Aim of the present study was to evaluate the impact of once-weekly semaglutide on different end-points indicative of metabolic control, cardiovascular risk, dietary behavior, and treatment satisfaction in T2DM.This was a retrospective observational study conducted in a diabetes clinic. Changes in HbA1c, fasting blood glucose (FBG), weight, blood pressure, lipid profile, and number of antihypertensive drugs at 32 weeks (T1) after the first prescription of semaglutide (T0) were analyzed. Furthermore, at T1 patients were asked to fill-in the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Control of Eating Questionnaire (COEQ).Overall, 104 patients were identified . After 32 weeks of treatment with semaglutide, HbA1c levels were reduced by 1.38%, FBG by − 56.53 mg/dl, weight by 6.03 kg. Systolic and diastolic blood pressure, total, HDL-, LDL-, and non –HDL cholesterol, and triglycerides significantly improved. The number of glucose-lowering and antihypertensive drugs also decreased. At T1, DTSQ score was 32.23 ± 1.44, whereas COEQ indicated low levels of hunger and good control of eating.The study documented benefits of semaglutide on metabolic control and multiple CV risk factors, simplification of therapeutic schemes and high satisfaction with diabetes treatment, and eating behaviors indicative of healthy diet and reduced food intake. GLP1-RAs also preserve the function of β-cells, stimulating their proliferation and differentiation and inhibiting apoptosis [Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia caused by insulin resistance and deficiency of insulin secretion by the beta cells of the pancreas . In the poptosis . GLP-1 rpoptosis , 5. In apoptosis . Due to poptosis .In most patients with T2DM the lipid profile is altered with hypertriglyceridemia, increased total cholesterol and low-density lipoproteins (LDL) cholesterol levels, and decreased high-density lipoproteins (HDL) cholesterol levels. All of these alterations constitute the “atherogenic dyslipidemia in diabetes” which contributes to the increase in cardiovascular risk typical of subjects with T2DM . The nonSemaglutide is an analogue of native GLP-1 with a prolonged half-life (165 h), suitable for administration once a week (ow). Semaglutide was shown to be effective in improving metabolic control in T2DM by reducing blood glucose and glycated hemoglobin (HbA1c), body weight, and cardiovascular risk .The side effects that may occur are nausea and, more rarely, vomiting and diarrhea, usually mild and limited to the first weeks of treatment .Aim of the present study was to evaluate the impact of semaglutide on different end-points indicative of metabolic control, cardiovascular risk, dietary behavior, treatment satisfaction in T2DM, and a possible reduction in the use of antihypertensive drugs.This was a retrospective observational study conducted in the diabetes clinic of S. Camillo Forlanini Hospital–Rome. Data on all patients treated with ow semaglutide were extracted from the electronic medical record system adopted in the hospital.Baseline visit was represented by the first prescription of semaglutide (T0); follow-up visits were based on routine clinical practice, usually every 4 months. Values recorded after 32 weeks from baseline were used for this study (T1).According to the summary of product characteristics, all patients were first prescribed with semaglutide 0.25 mg; semaglutide was then titrated up to 0.50 mg and successively 1.0 mg (based on patient needs).Baseline characteristics were collected including: age, gender, diabetes duration, obesity indices , smoke, HbA1c, fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile , estimated glomerular filtration rate (eGFR), albuminuria, micro- and macro-vascular diabetes complications, comorbidities, diabetes treatment before and at initiation of semaglutide, and antihypertensive treatment.At follow-up visit, data on changes in HbA1c, FBG, BMI, body weight, blood pressure, lipid profile, number of antihypertensive drugs were collected.Furthermore, at T1 patients were asked to fill-in the Diabetes Treatment Satisfaction Questionnaire (DTSQ) , 16 and DTSQ has been specifically designed to measure satisfaction with diabetes treatment regimens . It is cControl of eating and the degree of food cravings were measured using a modified version of the validated 16-item short form COEQ, which includes questions related to food cravings, control of eating, hunger and fullness. Based on the previous 7 days, subjects were asked to rate the first 14 questions of the original COEQ on a 10 cm visual analogue scale (VAS); 1 question with categorical response was added to investigate about type of food least liked by the patient , 18.The study protocol was approved by the local ethics committee. Informed consent was obtained from all patients for being included in the study.In Italy, GLP1-RA therapy is reimbursed by the national healthcare system in all patients with T2DM and HbA1c > 7.0% as a monotherapy (when metformin is contraindicated or not tolerated) or in combination with other antihyperglycemic agents.Considering the preliminary, descriptive nature of this study, a formal sample size calculation was not performed. However, a minimum sample size of 47 patients allowed to detect with a statistical power of 90% a decrease in HbA1c levels of at least 0.5%, assuming an estimated standard deviation of differences of 1.0 and with a significance level  of 0.05.Descriptive data were summarized as mean and standard deviation for continuous variables or frequency and proportion for categorical variables.p-value was < 0.05.Changes in continuous study endpoints were assessed using mixed models for repeated measurements. Results are expressed as estimated mean or estimated mean difference from T0 with their 95% confidence interval (95% CI). Paired t-test derived from linear mixed models for repeated measurements were applied for within group comparisons. Statistical significance was declared if Overall, 104 patients receiving the first prescription of semaglutide between January and March 2021 were identified through electronic medical records adopted in the clinic. Baseline patient characteristics are reported in Table Metabolic control was poor .At T0, patients showed poor metabolic control, high mean BMI, and poor control of cardiovascular risk factors. Furthermore, organ damage was recorded in one half of patients. Before starting semaglutide, 6 (5.8%) patients were already treated with another GLP1-RA. Furthermore, 98 (94.2%) patients were treated with oral hypoglycemic agents (OHA), of whom 72 (69.2%) with 1 OHA and 26 (25.0%) with  ≥ OHAs. Moreover, 11 (10.6%) patients were treated with schemes including insulin.At initiation of semaglutide, 20 (19.2%) patients were treated with semaglutide only, 79 (76.0%) patients were treated with OHAs, of whom 75 (72.1%) with 1 OHA and 4 (3.9%) with 2 OHAs, and 8 (7.7%) patients were treated with schemes including insulin.After 32 weeks of treatment with semaglutide, HbA1c levels were reduced by 1.38% and all continuous endpoints showed statistically significant and clinically relevant improvements .As for the use of antihypertensive drugs, at T0, 40 patients (38.8%) were not treated with antihypertensive drugs, while 34 (33.0%), 24 (23.3%), and 5 (4.9%) were treated with 1, 2, 3 antihypertensive drugs, respectively. At T1, 39 patients (37.5%) were not treated with antihypertensive drugs, while 38 (36.5%), 23 (22.1%), and 4 (3.8%) were treated with 1, 2, 3 antihypertensive drugs, respectively.Overall, 17 out of 104 (16.3%) patients reported side effects, of whom 13 (12.5%) nausea and 4 (3.8%) abdominal bloating. These symptoms were generally mild and decreased over time. Two patients discontinued the treatment with semaglutide during 32-week follow-up. No episode of severe (requiring third part assistance) or clinically relevant (blood glucose < 54 mg/dl) hypoglycemia occurred.This study documented the effectiveness and tolerability of semaglutide in patients with uncontrolled T2DM.After 32 weeks of treatment, HbA1c levels and body weight significantly decreased  and the entity of the reduction was in line with results obtained in the SUSTAIN program , 19, 20,In addition to the effect on HbA1c and weight, in our study we documented improvements in lipid profile and blood pressure.Finally, our population presented multiple associated risk factors , 50% had organ damage and 23.1% had history of cardiovascular event.The recent documentation of the positive CV effects of semaglutide in reducing the MACE risk  is extreFollowing these findings, in July 2021 new AMD-SID  Italian Guidelines stated that GLP1-RA can be prescribed as a first line therapy in T2DM with a previous cardiovascular event. ADA Guidelines (ADA 2022) also suggested to consider GLP1-RA as a first choice therapy in high cardiovascular risk patients , 30.In our study population and in general T2DM population, obesity is present in the majority of patients and its role as main driver of the disease is well known . Weight Semaglutide produces significant benefits on cardiovascular risk, as demonstrated in SUSTAIN 6, where a significant lower rate vs. placebo of 3 points MACE was documented . The redImportant information comes also from the analysis of treatment schemes. The present study substantially involved T2DM patients treated with 1 or 2 OHAs with elevated baseline levels of HbA1c. A small minority of patients were already treated with GLP1-RA and 1 out of 10 patients were treated with insulin before starting semaglutide. This picture underlines the existence of a certain clinical inertia, due, as known, to multifactorial reasons, such as COVID-19 pandemics, long waiting lists, transfer of new patients from other hospitals, low patient adherence, etc.… However, at semaglutide initiation, the proportion of patients treated with insulin and with more than 1 OHA decreased. Even the use of antihypertensive drugs slightly diminished. These data support the most recent evidence on simplification of therapy as a key strategy to overcome clinical inertia .Finally, DTSQ average values documented high levels of satisfaction with treatment (median score was 33 against a maximum score of 36) , 16. SatReduced appetite and energy intake, with less preference for energy‐rich foods, were investigated in previous studies and were identified as a possible mechanism to explain the weight loss observed with once-weekly and oral semaglutide , 39, 40.In our setting, we administered a translated and modified version of COEQ adapted for Italian T2DM patients: after 32 weeks of therapy a lower fatty food preference was declared (61%) with a relatively preserved proteic  and carbohydrate rich food  intake. In another study on 3685 obese subjects, semaglutide induced specific fat mass loss, and energy intake reduction; COEQ questionnaire documented food habits changes with lower craving .In our study, semaglutide significantly improved glucose control and reduced body weight  confirming or even surpassing results of SUSTAIN studies , 37, 41.The major strength was the inclusion of clinically important but seldom investigated endpoints: non-HDL cholesterol, reduction of antihypertensive drugs prescribed, treatment satisfaction, and eating behaviors. Among limitations, it should be underlined the lack of administration of DTSQ and COEQ at T0 to assess changes over time in the scores and the lack of information about mild hypoglycemia and glycemic variability.The study documented benefits of treatment with once-weekly semaglutide on metabolic control and CV risk factors, simplification of therapeutic schemes and high satisfaction with diabetes treatment, and eating behaviors indicative of healthy diet and reduced food intake. GLP1-RAs represent a pivotal drug class that can change favorably the natural history of diabesity.


Beta‐blockers are beneficial in coronary artery disease but less so in stroke prevention and dementia, potentially due to reduced heart rate (HR). Cerebral pulsatility is strongly associated with cerebral small vessel disease (SVD) and may be increased by lower diastolic pressures resulting from longer cardiac cycles.Patients 4–6 weeks after TIA or non‐disabling stroke (Oxford Vascular Study) underwent 5 minutes continuous monitoring of blood pressure (BP), electrocardiogram (ECG), and middle cerebral artery flow velocity . Beat‐to‐beat relationships between HR, blood pressure and Gosling's pulsatility index (MCA‐PI) are reported as beta‐coefficients from general linear models for each individual.p < 0.001), with HR particularly associated with low end‐diastolic cerebral velocity . Beat‐to‐beat HR was strongly associated with concurrent low DBP and high SBP, potentially mediating the association with greater beat‐to‐beat cerebral pulsatility . The beat‐to‐beat association between HR and MCA‐PI increased with age, beta‐blockers, arterial stiffness, low HR , and severe SVD on MRI , with interactions between age, severe SVD, and low HR synergistically increasing MCA‐PI.Across 759 patients, average MCA‐PI during monitoring was associated with lower HR and diastolic BP (DBP) and greater systolic BP (SBP) (∆MCA‐PI per 10 bpm/mmHg: −0.02, −0.04, 0.03, all Low HR is associated with greater cerebral pulsatility in patients with SVD, potentially mediated by lower diastolic blood flow and representing a novel potential treatment target. ANN NEUROL 2022;92:909–920 Elevated heart rate (HR) is associated with an increased risk of all‐cause mortality and cardiovascular eventsCerebral arterial pulsatility is strongly associated with severity of cerebral small vessel disease (SVD),A low HR may increase cerebral arterial pulsatility by causing a lower diastolic pressure, especially in the cerebral circulation. During a cardiac cycle, once the pressure wave of systolic contraction has passed, the blood pressure falls until the next cardiac contraction. As such, DBP falls further with lower HRs and longer cardiac cycles. In normal vessels, the diastolic pressure is sustained by elastic recoil of the aorta returning some of the energy of systolic contraction to the blood (“Windkessel” effect) and by reflection of the outgoing systolic pressure wave from points of distal resistance producing a reverse travelling wave that reaches the aorta in diastole, enhancing the diastolic pressure. However, in stiffer, older vessels, the effect of long cardiac cycles on DBP may be exacerbated by reduced elastic recoil and the reverse wave arriving earlier in systole, resulting in less support for the diastolic pressure.Therefore, we hypothesized that, although a lower HR may be beneficial for prevention of cardiac events, it may be associated with increased cerebral pulsatility in elderly patients with stiff vessels. In the OXVASCConsecutive, consenting patients with transient ischemic attack (TIA) or minor stroke were recruited between September 2010 and September 2019, as part of the Phenotyped Cohort of the Oxford Vascular Study (OXVASC).In a quiet, dimly‐lit, temperature‐controlled room (21‐23°C), after approximately 15 minutes supine rest, patients underwent physiological monitoring over 5 minutes at the ascertainment visit or 1 month clinic, consistent with recommendations for monitoring effects of variability in HR,Cerebral blood flow velocity (CBFV) from bilateral middle cerebral arteries (MCAs) was simultaneously measured using transcranial Doppler (TCD) ultrasound  with a 2‐MHz probe at the temporal bone window held by a Diamon monitoring headset, recording the highest velocity trace between 50 and 55 mm depth. BP and ECG waveforms were acquired at 200 Hz and TCD at 100 Hz. Consecutive beat‐to‐beat signals of BP and CBFV from bilateral MCAs were median filtered (7 data points), with automatic detection and linear interpolation of ectopic beats, and were then visually reviewed by an experienced operator (A.J.S.W.) for blinded quality assessment with linear interpolation of artifacts.Applanation tonometry  was used to measure carotid‐femoral pulse wave velocity (aortic‐PWV) and aortic systolic and diastolic BP and pulse pressure .Demographic characteristics of the population were described as mean and standard deviation, or as median and interquartile range for non‐normal characteristics. Cross‐sectional associations were derived between average HR, BP, and CBFV during monitoring by general linear models, unadjusted; adjusted for age, gender, and cardiovascular risk factors  and adjusted for blood pressure. Associations were expressed per 10 unit change in the predictor . Each predictor was also stratified into quintiles, and the mean value and confidence interval within each quintile calculated.p < 0.05), by quintile of systemic characteristics  and for participants using each specific class of antihypertensive medication compared to patients not using that class of medication. Factors predicting the presence of a significant association (p < 0.05) were identified by logistic regression.For each patient, beat‐to‐beat associations between change in HR, SBP, or DBP with cerebral indices  were determined by general linear models, with and without adjustment for the other concurrent predictors . Distributions of these beta‐coefficients were plotted as kernel density plots, and were averaged across the entire population, across those in whom the beat‐to‐beat association was significant  to the brain, with later measures physiologically dependent upon earlier variables. Each relationship was classified as no association, a purely direct association, an association that was fully mediated by another index or an association that was partially direct and partially mediated.Severity of WMH on MRI were determined by an experienced reviewer (L.L.) according to the Fazekas score and classified as none, mild,Analyses were performed in R and Matlab r2018, using in‐house software.The study included 759 patients with good or adequate quality BP and transcranial ultrasound monitoring, allowing calculation of the beat‐to‐beat relationship between HR and pulsatility index (PI), with 808 patients with measures of aortic stiffness. A total of 497 patients (65%) had a stroke, whereas 262 had a TIA (35%). Demographics of the population are shown in Table In cross‐sectional analyses, a higher average MCA‐PI during monitoring was associated with a lower average HR, higher SBP, and lower DBP, although the magnitude of the effect was limited Table . A 10 mmMean PSV was weakly associated with blood pressure indices, with an association only between a higher DBP and higher PSV. In contrast, EDV was associated with HR, arterial stiffness and SBP, although this diminished after adjustment Table .Within‐individual, beat‐to‐beat associations between HR and cerebral PI were stronger than cross‐sectional associations between average values during monitoring. There was a 0.062 fall in PI for a 10 bpm increase in HR Table , equatinIncreases in beat‐to‐beat HR, SBP, or DBP were all associated with an increase in PSV or EDV, with a stronger relationship between HR and EDV than HR and PSV, although relationships between HR and cerebral blood flow indices diminished upon adjustment for blood pressure changes. However, there was a stronger relationship between BP level and CBFV than with HR, in contrast to a stronger relationship between HR and MCA‐PI Fig .There was significant heterogeneity between patients (p < 0.001) and not all patients had a significant beat‐to‐beat relationship between HR and PI, although relationships were similar in men and women. When limiting the analysis to patients with a significant beat‐to‐beat association, the magnitude of the association between HR and pulsatility rose to 0.072 per 10 bpm (unadjusted) and 0.057 following adjustment for beat‐to‐beat blood pressure changes Table .A similar proportion of patients had significant beat‐to‐beat relationships between SBP and PSV, or DBP and EDV Table , with a p < 0.001) or aortic PP  across the population, whereas increases in either PWV or aortic PP were associated with a greater beat‐to‐beat relationship between HR and MCA‐PI .p = 0.021, ordinal regression), although there was no cross‐sectional association with average HR. However, there was a significantly stronger beat‐to‐beat relationship between HR and MCA‐PI in patients with severe WMH compared to no WMH , with a significant interaction between age and severe WMH . When considering other markers of SVD, the relationship between HR and MCA‐PI also increased with increasing perivascular spaces in the basal ganglia (p = 0.003), although this was not significant after adjustment for age and gender. There was no significant increase in the relationship between HR and MCA‐PI with increasing number of microbleeds or the presence of lacunar strokes, although the prevalence of these was less than with WMH.p = 0.03), and a borderline 3‐way synergistic interaction between severe WMH, age, and HR (p = 0.06) with increased MCA‐PI with increased age and WMH and lower HR.A total of 662/759 (87%) of patients with valid physiological monitoring had MRI imaging at baseline. Increased Fazekas score was strongly associated with cerebral pulsatility in cross‐sectional analyses (Fig In a population of patients with a recent TIA or minor stroke, a lower HR was associated with increased cerebral pulsatility. Although there was a relatively weak cross‐sectional association for average values across the population, there was a much stronger relationship for beat‐to‐beat changes between HR and resulting MCA‐PI. Beat‐to‐beat MCA‐PI was more strongly associated with lower end‐diastolic cerebral blood flow than raised systolic flow, whereas effects of HR on EDV were mediated by DBP. The relationship between low HR and increased MCA‐PI was greater in patients who were older, had increased arterial stiffness, were on beta‐blockers or had lower mean HRs, and was particularly strong in patients with severe cerebral SVD, with synergistic interactions between age, low HR and severe cerebral SVD.Cerebral SVD is the most prevalent cause of significant neurological disability in developed nations. It is associated with 30% of ischemic strokes, 80% of hemorrhagic strokes and 45% of dementia, as well as late‐onset refractory depressionThe only intervention shown to reduce WMH progression is a moderate effect of blood pressure control to normotensive levels.Our study supports the hypothesis that increases in HR are associated with reduced cerebral pulsatility, explicable by a shorter period for diastolic blood flow to fall during shorter cardiac cycles. We also demonstrated that a reduction in BP is consistent with a beat‐to‐beat reduction in cerebral pulsatility, as expected if SBP is proportionally reduced more than DBP. If this hypothesis is correct, the association with HR would be proportionally greater at a lower resting HR, as was the case in our population and consistent with a stronger association between HR and PI in patients on beta‐blockers in this study, and the greater pulsatility on beta‐blockers compared to amlodipine in previous studies.Increases in resting HR are associated with increased cardiovascular morbidity and mortality in observational studies.This study does have some limitations. It is an observational study in a selective population of patients with recent TIA or minor stroke, focused on an older age group; therefore, this mechanism cannot be generalized to other populations. However, these are the patients most likely to benefit from interventions to target SVD. Second, not all the patients had TCD performed. This largely reflects the relatively high proportion of elderly patients in the population who are most likely to lack acoustic bone windows. Third, only 87% of the studied population had an MRI scan, as is common in a clinical service due either to patient preference or contraindications. Fourth, the use of multiple antihypertensive medications in combination, and indication bias in which patients are given which drug, prevents reliable conclusions regarding the effects of different antihypertensive classes. However, a greater effect of beta‐blockers on the relationship between HR and MCA‐PI is consistent with the greater relationship between HR and MCA‐PI at lower resting HRs, and with previous evidence for a detrimental effect of beta‐blockers on cerebral pulsatility.This is an observational study and therefore does not confirm that there is a causative relationship between HR, cerebral pulsatility, resulting SVD, and subsequent clinical harms, which could only be proven by randomized controlled trials that increase HR. However, by demonstrating a direct, within‐individual, beat‐to‐beat relationship between spontaneous changes in HR or BP with changes in cerebral pulsatility, we can provide stronger support for this postulated mechanism than is possible through cross‐sectional epidemiology. However, interventional studies are required to determine whether there is a causative relationship between low HR, SVD, and clinical outcomes in patients at an increased risk of vascular dementia due to severe SVD; to test whether interventions to alter HR improve cerebral pulstatility in this population; and to pursue randomized trials of heart‐rate increases in patients at an increased risk of vascular dementia.Our study identifies that in patients with a recent TIA or minor stroke changes in HR are associated with concurrent changes in cerebral pulsatility, with a low HR being a potential key determinant of increased cerebral arterial pulsatility. This association is particularly strong in older patients with lower mean HRs and with severe SVD, likely inducing lower end‐diastolic BP and resulting in low cerebral perfusion between heart beats. Cerebral pulsatility and low end‐diastolic cerebral blood flow are strongly, and potentially causally, associated with cerebral SVD, the most prevalent cause of significant neurological disability, causing both stroke and dementia. As such, bradycardia may explain the less beneficial effects of beta‐blockers on cerebrovascular outcomes, and represents a new potential treatment target for the prevention of stroke and vascular cognitive impairment. Further research is required to test whether this mechanism is evident in non‐stroke patients, whether randomized controlled trials of interventions increasing HR induce changes in cerebral pulsatility, and whether this translates into a reduction in SVD, stroke, and vascular cognitive impairment, without an excessive increase in cardiac morbidity.A.W. and P.M.R. contributed to the conception and design of the study; A.W., K.W., L.L., and K.W. contributed to the acquisition and analysis of data; A.W. and P.M.R. contributed to drafting the text and preparing the figures.There are no conflicts of interest.


The pulse wave attenuation was measured under different ranges of induced intraocular pressure (IOPi), as a function of distance along the vessel (VDist). Intracranial pressure (ICP) was measured using lumbar puncture. A linear mixed-effects model was used to estimate the correlations between the Yeo-Johnson transformed harmonic regression wave amplitude (HRWa-YJt) with the predictors . A comparison of the model coefficients was done by calculating the weighted Beta (βx) coefficients.Twenty-one subjects were examined using modified photoplethysmography with simultaneous ophthalmodynamometry. A harmonic regression model was fitted to each pixel in the time-series, and used to quantify the retinal vascular pulse wave parameters including the harmonic regression wave amplitude  = 3.656) compared to the retinal arteries , p<0.0001. In contrast, the ICPh group demonstrated a reduction in the median venous HRWa  and an elevation in the median arterial HRWa , p<0.0001. Interactions of the pulsation amplitude with ICP showed a significant disordinal interaction and the loss of a main effect of the Fourier sine coefficient (bn1) in the ICPh group, suggesting that this coefficient reflects the retinal vascular response to ICP wave. The linear mixed-effects model (LME) showed the decay in the venous (HRWa-YJt) was almost twice that in the retinal arteries . The overall interaction models had a total explanatory power of  38.7%, and 42% of which the fixed effects explained 8.8%, and 5.8% of the variance  for the venous and arterial models respectively. A comparison of the damping effect of VDist and ICP showed that ICP had less influence on pulse decay than distance in the retinal arteries .The median HRWh group showed high retinal arterial and low venous pulsation amplitudes. Interactions between retinal vascular pulsation amplitude and ICP suggest that the Fourier sine coefficient bn1 reflects the retinal vascular response to the ICP wave. Although a matrix of regression lines showed high linear characteristics, the low model explanatory power precludes its use as a predictor of ICP. These results may guide future predictive modelling in non-invasive estimation of ICP using modified photoplethysmography.The retinal vascular pulsation characteristics in the ICP Linear mixed effect model goodness fit statistics were assessed using conditional R2, which describes the proportion of variance explained by all factors in the model including the predictors, ICP, Vdist and IOPi and random factors , whereas marginal R2 describes the proportion of variance explained by the predictors ICP, Vdist, and IOPi alone [Interaction plots were created to determine the Fourier coefficients influenced by increased ICP. The regression equations consisted of a five-level hierarchical linear mixed-effects model, with and without interaction effects was used to analyze the correlations of both the HRWPi alone . Beta con group the median was 18.50 cm water , the corresponding values in the ICPh group were 31cm water .The age of the population demonstrated a bimodal distribution with a mean of 30 years (range 17–47 years). There were 20 (95.2%) females and 1 (4.8%) male. Whereas in the ICPa was higher in the ICPn group  compared to the ICPh group , this was in contrast to the arterial pulsation amplitude where the median arterial HRWa was higher in the ICPh group  compared to the ICPn group . Between (ICPh and ICPn) and within (artery and vein) group differences in the median pulsation amplitudes achieved statistical significance (p<0.0001) for all, except the venous an1 coefficient between groups and the bn1,2 within in the ICPh group (h group (t) was undertaken to normalize the HRWa and the Fourier coefficients. As in the non-transformed Fourier terms, statistical significance in the differences between the mean HRWa was sustained between the venous (1.502 and 1.368) and arterial (1.435 and 1.466)(p<0.001) of the ICPn and ICPh groups respectively. Between-group differences were statistically significant in all (p<0.001) except the arterial an2 coefficient. Both within and between-group heterogeneity of the variances was demonstrated using the Levene test (p<0.0001) for the transformed and non-transformed Fourier terms.The median venous HRWPh group . Therefo measured in millimeters (mm) from the center of the optic disc, intracranial pressure (ICP) measured in centimeters water (cm water) and induced intraocular pressure (IOPi) measured in millimeters mercury (mmHg). There was a decay in the venous Yeo-Johnson transformed HRWa with both predictors VDist and ICP. The slope of regression line correlating the HRWa with VDist was -0.071±0.002  whereas that correlating with ICP was -0.0059±0.0004 . There was amplification of the HRWa as indicated by a positive slope of regression with IOPi, was 0.0051±0.00006 . The corresponding values for the retinal arterial system were -0.028±0.0021, -0.0031±0.0004 and 0.0071±0.000065  respectively  and with increasing intracranial pressure (ICP). Amplification of the HRWa with an increase in the induced intraocular pressure (IOPi) is noted.Correlations between the predictors of the hierarchical multivariate linear regression were undertaken in the YJa-YJtV, and arterial HRWa-YJtA can be derived:The equations of the regression lines for both the venous HRWDist and ICP indicate that decay in retinal venous pulsation amplitude in response to these predictors and a positive correlation with IOPi. From Eqs Where the coefficients of all equations were highly statistically significant (p<0.00001). For both retinal vascular systems, the negative coefficients of Va-YJt and Fourier coefficients, which are the cosine (an) and sine (bn)) and the independent variable on the x-axis i.e. vessel type (artery and vein), also called the main effect. This relationship is evaluated under different ICP levels grouped into two factor levels . It is worth considering the specific terminology used when describing interaction plots, these pertain to two observations reported from these plots. The first if there is a main effect, this is present when the line connecting the mean pulsation amplitudes between two different vessel types is sloped, which indicates the difference in the mean pulsation amplitude between is statistically significant. The steeper the slope of the line, the greater the magnitude of the main effect. In contrast, a main effect is absent when the line connecting the mean pulsation amplitudes is horizontal and therefore parallel to the x-axis, in this state, there is no statistically significant difference in the mean pulsation amplitude between the artery and vein. The second observation is the presence of an interaction with the grouping factor (ICP), this may be disordinal when there is an intersection of the two lines connecting the means, or ordinal when the lines are non-parallel and non-intersecting [A graphical display of the interactions is demonstrated in rsecting .a pulsation amplitudes between the vessels. Also, there is disordinal (cross-over) interaction between the two ICP groups. Noted are a high mean arterial and low mean venous HRWa-YJt pulsation amplitude in the ICPh group and conversely for the ICPn group. The an1 showed no interaction between the ICP groups, however, there was a significant main effect. Based on a lack of interaction with ICP, the coefficient follows the effect of the IOP wave, and therefore the effects of IOPi on the retinal vessel wall. The an2 showed ordinal  interaction where between-group differences in the value of this coefficient existed only in the retinal veins (n1) coefficient show a strong interaction between ICP groups and the loss of main effects in the ICPh group as indicated by the parallel line joining the mean pulsation values to the x-axis. The sine (bn2) coefficient showed ordinal interaction with ICP but there was a loss of a main effect in the ICPh group. Based on these observations the bn1 and the second harmonic coefficients mirror the retinal vascular response to the ICP wave.From al veins . The inta-YJt, for the retinal veins . The overall interaction model predicting the HRWa-YJtV had a total explanatory power  of 38.7%, in which the fixed effects explained 8.8% of the variance . Within this model the effect of VDist and ICP were significant . Whereas that for IOPi was small , except the arterial IOPi (rows). Whereas the intercept of the regression lines are reduced with increased ICP, observed as a progressive reduction in venous pulsation, the converse occurs with raised IOPi. Following a diagonal of the trellis graph  of 42%, in which the fixed effects explained 5.8% of the variance . Within this model the effect of VDist and ICP were significant . Whereas that for IOPi was small and did not achieve statistical significance  in the vascular pulsation amplitudes precludes the use of the model as a predictor of ICP. However, the interpretive nature of the linear models allowed further analysis of the retinal vascular responses to a range of ICP values.a in the ICPh group . As described above, reduction in venous wall compliance as a result of venous distension accounts for this effect, the damping effect of ICP on the arterial wall is less than VDist , both structural differences of different vessel types may account for differences in pulsation decay rates.Differences between the retinal arterial and venous pulsation amplitude, patterns, and attenuation distance arise from unique properties of the pressure-flow wave, resistance, and vessel wall structural characteristics. Consequently, a range of reported prevalences of detectable retinal vascular pulsation is dependent on the measurement methodology. Clinically observable spontaneous retinal venous pulsations are reported in 67% to 98% of normal eyes , 58, 59,ions Eqs  it is noDist, ICP and IOPi In previous work, we quantified the decay in the retinal vascular pulse amplitude from a population of healthy subjects and reported that although the amplitude of the retinal venous pulse is higher it decays over a shorter distance compared to that of the arterial . DiffereOPi Figs  and 4 ari and ICP influence the mural tension. The retinal veins are more susceptible than arteries to changes in IOPi and ICP due to the thinner walls, wider radius, lower intraluminal pressure, and hence lower resistance in the veins compared to the arteries. There are two mechanisms by which ICP and IOPi can influence wall tension and therefore the retinal vascular pulse:For pulsations to occur in a vessel segment, either a pressure gradient must exist or the transmural pressure must be reduced to overcome this mural tension. Both IOPi, therefore the central retinal venous pressure must exceed IOPi to prevent venous wall collapse [i rises, transmural pressure decreases, resulting in an increase in vessel wall compliance through lowering wall tension. The vessel collapses partially or completely during a period of the cardiac cycle when the transmural pressure is between diastolic and systolic intra-luminal retinal vascular pressure (within the pulse pressure range). As systolic pressure exceeds the transmural pressure, the vessel re-fills, producing vascular pulsations. [i) influences the thicker-walled arteries after venous wall collapse occurs, which may explain the different IOPi ranges to induce pulsations in the retinal veins and arteries.Reduction in transmural pressure: The lower limit for retinal venous pressure is determined by the ocular perfusion pressure, which is the difference between mean arterial pressure and IOPcollapse . The lowcollapse , 83. As sations. , 84. Whei above central retinal arterial diastolic pressure as hypothesized with pulsations of the central retinal artery occurring due to ophthalmodynamometry [Elevated IOPamometry , 83. Togamometry .Augmentation of the vascular pressure wave through wave reflections and possibly widening of the retinal vascular pulse pressure. Although this mechanism has not been demonstrated in the retinal vessels, wave reflections are ubiquitous throughout the circulation, particularly at sites of higher input impedance. Impedance is a complex value frequency domain parameter with both magnitude and phase, it indicates alterations in compliance, resistance, and inertance. Mismatching vascular impedances reduces the pulse transmission efficiency for the propagating pulse towards the venous side of the circulation, consequently wave reflections arise, which augment the pressure wave amplitude and reduce flow due to phase differences , 87, 88.Reduction in retinal venous compliance: The effect of raised ICP on the retinal circulation is to increase resistance in the venous circulation  combinedi have different influences on the retinal vascular pulse, primarily through the venous side of the circulation due to the thinner wall, lower resistance, and higher compliance.We hypothesize these mechanisms could explain the changes with the pulsation amplitudes in Figs n1) and sine coefficient (bn1) mirror the effects of IOPi, and the ICP wave, respectfully. Other investigators reported on the spectral properties of the latter two pressure waves, Evans et al. analyzed the IOP pulse’s higher spectral components up to the fourth harmonic and Bozic et al. compared the spectral components of the IOP pulse wave up to the fifth harmonic, however, the hemodynamic significance of the Fourier analysis remains obscure [We did not evaluate the spectral properties of the IOP nor the ICP wave in our study. However, the interaction plots , which c obscure –91. Taki obscure . None of obscure . During  obscure . They po obscure –97. Non-In summary, the retinal vascular changes are a consequence of a complex interaction between the retinal hemodynamics , IOP, ICP, and systemic blood pressure, in addition to biomechanical properties of the lamina cribrosa , 54, 98.Limitations of our study include the limited number of subjects and the lack of simultaneous blood pressure measurements, which may have assisted in the interpretation of the findings in the retinal arterial system.h group showed high retinal arterial and low venous pulsation amplitudes. Interactions between retinal vascular pulsation amplitude and ICP suggest that the Fourier sine coefficient bn1 reflects the retinal vascular response to the ICP wave. Although a matrix of regression lines showed high linear characteristics, the low model explanatory power precludes its use as a predictor of ICP. These results may guide future predictive modelling in non-invasive estimation of ICP using modified photoplethysmography.The retinal vascular pulsation characteristics in the ICPS1 Data(CSV)Click here for additional data file.


Even a small change in the pressure gradient between the venous system and the right atrium can have significant hemodynamic effects. Mean systemic filling pressure (MSFP) is the driving force of the venous system. As a result, MSFP has a significant effect on cardiac output. We aimed to test the hypothesis that the hemodynamic instability during induction of general anesthesia by intravenous propofol administration is caused by changes in MSFP.We prospectively collected data from 15 patients undergoing major surgery requiring invasive hemodynamic monitoring. Hemodynamic parameters, including MSFP, were measured before and after propofol administration and following intubation, using venous return curves at a no-flow state induced by a pneumatic tourniquet.p = 0.001). The pressure gradient for venous return  also decreased following propofol administration from 19 (8) to 12 (6) mmHg, p = 0.001. Central venous pressure did not change.A significant decrease in MSFP was observed in all study patients after propofol administration (median (IQR) pressure 17 (9) mmHg compared with 25 (7) before propofol administration, These results support the hypothesis that induction of anesthesia with propofol causes a marked reduction in MSFP. A possible mechanism of propofol-induced hypotension is reduction in preload due to a decrease in the venous vasomotor tone.The online version contains supplementary material available at 10.1186/s12871-022-01773-8. Preload and cardiac output (CO) are tightly regulated by the maintenance of a pressure gradient between the low-pressure venous system and the right atrium . Mean SyRA), divided by the venous resistance [VR), compensating for any increase in the MSFP-CVP gradient  [VR will increase the preload and contractility but with a smaller change in the VR, thus creating a new equilibrium of the system when VR equals CO again. Global cardiac efficiency (Eh) is another parameter based on the MSFP providing an estimate of cardiac performance [Approximately 70% of the blood volume is contained in the venous system, and compliance is about 30 times greater than in the arterial system, which allows the venous system to function as a reservoir . Accordisistance . Changessistance . Since Vrn; PVR) . On the rn; PVR) . This informance .Propofol is the most common intravenous agent used to induce general anesthesia. It is known to cause hypotension , 12, witOnly few studies evaluated propofol’s effects on the venous system during anesthesia induction or maintenance –21. HoweWe therefore aimed to characterize changes in hemodynamic parameters of the venous system during induction of general anesthesia by propofol, in order to better describe the underlying mechanism of propofol-induced hypotension. Specifically, we aimed to measure changes in MSFP and CVP and their effect on venous return and cardiac output.We conducted a prospective observational single-center study between January and October 2019. Ethical approval (0393–18 TLV) was granted by the institutional review board of the Tel-Aviv Sourasky medical center, Tel Aviv, Israel on the 23/07/2018. Written informed consent was obtained from all subjects prior to enrollment.The study enrolled patients 18 years or older, with American Association of Anesthesiologists (ASA) physical status score I-III, scheduled for major elective surgery that dictated the use of invasive hemodynamic monitoring including CVP  and invasive continuous arterial blood pressure monitoring.Patients with heart failure (New York Heart Association (NYHA) classification grade 3 or more), moderate to severe pulmonary hypertension, end-stage renal disease, or peripheral vascular disease were excluded. Patients appointed to surgeries involving major vessels such as vena cava, right atrium, etc.; cases involving hemodynamically compromised patients due to mass effect or pressure on major vessels and cases involving combined multidisciplinary teams  were also excluded.− 1 titrated to light sedation. The arterial and peripheral venous lines were inserted in the same arm, and all lines were connected to pressure transducers located close at the mid-axillary line, in level with the phlebostatic line. The CVP transducer was placed close to the fourth intercostal space. Patients were supine during the whole study protocol, and the hand with the arterial and venous cannulations was in level with the arterial and venous transducers.Prior to surgery, a radial artery cannulation, central venous line, and an antecubital fossa venous line were inserted under a continuous infusion of remifentanil at a starting dose of 0.05 mcg·min·kgApproximately half the cases required epidural anesthesia, which was conducted before the commencement of anesthesia. A test dose and/or a therapeutic dose of local anesthetics were injected only after the hemodynamic measurements were taken. None of the cases required peripheral nerve blocks.2) of 1. An induction dose of 2 mg/kg propofol bolus was administered, followed by a second MSFP measurement (post-induction) which was aimed to be measured when we assumed the propofol effect was maximal . Endotracheal intubation was facilitated by administration of 1 mcg/kg of fentanyl and 0.6 mg/kg of rocuronium. A third MSFP measurement (post-intubation) was performed 2 min after intubation. Ventilation parameters were unified during the study, including positive end expiratory pressure (PEEP) values of 5 mmHg, respiratory rate of 12 per minute and tidal volume calculated as 7ccXkg of ideal body weight.Remifentanil was discontinued immediately after lines insertion and before MSFP measurements. After patients regained full consciousness, a first MSFP measurement (pre-induction) was conducted. The patients were then pre-oxygenated using a fraction of inspired oxygen  arterial blood pressures, heart rate, CVP, peripheral venous pressure, CO, and MSFP recordings. All values were recorded from the monitor in real-time in our case report form (CRF).MSFP was measured using the Parm method, which was described elsewhere . A surgisys) was determined by the dividing the pressure gradient between the aortic blood pressure (PAO) and the right atrial pressure (PRA) by the venous return (VR). PAO, PRA, and VR were represented by MAP, CVP, and CO, respectively.Systemic vascular resistance (RVR) was calculated using the following equation, where PRA and VR are represented by CVP and CO, respectively:Resistance to venous return (Rh) was calculated using the following equation:Global cardiac efficiency . Categorical variables are reported as incidence and percentage. Statistical significance was tested using the Wilcoxon test, a non-parametric test designed to analyze paired or repeated measures, when assumptions for normal distribution are not met. A Eighteen patients were enrolled; three were excluded from the study due to surgery cancellation or delay. Of the remaining 15, 6 were females, with median age of 66 (range 40–76) years. Demographic and baseline characteristics are detailed in Table P = 0.001. MSFP significantly increased after intubation (25 (9) mmHg, P = 0.003 compared to post-induction values). Of note, CVP values did not show a clinically important decrease before and after induction, with a mean (SD), decrease of 0.4 (3.5) mmHg. PVR decreased from a median baseline of 19 (8) to 12 (6) mmHg after induction (P = 0.001) and increased to 19 (7) after intubation; .The measurements recorded before induction with propofol, following induction, and 2 min after intubation are presented in Table P = 0.002. Rsys, RVR and Eh did not change significantly after propofol administration. The effects of propofol administration on MSFP, CVP, PVR, CO and RVR are presented in Fig. CO decreased from 6.1 (1.6) L/min before induction to 4.8 (2.3) L/min after induction; An estimation of the venous return curves using CO, CVP, and MSFP values is presented in Fig. According to medical records, 33% of the patients had hypertension and 47% were treated with antihypertensive drugs, but only 20% of them took antihypertensive medication in the 24 h prior to surgery . We conducted statistical analysis comparing the group with a medical record of hypertensive drugs use with the group without such record. We had then conducted a sub-analysis of our study population again, comparing the three patients who used these drugs 24 hours before surgery with those who did not use antihypertensive drugs in those 24 hours. We analyzed all the main hemodynamic parameters using the non-parametric Mann Whitney test and found no significant statistical difference between these groups, the analysis is presented in Table 1 in the VR) and the CO. In contrast, CVP did not decrease significantly during induction, as seen in Fig. Our results show that induction of anesthesia using propofol causes a significant reduction in MSFP. Similar effects were evident on the pressure gradient of venous return , the observed reduction of CO in our study is probably the reason for the nonsignificant change in CVP. When a low EVR duo to propofol bolus administration. However, according to our observations, RVR trended towards a decrease (from 3.1 p = 0.069)). Since RVR is close to significance, we can only assume that a larger sample size could show a significant reduction. Post-hoc power justification of our study found it to be well powered to detect changes in MSFP. However, it may not be powered to detect changes in RVR.We would have expected a reduction in Rh) is a dimensionless ratio (0 < Eh < 1) and equals the difference between MSFP and PRA divided by MSFP. Eh may be used as an estimate of inotropic function. For example, Eh approaches zero when cardiac output seizes and PRA equals MSFP. The change we observed in cardiac efficiency was mostly proportional to the change in MSFP, while the change in CO originated from two contradicting mechanisms: reduced PVR (decreasing VR and CO) and reduced RVR (increasing VR and CO).Following propofol induction, cardiac output was significantly reduced, and cardiac efficiency demonstrated a trend of reduction, but it was not statistically significant. Global cardiac efficiency (ERA, MSFP will rise to maintain the driving pressure, but the rise in RVR will decrease the VR and, consequently, decrease the stroke volume. CO remained stable due to the increase in HR. The increase in HR may be compensatory to the decrease in preload, response to the stress of intubation, or a combination of both.Intubation resulted in increase in MSFP, MAP and HR, but there was no change in CO. Our interpretation of those results is that as positive pressure ventilation increases PThe decrease in MAP after propofol administration for induction of anesthesia has been previously demonstrated , 15. OthAlthough the negative hemodynamic effects of propofol are well known, recent studies, including the current one, endeavoured to evaluate potential mechanisms involving the venous system. MSFP is a genuine indicator of the venous system; however, due to its infrequent use in clinical practice, the potential changes in response to hypnotic drugs such as propofol have been tested on humans scarcely. While analysing our results together with the study by de Wit and colleagues , we can As the venous system, and the stressed volume in particular, constitute a key component in post-induction hypotension, propofol administration should be carried out carefully in hypovolaemic patients. Furthermore, the management of hemodynamic deterioration after propofol administration in a fluid-responsive patient may benefit from the use of vasoactive drugs alongside fluid loading in order to increase the stressed volume and the MSFP.This was a pilot study, and as such, we chose to adhere to a strict protocol of induction in relatively healthy and hemodynamically patients. Aside of two patients who received a 200 ml fluid bolus prior to induction, the drug administration was identical in all patients. We were therefore able to isolate the effect of propofol by evaluating the pre-induction and post-induction measurements with no additional influences, such as other hypnotic or vasoactive drugs or positive-pressure ventilation. Our results are therefore of limited generalizability to other patient populations or clinical situations, such as patients with active cardiovascular disease or hemodynamic instability. It is plausible that propofol administration has a more profound effect on patients with initially lower MSFP values.The average age of the study population was correlated with high prevalence of hypertension, and antihypertensive medications, including BB, CCB, ARBs, thiazides and ACE inhibitors can influence CO in several mechanisms. Since our study focused on the CO change from baseline values rather than the absolute value, we assumed that the use of hypertensive drugs will not influence our results significantly. Nevertheless, statistical analysis conducted for this sub-group showed no statistically significant difference in their hemodynamic parameters.Another possible limitation is the difficulty in evaluating the influence of propofol on cardiac contractility. Since it was not feasible to maintain a constant VR throughout the experiment, we cannot comment on the precise effects of propofol administration on cardiac contractility.Due to practical limitations, our attempt to reduce patient inconvenience, and the short time interval between induction and tracheal intubation, we only acquired a single MSFP measurement in each time period. Nonetheless, repeated measurements of MSFP in other studies showed no significant difference, with a coefficient variance for a single measurement of 5% .Future studies are necessary, and should include larger cohorts, preferably also evaluating hemodynamically unstable patients. Additionally, obtaining more MSFP measurements before and after inotropes administration may shed more light on mechanisms affecting MSFP.Induction of anesthesia using a bolus dose of propofol causes hemodynamic deterioration, evidenced by a decrease in MAP that is largely mediated by reduction in MSFP and its effects on the pressure gradient of venous return, which reflects its main effect on the venous system. The use of propofol bolus during induction of anesthesia in hemodynamically unstable patient should be avoided if possible.Additional file 1: Table 1. Sub-analysis for patients receiving antihypertensive drugs


Furthermore, we evaluated the factors that determine access hand rSO2 without stenosis after PTA. Brachial arterial FV increased after PTA (p < 0.001), and carotid FV decreased (p = 0.008). Access hand rSO2 significantly decreased after PTA (p < 0.001), but cerebral rSO2 did not significantly change (p = 0.317). In multivariable linear regression analysis of factors associated with access hand rSO2, serum creatinine (standardized coefficient: 0.296) and hemoglobin (standardized coefficient: 0.249) were extracted as independent factors for access hand rSO2. In conclusion, a decrease in access hand oxygenation and maintenance of cerebral oxygenation were observed throughout PTA. To maintain access hand oxygenation, it is important to adequately manage Hb level and maintain muscle mass, in addition to having an AVF with appropriate blood flow.In hemodialysis (HD) patients with arteriovenous fistula (AVF), changes in systemic or peripheral tissue circulation occur non-physiologically via the presence of AVF; however, associations between blood flow and tissue oxygenation in the brain and access hand are uncertain. In this study, 85 HD patients with AVF were included and evaluated for changes in flow volume (FV) and regional oxygen saturation (rSO However, AVF may present some problems. AVF veins may become stenosed and occluded frequently due to the burden of the pressure from the artery or the effects of vascular puncture for HD therapy. In general, Doppler ultrasonography could be used as a device in the surveillance of AVF for assessing vascular stenosis or function including AVF blood flow or morphology1. When an AVF has stenosis, percutaneous transluminal angioplasty (PTA) might be performed, and appropriate PTA allows HD patients to maintain AVF patency and adequate blood flow during HD1. Mature AVF, with a blood flow of approximately 500 mL/min and non-physiological circulation2, may also affect systemic hemodynamics, including cardiac output3 or peripheral tissue circulation4. In particular, steal syndrome, which can lead to severe ischemia, should be paid attention to in clinical setting of HD facilities.An arteriovenous fistula (AVF) is one of the main options for vascular access in hemodialysis (HD) therapy. An AVF is usually created by anastomosing the arterial and venous vessels in the upper extremity, potentially reducing the risk of thrombosis and infection, compared to arteriovenous grafts or long-term indwelling catheters. Therefore, AVF creation is recommended as the first choice of HD access in Japan2). This rSO2 measurement could enable non-invasive and real-time monitoring of tissue oxygenation, and has been utilized in various fields, including perioperative patients and newborns7. In HD patients, cerebral rSO2 was reported to be lower than that in healthy controls or patients with chronic kidney disease without dialysis therapy9, and access hand rSO2 was lower than that in healthy controls10. However, tissue oxygen dynamics in HD patients still need to be clarified and especially, how the presence of an AVF can affect tissue oxygenation via non-physiological circulation requires further study. Angiostomy between the artery and vein or PTA for the AVF might have a strong impact on blood flow or systemic circulation. However, thus far, reports about changes in tissue oxygenation, including in the brain and access hand, are limited. Therefore, in this study, we aimed to investigate the changes in rSO2 values in the brain and access hand before and after PTA, which caused changes in vascular resistance and blood flow at the AVF. Furthermore, we evaluated the factors that determined access hand rSO2 without stenosis after PTA.Recently, near-infrared spectroscopy (NIRS) has been used to measure regional oxygen saturation , hemoglobin (Hb) level, serum albumin concentration, blood urea nitrogen, and serum creatinine, as well as negative correlations with age and the use of antiplatelet agents. In the multivariable linear regression analysis, serum creatinine (standardized coefficient: 0.296) and Hb levels (standardized coefficient: 0.249) were extracted as independently associated factors for access hand rSO2 after PTA  measurement is one of the tissue oxygenation evaluations and its decrease in access hand was associated with the development of the steal syndrome or access-induced distal ischemia12. Skin perfusion pressure (SPP) at access hand was possible to detect ischemic steal syndrome because of the significant decreases in the amount or rate of changes in SPP after AVF creation13. In this study, there were significant decreases in SpO2 after PTA compared to that before; however, the differences were small. In addition, there was no equipment for measuring SPP in this study; therefore, we cannot directly comment on the usefulness of SPP measurement for evaluating changes in access hand circulation before and after PTA. However, access hand rSO2 measurement was also reported as a marker of tissue oxygenation, including the thenar muscle, and reflected the regional hemodynamic changes16. In addition, this instrument has the advantage of being able to measure the rSO2 up to four other tissues simultaneously. In this study, we aimed to investigate the influence of PTA procedure with changes in rSO2 values in the brain and access hand simultaneously; therefore, we performed this study using INVOS 5100c oxygen saturation monitor.Previous reports confirmed the usefulness of several methods for evaluating access hand circulation in patients undergoing HD. Saturation of percutaneous oxygen  in this study. Such differences in FV changes might affect changes in cerebral rSO2. In addition, changes in carotid blood flow before and after PTA were significantly smaller than those in brachial artery blood flow in this study. Polinder-Bos et al. reported that cerebral rSO2 did not significantly change during HD, despite decreasing cerebral blood flow17. Several other studies also reported that cerebral rSO2 did not change during HD, although patients received ultrafiltration and their blood volume was concentrated19. Additionally, in some reports comparing rSO2 between the brain and other organs under various conditions, changes in cerebral rSO2 were relatively small compared to oxygenation in other organs21. Thus, cerebral oxygenation would be maintained as the mechanism of brain autoregulation, especially if the patients’ BP remained22.In this study, PTA for AVF with stenosis caused a decrease in access hand rSO2 was investigated in the brain, liver and muscle25. Low tissue oxygenation may have negative influence on HD patients. Anemic conditions, overhydrated status, and hypotension could induce organ hypoxia in the brain or intra-abdominal organs28. Furthermore, cerebral oxygenation impairment could be related to cognitive impairment30, and access hand rSO2 was reportedly associated with grip strength31. Therefore, tissue hypoxia may affect the functional performance and prognosis of each organ. In this study, we analyzed the factors associated with access hand rSO2 after PTA, which could be an appropriate condition without stenosis as an AVF, and Hb and serum Cr levels were extracted as independently associated factors for access hand rSO2. Hb plays an important role as a transporter for carrying oxygen to systemic tissues, and tissue oxygenation is associated with Hb level. The maintenance of Hb level could contribute to maintaining access hand oxygenation, similar to the positive correlation between Hb levels and cerebral or hepatic rSO2 values25. Serum Cr is generally an indicator of kidney function and is also a metabolic product derived from the muscle. In patients with kidney dysfunction, such as HD patients, Cr would accumulate in the serum because of impaired Cr excretion from the kidney. Therefore, serum Cr levels could depend on individual muscle mass, and the serum Cr or Cr index would reportedly reflect muscle mass or sarcopenia, which involved lessened muscle mass or weakened muscle strength33. Furthermore, when patients have high muscle mass, blood volume into the muscle is high34.In HD patients at their forearm, an increase of muscle mass by hand exercise was associated with an increase in FV35, and less circulation into the muscle was related to low oxygenation36. Therefore, it is important to maintain muscle mass from the viewpoint of keeping peripheral circulation and tissue oxygenation, and it would be consistent that access hand rSO2 had a positive association with serum Cr in this study. However, we did not measure muscle mass at the AVF limb in patients included in this study; therefore, further studies are needed to confirm the association between serum Cr levels and muscle mass in patients undergoing HD.Tissue oxygenation evaluation was recently performed in patients undergoing HD, and rSO2 in multivariable linear regression analysis. Access hand (thenar muscle) oxygenation would be influenced by the oxygen delivery throughout regional blood flow and oxygen demand at the muscle mass. Furthermore, this study used FV at the brachial artery as a substitute for FV at the AVF limb, which may not necessarily reflect hand circulation, including that of the thenar muscle, and we could not measure the direct blood flow into the thenar muscle. Therefore, parameters with oxygen delivery and demand at access hand were missing as a confounding factor associated with access hand oxygenation in multivariable linear regression analysis in this study. Under the addition of these parameters to this analysis, the results of the significant associations between access hand rSO2 and each Hb and serum Cr level might change. However, numerous studies reported the thenar oxygenation using NIRS to be a valid and reliable tool in clinical settings39; therefore, access hand rSO2 evaluated in this study would reflect the actual thenar muscle oxygenation. Third, this study evaluated AVF using only the radial artery which was used for angiostomy in many HD patients. However, when the AVF is operated using a brachial artery or synthetic graft and when patients had anatomical malformations of the artery at the AVF limb, such as brachial artery bifurcation centrally, other results might be obtained regarding factors affecting access hand rSO2 or changes in cerebral and hand oxygenation. Finally, we could not evaluate cardiac function in the study participants. The presence of AVF would lead to non-physiological hemodynamic effects on cardiac outputs41; therefore, cardiac function or outputs might have changed before and after PTA. Thus, to clarify the factors affecting hand oxygenation and changes in cerebral oxygenation influenced by PTA procedure, further studies are needed for the future.This study had several limitations. First, the sample size was relatively small. Second, in this study, Hb and serum Cr levels were significantly associated with access hand rSO2 was positively associated with Hb levels and serum Cr in patients undergoing HD. To maintain access hand oxygenation, it is important to adequately manage Hb level and maintain muscle mass, in addition to having an AVF with appropriate blood flow.In conclusion, a decrease in access hand oxygenation and maintenance of cerebral oxygenation were observed throughout PTA, and access hand rSOIn this study, 85 HD patients (59 men and 26 women) who needed to perform PTA of their AVF were recruited. The causes of chronic renal failure were diabetes mellitus (50 patients), nephrosclerosis (10 patients), chronic glomerulonephritis (12 patients), and others (13 patients). Each patient received maintenance HD two or three times per week, and their HD time per session was three or four hours. AVF were anastomosed using a radial artery. We excluded patients with an AVF that was anastomosed using the ulnar artery or brachial artery and those with AVF that were anastomosed using synthetic grafts. Among the recruited patients, 60 patients had AVF on their left arm and 25 patients on their right arm. The patients’ general characteristics are summarized in Table 2 and brachial and common carotid artery blood FV with ipsilateral AVF before and after PTA. BP and heart rate were measured in the upper limb without an AVF because the AVF needed to be protected from strong pressurization. Before measurement, the patients were at rest in the supine position in the bed for at least 5 min. Blood flow was evaluated using Doppler ultrasound  with a linear probe (12.0 MHz). One examiner measured blood flow at the vessel site with less meandering and turbulence, three times before and after PTA respectively, and used their average value as the results.We measured blood pressure (BP), heart rate, SpOPatients’ baseline characteristics and clinical and laboratory data were collected from their medical charts. BMI was defined using dry weight. Calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, β-blockers and α-blockers were defined as antihypertensive drugs.2 in the brain and access hand to observe the difference in each rSO2 before and after PTA and evaluated related factors to assess hand rSO2. Measured rSO2, which is a marker of tissue oxygenation, was monitored using by INVOS 5100c saturation monitor . The principles of measurement using this monitor have been previously reported8. Briefly, this instrument uses a light-emitting diode that transmits near-infrared light at two wavelengths (735 and 810 nm), and two silicon photodiodes that act as light detectors to measure oxygenated and deoxygenated hemoglobin (Hb) levels. The ratio of the signal strengths of oxygenated and total Hb (oxygenated + deoxygenated Hb) was calculated, and the corresponding percentage was recorded as a single numerical value that represented the rSO2 level43. Furthermore, the light paths leading from the emitter to the different detectors share a common part: the 30-mm detector assesses superficial tissue, whereas the 40-mm detector assesses deep tissue. By analyzing the differential signals collected by the two detectors, the rSO2 values in the deep tissue were obtained45. The rSO2 measurement sensor was attached to the patient’s forehead , and the thenar muscle of the access hand (access hand rSO2). Thereafter, each rSO2 measurement was performed at rest in the supine position in the bed for at least 5 min, and mean values were defined as the measured rSO2 values. The attachment parts of the sensor and monitoring time of rSO2 were determined based on previous reports27. Measured rSO2 values were shown as results before and after PTA. The rSO2 values after PTA, which were evaluated in the state where the AVF was without stenosis, were used to evaluate the factors related to access hand rSO2.We measured the rSO2 and FV before and after PTA. Correlation between clinical parameters and access hand rSO2 after PTA were evaluated using Pearson’s correlation or Spearman’s rank correlation for data with normal and skewed distribution, respectively. Multivariate linear regression analysis was performed to identify the independent factors of access hand rSO2 after PTA. All analyses were performed using IBM SPSS Statistics for Windows . Statistical significance was set at p < 0.05.Data are expressed as the mean ± standard deviation or median and interquartile range. To determine whether the data showed a normal distribution, we performed the Shapiro–Wilk test to evaluate each variable. The paired Student’s t-test was used for values showing normal distribution, and the Wilcoxon signed-rank test was used for values that did not show normal distribution in the comparisons of clinical parameters including various rSOAll participants provided written informed consent to participate in this study. This study was approved by the institutional ethics committee of Hakuyukai Medical Corporation  and was performed in accordance with the provisions of the Declaration of Helsinki (as revised in Tokyo in 2004).


Cannabinoids may be useful to treat pain, epilepsy and spasticity, although they may bear an increased risk of cardiovascular events. This study aims to evaluate the cardiovascular safety of nabiximols, a cannabis-based drug, in patients with spasticity following stroke, thus presenting an increased cardiovascular risk.This is an ancillary study stemming from the SativexStroke trial: a randomized double-blind, placebo-controlled, crossover study aimed at assessing the effect of nabiximols on post-stroke spasticity. Patients were treated with nabiximols oromucosal spray or placebo and assessed before and after two phases of 1-month duration each. Only the phase with the active treatment was considered for each patient who completed the study. The average values of blood pressure  and heart rate from the first 5 days of the phase (lowest nabiximols dosage) were compared to the average values recorded during the last 5 days at the end of the phase (highest nabiximols dosage). Baseline comparisons between gender, stroke type and affected side and correlation between age and blood pressure and heart rate were performed. The study was registered with the EudraCT number 2016-001034-10.Thirty-four patients completed the study and were included in the analysis. Thirty-one were taking antihypertensive drugs and, among these, 12 were taking beta-blockers. During the study, no arrhythmic events were recorded, blood pressure and heart rate did not show pathological fluctuations, and no cardiovascular or cerebrovascular events occurred. At baseline blood pressure and heart rate were comparable concerning gender, stroke type and affected side. A significant direct correlation emerged between differential blood pressure and age and an inverse correlation between diastolic blood pressure and age. No correlation emerged between systolic blood pressure or heart rate and age. Blood pressure and heart rate did not change during nabiximols treatment compared to the baseline condition.This ancillary study adds evidence that, in patients who already underwent a cerebrovascular accident, nabiximols does not determine significant blood pressure and heart rate variation or cardiovascular complications. These data support the cardiovascular safety of nabiximols, encouraging more extensive studies involving cannabinoids characterized by slow absorption rates. Cannabis sativa. Cannabinoids are a group of substances found in the cannabis plant. The main cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the substance that is primarily responsible for the effects of marijuana on a person’s mental state  is the fastest method of intoxication, the availability of THC is predictable  in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The trial has been registered on the EudraCT platform with number 2016-001034-10.This study lasted 10 weeks and consisted into two phases: phase 1 and 2, both of them lasting 4 weeks. Phase 1 and 2 were separated by a 2-weeks wash-out interval. During each phase, patients had been taking nabiximols and then placebo or vice-versa in a crossover design following 1:1 randomization.Each patient was examined 4 times during 10 weeks: before (T0) and after (T1) phase 1, as well as before (T2) and after (T3) phase 2.Adult stroke survivors were recruited according to the following inclusion criteria: (1) male or female patients of at least 18 years of age; (2) spasticity secondary to stroke that occurred at least 3 months earlier; (3) CHA2DS2VASc score < 7 assessed by the cardiologist and reflecting acceptable cardiovascular risk; (4) spasticity rated between 1 and 3 on the Modified Ashworth Scale at the level of at least one of the following muscle groups: wrist flexors, elbow flexors, knee extensors, foot plantar flexors; (5) ability  to comply with the study requirements correctly and to follow the study procedure and restrictions.Exclusion criteria were: (1) presence of concomitant parkinsonism; (2) significant peripheral nervous system pathology detectable on clinical basis; (3) current smokers; (4) contraindication to treatment with nabiximols; (5) alcohol or drug abuse, including current consumption of cannabis herb or other cannabinoid-based drugs within 30 days prior to study entry; (6) treatment with botulinum toxin injection in the last 4 months; (7) clinically significant impaired renal function or impaired hepatic function at baseline, (8) females of child bearing potential, pregnant or lactating and male patients whose partner is of child bearing potential who are not willing to use effective contraception.Patients who gave informed consent to participate underwent a preliminary screening visit to ensure that they fulfilled the study selection criteria, followed by a cardiological evaluation (including ECG and echocardiogram) to assess cardiovascular risk.At the beginning of each phase (T0 and T2), patients were provided with a form to daily record heart rate, blood pressure (systolic/diastolic) and adverse events. Outcome measures were collected and instructions on how to take the oromucosal spray were provided, along with a schedule to gradual increase daily sprays to reach the highest tolerable dose up to a maximum of 12 sprays/day in a 14-days period and then maintain such daily dose until the end of each phase (T1 and T3) .Patients were required to continue all concomitant medications throughout the study.The main and secondary outcomes have been reported in the first report .To the aim of this ancillary study, we considered the daily measurement of blood pressure and heart rate as reported by the patients in the provided form. For each patient who completed the study, we considered only the phase with the active treatment. The average values of blood pressure and heart rate from the first 5 days of the phase  were considered baseline T0 values. The average values recorded during the last 5 days at the end of the phase (while taking the highest number of sprays) were considered T1 values. Regarding heart rate, we consider the self-reported average number of beats per minute, regardless of the presence of an arrhythmia.Cardiovascular parameters  are reported as mean ± standard deviation. Sprays number is reported as median (range).p < 0.05.Baseline comparisons where performed using Mann-Whitney U test. Baseline correlations between age and cardiovascular parameters and between the number of sprays taken at T1 and T0-T1 difference of blood pressure and heart rate were performed using Spearman rank test. Cardiovascular parameter comparisons between baseline condition and during nabiximols treatment were performed using Wilcoxon signed rank test. This is a pilot study and no preliminary data about cardiovascular parameter variation during nabiximols treatment were available, so power analysis was not performed. For all tests significance level was set at Only the 34 subjects who completed nabiximols cycles where included in the study .Patients taking anti-hypertensive drugs were 31, among these those taking beta-blockers were 12.U = 77, p = 0.1), systolic , differential  and heart rate .Comparing the 24 male and 10 female patients, no difference emerged for baseline diastolic , systolic , differential  and heart rate .Comparing the 21 patients who had an ischemic stroke and the 13 who had a hemorrhagic stroke, no difference emerged for baseline diastolic , systolic , differential  and heart rate   .p = 0.014), while systolic pressure did not . A significant direct correlation emerged between age and differential blood pressure  (p = 0.7).Diastolic blood pressure inversely correlated with age  . Age andOn average, at T1 patients were taking 9 nabiximols sprays (range 1–12), corresponding to 24.3mg of THC and 22.5mg of CBD.Z = −1.2, p = 0.2), systolic  and differential  blood pressure as well as heart rate  before and during nabiximols treatment (p = 0.4), systolic  and differential  blood pressure, nor variation of heart rate .No significant changes of diastolic  in patients with post-stroke spasticity. This drug has been widely studied in patients with multiple sclerosis , 3 and aOnly one patient complained of tachycardia during phase 2, when on active treatment, and decided to exit the study . As regards the differential pressure, our population behaves like the general population since we have observed that the differential blood pressure increases with age.No cardiovascular treatment-emergent adverse drug effects emerged during nabiximols treatment, namely no significant fluctuation of blood pressure and heart rate, nor ischemic or hemorrhagic events occurred. During nabiximols treatment (T1), self-assessed blood pressure and heart rate did not change compared to the baseline condition. No patients showed significant acceleration or decrease in heart rate or change in rhythm and none required an additional ECG or cardiological evaluation during the study.The patients reached a very variable number of sprays at T1, depending on the individual highest tolerated dose. To further investigate a possible dose-related effect of nabiximols on blood pressure and heart rate we sought a correlation between the number of sprays at T1 and cardiovascular parameter variation between T0 and T1, however, the lack of correlation confirms that, nabiximols did not affect blood pressure and heart rate in our population over 4 weeks. This may be also ascribed to the fact that oromuscosal administration allows different pharmacokinetics with fewer fluctuations in blood pressure and heart rate. Unfortunately, however, the expected improvement in spasticity in stroke patients was not found, as previously published . This adThe main limitation of the present study is the low number of participants since it was single-center. Another limitation of the study is the fact that, as regards the cardiovascular effects of nabiximols, we considered baseline (T0) values those obtained at the beginning of the active phase, while patients had already started nabiximols, although at a very low dosage. If nabiximols effect on cardiovascular parameters was not dose-dependent and effective even while taking a small number of sprays and consequently before nabiximols could reach plasma steady state, such effect cannot be appreciated by our protocol. Further studies are needed to clarify this aspect. Blood pressure and heart rate were self-assessed by patients. This might have introduced inaccuracies related to a systematic or occasional error in parameter sampling. We tried to mitigate possible measurement errors by analyzing the average values across 5 consecutive days, although this approach, along with the requirement to measure parameters only once per day, greatly reduced the temporal resolution of outcome assessments. It is therefore obvious that short-term (minutes and hours) fluctuations of blood pressure and heart rate could not have been appreciated in this study.In conclusion, an interesting result of this pilot study is the good cardiovascular safety profile of nabiximols in patients with stroke. In these patients, the possible beneficial effect of cannabinoids, such as delaying atherosclerotic progression and inflammation, may deserve further investigation. Furthermore, because of the rapidly changing landscape of cannabis laws and marijuana use in western countries, there is a pressing need for refined policy, education of both clinicians and the public, and new research. Carefully designed, prospective, short- and long-term studies are needed to obtain conclusive data on the safety and efficacy of cannabinoid drugs.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Comitato Etico Regionale della Liguria. The patients/participants provided their written informed consent to participate in this study.LMa conceived and designed the study, collected data as principal investigator, performed statistical analyses, and drafted the manuscript. LP and LMo performed patients evaluation and collected data. GR performed the cardiological evaluation and revised the manuscript. AC, FF, IP, NB, and CT critically revised the work for important intellectual content. All authors approved the final version.


Secondary objectives include determining predictors of histologically severe CKD and risk factors for kidney biopsy complications.One of the challenges physicians face while evaluating patients with markedly reduced kidney function is distinguishing between acute kidney injury and chronic kidney disease (CKD). The coexistence of more than one disorder is well recognized as CKD is a major risk factor for acute kidney injury, from which the patient may not recover completely, leading to accelerated renal dysfunction.n = 109) had unknown baseline creatinine level and negative immunology screening result and were included in the study , nontreatable acute pathological findings , and postbiopsy complications . Patients’ demographics are summarized in Between April 1, 2017, and April 1, 2019, 363 patients were admitted and underwent native kidney biopsy; 30% . Acute interstitial nephritis was the most common finding, followed by immunoglobulin A nephropathy with crescents. Only 1 patient recovered kidney function after treatment (n = 25) required hemodialysis initiation during admission. Immunoglobulin A nephropathy and hypertensive nephrosclerosis were the most identified causes (P = 0.005). Other variables were similar between both groups . The decision to transfuse was influenced by several factors, including clinical evidence of active bleeding, substantial drop in hemoglobin level postbiopsy, and the absolute level of postprocedure hemoglobin concentration, rather than the size of the hematoma. Patients who developed complications had lower baseline hemoglobin than patients with no complications . The risk of hematoma was also higher in patients undergoing hemodialysis prebiopsy, but it did not reach significance (P = 0.06). All other variables were similar between both groups (Of 47 patients with eGFR < 15 ml/min per 1.73 mreatment . The remd causes . Patienth groups . Biopsy h groups .2), unknown baseline serum creatinine level, normal-sized kidneys, and negative immunology screening result. More than 95% of patients were found to have moderate to severe chronic changes on their kidney biopsy samples. Most patients were emigrants from Asia and were unaware of preexisting kidney disease. CKD in this population stratum is often not previously identified because either the CKD screening programs are not effectively implemented in their native countriesKidney biopsy is the gold standard test that provides crucial information on the diagnosis, prognosis, and management of renal diseases. However, there is no universal consensus on the indications of renal biopsy.2 compared with <2% in patients with higher eGFR. Severe renal dysfunction poses a higher risk for bleeding because of (i) its association with scarred kidneys that are more likely to bleed and (ii) the coexistence of other risk factors, such as lower prebiopsy hemoglobin and higher urea and creatinine levels.P = 0.02). Anemia alters the flow of platelets in the bloodstream, decreasing the interaction between the platelets and the endothelium.P = 0.06). Although dialysis therapy ameliorates platelet hemostatic dysfunction associated with uremia, there is evidence that interaction between the blood and the dialysis circuit can enhance bleeding, even in the absence of heparin, by temporarily worsening platelet aggregation and function.Predicting the degree of chronic histologic changes from clinical or diagnostic studies in patients with reduced kidney function continues to be a challenge. Besides nausea and vomiting, we did not find any specific clinical, laboratory, or radiologic findings correlating with renal histologic chronicity score. The overall incidence of postbiopsy hematoma was 28% in patients with eGFR < 15 ml/min per 1.73 m2 on presentation had a treatable cause of the acute kidney injury. Of those, only 1 recovered kidney function. However, the rate of severe complications in that group exceeded 10%. Thus, discussing this risk-benefit ratio in the context of decision-making for a kidney biopsy in these patients would be necessary.This study is limited by its retrospective nature and the number of patients, which might influence the statistical power. Furthermore, the decision to biopsy patients was determined by the nephrologist; hence, higher risk patients might not have been biopsied, a potential selection bias. Our study revealed that most patients with markedly reduced kidney function on presentation, unknown baseline creatinine level, normal-sized kidneys, and negative immunology screening result had advanced CKD with irreversible glomerular, tubulointerstitial, and vascular lesions, not amenable to treatment. Only 1 in 8 patients with an eGFR < 15 ml/min per 1.73 m