013L median prediction error for both prediction groups and overall R2 of 0.84. CONCLUSIONS: Overall results demonstrate nonlinear distension mechanics are accurately captured in virtual lung mechanics patients for mechanical ventilation, for the first time. This result can minimise the risk of lung injury by predicting its potential occurrence of distension before changing ventilator settings. The overall outcomes significantly extend and more fully validate this virtual mechanical ventilation patient model.

Predicting fluid-response, the heart of hemodynamic management: A model-based solution.

BACKGROUND: Intravenous fluid infusions are an important therapy for patients with circulatory shock. However, it is challenging to predict how patients' cardiac stroke volume (SV) will respond, and thus identify how much fluids should be delivered, if any. Model-predicted SV time-profiles of response to fluid infusions could potentially be used to guide fluid therapy. METHOD: A clinically applicable model-based method predicts SV changes in response to fluid-infusions for a pig trial (N = 6). Validation/calibration SV, SVmea, is from an aortic flow probe. Model parameters are identified in 3 ways: fitting to SVmea from the entire infusion, SVflfit, from the first 200 ml, SVfl200, or from the first 100 ml, SVfl100. RMSE compares error of model-based SV time-profiles for each parameter identification method, and polar plot analysis assesses trending ability. Receiver-operating characteristic (ROC) analysis evaluates ability of model-predicted SVs, SVfl200 and SVfl100, to distinguish non-responsive and responsive infusions, using area-under the curve (AUC), and balanced accuracy as a measure of performance. RESULTS: RMSE for SVflFit, SVfl200, and SVfl100 was 1.8, 3.2, and 6.5 ml, respectively, and polar plot angular limit of agreement from was 11.6, 28.0, and 68.8°, respectively. For predicting responsive and non-responsive interventions SVfl200, and SVfl100 had ROC AUC of 0.64 and 0.69, respectively, and balanced accuracy was 0.75 in both cases. CONCLUSIONS: The model-predicted SV time-profiles matched measured SV trends well for SVflFit, SVfl200, but not SVfl100. Thus, the model can fit the observed SV dynamics, and can deliver good SV prediction given a sufficient parameter identification period. This trial is limited by small numbers and provides proof-of-method, with further experimental and clinical investigation needed. Potentially, this method could deliver model-predicted SV time-profiles to guide fluid therapy decisions, or as part of a closed-loop fluid control system.

Model-based estimation of negative inspiratory driving pressure in patients receiving invasive NAVA mechanical ventilation.

BACKGROUND: Optimisation of mechanical ventilation (MV) and weaning requires insight into underlying patient breathing effort. Current identifiable models effectively describe lung mechanics, such as elastance (E) and resistance (R) at the bedside in sedated patients, but are less effective when spontaneous breathing is present. This research derives and regularises a single compartment model to identify patient-specific inspiratory effort. METHODS: Constrained second-order b-spline basis functions (knot width 0.05 s) are used to describe negative inspiratory drive (Pp, cmH2O) as a function of time. Breath-breath Pp are identified with single E and R values over inspiration and expiration from n = 20 breaths for N = 22 patients on NAVA ventilation. Pp is compared to measured electrical activity of the diaphragm (Eadi) and published results. RESULTS: Average per-patient root-mean-squared model fit error was (median [interquartile range, IQR]) 0.9 [0.6-1.3] cmH2O, and average per-patient median Pp was -3.9 [-4.5- -3.0] cmH2O, with range -7.9 - -1.9 cmH2O. Per-patient E and R were 16.4 [13.6-21.8] cmH2O/L and 9.2 [6.4-13.1] cmH2O.s/L, respectively. Most patients showed an inspiratory volume threshold beyond which Pp started to return to baseline, and Pp at peak Eadi (end-inspiration) was often strongly correlated with peak Eadi (R2=0.25-0.86). Similarly, average transpulmonary pressure was consistent breath-breath in most patients, despite differences in peak Eadi and thus peak airway pressure. CONCLUSIONS: The model-based inspiratory effort aligns with electrical muscle activity and published studies showing neuro-muscular decoupling as a function of pressure and/or volume. Consistency in coupling/dynamics were patient-specific. Quantification of patient and ventilator work of breathing contributions may aid optimisation of MV modes and weaning.

Preload & Frank-Starling curves, from textbook to bedside: Clinically applicable non-additionally invasive model-based estimation in pigs.

BACKGROUND: Determining physiological mechanisms leading to circulatory failure can be challenging, contributing to the difficulties in delivering effective hemodynamic management in critical care. Continuous, non-additionally invasive monitoring of preload changes, and assessment of contractility from Frank-Starling curves could potentially make it much easier to diagnose and manage circulatory failure. METHOD: This study combines non-additionally invasive model-based methods to estimate left ventricle end-diastolic volume (LEDV) and stroke volume (SV) during hemodynamic interventions in a pig trial (N = 6). Agreement of model-based LEDV and measured admittance catheter LEDV is assessed. Model-based LEDV and SV are used to identify response to hemodynamic interventions and create Frank-Starling curves, from which Frank-Starling contractility (FSC) is identified as the gradient. RESULTS: Model-based LEDV had good agreement with measured admittance catheter LEDV, with Bland-Altman median bias [limits of agreement (2.5th, 97.5th percentile)] of 2.2 ml [-13.8, 22.5]. Model LEDV and SV were used to identify non-responsive interventions with a good area under the receiver-operating characteristic (ROC) curve of 0.83. FSC was identified using model LEDV and SV with Bland-Altman median bias [limits of agreement (2.5th, 97.5th percentile)] of 0.07 [-0.68, 0.56], with FSC from admittance catheter LEDV and aortic flow probe SV used as a reference method. CONCLUSIONS: This study provides proof-of-concept preload changes and Frank-Starling curves could be non-additionally invasively estimated for critically ill patients, which could potentially enable much clearer insight into cardiovascular function than is currently possible at the patient bedside.

Increased insulin resistance in intensive care: longitudinal retrospective analysis of glycaemic control patients in a New Zealand ICU.

BACKGROUND: Critical care populations experience demographic shifts in response to trends in population and healthcare, with increasing severity and/or complexity of illness a common observation worldwide. Inflammation in critical illness impacts glucose-insulin metabolism, and hyperglycaemia is associated with mortality and morbidity. This study examines longitudinal trends in insulin sensitivity across almost a decade of glycaemic control in a single unit. METHODS: A clinically validated model of glucose-insulin dynamics is used to assess hour-hour insulin sensitivity over the first 72 h of insulin therapy. Insulin sensitivity and its hour-hour percent variability are examined over 8 calendar years alongside severity scores and diagnostics. RESULTS: Insulin sensitivity was found to decrease by 50-55% from 2011 to 2015, and remain low from 2015 to 2018, with no concomitant trends in age, severity scores or risk of death, or diagnostic category. Insulin sensitivity variability was found to remain largely unchanged year to year and was clinically equivalent (95% confidence interval) at the median and interquartile range. Insulin resistance was associated with greater incidence of high insulin doses in the effect saturation range (6-8 U/h), with the 75th percentile of hourly insulin doses rising from 4-4.5 U/h in 2011-2014 to 6 U/h in 2015-2018. CONCLUSIONS: Increasing insulin resistance was observed alongside no change in insulin sensitivity variability, implying greater insulin needs but equivalent (variability) challenge to glycaemic control. Increasing insulin resistance may imply greater inflammation and severity of illness not captured by existing severity scores. Insulin resistance reduces glucose tolerance, and can cause greater incidence of insulin saturation and resultant hyperglycaemia. Overall, these results have significant clinical implications for glycaemic control and nutrition management.

The goldilocks problem: Nutrition and its impact on glycaemic control.

BACKGROUND: Glucose intolerance and insulin resistance manifest as hyperglycaemia in intensive care, which is associated with mortality and morbidities. Glycaemic control (GC) may improve outcomes, though safe and effective control has proven elusive. Nutritional glucose intake affects blood glucose (BG) outcomes, but few protocols actively control it. This study aims to examine BG outcomes in the context of nutritional management during GC. METHODS: Retrospective cohort analysis of 5 glycaemic control cohorts spanning 4 years (n = 273) from Christchurch Hospital Intensive Care Unit (ICU). GC is delivered using a single model-based protocol (STAR), with default 4.4-8.0 mmol/L target range via. modulation of insulin and nutrition. Clinical adaptations/cohorts include variations on upper target (UL-9 with 9.0 mmol/L, reducing workload and nutrition responsiveness), and insulin only (IO) with clinically set nutrition at 3 glucose concentrations (71 g/L vs. 120 and 180 g/L in the TARGET study). RESULTS: Percent of BG hours in the 4.4-8.0 mmol/L range highest under standard STAR conditions (78%), and was lower at 64% under UL-9, likely due to reduced time-responsiveness of nutrition-insulin changes. By comparison, IO only resulted in 64-69% BG in range across different nutrition types. A subset of patients receiving high glucose nutrition under IO were persistently hyperglycaemic, indicating patient-specific glucose tolerance. CONCLUSION: STAR GC is most effective when nutrition and insulin are modulated together with timely responsiveness to persistent hyperglycaemia. Results imply modulation of nutrition alongside insulin improves GC, particularly in patients with persistent hyperglycaemia/low glucose tolerance.

Tube-load model: A clinically applicable pulse contour analysis method for estimation of cardiac stroke volume.

BACKGROUND AND OBJECTIVES: Accurate, reproducible, and reliable real-time clinical measurement of stroke volume (SV) is challenging. To accurately estimate arterial mechanics and SV by pulse contour analysis, accounting for wave reflection, such as by a tube-load model, is potentially important. This study tests for the first time whether a dynamically identified tube-load model, given a single peripheral arterial input signal and pulse transit time (PTT), provides accurate SV estimates during hemodynamic instability. METHODS: The model is tested for 5 pigs during hemodynamic interventions, using either an aortic flow probe or admittance catheter for a validation SV measure. Performance is assessed using Bland-Altman and polar plot analysis for a series of long-term state-change and short-term dynamic events. RESULTS: The overall median bias and limits of agreement (2.5th, 97.5th percentile) from Bland-Altman analysis were -10% [-49, 36], and -1% [-28,20] for state-change and dynamic events, respectively. The angular limit of agreement (maximum of 2.5th, 97.5th percentile) from polar-plot analysis for state-change and dynamic interventions was 35.6∘, and 35.2∘, respectively. CONCLUSION: SV estimation agreement and trending performance was reasonable given the severity of the interventions. This simple yet robust method has potential to track SV within acceptable limits during hemodynamic instability in critically ill patients, provided a sufficiently accurate PTT measure.

High Inter-Patient Variability in Sepsis Evolution: A Hidden Markov Model Analysis.

BACKGROUND: Severe sepsis and septic shock are common in the intensive care unit (ICU) and contribute significantly to cost and mortality. Early treatment is critical but is confounded by the difficulty of real-time diagnosis. This study uses hidden Markov models (HMMs) to examine whether the time evolution of sepsis can add diagnostic accuracy or value using a proven set of bio-signals. METHODS: Clinical data (N=36 patients; 6071 hours), including an hourly personalised insulin sensitivity metric. A two hidden state HMM is created to discriminate diagnosed cases (Severe Sepsis, Septic Shock) from controls (SIRS, Sepsis) states. Diagnostic performance is measured by ROC curves, likelihood ratios (LHRs), sensitivity/specificity, and diagnostic odds-ratios (DOR), for a best-case resubstitution estimate and a worst-case 80/20% repeated holdout analysis. RESULTS: The HMM delivered near perfect results (95% Sensitivity; 96% Specificity) for best-case resubstitution estimates, but was comparatively poor (59% Sensitivity; 61% Specificity) for worst-case repeated holdout estimations. Adding the time evolution of sepsis did not add to the accuracy of diagnosis from using the signals alone without time history. CONCLUSIONS: These potentially surprising results indicate significant inter-patient variability in the time evolution of sepsis, preventing effective diagnosis in the context of the bio-signals, data, and HMM topology used. Efforts for improved real-time, early sepsis diagnosis should concentrate on the robustness and efficacy of the bio-signals and data used, as well as the level of model complexity, to create more effective real-time classifiers.

Insulin sensitivity in critically ill patients: are women more insulin resistant?

BACKGROUND: Glycaemic control (GC) in intensive care unit is challenging due to significant inter- and intra-patient variability, leading to increased risk of hypoglycaemia. Recent work showed higher insulin resistance in female preterm neonates. This study aims to determine if there are differences in inter- and intra-patient metabolic variability between sexes in adults, to gain in insight into any differences in metabolic response to injury. Any significant difference would suggest GC and randomised trial design should consider sex differences to personalise care. METHODS: Insulin sensitivity (SI) levels and variability are identified from retrospective clinical data for men and women. Data are divided using 6-h blocks to capture metabolic evolution over time. In total, 91 male and 54 female patient GC episodes of minimum 24 h are analysed. Hypothesis testing is used to determine whether differences are significant (P < 0.05), and equivalence testing is used to assess whether these differences can be considered equivalent at a clinical level. Data are assessed for the raw cohort and in 100 Monte Carlo simulations analyses where the number of men and women are equal. RESULTS: Demographic data between females and males were all similar, including GC outcomes (safety from hypoglycaemia and high (> 50%) time in target band). Females had consistently significantly lower SI levels than males, and this difference was not clinically equivalent. However, metabolic variability between sexes was never significantly different and always clinically equivalent. Thus, inter-patient variability was significantly different between males and females, but intra-patient variability was equivalent. CONCLUSION: Given equivalent intra-patient variability and significantly greater insulin resistance, females can receive the same benefit from safe, effective GC as males, but may require higher insulin doses to achieve the same glycaemia. Clinical trials should consider sex differences in protocol design and outcome analyses.

Virtual patients for mechanical ventilation in the intensive care unit.

BACKGROUND: Mechanical ventilation (MV) is a core intensive care unit (ICU) therapy. Significant inter- and intra- patient variability in lung mechanics and condition makes managing MV difficult. Accurate prediction of patient-specific response to changes in MV settings would enable optimised, personalised, and more productive care, improving outcomes and reducing cost. This study develops a generalised digital clone model, or in-silico virtual patient, to accurately predict lung mechanics in response to changes in MV. METHODS: An identifiable, nonlinear hysteresis loop model (HLM) captures patient-specific lung dynamics identified from measured ventilator data. Identification and creation of the virtual patient model is fully automated using the hysteresis loop analysis (HLA) method to identify lung elastances from clinical data. Performance is evaluated using clinical data from 18 volume-control (VC) and 14 pressure-control (PC) ventilated patients who underwent step-wise recruitment maneuvers. RESULTS: Patient-specific virtual patient models accurately predict lung response for changes in PEEP up to 12 cmH2O for both volume and pressure control cohorts. R2 values for predicting peak inspiration pressure (PIP) and additional retained lung volume, Vfrc in VC, are R2=0.86 and R2=0.90 for 106 predictions over 18 patients. For 14 PC patients and 84 predictions, predicting peak inspiratory volume (PIV) and Vfrc yield R2=0.86 and R2=0.83. Absolute PIP, PIV and Vfrc errors are relatively small. CONCLUSIONS: Overall results validate the accuracy and versatility of the virtual patient model for capturing and predicting nonlinear changes in patient-specific lung mechanics. Accurate response prediction enables mechanically and physiologically relevant virtual patients to guide personalised and optimised MV therapy.