[The register GiViTI about the use of the drug Xigris® in the Italian intensive care units]. / Il registro GiViTI sull'utilizzo del farmaco Xigris® nelle Terapie Intensive italiane.

INTRODUCTION: The Register was aimed at monitoring the use, possible side effects, and clinical effectiveness of Xigris® - drotrecogin alfa (activated) - for the treatment of severe sepsis in Italian intensive care units (ICUs). METHODS: Data collection was performed using an online web form or a specific electronic module of the software Margherita, available only for the ICUs adhering to the GiViTI. Drug purchase information available for each center was used to identify and stimulate collaboration of non-compliant centers. Several countermeasures were taken to have the largest participation. RESULTS: We analyzed data from 1001 patients treated in 161 ICUs between July 2003 and September 2007, corresponding to 70% of all the patients who received the drug in that period. The off-label use of the drug was frequent: 15.6% of cases before and 27.3% after the label change with the introduction of timing restrictions. Treatment was temporarily interrupted in 10%, and definitely stopped in 25% of cases, after the occurrence of adverse events, the most frequent being bleeding. Severe bleeding occurred in 3.8% of patients. Multivariable analysis, which allowed an adjusted comparison with a control group, showed that treatment increased mortality among elective-surgery patients (OR 2.79, 95%CI 1.31-5.97). DISCUSSION: The results of this study and other evidences led the European Medicines Agency (EMA) to require a confirmatory trial in 2007. In October 2011 Ely-Lilly, the producer of the drug, announced the worldwide withdrawal from the market of Xigris®, on the basis of the negative results of the confirmatory trial. CONCLUSIONS: The availability of purchase information is essential to carry out post-marketing drug surveillance studies, since it allows to identify and contact non-compliant centers. Actually, a representative sample of treated patients provides reliable information on the use, efficacy, and safety of the drug in daily clinical practice that could positively influence healthcare policies.

Use of Drotrecogin alfa (activated) in Italian intensive care units: the results of a nationwide survey.

OBJECTIVE: To monitor the use of drotrecogin alfa activated (DrotAA) in Italy and its effects on patients' health. DESIGN: Prospective pharmaco-surveillance program with a parallel non-randomized control group. SETTING: The Ministry of Health required all intensive care units (ICUs) using DrotAA to participate in the pharmaco-surveillance program. Our control group was formed of patients eligible for treatment with DrotAA but who had not received it. PATIENTS AND PARTICIPANTS: The data we collected included basic demographic characteristics, indications, modalities of use, adverse events, and ICU mortality. We identified potentially non-collaborating centres on the basis of data on DrotAA purchasing by hospitals. MEASUREMENTS AND RESULTS: From 2003 to 2006, 668 cases of treatment with DrotAA were reported. We estimate that 79.3% of all patients treated in Italy in this period were recruited. Off-label use was common. Delayed start was the main reason for off-label prescription. Bleeding during infusion occurred in 73 patients (10.9%). The ICU mortality was higher in patients with bleeding (57.5 vs. 44.9%; p=0.041). Crude ICU mortality was lower in patients receiving DrotAA than in controls (46.4 vs. 54.9%; p=0.0004); however, multivariate analysis, which adjusted for certain relevant differences, showed that DrotAA treatment was associated with higher mortality after scheduled surgery. CONCLUSIONS: These results question the way in which the drug is used in everyday clinical practice and its efficacy in a selected subgroup, and reinforce the need for a new, independent, confirmatory trial to reassess the risk-to-benefit ratio of DrotAA.

Radial artery remodeling in response to shear stress increase within arteriovenous fistula for hemodialysis access.

It is known that changes in blood flow induce vascular remodeling and that shear stress, the tractive force acting on the vessel wall due to blood flowing, influences endothelial cell function. The aim of the present study was to investigate the relation between changes in pulsatile shear forces and arterial remodeling in response to chronic elevation in blood flow within the radial artery. The authors studied vessel diameter, flow rate, and shear stress in the radial artery of uremic patients before and after surgical creation of a native arteriovenous fistula for hemodialysis access. For this purpose, the authors used echo-color-Doppler ultrasound to perform diameter and blood velocity measurements. Time-function blood flow rate and wall shear stress were calculated based on arterial diameter, center-line velocity wave-form, and blood viscosity, using a numerical method developed according to Womersley's theory for unsteady flow in tubes. The results confirmed that the radial artery diameter increases in response to a chronic increase in blood flow in uremic patients. Moreover, it seems that the radial artery dilates in such a way as to maintain the peak wall shear stress constant, suggesting that endothelial cells sense the maximum rather than the time-averaged wall shear stress. This finding may lead to further understanding of the mechanisms responsible for endothelial response to physical stimulation by flowing blood.

Radial artery wall shear stress evaluation in patients with arteriovenous fistula for hemodialysis access.

It has been extensively documented that changes in blood flow induce vascular remodeling and this phenomenon seems to be correlated to the shear forces imposed on the vessel wall by motion of blood. Wall shear stress, the tractive force that acts on the endothelium, has been shown to influence endothelial cell function. To study changes in wall shear stress that develop on the vessel wall upon changes of blood flow, we set up a technique that allows estimation of shear stress in the radial artery of patients on chronic hemodialysis therapy. The technique is based on color-flow Doppler examination of the radial artery before and after surgical creation of radiocephalic fistula for hemodialysis. Calculation of time function wall shear stress and blood flow rate in the radial artery is performed on the basis of arterial diameter, center-line velocity waveform and blood viscosity, using a numerical method developed according to Womersley's theory for pulsatile flow in tubes. The results presented confirm that the model developed is suitable for calculation of the wall shear stress that develops in the radial artery of patients before and after surgical creation of an arteriovenous fistula for hemodialysis. This methodology was developed for characterization of wall shear stress in the radial artery but may be well applied to other vessels that can be examined by echo-Doppler technique.

External validation of the Simplified Acute Physiology Score (SAPS) 3 in a cohort of 28,357 patients from 147 Italian intensive care units.

OBJECTIVE: To evaluate the SAPS 3 score predictive ability of hospital mortality in a large external validation cohort. DESIGN: Prospective observational study. SETTING AND PATIENTS: A total of 28,357 patients from 147 Italian ICUs joining the Project Margherita national database of the Gruppo italiano per la Valutazione degli interventi in Terapia Intensiva (GiViTI). INTERVENTIONS: None. MEASUREMENT: Evaluation of discrimination through ROC analysis and of overall goodness-of-fit through the Cox calibration test. MAIN RESULTS: Although discrimination was good, calibration turned out to be poor. The general and the South-Europe Mediterranean countries equations overestimated hospital mortality overall (SMR values 0.73 with 95% CI 0.72-0.75 for both equations) and homogeneously across risk classes. Overprediction was confirmed among important subgroups, with SMR values ranging between 0.47 and 0.82. CONCLUSIONS: The result strictly supported by our data is that the SAPS 3 score calibrates inadequately in a large sample of Italian ICU patients and thus should not be used for benchmarking, at least in Italian settings.

Geographical differences in mortality of severely injured patients in Italy.

BACKGROUND: In Italy there are no accepted standards for trauma care nor dedicated programs for quality assessment on a national scale, like trauma registries. At the same time there seems to be a north-south gradient in the quality of health care. We hypothesized that geographical inequalities of health-care quality may affect trauma mortality. METHODS: Retrospective comparison of hospital mortality by Cox regression in three main areas of Italy adjusted for age, Glasgow Coma Scale and source of admission. A leading national database on patients admitted to intensive care units (ICU) in the years 2002-2005 was used. 9162 adult trauma cases admitted to the ICU from the emergency department were included. RESULTS: There is a significant north-south gradient of risk. Compared to the north, the risk of death is about 60% higher in the south and about 30% higher in the central region. These figures are similar in both referral centres and other hospitals and both in the head-injured only and total injured cases. CONCLUSION: Despite the limitations of this study, mainly related to sampling issues, risk-adjustment and incomplete follow-up, the large geographic differences in mortality that we found highlight likely deficiencies in the quality of trauma care that deserve further accurate assessment.