Gianpaolo Molino

A modular approach for representing and executing clinical guidelines

In this paper, we propose an approach for managing clinical guidelines. We outline a modular architecture, allowing us to separate two conceptually distinct aspects: the representation (and acquisition) of clinical guidelines and their execution. We propose an expressive formalism, which allows one to deal with the context-dependent character of clinical guidelines and also takes into account different temporal aspects. We also describe our tool for acquiring clinical guidelines, which provides a user-friendly interface to physicians, and automatically detects many forms of syntactic and semantic inconsistencies in the guidelines being acquired. In the second part of the paper, we describe a flexible engine for executing clinical guidelines (e.g. for clinical decision support applications, for medical education, or for integrating guidelines into the clinical practice), focusing our attention on temporal issues.

Hyperdynamic circulation in patients with cirrhosis: direct measurement of nitric oxide levels in hepatic and portal veins

BACKGROUND/AIMS Peripheral vasodilation represents the main vascular dysfunction associated with the hyperdynamic circulation of liver cirrhosis. This study was intended to measure directly regional and systemic levels of nitric oxide, a potent vasorelaxing mediator, in order to assess its role in the development of hemodynamic changes of cirrhosis. METHODS We compared nitric oxide levels in the splanchinic and systemic circulation of 25 patients with cirrhosis undergoing transjugular intrahepatic portosystemic stent shunt and in the hepatic vein and peripheral blood of 10 patients without cirrhosis submitted to venous catheterization. Nitric oxide levels were measured through electron paramagnetic resonance spectroscopy as nitrosylhemoglobin complexes. RESULTS Significantly higher nitric oxide levels were calculated in patients with cirrhosis with respect to controls, both in the peripheral and hepatic veins. In patients with cirrhosis, nitric oxide levels in the portal vein (3.44 +/- 2.17, expressed in arbitrary units) were higher than in the systemic circulation (1.89 +/- 1.15), but lower than in the hepatic vein (4.75 +/- 2.53; p < 0.001 by variance analysis). CONCLUSIONS These data suggest that nitric oxide synthetic pathway activity as well as nitric oxide release are enhanced at the level of splanchnic vasculature and, more important, in the hepatic tissue, confirming evidence of the predominant role of nitric oxide in the pathogenesis of hemodynamic changes in patients with cirrhosis with portal hypertension.

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered by drugs or disease. The model can be extended to describe completely the metabolism and enterohepatic circulation of any bile acids in man in health and digestive disease. The model should also be broadly applicable to the description of the pharmacokinetics of all other drugs whose metabolism is similar to that of bile acids, i.e., drugs for which there are tissue and bacterial biotransformations, enterohepatic cycling, and appreciable first-pass clearance.

Hepatic clearance of D-sorbitol: noninvasive test for evaluating functional liver plasma flow

The hepatic clearance of D-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction of D-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-to-day reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (+/- SD) hepatic clearance in the normal subjects (911 +/- 137 ml/min) was significantly greater (P less than 0.001) than that of the cirrhotics (456 +/- 181 ml/min).The hepatic clearance ofd-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction ofd-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-today reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (±sd) hepatic clearance in the normal subjects (911±137 ml/min) was significantly greater (P<0.001) than that of the cirrhotics (456±181 ml/min).

Prognostic value of the galactose test in predicting survival of patients with cirrhosis evaluated for liver transplantation: A prospective multicenter italian study

AIMS/METHODS The present study aimed to examine whether the galactose elimination capacity can be used to predict the survival of patients with advanced liver disease. We studied 194 patients with cirrhosis, belonging to Child class B and C, for 2 years each. RESULTS The overall probability of survival was 79% at 6 months, 72% at 1 year and 62% at 2 years. Variables significantly associated with the duration of survival, as assessed by univariate analysis, were the Child-Pugh score, presence of ascites, size of esophageal varices, prothrombin time, albumin, bilirubin, urea, creatinine, glucose and galactose elimination capacity. By a multivariable analysis, only Pugh score (p = 0.005), creatinine (p < 0.001), varices (p = 0.001) and galactose elimination capacity (p < 0.001) were independent predictors of mortality. The galactose elimination capacity was even more sensitive when the end-point was limited to deaths due to liver failure and hepatorenal syndrome. A new score obtained by summing the Pugh score with a score derived from galactose elimination capacity was quite simple and accurate for predicting survival. CONCLUSIONS The quantitative measurement of liver function as the galactose elimination capacity could be of use to identify patients with cirrhosis and probable short survival who might benefit most from urgent transplantation.

Adopting model checking techniques for clinical guidelines verification

OBJECTIVES Clinical guidelines (GLs) are assuming a major role in the medical area, in order to grant the quality of the medical assistance and to optimize medical treatments within healthcare organizations. The verification of properties of the GL (e.g., the verification of GL correctness with respect to several criteria) is a demanding task, which may be enhanced through the adoption of advanced Artificial Intelligence techniques. In this paper, we propose a general and flexible approach to address such a task. METHODS AND MATERIALS Our approach to GL verification is based on the integration of a computerized GL management system with a model-checker. We propose a general methodology, and we instantiate it by loosely coupling GLARE, our system for acquiring, representing and executing GLs, with the model-checker SPIN. RESULTS We have carried out an in-depth analysis of the types of properties that can be effectively verified using our approach, and we have completed an overview of the usefulness of the verification task at the different stages of the GL life-cycle. In particular, experimentation on a GL for ischemic stroke has shown that the automatic verification of properties in the model checking approach is able to discover inconsistencies in the GL that cannot be detected in advance by hand. CONCLUSION Our approach thus represents a further step in the direction of general and flexible automated GL verification, which also meets usability requirements.

Combined evaluation of total and functional liver plasma flows and intrahepatic shunting

A diagnostic protocol was studied, designed to evaluate the main parameters of liver circulation in man. A water solution ofd-sorbitol (S) and indocyanine green (ICG) was infused intravenously in six controls and nine cirrhotics. Steady-state renal and hepatic S clearances as well as hepatic ICG clearance were calculated. In controls the values (mean ±sd) of the independent measurements of S and ICG hepatic clearance were 978±107 and 519±142 ml/min, respectively, while in cirrhotic patients they were 554±238 and 231±90 ml/min. Owing to the kinetic properties of S, its hepatic clearance may be regarded as a measure of functional liver plasma flow (FLPF). The total liver plasma flow (TLPF) values (mean±sd), calculated according to Ficks principle, were 1091±157 ml/min (S method) and 1033±153 ml/min (ICG method) in controls, and 1251±554 and 1284±677 ml/min in cirrhotics. In controls, FLPF was found to be very close to TLPF. In cirrhotic patients the difference between TLPF and FLPF (ranging from 169 to 2093 ml/min when measured by S method) was considered as an approximate estimate of intrahepatic shunting. The procedure is safe and simple and may add a new dimension to the investigation of hepatic circulation.

Applying Artificial Intelligence to Clinical Guidelines: The GLARE Approach.

In this paper, we present GLARE, a domain-independent system for acquiring, representing and executing clinical guidelines. GLARE is characterized by the adoption of Artificial Intelligence (AI) techniques at different levels in the definition and implementation of the system. First of all, a high-level and user-friendly knowledge representation language has been designed, providing a set of representation primitives. Second, a user-friendly acquisition tool has been designed and implemented, on the basis of the knowledge representation formalism. The acquisition tool provides various forms of help for the expert physicians, including different levels of syntactic and semantic tests in order to check the “well-formedness” of the guidelines being acquired. Third, a tool for executing guidelines on a specific patient has been made available. The execution module provides a hypothetical reasoning facility, to support physicians in the comparison of alternative diagnostic and/or therapeutic strategies. Moreover, advanced and extended AI techniques for temporal reasoning and temporal consistency checking are used both in the acquisition and in the execution phase. The GLARE approach has been successfully tested on clinical guidelines in different domains, including bladder cancer, reflux esophagitis, and heart failure.

Assessment of the hepatic circulation in humans: new concepts based on evidence derived from a D-sorbitol clearance method.

D-Sorbitol (SOR) is safe, is easy to measure, and has an exceptionally high extraction ratio in the normal liver of 0.93+/-0.05 (mean+/-SD). Together with the general interest in hepatic hemodynamics, these facts motivated us to review the usefulness of this compound for the assessment of liver plasma flow in humans. We concluded that in subjects without liver disease the nonrenal clearance of SOR-measured noninvasively-very closely approximates hepatic plasma flow. Because of its lower and more variable extraction ratio, indocyanine green should no longer be used without hepatic vein catheterization. Even in patients with cirrhosis, SOR exhibits higher hepatic extraction ratios than indocyanine green. To fully explore the potential of SOR in the evaluation of such patients attention needs to be paid to the complex changes in architecture and function occurring in this disease. In cirrhotics the noninvasively measured nonrenal clearance of SOR presumably approximates the flow through intact and capillarized sinusoids (functional flow) and reflects the amount of blood having functional contact with hepatocytes. The theoretic background of the method, its accuracy, further research needs, and potentials of various approaches are discussed in detail.

Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model

Abstract The metabolism and enterohepatic circulation of chenodeoxycholic acid (CDC), a major primary bile acid in man, has been stimulated using a multicompartmental physiological pharmacokinetic model which was previously reported and used to simulate the metabolism of cholic acid. The model features compartments and linear transfer coefficients. Compartments, which are defined as the pools of single chemical species in well defined anatomical volumes, are aggregated into nine ‘spaces’ based on anatomical and physiological considerations (liver, gall‐bladder, bile ducts, duodeno‐jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). Each space contains several compartments which correspond to the compounds present in that space, for example, the compound in question and its biotransformation products. For CDC (as for cholic acid in the previous simulation) each space contains three compartments corresponding to the unconjugated bile acid, its glycine amidate, and its taurine amidate. Transfer coefficients, which denote the fractional amount of the compartments contents exiting per unit time, are categorized according to function: flow, for example gall‐bladder contraction (which involves transfer of all substances contained in the space at the same fractional rate); biotransformation (which transfers the substrate from one compartment to another within the same space); or transport (which denotes movements between contiguous compartments, belonging to different spaces across a diffusion membrane or a cellular barrier). The model is made time‐dependent by incorporating meals which trigger gall‐bladder emptying and modify intestinal flow. The transfer coefficients in the cholic acid model were modified for the CDC model since (a) there is indirect evidence that CDC amidates (probably chenodeoxycholylglycine) are absorbed from the duodeno‐jejunum and (b) the first pass hepatic clearance of CDC species differs from that of cholyl species. The model was then used with all existing experimental data to simulate CDC metabolism in healthy humans over a 24‐h period during which three meals were ingested. Satisfactory agreement was obtained between simulated and experimental data indicating that this model continues to be useful for describing the metabolism of bile acids and may also be of value for describing the metabolism of drugs whose metabolism is similar to that of bile acids.