Discussion. Validation Analysis

Results

Validation Analysis

Glucontrol Protocol and Patient Cohorts

Methods

The Glucontrol trial [26] randomised patients into two groups: Group A and Group B. Group A received intensive insulin therapy and Group B received conventional insulin therapy, with target ranges of 4.4-6.1 mmol/L and 7.8-10 mmol/L, respectively. Insulin was administered as a continuous intravenous (IV) infusion. Hourly blood glucose (BG) measurements were recorded when the glycemic level was not within the target range. Otherwise, 2-hourly measurements were taken in the case of limited variation of glycemia, defined as less than a 50% change from the previous glycaemia in 2-hour range. Finally, 4-hourly measurements were taken when the glycemic level was less than 50% of the highest glycemia of the four last hours. If other BG measurements were taken, they were not recorded and did not result in changes to the insulin infusion rate.

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In this study, data was used from 350 patients (175 in each arm) treated using the Glucontrol protocol at CHU de Liege, Belgium, between March 2004 and April 2005. Thus, the Glucontrol data used in this study is from only one centre out of the full study [26]. The selection criteria for patients used in this analysis to generate virtual patients with sufficient data density [15,16,27] are shown in Figure 1. Patients were eliminated from the analysis if they received no insulin for their entire stay (per protocol), had less than 5 BG measurements or received little or no (recorded) carbohydrate administration (in any form) for more than 48 hours of their stay.

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Patients in Group A were slightly older than Group B. However, there were no significant differences in sex, weight, BMI, severity of illness as measured by APACHE II score or initial BG level. Group B received less insulin and more carbohydrate, in alignment with its higher glycemic target.

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This study performs three major forms of validation using virtual trials. These three tests provide both per-patient and cohort-wide validation of this in silico approach.

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The virtual trials approach here treats each group as being treated differently, including the carbohydrate and glucose infusions administered. These infusions were patient-specific and specified based on local and individual clinician standards, rather than per a protocol of any type. Thus, they were kept for each patient. As a result, Glucontrol B patients with the higher target had 2.6× higher glucose administration, which in cross validation was offset by 3.2× more insulin in the virtual trials. Differences in insulin rates between per protocol (as the cross validation was done) and per actual measurement rates makes these differences almost equal at 2.6× higher glucose administration and 2.4× greater insulin required to achieve the almost identical glycemic outcomes. Hence, the patients display similar overall insulin sensitivity, and the virtual trials took independently treated, matched patients and achieved the same outcome despite different initial treatments in the clinical data used to create the virtual patient. More specifically, nutritional treatment differences, within reason, did not affect or influence the results outside of expectations.

More importantly, the relatively small differences show the strength of model-fitted insulin sensitivity as a description of patient metabolic state, rather than as a therapy-specific parameter value. Other causes for remaining differences may also be a function of remaining model approximations or errors. As noted, inter-patient variability in some fixed model parameters is at least one cause of model limitations and errors. However, the limited glucose data with no added or real time insulin data limits the ability to uniquely identify these parameters [27,32].

Finally, this paper shows the potential for TGC protocols to be readily optimised and implemented using model based TGC. The low prediction errors indicate an ability to minimize the risk of hypoglycaemia as well as provide tight control. Even though some TGC clinical trials have not achieved any benefit from TGC [12,38], only 2 protocols have been first optimized with virtual trials [11,17,21]. Both delivered safe, effective TGC with reduced or zero hypoglycaemia.

Дата добавления: 2014-10-31