Compared with unaffected individuals, patients with type 2 diabetes (T2DM) have higher risk of hypertension, and diabetes combined with hypertension can lead to server cardiovascular disease. Therefore, the purpose of this study was to establish a simple nomogram model to identify the determinants of hypertension in patients with T2DM and to quickly calculate the probability of hypertension in individuals with T2DM.A total of 643,439 subjects participating in the national physical examination has been recruited in this cross-sectional study. After excluding unqualified subjects, 30,507 adults with T2DM were included in the final analysis. 21,355 and 9,152 subjects were randomly assigned to the model developing group and validation group, respectively, with a ratio of 7:3. The potential risk factors used in this study to assess hypertension in patients with T2DM included questionnaire investigation and physical measurement variables. We used the least absolute shrinkage and selection operator models to optimize feature selection, and the multivariable logistic regression analysis was for predicting model. Discrimination and calibration were assessed using the receiver operating curve (ROC) and calibration curve.p values of the two calibration curves are 0.625 and 0.445, suggesting that the nomogram gives good calibration.The results showed that the major determinants of hypertension in patients with T2DM were age, gender, drinking, exercise, smoking, obesity and atherosclerotic vascular disease. The area under ROC curve of developing group and validation group are both 0.814, indicating that the prediction model owns high disease recognition ability. The The individualized nomogram model can facilitate improved screening and early identification of patients with hypertension in T2DM. This procedure will be useful in developing regions with high epidemiological risk and poor socioeconomic status just like Urumqi, in Northern China. Diabetes, cancer and cerebrovascular and cardiovascular diseases (CCVd) are known as the major chronic diseases in the world, which threatening human life and people's physical and mental health with the rising trend. Blood glucose and blood pressure control are the priority of national public health in China . The sevIn general, diabetes and hypertension coexist, and the two diseases will aggravate each other , 6. A naAt present, many studies aim at the situation that the prevalence of other diseases increases while both hypertension and diabetes show up, such as cardiovascular disease , kidney The objective of this study is to use easily obtained data to construct a nomogram model to identify T2DM patients with a high likelihood of hypertension. Our approach will be useful in locations with high epidemiological risk and poor socioeconomic status, which do not pay attention to regular blood pressure monitoring, such as Xinjiang, China.The Xinjiang physical examination is a free physical examination provided by the Chinese government for all Xinjiang people. A total of 643,439 citizens participating in the physical examination of Urumqi in 2018 was recruited, and we had access to information that could identify individual participants during or after data collection. Subjects who met the following inclusion criteria were eligible to participate in the study: (1) age over 20; (2) Type 2 diabetes mellitus (T2DM) patients; (3) participants signed a written informed consent. After a strict data filtration 30,507 were enrolled, finally. The data were randomly divided into development group  and validation group . We have used the data from the development set to build the nomograms and used the data from the validation set to verify the model. This study was performed in accordance with the principles outlined in the Declaration of Helsinki and approved by Xinjiang Uygur Autonomous Region CDC ethical committee and the institutional review board.The Xinjiang physical examination variables include 3 parts: questionnaire, physical examination and laboratory testing. The questionnaire includes information on medical history and lifestyle, such as smoking, drinking, diet and exercise habits. Physical measurement indexes include height, body weight, heart rate, waist circumference and abdominal ultrasound. Abdominal ultrasound can observe the shape and size of the abdominal organs, as well as determine whether these organs have tumors, cysts or stones, including liver, kidney, gallbladder and other organs. Laboratory test indicators include blood glucose and blood biochemistry. In this study, we wanted to establish a simple model that can calculate the possibility of hypertension when it comes to patients with T2DM, only through questionnaire and physical measurement indicators, so this study didn’t include the laboratory test indicators.The definition of T2DM in this study was: 2 hours after meal, blood glucose ≥ 11.1mmol/l, fasting blood glucose ≥ 7.0mmol/l, or the main complaint of T2DM and taking hypoglycemic drugs, the final incidence of adult T2DM was 10.5%, excluding gestational diabetes and T1DM. The prevalence was equivalent to the incidence of previous studies .Blood pressure was measured on both arms of the participants. Hypertension was defined as simultaneous systolic blood pressure ≥ 140 mmHg, simultaneous diastolic blood pressure ≥ 90 mmHg or hypertension with antihypertensive drugs. According to the analysis, the prevalence of hypertension in patients with T2DM included in the study was 43.7%, which was 1.49 times of the prevalence of hypertension in people without T2DM in this study, which was equivalent to the incidence in the previous study .The potential risk factors used in this study to assess hypertension in patients with T2DM included: age, gender, ethnicity, career, smoking, drinking, exercise, diet habits, obesity, atherosclerotic vascular disease (ASCVD), kidney disease, eye diseases, psychosis, gallbladder_disease, bronchitis and tuberculosis.Basic information of participants: gender included "male" and "female"; career included "trader or service people", "agriculture workers", "factory workers", "soldier" and "others"; ethnic groups were divided into six categories: "Han", "Uygur", "Kazak", "Hui", "Mongolian" and "other nationalities"; living habits included smoking, drinking, exercise and eating habits. Drinking included drinking/time(g) and drinking frequency: “never”, “occasionally”, “regularly” and “daily”; exercise frequency were divided into four levels:”never”, “occasionally”, “>1 per week” and “daily”; smoking included smoking amount/day (cigarettes) and smoking situation: "non-smoker",”ever-smoker” and “current-smoker”; diet habits were divided into three categories: "meat based", "meat balanced" and "vegetarian based";2 was identified as obesity. The diagnosis of gallbladder disease and kidney diseases were based on the description from the patients and in conjunction with B ultrasonic examination. Gallbladder disease include cholecystitis, cholecystectomy and gallstone, kidney diseases included: diabetic nephropathy, renal failure, acute/chronic nephritis, hydronephrosis, and renal calculus. The other baseline comorbidities considered in this study were determined by health questionnaire survey of morbidities, whether the participant has previously been diagnosed by a doctor. The presence of eye diseases was defined as diagnosis of one or more of the following: retinal hemorrhage, papilledema and cataract; coronary, cerebrovascular or peripheral disease were collectively called ASCVD, participants were asked to answer the question "have you ever had a heart attack, or have you used a stent or taken a bridge?", ASCVD in this study included: myocardial infarction, cerebral infarction, angina pectoris, stroke, cerebral hemorrhage and coronary heart disease. While patients had one or more diseases, the relative variable would be defined as yes, otherwise would be defined as no.In this study, BMI (Body Mass Index) > 28 kg/mThe data of national physical examination are large, and with jumbled variables, existing many missing and abnormal values. So data pre-processing is a very important step, the quality of preprocessing will directly affect the performance of the later prediction models . Firstlyp-value of <0.05 were deemed statistically significant. Categorical variables were presented as the number (percentage). Continuous variables consistent with a normal distribution were presented as mean±standard deviation; otherwise, the median and quartile are used. Chi-square test were used to compare the differences in categorical variables. Independent sample t-tests were used to compare the differences in normal continuous variables, while the Wilcoxon test was used for nonnormal continuous variables.While comparing the baseline characteristics between the development group and validation group, differences with a two-sided p-value. The statistical significance levels were all two-sided. Variables with the p-value of 0.05 were included in the model [Lasso regression was used to screen the risk factors. Lasso regression is a kind of shrinkage method in linear regression model. It shrinks the estimated value of uncorrelated variables to close to zero, and then filter out non-zero variables. Lasso combines the advantages of selection process (easy to explain) and expression (robust), which is particularly useful in large data sets requiring efficient and fast algorithms . Analysihe model , 20. Finp value is, the better the calibration of the prediction model will be. If the test results show statistical significance (p < 0.05), it shows that there is a certain difference between the predicted value of the model and the actual observed value, and the model calibration is poor [The resolution of the prediction model referred to its ability to distinguish people with hypertension from people without hypertension. The area under the curve (AUC) of ROC was used to evaluate whether the prediction results of the model meet the requirements . AUC is  is poor .https://www.python.org) was used for data pre-processing, Pandas library and NumPy library were used for interpolation and processing of outliers, and Matplotlib library was used for data description and outliers judgment; the open source R software Version 3.6.1(http://www.r-project.org) was used for data modeling, CARET-package was used to divide the data into development and validation group randomly, LASSO analysis was performed with glmnet-packages, RMS-package was used to establish a nomogram model, the nomogramEx-package was used to figure the scores of every character in nomogram, the ROC was plotted using ROCR- package and PROC-package, and the calibration curves had been drawn by RMS-package.The open source Python software Version 3.7.2 and support preventive guidelines and interventions for patients who have survived T2DM.


No other significant correlations of any NO synthesis markers with blood pressure or PWV were observed. In line with previous studies, there were inverse associations between homoarginine and age and between ADMA or SDMA and GFR . This study did not reveal a significant association between homoarginine, ADMA or SDMA and blood pressure or PWV in hypertensive adults. These results suggested that the associations of these parameters with adverse outcome may not be mediated by hypertension and/or endothelial dysfunction.Nitric oxide (NO) synthesis markers, comprising L-homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are significantly associated with cardiovascular events and mortality. Being involved in NO pathways, they may be of high importance regulating vascular tone and arterial hypertension, but data on this topic are sparse and controversial. In this study, we evaluated whether these NO synthesis markers are associated with blood pressure values and pulse wave velocity (PWV). This analysis was based on the data of the Styrian Vitamin D Hypertension Trial, which included adults with arterial hypertension. We analyzed correlations of NO synthesis markers with 24 h ambulatory blood pressure values and PWV (primary outcomes), as well as with anthropometric and laboratory data. A total of 509 patients were included in the present analysis. The mean age was 61.2 ± 10.5 years, mean PWV was 8.6 ± 2.4 m/s, mean 24 h systolic blood pressure was 127.5 ± 13.8 mmHg and mean 24 h diastolic blood pressure was 76.4 ± 9.5 mmHg. In bivariate analyses, there was a significant positive correlation between homoarginine and 24 h diastolic blood pressure (r = 0.1;  Well-established risk factors in cardiovascular disease (CVD) comprise, inter alia, arterial hypertension, hypercholesterinemia, diabetes mellitus and smoking. CVD management focusing on these modifiable risk factors resulted in a reduction of cardiovascular mortality over the last decades, but it remains the leading cause of death worldwide ,2. NitriSeveral biochemical parameters with relevance for NO metabolism, i.e., L-homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), may therefore be involved in the pathogenesis of arterial hypertension and endothelial dysfunction. Homoarginine, a homologue of L-arginine, is synthesized enzymatically from L-arginine by arginine:glycine amidinotransferase and possibly also by enzymes of the urea cycle but can also be derived from food intake to an unknown extent . ServingAsymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous products and are increasingly being recognized to be involved in the pathophysiology of endothelial dysfunction ,16,17,18Altogether, there is a knowledge gap regarding the link between homoarginine, ADMA or SDMA and arterial hypertension as well as endothelial dysfunction. Hence, we report measurements of these parameters derived from the Styrian Vitamin D Hypertension Trial , a cohorwww.clinicaltrialsregister.eu (EudraCT Number 2009-018125-70) and clinicaltrials.gov (Identifier NCT02136771)]  . In thislsewhere ,29,30.SDMA, ADMA and homoarginine were measured from frozen serum (−70 °C) by high-performance liquid chromatography  with solid phase extraction and precolumn derivatization . Within-p-values of <0.05 were considered statistically significant. The statistical software package used was IBM® SPSS® Statistics Version 26 .Data were reported as mean and standard deviation for continuous variables with normal distribution and as median with interquartile range for continuous variables with non-normal distribution. Categorical data were presented as percentages. The cohort was stratified into quartiles of homoarginine, ADMA and SDMA levels. To assess differences of variables between quartiles we performed an analysis of variance (ANOVA). To assess whether there was a trend across the quartiles, a trend test was performed using linear degree. Differences in categorical variables were assessed using the chi-squared test with p for linear by linear test. To investigate the relationships of homoarginine, ADMA and SDMA levels with PWV and blood pressure values, Pearson’s correlation coefficient was used and linear regression analyses with adjustments for age, gender and GFR. Non-normally distributed variables were logarithmically transformed before use in parametric procedures. Among a total of 514 study participants, 509 had available values of homoarginine, ADMA, SDMA and 24 h blood pressure measurements and were thus included in the current analysis. The mean age was 61.2 ± 10.5 years, mean PWV was 8.6 ± 2.4 m/s, mean systolic blood pressure was 127.5 ± 13.8 mmHg and mean 24 h diastolic blood pressure was 76.4 ± 9.5 mmHg. Patient characteristics were stratified by quartiles of homoarginine, ADMA and SDMA, as shown in Bivariate analysis revealed lower homoarginine levels in females. Homoarginine, ADMA and SDMA differed by BMI as well as age. No significant differences were found between quartiles of homoarginine and ADMA regarding medication, except ACE inhibitors regarding homoarginine levels and beta-blockers regarding ADMA levels. However, for SDMA quartiles, there were multiple significant differences regarding antihypertensive drug intakes see . Higher p = 0.43).Analyzing continuous variables for our primary outcome measures , bivariaIn this retrospective analysis of the Styrian Hypertension Study, we were not able to show a significant and independent association of ADMA, SDMA and homoarginine with blood pressure values and PWV.Our findings of no significant association of NO synthesis markers with PWV and 24 h blood pressure values significantly add to the sparse and controversial literature on this topic. In the light of all evidence, results regarding the link between NO synthesis markers and arterial hypertension remain heterogeneous, as some studies showed a positive , but othApart from our null findings on the primary outcome measures in our investigation, we confirmed previously established associations of NO synthesis markers with some clinical and laboratory characteristics. For example, levels of ADMA and SDMA were reported to increase with age, while homoarginine decreases , which iOur study should be interpreted within the context of its strengths and limitations. Antihypertensive treatment rates between quartiles appeared heterogeneous and may have a significant impact on blood pressure values. However, bivariate correlations did not indicate a significant association between blood pressure values and homoarginine, ADMA or SDMA. Due to multiple testing in this analysis, statistical significances may result by chance but our null findings obviate the need to consider p-value adjustments for multiple testing. Further, NO synthesis parameters do not only derive from metabolism, but can also be derived from or modified by food intake, and no details regarding diet were assessed. However, we assumed that the impact of homoarginine as well as ADMA and SDMA derived from food intake on serum levels was small and that the majority derives from endogenous synthesis. A further limitation is that we did not perform more in-depth measurements of vascular function, such as brachial artery dilation tests. Based on the data of the Styrian Vitamin D Hypertension Trial, the patient cohort was a selected population and results may not easily transfer to other population groups. A strength of this study is the simultaneous performance of blood sampling and 24 h blood pressure measurement.In conclusion, this analysis did not reveal a significant association between NO synthesis markers and blood pressure values or PWV in hypertensive adults. These results suggest that the associations of these parameters with adverse outcomes may not be mediated by hypertension and/or endothelial dysfunction. Based on the current knowledge, homoarginine supplementation appears to be safe and well tolerated and, thus, may represent a new therapeutic strategy in CVD management. Given that NO synthesis markers may represent a modifiable cardiovascular risk factor in CVD, the current data may further encourage larger RCTs to shed light on the potential causal role of homoarginine, ADMA and SDMA in CVD, and to achieve a better understanding of the processes leading to variations in levels of those parameters in specific patient populations.


Macrocirculatory effects were assessed by cardiac output measurements, microcirculatory changes were investigated by sidestream dark-field imaging in the sublingual capillary bed and videocapillaroscopy at the nailfold. Exposure to hypoxia resulted in a decrease of systemic vascular resistance (p < 0.0001) and diastolic blood pressure (p = 0.014). Concomitantly, we observed an increase in heart rate (p < 0.0001) and an increase of cardiac output (p < 0.0001). In the sublingual microcirculation, exposure to hypoxia resulted in an increase of total vessel density, proportion of perfused vessels and perfused vessel density. Furthermore, we observed an increase in peripheral capillary density. Exposure to acute hypoxia results in vasodilatation of resistance arteries, as well as recruitment of microvessels of the central and peripheral microcirculation. The observed macro- and microcirculatory effects are most likely a result from compensatory mechanisms to ensure adequate tissue oxygenation.Although acute hypoxia is of utmost pathophysiologic relevance in health and disease, studies on its effects on both the macro- and microcirculation are scarce. Herein, we provide a comprehensive analysis of the effects of acute normobaric hypoxia on human macro- and microcirculation. 20 healthy participants were enrolled in this study. Hypoxia was induced in a normobaric hypoxia chamber by decreasing the partial pressure of oxygen in inhaled air stepwisely (pO Current evidence suggests that the microcirculation plays a paramount role in the pathophysiology of multi-organ failure in critically ill patients, which is why the evaluation of microcirculatory disorders is gaining increasing recognition in intensive care medicine2. In fact, reduced cardiac output, changes in peripheral vascular resistance or alterations of the volume status or pH-value can lead to microcirculatory disorders, which result in tissue edema4, inadequate tissue perfusion and, subsequently, reduced cellular oxygen supply5. The resulting tissue hypoxia markedly aggravates tissue damage and thus promotes end-organ dysfunction in critically ill patients with sepsis or shock6, which is why the restoration of tissue perfusion and oxygenation constitutes a paramount treatment goal in clinical practice5.The microcirculatory system comprises a network of small blood vessels with a pivotal role in maintaining adequate tissue perfusion, oxygenation and nutrient supply at the cellular level. Anatomically, the network consists of arterioles, venules and capillaries, with diameters well below 100 µm7. Since hypoxaemia, defined as a decrease in arterial oxygen tension8, is also a predominant feature of the high-altitude environment, research on the pathophysiologic processes behind hypoxia was significantly facilitated with the advent of altitude simulation tests9. On the cellular level, hypoxic stress initiates a transcriptional response by hypoxia inducible factors , which leads to a reduction of cellular energy consumption, a secretion of pro-angiogenic and survival factors10, and qualitative changes in mitochondrial function13, which in turn results in alterations of the cardiovascular, haematological and even urinary physiology15. Among the observed physiological alterations in response to hypoxia, the effects on the human macrocirculatory system have been subject to several extensive scientific investigations in the past. Hence, acute hypoxia is known to result in an initial increase in heart rate, blood pressure and cardiac output, whereas a decrease in stroke volume can be observed only after a few days of exposure18. In contrast, studies concerning the effects of hypoxia on the microcirculatory system are comparatively scarce. For example, previous studies reported an increase in sublingual microcirculatory blood flow and capillary density after ascent to high altitudes20, which suggests microvascular recruitment after exposure to hypobaric hypoxia21. However, recent studies also reported that the physiological adaptions to hypobaric hypoxia can differ substantially from those to normobaric hypoxia23, which is why the results of studies conducted in high altitude can not be fully applied to the normobaric environment.Tissue hypoxia resulting from an inadequate uptake of ambient oxygen or an increase in cellular oxygen demand is one of the key features of the critically ill patientSince the microcirculation constitutes one of the central components where hypoxia mediates its unfavourable effects in critically ill patients, a thorough investigation of the effects of normobaric hypoxia on the microcirculatory system, with regards to its interplay with larger vessels, is of interest. To further elucidate this matter, we conducted an altitude simulation test and investigated both the macro- and microcirculatory effects of acute normobaric hypoxia . At baseline, the median systolic blood pressure (SBP) was 115 mmHg (IQR 106–128), the median diastolic blood pressure (DBP) was 70 mmHg (IQR 64.5–75), the median heart rate (HR) was 67 beats per minute , the median peripheral oxygen staturation (SpO2) was 97% (IQR 96–98) and the median respiratory rate was 16 min−1 , the median age was 29 years (IQR 25–31) and the median body mass index (BMI) was 23 kg/m1, 55%, t2) in ambient air decreased significantly throughout the two hypoxia runs, whereas humidity, temperature, overall pressure and the partial pressure of carbon dioxide (pCO2) remained relatively stable.The atmospheric data of the two hypoxia runs are displayed in Supplementary Figure Regarding symptoms of acute mountain sickness (AMS), the median Lake Louise Score (LLS) at baseline was 0.2 points (IQR 0.0–0.6), with a gradual increase to the median LLS of 3.8 points (IQR 1.7–4.4) at 6 k.2 and a signficant increase in respiratory rate, as expected (see Table 2), although a trend towards an initial decrease, followed by an increase to 6 k, was observed  and cardiac performance index (CPI) increased significantly see Fig. . FurtherIn the sublingual microcirculation, acute hypoxia resulted in an increase in the number of crossings (NC), total vessel density (TVD), perfused number of crossings (PNC), proportion of perfused vessels (PPV) and perfused vessel density  and 2% at 4 k (apex significant at p = 0.049). As estimated by the law of Hagen-Poiseuille24, which states that the flow rate is proportional to the radius of the vessel to the fourth power, the average flow increases corresponded to 17% (2 k) and 8% (4 k) and additionally 5% due to the increased capillary recruitment. Notably, the initial increase in PCD and CD was followed by a decrease in both variables at 6 k  at 2 k and 4 k when compared to the baseline values  and of the vastus lateralis muscle at 6 k  when compared to the respective baseline values. In the tongue, however, the decrease in TSI in reponse to hypoxia reached statistical significance at more moderate levels of hypoxia and was in total more pronounced than in the vastus lateralis muscle. The THb was not significantly influenced by exposure to hypoxia  in both muscles at rest  had a significantly higher LLS at 2 k , but a significantly lower respiratory rate at 6 k (median 21.3 breathspm vs. 27.7 breathspm p = 0.026). Moreover, the increase in HR from baseline to 6 k was significantly higher in these patients .Participants who showed objective hypoxia, as portrayed by an SpOSupplementary Table 26, as well as a downregulation of endothelial NO synthase (eNOS)27. Hence, long-term hypoxia is regarded a key precursor in the pathogenesis of arterial hypertension in patients with obstructive sleep apnea (OSA)28. In contrast, acute hypoxia is known to result in local or systemic vasodilatation via nitric oxide (NO), which is a direct result of enhanced secretion of adenosine, adenosine triphosphate (ATP), prostaglandins (PGs) and adrenaline29, and constitutes a compensatory mechanism to ensure adequate tissue perfusion31.In the last decades, several studies have investigated the effects of hypoxia on the human macrocirculation. According to current evidence, chronic hypoxia leads to a significant increase of systolic and diastolic blood pressure by an overstimulation of the adrenergic and renin-angiotensin system2. In contrast, decreases in TSI of the tongue and of the vastus lateralis muscle were comparatively low and probably clinically irrelevant. However, the response of TSI to hypoxia was more sensitive and pronounced in the tongue than in the leg muscle  and CPI.Similar to previous studies32. In fact, only 20–30% of the capillaries are actively participating in tissue perfusion under resting conditions33. Therefore, capillary recruitment constitutes an important compensatory mechanism to ensure adequate tissue perfusion and oxygenation in the capillary beds of several muscles34 and the lungs35. Notably, our findings are in line with the results of a previous study by Hilty et al.21, who found that exposure to high altitudes was associated with capillary recruitment of sublingual capillaries and thus an increase in microcirculatory oxygen extraction capacity.The observed macrocirculatory effects of systemic hypoxaemia were accompanied by microcircultatory changes, which indicate an increase in organ perfusion. Hence, we found that exposure to normobaric hypoxia leads to a significant increase in TVD, PPV and PVD of the sublingual microcirculation, which can be interpreted as a result of capillary recruitment. Capillary recruitment is known as an opening of previously closed capillaries by dilatation of the precapillary sphincters in response to unmet metabolic demands36. Since capillary recruitment is a rapid adaptation, the short duration of hypoxia in this study is no plausible explanation for the discrepancy of the study’s results to our current findings. In our study cohort, however, we were able to identify identical areas of the nailfold where we could demonstrate capillary recruitment directly  and conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained from all subjects before enrollment.https://www.dlr.de/envihab/), Cologne, Germany. In total, 20 healthy subjects without significant experience in climbing or competitive sports were enrolled by an announcement at the University of Düsseldorf. The anthropometric data and baseline characteristics of the study participants are depicted in Table The study was conducted at the ‘DLR:envihab’ of the German Aerospace Center , 2000 m (2 k), 4000 m (4 k) and 6000 m (6 k) above sea level). Throughout the test, the partial pressure of nitrogen in ambient air was gradually increased, which led to a reduction of the partial pressure of oxygen , 16.42 kPa (2 k), 12.63 kPa (4 k) and 9.64 kPa (6 k), FiO2: median 0.21 (0 k), 0.16 (2 k), 0.12 (4 k), 0.10 (6 k), see Supplementary Figure 2 median 0.046 kPa (0 k), 0.060 kPa (2 k), 0.72 kPa (4 k) and 0.059 kPa (6 k)). The subjects were exposed to an ‘altitude’ for two hours before proceeding to the next level. Measurements were performed at each oxygen level to investigate the effects of hypoxia on the micro- and macrocirculation  was calculated as previously published (DO2 = cardiac output (CO) × CaO2 × 10; where CaO2 was the arterial O2-content defined as: (1.34 × hemoglobin concentration × SpO2) + (0.003 × PaO2) and the amount of dissolved oxygen in blood was estimated by 0.003 × pO2)41. Hemoglobin concentration and red blood cell count (RBC) were measured at each of the four different altitudes using an ABL800 FLEX blood gas analyzer .Oxygen delivery (DO42.Symptoms of hypoxia and severity of acute mountain sickness (AMS) were assessed by the Lake Louise Score (LLS), as previously published. Mild AMS was defined as LLS 3–5 points, moderate AMS as 6–9 points, and severe AMS as 10–12 pointsSystolic and diastolic blood pressure (SBP and DBP) were assessed using a ProBP 3400  blood pressure monitor, peripheral oxygen saturation was assessed using a PULOX PO-300  pulse oximeter. Systemic vascular resistance (SVR), heart rate (HR), cardiac output (CO), cardiac performance index (CPI) and stroke volume (SV) were measured using transthoracic impedance cardiography  and non-invasive Electrical Cardiometry .43. Only sufficiently trained researchers performed measurements. In brief, on the tip of this device, a highly sensitive camera digitally recorded the sublingual capillary network. Different regions under the tongue were used for all videos and at least four videos were taken per area. In the next step, a tablet computer was used ) for video analysis. After recording videos with sufficient quality, a validated automatic algorithm-software  was used to perform the offline analysis. Agreeing to the second consensus on the assessment of sublingual microcirculation in critically ill patients (European Society of Intensive Care Medicine), the following variables were assessed44:A sidestream darkfield microscope  was used to assess the sublingual microcirculation as described previously45. In brief, MIQS rates the acquired videos into three categories: “good”, “acceptable”, and “non-acceptable”. Overall, six different criteria are evaluated: illumination, focus, content, stability, pressure, and the duration was not rated. A video without significant impairment in all criteria gets zero points. Mild impairment results in 1 point for each impaired criterion. Severe impairment in one criterion is defined to be rated with 10 points, which results in the category “non-acceptable”.Microvascular values can offer information about both convexity and diffusion. The proportion of perfused vessels  gives information both about convexity and perfusion. Diffusion can be assessed by the total vessel density (TVD) and the number of crossings (NC). Density was evaluated by the total vessel density and the number of crossings. With both information, the perfused vessel density  and perfused number of crossings (PNC = number of vessel crossings with continuous flow) can be calculated. Vessels with diameters of less than 20 mm correspond mostly to capillaries and are primarily responsible for the microcirculation. These small vessel values are signed with the prefix “s” . The values for all vessels can be considered as a quality check to exclude for example pressure artifacts. Before AVA 4.3C analysis, all videos were evaluated according to the microcirculation image quality score (MIQS), that were originally introduced by Massey et al.Peripheral microcirculation at the nailfold was assessed at two areas of fingers III-V of both hands, images of the nailfold of 1 mm were obtained using videocapillaroscopy . The acquired images were assigned to each other and identical capillaries were compared in density (PCD), visibility , shape , distance (to the right capillary 50 μm before apex in μm), diameter (CD) of the arterial limb (50 μm before apex in μm), apical (in the middle in μm), venous limb (50 μm behind apex in μm) and tail .44.Assessment of the microcirculation was conducted according to the current recommendations of the European Society of Intensive Care MedicineTo investigate whether microcirculatory disorders resulting from generalized hypoxia cause peripheral edema, we performed ultrasonographic measurements of the tissue thickness of the leg and the forehead in supine position. Measurements were conducted in the evening before the hypoxia tests and immediately after the subject left the hypoxic atmosphere. Tissue thickness was measured repeatedly by ultrasound (10–18 MHz linear-probe) at both the anterior tibia and the midline forehead locations . In more detail, a self-made mechanical fixture device was used to avoid measurement bias due to hand-held measurements and different surface pressure of the ultrasound probe on tissue. In addition an automatic, Matlab  based tissue identification software was used to reliably estimate tissue thickness. The software enables automatic and robust tissue thickness estimation from the ultrasound images to minimize analysis biases and improves analysis efficiency during tissue thickness identification and evaluation. The average tissue thickness was calculated from the central section of the ultrasound image (only 50% of the image at the center) to reduce calculation bias caused by the imaging technique. Tissue thickness was defined as the distance between the surfaces of the skin and the tibia and frontal bone, respectively.2Hb)/(O2Hb + (HHb); O2Hb = oxygenated hemoglobin, HHb = desoxygenated hemoglobin) and the content of total hemoglobin (THb = O2Hb + HHb) in the vastus lateralis muscle and the tongue by near-infrared spectroscopy (NIRS) at each of the different altitude levels and after the end of the hypoxia tests. For the examination of vastus lateralis muscle we placed a PortaMon device  over the belly of the muscle. For measuring the tongue we used the PortaLite device  placing the sensor part on the tongue after shielding it from saliva fluid using a thin plastic foil.We investigated the effects of hypoxia on oxygen saturation and blood content of the muscles by assessing the tissue saturation index  and SPSS . Normally distributed data were expressed as mean and standard error of the mean (SEM), whereas not normally distributed data were shown as median and interquartile range (IQR). A Kolmogorov–Smirnov test was used to test the distribution of data for normality. Medians of the data on micro- and macrocirculation were analyzed using a Kruskal–Wallis test with Dunn’s post-hoc test, data on the tissue thickness were analyzed using a Wilcoxon signed-rank test, and data on the TSI and THb of the muscles were interpreted by applying a Student’s t-test and a Linear Mixed Effects (LME)-analysis. A The study was reviewed and approved by the ethics committee of the Heinrich-Heine-University, Düsseldorf, Germany (5925R) and conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained from all subjects before enrollment.Exposure to acute normobaric hypoxia results in enhanced perfusion of the central and peripheral microcirculation, as well as an increase in cardiac output. The observed macro- and microcirculatory effects are most likely a result from compensatory mechanisms to ensure adequate tissue perfusion in case of profound hypoxaemia.47, which have to be taken into consideration when interpreting the findings of our study. However, invasive methods, such as thermodilution, are labor- and time-intensive and unsuitable for the narrow setting of a hypoxia chamber. Hence, we chose transthoracic impedance cardiography over invasive methods in our study.Since this study was an exploratory study, we did not conduct a statistical power calculation prior to enrollment. Hence, a type one error can not certainly be excluded. Another limitation is that SVR, CO, CPI and SV were investigated using transthoracic impedance cardiography, which is less accurate than invasive methods. Due to the technique of impedance cardiography, which is based on calculations derived from the basic laws of electricity, several limitations and possibilities for bias ariseHerein, we provide a comprehensive analysis of the effects of acute normobaric hypoxia on the macro- and microcirculation in healthy subjects. Our findings can contribute to the understanding of health and disease, since hypoxia and the following systemic reactions are of utmost relevance in the pathophysiology of various diseases.Supplementary Legends.Supplementary Information.


P for trend = 0.02), respectively, for sodium-to-creatinine ratio. The association between urinary sodium-to-creatinine and systolic blood pressure was more pronounced among individuals whose body mass index (BMI) was less than 25 kg/m2 (P for interaction = 0.03). We found that vegetables, kimchi and seaweed intake contributed to high sodium intake and a sodium-contributing food score were associated with increased blood pressure. In our study, we identified the food groups contributing to high sodium intake and found that high urinary sodium levels were associated with increasing blood pressure among Korean adults.The purpose of this study was to examine the association of urinary sodium-to-creatinine ratio and potassium-to-creatinine ratio with blood pressure in a cross-sectional study comprising Korean adults who participated in the Healthy Twin Study. The participants consisted of 2653 men and women in the Healthy Twin Study aged ≥19 years. Participants’ urinary excretion of sodium, potassium, and creatinine was measured from overnight half-day urine samples. Food intake was assessed using a validated food frequency questionnaire. We examined systolic and diastolic blood pressures according to sodium- or potassium-to-creatinine ratios using the generalized linear model. We determined food groups explaining high urinary sodium- or potassium-to-creatinine ratio using the reduced rank regression and calculated sodium- or potassium-contributing food score. We observed that systolic blood pressure was higher among men and women in the highest quintile of urinary sodium-to-creatinine ratio or sodium-to-potassium ratio than it was in the lowest quintile. Geometric means (95% CIs) of the lowest and the highest quintiles of systolic blood pressure (mmHg) were 113.4 (111.8–115.0) and 115.6 (114.1–117.2;  Hypertension is a major risk factor for cardiovascular disease , some caDietary assessment of sodium intake tends to underestimate the actual sodium intake  because The associations between urinary sodium levels and hypertension or blood pressure have been studied in several Western ,16,17,18In this study of more than 2000 adult participants, we examined the association between the sodium-to-creatinine ratio and potassium-to-creatinine ratio in urine and blood pressure in a cross-sectional study of Korean adults participating in the Healthy Twin Study, a large cohort study of twin families. We also determined food groups contributing to the higher sodium-to-creatinine ratio in urine, calculated the reduced rank regression (RRR) pattern score, and examined their associations with systolic and diastolic blood pressures.The Healthy Twin Study comprised of same-sex adult twin pairs aged 30 years or older and their first-degree family members; these participants were the ones who volunteered in response to a nationwide media advertisement and mailing campaign open to the general population. From August 2005 to January 2012, a total of 3320 study participants (1333 men and 1987 women) have been enrolled. Study design and methodology have been described elsewhere . n = 9), did not have information on blood pressure (n = 8), or did not have measurements of urinary sodium/potassium or creatinine (n = 275). We also excluded those who had been diagnosed with hypertension (n = 324) or cancer (n = 51) to avoid the potential effect of low sodium intake among participants with previous illnesses. Consequently, a total of 1034 men and 1619 women were included in the analysis of urinary sodium and potassium. When we examined the association of blood pressure with urinary concentrations of sodium and potassium; we excluded participants if they were not adults , as well as those whose total energy intake was beyond three standard deviations from the loge-transformed mean energy intake (n = 27). Consequently, a total of 961 men and 1501 women were included in the analysis. The study was approved by the ethics committees at the Samsung Medical Center (IRB No. 2005-08-113), Busan Paik Hospital (IRB No. 05-037), and Dankook University Hospital (IRB No. 2005-6), and written informed consent was obtained from all study participants. In the analysis of food groups and blood pressure, we excluded study participants who did not answer questions pertaining to rice items or left questions for more than 50 items unanswered on the food frequency questionnaire (FFQ)  between sodium excretion directly from 24-h urine and estimated sodium excretion from overnight half-day urine using Kawasaki formula in 44 participants [Participants voided all urine at 7 pm and collected urine in plastic containers until the next day morning. They recorded the start and the end time of urine collection. All participants collected urine for more than eight hours. We also considered creatinine concentrations to adjust for different volume. When we adjusted for hours of urine collection, the results did not differ. Urinary sodium and potassium after >8 h of urine collection were measured using indirect ion-selective electrodes, and urinary creatinine concentration was measured using Jaffè reaction on Siemens Advia 1800 analyzers . We collected overnight urine because participant burden is lower compared to 24-h urine collection and sodium from overnight urine has been considered as an alternative approach to replace 24-h urine . In our icipants . We did icipants . HoweverFood intake of each participant was assessed using a validated semi-quantitative food-frequency questionnaire . Partici2). Pack-years smoked were calculated by multiplying the number of years smoked by the average number of cigarettes smoked per day. A woman was considered as postmenopausal if she did not experience menstruation for more than 12 months. If menopausal status was not reported (n = 33), we defined a woman as postmenopausal if the age was ≥50 years  when menopausal status was included as a covariate. The estimated glomerular filtration rate (eGFR) was determined based on the equation developed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) research group [Participants provided information on smoking status, alcohol consumption, education level, marital status, and medical history and menopausal status in women through a questionnaire. Additionally, a trained and experienced interviewer conducted face-to-face interview to clarify incomplete or equivocal responses. Each participant visited one of the centers to undergo physical examination, biochemical assessment, and anthropometric measurements. We calculated the body mass index (BMI) by dividing the weight (kg) by the height squared , age square , BMI , total alcohol consumption , marital status , pack-years of smoking , education level , and menopausal status  for women. We additionally adjusted for total energy intake in food group analysis, urinary potassium  in sodium analysis, and urinary sodium  in potassium analysis. We examined whether the associations varied by BMI , smoking status , alcohol consumption , eGFR levels , urinary potassium , education level , and marital status . The statistical significance of interaction was tested by using a Wald test of the beta coefficient of the cross-product term. We applied the RRR method to determine food groups explaining urinary sodium- or potassium-to-creatinine ratio [P value < 0.05.We calculated geometric means and 95% confidence intervals (CIs) of systolic and diastolic blood pressures according to quintiles of urinary sodium-to-creatinine ratio, potassium-to-creatinine ratio, and sodium-to-potassium ratio using the generalized linear model (GLM). We categorized the exposure by quintile for men and woman, separately. We added a random effect to the model to take family into account. We logne ratio . RRR extThe mean overnight half-day urinary sodium excretion was 134.7 mmol/L in men and 122.0 mmol/L in women. The mean overnight half-day urinary potassium excretion was 42.3 mmol/L in men and 41.7 mmol/L in women. Baseline characteristics of participants according to the quintile of urinary sodium-to-creatinine ratio, potassium-to-creatinine ratio, and sodium-to-potassium ratio are presented in P for trend = 0.02), respectively, for sodium-to-creatinine ratio, 115.1 (113.5–116.8) and 113.1 , respectively, for potassium-to-creatinine ratio, and 112.4 (110.9–113.9) and 115.6 , respectively, for sodium-to-potassium ratio. When we separated men and women, we observed increasing systolic blood pressure with increasing half-day urinary sodium-to-potassium ratio with systolic blood pressure in both men and women (P for trend < 0.05) ( < 0.05) . 2), smoking status , alcohol consumption  (2), or urinary potassium   , eGFR (< median) . 2) (P for trend < 0.03). We found positive association for intakes of vegetables, potato and sweet potato, and fruit, but negative association for intakes of ramen, soft drink, poultry, red meat and beef soup, processed meat, noodle, and pizza, with urinary potassium-to-creatinine ratio , and seaweed to be positively and the intake of poultry and pizza to be inversely associated with high urinary sodium-to-creatinine ratio . A highe2) . Table 6ne ratio . Potassine ratio . 2, never smokers, or current alcohol drinkers. We identified food groups contributing to urinary sodium-to-creatinine ratio. Intake of vegetables, kimchi, and seaweed were identified to explain the variability of urinary sodium-to-creatinine ratio and were positively associated with increased blood pressure. We observed that urinary sodium-to-creatinine and sodium-to-potassium ratios were positively associated with systolic blood pressure and potassium-to-creatinine ratio was inversely associated with systolic blood pressure in 2653 men and women aged 19 years or older. We found more pronounced positive associations for sodium-to-creatinine ratio in the participants with BMI < 25 kg/mCollecting spot urine samples reduces the low compliance problem in large population study. Therefore, large epidemiologic studies often used 12-h urine replaced for 24-h urine and several studies suggested that 12-h urine sodium excretion may reflect dietary sodium intake . For exaP for trend < 0.001) [Our findings of positive association between urinary sodium-to-creatinine ratio and blood pressure are consistent with previous studies, which have reported a positive association between urinary sodium concentration and blood pressure in general populations. In a cross-sectional, community-based study, the 24-h urine sodium-to-potassium ratio was linearly associated with nighttime systolic blood pressure (beta-coefficient = 0.142 in linear regression) and diastolic blood pressure (beta-coefficient = 0.144) in 217 participants aged ≥ 55 years . In the < 0.001) . The Nor< 0.001) . Differe< 0.001) . In a me< 0.001) . The pos< 0.001) . Several epidemiologic and intervention studies reported an inverse association between potassium intake or urinary potassium excretion and blood pressure. The INTERSALT study observed that systolic and diastolic blood pressure levels increased by 3.4 mmHg and 1.9 mmHg, respectively, according to 50 nmol per day of 24-h urinary potassium excretion among 10,079 participants . A recenThe reasons for the significant interaction by BMI were not clear. The US National Health and Nutrition Examination Survey (NHANES) Epidemiologic Follow-up Study reported increase in cardiovascular disease mortality only among overweight individuals . HoweverRRR, a new method of dietary pattern analysis, identifies linear combinations of dietary intake variables that explain the variance in a set of intermediated response variables . We deteThere are some limitations in our study. We did not take into account dietary intake of sodium or correlation between urinary sodium intake and dietary sodium intake. Measurement error in estimating food intake from FFQs could attenuate to some extent the associations for food groups contributing to urinary sodium levels. Our cross-sectional study design may not infer the temporal relationship between urinary sodium and blood pressure. Further prospective studies are warranted to replicate the association we observed. The strengths of our study include a large number of participants and measurements of overnight urine for over 2500 participants.Our study included a large number of participants in Korean population whose sodium intake is high and found that sodium intake was associated with increased levels of blood pressure. Although the association between sodium intake and blood pressure has been supported by several epidemiologic studies, urinary sodium, a better indicator for sodium intake than dietary intake, has not been well studied especially in Asian populations. Our study supports that even in population with high sodium intake, blood pressure increases with sodium intake. Our study suggests that sodium intake and food groups with high sodium levels lead to high urinary sodium concentration and are associated with increasing blood pressure among Korean healthy adults.


P value much <0.05. These results show the validity of the developed system for cuffless and continuous blood pressure estimation.In order to realise low-load cuffless and continuous blood pressure measurement in daily life, the authors developed a blood pressure estimation system combining human body communication-based wearable electrocardiograph and reflectance photoplethysmography. The principle is based on a relationship between the pulse arrive time and the systolic blood pressure. The pulse arrive time is the time period between the R-wave in electrocardiograph and peak of pulse wave. The greatest feature is the use of a human body communication-based electrocardiograph which can provide automatic synchronisation in time between the measured electrocardiograph and pulse wave signals to obtain the pulse arrive time so that no additional synchronisation circuit is required. Using this system, the authors measured the pulse arrive time from the electrocardiograph and pulse wave signals in real time, estimated the systolic blood pressure and compared the result with that measured by a cuff sphygmomanometer. The authors found that the root mean square error of the estimated blood pressure and the actual value measured using the cuff sphygmomanometer was 4.5 mmHg or less, and the correlation coefficient was >0.6 with a  Some In view of the necessary to form a body area network for medical and health care applications, the on-body vital sensors should have a wireless function. Since the human body is a lossy dielectric body, the on-body path loss becomes larger at higher frequencies. Compared to the popularly used 2.4 GHz band for short-range communications, human body communication (HBC) technology exhibits more advantages in not only its low propagation loss compared to 2.4 GHz band but also its high security because of low radiation towards outside of the human body , 13, 14.In this study, we aim to develop a system for cuffless BP estimation from HBC-based ECG and reflectance PPG. Although the concept of estimating BP from PAT is not new, the use of HBC-based ECG to obtain PAT is a new attempt. This study is organised as follows. Section 2 describes the principle of BP estimation from PAT. Section 3 describes the configurations of HBC-based wearable ECG module and reflectance PPG module, respectively. Section 4 gives the experimental verification results and Section 5 concludes this study.2Fig. E of the blood vessel wall by [h is the thickness of blood vessel wall, r is the inner radius of blood vessel. On the other hand, the systolic BP is related to the modulus of elasticity E of blood vessel wall by [E, h, r and According to Moens–Korteweg formula, the PAT  wall by 1)\docu wall by 2)\docu\docu wal\docu\docMoreover, it is suggested that there is a linear relationship between the BP and heart rate. Since we can obtain the heart rate from the acquired ECG signal in real time, also taking this factor into account is expected to improve the estimation accuracy. We thus add a new term related to the heart rate in , i.e...\documen33.1Fig. Table 3.2Reflectance PPG is based on optical detection of blood volume changes in the micro-vascular bed of the tissue. A reflectance PPG sensor consists of an infrared LED as the light source and a PD as the light detector. They are placed in proximity to each other on the skin surface where there is a detectable concentration of blood vessels. The sensor monitors changes in the light intensity via reflection from the tissue. The changes in light intensity are associated with small variations in blood perfusion of the tissue and provide information on the pulse rate. Fig. 4TP was obtained, and the systolic BP was estimated using . . TP was Fig. 4.1The verification experiment was conducted for five subjects. The five subjects were men aged 21–24 years old, except for one with mild hypertension in 50 s. For prior calibration, we measured the ECG and PW for >30 times (more than one second each time), and calculated the PAT and systolic BP for each subject. On the other hand, we obtained the systolic BP from the average before and after each ECG and PW measurement using a cuff sphygmomanometer. Fig. 4.2The BP estimation was made using either  or 4). . 4). ThaP value based on a t-test. P-value is a reference probability to determine whether or not a null hypothesis (no correlation between them) can be rejected, and that the P-value of 0.05 is usually used as a significance level for a statistical test. First, it is assumed that there is no correlation between the estimated and measured BP values. Then, if P values for the estimated BPs and that measured by the cuff sphygmomanometer. The correlation coefficients were found to be >0.55 using (P-value was always much <0.05, which means that the correlations are sufficiently significant from a statistical point of view. In addition, it was also confirmed that the correlation coefficient can be improved if the BP is estimated using (Moreover, the correlation coefficients were also calculated for estimated and measured BP values along with a 55 using  and 0.6 55 using  for all ed using  in consied using .Table 45P-value much <0.05. These results show the validity of the developed system for cuffless and continuous BP estimation.In this study, we have developed a systolic BP estimation system which combines an HBC-based wearable ECG module and a reflectance PPG module to realise a low-load cuffless BP measurement in daily life. The developed HBC-based wearable ECG automatically synchronises with PW because it uses the human body itself as a transmission route. This is the greatest feature of this system and no additional synchronisation circuit is required. Furthermore, by adopting a wide band IR modulation method between 10 and 60 MHz, the anti-electromagnetic interference performance has also been improved. Using the developed system, we simultaneously measured the ECG and PW waveforms, estimated the systolic BP form derived PAT, and compared the result with that measured by a cuff sphygmomanometer. We have found that the RMSE of the estimated BP and the actual measured one was 4.5 mmHg or less, and the correlation coefficient was >0.6 with a statistical This method is expected to be contactless. However, the capacitive-coupling impedance between the ECG electrodes and the human body can have a significant impact on signal detection quality , and bot


Letter to the EditorWhy complex calculations  in a complex circulation is believed to be needed? Although it is known, that it already contains calculation errors. Why do the authors not base their decisions on pure measured raw data as pressures and oxygen saturations?Why are the examinations carried out under general anesthesia, although the hemodynamics of the “passive” pulmonary circulation  is significantly influenced, which is distinct following complete Fontan, but is in no way comparable to “real” life under spontaneous breathing at rest.2 level to retrace the calculated measurements and in particular the pulmonary artery pressure, inferior caval pressure both in relation to the systemic arterial pressures and saturations as well?Therefore, in the light that NEEP (negative endexspired pressure = spontaneous breathing) is in either case better for pulmonary and consecutively systemic blood flow than PEEP (= ventilation) in a (hemi-) Fontan circulation, the methods of the electively intubated positive pressure ventilated patients should present some settings at least the mean airway pressures during controlled ventilation and the FiOLast but not least, would it be interesting to know how the decision for general anesthesia is argued or whether it is based on the anesthesiologic preference?Regarding the article of Sanchitha Guruchandrasekar et al. . With hi2 40–45 mmHg). General anesthesia in infant according to Norwood or Hybrid stage-I (S1P) can be dangerous because systemic blood flow is impaired by a pulmonary run-off and according to S2P (Glenn) or S3P (Fontan) due to a compromised pulmonary blood flow with possible problems achieving a sufficient preload for the SV.It remains a mystery to me why it is the rule and not the exception in some facilities for patients with SV-pathophysiology to perform particularly diagnostic cardiac catheterizations under general anesthesia? Experienced doctors/anesthesiologists are easily able to establish a balanced analgo-sedation with a sufficiently spontaneous breathing SV-patient (paCO


Thirty-four controls and 28 patients underwent additional near-infrared spectroscopy recordings (oxygenated [O2Hb] and deoxygenated [HHb] hemoglobin). Degree of microcirculatory white matter lesions was graded by Fazekas scale. Dynamic cerebral autoregulation (dCA) was assessed by transfer function analysis. BP was successfully lowered , but cerebrovascular resistance was higher in BP patients (p < 0.05). BP-CBFV phase was lower in very low frequency (VLF)  and low frequency (LF)  ranges. Gain was higher in VLF range . BP-CBFV phase and gain did not differ across Fazekas groups. Across all patients, the capillary phases and gains  were comparable to controls. Successfully treated chronic HBP results in normal brain capillary hemodynamics while the resistance vessel state is disturbed .The mechanisms of high blood pressure (HBP) -related brain pathology progression remain relatively unclear. We investigated whether lowering BP in chronic HBP patients normalizes cerebral perfusion dynamics at resistance vessel and capillary levels. Sixty-seven patients with HBP and 49 age- and sex-matched healthy controls underwent simultaneous recordings of middle cerebral artery blood flow velocity (CBFV), BP, and end-tidal CO Small vessel disease has also been reported to contribute to the pathogenesis of Alzheimer’s disease3. The pathological mechanisms of HBP-related brain pathology progression, however, are unclear. Among others, a constant elevated level of mean systolic or diastolic BP and their variabilities5, autonomic BP regulation disturbances6, increased pulse pressure amplitudes7, ischemic effects on the brain due to cerebral autoregulation (CA) failure11, and capillary dysfunction12 are proposed mechanisms of continuous cerebral tissue damage. More recently, aging is assumed to accelerate the HBP-driven pathologies13.The cerebral consequences of chronic high blood pressure (HBP) are manifold: the most frequent are hemorrhagic and nonhemorrhagic stroke, cerebral small vessel disease with white matter lesions (WML), microbleeds, or brain atrophy which can lead to cognitive decline and dementia16. Anatomically, CBFV mirrors the regulatory effects in front of the resistance vessel in the large (macrocirculatory) brain supplying arteries such as the middle cerebral artery, while the concentration changes in oxygenated and deoxygenated Hb indicate effects behind the resistance vessel predominantly in the capillary bed. For clarification, the resistance vessels are part of the cerebral microvasculature and cannot directly be assessed noninvasively but only deducibly in the upstream macrocirculatory vessels. The other part of cerebral microvasvulature is the capillary bed which is approachable via NIRS. Together with noninvasive estimation of BP, CBFV and NIRS parameters offer sufficient resolution to analyze the dynamics of the regulatory processes from BP to the venous capillary bed.Cerebral blood flow is determined by BP-dependent regulatory effects and by metabolic influences on the resistance vessels via feedback mechanisms. These regulatory mechanisms can be observed noninvasively by cerebral blood flow velocity (CBFV) and its wave form, and by changes in the microcirculatory concentrations of oxygenated and deoxygenated hemoglobin (Hb) via near-infrared spectroscopy (NIRS)21: at a given cycle of BP and CBFV changes, e.g. BP and CBF changes with a cycle duration of 10 seconds (=0.1 Hz) gain describes the power transformation from BP to CBFV, and phase shift indicates how much earlier or later in time the BP cycle will be found in the CBFV. A characteristic finding is that BP cycles around 0.1 Hz are delayed by approximately 1.10–1.70 seconds compared to the corresponding CBFV cycle. In patients with recently diagnosed, untreated HBP, or in subjects in which BP was elevated by phenylephrine, gain was shown to be reduced and the phase was either unchanged or decreased24; after lowering BP in these two populations, the phase shift and gain normalized. However, this reversibility might not be present in patients with chronic HBP25. We used this dynamic approach in accordingly treated chronic HBP patients and hypothesize that the regulatory effects of the resistance vessels as indicated by phase and gain are normalized in the macrocirculatory system BP - CBFV . Consequently, if treatment normalizes these resistance vessel measures, the capillary blood flow compartment should then be responsible for small vessel disease propagation. Our second hypothesis, therefore, is that the TFA parameters and/or the capillary transit time between CBFV and the concentrations of oxygenated Hb or deoxygenated Hb demonstrate pathological results which ideally should additionally demonstrate a relationship with the amount of WMLs as classified by the Fazekes scale26 score.A frequently-used approach to describe these dynamics is the estimation of phase shift and gain derived from transfer function analysis (TFA)The study was approved by the Ethics Committee of Northwest and Central Switzerland and was performed in accordance with the Declaration of Helsinki, using good standards of clinical practice. Written informed consent was obtained from all participants. All data is available on request from the authors.The control population consisted of 49 healthy individuals  (Table 2), absence of cardiac arrhythmias , or a clinically manifest heart failure, no new symptoms suggestive for a ischemia relapse. Only treated dyslipidemia was allowed as an additional risk factor. After enrollment BP was controlled by regular follow-up visits to general physicians for 3 months. The study investigations were performed after these 3 months time periods at stage 2. Upon enrollment, the final diagnoses were microangiopathic minor stroke in 18 patients, transient ischemic attack in 12, and 37 patients were asymptomatic. All MRIs were examined by the same neuroradiologist (AvH), who made assessments about the presence of WML according to the grading schema by Fazekas et al.26: WML originate from microvascular changes, and the amount of WML correlate with the severity of small vessel disease ; the Fazekas grading schema is robust, exhibits a good inter-rater reliability when grading is based on MRIs, and is clinically widely used. We graded MRIs without any WML as Fazekas 0.The patient group consisted of 67 consecutive HBP patients . Infrared light is emitted at 3 frequencies  through the skull and absorpt in the upper cortical layers by oxygenated Hb and deoxygenated Hb. Both Hbs backscatter the light with different intensities which correlate with the concentrations of oxygenated and deoxygenated Hb. We used self-adhesive NIRS probes: the detecting probe was placed at the lateral frontotemporal skull to ensure it was above the MCA territory, and the emitting probe was placed at a fixed distance of 4 cm at the frontal skull. After initial adjustments to determine the baseline hemoglobin concentration (in µmol/L), the NIRS device provided continuous percentage changes in oxygenated and deoxygenated Hb concentrations.2 was measured via a small nostril tube connected to a capnograph embedded in the TCD device.The cerebral blood flow velocity in the middle cerebral artery using transcranial Doppler (TCD) ultrasound . After attaching the NIRS probes, a head holder to affix the TCD probes was positioned and both middle cerebral arteries were identified using common criteria . End-tidal CO2.Blood pressure by finger plethysmography  placed at the fingertip of the right index finger with special attention to calibrate it to the brachial artery. The blood pressure signal was imported into the TCD device and simultaneously recorded along with the cerebral blood flow velocity and End-tidal COAs described in detail in a previous reportAfter all probes were placed and participants were familiar with their surroundings and the experimental setting, we began recordings of ≥5 min.2 data were collected at 100 Hz. Oxygenated and deoxygenated Hb concentration changes via NIRS were collected at 5 Hz. The data were analyzed using Matlab . Only artifact-free 5 min periods were used. After aligning the common starting point, each raw data time series was resampled by averaging over 1 s intervals . The mean of the data series was then subtracted in each data series. Form these resampled and mean subtracted time series, the coherence and the TFA estimates of phase (in degrees) and gain between the different time series were extracted from their respective power auto-spectra or cross-spectra using Welch’s averaged periodogram method with a Hanning window length of 100 s, a window overlap of 50%, and a total Fast Fourier Transformation data length of 300 s, thereby allowing for calculations over a frequency range of 0.02–0.40 Hz.Cerebral blood flow velocity, blood pressure, and End-tidal CO18, we decided to use the frequency range of 0.02–0.15 Hz only for analysis which included NIRS parameters. To calculate means over each frequency range, we averaged phase and gain values with a coherence ≥0.3417. Cerebral mean transit times were calculated as phase differences between phase  – phase . In addition, cerebrovascular resistance was calculated as mean blood pressure /mean cerebral blood flow velocity, and heart rate was derived from the blood pressure signal trace.Blood pressure - cerebral blood flow velocity TFA results are reported over the total frequency range . Because coherence has been shown to be low in frequency ranges >0.15 Hz when oxygenated and deoxygenated Hb concentrations are involved2, BP variability , cerebrovascular resistance, or age. If 2 or more variables predicted a target variable, stepwise regression analysis was used to determine their effects. P-values ≤ 0.05 were considered statistically significant.Matlab Statistical Toolbox was used for all data analyses. Using a Kolmogorov-Smirnov test, all data were shown to have a normal distribution, and the data are reported as mean ± SD. We used the t-test for comparisons between the 2 participant groups, and one-way analysis of variance (ANOVA), which includes a correction for multiple comparisons (Tukey-Kramer procedure) for within-group comparisons. A regression analysis was used to test whether the results showed any dependency on End-tidal CO2, and heart rate. BP variability and cerebrovascular resistance were significantly larger in the HBP patients than in controls  = 8.20, R2 = 0.148, t = 2.86, p < 0.01) and decreasing CBFV  = 7.90, R2 = 0.144, t = −2.81, p < 0.01; right: F = 11.5, R2 = 0.196, t = −3.38, p < 0.01); all TFA parameters were unrelated to age. In the patient group, neither cerebrovascular resistance, nor CBFV, nor TFA parameters were age-related.Patient and control groups were not different regarding age, sex, mean BP levels, End-tidal COls Table . In the 2 = 0.24, t = 4.09, p < 0.005, d = 0.93; right: F = 22.6, R2 = 0.26, t = 4.75, p < 0.005, d = 0.90). Regarding the initial clinical presentation, there were no differences in TFA parameters between asymptomatic patients, formerly symptomatic patients with transient ischemic attack, or those with minor stroke.In the HBP patients, 66 left and 65 right middle cerebral arteries could be assessed by transcranial Doppler ultrasound. In TFA of the BP-CBFV systems Table , the pha15) also did not differ between controls and the patient group (range: 4.14–4.84 s).We used the CBFV-NIRS parameter to characterize the capillary dynamics. For all patients, concentration changes in oxygenated Hb followed CBFV about 50°; the concentration changes in deoxygenated Hb followed about 260–280° without many differences between VLF and LF ranges. These phase values did not differ from the corresponding values in controls Table . %/% gai11. High BP leads to changes in the dynamics  of the resistance vessel which can be derived from analyzing the (macrocirculatory) BP-CBFV relationship. Sufficient treatment of HBP should consecutively normalize any disturbances in the BP-CBFV relationsship. We, therefore, hypothesized that the propagation of small vessel disease could be allocated at the capillary level of cerebral blood flow regulation by demonstrating disturbed TFA parameters here. In contrast to our hypotheses however, we found that, despite normalizing BP, the cerebral blood flow regulating system is still disturbed at the resistance vessel level as indicated by the BP-CBFV system, and that the cerebral blood flow regulating system is normal at the capillary level indicating that the main task of the resistance vessel is still achieved.Physiologically, the main purpose of the cerebral resistance vessel is to provide a relatively constant blood supply to the brain’s capillary bed. These efforts can be characterized by functional/dynamical parameters such as phase and gain, or by static CBF measurements via e.g. perfusion computed tomography or perfusion MRI technology33. If we consider structural vessel changes only, then our cohort represents patients at a disease stage with irreversible resistance vessel changes. In this condition, dynamic CA responded with gain increase and phase decrease. Similar findings were reported by Immink et al.34 in a small number of patients with long-term hypertension who also presented with secondary hypertensive ocular complications. Together, these findings may hint towards a suggestion that the dynamic CA response of patients at an advanced disease stage is distinctly different from that of healthy subjects or patients with recently diagnosed HBP; in these latter patients, gain decreases and normalizes after treatment, and phase changes are usually not present35. A low gain in an arterial vessel indicates a good ability to buffer , and a high gain indicates a loss of this ability36. Thus, at an early HBP disease stage, the CA responds at the resistance vessel level with a gain decrease indicating an adequate capability to buffer BP increases; and at an advanced stage, CA responds with a phase decrease and a gain increase indicating a poor buffer capability leading to a high amount of energy to be transported transmurally. Speculatively, the increased BP variability in our patient group is also less well-buffered and could contribute to further brain damage.The elevated cerebrovascular resistance in our patient group was not normalized and dynamic CA remained disturbed despite sufficient BP lowering. This suggests that the continuously-elevated cerebrovascular resistance trended toward (1) either an incomplete structural recovery of resistance vessels from vessel rarefication, (2) lumen narrowing, or (3) an ongoing and not necessarily pressure-dependent vessel dysfunction as a reason for the elevated resistance 37 or of prolongation the mean transit time39 via delaying venous outflow15. Our results at the capillary level support recent CBF studies which demonstrate that cerebral hypoperfusion is not always present in patients with HBP41, and that an intensive BP lowering was tolerated well by patients with severe SVD41.The second result of our study was that, irrespective of the exact mechanism for the cerebrovascular resistance increase, the mechanisms of the cerebrovascular system consisted of compromised dynamics of CA in the BP-CBFV system, and normal dynamics of cerebral blood flow regulation at the capillary level. If HBP patients are sufficiently treated, our overall findings indicate that the extent of the hemodynamic compromise of the resistance vessels does not exceed a point at which the capillary compensatory mechanisms become effective, such as shortening of the mean transit time by opening up of functional shortcuts due to capillary transit time homogenizationet al.42 used another method to test dynamic CA between BP and CBFV, and also found that dynamic CA disturbances did not correlate with the total amount of WML. Thus, BP-CBFV dynamic CA disturbances are quite similar across all Fazekas groups, making it difficult to attribute dCA at the resistance vessel level with the responsibility for the different SVD stages. Age and other factors (not investigated by us) may therefore be more relevant. Nevertheless, one has cautiously to keep in mind that our number of patients with severe WML was low, a fact that could have hindered the detection of relevant hemodynamic relationships.Neither the findings at the BP-CBFV level nor the findings at the capillary level demonstrated a correlation to the amount of WMLs. This contradicts our hypothesis that CBF regulation at the capillary level would be the more disturbed the lager the WML amount is. Our results are surprising and may favor the view that the primary location of small vessel disease propagation is at the resistance vessel level due to CBF regulation failure. However, Birns 43: Ca-Antagonist dilate the resistance vessel, ACE inhibitors and AT1- receptor blockers can vasodilate larger arteries but can also vasoconstrict small vessels; diuretics, ACE-inhibitors and AT1 receptor blockers lower BP additionally by reducing the intravascular volume. Thus, our results might be based on different pathophysiological conditions which met the different effects of each individual drug class. To this end, we cannot differentiate by our used methods which underlying condition meets which drug effect. In an additional multiple regression analysis with all drug classes as the independent variables in the model and phase and gain as the dependent (to be predicted) variable, the models did not reveal that any drug class predicted either gain nor phase. However, we consider the number of patients too low to allow for an analysis of such drug effects.In our patients CVR was still increased despite adequate BP lowering therapy. We assumed that this CVR increase is present in every patient irrespectively of its underlying condition such as an anatomical vessel rarefication, an increased vessel stiffness or an unknown metabolic change. Each of the used drug class influences the vascular tone/resistance differentlyet al.35 (and the current study) used TFA on spontaneous CBF oscillation for analysis. Birns et al.42 used the thigh cuff test for dCA evaluation in their HBP patients, and also did not find any dependency of WML severity on dCA results. Thus, both analysis methods seemed comparable in this respect44 and might not fully portray the progression of HBP-related small vessel disease. We investigated roughly half of our patients 3 months after a clinical event, which may have influenced our results. Clinical events, especially strokes, can lead to a disturbed dynamic CA, although this is usually transient and resolves after 2 weeks46.Given the penetration depth of NIRS wavelengths, it is assumed that the dynamic CA patency in the upper cortical layer was comparable to the deep white matter conditions. Whether this assumption is correct has not been demonstrated, as clinical experience suggests that the lesion load of WML in the deep white matter is higher than that in the subcortical brain tissue. Immink In successfully treated patients with an HBP history of ≥2 years, BP lowering therapy results in an overall normal brain capillary hemodynamic state at the expense of the resistance vessel system that shows a disturbed dynamic autoregulation ability with phase decrease and gain increase. The increased gain indicates that the vessel’s ability to buffer pressure or flow across the vessel wall is compromised at CBF period lengths between 13 and 50 s. This dynamic approach to CA should be evaluated further to determine whether it could play a role in guiding HBP treatment in the future.


To date, no study has evaluated blood pressure following administration of each carpule given for dental procedures using a computerized dental anesthesia system. Blood pressures taken prior to performing invasive periodontal procedures were compared with those readings measured following delivery of each of up to three consecutive carpules of Marcaine or Xylocaine in varying order. Pressure differences were also adjusted for age, sex, race, and whether a prescribed anxiolytic was taken beforehand. Neither systolic nor diastolic blood pressures changed significantly as compared to initial blood pressure readings. However, compared with Whites, Hispanics, and Middle Easterners, Blacks had significantly higher systolic pressure at the third carpule delivery, the cause being unknown. Blood pressure in patients being anesthetized for root planing and various periodontal surgical procedures will not increase significantly when administering up to three carpules, whether Marcaine or Xylocaine, in varying order, using controlled flow dental anesthesia, and this method may be preferable to syringes in managing dental procedural stress. Pain and other stressors can result in a dramatic endogenous release of epinephrine and norepinephrine, which can affect heart disease deleteriously; therefore, the importance of good local anesthetic technique cannot be over emphasized.5The injection of local anesthesia can inflict discomfort, which may elicit cardiovascular changes such as hypertension or tachycardia.6 Quite commonly, a longer lasting anesthetic with 1:200,000 epinephrine in 0.05% Marcaine is employed in root planing and surgical procedures, depending on patient circumstance.Epinephrine is widely used as an additive in local anesthetics, most typically in concentrations of 1:100,000 in 2% Xylocaine. This improves the depth and duration of the anesthesia, and reduces bleeding in the operative field. Epinephrine counteracts the anesthetic’s localized vasodilator effects in subcutaneous and submucosal vessels, thereby reducing the risk of anesthetic toxicity while decreasing the rate of systemic absorption from the site of the injection.7For certain patients, the stress and anxiety associated with even simple, noninvasive dental visits is enough to increase blood pressure. The common medical condition called white coat hypertension (or white coat syndrome) is important for dental professionals to acknowledge, and routine monitoring of patients in this situation can help prevent possible negative effects associated with this situation. Carotid atherosclerosis is considerably greater in patients with white coat hypertension when compared to those without; therefore, it has been stated that white coat hypertension is a risk factor for heart attack, heart failure, and stroke.8 Optimal blood pressure is <120 systolic and <80 diastolic, and roughly one in three adults in the United States is diagnosed as having hypertension.7New guidelines from the American Heart Association and the American College of Cardiology in December of 2017 have redefined hypertensive thresholds, with readings of 130/80 now considered to be elevated, or definable as hypertension stage one.9 Monitoring of vital signs can help minimize potentially serious adverse drug events.10 The dentist’s role in screening for hypertension as part of a comprehensive dental care evaluation is very important.11 Risks for hypertension associated with epinephrine include increased acute hypertensive or hypotensive episodes, angina pectoris, arrhythmias, and myocardial infarction.12Hypertension is a highly prevalent cardiovascular disease, which affects over 1 billion people worldwide.13 while other factors that may influence discomfort are fluid temperature and management of the needle upon full penetration of the tissue. Many patients associate injections of local anesthetic with pain, despite its benefits in treatment.The perception of pain during administration of local anesthesia can contribute to the stress of the dental visit. Discomfort can be attributed to tissue puncture, fluid pressure, and the flow rate of the drug administered,14The most widely used method of injection continues to be the metallic aspirating cartridge syringe system where flow rate and pressure are operator dependent, making it rather difficult to manage injection discomfort. Alternatively, a computerized dental anesthesia delivery system more precisely controls flow rate and fluid pressure by the use of a microprocessor and electronically controlled motor.13 It is operated by means of a small rheostat placed on the floor and which delivers local anesthetic at controllable pressure and volume rates.15The computer-controlled delivery device accommodates a conventional local anesthetic cartridge that is linked by tubing to a disposable pen-like plastic dispenser with an attached luer-lok needle.16 Additionally, a split-mouth study in which 50 subjects used subjective scales to describe pain experience found the computer to be on average two to three times less painful than manual injection.14Several studies have shown this device to be well-received by patients. Twenty subjects undergoing scaling and root planing reported less pain with computer-controlled injections versus that from a traditional syringe as indicated by a visual analog scale.17Another study in Turkey analyzed 40 patients between the ages of 18 and 30 over two separate dental visits, each subject randomly having traditional delivery of anesthetic at one appointment versus computer-controlled delivery at a subsequent appointment. The subjects then assigned a pain rating score to the two methods, and indicated they would prefer the computer delivery system for future injections.18 Another study found blood pressure increased during injections by syringe in four groups of patients undergoing extraction, regardless of their ASA status.19 Furthermore, Japanese researchers found with the use of a Holter monitor, dental surgery using local anesthesia caused a significant increase in systolic blood pressure, but not in the diastolic, and that the increase in pressure was greater in middle aged and older patients.20Blood pressure monitoring, likely a more reliable indicator of the physiologic effects of stress in response to injection than the aforementioned subjective response analyses, has been employed in several syringe-employed anesthetic studies. One study comparing blood pressure readings while using a syringe to administer differing concentrations of epinephrine found no significant variances among the three groups which were studied.21 Additionally, in a study of four groups of patients ranging from normotensive to severely hypertensive and who were undergoing tooth extraction with local anesthetic, again utilizing syringes, it was found that blood pressure increased in all groups, with the greatest increase found in those already diagnosed as hypertensive.19In another study where blood pressures were monitored with and without administration of local anesthetic using a syringe, a transient blood pressure increase was found followed by a decrease shortly after removal of the needle from the mouth.It appears to date, however, that no prior study has been conducted measuring physiologic response via blood pressure monitoring with the use of the computerized controlled flow anesthesia delivery system, nor has there been any dental anesthetic blood pressure study performed to assess blood pressure following administration of each carpule of anesthetic administered for dental procedures. Furthermore, this study separated for differences in age, sex, race and effects of the use of an anxiolytic. Seeing as how anesthetic can cause anxiety, and because patient monitoring is important in measuring such stress, this study was undertaken to evaluate blood pressure readings in up to 149 patients at baseline, as well as after each carpule administered, varying second and third carpules between Xylocaine and Marcaine, using a computerized controlled-delivery anesthesia system.The null hypothesis in this study was that blood pressure (both systolic and diastolic) will not increase significantly during administration of anesthesia as compared to the patients’ initial readings when using the computer-controlled delivery system.IRB exempt status was obtained due to the blind nature of this study. Blood pressure was measured at baseline and again following delivery of each of three consecutively administered carpules of dental anesthetic in 149 periodontal patients previously scheduled for either root planing or periodontal surgical procedures which included cosmetic and functional crown lengthening, osseous surgery, and soft tissue grafting. Blood pressure readings were taken at baseline and immediately following the emptying of each consecutive carpule. The blood pressure monitor used was the Mindray Datascope Trio Patient Monitor, which also monitored pulse oximetry and electrocardiogram activity throughout procedures. The anesthetic delivery system employed, whereby carpule administration occurs via a flow rate that is controlled by use of a microprocessor and electric motor, was used in all patients. No adverse effects were noted during any of the procedures, while a variety of injection types were employed, all with 27 gauge needles, with approximately half of the patients receiving palatal injections. Vasoconstriction was utilized due to the need for increased anesthesia duration.Patients were previously prescribed 0.5 mg of Alprazolam, to be taken 1 h prior to the scheduled procedure . The first carpule given to all patients was exclusively Xylocaine 2% with 1:100,000 epinephrine. In 116 of these patients, the second carpule given was another Xylocaine 2% with 1:100,000 epinephrine, while in 33 of these patients the second was 0.5% Marcaine with 1:200,000 epinephrine. A third carpule was then given in 116 patients, wherein 99 patients had another carpule of 2% Xylocaine with 1:100,000 epinephrine, while 17 had a carpule of 0.5% Marcaine with 1:200,000 epinephrine only in those patients whose first two carpules had been exclusively Xylocaine. Of these, 34 patients had not taken any antianxiety medication, and 4 opted to take their own already-prescribed medication.t-test to compare blood pressure following administration of each carpule separately with the initial blood pressure reading was utilized. Because there was a maximum of three carpules in total for each subject, separate hypothetical comparisons were conducted for carpules 1–3 where applicable. The Bonferroni correction method was employed to control the familywise type one error rate at a 0.05 level for multiple comparisons. Linear regressions were also adopted to compare differences controlling for age, sex, race, and whether patients had antianxiety medication or not before the procedure.A one-sided paired t-test results for the relationship between the type of second carpule, following a first carpule of Xylocaine, and the difference in systolic pressure from the initial pressure reading. Using Xylocaine as carpule 2, the average change in systolic pressure is positive , while the average change is negative (lower at carpule 2) when using Marcaine as the second carpule. However, the p value from a one-way ANOVA test is 0.80, indicating that the relationship between the type of second anesthetic carpule and the change in systolic pressure is not different at a significance level of 0.05.Figure t-test results. The p value of 0.79 indicates that there is no significant relationship between the type of second anesthetic carpule and the change in diastolic pressure.Figure p value of 0.87 indicates that when adjusting for age, sex, race, and anxiolytic, the type of second anesthetic has no significant effect on the change of systolic pressure. In addition, none of these factors significantly relate to change in systolic blood pressure.Table p value of 0.81 indicates that there is no significant relationship between the type of third anesthetic carpule and the change in diastolic pressure when controlling for age, sex, race, and anxiolytic. Also these other factors do not significantly relate with the change of diastolic pressure.Table t-test results. The p value of 0.14 indicates that there is no significant relationship between the type of the third anesthetic carpule and the change in systolic pressure among individuals whose first two carpules were both Xylocaine.Figure t-test results. The p value of 0.1519 indicates that there is no significant relationship between the type of the third carpule and change in diastolic pressure among individuals whose first two carpules were both Xylocaine.Figure Table Table This study showed no difference in adjusting for race except that compared with Whites, Hispanics, and Middle Easterners, Blacks had a significantly larger change in systolic pressure at the third carpule delivery with the computer-controlled-flow anesthesia system. The reason for this within the parameters of this study is unclear. However, generally, it was found that both systolic and diastolic blood pressures did not increase significantly as compared to initial blood pressure readings following administration of three carpules of Marcaine or Xylocaine, in varying order, using the computerized delivery anesthetic system, showing this to be a possible method of reducing stress in anesthesia administration.This study showed no difference in adjusting for age and sex. Regarding the effects of anxiolytics, and using Alprazolam as a reference group, while some anxiolytic response showed a relative lower (negative coefficient) blood pressure effect, and others showed a relatively higher (positive coefficient) blood pressure effect, none were significant. In other words, no group was significantly different from the group receiving Alprazolam after adjusting for other variables.Stress during injections can be a deterrent to successful and less eventful patient treatment, especially in cases of hypertension, yet no study to date has monitored blood pressure with controlled flow or following each carpule administered, separating for age, sex, race, and use of anxiolytic.22 Of significance is the fact that elevations in both systolic and diastolic blood pressures can be used to make a diagnosis of hypertension, and the risk of death from ischemic heart disease and stroke has been found to double with every 20 mm of mercury (systolic) or 10 mm mercury (diastolic) in persons aged 40–89.23 Thus, dental professionals must be on the frontlines of prevention of hypertension by evaluating preoperative blood pressure readings, performing risk assessments, and knowing when to refer a patient for medical consultation in a dental setting.12 Studies of the prevalence of dental anxiety in the general population show a range of 2.6–20.4%,24 and measurement of blood pressure during the stressful moments surrounding injection-giving helps dentists to avoid untoward cardiovascular events. High levels of stress, including that from dental anesthetic, can indeed lead to increases in blood pressure, even if temporary.27 Anesthetics were selected according to what best suited each individual patient depending on duration of anesthesia and hemostasis needed. The Lidocaine HCl 2% solution with a 1:100,000 epinephrine concentration used in this study provides average pulpal anesthesia for 60 min, with soft tissue anesthesia for ~2.5 h.28 The concentration of 0.5% Marcaine with 1:200,000 epinephrine employed yields a duration of anesthesia two to three times longer than that of the Lidocaine, in many patients lasting up to 7 h.29 Furthermore, measuring vital signs frequently where multiple injections are performed has been advised as a consideration and prevention of anesthetic emergencies.28This is of interest for several reasons. Currently, up to 46% of United States adults are identified as having high blood pressure.30 This computerized local anesthesia delivery system offered several advantages over a conventional syringe, including controlled, slow flow delivery, likely improved tactile sensation with the lightweight plastic handle, and the ability to rotate the needle as it is introduced into tissue, as well as while aspirating. Disadvantages include the fact that the system is costly, rather complex, bulky, and generally consumes more time for administration of anesthetic.The rate at which anesthetic is injected is seemingly very important in preventing stress in dental patients. Slower administration of a carpule over a period of a maximum of 60 s is recommended for optimal reduction of pain during injection.31 This current study showed that following each of up to three carpules given, no significant increase in blood pressure, except with systolic pressure in Blacks when the third carpule was administered. The cause of this is uncertain. Because hypertension affects ~75 million United States residents,32 as well as the fact that the administration of local anesthesia containing epinephrine can affect the cardiovascular system, gentle anesthesia management, and proper monitoring of patients receiving injections is crucial.5Interest in race and age differences in blood pressure within this study stems from prior variances in these parameters. Data from a National Health and Nutrition Examination Survey showed that between 2015 and 2016, prevalence of hypertension was 29% and increased with age, with 18–39 years old at 7.5% and those over 60 at 63.1%. Hypertensive prevalence was higher in non-Hispanic blacks at 40.3% than non-Hispanic whites at 27.8%, non-Hispanic Asians at 25.0% or Hispanics at 27.8% in adults. However, hypertension control was higher among the non-Hispanic whites at 50.8% then non-Hispanic blacks at 44.6% or non-Hispanic Asians at 37.4%.33 possibly exacerbating or compounding the effects of the stress of the injection and the epinephrine contained within the anesthetic.Patient variables that were not controlled in this study include the possibility that patients had variances in presurgical meal content, or other drugs which may have affected blood pressure responses,34 were not standardized, and therefore could have affected patient-to-patient comparisons. It is conceivable that implementing a future study that controls these factors more astutely and which would employ a larger patient population with each individual factor would likely create greater reliability of the results found herein.Also, time between injections and the locale of each injection, as some anatomical locations in the mouth have different tissue resistance,