Influence of regulatory measures on the rate of spontaneous adverse drug reaction reporting in Italy.

BACKGROUND: The reporting of adverse drug reactions (ADRs) is the mainstay of post-marketing surveillance systems. Under-reporting and selective reporting are considered the main limitations of a spontaneous reporting-based pharmacovigilance system. However, excessive reporting induced by external events may also impair signal detection by increasing the noise level. OBJECTIVE: The aim of this study was to examine the influence of regulatory measures and other external factors on the rate of ADR reporting in Italy, focusing on four situations occurring in the last 10 years: ACE inhibitor-induced cough; HMG-CoA reductase inhibitors ('statins') and rhabdomyolysis; nimesulide and hepatic toxicity; and cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') and increase in cardiovascular risk. METHODS: The study was based on data from spontaneous reporting in six Italian regions collected from January 1995 to December 2005. We analysed a 10-year period as a reasonable time interval around the four situations of interest, highlighting the influence of regulatory measures on the rate of ADR reporting (number of reports per million inhabitants). Chi-squared tests were used to assess the statistical significance of any changes in ADR reporting. Drug sales data were also studied to examine possible changes in drug use. Sales data were expressed as daily defined dose per 1000 inhabitants per day. RESULTS: ACE inhibitors: a 5-fold increase in the reporting rate of ACE inhibitor-induced cough was observed in 1998 and 1999 following a restriction on reimbursement for angiotensin receptor blockers introduced in 1998 and removed at the end of 1999. Statins: after the withdrawal of cerivastatin in 2001, the ADR reporting rate increased more than 4-fold, with musculoskeletal ADRs representing about 60% of all the ADRs reported in that year, and progressively decreased in the following years. Nimesulide: an increase in hepatic ADR reporting was observed after withdrawal of the drug from the Finnish and Spanish markets in 2002. Coxibs: no important changes in the rate of cardiovascular events reporting in the period 2000-4 were observed. In 2005, after the withdrawal of rofecoxib in September 2004, both the ADR reporting rate and sales of the drug decreased drastically. CONCLUSION: Our data suggest that spontaneous ADR reporting can be influenced in different ways by external events. Our data emphasize the need for educational initiatives aimed at increasing the doctor's and patient's awareness of the usefulness and the limitations of spontaneous reporting in the pharmacovigilance system. Such initiatives should use appropriate risk communication strategies in order to avoid unnecessary alarm, which could cause unjustified interruption of therapies or misplaced confidence in new drugs.     

No evidence of hematopoietic stem cell mobilization in patients submitted to hepatectomy or in patients with acute on chronic liver failure

BACKGROUND: Liver regeneration is a heterogeneous phenomenon involving the proliferation of different cell lineages in response to injury. Under a strong positive selection pressure bone marrow derived stem cells may be involved in this process, by making a contribution to both parenchymal restoration and endothelial cell replacement. We investigate bone marrow stem cell migration to the liver in patients undergoing hepatectomy or with acute on chronic liver failure. METHODS: We enrolled 6 patients submitted to hepatectomy, 6 patients to cholecystectomy and 8 patients with acute decompensation of liver cirrhosis. Mobilization of CD34+ cells was evaluated by cytofluorimetry on peripheral blood samples at different time points; baseline, 1, 3, 7, 15 and 30 days after surgery and at admission, 1, 7 and discharge among patients with acute on chronic liver failure. 10 healthy subjects undergoing blood donation were also enrolled to evaluated the basal value of CD34+ cells. RESULTS: White blood cell counts remained in the normal range (4.1-9.8 x 10(9)/L) in all groups throughout the follow-up. In all patients of Groups 1, 2 and 3, circulating CD34+ failed to show statistically significant differences both as the absolute number and as the percentage at any time point compared to healthy controls. CONCLUSIONS: Bone marrow derived cell mobilization can not be detected after hepatectomy or during an acute decompensation on a cirrhotic liver. Under these circumstances liver regeneration can probably call upon mature hepatocytes and endogenous progenitor cells. The involvement of extrahepatic progenitors if any, is a rare and limited phenomenon.     

Predictive perioperative factors for developing severe sepsis after major surgery

Background. Early identification of high-risk patients undergoingmajor surgery can result in an aggressive management affectingthe outcome. Methods. We designed a prospective cohort study of 93 adultpatients undergoing major oncological surgery to identify thepredictive risk factors for developing postoperative severesepsis. Results. Nineteen of 93 patients developed a severe sepsis aftersurgery; seven of the septic patients died in intensive careunit. Multivariate analysis discriminated preoperative and postoperative(first and second day after surgery) predictive risk factors.The postoperative severe sepsis was independently associatedwith preoperative factors like male gender (OR 4.7, 95% CI between1.5 and 15.5, P<0.01) and Charlson co-morbidity index (OR1.3, 95% CI between 1.07 and 1.6, P<0.01). After the surgery,the presence of systemic inflammatory response syndrome (OR4.0, 95% CI between 1.02 and 15.7, P<0.05) and a logisticorgan dysfunction score on day 2 (OR 3.3, 95% CI between 1.9and 5.7, P<0.001) were found as independent predictive factors. Conclusion. We have shown that some of the markers that canbe easily collected in the preoperative or postoperative visitscan be used to screen the patients at high risk for developingsevere sepsis after major surgery.     

Selective digestive decontamination: the light as changed from red to green

OBJECTIVES: To study the efficacy of selective digestive decontamination (SDD) for the prevention of nosocomial infections, particularly pneumonia, as well as its impact on the emergence of multiresistant bacteria. DATA SOURCES: Data collected from the Pubmed: original articles, review articles and editorial published on SDD. The keywords were: selective digestive decontamination, pneumonia, intensive care unit, infection. DATA SELECTION: Ten randomized clinical trials performed since 1995 in mechanically ventilated adult patients hospitalized in intensive care unit. RESULTS: The rationale for the use of SDD consists on the parenteral administration of a short course of antibiotic associated with the topical use of non-absorbable antibiotics directed against Gram negative bacteria. Five randomized studies described a reduction in the incidence of pneumonia associated with SDD. Only one study has showed a decrease in mortality rate. The other five studies, which present some methodological limitations, concluded the lack of efficacy of SDD. Regarding the emergence of multiresistant bacteria, the literature underlines the role of environment. The use of SDD seems to trigger the resistance in endemic areas, while these are softened in the units with a good control of their ecology. CONCLUSION: The data from the literature provide arguments to use SDD in targeted patient populations like multiple traumas in intensive care units, which have a low rate of multiresistant bacteria.     

Split onlay skin flap for the salvage hypospadias repair

PURPOSE: Following failed hypospadias repair absence of the penile foreskin, a shortage of ventral skin and residual chordee may all contribute to poor long-term results. We describe a technique called the split onlay skin (SOS) flap that has improved our surgical outcomes in boys requiring salvage hypospadias repair. MATERIALS AND METHODS: The SOS flap uses a transverse island of penile shaft skin that is mobilized on its vascular pedicle and rotated into position to the ventrum of the penis at the site of the urethral defect. The flap is transected transversely, and half of the flap is used as an onlay to repair the urethra and the other half is used for additional skin coverage where needed on the penile shaft. We treated 11 boys 30 to 124 months old (mean age 60.3 months) who had a mean of 2 previous failed hypospadias repairs. All 11 boys presented with complex combinations of urethrocutaneous fistulas, stricture or urethral diverticula. RESULTS: Of the 11 patients 6 (54.5%) had development of postoperative fistulas. Five of these fistulas were surgically closed with no further complications. One penoscrotal fistula closed spontaneously after 7 months. Mild chordee from contraction of the flap and a urethral diverticulum developed in 1 boy. At a mean followup of 24.5 months all patients, including those who underwent closure of the secondary fistula, were voiding well with excellent appearance. CONCLUSIONS: In cases where little local tissue is present the SOS flap procedure is an excellent way to transfer healthy dorsal tissue to the ventrum for an onlay salvage urethroplasty while providing additional coverage of the urethral defect and a tension-free skin closure. Despite the high fistula rate we encountered following the initial SOS procedure, we endorse this technique because the transferred dartos provides additional tissue, which facilitates subsequent fistula repair. These boys can achieve a successful cosmetic result without incorporation of scrotal tissue or a free graft, which we believe leads to more predictable results.     

Magnesium and intrauterine growth restriction

BACKGROUND: The presence of intrauterine growth restriction (IUGR), could potentially lead to imbalances of Mg homeostasis, which have not yet been fully clarified. OBJECTIVE: To describe, in term newborn (NB) without IUGR, ionized magnesium (iMg) and total magnesium (TMg) concentrations in umbilical cord blood, on the third and seventh days of life and to compare these values with those of term NB with IUGR. METHODS: A prospective study was performed on 70 term NB divided into two groups: Group I-30 NB without IUGR and Group II-40 NB with IUGR. TMg concentrations were determined in sera by a classical colorimetric end point method (Cobas-Mira, Roche), and iMg was determined in whole blood by means of the Stat Profile-M analyzer (NOVA Biomedical). RESULTS: We found that in term NB without IUGR, TMg concentrations increased during the first week of life and were lower than those of NB with IUGR in cord blood (p < 0.05). NB without IUGR had decreased iMg concentrations in comparison to NB with IUGR in all sampling times, i.e., cord blood, third and seventh days of life (p < 0.001). iMg concentrations remained unchanged during the study period. We also found that all NB enrolled in the study presented with low iMg concentrations (reference interval 0.4-0.6 mmol/L). CONCLUSION: The presence of IUGR may influence neonatal levels of magnesium, suggesting an effect on the modulation of this ion homeostasis, during the perinatal period.     

Discontinuation of risperidone and reversibility of weight gain in children with disruptive behavior disorders

Although atypical antipsychotics generally have a good side effect profile and are clinically very effective, weight gain and associated problems accompany their use. The authors followed up 14 subjects who were in studies of risperidone for management of disruptive behavior disorders. The subjects exited after a mean exposure of 8.9 months because of excessive weight gain, or excessive appetite, or insufficient clinical response. Weight was monitored for the full cohort before risperidone treatment, at termination, and (for various subgroups) at 3, 9-12, and 24 months after termination. Analysis of standardized weight scores in relation to standardized BMI scores suggested marked similarity between them at all time points. Comparison of standardized weights at time of drug termination with 3, 9-12, and 24 months after termination indicated that weight gain during risperidone treatment is reversible (i.e., significantly less weight after risperidone was discontinued) at all time points after termination. Furthermore, standardized weight at 12 and 24 months after discontinuation of risperidone was not distinguishable from standardized weight before risperidone. The prospect of reversibility may provide some comfort for clinicians and parents alike, but far more data are needed before an assumption can be made that this is the case for all children. The authors provide several recommendations for clinicians and researchers working with atypical antipsychotics.     

Hepatobiliary cystadenoma: diagnostic uncertainty

Background

Hepatobiliary cystadenoma is a rare tumour that can be clinically ‘silent’ and only discovered as an incidental finding on ultrasonography (US). It can also be symptomatic with abdominal pain and jaundice or develop internal bleeding and (exceptionally) malignant degeneration. Therefore the treatment of choice is liver resection.

Case outline

A 77-year-old woman was admitted with mild jaundice and right hypochondrial pain. For 7 years she had been known to have a silent liver lesion, always considered to be a simple cyst on US. US and CT scan revealed a multi-septate mass involving segments IV, V and VIII of the liver, with thick walls, no calcifications and no contrast enhancement. US-guided aspiration showed the presence of old blood-stained material. The patient was operated with a suspected diagnosis of bleeding into a simple cyst. A Lin fenestration was performed with wide excision of the anterior wall of the cyst. Pathological examination demonstrated a mucinous hepatobiliary cystadenoma. The postoperative course was uneventful, and follow-up at 2 years confirmed no recurrence.

Discussion

Imaging will normally help to distinguish the occasional hepatobiliary cystadenoma from the common simple cyst. Otherwise, when a complication occurs, preoperative differentiation may become impossible, and requires histological examination of the cyst after surgical removal.