NAVA enhances tidal volume and diaphragmatic electro-myographic activity matching: a Range90 analysis of supply and demand.

Neurally adjusted ventilatory assist (NAVA) is a ventilation assist mode that delivers pressure in proportionality to electrical activity of the diaphragm (Eadi). Compared to pressure support ventilation (PS), it improves patient-ventilator synchrony and should allow a better expression of patient's intrinsic respiratory variability. We hypothesize that NAVA provides better matching in ventilator tidal volume (Vt) to patients inspiratory demand. 22 patients with acute respiratory failure, ventilated with PS were included in the study. A comparative study was carried out between PS and NAVA, with NAVA gain ensuring the same peak airway pressure as PS. Robust coefficients of variation (CVR) for Eadi and Vt were compared for each mode. The integral of Eadi (ʃEadi) was used to represent patient's inspiratory demand. To evaluate tidal volume and patient's demand matching, Range90 = 5-95 % range of the Vt/ʃEadi ratio was calculated, to normalize and compare differences in demand within and between patients and modes. In this study, peak Eadi and ʃEadi are correlated with median correlation of coefficients, R > 0.95. Median ʃEadi, Vt, neural inspiratory time (Ti_ ( Neural )), inspiratory time (Ti) and peak inspiratory pressure (PIP) were similar in PS and NAVA. However, it was found that individual patients have higher or smaller ʃEadi, Vt, Ti_ ( Neural ), Ti and PIP. CVR analysis showed greater Vt variability for NAVA (p < 0.005). Range90 was lower for NAVA than PS for 21 of 22 patients. NAVA provided better matching of Vt to ʃEadi for 21 of 22 patients, and provided greater variability Vt. These results were achieved regardless of differences in ventilatory demand (Eadi) between patients and modes.

Second pilot trials of the STAR-Liege protocol for tight glycemic control in critically ill patients.

BACKGROUND: Critically ill patients often present increased insulin resistance and stress-induced hyperglycemia. Tight glycemic control aims to reduce blood glucose (BG) levels and variability while ensuring safety from hypoglycemia. This paper presents the results of the second Belgian clinical trial using the customizable STAR framework in a target-to-range control approach. The main objective is reducing measurement frequency while maintaining performance and safety of the glycemic control. METHODS: The STAR-Liege 2 (SL2) protocol targeted the 100-140 mg/dL glycemic band and offered 2-hourly and 3-hourly interventions. Only insulin rates were adjusted, and nutrition inputs were left to the attending clinicians. This protocol restricted the forecasted risk of BG < 90 mg/dL to a 5% level using a stochastic model of insulin sensitivity to assess patient-specific responses to insulin and its future likely variability to optimize insulin interventions. The clinical trial was performed at the Centre Hospitalier Universitaire de Liege and included 9 patients. Results are compared to 24-hour pre-trial and 24-hour post-trial, but also to the results of the first pilot trial performed in Liege, STAR-Liege 1 (SL1). This trial was approved by the Ethics Committee of the Medical Faculty of the University of Liege (Liege, Belgium). RESULTS: During the SL2 trial, 91 measurements were taken over 194 hours. BG levels were tightly distributed: 54.9% of BG within 100-140 mg/dL, 40.7% were ≥ 140 mg/dL and 4.4% were < 100 mg/dL with no BG < 70 mg/dL. Comparing these results with 24-hour pre-trial and post-trial shows that SL2 reduced high and low BG levels and reduced glycemic variability. Nurses selected 3-hourly measurement only 5 of 16 times and overrode 12% of 91 recommended interventions (35% increased insulin rates and 65% decreased insulin rates). SL1 and SL2 present similar BG levels distribution (p > 0.05) with significantly reduced measurement frequency for SL2 (p < 0.05). CONCLUSIONS: The SL2 protocol succeeded in reducing clinical workload while maintaining safety and effectiveness of the glycemic control. SL2 was also shown to be safer and tighter than hospital control. Overall results validate the efficacy of significantly customizing the STAR framework.

First pilot trial of the STAR-Liege protocol for tight glycemic control in critically ill patients.

Tight glycemic control (TGC) has shown benefits in ICU patients, but been difficult to achieve consistently due to inter- and intra- patient variability that requires more adaptive, patient-specific solutions. STAR (Stochastic TARgeted) is a flexible model-based TGC framework accounting for patient variability with a stochastically derived maximum 5% risk of blood glucose (BG) below 72 mg/dL. This research describes the first clinical pilot trial of the STAR approach and the post-trial analysis of the models and methods that underpin the protocol. The STAR framework works with clinically specified targets and intervention guidelines. The clinically specified glycemic target was 125 mg/dL. Each trial was 24 h with BG measured 1-2 hourly. Two-hourly measurement was used when BG was between 110-135 mg/dL for 3 h. In the STAR approach, each intervention leads to a predicted BG level and outcome range (5-95th percentile) based on a stochastic model of metabolic patient variability. Carbohydrate intake (all sources) was monitored, but not changed from clinical settings except to prevent BG<100 mg/dL when no insulin was given. Insulin infusion rates were limited (6 U/h maximum), with limited increases based on current infusion rate (0.5-2.0 U/h), making this use of the STAR framework an insulin-only TGC approach. Approval was granted by the Ethics Committee of the Medical Faculty of the University of Liege (Liege, Belgium). Nine patient trials were undertaken after obtaining informed consent. There were 205 measurements over all 9 trials. Median [IQR] per-patient results were: BG: 138.5 [130.6-146.0]mg/dL; carbohydrate administered: 2-11 g/h; median insulin:1.3 [0.9-2.4]U/h with a maximum of 6.0 [4.7-6.0]U/h. Median [IQR] time in the desired 110-140 mg/dL band was: 50.0 [31.2-54.2]%. Median model prediction errors ranged: 10-18%, with larger errors due to small meals and other clinical events. The minimum BG was 63 mg/dL and no other measurement was below 72 mg/dL, so only 1 measurement (0.5%) was below the 5% guaranteed minimum risk level. Post-trial analysis showed that patients were more variable than predicted by the stochastic model used for control, resulting in some of the prediction errors seen. Analysis and (validated) virtual trial re-simulating the clinical trial using stochastic models relevant to the patient's particular day of ICU stay were seen to be more accurate in capturing the observed variability. This analysis indicated that equivalent control and safety could be obtained with similar or lower glycemic variability in control using more specific stochastic models. STAR effectively controlled all patients to target. Observed patient variability in response to insulin and thus prediction errors were higher than expected, likely due to the recent insult of cardiac surgery or a major cardiac event, and their immediate recovery. STAR effectively managed this variability with no hypoglycemia. Improved stochastic models will be used to prospectively test these outcomes in further ongoing clinical pilot trials in this and other units.

Mathematical multi-scale model of the cardiovascular system including mitral valve dynamics. Application to ischemic mitral insufficiency.

BACKGROUND: Valve dysfunction is a common cardiovascular pathology. Despite significant clinical research, there is little formal study of how valve dysfunction affects overall circulatory dynamics. Validated models would offer the ability to better understand these dynamics and thus optimize diagnosis, as well as surgical and other interventions. METHODS: A cardiovascular and circulatory system (CVS) model has already been validated in silico, and in several animal model studies. It accounts for valve dynamics using Heaviside functions to simulate a physiologically accurate "open on pressure, close on flow" law. However, it does not consider real-time valve opening dynamics and therefore does not fully capture valve dysfunction, particularly where the dysfunction involves partial closure. This research describes an updated version of this previous closed-loop CVS model that includes the progressive opening of the mitral valve, and is defined over the full cardiac cycle. RESULTS: Simulations of the cardiovascular system with healthy mitral valve are performed, and, the global hemodynamic behaviour is studied compared with previously validated results. The error between resulting pressure-volume (PV) loops of already validated CVS model and the new CVS model that includes the progressive opening of the mitral valve is assessed and remains within typical measurement error and variability. Simulations of ischemic mitral insufficiency are also performed. Pressure-Volume loops, transmitral flow evolution and mitral valve aperture area evolution follow reported measurements in shape, amplitude and trends. CONCLUSIONS: The resulting cardiovascular system model including mitral valve dynamics provides a foundation for clinical validation and the study of valvular dysfunction in vivo. The overall models and results could readily be generalised to other cardiac valves.

Modelling acute renal failure using blood and breath biomarkers in rats.

This paper compares three methods for estimating renal function, as tested in rats. Acute renal failure (ARF) was induced via a 60-min bilateral renal artery clamp in 8 Sprague-Dawley rats and renal function was monitored for 1 week post-surgery. A two-compartment model was developed for estimating glomerular filtration via a bolus injection of a radio-labelled inulin tracer, and was compared with an estimated creatinine clearance method, modified using the Cockcroft-Gault equation for rats. These two methods were compared with selected ion flow tube-mass spectrometry (SIFT-MS) monitoring of breath analytes. Determination of renal function via SIFT-MS is desirable since results are available non-invasively and in real time. Relative decreases in renal function show very good correlation between all 3 methods (R²=0.84, 0.91 and 0.72 for breath-inulin, inulin-creatinine, and breath-creatinine correlations, respectively), and indicate good promise for fast, non-invasive determination of renal function via breath testing.

Validation of a model-based virtual trials method for tight glycemic control in intensive care.

BACKGROUND: In-silico virtual patients and trials offer significant advantages in cost, time and safety for designing effective tight glycemic control (TGC) protocols. However, no such method has fully validated the independence of virtual patients (or resulting clinical trial predictions) from the data used to create them. This study uses matched cohorts from a TGC clinical trial to validate virtual patients and in-silico virtual trial models and methods. METHODS: Data from a 211 patient subset of the Glucontrol trial in Liege, Belgium. Glucontrol-A (N = 142) targeted 4.4-6.1 mmol/L and Glucontrol-B (N = 69) targeted 7.8-10.0 mmol/L. Cohorts were matched by APACHE II score, initial BG, age, weight, BMI and sex (p > 0.25). Virtual patients are created by fitting a clinically validated model to clinical data, yielding time varying insulin sensitivity profiles (SI(t)) that drives in-silico patients.Model fit and intra-patient (forward) prediction errors are used to validate individual in-silico virtual patients. Self-validation (tests A protocol on Group-A virtual patients; and B protocol on B virtual patients) and cross-validation (tests A protocol on Group-B virtual patients; and B protocol on A virtual patients) are used in comparison to clinical data to assess ability to predict clinical trial results. RESULTS: Model fit errors were small (<0.25%) for all patients, indicating model fitness. Median forward prediction errors were: 4.3, 2.8 and 3.5% for Group-A, Group-B and Overall (A+B), indicating individual virtual patients were accurate representations of real patients. SI and its variability were similar between cohorts indicating they were metabolically similar.Self and cross validation results were within 1-10% of the clinical data for both Group-A and Group-B. Self-validation indicated clinically insignificant errors due to model and/or clinical compliance. Cross-validation clearly showed that virtual patients enabled by identified patient-specific SI(t) profiles can accurately predict the performance of independent and different TGC protocols. CONCLUSIONS: This study fully validates these virtual patients and in silico virtual trial methods, and clearly shows they can accurately simulate, in advance, the clinical results of a TGC protocol, enabling rapid in silico protocol design and optimization. These outcomes provide the first rigorous validation of a virtual in-silico patient and virtual trials methodology.

Organ failure and tight glycemic control in the SPRINT study.

INTRODUCTION: Intensive care unit mortality is strongly associated with organ failure rate and severity. The sequential organ failure assessment (SOFA) score is used to evaluate the impact of a successful tight glycemic control (TGC) intervention (SPRINT) on organ failure, morbidity, and thus mortality. METHODS: A retrospective analysis of 371 patients (3,356 days) on SPRINT (August 2005 - April 2007) and 413 retrospective patients (3,211 days) from two years prior, matched by Acute Physiology and Chronic Health Evaluation (APACHE) III. SOFA is calculated daily for each patient. The effect of the SPRINT TGC intervention is assessed by comparing the percentage of patients with SOFA ≤5 each day and its trends over time and cohort/group. Organ-failure free days (all SOFA components ≤2) and number of organ failures (SOFA components >2) are also compared. Cumulative time in 4.0 to 7.0 mmol/L band (cTIB) was evaluated daily to link tightness and consistency of TGC (cTIB ≥0.5) to SOFA ≤5 using conditional and joint probabilities. RESULTS: Admission and maximum SOFA scores were similar (P = 0.20; P = 0.76), with similar time to maximum (median: one day; IQR: 13 days; P = 0.99). Median length of stay was similar (4.1 days SPRINT and 3.8 days Pre-SPRINT; P = 0.94). The percentage of patients with SOFA ≤5 is different over the first 14 days (P = 0.016), rising to approximately 75% for Pre-SPRINT and approximately 85% for SPRINT, with clear separation after two days. Organ-failure-free days were different (SPRINT = 41.6%; Pre-SPRINT = 36.5%; P < 0.0001) as were the percent of total possible organ failures (SPRINT = 16.0%; Pre-SPRINT = 19.0%; P < 0.0001). By Day 3 over 90% of SPRINT patients had cTIB ≥0.5 (37% Pre-SPRINT) reaching 100% by Day 7 (50% Pre-SPRINT). Conditional and joint probabilities indicate tighter, more consistent TGC under SPRINT (cTIB ≥0.5) increased the likelihood SOFA ≤5. CONCLUSIONS: SPRINT TGC resolved organ failure faster, and for more patients, from similar admission and maximum SOFA scores, than conventional control. These reductions mirror the reduced mortality with SPRINT. The cTIB ≥0.5 metric provides a first benchmark linking TGC quality to organ failure. These results support other physiological and clinical results indicating the role tight, consistent TGC can play in reducing organ failure, morbidity and mortality, and should be validated on data from randomised trials.

Derivative weighted active insulin control modelling and clinical trials for ICU patients.

Close control of blood glucose levels significantly reduces vascular complications in Type 1 and Type 2 diabetic individuals. Heavy derivative controllers using the data density available from emerging biosensors are developed to provide tight, optimal control of elevated blood glucose levels, while robustly handling variation in patient response. A two-compartment glucose regulatory system model is developed for intravenous infusion from physiologically verified subcutaneous infusion models enabling a proof-of-concept clinical trial at the Christchurch Hospital Department of Intensive Care Medicine. This clinical trial is the first of its kind to test a high sample rate feedback control algorithm for tight glucose regulation. The clinical trial results show tight control with reductions of 79-89% in blood glucose excursions for an oral glucose tolerance test. Experimental performance is very similar to modelled behaviour. Results include a clear need for an additional accumulator dynamic for insulin behaviour in transport to the blood and strong correlation of 10% or less between modelled insulin infused and the amounts used in clinical trials. Finally, the heavy derivative PD control approach is seen to be able to bring blood glucose levels below the (elevated) basal level, showing the potential for truly tight control.

Automated insulin infusion trials in the intensive care unit.

The objective is to demonstrate the effectiveness of a simple automated insulin infusion for controlling the rise and duration of blood glucose excursion following a glucose challenge in critically ill patients with impaired glucose tolerance. A two-compartment model of the glucose regulatory system was developed for intravenous infusion control design. On two subsequent days a critically ill patient with impaired glucose tolerance was given a 75 g oral glucose tolerance test (OGTT), and the glucose level was measured every 15 min. The first day's data were used to design a heavy-derivative insulin infusion controller for the second day. Ethics approval was granted for this test. Five patients were studied. In four patients, the magnitude and duration of blood glucose excursion were reduced over 50%. Fasting level was reduced 15%, from an average of 7.2 mmol/L to 6.1 mmol/L. The fifth patient's results showed a diminished response due to the antagonistic effects of hydrocortisone on insulin, a data point not provided prior to testing. Modeling to account for this effect yielded better correlation with the test. The automated algorithm provided rapid, effective control of the blood glucose rise in response to an OGTT input. These results highlight the effectiveness of automated infusions for regulating blood glucose rise and excursions, and the potential of this approach for non-hospitalized individuals.