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Conclusions SC therapy is effective for PAH in pre clinical studies . These results may help to st and ardise pre clinical animal studies and provide a theoretical basis for clinical trial design in the future .

Background Despite significant progress in drug treatment , the prognosis of patients with advanced pulmonary arterial hypertension ( PAH ) remains extremely poor . Many pre clinical studies have reported the efficacy of stem cell ( SC ) therapy for PAH ; however , this approach remains controversial . The aim of this systematic review and meta- analysis is to assess the potential efficacy of SC therapy for PAH .

Although transplantation of adult bone marrow mesenchymal stem cells ( BM-MSCs ) holds promise in the treatment for pulmonary arterial hypertension ( PAH ) , the poor survival and differentiation potential of adult BM-MSCs have limited their therapeutic efficiency . Here , we compared the therapeutic efficacy of human embryonic stem cell-derived MSCs ( hESC-MSCs ) with adult BM-MSCs for the treatment of PAH in an animal model . One week following monocrotaline (MCT)-induced PAH , mice were r and omly assigned to receive phosphate-buffered saline ( MCT group ) ; 3.0 × 106 human BM-derived MSCs ( BM-MSCs group ) or 3.0 × 106 hESC-derived MSCs ( hESC-MSCs group ) via tail vein injection . At 3 weeks posttransplantation , the right ventricular systolic pressure ( RVSP ) , degree of RV hypertrophy , and medial wall thickening of pulmonary arteries were lower= , and pulmonary capillary density was higher in the hESC-MSC group as compared with BM-MSC and MCT groups ( all p < 0.05 ) . At 1 week posttransplantation , the number of engrafted MSCs in the lungs was found significantly higher in the hESC-MSC group than in the BM-MSC group ( all p < 0.01 ) . At 3 weeks posttransplantation , implanted BM-MSCs were undetectable whereas hESC-MSCs were not only engrafted in injured pulmonary arteries but had also undergone endothelial differentiation . In addition , protein profiling of hESC-MSC- and BM-MSC-conditioned medium revealed a differential paracrine capacity . Classification of these factors into bioprocesses revealed that secreted factors from hESC-MSCs were preferentially involved in early embryonic development and tissue differentiation , especially blood vessel morphogenesis . We concluded that improved cell survival and paracrine capacity of hESC-MSCs provide better therapeutic efficacy than BM-MSCs in the treatment for PAH Abstract We investigated the effect of adipose-derived stem cells ( ADSCs ) transplantation effects on structural remodeling and pulmonary artery pressure in monocrotaline (MCT)-induced pulmonary hypertensive rats . In the first experiment , 32 male Sprague-Dawley ( SD ) rats were r and omly divided into four groups ( n = 8/group ) : 3 ADSCs treated groups and normal control ( Ctrl ) . ADSCs were administered through the left jugular vein at 105 , 106 and 107 cells , respectively , and a cell density of 106cells/ml was shown to be optimal . The GFP-tagged ADSCs were identified in the lungs and differentiated into endothelial-like cells . In the second experiment , 96 male SD rats were r and omly divided into three groups ( n = 32/group ) : Ctrl , MCT-induced pulmonary arterial hypertension ( PAH ) , and PAH treated with ADSCs ( ADSCs ) . Two weeks post-MCT administration , the ADSCs group received 1 × 106 ADSCs via the external jugular vein . Compared to PAH rats , mean pulmonary arterial pressure was decreased in rats at 1 , 2 , and 3 weeks after ADSCs-treatment ( 18.63 ± 2.15 mmHg versus 24.53 ± 2.90 mmHg ; 23.07 ± 2.84 mmHg versus 33.18 ± 2.30 mmHg ; 22.98 ± 2.34 mmHg versus 36.38 ± 3.28 mmHg , p < 0.05 ) . Meanwhile , the right heart hypertrophy index ( 36.2 1 ± 4.27 % versus 41.01 ± 1.29 % ; 39.47 ± 4.02 % versus 48.75 ± 2 .13 % ; 41.02 ± 0.9 % versus 50.52 ± 1.49 % , p < 0.05 , respectively ) , ratio of wall/lumen thickness , as well as the wall/lumen area were significantly reduced in PAH rats at these time points following ADSCs-treatment , as compared with untreated PAH rats . In summary , ADSCs may colonize the pulmonary arteries , attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling The aim of the present study was to investigate the effect of bone marrow mesenchymal stem cell ( BMSC ) transp1antation on lung and heart damage in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension ( PAH ) . The animals were r and omly divided into 3 groups : control , PAH and BMSC implantation groups . Structural changes in the pulmonary vascular wall , such as the pulmonary artery lumen area ( VA ) and vascular area ( TAA ) were measured by hematoxylin and eosin ( H&E ) staining , and the hemodynamics were detected by echocardiography . Two weeks post-operation , our results demonstrated that sublingual vein injection of BMSCs significantly attenuated the pulmonary vascular structural and hemodynamic changes caused by pulmonary arterial hypertension . The mechanism may be executed via paracrine effects OBJECTIVE To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival . DESIGN Registry with prospect i ve follow-up . SETTING Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart , Lung , and Blood Institute . PATIENTS Patients ( 194 ) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988 . MEASUREMENTS At diagnosis , measurements of hemodynamic variables , pulmonary function , and gas exchange variables were taken in addition to information on demographic variables , medical history , and life-style . Patients were followed for survival at 6-month intervals . MAIN RESULTS The estimated median survival of these patients was 2.8 years ( 95 % Cl , 1.9 to 3.7 years ) . Estimated single-year survival rates were as follows : at 1 year , 68 % ( Cl , 61 % to 75 % ) ; at 3 years , 48 % ( Cl , 41 % to 55 % ) ; and at 5 years , 34 % ( Cl , 24 % to 44 % ) . Variables associated with poor survival included a New York Heart Association ( NYHA ) functional class of III or IV , presence of Raynaud phenomenon , elevated mean right atrial pressure , elevated mean pulmonary artery pressure , decreased cardiac index , and decreased diffusing capacity for carbon monoxide ( DLCO ) . Drug therapy at entry or discharge was not associated with survival duration . CONCLUSIONS Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables : mean pulmonary artery pressure , mean right atrial pressure , and cardiac index . Such an equation , once vali date d prospect ively , could be used as an adjunct in planning treatment strategies and allocating medical re sources BACKGROUND Sildenafil inhibits phosphodiesterase type 5 , an enzyme that metabolizes cyclic guanosine monophosphate , thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells , including those in the lung . METHODS In this double-blind , placebo-controlled study , we r and omly assigned 278 patients with symptomatic pulmonary arterial hypertension ( either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts ) to placebo or sildenafil ( 20 , 40 , or 80 mg ) orally three times daily for 12 weeks . The primary end point was the change from baseline to week 12 in the distance walked in six minutes . The change in mean pulmonary-artery pressure and World Health Organization ( WHO ) functional class and the incidence of clinical worsening were also assessed , but the study was not powered to assess mortality . Patients completing the 12-week r and omized study could enter a long-term extension study . RESULTS The distance walked in six minutes increased from baseline in all sildenafil groups ; the mean placebo-corrected treatment effects were 45 m ( + 13.0 percent ) , 46 m ( + 13.3 percent ) , and 50 m ( + 14.7 percent ) for 20 , 40 , and 80 mg of sildenafil , respectively ( P<0.001 for all comparisons ) . All sildenafil doses reduced the mean pulmonary-artery pressure ( P=0.04 , P=0.01 , and P<0.001 , respectively ) , improved the WHO functional class ( P=0.003 , P<0.001 , and P<0.001 , respectively ) , and were associated with side effects such as flushing , dyspepsia , and diarrhea . The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo . Among the 222 patients completing one year of treatment with sildenafil monotherapy , the improvement from baseline at one year in the distance walked in six minutes was 51 m. CONCLUSIONS Sildenafil improves exercise capacity , WHO functional class , and hemodynamics in patients with symptomatic pulmonary arterial hypertension BACKGROUND Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point . We assessed the efficacy of macitentan , a new dual endothelin-receptor antagonist , using a primary end point of morbidity and mortality in a long-term trial . METHODS We r and omly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily , macitentan at a once-daily dose of 3 mg , or macitentan at a once-daily dose of 10 mg . Stable use of oral or inhaled therapy for pulmonary arterial hypertension , other than endothelin-receptor antagonists , was allowed at study entry . The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death , atrial septostomy , lung transplantation , initiation of treatment with intravenous or subcutaneous prostanoids , or worsening of pulmonary arterial hypertension . RESULTS A total of 250 patients were r and omly assigned to placebo , 250 to the 3-mg macitentan dose , and 242 to the 10-mg macitentan dose . The primary end point occurred in 46.4 % , 38.0 % , and 31.4 % of the patients in these groups , respectively . The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 ( 97.5 % confidence interval [ CI ] , 0.52 to 0.96 ; P=0.01 ) , and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 ( 97.5 % CI , 0.39 to 0.76 ; P<0.001 ) . Worsening of pulmonary arterial hypertension was the most frequent primary end-point event . The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline . Adverse events more frequently associated with macitentan than with placebo were headache , nasopharyngitis , and anemia . CONCLUSIONS Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study . ( Funded by Actelion Pharmaceuticals ; SERAPHIN Clinical Trials.gov number , NCT00660179 . ) Our previous studies have shown that bone marrow mesenchymal stem cells ( BMSCs ) can inhibit the progression of pulmonary artery hypertension ( PAH ) in the monocrotaline ( MCT ) model in the short term . The aim of this study was to further investigate the long-term effect of BMSCs on PAH and to explore the mechanism of the protective effect including the pulmonary vascular remodeling and cell differentiation . PAH model was established by subcutaneous injection of 50 mg/kg MCT as previously study . Postoperatively , the animals were r and omly divided into three groups ( n = 10 in each group ) : control , PAH group , and BMSCs implantation group . Six months after injection , immunology and immunohistochemistry analysis indicated the MCT-induced intima-media thickness in muscular arteries was reduced ( P < 0.05 ) ; the area of collagen fibers in lung tissue was lower ( P < 0.05 ) , and the proliferating cell nuclear antigen level in pulmonary artery smooth muscle cells was decreased ( P < 0.05 ) . Immunofluorescence showed that the cells have the ability to differentiate between von Willebr and factor and vascular endothelial growth factor . Six months after intravenous injection , BMSCs could significantly improve pulmonary function by inhibiting the ventricular remodeling and the effect of cell differentiation Experimental data suggest that transplantation of EPCs attenuates monocrotaline-induced pulmonary hypertension in rats and dogs . In addition , our previous studies suggested that autologous EPC transplantation was feasible , safe , and might have beneficial effects on exercise capacity and pulmonary hemodynamics in adults with IPAH . Thus , we hypothesized that transplantation of EPCs would improve exercise capacity and pulmonary hemodynamics in children with IPAH . Thirteen children with IPAH received intravenous infusion of autologous EPCs . The right-sided heart catheterization and 6-MWD test were performed at baseline and at the time of 12 wk after cell infusion . At the time of 12 wk , mPAP decreased by 6.4 mmHg from 70.3 + /- 19.0 to 63.9 + /- 19.3 mmHg ( p = 0.015 ) . PVR decreased by approximately 19 % from 1118 + /- 537 to 906 + /- 377 dyn s/cm(5 ) ( p = 0.047 ) . CO increased from 3.39 + /- 0.79 to 3.85 + /- 0.42 L/min ( p = 0.048 ) . The 6-MWD increased by 39 m from 359 + /- 82 to 399 + /- 74 m ( p = 0.012 ) . NYHA functional class also improved . There were no severe adverse events with cell infusion . The small pilot study suggested that intravenous infusion of autologous EPCs was feasible , safe , and associated with significant improvements in exercise capacity , NYHA functional class , and pulmonary hemodynamics in children with IPAH . Confirmation of these results in a r and omized controlled trial are essential BACKGROUND Uncontrolled studies suggested that aerosolized iloprost , a stable analogue of prostacyclin , causes selective pulmonary vasodilatation and improves hemodynamics and exercise capacity in patients with pulmonary hypertension . METHODS We compared repeated daily inhalations of 2.5 or 5.0 microg of iloprost ( six or nine times per day ; median inhaled dose , 30 microg per day ) with inhalation of placebo . A total of 203 patients with selected forms of severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension ( New York Heart Association [ NYHA ] functional class III or IV ) were included . The primary end point was met if , after week 12 , the NYHA class and distance walked in six minutes were improved by at least one class and at least 10 percent , respectively , in the absence of clinical deterioration according to predefined criteria and death . RESULTS The combined clinical end point was met by 16.8 percent of the patients receiving iloprost , as compared with 4.9 percent of the patients receiving placebo ( P=0.007 ) . There were increases in the distance walked in six minutes of 36.4 m in the iloprost group as a whole ( P=0.004 ) and of 58.8 m in the subgroup of patients with primary pulmonary hypertension . Overall , 4.0 percent of patients in the iloprost group ( including one who died ) and 13.7 percent of those in the placebo group ( including four who died ) did not complete the study ( P=0.024 ) ; the most common reason for withdrawal was clinical deterioration . As compared with base-line values , hemodynamic values were significantly improved at 12 weeks when measured after iloprost inhalation ( P<0.001 ) , were largely unchanged when measured before iloprost inhalation , and were significantly worse in the placebo group . Further significant beneficial effects of iloprost treatment included an improvement in the NYHA class ( P=0.03 ) , dyspnea ( P=0.015 ) , and quality of life ( P=0.026 ) . Syncope occurred with similar frequency in the two groups but was more frequently rated as serious in the iloprost group , although this adverse effect was not associated with clinical deterioration . CONCLUSIONS Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension BACKGROUND High pulmonary vascular resistance ( PVR ) may be a risk factor for early and late mortality in both Glen shunt and Fontan operation patients . Furthermore , PVR may increase long after the Fontan operation . Whether pulmonary vasodilators such as phosphodiesterase 5 inhibitors can decrease PVR in patients with single ventricular physiology remains undetermined . METHODS AND RESULTS This was a prospect i ve , multicenter study . Patients with single ventricular physiology who have a PVR index higher than 2.5 Wood units · ㎡ ( WU ) were enrolled . Cardiac catheterization was performed before and after administration of sildenafil in all patients . After the Fontan operation , a six minute walk test ( 6MWT ) was also performed . A total of 42 patients were enrolled . PVR was significantly decreased in each stage of single ventricular physiology after sildenafil administration : from 4.3±1.5WU to 2.1±0.6WU ( p<0.01 ) in patients before a Glenn shunt , from 3.2±0.5WU to 1.6±0.6WU ( p<0.001 ) in patients after a Glenn shunt , and from 3.9±1.7WU to 2.3±0.8WU ( p<0.001 ) in patients after Fontan . In patients after Fontan , the 6MWT increased from 416±74 m to 485±72 m ( p<0.01 ) , and NYHA functional class improved significantly ( p<0.05 ) after sildenafil administration . No major side effects were observed in any patients . CONCLUSIONS Sildenafil reduced PVR in patients with single ventricle physiology . Sildenafil increased exercise capacity and improved NYHA functional class in patients after a Fontan operation . This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated PVR with single ventricle physiology . Long-term clinical significance warrants further study OBJECTIVES The purpose of this study was to examine the efficacy and safety of four doses of ambrisentan , an oral endothelin type A receptor-selective antagonist , in patients with pulmonary arterial hypertension ( PAH ) . BACKGROUND Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options . Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH . METHODS In this double-blind , dose-ranging study , 64 patients with idiopathic PAH or PAH associated with collagen vascular disease , anorexigen use , or human immunodeficiency virus infection were r and omized to receive 1 , 2.5 , 5 , or 10 mg of ambrisentan once daily for 12 weeks followed by 12 weeks of open-label ambrisentan . The primary end point was an improvement from baseline in 6-min walk distance ( 6MWD ) ; secondary end points included Borg dyspnea index , World Health Organization ( WHO ) functional class , a subject global assessment , and cardiopulmonary hemodynamics . RESULTS At 12 weeks , ambrisentan increased 6MWD ( + 36.1 m , p < 0.0001 ) with similar and statistically significant increases for each dose group ( range , + 33.9 to + 38.1 m ) . Improvements were also observed in Borg dyspnea index , WHO functional class , subject global assessment , mean pulmonary arterial pressure ( -5.2 mm Hg , p < 0.0001 ) , and cardiac index ( + 0.33 l/min/m2 , p < 0.0008 ) . Adverse events were mild and unrelated to dose , including the incidence of elevated serum aminotransferase concentrations > 3 times the upper limit of normal ( 3.1 % ) . CONCLUSIONS Ambrisentan appears to improve exercise capacity , symptoms , and hemodynamics in patients with PAH . The incidence and severity of liver enzyme abnormalities appear to be low UNLABELLED Pulmonary arterial hypertension ( PAH ) is characterized by functional and structural changes in the pulmonary vasculature , and despite the drug treatment that made significant progress , the prognosis of patients with advanced PH remains extremely poor . In the present study , we investigated the early effect of bone marrow mesenchymal stem cells ( BMSCs ) on experimental high blood flow-induced PAH model rats and discussed the mechanism . BMSCs were isolated , cultured from bone marrow of Sprague-Dawley ( SD ) rat . The animal model of PAH was created by surgical methods to produce a left-to-right shunt . Following the successful establishment of the PAH model , rats were r and omly assigned to three groups ( n=20 in each group ) : sham group ( control ) , PAH group , and BMSC group ( received a sublingual vein injection of 1 - 5 × 10(6 ) BMSCs ) . Two weeks after the administration , BMSCs significantly reduced the vascular remodeling , improved the hemodynamic data , and deceased the right ventricle weight ratio to left ventricular plus septal weight ( RV/LV+S ) ( P<0.05 ) . Real-time reverse transcription-polymerase chain reaction ( RT-PCR ) and immunohistochemistry analysis results indicated that the inflammation factors such as interleukin-1β ( IL-1β ) , IL-6 , and tumor necrosis factor-α ( TNF-α ) were reduced ( P<0.05 ) ; the expression of matrix metallo proteinase-9 ( MMP-9 ) was lower ( P<0.05 ) ; vascular endothelial growth factor ( VEGF ) was higher in BMSC group than those in PAH group ( P<0.05 ) . CONCLUSION Sublingual vein injection of BMSCs for 2 weeks , significantly improved the lung and heart injury caused by left-to-right shunt-induced PAH ; decreased pulmonary vascular remodeling and inflammation ; and enhanced angiogenesis Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous prostacyclin has proven to be effective . However , this treatment requires a permanent central venous catheter with the associated risk of serious complications such as sepsis , thromboembolism , or syncope . Treprostinil , a stable prostacyclin analogue , can be administered by a continuous subcutaneous infusion , avoiding these risks . We conducted a 12-week , double-blind , placebo-controlled multicenter trial in 470 patients with pulmonary arterial hypertension , either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts . Exercise capacity improved with treprostinil and was unchanged with placebo ; the between treatment group difference in median six-minute walking distance was 16 m ( p = 0.006 ) . Improvement in exercise capacity was greater in the sicker patients and was dose-related , but independent of disease etiology . Concomitantly , treprostinil significantly improved indices of dyspnea , signs and symptoms of pulmonary hypertension , and hemodynamics . The most common side effect attributed to treprostinil was infusion site pain ( 85 % ) leading to premature discontinuation from the study in 8 % of patients . Three patients in the treprostinil treatment group presented with an episode of gastrointestinal hemorrhage . We conclude that chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension BACKGROUND Endothelin 1 , a powerful endogenous vasoconstrictor and mitogen , might be a cause of pulmonary hypertension . We describe the efficacy and safety of bosentan , a dual endothelin-receptor antagonist that can be taken orally , in patients with severe pulmonary hypertension . METHODS In this double-blind , placebo-controlled study , 32 patients with pulmonary hypertension ( primary or associated with scleroderma ) were r and omly assigned to bosentan ( 62.5 mg taken twice daily for 4 weeks then 125 mg twice daily ) or placebo for a minimum of 12 weeks . The primary endpoint was change in exercise capacity . Secondary endpoints included changes in cardiopulmonary haemodynamics , Borg dyspnoea index , WHO functional class , and withdrawal due to clinical worsening . Analysis was by intention to treat . FINDINGS In patients given bosentan , the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline , whereas it worsened by 6 m in those on placebo ( difference 76 m [ 95 % CI 12 - 139 ] , p=0.021 ) . The improvement was maintained for at least 20 weeks . The cardiac index was 1.0 L min(-1 ) m(-2 ) ( 95 % CI 0.6 - 1.4 , p<0.0001 ) greater in patients given bosentan than in those given placebo . Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5 ) with bosentan , but increased by 191 dyn s cm(-5 ) with placebo ( difference -415 [ -608 to -221 ] , p=0.0002 ) . Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class . All three withdrawals from clinical worsening were in the placebo group ( p=0.033 ) . The number and nature of adverse events did not differ between the two groups . INTERPRETATION Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension , suggesting that endothelin has an important role in pulmonary hypertension Background Systematic Review s ( SRs ) of experimental animal studies are not yet common practice , but awareness of the merits of conducting such SRs is steadily increasing . As animal intervention studies differ from r and omized clinical trials ( RCT ) in many aspects , the methodology for SRs of clinical trials needs to be adapted and optimized for animal intervention studies . The Cochrane Collaboration developed a Risk of Bias ( RoB ) tool to establish consistency and avoid discrepancies in assessing the method ological quality of RCTs . A similar initiative is warranted in the field of animal experimentation . Methods We provide an RoB tool for animal intervention studies ( SYRCLE ’s RoB tool ) . This tool is based on the Cochrane RoB tool and has been adjusted for aspects of bias that play a specific role in animal intervention studies . To enhance transparency and applicability , we formulated signalling questions to facilitate judgment . Results The result ing RoB tool for animal studies contains 10 entries . These entries are related to selection bias , performance bias , detection bias , attrition bias , reporting bias and other biases . Half these items are in agreement with the items in the Cochrane RoB tool . Most of the variations between the two tools are due to differences in design between RCTs and animal studies . Shortcomings in , or unfamiliarity with , specific aspects of experimental design of animal studies compared to clinical studies also play a role . Conclusions SYRCLE ’s RoB tool is an adapted version of the Cochrane RoB tool . Widespread adoption and implementation of this tool will facilitate and improve critical appraisal of evidence from animal studies . This may subsequently enhance the efficiency of translating animal research into clinical practice and increase awareness of the necessity of improving the method ological quality of animal studies

There was a trend for endothelin receptor antagonists to reduce mortality ( OR 0.48 ; 95 % CI 0.21 to 1.09 ) , and limited data suggest that endothelin receptor antagonists improve Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients . Hepatic toxicity was not common , and endothelin receptor antagonists were well tolerated in this population . Endothelin receptor antagonists can increase exercise capacity , improve WHO/NYHA functional class , prevent WHO/NYHA functional class deterioration , reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III . However , there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension . Efficacy data are strongest in those with idiopathic pulmonary hypertension

BACKGROUND Pulmonary arterial hypertension is a devastating disease , which leads to right heart failure and premature death . Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension . OBJECTIVES To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension .

BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospect i ve , r and omized trial to improve survival . METHODS We conducted a 12-week prospect i ve , r and omized , multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol ( formerly called prostacyclin ) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension ( New York Heart Association functional class III or IV ) . RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol ( median distance walked in six minutes , 362 m at 12 weeks vs. 315 m at base line ) , but it decreased in the 40 patients treated with conventional therapy alone ( 204 m at 12 weeks vs. 270 m at base line ; P < 0.002 for the comparison of the treatment groups ) . Indexes of the quality of life were improved only in the epoprostenol group ( P < 0.01 ) . Hemodynamics improved at 12 weeks in the epoprostenol-treated patients . The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and + 3 percent , respectively ( difference in mean change , -6.7 mm Hg ; 95 percent confidence interval , -10.7 to -2.6 mm Hg ; P < 0.002 ) , and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and + 9 percent , respectively ( difference in mean change , -4.9 mm Hg/liter/min ; 95 percent confidence interval , -7.6 to -2.3 mm Hg/liter/min ; P < 0.001 ) . Eight patients died during the study , all of whom had been r and omly assigned to conventional therapy ( P = 0.003 ) . Serious complications included four episodes of catheter-related sepsis and one thrombotic event . CONCLUSIONS As compared with conventional therapy , the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement , as well as improved survival in patients with severe primary pulmonary hypertension BACKGROUND Patients with precapillary pulmonary hypertension ( PH ) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries . By causing the pulmonary artery to dilate , inhaled nitric oxide ( NO ) may allow an increase in exercise capacity in patients with PH . METHODS AND RESULTS On 2 separate days , 3 days apart , 14 patients with precapillary PH ( 10 primary PH , 4 residual PH after correction of an intracardiac shunt ; age , 40+/-12 years ; mean pulmonary artery pressure , 60+/-23 mm Hg ) performed exercise , with and without inhalation of 20 ppm NO , on a cycle ergometer . The work rate was increased 15 W/min until their symptom-limited maximum , with breath-by-breath gas analysis . Patients were r and omly and blindly selected to inhale NO on either their first or second test . Peak exercise load and anaerobic threshold tended to increase , but not significantly . Peak oxygen consumption ( f1.gif " BORDER="0" > O(2 ) ) and Deltaf1.gif " BORDER="0" > O(2)/DeltaW ratio increased significantly , by 18 % and 22 % , respectively ( peak f1.gif " BORDER="0" > O(2 ) , 13.6+/-3.6 to 16.0+/-4 . 1 mL. kg(-1 ) . min(-1 ) ; Deltaf1.gif " BORDER="0" > O(2)/DeltaW ratio , 5 . 8+/-2.4 to 7.1+/-2.3 mL. kg(-1 ) . min(-1 ) . W(-1 ) ; both P<0.01 ) . Peak f1.gif " BORDER="0" > O(2 ) increased > 10 % in 12 of the 14 patients . However , respiratory quotient at peak exercise decreased from 1 . 22+/-0.15 to 1.09+/-0.15 ( P<0.01 ) . CONCLUSIONS Inhaled NO substantially increases oxygen consumption at the same workload during exercise . This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH After the approval of bosentan for the treatment of pulmonary arterial hypertension ( PAH ) , European authorities required the introduction of a post-marketing surveillance system ( PMS ) to obtain further data on its safety profile . A novel , prospect i ve , internet-based PMS was design ed , which solicited reports on elevated aminotransferases , medical reasons for bosentan discontinuation and other serious adverse events requiring hospitalisation . Data captured included demographics , PAH aetiology , baseline functional status and concomitant PAH-specific medications . Safety signals captured included death , hospitalisation , serious adverse events , unexpected adverse events and elevated aminotransferases . Within 30 months , 4,994 patients were included , representing 79 % of patients receiving bosentan in Europe . In total , 4,623 patients were naïve to treatment ; of these , 352 had elevated aminotransferases , corresponding to a crude incidence of 7.6 % and an annual rate of 10.1 % . Bosentan was discontinued due to elevated aminotransferases in 150 ( 3.2 % ) bosentan-naïve patients . Safety results were consistent across subgroups and aetiologies . The novel post-marketing surveillance captured targeted safety data ( “ potential safety signals ” ) from the majority of patients and confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials . These data complement those from r and omised controlled clinical trials and provide important additional information on the safety profile of bosentan Background : Endothelin-1 is considered to be a central pathogenic factor in connective tissue diseases ( CTDs ) such as systemic sclerosis ( SSc ) , leading to vasoconstriction , fibrosis , hypertrophy and inflammation . A frequent complication of CTD is pulmonary arterial hypertension ( PAH ) , which has a major effect on functioning and quality of life , and is associated with a particularly poor prognosis . Objective : To present a subgroup analysis that summarises experiences from the pivotal studies and their open-label extensions with the oral dual endothelin-1 receptor antagonist bosentan in patients with PAH and CTD , mostly SSc and lupus erythematosus . Methods : 66 patients with PAH secondary to CTD , in World Health Organization functional class III or IV , were r and omised to two double-blind , placebo-controlled studies and followed up for 12 and 16 weeks , respectively . The primary end point was change in exercise capacity , assessed using the 6-min walk test . In both studies and their extensions , survival was assessed from start of treatment to death or data cut-off and analysed as Kaplan – Meier estimates . Results : 44 patients with PAH secondary to CTD who were treated with bosentan were stable in 6-min walk distance at the end of the study ( + 19.5 m , 95 % confidence interval ( CI ) −3.2 to 42.2 ) , whereas patients treated with placebo deteriorated ( −2.6 m , 95 % CI −54.0 to 48.7 ) . 64 patients subsequently received bosentan in an open-label long-term extension study . Mean ( st and ard deviation ( SD ) ) exposure to bosentan was 1.6 ( 0.9 ) years , and duration of observation was 1.8 ( 0.8 ) years . 8 ( 16 % ) patients received epoprostenol as add-on treatment and 7 ( 14 % ) after discontinuation of bosentan . Survival in those receiving bosentan was 85.9 % after 1 year and 73.4 % after 2 years . Conclusion : Short-term bosentan treatment in a subgroup of patients with PAH secondary to CTD seems to have a favourable effect compared with placebo . The long-term follow-up of these patients suggests that first-line bosentan , with the subsequent addition of other PAH treatments if required , is safe for long-term treatment and may have a positive effect on outcome Pulmonary hypertension is characterized by progressive elevation of pulmonary artery pressure and vascular resistance , often leading to right ventricular failure and death ( 1 - 3 ) . Continuous intravenous infusion of epoprostenol improves prognosis and symptoms in patients with primary ( idiopathic ) pulmonary hypertension ( 4 - 8 ) . R and omized , controlled clinical trials of epoprostenol for secondary pulmonary hypertension have not been conducted . Pulmonary hypertension frequently complicates the scleroderma spectrum of disease , which includes diffuse scleroderma , limited scleroderma ( the CREST syndrome [ calcinosis cutis , the Raynaud phenomenon , esophageal dysfunction , sclerodactyly , and telangectasia ] ) , and the overlap syndrome . These multisystem diseases are characterized by connective tissue and vascular abnormalities ; vascular lesions are prominent in all affected tissues ( 9 ) . Pulmonary hypertension occurs in up to 33 % of patients with diffuse scleroderma and 10 % to 50 % of those with the CREST syndrome ( 10 , 11 ) , in which it is one of the leading causes of death ( 12 , 13 ) . Pulmonary hypertension in the scleroderma spectrum of disease may be associated with interstitial pulmonary fibrosis or may consist of a direct involvement of small and medium-sized pulmonary arteries and arterioles with smooth-muscle hyperplasia , medial hypertrophy , and intimal proliferation ( 10 , 13 , 14 ) . Principal involvement of the pulmonary vasculature is more common in the CREST syndrome , whereas patients with pulmonary hypertension and diffuse scleroderma more often have interstitial lung disease ( 13 ) . No therapies have been proven effective for pulmonary hypertension secondary to the scleroderma spectrum of disease . Small numbers of patients have responded to captopril ( 15 ) , nifedipine ( 16 - 20 ) , and prazosin . In a short-term study of intravenous epoprostenol in seven patients with scleroderma ( two with diffuse scleroderma and five with limited scleroderma ) , six had a decrease in mean pulmonary artery pressure and pulmonary vascular resistance ( 21 ) . In a small study of pulmonary hypertension secondary to connective tissue disease , long-term infusion therapy with a prostacyclin analogue , iloprost , result ed in improvement in New York Heart Association ( NYHA ) functional class and quality of life but a variable hemodynamic response ( 22 ) . Results from a single-center , uncontrolled study suggest that long-term , continuously infused epoprostenol therapy can produce hemodynamic and symptomatic responses in patients with connective tissue disease who have severe pulmonary hypertension that is refractory to conventional medical therapy ( 23 ) . The rationale for using continuous epoprostenol infusion to treat pulmonary hypertension secondary to the scleroderma spectrum of disease was based on the efficacy of this therapy for primary pulmonary hypertension ( 4 - 8 ) and recognition that scleroderma is a disease characterized by vasospasm and structural changes in the walls of blood vessels . Prostacyclin is a naturally occurring substance produced by vascular endothelium that has vasodilating , antiplatelet aggregation , and cytoprotective effects ( 24 - 33 ) . Endogenous production of prostacyclin is decreased in an animal model of neonatal pulmonary hypertension ( 34 ) and in adult humans with pulmonary hypertension ( 35 ) . Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in patients with primary pulmonary hypertension ( 36 ) . Endothelial dysfunction also plays an important role in the vascular manifestations of the scleroderma spectrum of disease ( 37 , 38 ) , including the Raynaud phenomenon and digital ischemia , which cause considerable morbidity . Calcium-channel blockers ( 39 - 45 ) , enalapril ( 46 ) , and intermittent intravenous infusions of prostacyclin ( 47 - 49 ) and iloprost ( 50 - 54 ) improve the Raynaud phenomenon in some patients . Mixed results have been obtained with oral prostacyclin analogues ( 55 , 56 ) , and a recent multicenter trial of oral iloprost showed no benefit ( 57 ) . The effect of long-term , continuously infused epoprostenol on the severity of the Raynaud phenomenon and on digital ulcer counts has not been previously evaluated . Our 12-week multicenter , open-label , r and omized study was design ed to determine whether the beneficial effect of epoprostenol seen in patients with primary pulmonary hypertension could be extended to patients with pulmonary hypertension secondary to the scleroderma spectrum of disease . Our objective was to evaluate the effects of continuous infusion of epoprostenol on exercise capacity in patients with pulmonary hypertension secondary to the scleroderma spectrum of disease . A secondary objective was assessment of the effects of long-term continuous epoprostenol infusion on cardiopulmonary hemodynamics , Borg Dyspnea Score , Dyspnea-Fatigue Rating , NYHA functional class , survival , and safety . Vasospastic manifestations , such as the Raynaud phenomenon and digital ulcerations , were also followed . Methods Patient Selection Eligible patients had pulmonary hypertension secondary to the scleroderma spectrum of disease in accordance with the inclusion and exclusion criteria summarized in Table 1 . For the purpose s of this study , the scleroderma spectrum of disease was defined as systemic sclerosis with diffuse or limited scleroderma ( 58 ) ; systemic sclerosis that overlapped with another connective tissue disease ; or the presence of definite features of systemic sclerosis , including the Raynaud phenomenon and positive test result for antinuclear antibody , plus positive test results for anticentromere antibody , anti-Scl 70 antibody , or nailfold capillary abnormalities . Systemic sclerosis with limited cutaneous involvement ( the CREST syndrome ) was defined as the presence of any three of the following conditions : subcutaneous calcinosis , the Raynaud phenomenon , esophageal dysfunction ( defined clinical ly ) , sclerodactyly , or telangectasia . Patients with interstitial lung disease of a more than mild degree were not included in the study because such patients were thought to be less likely to show benefit . Table 1 . Key Inclusion and Exclusion Criteria On the basis of a previous 12-week study of the effects of epoprostenol infusion in patients with severe primary pulmonary hypertension ( 6 ) and using the 6-minute walk test as the primary outcome measure , we calculated that 50 patients per treatment group would provide 80 % power to detect a difference of 50 meters in the average change from baseline , at an level of 0.05 ( two-tailed t-test ) . R and omization and Treatment The protocol was approved by the institutional review boards of the 17 participating centers . After giving informed consent , 111 eligible patients were r and omly assigned ( 1:1 ) to receive continuous epoprostenol infusion ( Flolan , Glaxo Wellcome , Inc. , Research Triangle Park , North Carolina ) plus conventional therapy or to receive conventional therapy alone . Investigators contacted a central r and omization center to obtain treatment assignment , which was based on a stratified r and omized block design . Assignments were stratified on the basis of vasodilator use at baseline ( yes or no ) and exercise capacity at baseline ( 50 to<200 m or 200 m ) and were r and omized within blocks . Fifty-six patients were assigned to receive epoprostenol plus conventional therapy , and 55 patients were assigned to receive conventional therapy alone . Investigators were not blinded to treatment group assignment ; however , independent blinded observers assessed the primary efficacy measure , exercise capacity . Patients taking calcium-channel blockers at study entry continued to take them during the study period . Adjustments in concomitant medications were allowed during the study on the basis of clinical judgment . Patients in both groups were to receive oral anticoagulants during the study ; 94 of the 111 enrolled patients took warfarin . Venous access for epoprostenol infusion ( in the epoprostenol group only ) was obtained by insertion of a permanent indwelling central venous catheter . Epoprostenol was infused continuously by a portable infusion pump ( CADD-1 Model 5100 HF , SIMS Deltec , St. Paul , Minnesota ) . Patients were instructed in sterile technique , catheter care , and drug preparation and administration . Epoprostenol therapy was initiated at a low dose ( usually 2 ng/kg of body weight per minute ) . During the 12-week study , doses were adjusted on the basis of signs or symptoms consistent with persistent pulmonary hypertension in the absence of intolerable adverse effects ( Figure 1 ) . Figure 1 . Epoprostenol dosing . Outcome Measures The primary measure of efficacy was exercise capacity , as defined by the distance a patient could walk in 6 minutes . Trained observers at each site who were not otherwise involved in patient care administered the 6-minute walk test . All patients wore an ambulatory infusion pump and a hospital gown over their clothes to mask the presence or absence of a long-term indwelling catheter , thereby blinding testers to the patients ' treatment groups . Each patient performed one practice walk test . A st and ardized , unencouraged 6-minute walk test was performed as described elsewhere ( 59 ) at baseline and at 1 , 6 , and 12 weeks . The 6-minute walk test has been shown to provide meaningful outcome data in assessing potential therapy for patients with pulmonary hypertension ( 6 ) . Secondary measures of efficacy were cardiopulmonary hemodynamics measured by performing right-heart catheterization using st and ard techniques at baseline and week 12 ; the Borg Dyspnea Score ( 60 ) , obtained immediately after completion of the 6-minute walk test at baseline and 1 , 6 , and 12 weeks ( 6 , 59 ) ; the Dyspnea-Fatigue Rating , obtained before the 6-minute walk test at baseline and weeks 1 , 6 , and 12 ( 61 ) ; NYHA functional class ( 62 ) , measured at baseline and weeks 1 , 6 , and 12 ; digital ulcer counts , done at baseline and weeks 6 and 12 ; and the severity of the Raynaud phenomenon ,

This present meta- analysis suggests that statin pretreatment might be effective in improving myocardial perfusion in STEMI patients

BACKGROUND To achieve sufficient myocardial perfusion in ST-segment elevation myocardial infa rct ion ( STEMI ) patients receiving primary percutaneous coronary intervention ( PPCI ) , many adjunctive therapies have been proposed . Previous trials have reported variances in myocardial perfusion improvement for statin pretreatment , which made it inconvincible to confirm the beneficial effects of statins . Therefore , we performed a systematic review and meta- analysis to determine whether statin pretreatment was effective in improving myocardial perfusion . HYPOTHESIS Statin pretreatment could improve myocardial perfusion in STEMI patients undergoing PPCI .

BACKGROUND Although improved epicardial blood flow ( as assessed with either TIMI flow grade s or TIMI frame count ) has been related to reduced mortality after administration of thrombolytic drugs , the relationship of myocardial perfusion ( as assessed on the coronary arteriogram ) to mortality has not been examined . METHODS AND RESULTS A new , simple angiographic method , the TIMI myocardial perfusion ( TMP ) grade , was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI ( Thrombolysis In Myocardial Infa rct ion ) 10B trial , and its relationship to mortality was examined . TMP grade 0 was defined as no apparent tissue-level perfusion ( no ground-glass appearance of blush or opacification of the myocardium ) in the distribution of the culprit artery ; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature ( blush or a stain was present on the next injection ) ; TMP grade 2 blush clears slowly ( blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase ) ; and TMP grade 3 indicates that blush begins to clear during washout ( blush is minimally persistent after 3 cardiac cycles of washout ) . There was a mortality gradient across the TMP grade s , with mortality lowest in those patients with TMP grade 3 ( 2.0 % ) , intermediate in TMP grade 2 ( 4.4 % ) , and highest in TMP grade s 0 and 1 ( 6.0 % ; 3-way P=0.05 ) . Even among patients with TIMI grade 3 flow in the epicardial artery , the TMP grade s allowed further risk stratification of 30-day mortality : 0.73 % for TMP grade 3 ; 2.9 % for TMP grade 2 ; 5.0 % for TMP grade 0 or 1 ( P=0.03 for TMP grade 3 versus grade s 0 , 1 , and 2 ; 3-way P=0.066 ) . TMP grade 3 flow was a multivariate correlate of 30-day mortality ( OR 0.35 , 95 % CI 0.12 to 1.02 , P=0.054 ) in a multivariate model that adjusted for the presence of TIMI 3 flow ( P = NS ) , the corrected TIMI frame count ( OR 1.02 , P=0.06 ) , the presence of an anterior myocardial infa rct ion ( OR 2.3 , P=0.03 ) , pulse rate on admission ( P = NS ) , female sex ( P = NS ) , and age ( OR 1.1 , P<0.001 ) . CONCLUSIONS Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery . Patients with both normal epicardial flow ( TIMI grade 3 flow ) and normal tissue level perfusion ( TMP grade 3 ) have an extremely low risk of mortality Background —We hypothesized that preserved microvascular integrity in the area at risk would favorably influence left ventricular ( LV ) remodeling and long-term outcome after acute myocardial infa rct ion . Methods and Results —Before and after successful primary angioplasty ( percutaneous transluminal coronary angioplasty [ PTCA ] ) , 124 patients with acute myocardial infa rct ion underwent intracoronary myocardial contrast echo ( MCE ) . An MCE score index ( MCESI ) was derived by averaging the single-segment score ( 0=not visible , 1=patchy , 2=homogeneous contrast effect ) within the area at risk . An MCESI ≥1 was considered adequate reperfusion . Mean follow-up was 46±32 months . After PTCA , 100 patients showed adequate reperfusion ( no microvascular dysfunction , NoMD ) , whereas 24 did not ( MD ) . MD patients had a higher mean creatine kinase ( 4153±2422 versus 2743±1774 U/L ; P = 0.002 ) and baseline wall-motion score index ( 2.61±0.31 versus 2.25±0.42 ; P < 0.001 ) and a lower baseline ejection fraction ( 33±8 % versus 40±7 % ; P < 0.001 ) . From day 1 on , LV volumes progressively increased in the MD patients ( n=19 ) and were larger than those of NoMD patients ( n=85 ) at 6 months ( end-diastolic volume 170±55 versus 115±29 mL ; P < 0.001 ) . MCESI was the most important independent predictor of LV dilation ( OR 0.61 , 95 % CI 0.52 to 0.71 , P < 0.000001 ) . By Cox analysis , MD represented the only predictor of cardiac death ( OR 0.26 , 95 % CI 0.09 to 0.72 , P = 0.010 ) and combined events ( cardiac death , reinfa rct ion , and heart failure ; OR 0.44 , 95 % CI 0.23 to 0.85 , P = 0.014 ) . MD patients showed worse survival in terms of cardiac death ( P < 0.0001 ) and combined events ( P < 0.0001 ) . Conclusions —In reperfused acute myocardial infa rct ion , MD within the risk area is an important predictor of both LV remodeling and unfavorable long-term outcome Increased neutrophil counts have been associated with an increased risk of adverse clinical events after acute myocardial infa rct ion ( AMI ) . We examined the association of neutrophil counts on admission with degree of microvascular injury and left ventricular functional recovery after primary coronary angioplasty in AMI . We studied 116 patients with a first anterior wall AMI who underwent primary coronary angioplasty within 12 hours of onset . Patients were categorized into 3 groups based on initial neutrophil count : low ( < 5,000/mm(3 ) ) , intermediate ( 5,000 to 10,000/mm(3 ) ) , and high ( > 10,000/mm(3 ) ) . Coronary flow velocity parameters were assessed immediately after reperfusion using a Doppler guidewire . We defined severe microvascular injury as the presence of systolic flow reversal and a diastolic deceleration time < 600 ms . Echocardiographic wall motion was analyzed before revascularization and 4 weeks after revascularization . In patients with a high neutrophil count , systolic flow reversal was more frequently observed , diastolic deceleration time was shorter , and coronary flow reserve was lower . By regression analysis , neutrophil count significantly correlated with diastolic deceleration time ( r = -0.38 , p < 0.0001 ) , coronary flow reserve ( r = -0.33 , p = 0.0004 ) , and score for change in wall motion ( r = -0.36 , p = 0.0004 ) . Multivariate analysis showed that neutrophil count on admission was an independent predictor of severe microvascular injury ( odds ratio 2.94 , p = 0.02 ) . In conclusion , neutrophilia on admission is associated with impaired microvascular reperfusion and poor functional recovery after primary coronary angioplasty Objective : The aim of this pilot study was to determine whether early atorvastatin treatment will reduce left ventricle ( LV ) remodeling , infa rct size , and improve microvascular perfusion . Background : In animal studies , early statin therapy reduces reperfusion injury after a percutaneous coronary intervention ( PCI ) for acute myocardial infa rct ion ( AMI ) . Methods : Forty‐two consecutive patients ( 82 % male , mean age 61.2 ± 9.8 ) who underwent a primary PCI for a first ST‐elevated AMI were r and omized for pretreatment with atorvastatin 80 mg ( n = 20 ) or placebo ( n = 22 ) and continued with the same dosage daily for 1 week . All patients received atorvastatin 80 mg once daily 7 days after primary PCI . The LV function and infa rct size were measured by magnetic resonance imaging within 1 day , at 1 week , and 3 months follow up . The primary endpoint was the end‐systolic volume index ( ESVI ) at 3 months . Secondary endpoints were global LV function measurements , myocardial infa rct size , biochemical cardiac markers , TIMI flow , and ST‐T elevation resolution . Results : ESVI 3 months after AMI was 25.1 mL/m2 in the atorvastatin arm and 25.0 mL/m2 in the placebo arm ( P = 0.74 ) . The differences in change from baseline to 3 months follow up in global LV function and myocardial infa rct size did not differ between both treatment arms . Furthermore , biochemical markers , TIMI flow , and ST‐T elevation resolution did not differ between atorvastatin and placebo arm . Conclusions : In this pilot study , pretreatment with atorvastatin in an acute myocardial infa rct ion does not result in an improved cardiac function , microvascular perfusion , or decreased myocardial infa rct size . © 2012 Wiley Periodicals Primary and secondary prevention with statins reduce major cardiac events in patients with coronary artery disease . The impact of pretreatment with statins prior to percutaneous coronary intervention ( PCI ) is not well established . The objective of this study was to determine if pretreatment with statins prior to PCI reduce myonecrosis and improve clinical outcome . One hundred nineteen consecutive patients with acute coronary syndrome who underwent PCI were identified . We compared the incidence of myonecrosis defined as peak elevation of CK‐MB or CK three time above upper limit of normal within 24 hr and the 6‐month cardiovascular event rate ( death , nonfatal myocardial infa rct ion unrelated to PCI , target vessels revascularization , and unstable angina requiring hospitalization ) among patients who received statins prior to PCI ( n = 63 ) to those who did not ( n = 56 ) . Pretreated patients were more likely to have history of myocardial infa rct ion or revascularization ( 63 % vs. 43 % ; P = 0.015 ) , hyperlipidemia ( 80 % vs. 48 % ; P = 0.001 ) , hypertension ( 83 % vs. 49 % ; P = 0.02 ) , and use of angiotensin‐converting enzyme inhibitor ( 62 % vs. 38 % ; P = 0.008 ) . The rest of baseline characteristics were similar between the two groups , including use of glycoprotein IIb/IIIa inhibitors , number of diseased vessels , and type of lesions . Patients pretreated with statins had a significantly lower incidence of myonecrosis ( 2 % vs. 10 % ; P = 0.04 ) at 24 hr and a significantly lower clinical event ( CE ) rate at 6 months ( 17 % vs. 21 % ; P = 0.015 ) . Of patients not pretreated with statins , 72 % were taking statins at 6 months as compared to 98 % of pretreated patients . After adjusting for all baseline characteristics , use of statins prior to PCI was associated with a marked decrease in risk of all CEs ( OR = 0.2 ; CI = 0.06–0.63 ; P = 0.006 ) . Statin therapy prior to PCI may reduces peri‐PCI myonecrosis and late cardiac events . These results need to be confirmed in large prospect i ve r and omized trials . Catheter Cardiovasc Interv 2004;62:193–197 . © 2004 Wiley‐Liss , OBJECTIVES This study sought to determine the efficacy of high-dose atorvastatin in patients with ST-segment elevation myocardial infa rct ion ( STEMI ) undergoing primary percutaneous coronary intervention ( PCI ) . BACKGROUND Previous r and omized trials have demonstrated that statin pre-treatment reduced major adverse cardiac events ( MACEs ) in patients with stable angina pectoris and acute coronary syndrome . However , no r and omized studies have been carried out with STEMI patients in a primary PCI setting . METHODS A total 171 patients with STEMI were r and omized to 80-mg atorvastatin ( n = 86 ) or 10-mg atorvastatin ( n = 85 ) arms for pre-treatment before PCI . All patients were prescribed clopidogrel ( 600 mg ) before PCI . After PCI , both groups were treated with atorvastatin ( 10 mg ) . The primary end point was 30-day incidence of MACE including death , nonfatal MI , and target vessel revascularization . Secondary end points included corrected thrombolysis in myocardial infa rct ion frame count , myocardial blush grade , and ST-segment resolution at 90 min after PCI . RESULTS MACE occurred in 5 ( 5.8 % ) and 9 ( 10.6 % ) patients in the 80-mg and 10-mg atorvastatin pre-treatment arms , respectively ( p = 0.26 ) . Corrected thrombolysis in myocardial infa rct ion frame count was lower in the 80-mg atorvastatin arm ( 26.9 + /- 12.3 vs. 34.1 + /- 19.0 , p = 0.01 ) . Myocardial blush grade and ST-segment resolution were also higher in the 80-mg atorvastatin arm ( 2.2 + /- 0.8 vs. 1.9 + /- 0.8 , p = 0.02 and 61.8 + /- 26.2 vs. 50.6 + /- 25.8 % , p = 0.01 ) . CONCLUSIONS High-dose atorvastatin pre-treatment before PCI did not show a significant reduction of MACEs compared with low-dose atorvastatin but did show improved immediate coronary flow after primary PCI . High-dose atorvastatin may produce an optimal result for STEMI patients undergoing PCI by improving microvascular myocardial perfusion . ( Efficacy of High-Dose AtorvaSTATIN Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infa rct ion [ STATIN STEMI ] ; NCT00808717 ) Background Recent data have demonstrated a lower mortality in acute ST-elevation myocardial infa rct ion ( STEMI ) patients with previous treatment with statins , especially in patients with high risk profiles . Moreover , a significant reduction in enzymatic infa rct size in non-STEMI patients could be observed . However , systematic data of the impact of chronic statin pre-treatment on myocardial damage and reperfusion injury assessed with the gold st and ard cardiac magnetic resonance imaging ( CMR ) are lacking . The aim of our prospect i ve study was therefore to assess the effects of a chronic statin pre-treatment on myocardial damage as assessed by CMR in patients with acute reperfused STEMI . BACKGROUND Atorvastatin pretreatment has been reported to reduce myocardial damage in patients undergoing percutaneous coronary intervention ( PCI ) . We sought to investigate the effect of atorvastatin pretreatment on infa rct size in patients with ST-segment elevation myocardial infa rct ion ( STEMI ) . METHODS Patients undergoing primary PCI for ST-segment elevation myocardial infa rct ion within 12 hours after symptom onset were r and omized to an atorvastatin group ( 80 mg before PCI and for 5 days after PCI [ n = 89 ] ) or a control group ( 10 mg daily after PCI [ n = 84 ] ) . The primary end point was infa rct size measured by technetium Tc 99 m tetrofosmin single-photon emission computed tomography between days 5 and 14 . RESULTS Baseline clinical , angiographic , and procedural characteristics were not significantly different between groups except for age and current smoking status . There was no significant difference in infa rct size ( as a percentage of the left ventricle ) between groups ( 22.2 % ± 15.5 % in the atorvastatin group vs 21.6 % ± 15.4 % in the control group , P = .79 ) . The median infa rct size was 19.0 % ( interquartile range 9.0 - 32.0 ) in the atorvastatin group and 18.0 % ( 9.3 - 32.5 ) in the control group ( P = .76 ) . Achievement of myocardial blush grade 2/3 and complete ST-segment resolution at 60 minutes after PCI occurred with similar frequency ( 72.8 % vs 81.9 % , P = .33 and 43.2 % vs 47.5 % , P = .57 , respectively ) . CONCLUSIONS Pretreatment with high-dose atorvastatin followed by further treatment for 5 days did not reduce infa rct size measured by single-photon emission computed tomography in patients undergoing primary PCI BACKGROUND Studies have reported an association between receipt of statin therapy and a reduction in complications after elective percutaneous coronary intervention ( PCI ) . However , there are limited data on the effects of chronic statin therapy before the occurrence of an acute myocardial infa rct ion ( AMI ) . OBJECTIVE This study investigated whether administration of chronic statin therapy before AMI was associated with a reduction in reperfusion injury in AMI patients undergoing PCI . METHODS This was a retrospective study of consecutive patients with a first AMI who underwent successful reperfusion therapy with PCI within 24 hours after the onset of AMI between April 1998 and October 2003 . Patients were stratified according to whether they had or had not been receiving chronic statin therapy for > or = 1 month before the onset of AMI . The following end points were compared after PCI : electrocardiographic resolution of ST segment elevation , defined as a reduction of > or = 50 % from the initial value ; achievement of Thrombolysis in Myocardial Infa rct ion ( TIMI ) grade 3 flow ; corrected TIMI frame count ( cTFC ) ; maximum serum creatine kinase ( CK ) level ; and the type and frequency of ventricular arrhythmias . RESULTS The study enrolled 386 patients , 40 of whom had been receiving statin therapy before the onset of AMI . The clinical characteristics of the 2 groups were similar at baseline , with the exceptions of a significantly higher rate of hyperlipidemia in the statin group compared with the nonstatin group ( P < 0.001 ) , significantly greater chronic use of aspirin therapy ( P < 0.001 ) , and significantly greater chronic use of antihypertensive medications ( beta-blockers : P = 0.004 ; angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers : P = 0.007 ; calcium channel blockers : P = 0.006 ) . Electrocardiographic ST segment resolution after PCI was observed in 87.5 % and 69.9 % of the statin and nonstatin groups , respectively ( hazard ratio [ HR ] : 3.01 ; 95 % CI , 1.15 - 7.90 ; P = 0.025 ) . Achievement of TIMI grade 3 flow after PCI was seen in 95.0 % of the statin group and 83.5 % of the nonstatin group ( HR : 3.75 ; 95 % CI , 0.88 - 16.0 ; P = NS ) . Patients treated with a statin had a significantly lower mean ( SD ) maximum CK level compared with the nonstatin group ( 2300 [ 1449 ] vs 3538 [ 3170 ] IU/mL , respectively ; P = 0.015 ) and a lower cTFC after PCI ( 18.8 [ 4.0 ] vs 24.2 [ 14.2 ] ; P = 0.017 ) . The difference in reperfusion arrhythmias between groups was not statistically significant . After adjustment for baseline covariates , pretreatment with a statin was found to be an independent predictor of ST segment resolution after PCI ( HR : 2.95 ; 95 % CI , 1.08 - 8.09 ; P = 0.035 ) and prevention of impaired coronary flow ( HR : 3.00 ; 95 % CI , 1.63 - 5.55 ; P < 0.001 ) . CONCLUSION In this study , receipt of chronic statin therapy before the onset of AMI was associated with improvement in epicardial perfusion and a reduction in myocardial necrosis after PCI Recent studies emphasized the non-lipid-lowering effects of hydroxymethylglutaryl coenzyme A reductase inhibitors on endothelial function , inflammation , and platelet activation in patients with stable atherosclerosis . This study sought to evaluate the impact of statin pretreatment in patients with acute myocardial infa rct ion ( AMI ) on level of systemic inflammation and myocardial perfusion . A total of 253 consecutive patients undergoing primary angioplasty on a native vessel within 12 hours of AMI were divided into a group with statin pretreatment ( n = 86 ) and control patients ( n = 167 ) . Angiographic myocardial blush grade ( MBG ) after revascularization of the infa rct -related artery was determined to evaluate myocardial perfusion . Statin pretreatment was associated with a lower frequency of increased C-reactive protein ( > or=5 mg/L ) on admission compared with the control group ( 48 % vs 64 % ; p = 0.019 ) . The frequency of normal perfusion ( MBG 3 ) was higher in the statin-pretreatment group than the control group ( 45 % vs 26 % , respectively ; p < 0.001 ) . Statin pretreatment was an independent predictor of normal myocardial perfusion ( MBG 3 ; odds ratio 2.53 , 95 % confidence interval 1.15 to 9.53 , p = 0.022 ) in addition to age < or=70 years and C-reactive protein < 5 mg/L. In conclusion , statin pretreatment in patients with AMI was associated with decreased systemic inflammation and better perfusion after primary angioplasty of the infa rct -related artery

In conclusion , there is a lack of evidence of effectiveness for most waterpipe interventions .

Waterpipe tobacco smoking is growing in popularity despite adverse health effects among users . We systematic ally review ed the literature , search ing MEDLINE , EMBASE and Web of Science , for interventions targeting prevention and cessation of waterpipe tobacco smoking .

INTRODUCTION We explored the differential effect of cessation interventions ( behavioral support sessions with [ BSS+ ] and without [ BSS ] bupropion ) between hookah and cigarette smokers . METHODS We reanalyzed the data from a major cluster-r and omized controlled trial , ASSIST ( Action to Stop Smoking In Suspected Tuberculosis ) , which consisted of 3 conditions : ( a ) behavioral support sessions ( BSS ) , ( b ) behavioral support sessions plus 7 weeks of bupropion therapy ( BSS+ ) , and ( c ) controls receiving usual care . The trial originally recruited 1,955 adult smokers with suspected tuberculosis from 33 health centers in the Jhang and Sargodha districts of Pakistan between 2010 and 2011 . The primary endpoint was continuous 6-month smoking abstinence , which was determined by carbon monoxide levels . Subgroup-specific relative risks ( RRs ) of smoking abstinence were computed and tested for differential intervention effect using log binomial regression ( generalized linear model ) between 3 subgroups ( cigarette-only : 1,255 ; mixed : 485 ; and hookah-only : 215 ) . RESULTS The test result for homogeneity of intervention effects between the smoking forms was statistically significant ( p-value for BSS+ : .04 and for BSS : .02 ) . Compared to the control , both interventions appeared to be effective among hookah smokers ( RR = 2.5 ; 95 % CI = 1.3 - 4.7 and RR = 2.2 ; 95 % CI = 1.3 - 3.8 , respectively ) but less effective among cigarette smokers ( RR = 6.6 ; 95 % CI = 4.6 - 9.6 and RR = 5.8 ; 95 % CI = 4.0 - 8.5 ) , respectively . CONCLUSIONS The differential intervention effects on hookah and cigarette smokers were seen ( a ) because the behavioral support intervention was design ed primarily for cigarette smokers ; ( b ) because of differences in demographic characteristics , behavioral , and sociocultural determinants ; or ( c ) because of differences in nicotine dependency levels between the 2 groups INTRODUCTION Tobacco use in low- to middle-income countries is a major public health concern for both smokers and those exposed to environmental tobacco smoke ( ETS ) . Egypt has made important strides in controlling tobacco use , but smoking and ETS remain highly prevalent . This r and omized intervention sought to improve the target population 's knowledge regarding the hazards of smoking and ETS and to change attitudes and smoking behaviors within the community and the household . METHODS In this 2005 - 2006 study in Egypt 's Qalyubia governorate , trained professionals visited schools , households , mosques , and health care centers in rural villages r and omly selected for the intervention to discuss the adverse effects of smoking and ETS exposure and ways to reduce one 's ETS exposure . Data collected in interviewer-facilitated surveys before and after the intervention period were analyzed in pairwise comparisons with data from control villages to assess the effectiveness of the intervention in achieving its aims . RESULTS The intervention group showed a greater increase in underst and ing the dangers associated with smoking cigarettes and waterpipes and became more proactive in limiting ETS exposure by asking smokers to stop , avoiding areas with ETS , and enacting smoking bans in the home . However , the intervention had little to no impact on the number of smokers and the amount of tobacco smoked . CONCLUSIONS Results are consistent with previous studies showing that changing smokers ' behavior can be difficult , but community-wide efforts to reduce ETS exposure through smoking bans , education , and empowering people to ask smokers to stop are effective . The method can be generalized to other setting In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias INTRODUCTION Tobacco use remains a major public health problem worldwide . Water-pipe smoking is spreading rapidly and threatening to undermine the successes achieved in tobacco control . METHODS A school-based longitudinal study in the city of Irbid , Jordan , was performed from 2008 to 2010 . All seventh- grade students in 19 r and omly selected schools , out of a total of 60 schools in the city , were enrolled at baseline and surveyed annually . RESULTS Of the 1781 students enrolled at baseline 1,701 ( 95.5 % ) were still in the study at the end of the second year of follow-up ( 869 boys , median age at baseline 13 years ) . Ever and current water-pipe smoking were higher than those of cigarette smoking at baseline ( ever smoking : 25.9 % vs. 17.6 % and current smoking : 13.3 % vs. 5.3 % for water-pipe and cigarette smoking , respectively ; p < .01 for both ) but cigarette smoking caught up by the second year of follow-up ( ever smoking : 46.4 % vs. 44.7 % ; p = .32 and current smoking : 18.9 % vs. 14.9 % ; p < .01 ) . Water pipe-only smokers at baseline were twice as likely to become current cigarette smokers after 2 years compared with never smokers ( relative risk ( RR ) = 2.1 ; 95 % CI = 1.2 , 3.4 ) . A similar pattern was observed for cigarette-only smokers at baseline ( RR = 2.0 ; 95 % CI = 0.9 , 4.8 ) . CONCLUSIONS Prevalence of water-pipe and cigarette smoking increased dramatically over the 2-year follow-up period with similar patterns in boys and girls , although girls had lower prevalence in all categories . Water-pipe smoking at baseline predicted the progress to cigarette smoking in the future and vice versa Background Involving children in research studies requires obtaining parental permission . A school-based intervention to delay/prevent waterpipe use for 7th and 8th grade rs in Qatar was developed , and parental permission requested . Fifty three percent ( 2308/4314 ) of the parents returned permission forms ; of those 19.5 % of the total ( 840/4314 ) granted permission . This paper describes the challenges to obtaining parental permission . No research to date has described such challenges in the Arab world . Methods A r and om sample of 40 schools in Doha , Qatar was selected for inclusion in the original intervention . Permission forms were distributed to parents for approval of their child ’s participation . The permission forms requested that parents indicate their reasons for non-permission if they declined . These were categorized into themes . In order to underst and reasons for non-permission , interviews with parents were conducted . Phone numbers of parents were requested from the school administration ; 12 of the 40 schools ( 30 % ) agreed to provide the contact information . A r and om sample of 28 parents from 12 schools was interviewed to reach data saturation . Thematic analysis was used to analyze their responses . Results Reasons for non-permission documented in both the forms and interviews included : poor timing ; lack of interest ; the child not wanting to participate ; and the child living in a smoke-free environment . Interviews provided information on important topics to include in the consent forms , parents ’ decision-making processes regarding their child ’s participation , and considerations for communicating with parents . Many parents also indicated that this was the first time they had been asked to give an informed consent for their child ’s participation in a study . Conclusions Results indicate that more attention needs to be given to the informed parental consent process . Research ers should consider enhancing both the methods of communicating information as well the specific information provided . Before embarking on recruitment of children for studies , formative research on the parental consent process is suggested Background Among Arab citizens in Israel , cigarette and nargila ( hookah , waterpipe ) smoking is a serious public health problem , particularly among the young adult population . With the dramatic increase of Internet and computer use among Arab college and university students , a Web-based program may provide an easy , accessible tool to reduce smoking rates without heavy re source dem and s required by traditional methods . Objective The purpose of this research was to examine the acceptability and feasibility of a pilot Web-based program that provides tailored feedback to increase smoking knowledge and reduce cigarette and nargila smoking behaviors among Arab college/university students in Israel . Methods A pilot Web-based program was developed , consisting of a self-administered question naire and feedback system on cigarette and nargila smoking . Arab university students were recruited to participate in a mixed- methods study , using both quantitative ( pre-/posttest study design ) and qualitative tools . A posttest was implemented at 1 month following participation in the intervention to assess any changes in smoking knowledge and behaviors . Focus group sessions were implemented to assess acceptability and preferences related to the Web-based program . Results A total of 225 participants —response rate of 63.2 % (225/356)—completed the intervention at baseline and at 1-month post study , and were used for the comparative analysis . Statistically significant reductions in nargila smoking among participants ( P=.001 ) were found . The intervention did not result in reductions in cigarette smoking . However , the tailored Web intervention result ed in statistically significant increases in the intention to quit smoking ( P=.021 ) . No statistically significant increases in knowledge were seen at 1-month post study . Participants expressed high satisfaction with the intervention and 93.8 % ( 211/225 ) of those who completed the intervention at both time intervals reported that they would recommend the program to their friends , indicating excellent acceptability and feasibility of the intervention . This was further emphasized in the focus group sessions . Conclusions A tailored Web-based program may be a promising tool to reduce nargila smoking among Arab university students in Israel . The tailored Web intervention was not successful at significantly reducing cigarette smoking or increasing knowledge . However , the intervention did increase participants ’ intention to quit smoking . Participants considered the Web-based tool to be an interesting , feasible , and highly acceptable strategy . Trial Registration Trial Registration : IS RCT N registry IS RCT N59207794 ; http://www.is rct n.com/IS RCT N59207794 ( Archived by WebCite at http://www.webcitation.org/6VkYOBNOJ ) Objectives : This research was undertaken with the aim of assessing the indoor air quality in popular hospitality venues , as also to evaluate the effectiveness of the nationwide comprehensive public smoking ban . The analysis was split into two halves – baseline study taken up prior to implementation of the said ban on 2nd October 2008 , and the follow-up study after it came into effect . Material s and Methods : Twenty-five venues including five restaurants , fourteen resto-bars , two hookah ( smoking water-pipe ) cafes and four pubs were selected using a mix of r and om , convenience and purpose ful sampling . Particulate matter ( PM2.5 ) measurements at these venues were made using TSI SidePak AM510 Personal Aerosol Monitor . Results : The average PM2.5 level in venues where smoking was permitted prior to implementation of ban was found to be 669.95 μg/m3 in the baseline study . Post ban , the average PM2.5 level in same test venues reduced to 240.8 μg/m3 . The hookah cafes were an exception as the average PM2.5 levels exceeded the permissible limits before as well as post ban . Conclusion : The baseline study showed that the hospitality venues had hazardous levels of PM2.5 particles arising from second-h and smoke prior to smoking ban . These decreased by a maximum of 64 % after the law took effect . A substantial improvement in air quality at these venues post implementation of the smoking ban indicated the effectiveness of the law BACKGROUND Waterpipe use has increased dramatically in the Middle East and other parts of the world . Many users exhibit signs of dependence , including withdrawal and difficulty quitting , but there is no evidence base to guide cessation efforts . METHODS We developed a behavioral cessation program for willing-to-quit waterpipe users , and evaluated its feasibility and efficacy in a pilot , two arm , parallel group , r and omized , open label trial in Aleppo , Syria . Fifty adults who smoked waterpipe ≥3 times per week in the last year , did not smoke cigarettes , and were interested in quitting were r and omized to receive either brief ( 1 in-person session and 3 phone calls ) or intensive ( 3 in-person sessions and 5 phone calls ) behavioral cessation treatment delivered by a trained physician in a clinical setting . The primary efficacy end point of the developed interventions was prolonged abstinence at three months post-quit day , assessed by self-report and exhaled carbon monoxide levels of < 10 ppm . Secondary end points were 7 day point-prevalent abstinence and adherence to treatment . RESULTS Thirty percent of participants were fully adherent to treatment , which did not vary by treatment group . The proportions of participants in the brief and intensive interventions with prolonged abstinence at the 3-month assessment were 30.4 % and 44.4 % , respectively . Previous success in quitting ( OR=3.57 ; 95 % CI=1.03 - 12.43 ) predicted cessation . Higher baseline readiness to quit , more confidence in quitting , and being unemployed predicted a better adherence to treatment ( all p-values < 0.05 ) . CONCLUSIONS Brief behavioral cessation treatment for waterpipe users appears to be feasible and effective OBJECTIVE To determine the feasibility of implementing cessation interventions in Syria . METHODS We r and omized 50 smokers to either a brief or intensive behavioral cessation intervention . Adherence to treatment and cessation through 3 months postcessation were calculated . RESULTS Adherence in the intensive group was only moderate and was associated with smoking for more years and higher self-efficacy . Cessation rates in the brief and intensive intervention groups were 16 % and 4 % , respectively . Nicotine dependence predicted abstinence at 3 months . CONCLUSION Important barriers to cessation included perceived dependence , lack of access to pharmacotherapy , poor social support , and water pipe smoking INTRODUCTION Waterpipe tobacco smoking is highly prevalent among young people in some setting s. There is an absence of nationally representative prevalence studies of waterpipe tobacco use and dual use with other tobacco products in young people . METHODS We conducted a secondary analysis of the Global Youth Tobacco Survey , a nationally representative cross-sectional study of students aged 13 - 15 years . Of 180 participating countries , 25 included optional waterpipe tobacco smoking questions : 15 Eastern Mediterranean and 10 Eastern European countries . We calculated the prevalence of current ( past 30-day ) waterpipe tobacco use , including dual waterpipe and other tobacco use , and used logistic regression models to identify sociodemographic correlates of waterpipe tobacco smoking . Individual country results were combined in a r and om effects meta- analysis . RESULTS Waterpipe tobacco smoking prevalence was highest in Lebanon ( 36.9 % ) , the West Bank ( 32.7 % ) and parts of Eastern Europe ( Latvia 22.7 % , the Czech Republic 22.1 % , Estonia 21.9 % ) . These countries also recorded greater than 10 % prevalence of dual waterpipe and cigarette use . In a meta- analysis , higher odds of waterpipe tobacco smoking were found among males ( Adjusted odds ratio [ AOR ] = 1.37 , 95 % confidence interval [ CI ] = 1.18 % to 1.59 % ) , cigarette users ( AOR = 6.95 , 95 % CI = 5.74 % to 8.42 % ) , those whose parents ( AOR = 1.54 , 95 % CI = 1.31 % to 1.82 % ) or peers smoked ( AOR = 3.53 , 95 % CI = 2.97 % to 4.20 % ) and those whose parents had higher educational attainment ( Father , AOR = 1.47 , 95 % CI = 1.14 % to 1.89 % ; Mother , AOR = 1.62 , 95 % CI = 1.07 % to 2.46 % ) . We report on regional- and country income-level differences . CONCLUSIONS Waterpipe tobacco smoking , including dual waterpipe and cigarette use , is alarmingly high in several Eastern Mediterranean and Eastern European countries . Ongoing waterpipe tobacco smoking surveillance is warranted

Several PROMs have been identified to evaluate sexual function in neurologic patients . Strong evidence was found only for the Multiple Sclerosis Intimacy and Sexuality Question naire-15 and Multiple Sclerosis Intimacy and Sexuality Question naire-19 for patients with MS , although evidence was lacking for certain measurement properties as well .

CONTEXT Impaired sexual function has a significant effect on quality of life . Various patient-reported outcome measures ( PROMs ) are available to evaluate sexual function . The quality of the PROMs to be used for neurologic patients remains unknown . OBJECTIVE To systematic ally review which vali date d PROMs are available to evaluate sexual function in neurologic patients and to critically assess the quality of the validation studies and measurement properties for each identified PROM .

INTRODUCTION Cultural sensitivities tend to limit assessment s of sexual dysfunction ( SD ) in Parkinson 's disease ( PD ) . OBJECTIVE To assess the validity and reliability of the Thai translation ( ASEX-Thai ) of the Arizona Sexual Experiences Scale ( ASEX ) . METHOD The validity and reliability of ASEX-Thai were assessed with a r and om sample of 40 PD patients . Back translation and cross-cultural modifications assured content validity . Criterion validity used DSM-IV-TR criteria and receiver operating characteristics ( ROC ) analysis was calculated for cutoff points plus sensitivity and specificity . Internal consistency was assessed with Cronbach 's alpha coefficient . Test-retest reliability was assessed by Pearson 's correlation at baseline and at a 2-month follow-up . RESULT Criterion validity was conducted with a positive correlation between the clinical diagnosis of SD and DSM-IV-TR ( r = 0.601 ; p < 0.001 ) . The ROC analysis differentiated between SD and non-SD patients ( p < 0.001 ) . The cutoff point of ASEX-Thai at ≥16 points effectively screened for SD ( sensitivity 96.2 % , specificity 92.9 % ) . Reliability was documented with the Cronbach 's alpha of all items at baseline and at a 2-month follow-up with values of 0.948 and 0.962 respectively . The Pearson 's correlation also showed highly significant test-retest reliability [ Item 1 ( r = 0.959 , p < 0.001 ) , Item 2 ( r = 0.914 , p < 0.001 ) , Item 3 ( r = 0.944 , p < 0.001 ) , Item 4 ( r = 0.992 , p < 0.001 ) , Item 5 ( r = 0.930 , p < 0.001 ) , and total ASEX-Thai score ( r = 0.883 , p < 0.001 ) ] . CONCLUSION ASEX-Thai is a valid and reliable instrument for the assessment of sexual dysfunction in Thai PD patients Study design : Two r and omized , double-blind , placebo-controlled trials . Objective : To evaluate the efficacy and safety of fampridine sustained-release tablets ( fampridine-SR ) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury ( SCI ) . Setting : United States and Canada . Methods : Patients with incomplete chronic SCI were r and omized to twice daily fampridine-SR 25 mg or placebo , with a 2-week single-blind placebo run-in , a 2-week titration , 12 weeks of stable dosing , 2 weeks of downward titration and 2 weeks of untreated follow-up . Co- primary end points were the change from baseline , averaged over the double-blind treatment period , for Ashworth score ( bilateral knee flexors and extensors ) and a 7-point Subject Global Impression of treatment ( SGI ; 1 , terrible ; 7 , delighted ) . Secondary end points were : Penn Spasm Frequency Scale ; the motor/sensory score from the International St and ards for Neurological Classification of SCI ; Clinician ’s Global Impression of Change of neurological status ; and the International Index of Erectile Function ( men ) or the Female Sexual Function Index ( women ) . Results : The population s were 212 and 203 patients in the two studies , respectively . Changes from baseline in Ashworth score were −0.15 ( placebo ) and −0.19 ( fampridine-SR ) in the first study , and −0.16 ( placebo ) and −0.28 ( fampridine-SR ) in the second study . The between-treatment difference was not significant for either the Ashworth score or the SGI and , with few exceptions , neither were the secondary end points . Fampridine-SR was generally well tolerated ; treatment-emergent adverse events ( TEAEs ) and serious TEAEs were reported with similar frequency between treatments . Conclusion : Fampridine-SR was well tolerated . No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI Introduction and hypothesisThe objective of this study was to create a valid , reliable , and responsive sexual function measure in women with pelvic floor disorders ( PFDs ) for both sexually active ( SA ) and inactive ( NSA ) women . Methods Expert review identified concept gaps and generated items evaluated with cognitive interviews . Women underwent Pelvic Organ Prolapse Quantification ( POPQ ) exams and completed the Incontinence Severity Index ( ISI ) , a prolapse question from the Epidemiology of Prolapse and Incontinence Question naire ( ISI scores ) , the Pelvic Floor Distress Inventory-20 ( PFDI-20 ) , and the Female Sexual Function Index ( FSFI ) . Principle components and orthogonal varimax rotation and principle factor analysis with oblique rotation identified item grouping . Cronbach ’s alpha measured internal consistency . Factor correlations evaluated criterion validation . Change scores compared to change scores in other measures evaluated responsiveness among women who underwent surgery . Results A total of 589 women gave baseline data , 200 returned surveys after treatment , and 147 provided test-retest data . For SA women , 3 subscales each in 2 domains ( 21 items ) and for NSA women 2 subscales in each of 2 domains ( 12 items ) emerged with robust psychometric properties . Cronbach ’s alpha ranged from .63 to .91 . For SA women , correlations were in the anticipated direction with PFDI-20 , ISI , and FSFI scores , POPQ , and EPIQ question # 35 ( all p < .05 ) . PFDI-20 , ISI , and FSFI subscale change scores correlated with Pelvic Organ Prolapse/Urinary Incontinence Sexual Question naire International Urogynecological Association-revised ( PISQ-IR ) factor change scores and with mean change scores in women who underwent surgery ( all p < .05 ) . For NSA women , PISQ-IR scores correlated with PFDI-20 , ISI scores , and with EPIQ question # 35 ( all p < .05 ) . No items demonstrated differences between test and retest ( all p ≥ .05 ) , indicating stability over time . Conclusions The PISQ-IR is a valid , reliable , and responsive measure of sexual function OBJECTIVE To identify determinants of sexual adjustment by persons with spinal cord injury ( SCI ) and quality of the relationship compared with persons in the general population . DESIGN Controlled survey . SETTING Postdischarge community setting . PARTICIPANTS A consecutive series of 252 persons admitted to our spinal unit between November 1982 and July 1991 with traumatic SCI were contacted , 85 of whom persons were excluded : 36 were dead , 37 had recovered , 5 could not be located , 4 were younger than 18 years , 2 had language difficulties , and 1 had a psychiatric illness . Of the remaining 167 persons with SCI , 85 had a stable partner relationship , 75 of whom ( 88 % ) completed and returned the question naires ( median age , 33 years ; range 19 to 76 ) . An age- and sex-matched control group was r and omly selected from the general population . Of the 264 respondents , 155 ( 59 % ) had a stable partner relationship . MAIN OUTCOME MEASURES The 80-item question naire addressed experiences concerning sexual functioning , desire , and activity , sexual behavior , satisfaction with sex life , and aspects of the emotional quality of the relationship . RESULTS Sexual activity and satisfaction was lower among persons with SCI compared with the controls ; the emotional quality of the relationship did not differ . The most important correlates for sexual fulfillment in both groups were found to be the use of a varied repertoire of sexual behaviors and the perception that the partner enjoys and is satisfied with the sexual part of the relationship . CONCLUSION Psychosocial rather than physical factors were important for a satisfying sexual life and relationship . A qualitative study should be undertaken to further explore the complexity of sexual adjustment after SCI OBJECTIVE To describe sexual life in women with spinal cord injury . DESIGN Controlled cross-sectional , question naire . PARTICIPANTS AND METHODS Women , 18 - 65 years , treated at spinal cord centres in Sweden , Denmark , Norway , Finl and and Icel and . 545 women ( 57 % ) completed the question naires . The age-matched control group consisted of 507 women . The 104-item Spinal Cord Injury Women Question naire , was design ed to assess different dimensions of sexuality . RESULTS 80 % of the women with spinal cord injury had engaged in sex after the injury . Reasons for not wanting or not having the courage to be intimate and sexual were physical problems , low sexual desire , low self-esteem and feelings of being unattractive . The motivations of both the women with spinal cord injury and controls to engage in sexual activity were intimacy-based rather than primarily sexual . Being in the right mood both before and during sex to become receptive to sexual stimulation was important . CONCLUSION For women who are able to overcome the physical restrictions and mental obstacles due to injury , it is possible to regain an active and positive sexual life together with a partner . Sexual information and counselling should be available both during initial rehabilitation and later when the women have returned to their homes

Preoperative carbohydrate drinks significantly improved insulin resistance and indices of patient comfort following surgery , especially hunger , thirst , malaise , anxiety and nausea . No definite conclusions could be made regarding preservation of muscle mass . Following ingestion of carbohydrate drinks , no adverse events such as apparent or proven aspiration during or after surgery were reported . Administration of oral carbohydrate drinks before surgery is probably safe and may have a positive influence on a wide range of perioperative markers of clinical outcome .

INTRODUCTION Surgical stress in the presence of fasting worsens the catabolic state , causes insulin resistance and may delay recovery . Carbohydrate rich drinks given preoperatively may ameliorate these deleterious effects . A systematic review was undertaken to analyse the effect of preoperative carbohydrate loading on insulin resistance , gastric emptying , gastric acidity , patient wellbeing , immunity and nutrition following surgery .

The effect on gastric pH and volume of 0 , 6 and 10 ml · kg−1 , of apple juice given 2.5 hours before surgery to children aged five to ten years was investigated in this prospect i ve , r and omized , single-blind study . Gastric contents were aspirated after induction of anaesthesia , and the volume measured . The pH of the gastric aspirate was then assessed using pH paper . Neither gastric volume nor pH immediately following the induction of general anaesthesia were significantly different among the three groups . Gastric volumes after 0 , 6 and 10 ml · kg−1 , of juice averaged ( mean ±SD ) 0.45 ±0.31 , 0.66 ±0.79 and 0.71 ±0.76 ml · kg−1 , respectively ; gastric pH averaged 1.7 ±0.6 , 1.7 ±0.6 and 1.8 ±0.8 , respectively . On the basis of questions asked immediately before induction of anaesthiesia , patients who drank 6 ml · kg−1 of apple juice had decreased thirst and were less irritable and upset before anaesthesia than those who had not ( P < 0.05 ) . It is concluded that drinking large volumes of clear apple juice 2.5 hours before scheduled surgery does not have a measurable effect on gastric volume and pH and may offer benefits such as improved patient comfort . RésuméL’effet sur le volume et le pH gastrique de 0,6 et 10 ml · kg−1 de jus de pomme donné 2.5 heures avant la chirurgie aux enfants âgés de cinq à dix ans a été investigué dans cette étude prospect i ve r and omisée et a simple insu . Le contenu gastrique fut aspiré après induction de l’anesthésie et le volume mesuré . Le pH du sue gastrique aspiré a par la suite été évalué par un papier à pH. Ni le volume gastrique ni son pH n’était significativement différent pour les trois groupes après l’induction de l’anesthesie générale . Le volume gastrique après 0,6 et 10 ml · kg−1 de jus de pomme était en moyenne ( moyenne ±SD ) respectivement 0,45 ±0,31 , 0,66 ±0,79 et 0,71 ±0,76 ml · kg−1 , en moyenne le pH gastrique était de 1,7 ±0,6 , 1,7 ±0,6 et 1,8 ±0,8 . Pour les avoir question né immédiatement avant l’induction de l’anesthésie les patients ayant bu 6 ml · kg−1 de jus de pomme avaient moins soif et étaient moins irritables avant l’anesthésie que ceux qui n’en ont pas eu ( P < 0.05 ) . On conclut que l’ingestion dun large volume de jus de pomme 2.5 heures avant la chirurgie n’a pas d’effet mesurable sur le volume et le pH gastrique et peut offrir des bénéfices tel que l’amélioration du confort du patient The effect of preoperative glucose infusion on preoperative alterations in hepatic glycogen content , the activity of key hepatic glucoregulatory enzymes ( fructose 1,6-diphosphatase [ FDPase ] ) , pyruvate kinase ( PK ) , hormonal developments , and plasma levels of free fatty acids ( FFA ) were investigated in 16 patients undergoing open cholecystectomy . Patients were r and omized to receive ( group G ) or not receive ( group C ) overnight glucose infusion ( 5 mg.kg-1.d-1 ) preoperatively . Infusion of glucose overnight result ed in preoperative elevations of insulin and c-peptide ( P < 0.05 ) and lower plasma levels of FFA , while the same glucose levels were found in both groups , 4.6 mmol/L. During and after surgery , only minor changes in the plasma levels of insulin , c-peptide , catecholamines , glucagon , cortisol , growth hormone , and FFA were found , with minimal differences between groups . The hepatic glycogen content was 65 % higher in group G and a significant reduction was confirmed only in this group of patients during surgery . The higher glycogen content was associated with a higher FDPase activity ratio ( P < 0.05 ) , which remained unchanged during surgery . In contrast , a significant ( P < 0.05 ) increase in the activity of this enzyme was found in group C. The PK activity ratio did not differ between groups and remained unchanged during surgery . The finding of enhanced FDPase activity suggests that the indirect route ( via gluconeogenesis ) represents an important contributor to the increased glycogen formation during glucose infusion . Additionally , surgery in the overnight fasted patient induces enzymatic changes favoring gluconeogenesis . Lastly , preoperative high-dose glucose infusion has only minor effects on the endocrine response , plasma levels of FFA , and glycogen depletion during elective open cholecystectomy The effect of 3 ml·kg-1 of apple juice given 2.6 ± 0.4 hours preoperatively was investigated in 80 healthy children of ages five to ten years in this prospect i ve , r and omized , single blind study . The children who drank apple juice preoperatively had decreased gastric volume , thirst , and hunger ( p < 0.05 ) . The gastric volume in the control group was 0.43 ± 0.46 ml·kg-1 and in the patients who received apple juice the gastric volume was 0.24 ± 0.31 ml·kg-1 . The gastric pH was not significantly different , with the control group ’s gastric pH being 1.7 ± 0.6 and the treated group ’s pH was 2.2 ± 1.2 . Further studies of the effects of different volumes and timing of preoperative clear fluids are indicated in paediatric patients .RésuméNous avons entrepris une étude prospect i ve , r and omisée et à ľaveugle pour déterminer ľeffet de 3 ml · kg-1 de jus de pomme donné 2.6 ± 0.4 h. avant ľopération à 80 enfants agés de 5 à 10 ans . Les enfants qui avaient bu du jus avant ľopération avaient moins f aim et soif et leurs volumes gastriques étaient moindres ( p < 0.05 ) . Le volume gastrique était de 0.43 ± 0.46 ml · kg-1 chez le groupe contrôle , et de 0.24 ± 0.31 ml · kg-1 chez le groupe “ jus de pomm ” . Le pH du liquide se chiffrait à 1.7 ± 0.6 pour les contrôles et à 2.2 ± 1.2 pour les buveurs de jus , écart non significatif . On aura besoin ďautres études pour préciser ľimpact du volume et de ľintervalle ďadministration des liquides clairs chez les enfants Background : Post‐operative insulin resistance and hyperglycaemia are associated with an impaired outcome after surgery . Pre‐operative oral carbohydrate loading ( CHO ) reduces post‐operative insulin resistance with a reduced risk of hyperglycaemia during post‐operative nutrition . Insulin‐resistant diabetic patients have not been given CHO because the effects on pre‐operative glycaemia and gastric emptying are unknown BACKGROUND AND AIMS Preoperative intake of a clear carbohydrate-rich drink reduces insulin resistance after surgery . In this study , we evaluated whether this could be related to increased insulin sensitivity at the onset of surgery . Furthermore , we aim ed to establish the optimal dose-regimen . METHODS Six healthy volunteers underwent hyperinsulinaemic ( 0.8 mU/kg/min ) , normoglycaemic ( 4.5 mmol/l ) clamps and indirect calorimetry on four occasions in a crossover-r and omised order ; after overnight fasting ( CC ) , after a single evening dose ( 800 ml ) of the drink ( LC ) , after a single morning dose ( 400 ml , CL ) and after intake of the drink in the evening and in the morning before the clamp ( LL ) . Data are presented as mean+/-SD . Statistical analysis was performed using the Student 's t-test and ANOVA . RESULTS Insulin sensitivity was higher in CL and LL ( 9.2+/-1.5 and 9.3+/-1.9 mg/kg/min , respectively ) compared to CC and LC ( 6.1+/-1.6 and 6.6+/-1.9 mg/kg/min , P<0.01 vs. CL and LL ) . CONCLUSIONS A carbohydrate-rich drink enhances insulin action 3 h later by approximately 50 % . Enhanced insulin action to normal postpr and ial day-time level at the time of onset of anaesthesia or surgery is likely to , at least partly , explain the effects on postoperative insulin resistance Background Studies showing the improvement of insulin sensitivity by reducing the term of preoperative fasting are mostly done in patients undergoing major operations . More information about the role of shortened preoperative fasting in perioperative metabolism is needed for such elective minor/moderate abdominal procedures as laparoscopic cholecystectomy . We investigated the influence of a carbohydrate-rich drink given 2 h before laparoscopic cholecystectomy on insulin resistance and the metabolic response to trauma . Methods A group of 21 female c and i date s ( 18–65 years old ) for elective laparoscopic cholecystectomy were r and omized to either an 8 h fasting group ( control group : n = 10 ) or to a group receiving 200 ml of a carbohydrate beverage containing 12.5 % ( 25 g , 50 kcal per 100 ml and approximately 285 mOsm ) of maltodextrine 2 h before operation ( CHO group : n = 11 ) . Blood sample s for various biochemical assays were collected both at induction of anesthesia and after the 10th postoperative hour . Insulin resistance was assessed by the HOMA-IR equation ( Insulin ( μU/ml ) × blood glucose (mg/dl)/405 ) . Results There were no postoperative complications . Seventy percent ( 7/10 ) of the controls and 27.3 % ( 3/11 ) of the CHO group experienced at least one episode of vomiting ( RR = 2.42 , 95 % Confidence Interval [ CI ] = 0.88–6.68 ; P = 0.08 ) . Biochemical analysis showed that serum glucose ( P < 0.01 ) , insulin ( P < 0.01 ) , lactate/pyruvate ratio ( P = 0.03 ) , and triglycerides ( P < 0.01 ) for the control group were higher than for the CHO group . The value of HOMA-IR was significantly greater ( P = 0.03 ) in the conventionally fasted patients than in the CHO group . Conclusions Abbreviation of the period of preoperative fasting and administration of a carbohydrate beverage diminishes insulin resistance and the organic response to trauma BACKGROUND Diabetes mellitus is a risk factor for deep sternal wound infection after open heart surgical procedures . We previously showed that elevated postoperative blood glucose levels are a predictor of deep sternal wound infection in diabetic patients . Therefore , we hypothesized that aggressive intravenous pharmacologic control of postoperative blood glucose levels would reduce the incidence of deep sternal wound infection . METHODS In a prospect i ve study of 2,467 consecutive diabetic patients who underwent open heart surgical procedures between 1987 and 1997 , perioperative blood glucose levels were recorded every 1 to 2 hours . Patients were classified into two sequential groups : the control group included 968 patients treated with sliding-scale-guided intermittent subcutaneous insulin injections ( SQI ) ; the study group included 1,499 patients treated with a continuous intravenous insulin infusion in an attempt to maintain a blood glucose level of less than 200 mg/dL. There were no differences between these groups with respect to age , sex , procedure , bypass time , antibiotic prophylaxis , or skin preparation methods . RESULTS Compared with subcutaneous insulin injections , continuous intravenous insulin infusion induced a significant reduction in perioperative blood glucose levels , which led to a significant reduction in the incidence of deep sternal wound infection in the continuous intravenous insulin infusion group ( 0.8 % [ 12 of 1,499 ] ) versus the intermittent subcutaneous insulin injection group ( 2.0 % [ 19 of 968 ] , p = 0.01 by the chi2 test ) . Multivariate logistic regression revealed that continuous intravenous insulin infusion induced a significant decrease in the risk of deep sternal wound infection ( p = 0.005 ; relative risk , 0.34 ) , whereas obesity ( p < 0.03 ; relative risk , 1.06 ) and use of an internal thoracic artery pedicle ( p = 0.1 ; relative risk , 2.0 ) increased the risk of deep sternal wound infection . CONCLUSIONS Use of perioperative continuous intravenous insulin infusion in diabetic patients undergoing open heart surgical procedures significantly reduces major infectious morbidity and its associated socioeconomic costs Glucose metabolism is adversely affected in patients following major surgery . Patients may develop hyperglycemia due to a combination of surgical stress and postoperative insulin resistance . A r and omized trial was conducted to eluci date the effect of preoperative supplementation with carbohydrates and branched-chain amino acids on postoperative insulin resistance in patients undergoing hepatic resection . A total of 26 patients undergoing a hepatectomy for the treatment of a hepatic neoplasm were r and omly assigned to receive a preoperative supplement of carbohydrate and branched-chain amino acid-enriched nutrient mixture or not . The postoperative blood glucose level and the total insulin requirement for normoglycemic control during the 16 h following hepatic resection were determined using the artificial pancreas STG-22 . Postoperative insulin requirements for normoglycemic control in the group with preoperative nutritional support was significantly lower than that in the control group ( P = 0.039 ) . There was no incidence of hypoglycemia ( < 40 mg/dL ) observed in patients , including those with diabetes mellitus , when the STG-22 was used to control blood glucose levels . STG-22 is a safe and reliable tool to control postoperative glucose metabolism and evaluate insulin resistance . The preoperative oral administration of carbohydrate and branched-chain amino acid-enriched nutrient is of clinical benefit and reduces postoperative insulin resistance in patients undergoing hepatic resection Background and objective We studied the effect of three different fasting protocol s on preoperative discomfort and glucose and insulin levels . Methods Two hundred and ten ASA I – III patients undergoing general or gastrointestinal surgery were r and omly assigned to three groups : overnight intravenous 5 % glucose infusion ( 1000 ml ) , carbohydrate-rich drink ( 400 ml ) at 6–7 a.m. , or overnight fasting . The subjective feelings of thirst , hunger , mouth dryness , weakness , tiredness , anxiety , headache and pain of each patient were question ed preoperatively using a visual analogue scale . Serum glucose and insulin levels were measured at predetermined time points preoperatively . Results During the waiting period before surgery , the carbohydrate-rich drink group was less hungry than the fasting group ( P = 0.011 ) . No other differences were seen in visual analogue scale scores among the study groups . Trend analysis showed increasing thirst , mouth dryness and anxiety in the intravenous glucose group ( P < 0.05 ) . The carbohydrate-rich drink group experienced decreasing thirst but increasing hunger and mouth dryness ( P < 0.05 ) . In the fasting group , thirst , hunger , mouth dryness , weakness , tiredness and anxiety increased ( P < 0.05 ) . Both intravenous and oral carbohydrate caused a significant increase in glucose and insulin levels . Conclusion Intravenous glucose infusion does not decrease the sense of thirst and hunger as effectively as a carbohydrate-rich drink but does alleviate the feelings of weakness and tiredness compared with fasting AIM Recent evidence suggests that the provision of energy-containing fluids is safe and may impact positively on markers of recovery . The aims of this study were to assess the tolerance of preoperative carbohydrate fluid administration and to determine its effect on postoperative metabolic and clinical responses . METHODS Patients admitted to the Royal Infirmary of Edinburgh for major , elective abdominal surgery were recruited to this double-blind , r and omised study and received either a placebo drink or carbohydrate ( 12.6g/100ml ) drink ( CHOD ) . Patients consumed 800 ml of their drink on the evening before surgery and 400 ml on the day of surgery 2 - 3 h before the induction of anaesthesia . Nutritional status was determined using body mass index ( BMI ) and upper arm anthropometry ; all measurements were taken preoperatively , postoperatively and at discharge . Blood glucose and insulin concentrations were also measured preoperatively and on the first post operative day . Length of hospital stay ( LOS ) and postoperative complications were recorded . RESULTS Seventy-two patients were recruited and 65 ( 34 male:31 female ) completed this study . Thirty-four patients were r and omised to receive the placebo drink ( control group ) and 31 patients to receive the carbohydrate drink ( CHOD group ) . Groups were well-matched in terms of gender and age . There were no differences between the two groups at baseline for BMI ( control : -25.1+/-1.7 kg/m2 ; CHOD -25.2+/-1.2 kg/m2 ) , upper arm anthropometry or surgical procedure . At discharge loss of muscle mass ( arm muscle circumference ) was significantly greater in the control group when compared with the CHOD group ( control : -1.1+/-0.15 cm ; CHOD : -0.5+/-0.16 cm ; P<0.05 ) . Baseline insulin ( control : 20.7+/-4.9 mU/l ; CHOD : 24.6+/-6.2 mU/l ) and glucose ( control : 6.0+/-1.4 mmol/l ; CHOD 5.7+/-1.4 mmol/l ) were comparable in the two groups and did not differ postoperatively . No complications were recorded as a result of preoperative fluid consumption . Postoperative morbidity occurred in six patients from each group . Median LOS in the control group was 10 days ( IQR=6 ) , and 8 days ( IQR=4 ) in the CHOD group . CONCLUSION Preoperative consumption of carbohydrate-containing fluids is safe . Provision of a carbohydrate energy source prior to surgery may attenuate depletion of muscle mass after surgery . Further studies are required to determine if this preservation of muscle mass is reflected in improved function and reduced rehabilitation time UNLABELLED Infusions of carbohydrates before surgery have been shown to reduce postoperative insulin resistance . Presently , we investigated the effects of a carbohydrate drink , given shortly before surgery , on postoperative insulin sensitivity . METHODS Insulin sensitivity and glucose turnover ( [ 6 , 6,(2)H(2)]-D-glucose ) were measured using hyper-insulinemic , normoglycemic clamps before and after elective surgery . Sixteen patients undergoing total hip replacement were r and omly assigned to preoperative oral carbohydrate administration ( CHO-H , n = 8) or the same amount of a placebo drink ( placebo , n = 8) before surgery . Insulin sensitivity was measured before and immediately after surgery . Patients undergoing elective colorectal surgery were studied before surgery and 24 h postoperatively ( CHO-C ( n = 7 ) , and fasted ( n = 7 ) , groups ) . The fasted group underwent surgery after an overnight fast . In both studies , the CHO groups received 800 ml of an isoosmolar carbohydrate rich beverage the evening before the operation ( 100 g carbohydrates ) , as well as another 400 ml ( 50 g carbohydrates ) 2 h before the initiation of anesthesia . RESULTS Immediately after surgery , insulin sensitivity was reduced 37 % in the placebo group ( P < 0.05 vs. preoperatively ) while no significant change was found in the CHO-H group ( -16 % , p = NS ) . During clamps performed 24h postoperatively , insulin sensitivity and whole-body glucose disposal was reduced in both groups , but the reduction was greater compared to that in the CHO-C group ( -49 + /- 6 % vs. -26 + /- 8 % , P > > 0.05 fasted vs. CHO-C ) . CONCLUSIONS Patients given a carbohydrate drink shortly before elective surgery displayed less reduced insulin sensitivity after surgery as compared to patients undergoing surgery after an overnight fast We studied the effects of different preoperative oral fluid protocol s on preoperative discomfort , residual gastric fluid volumes , and gastric acidity . Two-hundred-fifty-two elective abdominal surgery patients ( ASA physical status I – II ) were r and omized to preparation with a 12.5 % carbohydrate drink ( CHO ) , placebo ( flavored water ) , or overnight fasting . The CHO and Placebo groups were double-blinded and were given 800 mL to drink on the evening before and 400 mL on the morning of surgery . Visual analog scales were used to score 11 different discomfort variables . CHO did not increase gastric fluid volumes or affect acidity , and there were no adverse events . The visual analog scale scores in a control situation were not different between groups . During the waiting period before surgery , the CHO-treated group was less hungry and less anxious than both the other groups ( P ≤ 0.05 ) . CHO reduced thirst as effectively as placebo ( P < 0.0001 versus Fasted ) . Trend analysis showed consistently decreasing thirst , hunger , anxiety , malaise , and unfitness in the CHO group ( P < 0.05 ) . The Placebo group experienced decreasing unfitness and malaise , whereas nausea , tiredness , and inability to concentrate increased ( P < 0.05 ) . In the Fasted group , hunger , thirst , tiredness , weakness , and inability to concentrate increased ( P < 0.05 ) . In conclusion , CHO significantly reduces preoperative discomfort without adversely affecting gastric contents OBJECTIVE To assess the effect of an intensive glucose management protocol in a heterogeneous population of critically ill adult patients . PATIENTS AND METHODS This study consisted of 800 consecutive patients admitted after institution of the protocol ( treatment group , between February 1 , 2003 , and January 10 , 2004 ) and 800 patients admitted immediately preceding institution of the protocol ( baseline group , between February 23 , 2002 , and January 31 , 2003 ) . The setting was a 14-bed medical-surgical intensive care unit ( ICU ) in a university-affiliated community teaching hospital . The protocol involved intensive monitoring and treatment to maintain plasma glucose values lower than 140 mg/dL. Continuous intravenous insulin was used if glucose values exceeded 200 mg/dL on 2 successive occasions . RESULTS The 2 groups of patients were well matched , with similar age , sex , race , prevalence of diabetes mellitus , Acute Physiology and Chronic Health Evaluation II scores , and distribution of diagnoses . After institution of the protocol , the mean glucose value decreased from 152.3 to 130.7 mg/dL ( P<.001 ) , marked by a 56.3 % reduction in the percentage of glucose values of 200 mg/dL or higher , without a significant change in hypoglycemia . The development of new renal insufficiency decreased 75 % ( P=-.03 ) , and the number of patients undergoing transfusion of packed red blood cells decreased 18.7 % ( P=.04 ) . Hospital mortality decreased 29.3 % ( P=.002 ) , and length of stay in the ICU decreased 10.8 % ( P=.01 ) . CONCLUSION The protocol result ed in significantly improved glycemic control and was associated with decreased mortality , organ dysfunction , and length of stay in the ICU in a heterogeneous population of critically ill adult patients . These results support the adoption of this low-cost intervention as a st and ard of care for critically ill patients A carbohydrate‐rich drink ( CHO ) has been shown to reduce preoperative discomfort . It was hypothesized that it may also reduce postoperative nausea and vomiting ( PONV ) Preoperative oral carbohydrate can attenuate postoperative insulin resistance and catabolism , and may have the potential to improve postoperative recovery . There are no data from r and omized studies on postoperative clinical outcome after specific surgical procedures . This study evaluated the clinical effects of a preoperative carbohydrate beverage in patients undergoing laparoscopic cholecystectomy Major surgery is associated with postoperative insulin resistance which is attenuated by preoperative carbohydrate ( CHO ) treatment . The effect of this treatment on clinical outcome after major abdominal surgery has not been assessed in a double‐blind r and omized trial Background : Surgery is succeeded by long‐lasting state of relative peripheral insulin resistance , which is reduced by giving glucose infusion or oral carbohydrate‐rich drinks immediate before operating instead of fasting . The aim of the present study was to investigate whether oral carbohydrate or carbohydrate with peptide drinks preoperatively instead of fasting would improve postoperative voluntary muscle strength , nutritional intake and ambulation , decrease postoperative fatigue , anxiety and discomfort , and reduce the endocrine response to surgery Preoperative oral carbohydrate ( CHO ) reduces postoperative insulin resistance . In this r and omized trial , the effect of CHO on postoperative whole‐body protein turnover was studied

Conclusions — In observational studies , reinstitution of anticoagulation after ICH was associated with a lower risk of thromboembolic complications and a similar risk of ICH recurrence .

Background and Purpose — The safety and efficacy of restarting anticoagulation therapy after intracranial hemorrhage ( ICH ) remain unclear . We performed a systematic review and meta- analysis to summarize the associations of anticoagulation resumption with the subsequent risk of ICH recurrence and thromboembolism .

Background : For patients who survive intracerebral haemorrhage ( ICH ) during treatment with oral anticoagulation ( OAC ) , the balance between the benefits and risks of restarting OAC is unclear . The decision to restart OAC or to start antiplatelet therapy in these patients therefore poses a dilemma for all physicians involved . We assessed the long-term outcome of patients who did or did not restart antithrombotic therapy after OAC-associated ICH . Methods : We conducted a retrospective follow-up study of all patients discharged from our institution after OAC-associated ICH over a 10-year period . Data on the use of OAC or platelet inhibitors and the occurrence of vascular events during follow-up were assessed through question naires and patient files . The primary outcome was recurrent fatal or non-fatal stroke . Secondary outcomes were the occurrence of other haemorrhagic , thrombotic or thromboembolic events . With patients without antithrombotic treatment as reference , we calculated incidence ratios with corresponding 95 % confidence intervals ( CI ) for treatment with OAC and for treatment with antiplatelet therapy . Results : We included 38 patients , of whom 21 ( 55 % ) died during a mean follow-up of 3.5 years . The medication regime changed frequently during follow-up , illustrated by the fact that two thirds of the patients who had resumed OAC within 2 months of ICH terminated this at later points in time . Two recurrent strokes occurred during 35.4 patient-years without antithrombotic medication , 7 during 63.8 patient-years on antiplatelet medication ( incidence ratio 1.9 ; 95 % CI , 0.4 - 9.4 ) , and 3 during 19.5 patient-years on OAC ( incidence ratio 2.7 ; 95 % CI , 0.5 - 16.3 ) . There was only 1 recurrent ICH , which occurred during treatment with OAC . Conclusion : In this observational study , no significant difference in the primary outcome measure was found between the treatment groups , but there was a tendency towards a higher long-term risk of any stroke in patients who resumed OAC or started antiplatelet therapy . However , based on these results it is difficult to draw any concrete conclusions or make any strong recommendations . A r and omized trial to assess the optimal long-term strategy after OAC-related ICH is warranted . Based on the point estimates of our study , such a trial should involve at least 300 patient-years of follow-up BACKGROUND While warfarin-related intracranial hemorrhage ( ICH ) occurs in 0.25%-1.1 % patients per year , little is known about the practice and outcomes of anticoagulant reinitiation . METHODS We studied a cohort of consecutive patients with warfarin-related ICH ( intracerebral or subarachnoid ) admitted to 13 stroke centres in the Registry of the Canadian Stroke Network between July 2003 and March 2008 . We examined patterns of warfarin reinitiation and variables associated with 30-day and 1-year outcomes . RESULTS Among the 284 patients studied ( mean age 74 ± 12 years ) , warfarin was restarted in-hospital in 91 patients ( 32 % ) . Factors associated with restarting warfarin were lower stroke severity ( adjusted odds ratio [ aOR ] 2.07 , 95 % confidence interval [ CI ] ; 1.20 - 3.57 , P = 0.009 ) or presence of valve prosthesis ( aOR 3.07 , 95 % CI ; 1.29 - 7.27 , P = 0.011 ) . Mortality rates were not higher in those who restarted warfarin in-hospital : 31.9 % vs 54.4 % ( 30-day , P < 0.001 ) and 48 % vs 61 % ( 1-year , P = 0.04 ) , and bleeding was not increased . Multivariable predictors of mortality included initial international normalized ratio > 3.0 ( aOR , 3.28 [ 30-day , P < 0.001 ] and 3.32 [ 1-year , P = 0.003 ] ) , greater stroke severity ( aOR , 6.04 [ 30-day ] and 4.22 [ 1-year ] ; both P < 0.001 ) , and intraventricular hemorrhage ( aOR , 2.19 [ 30-day ; P = 0.03 ] and 2.04 [ 1-year ; P = 0.04 ] ) . In selected patients who reinitiated warfarin , there was no increase in 30-day ( aOR , 0.49 ; P = 0.03 ) or 1-year mortality ( aOR , 0.79 ; P = 0.43 ) . CONCLUSIONS In selected patients at high thrombosis risk , reinitiation of warfarin after ICH did not confer increased mortality or bleeding events OBJECT Aneurysmal subarachnoid hemorrhage ( aSAH ) predisposes to delayed neurological deficits , including stroke and cognitive and neuropsychological abnormalities . Heparin is a pleiotropic drug that antagonizes many of the pathophysiological mechanisms implicated in secondary brain injury after aSAH . METHODS The authors performed a retrospective analysis in 86 consecutive patients with Fisher Grade 3 aSAH due to rupture of a supratentorial aneurysm who presented within 36 hours and were treated by surgical clipping within 48 hours of their ictus . Forty-three patients were managed postoperatively with a low-dose intravenous heparin infusion ( Maryl and low-dose intravenous heparin infusion protocol : 8 U/kg/hr progressing over 36 hours to 10 U/kg/hr ) beginning 12 hours after surgery and continuing until Day 14 after the ictus . Forty-three control patients received conventional subcutaneous heparin twice daily as deep vein thrombosis prophylaxis . RESULTS Patients in the 2 groups were balanced in terms of baseline characteristics . In the heparin group , activated partial thromboplastin times were normal to mildly elevated ; no clinical ly significant hemorrhages or instances of heparin-induced thrombocytopenia or deep vein thrombosis were encountered . In the control group , the incidence of clinical vasospasm requiring rescue therapy ( induced hypertension , selective intraarterial verapamil , and angioplasty ) was 20 ( 47 % ) of 43 patients , and 9 ( 21 % ) of 43 patients experienced a delayed infa rct on CT scanning . In the heparin group , the incidence of clinical vasospasm requiring rescue therapy was 9 % ( 4 of 43 , p = 0.0002 ) , and no patient suffered a delayed infa rct ( p = 0.003 ) . CONCLUSIONS In patients with Fisher Grade 3 aSAH whose aneurysm is secured , postprocedure use of a low-dose intravenous heparin infusion may be safe and beneficial Abstract Purpose s : Intracranial haemorrhage ( ICH ) is a rare but potentially devastating complication of oral anticoagulants ( OAC ) . This raises the difficult clinical choice between either permanent cessation of OAC , or continuing OAC and if so , when to restart . To make this choice , one needs to balance the thrombo-embolic risk after cessation of OAC against the risk of recurrent intracranial haemorrhage when OAC are restarted . There are few published data to base this difficult clinical decision on . Methods : We present an observational study of a consecutive series of 108 patients , collected prospect ively and admitted to our department , with an OAC-related intracranial haemorrhage , in whom we assessed the thrombotic event rate and the recurrent intracranial bleeding rate during follow-up . Results : In the 25 patients in whom OAC were reinstituted no new thrombo-embolic events occurred ( 0/506 unprotected patient-days ) . In the group of patients in whom OAC were not restarted ( n = 81 ) , the thrombo-embolic event rate was 8/11590 unprotected patient-days , of which only 2 were cerebrovascular thrombo-embolisms . The overall risk of a thrombo-embolic complication can be estimated to be 0.66 events/1000 patient-days at risk ( 95 % exact confidence limits of 0.3 to 1.3 events/1000 patient-days at risk ) . In three patients the thrombo-embolic event was fatal . We saw recurrent intracranial bleeding in eight patients , 2 of which were fatal . Seven of these occurred before the restarting of the OAC . Conclusions : In OAC-related intracranial haemorrhages , OAC can be stopped safely for a considerable period , with a very low overall thrombotic event rate . The recurrent bleeding risk after restarting OAC is low . Recurrent bleeding mostly occurred before restarting OAC and is probably caused by insufficient or unsustained correction of the initial coagulation deficit . Immediate reversal of anticoagulation provides the patient with the best possible treatment options including surgery . OAC-related intracranial haemorrhages can therefore be actively treated IMPORTANCE Although use of oral anticoagulants ( OACs ) is increasing , there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage ( ICH ) . OBJECTIVE To assess the association of anticoagulation reversal and blood pressure ( BP ) with hematoma enlargement and the effects of OAC resumption . DESIGN , SETTING , AND PARTICIPANTS Retrospective cohort study at 19 German tertiary care centers ( 2006 - 2012 ) including 1176 individuals for analysis of long-term functional outcome , 853 for analysis of hematoma enlargement , and 719 for analysis of OAC resumption . EXPOSURES Reversal of anticoagulation during acute phase , systolic BP at 4 hours , and reinitiation of OAC for long-term treatment . MAIN OUTCOMES AND MEASURES Frequency of hematoma enlargement in relation to international normalized ratio ( INR ) and BP . Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption . Factors associated with favorable ( modified Rankin Scale score , 0 - 3 ) vs unfavorable functional outcome . RESULTS Hemorrhage enlargement occurred in 307 of 853 patients ( 36.0 % ) . Reduced rates of hematoma enlargement were associated with reversal of INR levels < 1.3 within 4 hours after admission ( 43/217 [ 19.8 % ] ) vs INR of ≥1.3 ( 264/636 [ 41.5 % ] ; P < .001 ) and systolic BP < 160 mm Hg at 4 hours ( 167/504 [ 33.1 % ] ) vs ≥160 mm Hg ( 98/187 [ 52.4 % ] ; P < .001 ) . The combination of INR reversal < 1.3 within 4 hours and systolic BP of < 160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement ( 35/193 [ 18.1 % ] vs 220/498 [ 44.2 % ] not achieving these values ; OR , 0.28 ; 95 % CI , 0.19 - 0.42 ; P < .001 ) and lower rates of in-hospital mortality ( 26/193 [ 13.5 % ] vs 103/498 [ 20.7 % ] ; OR , 0.60 ; 95 % CI , 0.37 - 0.95 ; P = .03 ) . OAC was resumed in 172 of 719 survivors ( 23.9 % ) . OAC resumption showed fewer ischemic complications ( OAC : 9/172 [ 5.2 % ] vs no OAC : 82/547 [ 15.0 % ] ; P < .001 ) and not significantly different hemorrhagic complications ( OAC : 14/172 [ 8.1 % ] vs no OAC : 36/547 [ 6.6 % ] ; P = .48 ) . Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 ( 95 % CI , 0.125 - 0.534 ; P < .001 ) for long-term mortality . Functional long-term outcome was unfavorable in 786 of 1083 patients ( 72.6 % ) . CONCLUSIONS AND RELEVANCE Among patients with OAC-associated ICH , reversal of INR < 1.3 within 4 hours and systolic BP < 160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement , and resumption of OAC therapy was associated with lower risk of ischemic events . These findings require replication and assessment in prospect i ve studies . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01829581

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