Ineffective off-label use of recombinant activated factor VII in a case of bone-marrow transplantation-related gastrointestinal bleeding

BACKGROUND: For patients with a normal coagulation system, who experience serious bleeding, sound evidence for recombinant activated factor VII (rFVIIa) as an effective haemostatic agent is only scarcely available so far from controlled clinical trials. In systematic reviews on the clinical use of rFVIIa, treatment failures were only rarely reported. CASE PRESENTATION: We present a 45-year old, Caucasian male with persistent intestinal bleeding due to enterocolitis associated with cytomegalovirus infection and acute graft-versus-host-disease. He had received allogeneic peripheral blood stem cell transplantation from an unrelated HLA-identical donor because of chronic myelogenous leukaemia diagnosed two years earlier. Bleeding started at day 18 after transplantation with bloody diarrhea, which was treated with multiple transfusions of fresh frozen plasma, platelet, and red blood cell concentrates, and continued relentlessly, despite all efforts, including continued transfusions, high-dose prednisolone, broad antibiotic and antiviral coverage, and tranexamic acid. Recombinant FVIIa was started at boluses of 90–120 μg/kg every 4–8 hours. Despite more than 10 doses, recurrent severe bleeding progressed to refractory shock, multiorgan failure and death. CONCLUSIONS: Little can be concluded from single case reports of clinical improvement, because publication bias in favour of positive effects is likely. Our case suggests that rFVIIa is not a panacea, in particular for severe bleeding after bone-marrow transplantation. As long as rigorous, controlled studies or comprehensive registries are lacking, conventional interventions remain the standard of care in non-haemophilic patients with severe bleeding

A meta-analysis of controlled trials of recombinant human activated protein C therapy in patients with sepsis

BACKGROUND: Meta-analysis of two randomised controlled trials in severe sepsis performed with recombinant human activated protein C may provide further insight as to the therapeutic utility of targeting the clotting cascade in this syndrome. METHODS: In search for relevant studies published, two randomized clinical trials were found eligible. RESULTS: The studies, PROWESS and ADDRESS, enrolled a total of 4329 patients with risk ratio (RR) and 95% confidence interval (CI) data for effect on 28-day mortality relative to control treatment of 0.92 (0.83–1.02) suggesting that recombinant human activated protein C is not beneficial in severe sepsis. In PROWESS, 873 of 1690 patients presented with low risk, and 2315 of 2639 patients in ADDRESS as defined by APACHE II score < 25. In this low-risk stratum, no effect of recombinant human activated protein C administration on 28-day mortality was observed. This observation appears to be consistent and homogenous. Heterogeneity between the two studies, however, was seen in patients with APACHE II score ≥ 25 in whom recombinant activated protein C was effective in PROWESS (n = 817; RR 0.71, CI 0.59–0.85) whereas a tendency toward harm was present in ADDRESS (n = 324; RR 1.21, CI 0.85–1.74). Even though the overall treatment effect in this high-risk population was still in favour of treatment with recombinant activated protein C (n = 1141; RR 0.80, CI 0.68–0.94), the observed heterogeneity suggests that the efficacy of recombinant human activated protein C is not robust. Not unlikely, the adverse tendency observed could have become significant with higher statistical power would ADDRESS not have been terminated prematurely. CONCLUSION: This meta-analysis, therefore, raises doubts about the clinical usefulness of recombinant activated protein C in patients with severe sepsis and an APACHE II score ≥ 25 which can only be resolved by another properly designed clinical trial

Nosocomial diarrhoea in adult medical patients: the role of Clostridium difficile in a North Italian acute care teaching hospital

Background. The number of patients with severe Clostrid- ium difficile-associated diarrhoea (CDAD) increases. Health care facilities are requested to establish rates of nosocomially acquired CDAD (N-CDAD) to understand the impact of control or prevention measures, and the burden of N-CDAD on health care resources. Objective. Aim of the single-center surveillance project was to establish local prevalence rates of N-CDAD in adult acute care medical patients. Methods. For a period of at least one year, all diarrhoeal stools from inpatients of a general internal medicine ward were tested for Clostridium difficile toxin A. Case record files were retrospectively analysed and questionnaires were completed for patients with positive stool assays who met the case definitions. Results and discussion. During the surveillance period, 2,610 medical patients had been acutely hospitalized. Stools had been submitted to the hospital laboratory from 163 patients (6.2%) because of diarrhoea and were screened for Clostridium difficile cytotoxin. Complete data sets were available for analysis from 150 patients. Of 137 identified potential cases, 77 (56.2%) met the case definitions for nosocomial diarrhoea. Thirteen of the patients with nosocomial diarrhoea (16.9%) were detected positive by the Clostridium difficile toxin A assay. The overall prevalence of N-CDAD among inpatients was 8.7 cases/100 diarrhoeal stools. The mean number of N-CDAD cases was 62.3 cases/100,000 patient days and 5 cases/1,000 patient admissions. The mean age of N-CDAD patients was 79.4 years (range 71 to 92). All patients were given broad-spectrum antibiotics before acute diarrhoea developed. Four patients died for reasons not directly related to N-CDAD which confirms increased disease severity as an important risk factor . Conclusions. This single-center surveillance project, which established N-CDAD rates at frequencies currently reported from international surveys, is useful as benchmark and will help in understanding patterns and impact of N-CDAD at the regional level