RS) is an important determinant of the responsiveness of intracranial pressure (ICP) to positive end-expiratory pressure (PEEP). However, lung elastance (EL) and chest wall elastance (ECW) were not differentiated in previous studies. We tested the hypothesis that patients with high ECW or a high ECW/ERS ratio have greater ICP responsiveness to PEEP.Respiratory system elastance  after PEEP adjustment. ECW and the ECW/ERS ratio were significantly higher in ICP responders than in non-responders at both low PEEP (p = 0.021 and 0.017) and high PEEP (p = 0.011 and 0.025) levels. No significant differences in ERS and EL were noted between the two groups at both PEEP levels.The magnitude of the increase in esophageal pressure (median [interquartile range]) at end-expiratory occlusion was significantly increased in the responder group compared with that in the non-responder group  contains supplementary material, which is available to authorized users. Acute lung injury is prevalent in patients with acute brain injury –4. MechaL) and chest wall elastance (ECW) in respiratory system elastance (ERS). Although clinical studies have suggested that an increased ERS might attenuate the effect of PEEP on ICP, EL and ECW were not differentiated in these studies  mm Hg) and increased after the PEEP level was adjusted to 15 cm H2O (7.0 [5.8–11.0] mm Hg). The difference in ICP at the two PEEP levels (2.5 [1.0–4.0] mm Hg) in our patients was comparable to those previously reported [Regarding the influence of PEEP on ICP, clinical studies have reported conflicting results, with ICP increasing –18, not reported , 14.The PEEP-induced increase of pleural pressure may reduce cerebral venous drainage and eventually increase ICP . The pleL and ECW in ERS. The higher the proportion of ECW is, the greater the impact of PEEP on pleural pressure [CW and the ECW/ERS ratio may be a more important determinant of ICP responsiveness to PEEP. In previous clinical studies, only ERS was used to explore the influence of respiratory mechanics in the PEEP and ICP relationship [L and ECW from ERS, we found that the effect of PEEP on ICP was more profound in patients with higher ECW and a higher ECW/ERS ratio  in previous studies [CW and the ECW/ERS ratio measured in our group of patients were relatively “normal”  and VvDal/VT (13.2 to 18.8%). Despite lacking statistical significance, PaCO2 and VDalv/VT were high in ICP responders. Therefore, PEEP-induced hyperinflation might also contribute to ICP responsiveness in our patients.There are two consequences after the application of PEEP: recruitment of collapsed alveoli and/or overdistention of normal alveoli. In patients with severe brain injury and acute lung injury or ARDS, Mascia et al. defined two groups based on recruitment volume: ≥ 110 mL as recruiters and < 110 mL as non-recruiters . As the H2O PEEP . In our The effect of PEEP on ICP might be affected by ventricular compliance , 16. ApuIncrease in PEEP decreases systematic venous return and potentially lowers the cardiac output, this will lower blood pressure and cerebral perfusion pressure. If the cerebral perfusion pressure break through the lower limit of cerebral autoregulation, cerebral perfusion will not be maintained and thus decrease cerebral blood flow, cerebral blood volume and ICP. In this case, the decrease of cerebral perfusion (and thereby decrease in ICP) will somehow contaminate the effect of PEEP on the venous side. In our study, blood pressure and cerebral perfusion pressure were maintained in a normal range, even in a high PEEP level. Therefore, although without cerebral blood flow being measured, we assumed that the cerebral perfusion was comparable between the two groups.CW due to structural changes to the thoracic cage [CW in the elders, probably due to the same reason. The responders also had significantly lower BMI. Although obesity people have higher ERS, it can be the result of either increased EL or increased ECW, or even both [CW unpredictable simply base on BMI. Moreover, our patients had relatively normal BMI, the small difference of BMI between the two group  is unlikely the determinant of the difference of ECW.The responders were significant older in this study. It has been reported that the elders have higher Ecic cage , 34, whiven both . This maCW and a higher ECW/ERS ratio. Our data suggest the potential necessity of respiratory mechanics monitoring when applying PEEP in brain-injured patients, especially in patients with a risk of chest wall impairment.The main strength of the present study was that the contribution of the chest wall and the lung in ICP responsiveness to PEEP was distinguished. The adverse effect of PEEP on ICP may be amplified in patients with higher ECW, we used the change in esophageal pressure between end-inspiration and end-expiration occlusion, which has been shown to reliably reflect the change in pleural pressure [There were several limitations of the study. First, we used the median of the increased value rather than other physiological parameters to define the ICP responders and non-responders. Given that no widely accepted standard is available to discriminate whether the patient’s ICP is responsive to increased PEEP, the division of patients into two groups is reasonable and enables us to compare potential determinants between the two groups. Second, we only included postoperative subarachnoid hemorrhage patients with relatively normal ICP and respiratory mechanics. Therefore, our results might not be directly applied to other populations. Third, although esophageal pressure has been employed as a surrogate of pleural pressure, the use of the absolute value of esophageal pressure remains questionable . Howeverpressure , 36, 37.CW and a higher ECW/ERS ratio. Potential factors contributing to the increase in ECW and the ECW/ERS ratio should be assessed and eliminated if possible to avoid the adverse effects of high PEEP levels on the brain.Patients with greater ICP responsiveness to increased PEEP had higher EAdditional file 1:Detailed methods of the study procedures, measurements and parameter derivations. (PDF 186 kb)Additional file 2:Detailed results of respiratory mechanics, intracranial pressure, hemodynamics parameters and blood gas. Values of respiratory mechanics (Table E1), intracranial pressure and hemodynamics parameters (Table E3) and blood gas (Table E5) at low and high positive end-expiratory pressure (PEEP) levels were provided. Changes in respiratory mechanics (Table E2), intracranial pressure and hemodynamics parameters (Table E4) and blood gas (Table E6) from low to high PEEP were also provided. (PDF 177 kb)


Disagreements between clinic and ambulatory blood pressure (BP) measurements are well-described in the general population. Though hypertension is frequent in renal transplant recipients, only a few studies address the clinic-ambulatory discordance in this population. We aimed to describe the difference between clinic and ambulatory BP in kidney transplant patients at our institution.We compared the clinic and ambulatory BP of 76 adult recipients of a kidney allograft followed at our transplant center and investigated the difference between these methods, considering confounding by demographic and clinical variables.p = 0.026) and with tacrolimus use compared to cyclosporine (p = 0.046). Sleep SBP and DBP were 139 ± 21/78 ± 11 mmHg. A non-dipping sleep BP pattern was noted in 73% of patients and was associated with tacrolimus use (p = 0.020).Clinic systolic BP (SBP) and diastolic BP (DBP) were 128 ± 13/79 ± 9 mmHg. Awake SBP and DBP were 147 ± 18/85 ± 10 mmHg. The clinic-minus-awake SBP and DBP differences were − 18 and − 6 mmHg, respectively. The negative clinic-awake ΔSBP was more pronounced at age > 60 years  contains supplementary material, which is available to authorized users. In kidney transplant recipients, hypertension (HTN) is an independent risk factor for cardiovascular diseases (CVD) , 2, deatIn the general population, clinic BP measurement often differs from ambulatory BP monitoring (ABPM) . AmbulatIn addition to measuring mean BP, ABPM reveals important data on other values, including awake period BP, asleep period BP, BP variability, morning surge and the sleep-related dipping pattern . FurtherOnly a few studies have examined the concordance between clinic BP and ABPM in kidney transplant recipients. Though some found a high rate of white-coat hypertension –29, otheA non-dipping BP pattern (defined as a < 10% reduction in asleep period BP relative to awake period BP) was reported in up to 79% of the patients with kidney allografts , 29. In The lack of well-established data with regards to diagnosis, treatment and monitoring of hypertension in the renal transplant population gave rise to a contemporary “Call to Action” published by several European scientific societies, encouraging performance of surveys aimed at assessing the prevalence of hypertension (including white-coat and masked hypertension) . AccordiWe enrolled patients post kidney transplantation followed-up in our renal transplant clinic. Inclusion criteria were age 18 years and above and a period of at least 3 months from the transplantation. Pregnant women were not included. Renal transplant physicians recruited potential participants during regular clinic visits. The Helsinki Committee of the Hadassah Medical Organization approved the protocol for this study. All volunteers provided written informed consent prior to participation.We collected baseline data including age, weight, transplantation details, underlying kidney disease, medications and BP measurements from medical files, and height and missing information directly from the patients. We calculated the aggregate dose of antihypertensive medications as the sum of percentages of each drug’s dose from its maximal dose. We quantified urinary protein excretion and creatinine clearance from a 24-h urine collected during a period before or after the monitoring . Hemoglobin and serum creatinine were measured in the day of monitoring in most patients; in 10 patients, they were measured up to 1 month before or after the monitoring. In a single patient, we collected data from a visit that occurred 4 months before the ABPM. We estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Trough levels of tacrolimus, everolimus, sirolimus and cyclosporine were measured in the morning of monitoring, before taking the morning dose. In five patients, plasma levels were measured within 8 days after the monitoring; in ten patients, they were measured up to 14 days before the monitoring; in a single patient it was measured 4 months before the monitoring, and in two patients, plasma levels are missing. We make use of information from our institution’s ABPM dataset of referred patients for perspective and comparison with this study’s patients (registry control) . This reeither by a nurse (observed) using an oscillometric device  before entering the physician’s office (n = 16), or by the physician, using aneroid auscultatory sphygmomanometry , at least 5 min after arrival at the clinic (n = 60). Typically, single measurements were performed. Our study protocol did not address the particulars of clinic measurements, as our aim was to compare real-life clinic measurements with standardized ambulatory monitoring. Measurements were done on an arm without an arterio-venous fistula, while it rested on a table. Clinic BP was calculated as an average of 2–3 visits during the 3 months before conducting ABPM. If only one measurement was performed in this period, an additional measurement taken 3–12 months before the ABPM was included in the average clinic BP. Hypertension medications were in general not changed during this period. However, adherence and as needed use were not systematically assessed.BP was measured Ambulatory BP was monitored with Oscar2 devices . Three adult cuff sizes were available. Measurements were recorded every 20 min during the day and every 30 min during nighttime sleep (according to the participant’s projection) over a 24-h monitoring period. In the ABPM analysis, awake period limits and asleep period limits were further defined according to the participant’s log. Participants with at least 20 awake period measurements and 8 sleep measurements were considered to have a valid ABPM recording. One participant discontinued the monitoring before sleep; his 20 awake period records were included in the study. ABPMs were processed with AccuWin Pro v3 .Clinic HTN was defined as mean clinic SBP ≥ 140 mmHg and/or mean clinic DBP ≥ 90 mmHg, according to JNC 8 report . Awake pThe primary outcomes of this study were the differences between clinic SBP/DBP and ambulatory awake period SBP/DBP. The secondary outcomes were prevalence of clinic HTN, awake period ambulatory HTN, asleep period ambulatory HTN; white-coat HTN (defined as clinic HTN without awake period ambulatory HTN); masked HTN (defined as awake period ambulatory HTN without clinic HTN); isolated nocturnal HTN; non-dipping pattern (defined as < 10% reduction in SBP from awake period to sleep time) and a reverse-dipping pattern (defined as higher sleep SBP than awake SBP); as well as assessment of awake and sleep periods’ SBP and DBP variability , and average awake period and sleep period heart rates.P-values < 0.05 were considered statistically significant. P-value adjustment for multiple comparisons and post-hoc analyses was done by the Benjamini & Hochberg method.Sample size calculation for our study was driven by the main hypothesis, that in kidney transplantation, clinically meaningful differences exist between office and ambulatory blood pressure. We estimated that roughly 80 patients are required to detect such differences with 80–85% power. Patients’ characteristics are summarized as percentages, means and standard deviations or medians and 1st-3rd quartile values, as appropriate. 95% confidence intervals (CI) for the means of clinic-awake BP differences were calculated using quantile of t-distribution (R package ‘Publish’). We evaluated associations between clinic and ambulatory BP means or indices  and demographic and clinical characteristics with general linear (and logistic) regression models using the R statistical environment (and packages including ‘Rmisc’ and ‘nlme’). Proteinuria (mg/d) was log-transformed prior to inclusion in models. Plots were generated using R base functions and the ‘ggplot2’, ‘BlandAltmanLeh’ and ‘waffle’ packages. Two-tailed Between 12/2016 and 2/2018 seventy-six subjects were recruited to the study. Their demographic, anthropometric and clinical characteristics appear in Table BP average across the 2–3 most recent clinic visits was 128 ± 13/79 ± 9 mmHg, Table Awake, sleep and 24 h BP as well as sleep-related dipping averages are displayed in Table Isolated nocturnal HTN was present in 11% of participants. Rates of normal systolic BP dipping pattern, non-dipping pattern and reverse dipping pattern were 26.7% (20 patients), 53.3% (40 patients) and 20% (15 patients), respectively. In contrast, non-dipping of heart rate (< 10% reduction during sleep) was noted in only 43% of subjects.p = 0.026), on the immunosuppressive regimen  and on the variability of awake systolic BP (p = 0.034) , as did the dependence on age as a continuous variable (p = 0.064). The association of ΔSBP with the immunosuppressive regimen did not lose significance after adjustment for time since transplantation (p = 0.048) or for diabetes (p = 0.046).The discrepancy between ambulatory and clinic BP was expressed as clinic minus awake SBP, ΔSBP, and clinic minus awake DBP, ΔDBP. The distribution of ΔSBP  and ΔDBP  values is shown in Fig. Figure p-values< 0.0001), while the interaction between medication and time interval predicted SBP (p = 0.061) and DBP (p = 0.013).To further characterize diurnal BP patterns in relation to calcineurin inhibitor use we extracted individual patients’ BP measurements from all ABPM tracings. Hourly averages as well as 3 h interval averages are plotted according to calcineurin inhibitor use in Fig. According to JNC8 definitions for clinic HTN and to ESC-ESH recommendations for ambulatory HTN, rates of white coat HTN, masked HTN, sustained HTN and normotension were 1.3, 51.3, 26.3, 21.1%, respectively Fig. a. HoweveIn our study, employing ambulatory blood pressure monitoring, we found that patients followed at our kidney transplant clinic have appreciably higher systolic and diastolic BP levels outside the office as compared to their clinic measurements. The differences, averaging 18 and 6 mmHg, respectively, expose widespread underestimation of BP, misclassification of BP control and masked hypertension in our kidney transplantation clinic. The limits of agreement between ambulatory awake and clinic BP measurements were wide  was more pronounced with age over 60 years and with tacrolimus use (versus cyclosporine). In the general population, one study found age to be a risk factor for masked HTN ; other sAs a result of the negative clinic-awake BP difference in our patients, masked HTN was uncovered much more commonly than white coat HTN. This finding is sensitive to clinic HTN definitions. The ACC/AHA and KDIGO-adopted lower clinic BP thresholds amplify the prevalence of sustained HTN on account of masked HTN and that of white coat HTN on account of normotension. Overall, KDIGO/ACC/AHA guideline cutoffs lead to more agreement between clinic- and ABPM awake-based determinations than JNC 8 cutoffs (69% vs. 47%).Previous studies have also shown negative clinic-ambulatory BP differences in renal transplant populations, albeit of lesser extent. However, in several other studies opposing results have been noted. These previous studies differ one from another in patients’ age, clinic BP and ABPM methods and in exclusion criteria Table .Table 6cIn a study of 98 patients from New-Zealand , the meaOn the other hand, in a 260-patient Italian study, the clinic – awake SBP and DBP differences were + 6 and 0 mmHg, respectively . The cli2 were not included, and description of clinic and ABPM measurement methodology is lacking. In a 94-patient Italian study, the clinic – awake SBP and DBP differences were + 4 and − 1 mmHg, respectively [In a 49-patient Indian study, the clinic – awake SBP and DBP differences were positive at 2, 4, 6, and 9 months after transplantation ; howeverectively . A possiAs in our study, the tendency for a negative clinic–awake BP difference has been observed in other (non-transplant) CKD populations. In an US cross-sectional study on 1492 CKD patients, the differences between clinic and ambulatory awake SBP and DBP were − 5.9 and − 6.4 mmHg, respectively . In a JaIn addition to the clinic-awake discrepancy, nocturnal measurements have revealed that 83% of our patients have sleep HTN. This finding is in line with previous results 69% , 71% 3030). Also1% 3030. In the absence of significant relationships with age, diabetes and BMI, the elevated magnitude of BP masking and non-dipping observed in our patients is possibly a consequence of disturbed volume status, as has been shown for tacrolimus treatment , and derRecruitment of participants was performed predominantly by their transplant nephrologists, possibly leading to referral biases toward patients who their physicians thought them to have indications for ABPM. Also, clinic BP measurements were not done in a uniform manner: 5 of 7 physicians used aneroid sphygmomanometry, while two relied on oscillometric measurements taken by the clinic nurse. Only one measurement was typically recorded in each visit. Our study has no dedicated control group, although we did use parallel information from our institution’s general ABPM dataset for perspective. Our study’s relatively small size (76 patients who take different antihypertensive medications) is a limitation too, and caution is advised in interpreting some results also due to their post-hoc nature.On the other hand, our study’s strength is in examining the clinic-awake BP difference as a continuous variable, and therefore independent of hypertension definitions. To our knowledge, it is the first study that describes diurnal-based BP differences between immunosuppressant regimens, thus generating hypothesis for further studies.We conclude that ABPM is justified in the renal transplant population. This is due to the high proportion of masked hypertensives and a predominating negative clinic-awake BP difference, and due to the lack of robust predictors of masking.Additional file 1:Supporting description and correlation analysis of blood pressure parameters. A Microsoft Word file with supplementary results. (DOCX 32 kb)Additional file 2:PDF file containing 4 supplementary figures. (PDF 440 kb)Additional file 3:Table S1. Benjamini-Hochberg adjusted p-values corresponding to the association matrix presented in Table


In the multivariate analysis, the association with microalbuminuria was maintained (p=0.007). In a population free from the long-standing effects of hypertension, increased salt intake appears to be associated with early signs of vascular kidney damage, rather than a diffuse micro- and macrovascular impairment.Evidence suggests that increased salt consumption induces blood pressure- (BP) mediated organ damage, yet it remains unclear whether it reflects a generalized micro- and macrovascular malfunction independent of BP. We studied 197 newly diagnosed and never-treated individuals with hypertension, intermediate hypertensive phenotypes, and normal BP, classified by use of 24-hour ambulatory BP monitoring. Sodium excretion and microalbuminuria were estimated in 24-hour urine samples, dermal capillary density was estimated from capillaroscopy, and arterial stiffness was estimated with pulse wave velocity (PWV) and augmentation index (AIx). Sodium excretion correlated with microalbuminuria ( Excessive dietary sodium chloride intake has been acknowledged as a pivotal modifiable environmental risk factor for cardiovascular events that accounts for a rise in blood pressure and promotes hypertension-related target organ damage . Salt coOn the other hand, the impact of salt intake on other vascular beds has not been thoroughly investigated, and only a few data exist regarding the association between salt intake and either arterial stiffness , 9, 10 oOf note, the majority of the previous studies investigating the effects of salt intake on the cardiovascular system have used office blood pressure measurements for the assessment of blood pressure status of the participants. However, 24-hour ambulatory blood pressure monitoring (ABPM) is now being widely used and provides a reliable prognostic index in terms of cardiovascular morbidity and mortality, considered by many as superior to office blood pressure recordings . It is tThe primary aim of the present study was to investigate whether an association exists between urinary sodium excretion and different forms of subclinical micro- and macrovascular organ damage  independent of blood pressure levels, at the same time and long before the establishment of overt cardiovascular or renal disease. We additionally investigated whether increased salt excretion (i) correlates with 24-hour ABPM parameters and (ii) is related to blood pressure status, classified by use of ABPM, in a naïve population of newly diagnosed individuals, never-treated individuals, otherwise healthy patients with hypertension, and intermediate hypertensive phenotypes, as well as normotensive individuals.2 (m2).The study population consisted of consecutive patients who attended our Hypertension Unit and normotensive, healthy individuals admitted for regular check-up. All participants were Caucasians and gave written informed consent. The study was approved by the Ethics Committee of Aristotle University of Thessaloniki and was conducted in accordance with the principles of the Helsinki Declaration. In order to participate, all individuals had to not have been previously treated with antihypertensive agents, had to not receive medication of any kind, and had to be free of any other known health problems. History, medical examination, and laboratory tests were used as indicated to verify absence of secondary causes of hypertension and other comorbidities (including diabetes mellitus and cardiovascular diseases). Alcohol and smoking habits were recorded and body mass index (BMI) was calculated as weight (kg)/heightUsing standard methodology, office blood pressure (ofBP) was measured after 10 minutes at rest and was determined as the mean of the second and third value of three consecutive BP recordings taken at a 2-minute interval. A Spacelabs 90207 device was applied to all participants to obtain 24-hour ABPM recordings, which were performed every 20 minutes during a usual working day and every 30 minutes during the night. Successful readings should account for ≥70% in order to be considered technically sufficient. A dipping pattern was defined as a difference ≥10% between the daytime and nighttime systolic BP (SBP). Office and ABPM recordings were combined to classify participants into the following groups: patients with true hypertension (TH) (ofBP≥140/90 mmHg and daytime ABPM≥135/85 mmHg), patients with intermediate hypertensive phenotypes , those with ofBP <140/90 mmHg and daytime ABPM≥135/85 mmHg, and white-coat hypertensives (WCH), those with ofBP≥140/90 mmHg and daytime ABPM<135/85 mmHg)), and normotensive individuals (NT) (ofBP<140/90 mmHg and daytime ABPM<135/85 mmHg).Blood samples were derived from all patients in the morning after overnight fasting, with patients lying in the supine position for two hours before blood sampling. Lipids and kidney function were estimated from serology, while plasma renin activity (PRA) (ng/mL/h) and serum aldosterone (ng/dl) levels were estimated with the radioimmunoassay method. Glomelural Filtration Rate (GFR) estimation was based on the Cockcroft-Gault formula.24-hour urine samples were collected for the measurement of urinary sodium and albumin excretion. The latter was measured using the immunoturbidimetric method. Estimation of microalbuminuria, defined as urinary albumin excretion (UAE) rate between 30 and 300 mg/24h, with the above method in 24-hour urine samples is considered the most reliable method of microalbuminuria estimation . LikewisNailfold capillaroscopy  was applied to all participants. Semiautomated software was developed by our Hypertension Unit and FORTH (Foundation for Research and Technology-Hellas) for the detection and measurement of the number of capillaries in each obtained image. A grader masked to the subjects' identity and BP group assignment examined the microscopic images of each participant and chose a pair of them, according to their quality. A trained operator analyzed semiautomatically at least two measurements from each participant. Capillary rarefaction was defined as the lower tertile of a population consisting of 250 otherwise healthy, except for the high blood pressure, individuals. The intraclass correlation coefficient for a set of 20 patients was 0.951 . The applied software and protocol have been analyzed elsewhere in detail , 18.The SphygmoCor device  was used to assess arterial stiffness by measurement of pulse wave velocity (PWV), according to a standard protocol. After a 15-minute resting period in the supine position, waveforms at the right common carotid and right femoral site were recorded sequentially. Surface distance between the two recording sites was measured . Wave transit time was calculated using a simultaneously recorded electrocardiogram as a reference.The aortic augmentation index (AIx) was expressed as a percentage of the ratio of augmentation pressure to central pulse pressure . For the present analyses, we used AIx corrected for the mean (75) heart rate (AIx@75). p≤0.05 was considered statistically significant.Analysis was performed using the Statistical Package for Social Sciences (SPSS) 24. Differences between mean values for continuous variables were estimated by the analysis of variance (ANOVA) and with independent samples Kruskal-Wallis test for the parameters with normal and nonnormal distribution, respectively. A Bonferroni correction was used where necessary for making all eligible pairwise comparisons. Qualitative variables were compared by the chi-squared test. Continuous variables were described as mean ± standard deviation (SD) or as median (interquartile range) according to the normality of their distribution. Correlation coefficients were calculated with Pearson's rank test and the partial correlation coefficient after adjusting for age, BMI, and smoking. To explore if the relationship between sodium excretion and microalbuminuria remained after controlling for other covariates, we applied models of multivariate linear regression analysis. Where needing to transform a nonnormal to a normal distribution, we used the logarithmic mean of the parameter. A probability value ofp=0.034), PWV (p<0.001), BMI (p=0.029), and UAE (p=0.039) were significantly higher among ΤΗ compared to NΤ, whereas capillary rarefaction, though more pronounced in TH compared to NT (37% vs. 24%), did not significantly differ between the groups.A total of 197 individuals with a mean age of 43.7 ± 12.1 years were studied: 109 true hypertensives, 43 with intermediate hypertension phenotypes, and 45 normotensive individuals. Baseline characteristics of the above groups are depicted in  p<0.001), but not with AIx (p=0.096), PWV (p=0.895), or capillary density (p=0.206). In addition, sodium excretion correlated with BMI  and HDL , but no significant associations were observed with age (p=0.755), total cholesterol (p=0.422), PRA (p=0.116), or aldosterone levels (p=0.608).We further investigated whether any associations existed between sodium excretion and indices of micro- and macrovascular function. In the univariate analysis, sodium excretion significantly correlated with UAE , daytime SBP (p<0.01), and nighttime SBP (p<0.01), but not with office blood pressure measurements (p<0.05), as well as nighttime SBP (p<0.05) and daytime SBP (p<0.05), remained statistically significant . On the contrary, UAE was significantly increased in nondippers as compared to dippers (25.5 (13.3-45.2) vs. 15.3 (7.3-29) mg/24 hours, p=0.001).Further classification of our population according to their dipping status showed that sodium excretion was not statistically different between dippers and nondippers (153.9 (96.5-224.1) vs. 135.2 (83.25-183.6) mmol/24 hours,p=0.007) remained significant in the multivariate regression model.To verify whether the above associations remained statistically significant independently of other covariables, we developed a multivariable linear regression model . Only thA large body of evidence suggests that sodium intake in excess of physiological needs represents an essential contributor to hypertension and mediates cardiovascular and renal dysfunction. In the present study, we investigated whether an association exists between sodium excretion and indices of micro- and macrovascular function independent of blood pressure levels, in a population including all blood pressure phenotypes . Of the microvascular indices that were applied, urinary sodium excretion significantly correlated with microalbuminuria in our population. This result is consistent with findings from previous studies –8 and inOf the macrovascular markers that were studied , none was associated with sodium excretion. Previous studies focusing on the association between salt intake and arterial stiffness are rare and there is still no consolidation regarding whether salt excretion exerts any effects independent of BP on the large artery walls. A previous study of 49 community-dwelling individuals failed to demonstrate a relationship between 24-hour sodium excretion and brachial-ankle PWV. However, the study was methodologically limited and the sample was relatively small . The larAnother important finding of our study is the association between sodium intake and 24-hour ABPM parameters. We showed for the first time that urinary sodium excretion significantly correlated with 24-hour and day- and nighttime SBP, even after adjustment for other parameters, in a meticulously selected sample of 197 normotensive and newly diagnosed hypertensive individuals. A significant positive correlation between ambulatory mean blood pressure and urinary sodium excretion has been previously found in a study of 12 normotensive individuals, conducted by Centonza et al. . PreviouRegarding nighttime dipping, sodium excretion in our population did not differ according to dipping status. This result is consistent with a recent study which reported similar levels of sodium excretion regardless the dipping category among 269 hypertensive patients , in spitInterestingly, an association of urinary sodium excretion was not observed with office blood pressure levels in our study. Although the jury is still out on whether ABPM represents a more accurate prognostic index in terms of cardiovascular morbidity, mortality, and target organ damage, compared to office blood pressure measurements , our finFinally, the fact that 24-hour urinary sodium excretion can change rapidly and sodium intake effect on blood pressure can be evident within a relatively short time frame needs to be remembered ; the chaIn the present study, we showed that UAE, but not capillary rarefaction of the skin or arterial stiffness, correlated with increased sodium excretion independently of blood pressure levels, for the first time in an untreated, free-from-other-comorbidities population of different blood pressure phenotypes. Our findings suggest that increased salt excretion primarily affects the kidney and it is probably not accompanied by pronounced vascular dysfunction in other vascular beds, in a population free from the long-term effects of hypertension. In addition, we showed that even though salt excretion was comparable between the study subgroups, it was significantly associated with both 24-hour and day- and nighttime SBP, but not with office blood pressure, suggesting that dietary sodium intake might be more accurately reflected in ambulatory rather than conventional office blood pressure recordings. Hence, modification of salt intake could influence cardiovascular risk through effects on the renal microvasculature and blood pressure variations over the whole day- and nighttime period.


Worldwide treatment recommendations for lowering blood pressure continue to be guided predominantly by blood pressure thresholds, despite strong evidence that the benefits of blood pressure reduction are observed in patients across the blood pressure spectrum. In this study, we aimed to investigate the implications of alternative strategies for offering blood pressure treatment, using the UK as an illustrative example.We did a retrospective cohort study in primary care patients aged 30–79 years without cardiovascular disease, using data from the UK's Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality. We assessed and compared four different strategies to determine eligibility for treatment: using 2011 UK National Institute for Health and Care Excellence (NICE) guideline, or proposed 2019 NICE guideline, or blood pressure alone (threshold ≥140/90 mm Hg), or predicted 10-year cardiovascular risk alone (QRISK2 score ≥10%). Patients were followed up until the earliest occurrence of a cardiovascular disease diagnosis, death, or end of follow-up period . For each strategy, we estimated the proportion of patients eligible for treatment and number of cardiovascular events that could be prevented with treatment. We then estimated eligibility and number of events that would occur during 10 years in the UK general population.Between Jan 1, 2011, and March 31, 2016, 1 222 670 patients in the cohort were followed up for a median of 4·3 years (IQR 2·5–5·2). 271 963 (22·2%) patients were eligible for treatment under the 2011 NICE guideline, 327 429 (26·8%) under the proposed 2019 NICE guideline, 481 859 (39·4%) on the basis of a blood pressure threshold of 140/90 mm Hg or higher, and 357 840 (29·3%) on the basis of a QRISK2 threshold of 10% or higher. During follow-up, 32 183 patients were diagnosed with cardiovascular disease . Cardiovascular event rates in patients eligible for each strategy were 15·2 per 1000 person-years (95% CI 15·0–15·5) under the 2011 NICE guideline, 14·9 (14·7–15·1) under the proposed 2019 NICE guideline, 11·4 (11·3–11·6) with blood pressure threshold alone, and 16·9 (16·7–17·1) with QRISK2 threshold alone. Scaled to the UK population, we estimated that 233 152 events would be avoided under the 2011 NICE guideline (28 patients needed to treat for 10 years to avoid one event), 270 233 under the 2019 NICE guideline (29 patients), 301 523 using a blood pressure threshold (38 patients), and 322 921 using QRISK2 threshold (27 patients).A cardiovascular risk-based strategy (QRISK2 ≥10%) could prevent over a third more cardiovascular disease events than the 2011 NICE guideline and a fifth more than the 2019 NICE guideline, with similar efficiency regarding number treated per event avoided.National Institute for Health Research. Randomised trials5In the UK, guidanceEvidence before this studyStrong evidence has shown that the benefits of blood pressure reduction are observed in patients across the blood pressure spectrum and that the absolute benefits of treatment are proportional to a patient's pretreament absolute cardiovascular risk. However, blood pressure treatment guidelines worldwide continue to be guided predominantly by blood pressure thresholds and the concept of hypertension. We searched PubMed for studies published in English from Feb 11, 2009, to Feb 11, 2019, that compared a risk-based approach to blood pressure treatment with either a blood pressure-only approach or a combination approach . For this search, we used the terms “blood pressure lowering OR blood pressure treatment OR antihypertensive*” AND “strateg* OR approach OR policy” AND “compare OR contrast” AND “cardiovascular risk OR cardiovascular disease risk OR absolute risk OR QRISK2”. The search generated 228 studies, of which five were relevant; three showed the superiority of a risk-based approach over an entirely blood pressure-based approach. Two studies from low-income and middle-income countries additionally investigated combination approaches: both showed that a risk-based approach was superior to both a blood pressure only and a combination approach. All studies used trial populations or simulated data to compare strategies. Therefore, the potential effect of using a risk-based approach to determine treatment eligibility and subsequent cardiovascular disease burden in a real-life population was unclear.Added value of this studyUsing the UK as an illustrative population, our study showed that determining eligibility for blood pressure treatment with an absolute cardiovascular risk cutoff of 10% or higher (based on QRISK2) would increase the proportion of people who were eligible for treatment by 32%, compared with that of the 2011 National Institute for Health and Care Excellence (NICE) UK guideline. This QRISK2-based strategy would prevent over a third more cardiovascular disease events than would the 2011 NICE guideline, with the same efficiency, and would also prevent a fifth more events than the proposed 2019 NICE guideline, with similar or better efficiency. Over 10 years, we estimated that an absolute risk-based guideline could prevent nearly 90 000 more cardiovascular events in the UK than the 2011 NICE guideline that is currently in use.Implications of all the available evidenceOur analyses and the evidence to date illustrate that the potential benefits of an absolute risk-based approach to assess eligibility for blood pressure-lowering treatment surpass those of approaches recommended by international guidelines. These findings show the need to re-assess blood pressure treatment guidelines that are based on blood pressure cutoffs.However, strong evidence suggests that using a blood pressure threshold to make treatment decisions might not be the optimal strategy. Meta-analyses of randomised and non-randomised studiesTwo key considerations in determining the optimal strategy for blood pressure-lowering treatment are the number of patients who would be eligible for treatment and the degree to which treatment is prioritised to those people most likely to have future cardiovascular disease. The 2011 NICE guidelinesBefore the 2011 NICE guidance, treatment recommendations were based solely on blood pressure thresholds, treating patients with hypertension. Some evidence exists that general practitioners continue to use a blood pressure threshold of 140/90 mm Hg to guide treatment decisions.In our study, we investigated how these alternative strategies would affect eligibility for blood pressure-lowering treatment in the UK. Our aim was to describe and compare eligibility for blood pressure-lowering treatment of four different strategies, relate this to subsequent cardiovascular disease burden, and estimate the efficiency of each strategy on the basis of the number treated over 10 years to avoid a cardiovascular disease diagnosis.We did a retrospective cohort study using data from the UK's Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and mortality data from the Office for National Statistics (ONS). The CPRD is a primary care database containing anonymised data from approximately 6·9% of the UK population.Participants were aged 30–79 years and registered with a participating CPRD practice  on Jan 1PanelBlood pressure threshold alonePatients were eligible if they either had a blood pressure of 140/90 mm Hg or higher in the last measurement before enrolment or were using blood pressure-lowering medication at enrolment and had one of the following: two previous blood pressure measures of 140/90 mm Hg or higher within a 3-month period,2011 National Institute for Health and Care Excellence (NICE) guidelinePatients were eligible if they either met the criteria for the blood pressure strategy plus one or more of target organ damage,Proposed 2019 NICE guidelinePatients were eligible if they either met the criteria for the blood pressure strategy plus one or more of target organ damage,QRISK2 threshold alonePatients were eligible if they had a QRISK2We investigated four strategies to define treatment , with elPatients were followed up from Jan 1, 2011, and were categorised as eligible or ineligible for blood pressure-lowering treatment under the four different strategies . PatientA cardiovascular disease diagnosis was defined as the following: any record of coronary heart disease  or cerebrovascular disease .We estimated the number of patients needed to treat (NNT) to avoid an event to compare the efficiency of each strategy. For each strategy, NNT was calculated as the number of patients eligible for treatment divided by the number of events avoided if all eligible patients were treated for 10 years, assuming a 20% reduction in risk in treated patients .We did secondary analysis to further investigate the predictive ability of blood pressure and QRISK2 for subsequent cardiovascular disease. Each category was split into the following standard groups: systolic blood pressure at enrolment , diastolic blood pressure at enrolment , and QRISK2 at enrolment . Systolic blood pressure, diastolic blood pressure, and QRISK2 10-year risk score were also split into quintile groups. In each group, the rate and proportion of cardiovascular disease events were calculated and compared across treatment strategies.To maximise comparability between strategies, we stratified rates of cardiovascular disease according to use of blood pressure-lowering treatment at enrolment (on the basis of an issued prescription at enrolment) and whether their blood pressures were higher or lower than 140/90 mm Hg. Treated systolic blood pressures at enrolment were also plotted.We did three post-hoc sensitivity analyses. We calculated NNT for 5 years to prevent one cardiovascular event to assess whether extrapolation of our rates to 10 years was an acceptable approach. We assessed the primary outcome restricted to acute events . Lastly, we assessed the rate of haemorrhagic stroke by eligibility for each strategy. QRISK2 does not include haemorrhagic stroke, an important outcome when considering blood pressure treatment.All analyses were done with Stata (version 14).The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Between Jan 1, 2011, and March 31, 2016, 1 222 670 patients in the cohort were followed up for a median of 4·3 years . During follow-up, 32 183 patients were diagnosed with cardiovascular disease . Median age at entry was 51 years (IQR 41–62). Cohort demographic and risk factor characteristics are shown for the total cohort and by eligibility for each strategy in Of the 1 222 670 patients in the cohort, 271 963 (22·2%) were eligible for treatment at cohort entry under the 2011 NICE guideline, 327 429 (26·8%) were eligible under the proposed 2019 NICE guideline, 481 859 (39·4%) were eligible on the basis of blood pressure alone (treating those with hypertension), and 357 840 (29·3%) were eligible on the basis of a QRISK2 10-year risk of 10% or higher , table 1We assessed how eligibility for treatment changed from the 2011 NICE guideline to the QRISK2 strategy: patients who lost eligibility with QRISK2 tended to be younger and had fewer cardiovascular risk factors  were in patients eligible under the 2011 NICE guideline, 17 899 (55·6%) under the proposed 2019 NICE guideline, 20 388 (63·4%) under a blood pressure alone strategy, and 21 851 (67·9%) under the QRISK2 strategy . Rates oCompared with the 2011 NICE guideline, eligibility was higher and more events would be prevented under all other strategies, but efficiency varied. Using blood pressure alone to determine treatment eligibility led to an additional 5 037 504 patients in the UK being eligible for treatment compared with the NICE 2011 strategy. We estimated that, over 10 years, this strategy would avoid an additional 68 371 cardiovascular events compared with the 2011 NICE strategy. Under a blood pressure alone strategy, more patients would be treated for 10 years per event avoided (NNT=38), compared with under the 2011 NICE guideline NNT=28; . We founIn the secondary analyses assessing groups of patients split by quintiles of QRISK2 score, systolic blood pressure, and diastolic blood pressure, we observed that the gradient of the rate of cardiovascular disease was steepest when the cohort was split by quintiles of QRISK2 score . Rates aIn the secondary analyses, we also stratified rates of cardiovascular disease according to use of blood pressure-lowering treatment at enrolment. Among patients eligible for treatment under the 2011 NICE guideline, 70% were receiving treatment at enrolment and approximately half of those had blood pressure lower than the target of 140/90 mm Hg . ApproxiWe did several post-hoc sensitivity analyses. We estimated that NNT for 5 years to prevent one event were greater than those calculated at 10 years for all strategies, but had the same between-strategy patterns as the main analysis . RestricOur contemporary cohort study of more than 1·2 million patients from primary care in the UK describes eligibility for blood pressure-lowering treatment and subsequent cardiovascular burden on the basis of four different strategies. A strategy based on blood pressure alone or the 2019 NICE guideline would recommend far more patients for treatment and would prevent more cardiovascular outcomes, but with less efficiency in terms of NNT compared with that of the 2011 NICE guideline. However, a strategy based on a QRISK2 10-year cardiovascular risk threshold of 10% (akin to statin guidelines in the UK) would result in a net increase in patients eligible for treatment compared with that of the 2011 NICE guideline, would prevent over a third more cardiovascular events, and would be at least as, or perhaps slightly more, efficient. In the UK, scaling up the results from this analysis suggested that a strategy based on cardiovascular risk for blood pressure-lowering treatment could prevent an additional 89 769 cardiovascular events over 10 years, with the potential for many more globally if guidance was based on absolute risk.Our findings suggest that substantial numbers of at-risk patients are being overlooked for treatment because guidance is too focused on blood pressure. The patients in our cohort who would gain eligibility under a QRISK2 of 10% or higher  had a 10-year cardiovascular risk at least equivalent to that of patients currently eligible for treatment and, therefore, have as much or more to gain as those currently being treated. By definition, patients who lost eligibility under a QRISK2 strategy had a low QRISK2 score (<10%), and this was reflected in the lower cardiovascular event rates of these patients. More than 60% of patients who would lose eligibility under a QRISK2 strategy were using blood pressure-lowering medication and thus, might be overtreated by existing guidance. Our analysis showed that an absolute cardiovascular risk score is more predictive of future cardiovascular burden than systolic blood pressure or diastolic blood pressure. The 2011 NICE guideline incorporates an element of absolute risk by targeting patients at high risk (≥20%), which the proposed 2019 guidance lowers to 10% or higher, but only if they have blood pressure of 140/90 mm Hg or higher.Large systematic reviewsPolicy makers and clinicians should use the best available tools to predict a patient's subsequent risk, on the basis of all the available evidence. In our study, a QRISK2-based treatment threshold outperformed the 2011 and 2019 NICE guidelines in predicting cardiovascular disease and thus, is likely to be a superior tool for determining treatment eligibility. Because European guidelinesGuidelinesA risk-based strategy might also be cost-effective, with projected savings in an Australian studyImportantly, drug treatment for blood pressure is only one component for reducing cardiovascular risk overall. We are not implying that immediate drug treatment should be recommended to patients when increased cardiovascular risk is first identified. Non-drug measures to reduce risk would remain an important component of any strategy.Our study has several limitations. Our analyses did not investigate the potential harms of changing eligibility for blood pressure treatment. For example, not treating patients who have high blood pressures but have low absolute risk could lead to target organ damage,37We assumed that the rate of cardiovascular disease occurring during follow-up (median 4·3 years) could be extrapolated to 10 years. Therefore, our absolute numbers and rates come with a degree of uncertainty, but our sensitivity analysis over 5 years showed that a shorter prediction period would lead to the same conclusion.Restricting our cohort to patients who had a recorded blood pressure might have biased it towards a sicker population who visit their general practitioner more frequently. The true proportion of the UK population who is eligible for any strategy and the true rates of cardiovascular disease might therefore be lower than reported here. However, patients who do not visit their GP cannot be captured or treated under any strategy, and our comparisons were made in patients who can be reached with preventive measures in real-world clinical practice.Our cohort was comprised of treated and untreated patients. Patients who were eligible for treatment under the 2011 NICE guideline were more likely to use blood pressure-lowering treatment, affecting the subsequent burden of cardiovascular disease for this strategy more than for other strategies. However, stratification by treatment showed that QRISK2 was superior to the 2011 NICE guideline in both treated and untreated groups. Our calculation of NNT assumed that all patients being treated were already receiving a treatment benefit of 20% reduction in events. However, only half of patients treated had a recently measured blood pressure lower than the UK target of 140/90 mm Hg. This suggests that even treated patients could benefit from further blood pressure lowering. Considering that very few patients in our cohort had systolic blood pressure lower than 120 mm Hg, there could be additional benefits from lowering systolic blood pressure below 120mm Hg.Eligibility for each strategy was based on data collected in 2011. Secular trends in cardiovascular disease, risk factors, and treatment will affect eligibility and the rate of cardiovascular disease, which might be higher in our cohort than in a more contemporary cohort.QRISK2 calculators are widely used in UK primary care. However, QRISK2 was developed on the basis of coronary and cerebrovascular outcomes. Other outcomes need to be considered in assessing a risk-based approach to treatment, including peripheral arterial disease, heart failure, and target organ damage. Our sensitivity analysis exploring haemorrhagic stroke showed that using QRISK2 to determine treatment eligibility was unlikely to lead to withdrawal of treatment in patients at risk of haemorrhagic stroke.Our study had several strengths. Our analysis was based on data from UK primary care. The CPRD is broadly representative of the UK population and thus, we were able to extend our results to the UK population. Linkage to hospital and mortality data allowed more cardiovascular events to be captured than by using CPRD alone.Some error in blood pressure measurement is likely to exist but, importantly, this strengthens our argument for a risk-based strategy. Blood pressures recorded in these data are those on which clinicians make treatment decisions. If a patient has unusually raised clinic blood pressure measures, they might be considered for therapy under the current approach. Because blood pressure is just one component of absolute risk, its effect on absolute risk is small. Therefore, errors in measurement or out-of-date measures will have less effect on eligibility for treatment.Our study shows the need for re-assessment of the 2011 and proposed 2019 NICE blood pressure treatment guidelines. A cardiovascular risk-based strategy would align with the lipid-lowering guideline and streamline provision of cardiovascular disease prevention, with the potential to prevent more cardiovascular disease and with more efficiency than current guidelines. Given the large numbers of patients who stand to benefit from a change in guideline, this work should be a priority for public health and cardiovascular disease prevention.data access with CPRD and must have their study protocol approved by the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research.Data were obtained from the CPRD. CPRD is a research service that provides primary care and linked data for public health research. CPRD data governance, and our own licence to use CPRD data, do not allow us to distribute or make available patient data directly to other parties. Researchers can apply for


The weight-based dosing of ondansetron to reduce hypotension has never been investigated. The aim of this study is to determine the optimal dose of ondansetron required based on the patient’s weight to reduce hypotension following spinal anesthesia for cesarean section.In this prospective, triple-blinded, parallel group, randomized controlled trial, a total of 228 pregnant women were randomized to receive either normal saline (group NS) or ondansetron 0.05 mg/kg (group O1) or ondansetron 0.1 mg/kg (group O2) intravenously 5 min before induction of spinal anesthesia. The incidence of hypotension, mean arterial pressure, heart rate, vasopressor requirements, and blood loss between the three groups were compared. Maternal and neonatal complications were also assessed. Changes in blood pressure and heart rate were compared using the generalized estimating equations method.n = 12) and protocol violation (n = 1). Two hundred and fifteen patients remained for the intention-to-treat analysis. The incidence of hypotension in groups NS (n = 72), O1 (n = 71), and O2 (n = 72) were 81.9%, 84.5%, and 73.6%, respectively (P = 0.23). The episodes of hypotension before delivery  were significantly higher in group O1 compared to NS . The overall heart rates throughout the operations were not different among the three groups. The ephedrine requirements and amount of blood loss were also similar among the three groups. The metoclopramide requirement was significantly lower in group O2 compared to group NS . There were no serious adverse events in terms of maternal or neonatal complications.Thirteen patients were excluded from the analysis because of no intervention (Ondansetron 0.05 mg/kg or 0.1 mg/kg administered before spinal anesthesia did not reduce the incidence of hypotension in this study.TCTR 20160323001, 22 March 2016.Thai Clinical Trials Registry,  Spinal anesthesia is now the technique of choice for women undergoing cesarean section. However, hypotension is a common problem after surgery with reported incidences varying from 53 to 85% worldwide , 2. The All of these studies used a fixed dose of ondansetron. To our knowledge, the optimal dose based on the patient’s weight has never been investigated. Using a weight-based dose of ondansetron might maximize its effect and prevent suboptimal dose or overdose in some parturients since they have a larger volume of distribution compared to normal patients. Hence, this study aims to determine the minimal weight-based dose of ondansetron required to reduce hypotension after spinal anesthesia in women undergoing cesarean section.Clinicaltrials.in.th number TCTR 20160323001 on March 22, 2016.This was a prospective triple-blinded parallel randomized controlled superiority trial. The study was approved by the Institutional Ethics Committee of The Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand on March 3, 2016 (EC 58382081), 2), abnormal pregnancy with intrauterine growth retardation, congenital anomalies, poly- or oligo-hydramnios, and placenta previa. These criteria were meant to exclude patients who had a high risk of hemodynamic instability.A written informed consent was obtained from all participants. The eligible participants were singleton pregnant women at a gestational age of 37–42 weeks who underwent elective cesarean section under spinal anesthesia and had no abnormal signs on electrocardiography. The study was carried out between May 2016 and February 2017 at Songklanagarind Hospital which is an 853–bed tertiary care hospital in southern Thailand. The exclusion criteria included the inability to communicate, history of hypertension, history of being allergic to ondansetron, congenital abnormality or acquired heart disease, coagulopathy, morbid obesity  or ondansetron 0.05 mg/kg (group O1) or ondansetron 0.1 mg/kg (group O2) . Block randomization was performed in blocks of three by computer generated tables by a hospital research assistant who was not involved in the trial. A 4 mL clear solution was prepared for all study participants in sequential numbers by a nurse anesthetist in the recovery room who was not involved in the operation. The vial containing the solution was put into a concealed envelope for the nurse anesthetist who was in charge in the operating room. The syringes had no identifying markers indicating group allocation. The patient, anesthesiologist in charge, and the investigators were blinded to the group allocation. The intention-to-treat protocol was applied in this study. Premedication by ranitidine or metoclopramide or both could be given according to the decision of the anesthesiologist in charge.In the operating room, 1000 mL of isotonic crystalloid was given to every patient. Philips IntelliVue MX700 was used to monitor non-invasive blood pressure, pulse oximetry, and electrocardiography during the period of anesthesia. Before spinal anesthesia was performed, the 4 mL clear solution containing the allocated treatment was administered intravenously five min before spinal anesthesia. Spinal anesthesia was performed at level L2–L3 or L3–L4 in the vertebral space with 2.0 mL of 0.5% hyperbaric bupivacaine and 0.2 mg of intrathecal morphine at a rate of 0.2 mL/sec by an experienced resident anesthetist. After spinal anesthesia was performed, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP) were recorded every one min for 15 min and then every five minutes, while the heart rates were recorded every five minutes until the end of the operation by a nurse anesthetist who was masked to the group allocation. Left uterine displacement of 15 to 20 degrees was performed after spinal anesthesia by placing a wedge under the right hip until the baby was delivered. After the baby was delivered, oxytocin  was routinely given while methylergometrine would be given only upon request of the gynecologist surgeon. The doses of oxytocin and methylergometrine were measured.The primary outcomes of the study were the incidence of hypotension and the change in MAP. Hypotension was defined as a decrease in MAP > 30% from baseline. If hypotension occurred, 6 mg of ephedrine or 5 mcg of norepinephrine was administered intravenously according to the discretion of the anesthesiologist in charge.The secondary outcomes were maternal complications during the intraoperative period and in the post-anesthetic care unit and neonatal complications 24 h postoperatively. If itching occurred, 10 mg of chlorpheniramine was given intravenously. Metoclopramide (10 mg) was given intravenously for treatment of nausea and vomiting during the intraoperative period. Any side effects from ondansetron such as burning and QT prolongation were evaluated. The QT prolongation was determined by a QT interval more than half of the preceding RR interval in 3-lead electrocardiogram monitoring intraoperatively and at post-anesthetic care unit. The well-being of the newborn baby was evaluated as well as any adverse events 24 h postoperatively.The sample size calculation was based on a difference in the incidence of hypotension between the control group (0.85) and the ondansetron group (8 mg) from a previous study which reported the incidence as 0.6 . For a pP value < 0.05 was considered statistically significant. Group allocation was also blinded to the statistician who analyzed the data.Continuous variables are presented as median and interquartile range for non-normally distributed data or mean and standard deviation for normally distributed data. Categorical variables are presented as frequency and percentage. Continuous variables were compared using two-way analysis of variance and the Kruskal–Wallis test for normally and non-normally distributed data, respectively. Categorical variables were compared using Pearson’s Chi-square test or Fisher’s exact test for normally and non-normally distributed data, respectively. Post-hoc analysis was performed for multiple comparisons between groups when the overall differences were significant. Changes in SBP, DBP, MAP, and heart rate were compared using the generalized estimating equations method. A P = 0.02) . The overall heart rates throughout the operations were not different among the three groups . There were also no differences in blood loss among the three groups: group NS (447.9 ± 201.3 mL), group O1 (490.8 ± 241.2 mL), and group O2 (440.3 ± 198.2 mL) (P = 0.32). Table P = 0.01). Table n = 5) compared to the control group  (P = 0.28). There were no reports of burning or QT prolongation in mothers and no reports of bradycardia or hypothermia in newborns in any group.Two hundred and twenty-eight women were enrolled in the study with details shown in the consort diagram in Fig. In this study, we found that a weight-based dose of prophylactic ondansetron did not influence the incidence of maternal hypotension. The results of this study were consistent with two other studies , 13 but P = 0.02), especially at 4 and 9 min after spinal anesthesia .In our study, ondansetron had little effect on hemodynamic stability after subarachnoid block in parturients. Factors that impact the level of anesthesia and analgesia given to the patient might also affect the patient’s arterial pressure as well as the way to measure arterial pressure. There are some possible reasons for the difference in the incidence of hypotension compared to other reports. First, we did not monitor invasive arterial blood pressure or cardiac output. Real time arterial pressure monitoring may be better at detecting actual variations of blood pressure than noninvasive blood pressure monitoring although we measured blood pressure every minute during the first 15 min after spinal anesthesia. A noninvasive blood pressure measurement might not be sufficiently sensitive to notice hemodynamic changes to promptly treat hypotension in parturients, especially in preeclamptic patients . LangesaThe definition of hypotension used in this study was a decrease in the MAP by 30% from the baseline level which was quite similar to many studies , 22, 23.P = 0.09). However, postoperative metoclopramide requirement was significantly lower in the high dose ondansetron compared to the normal saline group (P = 0.01). Therefore, the effect of ondansetron to prevent or treat nausea and vomiting was achieved as expected. There were no significant differences in terms of hypotension or tachypnea in newborns between the three groups. The incidence of tachypnea was slightly higher among the newborns of women who received the low dose of ondansetron compared to the control group (7% vs 2.8%). Tachypnea resolved within 2–3 h after oxygen therapy was administered. Although ondansetron can transfer across the placenta to newborn babies [Ondansetron did not cause any adverse events in our study. The parturients experienced neither QT abnormalities nor burning sensation during the injection and the newborns did not experience bradycardia or hypothermia 24 h postoperatively. The incidence of urticaria or arrhythmia was not higher in the two ondansetron groups. Although the incidence of vomiting was lower in the high dose ondansetron (0.1 mg/kg) group, the incidence was not statistically different . We used the intention-to-treat principle in the analysis which helped decrease the bias and ensure a balance of patients between the three groups. There are two weaknesses of this study. First, several resident anesthetists performed the spinal block which might have affected the level of anesthesia and incidence of hypotension in the study participants. However, these residents had a high level of experience  and a fixed rate of subarachnoid injection (0.2 mL/s) was used in all participants. Second, we did not monitor invasive arterial blood pressure because invasive monitoring is not routinely used in healthy parturients in our setting and it is also costly. However, the accuracy of the study is high and reproducibility of the results for a similar setting  should be achievable even though the study was conducted in a single hospital.Ondansetron administered at a dose of 0.05 mg/kg or 0.1 mg/kg before spinal anesthesia was not effective in reducing the incidence of hypotension in pregnant women undergoing cesarean section. Higher weight-based dosing of ondansetron should be examined keeping the safety issues in mind.


IntroductionOxygen delivery in patients with functionally univentricular hearts awaiting Norwood palliation depends on a balance between systemic blood flow (Qs) and pulmonary blood flow (Qp). Modulations of pulmonary vascular resistance and systemic vascular resistance are utilized to maintain balanced Qp:Qs in a circulation prone to pulmonary overcirculation at the expense of systemic perfusion. This study aimed to characterize changes in Qp:Qs and regional  oxygen delivery in patients awaiting Norwood palliation receiving hypoxic gas admixture therapy.MethodsPatients who received care prior to Norwood palliation were identified from 2014 to 2018. Of these patients, those with cerebral and renal near-infrared spectroscopy were identified (NIRS). Arterial oxygen saturation by pulse oximetry, renal NIRS, and cerebral NIRS prior to hypoxic gas admixture initiation were compared to values six hours, 12 hours, and 24 hours after initiation.ResultsA total of 28 patients were eligible for inclusion in the study. Arterial saturation by pulse oximetry was 91% prior to initiation and decreased to 86% 24 hours after initiation (p<0.001). Cerebral NIRS were a mean of 60 prior to initiation compared to 58 at 24 hours (p=0.187). Renal NIRS were a mean of 60 prior to initiation compared to 57 at 24 hours (p=0.120). Calculated Qp:Qs was 9.6 at baseline compared to 2.5 at 24 hours (p=0.006). Arteriovenous difference and lactate did not significantly change with hypoxic gas admixture administration.ConclusionAdministration of hypoxic gas admixture to patients with functionally univentricular hearts awaiting Norwood palliation decreases the ratio of Qp and Qs but does not improve regional oxygenation delivery. Patients with functionally univentricular hearts undergo staged palliation which often consists of a Norwood palliation, Glenn palliation, and then a Fontan palliation. Both the period prior to the Norwood and Glenn palliation are characterized by parallel circulation in which both the pulmonary and systemic circulations are receiving blood with the same saturation. There is a delicate balance between the pulmonary blood flow (Qp) and systemic blood flow (Qs) which is affected by the pulmonary and systemic vascular resistances. Changes in Qp:Qs may impair systemic oxygen delivery, and thus it may be necessary to modulate Qp:Qs to optimize systemic oxygen delivery -3.Newborns awaiting Norwood palliation will often have pulmonary overcirculation with a high Qp:Qs. Some institutions electively intubate patients and administer a hypoxic gas admixture to increase pulmonary vascular resistance and decrease pulmonary blood flow in hopes of increasing systemic blood flow and systemic oxygen delivery -8.This study aimed to characterize the effects of hypoxic gas administration on Qp:Qs as well as regional oxygen delivery.Study design and patient inclusionThis was a retrospective cohort study utilizing the clinical experience from a single center. The study protocol was approved by the Institutional Review Board. Patients with functionally univentricular hearts who received care prior to Norwood palliation at Advocate Children’s Hospital were identified. To be included in the study final analysis, the following inclusion criteria had to be met: 1) patients had to be awaiting Norwood palliation; 2) patients must not have had any prior interventions other than a balloon atrial septostomy; 3) patients must have received treatment with a hypoxic gas admixture that was administered through an endotracheal or nasotracheal tube using nitrogen; 4) patients must have had cerebral and renal near-infrared spectroscopy (cNIRS and rNIRS) monitoring from the initiation of hypoxic gas admixture administration; 5) hypoxic gas admixture therapy must have continued from its initiation until the Norwood palliation. Thus, those who underwent interventions such as pulmonary artery banding or stenting of the ductus arteriosus were excluded from this study. Patients who were not monitored with near-infrared spectroscopy were also excluded.Data collectionDemographic data including patient date of birth and date of Norwood palliation were collected. The date and time of the initiation of hypoxic gas admixture were also collected. Specific cardiac anatomy was not collected as this was not thought to affect the physiologic response to the hypoxic gas admixture. The fraction of inspired oxygen at the initiation of hypoxic gas admixture therapy as well as at its lowest point was recorded for each patient.The following clinical endpoints of interest were collected: arterial saturation by pulse oximetry, the arterial partial pressure of oxygen as measured by blood gas analysis, cNIRS value, rNIRS value, arterial lactate as measured by blood gas analysis, and systolic blood pressure. All of these values were recorded at the following timepoints: immediately prior to the initiation of hypoxic gas admixture (referred to as baseline), six hours after initiation, 12 hours after initiation, and 24 hours after initiation. Only a small number of patients had sub-ambient for greater than 36 hours so the further follow-up was not recorded and analyzed.The following values were calculated at each timepoint. First, an estimate of pulmonary blood flow (Qp) to systemic blood flow (Qs) ratio was calculated. This will be referred to as the bedside Qp:Qs for the remainder of the text. The calculation of Qp:Qs is as follows: /. The assumptions for this calculation were: 1) pulmonary artery saturation was assumed to be equal to the arterial saturation as measured by pulse oximetry; 2) pulmonary venous saturation was assumed to be 100%; 3) pulmonary venous saturation was considered to be constant at all time points; 4) rNIRS was used as a surrogate for the mixed venous saturation. Regarding assumption two, chest X-rays at the time of initiation of hypoxic gas admixture were reviewed and were not found to be concerning for pulmonary disease that could lead to pulmonary venous desaturation. Regarding assumption four, there are various proposed calculations for mixed venous saturation using both the cNIRS and rNIRS value in varying proportions. As there was minimal difference between cNIRS and rNIRS values at all timepoints, it was decided to simply use the rNIRS value. Additionally, bedside rNIRS value is more often used clinically compared to the cNIRS. The absolution correlation between the bedside Qp:Qs and catheter-based Qp:Qs is not the purpose of this manuscript. The bedside Qp:Qs is a value which the provider can trend to provide a general overview of the physiology. It is not meant to be used an absolute and certain measure of Qp:Qs. An arteriovenous difference of oxygen (AVDO2) was also calculated at each timepoint. The AVDO2 was calculated for the study as follows: arterial saturation as measured by pulse oximetry - rNIRS.Statistical analysesClinical values collected and calculated at the various timepoints were compared between each timepoint and the timepoint immediately preceding it using paired T-tests. Additional comparisons were conducted between the baseline and 12-hour timepoint as well as the baseline and 24-hour timepoint.Continuous variables are represented as mean and standard deviation. All statistics were done utilizing the statistical package for social sciences (SPSS), version 23 . A p-value of less than 0.05 was statistically significant.Clinical careAt our institution, most neonates awaiting Norwood palliation are cared for in the neonatal intensive care unit with both the neonatology and cardiology teams co-managing these patients. Umbilical venous and arterial access is obtained in all patients if possible. A prostaglandin E1 infusion is started immediately once central access is obtained with initial doses ranging from 0.01 mcg/kg/min to 0.03 mcg/kg/min. Respiratory support is titrated as needed and is most often noninvasive. Inotropes are rarely required preoperatively as are diuretics. In the instance that inotropes are needed, dopamine, milrinone, and epinephrine are the most frequently used. If diuretics are required furosemide and chlorothiazide are the most frequently used. Children are allowed to orally feed as much as they can tolerate with close monitoring of systemic perfusion and respiratory status. Nutrition is otherwise supplemented with total parenteral nutrition.Routine monitoring consists of transduction of the arterial line for blood pressure monitoring and strict monitoring of intake and output. Central venous pressure is not routinely transduced and the use of cNIRS and rNIRS is at the discretion of the clinical team.Administration of a hypoxic gas admixture has been utilized at the institution nearly routinely in such patients for several years. All patients are electively intubated 24-48 hours prior to scheduled Norwood procedure for hypoxic conditioning. For patients deemed to have high Qp:Qs and clinical signs of systemic hypoperfusion, intubation for hypoxic gas admixture administration is done at the discretion of the clinical team.Cohort informationA total of 28 patients met the inclusion criteria described above and were included in the final analyses. The average age at the initiation of hypoxic gas admixture was 3.5 days with the average age at Norwood palliation being 6.1 days. This resulted in an average duration of hypoxic gas admixture administration of 2.6 days. The average fraction of inspired oxygen at the time of initiation was 17% with an average minimum of 15% during hypoxic gas admixture administration (Table Clinical information with hypoxic gas admixture administrationAverage baseline pulse oximetry was 91.7%. At six hours this was 90.4%, at 12 hours - 89.8%, and at 24 hours - 86.0%. There was a statistically significant difference between the values at 12 hours and 24 hours as well as prior to initiation and at 24 hours (Table Average baseline arterial partial pressure of oxygen was 45.3 mmHg. At six hours this was 40.9 mmHg, at 12 hours this was 40.8 mmHg, and at 24 hours was 36.3 mmHg. There was a statistically significant difference between the values at 12 and 24 hours, prior to initiation and 6 hours, prior to initiation and 12 hours, and prior to initiation and 24 hours (Table Average baseline cNIRS was 60.1. At six hours this was 58.5, at 12 hours this was 61.8, and at 24 hours this was 58.8. There was no statistical significance in the difference between the values at any timepoints (Table Average baseline rNIRS was 60.5. At six hours this was 58.5, at 12 hours this was 61.8, and at 24 hours this was 58.8. There was no statistical significance in the difference between the values at any timepoints (Table Average baseline AVDO2 difference was 30.8. At six hours this was 31.1, at 12 hours this was 31.0, and at 24 hours this was 29.6, There was no statistical significance in the difference between the values at any timepoints (Table Average baseline bedside Qp:Qs was 9.6. At six hours this was 7.2, at 12 hours this was 5.1, and at 24 hours this was 3.3. There was a statistically significant difference between the values prior to initiation and at 24 hours (Table Average baseline lactate was 2.2 mg/dl. At six hours this was 1.6 mg/dl, at 12 hours this was 1.5 mg/dl, and at 24 hours this was 1.9 mg/dl. There was no statistically significant difference between the values at any time points (Table Average baseline systolic blood pressure was 65.5 mmHg. At six hours this was 63.0, at 12 hours this was 65.1, and at 24 hours this was 67.6. The only statistical significance found was noted between the value prior to initiation and the value at 24 hours (Table This study finds that administration of a hypoxic gas admixture to those with functionally univentricular hearts awaiting Norwood palliation is associated with decreased arterial saturation and Qp:Qs as demonstrated by pulse oximetry and arterial partial pressure of oxygen but is not associated with increased oxygen delivery as witnessed by cNIRS, rNIRS, arteriovenous difference, and lactate values.Balance of the pulmonary and systemic blood flow in the setting of parallel circulation in those awaiting Norwood palliation is of great importance. Without a change in cardiac output, any change in pulmonary or systemic blood flow will lead to an obligate reciprocal change to the other circulation’s blood flow. Thus, an increase in pulmonary blood flow will be at the expense of systemic blood flow and can be problematic if the systemic blood flow becomes inadequate with respect to systemic oxygen delivery -3.As pulmonary vascular resistance naturally decreases after birth, those with parallel circulation have an increase in Qp:Qs. Maintaining a balance of the two circulations can be done by modulation of pulmonary vascular resistance and systemic vascular resistance. Modulation of pulmonary vascular resistance, specifically increasing it, can be difficult. Inhaled hypoxic gas admixture has been used to increase pulmonary vascular resistance. Anecdotally, fewer institutions are now focusing primarily on increasing pulmonary vascular resistance although there are still some who intubate patients to administer a hypoxic gas admixture -5. Our iAs noted by the presented data, Qp:Qs is in fact significantly decreased after 24 hours of hypoxic gas administration. Systemic oxygen delivery, however, seems to be unchanged. Both cNIRS and rNIRS remain unchanged as did the arteriovenous difference. Lactate levels also remain unchanged which is consistent with the lack of significant change in the NIRS. Systolic blood pressure difference before and after, although statistically significantly higher at 24 hours at a difference of 2 mmHg, was not clinically significant.Without an improvement in oxygen delivery, the decrease in Qp:Qs may not provide any true clinical advantage. This illustrates the concept that if the total of pulmonary and systemic blood flow is high then systemic blood flow may be adequate even in the setting of a high Qp:Qs. This study demonstrates that oxygen delivery can remain adequate at a Qp:Qs of 9.6:1 and 3.3:1. If systemic oxygen delivery can be maintained at a high range of Qp:Qs, then the clinical utility of altering Qp:Qs must be questioned. If the physiology is being well tolerated then elective intubation of a child awaiting Norwood palliation simply for the purpose of hypoxic gas administration may not be necessary.In the situation where a child with parallel circulation demonstrates pulmonary overcirculation and poor systemic oxygen delivery, perhaps would it be more beneficial to attempt to lower systemic vascular resistance first -10. CertRamamoorthy and colleagues looked at the effects of inspired hypoxic and hypercapnic gas admixtures on cerebral oxygen saturation in neonates with univentricular heart defects. Even at a fraction of inspired oxygen of 17% there was no significant change in cerebral oxygenation or mean arterial pressure . TabbuttThis study demonstrates that hypoxic gas admixtures do not negatively impact oxygen delivery while other studies have demonstrated that hyperoxic gas admixtures also do not negatively impact oxygen delivery by increasing Qp:Qs . Thus, tThe findings of this study echo previously published findings but also add the additional components of rNIRS and lactate. While the data is helpful it is not without its limitations. Obviously, this is a single center study and there could be elements not accounted for that could limit the data’s generalizability. This seems to be less of an issue as components of the findings have been demonstrated before. Another limitations comes in the form of the bedside Qp:Qs calculations. These should not be taken to be accurately measured Qp:Qs but rather a bedside estimation that can often be clinically helpful to trend. To account for this, we have also included absolute data for arterial saturation by pulse oximetry and arterial partial pressure of oxygen.An additional consideration with the study is that many centers have now discontinued utilizing hypoxic gas admixtures. There are centers in developing countries and even some in developed countries that still continue to use this therapy. Thus, it does become necessary to evaluate contemporary data regarding the intervention. While specific centers may believe the use of hypoxic gas mixtures is now out of vogue it is still used internationally.In this single-center retrospective study characterizes the effects of administering a hypoxic gas admixture to functionally univentricular children with parallel circulation awaiting a Norwood procedure. Administration of hypoxic gas admixture to children with functionally univentricular hearts awaiting Norwood palliation decreases the ratio of pulmonary to systemic blood flow but does not improve systemic oxygen delivery as evidenced by near-infrared spectroscopy data and lactate. The lack of improvement in systemic oxygen delivery brings into the question of the utility in decreasing the ratio of pulmonary to systemic blood flow using a hypoxic gas admixture as the purpose of this decrease of the ratio is to ultimately help improve systemic oxygen delivery.