Acquired von Willebrand disease--hemostatic management of major orthopedic surgery with high-dose immunoglobulin, desmopressin, and continuous factor concentrate infusion

Acquired von Willebrand disease (aVWD) is a rare bleeding disorder that mimics congenital VWD in previously healthy individuals; it is most frequently associated with monoclonal gammopathy. Hemostatic therapy of aVWD is challenging due to the extremely shortened half-life of endogenous and exogenous VWF. High-dose intravenous immunoglobulin (ivIG) is recommended as the treatment of choice, usually rapidly normalizing coagulation; but in case of failure, alternative treatment options are not well explored. We report successful major orthopedic surgery in a 61-year-old woman with multiple myeloma IgG lambda and aVWD. IvIG alone failed to correct hemostasis. However, ivIG pretreatment improved the VWF ristocetin cofactor (VWF:RCo) half-life from only 1.5 hr to more than 4 hr, allowing desmopressin infusions twice daily to maintain sufficient VWF:RCo levels. Because of diminishing desmopressin effect, we attempted for the first time in aVWD a continuous VWF/FVIII infusion (Haemate HS), 2.1-2.7 FVIII U/kg/hr or 51-64 U/kg/day, respectively 4.6-6.0 VWF:RCo U/kg/hr or 110-145 U/kg/day) to reach constant factor levels. The steady-state clearance was 2.4 mL/kg/hr for FVIII:C and 13.5 mL/kg/hr for VWF:RCo. During surgery, VWF:RCo, FVIII:C, and PFA-100 closure time were normalized. Until day 5, VWF:RCo was kept above 50%, from day 6 to 10 at least 30% activity were attained. FVIII:C levels were always >70%. The clinical course was uneventful without bleeding. Two weeks after hip surgery the patient was discharged from the hospital without complaints. The therapy described can be recommended as safe and feasible for further evaluation in aVWD patients who are hyporesponsive to ivIG treatment alone. Continuous VWF/FVIII infusion can improve substitution therapy in aVWD.     

Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia

OBJECTIVES: Systemic endotoxemia has been implicated in various pathophysiological sequelae of chronic liver disease. One of its potential causes is increased intestinal absorption of endotoxin. We therefore examined the association of small intestinal bacterial overgrowth with systemic endotoxemia in patients with cirrhosis. METHODS: Fifty-three consecutive patients with cirrhosis (Child-Pugh group A, 23; group B, 18; group C, 12) were included. Jejunal secretions were cultivated quantitatively and systemic endotoxemia determined by the chromogenic Limulus amoebocyte assay. Patients were followed up for 1 yr. RESULTS: Small intestinal bacterial overgrowth, defined as > or = 10(5) total colony forming units per milliliter of jejunal secretions, was present in 59% of patients and strongly associated with acid suppressive therapy. The mean plasma endotoxin level was 0.86 +/- 0.48 endotoxin units/ml (range = 0.03-1.44) and was significantly associated with small intestinal bacterial overgrowth (0.99 vs 0.60 endotoxin units/ml, p = 0.03). During the 1-yr follow-up, seven patients were lost to follow up or underwent liver transplantation and 12 patients died. Multivariate Cox regression showed Child-Pugh group to be the only predictor for survival. CONCLUSIONS: Small intestinal bacterial overgrowth in cirrhotic patients is common and associated with systemic endotoxemia. The clinical relevance of this association remains to be defined.     

A case of systemic mastocytosis associated with severe osteoporosis and pathologic fractures

We describe the case of a 56-year-old man with rapidly progressive osteoporosis culminating in pathologic fractures of multiple lumbar vertebrae. With the exception of discrete brown-reddish cutaneous lesions, low back pain was the only prominent symptom. Laboratory evaluations excluded metabolic or endocrinological abnormalities. Serum tryptase was highly increased, as was urinary excretion of histamine. Iliac crest biopsy demonstrated mastocytosis, which was confirmed by skin biopsy and which was consistent with teleangiectasia macularis eruptiva perstans, a rare form of cutaneous mastocytosis. In cases of unusually marked osteoporosis, especially in men, mastocytosis should be considered in the differential diagnosis.     

Screening for prostate cancer: updated experience from the tyrol study

The aim of the Tyrol study was to monitor the impact of screening in a natural experiment by comparing prostate cancer mortality in Tyrol, where prostate-specific antigen (PSA) testing was introduced at no charge, with the rest of Austria, where it was not strictly organized and not free of charge. In 1993, PSA testing was made freely available to men between the ages of 45 and 75 years in the Federal State of Tyrol, Austria. At least 70% of all of the men in this age range have been tested at least once during the first 10 years of the study. Initially, only total PSA was measured, but free PSA measurement was added in 1995. Since 2001, complexed PSA also has been measured. Digital rectal examination was not part of the screening examination. Significant migration to lower clinical and pathological stages has been observed since the introduction of this screening program. These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance by men in the population, is associated with a reduction in prostate cancer mortality in an area in which urology services and radiotherapy are available freely to all patients. It is our opinion that most of this decline is likely a result of aggressive downstaging and successful treatment and that any contribution from detecting and treating early cancers will become apparent in the years to come.     

Heterogenous haemodynamic effects of adaptive servoventilation therapy in sleeping patients with heart failure and Cheyne–Stokes respiration compared to healthy volunteers

This study investigated the haemodynamic effects of adaptive servoventilation (ASV) in heart failure (HF) patients with Cheyne–Stokes respiration (CSR) versus healthy controls. Twenty-seven HF patients with CSR and 15 volunteers were ventilated for 1 h using a new ASV device (PaceWave?). Haemodynamics were continuously and non-invasively recorded at baseline, during ASV and after ventilation. Prior to the actual study, a small validation study was performed to validate non-invasive measurement of Stroke volume index (SVI). Non-invasive measurement of SVI showed a marginal overall difference of ?0.03 ± 0.41 L/min/m² compared to the current gold standard (Thermodilution-based measurement). Stroke volume index (SVI) increased during ASV in HF patients (29.7 ± 5 to 30.4 ± 6 to 28.7 ± 5 mL/m², p < 0.05) and decreased slightly in volunteers (50.7 ± 12 to 48.6 ± 11 to 47.9 ± 12 mL/m²). Simultaneously, 1 h of ASV was associated with a trend towards an increase in parasympathetic nervous activity (PNA) in HF patients and a trend towards an increase in sympathetic nervous activity (SNA) in healthy volunteers. Blood pressure (BP) and total peripheral resistance response increased significantly in both groups, despite marked inter-individual variation. Effects were independent of vigilance. Predictors of increased SVI during ASV in HF patients included preserved right ventricular function, normal resting BP, non-ischaemic HF aetiology, mitral regurgitation and increased left ventricular filling pressures. This study confirms favourable haemodynamic effects of ASV in HF patients with CSR presenting with mitral regurgitation and/or increased left ventricular filling pressures, but also identified a number of new predictors. This might be mediated by a shift towards more parasympathetic nervous activity in those patients.     

Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis

In this randomized controlled multicenter trial, we compared endoscopic variceal banding ligation (VBL) with propranolol (PPL) for primary prophylaxis of variceal bleeding. One hundred fifty-two cirrhotic patients with 2 or more esophageal varices (diameter >5 mm) without prior bleeding were randomized to VBL (n = 75) or PPL (n = 77). The groups were well matched with respect to baseline characteristics (age 56 +/- 10 years, alcoholic etiology 51%, Child-Pugh score 7.2 +/- 1.8). The mean follow-up was 34 +/- 19 months. Data were analyzed on an intention-to-treat basis. Neither bleeding incidence nor mortality differed significantly between the 2 groups. Variceal bleeding occurred in 25% of the VBL group and in 29% of the PPL group. The actuarial risks of bleeding after 2 years were 20% (VBL) and 18% (PPL). Fatal bleeding was observed in 12% (VBL) and 10% (PPL). It was associated with the ligation procedure in 2 patients (2.6%). Overall mortality was 45% (VBL) and 43% (PPL) with the 2-year actuarial risks being 28% (VBL) and 22% (PPL). 25% of patients withdrew from PPL treatment, 16% due to side effects. In conclusion, VBL and PPL were similarly effective for primary prophylaxis of variceal bleeding. VBL should be offered to patients who are not candidates for long-term PPL treatment.     

Regulation of the somatotropic axis by intensive insulin therapy during protracted critical illness

The catabolic state of critical illness has been linked to the suppressed somatotropic GH-IGF-binding protein (IGFBP) axis. In critically ill patients it has been demonstrated that, compared with the conventional approach, which only recommended insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels below 6.1 mmol/liter with intensive insulin therapy almost halved intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections. Poor blood glucose control in diabetes mellitus has also been associated with low serum IGF-I levels, which can be increased by insulin therapy. We hypothesized that intensive insulin therapy would improve the IGF-I axis, possibly contributing to the clinical correlates of anabolism. Therefore, this study of 363 patients, requiring intensive care for more than 7 d and randomly assigned to either conventional or intensive insulin therapy, examines the effects of intensive insulin therapy on the somatotropic axis. Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The suppression of IGF-I in association with the increased GH levels suggests GH resistance induced by intensive insulin therapy, which was reflected by the decreased serum GH-binding protein levels. Intensive insulin therapy did not affect IGFBP-3 proteolysis, which was markedly higher in protracted critically ill patients compared with healthy controls. Also, intensive insulin therapy did not suppress the urea/creatinine ratio, a clinical correlate of catabolism. In conclusion, our data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive.     

Screening for Celiac Disease: A Prospective Study on the Value of Noninvasive Tests

Objective : Celiac disease is frequently diagnosed in patients with nonspecific ahdominal symptoms. Therefore, highly sensitive, specific, and simple noninvusive screening tests are needed. Methods : This study compared the usefulness of IgG- and IgA-antigliadin antibodies, IgA-endomysial antibodies, and intestinal permeability in diagnosing celiac disease in 102 adult patients with nonspecific ahdominal symptoms. In addition, all patients underwent small bowel biopsy as a gold standard for the diagnosis of celiac disease. Results : Forty-nine patients were ultimately diagnosed as having celiac disease because of flat mucosa. Flatulence and signs and symptoms dating back to childhood were more frequent and abdominal pain less frequent ( p < 0.05) in celiac disease but were not helpful for screening. IgA-endomysiul antibodies showed a sensitivity and specificity of 1(M)%; an altered intestinal permeability had also a 100% sensitivity, but only 55% specificity. IgG- and IgA-untigliadin antibodies' sensitivity (73% and 82%, respectively) and specificity (74% and 83%, respectively) were much lower. Combining the two antigliadiu antibodies did not significantly improve the sensitivity and specificity. Conclusion : Our data show the advantage of IgA-endomysial antibodies for screening of celiac disease except in the case of patients with IgA-deficiency or dermatitis herpetiformis. In these patients, the permeability test could improve noninvasive differential diagnosis.