Travel to mountain areas is popular. However, the effects of acute exposure to moderate altitude on the cardiovascular system and metabolism are largely unknown.To investigate the effects of acute exposure to moderate altitude on vascular function, metabolism and systemic inflammation.In 51 healthy male subjects with a mean (SD) age of 26.9 (9.3) years, oxygen saturation, blood pressure, heart rate, arterial stiffness, lipid profiles, low density lipoprotein (LDL) particle size, insulin resistance (HOMA-index), highly-sensitive C-reactive protein and pro-inflammatory cytokines were measured at 490 m (Zurich) and during two days at 2590 m,  in randomized order. The largest differences in outcomes between the two altitudes are reported.Mean (SD) oxygen saturation was significantly lower at 2590 m, 91.0 (2.0)%, compared to 490 m, 96.0 (1.0)%, p<0.001. Mean blood pressure  and heart rate  were significantly higher at 2590 m, compared to 490 m, but this was not associated with increased arterial stiffness. At 2590 m, lipid profiles improved , LDL particle size increased  and hsCRP decreased  compared to 490 m. No significant change in pro-inflammatory cytokines or insulin resistance was observed upon ascent to 2590 m.Short-term stay at moderate altitude is associated with increased blood pressure and heart rate likely due to augmented sympathetic activity. Exposure to moderate altitude improves the lipid profile and systemic inflammation, but seems to have no significant effect on glucose metabolism.NCT01130948ClinicalTrials.gov  Travel to mountain areas for leisure activities or a professional reason has become increasingly popular for lowland residents. It has been estimated that several million people in the US and Europe travel to moderate altitude each year, many of which have known or unknown arterial hypertension, diabetes mellitus, disturbances in lipid metabolism and cardiovascular disease. Understanding the interactions between hypoxia, measures of cardiovascular function and metabolism is an important requirement for counselling persons travelling to altitude. However, the acute effects of moderate altitude exposure on measures of cardiovascular function and metabolism are still incompletely defined. This is because very few studies, most of which included a small number of subjects and differed regarding the duration of altitude exposure, looked at the effects of moderate altitude on measures of cardiovascular function, glucose and lipid metabolism. In addition, the studied populations differed considerably, with some studies including healthy men and women and others including patients with several comorbidities, thus resulting in contradictory findings do not allow to draw final conclusions We have addressed this uncertainty by performing a randomized, controlled, cross-over trial investigating the effects of acute exposure to moderate altitude on measures of cardiovascular function, glucose and lipid metabolism as well as on measures of systemic inflammation in healthy male adults. We hypothesized that acute exposure to moderate altitude leads to hypoxemia associated with worsening of cardiovascular function, glucose and lipid metabolism as well as with an increase in systemic inflammation.The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.www.consort-statement.org).This was a randomized cross-over trial evaluating the acute effects of hypobaric hypoxia at moderate altitude on measures of vascular function, metabolism, sleep, and psychomotor performance in healthy men. The trial was conducted between June and October 2010 and comprised a baseline study in Zurich and an altitude sojourn of 4 days in Davos (Switzerland). Assessments were performed at 3 elevations: 1) Zurich, 490 m, barometric pressure (PB) 958.59 hPa; 2) Davos Wolfgang, 1630 m, PB 839.93 hPa) Davos Jakobshorn, 2590 m (PB 749.27 hPa). Assessments of vascular function and metabolism were performed at 490 m as baseline and daily during two following days at 2590 m. The trials' outcomes on sleep, vigilance and psychomotor performance will be reported elsewhere. The trial was performed and analysed according to CONSORT guidelines  <18 or >30 kg/mThe study was approved by the local Zurich ethics committee (KEK ZH 2010–0054/1) and registered (NCT01130948). Written informed consent was obtained from all participants.The experiments were conducted according to the standards of the Declaration of Helsinki.Participants were randomized to 4 groups with permuted sequences of altitude exposure according to a balanced block design: group A) 490 m/1630 m/1630 m/2590 m/2590 m, B) 490 m/2590 m/2590 m/1630 m/1630 m, C) 1630 m/1630 m/2590 m/2590 m/490 m, D) 2590 m/2590 m/1630 m/1630 m/490 m . The parAll examinations on cardiovascular and metabolic outcomes reported in this manuscript have only been collected at 490 m and 2590 m. On study days all participants were asked to abstain from sporting activities and received standard meals with an energy content of 600–800 kcal consisting of approximately 50% carbohydrates, 30% protein and 20% fat three times daily . All daytime examinations were performed after waking in the morning after an overnight fast. All clinical measurements were performed by trained physicians. Laboratory and statistical analyses were performed by personnel blinded to randomisation, the altitude and clinical data.Blood pressure and heart rate were measured in triplicate in the morning with a standard digital automatic monitor  in supine position after a period of rest of 5 minutes. The average of the three blood pressure measurements was used for further analysis.Arterial stiffness was estimated by digital volume pulse (DVP) analysis as previously described and validated  Blood was drawn in the morning between 6–7 am and blood samples were stored at −80°C for later analysis. Measurements of highly-sensitive C-reactive protein (hsCRP), IL-6, IL-10 and tumor necrosis factor (TNF)-α, lipid profiles and insulin resistance by homeostatic model assessment (HOMA) were performed from plasma samples as previously described The Dade Behring BN method  was used to measure hsCRP as previously described and validated IL-6, IL-10 and TNF-α were measured by ELISA with commercially available kits . The lower limit of detection for IL-6, IL-10 and TNF-α were 0.03 pg/ml, 0.05 pg/ml and 0.13 pg/ml respectively. The intra- and interassay coefficients of variation were 4.9 % and 6.0 %, respectively for IL-6 and 6.8 % and 7.5 % for IL-10, and 8.5 % and 9.8 % for TNF-α. All blood markers of systemic inflammation were measured in duplicate and in the same batch.Gradient gel electrophoresis was performed at 10–14°C in 2–16% polyacrylamide gradient gels. Gels were subjected to electrophoresis 24 h at 125 V in tris borate puffer (ph 8.3) as previously described Primary outcomes were blood pressure and arterial stiffness index. Additional outcomes were heart rate, blood markers of systemic inflammation, insulin resistance and lipid profiles. To detect clinically relevant differences in mean blood pressure of 5.0 mmHg (SD 6.0) and in stiffness index of 1.0 m/s (SD 1.2) with a two-sided significance level of 0.05 and a power of 80%, a sample size of 46 subjects was necessary All values are presented as mean (SD) or median (quartiles) as appropriate. Statistical analyses were performed with Statistica V6.0 .Changes in the measured variables from Zurich (490 m) to Davos Jakobshorn (2590 m) were assessed by ANOVA for repeated measurements with Fisher post hoc analysis or non- parametric Friedman ANOVA and Wilcoxon post hoc analysis as appropriate. Statistical significance was assumed at a probability of p<0.05 applying a Bonferroni correction.2.51 male subjects were eligible for entry, were randomised and completed the study protocol . The meaAs expected oxygen saturation was significantly lower on both days at 2590 m  and blooThere was no significant change in total and LDL cholesterol upon ascent to 2590 m . HoweverHsCRP decreased significantly upon ascent to 2590 m , howeverThere was no significant change in blood glucose, insulin and insulin resistance as assessed by HOMA upon ascent to 2590 m .This is the first randomised controlled study to investigate the effects of acute exposure to moderate altitude on vascular function, glucose and lipid metabolism as well as on systemic inflammation in healthy males. We found that exposure to moderate altitude was associated with significant increases in blood pressure and heart rate, possibly due to augmented sympathetic activity. Short-term stay at moderate altitude was associated with improvements in lipid profiles and a decrease in systemic inflammation. However, moderate altitude did not have a significant effect on glucose metabolism.2 91%). Exposure to mild hypobaric hypoxia was associated with considerable increases in both blood pressure and heart rate  did not change significantly at moderate altitude in the current study. This is concordant with the report of Rhodes et al. Upon ascent to moderate altitude lipid profiles improved significantly in our study, i.e. a decrease in triglycerides and total cholesterol/HDL ratio as well as an increase in HDL was observed . MoreoveThese effects may be sustained, as it has been found in epidemiological studies that HDL levels increase when living at higher altitude We observed no significant effect of acute exposure to moderate altitude on various measures of glucose metabolism in healthy humans. This is in contrast to a Chinese study which reported improvement of glucose tolerance as assessed by oral glucose tolerance testing (OGTT) after 3 days at 2400 m in 9 untrained subjects There is some evidence that severe hypobaric, hypoxic conditions at high altitude stimulate the expression of pro-inflammatory markers such as hsCRP and IL-6 Our study has some limitations; as it was designed to assess the short-term effects of moderate altitude exposure, we do not know whether the observed effects on the cardiovascular system, lipid metabolism and systemic inflammation are sustained during a longer stay at moderate altitude; a question that needs to be addressed in future studies. As we selectively included healthy male subjects to study the effects of moderate altitude in a large homogeneous population, the findings of the current study should be extrapolated with caution to females and patients with cardiovascular or metabolic disease. Although it is conceivable that similar effects can be expected in females and such patients, this will need to be proven in further studies.In conclusion, the current study has shown that a short-term stay at moderate altitude is associated with mild hypoxemia leading to increased blood pressure and heart rate, likely due to augmented sympathetic activity. In contrast, exposure to moderate altitude seems to improve the lipid profile and systemic inflammation, however, it seems to have no relevant effect on glucose metabolism.Checklist S1CONSORT Checklist.(DOC)Click here for additional data file.Protocol S1Trial Protocol.(PDF)Click here for additional data file.


This study describes the single center experience and long-term results of ABOi kidney transplantation using a pretransplantation protocol involving immunoadsorption combined with rituximab, intravenous immunoglobulins, and triple immune suppression. Fifty patients received an ABOi kidney transplant in the period from 2006 to 2012 with a follow-up of at least one year. Eleven antibody mediated rejections were noted of which 5 were mixed antibody and cellular mediated rejections. Nine cellular mediated rejections were recorded. Two grafts were lost due to rejection in the first year. One-year graft survival of the ABOi grafts was comparable to 100 matched ABO compatible renal grafts, 96% versus 99%. At 5-year follow-up, the graft survival was 90% in the ABOi versus 97% in the control group. Posttransplantation immunoadsorption was not an essential part of the protocol and no association was found between antibody titers and subsequent graft rejection. Steroids could be withdrawn safely 3 months after transplantation. Adverse events specifically related to the ABOi protocol were not observed. The currently used ABOi protocol shows good short and midterm results despite a high rate of antibody mediated rejections in the first years after the start of the program. Matching for the antigens of the human ABO blood group system is necessary when foreign cells or organs are considered for donation. If not matched properly, the circulating anti-A and/or anti-B blood group antibodies of the recipient will bind to the antigenic moieties of the cell surface-bound A and B blood group molecules within the kidney transplant . The antPretreatment of the recipient is aimed at substantial lowering of the concentration of circulation antibodies before transplantation and reducing the subsequent production of these antibodies. To this end, a number of protocols have been developed that originally included plasmapheresis for antibody removal and splenectomy for permanent reduction of antibody production. In most protocols, high dose intravenous immunoglobulins were also perioperatively given as they exert a pleiotropic immune suppressive effect, particularly in the case of antibody mediated immune diseases. However, in recent years new protocols have been developed based on the use of the B cell depleting antibody rituximab and the availability of an immunoadsorption column that specifically binds anti-A or anti-B antibodies. This column is able to clear efficiently these antibodies from the plasma, thereby obviating the need for plasma exchange. The Swedish ABOi kidney transplantation protocol was among the first that successfully combined these new treatment modalities into a highly effective pretreatment protocol . PublishIn our transplantation center in The Netherlands, we adopted the Swedish protocol and started the ABOi transplantation program in 2006. Over the years, we have left out parts of this protocol and the use of steroids was stopped after 3 months in the posttransplantation period, similar to our standard immune suppressive protocol for ABOc patients.The long-term results of the first 50 ABOi kidney transplants in a period of 5 years are now reported in detail and safety and long-term results are in accordance with other reports.However, early antibody mediated rejections were observed more frequently than previously described although in the majority timely treatment was effective. Postoperative removal of antibodies and continuation of prednisone beyond three months after transplantation did not appear to be essential for the success of the program.2) one month prior to kidney transplantation. Two weeks before transplantation, mycophenolic acid (1000 mg bid), tacrolimus twice daily (target through level 10–15 mg/L), and prednisone 20 mg once daily were given. The immunoadsorption procedure was performed daily before the transplantation. The number of sessions was dependent on the height of the titer of antidonor blood group antibodies and the rebound after every session. Therefore, the number of pretransplantation immunoadsorptions varied with a median of 4 sessions (range from 0 to 7). During the procedure, 6 liters of plasma was passed over the column and antibody titers were assessed before and after the procedure. The kidney transplantation was performed the day after the last immunoadsorption but only if the post-adsorption IgM and IgG antibody titers were below 1 : 8. In 4 patients no immunoadsorption was performed as the anti-ABO titers were already <1 : 8. Following the original protocol, we performed 3 immunoadsorptions at days 1, 4, and 7 postoperatively in the first 25 patients. The day before kidney transplantation, after the last immunoadsorption, 0.5 gram/kg IVIG was given. In all patients, prednisone was stopped 3 months after transplantation and tacrolimus and mycophenolic acid continued, following our standard posttransplantation treatment protocol. No T cell depleting agent was used for induction therapy.Living ABOi kidney donor-recipient combinations were evaluated for the ABOi procedure after routine pretransplantation screening. Patients with titers of IgM and IgG antibodies against blood group A or B below or equal to 1 : 128 were considered eligible for ABOi kidney transplantation. At first, only O recipients and AB donors were included. The remaining ABOi couples participated in the Dutch national kidney exchange program, because of their good chance to find suitable donors. The protocol described by Tydén et al.  was follThe percentage of CMV seropositive patients was 66% and routinely all our transplantation patients, except for CMV−/− combinations, received prophylaxis with valganciclovir during the first 6 months after kidney transplantation. Routine kidney biopsies were performed in the first years of our ABOi kidney transplantation program but this policy was abandoned, as it did not contribute to clinical decision-making see .A kidney biopsy by indication was performed if rejection was suspected on the grounds of an unexpected halt in improvement or worsening of kidney function. Histological confirmation of rejection was obtained by following the Banff criteria 07 for acute cellular and antibody mediated rejection (AMR). Acute AMR was treated with extra immunoadsorptions, high dose steroids (1000 mg prednisolone/day for 3 days), and IVIG (1 gram/kg). In case of unresponsiveness, T cell depleting therapy was given according to our local protocol. The first 25 patients received postoperative immunoadsorptions per protocol and were routinely monitored for isoagglutinin titers after transplantation. As the isoagglutinin titers remained low and no rebound occurred, we abandoned the policy of routine posttransplantation immunoadsorptions.For the purpose of comparison, 2 cases of ABO compatible kidney transplantation were selected from the same period and matched for age and number of HLA mismatches for every case of ABOi kidney transplantation. The posttransplantation immune suppressive medication protocol was similar to the ABOi protocol except for induction therapy with basiliximab in all patients from 2007 onwards.Patient serum was tested for the presence of IgM and IgG antibodies against the ABO-blood group antigens of the donor using the red blood cells (RBC) of the donor. Hemagglutination was assessed fully automated using the ORTHO BioVue system column agglutination technology. Test RBC, with or without serum, were placed in the chamber above the 6-microcolumn cassette preloaded with diluent and/or reagent and glass beads. Upon centrifugation, RBC are forced through the bead column where agglutinated cells are trapped, while unagglutinated RBC travel to the bottom of the column forming a discrete pellet. The isohemagglutinin titer is determined by the highest dilution of patient serum that still results in donor RBC agglutination.t-tests. Skewed distributed continuous variables are presented as medians and compared using the nonparametric Mann-Whitney U test. Categorical variables are presented as numbers and/or percentages. For selected comparison between two group proportions, the chi-square test was used. Survival percentages were analyzed with the Kaplan-Meier method. A P value of less than 0.05 was considered significant; all probabilities were 2-tailed.The SPSS software version 18.0 was used for all statistical tests. Descriptive statistics were used to summarize baseline characteristics. Distribution of data was tested using the Kolmogorov-Smirnov test. Continuous variables with a normal distribution are presented as means (SD) and compared using parametric From the start of the ABOi program in 2006 until March 2012, a total of 50 patients received an ABOi kidney transplant from a living donor and clinical follow-up was at least one year with a median follow-up of 38 months. The clinical and demographical patient characteristics are shown in P = 0.43). Two patients in the ABOi group died during follow-up; one committed suicide and one patient died because of abdominal sepsis due to an incarcerated hernia cicatricalis. Serum creatinine concentrations at 1 and 3 years follow-up were significantly higher (P < 0.05) in the ABOi group (median 137 μmol/L and 154 μmol/L) compared to the ABOc group (median 114 μmol/L and 123 μmol/L). This difference in graft function was largely attributable to the decreased graft function in ABOi patients after their AMR had resolved. The median serum creatinine concentration in the ABOi patient group without AMR was 135 μmol/L at 1 year and 124 μmol/L at 3 years follow-up. For ABOi patients with early AMR, these values were 172 μmol/L and 172 μmol/L, respectively. Two patients had an exceptionally poor renal function at 3 months after transplantation. One case was caused by a surgical problem leading to severe problems with renal blood supply and subsequent partial renal infarction and the other case was due to an AMR resistant to treatment. Of note is one patient that presented 5 months after transplantation with an urosepsis with Serratia species and a very severe acute AMR necessitating transplantectomy. Anti-A titers were sharply risen (IgM > 5000 and IgG 512).The majority of ABOi patients showed an uncomplicated clinical course and graft survival censored for death at 1 year, 3 years, and 5 years was 96%, 90%, and 90% compared to, respectively, 98%, 96%, and 96% in the ABOc group . ABOi grIn eleven patients, acute AMR was observed, all within the first week after transplantation except for the case of late acute AMR described above. Donor specific antibodies against HLA were only found in 2 patients, both having anti-HLA-DQ7 antibodies with a MFI of 20.000 in the single antigen beads Luminex assay. The C4d staining was positive in 8 biopsies, weak to focally positive in 2, and negative in 1 kidney biopsy. Five of these early rejections were categorized as AMR at the time of biopsy and responded to treatment with IVIG and steroids. In 5 cases, the renal biopsy showed a mixed type rejection with evidence for the coexistence of both cellular and AMR. T cell depleting therapy was used in case of an inadequate response to IVIG and steroids. In one of these patients, graft loss occurred 6 months after transplantation because of treatment resistant AMR. One patient had an acute cellular rejection at 7 months when his tacrolimus through level was inadvertently low.Routine allograft kidney biopsies at day 7 after kidney transplantation showed C4d positive staining in 8 out of 19 (42%) patients but without other positive criteria to support the diagnosis of AMR.We could not find any significant relation between antibody titers postoperatively and subsequent AMR, as all titers remained low after transplantation . Because of this observation, we stopped the posttransplantation immunoadsorptions after the first 25 patients. This change in protocol did not alter the frequency of AMR and, in fact, most AMR episodes were observed in the patients that received posttransplantation immunoadsorptions (9 out of 11 patients with AMR). In the group of ABOi patients with an early AMR episode, only one patient was diagnosed with transplant glomerulopathy seven years after transplantation.n = 2), BK virus (n = 3), and herpes zoster virus (n = 3). In addition, 1 case of Pneumocystis carinii pneumonia was recorded. The frequency of these infections is in the range of our ABO compatible program and cannot be specifically related to the use of rituximab or IVIG.All adverse events, possibly related to a change in immune suppression, notably the use of rituximab and IVIG, were recorded. The posttransplantation viral infections in the ABOi group were caused by cytomegalovirus (Newly developed desensitization protocols have greatly facilitated the development of ABOi kidney transplantation programs in many countries. Similar to other groups, we have successfully applied the Swedish desensitization protocol for more than 5 years and did not observe any significant side effects. By combining the immunoadsorption procedure with hemodialysis, it was also possible to reduce the total number of procedures. This is not only time-effective but also less burdensome for dialysis patients.In accordance with a number of other studies –11, the In agreement with the experience of others , 18, we We did not observe a relation between posttransplantation anti-A and B titers and rejection and all posttransplantation titers remained low. Therefore, we removed the posttransplantation immunoadsorptions from the protocol. As stated before, the frequency of AMR actually was lower in the 25 patients who did not receive the postoperative immunoadsorptions. Other groups have also reported on the results of ABO-incompatible transplantation without posttransplantation plasmapheresis or immunoadsorption, confirming that such a strategy can indeed be followed without a significant increase in the incidence of AMR , 15, 20.The combined elements of the current ABOi protocol have been chosen on a rationale based on the proposed mechanism of action of each drug. For instance, pretreatment with rituximab depletes the circulating B cell population. This may be important in the prevention of increased anti-A and anti-B antibody synthesis after ABOi kidney transplantation as rituximab treatment diminishes de novo humoral immune responses. However, a recent report showed that a rituximab-free ABOi protocol yields similar excellent short- and long-term results after kidney transplantation . This isGiven these results, it seems that a simplified protocol with immunoadsorption and immune suppressive drugs in the pretransplantation period is equally effective. The need for IVIG in the ABOi protocol remains to be established as this is not a standard procedure in some other ABO-incompatible kidney transplantation protocols , 20, 24.After transplantation, we routinely stopped prednisone and continued with tacrolimus and MMF. Others found that this policy may lead to an increase in the incidence of acute rejection and is associated with an decreased graft survival . HoweverIn conclusion, the “Swedish protocol” with immunoadsorption, IVIG, and rituximab, added to a standard triple immune suppressive regimen, has been used successfully for more than 5 years in our transplantation center despite an initial high frequency of AMR. It allows for ABOi kidney transplantation with good long-term graft survival comparable to ABO compatible kidney transplantation. Important questions, such as the upper level of anti-A and anti-B that can be accepted before kidney transplantation and the optimal preconditioning treatment, remain to be answered. The ABOi treatment protocol is of value for those patients that cannot be matched to a donor kidney because of blood group incompatibility. Although our center is involved in an effective national donor kidney exchange program, the O positive recipients benefit in particular from the ABOi protocol as they have the lowest chance of success in the kidney exchange program , 27.


Only approximately half of patients with hypertension have their blood pressure controlled, due in large part to the tendency of primary care providers (PCPs) not to intensify treatment when blood pressure values are elevated.This study tested the effect of an intervention designed to help patients ask questions at the point of care to encourage PCPs to appropriately intensify blood pressure treatment.PCPs and their patients with hypertension (N=500) were recruited by letter and randomized into 2 study groups: (1) intervention condition in which patients used a fully automated website each month to receive tailored messages suggesting questions to ask their PCP to improve blood pressure control, and (2) control condition in which a similar tool suggested questions to ask about preventive services . The Web-based tool was designed to be used during each of the 12 study months and before scheduled visits with PCPs. The primary outcome was the percentage of patients in both conditions with controlled blood pressure.P=.27) groups. More intervention condition participants discussed having a creatinine test  and urine protein test , but no group differences were observed in the rate of testing. The control condition participants reported more frequent discussions about tetanus and pneumonia vaccines and reported more tetanus  and pneumonia  vaccinations after 12 months.Of 500 enrolled patients , 418 (83.6%) completed the 12-month follow-up visit. At baseline, 289 (61.5%) of participants had controlled blood pressure. Most  participants used the intervention during at least 6 of 12 months and 222 (62.5%) reported asking questions directly from the Web-based tool. There were no group differences in asking about medication intensification and there were no differences in blood pressure control after 12 months between the intervention condition  and control condition  and the intervention condition led to more discussions of hypertension-relevant tests . By providing patients with individually tailored questions to ask during PCP visits, this study demonstrated that participants were likely to discuss the questions with PCPs. These discussions did not, however, lead to improvements in blood pressure control.ClinicalTrials.gov NCT00377208; http://clinicaltrials.gov/ct2/show/NCT00377208 (Archived by WebCite at http://www.webcitation.org/6IqWiPLon). Hypertension is one of the most common chronic illnesses in the United States, affecting more than 1 in 4 adults . ClinicaGiven the contribution of hypertension to cardiovascular disease and the relatively high rates of uncontrolled blood pressure, many intervention methods have been developed and tested. Team-based care, for example, in which the patient’s primary care provider works with other professionals, such as nurses, pharmacists, dietitians, social workers, and community health workers, has consistently been observed to improve blood pressure control ,5. The Gpatient activation, has been increasingly described as a strategy to improve self-management of chronic diseases such as hypertension .A fifth potential limitation is that detailed covariate data were not collected and may have differed between conditions, yet were not adjusted for. Physical activity, alcohol intake, and salt intake each can influence blood pressure , yet werThere are several strengths to our study. First, the study used an active treatment control group. Not only did this limit participant attrition and control for contact time, the active treatment control condition provided data to document that the intervention was effective at increasing preventive care, limiting concerns over whether participants had actually used the intervention as it was designed. Second, using the Internet as a communication medium makes what is learned easily disseminated. Although most Web-based studies to date have not shown major health benefits  , some in


We sought to investigate the capacity of cerebral autoregulation and cerebrovascular reactivity (CVR) in patients with middle cerebral artery (MCA) stenosis.Twenty-one patients with MCA stenosis diagnosed by magnetic resonance angiography and 15 healthy controls were enrolled. Cerebral autoregulation was assessed by autoregulatory parameters (rate of recovery/phase/gain) derived from transfer function from spontaneous oscillations of cerebral blood flow velocity and blood pressure. CVR was tested by a rebreathing maneuver.Rate of recovery, phase and CVR estimated from moderate MCA stenosis  were significantly different (p<0.05) from controls . Rate of recovery , phase ) and CVR  were all significantly correlated with the degree of stenosis.Cerebral autoregulation and CVR were impaired in patients with ≥ 50% MCA stenosis. The measures of both hemodynamic properties were inversely correlated with the stenotic degree. Intracranial artery occlusive diseases, especially middle cerebral artery (MCA) stenosis, are major causes of ischemic stroke in Asian, Black, and Hispanic populations 2), autonomic function, intracranial pressure, and etc., whereas CVR is solely in connection with vasodilation or vasoconstriction. It hence necessary to investigate these two mechanisms in patients with MCA stenosis.A number of studies reported that stenosis in internal carotid artery (ICA) may impair cerebral hemodynamics, including cerebral autoregulation and cerebrovascular reactivity (CVR), which increases the risk of cerebral ischemic events 2.With the advent of transcranial Doppler (TCD) and continuous blood pressure measurement techniques, dynamic cerebral autoregulation, considering short term dynamics between cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP), has been widely studied using transfer function analysis (TFA), providing information both in frequency and time domain Applying TFA, Haubrich et al. demonstrated that the phase shift between ABP and CBFV oscillations were reduced with increasing degree of MCA stenosis compared with controls The study was approved by the Peking Union Medical College Hospital Research Ethics Committee and each participant gave written informed consent.Twenty-one patients with stenosis in M1 segment of MCA diagnosed by magnetic resonance angiography were recruited from March to April, 2012. Patients were excluded from the study, if they had coexistent ≥50% ipsilateral ICA stenosis, stroke or TIA onset within 3 months, or severe WMD  Fifteen age-matched healthy individuals were recruited as control subjects. Controls who were found to have carotid artery and intracranial stenosis by TCD were excluded All patients were imaged using a 3T scanner . The typical magnetic resonance image (MRI) protocol included at least T1 and T2-weighted images, fluid- attenuated inversion recovery (FLAIR), and 3-dimensional time-of-flight magnetic resonance angiography (MRA). The FLAIR parameters were as follows: repetition time/echo time, 8000/165 ms; number of excitations, 1; flip angle, 90°; field of view, 24 cm × 24 cm; matrix size, 288×192; slice thickness, 6 mm; and slice gap, 1 mm. MRA was performed using the following parameters: repetition time/echo time, 27/6.9 ms; number of excitations, 1; flip angle, 20°; field of view, 24 cm × 16 cm; matrix size, 320×256; and slice thickness, 1.6 mm.The degree of MCA stenosis was graded as mild (<50%), moderate (50%–69%), or severe stenosis  The severity of white matter lesion was assessed by using FLAIR images, except for one patient using T2-weighted images, whose motion artifact was severe on FLAIR. Both the periventricular hyperintensity and deep white matter hyperintensity of each side were graded into 3 stages  by a radiologist, according to the Fazekas rating scale 2) was measured with an infrared capnometer  connected via a breathing mask cover the nose during nasal expiration. All the subjects breathed spontaneously in supine position. After a resting time of 10 minutes, the CBFV of bilateral MCAs, ABP, and PETCO2 were recorded for at least 5 minutes. And then a half blocked long tube  was connected with the mask for 2 minutes, which composed a semi-closed system for the accumulation of exhaled CO22 in the semi-closed tube, the CO2 inhalation of the subject was increased (2) were recorded online in a sample rate of 100 Hz and stored on a hard disk for further analysis.Bilateral flow velocity of MCAs was measured via TCD  by using 2 MHz transducers fixed to the head with the headframe . The distal segment of the affected MCA was insonated, at the depth of 45 to 50 mm. Continuous beat-to-beat ABP was registered by a servo-controlled finger plethysmograph  in the right hand positioned at the heart level. End-tidal partial pressure of carbon dioxide  The CVR was calculated as the maximum percentage increase of CBFV during hypercapnia per unit increase in PETCO2 was used to compare categorical variables between groups. The correlation between autoregulatory parameters and degree of MCA stenosis, was analyzed by Spearman's method. The correlation between phase shift and CVR was analyzed by Pearson's method. A p value less than 0.05 was considered statistically significant. All statistical analysis was done with SPSS 16.0 .In statistical analysis, Student's t-test, Analysis of variance (ANOVA) and SNK-q test were performed to compare the continuous variables across groups, and Pearson χAmong all the 21 patients recruited, six could be classified as symptomatic (four experienced ischemic stroke and two had TIA). More patients had history of hypertension compared with controls, but there were no significant difference between cases and controls in age, sex, history of diabetes, and previous or current smoking .All subjects were examined bilaterally except for 2 patients with inadequate temporal window of the unaffected side. Thus, a total of 70 MCAs were investigated including 32 stenotic MCAs and 38 normal MCAs . The distribution of the 32 stenotic MCAs was as follows: mild stenosis, 8 hemispheres; moderate stenosis, 11 hemispheres; and severe stenosis, 13 hemispheres.2 was 33.10±5.06 mmHg during normocapnia, and 46.21±4.15 mmHg during hypercapnia. And the rebreathing procedure induced an increase of ABP about 3.98±4.23 mmHg.The average PETCOTime and frequency analysis of cerebral autoregulation using transfer function were shown in In the frequency domain, the gain estimated from the controls and the patients all showed the shape of a high-pass filter, suggesting autoregulation was active . HoweverWith respect to CVR, the value was also significantly reduced in hemispheres with moderate to severe stenosis compared with controls , Fig. 3CThe CVR was significantly correlated with phase shift and RoRc, with the correlation coefficient of 0.44 and 0.38 (p<0.001), pooling all hemisphere (n = 71).In general, the autoregulatory parameters (phase/RoRc) derived from transfer function showed that the effectiveness of cerebral autoregulation is inversely correlated with the degree of stenosis. CVR is also significantly decreased with respect to the degree of stenosis. We also found that the measures of both mechanisms were significantly correlated. These major findings are in line with previous studies on cerebral autoregulation and CVR 2It is however worth noting that the transfer function gain estimated in the patients with mild stenosis is higher than that in the controls. Though it is expected that impaired autoregulation results in higher gain as it indicates a less dampening effect, this finding, however, disagrees with previous studies on ICA and MCA stenosis We found significant but relatively low correlation coefficients between CVR and the autoregulatory parameters – the phase shift and RoRc . This is in consistent with previous study in ICA stenosis Although artery-to-artery embolism is considered as the major mechanism causing ischemia in intracranial atherosclerotic disease, hypo-perfusion with impaired embolism clearance may also play a role According to our results, cerebral autoregulation was significantly impaired in patients with moderate to severe MCA stenosis. Therefore, it should be cautious when considering antihypertensive therapy for these patients, as cerebral blood flow may become ‘vulnerable’ to the changes of ABP. For instance, drops in ABP might result in hypo-perfusion, that may impair the clearance of emboli and thereby increase the risk of ischemia. Thus assessment of cerebral hemodynamics in patients with intracranial stenosis should be considered, especially for the guidance of hypertensive therapy.In summary, this study shows that cerebral autoregulation and CVR are impaired in patients with moderate to severe MCA stenosis. Furthermore, with increasing degree of stenosis, the impairment of autoregulation and CVR tend to be worsened. The assessment of these two hemodynamic mechanisms might thus be helpful in monitoring the progress of MCA stenosis.


The paper reviews mechanisms underlying autonomic disorders, with a focus on cardiovascular dysfunction. Neurosurgical approaches are described for medically refractory hypertension and orthostatic hypotension. After review of microvascular decompression of the rostral ventrolateral medulla, stereotactic CT and MRI guided deep brain stimulation of the periaqueductal grey matter (PAG) is evaluated. Results are presented from patient studies showing reductions in blood pressure with ventral PAG stimulation and increases in blood pressure with dorsal PAG stimulation. A rationale for the treatment of autonomic disorders by neurosurgical intervention is discussed. The autonomic nervous system comprises segregated and differentially regulated neuronal pathways linking the central nervous system with endocrine glands, smooth muscle and visceral organs via central neuron groups and peripheral ganglia , 2. DisoOf the autonomic disorders, alongside the neuropathic complications of diabetes mellitus, the cardiovascular disorders of hypertension and orthostatic hypotension refractory to medical treatment present a considerable disease burden with high associated morbidity and mortality. Up to 27% of hypertensive people have poorly controlled blood pressure . 3% are A rationale for intracranial intervention to treat medically refractory hypertension developed from the hypothesis that exerting pressure upon cranial nerves by ectatic perimesencephalic vasculature could result in cranial nerve palsies. Cranial nerve dysfunction could be ameliorated by retromastoid craniectomy and microvascular decompression of the posterior fossa , 10. ConNeurosurgery has been transformed by the introduction of the operating microscope and endoscopes have proven advantageous in minimizing the invasiveness of microvascular decompression , 16. MorThe results of microvascular decompression of the glossopharyngeal and vagal cranial nerves for medically refractory hypertension suggest that one-third to one-half of patients show a sustained, long-term improvement , 27. NeuThe theoretical argument for microvascular decompression is that the RVLM is not only a centre for cardiovascular control, but vagal afferents from the myocardium to the nucleus of the solitary tract pass preferentially along the left aspect of the RVLM and therefore the sympathetic tone and cardiac contractility are particularly sensitive to prolonged pulsatile compression of this region. The argument is borne out by elegant animal models -30 and oThe periaqueductal grey area (PAG) is established as a region important to the modulation of pain. It has been targeted by deep brain stimulating electrodes for the treatment of chronic, intractable neuropathic pain for three decades -34. In m® and Stereoplan® programs to eliminate spatial distortions that arise from magnetic field effects [The technique of deep brain stimulation is an image-guided stereotactic neurosurgical intervention. Techniques vary between neurosurgical centres. Our technique is briefly outlined here. After a pre-operative T-1 weighted MRI scan, a Cosman-Roberts-Wells base ring is applied to the patient’s head under local anaesthesia. A stereotactic computerised tomography (CT) scan is then performed and the MRI scan is volumetrically fused to it using Radionics Image Fusion effects , 48. The effects , 49, 50.Preliminary evidence has associated efficacious PAG analgesia using deep brain stimulation in humans with hypertensive and chronotropic cardiovascular effects , 52. OurWe have shown that electrical stimulation of the human PAG alters blood pressure . In thisFor the subjects with reductions in blood pressure, the average reduction was 14.2±3.6 mmHg (range 7-25mmHg), or 13.9%, after 300 seconds stimulation. For those subjects experiencing increased blood pressure, the mean rise in SBP was 16.7 mmHg ±5.9 , equivalent to 16.4% at the end of a 400s period where stimulation was started at 100s. Identical stimulation parameters of frequency 10 Hz, pulse width 120 μs and up to 3V amplitude both raised and lowered blood pressure in different contact pairs. As with blood pressure reduction, increases were accompanied by a smaller rise in DBP of 4.9mmHg ±2.8 or 6.4% . An increase in mean pulse pressure was also observed. Maximum dP/dt increased by 212±97 mmHg/s . As for blood pressure reduction, the R-R interval did not change changed. Thus pressor and hypotensive related cardiac effects of stimulation appear to mirror each other.Six control patients with implanted neurostimulatory interventions were investigated . Despite extensive investigation using multifarious frequencies, pulse widths and voltages, and a variety of electrode contact configurations, we were unable to alter their blood pressure significantly. In addition to the control electrodes without cardiovascular effect, four patients with PAG electrodes  also failed to exhibit blood pressure changes.Because blood pressure changes in animals vary depending on whether the electrode is in ventral or dorsal PAG, electrode position was assessed. Electrodes were plotted on a brain atlas  using thComparing changes in blood pressure between the two groups of patients with ventrally and dorsally situated electrodes (n=8 and n=9 respectively) including those without significant changes, the mean peak change in SBP was -10.3±2.8 mmHg for the ventral group and +10.8±3.1 mmHg for the dorsal group . Similarly, the mean peak change in DBP was -4.6±1.2 mmHg and +3.5±0.8 mmHg respectively (p=0.007). Mean peak change in pulse pressure was -8.6±3.5 mmHg for the ventral and +7.4±2.1 mmHg for the dorsal group (p=0.01). dP/dt changes were -181.6±28 mmHg/s for ventral and 82±26 mmHg/s for dorsal electrode groups (p=0.007). Comparison of RR intervals between the two groups did not reveal significant differences (p=0.13).Analysis of the dominant frequencies in the blood pressure wave form clarifies the underlying mechanisms of blood pressure changes . Mayer’sWe have demonstrated that it is possible to increase or decrease blood pressure in humans with electrical stimulation of the PAG. Furthermore, the direction of blood pressure change can be controlled by placing the electrode in either ventral or dorsal PAG. Reducing blood pressure with deep brain stimulation is theoretically possible but in itself poses a risk. Whereas DBS surgery entails a 0.3% stroke risk and is not inexpensive , 63, theThe demonstration that PAG deep brain stimulation can increase and decrease blood pressure raises the possibility that orthostatic or postural hypotension might be treatable by neurosurgery. In the normal subject, assumption of an upright posture leads to pooling of venous blood in the lower extremities and splanchnic circulation. The resulting decrease in venous return to the heart leads to a compensatory, centrally mediated increase in sympathetic and decrease in parasympathetic activity (known as the baroreceptor reflex). Such activity normally causes a transient fall in SBP (5 to 10mmHg) a small rise in DBP (5 to 10mmHg) and a rise in heart rate of 10-25 beats per minute. In orthostatic hypotension, patients suffer troublesome low blood pressure on standing or symptoms of cerebral hypoperfusion . OccurinAssessing baroreflex sensitivity gives insight into the mechanisms underlying postural changes. In healthy subjects, baroreflex sensitivity decreases on standing , 72. In Neurosurgery for the treatment of autonomic disorders has thus far embraced two approaches. The first, posterior fossa decompression of the left RVLM utilising microscopy and also endoscopy has shown some sustained benefit in small case series and has been vindicated to some extent by MRA findings of perimesencephalic vascular compression as a risk factor for hypertension . HoweverThe second functional neurosurgical approach, utilising sterotaxy, CT, MRI and deep brain stimulation technology has demonstrated blood pressure changes in an intensively studied group of patients treated by electrodes in their midbrain PAG for chronic pain. Repeatable changes in blood pressure dependant upon whether an electrode is in ventral or dorsal PAG have been demonstrated, albeit over short periods of time. Theoretical foundations for the treatment of both essential hypertension and orthostatic hypotension have been derived from the results presented.Both interventions are exciting not only because they translate research directly from animal models to humans but because of their vivid illustration of potential clinical therapies. Essential hypertension treated without drugs appeals because their adverse effects would be avoided. Similarly, drug treatment of orthostatic hypotension cannot differentiate between the supine and standing positions and may therefore lead to nocturnal hypertension , 69, a p


The prevalence of asthma in our society is rising and there is need for better understanding of the asthma patients’ perception and treatment practice of physicians. The study was aimed at determining asthma attitudes and treatment practices among adult physicians and patients in Nigeria, with the goal of identifying barriers to optimal management.To assess asthma attitudes, treatment practices and limitations among adult physicians and patients in Nigeria, a questionnaire survey was conducted among 150 patients and 70 physicians.Majority (66.7%) of the patients reported their asthma as moderate to severe, 42.7% had emergency room visit and 32% had admission due to asthma in the previous 12 months. Physicians and patients perceptions significantly differed in the time devoted to educational issues (31.4% vs.18.7%) and its contents: individual management plan (64.3% vs.33.3%), correct inhaler technique (84.0% vs.71.0%), medication side effects (80.0% vs.60.0%) and compliance 100% of time (5.7% vs. 18.7%). Patients reported that non-compliance with medication causes increased symptoms (67.0%), exacerbations (60.0%), bronchodilator use (56.0%), urgent physician visit (52.0%) and hospitalizations /ER visits (38.7%). Asthma medication in patients caused short term (10.7%) and long term side effects (20.0%). Due to side effects, 28.0% skipped and stopped their medications. Most physicians (85.7%) and patients (56.0%) agreed on the need for new medication options. The need for new medication in patients was strongly related to asthma severity, limitation of activities, side effects, cost and lack of satisfaction with current medication. With the exception of pulmonologists, physicians did not readily prescribe ICS and their prescriptions were not in line with treatment guidelines.This study has highlighted the gaps and barriers to asthma treatment which need to be addressed to improve the quality of care in Nigeria. Asthma affects about 235 million people worldwide . The incThis survey was a cross sectional study conducted from 30th March to 24th September, 2012. The study settings were six tertiary and three private (primary care) hospitals in five out of the six geopolitical regions of Nigeria. Nigeria is in the West African sub-region and it is the most populous nation in Africa. The GAPP study  protocol2pq/d2, n = Sample Size, p = prevalence of asthma among adults in Ilorin, Nigeria which is 15.2% [The minimum sample size was arrived at using Cochran's formula n = Zis 15.2% . The q =The inclusion criteria for patients were: asthma patients attending participating hospitals must be least 18 years of age and their clinical diagnosis of asthma made at least 6 months prior to the study. Patients with cognitive impairment, a severe exacerbation of asthma, or co-morbid chronic pulmonary disease  were excluded from the study. For the physicians, the inclusion criteria to be eligible for recruitment were: working in the department of family and internal medicine, give written consent to participate in the study, practicing medicine for 3-30 years; sees at least three adult asthma patients per week; and writes at least one prescription for asthma medications per week. The investigators screened eligible patients and informed them about the study. The patients and physician who gave their consent and met the inclusion criteria were also recruited as study participants.The questionnaire used in the study was a modification of the GAPP Survey questionnaire . It was The questionnaires were reviewed manually for consistency and appropriate coding prior to data entry. The data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 15 . Descriptive and frequency statistics were obtained for the variables of interest.Chi square was used to test for statistical significance between categorical variables. Stratified analysis was performed to determine the relationship between impact of asthma, symptoms control, impact of medication side effect, level of satisfaction with current medication and the desire for new treatment options. All variables found to be significant were entered into bivariate analysis and Spearman's correlation coefficient was obtained. A P value of <0.05 was considered to be statistically significant.We interviewed 150 patients and 70 eligible doctors comprising of family physicians (FP)/ general practitioners (GP) and specialists . Of the 150 patients, 68% were females. General characteristics of the participating physicians and patients are shown in In this study, 33.3% of patients described their asthma severity as mild, 50.7% as moderate and 16.0% as severe. Almost 18.7% reported that asthma reduced their activity a great deal and 44.0% reported that they are somewhat limited by it. During the previous 12 months, 52.0% visited their physician for urgent care, 42.7% went to the hospital emergency room and 32.0% were admitted to hospital as a result of asthma .On their perception of asthma education, 38.6% of physicians and 18.7% of patients said that up to half of the clinic visit was devoted to educational issues. The physicians and patients perceptions significantly differed in 50% of clinic time devoted to educational issues and its contents: recommendation of individual management plan, correct inhaler technique. There were no significance difference in the perceptions of patients and physicians in the areas of monitoring of peak expiratory flow, using of symptoms/medication diary and asthma support organization .The majority of patients (60.0%) and physicians (80.0%), p≤0.004 reported that they had discussions with their doctors and patients respectively on medication side effects. Most physicians (61.4%) reported that they initiated discussions in contrast to 29.3% reported by the patients p≤0.001. The patients and physicians reported high percentages of lack of awareness of short term and long term side effects . Only 10The patients were questioned about the percentage of the time they took their asthma medication according to their doctor's or healthcare professional's instructions, 18.7% reported that they were 100% compliant and 13.3% were >80% compliant. The physicians were asked the same question and 5.7% of them reported their patients were 100% of time compliant and 17.1% were >80% compliant . PatientWe found that most of the participating physicians (81.9%) agreed that Inhaled corticosteroids (ICS) are the “gold standard” treatment for asthma. When the physicians were asked which medication or medications would they prescribe as first-line treatment for adult patients with intermittent and persistent asthma. For intermittent asthma, 100% of pulmonologist, 25.6% of internist, 25.0% of GP/FP would prescribed only a short acting ß 2 agonist SABA, and for persistent asthma all the pulmonologist, half (51.3%) of internist and 28.0% of the GP/FP) would prescribed ICS . About hThe physician respondents were least satisfied with the systemic and local side effect of ICS. The local side effects were greatly rated as a source of great concern and dissatisfaction. Majority of the physicians (85.7%) believed there were unmet needs in the area of ICS therapy, and 56.0% of patients thought there was a need for new medication options for asthma treatment. Asthma patients who described their disease as severe, limited by daily activities and switched medication because of side effects, cost and not satisfied with current medication were more likely to desire for new treatment options . PhysiciThe results of our study shows that the perception of physicians and patients of the educational content of discussion significantly differed in recommendation of individual management plan, correct inhaler technique, discussion of side effects and medication compliance. The level of medication compliance was very low and patients who were not compliant with medications all of the time experienced negative outcomes and increase in resource utilization. The level of reported short term and long term side effects of ICS was low and patients had to skip doses and stopped medications due to side effects. Most physicians (85.7%) and half of patients agreed on the need for new medication options. The need for new medication was strongly related to asthma severity, limitation by daily activities, side effects, cost and lack of satisfaction with current medication. With the exception of pulmonologists, other categories of physicians did not readily prescribed ICS and most of their prescriptions were not in line with treatment guidelines.In this study, asthma had a serious impact on the patients as 66.7% of them described their asthma as moderate to severe and 62.7% reported a limitation of activity due to the disease and almost half of the patient made unscheduled visits to their doctor or visited the emergency room for asthma attack. This is an indication of lack of disease control in a significant proportion and this finding is in keeping with the GAPP and other previous studies in Nigeria –16. The This study has exposed the low level of asthma education in Nigeria as corroborated by both the physicians and patients as one third of the physicians and one fifth of patients reported that half of the clinic visit was devoted to educational issues. In addition to poor level of education, we also observed a significant difference in their perceptions of the correct inhaler technique and development of an individual management plan by the physician and patients. Good asthma knowledge is well correlated to increase medication adherence, improved quality of asthma management, reduced health care utilization and better health outcomes . The lowMore than 70% of the patients were unaware of short and long term side effects of ICS and that physician tend to underestimate the lack of awareness among the patients. This result is in contrast to GAPP study where one third (31%) of patients were unaware of long term side effects . In thisWith regards to treatment compliance, we found that about one in five patients (18.7%) in this study were less likely to be 100% of time compliant with medication, similarly patients in the UK are less likely to comply with treatment instructions, in contrast to 36% in France, 49% of patients in Europe and 48% globally. PatientThis study also found that most physicians believed inhaled corticosteroids (ICS) are the “gold standard” treatment for asthma. Inhaled corticosteroids are essential for achieving these goals and managing patients with persistent asthma over the long-term , 2. WithMajority of physicians and patients believed there were unmet needs in the area of ICS therapy and there is a need for new medication options for treatment of bronchial asthma. Our result is in support of the need for new therapeutic options to meet the patients’ expectations and ensure compliance. The demand for new therapy may be explained by multiple dosages per day as reported by the patients in this study, lack of satisfaction with the use of ICS due to in correct inhalation device and subsequent ineffective delivery of the medication to the airway. This lack of satisfaction has made many patients to show preference for the oral medication despite the physician recommendation of inhaled medication. Another reason for request for a new therapy is the erroneous belief that that ICS does not appear to significantly modify the course of the disease and are not curative, because asthma symptoms and inflammation rapidly recur when the treatment is discontinued and this is a cause of concern as many patients who are also afraid of being addicted to the medications . The sidThe strength of this study is that it was conducted in five out of the six geographical region of Nigeria which is a good representation of country. It also included private hospitals that render primary care service and derive their patronage mainly from the higher socioeconomic class. The private hospitals and its clientele have often been excluded in previous asthma studies. The study is however limited by the few numbers of patients from inaccessible and remote rural areas who may have more serious challenges than those in sub- urban and urban areas. The non validation of the questionnaire in native languages used in about 4% of patients as Nigeria has over 200 local languages.In conclusion, this study has highlighted poor medication compliance which is related to side effects, lack of patients’ physician communication, poor prescription practices and lack of satisfaction with current medication as potential barriers to asthma treatment. These barriers often lead to poor asthma management and high prevalence of uncontrolled asthma, increased health resources utilization and cost of management in a large cohort of patients . The cor


Functioning paraganglioma is extra-adrenal catecholamine-secreting tumours that may cause secondary hypertension. Primary intrapericardial paragangliomas are very rare and are located adjacent to the great vessels or heart, typically near the left atrium. These tumours are an exceptionally uncommon finding during the investigation of refractory hypertension. However, in recent years, intrapericardial paragangliomas have been diagnosed incidentally with increased frequency, due to the extensive use of radiologic chest imaging. The mainstay of treatment of functioning intrapericardial paraganglioma is surgical removal, which usually achieves blood pressure normalization. Due to the locations of these tumours, the surgical approach is through a median sternotomy or posterolateral thoracotomy, and manipulation-induced catecholamine release may cause paroxysmal hypertension. Typically in these patients, blood pressure fluctuates dramatically intra- and post-operatively, increasing the risk of cardiovascular complications. We review here the current modalities of perioperative fluid and hypotensive drug administration in the setting of surgery for functioning intrapericardial paraganglioma and discuss the recently proposed paradigm shift that omits preoperative preparation. The Worocations .Catecholamine-secreting tumours occur in less than 0.1% of the hypertensive population; the peak incidence is between the third and fifth life decades, with both genders being equally affected. Twenty-five percent of pheochromocytoma and paraganglioma occur in the setting of familial syndromes . Thus, family history should be carefully investigated in patients with catecholamine-secreting tumours, and all relatives should be screened for hereditary syndromes –6. Most Less than 2% of reported paraganglioma are located in the chest and intrapericardial paraganglioma (IP) is even rarer .Most IPs are large, ranging in size from 3 to 8 cm , 7; in tLittle is known regarding long-term survival of IP patients, as long-term follow-up studies are not available.The rarity of IP is well documented, only 30 cases being reported until 1992 . We reviArterial hypertension is the most common clinical presentation of IP; about 10% of reported paragangliomas are clinically silent , the tumAbout 20% of IPs are nonfunctioning  and may The diagnosis of functioning paraganglioma requires biochemical testing to document elevated catecholamine secretion and is generally obtained by determining the plasma level of fractionated metanephrines during hypertensive crisis and the 24-hour urine normetanephrine level.Imaging exams to localize the tumour and its metastases include CT and MR imaging, coupled with 123-I-metaiodobenzylguanidine (MIBG) scintigraphy. These exams provide anatomical and functional information with good sensitivity and specificity .Some IP cases have been incidentally identified by chest radiography, as an enlargement of mediastinum or splaying of the carina by the tumour mass . On CT sSurgical resection is the mainstay of treatment for benign and malignant IP. Resection must be completed with minimal tumour manipulation to prevent hypertensive crisis and tumour seeding. Control of tumour vascular supply requires adequate operative field exposure to avoid injury to surrounding organs. The operative access to the mediastinum depends on location and size of the lesion, as well as on the adjacent structures involved. Generally, the surgical approach to IP is with sternotomy, as cardiopulmonary bypass (CPBP) is usually planned for tumour removal. Less commonly, IP can be resected without CPBP, through left or right thoracotomy, depending on tumour location. If size and location of the lesion are favourable, the approach can also be with minimally invasive videothoracoscopic technique.Patients with unresectable or metastatic disease may be treated with chemotherapy, radiofrequency thermoablation, cryoablation, and catecholamine blockade .Perioperative management of IP patients is a challenge for anaesthesiologists and surgeons. Over the last 50 years, shared management of the patient involving also endocrinologists and cardiologists translated into a marked reduction of perioperative mortality from 40–60% to 0–6% .In preparation for surgery, a detailed medical history is essential, along with physical examination, complete laboratory exams, and evaluation by cardiologist and anaesthesiologist. It is important to detect the presence of a cardiomyopathy or coronary artery disease by ECG, echocardiography, and coronary angiography, if necessary. However, for young patients without history of heart disease, it is debated whether preoperative ECG only is sufficient . EchocarIf hypertrophic cardiomyopathy as a result of chronic norepinephrine-induced hypertension is found, it is mostly symmetric and concentric , 13. DilAn interesting finding in patients with functioning chromaffin tumours is the stress-related Tako-Tsubo cardiomyopathy, also called left ventricular apical ballooning syndrome. The pathophysiology of stress-induced and chromaffin tumour-induced cardiomyopathy is believed to be similar and mediated by catecholamines causing myocardial stunning . Typicalα-adrenoceptor antagonists, calcium-channel blockers, or angiotensin-receptor blockers have all been recommended, there are no evidence-based guidelines on the preferred drugs for preoperative catecholamine blockade. Consequently, there are widely ranging practices and international differences in perioperative pharmacologic management and approved therapies. Importantly, β-blockers should be used only after adequate pretreatment with α-antagonists. Moreover, volemia expansion is also widely recommended before and after surgery [Preoperative medical management to block the deleterious effects of excess catecholamine release and to allow plasma volume expansion is recommended . Althoug surgery .Special preparation of the patient undergoing surgical removal of paraganglioma is necessary once clinical, instrumental, and laboratory evaluations are completed.Without preoperative medical treatment, induction of anaesthesia or other stimuli can cause a hypertensive crisis, cardiac arrhythmias, and infarction or stroke, due to massive catecholamine release. Pharmacological treatment should be instituted for 1 to 2 weeks before surgery, to optimize cardiovascular function by relaxation of the constricted vasculature, expansion of the reduced plasma volume, and normalization of blood pressure. Normalization of blood volume reduces the risk of prolonged hypotension after tumour removal .α- and β-blockers. Alpha-adrenergic blockade should be started prior to β-adrenergic blockade to prevent acute hypertensive crisis. Alpha-blockade is generally initiated 7 to 10 days before surgery, using different drugs  to achieve a systolic blood pressure below 120 mmHg when seated and below 90 mmHg when standing. It is recommended that no blood pressure >160/90 mmHg values should be evident 24 hours before surgery, and an orthostatic hypotensive response (blood pressure >80/45 mmHg) should be present. Moreover, no electrocardiographic ST/T segment changes at least for 1 week should be evident [β-blocker administration, using low dosages to reduce the risk of negative inotropy [Preoperative antihypertensive therapy is useful in patients with sustained or paroxysmal hypertension. In this setting, interventions are focused on maintaining adequate plasma volume and on lowering blood pressure using  evident . After rinotropy . Magnesiinotropy .During the operative period, it is essential to closely monitor cardiovascular function by electrocardiogram and to assess urine output, pulse oxinmetry, capnography, and body temperature. It may be necessary to monitor cerebral function with electroencephalography, if the patient has a recent history of cerebral infarction .Cardiovascular monitoring requires an intra-arterial catheter and a central venous catheter to respond quickly to haemodynamic changes with vasoactive agents or fluid administration . PulmonaGeneral anaesthesia is the most commonly chosen technique. Intravenous or inhalation agents have been used with success, but drugs that stimulate the sympathetic system responses or that may cause mechanical stimulation of the tumour by fasciculations, such as succinylcholine, should be avoided. Deep anaesthesia to inhibit cardiovascular response is more important than the specific agent used .α-adrenergic antagonist that can be given intravenously as continuous infusion or as boluses of 1 to 2 mg; it can cause tachycardia if the patient is not receiving β-blockers. Calcium channel blockers have some advantages over sodium nitroprusside, such as less risk of deep hypotension, no rebound hypertension, more controlled heart rate, and absence of cyanide toxicity [Several drugs are available to control blood pressure during tumour resection. Sodium nitroprusside should be used in patients with a history of acute myocardial infarction or congestive heart failure, although this drug has potential for overshoot hypotension . Phentoltoxicity . Fenoldoα-adrenergic antagonist effect, alteration of venous capacitance and haemorrhage. Priority should be given to volume replacement, which seems to be the main factor responsible for reduction of intraoperative mortality in chromaffin tumour surgery [After tumour removal, it is essential to control hypotension that may result from inadequate intravascular volume, residual  surgery , 22. In β-blocker and α-adrenergic antagonist administration in a case undergoing surgery for removal of IP at our institution. The patient, a 34-year-old woman with a history of recent episodes of headache, palpitation, and flushing, had hypertension (180/90 mm Hg) poorly controlled by ramipril. She was diagnosed with a functioning IP localized below the left atrial roof . Phentolamine was administered in boluses of 1-2 mg   . After sg total) , the patSome authors have questioned the validity of systematic preoperative optimization of blood pressure and volume expansion, drawing attention to the lack of evidence-based studies . HoweverWe experienced that preoperative medical preparation of cardiac paraganglioma patients is critical. Alpha-adrenergic blockade (phenoxybenzamine or phentolamine) is usually started at the time of diagnosis and it is carried on preoperatively under close blood pressure monitoring, to prevent cardiovascular complications that may occur during surgery due to excess catecholamine secretion. These complications include hypertensive crisis, arrhythmia, myocardial infarction, and pulmonary edema.The goal of intraoperative pharmacologic therapy is to prevent sudden rise and fall of blood pressure. Beta-adrenergic and calcium channel blockade can be used as adjuncts when blood pressure or tachycardia cannot be controlled .At the time of tumour vascular supply control, rapid decrease of catecholamine level and rebound hypotension should be expected , and preAfter surgical removal of IP, approximately 80% of patients become normotensive . PersistTumour recurrence in case of incomplete resection may occur; moreover, approximately 10% IPs were found to be malignant; therefore, systematic follow-up is recommended. There is no general agreement on the method and frequency of follow-up after paraganglioma resection. Long-term follow-up is recommended with blood pressure measurements and periodic determination of urinary metanephrines; if necessary, 123-I-MIBG scintigraphy and CT imaging should be obtained .β-blockers are usually started at the time of diagnosis and this treatment is carried on perioperatively under close monitoring of blood pressure. Due to the rarity of functioning paraganglioma, systematic perioperative optimization of blood pressure and volume expansion has not been validated by randomized studies. However, there is abundant literature to support the value of pharmacological preparation and volume expansion to prevent cardiovascular complications.IP is a rare tumour that may cause secondary hypertension. Surgical removal is the gold-standard treatment and normalizes blood pressure in about 80% of hypertensive cases; 20% remain hypertensive, likely due to associated essential hypertension. Preoperative medical preparation is critical to prevent cardiovascular complications that may result from excess catecholamine secretion during anaesthesia induction and surgical manipulation of the tumour. Alpha-adrenergic blockade and


Microcirculation plays a vital role in the development of multiple organ failure in severe sepsis. The effects of red blood cell (RBC) transfusions on these tissue oxygenation and microcirculation variables in early severe sepsis are not well defined.This is a prospective, observational study of patients with severe sepsis requiring RBC transfusions of one to two units of non-leukoreduced RBCs for a hemoglobin < 7.0, or for a hemoglobin between 7.0 and 9.0 with lactic acidosis or central venous oxygen saturation < 70%. This study took place in a 54-bed, medical-surgical intensive care unit of a university-affiliated hospital. Thenar tissue oxygen saturation was measured by using a tissue spectrometer on 21 patients, and a vaso-occlusive test was performed before and 1 hour after transfusion. The sublingual microcirculation was assessed with a Sidestream Dark Field device concomitantly on 11 of them.p < 0.001). RBC transfusion did not globally affect near-infrared spectrometry (NIRS)-derived variables. However, percent change in muscle oxygen consumption was negatively correlated with baseline . There was no statistically significant correlation between percent change in vascular reactivity and baseline (p = 0.275). There was a positive correlation between percent change in oxygen consumption and percent change in vascular reactivity . In the 11 patients, RBC transfusion did not globally affect NIRS-derived variables or SDF-derived variables. There was no statistically significant correlation between percent change in small vessel perfusion and baseline perfusion , between percent change in small vessel flow and baseline flow , or between percent change in small vessel perfusion and percent change in small vessel flow .RBC transfusion resulted in increase in hemoglobin (7.23 (± 0.87) to 8.75 (± 1.06) g/dl; In a small sample population, muscle tissue oxygen consumption, microvascular reactivity and sublingual microcirculation were globally unaltered by RBC transfusion in severe septic patients. However, muscle oxygen consumption improved in patients with low baseline and deteriorated in patients with preserved baseline. Future research with larger samples is needed to further examine the association between RBC transfusion and outcomes of patients resuscitated early in severe sepsis, with an emphasis on elucidating the potential contribution of microvascular factors. In the United States, approximately 750,000 cases of sepsis occur each year, of which at least 225,000 are fatal. One study that evaluated the epidemiology of sepsis between 1979 and 2000 demonstrated an 8.7% increase in the annual incidence of sepsis. The cost of management of one septic patient has been estimated at $50,000, amounting to annual costs of approximately $17 billion. Sepsis is the second-leading cause of death in noncoronary intensive care units (ICUs) and the tenth leading cause of death overall. Organ failure occurs in approximately one third of patients with sepsis and severe sepsis is associated with an estimated mortality rate of 30-50%. Seventy percent of patients with three or more organ failures (classified as severe sepsis or septic shock) die [Red blood cell transfusion is one of the most commonly used interventions in the ICU to treat severe anemia, which often occurs in sepsis. In the United States, more than 14 million units of packed red blood cells (RBCs) are administered annually, many of which are administered in the ICU . ApproxiPatients with sepsis develop alterations in microvascular circulation, tissue oxygenation, and oxygen metabolism, all of which play a major role in the development of organ failure. Orthogonal polarization spectral (OPS) and sidestream dark field (SDF) imaging devices both provide high-contrast images of underlying microvasculature . Using tAnother noninvasive technique used is near-infrared spectrometry (NIRS) ,19, whicThe primary objective of this study was to evaluate the effect of RBC transfusion in severe septic patients on sublingual microvascular perfusion and flow using SDF and on muscle tissue oxygenation, oxygen consumption, and microvascular reactivity using NIRS. A secondary objective was to correlate the variables obtained from NIRS with those obtained from SDF.This prospective, observational study included 21 severe septic patients according to standard definition . All patPacked red blood cell units were obtained from the blood bank . None of the RBC units transfused in this study were leukoreduced. Storage solution  was added to RBCs before storage. The storage period of RBCs is allowed up to 42 days.The temperature, heart rate, arterial pressure, central venous pressure (when available), hemoglobin, central venous oxygen saturation, lactic acid, and arterial blood gases were recorded before and 1 hour after transfusion. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score  was obta2) and the tissue hemoglobin index (THI), an indicator of the blood volume in the region of the microvasculature sensed by the NIRS probe [The thenar tissue oxygen saturation . Continuous measurements of the StO2 and THI were obtained during the vaso-occlusive test. Baseline StO2 and THI were recorded before the ischemic period and THI was recorded after 1 minute of occlusion. During occlusion, we calculated the StO2 desaturation slope (%/minute) obtained from the regression line of the first minute of StO2 decay after occlusion [2 upslope (%/second) was obtained from the regression line of the first 14 seconds of increased StO2  following the ischemic period. This StO2 upslope of the reperfusion phase was used to quantify the intensity of the reactive hyperemic response following release of the occluding cuff. The percent change in recovery (upslope) was calculated as the difference between the StO2 upslopes of the reperfusion phase after and before transfusion divided by the StO2 upslope before transfusion. Muscle oxygen consumption (NIRVO2) was calculated as the product of the inverse value of the StO2 desaturation slope and the mean THI over the first minute of arterial occlusion [During a period of hemodynamic stability , the NIRS probe was placed on the skin of the thenar eminence and a sphygmomanometer cuff was placed around the arm over the brachial artery. A large bore tube/cuff that inflates and deflates in less than one second was used to avoid cuff inflation and deflation from affecting the slope measurements. After a 3-minute period necessary to stabilize the StOcclusion . This iscclusion  and is ePercent change in NIRVO2 (downslope) was calculated as the difference between the NIRVO2 values after and before transfusion divided by NIRVO2 values before transfusion.2). To reduce observer measurement bias, sidestream darkfield images were analyzed off-line and in a blinded fashion by one of the investigators (FS), who was blinded to the patient's clinical course and the order of the sequences.Sidestream dark field imaging was performed by using a handheld device that illuminates an area of interest. Light is emitted by a circle of light-emitting diodes. The reflected light is returned through the inner image-conducting core, which is optically isolated from the light-emitting diodes and caught on camera. Although assessing the microcirculation is based on light absorption by the hemoglobin contained in RBCs, this technique remains valid in anemia, as well as during acute changes in hemoglobin concentration . SidestrPercent change in PPV was calculated as the difference between the PPV values after and before transfusion divided by PPV values before transfusion. Percent change in MFI was calculated as the difference between the MFI values after and before transfusion divided by MFI values before transfusion.t test. Mean, standard deviation and p value were reported for each comparison. Analysis for the full sample and subgroup were conducted separately. A Pearson correlation coefficient (PCC) was calculated to describe the association between percent change in NIRVO2 (downslope), baseline NIRVO2 (downslope), percent change in recovery (upslope), and baseline upslope using subjects in the full sample. This method was repeated for the subgroup with additional comparisons, including percent change in PPV for small vessels vs. baseline PPV, percent change in MFI, percent change in NIRVO2 (downslope), and percent change in recovery (upslope). Percent change in MFI for small vessels was correlated with baseline MFI, percent change in NIRVO2 (downslope) and percent change in recovery (upslope). All analyses were conducted with SPSS/PASW version 18  by an investigator (EA) who was not involved with data collection or analysis of sidestream darkfield images.Descriptive statistics were performed for the full and subgroup samples to assess similarities in patient characteristics, including age, gender, source of infection(s), age of blood, APACHE II score, and discharge status . Changes in hemodynamic and other observed measurements taken before (pre) and 1 hour after (post) the transfusion were assessed by a paired p = 0.08) in the full sample, and from 67.36 mmHg (± 7.97 mmHG) to 73.18 mmHg  in the subgroup sample (Table The study included 21 severe septic patients with NIRS-derived data (full sample), 11 of whom also had SDF-derived data  to 8.75 g/dl  to 8.95 g/dl ± 1.12 g/dl);  g/dl; p  g/dl to 2. For example, in the full sample before transfusion, THI positively correlated with StO2 . THI increased after transfusion in the full sample (Table p = 0.64) or after transfusion .THI variables behaved exactly similar to StO2 variables (data not shown). THI correlated with StOp = 0.141; Figure p = 0.201; Figure p = 0.182; Figure There was no statistically significant correlation between percent change in small vessel PPV and baseline small vessel PPV  in sepsis -39. ThesOur study differs from Creteur et al. in several points. We studied severe septic patients, whereas Creteur et al. studied hemodynamically stable patients, 41% of whom had sepsis. We transfused older (median RBC storage time = 32 vs. 18 days) RBCs; ours were all nonleukoreduced, whereas theirs were all leukoreduced. We used both NIRS and SDF in our study, whereas they only used NIRS. Our study also differed from Sakr et al. We transfused older blood (median RBC storage time = 32 vs. 24 days); ours were all nonleukoreduced, whereas theirs were all leukoreduced. We used both NIRS and SDF in our study, whereas they only used OPS (older version of SDF). In a very recent review on monitoring the microcirculation in critically ill patients, De Backer et al. concluded that a monitoring device should be able to detect capillary perfusion, flow, and heterogeneity of perfusion. This is best achieved with handheld microvideoscopic techniques, such as OPS and SDF. They also concluded that the use of vascular occlusion tests with laser Doppler or NIRS investigates microvascular reactivity, another important, but different, aspect of microvascular function. De Backer suggested that "Combining techniques may be of interest in the future" . To our In a recent study that evaluated perioperative RBC transfusions in patients who underwent cardiac surgery using SDF and sublingual reflectance spectrophotometry, Yuruk et al. showed that RBC transfusion improved sublingual microcirculatory density, but not perfusion velocity, and improved microcirculatory oxygen saturation . Their sWhy do some patients show beneficial effects of RBC transfusions while others do not? Friedlander et al. observed that RBC transfusions improved RBC deformability in patients with sepsis, probably by replacing rigid, endogenous RBCs by less dysfunctional, exogenous RBCs . TransfuInterestingly, RBC transfusion-induced changes in NIRVO2, in the recovery upslope of the reperfusion phase, in PPV, and in MFI were all in the same direction, suggesting that an improvement or worsening in microvascular reactivity, microvascular perfusion, and microvascular blood flow may be associated with an increase or decrease in local muscle oxygen consumption, respectively.NIRS-derived variables showed changes in the same direction compared with SDF-derived variables Figures  and 3. Tp = 0.64) or after transfusion . Moreover, despite the increase in THI in the full sample, there was an improvement in NIRVO2 in patients with altered baseline and deterioration in NIRVO2 in patients with preserved baseline in both the full sample and the subgroup sample, suggesting that this relationship is real. Because StO2 represents the average of the hemoglobin oxygen saturation in arterioles, venules and capillaries in the whole tissue sample, NIRS is not able to demonstrate changes on microvascular density or heterogeneity. As a result, we must continue to explore the meaning of reactive hyperemia as a surrogate of microvascular functionality.Our study has its limitations. Our small sample size and the fact that some variables could not be obtained in some patients is an obvious limitation. The limited number of patients does not make it possible to determine whether initial deranged microcirculatory parameters could really influence the final response to RBC transfusion. NIRS monitors hemoglobin oxygen saturation in arterioles, venules, and capillaries in the measured volume of tissue, and the relative contributions of arterial, venous, and capillary blood within the measured volume of tissue cannot be determined. NIRS does not measure microcirculatory blood flow or perfusion. It also targets muscle tissue, specifically the thenar muscle. SDF monitors the capillaries and venules (not arterioles), but this device monitors the actual flow and perfusion and their heterogeneity in the microvessels. SDF data could be analyzed only semiquantitatively. SDF targets the sublingual mucosa, which shares a similar embryonic origin with the digestive mucosa  but may not reflect other microcirculatory beds. Our measurements were restricted to 1 hr after RBC transfusion, therefore, later alterations due to transfusion may have been missed. However, longer follow-up periods are practically difficult because of inevitable changes in therapy and procedures in these critically ill patients that could themselves affect the microcirculation and other outcomes. THI increased after transfusion in the full sample Table , which cThe effects of RBC transfusions on microvascular oxygenation, consumption, reactivity, perfusion, and flow are quite variable and may be dependent on baseline values. In this observational study of limited size, no effect of RBC transfusion on any measured microcirculation variables in severe septic patients was observed. This study does suggest that better means of identifying the need for transfusion are needed and that blindly transfusing to an arbitrarily set (and high) Hb may be detrimental. This study involves a small sample of patients, based on which strong recommendations cannot be made. Future research with larger samples is needed to further examine the association between RBC transfusion and outcomes of patients resuscitated early in severe sepsis, with an emphasis on elucidating the potential contribution of microvascular factors.The authors declare that they have no competing interests.All authors report that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.FS contributed to conceiving the study, acquiring and managing the data, analyzing the data and interpreting the results, drafting and revising the manuscript, and approving the manuscript in its final form. RA, KK, and JO contributed to acquiring and managing the data, revising the manuscript, and approving the manuscript in its final form. EA contributed to performing statistical analysis, acquiring and managing the data, revising the manuscript, and approving the manuscript in its final form. RT contributed to analyzing the data and interpreting the results, revising the manuscript, and approving the manuscript in its final form.