Paolo Feltracco

Hepatocyte transplantation as a treatment for glycogen storage disease type 1a

Treatment of many inherited disorders of hepatic metabolism is still challenging. Hepatocyte transplantation was done in a 47-year-old woman who had glycogen storage disease type 1a and severe fasting hypoglycaemia. 2 billion viable hepatocytes were infused via an indwelling portal-vein catheter, followed by a triple immunosuppression regimen with mycophenolate mofetil, tacrolimus, and steroids. 9 months after transplantation, on only tacrolimus, she eats a normal diet and can fast for 7 h without experiencing hypoglycaemia. Our results show that hepatocyte transplantation might be an alternative to liver transplantation in glycogen storage disease type 1a.

Randomized Evidence for Reduction of Perioperative Mortality

OBJECTIVE With more than 220 million major surgical procedures performed annually, perioperative interventions leading to even minor mortality reductions would save thousands of lives per year. This international consensus conference aimed to identify all nonsurgical interventions that increase or reduce perioperative mortality as suggested by randomized evidence. DESIGN AND SETTING A web-based international consensus conference. PARTICIPANTS More than 1,000 physicians from 77 countries participated in this web-based consensus conference. INTERVENTIONS Systematic literature searches (MEDLINE/PubMed, June 8, 2011) were used to identify the papers with a statistically significant effect on mortality together with contacts with experts. Interventions were considered eligible for evaluation if they (1) were published in peer-reviewed journals, (2) dealt with a nonsurgical intervention (drug/technique/strategy) in adult patients undergoing surgery, and (3) provided a statistically significant mortality increase or reduction as suggested by a randomized trial or meta-analysis of randomized trials. MEASUREMENTS AND MAIN RESULTS Fourteen interventions that might change perioperative mortality in adult surgery were identified. Interventions that might reduce mortality include chlorhexidine oral rinse, clonidine, insulin, intra-aortic balloon pump, leukodepletion, levosimendan, neuraxial anesthesia, noninvasive respiratory support, hemodynamic optimization, oxygen, selective decontamination of the digestive tract, and volatile anesthetics. In contrast, aprotinin and extended-release metoprolol might increase mortality. CONCLUSIONS Future research and health care funding should be directed toward studying and evaluating these interventions.

Mortality in multicenter critical care trials: An analysis of interventions with a significant effect

Objectives:We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians’ opinion and usual practice for the selected interventions. Data Sources:MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references. Study Selection:We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility. Data Extraction:For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up. Data Synthesis:We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions. Conclusions:We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied.

Reducing Mortality in Acute Kidney Injury Patients: Systematic Review and International Web-Based Survey

OBJECTIVE To identify all interventions that increase or reduce mortality in patients with acute kidney injury (AKI) and to establish the agreement between stated beliefs and actual practice in this setting. DESIGN AND SETTING Systematic literature review and international web-based survey. PARTICIPANTS More than 300 physicians from 62 countries. INTERVENTIONS Several databases, including MEDLINE/PubMed, were searched with no time limits (updated February 14, 2012) to identify all the drugs/techniques/strategies that fulfilled all the following criteria: (a) published in a peer-reviewed journal, (b) dealing with critically ill adult patients with or at risk for acute kidney injury, and (c) reporting a statistically significant reduction or increase in mortality. MEASUREMENTS AND MAIN RESULTS Of the 18 identified interventions, 15 reduced mortality and 3 increased mortality. Perioperative hemodynamic optimization, albumin in cirrhotic patients, terlipressin for hepatorenal syndrome type 1, human immunoglobulin, peri-angiography hemofiltration, fenoldopam, plasma exchange in multiple-myeloma-associated AKI, increased intensity of renal replacement therapy (RRT), CVVH in severely burned patients, vasopressin in septic shock, furosemide by continuous infusion, citrate in continuous RRT, N-acetylcysteine, continuous and early RRT might reduce mortality in critically ill patients with or at risk for AKI; positive fluid balance, hydroxyethyl starch and loop diuretics might increase mortality in critically ill patients with or at risk for AKI. Web-based opinion differed from consensus opinion for 30% of interventions and self-reported practice for 3 interventions. CONCLUSION The authors identified all interventions with at least 1 study suggesting a significant effect on mortality in patients with or at risk of AKI and found that there is discordance between participant stated beliefs and actual practice regarding these topics.

Intraportal hepatocyte transplantation in the pig: a hemodynamic and histopathological study1

Background. Hepatocyte transplantation is an attractive treatment for various liver diseases. The intraportal route of transplantation is favored, but little information is available on the possible adverse effects in this technique. We investigated the influence of intraportal loads of hepatocytes on portal, pulmonary, and systemic hemodynamics in 13 pigs. Methods. Under general anesthesia, pigs were provided with an arterial line, a Swan-Ganz catheter, and two intraportal catheters, one for cell infusion and one for heparin infusion and portal pressure measurement. Pig hepatocytes were infused at a rate of 25 million cells/min. Results. The first six animals were used to develop the infusion technique. In the last seven animals, portal pressure increased linearly with cell load upon infusion of 400–2400×106 hepatocytes (r2=0.704;P <0.05). Portal flow measured by Doppler sonography decreased by 23–66% below basal values. An inverse linear relationship was found between portal pressure and portal flow (r2=0.679;P <0.05), portal flow approaching zero for portal pressure >40 mmHg. Pulmonary arterial pressure increased by 11–62%. AST increased up to 10-fold, and platelets decreased by 22–58%. Hepatocytes-containing thrombi were present in segmental and in smaller portal branches. Hepatocytes were always identified in lung sinusoids 48 hr after infusion, and a small basal pulmonary infarction was found in one animal. Conclusions. These data suggest that up to 2.4% of total hepatocyte mass can be infused in this large animal model. However, the risk of significant thrombotic complications should be considered for clinical applications.

Validation of the BCLC Prognostic System in Surgical Hepatocellular Cancer Patients

BACKGROUND/AIM Prognosis assessment in surgical patients with hepatocellular carcinoma (HCC) remains controversial. The most widely used HCC prognostic tool is the Barcelona Clinic Liver Cancer (BCLC) classification, but its prognostic ability in surgical patients has not been yet validated. The aim of this study was to investigate the value of known prognostic systems in 400 Italian HCC patients treated with radical surgical therapies. METHODS We analyzed a prospective database collection (400 surgical, 315 nonsurgical patients) observed at a single institution from 2000 and 2007. By using survival times as the only outcome measure (Kaplan-Meier method and Cox regression), the performance of the BCLC classification was compared with that of Okuda, Cancer of the Liver Italian Program, United Network for Organ sharing TNM, and Japan Integrated Staging Score staging systems. RESULTS Two hundred twenty-five patients underwent laparotomy resection; 55, laparoscopic procedures (ablation and/or resection); and 120, liver transplantations. In the surgical group, BCLC proved the best HCC prognostic system. Three-year survival rates of patients in BCLC Stages A, B, and C were 81%, 56%, and 44% respectively, (P < .01); whereas all other tested staging systems did not show significant stratification ability. When all 715 HCC patients were considered, surgery proved to be a significant survival predictor in each BCLC stage (A, B, and C). CONCLUSIONS BCLC staging showed the best interpretation of the survival distribution in a surgical HCC population. The BCLC treatment algorithm should consider the role of surgery also for intermediate-advanced stages of liver disease.

Continuous right ventricular end diastolic volume and right ventricular ejection fraction during liver transplantation: A multicenter study†

Cardiac preload is traditionally considered to be represented by its filling pressures, but more recently, estimations of end diastolic volume of the left or right ventricle have been shown to better reflect preload. One method of determining volumes is the evaluation of the continuous right ventricular end diastolic volume index (cRVEDVI) on the basis of the cardiac output thermodilution technique. Because preload and myocardial contractility are the main factors determining cardiac output during liver transplantation (LTx), accurate determination of preload is important. Thus, monitoring of cRVEDVI and cRVEF should help with fluid management and with the assessment of the need for inotropic and vasoactive agents. In this multicenter study, we looked for possible relationships between the stroke volume index (SVI) and cRVEDVI, cRVEF, and filling pressures at 4 predefined steps in 244 patients undergoing LTx. Univariate and multivariate autoregression models (across phases of the surgical procedure) were fitted to assess the possible association between SVI and cRVEDVI, pulmonary artery occlusion pressure (PAOP), and central venous pressure (CVP) after adjustment for cRVEF (categorized as ≤30, 31–40, and >40%). SVI was strongly associated with both cRVEDVI and cRVEF. The model showing the best fit to the data was that including cRVEDVI. Even after adjustment for cRVEF, there was a statistically significant (P < 0.05) relationship between SVI and cRVEDVI with a regression coefficient (slope of the regression line) of 0.25; this meant that an increase in cRVEDVI of 1 mL m−2 resulted in an increase in SVI of 0.25 mL m−2. The correlations between SVI and CVP and PAOP were less strong. We conclude that cRVEDVI reflected preload better than CVP and PAOP. Liver Transpl 14:327–332, 2008.

Morbidity, mortality, and survival after bronchoplastic procedures for lung cancer.

OBJECTIVE Bronchoplastic procedures represent an effective surgical therapy for benign lesions, tumors of low-grade malignancy and also bronchogenic carcinoma in patients with a limited pulmonary function. We analyzed our experience in order to verify the mortality, morbidity, and long term survival in our patients. METHODS From 1980 to 1994, 217 patients underwent bronchoplastic procedures. We performed 92 bronchoplasties, 94 bronchial sleeves, and 31 tracheo-bronchial sleeves. Histologic examination revealed 133 epidermoid carcinomas, 28 adenocarcinomas, 11 small cells lung cancers, 5 large cells carcinomas, 2 adenosquamous carcinomas, 29 bronchial carcinoids, 6 adenoidocistic carcinomas, and 3 mucoepidermoid tumors. Regarding nodal status, 99 patients had N0 disease, 64 patients had N1 disease, and 54 patients had N2 disease. Thirty-six patients had preoperative irradiation and 181 patients had no preoperative irradiation. In 63 patients we used a perianastomotic pedicled flap; in 154 we did not use it. We considered all the 217 patients for the analysis of 30-day mortality and morbidity; of the 217 patients we analyzed long-term survival only in 179 because we excluded 38 patients with low grade malignant neoplasm. RESULTS Twenty-seven patients (12.5%) had postoperative complications. The 30-day mortality was 6.2% (14 patients). Survival at 5 and 10 years for all patients but those with low grade malignant neoplasm was 49 and 38%, respectively. For patients with N0 status 5- and 10-year survival was 72.4 and 59.4%; for patients with N1 status these rates were 35.7 and 26.8%; for patients with N2 status, 5- and 10-year survival was 22 and 14.4%. Postoperative complication rates for patients with or without pedicled flap are not significantly different; however, the rates for patients with or without preoperative irradiation are significantly different. CONCLUSIONS Bronchoplastic procedures are a safe and effective therapy for selected patients with pulmonary malignancy. Tracheo-bronchial sleeves are associated with high postoperative mortality and complication rates and these procedures should be limited to patients without N2 disease. Preoperative irradiation increases significantly the mortality and morbidity. A multivariate analysis shows that only the nodal status affects long-term survival (P = 0.0002).

Perioperative thrombotic complications in liver transplantation

Although the perioperative bleeding complications and the major side effects of blood transfusion have always been the primary concern in liver transplantation (OLT), the possible cohesion of an underestimated intrinsic hypercoagulative state during and after the transplant procedure may pose a major threat to both patient and graft survival. Thromboembolism during OLT is characterized not only by a complex aetiology, but also by unpredictable onset and evolution of the disease. The initiation of a procoagulant process may be triggered by various factors, such as inflammation, venous stasis, ischemia-reperfusion injury, vascular clamping, anatomical and technical abnormalities, genetic factors, deficiency of profibrinolytic activity, and platelet activation. The involvement of the arterial system, intracardiac thrombosis, pulmonary emboli, portal vein thrombosis, and deep vein thrombosis, are among the most serious thrombotic events in the perioperative period. The rapid detection of occlusive vascular events is of paramount importance as it heavily influences the prognosis, particularly when these events occur intraoperatively or early after OLT. Regardless of the lack of studies and guidelines on anticoagulant prophylaxis in this setting, many institutions recommend such an approach especially in the subset of patients at high risk. However, the decision of when, how and in what doses to use the various chemical anticoagulants is still a difficult task, since there is no common consensus, even for high-risk cases. The risk of postoperative thromboembolism causing severe hemodynamic events, or even loss of graft function, must be weighed and compared with the risk of an important bleeding. In this article we briefly review the risk factors and the possible predictors of major thrombotic complications occurring in the perioperative period, as well as their incidence and clinical features. Moreover, the indications to pharmacological prophylaxis and the current treatment strategies are also summarized.

Dexmedetomidine as a Sedative Agent in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials

Introduction The effect of dexmedetomidine on length of intensive care unit (ICU) stay and time to extubation is still unclear. Materials and Methods Pertinent studies were independently searched in BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials (updated February first 2013). Randomized studies (dexmedetomidine versus any comparator) were included if including patients mechanically ventilated in an intensive care unit (ICU). Co-primary endpoints were the length of ICU stay (days) and time to extubation (hours). Secondary endpoint was mortality rate at the longest follow-up available. Results The 27 included manuscripts (28 trials) randomized 3,648 patients (1,870 to dexmedetomidine and 1,778 to control). Overall analysis showed that the use of dexmedetomidine was associated with a significant reduction in length of ICU stay (weighted mean difference (WMD) = −0.79 [−1.17 to −0.40] days, p for effect <0.001) and of time to extubation (WMD = −2.74 [−3.80 to −1.65] hours, p for effect <0.001). Mortality was not different between dexmedetomidine and controls (risk ratio = 1.00 [0.84 to 1.21], p for effect = 0.9). High heterogeneity between included studies was found. Conclusions This meta-analysis of randomized controlled studies suggests that dexmedetomidine could help to reduce ICU stay and time to extubation, in critically ill patients even if high heterogeneity between studies might confound the interpretation of these results.