A novel, model-based insulin and nutrition delivery controller for glycemic regulation in critically ill patients.

BACKGROUND: Critically ill patients are often hyperglycemic and insulin resistant, as well as highly dynamic. Tight glucose control has been shown to significantly reduce mortality in critical care. A physiological model of the glucose-insulin regulatory system is improved and used to develop an adaptive control protocol utilizing both nutritional and insulin inputs to control hyperglycemia. The approach is clinically verified in a critical care patient cohort. METHODS: A simple two-compartment model for glucose rate of appearance in plasma due to stepwise enteral glucose fluxes is developed and incorporated into a previously validated system model. A control protocol modulating intravenous insulin infusion and bolus, with an enteral feed rate, is developed, enabling tight and predictive glycemic regulation to preset targets. The control protocol is adaptive to patient time-variant effective insulin resistance. The model and protocol are verified in seven 10-h and one 24-h proof-of-concept clinical trials. Ethics approval was granted by the Canterbury Ethics Committee. RESULTS: Insulin requirements varied widely following acute changes in patient physiology. The algorithm developed successfully adapted to patient metabolic status and insulin sensitivity, achieving an average target acquisition error of 9.3% with 90.7% of all targets achieved within +/-20%. Prediction errors may not be distinguishable from sensor measurement errors. Large errors (>20%) are attributable to highly dynamic and unpredictable changes in patient condition. CONCLUSIONS: Tight, targeted stepwise regulation was exhibited in all trials. Overall, tight glycemic regulation is achieved in a broad critical care cohort with optimized insulin and nutrition delivery, effectively managing glycemia even with high effective insulin resistance.

Model predictive glycaemic regulation in critical illness using insulin and nutrition input: a pilot study.

Stress-induced hyperglycaemia is prevalent in intensive care, impairing the immune response. Nutritional support regimes with high glucose content further exacerbate the problem. Tight glucose control has been shown to reduce mortality by up to 43% if levels are kept below 6.1 mmol/L. This research develops a control algorithm with insulin and nutritional inputs for targeted glucose control in the critically ill. Ethics approval for this research was granted by the Canterbury Ethics Committee. Proof-of-concept clinical pilot trials were conducted on intubated, insulin-dependent Christchurch ICU patients (n=7) on constant nutritional support. A target 10-15% reduction in glucose level per hour for a desired glucose level of 4-6 mmol/L was set. 43% and 91% of glucose targets were achieved within +/-5 and +/-20%, respectively. The mean error was 8.9% (0.5 mmol/L), with an absolute range [0, 2.9] mmol/L. End glucose levels were 40% lower compared to initial values. All large target errors are attributable to sudden changes in patient physiology at low glucose values, rather than systemic deficiencies. Target errors are consistent with and explainable by published sensor error distributions. The results show that intensive model-based glucose management with nutrition control reduced absolute glucose levels progressively while reducing the severity of glycaemic fluctuation even with significant inter-patient variability and time-varying physiological condition. Trials spanning longer periods of time are in development to verify the short-term pilot studies performed and to test the adaptability of the controller. Clinically, these results indicate potential in clinical use to reduce ICU mortality as well as reduce risk of severe complications.

A comparison of manual and remote afterloading in the treatment of carcinoma of the cervix: increasing dose rate with a flexible applicator.

A historical cohort design was used to assess the effect of introducing a remote afterloading system with a flexible applicator for the intracavitary treatment of cervical cancer. One hundred and sixty-eight patients treated for the 5 years prior to its introduction were compared to 84 patients treated for the first 3 years of its use. Patients were comparable with respect to age and stage. Treatment policies and techniques remained the same during the study period. Average dose rate to point A increased from 0.46 Gy/hr to 0.67 Gy/hr. The 3-year actuarial survival was equivalent between the two treatment modalities: 67.7% (manual), and 60.6% (remote). Patterns of local recurrence and distant failure were also equivalent between the two groups. Severe complication rates were comparable (8.3% manual, 6.3% remote) despite the increase in dose rate, confirming that the remote afterloading system can be safely adapted to a flexible applicator. The introduction of the remote afterloading system resulted in a 72% reduction in radiation exposure to staff.

Stereo-specific analysis of a novel protein kinase C inhibitor.

SPC-100270 drug substance ((2S,3S)-2-aminooctadecane-1,3-diol) is a synthetic sphingosine analogue possessing limited ultraviolet absorbance (UV) and two chiral centres. Analytical methodology employing derivatization of SPC-100270 with o-phthaldialdehyde (OPA) and a chiral thiol, N-acetyl-D-penicillamine, was developed to assess the isomeric purity of SPC-100270 in the presence of two of its three stereoisomers. Separation of the isoindole derivatives was achieved with isocratic reversed-phase column chromatography with detection at 330 nm. Under the conditions studied, the derivatization was complete within 3 h at 50 degrees C. The standard and derivatized solutions were stable for 7 days under refrigerated conditions. The limit of detection was 0.036 micrograms SPC-100270 per ml and the limit of quantitation was 0.237 micrograms SPC-100270 per ml. The assay response was linear over a concentration range of 4.7-376 micrograms SPC-100270 per ml with a coefficient of determination of greater than 0.9999. The precision, ruggedness and specificity of the assay were acceptable for determination of SPC-100270 in the presence of its stereoisomers and under forced degradation conditions. The method has been applied successfully in two independent laboratories for quality control release and stability assessment of SPC-100270 drug substance for early clinical studies.

Determination of fluorescent cyanobenz[f]isoindole derivatives of dopamine and norepinephrine using high performance liquid chromatography with chemiluminescence detection.

Dopamine (DA), norepinephrine (NE) and 3,4-dihydroxybenzylamine (DHBA) are converted to highly fluorescent cyanobenz[f]isoindole (CBI) derivatives by reacting these amines with naphthalene-2,3-dicarboxaldehyde in the presence of cyanide ion. Femtomole amounts of these CBI derivatives separated by reverse-phase high performance liquid chromatography can be detected by a post-column chemiluminescence system utilizing bis(2,4-dinitrophenyl) oxalate and hydrogen peroxide. Linear detection response was observed between 1 to 600 fmol, giving a signal to noise ratio of approximately 15 at the 1 fmol level. An assay procedure was developed for the determination of DA and NE in 20 microL of urine sample using DHBA as the internal standard.

Determination of dopamine, norepinephrine, and related trace amines by prechromatographic derivatization with naphthalene-2,3-dicarboxaldehyde.

Dopamine, norepinephrine, octopamine, tyramine, and 3,4-dihydroxybenzylamine react readily with naphthalene-2,3-dicarboxaldehyde in the presence of cyanide ion under mild conditions to give highly fluorescent cyanobenz[f]isoindole (CBI) products. The CBI products exhibit good solution chemical stability. The high-fluorescence quantum efficiency of the CBI fluorophore and the ability to excite these adducts in the visible region (420-450 nm) enhance the sensitivity and selectivity of this derivatization detection technique. The CBI products of catecholamines and "trace" amines are readily separated by reverse-phase HPLC giving detection limits in the 20 to 60 fmol range (S/N = 3). A prechromatographic derivatization HPLC assay for the trace analysis of dopamine and norepinephrine in urine is described.

Determination of desmosine, isodesmosine, and other amino acids by liquid chromatography with electrochemical detection following precolumn derivatization with naphthalenedialdehyde/cyanide.

Naphthalenedialdehyde (NDA) in the presence of cyanide (CN) reacts with primary amines to produce fluorescent cyano[f]benzoisoindole (CBI) derivatives. These derivatives have been shown to be substantially more stable than the corresponding o-phthalaldehyde derivatives. However, one drawback of this method is that compounds derivatized at more than one site exhibit quenching, precluding the use of fluorescence detection. The CBI derivatives have been found to be electroactive and are oxidized at a modest oxidation potential (+750 mV). Electrochemical detection is especially useful for the analysis of compounds containing more than one primary amine site because the response is not attenuated as it is in fluorescence detection. Desmosine and isodesmosine were of particular interest because of their importance in elastic fiber and the lack of highly sensitive HPLC methods for the determination of these compounds. Both of these compounds react with NDA/CN to produce electrochemically active derivatives. The combination of derivatization with NDA/CN and electrochemical detection was found to be linear over three orders of magnitude. Detection limits for CBI-lysine and CBI-desmosine were 100 fmol at a S/N of 2. Amino acids in elastin were quantitated using this method. The results correlate well with what has been reported previously in the literature. A significant advantage of the use of liquid chromatography with electrochemical detection with precolumn derivatization with NDA/CN for the analysis of desmosine and isodesmosine is that they can be separated and quantitated individually using this method. In addition, the unique voltammetry of multiderivatized CBI-amino acids can be used to verify peak purity.

Determination of amphetamine-related compounds by high-performance liquid chromatography with chemiluminescence and fluorescence detections.

High-performance liquid chromatography with chemiluminescence detection has been established for the determination of trace levels of amphetamine-related compounds (APs) after fluorigenic derivatization. Bis(2,4,6-trichlorophenyl) oxalate and hydrogen peroxide in acetonitrile was used as a post-column chemilumigenic reagent. As derivatization reagents, dansyl chloride (Dns-Cl), 4-fluoro-7-nitrobenzoxadiazole (NBD-F) and naphtalene-2,3-dicarbaldehyde (NDA) were compared. Dns-Cl was the most suitable of the three for the simultaneous determination of both primary and secondary amino APs. The on-column detection limits for Dns-derivatives were 3.10(-15) - 4.10(-15) mol. NDA gave the most sensitive derivatives (cyanobenz[f]isoindole, CBI derivatives) with only primary amino APs. The detection limits for CBI derivatives were as low as 2.10(-16) mol. The present method was applied to the determination of methamphetamine in human urine. Only diethyl ether extraction was necessary as a clean-up treatment before Dns derivatization, because diethyl ether extracted methamphetamine quantitatively from urine at strong alkaline pH and the extract showed few interfering peaks around the retention time of methamphetamine after the derivatization. Methamphetamine concentrations as low as 1.10(-7) M in urine were determined after the above treatments.

Pelvic radiation therapy for gynecologic malignancy in geriatric patients.

Thirty-one patients, aged 75 years or older, who received pelvic radiation therapy as part of primary treatment for a gynecologic malignancy, were reviewed. Ten patients (32%) failed to complete their treatment and 4 patients (13%) died of treatment-related complications. The treatment-related complications were independent of increasing age, but did correlate closely with the patients' pretreatment ECOG performance status. Ten patients with performance levels of 2 or higher had a mortality rate of 30%, while 70% failed to complete treatment. Treatment fractions of greater than 220 cGy per day also resulted in unacceptably high complication rates. Alternative treatment formats should be considered in geriatric patients with poor initial performance levels.