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.

A physiological Intensive Control Insulin-Nutrition-Glucose (ICING) model validated in critically ill patients.

Intensive insulin therapy (IIT) and tight glycaemic control (TGC), particularly in intensive care unit (ICU), are the subjects of increasing and controversial debate in recent years. Model-based TGC has shown potential in delivering safe and tight glycaemic management, all the while limiting hypoglycaemia. A comprehensive, more physiologically relevant Intensive Control Insulin-Nutrition-Glucose (ICING) model is presented and validated using data from critically ill patients. Two existing glucose-insulin models are reviewed and formed the basis for the ICING model. Model limitations are discussed with respect to relevant physiology, pharmacodynamics and TGC practicality. Model identifiability issues are carefully considered for clinical settings. This article also contains significant reference to relevant physiology and clinical literature, as well as some references to the modeling efforts in this field. Identification of critical constant population parameters was performed in two stages, thus addressing model identifiability issues. Model predictive performance is the primary factor for optimizing population parameter values. The use of population values are necessary due to the limited clinical data available at the bedside in the clinical control scenario. Insulin sensitivity, S(I), the only dynamic, time-varying parameter, is identified hourly for each individual. All population parameters are justified physiologically and with respect to values reported in the clinical literature. A parameter sensitivity study confirms the validity of limiting time-varying parameters to S(I) only, as well as the choices for the population parameters. The ICING model achieves median fitting error of <1% over data from 173 patients (N=42,941 h in total) who received insulin while in the ICU and stayed for ≥ 72 h. Most importantly, the median per-patient 1-h ahead prediction error is a very low 2.80% [IQR 1.18, 6.41%]. It is significant that the 75th percentile prediction error is within the lower bound of typical glucometer measurement errors of 7-12%. These results confirm that the ICING model is suitable for developing model-based insulin therapies, and capable of delivering real-time model-based TGC with a very tight prediction error range. Finally, the detailed examination and discussion of issues surrounding model-based TGC and existing glucose-insulin models render this article a mini-review of the state of model-based TGC in critical care.

Impact of glucocorticoids on insulin resistance in the critically ill.

Glucocorticoids (GCs) have been shown to reduce insulin sensitivity in healthy individuals. Widely used in critical care to treat a variety of inflammatory and allergic disorders, they may inadvertently exacerbate stress-hyperglycaemia. This research uses model-based methods to quantify the reduction in insulin sensitivity from GCs in critically ill patients, and thus their impact on glycaemic control. A model-based measure of insulin sensitivity (S(I)) was used to quantify changes between two matched cohorts of 40 intensive care unit (ICU) patients. Patients in one cohort received GC treatment, while patients in the control cohort did not. All patients were admitted to the Christchurch hospital ICU between 2005 and 2007 and spent at least 24h on the SPRINT glycaemic control protocol. A 31% reduction in whole-cohort median insulin sensitivity was seen between the control cohort and patients receiving glucocorticoids with a median dose equivalent to 200mg/d of hydrocortisone per patient. Comparing percentile patients as a surrogate for matched patients, reductions in median insulin sensitivity of 20%, 25%, and 21% were observed for the 25th-, 50th- and 75th-percentile patients, respectively. These cohort and percentile patient reductions are less than or equivalent to the 30-62% reductions reported in healthy subjects especially when considering the fact that the GC doses in this study are 1.3-4.0 times larger than those in studies of healthy subjects. This reduced suppression of insulin sensitivity in critically ill patients could be a result of saturation due to already increased levels of catecholamines and cortisol common in critically illness. Virtual trial simulation showed that reductions in insulin sensitivity of 20-30% associated with glucocorticoid treatment in the ICU have limited impact on glycaemic control levels within the context of the SPRINT protocol.

Development of a model-based clinical sepsis biomarker for critically ill patients.

Sepsis occurs frequently in the intensive care unit (ICU) and is a leading cause of admission, mortality, and cost. Treatment guidelines recommend early intervention, however positive blood culture results may take up to 48 h. Insulin sensitivity (S(I)) is known to decrease with worsening condition and could thus be used to aid diagnosis. Some glycemic control protocols are able to accurately identify insulin sensitivity in real-time. Hourly model-based insulin sensitivity S(I) values were calculated from glycemic control data of 36 patients with sepsis. The hourly S(I) is compared to the hourly sepsis score (ss) for these patients (ss=0-4 for increasing severity). A multivariate clinical biomarker was also developed to maximize the discrimination between different ss groups. Receiver operator characteristic (ROC) curves for severe sepsis (ss ≥ 2) are created for both S(I) and the multivariate clinical biomarker. Insulin sensitivity as a sepsis biomarker for diagnosis of severe sepsis achieves a 50% sensitivity, 76% specificity, 4.8% positive predictive value (PPV), and 98.3% negative predictive value (NPV) at an S(I) cut-off value of 0.00013 L/mU/min. Multivariate clinical biomarker combining S(I), temperature, heart rate, respiratory rate, blood pressure, and their respective hourly rates of change achieves 73% sensitivity, 80% specificity, 8.4% PPV, and 99.2% NPV. Thus, the multivariate clinical biomarker provides an effective real-time negative predictive diagnostic for severe sepsis. Examination of both inter- and intra-patient statistical distribution of this biomarker and sepsis score shows potential avenues to improve the positive predictive value.

Tight glycemic control in critical care--the leading role of insulin sensitivity and patient variability: a review and model-based analysis.

Tight glycemic control (TGC) has emerged as a major research focus in critical care due to its potential to simultaneously reduce both mortality and costs. However, repeating initial successful TGC trials that reduced mortality and other outcomes has proven difficult with more failures than successes. Hence, there has been growing debate over the necessity of TGC, its goals, the risk of severe hypoglycemia, and target cohorts. This paper provides a review of TGC via new analyses of data from several clinical trials, including SPRINT, Glucontrol and a recent NICU study. It thus provides both a review of the problem and major background factors driving it, as well as a novel model-based analysis designed to examine these dynamics from a new perspective. Using these clinical results and analysis, the goal is to develop new insights that shed greater light on the leading factors that make TGC difficult and inconsistent, as well as the requirements they thus impose on the design and implementation of TGC protocols. A model-based analysis of insulin sensitivity using data from three different critical care units, comprising over 75,000h of clinical data, is used to analyse variability in metabolic dynamics using a clinically validated model-based insulin sensitivity metric (S(I)). Variation in S(I) provides a new interpretation and explanation for the variable results seen (across cohorts and studies) in applying TGC. In particular, significant intra- and inter-patient variability in insulin resistance (1/S(I)) is seen be a major confounder that makes TGC difficult over diverse cohorts, yielding variable results over many published studies and protocols. Further factors that exacerbate this variability in glycemic outcome are found to include measurement frequency and whether a protocol is blind to carbohydrate administration.