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1.  Variability of insulin sensitivity during the first 4 days of critical illness: implications for tight glycemic control 
Background
Effective tight glycemic control (TGC) can improve outcomes in critical care patients, but it is difficult to achieve consistently. Insulin sensitivity defines the metabolic balance between insulin concentration and insulin-mediated glucose disposal. Hence, variability of insulin sensitivity can cause variable glycemia. This study quantifies and compares the daily evolution of insulin sensitivity level and variability for critical care patients receiving TGC.
Methods
This is a retrospective analysis of data from the SPRINT TGC study involving patients admitted to a mixed medical-surgical ICU between August 2005 and May 2007. Only patients who commenced TGC within 12 hours of ICU admission and spent at least 24 hours on the SPRINT protocol were included (N = 164). Model-based insulin sensitivity (SI) was identified each hour. Absolute level and hour-to-hour percent changes in SI were assessed on cohort and per-patient bases. Levels and variability of SI were compared over time on 24-hour and 6-hour timescales for the first 4 days of ICU stay.
Results
Cohort and per-patient median SI levels increased by 34% and 33% (p < 0.001) between days 1 and 2 of ICU stay. Concomitantly, cohort and per-patient SI variability decreased by 32% and 36% (p < 0.001). For 72% of the cohort, median SI on day 2 was higher than on day 1. The day 1–2 results are the only clear, statistically significant trends across both analyses. Analysis of the first 24 hours using 6-hour blocks of SI data showed that most of the improvement in insulin sensitivity level and variability seen between days 1 and 2 occurred during the first 12–18 hours of day 1.
Conclusions
Critically ill patients have significantly lower and more variable insulin sensitivity on day 1 than later in their ICU stay and particularly during the first 12 hours. This rapid improvement is likely due to the decline of counter-regulatory hormones as the acute phase of critical illness progresses. Clinically, these results suggest that while using TGC protocols with patients during their first few days of ICU stay, extra care should be afforded. Increased measurement frequency, higher target glycemic bands, conservative insulin dosing, and modulation of carbohydrate nutrition should be considered to minimize safely the outcome glycemic variability and reduce the risk of hypoglycemia.
doi:10.1186/2110-5820-2-17
PMCID: PMC3464183  PMID: 22703645
Critical care; Hyperglycemia; Insulin resistance; Mathematical model; Algorithms
2.  Pilot proof of concept clinical trials of Stochastic Targeted (STAR) glycemic control 
Introduction
Tight glycemic control (TGC) has shown benefits but has been difficult to achieve consistently. STAR (Stochastic TARgeted) is a flexible, model-based TGC approach directly accounting for intra- and inter- patient variability with a stochastically derived maximum 5% risk of blood glucose (BG) < 4.0 mmol/L. This research assesses the safety, efficacy, and clinical burden of a STAR TGC controller modulating both insulin and nutrition inputs in pilot trials.
Methods
Seven patients covering 660 hours. Insulin and nutrition interventions are given 1-3 hourly as chosen by the nurse to allow them to manage workload. Interventions are calculated by using clinically validated computer models of human metabolism and its variability in critical illness to maximize the overlap of the model-predicted (5-95th percentile) range of BG outcomes with the 4.0-6.5 mmol/L band while ensuring a maximum 5% risk of BG < 4.0 mmol/L. Carbohydrate intake (all sources) was selected to maximize intake up to 100% of SCCM/ACCP goal (25 kg/kcal/h). Maximum insulin doses and dose changes were limited for safety. Measurements were made with glucometers. Results are compared to those for the SPRINT study, which reduced mortality 25-40% for length of stay ≥3 days. Written informed consent was obtained for all patients, and approval was granted by the NZ Upper South A Regional Ethics Committee.
Results
A total of 402 measurements were taken over 660 hours (~14/day), because nurses showed a preference for 2-hourly measurements. Median [interquartile range, (IQR)] cohort BG was 5.9 mmol/L [5.2-6.8]. Overall, 63.2%, 75.9%, and 89.8% of measurements were in the 4.0-6.5, 4.0-7.0, and 4.0-8.0 mmol/L bands. There were no hypoglycemic events (BG < 2.2 mmol/L), and the minimum BG was 3.5 mmol/L with 4.5% < 4.4 mmol/L. Per patient, the median [IQR] hours of TGC was 92 h [29-113] using 53 [19-62] measurements (median, ~13/day). Median [IQR] results: BG, 5.9 mmol/L [5.8-6.3]; carbohydrate nutrition, 6.8 g/h [5.5-8.7] (~70% goal feed median); insulin, 2.5 U/h [0.1-5.1]. All patients achieved BG < 6.1 mmol/L. These results match or exceed SPRINT and clinical workload is reduced more than 20%.
Conclusions
STAR TGC modulating insulin and nutrition inputs provided very tight control with minimal variability by managing intra- and inter- patient variability. Performance and safety exceed that of SPRINT, which reduced mortality and cost in the Christchurch ICU. The use of glucometers did not appear to impact the quality of TGC. Finally, clinical workload was self-managed and reduced 20% compared with SPRINT.
doi:10.1186/2110-5820-1-38
PMCID: PMC3224394  PMID: 21929821
3.  Clinical detection and monitoring of acute pulmonary embolism: proof of concept of a computer-based method 
Background
The diagnostic ability of computer-based methods for cardiovascular system (CVS) monitoring offers significant clinical potential. This research tests the clinical applicability of a newly improved computer-based method for the proof of concept case of tracking changes in important hemodynamic indices due to the influence acute pulmonary embolism (APE).
Methods
Hemodynamic measurements from a porcine model of APE were used to validate the method. Of these measurements, only those that are clinically available or inferable were used in to identify pig-specific computer models of the CVS, including the aortic and pulmonary artery pressure, stroke volume, heart rate, global end diastolic volume, and mitral and tricuspid valve closure times. Changes in the computer-derived parameters were analyzed and compared with experimental metrics and clinical indices to assess the clinical applicability of the technique and its ability to track the disease state.
Results
The subject-specific computer models accurately captured the increase in pulmonary resistance (Rpul), the main cardiovascular consequence of APE, in all five pigs trials, which related well (R2 = 0.81) with the experimentally derived pulmonary vascular resistance. An increase in right ventricular contractility was identified, as expected, consistent with known reflex responses to APE. Furthermore, the modeled right ventricular expansion index (the ratio of right to left ventricular end diastolic volumes) closely followed the trends seen in the measured data (R2 = 0.92) used for validation, with sharp increases seen in the metric for the two pigs in a near-death state. These results show that the pig-specific models are capable of tracking disease-dependent changes in pulmonary resistance (afterload), right ventricular contractility (inotropy), and ventricular loading (preload) during induced APE. Continuous, accurate estimation of these fundamental metrics of cardiovascular status can help to assist clinicians with diagnosis, monitoring, and therapy-based decisions in an intensive care environment. Furthermore, because the method only uses measurements already available in the ICU, it can be implemented with no added risk to the patient and little extra cost.
Conclusions
This computer-based monitoring method shows potential for real-time, continuous diagnosis and monitoring of acute CVS dysfunction in critically ill patients.
doi:10.1186/2110-5820-1-33
PMCID: PMC3224493  PMID: 21906388
4.  Physiological modeling, tight glycemic control, and the ICU clinician: what are models and how can they affect practice? 
Critically ill patients are highly variable in their response to care and treatment. This variability and the search for improved outcomes have led to a significant increase in the use of protocolized care to reduce variability in care. However, protocolized care does not address the variability of outcome due to inter- and intra-patient variability, both in physiological state, and the response to disease and treatment. This lack of patient-specificity defines the opportunity for patient-specific approaches to diagnosis, care, and patient management, which are complementary to, and fit within, protocolized approaches.
Computational models of human physiology offer the potential, with clinical data, to create patient-specific models that capture a patient's physiological status. Such models can provide new insights into patient condition by turning a series of sometimes confusing clinical data into a clear physiological picture. More directly, they can track patient-specific conditions and thus provide new means of diagnosis and opportunities for optimising therapy.
This article presents the concept of model-based therapeutics, the use of computational models in clinical medicine and critical care in specific, as well as its potential clinical advantages, in a format designed for the clinical perspective. The review is presented in terms of a series of questions and answers. These aspects directly address questions concerning what makes a model, how it is made patient-specific, what it can be used for, its limitations and, importantly, what constitutes sufficient validation.
To provide a concrete foundation, the concepts are presented broadly, but the details are given in terms of a specific case example. Specifically, tight glycemic control (TGC) is an area where inter- and intra-patient variability can dominate the quality of care control and care received from any given protocol. The overall review clearly shows the concept and significant clinical potential of using computational models in critical care medicine.
doi:10.1186/2110-5820-1-11
PMCID: PMC3224460  PMID: 21906337

Results 1-4 (4)