The purpose of this study was to determine the optimal carbon dioxide (CO2), pH, cardiac output, heart rate, and mean arterial pressure were measured at baseline, 30 min and 1, 1.5, and 2 hours after CO2 insufflation, and 30 min after desufflation.A total of 32 patients underwent thyroid surgery at 6 (n = 15), 9 (n = 15), and 12 (n = 2) mmHg. The partial pressure of carbon dioxide (PaCO2 insufflation of 12 mmHg caused severe facial subcutaneous emphysema, hypercarbia, and acidosis during robot-assisted thyroidectomy with BABA. The study was stopped before completion for the patients’ safety in accordance with the study protocol. Applying 6- or 9- mmHg of CO2 insufflation pressure caused increases in PaCO2 and decreases in arterial pH. However, vital signs were stable and pH and PaCO2 were within the physiologic range during the surgery in the 6- and 9-mmHg groups.CO2 insufflation pressure under 10 mmHg in robot-assisted thyroidectomy with BABA is the optimal insufflation pressure for patient safety.We propose that a CO Since endoscopic neck surgery was introduced into clinical practice in 1995 by Gagner ,3. BABA 2) gas is usually insufflated into the body cavity, and an electronic variable-flow insufflator controls the insufflation pressure [2 insufflation pressure allows a better view of the surgical field. However, because the insufflation pressure can affect the severity of hypercarbia, balancing the insufflation pressure between a better view of the surgical field and preventing hypercarbia is very important. In laparoscopic surgery, the insufflation pressure should be maintained below 16 mmHg in order to prevent significant hypercarbia [During laparoscopic surgery, carbon dioxide .The use of COmphysema . Accordi 15 mmHg . They pridectomy ,4. Howev2 insufflation pressure in patients undergoing RaBABA.Therefore, the purpose of the present study was to determine the optimal COAfter obtaining approval from the institutional review board and written informed consent, 32 patients with American Society of Anesthesiologists (ASA) physical status I–II undergoing elective RaBABA were randomly assigned to the three groups described below. The ages of the patients ranged from 18 to 60 years.2 gas pressure used to insufflate the peritoneal cavity. Patients with previous neck or breast surgery, severe cardiopulmonary disease, morbid obesity, and neck or vertebral abnormality were excluded from this study.Patients were randomly assigned to one of the three groups. The groups were named on the basis of the CO2, bispectral index, and expiratory gas concentration. Anesthesia was induced with intravenous propofol and was maintained with 50% nitrous oxide in oxygen and an end-tidal concentration of 2 to 3 vol% of sevoflurane. Intravenous rocuronium bromide was used to facilitate tracheal intubation. The radial artery was cannulated with a 20-gauge catheter to monitor arterial blood pressure. The VigileoTM System  was connected to the arterial line to monitor the cardiac index (CI) and cardiac output (CO). Mechanical ventilation was maintained with oxygen with air (FiO2 0.5) at a constant tidal volume (8 mL/kg) and frequency (12 breaths/min) during the study. Lactated Ringer’s solution was used for volume replacement during surgery.The patients were premedicated with midazolam (2 mg) and glycopyrrolate (0.2 mg) intramuscularly 30 min before anesthesia. Standard monitoring included electrocardiogram, noninvasive arterial blood pressure, pulse oximetry, end-tidal CO2) ≥50 mmHg) for 30 min; (2) the mean blood pressure decreased to below 50 mmHg; (3) the CI decreased to below 2 L/min; (4) the heart rate increased to over 110 beat/min; and (5) the occurrence of serious adverse events, such as subcutaneous emphysemas, as determined by the attending anesthesiologists.If any one of the termination criteria was met during the surgery, insufflation pressure was reduced to below 5 mmHg. If the study was terminated in two consecutive cases within the same group, the study group was excluded and a new randomization code was generated between the remaining groups. The termination criteria of the study were as follows: (1) persistent acidosis (pH ≤7.15) or hypercarbia , CI and CO were measured at baseline, 0 min, 30 min, 1 hour, 1.5 hours, and 2 hours after CO2 insufflation and desufflation, and at 30 min after desufflation.Heart rate, mean arterial pressure (MAP), pH, PaCOt-test or Mann–Whitney rank sum test. Variables at each time point within a group were compared using repeated measures analysis of variance. A P value <0.05 was considered statistically significant.Statistical analysis was conducted using SigmaStat 3.5 for Windows . Variables between groups were compared using the two-sample 2 insufflation in the two patients in whom the surgery was conducted using a CO2 insufflation pressure of 12 mmHg. Furthermore, rapid progression of hypercarbia and acidosis was observed. The study was stopped midway in accordance with the termination criteria. In addition, the 12-mmHg group was dropped because two consecutive cases developed severe facial subcutaneous emphysemas, hypercarbia, and acidosis. The remaining patients in the 12-mmHg group were randomly allocated to the other two groups and successfully participated in this study. Statistically significant differences were not observed in any of the variables, including neck circumstance before and after CO2 insufflation, between the two groups , the 9-mmHg group (n = 15), and the 12-mmHg group (n = 2). Severe facial subcutaneous emphysema was observed at 15 and 30 minutes after the initiation of CO5, the 9-P <0.05) , CO, and CI were not observed between the groups at any of the time points. After desufflation, the MAP was increased compared to the baseline value in the 9-mmHg group  Figure . The HR ) Figure . The CO ) Figure .2 were within the physiologic range at each time point. In addition, no differences in pH and PaCO2 were observed between the groups at any of the time points. In the 6-mmHg group, decreased pH and increased PaCO2 compared to the baseline value was observed at 30 min and at 1, 1.5, and 2 hours after insufflation. The pH and PaCO2 levels returned to the baseline value at 30 min after desufflation. In the 9-mmHg group, decreased pH and increased PaCO2 compared to baseline was observed at 30 min and 1, 1.5, and 2 hours after insufflation. PaCO2 levels returned to the baseline value at 30 min after desufflation. However, the pH was decreased until 30 min after desufflation.Patients undergoing surgery did not develop acidosis or hypercarbia in the 6- or 9-mmHg groups Figures , 5. Chan2 insufflation pressure of 12 mmHg caused severe facial subcutaneous emphysema, hypercarbia, and acidosis during RaBABA. Although applying 6- or 9-mmHg of CO2 insufflation pressure increased PaCO2 and decreased arterial pH, the vital signs were stable and pH and PaCO2 were within the physiologic range during surgery.Our results showed that a COet al. [2 insufflation pressure of 20 mmHg. According to Bellantone et al., hypercarbia, moderate acidosis, and a slight increase in mean arterial pressure occurred in pigs undergoing endoscopic neck surgery at 15 mmHg [2 insufflation of 15 mmHg caused CO2 accumulation and acute hypercarbia, which can lead to intracranial angiectasis, increased brain blood volume, and subsequent intracranial hypertension [Subcutaneous emphysema is a frequent complication during endoscopic surgery ,9. Subcuet al.  reported 15 mmHg . In addirtension ,12. Therrtension ,8 sugges2 insufflation may give us several advantages over 6 mmHg pressure of insufflation when performing RaBABA. First, 9 mmHg insufflation provides wider operative space than 6 mmHg insufflation. Unlike the case with non-articulating linearly moving instruments used in conventional endoscopic thyroidectomy, various kinds of articulating instruments which enable almost 360 degrees of freedom of movement are applied through the robotic arms during robotic thyroidectomy, and to use the articulating instruments effectively a wider operative space is needed than is in conventional endoscopic thyroidectomy. In other words, higher flap and wider operative space are necessary to fully take advantage of robotic arm movements during RaBABA. This wider space may be achieved by the maximal safe CO2 insufflation pressure which turned out to be 9 mmHg in this study. Second, a higher raised flap in higher CO2 insufflation pressure helps to keep the surgeon's view clear for a longer time and lessens the need to cleanse the lens of the endoscopic camera during RaBABA. The surgeons performing RaBABA are hindered by the visual disturbance that results from the contamination of the endoscopic camera lens by subcutaneous and subplatysmal fat tissues, especially in obese patients. A more highly elevated flap in 9 mmHg CO2 insufflation pressure than in 6 mmHg helps to keep the camera view clear for a longer operative time in these obese patients undergoing RaBABA. Third, in turn, higher insufflation pressure can be somewhat helpful in diminishing the total operation time of RaBABA, especially in obese patients. However, in our study, there was no statistically significant difference in total operation time between the 6 mmHg and 9 mmHg groups (240.3 min in the 6 mmHg group versus 220.6 min in the 9 mmHg group), which might be a result of the limited numbers of enrolled patients in the two groups and also the lack of morbidly obese patients in either group.From the surgeon’s point of view, 9 mmHg pressure of CO2 has a high solubility, the absorption dose of CO2 is proportional to CO2 pressure and the duration of insufflation [2 gas is easily diffused in loose areolar and rough tissue [2 increased and pH decreased slightly without acidosis or adverse hemodynamic changes in the 10-mmHg group [2 and pH were changed after CO2 insufflation in the 6- and 9-mmHg groups. The increased PaCO2 caused the decrease in pH. However, the changes in pH and PaCO2 were within the physiologic range in the 6- and 9-mmHg groups during the insufflation period. Hypercarbia due to CO2 insufflation can cause epinephrine and norepinephrine release, resulting in hypertension and tachycardia [2 insufflation [Because COfflation . CO2 gash tissue , such asHg group ,15. In ohycardia . Howeverhycardia ,17. In afflation , previoufflation . In our This study had several limitations. Our results showed that the CO was not changed in the 6- or 9-mmHg groups compared to the baseline value during the study period. The continuous thermodilution technique using a catheter placed in the pulmonary artery is widely used to assess CO in critically ill patients ,20. Alth2 insufflation pressure below 10 mmHg in robot-assisted thyroidectomy with BABA is an optimal insufflation pressure.In conclusion, we propose that a COBP: blood pressure; BABA: bilateral axillo-breast approach; CI: cardiac index; CO: cardiac output; HR: heart rate; MAP: mean arterial pressure; RaBABA: robotic bilateral axillo-breast approach.The authors declare that they have no competing interests.HYK helped conduct the study and write the manuscript, YJC helped analyze the data and write the manuscript, HNY writed the manuscript and SZY helped design the study, conduct the study, analyze the data, and write the manuscript. All authors read and approved the final manuscript.


Prediabetes (PreDM) in asymptomatic adults is associated with abnormal circadian blood pressure variability .Systemic inflammation and glycemia influence circadian blood pressure variability.Dahl salt-sensitive (S) rats (n = 19) after weaning were fed either an American (AD) or a standard (SD) diet. The AD  simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD  mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG), adipokines (leptin and adiponectin), and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α)] were measured. Rats were surgically implanted with C40 transmitters and blood pressure  and heart rate (HR) were recorded by telemetry every 5 minutes during both sleep (day) and active (night) periods. Pulse pressure (PP) was calculated (PP = SBP-DBP).[mean(SEM)]: The AD fed group displayed significant increase in body weight . Fasting glucose, adipokine (leptin and adiponectin) concentrations significantly increased , along with a trend for increased concentrations of systemic pro-inflammatory cytokines (MCP-1 and TNF-α) on day 90. The AD fed group, with significantly higher FG, also exhibited significantly elevated circadian (24-hour) overall mean SBP, DBP, PP and HR .These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms  which generate abnormal CBPV. Obesity is universally associated with excess adipose tissue distribution ,2. ExcesAsymptomatic overweight adults with prediabetes, when compared to overweight adults with normal glucose, were observed to have abnormal circadian blood pressure variability . In a seThese results led us to formulate our overall hypothesis that short term caloric excess results in adipose tissue deposition. The excess ectopic adipose tissue alters its adipokine secretion menu tipping the pro-inflammatory and anti-inflammatory balance in favor of inflammation  and potentiating the elements of the renin-angiotensin-aldosterone system (resulting in a loss of blood pressure control). This latent high cardiovascular risk is clinically manifest as prediabetes and/or prehypertension and functionally as abnormal circadian blood pressure variability and/or endothelial dysfunction.Using an animal model with a permissive genetic background we tested the hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability.All animal procedures and protocols used in this report were approved by the University of Toledo Health Science Campus Institutional Animal Care and Use Committee .The animal experiments were performed at the Physiological Genomics Laboratory, Department of Physiology and Pharmacology, University of Toledo College of Medicine. Dahl salt-sensitive (S) rats (n = 19) from the colony maintained at the University of Toledo College of Medicine and Life Sciences, Toledo, Ohio were used. These rats with a genetically permissive background allowed us to simulate the changes that occur with the feeding of an American diet and compare them to a standard diet. We were able to demonstrate the early effects of caloric excess, the metabolic changes and their physiologic consequences. The rats were weaned at 30 days and fed either an American diet (AD) or a standard diet (SD) for the duration of the study (six months).American diet  was designed to simulate the customary every day human diet which due to its overabundant calories on a daily basis, over time, leads to body weight gain. The standard diet  was designed to mirror the desirable balanced human diet which would sustain growth and maintain body weight.Individual body weight of rats in the AD and SD fed groups was measured at 90,120,135, 160 and 172 days of age. A group mean(SEM) body weight was reported at these time points.The blood glucose concentrations were measured using a commercially available 'One Touch Ultra Smart' kit according to the manufacturer's instructions. Rats were fasted overnight and individual blood samples were collected at age 90 and 172 days. The group (AD or SD) mean(SEM) fasting glucose were calculated from individual measurements and were reported.All the cytokine analysis  were performed using a Multiplex Adipokine/Adipocyte Panels  according to the manufacturer's instructions. The blood samples were collected for cytokine analysis from individual rats included in the AD and SD fed groups. The individual mean of duplicate measures from each individual rat were used to report the group mean(SEM) concentration. At the end of study all the animals were euthanized. Individual body weights, heart and kidney weights were recorded. A group mean(SEM) heart and kidney weight was reported as a surrogate measure for ectopic fat deposition.Systolic blood pressure, diastolic blood pressure and heart rate were obtained by using a telemetry system  as previously detailed . Pulse pData were analyzed using the student's t-test to assess statistical significance. Data are presented as the mean(standard error of mean). Statistical significance was reported as p ≤ 0.001, ≤ 0.01 or ≤ 0.05.Dahl salt-sensitive (S) rats n = 19) were weaned and fed either an American diet  or a standard diet  for six months. There were no significant differences in the mean body weight of the group fed with the AD in comparison with the group fed SD at 90 days. A significant differential increase in mean body weight  then ensued in the AD fed group, which persisted until the end of the experiment . Figure 9 were weFasting glucose assessments were obtained with a One Touch Ultra Smart kit at two different time points: 90 and 172 days of age. At the age of 90 days the AD fed group displayed significantly increased fasting blood glucose (FBG) 90.1(5.38) mg/dL compared to SD fed group 63.7(1.98) mg/dL, (p < 0.001). The AD fed group at the age of 172 days exhibited an even higher mean FBG 102(5.4) mg/dL (compared to SD fed group 87(2.33) mg/dL, p < 0.05). Fasting serum glucose concentrations above 100 mg/dL in humans are associated with a diagnosis of prediabetes, a recognized pre-disease state with high covert risk of cardiovascular disease, and the potential for conversion to diabetes mellitus. Figure All the cytokine analysis  were performed using a Multiplex Adipokine/Adipocyte Panels . A significant increase in serum leptin  in the group fed with AD (in comparison to the group fed SD) was seen at both 90 (p < 0.01) and 172 days of age (p < 0.001). This figure also demonstrates the beginning of an increase in serum adiponectin with AD at three months, which attained significance (p < 0.01) at the end of the study. This is indicative of a functional adipose tissue increasing the secretion of its major adopokine, adiponectin with the increase in adipose tissue mass. Figure An initial increase in the systemic pro-inflammatory cytokines, MCP-1 and TNF-α in the AD fed group (in comparison to the group fed SD) at three months, subsequently declined at end of the study. Although the means from the groups did not reach significance at either time point, this increase is indicative of ectopic adipose tissue deposition, adipose tissue dysfunction and an augmented systemic pro-inflammatory secretory activity. Figure After being euthanized at the end of the experiment, total body and organ (heart and kidney) weights were obtained. AD fed group showed significantly (p < 0.001 and p < 0.05) increased heart and kidney weights, when compared with SD fed rats. The higher organ weights denote ectopic fat deposition and the likely consequent organ dysfunction. Figure The blood pressure was recorded by radio-telemetry every five minutes for several days and nights at two different time points (TP-1: age 85-94 days and TP-2: 106-116 days). The daily average for each day for TP-1 (days 85-94) and TP-2 (days 106-116) in each AD fed rat was significantly higher (p < 0.001) than each SD fed rat. The overall mean(SEM) of 2318 and 2782 individual measures obtained during the TP-1 and TP-2 from each member rat in the AD and the SD fed groups, respectively, were used to report the results below.The American diet fed rats exhibited significantly increased overall mean systolic and diastolic blood pressures compared with standard diet fed for all the time points: TP-1 SBP 165.05(0.17) vs. 148.23(0.14) mm Hg, p = 0.02; DBP 124.89(0.14) vs. 111.87(0.13) mm Hg, p = 0.02; TP-2 SBP 174.78(0.15) vs. 153.14(0.12) mm Hg, p = 0.01; DBP 132.34(0.13) vs. 116.63(0.11) mm Hg, p = 0.03.The mean night time (active period) systolic and diastolic pressures in the AD fed group were significantly higher when compared with SD fed group: TP-1 SBP 168.91(1.07) vs. 151.40(0.96) mm Hg, p = 0.02; DBP 128.06(0.78) vs. 114.78(0.86), p = 0.03; TP-2 SBP 173.86(1.69) vs. 152.58(1.06) mm Hg, p = 0.02; DBP 131.56(1.40) vs. 116.45(0.76) mm Hg, p = 0.04.The mean day time (sleep period) systolic and diastolic pressures in the AD fed group were significantly higher when compared with SD fed group: TP-1 SBP 160.94(1.01) vs. 145.23(0.95) mm Hg, p = 0.02; DBP 121.57(0.89) vs. 109.1(0.91) mm Hg, p = 0.03; T2 SBP 175.42(0.66) vs. 153.57(0.38) mm Hg, p = 0.02; DBP 132.83(0.54) vs. 116.62(0.35) mm Hg, p = 0.03.The night time increase in mean SBP (17.51 mm Hg) and DBP (13.28 mm Hg) in AD fed rats during TP-1 not only persisted, but was higher during TP-2 SBP (21.28 mm Hg) DBP(15.11 mm Hg).Figures Figure Figure Figure Figures Figure Figure Figure This study illustrates the early relationship between caloric over-loading , an increased systemic inflammation, fasting serum glucose and loss of blood pressure control. The biphasic response (possibly T-cell mediated) of the pro-inflammatory cytokines  is evident with the increased serum concentrations at three months, followed by a decrease at six months Figure . This chIn conjunction with the persistently high and escalating fasting glucose, at both three and six months, , we elucidate abnormalities of circadian blood pressure variability. We demonstrate an increase in each of the 2318 and 2782 individual blood pressure measures, obtained during the reference days  from each American diet fed rat, compared with a standard diet fed rat. We report that all the isolated 288 blood pressure measures on day 90, during demonstrated increased systemic inflammation , loss of blood pressure control (prehypertension) and the alteration in circadian blood pressure variability.The conventional American diet  fed to rats after weaning, would lead to both hyperplasia (increase in number) and hypertrophy (increase in size) of adipose tissue cells . This woThe earliest change in a hypertrophic and hyperplastic adipose tissue is the infiltration of inflammatory cells. While a significant increase in the number of normal resident adipose tissue macrophages is widely known to ensue with obesity , the firLimitations: This well designed experiment was done in genetically permissible rats to allow us to elucidate the early influence of caloric excess upon systemic inflammation and glycemia and their impact on circadian blood pressure variability. Although these results cannot be directly extrapolated to humans, the differences between the control group on usual diet and the test group fed with the American diet have validated our stated hypothesis. We were able to show that both systemic inflammation and glycemia influence circadian blood pressure variability. We were further able to demonstrate that dysglycemia induces abnormal circadian blood pressure variability.This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal circadian (24-hour) blood pressure variability.SK, KG, DHK, NGA, WDJ, BJ and AKG do not report any conflicts of interests.AKG conceived the study, arranged the collaboration, initiated the manuscript, edited and compiled the final version for submission. SK, KG, DHK, NGA and BJ performed the experiments and gathered the data. WDJ directed the statistical analyses and participated in editing of the manuscript. SK, WTC, and BJ participated in editing of the manuscript. All authors have read and agree for the publication of this manuscript.


Description of a continuous hypertonic saline solution (HSS) infusion using a dose-adaptation of natremia in traumatic brain injured (TBI) patients with refractory intracranial hypertension (ICH).a priori calculated according to natriuresis, and the current and target natremia that were assessed every 4 hours.We performed a single-center retrospective study in a surgical intensive care unit of a tertiary hospital. Fifty consecutive TBI patients with refractory ICH treated with continuous HSS infusion adapted to a target of natremia. In brief, a physician set a target of natremia adapted to the evolution of intracranial pressure (ICP). Flow of NaCl 20% was P < 0.05). Cerebral perfusion pressure increased from 61 (50 to 70) (61 ± 13) mm Hg at H0 up to 67 (60 to 79) (69 ± 12) mm Hg at H1 (P < 0.05). No rebound of ICH was reported after stopping continuous HSS infusion. Natremia increased from 140 (138 to 143) (140 ± 4) at H0 up to 144 (141 to 148) (144 ± 4) mmol/L at H4 (P < 0.05). Plasma osmolarity increased from 275 (268 to 281) (279 ± 17) mmol/L at H0 up to 290 (284 to 307) (297 ± 17) mmol/L at H24 (P < 0.05). The main side effect observed was an increase in chloremia from 111 (107 to 119) (113 ± 8) mmol/L at H0 up to 121 (117 to 124) (121 ± 6) mmol/L at H24 (P < 0.05). Neither acute kidney injury nor pontine myelinolysis was recorded.The HSS infusion was initiated for a duration of 7 (5 to 10) (8 ± 4) days. ICP decreased from 29 (26 to 34) (31 ± 9) mm Hg at H0 to 20 (15 to 26) (21 ± 8) mm Hg at H1 (Continuous HSS infusion adapted to close biologic monitoring enables long-lasting control of natremia in TBI patients along with a decreased ICP without any rebound on infusion discontinuation. Refractory intracranial hypertension (ICH) is the most frequent cause of death after traumatic brain injury (TBI) . In braiThe first-line treatment of ICH is osmotherapy . HSS draThis retrospective descriptive study was performed from 1 January 2001 to 31 December 2009 in a surgical ICU of a tertiary hospital. No change in our current clinical practice and no randomization were performed. As it was an observational retrospective study, according to the French legislation , neither informed consent nor approval of the ethics committee was needed to use data for an epidemiologic study.≤ 8 after initial care; (b) ICP monitored with an intraparenchymal probe; (c) treated with a continuous HSS infusion adapted to a target of natremia; and (d) in the purpose of refractory ICH. ICH was defined as an ICP > 20 mm Hg for more than 15 minutes [Patients were identified from an electronic registry prospectively recorded. Inclusion criteria were as follows: (a) traumatic brain-injured patients defined as having a Glasgow Coma Score (GCS)  minutes . Refract-1.hr-1) and midazolam (0.2 to 0.5 mg.kg-1.hr-1) and were mechanically ventilated. Apart from counterindications, sedated patients were kept in a semirecumbent position. Secondary brain injuries were prevented by keeping the body temperature between 36.0°C and 37.0°C, ensuring normoglycemia and normocapnia, and by avoiding hypoxemia. In severe TBI patients, natremia and blood gases were assessed at least twice a day, and expiratory end-tidal (Et) CO2 was continuously monitored. Patients were monitored with invasive arterial pressure, and mean arterial pressure was measured up to the brain for the calculation of the CPP. For patients with severe TBI and with an abnormal computed tomography , the ICP was monitored [All patients were sedated with a continuous intravenous infusion of fentanyl (2 to 5 μg.kgonitored  with an onitored . For eacThe attending physician set a target of natremia (from 145 to 155 mmol/L) adapted to the evolution of ICP. When ICP was > 20 mm Hg, the target of natremia was increased by an increment of 5 mmol/L every 4 hours, and a bolus of HSS was infused  was adapted to the urinary excretion of sodium, and the extraurinary sodium loss was neglected. The flow of NaCl 20% was calculated as follows:3. When the natremia was above the target, the infusion of NaCl (20%) was discontinued for 1 hour. Then the continuous infusion of NaCl was resumed for the remaining 3 hours.A polyuria has been described with the intravenous infusion of HSS . In an aLocal normal ranges for natremia were 137 to 145 mmol/L. Acute kidney injury was defined by a 200% increase in serum creatinine concentration as compared with a previous assessment of renal function . Severe The following data were recorded in the electronic medical file prospectively completed: age, sex, GCS, ICH management, continuous infusion of HSS , and evolution of ICP and CPP during the infusion. Serum creatinine concentration, coagulation tests, and central pontine myelinolysis were also recorded, as well as the Glasgow Outcome Scale (GOS) and death at 1 year.post hoc tests based on estimated marginal means were performed for comparing the levels of the studied variables at different times. Skewed variables were log-transformed, and statistical analyses were performed with SAS 9.1 statistical software . Continuous variables were expressed as median . The P values for each variable tested are presented in Additional file P values < 0.05 were considered to be statistically significant.To account for the correlation between measurements from the same individual, repeated measures analysis of variance (ANOVA) using linear mixed models, allowing random effects with restricted maximum-likelihood estimation, was used to examine changes in variables over time. Time effect was included in the models along with baseline measurements. Several covariance structures among the repeated measurements  were compared by using Akaike's Information Criterion . ResiduaDuring the 9-year study period, 780 patients with TBI were admitted into the ICU. Among the 243 31.2%) patients with a severe TBI monitored with an ICP, 50 (20.6%) patients developed a refractory ICH and were treated with a continuous HSS infusion  for a duration of 7  days. After the first 96 hours, the number of patients still receiving continuous HSS decreased considerably (discontinuation of HSS infusion or death); see Additional File P < 0.05 versus H0), and from 22  mm Hg at H4 to 20  mm Hg at H8 (P < 0.05 versus H4). Afterward, ICP was stable until H96 . CPP was stable until H96  mm Hg at H0 down to 20  mm Hg at H1 , and remained stable until H96  (140 ± 4) at H0 to 144 (141 to 148) (144 ± 4) mmol/L at H4 . Natriuresis increased from 25 (20 to 40) g (30 ± 18) in the first 24 hours up to 31 (24 to 45) (38 ± 25) g from H24 to H48 (P < 0.05) and remained unchanged afterward (NS). Natriuresis decreased from 18 (13 to 20) (17 ± 5) g/day at H-24 after the infusion ended, down to 12 (9 to 16) (12 ± 4) g/day at H-48 (P < 0.05).The amount of sodium administered was not significantly different during the study period: 32 (17 to 46) (36 ± 23) g in the first 24 hours, and 25 (11 to 45) (32 ± 28) g from H72 to H96 (NS). After we stopped the HSS infusion, a bolus of 7 (5 to 11) (7 ± 4) g of sodium  was administered at H-24, and a bolus of 1 (0 to 4) g (2 ± 3) was administered at H-24  (113 ± 8) mmol/L at H0 to 121 (117 to 124) (121 ± 5) mmol/L at H96  may reduce the frequency of ICP crises and the mortality rate [In a randomized study in TBI patients, continuous infusion of HSS for 5 days increased both natremia and osmolarity but did not decrease ICP, as compared with hypotonic infusion . In thisity rate . In patiity rate , an inveity rate ), but fea priori dose adaptation decreased ICP but induced severe hypernatremia that reached up to 180 mmol/L, and concerns regarding neurologic complications and kidney failure have been raised. In the study by Qureshi et al. [In this study, a 20% saline infusion was used to decrease the risk of fluid overload, and no pulmonary edema or acute kidney injury was recorded. However, because of the retrospective design of our study, the potential side effects of HSS were recorded from the ICU report. The risk of uncontrolled metabolic disorder associated with HSS infusion remains problematic, poorly described, and has probably limited the widespread use of HSS . In two i et al. , risks oi et al. -14,30, ii et al.  but not i et al. .The main side effect reported in the present report was hyperchloremia. Excessive chloride infusion is a major factor with hyperchloremic acidosis. Thus, it is likely that hyperchloremic acidosis developed in TBI patients treated with continuous HSS infusion. Hyperchloremic acidosis increases the symptoms of postoperative ileus and induces biologic hemostasis perturbation . To dateFinally, a dose adaptation of HSS infusion with rigorous biologic monitoring may explain the lack of an uncontrolled metabolic disorder, except for a probable hyperchloremic acidosis, in our results.et al. [How to stop the infusion is of major importance to prevent a rebound of ICH, and few data are available. In the study by Qureshi et al. , half ofet al. ,28,32. FSeveral therapeutics have been tested for decreasing ICP in case of refractory ICH. Despite an improvement of the neurologic recovery in patients with moderate to severe TBI , moderatOur study encountered limitations. First, the study had a retrospective design, and a randomized trial is necessary to confirm these results. Second, the external validity of this single-center study may be limited. However, our findings may be relevant to the vast majority of level I trauma centers routinely practicing TBI management. We did not report any significant adverse events related to the use of continuous HSS infusion, but this study is not powered to confirm its safety. Finally, a comparison with an untreated group would have strengthened our conclusions, and a larger study with a prospective randomized design is required.We describe for the first time a well-tolerated and reproducible adaptation of continuous HSS infusion for refractory ICH that relies on a closed biologic control of natremia. An increased CPP together with a decrease in ICP was observed during continuous HSS infusion without any development of severe hypernatremia or rebound of ICP. Continuous infusion of HSS with a dose adaptation to a target natremia could therefore be an attractive alternative for patients treated with barbiturates for refractory ICH. Prospective studies are required to confirm the effects and safety of the current dose adaptation of HSS infusion.▪ Continuous hypertonic saline infusion may decrease intracranial pressure in traumatic brain-injured patients with refractory intracranial hypertension▪ The current dose adaptation of hypertonic saline infusion, based on a target of natremia, is reliable and well tolerated▪ Close biologic monitoring within continuous hypertonic saline infusion prevents severe hypernatremia▪ No rebound of intracranial pressure was observed after the infusion ended▪ Continuous infusion of hypertonic saline infusion could be an attractive alternative to treating patients with refractory intracranial hypertensionCPP: Cerebral perfusion pressure; GCS: Glasgow Coma Scale; GOS: Glasgow Outcome Scale; HSS: hypertonic saline solution; ICH: intracranial hypertension; ICP: intracranial pressure; ICU: intensive care unit; TBI: traumatic brain injury.The authors declare that they have no competing interests.AR, PJM, DD, OL, PC, CL, and KA designed the study. AR, PJM, DD, CDF, AC, OL, and PC collected the clinical information. VS analyzed the raw data, performed statistical analysis, and drafted and contributed to the writing of the article. AR, PJM, DD, OL, PC, CDL, AC, KB, OH, and KA included patients, and drafted and contributed to the writing of the article. CL participated in the interpretation of all data, revising the manuscript critically for important intellectual content. All the authors contributed to the final approval of the manuscript.Table S1. Linear mixed-models analyses of the evolution of intracranial pressure, cerebral perfusion pressure, delta natremia, osmolarity, kaliemia, chloremia, creatininemia, and natriuresis with time. Figure S1. Kaplan-Meier curve for the number of patients treated with continuous HSS.Click here for file


Current asthma management guidelines are based on the level of asthma control. The impact of asthma control on health care resources and quality of life (QoL) is insufficiently studied. EUCOAST study was designed to describe costs and QoL in adult patients according to level of asthma control in France and Spain.®.An observational cost of illness study was conducted simultaneously in both countries among patients age greater or equal to 18 with a diagnosis of asthma for at least 12 months. Patients were recruited prospectively by GPs in 2010 in four waves to avoid a seasonal bias. Health care resources utilization of the three months before the inclusion was collected through physician questionnaires. Asthma control was evaluated using 2009 GINA criteria over a 3-month period. QoL was assessed using EQ-5D-3L2,671 patients  were enrolled. Asthma was controlled in 40.6% [95% CI: 37.7% - 43.4%] and 29.9% [95% CI: 27.6% - 32.3%] of French and Spanish patients respectively.® score was higher (p<0.0001) in patients with controlled asthma compared to partially controlled and uncontrolled asthma in both countries .For all types of costs, the percentage of patients using health care resources varied significantly according to the level of asthma control. The average cost (euros/3-months/patient) of controlled asthma was €85.4 (SD: 153.5) in France compared with €314.0  for partially controlled asthma and €537.9  for uncontrolled asthma (p<0.0001). In Spain, the corresponding figures were €152.6 (SD: 162.1), €241.2 (SD: 266.8), and €556.8 (SD: 762.4). EQ-5D-3LIn both countries, patients presenting with uncontrolled asthma had a significantly higher asthma costs and lower scores of Qol compared to the others. Asthma is a chronic disease with an estimated 300 million affected individuals throughout the world,2. In a The recent publication from the Global Initiative for Asthma (GINA) updated international guidelines and highlighted the importance of achieving and maintaining control as a goal of treatment,5. StandUntil now, some studies on asthma control based on data from large samples of asthmatic patients have already been published in Europe,11. HowePoor control of asthma may result in adverse clinical outcomes as well as substantial economic costs. The totConsequently, the EUCOAST (EUropean COst of ASthma Treatment) study was designed to assess utilisation of healthcare resources, costs and HRQL in adult patients with asthma in a real life setting in France and Spain accordingly to the level of asthma control.An observational study was conducted in primary care settings in France and Spain in order to estimate the societal costs and the HRQL according to the level of asthma control in adult patients.The study design required a single visit per patient. Data collection was performed on the three-month period before the inclusion. To take into account seasonality which has a major impact on asthma in both countries, patientThe EUCOAST study was approved by the French Consultative Committee for the data processing in health research (CCTIRS) and by the National commission for the personal data protection (CNIL). In Spain, the study obtained the authorisation of the Spanish Agency of Medicines and Medical Devices (AEMPS) and the favourable opinion of the Clinical research Ethics Committee (CEIC) Hospital Clínico y Provincial de Barcelona.Patients were included if they met the following inclusion criteria: adults aged 18 or over, diagnosed with asthma for at least 12 months and having received at least one anti-asthmatic treatment (whatever the treatment) within the past 12 months.Exclusion criteria were participation into a clinical trial during the past 6 months, aged 45 years and over with a history of smoking of at least 20 pack years, chronic obstructive pulmonary disease (COPD) or pregnancy.Based on the percentage of patients with controlled asthma estimated to represent 40% to 50% of the overall population in previous studies, and knoIn France, investigators were a sample of GPs selected from a representative panel of 1,200 general practitioners. The panel's representativeness was established by three criteria: age, sex and region of practice. The study was proposed to 750 GPs of this panel, randomly selected and 230 agreed to participate.In Spain, 105 general practitioners of 18 autonomous communities belonging to 3 regions  were contacted and 87 agreed to participate. A territorial representativeness was able to be obtained when the sample was constituted.Practitioners had to include patients in the usual context of their practice. To avoid a selection bias, the first two consecutive patients (the first five in Spain) corresponding to the inclusion/exclusion criteria visiting their doctor were included in each wave.Data collected retrospectively (over the last 3 months) during the single study visit by the GP were: socio-demographic characteristics, medical history of patients, GINA criteria  and healthcare resource use due to asthma.For all medical resources consumption (including sick leaves) during the 3 months prior to GP visit, data were provided by GPs through the questionnaires used in the study. In France some data .Force Expiratory Volume in one second (FEV1) was collected only in a single visit (FEV1 was measured by GPs three times consecutively as recommended by GINA). As in France and Spain, all investigators were given a digital device  which allowed FEV1 measurements.® questionnaire comprising a Visual Analog Scale (VAS). This questionnaire is a generic instrument, 34.1% [95% CI: 31.6% - 36.5%] and 36.0% [95% CI: 33.6%-38.5%], respectively. The level of asthma control was lower in Spain than in France (p<0.001). Patients with controlled asthma were younger than patients with uncontrolled asthma (p<0.0001).There was a significant relation between asthma control and rate of allergic rhinitis, atopic dermatitis, and gastroesophageal reflux as well as depression with more frequent comorbidities in patients with uncontrolled asthma. 43.6% of patients suffered from asthma exacerbations during the last 3 months with an average number of 1.8 (SD1.7) episodes/patient with exacerbations/quarter: 74.4% of those with uncontrolled asthma, 41.3% with partially controlled and 9.2% with controlled asthma.vs. 74.4% with partially controlled vs. 72.0% with uncontrolled asthma).Overall, 78.7% of patients had a normal lung function . Antiasthmatic drugs represented the main driver of direct costs, 86.2%, 81.9% and 61.5% in controlled, partially controlled and uncontrolled patients, respectively.Indirect costs were marginal in controlled patients  but represented a major driver in partially controlled and uncontrolled patients (respectively 62.8% and 58.1%) Table .vs. controlled), older people (≥65) rather than younger ones patients (+€49.), experiencing exacerbations (+€75.5), treated with controller treatment ,  Table . 92.9% oAntiasthmatic medications represented the main driver of direct costs for controlled and partially controlled asthma (respectively 59.0% and 52.7%) but not for uncontrolled asthma (36.5%). For the latter GPs visits had also a major impact on costs accounting for 32.9% of the mean per-patient direct costs.Indirect costs were marginal in controlled and in partially controlled patients  but much more important (22%) in uncontrolled patients.In multivariable analyses, factors predicting asthma costs were the same in both countries except for gender which had a significant impact in Spain but not in France Table .® quality of life scores were higher for patients with controlled asthma than patients with partially controlled or uncontrolled asthma .In both countries Table , average® results per dimension  showed consistent differences between controlled, partially controlled and uncontrolled patients. For all dimensions, quality of life scores were better for controlled patients (p<0.0001) (data not shown).Detailed analyses of EQ-5D-3LThe Visual Analog Scale (VAS) quality of life scores were also significantly associated with the level of asthma control in both countries . Average VAS scores were 77.33, 70.27, 57.41 in France and 80.00, 75.13, 62.81 in Spain for controlled, partially controlled and uncontrolled patients, respectively .®. In addition, exacerbations were significantly associated with a lower VAS score in both countries.Results of the multivariable analysis using the VAS score as the dependent variable were consistent with those reported above for the EQ-5D-3L®) were 0.88, 0.78 and 0.63 in France (p<0.0001) and 0.89, 0.82 and 0.69 (p<0.0001) in Spain, for patients with controlled, partially controlled and uncontrolled asthma, respectively. According to the GINA 2009 Guidelines[In this observational study we found that the proportion of patients with controlled asthma was significantly higher in France 41%) than in Spain (30%). In both countries, costs were higher and HRQL lower as level of asthma control decreased. The average asthma-related total health care costs over a three-month period were €85.4, €314.4 and €537.9 in France and €152.6, €241.2 and €556.8 in Spain for patients with controlled, partially controlled and uncontrolled asthma, respectively. The HRQL scores . This result is in line with previous European results[In our study, the average total cost per patient over a 3-month period was higher when asthma was poorly controlled. Hospitalizations for asthma and emergency room visits associated costs were higher in patients with uncontrolled asthma and they represent a higher percentage of the total direct costs .The EUCOAST study presents several limits. First, both the sampling frame and the sampling method used did not ensure the representativeness of the investigators even if their main characteristics were comparable to those of all French and Spanish GPs.Secondly, as investigators had to recruit several patients (until 5 in Spain) there was a potential within-unit correlation in the data which was not taken into account in the statistical analysis.Thirdly, due to a possible short term memory bias GPs and patients may have under-reported healthcare consumptions. Therefore, costs may be lower than those found in studies based on claims databases or systematic healthcare data. However, it is difficult to know whether, or to what extent, this might have biased our estimates of the effects associated with level of asthma control. Indeed, the existence of such bias would depend on whether under-reporting of costs was differential according to level of asthma control.Costs of medications were based on prescription data. As some patients may not have been compliant, our estimates may be over-estimates of the true medication-related costs.® was lower in France as compare to Spain (73% vs. 97%). This was likely the consequence of differences in the HRQL data collection method in the two countries. In France, patients were asked to send back their questionnaires to the study center whereas in Spain most patients completed the questionnaire in the physician’s office. However, we did not find significant differences between responders and non-responders in their level of asthma control or overall costs.The response rate for the EQ-5D-3LAsthma control was significantly associated with costs and health-related quality of life in both France and Spain. Despite differences in health care systems and after adjustment for several potentially confounding factors, in both countries, costs were higher and HRQL lower as level of asthma control decreased.These results suggest that implementation of measures to improve asthma control may improve patients’ quality of life and reduce related costs for National Health Systems and for the society.aIn France: public prices inclusive of tax were used to get the unit cost of drugs; the rates for all medical and paramedical procedures were established from national conventions and from the Common Classification of Medical Procedures for the year remove one as it is written twice 2010.bIn Spain, the database used for drug costing was that of the Consejo General de Colegios Oficiales de Farmacéuticos . For other resources, costing was carried out using a national Spanish base .AEMPS: Spanish Agency of Medicines and Medical Devices, CCTIRS, Consultative Committee for the data processing in health research; CEIC: Clinical research Ethics Committee; CI: Confidence interval; CNIL: National commission for the personal data protection COPD, chronic obstructive pulmonary disease, CSD, Cegedim Strategic Data; ECRHS-II: European Community Respiratory Health Survey-II; ESPS: Enquête Santé Protection Sociale; EUCOAST: EUropean COst of ASthma Treatment; FEV1: Force expiratory volume in one second; GERD: Gastroesophageal reflux disease; GINA: Global initiative for asthma; GPs: General practitioners; HRQL: Health related quality of life; QoL: Quality of life; SD: Standard deviation; SRAP: Sociedad de Respiratorio de Atención Primaria; VAS: Visual analog scaleDoz M, Robert J and Detournay B are consultants for CEMKA-EVAL, a company providing consultancy services for most pharmaceutical companies and public institutions involved in health care in France. Chouaid C has received consulting fees or honoraria from Novartis, Boehringer Ingelheim, AstraZeneca and GlaxoSmithKline. Calvo E has worked as national coordinator for primary care in international clinical trials sponsored by Astra Zeneca and has been principal or secondary investigator in national studies conducted by Astra Zeneca, Boehringher, MSD, GlaxoSmithKline and Abbott. He has also written papers or given courses and conferences sponsored by Boehringher, Pfizer, AstraZeneca, GlaxoSmithKline, Chiesi, Merck and Almirall. He has participated in advisory committees for GlaxoSmithKline, Nycomed and Novartis. Com-Ruelle L received consulting fees or honoraria from GlaxoSmithKline as an expert of the study scientific committee. Brosa M is consultant for Oblikue, a company providing consultancy services for most pharmaceutical companies and public institutions involved in health care in Spain. Decuypère L and Pribil C are employed at GlaxoSmithKline France. Huerta A is employed at GlaxoSmithKline Spain.DM coordinated the data collection and wrote the manuscript. CC, CRL, CE, BM and DL participated in the interpretation of data, were involved in drafting the manuscript and revised it critically for important intellectual content. RJ performed all statistical analysis. PC and HA participated in study conception and interpretation of data and revised the manuscript. DB participated to conception and design, acquisition and interpretation of data, was involved in drafting the manuscript and revised it critically for important intellectual content. All authors have read and approved the final manuscript.Financial support for this study has been provided by GlaxoSmithKline, Access to Medicines Centre of Excellence, UK.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/13/15/prepub


The practice of using medical service claims in epidemiologic research on hypertension is becoming increasingly common, and several published studies have attempted to validate the diagnostic data contained therein. However, very few of those studies have had the benefit of using actual measured blood pressure as the gold standard. The goal of this study is to assess the validity of claims data in identifying hypertension cases and thereby clarify the benefits and limitations of using those data in studies of chronic disease etiology.Disease status was assigned to 19,150 employees at a U.S. manufacturing company where regular physical examinations are performed. We compared the presence of hypertension in the occupational medical charts against diagnoses obtained from administrative claims data.After adjusting for potential confounders, those with measured blood pressure indicating stage 1 hypertension were 3.69 times more likely to have a claim than normotensives  and those indicating stage 2 hypertension were 7.70 times more likely to have a claim than normotensives . Comparing measured blood pressure values identified in the medical charts to the algorithms for diagnosis of hypertension from the claims data yielded sensitivity values of 43-61% and specificity values of 86–94%.The medical service claims data were found to be highly specific, while sensitivity values varied by claims algorithm suggesting the possibility of under-ascertainment. Our analysis further demonstrates that such under-ascertainment is strongly skewed toward those cases that would be considered clinically borderline or mild. Healthcare claims data play a vital role in research aimed at crafting health policy, establishing medical standards of care, and understanding disease etiology. While the ideal methods of collecting clinical data for epidemiologic research are medical chart review and physical examination , these mSeveral studies have evaluated the use of claims data in accurately identifying cases of hypertension ,3-9, thoWith the vast majority of healthcare dollars being spent on chronic conditions, it is essential for researchers to continue to assess the benefits and limitations of administrative datasets for the scientific study of the causes and outcomes of chronic diseases, as well as to better understand which strategies of disease ascertainment are the most useful in conducting etiologic research. The objective of this study is to assess the use of administrative data for identifying cases of hypertension in a large industrial cohort which has been under long-term scrutiny. Using medical claims data, we examine the presence of hypertensive disease in employees with measured blood pressure readings from routine physical examinations at the workplace as a job safety requirement.The study company is a multinational producer of aluminum and related products, operating in 24 states and around the world. The US workforce has varied from over 50,000 to around 30,000, with the majority of workers in hourly manufacturing jobs. Notably, although workers may select from a menu of health benefits in terms of cost, there is only a single preferred provider organization (PPO) network available at each location; managed care organization (MCO) alternatives are offered at a small handful of locations. Because the offered plans are rich in terms of coverage, the vast majority of employees and their families enroll in them.All data are available as part of a unique academic-corporate partnership that began in 1997 for the purpose of developing and implementing workplace safety and occupational health policies for this large, multi-site aluminum manufacturer. The research agreement allows the investigators regularly updated company databases which are then de-identified and linked. The databases have been described in greater detail in previous publications ,14. BrieProvided annually, this database contains all employee demographic information, including date of birth, race, and sex. Files are created at the start of employment and document all changes in job title, job grade, job status , job category , and plant location.This database provides basic health screening information for employees who participate in fitness-for-duty evaluations at the start of employment and medical surveillance programs which are typically performed every three years of employment. Although the extent of screening an employee participates in varies by job, all employees in this study participated in at least one medical screening program in which blood pressure measurements were collected. Occupational health data were provided to the investigators in one of two ways: some plants maintain an electronic database, to which the investigators have access, of data gathered from mandatory health screenings, while other plants merely record such data in the employees' paper charts. Beginning in 2002 the investigators, in an attempt to collect more comprehensive data on employee health risk factors, began abstracting health data from the individual plant medical departments. Data collected include smoking history, cholesterol, blood pressure, height, weight, education status, and marital status. Chart notes, such as physician comments regarding diagnosis or history of hypertension, are not available.Investigators annually receive medical and pharmacy claims from a central data processing center, which in turn receives the data from each individual third party administrator. Data include ICD-9 codes for disease diagnosis  and NatiDatabases were linked by using an encrypted unique identifier created by the investigators to ensure human subject privacy.A study set was created by first selecting all active employees who had one or more systolic (SBP) and diastolic (DBP) blood pressure measurements in their occupational health screening records for the period 2003 – 2009 and were enrolled in a PPO health insurance plan. Plants represented in this sample encompassed all aspects of the company’s sectors, including smelting and fabricated aluminum products, and employees were included regardless of job.We examined the cohort in two ways: first, actual blood pressure measurements from the occupational health records were categorized into four groups: normotensive (SBP <120 and DBP <80), pre-hypertensive (SBP of 120–139 or DBP of 80–89), stage 1 hypertensive (SBP of 140–159 or a DBP of 90–99), or stage 2 hypertensive (SBP of ≥160 or a DBP ≥100). If an employee’s blood pressure values overlapped between 2 groups, he was placed in the higher group. Second, each employee was classified into one of two categories: normal blood pressure or high blood pressure based on the pattern of their measurements in their medical charts. If an employee had at least one high blood pressure reading, they were classified as having high blood pressure; if they only had normal readings, they were classified as having normal blood pressure. The borderline category was omitted from this part of the analysis to allow us to calculate sensitivity and specificity values.Administrative claims data  for the study individuals for the same time period were then examined by defining hypertension using the following possible algorithms: 1) at least one medical claim based on a face-to-face examination or hospitalization or 2) at least two separate medical claims. No time gap was required between separate medical claims.A Monte Carlo logistic regression was performed on all blood pressure measurements to elucidate the predictors of having at least one claim for hypertension while adjusting for covariates. The simulation was chosen whereby a single, randomly selected blood pressure reading was included for ordinal logistic regression analysis. This approach was conducted in order to account for the varied number of repeated blood pressure measurements per employee. Further, it allowed us to tease out the potentially confounding influence of those in the borderline category, as well as control for disease severity and other individual covariates. The resulting adjusted odds ratio estimate for the effect of blood pressure category on having a hypertensive claim was recorded. This simulation was conducted 10,000 times in order to determine the central tendency for the odds ratio as well as the 95% confidence interval.Frequency (2×2) tables were then constructed for each algorithm used to define employees’ hypertension status from the administrative claims data. Sensitivity was defined as the proportion of employees with high blood pressure measurements in their occupational health records that were identified as hypertensive by a claims-based algorithm. Specificity was calculated as the proportion of employees with normal blood pressure measurements in their medical charts and not identified by a claims-based algorithm as having hypertension. The positive predictive value (PPV) of using claims was calculated as the proportion of employees with claims for hypertension who had normal blood pressure measurements in their medical charts. The negative predictive value (NPV) of using claims was calculated as the proportion of employees without a claim for hypertension who had normal blood pressure measurements in their medical charts.Statistical analyses were performed with SAS version 9.2.Our final cohort consisted of 19,150 employees, representing over 30 U.S. plants for the period 2003–2009. Table Table Only employees with high or normal blood pressure measurements were included for the sensitivity and specificity analyses. 54%  met this criterion, while 46%  were excluded. 40.6% had high blood pressure measurements in their charts, while 13.8% were in the normal range and 45.6% did not fit either category and were labeled as borderline. Of those borderlines that were excluded, 72% had only pre-hypertensive readings (defined as SBP between 120–139 or DBP between 80–89), while the remaining 28% had mixed normal/pre-hypertensive readings. Males were more likely to have hypertensive readings in their charts compared with females (p < 0.0001), and hourly employees were more likely to have hypertensive readings in their charts compared with salaried employees (p < 0.0001). Those in the high blood pressure category had an average tenure of 15 years, whereas those in the normal category had an average tenure of 11 years. Likewise, the average age was 5 years older in the hypertensive category.As Table In an attempt to avoid inaccurate classification of cases due to blood pressure variability , we condIn this study, we examined the relationship between measured blood pressure values and administrative medical claims for hypertension. By first including all measurements for all employees in a multivariate simulation, we found the odds of having a claim of hypertension were significantly increased for those employees with actual blood pressure reading suggesting stage 1 hypertension as compared to those with normal measurements, and increased even more dramatically for those with readings suggesting stage 2 hypertension. This model allowed us to control for several potentially confounding variables such as an unequal number of repeated measures per employee, age, sex, employee type and race.We next assessed the accuracy of two algorithms for defining hypertension using claims data compared to actual blood pressure measurements from occupational health records. Our results show a sensitivity of 42–52% and a specificity of 86–90% depending on the algorithm used. These results are comparable to other studies utilizing different methods including self-reported survey data on hypertension and review of medical records to validate claims data. These studies have reported sensitivity values ranging from 52–75% and specificity values ranging from 75–94% ,13.In a study of claims-based algorithms for identifying chronic medical conditions, Rector et al. reported a sensitivity and specificity of 52% and 91% respectively in diagnosing hypertension using a combination of one medical claim and one pharmacy claim when compared with self-reported surveys . The senIn our claims dataset, the more sensitive algorithm was to use at least one medical claim for identifying disease; changing the algorithm to at least two medical claims decreased the sensitivity and only modestly increased the specificity. We initially conducted this analysis using all employees who had at least one high blood pressure measurement as the source of comparison; however, we repeated the analysis using a more stringent case definition of classifying employees who had two or more consistent readings during this period. The study population dropped from 10,415 in the initial analysis to 1766 in the subanalysis. Although the specificity values did not significantly change, sensitivity values improved.All analyses were conducted regardless of whether or not the employee was using prescription medication for lowering blood pressure, an obvious reason for a false positive. Because these medications are commonly used for conditions not associated with high blood pressure, removing those employees from the analysis would have limited impact. Indeed in a sensitivity analysis where we eliminated normotensives on blood pressure lowering medications, our results did not change substantively for the ≥1 and ≥2 medical claim algorithms: sensitivity values remained unchanged, specificity values increased to 95.51% and 98.44%, positive predictive values increased to 97.55% and 98.96%, and negative predictive values decreased modestly to 36.41% and 33.38%, respectively. With nearly 70% of false positives using blood pressure lowering medications, the specificity rates reflected in this study are likely lower than previously found because of this phenomenon.This study has certain limitations. First, although we are confident from our multivariate model that sex, race and employee type are unlikely to be the source of significant confounding, we are less confident about job type, as only certain jobs require regular examinations which in turn might lead to referral for treatment, while other jobs have no such “screening”. Second, by choosing a cross-sectional study design, we were able to take advantage of a large and robust dataset that includes a varied number (sometimes only one) of intermittent blood pressure readings per person. However, by allowing for the inclusion of all individuals with at least one blood pressure reading, we sacrificed our ability to examine the data in a temporal manner. Specifically, those who entered the cohort later in the study period have shorter windows of opportunity for having a claim in the administrative dataset. This likely contributed to conservative estimates. The third limitation was the unbalanced nature of the data. In particular, not all employees had the same number of blood pressure measurements. The Monte Carlo simulation mitigated the problem of increased probability of a hypertensive reading with increased measurements. Lastly, inherent in the use of claims data is the potential for missing claims due to physician preference in choosing a diagnostic code for patients with comorbidities. In this study, the frequency of hypertension claims suggests that such a bias is not likely leading to an underestimation of disease.This study not only provides evidence of the potential value of using administrative claims in epidemiologic research on hypertension, but also demonstrates that the inevitable under-ascertainment from using claims data to study hypertension is not at random. Those most likely to be missed through the use of claims driven analyses are those with the least severe disease. Conversely, specificity appears to be lost in large measure because of treatment. One of the major strengths of this study was the use of actual blood pressure measurements from employee health records as the comparison data source. This is likely superior to self-reported survey data for verification of hypertension and is more comparable to using physician diagnosis of hypertension abstracted from medical records as the gold standard.While the wide availability of administrative health datasets provides researchers with boundless opportunities for analyzing data, analyzing subsets of claims data, as was done in this study, should allow investigators to more thoroughly understand the strengths and limitations of using claims datasets for etiologic research in hypertension. Although our high specificity values demonstrates the value of using claims data in defining a cohort of hypertensives, using the claims data to identify cases of hypertension as a covariate in statistical models may introduce under-ascertainment. Mitigating this, however, our analysis strongly suggests that such under-ascertainment is skewed toward those cases that would be considered clinically borderline or mild.There are no competing interests to declare with this submission, and this manuscript has been read and approved by all authors. The authors acknowledge that this research was supported by a grant from the National Institute on Aging and a contract with Alcoa, Inc. Funding agencies had no direct influence on the design, analysis, or preparation of this manuscript for publication. Ethical approval for this study was granted by the Yale Human Investigations Committee.In the preparation of this manuscript, OAT, MRC, and BTS conceived of and developed the study design. BTS, DG, and MDS conducted the data analysis, and BTS, LC, and MRC participated in data interpretation and drafting the final paper. SRK was involved in project coordination, data interpretation, and critical revisions. All authors have read and approved the final manuscript.As an alternative to providing a de-identified data set to the public domain, we allow access for the purpose of re-analyses or appropriate “follow-on” analyses by any qualified investigator willing to sign a contractual covenant with the host Institution limiting use of data to a specific agreed upon purpose and observing the same restrictions as are limited in our contract with Alcoa, such as a 60-day manuscript review for compliance purposes.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/51/prepub


The role of small solute clearance on mortalities in patients with CAPD has been controversial. We therefore conducted a study with 3 years' follow up in adult patients who participated in the CAPD-first policy.There were 11,523 patients with end-stage renal disease who participated in the CAPD-first policy between 2008 and 2011. Among them, 1,177 patients were included in the retrospective cohort study. A receiver operating characteristic curve was applied to calibrate the cutoffs of tKt/V, rKt/V and tCrcl. Kaplan-Meier and Cox-regression models with time varying covariates were applied to estimate overall death rate, probability of death and prognosis, respectively.The cutoffs of rKt/V and tKt/V were 0.25 and 1.75, respectively. The Cox regression suggested that the higher these clearance parameters, the lower the risks of death after adjusting for covariables. The risks of death for those above these cutoffs were 57%  and 29%  lower for rKt/V and tKt/V, respectively. Age, serum albumin, hemoglobin, systolic blood pressure, and ultra-filtration volume significantly affected the mortality outcome.Our study suggested that the cutoffs of 0.25 and 1.75 for rKt/V and tKt/V might be associated with mortality in CAPD patients. A minimum tKt/V of 1.75 should be targeted, but increased dialysis dosage to achieve tKt/V > 2.19 adds no further benefit. Serum albumin, hemoglobin, SBP, and UF volume are also associated with mortality. However, our study may face with selection and other unobserved confounders, so further randomized controlled trials are required to confirm these cutoffs. The global burden of end-stage kidney disease (ESRD) is increasing rapidly-3 with aAdequacy targets for CAPD are primarily based on the weekly clearances of urea (Kt/V) or creatinine (Crcl) which are expressed as renal Kt/V (rKt/V), peritoneal Kt/V (pKt/V), total Kt/V (tKt/V); or renal Crcl (rCrcl), peritoneal Crcl (pCrcl), and total Crcl (tCrcl) respectively. The effect of rKt/V on survival in CAPD patients has been well-documented-14, but We therefore conducted a cohort study with 3 years’ follow up to answer the following research questions: Can tKt/V, rKt/V, and tCrcl significantly predict disease prognosis in CAPD patients? If so, what are the cutoffs that can be used to predict patients’ outcomes?This cohort study covered patients receiving four 2-L CAPD exchanges at 82 general hospitals, belonging to the Ministry of Public Health, Thailand. Data from the National Health Security Office (NHSO) were retrieved between January 2008 and April 2011. The study was approved by the Ramathibodi Hospital Ethical Committees.Patients aged 15 years or older were eligible if they met the following criteria: Firstly initiated CAPD and participated in the CAPD first-policy from January 2008 to April 2011, survived more than 1 month after initiating CAPD, and had at least 1tKt/V during the studied period.2, serum albumin level < 0.3 or > 6 g/dl, hemoglobin level < 3 or > 20 g/dl, urine volume < 0 or > 4,000 ml, ultra-filtration (UF) volume < −2,000 or > 4,000 ml, systolic blood pressure (SBP) < 40 or > 300 mmHg, or diastolic blood pressure (DBP) < 10 or > 200 mmHg.Patients were ineligible if they had the following criteria: on CAPD due to acute renal failure, aged > 100 years, tKt/V < 0.5 or > 5, tCrcl < 10 or > 400 L/week/1.73 mThe primary outcome of the study was time since first initiation of CAPD therapy to death. Patients were censored if they were lost to follow up, or survived at the end of the study (May 2011). Death referred to all cause mortality and the data were validated by cross-referencing with the death certificate database from the Ministry of the Interior.The studied prognostic factors were renal  and peritoneal  small solute clearances. The former clearance was estimated using a ratio of concurrent urea/creatinine excretion in 24-hour urine whereas the latter clearance was estimated using 24-hour dialysate effluent. The total small solute clearance  was the summation of renal and peritoneal small solute clearance. Urea distribution volume (V) was measured using Watson's formula.These small solute clearances  and other variables were considered in the prognostic model, which included age, gender, body mass index (BMI), serum albumin, hemoglobin, UF volume, SBP, DBP, and co-morbidities ). Among these variables, tKt/V, rKt/V, tCrcl, BMI, serum albumin, hemoglobin, UF volume, SBP, and DBP were considered in the analysis as time-varying covariates, whereas the rest were fixed variables.Among 1,177 eligible patients, the data for UF volume, hemoglobin, serum albumin, rKt/V, BMI, tCrcl, and co-morbidities were missing in 0.3%, 1.1%, 3.3%, 6.5%, 11.5%, 16.7%, and 36.3% of patients, respectively. For each patient, the last observed value was carried forward to replace missing data. Then, the rest of the missing data were imputed using multivariate chain equations. A simulation-based procedure with theThe received operative characteristic (ROC) curve was used to determine the cutoff of tKt/V, rKt/V, and tCrcl that could discriminate death from living patients. Each variable was fitted in the ROC model as both continuous and categorized variables, separately. For categorical variables, they were categorized according to tertile distributions. The likelihood ratio positive (LR+) and Youden’s index  were theKaplan-Meier was applied to estimate the overall death rate and probability of death at 12-, 24-, and 36- months after first-initiated CAPD. A patient was censored if s/he had one of the following events: loss to follow-up, withdrew from the CAPD program, or alive at the end of follow up period. Cox-regression models with time varying covariates were applied to assess prognostic effects by fitting equations that separately contained rKt/V and tKt/V. Prognostic scores were then calculated from the final Cox models. The ROC curve analysis was used to estimate the area under the ROC curves (AUC) between the two prognostic scores.All analyses were done using STATA software version 12. The p-value of less than 0.05 was considered statistically significant.We identified 11,523 patients in the CAPD registry and follow-up databases from January 2008 to May 2011. Among them, 11,352 patients were aged 15 years or older, but only 1,188 (10.5%) patients had at least one tKt/V data. Eleven patients had a tKt/V out of the acceptable range  and thus they were excluded, leaving 1,177 patients with 23,144 observations for the primary analysis, see Figure+ of this cutoff were 0.40, 0.74, and 1.50, respectively. Fitting a categorical tKt/V in the ROC analysis suggested that a cutoff of 1.75 yielded sensitivity, specificity, and LR+ of 0.45, 0.65, and 1.31, respectively. The AUCs were similar for both variables, i.e., 0.556  vs. 0.551 , respectively. The final cutoff of 1.75 was chosen because it provided higher sensitivity.Data for the tKt/V were categorized as < 1.75 (n = 384), 1.75-2.19 (n = 384), and > 2.19 (n = 409) using a tertile distribution. Fitting a continuous tKt/V in the ROC curve analysis yielded an optimum cutoff based on Youden’s index of 1.65. Sensitivity, specificity, and LR+ of 0.45, 0.77, and 1.96, respectively. The rKt/V was categorized into 3 groups according to a tertile distribution, i.e., < 0.25, 0.25-0.49, and > 0.49; fitting this categorical variable yielded the AUC of 0.612 . Although this cutoff yielded slightly inferior performance , this rKt/V cutoff of 0.25 was chosen for further analyses because it provided higher sensitivity.Fitting rKt/V as a continuous variable in the ROC analysis resulted in an AUC of 0.632 . Applying Youden’s index suggested the cutoff of 0.15 with sensitivity, specificity, and LRFitting the tCrcl variable did not discriminate well between dead and surviving patients with the AUCs of 0.519  and 0.513  for continuous and categorical variables, respectively.Among 1,177 patients, the person-time at risk was 21,831 patient-months with a median follow-up of 22.9 months (range: 1.8–43.5 months). One-hundred and eighty eight patients died which resulted in an overall death rate of 9.9  per 100 patient-years. The probabilities of death at 12-, 24- and 36-months were 6.7% , 19.4%  and 29.2% , respectively.Kaplan-Meier curves were plotted by tKt/V groups  significantly lower risk of death than patients with tKt/V < 1.75  and 2.70  times higher risk of death than patients aged younger than 45 years. High serum albumin resulted in better prognosis with 52% , and 75%  lower risk of death for serum albumin 3.0–3.4 g/dl and > 3.4 g/dl respectively, when compared to albumin below 3.0 g/dl.Hemoglobin showed an inverse dose–response relationship with death; those with hemoglobin levels of 9.0-10.9 and > 10.9 g/dl had 32%  and 56%  respectively significantly lower risk of death than those with a hemoglobin level below 9.0 g/dl. UF volume 1,000 ml per day or higher reduced the risk of death by 47% . Patients whose SBP were 140 mmHg or higher had 31%  significantly lower risk of death than those whose SBP were below 140 mmHg.2 or higher when compared with BMI less than 21 kg/m2, but this was not statistically significant. The presence of diabetes increased the risk of death by 43% with the adjusted HR of 1.43 , but this was also not statistically significant.Higher BMI were associated with lower mortality with the adjusted HR of 0.73  for BMI 21 kg/m2 had 20%  lower risk of death than patients with tCrcl < 50 L/wk/m2; although this was not statistically significant, data have not been shown.After adjusting for covariables, patients with tCrcl ≥ 50 L/wk/mWe conducted a retrospective cohort study of first-initiated CAPD patients with a median follow-up time of 22.9 months. The 12-, 24- and 36-months probabilities of death were 6.7% , 19.4% , and 29.2% , respectively with the overall death rate of 9.9  per 100 patient-years. Prognostic factors of death were explored suggesting that rKt/V was the strongest predictor of death followed by tKt/V. The cutoff thresholds of these parameters that discriminated poor from good prognosis were ≥ 0.25 for rKt/V and ≥ 1.75 for tKt/V. Patients with the rKt/V and tKt/V higher than the cutoffs had respectively 65% and 29% lower risk of death than patients with lower levels than the cutoffs.The mortality rate for our cohort was quite low  when compared with the mortality rates in other Asian countries, e.g., Indian (20% and 40% ), and ChiUnlike rKt/V, the roles of tKt/V on mortality has not been consistently demonstrated by previous studies-14,20-242 with the four 2-L daily exchanges of standard PD solution. They found no significant differences in patient survival, technique survival, and quality of life between intervention and control groups. The Hong Kong study[A target small solute clearance has long been a critical issue. Since increasing the peritoneal dialysis prescription may increase the patients' discomfort, decrease the quality of life, and harm by metabolic glucose load, the advantages from increased dialysis dose and potential harms should be well-balanced. Unfortunately, the optimum target clearance has not been well-formulated due to lack of previous evidence and our study should be able to fill information for this issue. Both continuous and categorical variables for small solute clearances were explored in the ROC curve analyses and suggested the optimum cutoffs for tKt/V and rKt/V. These cutoffs were similar to the current tKt/V target suggested by the Kidney Disease Outcome Quality Initiative (KDOQI) guideline. Two ranng study which haSome studies,11,12 coIncreased serum albumin, hemoglobin, UF volume, and SBP > 140 mmHg were also associated with a lower risk of mortality. Interestingly, we found an inverse relationship between high SBP and risk of death. This finding is consistent with recent findings in chronic kidney disease/dialysis patients which suggested that low blood pressure could be related to coexisting co-morbidities such as heart failure, autonomic neuropathy, decreased food intake, and worse nutritional status-29. ThesOur study has some strengths. Our study is a large CAPD cohort with a median follow up time of nearly 2 years. We properly calibrated the rKt/V and tKt/V cutoffs using ROC curve analysis. We considered study factors  and other observed prognostic factors as time-varying co-variables in the survival analyses, which should be better in explaining disease prognosis than using only single measurements. However, our study also has some limitations. First, the study was not a randomized controlled trial and thus selection and unobserved confounding biases could not be avoided. Second, patients were only eligible if they had data for tKt/V, which was about 10% of the entire cohort; so the representativeness of the whole CAPD patients was limited. Third, we might face with survival bias because of our inclusion criteria and differences of characteristics of eligible versus ineligible patients. Our results may be generalizable to patients who firstly received CAPD with stable conditions, not patients with critical conditions. The specific etiologies of death including their prognostic factors were not evaluated due to lack of information. Among eligible patients, some variables were missing and thus multiple imputation using regression analysis was applied to predict missing values. Twenty imputations were applied taking into account the between-imputation variability.The cutoffs of 0.25 and 1.75 for rKt/V and tKt/V might be targeted to prevent mortality in CAPD patients. Serum albumin, hemoglobin, SBP, and UF volume are also associated with mortality. However, our study may face with selection and other unobserved confounders. Further randomized control trial is required to confirm these cutoffs.Phisitt Vejakama is a Ph.D. student of Clinical Epidemiology, Faculty of Medicine Ramathibodi Hospital and Faculty of Graduate Studies, Mahidol University. This study is a part of his dissertation which will be applied for granting graduation. All other authors declare that there is no duality of interest associated with this manuscript.AT had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: PV, AT, AI, JA, Acquisition of data: PV, PD. Analysis and interpretation of data: PV, AT, AI, JA. Drafting of the manuscript: PV, AT. Critical revision of the manuscript for important intellectual content: JA, AT, AI, PD. Final approval of the version to be published: all authors.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/28/prepub


Hypertension (HTN) is a serious health problem that threatens one fourth of the adult population in some countries.This study aimed to assess the prevalence and outcome of undiagnosed hypertensive patients admitted to the emergency department.This cross-sectional study was conducted from March 2009 to March 2010 at Imam Hossein Medical and Educational Center, Teheran, Iran. A total of 2070 patients aged 18 years and older were admitted to the emergency department without previous HTN history. Blood pressure was taken and repeated 10 minutes later if initial systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg. Those who matched the inclusion criteria entered the study for further follow-up. A numerical pain score was also used for pain intensity assessment. Chi-Square and Mann Whitney U tests were performed to compare differences between sex, age and education of the participants.Based on the inclusion criteria, 346 patients entered the study, out of which 168 qualified for further evaluation and follow-up. Forty eight patients (28.6%) were finally diagnosed with high blood pressure. Our study showed that the prevalence of undiagnosed HTN was 4.8%. Significant differences between blood pressure, age, pain score and education level (P < 0.001) were found. This implies that old age, poor education and low pain score are positively associated with hypertension.Blood pressure readings in emergency departments should not be readily attributed to pain or anxiety. Diagnosis must be based on meticulous follow-up and precise examinations. Hypertension (HTN) is a serious health hazard. In some countries, nearly one fourth of the adult population suffers from HTN . About 7In this prospective cross-sectional study the aim was to follow up the patients with no history of HTN but with high BP readings to further assess the prevalence of undiagnosed HTN. A prospective cross-sectional study was designed to assess the prevalence of undiagnosed HTN among the patients admitted to the Emergency Department of the Imam Hossein Medical and Educational Center, Teheran, Iran, from March 2009 to March 2010. This study was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences, Teheran, Iran. All trauma and non-trauma patients with elevated BP were admitted to the triage room first and then referred to the emergency physician. According to the 7th Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure, HTN is defined as diastolic BP ≥ 90 mmHg or systolic BP ≥ 140 mmHg (5). Patients over 18 years-old with elevated BP and no history of HTN were held under observation for 10 minutes. If the BP remained high at the second reading, they were enrolled in the study. Pregnant women and patients with an arm circumference greater than 45 cm or lower than 19 cm were excluded. A structured questionnaire was used for each patient in order to collect contact information, demographic data, medical history, reason for admission and a complete list of medications. Pain intensity was recorded using a numerical pain score with two anchor points from 0 to 10 (0 indicating no pain and 10 indicating the worst pain ever experienced), just before the second BP measurement. If the patient did not need urgent medical help for high BP, he/she was discharged and advised for further follow-up one month later. In case the patient was found to have a high BP reading during the follow up visit, he was then referred to the internist for medical treatment. Blood pressure was measured with a standardized mercury sphygmomanometer with the patient in supine position with the right arm at the level of the heart and after 5 minutes of rest. Statistical analysis was carried out using the SPSS software, version 17 . The Chi-Square and Mann Whitney U tests were used for prevalence comparison of HTN between sex, education and age groups .Two thousand and seventy patients (65.9% men) underwent BP measurement, out of which 346 (16.7%) had two elevated BP readings at 10 minutes intervals and entered the study. The sample had a mean (± SD) age 46.7 ± 12.4 years. The demographic data is summarized in In this study, one month follow-up depicted a prevalence of 4.8% newly diagnosed HTN, which was positively associated with low education, old age and non-traumatic cases. Epidemiological studies have reported different prevalence of undiagnosed HTN in apparently healthy individuals . For exa