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See detailOrgan failure and tight glycemic control in the SPRINT study.
Chase, J Geoffrey; Pretty, Christopher G; Pfeifer, Leesa et al

in Critical Care (2010), 14(4), 154

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 ... [more ▼]

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. [less ▲]

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See detailWhat makes tight glycemic control tight? The impact of variability and nutrition in two clinical studies.
Suhaimi, Fatanah; Le Compte, Aaron; Preiser, Jean-Charles ULg et al

in Journal of Diabetes Science and Technology (2010), 4(2), 284-98

INTRODUCTION: Tight glycemic control (TGC) remains controversial while successful, consistent, and effective protocols remain elusive. This research analyzes data from two TGC trials for root causes of ... [more ▼]

INTRODUCTION: Tight glycemic control (TGC) remains controversial while successful, consistent, and effective protocols remain elusive. This research analyzes data from two TGC trials for root causes of the differences achieved in control and thus potentially in glycemic and other outcomes. The goal is to uncover aspects of successful TGC and delineate the impact of differences in cohorts. METHODS: A retrospective analysis was conducted using records from a 211-patient subset of the GluControl trial taken in Liege, Belgium, and 393 patients from Specialized Relative Insulin Nutrition Titration (SPRINT) in New Zealand. Specialized Relative Insulin Nutrition Titration targeted 4.0-6.0 mmol/liter, similar to the GluControl A (N = 142) target of 4.4-6.1 mmol/liter. The GluControl B (N = 69) target was 7.8-10.0 mmol/liter. Cohorts were matched by Acute Physiology and Chronic Health Evaluation II score and percentage males (p > .35); however, the GluControl cohort was slightly older (p = .011). Overall cohort and per-patient comparisons (median, interquartile range) are shown for (a) glycemic levels achieved, (b) nutrition from carbohydrate (all sources), and (c) insulin dosing for this analysis. Intra- and interpatient variability were examined using clinically validated model-based insulin sensitivity metric and its hour-to-hour variation. RESULTS: Cohort blood glucose were as follows: SPRINT, 5.7 (5.0-6.6) mmol/liter; GluControl A, 6.3 (5.3-7.6) mmol/liter; and GluControl B, 8.2 (6.9-9.4) mmol/liter. Insulin dosing was 3.0 (1.0-3.0), 1.5 (0.5-3), and 0.7 (0.0-1.7) U/h, respectively. Nutrition from carbohydrate (all sources) was 435.5 (259.2-539.1), 311.0 (0.0-933.1), and 622.1 (103.7-1036.8) kcal/day, respectively. Median per-patient results for blood glucose were 5.8 (5.3-6.4), 6.4 (5.9-6.9), and 8.3 (7.6-8.8) mmol/liter. Insulin doses were 3.0 (2.0-3.0), 1.5 (0.8-2.0), and 0.5 (0.0-1.0) U/h. Carbohydrate administration was 383.6 (207.4-497.7), 103.7 (0.0-829.4), and 207.4 (0.0-725.8) kcal/day. Overall, SPRINT gave approximately 2x more insulin with a 3-4x narrower, but generally non-zero, range of nutritional input to achieve equally TGC with less hypoglycemia. Specialized Relative Insulin Nutrition Titration had much less hypoglycemia (<2.2 mmol/liter), with 2% of patients, compared to GluControl A (7.7%) and GluControl B (2.9%), indicating much lower variability, with similar results for glucose levels <3.0 mmol/liter. Specialized Relative Insulin Nutrition Titration also had less hyperglycemia (>8.0 mmol/liter) than groups A and B. GluControl patients (A+B) had a approximately 2x wider range of insulin sensitivity than SPRINT. Hour-to-hour variation was similar. Hence GluControl had greater interpatient variability but similar intrapatient variability. CONCLUSION: Protocols that dose insulin blind to carbohydrate administration can suffer greater outcome glycemic variability, even if average cohort glycemic targets are met. While the cohorts varied significantly in model-assessed insulin resistance, their variability was similar. Such significant intra- and interpatient variability is a further significant cause and marker of glycemic variability in TGC. The results strongly recommended that TGC protocols be explicitly designed to account for significant intra- and interpatient variability in insulin resistance, as well as specifying or having knowledge of carbohydrate administration to minimize variability in glycemic outcomes across diverse cohorts and/or centers. [less ▲]

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See detailValidation of a model-based virtual trials method for tight glycemic control in intensive care.
Chase, J Geoffrey; Suhaimi, Fatanah; Penning, Sophie ULg et al

in BioMedical Engineering OnLine (2010), 9

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 ... [more ▼]

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. [less ▲]

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