P < 0.05) higher during the nighttime period compared with the daytime period when mice are typically sleeping . The higher arterial pressure during the nighttime period was mediated by higher cardiac output  in association with lower peripheral resistance . The increased cardiac output during the nighttime was mainly mediated by increased heart rate , as stroke volume increased minimally at night . These results indicate that in C57BL/6J mice, the 24 h pattern of blood pressure is hemodynamically mediated primarily by the 24 h pattern of cardiac output which is almost entirely determined by the 24 h pattern of heart rate. These findings suggest that the differences in blood pressure between nighttime and daytime are mainly driven by differences in heart rate which are strongly correlated with differences in locomotor activity.Few studies have systematically investigated whether daily patterns of arterial blood pressure over 24 h are mediated by changes in cardiac output, peripheral resistance, or both. Understanding the hemodynamic mechanisms that determine the 24 h patterns of blood pressure may lead to a better understanding of how such patterns become disturbed in hypertension and influence risk for cardiovascular events. In conscious, unrestrained C57BL/6J mice, we investigated whether the 24 h pattern of arterial blood pressure is determined by variation in cardiac output, systemic vascular resistance, or both and also whether variations in cardiac output are mediated by variations in heart rate and or stroke volume. As expected, arterial pressure and locomotor activity were significantly ( In C57BL/6J mice, the 24 h pattern of blood pressure is hemodynamically mediated primarily by the 24 h pattern of cardiac output which is almost entirely determined by the 24 h pattern of heart rate. These findings suggest that the differences in blood pressure between nighttime and daytime are mainly driven by differences in heart rate which are strongly correlated with differences in locomotor activity. The risk of occurrence of adverse cardiovascular events varies during the 24 h day. Incidents of myocardial ischemia, infarction, and cerebrovascular accidents occur more frequently during early morning hours than during any other times of the 24 h day . Mice were instrumented with an intra‐arterial telemetry device  for recording arterial pressure, heart rate, and locomotor activity and with an ascending aorta Doppler ultrasonic flow probe for recording cardiac output. After recovery, continuous 24‐h patterns of mean arterial pressure, cardiac output, heart rate, peripheral resistance, stroke volume, and locomotor activity were obtained over 5 consecutive days and nights as described below.All surgical procedures were performed using aseptic surgical techniques. Mice were anesthetized with pentobarbital sodium (50 mg/kg ip), atropinized (0.05 mg/kg ip), intubated, and prepared for aseptic surgery. Supplemental doses of pentobarbital sodium (10–20 mg/kg ip) were administered if the mice regained the blink reflex or responded during the surgical procedures.The hearts were approached via a left thoracotomy through the second intercostal space . Animals were returned to the housing room when fully recovered from the anesthesia and gained the ability to maintain body temperature. The nonsteroidal anti‐inflammatory agent ketoprofen , and the antibiotic cefazolin  were continued for 2 days. At least 10 days were allowed for recovery. During the recovery period, the mice were handled, weighed, and acclimatized to the laboratory and investigators.All animals remained on the feedback‐based temperature control system and ventilator until recovered from the anesthesia. Once the animals regained consciousness, they were placed in a “rodent recovery cage”  and the mouse cage was placed on radio‐telemetry receivers. This permitted 24‐h recording of arterial pressure, heart rate, cardiac output, and locomotor activity Fig. . Total pt‐tests were used to compare the study average daytime versus nighttime values within the animals. To obtain nighttime–daytime differences for each variable, the difference between the 12 h nighttime average minus the 12 h daytime average was calculated for each animal for each of the five 24 h periods. These nighttime–daytime differences in each of the five 24 h periods were then averaged to obtain the study average nighttime–daytime difference for each animal. These study average nighttime–daytime differences from each animal were then averaged to give the group means for the nighttime–daytime differences. Data are expressed as means ± SE.All physiological recordings were sampled continuously at 2 kHz, beat to beat 24 h/day for 5 consecutive days and nights. Subsequently, 1 h averages for each variable were calculated over each 24 h period and are presented in P value of <0.05 was considered statistically significant.Pearson product moment correlations were used to measure the degree of linear dependence between the average levels of locomotor activity each hour versus the average levels of heart rate, cardiac output, arterial pressure, and peripheral resistance each hour. A Q), in mL/min, was calculated by:K =1.24 × d2, (where d is the cuff diameter of the flow probe measured in millimeters). Using this system, the Doppler shift frequency (kHz) is directly proportional to blood flow , in P < 0.05) positive correlations were observed between the average levels of locomotor activity each hour and the average levels of heart rate (r2 = 0.944), cardiac output (r2 = 0.941), and arterial pressure (r2 = 0.936) each hour. A significant (P < 0.05) negative correlation was observed between locomotor activity and peripheral resistance (r2 = −0.822).Original recordings of arterial pressure and ascending aortic blood flow (cardiac output) in an intact, conscious, mouse are shown in In humans, arterial blood pressure is lower during the nighttime period when sleep and rest predominate than during the daytime period when wakefulness and activity predominate. The factors that determine the variation in blood pressure over the 24 h period are of considerable interest because the patterns of blood pressure over 24 h may influence cardiovascular risk and may also be relevant to pharmacologic approaches to the management and prevention of target organ damage (Mancia and Parati Little information is available on the basic hemodynamic mechanisms that mediate the 24 h patterns of blood pressure in states of health and disease. Specifically, there is a paucity of studies examining the relationships between the 24 h pattern of blood pressure and the 24 h patterns of cardiac output and peripheral resistance in ambulatory humans or animals with or without hypertension. Moreover, there do not appear to be any previous reports showing continuous changes in cardiac output and peripheral resistance occurring throughout two or more consecutive 24 h periods. Because the mouse can be genetically manipulated and studied in ways that are not possible in humans, mice are frequently used to investigate the genetic and behavioral factors that influence the changes in blood pressure that occur between the daytime and nighttime periods (Mitler et al. In the current study, we used a radio‐telemetry method for continuously measuring blood pressure together with a miniaturized Doppler flow probe technique for continuously measuring cardiac output to determine the 24 h patterns of blood pressure, cardiac output, heart rate, stroke volume, and peripheral resistance in conscious, unrestrained mice over a period of 5 days. In C57BL/6J mice, we found that the increase in blood pressure that occurs during the period of wakefulness and activity is hemodynamically determined by an increase in cardiac output in association with a decrease in peripheral resistance. The increase in cardiac output is mainly determined by an increase in heart rate which is strongly correlated with increased locomotor activity. Thus, in C57BL/6J mice, the blood pressure pattern over 24 h is largely determined by changes in cardiac output that are mainly driven by changes in heart rate associated with changes in locomotor activity.In humans, the hemodynamic determinants of the pattern in arterial pressure over 24 h are inconclusive (Khatri and Freis In unanesthetized, unrestrained rats studied for a full 24 h, and in few monkeys studied for periods of 18 h while chronically restrained in chairs, the increases in blood pressure associated with the periods of wakefulness and activity have also been associated with increases in cardiac output, reductions in peripheral resistance, and increases in heart rate with little or no change in stroke volume (Engel and Talan In the current study, sharp increases in cardiac output occurred within the first hour of the transition from the inactive period to the active period. These sharp increases in cardiac output were largely driven by increases in heart rate and were mainly responsible for the sharp increases in blood pressure that occurred during this transition phase. These observations are consistent with the idea that changes in arousal and locomotor activity are largely responsible for the hemodynamic changes that occur between the period in which rest and sleep predominate and the period when wakefulness and activity predominate (Mann et al. It would seem reasonable to speculate that during transition from the inactive period to the active period, increases in arousal may lead to neurally mediated increases in heart rate that determine the increases in cardiac output we observed to mediate increases in blood pressure. Increased demand for oxygen stimulated by increases in activity may be a further determinant of the increased cardiac output and decreased peripheral resistance that together determined the magnitude of the increase in blood pressure during transition from the inactive period to the active period. It is expected that the technology we describe for continuously monitoring blood pressure, cardiac output, heart rate, stroke volume, and peripheral resistance over extended periods will enable future studies to identify the hemodynamic mechanisms that mediate disturbances in the 24 h blood pressure patterns known to be associated with increased cardiovascular risk in disorders such as hypertension.Although 24 h patterns of blood pressure have been extensively studied in animals and humans including in those with cardiovascular disorders such as hypertension, little is known about the 24 h patterns of cardiac output and peripheral resistance that together determine the 24 h patterns of blood pressure in health or in disease. Investigation of the hemodynamic mechanisms that determine the 24 h patterns of blood pressure may lead to a better understanding of how such patterns become disturbed in hypertension and influence risk for cardiovascular events. This paper describes the use of Doppler flow probe technology and radio‐telemetry blood pressure monitoring techniques to determine the 24 h patterns of cardiac output and peripheral resistance which mediate the 24 h pattern of blood pressure in unanesthetized, unrestrained C57BL/6J mice. The current findings should open the door to future studies to determine the hemodynamic mechanisms that mediate disturbances of the 24 h patterns of blood pressure in hypertension and other disorders associated with increased risk of adverse cardiovascular events such as stroke and myocardial infarction. Given the large numbers of genetically manipulated strains of mice that are available, the techniques described in this manuscript should also be useful for determining the hemodynamic mechanisms whereby targeted genetic alterations influence the 24 h pattern of blood pressure. In addition, as proposed by Snelder and colleagues (Snelder et al. We thank H. Janbaih for his expert technical assistance..No conflicts of interest, financial or otherwise, are declared by the authors


Fluid administration is a first-line therapy for acute kidney injury associated with circulatory failure. Although aimed at increasing renal perfusion in these patients, this intervention may improve systemic hemodynamics without necessarily ameliorating intrarenal flow distribution or urine output. We used Doppler techniques to investigate the effects of fluid administration on intrarenal hemodynamics and the relationship between changes in renal hemodynamics and urine output. We hypothesized that, compared to systemic hemodynamic variables, changes in renal hemodynamics would better predict increase in urine output after fluid therapy.We measured systemic hemodynamic variables and performed renal interlobar artery Doppler on both kidneys before and after volume expansion in 49 adult patients with acute circulatory failure. We measured systolic and diastolic velocities and computed the resistivity index (RI). We recorded urine output for 3 h before and after the fluid challenge.p < 0.01). There was a concomitant increase in mean arterial pressure , pulse pressure  and urine output . Changes in RI were negatively correlated with changes in urine output and mean arterial pressure but not in pulse pressure. The increase in urine output was predicted by changes in RI but not by changes in systemic hemodynamics.Fluid administration resulted in a small but consistent decrease in RI (from 0.73 ± 0.09 to 0.71 ± 0.09, Changes in renal hemodynamics during a fluid challenge can be observed by Doppler ultrasonography before urine output increases. Moreover, these changes are better predictors of an increase in urine output than are mean arterial pressure and pulse pressure. Imbalance in oxygen delivery and oxygen demand is common in critically ill patients, especially those with acute circulatory failure of septic, hypovolemic or cardiogenic origin. Acute kidney injury (AKI) is a frequent complication of circulatory failure and associated with increased morbidity and mortality , 2. FluiRecently, interlobar artery (ILA) resistivity index (RI), a reliable surrogate of intrarenal vascular tone measured by renal interlobar artery Doppler (RIAD), has been proposed for bedside evaluation of intrarenal hemodynamics in critically ill patients –9. This The aim of this study was to evaluate changes in ILA RI, using Doppler techniques, during volume expansion in critically ill patients and, in addition, to compare the performance of these changes with that of changes in systemic hemodynamics for the prediction of subsequent variations in urine output. We hypothesized that dynamic analysis of intrarenal hemodynamics using RIAD following a fluid challenge may help to identify responders to fluids better than systemic hemodynamics.Erasme University Hospital Ethics Committee approved this interventional study (P2011/125) and informed consent was obtained from the patients or their next of kin. In a convenience sample of patients admitted between April 2011 and March 2012, three groups were studied: two control groups and an interventional group. The control groups included ICU patients with stable systemic hemodynamics receiving no specific intervention. In the first control group, A, we evaluated intra-observer variability in RIAD measurements by performing three measurements 15 min apart. The ultrasound measurements for this assessment were performed by the same technician but the calculations of RI were performed by a statistician not involved in the measurements or the design of the study. In control group B, we assessed stability of the Doppler variables over time, by performing two measurements 60 min apart.2) or mixed (SvO2) venous oxygen saturations <70 % or <65 %, respectively. Exclusion criteria were age <18 years, atrial fibrillation or frequent ventricular arrhythmias, history of renal transplantation or stenosis of renal arteries, end-stage renal disease, known unilateral kidney, pregnancy, and body mass index >40 kg/m2. Patients were also excluded from the study if they were given diuretics or there were any changes in vasopressor administration during the study period. AKI was defined as an increase in serum creatinine ≥0.3 mg/dl over 24 h and/or a 1.5-fold increase in baseline serum creatinine over 7 days, and/or oliguria with a reduction in urine output <0.5 ml/kg/hour over 6 h [The interventional group consisted of patients with acute circulatory failure who required a fluid challenge. Acute circulatory failure was defined as the association of arterial hypotension  or need for vasopressor to correct hypotension, and/or oliguria defined as urine output <0.5 ml/kg/hour with at least one of the following criteria: impaired mentation, mottled extremities, arterial lactate >2 mmol/l, and superior vena cava (ScvOover 6 h .2/SvO2. One investigator (MDM) performed all Doppler measurements using a convex 2–5.5 MHz probe , with the transducer applied in a lateral or postero-lateral view to visualize the kidneys. Intrarenal vessels were observed using color Doppler, then a pulsed Doppler signal was obtained on the ILA. Three consecutive measurements displaying at least three ILA Doppler waves each (corresponding to three cardiac beats) were performed in the upper, middle and lower poles of both kidneys and averaged. Failure to meet these criteria or a difference of more than 5 % in RI between the kidneys was considered as a failure in measurement. Systolic (SV) and diastolic (DV) velocities were measured on each wave. Interlobar RI was calculated using the formula: RI = (SV – DV)/SV.Monitoring included continuous electrocardiogram and heart rate recording and invasive measurement of MAP and pulse pressure (PP) through a radial or femoral catheter. We also measured arterial lactate and ScvOFluid challenge consisted of a minimum volume of 500 ml crystalloid  or hydroxyethyl starch 6 % ) infused at a minimum rate of 1,000 ml/hour under arterial pressure guidance . Fluid aOur primary objective was to describe whether the fluid challenge induced changes in RI. Our secondary objective was evaluation of the relationship between changes in renal Doppler and urine output. We evaluated the performance of renal RI, compared to MAP and PP, to predict an increase in urine output after fluid administration  using three predefined arbitrary thresholds: increase in urine output by at least 0.1 ml/kg/hour, 0.2 ml/kg/hour and 0.3 ml/kg/hour. The 0.3 ml/kg/hour threshold was used because such an increase in urine output implies improvement to a better class of the AKIN  or RIFLEWe also separated patients into systemic hemodynamic responders  and non-responders to fluid challenge. Change in RI was calculated as the difference in RI divided by baseline RI. Similarly, changes in MAP and PP were calculated as the absolute difference observed after fluid challenge divided by the baseline value.Data distribution was verified using a Kolmogorov-Smirnov test. Continuous variables are presented as median (interquartile range) or mean ± standard deviation. Baseline characteristics of responders and non-responders were compared using Fisher’s exact test or chi square test and Mann Whitney’s rank sum test as appropriate. In control group A, an intraclass correlation was used to evaluate variability of measurements. In control group B, we calculated the coefficient of variation (CV) of RI and computed the coefficient of error (CE) using the formula CE = CV/√n, where n is the number of measurements in each patient. The precision of the RI measurements was calculated as two CE for average measurements with a level ≤10 % considered acceptable as recommended . We compt test or Wilcoxon rank test were used for paired comparisons. Changes in RI and in MAP, PP and urine output were examined for correlations using Pearson’s linear correlation coefficient. In subgroups of patients , median values were compared using the Wilcoxon rank test and linear correlation was verified using Spearman’s correlation coefficient. A mix model analysis was performed considering subgroups and the time of measurement.In the intervention group, paired Student’s p value < 0.05. All statistical analyses were performed using SPSS 19 for Windows .Receiver operating characteristic curves were generated to test the predictive discrimination of renal responders and non-responders to fluid therapy. Areas under the curve of changes in Doppler variables and of changes in systemic hemodynamic variables were generated and tested for significant differences using the DeLong test. These analyses were also performed for systemic hemodynamic fluid responsiveness. Significance was assumed for a two-sided p < 0.001).We studied 29 patients in the control groups  to evaluate the variability of the renal Doppler measurements Fig. , with a 2 or SvO2 was low in 13 (68 %). The patients received 1,224 ± 717 ml of fluids, primarily as crystalloids .Of the 80 patients assessed for inclusion in the intervention group, 31 were excluded  and 23 for concurrent changes in vasoactive support)  and changes in MAP  but not with changes in PP. We found no correlation between changes in urine output and changes in MAP or PP. The total amount of fluid was correlated to changes in MAP  and PP  but not to changes in RI  or urine output .Changes in Doppler RI correlated significantly with changes in urine output . RI decreased significantly in AKI and non-AKI patients (Table p = 0.22).The changes in RI were observed in oliguric and non-oliguric patients Table  with no ts Table , with nop < 0.01). Changes in RI after fluid challenge in patients who were hemodynamic non-responders but had increased urine output are shown in Table A total of 30 61 %) patients responded to the fluid challenge by an increase of at least 10 % in MAP or PP (Table 1 % patieThis study shows that fluid loading in critically ill patients with acute circulatory failure was associated with significantly decreased RI as assessed by RIAD. In addition, changes in RI were correlated with changes in urine output and better predicted the increase in urine output after fluid administration than changes in MAP and PP at the three urine output thresholds.These data provide interesting insights into the mechanisms of the renal response to fluids. First, the decrease in RI suggests that renal perfusion increased in these patients. The correlation of changes in urine output with changes in RI but not with changes in MAP or PP suggests that regional factors play a more important role than systemic hemodynamic factors in the regulation of urine production. Direct assessment of intrarenal vasoreactivity may, therefore, better reflect intrarenal pathophysiological features than systemic changes in MAP or PP . Second,The poor ability of systemic hemodynamic variables to predict an increase in urine output following fluid challenge was notable. Although renal responders had higher baseline MAP, changes in MAP and PP were not associated with renal response to fluids. This observation is consistent with previous investigations by Bourgoin et al.  and LeDoIn apparent contrast to our observations, Schnell et al.  did not Of note, the changes in renal Doppler variables, although statistically significant, were relatively limited. The observed changes in RI were just above the LSC. Thus, clinical applicability of the observed differences is questionable, especially if multiple and potentially less experienced investigators are performing the examinations . NeverthThe technique has some limitations. First, changes in RI may not reflect changes in renal perfusion gradient, as several other confounding factors may be present, including changes in intrarenal compliance, renal interstitial pressure, heart rate, and intra-abdominal pressure. Second, pulsed Doppler techniques provide focal measurements that may not reflect heterogeneous changes in the vascular tone of the entire kidney. In addition, RI measured at the ILA level may not indicate afferent arteriolar or interlobular tone, and these vessels are known to be the most important site of renal myogenic tone regulation . Third, We showed that fluid administration reduces intrarenal vasoconstriction and that changes in RI are more effective than changes in MAP and PP to predict an increase in urine output after fluid challenge. Dynamic analysis of intrarenal hemodynamics using RIAD can identify renal responsive patients. However, the use of RI to guide fluid therapy for renal hemodynamic management may be limited by the small magnitude of the changes and potential technical limitations.Fluid challenge results in reduced intrarenal vasoconstriction in hemodynamically impaired ICU patients.In hemodynamically impaired patients, changes in MAP after a fluid challenge cannot predict an increase in urine output.However, changes in renal interlobar artery resistivity index in these patients can predict an increase in urine output.Nevertheless, interlobar resistivity index cannot be recommended for routine use, because of the relatively limited magnitude of the changes and need for experienced ultrasonographers.


Participation in aerobic exercise generates increased cardiorespiratory fitness, which results in a protective factor for cardiovascular disease and all-cause mortality. High-intensity interval training might cause higher increases in cardiorespiratory fitness in comparison with moderate-intensity continuous training; nevertheless, current evidence is not conclusive. To our knowledge, this is the first study to test the effect of high-intensity interval training with total load duration of 7.5 min per session.n = 44). The study protocol will include 24 exercise sessions, three times a week, including aerobic training on a treadmill and strength training exercises. The intervention group will perform 15 bouts of 30 s, each at an intensity between 90 % and 95 % of maximal heart rate. The control group will complete 40 min of continuous exercise, ranging between 65 % and 75 % of maximal heart rate. The primary outcome measure to be evaluated will be maximal oxygen uptake (VO2max), and systolic and diastolic blood pressure will be evaluated as secondary outcome measures. Waist circumference, body mass index, and body composition will also be evaluated.A randomized controlled trial will be performed on two groups of healthy, sedentary male volunteers (2max and its association with chronic conditions that trigger CVD. Therefore, finding ways to improve VO2max and reduce blood pressure it is of vital importance to public health.Epidemiological evidence shows the link between VONCT02288403. Registered on 4 November 2014. VO2max is currently deemed the best indicator to assess cardiorespiratory fitness [2max is directly related to cardiovascular health, and its improvement has been linked to decreases in risk of death from cardiovascular disease [2max, mortality rates have been shown to decrease by about 8–17 % [et al. [2max (<27.6 ml/(kg min)) and premature death and found that unfit men had more than twice the risk of overall death  and over three times the risk of cardiovascular-disease-related death  in comparison with fit men (VO2max >37.1 ml/kg/min).Maximal oxygen consumption ); meanwhile, when comparing high-intensity interval training with aerobic training, this improvement was reduced (1.2 ml/(kg min)).The worldwide survey on fitness trends has ranked high-intensity interval training at the top of the top 20 trends for the past two consecutive years , 9, whic2max –16. The sessions , 18. In d trials . Milanov2max, the prevalence of hypertension is reduced by 1.04 times  [High blood pressure is one of the most common health disorders; it is associated with an increase in the incidence of all-cause mortality and cardiovascular disease. It has been reported that people with systolic blood pressure between 130 and 139 mmHg, and diastolic blood pressure between 85 and 89 mmHg have a greater risk of cardiovascular events than those who present with optimal blood pressure values , with hazard ratio = 2.5; 95 % confidence interval = 1.6–4.1 for women, and hazard ratio = 1.6; 95 % confidence interval = 1.1–2.2 for men. Likewise, individuals with high blood pressure  have greater risk of cardiovascular events than individuals with optimal values . Moreove05–1.02) . In thei05–1.02)  reported05–1.02) .2max, as well as between high-intensity interval training and blood pressure. Although evidence exists that suggests the benefits of high-intensity interval training in VO2max and blood pressure in individuals with cardiovascular disease [2max and decreases in systolic and diastolic blood pressure in healthy individuals, as the potential benefits of this type of training are still unclear in this group [2max) and were not randomized control trials [Even though exercising is a fundamental aspect in primary prevention, treatment, and control of hypertension, the optimal frequency, intensity, time, and mode of exercise to reduce systolic blood pressure and diastolic blood pressure values are still unclear . In this disease , the eff disease , 19, 20.is group , 27 Takiis group , we belil trials , 30. In 2max. A secondary objective is to examine the effects of both training programs on systolic and diastolic blood pressure.The main objective of this randomized controlled trial is to determine the effect of a high-intensity interval training program in comparison with a moderate-intensity continuous training program on VO2max in a group of 18–44-year-old men. A secondary hypothesis proposes that, in comparison with a moderate-intensity continuous training program, there is a significant positive effect on systolic and diastolic blood pressure with a high-intensity interval training program.The primary hypothesis of this study is that compared with an 8 week moderate-intensity continuous training program, a high-intensity interval training program will have a significant effect on VOThis study is a randomized controlled trial with parallel arms conducted and reported in accordance with CONSORT guidelines for non-pharmacologic treatment .Volunteers will be recruited through posters sent via email to the academic community throughout the Universidad de Antioquia, and located in various places on the university campus and nearby educational institutions, as well as via Facebook. Recruiting will finish once the number of volunteers required is complete. There will be no paid incentives to participate in this study.Assessments will be performed at the Laboratory for Physical Activity and Sports Sciences, Universidad de Antioquia. The interventions will be conducted at the sporting facilities of the Universidad de Antioquia.Forty-four healthy but sedentary  young mThe random allocation sequence will be created in permuted blocks of four and six using random allocation software . AllocatAfter obtaining volunteers’ consent, volunteers will be sent reminders to attend their sessions through text messages, emails, and phone calls. Volunteers may contact the intervention coordinator and researchers 24 hours a day via email or by calling their cell phones.Files with participant’s information will be coded with individual identification codes. Data will be stored in a locked filing cabinet and in a password-protected computer, to which only researchers will have access. The computer password will be changed once a month throughout the duration of the research study; furthermore, a backup copy of all the information will be made once a month.Twenty-four sessions of aerobic exercise on a treadmill, plus strength training exercises, will be completed as a non-differential co-intervention in both groups, based on the recommendations set forth by the American College of Sports Medicine for healthy beginners or intermediate-level adults . Each pa2max with an effort:recovery ratio of 1:2. The intensity of each high-intensity interval training session will be reached and adjusted manually throughout the session by a trained investigator manipulating the speed of the treadmill to reach the target heart rate, while maintaining a constant 10 % elevation. It is worth highlighting that this intervention proposes short load times with double recovery time, which is different from those used in similar studies, which provided long load times with a recovery time similar to or less than the load time [2max than longer load interventions. This change may be important, considering the fact that current public health guidelines regarding the minimum dose of exercise required to improve cardiovascular health seem difficult to follow, owing to barriers related to users’ lack of time [The intervention group , will undergo 15 bouts of 30 s loads at 90–95 % of maximal heart rate followed by a 60 s recovery at 50–55 % of baseline VOoad time , 38, 39.oad time , 40, andoad time . Neverth of time .The control group (moderate-intensity continuous training) will do 40 min of continuous treadmill exercise at 65–75 % of maximal heart rate. Throughout the intervention, volunteers will be encouraged to continue with their regular daily routine and not engage in any other exercises different form the ones proposed in the research study. Furthermore, they will asked to wear an Omron® HJ-112 pedometer  to monitThe evaluation of primary and secondary outcome measures will follow the order established by the American College of Sports Medicine for health-related physical assessment  and willThe evaluation of blood pressure will be conducted first during each testing session and will be performed using an Omron® M3 HEM-7200-E  automatic blood pressure monitor  to measuTo assess body composition, an Omron® HBF-510  bioelectrical impedance machine will be used, following manufacturer protocols. Briefly, individuals will be instructed to wear light clothing, and stand barefoot on the device, which includes four electrodes on the feet and two electrodes on the handle. Participants will each be asked to hold the handle in their hands during the measurement, with the arms extended in front of them at eye level. The Omron® HBF-510 will measure weight, percentage of body fat, percentage of lean tissue and body mass index. To measure height, volunteers will be asked to stand on a stadiometer without shoes and with their heels together, while looking straight ahead. Participants will each be asked to inhale deeply, and hold their breath briefly while the evaluator slides the stadiometer set square to the top of their head and records the height in centimeters. Waist circumference will be measured following standard procedures, at the mid-point between the lower costal edge and the iliac crest .2max will be obtained using a graded exercise test on a treadmill (Trackmaster® model TMX 425C) using a portable K4b2 gas analyzer , which has been validated and utilized in previous studies [Measurements of VO studies –50. The 2max, the following criteria will be followed: respiratory quotient >1.10, maximal heart rate ≥95 %, following the 220-age equation [2 plateau despite an increase in load (VO2 does not increase or go less than 2 ml/(kg min)) [To conduct the stress test, participants will warm up for 3 min at 5 km/h. Immediately following the warm-up period, the test will begin at a speed of 4 km/h and will increase by 1 km/h every minute with a constant 10 % gradient (5.7°) until maximal effort is achieved. To determine VOequation , and reakg min)) , 51. The2max was considered as a minimum effect to decrease the risk of cardiovascular disease [To calculate sample size, a 3.5 ml/(kg min) difference of measurements in VO disease , 5 with  disease , assuminP < 0.05 and a 95 % confidence level will be used. To manage missing data, multiple imputation procedures will be used to replace missing values for the primarily variables of interest, following the guidelines set forth by Stern et al. [All analyses will be conducted according to the intention-to-treat principle, using a normality test, homoscedasticity test, or linearity test as necessary, to verify assumptions for the use of parametric statistics. As long as all assumptions of normality are met, analysis of covariance (ANCOVA)  will be n et al. . Briefly2max is considered one of the most important predictors of CVD mortality; in addition to smoking, high blood pressure (hypertension) and cholesterol disorders, low CRF levels increase the risk of CVD, is associated with morbidity and mortality from the same cause, as well as with all-cause mortality [2max and its association with chronic conditions that trigger CVD, and subsequently increase the likelihood of death [2max and reduce SBP and DBP it is of vital importance to public health. Recently the cardiorespiratory improvements obtained with HIIT have been examined; however, the optimal dose necessary requires further inquiry [2max, as well as HIIT and SBP-DBP. This research is novel since it is the first to examine a HIIT workout with a heavy load with a total length 7.5 minutes per session, compared with other studies using longer load periods [2max produced by a HIIT vs MICT program.VOortality –6, 54–58of death . Similarof death . Therefo inquiry ; thus, i periods , 38, 39. periods . AnotherThe call for participants started on April 25, 2015. We have enrolled 29 volunteers as of the submission of this manuscript. Of those 29, 18 have finished the interventions, and two withdrew from the study for personal reasons. The remaining volunteers are active. Recruitment of all volunteers is expected to finish in June 2016.2max, maximal oxygen uptake.ANCOVA, analysis of covariance; CONSORT, Consolidated Standards of Reporting Trials; VO


Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.ClinicalTrials.gov number, NCT02369081.In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18–79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin modified release (4–8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo , superior to the mean of the other two active treatments , and superior when compared with the individual treatments; versus doxazosin  and versus bisoprolol . Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion.Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.The British Heart Foundation and National Institute for Health Research. Resistant hypertension, defined as suboptimal blood pressure control despite treatment with at least three blood pressure-lowering drugs, is associated with a poor prognosis. This is caused by organ damage from prolonged exposure to suboptimal blood pressure control, and to the association with diabetes, chronic kidney disease, and obesity.Evidence before this studyInternational guidelines have converged on a definition of resistant hypertension as blood pressure that is not controlled to target despite treatment with three recommended blood pressure-lowering drugs at maximum tolerated doses—namely, an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin II receptor blocker , plus a calcium channel blocker , plus a thiazide-like diuretic (“D”)—ie, A + C + D. We searched MEDLINE, Embase, and the Cochrane CENTRAL register, for English language publications published up to July, 2015, for randomised controlled trials, and open and observational studies, of the drug treatment of resistant hypertension. This review was cross-referenced to the National Institute for Health and Care Excellence (NICE) hypertension clinical guideline review of drug treatment of resistant hypertension (CG 127) from 2011 and a recently published meta-analysis of randomised controlled trials and non-randomised studies of drug treatment of resistant hypertension with aldosterone antagonists. The meta-analysis suggested that spironolactone can be an effective blood pressure-lowering treatment for patients with resistant hypertension, however, the NICE review concluded that the quality of existing evidence was low. Three randomised controlled trials, of 135 patients (combined), had shown spironolactone to be superior to the placebo in reducing seated clinic blood pressure, when added to existing treatment for resistant hypertension. But there had been no previous randomised controlled trials comparing spironolactone with other blood pressure-lowering drugs to determine if it is the most effective treatment for resistant hypertension.Added value of this studyPATHWAY-2 is, to our knowledge, the first randomised controlled trial to compare different blood pressure-lowering treatments in rigorously assessed patients with resistant hypertension, and the first comparison of mineralocorticoid receptor blockade with alternative recommended classes that block the sympathetic nervous system (α blockers and β blockers). The size, crossover design, and hierarchical primary endpoints of PATHWAY-2 enabled demonstration at high significance (p<0·0001) that spironolactone 25–50 mg/day is by far the most effective drug added to A + C + D, for the treatment of resistant hypertension; blood pressure was controlled (home systolic blood pressure <135 mm Hg) in 60% of patients. The role of sodium retention in causing resistant hypertension was strongly suggested by a low baseline plasma renin, despite treatment with three drugs which usually elevate renin, and by a significant inverse correlation between renin and blood pressure reduction by spironolactone. The individual crossover data show that spironolactone is the most effective add-on drug, by a large margin, in the overwhelming majority of patients confirmed as adherent, but resistant, to treatment with A + C + D.Implications of all the available evidenceThe unequivocal superiority of spironolactone, together with supportive efficacy and safety data from longer term observational studies, should influence treatment guidelines globally. Whether the superiority is specific for mineralocorticoid receptor blockade, reflecting overlap between primary aldosteronism and resistant hypertension, will require comparison of spironolactone with other types of diuretic. Meanwhile, truly resistant hypertension can now be considered rare and redefined as blood pressure not controlled by A + C + D + spironolactone.For drug treatment of resistant hypertension, international guidelines specifically refer to fourth-line therapy for patients, whose blood pressure is not controlled by treatment with three drugs, typically A + C + D, where “A” is an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), “C” is a calcium channel blocker (CCB), and “D” is a thiazide or thiazide-like diuretic.One hypothesis is that resistant hypertension is predominantly caused by sodium retention, due in part to the reduced doses of diuretics prescribed in recent years; if so, drugs with a diuretic action would be the most effective additional treatment.We selected spironolactone as the drug with diuretic action  because of observational and limited randomised controlled trial data suggesting good blood pressure-lowering efficacy in resistant hypertension, recently summarised in a meta-analysis.In this 12-month double-blind, placebo-controlled, crossover phase 4 trial, patients were enrolled from 12 secondary care and 2 primary care sites in the UK. The protocol has been published.All patients gave informed written consent. The protocol was approved by Cambridge South Ethics Committee. There was no data monitoring board.The full trial protocol is summarised in the The treatment cycles were initiated for 6 weeks at the lower dose, followed by forced titration to twice this dose for a further 6 weeks . Patients unable to tolerate a drug in a cycle were allowed to move to the next drug in sequence. There was no washout period between the four treatment cycles . The entire study, including placebo run-in, lasted 1 year. After this, patients were invited to participate in a further 12-week cycle of open-label amiloride 10 mg, titrated to 20 mg after 6 weeks.After initial screening and enrolment, there were nine subsequent visits on blinded medication: one after the placebo run-in, the remaining eight after the 6-weekly periods on each of the two doses of the three active drugs and placebo.The primary endpoint measurement was average home systolic blood pressure, recorded in the morning and the evening in triplicate, on 4 consecutive days before study visits. For analysis, a maximum of the last 18 recordings for each measurement period—ie, days 2–4—if all completed, were used. A minimum of six blood pressure recordings per measurement period was required for a valid measurement of the home systolic blood pressure average. The home systolic blood pressure average for the primary endpoint included all of the aforementioned measurements throughout each treatment cycle—ie, at week 6 and week 12). For seated clinic blood pressure, the mean of the last two measurements was recorded as the clinic blood pressure. The home and clinic blood pressures were measured for every patient using the approved, automated blood pressure monitor , which was allocated to the patient for their sole use for the duration of the trial. Patients were instructed by the specialist nurses in self-measurement of blood pressure and technique was visibly re-enforced at each visit, when the research nurse measured patients' blood pressure using the same monitor.Plasma renin was measured at baseline (following run-in on background “A + C + D” and placebo) with a Diasorin Liaison automated chemiluminescent immunoassay for direct renin mass.The primary objective was to test the hypothesis that spironolactone is the most effective add-on treatment for patients with resistant hypertension. The primary analysis used an average of home systolic blood pressure recorded throughout the treatment cycle. We prespecified hierarchical primary endpoints; (1) the difference in the home systolic blood pressure between spironolactone and placebo, followed if significant by (2) the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, (doxazosin and bisoprolol), followed if significant by (3) the difference in home systolic blood pressure between spironolactone and each of the other two active drugs.The secondary objectives included evaluation of; (1) clinic blood pressure responses to randomised treatments; (2) blood pressure control rates—ie, home systolic blood pressure less than 135 mm Hg; (3) whether plasma renin concentrations and other baseline characteristics could help personalise treatment by predicting the best drug treatment; and (4) adverse event rates during each treatment cycle.To test the hypothesis that plasma renin , will predict the most effective fourth-line drug, we examined the relationship between plasma renin and the reduction of home systolic blood pressure with each drug, adjusted for the placebo response. We also identified the best treatment for each patient—ie, the one on which they achieved the lowest blood pressure, and estimated for each drug the relationship between baseline renin and the likelihood that it would provide the best response. Adverse events were recorded at each visit.t test at the 0·003 significance level (this was chosen in order that the 0·01 level could be adjusted for three planned comparisons). However, the hierarchical analysis subsequently adopted negated the need to adjust p values.The sample size was estimated to be 294 patients, based on detecting a difference of 3 mm Hg (SD 12) in home systolic blood pressure between each of the experimental drugs and the placebo treatment, with 90% power using a single sample 2 tests and Fisher's exact p values are given. The probability that a drug would provide the best response as a function of baseline renin, was estimated from multinomial logistic regression.We tested hypotheses with the mixed effect models to analyse continuous variables, with unstructured covariances for repeated measures within a patient. We included prespecified baseline covariates  in the models. Least squares means for each treatment estimated from these models are presented. Blood pressure control and response rates were analysed with logistic regression models, which also included the baseline covariates. Comparisons of adverse event rates between treatments were done with χIntention-to-treat analyses excluded only those participants with no primary outcome data at any follow-up visit (21 patients). Other participants with missing data were included, and we assumed that data was missing at random .Analyses were done with SAS  version 9.3.ClinicalTrials.gov number, NCT02369081.The trial is registered with EudraCT number 2008-007149-30, and The funders had no role in the data collection, data analysis, or data interpretation, or the writing of the report. The investigators and all authors had sole discretion in the data analysis and interpretation, writing of the report, and the decision to submit for publication. The corresponding author had full access to all of the data and the final responsibility to submit for publication.Between May 15, 2009, and July 8, 2014, we screened 436 patients and randomised 335, of which 21 had no follow-up for any drug and were excluded from the intention-to-treat analysis, which comprised 314 patients who had any follow-up data. 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles . Last paThe average reduction in home systolic blood pressure throughout the treatment cycle with spironolactone was superior to each of: placebo ; the mean of the other two active treatments ; and each of the other individual treatments; doxazosin  and bisoprolol  of 314 patients achieved target home systolic blood pressure of less than 135 mm Hg. The comparison of control rates is shown in the The proportion of patients in whom spironolactone was their best drug for blood pressure lowering was most evident on the planned analyses of prediction by plasma renin of blood pressure response to each drug and the likelihood that different drugs would be best at different points in the plasma renin distribution. All active treatments were well tolerated with similar low rates of adverse events and withdrawals due to adverse events . Serum cPATHWAY-2 is the first randomised controlled trial to compare spironolactone with other blood pressure-lowering drug treatments in a well-characterised population of patients with resistant hypertension. The study shows that spironolactone was by far the most effective blood pressure-lowering treatment for patients with resistant hypertension. This was true in terms of the magnitude of the blood pressure response, the proportion of patients achieving a stringent measure of blood pressure control (home systolic blood pressure <135 mm Hg), and the proportion in whom it was more effective than either of the non-diuretic alternative drugs. These findings suggest that the predominant underlying pathophysiological cause of resistant hypertension is sodium retention, despite existing baseline diuretic therapy. This conclusion is supported by our finding that the response to spironolactone had a clear inverse relation with plasma renin, was especially effective at lower plasma renin levels, and yet the most effective drug throughout the range of plasma renin.Bisoprolol and doxazosin were more effective than placebo at reducing blood pressure as so-called add-on therapy for resistant hypertension, but significantly less effective than spironolactone. Thus, this study has for the first time, established a clear hierarchy for drug treatment of resistant hypertension in which spironolactone is the most effective add-on therapy  for most patients. Bisoprolol or doxazosin are less effective alternatives for those intolerant of spironolactone.PATHWAY-2 is the first study to use home blood pressure averages rather than clinic blood pressure to assess the primary outcome of blood pressure response in patients with resistant hypertension. This is important because home blood pressure measurement reduces the placebo effect, as was evident in our study, and eliminated patients whose blood pressure could have been spuriously elevated at baseline due to so-called white coat hypertension. Indeed, we noted a large placebo effect on clinic systolic blood pressure readings, exceeding 10 mm Hg , which pSpironolactone substantially increased the likelihood of achieving blood pressure control relative to bisoprolol or doxasosin, with almost 60% achieving blood pressure control within 3 months of starting treatment. This challenges the concept that resistant hypertension cannot be treated adequately with existing drug therapies, a concept that might have contributed to the growth of non-drug-based therapies such as renal denervation. Indeed, only 15 of 285 patients assessed on spironolactone failed to achieve a home systolic blood pressure lower than 150 mm Hg , the usual eligibility criterion for denervation. Furthermore, it is clear from our data that spironolactone, unlike bisoprolol or doxazosin, exhibited a significant dose response with regard to the magnitude of blood pressure lowering. A previous crossover comparison of spironolactone with even higher doses  in patients without resistant hypertension, also showed a dose response,The superior response to spironolactone, compared with the other drugs, particularly in patients at the lower end of the distribution of plasma renin, supports the hypothesis that the predominant cause of resistant hypertension is sodium retention. The fact that spironolactone was the most effective drug across a wide range of baseline plasma renin values does not negate the hypothesis, because one would expect plasma renin levels to be elevated in patients receiving treatment with A + C + D, all of which usually increase plasma renin levels. Indeed, because plasma renin is substantially affected by background antihypertensive treatment, the interpretation and recognition of so-called low renin status has been uncertain in such populations. The median renin in PATHWAY-2, 34 mU/L, is roughly three times higher than that in the PATHWAY-1 study, of 600 patients with untreated hypertension (unpublished). However, 34 mU/L is a lower median than expected if the sole influence on baseline renin was drug treatment.One contributor to the sodium retention could be under-dosing of background diuretic treatment. An alternative or additional possibility is that some patients with resistant hypertension have undetected aldosterone producing adenomas (APAs). Recent studies have shown that specific somatic mutations in the adrenal gland can result in micro-APAs, which are difficult to detect by conventional imaging.As well as being the most effective treatment for resistant hypertension, spironolactone was well tolerated. The doses of spironolactone used in the present study are low compared with the 200–400 mg daily used in other clinical circumstances. The 25–50 mg daily doses in PATHWAY-2 are consistent with previous studies of resistant hypertension in which 25 mg was the most common daily dose.The PATHWAY-2 study has some limitations. 3 months treatment exposure is relatively short. Nevertheless, observational studies of longer spironolactone treatment duration for resistant hypertension suggest that the magnitude of the initial blood pressure response is durable and that among adverse events, only gynaecomastia is exposure dependent.Our study also has a number of strengths. The patients in this study were particularly well characterised as resistant hypertension, with the use of home blood pressure monitoring to exclude so-called white coat hypertension, standardisation of background medication (A + C + D), directly observed therapy to exclude patients non-compliant with background medication, measurement of serum ACE to allow retrospective confirmation of the expected difference in distribution between patients receiving ACE inhibitor or ARB as one of their background drugs, and oversight by national specialist hypertension centres to exclude secondary hypertension. In the late stages of the study, we incorporated a new assay for monitoring all commonly administered antihypertensive drugs in patients' urine,The results of PATHWAY-2 have broad international relevance because of convergent guideline recommendations, which recommend A + C + D as the preferred three-drug combination at step 3.


The objectives of the present study were to determine whether variations in EtCO2 during volume expansion (VE) are correlated with changes in oxygen extraction (O2ER) and whether EtCO2 has predictive value in this respect.In a model of hemorrhagic shock, end-tidal carbon dioxide tension , blood gas levels, and mean arterial pressure (MAP) were measured before and after VE with 500 mL of lactated Ringer solution. DO2, VO2, and O2ER were calculated from the central arterial and venous blood gas parameters. EtCO2 responders were defined as patients with more than a 4% increase in EtCO2 after VE. A receiver-operating characteristic curve was established for EtCO2, with a view to predicting a variation of more than 10% in O2ER.All patients undergoing cardiac surgery admitted to intensive care unit in whom the physician decided to perform VE were included. EtCO2 responders. In EtCO2 nonresponders, VE increased MAP and CO. In EtCO2 responders, VE increased MAP, CO, EtCO2, and decreased O2ER. Changes in EtCO2 were correlated with changes in CO and O2ER during VE (P < 0.05). The variation of EtCO2 during VE predicted a decrease of over 10% in O2ER .Twenty-two (43%) of the 51 included patients were EtCO2 did not systematically reflect an increase in CO. Only patients with a high O2ER  display an increase in EtCO2. EtCO2 changes during fluid challenge predict changes in O2ER.During VE, an increase in EtCO Before critical O2ER values arise, DO2 can decrease independently of VO2 (because DO2 exceeds VO2) and O2ER will increase with demand .2 When O2ER cannot rise any further, VO2 decreases and the body's metabolism becomes partially anaerobic (with a resulting increase in blood lactate levels).3 In many pathological situations, VO2 remains constant over a wide range of DO2 values as a result of adjustments in tissue oxygen uptake.4 ScvO2 is a clinically meaningful measure of tissue oxygenation,5 since it assesses the adequacy of DO2 with regard to VO2.6 Several studies have shown that ScvO2-based hemodynamic resuscitation is associated with lower morbidity and mortality rates during anesthesia and intensive care.8 Exhaled CO2  is also monitored in patients in the intensive care unit (ICU) or during anesthesia.9 Over short periods (and assuming a constant metabolic state), there is a qualitative relationship between EtCO2 and CO.11 Thus, EtCO2 can be used as a noninvasive, continuous measure of CO during several clinical situations with low-flow states.13 These results have not been confirmed in patients scheduled for surgery, in whom CO increased upon volume expansion (VE).14 One possible explanation is that patients scheduled for surgery and patients in the ICU differ in terms of systemic oxygen supply dependency. Most of the literature studies were performed in low-flow states, in which patients have been on a dependence phase between DO2 and VO2. This is probably not the case for most patients in the operating theatre. Based on a model of hemorrhagic shock in dogs, Guzman et al12 demonstrated that EtCO2 can reflect the dependence of DO2 and VO2 at the onset of shock and during hemodynamic resuscitation. Thereafter, Dubin et al13 confirmed the relationship between EtCO2, DO2, and VO2. Lastly, EtCO2 may be a noninvasive indicator of O2ER (and its surrogate ScVO2). Hence, the primary objective of the present study was to confirm that variations in EtCO2 during VE are correlated with changes in O2ER. We also evaluated the ability of variations in EtCO2 to predict a decrease in O2ER during VE.The objective of volume-based hemodynamic resuscitation is to raise cardiac output (CO) and increase or restore the delivery of oxygen  was provided by the Comité de Protection des Personnes Nord-Ouest II CHU—Place V. Pauchet, 80054 AMIENS Cedex 1 (Chairperson Bourgueil Thierry) on June 26, 2014. All patients received written information on the study and gave their verbal consent to participation prior to surgery. The present manuscript was drafted in compliance with the STROBE checklist for cohort studies.This prospective, observational study started on June 30, 2014 at Amiens University Hospital's cardio vascular and thoracic ICU over a 6-month period. The inclusion criteria were any major patient over 18 years, ventilated with controlled positive ventilation, for whom the physician decided to do a VE within hours of admission to the ICU. The indications for VE were arterial hypotension , oliguria (urine output lower than 0.5 mL/kg per h over 1 h), clinical signs of hypoperfusion , and arterial hyperlactatemia . The noninclusion criteria were permanent arrhythmia, chronic obstructive pulmonary disease, and acute lung injury. The exclusion criteria were spontaneous ventilation, poor echogenicity, and arrhythmia.2) was calculated as π × LVOT2/4. The aortic velocity-time integral (VTIAo) was measured with pulsed Doppler and a 5-chamber apical view. Stroke volume (SV) (mL) was calculated as VTIAo × SAo. CO (in L/min) was calculated as SV × heart rate (HR). Mean echocardiographic parameters were calculated from 5 measurements (regardless of the respiratory cycle) and analyzed retrospectively. The intra and inter reproducibility of VTIAo measurements was tested prior to the study. Reproducibility values were 4.4 ± 3.9% and 4.4 ± 3.2%, respectively.An internal jugular vein central venous catheter and an arterial catheter were placed in all patients. Central venous pressure (CVP) and blood pressure were measured with a transducer zeroed at the mid-axillary line. Transthoracic echocardiography  was performed by a physician who was blinded to the study outcomes. The left ventricular ejection fraction was measured using Simpson biplane method with a 4-chamber view. The diameter of the left ventricular outflow tract (LVOT) was measured on a long-axis parasternal view upon patient inclusion. Aortic area . All parameters were measured on arterial and central venous blood gases. Arterial and venous blood gas levels, the lactate level, the blood hemoglobin concentration, and oxyhemoglobin saturation were assayed using an automated analyzer . Arterial oxygen content (CaO2) and venous oxygen content (CvO2) were calculated as follows: CaO2 = 1.34 × Hb × SaO2 + 0.003 × PaO2; CvO2 = 1.34 × Hb × ScvO2 + 0.003 × PvO2, where Hb is the hemoglobin concentration (in g/dL), PaO2 is the arterial oxygen pressure (in mm Hg), SaO2 is the arterial oxygen saturation (in %), PvO2 is the venous oxygen pressure (mm Hg), ScvO2 is the central venous oxygen saturation (in %), and 0.003 the solubility coefficient of oxygen. PCO2 gap was calculated as follow: PCO2 gap = PcvCO2 − PaCO2 (mm Hg).We recorded the ventilator settings  at baseline. Exhaled CO2 and VO2 were calculated from arterial and central venous blood gases as follows: DO2 (mL/min per kg) = (CaO2 × 10 × CO)/weight; VO2 (mL/min per kg) = the arteriovenous difference in oxygen content ([C(a − v)O2] × CO × 10)/weight. O2ER was defined as VO2/DO2 ratio. Arterial and venous CO2 contents  were calculated according to Douglas Formula.16 The alveolar dead space (Vd/Vt) was estimated from EtCO2 and PaCO2 as (PaCO2 − EtCO2)/PaCO2.17DO2, and arterial/venous blood gas levels were obtained. In the present study, VE always consisted in infusing 500 mL of lactated Ringer solution over 10 min; 10 min after VE, a second set of measurements  was recorded. All patients had been sedated via the continuous infusion of propofol and were fully accustomed to mechanical ventilation. All patients underwent mechanical ventilation in volume-controlled mode with a tidal volume set to 7 to 9 mL/kg of ideal body weight, and a positive end-expiratory pressure of 5 to 8 cm H2O. Ventilator settings  and norepinephrine dosage were not modified during the study period.The following clinical parameters were recorded: age, gender, weight, and main diagnosis. First, a passive leg-raising (PLR) test was performed in order to evaluate the effects on SV, and assess preload status. After an equilibration period, baseline measurements of HR, SAP, MAP, diastolic arterial pressure (DAP), CVP, SV, CO, EtCO2, ERO2, VO2, DO2, and CO. Fifty-five patients were therefore recruited, taking into account the exclusion criteria. The variables’ distribution was assessed using a Kolmogorov–Smirnov test. Data are expressed as the proportion (in %), the mean  or the median (interquartile range), as appropriate. We measured the magnitude of EtCO2 variations during VE by calculating the effect size (the mean divided by the SD).19 The effect size was 0.74. Then, we calculated the coefficient of variation (CV), precision and least significant change (LSC) for EtCO2. LSC is the least amount of EtCO2 change that can be considered statistically significant; that is, the minimum percentage change between successive measurements that can be considered not due to random error and therefore representing a real change in ETCO2. The EtCO2 CV and LSC were determined in all studied patients at baseline during stable respiratory and hemodynamic conditions. The CV  was 1.8% (0.9–2.7) and the LSC (95% CI) was 2.5% (1.3–3.8). EtCO2 responder was defined as an increase of EtCO2 of more than 4% in EtCO2 after VE. EtCO2 nonresponder was defined as an increase of EtCO2 of <4% in EtCO2 after VE. This cut off correspond to LSC with its 95% CI.20 Fluid responder was defined as an increase of more than 15% in the SV during VE.21 Fluid nonresponder was defined as an increase of <15% in the SV during VE. The nonparametric Wilcoxon rank sum test, Student paired t test, Student t test, and the Mann–Whitney test were used to assess statistical significance, as appropriate. Linear correlations were tested using Pearson or Spearman rank method. A receiver-operating characteristic curve was established for EtCO2, with a view to predicting a decrease of over 10% in O2ER, and a increase over 10% in ScVO2.22 The threshold for statistical significance was set to P < 0.05. SPSS software  was used to perform statistical analysis.We calculated that a sample of 50 patients would be sufficient to demonstrate a correlation of over 0.7 between EtCO2 responders and EtCO2 nonresponders (P > 0.05). Twenty (39%) of the 51 patients were classified as EtCO2 responders. All EtCO2 responders were also fluid responders and displayed a mean (95% CI) EtCO2 of 7% (6–9) during VE  change in EtCO2 of 0% (−1 to 1) during VE . At baseline, SV variations with PLR did not differ between EtCO2 responders and EtCO2 nonresponders . O2ER was not correlated with arterial lactate levels . Changes in EtCO2 during VE were correlated with those in CO, PvO2, DO2, VO2, ScVO2, and O2ER (Table 2 during VE predicted a decrease of more than 10% in the VO2/DO2 ratio with an area under the curve (95% CI) of 0.88 (0.77–0.96) (P < 0.0001), a sensitivity of 71% (53–85), a specificity of 94% (71–100), a positive likelihood ratio of 12, negative likelihood ratio of 0.31, a positive predictive value of 96, and a negative predictive value of 62. In the same way, change in EtCO2 during VE predicted an increase of more than 10% in ScVO2 with an area under the curve (95% CI) of 0.90 (0.78–0.97), P < 0.0001.In the overall population at baseline, EtCO2 and CO depends on the relationship between VO2 and DO2; an increase in CO was not necessarily accompanied by an increase in EtCO2. Only patients with a high extraction ratio  will display an increase in EtCO2. Thus, changes in EtCO2 during VE reflect changes in O2ER in response to a rise in DO2. Hence, during VE, EtCO2 may be a useful noninvasive indicator of changes in systemic oxygen supply dependency when fixed ventilation is maintained.Our results demonstrated that during VE, the occurrence of concomitant increases in EtCO2 can be used as a noninvasive, continuous measure of CO during low-flow states .11 Similarly, EtCO2 has been shown to reflect changes in VO2 and VCO2 during hemorrhagic shock.13 Our present results demonstrated that EtCO2 may reflect changes in systemic oxygen supply associated with changes in CO during VE in nonseptic patients. All the patients in our study were postoperative sedated and nonhypothermic. Alveolar ventilation procedures and norepinephrine dosage did not change over the study period, and CO increased during VE. Even then, only 50% of fluid responders displayed an increase in EtCO2, thus EtCO2 was poorly correlated with changes in CO. Our results confirm previous findings in the operating theatre, where EtCO2 and CO were rather low.14 To determine the mechanisms by which increase in CO increase EtCO2 during VE, 1 would have to consider the study population and the effects of increase CO on blood gas parameters.Several preclinical and clinical studies have demonstrated that EtCO2 responders had a lower MAP than EtCO2 nonresponders, whereas the 2 groups did not differ significantly in terms of preload status  and CO. Although EtCO2 responders and EtCO2 nonresponders did not differ in terms of DO2, the EtCO2 responders had a higher VO2 and thus a higher O2ER and lower ScVO2. VE led to an increase in CO (and thus DO2) and a decrease in PvCO2 in fluid responders. Nevertheless, VE in EtCO2 responders led to a recovery of DO2 in consistent with oxygen needs: the decrease in O2ER resulted in an increase in PvO2 and ScvO2. In contrast, EtCO2 nonresponsiveness was associated with an increase in DO2 and VO2 because baseline O2ER did not rise. Thus, concomitant increases in EtCO2 and CO may result from several different mechanisms.At baseline, EtCO2 elimination and therefore EtCO2 depend on several factors: CO2 production , alveolar ventilation , pulmonary perfusion (CO), and V/Q matching. VCO2 depends on pulmonary elimination and metabolic production of CO2. The changes in EtCO2 in our population could not be explained by metabolic production of CO2 for several reasons. In a model of hemorrhagic shock, Dubin et al13 demonstrated that VCO2 could decrease EtCO2 during the period of VO2 supply dependency at low CO. The alterations in VCO2 were statistically significant for changes in CO, DO2, and VO2 values that were greater than those observed in our study. A further mechanism might be related to removal of peripheral tissue CO2 produced under anaerobic conditions.23 In the present study, the baseline O2ER values were below critical literature values at which tissue hypoxia was associated with anaerobic metabolism.24 Moreover, no inter and intra group difference was shown for CaCO2 and CvCO2. One can hypothesize that decrease (increases) in O2ER (ScVO2) and CO will decrease the venous blood's capacity to carry CO2 at a given PvO2, which in turn will offset the increase in CO2 delivery when CO rises.25Under steady-state conditions, alveolar CO2 may decrease PvCO2 and increase CO2 delivery to the lung. At the same time, alveolar Vd/Vt fell in EtCO2 responders (despite constant minute ventilation) as a result of 2 mechanisms. The increases in PvO2 and CO may have improved alveolar perfusion pressure and the ventilation–perfusion ratio of the lung, which would tend to decrease PaCO2.27 In our population, changes in EtCO2 had good correlation with changes in PvO2 and ScVO2 whereas they were not associated to those in PaCO2 or PvCO2. These mechanisms may explain (at least in part) why EtCO2 did not change in EtCO2 nonresponders, whereas CO did.Thus, an increase in DO2 responders had a low DO2 with regard to their VO2 resulting in higher O2ER (lower ScVO2). VE restored the relationship between VO2/DO2 through CO changes and increasing PvO2 and CO2 delivery to the lung, which improved the patients’ ventilation–perfusion ratio and thus increased EtCO2.In summary, EtCO2 and VO2, and the extent of anaerobic metabolism may depend on the etiology of acute circulatory failure.30 We measured blood gas parameters from a central venous catheter and not from a pulmonary artery catheter. Although ScVO2 cannot give a precise absolute estimate of SvO2, it can serve as a guide to changes in SvO2 and VO2.31 Monnet et al used blood gas parameters from a central venous catheter to assess VO2, DO2, and their changes over time during fluid expansion in septic patients.31 In our study, changes in ScVO2 (measured) and O2ER  had good correlation . Moreover, predictive values of EtCO2 changes during VE did not differ to predict an increase of ScVO2 or a decrease of VO2/DO2 ratio. Since we performed repeated measurements of blood gas levels, mathematical coupling cannot be ruled out. But De Backer et al demonstrated that during controlled conditions, VO2 calculated from hemodynamic data is a valid alternative to VO2 derived from respiratory gas measurements.32 The method used to calculate alveolar dead space was not standardized and may have introduced bias into the determination. The difference between EtCO2 and PaCO2 is altered in patients with altered ventilation/perfusion ratios . In the present study, patients with chronic pulmonary disease or acute lung injury were excluded to limit this bias. Furthermore, these results cannot be extrapolated to EtCO2 changes that result from the administration of vasopressor drugs.33 EtCO2 changes seem small but they are similar to those used to predict fluid responsiveness.34 Lastly, given that we did not measure VCO2, we cannot rule out the occurrence of changes in metabolic production of CO2 during the VE-induced increase in CO.The present study had a number of limitations. The study population (patients after heart surgery) may have differed from septic shock patients. Most of our patients suffered from acute circulatory failure as a result of perioperative hypovolemia, whereas septic patients generally have acute circulatory failure that combines hypovolemia, changes in microvascular perfusion and cellular dysoxia. A patient's response to VE, the relationship between DO2. Only patients with a high O2ER  display an increase in EtCO2. Thus, EtCO2 changes during fluid challenge predict changes in O2ER  in response to an increase in DO2. EtCO2 may be a useful noninvasive indicator of changes in systemic oxygen supply dependency in operative patients when fixed ventilation is maintained.During VE, an increase in CO was not necessarily accompanied by an increase in EtCO18.


VT), ARF patients showed 30.0% and 27.8% decrease at 1 min and 10 min, respectively. Furthermore, the initial respiratory system compliance (Crs) decreased by 29.6% and 28.5% at 1 min and 10 min, respectively. Under VCV mode, compared with the initial level, 38.6% and 37.5% increase in peak airway pressure (PAP) were found at 1 min and 10 min, respectively. Under PCV mode, the initial PaO2 increased by 6.4% and 10.2 % at 3 min and 10 min, respectively, while 18.9% and 30.6% increase of the initial PaO2 were observed under VCV mode. Summarily, endotracheal suctioning may impair gas exchange and decrease lung compliance in ARF patients receiving mechanical ventilation under both PCV and VCV modes, but endotracheal suctioning effects on gas exchange were more severe and longer-lasting under PCV mode than VCV.This study was conducted to evaluate the effects of open endotracheal suctioning on gas exchange and respiratory mechanics in ARF patients under the modes of PCV or VCV. Ninety-six ARF patients were treated with open endotracheal suctioning and their variations in respiratory mechanics and gas exchange after the suctions were compared. Under PCV mode, compared with the initial level of tidal volume ( Respiratory failure is an acute or chronic condition with impaired gas exchange and pulmonary functions and is characterized by elevated carbon dioxide or decreased oxygen in the arterial blood . RespiraDue to establishment of artificial airway, most acute respiratory failure (ARF) patients receiving mechanical ventilation could not produce sputum. Suctioning could effectively eliminate airway secretions to maintain respiratory function . EndotraThe Ethics Committee of the First Affiliated Hospital of China Medical University approved this study. Written informed consent was acquired from all subjects using the procedures authorized by institutional review boards. Next of kin, caretakers, or guardians consented representing the study participants whose capacity to consent was reduced. The study was executed at the emergency intensive care units (EICU) at the First Affiliated Hospital of China Medical University.2 < 60 mmHg, PaCO2 < 50 mmHg; (2) type II: PaO2 < 60 mmHg, PaCO2 ≥ 50 mmHg. All patients received endotracheal intubation and continuous mechanical ventilation , continuous monitoring of heart rate (HR), blood pressure (BP), and SpO2 with Philips Intellivue MP60 monitor .This was a single center prospective study of acute respiratory failure (ARF) patients admitted to the EICU between October 2010 and February 2013. Patients met the following criteria to be enrolled in this study; patients lived up to the criteria for the diagnosis of ARF: (1) type I: PaOP > 0.05).In the present study, ninety-six acute respiratory failure (ARF) patients  were enrolled, with a mean age of 62 years (range: 26~84 years). They were divided into two groups: PCV and VCV. PCV group included 49 patients , with a mean age of (57 ± 21) years. And they were with an APACHE II score of (17.6 ± 10.3), a disease course of (4.6 ± 2.0) years. There were 15 patients who had complications, such as compensatory chronic respiratory failure, acidosis, pulmonary encephalopathy, and gastrointestinal bleeding. Compared with PCV, VCV group had 47 patients , with a mean age of (58 ± 26) years. Their APACHE II score was (17.2 ± 10.1) and disease course was (5.1 ± 2.2) years. Twenty among them had complications, including compensatory chronic respiratory failure, acidosis, pulmonary encephalopathy, and gastrointestinal bleeding. As shown in 2O (0.98 kPa) plateau airway pressure (Pplat) by increasing tidal volume (VT) under VCV mode and 10 cm H2O inspiratory pressure under PCV mode, maintaining ventilation and oxygenation for 20 s. According to the clinical need for suctioning, suction indications include visible secretions attached within the patient's endotracheal tube, auscultation of lung breath weak sound and sputum sound, patients with irritability and other poor performances, changes, or abnormities in breathing rate, slowness of heart rate, increase in blood pressure, reduction of ventilation, and detection of SpO2 less than 90%. Endotracheal suctioning was performed when alarm for peak airway pressure (Ppeak) under VCV mode, low tidal volume under PCV, or SpO2 decreased more than 5%. During endotracheal suctioning, endotracheal tube departed from Y-shaped tube. The 12F suction catheter (4 mm exterior diameter) was inserted into endotracheal tube about 30 cm after blocking negative pressure suction and then slowly rotated and the suction catheter was withdrawn at 150 mmHg. Endotracheal tube was connected with ventilator tube for mechanical ventilation after suctioning.The 96 ARF patients were randomly divided into the PCV and VCV groups using a random number generator. Diazepam (10 mg) was injected intravenously before suctioning. A standardized method was used for a standardized lung volume method after 1 h of mechanical ventilation: (1) sufficient suctioning for mouth, nasal, and airway secretions; (2) 10 cm HVT, Ppeak, and Pplat were recorded at 15 min after standardized lung volume (baseline), before suctioning, and 1, 3, 5, and 10 min after suctioning. Total respiratory system compliance (Crs) was reckoned by [Crs = VT/(Ppeak − PEEP(5–8 cm H2O))]. Values of VT, Ppeak, and Pplat were the average of five respiratory cycles. Dynamic changes in SpO2 were monitored. Arterial blood gas analysis was performed at baseline, before suctioning, and at 3 and 10 min after suctioning.The HR, mean arterial pressure (MAP), χ2 test was used to compare frequencies. One-way analysis of variance (ANOVA) and Student's t-test were applied to generally distributed variables, while the Mann-Whitney U test was applied to nonnormal distributed variables. Comparisons between two groups for nominal variables were made by the Fisher exact test. All of the statistical significance tests were two-sided, with a P value less than 0.05 considered as statistically significant. All the statistical analysis was performed by the use of SPSS 18.0 software .Data was presented as mean ± standard deviation (SD), median with interquartile ranges (IQR), or frequencies. A −1, P < 0.05; MAP: 91 ± 14 versus 82 ± 12 mmHg, P < 0.05, resp.). Under VCV mode, the HR and MAP increased by 10.4% and 11.1%, respectively, at 5 min after suctioning compared with the baseline level . No significant differences were found in changes in HR and MAP at 10 min after suctioning compared with the baseline level under both PCV and VCV modes . Furthermore, there were also no significant differences in HR and MAP between PCV and VCV modes at different time points after suctioning .Changes in heart rate (HR) and mean arterial pressure (MAP) before and after suctioning at different time points under PCV and VCV modes are shown in VT), Crs, and airway pressure in ARF patients before and after suctioning at different time points are shown in VT and Crs showed a decrease of 30.0% and 29.6%, respectively, at 1 min after suctioning, compared with the baseline level  . No significant differences were found for changes in the VT and Crs at 10 min after suctioning, compared with baseline level .Changes in tidal volume (Ppeak) and plateau pressure (Pplat) showed an increase of 38.6% and 17.2%, respectively, at 1 min after suctioning, compared with the baseline level , while Crs decreased by 32.5%  , while Crs decreased by 31.7% . Compared with the level before suction, t changes in the Ppeak and Crs at 10 min after suctioning also did not represent notable differences .Under VCV mode, peak airway pressure  . Under VCV mode, compared with the level before suction, PaO2 also showed an increase of 18.9% and 30.6% at 3 and 10 min, respectively, after suctioning . There was no obvious difference in PaO2 between the baseline level and the level at 10 min after suctioning . We have demonstrated that under PCV mode PaO2 had a mean increase (3 min: (6.4 ± 2.6) %; 10 min: (10.2 ± 6.2) %) for ARF patients after suctioning compared with before suctioning, and the increased ratio was lower than under VCV mode .Under PCV mode, compared with the initial level before suctioning, PaO, resp.) . HoweverMechanical ventilation mechanically assists or replaces spontaneous breathing . In geneVT, ARF patients showed a 30.0% and 27.8% decrease at 1 min and 10 min, respectively, after suctions under PCV mode. Alveolar collapse under PCV mode could lead to an increased respiratory resistance when the inspiratory pressure was stabilized on a fixed point, thereby causing VT to reduce [Crs decreased by 29.6% and 28.5% at 1 min and 10 min, respectively, after suctions under PCV mode. The major causes of suctioning effects on respiratory mechanics include alveolar collapse, lung volume, and compliance decrease [Pplat and a 32.5% and 31.7% decrease of Crs at 1 min and 10 min, respectively, after suctions under VCV mode. Given that VT under VCV mode was not changed, alveolar collapse would lead airway pressure to increase accordingly and overexpansion of the open alveolar may also cause increase in Pplat.In the present study, we evaluated endotracheal suctioning effects on gas exchange and respiratory mechanics in 96 ARF patients under PCV and VCV modes. Our results indicated that endotracheal suctioning under PCV and VCV modes impairs both gas exchange and respiratory mechanics in ARF patients receiving mechanical ventilation. Compared with the initial level of o reduce . Furtherdecrease . Under VPpeak under VCV mode and a decreased VT under PCV mode. In addition, our results also suggested that the initial PaO2 increased by 6.4% and 10.2% at 3 min and 10 min, respectively, after suctions under PCV mode, while 18.9% increase and 30.6% increase of the initial PaO2 were observed under VCV mode. There was a significant difference in the increment of the initial PaO2 between PCV and VCV modes. Our results are consistent with multiple previous studies [During mechanical ventilation, the retention of airway mucus causes increased airway resistance, which is manifested as increased airway pressure . However studies –25.In conclusion, our study provides a comprehensive and reliable evidence that endotracheal suctioning of ARF patients receiving mechanical ventilation may impair gas exchange and decrease lung compliance, under both PCV and VCV modes, but the effects of endotracheal suctioning on gas exchange were more severe and longer-lasting under PCV mode, in comparison to VCV mode.


Exposure to phthalates, a class of endocrine disrupting chemicals, is ubiquitous. We examined the association of urinary phthalate metabolite concentrations during pregnancy with maternal blood pressure and risk of pregnancy-induced hypertensive diseases.We used data from the Health Outcomes and Measures of the Environment Study, a prospective birth cohort of low-risk pregnant women recruited between March 2003 and January 2006. We analyzed maternal urine samples collected at 16 and 26 weeks gestation for 9 phthalate monoester metabolites reflecting exposure to 6 phthalate diesters. Outcomes included maternal blood pressure at <20 and ≥20 weeks gestation and pregnancy induced hypertensive diseases .Data were available for 369 women who gave birth to singleton, live-born infants without congenital anomalies. Of the phthalate metabolites evaluated, only mono-benzyl phthalate (MBzP) concentrations were significantly associated with maternal diastolic blood pressure at <20 weeks gestation. Women in the third MBzP tercile at 16 weeks gestation had diastolic blood pressure 2.2 (95 % CI: 0.5–3.9) mm Hg higher at <20 weeks gestation and 2.8 (95 % CI: 0.9–4.7) mm Hg higher at ≥20 weeks gestation compared to women in the first tercile. Compared to women in the first tercile, women in the top MBzP tercile at 16 weeks had an increased risk of developing pregnancy-induced hypertensive diseases . MBzP concentrations at 26 weeks gestation were not as strongly associated with blood pressure at ≥20 weeks gestation or risk of pregnancy-induced hypertensive diseases.This study suggests that maternal urinary MBzP concentrations may be associated with increased diastolic blood pressure and risk of pregnancy-induced hypertensive diseases. Recent studies have suggested that exposure to phthalic acid diesters  may be associated with elevated blood pressure and increased risk of cardiovascular disease. A cross-sectional analysis of the National Health and Nutrition Examination Survey suggested that increased urinary phthalate concentrations are associated with higher blood pressure in children . AdditioWomen of reproductive age in the United States have almost ubiquitous exposure to phthalates , 4. PhthWhile the exact mechanism by which phthalate exposure may influence cardiovascular health is unknown, phthalates are hypothesized to be endocrine disruptors that affect the action and metabolism of androgens, cortisol, and thyroid hormones –8. PhthaThis study is an analysis of data from The Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort study designed to examine the associations of environmental chemicals with maternal and child health outcomes. The HOME Study recruited pregnant women from 2003 to 2006 who were ≥ 18 years of age, 16 ± 3 weeks of gestation, and living in the Cincinnati, OH area in homes built before 1978 . Women wn = 389). We excluded two women whose offspring had congenital or chromosomal abnormalities as some fetal conditions (i.e. hydrops) can predispose women to hypertension in pregnancy. Finally, we excluded 18 women who were missing exposure (n = 5), outcome (n = 4), or covariate (n = 9) data, leaving 369 pregnancies for our primary analyses.This analysis included women who were still participating in the study at the time of delivery and who delivered a live singleton . We selected this as the primary outcome since maternal blood pressure in the first and early second trimester affects placentation and is known to predict preeclampsia risk , 12. AddStudy participants were defined as having gestational hypertension, preeclampsia, eclampsia or HELLP syndrome if their provider made the clinical diagnosis and documented it in their medical record. Additionally, we considered a woman to have gestational hypertension if either of her two blood pressure measurements at ≥ 20 weeks met at least one of the following conditions: elevated systolic blood pressure (>140 mm Hg) at both measurements, elevated diastolic blood pressure (>90 mm Hg) at both measurements, or elevated systolic blood pressure at one measurement and elevated diastolic blood pressure at the other measurement or vice versa. A woman was considered to have a pregnancy-induced hypertensive disease if she had one or more of the following diagnoses: gestational hypertension, preeclampsia, eclampsia or HELLP syndrome. Women with two blood pressures ≥140/90 prior to 20 weeks (chronic hypertension) could still be considered to have a pregnancy-induced hypertensive disease if they developed preeclampsia, eclampsia or HELLP (i.e. superimposed preeclampsia).We collected covariate information during home visits ~ 20 weeks gestation and at the prenatal visit at the time women completed their glucose tolerance test (~26 weeks gestation). Study staff surveyed participants’ about their socio-demographic status, including maternal age, race, income, marital status and insurance status using standardized interviews. Additionally, we obtained data on parity and body mass index (BMI) at 16 weeks from the medical record. We measured serum cotinine, a biomarker of tobacco smoke exposure, and blood lead in samples collected at approximately 16 and 26 weeks gestation. We also asked women if they had ever taken medication for high blood pressure.n = 3) of the 16 week samples were collected after 20 weeks of gestation. We collected urine into polypropylene specimen cups that had been lot tested for phthalate contaminants, refrigerated until processing, and stored at or below −20 °C until chemical analysis. Urinary phthalate metabolites were measured using previously described analytic methods [∑DBP) monoester metabolites. Thus, we examined five different phthalates in the analysis: monoethyl phthalate (MEP), mono-3-carboxylpropyl phthalate (MCPP), monobenzyl phthalate (MBzP), ∑DEHP, and ∑DBP. Phthalate metabolite concentrations were creatinine-normalized to account for maternal hydration by dividing urinary phthalate metabolite concentrations by urinary creatinine concentrations and multiplying this by 100.Maternal urinary phthalate metabolite concentrations were obtained from spot samples at an average of 16 (range: 10–23) and 26 (range: 19–35) weeks gestation. Less than 1 % , married (66 %), and Caucasian (62 %) Table . The aven = 13, 4 %), preeclampsia , or HELLP syndrome . No women were diagnosed with eclampsia. Both of the women with HELLP were also diagnosed with preeclampsia. The women who developed pregnancy-induced hypertensive disorders were most often non-white, overweight or obese, nulliparous, or reported previously taking high blood pressure medications (Table The average systolic and diastolic blood pressures were 110 (SD: 13) and 66 (SD: 10) mm Hg, respectively, and were first measured at an average of 11 weeks gestation (range 4–20). Thirteen women had blood pressures consistent with chronic hypertension (2 blood pressures ≥ 140/90 before 20 weeks gestation). A total of 34 (9.2 %) women developed at least one the following: gestational hypertension   . The association was strongest for the 16 week urinary MBzP concentrations. Women in the 3n = 28). The association between MBzP concentrations and maternal diastolic blood pressure <20 weeks did not change appreciably after this exclusion. Second, we accounted for urine dilution by adjusting for creatinine concentrations in our statistical models of 16 and 26 week urinary phthalate metabolites, rather than creatinine-normalizing urinary phthalate concentrations; again our results were relatively unchanged. Third, we also analyzed the data stratifying for the timing of blood pressure measurements prior to 20 weeks gestation relative to the timing of urine sample collection. We found a consistent association between MBzP concentrations and increased diastolic blood pressure at <20 weeks of pregnancy regardless of whether the blood pressure measurements were obtained before or after the urine sample collection. Finally, we excluded women who reported previously using medication for high blood pressure (n = 20) and our results were unchanged.We performed several sensitivity analyses to examine the robustness of our MBzP associations to various assumptions. First, given the potential for urinary phthalate concentrations to be significantly affected by renal function, we excluded women with low (<20 mg/dL) or high (>300 mg/dL) 16 week urinary creatinine concentrations  found that increased urinary concentrations of MEP were associated with increased blood pressure in children age 6 to 19 years  . In the In our study, we did not find an association between MEP or DEHP and maternal blood pressure or pregnancy-induced hypertensive disease. Only MBzP showed a significant association with both increased diastolic blood pressure and pregnancy-induced hypertensive diseases. Serum MBzP has previously been associated with cardiovascular disease risk factors in a study of elderly adults from Sweden . IndividThis study has several limitations. While the HOME Study collected a rich set of phthalate exposure biomarkers from pregnant women, the primary outcome of interest was not blood pressure or hypertensive disorders of pregnancy. Thus, we relied on chart-derived blood pressure measures rather than research quality blood pressure measures. Blood pressures can be falsely elevated if collected immediately after a patient enters the clinic, after smoking tobacco or if the blood pressure cuff is too small. In addition, we did not have detailed information on the quality controls used to ensure accurate blood pressures. However, this bias should be non-differential with respect to phthalate exposure. Another limitation of this analysis is that we do not have pre-pregnancy health status which may have contributed to the risk of increased blood pressures and pregnancy induced hypertensive diseases. We also evaluated five different types of phthalate metabolites and there is a chance of type I error due to multiple comparisons. However, it seems unlikely that our MBzP associations were spurious given that we saw consistent associations between urinary MBzP concentrations and blood pressure at two time points in pregnancy, as well as risk of pregnancy-induced hypertensive diseases. Furthermore, the MBzP concentration in the earlier pregnancy window (16 weeks rather than 26 weeks) was most strongly tied to pregnancy induced hypertensive disorders. This is consistent with the hypothesis that some pregnancy induced hypertensive disorders are the end result of an abnormal spiral artery invasion between mother and fetus that develops prior to 16 weeks gestation [The generalizability of these findings might be limited since our study participants were at lower-risk of pregnancy-induced hypertensive disorders then most obstetric populations. However, urinary phthalate concentrations among women in this cohort were similar to nationally-representative samples of women in the US . AdditioThis study has several strengths. First, it is a prospective cohort study that enrolled women in early pregnancy to investigate the impact of environmental chemicals. In addition, we made every effort to minimize exogenous contamination of our samples and quantified urinary levels of phthalate metabolites using state of the art analytic chemistry methods. This is particularly important because the parent phthalate diesters may be found in specimen collection materials and other medical equipment, thus potentially contaminating the samples . By examIn this cohort, we observed that higher urinary MBzP concentrations were associated with both elevated maternal diastolic blood pressure and increased risk of pregnancy-induced hypertensive diseases. While exposure to MBzP’s parent compound, BBzP, is nearly universal among pregnant women, exposure could be prevented. Thus, it is vital that additional studies more thoroughly evaluate how, and when phthalates can affect maternal and fetal health.