Hydrocortisone therapy for patients with septic shock

Background Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin. Methods In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. Results Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. Conclusions Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004 [ClinicalTrials.gov] .)Peer reviewedPublisher PD

Malignant neuroendocrine tumour of the appendix in childhood with loco-regional lymph node invasion

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1006600359152743 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13000-015-0287-z) contains supplementary material, which is available to authorized users

Neither a Nitric Oxide Donor Nor Potassium Channel Blockage Inhibit RBC Mechanical Damage Induced by a Roller Pump

Red blood cells (RBC) are exposed to various levels of shear stresses when they are exposed to artificial flow environments, such as extracorporeal flow circuits and hemodialysis equipment. This mechanical trauma affects RBC and the resulting effect is determined by the magnitude of shear forces and exposure time. It has been previously demonstrated that nitric oxide (NO) donors and potassium channel blockers could prevent the sub-hemolytic damage to RBC, when they are exposed to 120 Pa shear stress in a Couette shearing system. This study aimed at testing the effectiveness of NO donor sodium nitroprussid (SNP, 10-4 M) and non-specific potassium channel blocker tetraethylammonium (TEA, 10-7 M) in preventing the mechanical damage to RBC in a simple flow system including a roller pump and a glass capillary of 0.12 cm diameter. RBC suspensions were pumped through the capillary by the roller pump at a flow rate that maintains 200 mmHg hydrostatic pressure at the entrance of the capillary. An aliquot of 10 ml of RBC suspension of 0.4 L/L hematocrit was re-circulated through the capillary for 30 minutes. Plasma hemoglobin concentrations were found to be significantly increased (~7 folds compared to control aliquot which was not pumped through the system) and neither SNP nor TEA prevented this hemolysis. Alternatively, RBC deformability assessed by laser diffraction ektacytometry was not altered after 30 min of pumping and both SNP and TEA had no effect on this parameter. The results of this study indicated that, in contrast with the findings in RBC exposed to a well-defined magnitude of shear stress in a Couette shearing system, the mechanical damage induced by a roller pump could not be prevented by NO donor or potassium channel blocker

Vascular Endothelial Dysfunction in β-Thalassemia Occurs Despite Increased eNOS Expression and Preserved Vascular Smooth Muscle Cell Reactivity to NO

The hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments.Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside) produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO). While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS) in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall.A complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression

Corticosteroids for severe sepsis: an evidence-based guide for physicians

Septic shock is characterized by uncontrolled systemic inflammation that contributes to the progression of organ failures and eventually death. There is now ample evidence that the inability of the host to mount an appropriate hypothalamic-pituitary and adrenal axis response plays a major in overwhelming systemic inflammation during infections. Proinflammatory mediators released in the inflamed sites oppose to the anti-inflammatory response, an effect that may be reversed by exogenous corticosteroids. With sepsis, via nongenomic and genomic effects, corticosteroids restore cardiovascular homeostasis, terminate systemic and tissue inflammation, restore organ function, and prevent death. These effects of corticosteroids have been consistently found in animal studies and in most recent frequentist and Bayesian meta-analyses. Corticosteroids should be initiated only in patients with sepsis who require 0.5 μg/kg per minute or more of norepinephrine and should be continued for 5 to 7 days except in patients with poor hemodynamic response after 2 days of corticosteroids and with a cortisol increment of more than 250 nmol/L after a standard adrenocorticotropin hormone (ACTH) test. Hydrocortisone should be given at a daily dose of 200 mg and preferably combined to enteral fludrocortisone at a dose of 50 μg. Blood glucose levels should be kept below 150 mg/dL

Outcome reporting in randomised controlled trials and meta-analyses of appendicitis treatments in children: a systematic review

Background: Acute appendicitis is the most common surgical emergency in children. Despite this, there is no core outcome set (COS) described for randomised controlled trials (RCTs) in children with appendicitis and hence no consensus regarding outcome selection, definition and reporting. We aimed to identify outcomes currently reported in studies of paediatric appendicitis. / Methods: Using a defined, sensitive search strategy, we identified RCTs and systematic reviews (SRs) of treatment interventions in children with appendicitis. Included studies were all in English and investigated the effect of one or more treatment interventions in children with acute appendicitis or undergoing appendicectomy for presumed acute appendicitis. Studies were reviewed and data extracted by two reviewers. Primary (if defined) and all other outcomes were recorded and assigned to the core areas ‘Death’, ‘Pathophysiological Manifestations’, ‘Life Impact’, ‘Resource Use’ and ‘Adverse Events’, using OMERACT Filter 2.0. / Results: A total of 63 studies met the inclusion criteria reporting outcomes from 51 RCTs and nine SRs. Only 25 RCTs and four SRs defined a primary outcome. A total of 115 unique and different outcomes were identified. RCTs reported a median of nine outcomes each (range 1 to 14). The most frequently reported outcomes were wound infection (43 RCTs, nine SRs), intra-peritoneal abscess (41 RCTs, seven SRs) and length of stay (35 RCTs, six SRs) yet all three were reported in just 25 RCTs and five SRs. Common outcomes had multiple different definitions or were frequently not defined. Although outcomes were reported within all core areas, just one RCT and no SR reported outcomes for all core areas. Outcomes assigned to the ‘Death’ and ‘Life Impact’ core areas were reported least frequently (in six and 15 RCTs respectively). / Conclusions: There is a wide heterogeneity in the selection and definition of outcomes in paediatric appendicitis, and little overlap in outcomes used across studies. A paucity of studies report patient relevant outcomes within the ‘Life Impact’ core area. These factors preclude meaningful evidence synthesis, and pose challenges to designing prospective clinical trials and cohort studies. The development of a COS for paediatric appendicitis is warranted

Regulating inflammation through the anti-inflammatory enzyme platelet-activating factor-acetylhydrolase

Platelet-activating factor (PAF) is one of the most potent lipid mediators involved in inflammatory events. The acetyl group at the sn-2 position of its glycerol backbone is essential for its biological activity. Deacetylation induces the formation of the inactive metabolite lyso-PAF. This deacetylation reaction is catalyzed by PAF-acetylhydrolase (PAF-AH), a calcium independent phospholipase A2 that also degrades a family of PAF-like oxidized phospholipids with short sn-2 residues. Biochemical and enzymological evaluations revealed that at least three types of PAF-AH exist in mammals, namely the intracellular types I and II and a plasma type. Many observations indicate that plasma PAF AH terminates signals by PAF and oxidized PAF-like lipids and thereby regulates inflammatory responses. In this review, we will focus on the potential of PAF-AH as a modulator of diseases of dysregulated inflammation