Hypertensive emergencies are potentially life threatening and require prompt blood pressure control with intravenous agents. Preparation of intravenous infusions is time consuming. Usefulness of sublingual nitroglycerin in this setting is not known. We aimed to assess the benefit of sublingual nitroglycerin as a bridge to IV therapy. In a clinical audit in an emergency department, patients presenting with hypertensive emergencies requiring intravenous nitroglycerin were administered single spray of sublingual nitroglycerin awaiting commencement of intravenous infusion. Blood pressure was monitored every 5 min to observe the degree and speed of reduction.Thirty-seven patients met the selection criteria. Mean age was 65.8 years (SD 7.04), and 29 were males (88.4%). Mean values of systolic, diastolic and mean blood pressures on admission were 217, 137, 163 mmHg. At 5 and 10 min after sublingual nitroglycerin, mean reduction of mean arterial blood pressure by 12.3 and 16.3% was achieved. Only 2 patients (5.4%) showed an overcorrection of blood pressure. Minimum of 15 min were required to set up a nitroglycerin intravenous infusion. Sublingual nitroglycerin spray allows rapid blood pressure control in hypertensive emergencies and is a useful bridge during the time to prepare intravenous infusion. Hypertensive emergency is an acute elevation of blood pressure 180/120 mmHg) associated with end organ damage [0 mmHg asNitroglycerin is a potent venodilator, showing arterial dilation only at very high doses. The use of sublingual, topical or IV nitroglycerin infusion is recommended as a first line agent in blood pressure control in acute hypertensive pulmonary oedema and in acute coronary syndrome due to its favourable effect in reducing preload and cardiac output . It is uSublingual nitroglycerin is widely used for its antianginal properties. It is unlikely to be useful for definitive management of hypertensive emergencies or urgencies due to short duration of action and variable absorption. However, its convenient use, ease of administration and rapid onset of action make it an ideal agent for rapid blood pressure control until definitive therapy is commenced in the emergency department or in pre-hospital setting. There are no studies describing this utility of sublingual nitroglycerin. We analysed data from a clinical audit to assess the effectiveness of sublingual nitroglycerin spray, as a bridging option during the inevitable delay in setting up IV nitroglycerin.A clinical audit was conducted at the emergency department of a tertiary care centre in Sri Lanka from August, 2017 to December, 2017. Patients presenting with hypertensive emergencies who required intravenous nitroglycerin administration were selected by convenient sampling.Inclusion criteria were severe hypertension (defined as systolic blood pressure 180 mmHg or more and/or diastolic blood pressure 120 mmHg or more) with evidence of end organ dysfunction. Presence of clinical features of heart failure , or angina with electrocardiographic changes suggestive of ischemia or neurological symptoms and/or signs  were considered as evidence for end organ dysfunction. Suspected or confirmed aortic dissection, intracranial haemorrhage or stroke were excluded from the study as their blood pressure goals and pharmacological preferences are different. All participants or next of kin (where patients’ capacity was limited due to the acute illness) provided informed consent prior to selection.Upon diagnosis of hypertensive emergency that require IV nitroglycerin infusion, patients were administered single puff of nitroglycerin spray sublingually (0.4 mg). Blood pressure was monitored every 5 min by automated monitoring machines using arm blood pressure cuff and was confirmed with manual blood pressure measurement with a mercury sphygmomanometer and systolic, diastolic and mean arterial blood pressures  were recorded. Time taken to prepare the IV nitroglycerin infusion was noted. Other regular medical management was continued unchanged according to unit protocols.Thirty seven patients met the selection criteria for enrolment. Mean age was 65.6 years and 29 were males (88.4%). Their clinical presentations are summarized in Table Table Only one patient had over-reduction of MAP more than 25% at 5 min (28%), which improved to 22% at 10 min, while another patient who had 18% reduction at 5 min had further reduced MAP by 29.5% at 10 min.Minimum delay from decision to commence IV nitroglycerin to commencement of therapy was 15 min (mean 27 min) and was due to delays in gaining IV access and preparation and setting up of the solution for infusion.Rapid and controlled reduction of blood pressure is the main aim in management of hypertensive emergencies. Intravenous administration of antihypertensives are required. However, setting up an intravenous infusion consumes time, during which patient remains symptomatic and may even deteriorate. We observed that mean time taken for commencement of IV infusion from the time of deciding to treat is 27 min. Fastest time achieved was 15 min.Therefore it is important to have an alternative strategy which can be rapidly administered and could produce rapid effect. It is not critical for it to be highly efficacious or long lasting as its role is to bridge the time until definitive IV preparation is ready to use. Nitroglycerin sublingual spray has the advantages of being easy to administer (without a need for IV access) and having rapid absorption and onset of action. Therapeutic utility of nitroglycerin has been questioned at times due to its venodilatory effects, potential to reduce cardiac output and cause reflex tachycardia . HoweverFindings of this clinical audit demonstrate that sublingual nitroglycerin is efficacious, rapid in onset and achieved desired blood pressure control. This is in keeping with its known pharmacokinetic properties, being rapidly absorbed through mucous membrane of oral cavity. Only one patient experience sustained over correction of blood pressure, exceeding 25% reduction of MAP.These findings have two important implications. Firstly, we suggest that sublingual nitroglycerin spray can be a useful adjunct in the management of a hypertensive emergency until parental preparation is prepared, thus preventing complications due to unavoidable delays. Secondly, this also indicates the potential usefulness of sublingual nitroglycerin spray in out-of-hospital setting for paramedical services in better management of hypertensive emergencies.Therefore we conclude that sublingual nitroglycerin spray is effective in reducing blood pressure in a hypertensive emergency, until IV preparation is made available. We suggest that potential use of sublingual nitroglycerin in hypertensive emergencies should be studied further, in a larger population, with a control group with prospective follow up to determine final outcome.There are few limitations in our study. Firstly, it is limited by small sample size. Secondly, effect of nitroglycerin was not compared against a control or a placebo. Thirdly, effect of early correction of high blood pressure on mortality, duration of hospital stay, need for other antihypertensives or morbidity were not assessed. Fourthly we did not observe any adverse effects of therapy probably due to the good safety profile of this medication and also due to the small sample size that was not adequate to determine more rare adverse events.


Background. Increased arterial stiffness is an independent cardiovascular risk factor in diabetes patients and general population. However, the contribution of diabetes to arterial stiffness is often masked by coexistent obesity and hypertension. In this study, we assessed arterial stiffness in nonhypertensive, nonobese type 2 diabetes (T2DM) patients in Ghana. Methods. In case-control design, 166 nonhypertensive, nonobese participants, comprising 96 T2DM patients and 70 nondiabetes controls, were recruited. Peripheral and central blood pressure (BP) indices were measured, and arterial stiffness was assessed as aortic pulse wave velocity (PWVao), augmentation index (AIx), cardioankle vascular index (CAVI), and heart-ankle pulse wave velocity (haPWV). Results. With similar peripheral and central BP indices, T2DM patients had higher PWVao  and CAVI  than nondiabetic control. AIx and haPWV were similar between T2DM and nondiabetic controls. Multiple regression models showed that, in the entire study participants, the major determinants of PWVao were diabetes status, age, gender, systolic BP, and previous smoking status ; the determinants of CAVI were diabetes status, age, BMI, heart rate, HbA1c, total cholesterol, HDL cholesterol, and previous smoking status . Conclusion. Our findings suggest that nonhypertensive, nonobese T2DM patients have increased arterial stiffness without appreciable increase in peripheral and central pressure indices. Type 2 diabetes (T2DM) is a major risk factor for the development of cardiovascular diseases (CVDs) . It is eβ-stiffness and Bramwell-Hill's formula [ per se to arterial stiffness difficult to ascertain. In this study, we compared the levels of arterial stiffness in nonhypertensive, nonobese T2DM patients to age- and gender-matched nondiabetes controls. We hypothesize that, compared to age- and gender-match controls, nonhypertensive, nonobese T2DM patients would have higher levels of arterial stiffness.Assessment of arterial stiffness in T2DM patients using pulse wave velocity (PWV) is often confounded by coexistent hypertension and blood pressure variations at the time of measurement. In both diabetes and nondiabetes subjects, PWV is strongly associated with age and blood pressure (BP) . However formula . The hig2, history of hypertension treatment, and/or brachial blood pressure >140/90 mmHg were excluded from the study. Ethical approval for this study was given by the University of Ghana Medical School Ethical and Protocol Review Committee .The study was conducted at the National Diabetes Management and Research Centre, Korle-Bu Teaching Hospital, Accra, Ghana. A total of 166 nonhypertensive, nonobese volunteers, comprising 96 T2DM patients and age- and gender-matched 86 nondiabetes controls within the ages of 35–75 years, were recruited for the study. T2DM was assessed clinically; the patients were diagnosed with diabetes after 30 years of age and treated initially with lifestyle management or oral hypoglycaemic drugs for at least 2 years. T2DM patients were selected by systematic sampling as every 4th consenting patient visiting the clinic. Based on the gender and age decade of T2DM patients, nondiabetes controls were randomly recruited from the surrounding communities into the study. All the nondiabetes volunteers were screened using fasting plasma glucose (FPG) and 2-hour post-75 g glucose load plasma glucose (2 h PPG) to confirm their nondiabetes status. In all, 95 nondiabetes, nonobese volunteers with no history of hypertension were enrolled into the study. However, 9 participants were excluded from analysis; 6 had impaired fasting glucose and 3 were impaired glucose tolerant . Individuals with foot ulcers, established CVDs, BMI ≥ 30 kg/m2). Waist circumference was measured with nonelastic tape measure at the upper border of the iliac crest, parallel to the floor without compressing the skin. Body composition monitor  was used to assess percentage body.Using standard protocols , body weBlood samples were drawn in the morning, after 8–12 hours of overnight fasting, into plain vacuum tubes to measure plasma lipids and fluoride oxalate tubes for glucose levels. FPG, 2 h PPG, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) levels were analysed by colorimetric enzymatic assays using BS 120 chemical autoanalyzer  and commercial reagents . Low-density lipoprotein cholesterol levels were calculated using Friedewald's formula . HbA1c wArteriograph  was used to measure aortic pressure indices, aortic PWV (PWVao), and aortic augmentation index (AIx), with the subject lying supine for at least 10 minutes in a temperature controlled room (22 ± 2°C). The Arteriograph cuff was applied on the right arm over the brachial artery to detect arterial wall oscillations in the upper arm using the “stop-flow” principle previously described . To deteP1 is the amplitude of the first (direct) wave, P2 is the amplitude of the late (reflected) systolic wave, and PP is the pulse pressure.PWVao was calculated by using the formula: β, calculated from values of haPWV and BP as follows:ρ indicates blood density; ΔP pulse pressure; ln natural log; Ps systolic BP; and Pd diastolic BP [CAVI and heart-ankle (ha) PWV were measured using the Vasera 1500 N  with the participant resting supine for at least 10 minutes before the measurement. Electrocardiogram electrodes were placed on both wrists, a microphone for detecting heart sounds was placed on the sternum, and cuffs were wrapped around the upper arms and the ankles. CAVI values were computed automatically. Briefly, CAVI corresponds to the stiffness parameter tolic BP , 17.CAVI and Arteriograph measurements were performed in random order using a digital algorithm.t-test. Categorical data were presented as counts (percentages) analysed by the χ2 test. Multiple regression analysis was performed with PWVao and CAVI, as well as haPWV and AIx, as the dependent variable, and the following parameters were forced into the model as covariates: diabetes status, age, gender, duration of diabetes (for T2DM patients group), BMI, height, previous smoking status, alcohol intake, systolic BP, heart rate, HbA1c, total cholesterol, triglycerides, and HDL cholesterol. p values < 0.05 were considered statistically significant.Continuous data were analysed with the Shapiro-Wilk test to determine their distribution. Skewed data were logarithmically transformed. The data were presented as mean ± standard deviation and analysed by Student's 2, n = 94) had higher CAVI but similar PWVao and haPWV, when compared to normal participants  participants had higher PWVao than nonhypertensive participants , and anthropometric indices. Mean values of AIx and peripheral and central BP indices measured by the Arteriograph were similar between T2DM patients and nondiabetes controls. However, diastolic and pulse BPs measured with Vasera were higher in nondiabetes controls than T2DM patient. Compared to nondiabetes controls, T2DM patients had higher PWVao and CAVI . When thr = 0.33; p = 0.005), body fat , brachial systolic pressure , and heart rate . No association was found between PWVao and duration of diabetes , BMI , and waist circumference . CAVI was found to be positively associated with age  and duration of diabetes  but negatively associated with BMI . CAVI did not show any significant association with the components of brachial blood pressure parameters.In correlational analysis, PWVao increases with increasing age  and muscular arteries. The findings of this study show that haPWV was associated with most CVD risk factor. Diabetes affects the stiffness of central elastic arteries more drastically than peripheral muscular arteries , making The study was a case-control design with subjects recruited from a specialized clinical facility and nondiabetes controls were conveniently sampled from the general population. Hence, we cannot infer causality from the data and the conclusion cannot be generalized to the entire Ghanaian population. In addition, humoural biomarkers that underline the pathophysiological mechanisms of arterial stiffness were not assayed. Of particular importance is hypogonadism, assessed as low plasma testosterone levels, which has been associated with cardiovascular risk factors such as obesity, insulin resistance, metabolic syndrome, and high BP; all these conditions are associated with increased arterial stiffness . TestostIn summary, this study has shown that arterial stiffness, measured as PWVao and CAVI, is elevated in T2DM patients in the absence of obesity and hypertension. This increase in arterial stiffness was not accompanied with significant elevation of central haemodynamic pressure indices. Hence, in nonhypertensive T2DM patients, medication reducing arterial stiffness such as angiotensin conversion enzyme inhibitors, angiotensin receptor inhibitors, and calcium channel blockers may be beneficial . Also, p


Both pulmonary arterial stiffening and systemic arterial stiffening have been described in COPD. The aim of the current study was to assess pulse wave velocity (PWV) within these two arterial beds to determine whether they are separate or linked processes.In total, 58 participants with COPD and 21 healthy volunteers (HVs) underwent cardiac magnetic resonance imaging (MRI) and were tested with a panel of relevant biomarkers. Cardiac MRI was used to quantify ventricular mass, volumes, and pulmonary (pulse wave velocity [pPWV] and systemic pulse wave velocity [sPWV]).−1, p=0.006), higher right ventricular mass/volume ratio , higher left ventricular mass/volume ratio , and a trend toward a higher sPWV . Multiple biomarkers were elevated: interleukin-6 , high-sensitivity C-reactive protein , surfactant protein D , N-terminal pro-brain natriuretic peptide , and high-sensitivity troponin I . There was a significant relationship between sPWV and LVMVR (p=0.01) but not pPWV (p=0.97) nor between pPWV and RVMVR (p=0.27).Those with COPD had higher pPWV (COPD: 2.62 vs HV: 1.78 msPulmonary arterial stiffening and systemic arterial stiffening appear to be disconnected and should therefore be considered independent processes in COPD. Further work is warranted to determine whether both these cause an increased morbidity and mortality and whether both can be targeted by similar pharmacological therapy or whether different strategies are required for each. Despite being a disease of the pulmonary parenchyma, COPD is associated with significant cardiac morbidity and mortality, with up to 43% of mortality in COPD secondary to cardiovascular causes.7Arteriosclerosis is the stiffening of the arterial wall and is predominantly a result of aging and rising mean arterial pressure in both the systemic and pulmonary circulation.Thus, the aim of the current study was to examine the association between aortic and pulmonary arterial stiffening using pulse wave velocity (PWV) and their effects on cardiac remodeling with the hypotheses that 1) aortic stiffening and pulmonary stiffening occur in parallel; 2) inflammatory markers would explain this interaction; and 3) elevated PWV would be associated with adaptive ventricular remodeling with an increased ventricular mass to end diastolic volume ratio.Between July 2014 and May 2016, participants were recruited from primary and secondary care clinics and from community-based spirometry and research databases. Inclusion criteria for the study were the following: 40–85 years of age with a diagnosis of COPD, based on the current Global Initiative for Chronic Obstructive Lung Disease guidelines of postbronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 with a history of smoking.In total, 104 participants with COPD were screened with 37 excluded due to either coexistent coronary artery disease, atrial fibrillation, prior thoracotomy, coexistent lung condition, left ventricular systolic dysfunction on echo, or no history of smoking. This left 67 participants in the cohort. Of these, 56 participants were included in the final analysis . All the participants gave written informed consent for the study that was conducted in accordance with the Declaration of Helsinki and was approved by the East of Scotland Research Ethics Committee 1 (Reference Number: 14/ES/0034).A healthy control (HC) group was recruited with the age and sex of them approximately matched to the COPD cohort, with no prior history of cardiac or pulmonary pathology.All COPD participants underwent spirometry, single breath diffusion (diffusing capacity of the lungs for carbon monoxide [DLCO]), a 6-minute walk test (6MWT), and a cardiac MRI on the same day. All HCs underwent a cardiac MRI. Spirometry, DLCO, and 6MWT were performed as per European Respiratory Society/American Thoracic Society guidelines.Images were acquired on a 32–radiofrequency RF cardiac receiver channel, 3-Tesla MRI scanner . A three-plane localizer was first obtained, following which 4-chamber, 2-chamber, and short-axis localizers of the heart were obtained. An axial half-Fourier acquisition turbo spin echo stack was acquired of the chest.2, matrix =512×512) was then performed in the same position as previously described.2, bandwidth =475 Hz/pixel). Two-phase contrast sequences were then obtained, the first positioned through the aortic arch at the level of the pulmonary bifurcation and the second slice placed through the proximal abdominal aorta just distal to the aortic hiatus. The same phase contrast sequence was used as for the pulmonary PWV measurement.From these, a balanced steady-state free precession (bSSFP) stack was performed in breath-hold from the atrioventricular ring to the apex. To plan the main pulmonary artery (MPA) phase contrast sequence, a bSSFP sequence of the RV outflow tract was performed following which an orthogonal plane was acquired to optimally visualize the MPA and pulmonary valve. A bSSFP sequence was then performed through the MPA slice and was positioned midway between the valve and the bifurcation of the pulmonary artery in order to avoid both structures throughout the cardiac cycle. A free-breathing phase contrast sequence  =12/4 ms, number of averages =1, phases =80, velocity encoding =150 cm/s, bandwidth/pixel =340 Hz, flip angle =15°, field of view =320×320 mmThe images were exported with image analysis performed by using CVI 42 .1.7.Epicardial and endocardial contours were drawn around the right ventricle at end systole and end diastole. Trabeculae were included in the mass measurement and excluded from the volume calculation. The septum was treated as belonging to the left ventricle and was excluded from the RV mass. RV mass and volumes were normalized to heightFor the time component, the phase and magnitude images were pulled up side by side. A contour was manually drawn around the perimeter of the vessel, then propagated throughout the cardiac cycle, and corrected as when automatic contouring led to erroneous boundaries. The program then automatically calculated area, flow, and velocity data, which were exported to Excel 2010 . The area and flow were plotted against one another during early systole, which was defined as the time period in systole during which both the vessel area and flow were simultaneously increasing. The PWV was then calculated as described by Davies et al:TT stands for transit time, d stands for distance between the imaging planes, and t stands for time of systolic upstroke arrival.The distance was measured along the aorta between the two analysis planes  using candy stick FLASH and the time delay calculated as the time delay between the arrival of the foot of the pulse wave at the ascending aorta and abdominal aorta. To calculate the latter, the flow curves from the ascending thoracic aorta and the abdominal aorta were plotted, and the time to the systolic upstroke of the waves was then calculated. The arrival time of the flow wave was identified as the intersection between the systolic upstroke and baseline flow. The systolic upstroke was calculated as the line through the data points lying between 20% and 80% of the maximum flow rate.In order to better understand the links between COPD, vascular stiffening, and cardiac remodeling, several families of biomarkers were assessed: 1) connective tissue markers – carboxymethyllysine (CML), matrix metalloproteinase-9 (MMP-9), and fibroblast growth factor-23 (FGF-23); 2) inflammatory markers – high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and fibrinogen; 3) pulmonary markers – club cell secretory protein-16 (CC-16) and surfactant protein D (SPD); 4) cardiac markers – high-sensitivity troponin I (hsTrop I) and N-terminal pro-brain natriuretic peptide (NT-proBNP); and 5) lipid markers – total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides.g at room temperature for 15 minutes before the plasma from this was removed and then stored at −80°C. All the samples were stored until the study was completed and then analyzed en bloc. For this analysis, blood samples were drawn into 3×4 mL EDTA tubes, which were then centrifuged at 2,000× t-test was used to compare the differences in continuous variables between the HCs and COPD cohort. χ2, Fisher’s exact, and Mann–Whitney U tests were used as appropriate to compare differences in ordinal and nominal data between the groups. Pearson or Spearman rank coefficients were used to assess the correlation between aortic and pulmonary PWV and to look at the correlates of both of these with baseline demographic, spirometric, and MRI factors in the COPD cohort. Multiple linear regression analysis was performed with systemic pulse wave velocity (sPWV) and pulmonary pulse wave velocity (pPWV) entered separately as the dependent variables, with those factors which were (p<0.1) in single variable analysis entered as independent variables. All data were analyzed using SPSS package . Significance was assumed when p<0.05.Descriptive statistics were used for the analysis of the demographic and clinical features of the cohorts with data expressed as mean ± SD. Normality and equality of variances of the variables were tested. An independent sample p<0.001) and had a higher body mass index . While those with COPD had a significantly higher prevalence of hypertension, there was no significant difference in blood pressure or pulse pressure due to a higher prevalence of antihypertensive medication prescription. In total, 56 COPD patients  and 20 HCs  completed the study protocol. Despite approximate age and sex matching, those with COPD were significantly older  and a trend toward a higher aortic PWV . Compared with the HCs, those with COPD had a significantly lower RV stroke volume  and a higher RV mass/volume ratio . Those with COPD also had a significantly higher left ventricular mass/volume ratio , inversely correlated with BMI , and correlated with increasing diastolic blood pressure  with a trend toward a positive correlation with percentage predicted residual lung volume  and percentage predicted total lung capacity  remained significantly associated with pPWV.In those with COPD, pulmonary PWV was correlated with percentage predicted total lung capacity , systolic blood pressure , and percentage predicted transfer coefficient for carbon monoxide (KCO)  and a trend toward a significant association with percentage predicted DLCO  and pulse pressure (ρ=0.25 p=0.067). Applying a conservative Bonferroni correction for multiple comparisons would result in a significance level of p<0.0008, as a result of which only age would remain a significant correlate of sPWV. On linear regression, age , systolic blood pressure , and percentage predicted KCO  all remained significantly associated with aortic PWV.In comparison, aortic PWV showed a significant association with age , while no such correlation was found between pPWV and RVMVR . Similarly, there was no significant association between aortic and pulmonary PWV  and hsCRP ; connective tissue markers MMP-9 ; lung tissue marker SPD ; and cardiac markers NT-proBNP  and hsTrop I .Those with COPD showed significantly higher levels of the following: inflammatory markers IL-6 .No significant difference was found in FGF-23, CC-16, CML, fibrinogen, cholesterol, HDL, or LDL (p=0.04), TC , and NT-proBNP . However, on linear regression accounting for diastolic blood pressure, the significance of these was lost. For sPWV, there was a weak correlation with CC-16 , TC , and LDL . However, on linear regression accounting for age and systolic blood pressure, these associations were no longer significant.In those with COPD, there was a weak correlation between pPWV and hsCRP  both pulmonary and systemic arteries are stiffer in COPD compared with controls; 2) aortic PWV and pulmonary PWV are associated with different clinical parameters and biomarkers from one another; and 3) aortic but not pulmonary PWV is associated with ventricular hypertrophy.Our finding of increased aortic stiffness is consistent with previous work demonstrating increased aortic PWV in those with COPD.49Increased pulmonary arterial stiffness in COPD has been previously reported both invasively on right heart catheterization and using pulsatility on MRI.Despite those with COPD having significantly elevated hsCRP, IL-6, MMP-9, NT-proBNP, and hsTrop I, none of these markers showed any significant correlation with either aortic or pulmonary PWV. In the current study, we found no significant link between aortic and pulmonary PWV, with no overlap of clinical correlates or biomarkers. Thus, it would appear that the pulmonary vascular remodeling in COPD occurs separately to systemic arterial stiffening. Previous work has described pulmonary arterial stiffening to be significantly associated with exercise-induced elevations in pulmonary pressures;Given the lack of significant correlation between pulmonic and arterial stiffening and biomarkers, particularly the lack of association with inflammation, another link between COPD and arterial stiffening must also be considered. It has been previously demonstrated that the two strongest predictors of aortic PWV are age and blood pressure.58There are some limitations to the current study. Patients with known coronary artery disease were excluded; thus, the results may not be representative of the wider COPD cohort in whom cardiovascular disease is common. Despite attempted matching, the controls were younger than those with COPD and more likely to be on treatment for hypertension although the blood pressures were well matched. As age is a significant contributor to PWV, this may have contributed to the difference between the two groups although our observations are concordant with the current literature.In conclusion, both aortic and pulmonary arterial stiffening occurs in COPD, but these processes are independent of one another with aortic but not pulmonary PWV, demonstrating a significant association with remodeling in the ventricle. Further work is warranted to determine whether this stiffening causes an increased morbidity and mortality and whether both can be targeted by similar pharmacological therapy or whether different strategies are required for each.


Asthma is a chronic airway inflammation with a potential systemic impact. Atherosclerosis is a chronic inflammatory artery disease. The aim of our study was to prove if there is a correlation between the occurrence of asthma and increased atherosclerotic vessel disorders. Vessel status was compared between mild-to-moderate, severe allergic asthma and matched controls. Measurements of artery stiffness were calculated by central pulse wave velocity, ultrasonographic strain imaging and ankle-brachial index. Atherosclerotic plaque burden was assessed by colour-coded duplex sonography. Additionally, analysis of cardiovascular and asthma blood markers was conducted. Arterial stiffness expressed as an increased central pulse wave velocity and decreased circumferential and radial strains as well as the prevalence of media sclerosis were significantly higher among asthma patients compared to controls. Atherosclerotic plaque burden was relevantly increased in asthma groups vs. controls . Except for the elevated IgE and fibrinogen concentrations as well as leukocyte number there were no relevant differences in the blood parameters between the groups. Allergic asthma is associated with distinct atherosclerotic artery changes compared to the respectively matched control collective. The severity of asthma correlates with more pronounced pathological vessel alternations. Asthma is a chronic inflammatory disease of the airways. A growing body of evidence shows that asthma may affect also extrapulmonal tissue. Patients with asthma demonstrate an increased risk for cardiovascular complications . MoreoveThe research was conducted according to the principles of the Declaration of Helsinki and was approved by the local ethics committee at the Medical Faculty of the University of Bonn. Written informed consent has been obtained from all subjects. The study has been conducted between October 2015 and July 2016. A total of 82 consecutive outpatients with allergic asthma have been enrolled in the study during control visits in our pneumological department. Allergic asthma was defined as an increase in forced expiratory volume in 1 second (FEV1) of more than 12% following administration of short acting ß2-agonist or a decrease in FEV1 of more than 200ml in bronchial challenge test with methacholine and detection of at least three allegro-allergens in specific IgE blood measurements or in skin prick test. All patients presented stable disease without clinical exacerbation at the time point of the study performance. Patients with immunodeficiency or a history of autoimmune or other than asthma chronic inflammatory diseases were excluded. Asthma patients have been divided into two groups: mild-to-moderate (n = 24) and severe asthma (n = 58). Mild-to-moderate asthma patients were under inhaled therapy with no present or past treatment with omalizumab or oral cortisone. In contrast, severe asthma was characterized by a maximal inhaled therapy combined with a present or past administration of omalizumab and/or cortisone oral. 21 non-asthmatic patients served as controls. There were no significant differences in sex, age, body mass index and cardiovascular risk factors such as arterial hypertension, hypercholesterolemia, diabetes mellitus, nicotine abuse or history of artery disease between these three groups. Lung function showed significantly decreased absolute and predicted FEV1 values as well as significantly increased absolute and predicted total airway resistance values in asthma patients compared to controls. The exact baseline characteristic of the patients and controls is presented in the Classical parameters of vessel stiffness have been calculated by means of central pulse wave velocity (cPWV) and ankle-brachial index (ABI). Assessment of central pulse wave velocity (cPWV) was performed using AngE Pro8® . Ankle-brachial index (ABI), defined as the ratio of the systolic blood pressure (SBP) measured at the ankle to that measured at the brachial artery , was calUltrasonographic strain imaging included global average circumferential strains (% of vessel circumference changes), global average radial strains , radial displacement , global average circumferential strain rates (vessel circumference changes per second) and global average radial strain rates . Common carotid artery was shown in the two-dimensional short axis (Philips iE33). Four electrocardiography (ECG)-triggered cardiac cycles were stored for the offline analysis. Following creation of a region of interest, the frame-to-frame displacements of the speckles representing tissue movements were analyzed by using of a computer workstation equipped with a speckle-tracking software package . This method has been previously described , 13.The following cardiovascular risk and asthma markers in blood have been examined using standard laboratory tests: total cholesterol, HDL- and LDL-cholesterol, lipoprotein(a), C-reactive protein (CRP), interleukin-6, soluble interleukin-2 receptor (sIL-2R), immunoglobulin E (IgE), fibrinogen, d-dimer, leukocytes, lymphocytes, eosinophils, hemoglobin, thrombocytes.Mean values of the determined parameters ± standard error of the mean (SEM) were compared by means of ANOVA for three groups and by means of the Student's t-test for two selected groups. Potential differences between categorical variables were calculated by using of the chi-square test. P<0.05 was considered as statistically significant.As a key finding, the angiological results have shown an increased arterial stiffness and more manifest atherosclerosis in patients with asthma, especially in those with its severe form, compared to the baseline matched controls. In detail, central pulse wave velocity differed significantly across the groups studied  with the highest values in severe asthma collective  in comparison to control  showed significant elevated levels of fibrinogen  and leukocytes  with a reduced lymphocyte fraction  and a slightly increased number of eosinophils  compared to control  and thrombocytes in asthma patients  compared to controls  vs. patients on omalizumab without oral cortisone therapy  has been conducted. Baseline characteristics were similar in both groups. The only difference was that patients from group 1a had significantly lower FEV1 values in comparison with the group 1b : 67.0±5.2% vs. 85.8±3.4%, resp., p = 0.003). Angiological examinations have shown worse vessel status with a significantly higher percentage of atherosclerotic plaques in the group 1a vs. group 1b . Blood analysis demonstrated except for increased IgE levels and most likely cortisone-associated changes in the white blood cell count in group 1a  no relevant differences between both groups.Our data show pathological artery changes in asthma patients compared to the control collective. Specifically, asthma was not only associated with preatherosclerotic vessel alternations, such as higher arterial stiffness, but much more with increased prevalence of manifest atherosclerosis compared to non-asthma individuals. Indeed, asthma has already been described to be a risk factor for stroke and heart diseases ,15,1. GeChlamydia pneumoniae [As traditional cardiovascular risk factors, such as: arterial hypertension, diabetes mellitus, hypercholesterolemia, obesity and nicotine abuse were similar between asthma and control individuals, we aimed to determine other potential risk markers in the blood. As a result, only IgE and fibrinogen levels as well as leukocyte number and subtypes differed significantly between the groups. Fibrinogen is independently linked to enhanced rates of cardiovascular complications . It has eumoniae  are commIn our study, all vessel changes were more pronounced in severe asthma compared to mild-to-moderate asthma. Interestingly, patients on the add-on combined therapy of oral corticosteroid and omalizumab (group 1a) showed even greater atherosclerotic artery alternations than the patients with the same therapy except for oral corticosteroids (group 1b). Since the lung function was more impaired in group 1a vs. group 1b, it is difficult to judge if the severity of asthma, differences in the treatment or both influenced this finding. In this context, the role of antiasthmatic medication in the process of vasculopathy is not clear. Some works reported on the beneficial effects of inhaled glucocorticosteroids on the vessel changes . One couIn our present study, we did not observe any relevant cortisone-related side effects, such as: increase in blood pressure, induction of hypercholesterolemia or diabetes mellitus. One may assume that asthma-specific activity and adverse effects of a long-term high dose cortisone therapy may have led to the worst vessel status in patients with severe asthma under oral cortisone therapy.In conclusions, our data implicate an association between asthma, in particular severe asthma, and pathological artery changes, including a significantly increased atherosclerotic plaque load.


P = 0.001) and alleles (P < 0.001) of rs7119375 differed significantly between patients and controls in women. Carriers of rs7119375-AA genotype had significant higher systolic blood pressure (SBP) than carriers of rs7119375-GG genotype in both patients and controls of female gender (P < 0.01). Moreover, carriers of rs7119375-A allele were 1.80 times more likely to develop hypertension relative to carriers of rs7119375-GG genotype after adjusting for age, body mass index and glucose . Further allele combination analysis supported the leading contribution of rs7119375 to hypertension risk. Our findings demonstrated that the mutation of promoter polymorphism rs7119375 in APJ gene was significantly associated with elevated SBP and increased hypertension risk in Chinese women.The aim of this study was to interrogate the gender-specific association of 5 well-defined polymorphisms in apelin/APJ system with both blood pressure changes and hypertension risk in a northeastern Chinese population. This is a population-based case-control study, including 650 hypertensive patients and 645 normotensive controls. Data were analyzed by STATA and Haplo.Stats. The genotype distributions of 5 study polymorphisms were in Hardy-Weinberg equilibrium in both genders. The rs7119375 and rs10501367 were completely linked. The genotypes ( Many sum intake  and dietm intake . In lighm intake , 16. To P ≤ 0.001). For HDLC, an elevated level was seen in controls relative to patients for women only (P = 0.005). In contrast, circulating levels of apolipoprotein A and B were significantly higher in patients than in controls for men only .Table P > 0.05). The genotype distributions and allele frequencies of 4 polymorphisms are presented by gender in Table P = 0.001) and alleles (P < 0.001) of rs7119375 in women, even after the Bonferroni correction , and the power to detect this significance was over 95%. No significance was observed for the other genetic comparisons in both genders.Linkage disequilibrium analysis showed that rs7119375 and rs10501367 were completely linked . In addition, carriers of rs7119375-AA genotype had significant higher SBP than carriers of rs7119375-GG genotype in both patients and controls of female gender (P < 0.01). No significant changes were identified in women for DBP, and in men for both SBP and DBP (P > 0.05).The changes of SBP and DBP across genotypes of 4 examined polymorphisms are summarized in Table P = 0.040). No significance was detected for the other polymorphisms under both models.The risk prediction of single polymorphisms for hypertension is provided in Table P = 0.005) and 84%  increased risk before and after adjusting for age, BMI and glucose, respectively. Another allele combination T-A-G-T had a higher frequency in controls than in patients (P = 0.001) and was in turn associated with 66%  and 67%  reduced risk for hypertension before and after confounding adjustment, respectively. After the Bonferroni correction, significance persisted for the allele combination T-A-A-T in women .Summarized in Table APJ gene was associated with elevated SBP and increased hypertension risk in Chinese women. This finding not only suggests a gender-specific role of apelin/APJ system in the pathogenesis of hypertension, but also provides an alternative therapeutic target for hypertension.This is a replication study interrogating the association of five well-defined polymorphisms in apelin/APJ system with blood pressure changes and hypertension risk in a northeastern Chinese population. The key finding of this study was that the mutation of promoter polymorphism rs7119375, in complete linkage with rs10501367, in There is strong evidence that apelin/APJ system is implicated in the regulation of cardiovascular system . Apelin apelin and APJ genes were sequenced by a previous pilot study by Li et al, and 12 common polymorphisms were identified and further genotyped in 1015 Han Chinese from 248 families [APJ gene rs7119375 polymorphism in regulating SBP and predisposing to hypertension in women, partly in line with the findings by Niu et al. [APJ gene rs7119375 polymorphism was not significantly associated with blood pressure response to potassium supplement [APJ gene is a potential hypertension-susceptibility locus in women, and it might precipitate hypertension through regulating SBP.The families . Only 5 families . Howeverpplement . In addiAPJ gene in blood pressure regulation and hypertension predisposition. In fact, this gender-specific contribution may reflect the impact of some genes on sex chromosomes, such as apelin and angiotensin-converting enzyme 2 in X chromosome [apelin gene with hypertension in this study, we observed that SBP differed significantly between two homozygous genotypes of rs3761581 in apelin gene. As with most mutations, the relative risk conferred by a single polymorphism might be small, and it will be worthwhile analyzing this polymorphism further in independent populations with different genetic backgrounds.Another important finding of this study was the gender-specific involvement of romosome . Severalromosome , 25–27. Several limitations should be acknowledged for this study. The first limitation is the case-control study design with study group retrospectively collected. The second limitation is that this is a population-based study, which cannot be extrapolated to the general population. The third limitation might be the insufficient statistical power arising from the limited sample size, especially by gender. The fourth limitation is that only five promoter polymorphisms from apelin/APJ system were genotyped. The fifth limitation is that circulating apelin levels are not measured at enrollment, and it is of interest to analyze the relationship between blood pressure and circulating apelin. The sixth limitation is that information on drug regimens, salt consumption and menopause is not available to exclude the residual confounding effects. The seventh limitation is our conclusion was based on only Chinese population and the application of our findings cannot be generalized to non-Chinese groups.APJ gene was associated with elevated SBP and increased hypertension risk in Chinese women. In addition, our findings also highlighted the gender-specific involvement of APJ gene in blood pressure regulation and hypertension predisposition. Pending future successful validation, our findings may provide the basis for further personalized medicine, namely, individuals with mutant APJ gene could be identified early and treated with optimal regimens since they could carry a high hypertension risk.To sum up, our findings demonstrated that the mutation of promoter polymorphism rs7119375, in complete linkage with rs10501367, in The study group consisted of patients with essential hypertension and normotensive controls. In brief, they are unrelated local residents of Han nationality in Qiqihar city, Heilongjiang province, China. All study participants were enrolled between September 2013 and October 2015 from Qiqihar city and surrounding areas. Normotensive controls were enrolled from the participants who took part in the annual routine medical examinations at Qiqihar Jianhua Hospital and The Third Affiliated Hospital of Qiqihar Medical University. Each participant provided a written informed consent prior to participation. This study was approved by the institutional review boards at Qiqihar Medical University.Blood pressure was measured three times with a mercury sphygmomanometer after the participants had rested for at least 5 minutes in the sitting position. The mean level of last two measurements was used for analysis. Hypertension is diagnosed as mean systolic blood pressure (SBP) ≥ 140 mmHg or mean diastolic blood pressure (DBP) ≥ 90 mmHg or receipt of antihypertensive regimens. Normal blood pressure is defined as mean SBP < 140 mmHg and mean DBP < 90 mmHg. Patients were excluded if they were clinically identified with secondary hypertension, coronary artery disease and renal related disorders. This study group included 650 hypertensive patients and 645 normotensive controls.Age, body weight and height were taken down at the time of enrollment. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Plasma triglycerides and total cholesterol were determined by enzymatic methods, and high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), apolipoprotein A and apolipoprotein B were determined by homogeneous assays. Fasting plasma glucose was measured by the Glucorder analyzer.apelin gene and rs7119375, rs10501367, rs9943582 in APJ gene. All polymorphisms were located in the promoter regions of both genes. The Taqman probes and primers were obtained from the Applied Biosystems Assay-by-Design Service. The Universal PCR Master Mix from Applied Biosystems was used in a 5-μl total reaction volume containing 10-ng DNA per reaction. For the sake of accuracy, 100 randomly-selected samples were re-genotyped by TaqMan assay method. The results of two batches were exactly matched.Genomic DNA was extracted from peripheral blood leukocytes using the TIANamp Blood DNA Kit . A total of five well-defined polymorphisms in apelin/APJ system were genotyped by the TaqMan assay method, including rs3761581, rs56204867 in t-test or Mann-Whitney U test where appropriate. Genotype and allele distributions were compared between patients and controls by χ2 test or Fisher's exact test where appropriate. Deviation from Hardy-Weinberg equilibrium was evaluated by χ2 test in control participants. Linkage disequilibrium of five examined polymorphisms was assessed by Haploview v4.2 . The risk prediction for hypertension was determined by binary Logistic regression analysis under additive and dominant models. The effect-size estimates were denoted as odds ratio (OR) and its 95% confidence interval (95% CI). Multiple comparisons were controlled by the Bonferroni correction. Unless otherwise indicated, a two-tailed P value of < 0.05 was accepted as statistical significance.Continuous data are listed as mean (standard deviation) and compared by P values were based on 1000 replicates. The statistical power was estimated by the EpiCalc (v.2.15.1.0) under the “R-project v2.11.1” environment. Haploview plot of linkage disequilibrium was delineated to measure linkage disequilibrium [Allele combination of multiple polymorphisms was derived and its frequency was estimated by the haplo.em program. The risk prediction of derived allele combinations for hypertension was determined by the haplo.cc and haplo.glm programs. The relation between derived allele combinations as a whole and a certain phenotype was delineated by the haplo.score program. The haplo.em, haplo.cc, haplo.glm and haplo.score programs were obtained from the Haplo.stats (v1.4.0) under the “R-project v2.11.1” environment. Simulated ilibrium .


This prospective study focuses on risk factors for arterial damage in children with type 1 diabetes (T1D).Eighty children and adolescents with T1D were investigated twice, approximately 2 years apart, for carotid artery intima-media thickness (cIMT) and compliance (CAC), flow-mediated dilatation (FMD) of the brachial artery, and plasma levels of matrix metalloproteinase (MMP)-8. All subjects were genotyped for HLA. The number of respiratory tract infections (RTI) during the past year was obtained by a questionnaire in 56 patients.p = 0.04, r = − 0.3; n = 62) and FMD . In multivariate analysis, RTI frequency correlated significantly with cIMT progression irrespective of age, diabetes duration, BMI, and HbA1c . When patients were divided in relation to RTI, the association of DQ2/8 with cIMT progression remained significant in patients with over three infections/year . During follow-up, the group of DQ2/8 patients with hsCRP > 1 mg/l showed significantly higher levels of plasma MMP-8 than the non-DQ2/8 group.cIMT progression, defined as percentage (%) change of cIMT from baseline, correlated inversely with the % changes of both CAC (The diabetes-risk genotype DQ2/8 and systemic inflammation contribute to pro-atherosclerotic vascular changes in children and adolescents with T1D. Increased infection recurrence appears to be independent predictor of the risk of developing T1D , an indeAtherosclerosis develops faster in children with T1D . SeveralThe genetic HLA-related susceptibility is recognized in more than 80% of young patients with T1D . We haveThe HLA-mediated presentation of autoantigens by vascular endothelial cells, a key-event in the transmigration of auto reactive T-cells and diabetes development, seems to occur systemically . This coSerum and plasma matrix metalloproteinase-8 (MMP-8) levels have been demonstrated to reflect disease severity and plaque instability in cardiovascular diseases . MMP-8 cIn the present prospective study, we investigated whether DQ2/8, acute infections and plasma MMP-8 concentrations in children and young adults with T1D associate with adverse changes in arterial function and intima-media thickness.Eighty children and adolescents  with age between 8 and 20 (mean age 15) years with T1D duration for at least 6 months were recruited from the paediatric outpatient diabetes clinic at the Lund University Hospital. All patients were treated with daily insulin injections. Exclusion criteria were: family history for other major cardiovascular risk factors , active smoking, systemic hypertension, asthma and allergy. None of the patients were on corticosteroids or other type of immunosuppressive medication. All patients were followed for 1.40 ± 0.02 years (range 1.1–2.0 years).Body weight, height, and arterial blood pressure (systolic and diastolic) were measured at both visits. Data on demographic information were collected via questionnaire. Data on diabetes duration were obtained from the registry of the outpatient diabetes clinic.Detailed infection history including type and number of acute infections during the past year, duration and severity of symptoms, medication if any, and time between the latest infection and the ultrasound visits was also determined by questionnaire. Acute infection was defined by clinical symptoms. Patients were grouped in relation to the number of infections during the past year as follows: group 1 = 0 to 1 infection (low frequency), group 2 = 2 to 3 infections (moderate frequency), and group 3 = ≥ 3 infections (high frequency).Patients were also grouped based on the hsCRP levels as follows: ≤ 1 and > 1.0 mg/l.All blood samples were taken in connection with the ultrasound examination, and stored at − 80 °C until final analysis. High-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) and total cholesterol (TC) were analysed from lithium heparin plasma by enzymatic method . Plasma high-sensitivity C-reactive protein (hsCRP) was measured by enzyme-linked immunoassay using polyclonal antibodies .® hybridization assay /Dd)/(Ps − Pd), where Ds is systolic diameter, Dd is diastolic diameter, Ps is systolic blood pressure, and Pd is diastolic blood pressure. CAC reflects the ability of arteries to expand in response to the pulse pressure caused by cardiac contraction and relaxation. In a prior reproducibility study on 10 randomly selected patients, the coefficient of inter-observer variability was 6.2%.A high-resolution ultrasound system  equipped with a 15 MHz probe was used . Longitu™ C512  [Longitudinal scans of the brachial artery (non-dominant arm) were imaged several centimetres above the antecubital fossa via a 15-MHz linear ultrasound transducer of an Acuson SequoiaGermany) . The ultDifferences in the studied variables were assessed by ANOVA, and adjusted for covariates by ANCOVA. Eventual correlations between the hypothesised predictor variables and the dependent variable were assessed by logistic regression. When significant, multiple regression models were used to identify independent factors affecting the vascular indexes. hsCRP was logarithmically transformed due to its skewed distribution. All other numeric variables showed a Gaussian distribution. “cIMT progression” was defined as % increase in cIMT at 18 months from the baseline. Similarly, changes in FMD and CAC over the follow-up period were expressed as % change at 18 months from the corresponding baseline values.All data are expressed as mean ± SD unless otherwise specified. Statistical significance was accepted when p was less or equal to 0.05. All statistical analyses were performed with StatView for Windows .p = 0.23, r = 0.13). Baseline diabetes duration  and BMI , but not HbA1c, had a weak association with the final cIMT, but neither of these showed a significant correlation with % cIMT (p > 0.2). % cIMT correlated inversely with the % changes in CAC . The relationship between % cIMT and DQ2/8 remained significant after simultaneous adjustment for age, BMI, diabetes duration, HbA1c, and LDL-to-HDL ratio (p = 0.03 by ANCOVA). Although gender alone did not influence % cIMT , % cIMT was most increased in male DQ2/8 patients .% cIMT was increased in the DQ2/8 group compared to the non-DQ2/8 group . MMP-8 levels were significantly higher in those patients with hsCRP ≥ 1 compared to those with hsCRP ≤ 1at the follow-up (p = 0.045). However, only patients positive for DQ2/8 with hsCRP > 1 mg/L at follow-up had significantly higher levels of plasma MMP-8 than the non-DQ2/8 patients  and HbA1c , which were modestly associated with final MMP-8, no other variable showed correlation with it.There was no significant difference in MMP-8 concentrations between DQ2/8 groups p = 0.. MMP-8 lIn a multivariate model adjusted for age, BMI, diabetes duration, HbA1c, and the number of RTI during the year prior to the baseline ultrasound, infection frequency showed a significant relationship to % cIMT Table . % cIMT There is solid evidence for association of T1D with premature carotid atherosclerosis in childhood . In the Matrix metalloproteinases (MMPs) are structurally related but genetically distinct enzymes that can degrade almost all extracellular matrix components. Especially MMP-8 or collagenase-2 can also process various non-matrix bioactive substrates. Due to such decisive substrate cleavage(s) MMP-8 can mediate surrogate destructive pro-inflammatory immune reactions –25. ManyFunctional disturbances in the vasculature such as endothelial vasomotor dysfunction and decreased arterial elasticity are important signs of early vascular disease, and associate with arterial intima thickening . In a prEven children without conventional risk factors for atherosclerosis appear to be prone to carotid artery thickening already 3 months after an acute infectious illness . Acute iIntuitively, given the upregulatory effects exerted by systemic inflammation on both vascular adhesion molecules and HLA molecules, their putative detrimental influences on the vascular wall would become stronger in an inflammatory environment. In patients with rheumatoid arthritis (RA), another cardiovascular risk factor with important genetic susceptibility, the mortality from cardiovascular disease was most increased in patients with RA-risk HLA and inflammatory activity .Future large-scale studies of young patients with T1D are needed to confirm these findings and, if proven, to provide additional mechanistic insights into the putative HLA-infection interplay on vascular wall. Eventual relationship between the observed structural changes and accelerated atherosclerosis needs to be investigated as well.


The initial assessment of a patient with systemic arterial hypertension (SAH)comprises diagnostic confirmation, suspicion and identification of the secondarycause, and assessment of CV risks. In addition, target-organ damage (TOD) andassociated diseases should be investigated. Such assessment comprises BP measurementin the office and/or outside the office, by use of proper technique and validatedequipment, medical history , physical examination and clinicaland laboratory investigation.General assessments directed to all, and, in some cases, complementary assessmentsonly for specific groups are proposed.Blood pressure should be measured in all assessments performed by physiciansof any specialty and other health care professionals properly trained.1 Manual, semi-automated or automatedsphygmomanometers can be used. They should be validated, and calibratedannually following the INMETRO recommendations  during wakefulness.6Orthostatic hypotension should be suspected in elderly, diabetic anddysautonomic patients, as well as in those on any antihypertensivemedication. Thus, particularly in such conditions, BP should be read withthe patient standing for 3 minutes, and orthostatic hypotension beingdefined as a reduction in SBP > 20 mm Hg or in DBP > 10 mmHg.7Procedures recommended for BP measurement:Explain the procedure to the patient, who should be left to rest for3-5 minutes in a calm environment and instructed not to talk duringthe measurement. Possible doubts should be clarified before or afterthe procedure.Make sure the patient:- does not have a full urinary bladder;- did not practice physical exercise in the past 60minutes;- did not consume alcohol, coffee or any food;- did not smoke in the past 30 minutes.Position:- The patient should be sitting relaxed in a chair, with backsupported, legs uncrossed and feet on the floor;- The patient's arm should be supported at heart level, notcompressed by clothes, with hand palm turned upward.After 3 minutes, BP should be read in the upstanding position indiabetic and elderly patients, or in any other situation at risk fororthostatic hypotension.Determine arm circumference in the middle point between the acromionand olecranon;Select proper cuff size ;Place the cuff snugly, 2-3 cm above the cubital fossa;Centralize the compressive part of the cuff on the brachialartery;Estimate BP level based on palpation of the radial pulse*;Palpate the brachial artery on the cubital fossa and place thestethoscope's diaphragm without excessive compression*;Inflate cuff rapidly until the estimated SBP level obtained onpalpation is exceeded by 20-30 mm Hg*;Proceed to deflation slowly (velocity of 2 mm Hg/second)*;Determine SBP by auscultation of the first sound (Korotkoff phase I),and then, slightly increase the deflation velocity*;Determine DBP when the sounds disappear (Korotkoff phase V)*;Auscultate until 20-30 mm Hg below the last sound to confirm itsdisappearance, and then proceed to rapid and completedeflation*;If heart beats persist until level zero, determine DBP on themuffling of sounds (Korotkoff phase IV) and write down the values ofSBP/DBP/zero*;Take at least two measurements at 1-minute intervals. If the firsttwo are very different, additional readings should be taken. Whenappropriate, consider the mean value;Measure BP in both arms on the first medical visit and take thehigher value as reference;Inform the patient of the BP reading; andWrite down the exact BP values, with no rounding, and the arm usedfor the measurement.* Items performed exclusively in the auscultatory technique.8The use of validated and periodically calibrated equipment isparamount.10Outside the office, BP can be measured by use of home BP monitoring (HBPM),following a specific protocol, or by use of 24-hour ABPM.Outside-the-office BP measurements should be stimulated, and can be performedby using a patient's semi-automated device or one belonging to a health careprovider. The major advantages of outside-the-office BP measurements are asfollows:Higher number of BP readings;Assessment of the individuals' usual activities;Abolition or significant reduction of the 'white-coat effect'(WCE);Patients' higher adhesion to diagnosis and follow-up.1010 Because they are different assessment methods,certain values will be considered for the definition of abnormality. The methods usually used to measure BP outside the office are ABPM and HBPM.Both provide similar BP information, but only ABPM assesses BP during sleep.However, both estimate CV risk, and should be considered to assess BPoutside the office, provided their indications and limitations arerespected.11 The interpretation of theBP levels for children and adolescents should consider age, sex and height.The assessment of BP levels according to those variables should be based onspecific tables (Chapter 10 of this guideline) or smartphone applications,BP Kids and Ped(z).Measuring BP in children is recommended at all clinical assessments after theage of 3 years, at least once a year, as part of primary pediatric care, andshould abide by the standards established for adults.12 The higher occurrence ofWCE and orthostatic and postprandial hypotension, and the presence ofarrhythmias, such as atrial fibrillation, can hinder BP measurement.Special aspects of BP measurement in the elderly are due to changes resultingfrom aging, such as higher frequency of auscultatory gap, which is theabsence of sounds during cuff deflation, resulting in falsely low SBP orfalsely high DBP readings. The wide BP variability in the elderly throughout24 hours makes ABPM a useful tool. Pseudohypertension, associated with theatherosclerotic process, can be detected by use of Osler's maneuver, thatis, the radial artery remains palpable after cuff inflation at least 30 mmHg above the reading of radial pulse disappearance.13 When the arm circumference exceeds 50 cm, and a propercuff is not available, BP can be taken in the forearm, and the radial pulseshould be auscultated.13However, restrictions apply to that practice. Cone-shaped, wide, short arms,where large cuffs do not fit, represent a special difficulty.The BP measurement of obese patients requires longer and wider cuffs toprevent BP overestimation.14 White-coat hypertension(WCH) and masked hypertension (MH) are common during pregnancy, and, thus,ABPM and HBPM can be useful for clinical decision making. Chapter 9 providesfurther information on AH during pregnancy.The BP should be measured following the same methodology recommended foradults, emphasizing that it can also be taken on the left arm in the leftlateral decubitus position at rest, and should not differ from that obtainedin the sitting position. Consider Korotkoff's fifth sound as DBP.15 Another recommendation issuspected AH originating from auto-measurement, when ABPM or HBPM should be usedto confirm or rule out the suspected diagnosis of WCH or MH.16To establish the diagnosis and to identify WCH and MH, HBPM and ABPM arerecommended .15 Anoth18Home BP measurement is performed with a specific protocol, and consists in takingthree BP readings in the morning, prior to breakfast and medication intake, andthree in the evening, before dinner, for five days. Another option is to taketwo BP measurements in each of those sessions, for seven days.Blood pressure levels ≥ 135/85 mm Hg are considered abnormal.19Ambulatory BP monitoring allows indirect and intermittent BP recording during 24hours or longer, while the patient performs their usual chores duringwakefulness and sleep. One of its most specific characteristics is thelikelihood to identify BP circadian changes, especially during sleep, which hasconsiderable prognostic implications.18Currently, the following BP means are considered abnormal: 24-hour ≥130/80 mm Hg, wakefulness ≥ 135/85 mm Hg, and sleep ≥ 120/70 mmHg.The BP limits considered normal are arbitrary. However, the values to classify BP inadults by using casual or office measurements are shown in 20 Non-controlled SAH is defined as maintenanceof elevated BP, both in and outside the office, by use of either ABPM or HBPM,even under anti-hypertensive treatment.21 Controlled AH is defined as maintenance of controlledBP levels, both in the office and outside it, under anti-hypertensivetreatment.Blood pressure is considered normal when office BP levels are ≤ 120/80 mmHg, and outside-the-office measurements (ABPM or HBPM) confirm those normalreadings .2,21 Con22Prehypertension is characterized by SBP levels between 121 and 139 and/or DBPlevels between 81 and 89 mm Hg. Prehypertensive individuals are more likely tobecome hypertensive and at higher risk for CV complications than those withnormal BP levels, ≤ 120/80 mm Hg, requiring, thus, periodicalassessment.The WCE is the BP difference between measurements taken in the office and outside it,if that difference equals at least 20 mm Hg in SBP and/or 10 mm Hg in DBP. It doesnot change the diagnosis: if normotensive, the individual will remain normotensive;if hypertensive, the individual will remain hypertensive. However, the BP stage canchange and/or there might be a false impression of need for change in thetherapeutic regimen.24 However, in terms of prognosis,whether WCH is comparable to normal BP is still controversial, because some studieshave shown that its long-term CV risk is intermediate between that of AH and ofnormotension.25It is the clinical situation characterized by abnormal office BP levels, but normalBP readings on ABPM or HBPM . Basedo23 Several factors can elevate outside-the-office BP as comparedto office BP, such as young age, male sex, smoking habit, alcohol consumption,physical activity, exercise-induced hypertension, anxiety, stress, obesity, DM, CKDand family history of SAH. The MH prevalence is higher when office BP isborderline.26Meta-analyses of prospective studies report that the incidence of CV events is twicehigher in MH than in normal BP, and comparable to that in SAH.27 In diabeticindividuals, MH is associated with an increased risk of nephropathy, especially whenBP elevation occurs during sleep.29It is characterized by normal office BP, but elevated BP on ABPM or HBPM . The MH 30Isolated systolic hypertension (ISH) is defined as increased SBP with normal DBP,and, along with pulse pressure (PP), is an important cardiovascular risk factor(CVRF) in middle-aged and elderly patients.The recommendations are summarized in


Supplemental Digital Content is available in the text The relative efficacy of antihypertensive drugs/combinations is not well known. Identifying the most effective ones and the patients’ characteristics associated with best performance of the drugs will improve management of hypertensive patients.To assess the blood pressure (BP) reduction attributed to antihypertensive drugs and identify characteristics associated with BP decrease.MEDLINE, Cochrane Central Register of Controlled Trials from inception through July 2012 and selected papers.Double-blind, randomized clinical trials whose main result was the reduction in BP by antihypertensive treatment, with study population ≥50 or ≥25 if the study was a crossover, follow-up of at least 8 weeks, and available required data.Study data were independently extracted by multiple observers and introduced in an electronic database. Inconsistencies were resolved by discussion and referral back to the original articles. Meta-analysis was performed according to PRISMA statement and using a Bayesian framework.Mean decrease in systolic (SBP) and diastolic blood pressure (DBP) achieved by each drug or combination.Two hundred eight trials including 94,305 patients were identified. In monotherapy, most drugs achieved 10 to 15 mm Hg SBP and 8 to 10 mm Hg DBP decreases.2 were associated with more pronounced SBP and DBP reductions, whereas Afro-American ethnicity was associated with BP reductions smaller than the median. Results were adjusted by study duration, cardiovascular disease, and diabetes mellitus. Still, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats.Olmesartan/amlodipine, olmesartan/hydrochlorothiazide, felodipine/metoprolol, and valsartan/hydrochlorothiazide were the combinations leading to the greatest mean SBP reductions (>20 mm Hg). Female sex and body mass index >25 kg/mData corresponded to those obtained in each of the included trials; the analysis of the combinations was limited to the most recent ones; estimations were performed using the mean administered doses.Certain drug combinations achieve BP reductions ranging from 20 to 25/10 to 15 mm Hg. Sex, ethnicity, and obesity are associated with antihypertensive response. This information can contribute to better selection of the antihypertensive drug, depending on the magnitude of pretreatment BP elevation. Guidelines should be revised. However, most of these trials have been performed comparing just 2 agents, 2 combinations, or 2 treatment strategies, and they are considerably heterogeneous, with noncomparable study populations with respect to age, sex, and ethnic group, baseline BP or dose.Selection of antihypertensive drugs should be based on the knowledge of the drug's ability to reduce blood pressure (BP) levels, which is the main target factor to avoid cardiovascular complications in these patients.–7Therefore, the comparison of the relative antihypertensive effect of several drugs, or that of the most common combinations, is not well known. Moreover, the results obtained with their use, as well as the variables associated with treatment response, differ.,9 their ability to determine significant clinical differences among drugs was questioned, since they were restricted to certain pharmacological drugs, and no analyses of combinations were performed or they were performed as simple meta-analyses ; all of which, made it difficult to generalize the results.Although some meta-analyses have been published,Hypertension (HTN) guidelines recommend antihypertensive drug classes, without detailing specific drugs. As not all drugs from the same class have the same antihypertensive potency, their selection could potentially affect the probability of achieving BP control. Considering the aforementioned explanations, it would be of most importance to know the antihypertensive effect of the most frequently used drugs, adjusted according to the most relevant clinical variables, as well as the characteristics related to better or worse treatment response. This knowledge would potentially help the clinician to choose the most adequate treatment, since the response to a specific drug could be better predicted.The aim of the “Blood pressure-lowering effects of Anti-hyperTensive drugs and combinations: Meta-regression of published clinical trials” (ATOM study) consisted in determining the BP reduction attributed to the drugs of common use for HTN treatment, adjusted for the most relevant variables in the clinical practice, by means of a meta-analysis. In addition, we aimed to find out whether there were any clinical/phenotypic characteristics associated with the amount of decrease in BP with the use of the specific drug classes.22.1A systematic search for clinical trials assessing the efficacy of antihypertensive drugs was conducted following a triple strategy: search in the MEDLINE database with no oldest limit date and up to July 2012, according to the following syntax: “drug's generic name” AND “hypertension” OR “blood pressure” AND “efficacy” with the filters “human”, “randomized clinical trials,” and “English” ; search in the Cochrane Central Register of Controlled Trials database with the syntax “drug's generic name” AND “trials” AND “2012”; and review of selected papers aiming to find trials, whose main objective was determining the antihypertensive efficacy, which had not been found with the 2 previous strategies.2.2The initial selection of the studies obtained by the syntax search in the literature databases was assessed by reading the title or the abstract, when doubting the subject of the paper. In this first part, we selected those trials, which could be included, and then we obtained the original papers to be reviewed. The selection of the trials was performed according to the following inclusion criteria: double-blind, randomized clinical trial with a study population ≥50 patients or ≥25 if the study had a crossover design, this minimum patient number was established to reduce as much as possible the heterogeneity of patients included in the analysis; follow-up of at least 8 weeks; and data needed to carry out the meta-analysis had to be available.The explicit exclusion criteria were: clinical trials conducted exclusively in specific populations of hypertensive patients: diabetic, patients with resistant hypertension or who did not respond to a previous treatment with a specific drug in the same study, chronic kidney disease; clinical trials missing relevant information about the BP reduction obtained or about the dose administered in the different treatment periods; and clinical trials whose main reported outcomes were total mortality, cardiovascular morbidity and mortality, or evolution of the subclinical vascular disease.2.3Data were extracted and introduced in an electronic database (excel v.2007). Any inconsistencies were resolved by discussion and referral back to the original articles. The following variables were gathered from every original trial and for every arm of treatment: number of included patients; age; sex; ethnicity; baseline systolic (SBP) and diastolic blood pressure (DBP) (mm Hg)—mean and SD values; final SBP and DBP at the end of each period, before titration dose or drug combination; baseline and final heart rate (beats per minute); drug's dose in each study phase; body mass index (BMI); total duration of study (weeks); and presence or absence of diabetes (%).2.4The reductions in SBP and DBP, without eliminating the placebo effect, observed in the various treatments contained in the clinical trials meta-analyzed in this study were combined separately. The reduction in BP attributable to the placebo effect is available in the text. The mean summary combined was the average reduction in SBP and DBP for each drug or combination. which measures the degree of funnel plot asymmetry by the intercept from regression of standard normal deviates against precision. If the P-value of the intercept is ≤0.1, the asymmetry is considered to be statistically significant. The P-value of the intercept for every pharmacologic group in monotherapy and for the combinations was P > 0.10 , confirming, thus, the absence of bias in the assessed publications.The putative bias risk in the studies included in the meta-analysis was determined by means of the Egger test,I2 uncertainty parameter, which measures the percentage of variance of the observed results attributable to the heterogeneity. Given the low statistical power of this statistic, much less when, as in our case, the number of studies to be combined is limited, we considered the presence of heterogeneity with statistical significance of 10% and when I2 exceeded 30%.Heterogeneity was examined using the  This model allows taking into account both the within  and between study  heterogeneity. Furthermore, in order to obtain more homogeneous studies in every subgroup, we conducted subgroups analyses stratifying according to drug class and/or dose  for every active ingredient . Finally, we used meta-regression to control heterogeneity introducing potential explanatory variables of the heterogeneity.Since in all cases we found a very important heterogeneity, we combined the reductions in BP by means of a random effects model.The variables initially introduced were the baseline BP (previous to the intervention), dose , duration of treatment, percentage of women, age (standardized), BMI (standardized), percentage of Caucasian individuals, percentage of Afro-American/Afro-Caribbean individuals, and number of treated individuals. However, in those subgroups, in which the number of studies was less than 10, the scarcity of degrees of freedom led to the impossibility to estimate the model in some cases and in others, although the estimation was possible, it was very inefficient . In summary, in a third of the cases, when we stratified by pharmacologic groups, and in a half of the cases, when we stratified by active ingredient and dosage, we could not control the heterogeneity using a meta-regression.For this reason, a sensitivity analysis was performed to determine the minimum number of variables to control that, in turn, would allow controlling the heterogeneity in the majority of cases. In the end, only subgroups with 7 or more studies were combined using meta-regression. The variables finally included in the meta-regression were baseline BP, dose , age (standardized), and number of treated individuals. and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Due to the greater flexibility of the Bayesian estimation, a consequence of its hierarchical strategy, we chose to estimate the meta-regressions by means of a Bayesian framework. All analyses were conducted using the free software R (version 3.0.3), through the INLA library.,18This meta-analysis was performed in accordance with the Meta-Analysis of Observational Studies in Epidemiology (MOOSE)2.5The variables recorded come from clinical trials that do not contain any personal data. For this reason the approval of an ethics committee was not considered necessary.3Two hundred eight trials  out of the originally reviewed 779 were included. For each study, the following data were gathered: reference, study size, age, baseline SBP and DBP (mean ± SD), antihypertensive drug, and dose.The other 587  were excluded, since they did not meet the previously stated inclusion criteria or met some of the exclusion criteria.Figure It was not possible to include the variable sex in the meta-regression or the variable age in the multivariate models built to estimate treatment response, since the extremely high collinearity  that would cause their inclusion would imply confidence intervals of the coefficient of interest with limits close to infinity, making statistical inference impossible.3.1Although decreases in BP were overall similar among the different pharmacologic families Fig. , the spe3.2Although the mean SBP reduction of the studied combinations was −20.2 (−16.7 to −23.4), the combinations of valsartan/amlodipine, losartan/HCTZ and perindopril/indapamide showed much smaller reductions. On the other hand, the combinations of olmesartan/amlodipine, olmesartan/HCTZ, felodipine/metoprolol, and valsartan/HCTZ achieved SBP decreases larger than 20 mm Hg. The mean DBP decrease was −12.8 (−1.8 to −10.8). All of the studied combinations reduced DBP over 10 mm Hg with the exception of valsartan/amlodipine . Only the combination of olmesartan/amlodipine reduced DBP more than 15 mm Hg   6.05/DBP IQR 3.57), while the Afro-American ethnicity was associated with a reduction in BP smaller than the median reduction.Overall, female sex and BMI higher than 25 kg/mWith respect to different antihypertensive drug classes, women showed more pronounced BP reductions with thiazide diuretics , Angiotensin receptor blockers (ARBs)  and with drug combinations , as compared to men.2, 1.06, 1.02–1.11), calcium-channel blockers (CCBs) , and drug combinations , as compared to patients with normal BMI. The Afro-American ethnicity showed smaller reductions in BP when treated with beta-blockers , as compared to other ethnicities  guidelines 1 and with the report by the Eighth Joint National Committee (JNC-8),,9 regarding HCTZ, amlodipine, and enalapril, and different BP reductions for atenolol, lisinopril, verapamil, and diltiazem. However, those studies were performed as simple meta-analyses, with no meta-regression, and results were only adjusted by the number of subjects included in each assay, without taking into account other important variables such as the BP at the time of study inclusion.There are only few studies comparing the efficacy of the most commonly used antihypertensive drugs. The current meta-analysis shows similar results to those of Baguet et al,Additionally, our study shows variability in the strength of the different antihypertensive drugs to lower SBP, as well as DBP. These differences are important and may reach 9.3 and 6.0 mm Hg for SBP and DBP, respectively, when comparing the most and the least efficacious drugs. In the case of the studied drug combinations, these differences are greater, at 14.6 and 13.1 mm Hg for SBP and DBP, respectively.Although a similar antihypertensive effect of most drug classes was observed, the differences among specific drugs from the same class should probably be kept in mind for treatment selection. A general recommendation of a drug class could eventually be translated into the recommendation of a specific drug, which would not be able to achieve the therapeutic goal, even with its best response. On the other hand, no differences between indapamide and HCTZ were observed in our study, despite some meta-analyses showing the superiority of indapamide.,9 In the same context, the drugs showing the greatest efficacy were bisoprolol and olmesartan, although with very different confidence intervals. The wider confidence interval of bisoprolol implies large variability in the individual response. In contrast, olmesartan shows a much narrower confidence interval translating into a more predictable clinical response to this drug. Our data are in agreement with those of a meta-analysis conducted with 4892 patients showing that olmesartan has greater efficacy in BP reduction than losartan and valsartan.Compared to other agents, the smallest BP reductions observed with verapamil and lisinopril stand out in the evaluation of treatment responses according to drug. It must be pointed out, as it has been previously reported, that as compared to enalapril, the dose of lisinopril resulting in an equivalent BP reduction is about double.Overall, any of the assessed drug combinations guarantees SBP reductions >20 mm Hg and DBP reductions >10 mm Hg; and thus, they may be considered as the first option treatment when a reduction in BP of such magnitude is required. However, some combinations achieve greater BP reductions than others and this can also be taken into account in the process of drug selection. The reduction in BP varies depending on certain phenotypic characteristics of the population, such as sex, BMI, and ethnicity. also showed that women had better antihypertensive response to combinations  than men.When the characteristics of the patients showing the overall best antihypertensive response were assessed, the associated variables were female sex, higher BMI, and Caucasian ethnicity, whereas Afro-American ethnicity and normal weight were associated with a lower response to antihypertensive drugs. Women experienced better antihypertensive response overall, and specifically to thiazides, ARBs, and combinations. Agarwal et al showed greater cardiovascular morbidity and mortality in obese patients treated with benazepril/HCTZ as compared to patients with normal weight; and these differences disappeared when patients were treated with benazepril/amlodipine. The results of the current meta-regression show an intense association between BMI above 25 kg/m2 and overall BP reduction, and between BMI above 25 kg/m2 and BP reduction with CCBs, ARBs, and combinations.Regarding obesity, Weber et alThe recent meta-analysis published by the Blood Pressure Lowering Treatment Trialists’ Collaboration shows that angiotensin-converting-enzyme inhibitors (ACEIs) are more effective than CCBs in reducing the cardiovascular risk of patients with high BMI.The authors did not report data on ARBs in the same situation. Our study shows neutral ACEIs behavior regarding BP reduction according to BMI. This result does not disagree with those of the mentioned meta-analysis since at the same BP reduction, the ACEIs may lead to a greater reduction in cardiovascular risk by means of other physiopathologic mechanisms.,19,23,24 A smaller response of these patients to beta-blockers and to ACEIs/ARBs, as well as a greater BP reduction with diuretics and CCBs, has been reported.,5,6 The meta-regression shows an overall response lower than the median in Afro-American patients treated with beta-blockers as compared to other ethnicities.With respect to ethnicity, the use of diuretics or CCBs has been recommended in Afro-American patients. ESH, or JNC-8 guidelines.However, a smaller BP decrease with ACEIs/ARBs was not observed, neither an improved response to thiazides or CCBs. These results do not support the recommendations of NICE,2) a hypotensive response greater than 25%. This observation should be considered for the treatment of these patients.Our data show that overweight patients may especially benefit from using drug combinations of antihypertensive drugs, since they respond better to this type of treatment, showing a hypotensive response 5% greater than the median per every increased BMI unit with respect to those with normal BMI, achieving in obese patients  with HCTZ; and, finally, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats, although they are very close.In summary, our study shows that the expected mean BP reduction in monotherapy is overall between 10 and 15 mm Hg in SBP and between 8 and 10 mm Hg in DBP. The use of drug combinations at average/high doses achieves BP reductions ranging from 20 to 25/10 to 15 mmHg. Reductions in SBP/DBP higher than 20/10 mmHg are very unlikely to be achieved with monotherapy.5Even with the assumption that all drug classes promote similar BP reductions, clinically relevant differences exist among specific drugs. This should be reflected in hypertension guidelines, since a general drug class recommendation could eventually promote the use of a specific drug with not enough potency to achieve therapeutic goals.On the other hand, it is possible to identify phenotypic variables such as sex, ethnicity, or obesity associated with the antihypertensive response. This knowledge can contribute to a finer adjustment of the recommendations stated in the managing guidelines for this condition. In addition, it might justify future studies oriented to facilitate treatment individualization, taking into consideration these variables together with the cardiovascular risk profile of the patient and the presence or not of subclinical vascular disease.We thank Almudena Pardo Mateos who translated the manuscript and formatted it for publication.


The objective of our present study is to evaluate the impact of different PEEP levels on cerebral hemodynamic, gas exchanges and respiratory system mechanics in paediatric patients with post-traumatic brain swelling treated with decompressive craniectomy (DC).A prospective physiologic study was carried out on 14 paediatric patients presenting with severe traumatic brain swelling treated with DC. Transcranial Doppler ultrasonography was performed on the middle cerebral artery bilaterally after DC. After assessment at ZEEP, intracranial pressure (ICP), cerebral perfusion pressure (CPP), mean arterial pressure (MAP), central venous pressure (CVP) and gas exchanges were recorded at PEEP 4 and PEEP 8.From ZEEP to PEEP 8, the compliance of respiratory system indexed to the weight of the patient significantly increased (P = 0.02) without ICP modifications. No significant variation of the MAP, CPP, Vmed, the total resistance of respiratory system and ohmic resistance of the respiratory system indexed to the weight of the patients was observed. CVP significantly increased between ZEEP and PEEP 8 (P = 0.005), and between PEEP 4 and PEEP 8 (P = 0.05).PEEP values up to 8 cmH20 seem to be safe in paediatric patients with a severe post-traumatic brain swelling treated with DC. Traumatic Brain Injury (TBI) is a leading cause of death and disability in children ,2. The mCurrent Brain Trauma recommendations are based on early correction of hypoxemia and avoidance of hypocarbia after severe paediatric TBI . RecruitThe aim of medical and surgical therapy is to reduce the ICP after TBI: when other treatments have failed, decompressive craniectomy (DC) could allow a rapid decrease of ICP. This procedure allows the relieve intractable intracranial hypertension and/or to prevent or reverse cerebral herniation . The cliThe present is a single centre observational study. The Institutional Review Board approved the protocol and written informed consent was obtained from parents. Data were collected prospectively on 14 paediatric patients admitted to paediatric intensive care unit (PICU) of Catholic University Medical School, Rome, Italy, between May 2012 and December 2013. Participants were consecutive emergency department patients after diagnosis of severe post-traumatic brain swelling treated by DC in accordance with a standardised protocol. Inclusion criteria were: age between 4 and 16 years, TBI, DC, and the need for postoperative mechanical ventilation. Exclusion criteria were: age younger than 4 years and older than 16 years, cerebral infectious disease, hemodynamic instability requiring inotropic support, and cerebral disease requiring neurosurgery.2) 0.3, a square wave, an inspiratory-expiratory ratio of 1:2, a targeted tidal volume of 7–8 mL/kg and a frequency set to keep the partial pressure of carbon dioxide (PaCO2) at 32 to 36 mmHg; intracranial pressure (ICP) monitoring via intraparenchymal catheter or ventriculostomy, care aimed at maintaining ICP at <20 mmHg, cerebral perfusion pressure (CPP) at > 40 mmHg, PaCO2 at 35–40 mmHg, SaO2 at >90%; core body temperature maintained between 35 and 37.5°C with antipyretics, cooling/warming blankets, or intravascular cooling devices if needed.During the study period, patients were resuscitated according to institutional practice, which is consistent with the 2012 TBI Guidelines ,17. Genemin), the total resistance of the respiratory system (RRS max), and the compliance of the respiratory system (Crs) were determined. The RRSmin is defined as Pmax—P1/flow . The RRSmax is defined as (Pmax—P2)/flow , after subtraction of the value of endotracheal tube resistance. The Crs was calculated as TV expired/P2—PEEP. Respiratory mechanics data were indexed to the weight of the patients expressed in kg. The following parameters were recorded after 20 minutes: MAP, CVP, ICP, CPP, Vmed, and arterial blood gases. After the ZEEP assessment, the increments of PEEP at four and 8 cm H2O were applied while the ventilator setting remained unchanged. At each PEEP level, all above-mentioned parameters were recorded .The zero hydrostatic references were chosen at the mid-chest for CVP and mean arterial pressure (MAP), and at the external auditory meatus, corresponding to the foramen of Monroe, for ICP and CPP measurements. The head of the bed was kept at 30 degrees for all children. The middle cerebral artery (MCA) mean velocity (Vmed) of the most affected side was determined by Transcranial Doppler ultrasonography , using a hand-held probe. During the study period, patients with a CPP value below 50 mmHg, and/or an ICP value over 20 mmHg were excluded. When the absence of spontaneous inspiratory efforts was confirmed, the respiratory mechanics were measured at zero end-expiratory pressure (ZEEP). The end-inspiratory occlusion of 3 seconds was obtained by pressing the end-inspiratory hold knob on the ventilator. The ohmic resistance of the respiratory system  has been considered for post-hoc analysis. Data were analysed using STATA 9.1 software .Fourteen patients were enrolled between May 2012 and December 2013. All patients had a TBI with a severe post-traumatic brain swelling treated with DC . During The study suggests the impact of different PEEP levels on cerebral hemodynamic, gas exchanges, respiratory system mechanics in paediatric patients with a severe post-traumatic brain swelling treated with DC. PEEP-induced only modest increases in CVP. The application of different PEEP levels, from ZEEP to PEEP 8, induced a modest variation of CrsI associated with modest increases in CVP without ICP variations but also without effect on gas exchanges, respiratory system mechanics, and intracranial hemodynamics.In a previous studyon children with cerebral neoplasmwe demonstrated that PEEP provides changes in cerebral hemodynamics similar to those described for adults. In particular, PEEP-induced only modest increases in CVP (approximately 1 mm Hg from PEEP 4 to PEEP 8) small ICP rises but also without significant effect on gas exchanges, respiratory system mechanics, and intracranial hemodynamics . a closeAlthough, statistical analysis has not been performed, at this level of PEEP the CPP values calculated as CVP-ICP and MAP-CVP are similar., and it is advocated the early correction of hypoxemia avoiding hypocarbia. In this scenario, the use of PEEP could improve oxygenation, but it could affect intracranial pressure.However, the interactions between the respiratory system and intracranial hemodynamic in brain-injured patients are more complex, and the ventilatory management is challenging. Children with severe TBI could present initial mixed metabolic acidosis plus respiratory acidosis , and it Evidence in the literature demonstrates that, with close monitoring of cerebral and systemic haemodynamics, PEEP can be safely applied and titrated to an optimal level in the management of acute respiratory distress syndrome (ARDS) following traumatic brain injury . High PEThere is no evidence regarding the effect of PEEP on cerebral hemodynamic post-DC.In patients with normal compliance, PEEP application may raise right atrium pressure increasing internal jugular vein pressure . On the In adult patients, authors suggest that any factor likely to reduce the effect of Starling’s resistor significantly, such as decompressive craniectomy, should be considered in the evaluation of PEEP and any effect on the intracranial system .In paediatric patients with decompressive craniectomy, it is uncertain if a small increase in CVP could increase the jugular bulb pressure (Pj) and if a Starling resistor effect acting between dural sinuses and cerebral veins may have dampened it. In addition, when the head is kept at 30 degrees, the vertebral venous plexus may exert cerebral venous drainage better than the jugular veins .This study has several limitations. First, we assumed that the pressure measured at each point might be the same, but it may not be the same in an open skull. Secondly, we did not perform measurements of cardiac output after PEEP applications. Thirdly, we did not perform retrograde cannulation of the internal jugular vein. Thus, we have not prediction of venous drainage impairment. Fourthly, we did not perform the PEEP assessment in children with an increase in ICP or a decrease in CPP.Fifthly, the sample size was small, and further studies involve large and better-defined population should be performed to confirm our data.In conclusion, in the child aged 4–16 years, post-decompressive craniectomy, who has a stable measured ICP  and stable measured CPP , the addition of PEEP up to 8 cm H2O does not result in a change in the measurements of ICP or CPP.Probably, our results could suggest the use of PEEP (up to 8 cm H2O) to restore lung recruitment and improve oxygenation in paediatric patients with severe head injuries.S1 Fig* Statistical significance respect to ZEEP.† Statistical significance between PEEP4 and PEEP 8.(JPG)Click here for additional data file.S1 TableBA: Bicycle Accident; GCS: Glascow Coma Score; MVA: Motor Vehicle Accident; PA: Pedestrian Accident; ST: Sport Trauma.(DOCX)Click here for additional data file.S2 Table* Statistical significance respect to ZEEP.† Statistical significance between PEEP4 and PEEP 8.(DOCX)Click here for additional data file.S3 Table* Statistical significance respect to ZEEP.(DOCX)Click here for additional data file.