Study question Can routine antenatal blood pressure measurements between 20 and 36 weeks’ gestation contribute to the prediction of pre-eclampsia and its associated adverse outcomes? Methods This study used repeated antenatal measurements of blood pressure from 12 996 women in the Avon Longitudinal Study of Parents and Children (ALSPAC) to develop prediction models and validated these in 3005 women from the Southampton Women’s Survey (SWS). A model based on maternal early pregnancy characteristics only  plus initial mean arterial pressure was compared with a model additionally including current mean arterial pressure, a model including the deviation of current mean arterial pressure from a stratified normogram, and a model including both at different gestational ages from 20-36 weeks.Study answer and limitations The addition of blood pressure measurements from 28 weeks onwards improved prediction models compared with use of early pregnancy risk factors alone, but they contributed little to the prediction of preterm birth or small for gestational age. Though multiple imputation of missing data was used to increase the sample size and minimise selection bias, the validation sample might have been slightly underpowered as the number of cases of pre-eclampsia was just below the recommended 100. Several risk factors were self reported, potentially introducing measurement error, but this reflects how information would be obtained in clinical practice.What this study adds The addition of routinely collected blood pressure measurements from 28 weeks onwards improves predictive models for pre-eclampsia based on blood pressure in early pregnancy and other characteristics, facilitating a reduction in scheduled antenatal care.Funding, competing interests, data sharing UK Wellcome Trust, US National Institutes of Health, and UK Medical Research Council. Other funding sources for authors are detailed in the full online paper. With the exceptions of CM-W, HMI, and KMG there were no competing interests. Pre-eclampsia is the most severe form of hypertensive disorder of pregnancy and is associated with maternal and fetal mortality,14Several prediction models have shown the value of using blood pressure recorded at the first visit to the antenatal clinic alongside other maternal characteristics to predict the later development of pre-eclampsia.23We have previously developed stratified normal reference ranges for blood pressure, which allow for a different expected trajectory of blood pressure for different subgroups of women.This paper conforms to TRIPOD guidelines.25www.bris.ac.uk/alspac/researchers/data-access/data-dictionary). A total of 14 541 women were enrolled, 13 678 had a singleton pregnancy resulting in a live birth, and data on measurements of blood pressure were available for 12 996 of these women.For the development of the prediction models we used the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort study that recruited women with expected delivery dates between 1 April 1991 and 31 December 1992 living in a defined area of Avon during pregnancy. The study has been described in full elsewhere,Six trained research midwives abstracted all measurements of blood pressure and proteinuria that were taken as part of routine antenatal care by midwives or obstetricians from the women’s obstetric records. There was no variation between midwives in mean values of the data abstracted, and error rates were consistently <1% in repeated data entry checks. Measurements were taken once in women in the seated position with the appropriate cuff size, with Korotkoff phase V used for diastolic blood pressure.Maternal age at delivery and sex of the baby were obtained from obstetric records. Maternal weight and height before pregnancy, together with parity, smoking status, education, hypertension, and diabetes before the index pregnancy and ethnicity and household social class were obtained from questionnaires administered during pregnancy. Smoking during pregnancy was classed as “never” or “any smoking” for women who reported smoking either in the first three months of pregnancy or within two weeks of the 18 week questionnaire. Women who reported ever having hypertension outside of pregnancy were classed as having essential hypertension, while women who reported having hypertension only in pregnancy were classed as having previous gestational hypertension. Similarly, women who reported having ever had diabetes outside of pregnancy were defined as having diabetes while women who reported having diabetes only in a previous pregnancy were defined as having previous gestational diabetes.In accordance with recent guidelines on the development and assessment of prognostic models,A team of trained research midwives abstracted all measurements of blood pressure that were routinely collected during pregnancy from the women’s obstetric records after delivery following a strict protocol. The measurements were ordered by time, and the data checked for consistency.Maternal age at delivery and sex of offspring were obtained from obstetric records. Information on maternal parity, education, social class, and ethnicity was obtained at the initial interview before pregnancy, and height was measured. At the 11 week interview the mothers reported pre-pregnancy weight, any diabetes in a previous pregnancy or outside of pregnancy, and high blood pressure in a previous pregnancy or outside of pregnancy. Smoking status was obtained during interviews at 11 and 34 weeks’ gestation and classified as “never smoked in pregnancy” or “any smoking in pregnancy.” An algorithm that incorporated information recorded before pregnancy and at six months postpartum was used to estimate smoking in pregnancy when data at one or both time points were missing.As preliminary analysis suggested that mean arterial pressure was a stronger predictor of each outcome than systolic blood pressure (SBP) or diastolic blood pressure (DSP) separately, we used this as our measure of blood pressure in prediction models. This was defined as (SBP+2×DBP)/3. In both cohorts, the initial measurement of mean arterial pressure was defined as the first antenatal measurement, provided that this occurred before 18 weeks’ gestation. We also derived mean arterial pressure at 20, 25, 28, 31, 34, and 36 weeks’ gestation for each woman  criteriaTable A in appendix 1 gives a summary of definitions of all outcomes and predictor variables in ALSPAC and SWS for comparison.In the first stage of model development we developed expected trajectories of mean arterial pressure across pregnancy, or normograms, in ALSPAC, similarly to those described previously.For all women in the ALSPAC cohort  we then obtained a normative value of mean arterial pressure at 20, 25, 28, 31, 34, and 36 weeks’ gestation, which accounted for their parity and BMI before pregnancy and whether they smoked during pregnancy, and was conditional on their mean arterial pressure at their initial visit (before 18 weeks’ gestation). Appendix 2 gives further information on the derivation of this normative value.For both the ALSPAC and SWS datasets there were missing data on maternal characteristics and also for the derived values of initial mean arterial pressure and mean arterial pressure at 20, 25, 28, 31, 34, and 36 weeks for some women. To increase power and minimise selection bias in the second stage prediction models, we next used multivariable multiple imputation of missing data. Separate imputation models were used for the two cohorts, imputing to the full 12 996 women in ALSPAC and 3005 women in SWS who had any measurements of mean arterial pressure in pregnancy. For each imputation model, we included all early pregnancy characteristics and derived mean arterial pressure values as well as the outcomes. We imputed any missing data for the normative values of mean arterial pressure passively from imputed early pregnancy characteristics and initial mean arterial pressure. For each imputation we generated 20 imputed datasets and combined coefficient estimates across these using Rubin’s rules.In the second stage we used logistic regression to obtain separate prediction models for pre-eclampsia, preterm birth, and small for gestational age in ALSPAC based on the imputed datasets. Maternal predictors were selected from BMI before pregnancy, height, age ≥35, parity, smoking, essential hypertension, previous gestational hypertension, diabetes, previous gestational diabetes, and non-white ethnicity. This set of predictors was chosen because of strong prior evidence of their association with pre-eclampsia, ease of measuring in clinical practice, and generalisability to different settings. We used backward selection, with a P value threshold of 0.2, to select variables for inclusion in these early pregnancy characteristic models. Mean arterial pressure at the initial visit was forced to be included in all of these prediction models. The early pregnancy characteristic model was called model 1. We then added mean arterial pressure at gestational ages 20, 25, 28, 31, 34, or 36 weeks (each tested separately) to determine the added value of such measurements from 20 weeks in predicting outcomes (model 2). In model 3 we added the difference between the woman’s measurement of mean arterial pressure at each gestational age and their normative value  to model 1. Finally, model 4 combined models 2 and 3 by adding both the value of mean arterial pressure and the deviation from the normative value at each gestational age to model 1. Table B in appendix 1 gives a summary of variables included in each model. The areas under the receiver operating characteristics curves (ROCs) of the models were compared with a Wald test based on a bootstrapped standard error for the difference between areas. For predictions at each gestational age, we included in prediction models only women who had not yet delivered and aimed to predict the development of pre-eclampsia at any stage of pregnancy, any subsequent preterm births, and small for gestational age offspring measured at birth. Table C in appendix 1 shows the cumulative number of women who had delivered at each gestational age. We also considered including all measurements of mean arterial pressure up to a given gestational age in prediction models rather than just the initial and the current measure but found no meaningful improvement in the area under the curve.The parameters from the first stage multilevel model were then used to derive normative values of mean arterial pressure at each gestational age in SWS and these were combined with parameters from the second stage logistic regression model developed in ALSPAC and applied to women in the SWS cohort to externally validate our prediction model. The model parameters for all outcomes are given in appendix 2.We assessed the predictive ability of these models using the area under the receiver operating characteristic curve and the sensitivity, specificity, and positive and negative predictive values, together with positive and negative likelihood ratios. We assessed calibration by comparing the actual versus the predicted risk across 10ths of the risk score for each outcome. The prediction models were recalibrated for the SWS when necessary by adjusting the intercept and slope of the logistic regression model for this cohort (see appendix 2).33We assessed the expected numbers of women out of an initial cohort of 1000 who would be classified as low risk and high risk if we were to use a sequential screening strategy to rule out pre-eclampsia at each gestation considered up to 31 weeks. Model 1 was used at booking, followed by model 2 at 20, 25, 28, and 31 weeks. We tested two thresholds for the screening strategy , which were derived from the average threshold  required to give sensitivities of 95% and 99%, respectively, at each gestational age in ALSPAC. These thresholds were then applied to the SWS to produce a flowchart of the expected numbers of women in each group at each stage of testing.All analyses were completed in Stata version 13.1 and multilevel models were fitted using MLwiN version 2.30 through Stata using the runmlwin command.34This paper is based on two prospective cohort studies that collect data from members of the general population (not patients) on a large number of potential risk factors and health outcomes and that are used widely by the research community to examine a wide range of health related questions. Consequently no patients were involved in setting the research question or the outcome measures, nor were they involved in recruitment or the design and implementation of the study. There are no plans to involve patients in dissemination.Table 1 shows maternal and pregnancy related characteristics in the imputed data pre-eclampsia status.Table F in appendix 1 shows the unadjusted associations of each of the predictor variables with each of the outcomes.Table 2Table H in appendix 1 and figure 1Table 3Table I in appendix 1 shows predictive statistics fixing low false positive rates of 25%, 10%, and 5% (high specificities) for model 2 at 28 weeks. For a 5% false positive rate the sensitivity was 35% in ALSPAC and 32% in SWS, suggesting that the model had a weaker ability to rule in pre-eclampsia than to rule it out.In both ALSPAC and the SWS, the model including only maternal characteristics in early pregnancy and mean arterial pressure at the initial visit had an area under the curve of 0.61 for prediction of preterm birth . There was little improvement from including the current mean arterial pressure (model 2) or the deviation of mean arterial pressure from the normogram (model 3) until 31 weeks’ gestation, when the area under the curve rose to 0.63 in ALSPAC for models 2 and 3. Similar areas under the curve were seen in the SWS, except that an improvement was not seen until 34 weeks for models 2 and 3 compared with model 1.If we excluded cases of pre-eclampsia from our analysis, areas under the curve for prediction of preterm birth were generally slightly lower in both cohorts, but there remained an improvement from the addition of mean arterial pressure measurements from 31 weeks onwards in ALSPAC and at 34 weeks in SWS (table K in appendix 1).In ALSPAC and SWS, the model including only maternal characteristics and mean arterial pressure at the initial visit had an are under the curve of around 0.70 for the prediction of small for gestational age . Inclusion of either the current mean arterial pressure at any later gestational age (model 2) or deviation of mean arterial pressure from the normogram (model 3) or both (model 4) did not improve this in ALSPAC or SWS.We have developed and compared prediction models for pre-eclampsia and two of its associated adverse outcomes—preterm birth and small for gestational age—using observed antenatal blood pressure measurements . We did this at varying gestational ages during pregnancy and externally validated these models in a similar large population based prospective pregnancy cohort. From 28 weeks’ gestation onwards, the use of the current blood pressure in prediction models improved the identification of women who would develop pre-eclampsia compared with using maternal characteristics measured in early pregnancy including the first measurement; this could be used to facilitate stratified care. We found, however, that comparison against normograms allowing for distinctly different expected trajectories of blood pressure across pregnancy for different subgroups of women based on pre-pregnancy BMI, parity, smoking, and initial blood pressure did not improve the discriminative ability of the prediction models compared with using the observed measurement alone. Measures were of little value in predicting preterm birth until around 31 weeks’ gestation and did not aid in the prediction of small for gestational age at any gestational age after 20 weeks.We used two large prospective cohort studies, one to develop the prediction models and the second to externally validate them. The detailed measurements of blood pressure in each of the studies allowed us to evaluate the predictive ability of these measurements at multiple gestational ages across pregnancy. We also used multiple imputation to maximise the sample size available. The ALSPAC pregnancies occurred over 20 years ago, and, as then, there might have been changes in clinical practice. The models, however, were validated in the SWS, where the pregnancies occurred more recently (8-16 years ago). Several of the predictor variables used were self reported so could be prone to measurement error. This is likely to reflect the way that information is obtained in clinical practice. We needed to recalibrate the prediction model for pre-eclampsia in the SWS. This is probably because of different definitions of pre-eclampsia in the two cohorts; in ALSPAC pre-eclampsia was defined by applying a standard definition to all measurements of blood pressure and proteinuria in pregnancy whereas in SWS a record of a clinical diagnosis of pre-eclampsia during pregnancy was used. This suggests that the risk score requires recalibration according to different definitions of pre-eclampsia. The areas under the curve, however, were similar in the SWS to those in ALSPAC suggesting that the predictive ability of measurements of blood pressure in the second half of pregnancy is not dependent on the use of a particular definition of pre-eclampsia. The number of cases of pre-eclampsia in the SWS (n=88) was slightly lower than the recommended 100 events for validation,The area under the curve for our prediction model for pre-eclampsia using mean arterial pressure at 28 weeks was 0.81 in ALSPAC and 0.83 in SWS. This is higher than the area found in a model based on maternal clinical risk factors  in nulliparous women only in the SCOPE study at 15 weeks’ gestation .Current models of antenatal care focus on a series of repeat scheduled antenatal visits with recurrent screening for pre-eclampsia. In the UK, nulliparous women will have 12 healthcare assessments across gestation with nine of these visits occurring after 20 weeks’ gestation, while multiparous women will have nine assessments with six occurring after 20 weeks, missing appointments at 25, 31, and 40 weeks.Further qualitative research is required to evaluate the views of clinicians and pregnant women on the frequency of antenatal care as many women find this regular contact with healthcare professionals reassuring during pregnancy.In conclusion, measurements of blood pressure recorded during the second half of pregnancy, used in conjunction with blood pressure early in pregnancy and other maternal risk factors, can improve the identification of women who are at risk of developing pre-eclampsia later in pregnancy and could be used to differentiate women who require more intensive monitoring from those who are likely to have a normal pregnancy. As there is little value in additionally using these later pregnancy measurements to predict preterm birth and small for gestational age, however, disease specific models will be required to facilitate stratified care for the range of pregnancy complications.Blood pressure measured at the booking appointment for antenatal care is often used in combination with other clinical risk factors in prediction models to identify women at risk of developing pre-eclampsia later in pregnancyStudies that have compared patterns of change in blood pressure across pregnancy have shown that, as well as having a higher initial blood pressure, women who develop pre-eclampsia have a steeper rise in blood pressure in the second half of pregnancyThe addition of routinely collected measurements of blood pressure taken in the second half of pregnancy to prediction models for pre-eclampsia improves their performance compared with using early risk factors aloneUse of these prediction models sequentially at each antenatal appointment to rule out women who are at low risk of developing pre-eclampsia could enable these women to be transferred to a reduced antenatal care scheduleBlood pressure measurements in the second half of pregnancy are of little benefit in the prediction of preterm birth or small for gestational age offspring


Intracranial-pressure (ICP) monitoring is useful for patients with increased ICP following hemorrhagic stroke. In this study, the changes in pressure gradients between the two cerebral hemispheres were investigated after hemorrhagic stroke of one side, and after a craniotomy.Twenty-four patients with acute cerebral hemorrhages and intracerebral hematomas who exhibited mass effect and midline shift to the contralateral side on computed tomography were selected for this study. After admission, both sides of the cranium were drilled, and optical fiber sensors were implanted to monitor the brain parenchyma pressure (BPP) in both cerebral hemispheres. All patients underwent surgical hematoma evacuations. The preoperative and postoperative BPP data from both cerebral hemispheres were collected at various time points and compared pairwise.P < 0.01) in the preoperative BPP values between the two hemispheres at three different time points. Differences in the BPP values between the two hemispheres at the time of surgery, and 24 and 48 h after surgery, were not statistically significant (P > 0.05). The posteroperative BPPs of both hemispheres were statistically significantly lower than preoperative recordings.There were statistically significant differences (BPP sensors should be applied to the injured cerebral hemisphere, because this becomes the source of increased ICP. Hematoma evacuation surgery effectively decreases ICP and eliminates pressure gradients between the two cerebral hemispheres, consequently enabling brain shift correction. Rapid diagnosis and management of hemorrhagic stroke is essential because it often progresses rapidly during the initial hours following onset. The application of intracranial pressure(ICP) monitoring in patients with increased ICP due to spontaneous cerebral hemorrhage is important for determining any changes in the patients’ conditions and for guiding treatment methods . HoweverThis prospective study reviewed data from the three levels of first-class comprehensive hospital at Affiliated Hospital of Hangzhou Normal University and at the Second Affiliated Hospital, College of Medicine, Zhejiang University, China. According to Good Clinical Practice standards, the research protocol was approved by the Institutional Review Board and by the ethical committees of the Clinical Medical College of Hangzhou, and Declaration of Helsinki principles were strictly adhered to. Since the patients in this study were incapable of granting informed consent, the investigators obtained this from the patients’ legal guardians or by healthy proxy, before proceeding with the advised treatment.Twenty-four patients who were admitted between January 2006 and January 2012 with acute cerebral hemorrhages and intracerebral hematomas were enrolled in the study.All patients met the following criteria: supratentorial hemorrhagic stroke in the basal ganglion or brain lobe detected by computed tomography (CT) scan, with either (1) hemorrhage volume >30 ml, (2) midline shift >10 mm, or (3) obviously compressed basal cisterns.Patients were excluded if they were either under the age of 18 years or above 65 years, or if they had any of the following: a previous disabling neurological disease, previous craniectomy, fixed dilated pupils, or a Glasgow Coma Scale score of three, with no chance of survival.In total, 19 men and 5 women, aged between 19 and 65 years  in both cerebral hemispheres. All patients underwent surgical hematoma evacuations. Before and after surgical evacuation, nonsurgical interventions such as hyperventilation, the use of mannitol, or hypertonic saline were proposed. After admission, drilling was performed at the cranial poles on both sides in accordance with the procedures described by Gelabert . Two Camt-tests were conducted using SPSS statistical software.Monitoring data were presented as mean P < 0.01).In all patients, preoperative ICPs were recorded in both hemispheres at different time points. Since the timings of the craniotomies varied between patients (due to differences in severity and urgency), the number of ICP recordings for each patient was different. The first recording was performed in all 24 patients, but in 19 and 10 patients for the second and third recordings. The results of each recording are presented in Table P > 0.05).The postoperative ICPs were recorded in both cerebral hemispheres in all patients on the day of the craniotomy and 24 and 48 h after the craniotomy. The results of each recording are presented in Table The postoperative ICPs in both cerebral hemispheres in all patients were statistically significantly lower compared with those before surgery. Consistent with previous studies, craniotomies appeared to have significantly decreased the elevated ICP.The dynamic ICP value may be more sensitive and effective in preventing secondary brain herniation in patients with hemorrhagic stroke compared with guidance directed by clinical signs and radiological indicators. Currently, there are several clinical methods commonly used for monitoring ICP . Among tIncreased ICP can be divided into two types, diffuse and local –21: locaIn this study, following craniotomies to remove the source of intracranial hypertension in patients with local intracranial hypertension, ICP monitoring revealed a significant decrease in BPP and a disappearance of the BPP difference between the cerebral hemispheres. It is generally accepted that the purpose of various surgical treatment principles for brain injuries  is to lower ICP and eliminate brain compression. It has also been suggested that craniotomies can improve cerebral circulation and restore effective cerebral perfusion pressure on the lesion side. The results of the current study confirm that another therapeutic effect of craniotomies is the restoration of pressure balance between cerebral hemispheres. The consequent elimination of the pressure gradients between intracranial chambers enables correction of the brain shift. It would be better for future study to include the data of midline shift before and after surgical evacuation.In order to collect intracranial information quickly and accurately, BPP sensors should be applied to in the injured cerebral hemisphere. When injury and hemorrhage occur on one side of the brain, the injured cerebral hemisphere becomes the source of increased ICP, consequently forming a pressure gradient with the other cerebral hemisphere. Hematoma evacuation surgery effectively decreases ICP and eliminates the pressure gradients between the two cerebral hemispheres, consequently enabling brain shift correction.


Measurement of blood pressure (BP) is done poorly because of both human and machine errors.To assess the difference between BP recorded in a pragmatic way and that recorded using standard guidelines; to assess differences between wrist- and mercury sphygmomanometer-based readings; and to assess the impact on clinical decision-making.Royal Swaziland Sugar Corporation Mhlume hospital, Swaziland.After obtaining consent, BP was measured in a pragmatic way by a nurse practitioner who made treatment decisions. Thereafter, patients had their BP re-assessed using standard guidelines by mercury (gold standard) and wrist sphygmomanometer.The prevalence of hypertension was 25%. The mean systolic BP was 143 mmHg (pragmatic) and 133 mmHg (standard) using a mercury sphygmomanometer; and 140 mmHg for standard BP assessed using wrist device. The mean diastolic BP was 90 mmHg, 87 mmHg and 91 mmHg for pragmatic, standard mercury and wrist, respectively. Bland Altman analyses showed that pragmatic and standard BP measurements were different and could not be interchanged clinically. Treatment decisions between those based on pragmatic BP and standard BP agreed in 83.3% of cases, whilst 16.7% of participants had their treatment outcomes misclassified. A total of 19.5% of patients were started erroneously on anti-hypertensive therapy based on pragmatic BP.Clinicians need to revert to basic good clinical practice and measure BP more accurately in order to avoid unnecessary additional costs and morbidity associated with incorrect treatment resulting from disease misclassification. Contrary to existing research, wrist devices need to be used with caution. Obtaining accurate BP readings has been noted to be a challenge faced by health professionals at all levels.2 A large number of surveys have shown that physicians, along with other healthcare providers, seldom follow established guidelines for measurement of BP.3 This study analysed variations between pragmatic  and standardised (as per protocol) BP measurement. Technology has brought in various BP measuring devices, a common one in primary care being the wrist sphygmomanometer as opposed to the ‘gold standard’, but environmentally unfriendly, mercury sphygmomanometer. How does BP measurement from wrist device compare with the gold standard?Hypertension is a consistent, powerful and independent risk factor for cardiovascular disease, stroke and renal disease.4 The prevalence of high BP increases dramatically with age, with the lifetime risk of high BP approaching 100%.5 Extensive data have shown beyond doubt the benefit of controlling hypertension.6Hypertension is a common health burden affecting both developed and developing nations.6 The target BP for patients using anti-hypertensive treatment has been lowered for those with diabetes or renal disease,1 thus, it has become increasingly important to be able to detect small differences in BP. Whilst BP measurement is a vital clinical skill, it is performed poorly by all categories of healthcare professional.4 There are, in general, three sources of error in the indirect measurement of BP: (1) observer bias; (2) faulty equipment; and (3) failure on the part of clinicians to standardise the measurement techniques.7Control of BP begins with accurate measurement that leads to appropriate diagnosis, assessment of cardiovascular risk and treatment decisions.5 As a result of environmental awareness, there has been increasing pressure to remove medical devices containing mercury from clinical areas, which is leading to the gradual decline in use of the mercury sphygmomanometer and, as a result, automated BP devices have been adopted by clinicians for their convenience and ease of use.8The mercury sphygmomanometer, because of its accuracy and reliability, is widely regarded as being the gold standard against which all other devices for BP measurement should be compared.9 Petrie et al. declared that only an observer who is aware of the factors that lead to false readings should measure BP, because ‘wrong readings obtained through failure to use the proper technique often lead to the wrong diagnosis, which may result in unnecessary or inappropriate treatment and follow up’.10Rose suggested that the observer was the most critical component of accurate BP measurement.11 ‘Systolic BP underestimation of > 5 mmHg was as high as 57.5% by trained nurses [using the traditional device] versus 33.8% by the automatic device, indicating that nurses tended to underestimate BP in participants with more severe hypertension’.11 The BP measurements done by nurses were found to be consistently higher than those recorded by doctors.11 McKay et al. noted that few physicians ask their patients to rest for at least five minutes before BP measurement as recommended and, as a consequence, BP done by doctors was consistently high because of the ‘white-coat’ effect.12 Contrary to the recommended five minutes of rest, it appears that 10 minutes rest before clinic BP evaluation could improve further the precision and accuracy of the measurement and implies that the optimal time at rest before clinic BP measurement is still undefined.13In a study by Roubsanthisuk, Wongsurin and Saravich, physicians and trained nurses were compared, showing that trained nurses overestimated, rather than underestimated, blood pressure, but systolic BP underestimation was very common in participants with moderate to severe hypertension.14 For some patients, BP measurements taken in a doctor's rooms may not be an accurate representation of their typical BP. In up to 25% of patients, this measurement is higher than their typical BP – a phenomenon known as ‘white-coat hypertension’.14Clinicians should also be aware that BP in human beings is affected by multiple stimuli, such as respiration, temperature, body posture, emotional or physical stress, meals, alcohol, or caffeine and smoking and hence these factors should be taken into consideration during measurement of BP.10 In addition there are problems associated with pragmatic-nature BP measurement and other observer-related errors.10From the literature reviewed, it is clear that BP measurement is subject to errors, thus there are still some social and scientific questions which need clarity and further research, especially in resource-limited settings. Literature review concluded that with proper measurement technique, machine variation between the gold standard mercury sphygmomanometer and the wrist is minimal.Nearly all the articles found on literature review are from developed countries with a good patient-to-health-worker ratio. In a developing country setting, where the patient-to-health-worker ratio is low and resources limited, the potential for BP measurement errors may be worse. One obvious question was on assessment of the reliability of BP measurement methods, looking at both sphygmomanometer and observer differences in resource-limited settings. In so doing, such research will further enlighten health workers about the trustworthiness of BP readings and ensure that health workers are treating BP optimally. Problems related to over- or under-treatment may be serious and, if identified early, could reduce unnecessary morbidity and mortality. Most of the prior studies have focused mainly on sphygmomanometer-related differences.An analysis of variations between pragmatic or ‘real-life’ and standard BP measurement based on the ‘gold standard’ would be useful in improving chronic disease management and ensuring effective use of already-strained resources in primary care. This study will have an impact on increasing awareness of human-induced variation in BP measurement and its impact on therapeutic decisions; hence, it may motivate clinicians to follow protocol. In the long run, it may have some economic advantages in saving cost of drugs erroneously prescribed to those who, if BP had been recorded properly, would not need treatment.Is there a difference between pragmatic and standard BP measurement in primary care?To ascertain variations between standard and pragmatic BP measurements and comparison of wrist BP and mercury sphygmomanometer-based BP.To assess the impact of any differences on treatment decision.To quantify the existence of any differences between BP recorded in a pragmatic way and that recorded using standard BP measurement protocols.To quantify any discrepancy between BP measurements done by wrist sphygmomanometer when compared to mercury sphygmomanometers.To assess if the differences in BP measurement have impact on treatment decisions: whether or not to treat, to start anti-hypertensive treatment or to adjust hypertension treatment.A cross-sectional study design was used.This study was done at Royal Swaziland Sugar Corporation (RSSC) Mhlume hospital, targeting outpatients. RSSC Mhlume hospital is a rural primary care facility in the eastern part of Swaziland The facility has a turnover of about 5000 patients per month and offers mostly primary care with minor office procedures. It serves a catchment area of about 30 000.The study population comprised adult (> 18 years) patients, with or without hypertension, who accessed primary care at the RSSC hospital during the study period June 2011 to December 2011 and who gave consent to participate in the study.15 Statistically, two observations per subject achieves an 80% power to detect an intra-class correlation difference of 0.15 using an F-test with a significance level of 0.05. In a similar study of agreement, Bland recommends a sample size of 30 as a ‘good sample’ and 60 as ‘excellent’, as it gives a 95% confidence interval of +/-0.34s, where s is the standard deviation of the differences between measurements by the two methods.15Every fourth patient who had attended the outpatient clinic was eligible for selection. A sample size of 60 was used, based on statistical calculations and sample size from similar studies.® Excel spreadsheet for analysis.Informed consent was obtained from eligible patients. Participants had BP assessed in a pragmatic way by nurse practitioners who would give their therapeutic decision based on their readings. Participants had BP re-assessed according to the standard protocol, using mercury sphygmomanometer and wrist sphygmomanometer alternately. To reduce bias, the order of measurement for pragmatic or standard BP measurements was alternated for successive patients. Finally, demographic and relevant clinical data were collected into a ‘Data Collection’ form, which was subsequently entered into a MicrosoftTo improve internal validity, the potential biases were handled as laid out below.For the reduction of selection bias, a systematic random sample (every fourth patient) was used.16 the standard BP was measured within a few minutes before or after the pragmatic BP.This level of bias could occur at any stage during the measurement, recording, management or analysis of the data. Notable biases were the Hawthorne effect (nurses could change their BP measurement routine because they were aware of the investigation underway) and observer diagnostic suspicion bias. These were reduced by blinding the nurse researcher to results from the nurse practitioners and nurse practitioners were blinded to the ongoing study. Use of validated, standardised and calibrated sphygmomanometers reduced instrument variation. Batteries for the wrist devices were replaced regularly. To reduce subject physiologic variation, as well as the known regression to mean with repeated BP measurement phenomenon,13Time between performing the BP measurements was an important confounder. Blood pressure tends to come down with time, which is known as regression to the mean. The time between pragmatic and standard BP assessment was kept at a minimum so as to reduce the possibility of confounding bias. Previous studies indicate that a time lag of less than 10 minutes does not have any significant effect on the BP result.® Excel was used to capture the data and the data analysis software system, STATISTICA version 9 , was used to analyse the data. The statistical analysis comprised both descriptive and analytical statistics. For descriptive statistics, summary statistics were used to describe the variables. The Wilcoxon sign rank test was used to assess differences between means of BP. For analytical statistics, simple logistic regression, Pearson correlation (r), intra-class correlation coefficient (ICC) and Kappa were used appropriately. Standard reference scales were used for Pearson, ICC and Kappa. The Bland and Altman (BA) method of analysis of agreement was used for further assessment of agreement. Reference ranges for comparison of BA analysis were within 10 mmHg for diastolic BP and within 20 mmHg for systolic BP, because these are known ranges for hypertension severity grading.6 Throughout the analysis, a p-value of p < 0.05 represented statistical significance in hypothesis testing and 95% confidence intervals were used to describe the estimation of unknown parameters.MicrosoftEthical approval for the study was granted by the University of Stellenbosch Human Research Ethics Committee (reference number N10/11/394) on 13 May 2011. Institutional ethical approval was also obtained.Sixty outpatients consented to participate in the study, of which 32 were men. The mean age of the participants was 42.6 years, the mean weight 77.8 kg and the mean height 1.6 metres. The prevalence of hypertension was 25%. Twenty-eight per cent of the participants had co-morbid diseases.The mean systolic BP was 143 mmHg for pragmatic BP, 133 mmHg for standard BP using mercury sphygmomanometer and 140 mmHg for standard BP assessed using wrist device. The mean diastolic BPs were 90 mmHg, 87 mmHg and 91 mmHg for pragmatic, standard mercury and wrist, respectively. It took an average of 4.2 minutes between pragmatic and standard BP measurement.Three participants reported either having a full bladder or having eaten within 30 minutes before BP assessment, five had exercised, one had smoked and taken coffee and seven reported some degree of psychological stress. r) was the same, 0.9, for systolic and diastolic BP for all BP methods which were being compared, corresponding to ‘good association’ between pairs being compared. The ICC (model 2) was consistent with ‘almost perfect agreement’ for all methods compared. Thus r and ICC could not differentiate further the level of agreement between the methods in study. Adjustment for confounding was done: neither psychological stress, full bladder, eating a meal, exercise, smoking nor taking coffee within 30 minutes before BP assessment were confounding factors based on less than 10% difference of r, ICC, Kappa and BA results. The key results are presented in The Pearson correlation coefficient  = –10.7 + 1.2 SBPPr . For agreement, the bias was 9.6 mmHg with limits of agreement of –17.4 mmHg to 36.6 mmHg. Using the bias alone, 9.6 mmHg, this would equate to excellent clinical inter-changeability based on a clinically-significant BP range of within 20 mmHg. However, the limits of agreement were too wide for the two methods to be regarded as agreeing clinically. For systolic BP, the corresponding regression equation was SBPMc = −2.5 + 1.0 SBPWr . The BA analysis showed a bias of 7.1 mmHg and limits of agreement, −15.4 mmHg (lower) and 29.6 mmHg (upper), which were outside the clinical reference range for inter-changeability, within 20 mmHg. For diastolic regression the equation was linear, with DBPMc = 10.6 + 0.7 DBPWr , a sign of good positive association. The limits of agreement, −19.0 mmHg (lower) to 11.7 mmHg (upper), confirmed poor clinical agreement when compared to the clinically-acceptable range of agreement, within 10 mmHg. r had a positive association. The BA plot in Finally, pragmatic BP and wrist-based standard BP were also compared for completeness. For systolic BP, n = 8/41), were classified erroneously as requiring anti-hypertensive therapy when using pragmatic BP. Of those who needed to change treatment, the two BPs concurred (100%). Scores for treatment decisions  were subsequently compared between decisions based on pragmatic BP and those based on standard mercury-based BP. The Kappa score was 0.7 which equates to ‘good agreement’ based on the widely-accepted Byrt's criteria (see Note under B). Overall (without stratifying), the treatment outcomes concurred in 83.8% of the cases, hence 16.7% were misclassified when compared with the standard BP. For the decision not to start treatment 78% of instances concurred; for the decision to start treatment, 90.9% agreed; and for the decision to adjust treatment, the agreement was 100%. Of the patients who were not supposed to start treatment (basing on the standard mercury-based BP), 19.5%  South Africans have hypertension,17 In this study, there was no clinical agreement between pragmatic and standard BP measurements for both systolic and diastolic BP. Pragmatic systolic BP was at least 10.7 mmHg higher than standard mercury BP. For diastolic BP, pragmatic readings were at least 3 mmHg higher than the standard mercury readings. These results were similar to those from a study by Myers et al. which found that when the primary care physician recorded BP using a mercury or anaeroid device, the resulting value frequently tended to be higher than what it would be if measurement guidelines were adhered to strictly.18 Similarly Campbell and McKay concluded that pragmatic readings, namely, those obtained with little regard for patient factors or recommended technique, cause errors in BP assessment and do not correlate effectively with target organ damage; as such, no evidence exists to support the use of pragmatic readings in assessing a patient's need for pharmacologic treatment.19 However, standardised readings, namely, those that follow recommended protocols, demonstrate high correlation with hypertensive target organ damage and were used in the major randomised controlled trials that showed the benefits of pharmacotherapy.19The next step was a comparison of pragmatic and standard BP measurements. Health workers generally do not follow BP measurement guidelines. In a study on the BP measurement behaviour of clinicians done by Villegas et al., none of the physicians tested followed all the recommendations of the American Heart Association when measuring BP and a few recommendations were only followed by a minority of the physicians studied.20 People who are identified incorrectly as having hypertension may experience adverse effects of medication and have increased medical insurance and treatment costs.21 Conversely, consistent underestimation of diastolic pressure by the same margin would reduce by 62% the number of patients perceived as being hypertensive.21 These errors could deprive patients of therapy which has been proven to be beneficial, thus leading to possible increases in serious medical and social complications.21The clinical consequences of poor BP measurement are well documented in literature: consistent overestimation of diastolic BP by as little as 5 mmHg may more than double the number of patients with hypertension in a physician's practice.20 Overall, 16.7% of participants had their treatment outcomes misclassified. Of those who needed treatment, there was a concordance of 91% between pragmatic and standard BP-based decisions. However, for those hypertensive patients who needed to have their treatment adjusted, pragmatic and standard BP had 100% concordance. The likely explanation for this is that when BP was markedly elevated, there was no difference between pragmatic and standard BP.In this study, 19.5% of patients who were started on anti-hypertensive therapy based on pragmatic BP actually did not need any treatment. This trend was similar to many studies which showed increased diagnosis of hypertension if BP was not measured according to guidelines.22 We suspected that the difference was mostly because of the precise arm position and a known problematic phenomenon of wrist devices in which there is a systematic error introduced by the hydrostatic effect of differences in the position of the wrist relative to the heart.22 This can be avoided if the wrist is always at heart level when the readings are taken, but there is no way of knowing retrospectively whether this was performed when a series of readings are reviewed.22Comparison of wrist and mercury BP measurements was subsequently performed. Standard mercury diastolic and systolic BPs were consistently higher when using a wrist device. For systolic BP, the difference was as much as 20 mmHg, whilst it was approximately 10 mmHg for diastolic BP, a sharp contrast to previous studies which found similarities between mercury and wrist devices.5 However, recent studies have shown that ambulatory BP measurements correlate better with the exact BP. Hodgkinson et al. have recently concluded that ambulatory BP was more cost effective than clinic or home BP.23 However, guidelines for diagnosis and treatment of hypertension are still based on clinic BP measurements.10The mercury sphygmomanometer is generally regarded as the gold standard against which all other devices for BP measurement should be compared.23 Several papers have challenged the shortfalls of BA analysis,24 but Bland and Altman have stated that the use of correlation coefficients is wrong for these types of studies.25 In this study, intra-class correlation, Pearson's coefficient and linear regression both fell short of explicitly analysing the research question.Finally, a statistical lesson! Statistical methods for comparison methods have been subject of discussion amongst clinicians. The BA method is regarded as the gold standard.The main strength was that this study design was fast and inexpensive and was done in a resource-limited setting approximating most third-world institutions. It gave a useful initial overview of the problem, including the community prevalence. The statistical methods used were appropriate for studies of this nature.There was very limited potential to make causal inference of any differences, an obvious weakness of this study. Secondly, we could not claim success with minimising regression to mean with the serial BP measurements as the exact time to ensure that regression to mean is rectified, is unknown. In addition, it was impossible to totally eliminate observer bias despite ‘blinding’ the nurses as there was always room for discussion when they meet outside the study centre; hence, the ‘pragmatic’ BPs might not have been as pragmatic as we expected. The other potential confounder was that the pragmatic BP was done by different nurse practitioner. No adjustments were made for this as surely their BP measurement techniques would differ. The other problem was diagnostic on the part of nurses: the clinical decision to start treatment. Usually, a number of readings are required to start treatment unless there are risk factors, significant target organ damage or BP was markedly elevated. The nurse practitioners might have over-diagnosed hypertension as they relied erroneously on one reading, even when BP was mildly elevated.There are differences between pragmatic and standard BP but wrist and mercury BP readings are usually comparable.This study further confirmed the existence of differences between pragmatic and standard BP measurements in a resource-limited setting. The difference leads to 16.7% disease status misclassification. Wrist and mercury devices potentially lead to conflicting results, which is contrary to earlier studies. Pearson and Intra-class correlation coefficients are weak statistical methods in studies of this nature.There is a difference between pragmatic and standard BP measurements which affect the decision to start treatment and the decision to initiate treatment, but not the decision regarding alteration of regime for those already on treatment. There are also marked differences between wrist- and standard mercury-based BP devices which also affect treatment decision-making. In future, when assessing agreement between clinical methods, the BA method is more conclusive than correlation coefficients. Clinicians need to revert to basic good practice and measure BP more accurately so as to avoid unnecessary additional costs and morbidity associated with incorrect treatment resulting from disease misclassification. Wrist devices need to be used with caution.


The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline.2 and who were followed up for > 1 year were included in our analysis. Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in male and ≥ 6.0 mg/dL in female or when hypouricemic medications were prescribed.This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 per year, p = 0.001 by Wilcoxon signed-rank test).Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR . However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: −5.3 ± 8. 2 vs. 0.2 ± 6.2 mL/min/1.73 mAlthough hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency. Uric acid has been regarded as a marker rather than a risk factor for the development of chronic kidney disease (CKD) because a low glomerular filtration rate (GFR) induces elevation of serum uric acid (sUA) level despite compensatory increases in urinary and gastrointestinal urate excretions. However, recent studies suggested an independent role of uric acid in the development of CKD. For instance, hyperuricemia is shown to be associated with an increased risk of CKD in large cohort studies such as the Atherosclerosis Risk in Communities and the Cardiovascular Health Study  and the Association between autosomal dominant polycystic kidney disease (ADPKD) and hyperuricemia was first described by Rivera et al. . ADPKD i2 at the initial evaluation and who were followed up for > 1 year. Patients with certain conditions that can independently influence renal function such as diabetes [A total of 612 patients were screened at the ADPKD clinic in Seoul National University Hospital. ADPKD was diagnosed according to the unified criteria proposed by Pei et al. . We selediabetes , pregnandiabetes . This st2 or initiation of renal replacement therapy. Albuminuria was defined as a stick albumin level of >1+ by urine dipstick test. Urine albumin was quantified by the immunoturbidimetric assay using Toshiba-120FR. Hypertension was defined by a systolic blood pressure of >140 mmHg, diastolic blood pressure of >90 mmHg, or current use of antihypertensive medication.The sCr was measured at 3- or 6-month interval using the Jaffe method by Hitachi 7600 and Toshiba-200FR, which was calculated to Isotope Dilution Mass Spectrometry (IDMS)-traceable sCr. The Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) formula was used to calculate eGFR. Delta eGFR (ΔeGFR/year) was calculated using the equation /follow-up duration (years). The CKD stage was classified according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines . ESRD waThe sUA level was determined using the uricase method (Hitachi 7600 and Toshiba-200FR). Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in males and ≥ 6.0 mg/dL in females or when patients have received hypouricemic treatment. Hypouricemic medications were prescribed in patients with gout, a history of uric acid stones, or persistent elevation of sUA level of > 8.0 mg/dL that was not controlled by dietary modification in 2 successive visits.t -test was used to compare the continuous variables between the groups. Linear regression analysis was used to find the association between sUA and clinical variables. Cox proportional hazard model was used to compare renal survival between groups. Wilcoxon signed-rank test was used to evaluate the effect of hypouricemic medication on the rate of renal progression before and after the start of medication. P < 0.05 was considered statistically significant. All the statistical analyses were performed using SPSS version 19.0 .Continuous variables were expressed as mean ± standard deviation. Student The clinical characteristics of 365 patients on initial evaluation are summarized in Table 2, p < 0.001) compared to Group A.When compared with those in Group A, the patients in Group B were slightly older , had higher prevalence of hypertension , showed male predominance , and had shorter follow-up duration . Group B had higher sCr levels  and lower eGFR , ACR  and TKV  but negatively correlated with eGFR . Simple linear regression analysis in 353 patients without hypouricemic treatments at the initial evaluation revealed that age, albuminuria, TKV, and sUA level were correlated with reduced initial eGFR. After adjustment for age, male sex, blood pressure, albuminuria, and TKV, sUA levels still remained a significant factor  were analysed Figure . The sUA2 per year, p = 0.026) and relative values .Among 365 patients, 42 patients  progressed to ESRD during the follow-up . When evaluating the deterioration of eGFR, we examined 296 patients not taking hypouricemic medication (255 patients from Group A and 41 patients from Group B) to exclude the influence of hypouricemic agents  or benzbromarone (n = 41) more than a year.2 at the time of hypouricemic treatment initiation. The change in sUA and eGFR before and after 1 year of treatment initiation was analyzed . Further analysis showed that correction of hyperuricemia may attenuate renal function decline in early CKD stages (1 ~ 3a) whereas it may not attenuate renal function decline in advanced CKD stages (3b ~ 4). Serial changes in sUA and eGFR are presented in Figure Among them, 13 patients were included in CKD stage 1 or 2, 19 in CKD stage 3a, 11 in CKD stage 3b, and 10 in CKD stage 4 before treatment initiation. Mean sUA was 8.70 ± 0.78 mg/dL and mean eGFR was 47.9 ± 20.3 mL/min/1.73 med Table . After tIn our retrospective cohort study, we demonstrated that sUA level is associated with renal function in ADPKD. However, we were not able to show that hyperuricemia independently contributes to the renal progression.In our study, sUA level was associated with concurrent eGFR, independent of age, sex, albuminuria, and TKV. This result is consistent with those from previous studies reporting that hyperuricemia is associated with early-onset hypertension, TKV, and increased risk of ESRD . HyperurAlthough we failed to show independent effect of hyperuricemia on renal progression, we examined the effect of hypouricemic medication on the slope of annual eGFR change. Correction of hyperuricemia appeared to attenuate ΔeGFR/year, especially for the patients in early CKD stages (1~3a), suggesting that hyperuricemia may influence renal function deterioration in some patients. Although our result is limited by small number of patients and short observation time, this is consistent with the previous finding that allopurinol therapy preserved sCr level and lowered the risk of renal progression in hyperuricemic patients with mild to moderate CKD ,19. On tSeveral mechanisms were proposed to explain renal dysfunction by hyperuricemia. First, association between increased sUA level and cardiovascular disease has been reported . In our URAT1, GLUT9, NPT4, and OAT3) in 3 ADPKD kidneys and 1 normal control kidney, which revealed strong expression of all 4 urate transporters along the compressed proximal tubules nearby renal cysts [The pathogenic role of hyperuricemia in renal progression needs to be further investigated in regard to urate handling in ADPKD. In ADPKD, altered tubular membrane transport process might affect renal urate handling and homeostasis. Compared to general population, a higher prevalence of uric acid stone was noted in ADPKD. However, previous studies showed inconsistent data about urate handling in ADPKD ,11. We aal cysts  (AdditioOur study has several limitations. This is a single-center, retrospective cohort study. Therefore, further prospective study is warranted to evaluate the causal relationship between hyperuricemia and renal function decline. In addition, genetic factor, which is the strongest predictor of renal progression, has not been evaluated in this study. In the analysis of the hyperuricemia and annual eGFR decline, mixed effects model or generalized estimating equation model would be best suited. However, they could not be used due to some missing data of sUA and eGFR during follow-up period and the interval of measurement was not regular. Lastly, we failed to show the independent effect of hyperuricemia on renal progression.In conclusion, we failed to show the independent effect of hyperuricemia on renal progression. Nevertheless, for the first time, we demonstrated the correction of hyperuricemia with uric acid lowering agents may attenuate renal progression in the early CKD stages suggesting that treatment of hyperuricemia would be beneficial for some ADPKD patients to preserve renal function. Further prospective study is needed to verify the impact of hyperuricemia control on disease progression in ADPKD.ACR: Albumin to creatinine ratio; ADPKD: Autosomal dominant polycystic kidney disease; CKD: Chronic kidney disease; CKD-EPI: Chronic kidney disease epidemiology collaboration; CT: Computed tomography; ESRD: End-stage renal disease; GFR: Glomerular filtration rate; GWAS: Genome-wide association studies; IDMS: Isotope dilution Mass Spectrometry; KDIGO: Kidney disease improving global outcomes; RAS: Renin-angiotensin aldosterone system; sCr: Serum creatinine; sUA: Serum uric acid; TGF-β: Transforming growth factor beta; TKV: Total kidney volume; TNF-α: Tumor necrosis factor alpha.The authors declare that they have no competing interests.MH collected the data and drafted the manuscript. HP participated in the design of the study and drafted the manuscript. HK participated in the acquisition of data. HC, HH participated in the analysis and interpretation of data. JJ, AK carried out immunohistochemical staining. SK carried out kidney volume measurement. HC, DK participated in critical revising the manuscript. JY, KO participated in the design of the study and interpretation of data. YH helped interpretation of data and drafted the manuscript. CA conceived of the study, interpretation of data and revising the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/15/63/prepubTable S2. Average systolic, diastolic, and mean blood pressure at 1 year pre-and post-treatment.Serum uric acid and eGFR pre-/post-treatment 1 year. Click here for fileImmunohistochemcalstaining of URAT1, GLUT9, NPT4 and OAT3.Click here for file


Absences of normative, 10–20 % declines in blood pressure (BP) at night, termed nocturnal non-dipping, are linked to increased cardiovascular mortality risks. Current literature has linked these absences to psychological states, hormonal imbalance, and disorders involving hyper-arousal. This study focuses on evaluating associations between nocturnal non-dipping and indices of functional cardiac capacity and fitness.The current study was a cross-sectional evaluation of the associations between physical capacity variables e.g. Metabolic Equivalent (MET) and Maximum Heart Rate (MHR), Heart rate reserve (HRR), and degree of reduction in nocturnal systolic blood pressure (SBP) or diastolic blood pressure (DBP), also known as ‘dipping’. The study sample included 96 cardiac patient participants assessed for physical capacity and ambulatory blood pressure monitoring. In addition to evaluating differences between groups on nocturnal BP ‘dipping’, physical capacity, diagnoses, and medications, linear regression analyses were used to evaluate potential associations between nocturnal SBP and DBP ‘dipping’, and physical capacity indices.p = .01) and had a lower maximum heart rate during the Bruce stress test (p = .05), dipping was only significantly associated with Type 2 Diabetes co-morbidity and was not associated with type of medication. Within separate linear regression models controlling for participant sex, MHR , HRR , and METs  emerged as significant but small predictors of degree of nighttime SBP dipping. Similar relationships were not observed for DBP.45 males and 14 females or 61.5 % of 96 consented participants met criteria as non-dippers . Although non-dippers were older (Since the variables reflecting basic heart function and fitness (MHR and METs), did not account for appreciable variances in nighttime BP, nocturnal hypertension appears to be a complex, multi-faceted phenomena. Blood pressure (BP) reductions of 10–20 % during sleep are essential for heart health . When thRecent studies have linked ANBP and decreased nighttime BP reductions to disorders involving hyperarousal and disrupted sleep (e.g. chronic insomnia). In these studies, non-dipping was associated with greater beta frequency in sleep EEG , and PTSCurrently, ANBP diagnosis requires 24-h ambulatory blood pressure monitoring (ABPM), and despite epidemiological studies highlighting the importance of ANBP in improved hypertension management , 18, 19,While existing literature has focused on the link between hyper-arousal and ANBP , 10, 12,The current study is a cross-sectional evaluation of associations between the extent of nocturnal dipping in blood pressure and physical capacity variables assessed through a standard cardiovascular stress test. Study participants were enrolled in the Cardiovascular Prevention and Rehabilitation Program at Southlake Regional Health Centre . All individuals entering the program received information about the research study through an information sheet, and verbally through Rehabilitation Program staff. Individuals who expressed interest were directed to research staff who helped them complete an informed consent form for subsequent 24-h ambulatory blood pressure monitoring and to allow research staff to access their stress test results. A total of 96 individuals consented and took part in both the 24-h blood pressure monitoring and exercise capacity evaluation. The study was reviewed and approved by Human Participants Review Committee at York University in Toronto, Canada.The 24-h blood pressure (BP) assessment  entailed a BP measurement every 20 min during waking periods and every hour during sleep. The less frequent hourly assessments (during sleep) were deliberately selected because more frequent assessments (during sleep) were perceived to likely be sleep disruptive. We included a 24-h assessment of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), and heart rate (HR). To allow a better understanding of blood pressure variation in relation to their day and night activities, participants kept logs of daily activities, along with times for initiating and waking up from sleep. Participants had previously self-disclosed their typical bedtime and sleep time (prior to the 24 h ABPM), and we used their disclosures to conclude the assessments per 20 min intervals, and initiate the assessments per 60 min intervals. If patient logs during the 24 h ABPM diverged from their prior self-report, we corrected the record so actual bedtime and sleep times were actually associated with nocturnal BP assessments.The primary dependent measure was the percent nocturnal reduction in blood pressure in relation to both mean systolic blood pressure (SBP) and the diastolic blood pressure (DBP). This reduction value was calculated as [daytime SBP or DBP – nighttime SBP or DBP]/daytime SBP or DBP expressed as a percentage , 27. Part-test to evaluate potential differences between males and females and BP dippers and BP non-dippers in relevant demographic, clinical, body composition, fitness, and ambulatory blood pressure variables. Where applicable, we report t-tests with Welsh correction to account for unequal variances between groups. We used chi-square test for independence to explore associations between categorical study variables . Similarly, Pearson product–moment correlation coefficients are reported for continuous variables. Finally, associations between SBP and DBP dipping and functional capacity variables, such as metabolic equivalent (MET), MHR, or alternatively HRR were investigated within separate multiple linear regression models. In addition, we assessed possible interactions between these variables and sex within the regression models. All analyses were performed with SPSS v.19 .Descriptive statistics on all demographic and clinical variables are presented in Table p = .01) and achieved a lower maximum heart rate during the Bruce stress test (p = .05). Non-dippers had also lower mean daytime SBP (p = .006) and DBP (p = .02) and higher mean nocturnal SBP (p = .01) and DBP (p = .01) values. With regards to diagnostic and medication variables, as presented in Table χ2 = 4.23, p = .04), there were no associations between dipping status and other treatment-related variables, including medical diagnoses, cardiac procedure-treatment (including treatment for sleep apnea with chronic positive airway pressure) and, notably types of blood pressure medications.Participants included 96  individuals with complete 24-h ABPM and functional capacity measurements. On average, 41.1 successful readings were taken during the daytime and 8.6 readings during nighttime. Using the commonly applied abnormal nocturnal BP (non-dipping) criteria of < 10 % drop in nocturnal blood pressure relative to daytime values, 45 males and 14 females or 61.5 % of participants met criteria for abnormal nocturnal BP (non-dippers). Compared to dippers , non-dippers were older (p = .05) along with MHR  had a significant correlation with the degree of nocturnal dipping. In addition, within a linear regression model that included participant sex, with males as the reference group (see Table p = .01) emerged as a significant predictor of the degree of nighttime SBP dipping in a model that, altogether, accounted for a relatively modest amount of variance (Adjusted R2 = .06). To further address individual and sex-related differences in resting heart rate, we ran a separate model with Heart Rate Reserve (HRR) as predictor variables. In this model, HRR was only also associated, albeit modestly, with the degree of SBP dipping . Along similar lines, functional capacity expressed in METS only marginally correlated with the extent of nocturnal dipping , and within a regression model that included participant sex , was a significant but small predictor of the degree of nighttime SBP dipping . Altogether, the overall model accounted for only 4 % of variance in nighttime SBP dipping (Adjusted R2 = .04). Similar regression models ran for diastolic blood pressure dipping (DBP) as outcome variable did not reach statistical significance.Table In this study our objective was to understand the relationship between dipping status in systolic blood pressure (SBP) and functional capacity indices, notably the maximum heart rates (MHRs) and metabolic equivalents (METs) achieved during standard stress tests with patients enrolled in a cardiac rehabilitation program. In addition, to control for sex or individual differences in MHR, we used HRR to account for individual or sex-related differences in resting heart rate. The control of nocturnal BP is an important cardiac risk target. Although current data are insufficient to demarcate the pathways of effective reduction, our results indicated cardiac performance (reflected by the MHR) and functional capacity (reflected in METs) during stress testing, was significantly but modestly associated with systolic blood pressure dipping.N = 14), and worsened the status of more subjects than it improved (5 subjects who were dippers became non-dippers and 4 subjects who were non-dippers became dippers). These results again suggest the the complexity of nocturnal BP which may not be linearly influenced by exercise training. Training may require adjustments not typically undertaken in exercise programs targeted at generic fitness. When non-dippers are found to have Obstructive Sleep Apnea (OSA), the use of continuous positive airway pressure (CPAP) has been identified, in some cases, as effective [Since the variables measured, reflecting basic heart function and fitness, do not account for an appreciable variance in nighttime BP, the nocturnal hypertension phenomena appears to be multi-faceted and complex. This raises the question of the impact of factors relating more broadly to autonomic sympathetic hyperarousal, both behavioural and physiological, and possibly modifiable via medication and behavior modification. Along these lines, the interventions thus far most frequently applied employ exercise and use of continuous positive airway pressure (CPAP) in managing nocturnal hypertension . Wuerzneffective . In our N = 1042), and the New Zealand blood donor study  reported a 45 % prevalence of insomnia symptoms on at least one occasion per week [N = 2000) identified 40 % of individuals reporting 1 or more insomnia symptoms ≥ 3 times per week and a low incidence of help-seeking, reflecting an under-treatment of sleep disruption [In past research, multiple studies implicate disrupted sleep and autonomic hyperarousal as important factors that must be considered in the treatment of nocturnal hypertension. Population-based studies reveal an increased prevalence of sleep disorder likely attributable to increased daily stress. For example, the Sao Paulo Sleep Study  revealedper week . A Canadsruption . Along tsruption , raisingsruption .Although our study introduced novel findings, we must acknowledge limitations that indicate interpretive cautions. The sample was assessed while undergoing a Cardiac Rehabilitation Program, which bases referrals on recent cardiac events resulting in hospitalization. Accordingly, this group may represent a sample of patients more impaired with respect to cardiac function, compared to samples being followed by primary care physicians. Furthermore, the 24-h ambulatory monitoring assessment was voluntary and thus patients less able to tolerate ABPM were self-selected for exclusion. An additional point is that patients tolerate 24-h ABPM differently and thus some apparent nocturnal BP readings may be related to the variability of reactions to nighttime assessment. Until multiple serial ABPMs are undertaken, it is difficult to exclude the possibility that when patients better adjust to ambulatory assessments, their nocturnal BP reading may be reduced.In conclusion, our findings relate nocturnal hypertension (dipping vs. non-dipping) to fundamental indices of cardiac function and capacity but these factors accounted for a modest degree of variance. This suggests nocturnal BP is a complex multi-faceted phenomena, with mechanisms that may be better controlled through specific medical and behavioural treatments.


Intradialytic hypotension (IDH) is considered one of the most frequent complications of haemodialysis with an estimated prevalence of 20–50 %, but studies investigating its exact prevalence are scarce. A complicating factor is that several definitions of IDH are used. The goal of this study was, to assess the prevalence of IDH, primarily in reference to the European Best Practice Guideline (EBPG) on haemodynamic instability: A decrease in systolic blood pressure (SBP) ≥20 mmHg or in mean arterial pressure (MAP) ≥10 mmHg associated with a clinical event and the need for nursing intervention.During 3 months we prospectively collected haemodynamic data, clinical events, and nursing interventions of 3818 haemodialysis sessions from 124 prevalent patients who dialyzed with constant ultrafiltration rate and dialysate conductivity. Patients were considered as having frequent IDH if it occurred in >20 % of dialysis sessions.Decreases in SBP ≥20 mmHg or MAP ≥10 mmHg occurred in 77.7 %, clinical symptoms occurred in 21.4 %, and nursing interventions were performed in 8.5 % of dialysis sessions. Dialysis hypotension according to the full EBPG definition occurred in only 6.7 % of dialysis sessions. Eight percent of patients had frequent IDH.The prevalence of IDH according to the EBPG definition is low. The dominant determinant of the EBPG definition was nursing intervention since this was the component with the lowest prevalence. IDH seems to be less common than indicated in the literature but a proper comparison with previous studies is complicated by the lack of a uniform definition.The online version of this article (doi:10.1186/s12882-016-0231-9) contains supplementary material, which is available to authorized users. Intradialytic hypotension (IDH) is considered one of the most frequent complications of haemodialysis treatment and is associated with increased cardiovascular morbidity and mortality . VariousA complicating factor in the analysis of IDH is that many different definitions of hypotension are used in the literature. These vary from liberal definitions that only require a minimum fall (e.g. ≥20 or ≥30 mmHg) in systolic blood pressure (SBP) –21 to stThe goal of this study was to assess the prevalence of IDH and to identify patient and treatment factors that are associated with its presence. For this purpose, we prospectively collected the haemodynamic data, clinical events and nursing interventions of 3818 dialysis sessions from 124 patients. We primarily used the EBPG definition  and studThis multicenter prospective observational study included adult ≥18 years) incenter haemodialysis patients from the Dialysis Center Groningen and the dialysis unit of the University Medical Center Groningen  was not necessary. All personal information was de-identified and analyzed anonymously. Patients gave oral informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki.During 3 months  we prospectively collected the haemodynamic data of all the haemodialysis sessions from participating patients. At each session, patients were evaluated for pre- and postdialysis weight and pre-, intra-, and postdialysis blood pressures and heart rate, ultrafiltration volume, and the occurrence of clinical events possibly related to dialysis hypotension, and nursing interventions. Clinical events were defined as nausea, dizziness, light-headedness, fatigue occurring during haemodialysis, muscle cramps, loss of consciousness or any other additional complaint that was related to the dialysis procedure as judged by the patient and/or nurse . Nursing interventions were defined as temporary interruption of ultrafiltration, Trendelenburg position, and administration of intravenous fluids. All data were registered on a run sheet and stored electronically.Blood pressure and heart rate were measured with an automated oscillometric monitor at standardized intervals: before haemodialysis, at 10, 30, 60, 120, and 180 min intra-dialysis, and at the end of the dialysis session . Haemodialysis sessions during hospitalization were excluded from the analysis. Prescriptions regarding dry weight and antihypertensive medication were made by the nephrologists during their weekly visit to the participating patients. Dry weight was evaluated clinically  and by the cardiopulmonary radiological aspect. Ultrafiltration rate was calculated by dividing ultrafiltration volume by dialysis session length.Cardiovascular history was defined as any history of ischemic heart disease, congestive heart failure, stroke or peripheral vascular disease. Residual diuresis was defined as ≥200 ml/day. Equilibrated Kt/V was calculated from pre- and postdialysis plasma urea concentration according to the second-generation logarithmic Daugirdas equation .Dialysis hypotension was primarily defined according to the EBPG definition  as a decAll patients were dialysed with bicarbonate dialysis, thrice weekly for 3.5 to 4.5 h with a low-flux polysulphone hollow-fiber dialyser, F8 or F10 . Blood flow rates ranged between 250 and 350 ml/min. The dialysate flow rate was 500 or 700 ml/min. The blood flow and dialysate flow were kept constant throughout the study period in the individual patient. All patients were dialyzed with a constant dialysate conductivity of 13.9 mS/cm and a constant ultrafiltration rate. The dialysate temperature, 36.0 or 36.5 °C, was kept constant during the study period for the individual patient. The dialysate composition was as follows: sodium 139 mmol/l, potassium 1.0 or 2.0 mmol/l, calcium 1.5 mmol/l, magnesium 0,5 mmol/l, chloride 108 mmol/l, bicarbonate 34 mmol/l, acetate 3 mmol/l, glucose 1.0 g/l. Patients received a light meal and two cups of coffee or tea during haemodialysis as usual.Continuous variables with normal distributions are reported as mean ± SD, skewed data as median (interquartile range), and categorical data by number (percentage). Normality was tested with the Shapiro Wilkinson test. Comparisons of variables with a normal distribution were made with the T-test and comparisons of variables with a skewed distribution were performed with the Mann Whitney U test.For the analysis of the determinants of dialysis hypotension a multivariate repeated generalized (logistic) linear mixed model was estimated  followedP-values <0.05 were considered statistically significant.Analyses were performed with SPSS version 20.0, GraphPad Prism version 5.0 and statistical programming language R (R Development Core Team (2011). Two tailed One hundred twenty-four patients were included in this study. Patient characteristics are shown in Table In total 3818 haemodialysis sessions were analyzed. The average number of dialysis sessions per patient was 32 (range 9–36).The average pre- and postdialysis body weight was 74.7 ± 15.8 kg and 72.8 ± 15.8 kg, respectively. The average ultrafiltration volume and ultrafiltration rate in all 3818 dialysis sessions was 2386 ± 834 ml and 8.5 ± 3.3 ml/kg/h, respectively.Average courses of blood pressure and heart rate of the 3818 dialysis sessions are shown in Fig. As much as 63.8 % of dialysis sessions were complicated by a decrease in SPB of ≥20 mmHg  patients fulfilled the full EBPG definition of dialysis hypotension in more than 20 % of dialysis sessions Table .Similar analyses were performed for alternative cut-offs for SBP showing that 74.2 % of patients had a decrease in SBP ≥30 mmHg and 52.4 % of patients had a decrease in SBP ≥40 mmHg in more than 20 % of the dialysis sessions. A total of 6.5 % of patients had a decrease in SBP ≥30 mmHg in combination with a clinical event and a nursing intervention in more that 20 % of dialysis sessions; 5.6 % of patients had a decrease in SBP ≥40 mmHg in combination with a clinical event and a nursing intervention in more than 20 % of dialysis sessions.P = 0.001) and a greater decline in SBP during dialysis in comparison with patients without frequent IDH  compared with patients without frequent IDH. The proportion of patients that used a beta-blocker did not differ between these 2 groups, 70 % and 57 % in patients with and without frequent IDH, respectively  and a higher ultrafiltration volume (p = 0.0004) . Even if we use a more liberal definition, e.g., a fall in SBP >20 mmHg or a fall in MAP >10 mmHg in combination with a clinical event (thus without the need for nursing intervention), the prevalence of dialysis hypotension is 18.4 % which is still lower compared with the prevalence of 20–50 % stated in most reviews. It is unlikely that our study underestimated the true prevalence of dialysis hypotension since blood pressure was measured much more frequently than is usual in clinical practice, facilitating the finding of a minimum reduction in blood pressure. In addition, both patients and nurses were instructed to register any complaint or symptom that could be related to dialysis hypotension.It is evident that the prevalence of dialysis hypotension is influenced by the dialysis settings. Shorter treatment times , 30, higA fall in SBP ≥20 mmHg or a fall in MAP ≥10 mmHg occurred in more than three quarters of dialysis sessions. At patient level, as much as 96.8 % of patients had a decrease in SBP ≥20 mmHg or a decrease in MAP ≥ 10 mmHg in more than 20 % of dialysis sessions. It follows that a decrease in SBP ≥20 mmHg or a fall in MAP ≥ 10 mmHg is so common that it is not specific for symptomatic dialysis hypotension. Notably, in most (58.2 %) dialysis sessions that fulfilled the hypotension component of the EBPG definition, there was no clinical event or intervention. This raises the question whether a decrease in SBP ≥20 mmHg or a decrease in MAP ≥ 10 mmHg discriminates between patients with and without symptomatic dialysis hypotension. Various factors may affect predialysis blood pressure like stress due to transportation to the dialysis unit and anxiety for puncture of the fistula. When predialysis blood pressure is used as the reference point, part of the early intradialytic fall in blood pressure may be explained by the relief of stress/anxiety, e.g. after successful puncture of the fistula, and not by dialysis-specific haemodynamic stress. Conversely, haemodialysis may exert haemodynamic stress, including cardiac stunning, even in the absence of a significant blood pressure drop . Indeed,In a composited definition as the EBPG definition, the prevalence of dialysis hypotension can never be higher than the component with the lowest prevalence. The component with the lowest prevalence in this study was nursing intervention.In multivariate analyses, the strongest determinants of dialysis hypotension defined by the full EBPG definition were lower body height and higher ultrafiltration volume. Where there is abundant literature linking dialysis hypotension to higher ultrafiltration volumes and ultrafiltration rate , 17, 33,A limitation of our study is that we did not use an objective method to assess dry weight, e.g. bioimpedance. Therefore, we cannot exclude that a proportion of patients were not at their true dry weight at the end of dialysis which may have affected the course of blood pressure as well as the frequency of clinical events and nursing interventions. Bias in blood pressure measurements could be introduced by underlying vascular disease. Finally, it should be noted that the EBPG definition, like any other definition using clinical symptoms or nursing interventions is subject to bias. The interpretation of patient complaints as part of the symptomatology of dialysis hypotension as well as the threshold to perform an intervention may differ between nurses (and between physicians). Strong points of our study are the relatively long study duration of 3 months and the frequent measurement of blood pressure  which reduced the chance of underestimation of dialysis hypotension.In conclusion, the prevalence of dialysis hypotension according to the EBPG definition is low. The dominant determinant of the EBPG definition was nursing intervention since this was the component with the lowest prevalence. Dialysis hypotension might be less common than indicated in the literature however a proper comparison with previous studies is complicated by the lack of a uniform definition.All data underlying the findings are within the paper and the supporting information file (Additional file


N = 7; group II: six to seven weeks, N = 7) were studied. Mean arterial pressure, systolic and diastolic pressures, and heart rate were measured for 20 min before  and for 60 min after a fixed hemorrhage of 30% of blood volume. The arterial baroreflex control of heart rate was assessed before (C), and at 30 and 60 min intervals after hemorrhage. Mean arterial pressure decreased for up to 60 min after hemorrhage in both groups of lambs. In group I, heart rate decreased from 200 ± 29 (C) to 164 ± 24 beat min−1 at 30 min then increased to 232 ± 45 beat min−1 at 60 min, whereas heart rate remained unaltered in group II. With respect to the arterial baroreflex control of heart rate, by 30 min after hemorrhage in group I, there was a decrease in the heart rate range over which the baroreflex operates (P1) from 192 ± 13 (C) to 102 ± 9 beats min−1; by 60 min after hemorrhage, there was a decrease in minimum heart rate (P4) from 72 ± 10 (C) to 32 ± 25 beats min−1. In group II, P1 decreased to a lesser extent than group I from 134 ± 21 (C) to 82 ± 10 beats min−1 at 30 min; minimum heart rate (P4) decreased from 40 ± 15 (C) to 24 ± 9 and 20 ± 13 beats min−1 at 30 and 60 min, respectively. These results provide the first assessment of the arterial baroreflex control of heart rate following blood loss and new evidence that the cardiovascular responses to severe hemorrhage are developmentally regulated.The purpose of this study was to investigate in developing animals, the cardiovascular responses to severe hemorrhage at which compensatory mechanisms fail and when blood pressure remains decreased after blood loss. Two groups of conscious lambs (Group I: one to two weeks,  Hemorrhage elicits numerous physiological responses aimed at the preservation of arterial pressure and tissue perfusion. Initially, there is a tachycardia along with an increase in peripheral vascular resistance that matches the fall in cardiac output so that arterial pressure is maintained. There is also a redistribution of blood flow to vital organs, such as the brain and heart, at the expense of causing ischemia in other organs including the kidney. As blood loss proceeds, arterial pressure and tissue perfusion are not maintained and hypovolemic shock ensues.Management of hypovolemic shock is guided by the Adanced Trauma Life Support (ATLS®) which suggests classes based upon vital signs and percentage blood loss and has been widely implemented for several decades  during postnatal maturation . In addition, the arterial baroreflex control of heart rate was assessed before and after blood loss to evaluate the effects of this degree of hemorrhage on the baroreflex.N = 7, group II, 43 ± 7 days; N = 7). Animals were obtained from a local source  and housed with their mothers in individual pens in the vivarium of the Animal Resources Centre of the University of Calgary where they were provided with standard food and water, except during surgery, training, and experiments. All surgical and experimental procedures were carried out in accordance with the “Guide to the Care and Use of Experimental Animals” provided by the Canadian Council on Animal Care and with the approval of the Animal Care Committee of the University of Calgary.Experiments were carried out at least 4 days after the surgery in two separate age groups of conscious chronically instrumented lambs  were administered intramuscularly at 24-h intervals beginning from the day before surgery for a total period of 4 days. During the recovery period, animals were removed from the vivarium for ∼1 h daily to allow them to accommodate to a supportive sling in which they were housed during experiments. This training period ensured that animals were at ease and resting quietly in the laboratory setting during experiments.Surgery was performed using aseptic techniques as previously described  was started to assist in maintaining electrolyte balance throughout the experiment. The right femoral catheters were connected to pressure transducers  for measuring arterial pressure. Arterial pressure was recorded onto a polygraph  and simultaneously digitized at 200 Hz using the data acquisition and analysis software package, PolyVIEW™ . During experiments, body core temperature (Tc) was measured through a rectally inserted temperature probe .On the day of an experiment, each animal was removed from the −1 , or 0% of calculated vascular volume . The two experiments were carried out in random order at minimum intervals of 48 h using procedures similar to those previously detailed , and sodium nitroprusside  were administered over 20 sec using a programmable syringe pump  to increase and decrease arterial pressure from resting levels, and to allow the construction of the physiological range over which the arterial baroreflex operates including the upper and lower limits. Beat-to-beat systolic arterial pressure (SAP) and pulse interval were measured for 10 seconds before each intervention, and measurements continued until the maximum response was achieved. The arterial baroreflex was also assessed 30 min and 60 min after 0% (sham) and 30% hemorrhage.For each experiment, baseline cardiovascular variables were measured for a Control period of 30 min (C) at the end of which the arterial baroreflex control of heart rate was assessed ], where P1 is the heart rate range (beats min−1), P2 is the slope coefficient, P3 is SAP at the midpoint of heart rate range (mmHg), and P4 is the minimum heart rate (beats min−1), and maximum gain (Gmax) = −P1 × P2 × 0.25, and was considered to describe the sensitivity of the baroreflex control of heart rate [see also Jimbo et al. . The method used to assess the arterial baroreflex control of heart rate was that described by Kent et al.  and detao et al. ].t-tests, and between Control, 30-min, and 60-min using Student’s paired t-tests with a Bonferroni correction. Other cardiovascular variables were assessed for statistical significance using ANOVA for repeated measures over time, factors being age (group I and II) and treatment (0% or sham hemorrhage and 30% hemorrhage) and a Student Newman–Keuls multiple comparison procedure where appropriate (using SPSS-PC version 16).For parameters governing the arterial baroreflex control of heart rate, statistical comparisons between group I and II lambs were made using Student’s nonpaired Baseline variables for groups I and II are provided in TableF = 56.315, P < 0.001), systolic arterial pressure , and diastolic  but no age effects. Mean arterial pressure decreased by 10 min after hemorrhage and remained so for 60 min  and hemorrhage  on heart rate as well as a significant interaction between age and hemorrhage . In group I, heart rate decreased then returned toward control followed by an increase at 60 min. In contrast, heart rate remained constant after hemorrhage then increased  and treatment  on the heart rate range (P1). As illustrated in FiguresP1; by 60 min, values returned to C.With respect to parameters governing the arterial baroreflex control of heart rate, there was an overall effect of age (P3), there was an effect of age  and treatment . As shown in FiguresP3 in group I but not group II. Minimum heart rate (P4) decreased in both groups by 30 min after 30% hemorrhage; this response was greater at 30 min in group II as compared to group I, as reflected in an overall effect of age .For the systolic arterial pressure at the midpoint of the heart rate range  P1 returned to Control by 60 min, whereas P4 remained decreased; (5) sham hemorrhage elicited no physiological responses in either age group. These novel observations include the first assessment of the arterial baroreflex before and after hemorrhage in conscious newborn animals, and reveal age-dependent effects of severe degrees of blood loss on several parameters governing the arterial baroreflex early in life.The aim of the present study was to investigate in the newborn period and as postnatal maturation proceeds, hemodynamic responses to severe hemorrhage beyond the critical point and at which compensatory mechanisms fail. To this end, cardiovascular variables and the arterial baroreflex control of heart rate were assessed before and after hemorrhage of 30% as well as sham hemorrhage at two stages of postnatal maturation in conscious lambs. Novel findings of our study are as follows: (1) Within 30 min of severe hemorrhage, both age groups sustained a decrease in mean arterial pressure which resulted from changes in both systolic and diastolic blood pressures; (2) there was a decrease in heart rate in group I but not group II at 30 min followed by an increase at 60 min in both groups; (3) both Little evidence exists regarding hemorrhagic shock early in life. This is surprising because hypovolemia and hypovolemic shock are central entities in the pattern of morbidity and mortality and include blood loss before birth as well as at the time of delivery. In previous studies in conscious sheep, we reported some of the first comprehensive reports of the physiological responses to compensated hemorrhage in the newborn period  has a profound effect on the baroreflex in conscious lambs  were returning toward control levels although mean arterial pressure (MAP) remained decreased. Therefore, our data show that the decompensatory response present by 30 min after blood loss is not sustained. This could be the result of alterations in endocrine responses to blood loss , or decreased renal function, since the response was slowly occurring. Further studies are warranted to evaluate the possible mechanisms underlying the responses to blood loss that we have described herein for the developing conscious lamb.In conclusion, the results of the present research provide new information that cardiovascular responses to severe hemorrhage are age dependent. The mechanism(s) underlying these responses have not been determined but could be related to opioid receptors  or other factors that are known to modulate the arterial baroreflex. Future studies will be important to investigate the underlying mechanisms of these age-dependent responses to hemorrhage.