Pulse-pressure variation (PPV) due to increased right ventricular afterload and dysfunction may misleadingly suggest volume responsiveness. We aimed to assess prediction of volume responsiveness with PPV in patients with increased pulmonary artery pressure.Fifteen cardiac surgery patients with a history of increased pulmonary artery pressure  before fluid challenges) and seven septic shock patients  were challenged with 200 ml hydroxyethyl starch boli ordered on clinical indication. PPV, right ventricular ejection fraction (EF) and end-diastolic volume (EDV), stroke volume (SV), and intravascular pressures were measured before and after volume challenges.P = 0.485). PPV was ≥13% before 46 (67%) fluid challenges, and SV increased in 13 (28%). Right ventricular EF decreased in none of the fluid challenges, resulting in increased SV, and in 44% of those in which SV did not increase (P = 0.0003). EDV increased in 28% of fluid challenges, resulting in increased SV, and in 44% of those in which SV did not increase (P = 0.272).Of 69 fluid challenges, 19 (28%) increased SV > 10%. PPV did not predict volume responsiveness (area under the receiver operating characteristic curve, 0.555; Both early after cardiac surgery and in septic shock, patients with increased pulmonary artery pressure respond poorly to fluid administration. Under these conditions, PPV cannot be used to predict fluid responsiveness. The frequent reduction in right ventricular EF when SV did not increase suggests that right ventricular dysfunction contributed to the poor response to fluids. A main goal of cardiovascular support is to restore and maintain sufficient cardiac output. Whereas prompt treatment of hypovolemia is necessary to sustain tissue perfusion, too much volume administration may result in edema formation and impaired tissue perfusion, with consequent organ dysfunction and increased risk of death -5. BecauWe hypothesized that PPV does not predict volume responsiveness in the presence of increased pulmonary artery pressure, and that right ventricular dysfunction may contribute to this. To test this hypothesis, we measured PPV and the hemodynamic response to clinically indicated fluid challenges in patients with septic shock and in postoperative cardiac surgery patients with increased pulmonary artery pressure.The study was approved by the Ethics Committee of the Canton of Bern. Written informed consent was obtained from 20 cardiac surgery patients with a preoperative history of increased pulmonary artery pressure, and from both an independent physician and a close family member of 10 patients in septic shock.Cardiac surgery patients were included if they had an increased pulmonary artery pressure, as estimated during a preoperative echocardiogram  or a history of right ventricular myocardial infarction or right heart failure, and a clinical indication for a pulmonary artery catheter perioperatively, as judged by the patient's cardiac anesthetist, who was not involved in the study.3 per microliter) or leucopenia , and mean blood pressure < 60 mm Hg, despite volume resuscitation, or need for vasopressors to keep mean blood pressure ≥60 mm Hg. In addition, the patient had to have a clinically indicated pulmonary artery catheter ordered by the clinical team treating the patient.Patients with septic shock had septic shock defined as three of four systemic inflammatory-response syndrome criteria: (a) hyperthermia (≥38°C) or hypothermia (≤5.6°C); (b) tachycardia ; (c) tachypnea  or need for mechanical ventilation; and (d) leukocytosis  and cardiac output monitor  were used to measure cardiac output, pulmonary artery pressures, and right ventricular ejection fraction and end-diastolic volume. Systemic and pulmonary artery and central venous pressures were recorded with quartz pressure transducers and displayed continuously on a multimodular monitor . The pressure transducers were zeroed to the level of the heart. Heart rate was measured from the electrocardiogram (ECG), which was continuously monitored. Only the variables routinely available by using the patient-monitoring devices were made available to and were used by the clinical team.For the study purposes, the intravascular pressures and heart rate were also recorded at 50 Hz on a computer using AcqKnowledge software , and variables from the continuous cardiac-output monitor/mixed venous oxygen-saturation monitor  were recorded with a frequency of 0.5 Hz on the same computer by using the serial output from the monitor and a proprietary research software (Edwards Lifesciences) and analyzed off-line.2 signal displayed on the monitor were visually observed, and fluid challenges were included only if signs of spontaneous respiratory efforts were absent.If the intensivist in charge of the care of the patient considered a volume challenge to be clinically indicated, 200 ml of hydroxyethyl starch  were infused over a 10-minute period. The study personnel performed hemodynamic measurements immediately before and between 15 and 20 minutes after the end of the volume challenge. The ventilator airway-pressure signal on the ventilator screen and the end-tidal COThe semicontinuous cardiac-output values were obtained from the values captured from the serial port of the device . For each variable, artifact-free 2-minute mean values were used for analysis. The main reason(s) that the clinician in charge of the patient considered the fluid challenge necessary was recorded.max - Ppmin)/((Ppmax + Ppmin)/2). Only recordings made during volume-controlled mechanical ventilation were analyzed. Each beat-to-beat tracing of intravascular central venous and pulmonary artery pressures was independently assessed by two senior investigators  to verify the absence of any spontaneous respiratory activity.PPV analysis was performed on the arterial pressure curve of 20 consecutive heart beats by using the following algorithm (20): PPV (%) = 100 × (PpChanges in stroke volume (SV) were used to define response to volume challenge. An increase in stroke volume exceeding 10% after the volume challenge was considered a positive response. The volume challenge should increase the SV as a result of acutely increased preload in a heart operating on the steep portion of the cardiac-function curve ,21. The P value < 0.05 was considered statistically significant.To assess differences in proportions between groups of patients, Fisher's Exact test was used. The effect of a volume challenge on hemodynamic variables was assessed with ANOVA for repeated measurements by using one within-subject factor (hemodynamic variable) and two between-subject factors . With this approach, a different response of a given hemodynamic variable in responders versus nonresponders is indicated by a fluid challenge-responder interaction, and a difference in the behavior of responders versus nonresponders in the two patient groups is indicated by a fluid challenge/responder/diagnosis interaction. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive value of PPV. Best predictive threshold was defined as the highest sum of sensitivity and specificity. Data are presented as median and interquartile range (demographics and ventilator settings), as percentage , and as mean ± SD (hemodynamic variables). A Four cardiac surgery patients and two septic shock patients were excluded from the data analysis because of cardiac dysrhythmia during the study. Further, one cardiac surgery and one septic shock patient were excluded because of continuous spontaneous respiratory activity. Accordingly, 15 postoperative cardiac surgery patients and seven patients with septic shock were analyzed. Patient data are indicated in Table Sixty-nine fluid challenges were performed . The most common indications for fluid challenge were hypotension and peripheral vasoconstriction  were similar in cardiac surgery and septic patients Table . OverallNineteen (28%) of the 69 fluid challenges increased SV in 12 patients: in cardiac surgery patients, 12 of 44 fluid challenges  and in septic shock, seven of 25 fluid challenges . If only fluid challenges that increased CVP by > 1 mm Hg are considered , SV increased in 15 (28%) of 53 fluid challenges.P > 0.05).PPV did not predict an increase in SV. The area under the ROC curve . Inclusion of only those fluid challenges with CVP increase did not improve the prediction of increase in SV . The threshold value for best prediction  for all volume challenges was 21%.Inclusion of only the first fluid challenge from each patient (n = 22) revealed 23% responders (n = 5). The area under the ROC curve for predicting a positive response by PPV was 0.447 in this case . EDV increased in 28% of fluid challenges resulting in increased SV and in 45% of those in which SV did not increase .Right ventricular ejection fraction decreased in none of the fluid challenges resulting in increased SV, and in 44% of those in which SV did not increase  found in a recent systematic review .et al. [Our results are in sharp contrast to those of several previous studies in septic and postoperative patients, in which pulmonary artery pressure was either not increased or not reported -26,28-33et al.  reportedFailure to induce an increase in preload and failure to detect changes in stroke volume would be the most obvious alternative explanations for this controversial finding. We consider these explanations unlikely. First, any acute increase in central venous pressure in response to volume loading suggests an increase in preload and should result in an increase in stroke volume if the heart is operating in the volume-responsive part of the cardiac-function curve ,21,37. Tet al. [The potential of increased pulmonary artery pressure to interfere with the predictive value of pulse-pressure variation has been addressed previously, but its clinical relevance has been considered small ,14. Thiset al.  supportsThe dynamic association between volume status and PPV has been advocated as an alternative to predict which patients will respond to fluid administration ,14. We tWe believe that our findings are real, especially considering the persisting large PPV values. These increased PPV values cannot be explained by relative hypovolemia, but are rather the consequence of an impeded right systolic function, as a consequence of intrathoracic pressure changes in a situation in which the right ventricle is already at the flat part of preload dependence. Hence, PPV had no predictive value for volume responsiveness. Furthermore, clinical use of PPV to predict volume responsiveness may misleadingly suggest volume responsiveness when increased pulmonary artery pressure compromises right ventricular function, and further volume expansion may be harmful.We therefore performed a second, experimental study. In the accompanying article , we asseA limitation of this study is the lack of airway-pressure signal recording concomitant with the hemodynamic signals. Our approach does not guarantee 100% exclusion of data from patients with spontaneous respiratory activity, although respiratory efforts with an influence on PPV should mostly be detectable in central venous and pulmonary artery pressure tracings. Recording airway-pressure signals would also have enabled us to define whether PPV was the result of an increase in PP during inspiration, a decrease during expiration, or both.Another potential confounder is the use of a colloid rather than a crystalloid. It has been suggested that colloids may have effects on cardiac function independent of their volume-expanding effect. However, this should have tended to increase fluid responsiveness rather than to decrease it.We conclude that both early after cardiac surgery and in septic shock, patients with increased pulmonary artery pressure respond poorly to fluid administration. Under these conditions, PPV cannot be used to predict fluid responsiveness. We suggest that right ventricular dysfunction contributed to the poor response to fluids.• Septic shock and post-cardiac surgery patients with increased pulmonary artery pressure respond poorly to fluid administration.• Pulse-pressure variation does not predict fluid responsiveness in septic shock and post-cardiac surgery patients with increased pulmonary artery pressure.• Right ventricular dysfunction may contribute to poor fluid response in such patients.2: mixed venous oxygen saturation.AUC: area under the curve; CVP: central venous pressure; ECG: electrocardiogram; EDV: end-diastolic volume; EF: ejection fraction; PAOP: pulmonary artery occlusion pressure; PEEP: positive end-expiratory pressure; PPV: pulse-pressure variation; ROC: receiver operating characteristic; SAPS: simplified acute physiology score; SIRS: systemic inflammatory response syndrome; SOFA: sequential organ-failure assessment; SV: stroke volume. SvOThe Department of Intensive Care Medicine has, or has had in the past, research contracts with Abbott Nutrition International, B. Braun Medical AG, CSEM SA, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, and Orion Corporation; and research & development/consulting contracts with Edwards Lifesciences SA and Maquet Critical Care AB. The money is/was paid into a departmental fund; no author receives/received individual fees. The past contract with Edwards Lifesciences is unrelated to and did not influence the current study.MWvB analyzed the data and drafted the manuscript. JT and SMJ designed and supervised the study, performed the statistics, and critically revised the manuscript. MR, FP, DT, CCG, RS, HB, and BB performed the study. All authors read and approved the final manuscript.Clinical indications for fluid challenges. A table listing clinical indications for fluid challenges.Click here for file


L-arginine infusion improves endothelial function in malaria but its safety profile has not been described in detail. We assessed clinical symptoms, hemodynamic status and biochemical parameters before and after a single L-arginine infusion in adults with moderately severe malaria.Plasmodium falciparum malaria in addition to standard quinine therapy. Symptoms, vital signs and selected biochemical measurements were assessed before, during, and for 24 hours after infusion. No new or worsening symptoms developed apart from mild discomfort at the intravenous cannula site in two patients. There was a dose-response relationship between increasing mg/kg dose and the maximum decrease in systolic  and diastolic blood pressure , and with the maximum increment in blood potassium  and maximum decrement in bicarbonate concentrations  and pH . At the highest dose (12 g), changes in blood pressure and electrolytes were not clinically significant, with a mean maximum decrease in mean arterial blood pressure of 6 mmHg , mean maximal increase in potassium of 0.5 mmol/L , and mean maximal decrease in bicarbonate of 3 mEq/L  without a significant change in pH. There was no significant dose-response relationship with blood phosphate, lactate, anion gap and glucose concentrations. All patients had an uncomplicated clinical recovery.In an ascending dose study, adjunctive intravenous L-arginine hydrochloride was infused over 30 minutes in doses of 3 g, 6 g and 12 g to three separate groups of 10 adults hospitalized with moderately severe Infusion of up to 12g of intravenous L-arginine hydrochloride over 30 minutes is well tolerated in adults with moderately severe malaria, with no clinically important changes in hemodynamic or biochemical status. Trials of adjunctive L-arginine can be extended to phase 2 studies in severe malaria.NCT00147368ClinicalTrials.gov  Although treatment with the rapidly acting anti-parasitic drug, artesunate has significantly improved survival in severe malaria, the case-fatality rate remains high in vitroL-arginine is the substrate for synthesis of nitric oxide (NO) from NO synthase, and has been proposed as a potential adjunctive therapy in severe malaria Intravenous L-arginine has been used for over 40 years in routine clinical practice to assess the integrity and function of the hypothalamic-pituitary axis As a prelude to assessing the safety and potential utility of adjunctive L-arginine infusion in severe malaria, we undertook a safety, pharmacokinetic and efficacy study in patients with moderately severe falciparum malaria (MSM). The efficacy of L-arginine in improving endothelial function and NO production in these patients has been reported previously The protocol for this trial is available as supporting information; see Plasmodium falciparum and P. vivaxThe study was conducted at Mitra Masyarakat Hospital (RSMM) in Timika, Papua, Indonesia, a region with unstable transmission of multidrug-resistant P. falciparum parasites/µL  defined as fever or history of fever in the past 48 hours, with >1000 asexual L-arginine hydrochloride  was diluted in 100 ml normal saline (or sufficient to provide a concentration ≤10% w/v) and administered intravenously by an infusion pump over 30 minutes at doses of 3 g, 6 g and 12 g. Intravenous quinine was continued during infusion of L-arginine, through a separate cannula.Upon enrolment and before infusion, patients had a standardized clinical history and physical examination recorded. During infusion patients were monitored with serial assessments of the following symptoms  were measured at baseline and 24 hours after infusion.Electrolytes, glucose, acid-base parameters and were measured using a bedside biochemical analyser . Plasma phosphate, serum creatinine, bilirubin, liver enzymes and creatine kinase were measured using colorimetric and enzymatic methods .Mean values of the vital sign and biochemical parameters before infusion were compared to mean values obtained immediately after infusion using a paired t-test . If parameters were not normally distributed, values before and after infusion were compared by the Wilcoxon Signed Rank Test. Because analysis in this manner could mask transient but potentially clinically significant changes in a minority of subjects, we also analyzed the maximum change in the vital signs and biochemical markers at any time during and after L-arginine infusion compared to baseline readings. This gave a “worst-case scenario”, however transient, for each parameter. The mean of the pre-infusion values in each patient was subtracted from the lowest  and highest  measurement during infusion or in the two hours following infusion and expressed as mean maximum change. Relationships between the maximum changes and the dose weight ratio (expressed as mg/kg) were assessed by Pearson's correlation matrix (r), or Spearman's rank correlation coefficient (ρ) if the dependent variable was not normally distributed. A general linear model was used to assess dose-response relationships. All analyses were performed with Stata 9.2 software (Statacorp). A two sided value of p<0.05 was considered significant.Ethical approval was obtained from the respective committees of the National Institute of Health Research and Development, Jakarta, Indonesia and the Menzies School of Health Research, Darwin, Australia and the trial was registered in clinicaltrials.gov as NCT00147368. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript.A total of 30 patients received a single L-arginine infusion intravenously, at doses of 3 g (n = 10), 6 g (n = 10) and 12 g (n = 10). The corresponding mean mg/kg doses in each group were 53 mg/kg (range: 45–63), 105 mg/kg (range: 87–140) and 205 mg/kg (range: 155–240), respectively. Two patients, one receiving 3 g and another 12 g developed mild discomfort over the intravenous cannula site during infusion, but no signs of phlebitis were evident and no extravasations occurred. No other patients developed new symptoms. There was also no worsening of existing symptoms either during or after infusion of L-arginine; in particular, no new or worsening complaints of headaches, vomiting, nausea, flushing, giddiness, dyspnea, cough, diarrhea, lethargy and anorexia. No allergic reactions were seen.maximum falls in blood pressure at any time during or in the two hours after infusion were also assessed. The maximum decrease in both the systolic  and diastolic blood pressure  correlated with increasing mg per kg dose. Each increment of dose was associated with an increase in the mean maximum decrement in systolic blood pressure of 3 mmHg  but not in diastolic blood pressure (p = 0.094). Patients who received 3, 6 and 12 g had mean maximum decreases in mean arterial blood pressure of 1.2 mmHg (range 0 to 8), 4 mmHg (range 1 to 10) and 6 mmHg  respectively. In no patient did systolic blood pressure fall to 90 mmHg or less. There were no statistically or clinically significant effects on pulse rate (data not shown) or respiratory rate (data not shown) before and during or after infusion of any dose of L-arginine, with continuous electrocardiography remaining normal throughout. Although the mean systolic and diastolic blood pressure did not change significantly following the 3 g and 6 g arginine infusion, patients given 12 g had a transient mean decrease in systolic  and diastolic  blood pressures measured immediately at the end of infusion which returned towards baseline within 15 minutes . Following the 12 g dose, mean chloride concentrations increased from 101 (95%CI: 99 to 102) to 103 (95%CI: 102 to 104) mmol/L  , with a mean maximal increase of 3 mmol/L .The maximum increases in potassium, chloride and anion gap, and the maximum decreases in bicarbonate, pH, glucose, and phosphate were assessed following L-arginine infusion. Each dose increase of 100 mg per kg of L-arginine was associated with a mean maximum increment in blood potassium of 0.2 mmol/L(95%CI: 0.1–0.3) p<0.001), the mean maximum bicarbonate decrement  and the mean maximum pH decrement  . In addition, no significant changes were found in mean phosphate  in patients with end stage renal failure resulted in no change in arterial pH +>5.5 mmol/L) was found in 16%, and was associated with increased mortality As with other cationic amino acids, intracellular uptake of L-arginine results in displacement of intracellular potassium into the extracellular fluid increase in mean blood glucose following a dose of 0.5 g/kg Because L-arginine increases the secretion of insulin Transient pain at the infusion site seen in 7% of patients in this study has also been described in other settings and is likely related to the hypertonicity of the L-arginine solution. Other rare adverse effects reported as single case reports in the literature were not seen in this study including extravasation reactions There are limited data on the safety and efficacy of adjunctive L-arginine monotherapy in other severe infections in animals and humans A parallel efficacy study performed in the same patients reported here Protocol S1Trial Protocol.(0.53 MB DOC)Click here for additional data file.


Home blood pressure (BP) is closely linked to patient outcomes. However, the prevalence of its documentation has not been examined. The objective of this study was to analyze the prevalence and factors affecting documentation of home BP in routine clinical care.A retrospective study of 142,973 encounters of 9,840 hypertensive patients with diabetes from 2000 to 2005 was performed. The prevalence of recorded home BP and the factors associated with its documentation were analyzed. We assessed validity of home BP information by comparing the difference between home and office BP to previously published prospective studies.Home BP was documented in narrative notes for 2.08% of encounters where any blood pressure was recorded and negligibly in structured data (EMR flowsheets). Systolic and diastolic home BP in narrative notes were lower than office BP readings by 9.6 and 2.5 mm Hg, respectively (p < 0.0001 for both), consistent with prospective data. Probability of home BP documentation increased by 23.0% for each 10 mm Hg of office systolic BP (p < 0.0001), by 6.2% for each $10,000 in median income of zip code (p = 0.0055), and by 17.7% for each decade in the patient's age (p < 0.0001).Home BP readings provide a valid representation of the patient's condition, yet are seldom documented despite their potential utility in both patient care and research. Strong association between higher patient income and home BP documentation suggests that the cost of the monitors may be a limiting factor; reimbursement of home BP monitoring expenses should be pursued. Home blood pressure measurements provide valuable clinical information in the treatment of hypertension-3. They Based on these data, many physicians encourage their hypertensive patients to monitor their blood pressure at home and use home blood pressure information during the treatment of patients-16. SurvSensitivity, specificity and positive predictive value of classification of blood pressure readings in narrative provider notes by the software as "home" vs. "office" (i.e. measured during the provider-patient encounter) were evaluated by comparison of the software results with manual review.unit of analysis.We carried out a retrospective analysis of EMR data to identify the source of the blood pressure reading (home vs. office) and the location of the record in the EMR (structured flowsheets vs. narrative notes). A single encounter documented in either narrative or structured data served as the unit of analysis. Blood pressure level  served as the primary outcome variable. Blood pressure reading type  served as the independent variable.We carried out a retrospective analysis of EMR data to compare the magnitude of patient's home blood pressure readings to the office blood pressure readings found in structured flowsheets and in narrative text. An encounter for which both a home blood pressure and an office blood pressure of the specified type (structured or narrative) were recorded served as the primary outcome variable) and the following predictor variables: 1) patient's office systolic blood pressure during the encounter; 2) patient's office diastolic blood pressure during the encounter; 3) patient's income as represented by the median income of the patient's zip code; 4) patient's age; 5) patient's gender; 6) patient's ethnicity; 7) patient's primary language; and 8) patient's insurance. A single encounter served as the unit of analysis.It is not known how patient characteristics affect patterns of home blood pressure documentation in the EMR. We analyzed the relationship between the presence of a home blood pressure reading  system Longitudinal Medical Record (LMR). LMR allWe included in our study all patients who were followed in primary care practices at either Brigham and Women's Hospital or Massachusetts General Hospital for at least two years between 01/01/2000 and 08/31/2005, were at least 18 years old, and had a documented diagnosis of diabetes mellitus. Patients who did not have any office blood pressures recorded during the study, did not have a zip code listed, had an invalid zip code, or were from a zip code without median income data in the US census were excluded.The program used to extract the data from narrative notes employed a semantic algorithm to identify two sets of concepts: blood pressure values and type of blood pressure reading. Possible types of blood pressure readings as classified by the program were readings taken at home, readings taken during the encounter of record (henceforth referred to as "office" BP readings), and readings taken neither at home nor during the encounter. The program utilized as a foundation a previously validated algorithm used to identify blood pressure values in narrative notes. When a We evaluated the accuracy of identification of blood pressure readings taken at home or in the office on a dataset of 300 narrative physician notes. Each note was manually analyzed by two trained senior pharmacy students who did not participate in the development of the algorithm. The reviewers abstracted all blood pressure readings and assigned to each of them a categorization of "home", "office" (i.e. taken during the encounter of record) or "neither" (e.g. taken during a previous provider-patient encounter). Blood pressure readings for which the reviewers did not reach an agreement were re-analyzed to establish the consensus designation. The software output was compared to the consensus rating to determine sensitivity, specificity and positive predictive value (precision) for categorization of blood pressure readings.service date were treated as the same encounter for the purpose of data analysis. Service date in our institution's EMR indicates the date of the provider-patient encounter to which the electronic transaction pertains and may be different from the date when the record was actually modified. Home blood pressure measurements reported in provider notes were compared to office blood pressure measurements made on the day of the encounter that the note documented.Home blood pressure readings documented in the structured flowsheets in the EMR were identified using manually entered notes in the Comment field . Home blood pressure readings documented in the narrative notes were abstracted using the algorithm described above. Physician notes and EMR records that had the same For the analysis of the data collected from narrative notes, the minimum and maximum of any blood pressures represented as a range in the narrative notes were averaged to give a single blood pressure value. Then, for each encounter, the lowest home, office, and structured blood pressure readings were selected based on the mean arterial blood pressure ). If two blood pressure readings had the same MAP, the one with the lower systolic BP was selected as the lowest BP of the given type for the given encounter.For the multivariable analysis of the factors that may affect documentation of home blood pressure, the office blood pressure (structured or narrative) with the lowest MAP was used to establish the predictor variables of office systolic and diastolic blood pressure. For encounters that did not have an office blood pressure documented (301 encounters), systolic and diastolic blood pressures were imputed based on the patient's office blood pressures recorded during other encounters, home blood pressure readings and all other covariates used in the construction of the multivariable model using SAS multiple imputation procedures PROC MI and PROC MIANALYZE.Summary statistics were constructed by using frequencies and proportions for categorical data and by using means and standard deviations for continuous variables. Wilcoxon signed rank test was used for univariate analysis of the difference in magnitude between home and office blood pressure readings.To analyze the relative magnitude of home and office blood pressure readings documented in structured and narrative data, we constructed a hierarchical (multilevel) mixed multivariate linear regression model with random effects to account for clustering within patients. The model adjusted for the patients' age, gender, ethnicity, primary language, insurance status and income level.To analyze the factors that were associated with documentation of home blood pressure in narrative provider notes we constructed a hierarchical (multilevel) multiple logistic regression model. We used the GLIMMIX procedure to adjust for clustering within treating physicians and patients,23. The Partners HealthCare System institutional review board granted expedited approval of this study and waived the need for informed consent.The reviewers identified 675 blood pressure readings in the evaluation notes. Of these, 624 BP readings were identified by both reviewers. The reviewers agreed on 558 (89.4%) of the ratings of whether the blood pressure was taken at home (kappa = 0.666) and on 601 (96.3%) of the ratings of whether the blood pressure was taken in the office (kappa = 0.924) during the encounter.The software found 632 blood pressure readings in the same set of notes. Of the 675 blood pressure readings found by the reviewers and 632 blood pressure readings found by the software, 598 matched. These 598 instances of blood pressures were then used to evaluate the classifications of blood pressures as taken at home, taken at the office during the encounter of record, or neither as automatically generated by the software.The specificity, sensitivity, and positive predictive value for the software classifications of blood pressure readings as home or taken in the office during the encounter of record ranged from 83.7% to 95.5% Table .We identified 11,012 patients with a documented diagnosis of diabetes who were followed in a primary care clinic during the study period  were reported as a range. However, of the 2,060 home blood pressure readings, 619 (30.0%) were reported as a range.Out of 1,759 days when both office and home blood pressure readings were documented, home blood pressure was lower on 1,059 (60.2%) days. On average, office blood pressure readings documented in structured flowsheets showed systolic blood pressure 9.6 mm Hg higher and diastolic blood pressure 2.5 mm Hg higher than home blood pressure readings . Only 6 (2.0%) of the 304 physicians recorded home blood pressures in more than 10% of the notes, while 62 (20.4%) physicians never recorded any.The frequency of home blood pressure documentation rose steadily with the lowest office blood pressure recorded during the encounter Figure : from 0.In a multivariable analysis of 99,082 encounters Table , the proIn this retrospective study of over 140,000 encounters with over 9,800 patients, we found that home blood pressures are seldom documented in routine clinical care (only 2.08% of encounters that had any blood pressure recorded included a home blood pressure measurement). This relative scarcity of home blood pressure documentation may be partially attributable to a lack of reimbursement provided for the monitoring of home blood pressures, as our study implicates cost as a limiting factor in the use of home blood pressures. The limiting role of cost is shown through the finding that the likelihood of home blood pressure being documented increases 6.2% for every $10,000 increase in the median income of the patient's zip code. This lack of reimbursement is a situation which the American Heart Association(AHA), American Society of Hypertension (ASH), and Preventive Cardiovascular Nurses Association (PCNA) have highlighted as in need of remedy, and ourWhen home blood pressures were recorded, they were nearly always recorded in narrative notes rather than in the structured data. This difference is likely due to the extra time that it takes to record a blood pressure in the structured fields. Home blood pressure readings are typically reported by the patients directly to the providers whose time is more constrained than, for example, medical assistants, who enter the bulk of the structured blood pressure data. Faced with the pressure to make most efficient use of the 15-20 minute office visit, providers are more likely to include home blood pressure readings in the narrative of the encounter note but not take the time to also enter it into the appropriate structured field. As a result, home blood pressure readings recorded in narrative but not structured data are not easily accessible to other providers and are not available for quality of care monitoring and/or research. Improvement of reimbursement of healthcare providers for supporting, discussing and documenting home blood pressure monitoring (in addition to office blood pressure measurement) could potentially increase home blood pressure documentation overall and particularly in structured format. A compensated practice change that would include health care team providing education and self management support for patients to monitor their blood pressure at home, as well as coaching and regular discussions about and documentation of home blood pressures between patients and the health care team, would be an optimal approach.Data collected in the course of routine clinical care, and particularly data, such as home blood pressure readings, that are collected irregularly, could be subject to selection bias. It was therefore important to validate our findings to establish whether home blood pressure records in routine clinical care provided an adequate representation of reality. To this end we performed a quantitative comparison of home and office (which are recorded less selectively) blood pressure readings. Compared to the office blood pressure readings from structured data, home systolic blood pressures were 9.6 mm Hg lower and home diastolic blood pressures were 2.5 mm Hg lower, consistent with the findings of several prospective studies. This reOur study found that higher office systolic blood pressure, the patient's income as measured by median income of the patient's zip code, and older age were significantly associated with an increased probability of documentation of home blood pressure. For every 10 mm increase in office systolic blood pressure, the probability of home blood pressure being recorded rose by 23.0%. One explanation for this finding may be that physicians are unlikely to inquire about and/or record home blood pressure when office blood pressure is normal -- recording home blood pressure is usually done to justify treatment decisions that would have been different if only office blood pressure were available. For example, the physician may request home blood pressure readings to rule out white coat hypertension or to confirm that an unusually elevated blood pressure is inconsistent with the patient's long-term trend. Our study also showed a 6.2% increase in documentation of home blood pressure for every $10,000 increase in the median income of the patient's zip code. This finding could in part be attributed to an increased ability of individuals with higher income to afford a home blood pressure monitoring device and further supports the call by the AHA, ASH and PCNA for the reimbursement of home blood pressure monitoring costs, as it implies that the cost may be a key factor in determining whether a patient is able to monitor their blood pressure at home. We alsoOur investigation has several limitations. It was restricted in scope to diabetic hypertensive patients of physicians affiliated with two academic hospitals in Eastern Massachusetts; this could limit its generalizability. The data analyzed in our study was collected between 5 and 10 years ago and the patterns of documentation of home blood pressure measurements could have changed since that time. We have not conducted an analysis of the temporal order of factors that affect documentation of home blood pressure as precise temporal information is frequently not available in narrative documents. Due to the retrospective nature of our analysis, the data were collected for the purpose of routine care rather than for the analysis, and some of the data were missing. If the missing data were not missing at random with respect to the outcomes, our findings could be biased. However, our results were broadly consistent with previously reported prospective studies, supporting our conclusions. Most of the home blood pressure data in our study was computationally abstracted from narrative provider notes in the EMR. Narrative documents may not always contain information sufficient to make an unequivocal assessment of the location and/or timing of blood pressure measurement, as reflected in the disagreement between manual ratings of blood pressure readings in our study. However, overall our findings were congruent with previously published results of prospective studies, providing external validation to the technology.Home blood pressure readings in the documentation of routine clinical care provide a valid representation of the patient's condition and could be used in the care of individual patients, quality assurance and research. However, their documentation remains sporadic, and they are primarily recorded in narrative documents rather than structured data. Furthermore, our study suggests that the cost of home blood pressure monitoring may be a significant factor influencing the prevalence of its use, giving further support to the need for reimbursement of home blood pressure monitoring costs.The authors declare that they have no competing interests.MHK, MS and AT designed the study. MHK, EB, and KB collected the data. MHK, MS and AT conducted data analysis. MHK drafted the manuscript. MHK, EB, MS, KB, JSE, and AT critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/10/139/prepub


The prevention and control of high blood pressure or other cardiovascular diseases has not received due attention in many developing countries. This study aims to describe the epidemiology of high blood pressure among adults in Addis Ababa, so as to inform policy and lay the ground for surveillance interventions.Addis Ababa is the largest urban centre and national capital of Ethiopia, hosting about 25% of the urban population in the country. A probabilistic sample of adult males and females, 25–64 years of age residing in Addis Ababa city participated in structured interviews and physical measurements. We employed a population based, cross sectional survey, using the World Health Organization instrument for stepwise surveillance (STEPS) of chronic disease risk factors. Data on selected socio-demographic characteristics and lifestyle behaviours, including physical activity, as well as physical measurements such as weight, height, waist and hip circumference, and blood pressure were collected through standardized procedures. Multiple linear regression analysis was performed to estimate the coefficient of variability of blood pressure due to selected socio-demographic and behavioural characteristics, and physical measurements.2), with 10.8 % of the females being obese (body-mass-index ≥ 30 kg/m2). Similarly, 17% of the males and 31% of the females were classified as having low level of total physical activity. The age-adjusted prevalence  of high blood pressure, defined as systolic blood pressure (SBP) ≥ 140 mmHg (millimetres of mercury) or diastolic blood pressure (DBP) ≥ 90 mmHg or reported use of anti-hypertensive medication, was 31.5%  among males and 28.9%  among females.A total of 3713 adults participated in the study. About 20% of males and 38% of females were overweight (body-mass-index ≥ 25 kg/mHigh blood pressure is widely prevalent in Addis Ababa and may represent a silent epidemic in this population. Overweight, obesity and physical inactivity are important determinants of high blood pressure. There is an urgent need for strategies and programmes to prevent and control high blood pressure, and promote healthy lifestyle behaviours primarily among the urban populations of Ethiopia. Hypertension is an important public health problem worldwide. Analysis of the global burden of hypertension revealed that over 25% of the world's adult population had hypertension in 2000, and the proportion is expected to increase to 29% by 2025 . AccordiLimited data on the trends of prevalence of hypertension suggest that it has increased in economically developing countries in recent years while it remained stable or decreased in developed countries . Thus, mThe prevention and control of hypertension has not received due attention in many developing countries although it is one of the most modifiable risk factors of cardiovascular diseases. Awareness, treatment and control of hypertension is extremely low in these countries, as health care resources are overwhelmed by other priorities including HIV/AIDS, tuberculosis, and malaria.Reliable epidemiological data are useful for the design and implementation of effective strategies for the prevention and control of hypertension. There are, however, limited data on the epidemiology of hypertension and its control in many sub-Saharan African countries. In this regard, the recent efforts by the World Health Organization (WHO) to generate comparable data on chronic disease risk factors in developing countries, using the stepwise surveillance (STEPS) instrument  are yielIn this study, we report findings on the prevalence and some determinants of high blood pressure among adults in Addis Ababa, which were generated using the STEPS instrument. Addis Ababa represents the largest urban centre in Ethiopia, hosting about 25% of the urban population in the country. To date, Ethiopia has no national strategy for the prevention and control of chronic diseases or their risk factors. Findings of this study will, therefore, be useful to raise awareness among policy makers and the public at large, about the magnitude of high blood pressure and related risk factors of cardiovascular diseases, and thereby, contribute to the design and implementation of appropriate interventions.The present study, conducted in Addis Ababa City, constitutes part of a larger research project on chronic disease risk factors in Ethiopia. The city is organized into ten sub-cities, each of which are further divided into 9 or 10 administrative units known as 'kebeles', making up a total of 99 kebeles.This cross-sectional study employed a multi-stage sampling strategy, composed of random and cluster sampling techniques. Ten of the 99 kebeles were selected randomly, and smaller geographic units within the kebeles, known as zones or villages, were identified and listed for further random selection. Four zones were selected at random from each kebele, and the first household was randomly selected from each of the zones. Thereafter, subsequent households were selected on the basis of proximity to the first and the preceding household.A probabilistic sample of 4001 adults in the age group 25–64 years were selected to participate in the study. Of these, 3713 (93%) gave informed and written (signed) consent, while the remaining participated in the study willingly but were unable to sign the consent form. Those who failed to sign the consent form were significantly more likely (P < 0.001) to be unable to read or write. In the present study, we report data from 3713 study participants who signed the consent form.The WHO STEPS instrument  was used2]. Waist circumference was measured at the level of the iliac crest using a non-elastic tape measure. Hip circumference was measured at the maximum circumference of the hip. Waist-to-hip ratio (WHR) was calculated as a ratio of waist and hip circumference.Weight and height were measured with participants standing without shoes and wearing light clothing. Participants stood upright with the head in Frankfort plane for height measurement. Height was recorded to the nearest 0.5 cm, and weight was recorded to the nearest 100 g. Body-mass-index (BMI) was calculated as weight in kilograms over height in metres squared [weight (kg)/(height (m))The global physical activity questionnaire (GPAQ) section of the STEPS instrument was used for assessment of physical activity, and total physical activity was presented in MET  minutes per week. The instrument looks into three major domains of day-to-day activities; work (including domestic work), transport, and recreational activities. Level of total physical activity was subsequently classified into high, moderate, or low using the GPAQ analysis guideline provided along with the STEPS instrument .®M4-IOmron ) after the study participant rested for at least five minutes. Three consecutive measurements were made in an interval of at least 3 minutes. Mean systolic and diastolic blood pressures were determined from the second and third measurements.Blood pressure was measured in a sitting position using a digital device  for descriptive findings, while multiple linear regression analysis was used to estimate the coefficient of variability of blood pressure due to selected socio-demographic and behavioural characteristics, as well as BMI and WHR.Ethical clearance was obtained from the Faculty of Medicine, Addis Ababa University. Informed and written (signed) consent was obtained from each study participant. Ethical conduct was maintained during data collection and throughout the research process.A total of 3713 adults in the age group 25–64 years, from ten of the 99 kebeles  in Addis Ababa participated in the study. Median age of the study participants was 40 years, and 58.6% of them were females. The majority were Christians (93.1%), and from the Amhara (52.7%) or Oromo (20.2%) ethnic groups. About 23% had not had any formal education. Among the rest, the median duration of schooling was 9 years. About 72% of the males and 26% of the females were engaged in some income generating work through employment or self-employment (Table Cata edulis Forsk) chewing. Close to 16% of males chewed khat one or more days per week. Infrequent heavy alcohol intake, defined as consuming five or more standard units of alcohol per day on one or two days during the week prior to interview was significantly higher (P < 0.001) in males (10.4%) than in females (0.9%).About 13.5% of the males and less than 1% of the females reported 'current' cigarette smoking, while 11% of the males were 'current daily' smokers. Significantly higher (P < 0.001) proportion of males (18.6%) than females (2.1%) reported current khat .More males (12.5%) than females (9.4%) reported that they add salt to their plate after food has been served. Overall, 10.7%, 95% CI  adults reported regularly adding salt to their plate.Weight and height measurements were conducted in all but 10 0.3%) individuals. Mean (95% CI) BMI was 22.25  among males and 24.07  among females. The majority had a normal BMI, while 20.2% of males and 37.7% of females were overweight (BMI ≥ 25). The prevalence of overweight was significantly higher in females than in males (P < 0.001), and it increased with increasing age group . The prevalence of obesity (BMI ≥ 30) was significantly higher in females (10.8%) than males (2.0%) . On the other hand, significantly more males (12.8%) than females (9.4%) were underweight (BMI < 18.5) . (Tables % individThe mean (SD) WHR was 0.92 (0.19) in males and 0.88 (0.09) in females. About 13% of the males and 6.7% of the females had a WHR exceeding 1. Applying a separate cut-off point for WHR in females at >0.85, the proportion with high WHR  would be significantly (P < 0.001) higher in females (64.6%) than in males (12.9%). In 16 (0.4%) individuals, waist or hip measurements could not be taken due to lack of cooperation  was estimated to be 7967 in males and 4709 in females. About 52% of the males and 36% of the females were classified as having a high (vigorous) level of TPA. On the other hand, significantly more females (31.2%) than males (16.9%) were classified as having low level of TPA or being sedentary  (Tables Three consecutive measurements of blood pressure were taken from 3273 (88.1%) of the study participants. The remaining individuals refused to participate in the second or third measurement of blood pressure, mainly due to the discomfort that repeated measurements created. Those who declined for repeated measurements were significantly (P < 0.01) more likely to be females and Christians compared to their counter parts. A systematic decline was observed across the three consecutive measurements, such that the second measurement was lower than the first, and the third was lower than the second. Consequently, mean systolic and diastolic blood pressure levels were significantly higher among the participants on whom three measurements were not obtained, compared to those who participated in all three repeated measurements. We used the average of the second and third measurements in all the analyses related to blood pressure.Mean (95% CI) SBP was 129.4 mmHg  among males and 126.2 mmHg  among females. Similarly, mean (95% CI) DBP was 81.2 mmHg  among males and 80.0 mmHg  among females. Both mean SBP (P < 0.001) and DBP (P < 0.01) were significantly higher in males than in females. Overall, 31.5% of the males and 28.9% of the females had high blood pressure (defined as SBP/DBP ≥ 140/90 or reported use of anti-hypertensive medication). There was no significant difference between males and females in the prevalence of high blood pressure (P > 0.05). Among the 991 participants identified as having high blood pressure, 348 (35.2%) were aware of their blood pressure, but only 109 (11%) were receiving anti-hypertensive medication, of which 28 (25.6%) had normal (controlled) blood pressure at the time of the study.Considering the differences in age composition between the male and female study participants, adjusted means and prevalence of high blood pressure were calculated. Thus, the age adjusted mean SBP (mmHg) in males and females were 129.9 and 125.5, respectively. The age adjusted mean DBP (mmHg) in males and females were 81.5 and 79.8, respectively. Similarly, the age-adjusted prevalence of high blood pressure was 32.5% in males and 27.9% in females.The prevalence (95% CI) of isolated systolic hypertension was 8.9% 7.4, 10.3) in males and 8.3%  in females. Isolated diastolic hypertension was 5.8%  in males and 6.0%  in females. Combined systolic and diastolic hypertension was 16.0%  in males and 13.6%  in females , 28.4%  of males and 28.8%  of females had isolated systolic hypertension; and 18.4%  of males and 20.7%  of females had isolated diastolic hypertension. The prevalence (95% CI) of systolic and diastolic hypertension in this subgroup of adults was 50.9%  in males and 47.1%  in females  and DBP β = 2.5 mmHg), (P < 0.001), which led us to stratify subsequent analyses by sex. Age and BMI were significantly associated (P < 0.001) with mean SBP and DBP in both males and females, while educational level was inversely associated with both SBP and DBP in males. Waist-to-hip ratio was significantly (P < 0.05) associated with both mean SBP and DBP in females. Current daily smoking was associated with SBP, while level of total physical activity was inversely association with SBP in males   which inBoth studies revealed that BMI increased with increasing age. Thus, the wider age group and the consequently higher mean age of our study participants might have contributed to the higher overall prevalence of overweight in Addis. On the other hand, age-specific levels of overweight are markedly different between the two studies. We believe that the larger sample size and wider age representation of our study offers a more accurate estimate for prevalence of overweight among women in Addis.Our findings in Addis contrast sharply with the situation in Butajira, where data were generated using the same methodology and instrument (STEPS) from a sample composed of urban and rural populations . Mean BMMore comparable findings were reported from other sub-Saharan African countries that applied the STEPS methodology and instruments recently. According to the WHO Global InfoBase , the preIt is evident from the findings that the prevalence of overweight among adults in Addis is exceeding that of underweight or chronic energy deficiency. The large contrast between urban (overweight) and rural (underweight) populations signifies the rising burden of overweight in urban populations, and the double burden that countries like Ethiopia are faced with.Our estimate of the level of physical inactivity 25.3%) is higher than the global estimate, which ranges between 11% and 24% among adults 15 years and above [5.3% is hThe mean SBP among adults in Addis was higher than their counterparts in Butajira, which were 117.2 mmHg in males and 108.8 mmHg in females. The mean DBP was similarly lower in Butajira, 75.3 mmHg and 70.7 mmHg in males and females, respectively. The prevalence of high blood pressure was reported to be 12.3% in males and 8.3% in females in Butajira , and thrData on mean blood pressure levels in Ethiopia and other African countries are provided online by the WHO Global InfoBase . The repThe age-adjusted prevalence of hypertension revealed a gender gap  that is similar to other studies in Africa. Edwards et al.  also repBoth the mean SBP and DBP were significantly higher in males than females in Addis Ababa. A similar finding has been reported in Nigeria . Linear SBP decreased by about 0.45 mmHg in males and 0.48 mmHg in females for every additional year of schooling completed in our study population. Inverse relationship between education and blood pressure has been widely reported in studies from economically developed countries -28The INTERMAP study that included 4680 men and women aged 40–59 years from 17 diverse population samples in Japan, People's Republic of China, UK, and USA, demonstrated a strong significant inverse relationship between education and blood pressure, which was more manifest in the USA participants . The samThe INTERSALT study that involved 52 population samples in 32 countries worldwide, reported the inverse relationship in women for 38 samples and in men for 28 samples . In the Our findings reveal that mean SBP and DBP levels in both sexes were sub-optimal . The prevalence of elevated blood pressure is a cause for concern in Ethiopia as in other African countries. The WHO African Regional Office  reportedWe demonstrated a significant association between BMI and blood pressure in both sexes, which was consistent across mean SBP and DBP. A study in Tanzania  reportedSalt intake has been difficult to measure accurately or reliably at a population level. We were limited by resource constraints and the scope of the study to measure the 24-hour sodium excretion, which might have yielded a more quantitative account of the sodium balance. Thus we employed a qualitative approach in order to describe dietary salt use behaviour, by inquiring about 'adding salt on the plate' after food has been served . However, this approach could not detect those people who might have modified their behaviour due to awareness of their high blood pressure. This failure to establish a temporal relationship between salt intake behaviour and blood pressure, due to the cross-sectional design of the study, might have contributed to the lack of association between 'adding salt on the plate' and blood pressure in our study population. On the other hand, as salt use behaviour may be changing along with increasing urbanization and modernization, a qualitative assessment of salt use behaviour may still be valuable for the purpose of surveillance.As the scope of the present study does not include biochemical measurements, we were unable to determine the level of blood glucose or cholesterol. Similarly, we have not collected data on menopausal status among the women, and thus we have not controlled the potential effect of menopausal status on the risk of blood pressure in women.The prevalence of high blood pressure among adults in Addis Ababa is a cause for concern, as it constitutes a silent epidemic that is not matched with comparable level of awareness among policy makers or intervention by the health system. Considering the fact that there is only a limited pool of information on the burden of CVD or their risk factors in Ethiopia, an important input of this study would be to raise awareness about the problem among the population and policy makers so as to bring chronic diseases in general, and hypertension in particular, into the health research and policy agenda. Programs for the prevention and control of cardiovascular diseases and their risk factors should be designed and implemented as a matter of urgency.The authors declare that they have no competing interests.FT designed the study, developed survey instrument, supervised data collection and data entry, analyzed data and wrote manuscript. PB and SW participated in the study design, supervised instrument development, reviewed analysis and contributed to manuscript editing.The pre-publication history for this paper can be accessed here:


HNMT and ABP1 genes were found to be associated with altered enzyme activity. We hypothesized that alleles leading to decreased enzyme activity and, therefore, decreased inactivation of histamine may be responsible for altered susceptibility to asthma.Histamine-metabolizing enzymes (N-methyltransferase and amiloride binding protein 1) are responsible for histamine degradation, a biogenic amine involved in allergic inflammation. Genetic variants of HNMT and ABP1 genes in the group of 149 asthmatic children and in the group of 156 healthy children. The genetic analysis involved four polymorphisms of the HNMT gene: rs2071048 (-1637T/C), rs11569723 (-411C/T), rs1801105 (Thr105Ile = 314C/T) and rs1050891 (1097A/T) and rs1049793 (His645Asp) polymorphism for ABP1 gene. Genotyping was performed with use of PCR-RFLP. Statistical analysis was performed using Statistica software; linkage disequilibrium analysis was done with use of Haploview software.The aim of this study was to analyze polymorphisms within the HNMT gene with asthma. For other polymorphisms for HNMT and ABP1 genes, we have not observed relationship with asthma although the statistical power for some SNPs might not have been sufficient to detect an association. In linkage disequilibrium analysis, moderate linkage was found between -1637C/T and -411C/T polymorphisms of HNMT gene. However, no significant differences in haplotype frequencies were found between the group of the patients and the control group.We found an association of TT genotype and T allele of Thr105Ile polymorphism of Our results indicate modifying influence of histamine N-methyltransferase functional polymorphism on the risk of asthma. The other HNMT polymorphisms and ABP1 functional polymorphism seem unlikely to affect the risk of asthma. Histamine is a preformed mediator released during mast cell degranulation that plays a key role in the development of allergic inflammation and, subsequently, leads to atopic diseases such as bronchial asthma. Released histamine is metabolized by two enzymes: N-methyltransferase (HNMT) and diamine oxidase .HNMT gene is located on the chromosome 2q22.1 and within the gene region, several polymorphisms have been identified. A common C314T polymorphism leading to Thr105Ile substitution was discovered by Preuss et al. [HNMT gene have been also identified [N-methylation catalyzed by cytosolic HNMT enzyme is the primary pathway for histamine bio-transformation in bronchial epithelium . HNMT geABP1 gene has been localized on chromosome the 7q34-36 and within the gene region several polymorphisms have been identified. Among these, His645Asp substitution (rs1049793) was found to be functional and was associated with significant decrease in the serum enzyme activity in vivo [ABP1 enzyme is mainly expressed in kidney, colon, placenta, thymus and seminal vesicles and plays role in the inactivation of extracellular histamine -8. The Aion rs104793 was fHNMT and ABP1) was widely discussed in recent review on histamine pharmacogenomics where authors summarized association studies of those genes and their involvement in diverse diseases, including allergic diseases and asthma [The importance of genetic variation of genes related to histamine (including histamine-metabolizing enzymes d asthma .HNMT and ABP1) with the predisposition to asthma in the Polish population of pediatric patients.We hypothesized that polymorphisms within the HNMT and ABP1 genes responsible for individual variation of histamine metabolism might contribute to the pathophysiology of asthma. The aim of our study was to analyze a relationship between the polymorphisms of two genes encoding histamine metabolizing enzymes . Patients were recruited from inpatients from Wielkopolska region, considered as ethnically homogenous [®  following manufacturer’s instruction. The upper limits of normal range for total IgE was age-dependent .Clinical diagnosis of atopy depended on current or past symptoms of atopic dermatitis, allergic rhinoconjunctivitis  or food allergy. Atopy was confirmed when children fulfilled one of the following criteria: total IgE level higher than the upper normal limits for age; positive skin prick test to at least one aero-allergen . Any reaction with mean wheal diameter at least 3 mm greater than negative control was regarded positive and defined atopy. Total serum IgE level was measured by a fluoroimmunossay with Pharmacia UniCap 100 SystemControl group consisted of 156 healthy subjects of Caucasian origin . Control subjects were also recruited from the same geographic region (Wielkopolska) from the group of carefully chosen volunteers without asthma and allergy symptoms. Any allergic diseases or asthma were excluded based on clinical examination, history, spirometry and exhaled NO measurement.All participants as well as their parents have given written informed consent. Local ethics committee accepted the project. Study was performed in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki).HNMT and ABP1 polymorphisms were analyzed by PCR-RFLP method. The conditions of PCR-RFLP and sequences of the primers for the HNMT polymorphisms  were used as described previously [ABP1 His645Asp polymorphism, the genotyping was performed according to conditions described by Garcia-Martin et al. [The DNA was extracted from 10 ml of EDTA anticoagulated whole blood using the salting out method . The HNMeviously . For ABPHNMT polymorphisms were digested twice to confirm the results. The quality control of RFLP analysis was also performed (15% of randomly chosen samples from both groups) and the concordance between two assays was 100%. DNA samples were randomly plated during genotyping and reactions were performed without knowing the clinical outcome of the patient.The uncut PCR products for 2) test and Fisher’s exact test were used to test differences in the genotypic and allelic (respectively) distribution in case control. The alpha level < 0.05 was considered significant. Calculations were performed using the STATISTICA version 8.0 software. The association between HNMT 314 C/T and ABP1 polymorphisms and the risk of developing asthma was estimated by an odds ratio (OR) with a 95% confidence interval (CI) using demo of GraphPad InStat 3 programme. Concordance with Hardy-Weinberg law was performed using "Utility Programs For Analysis Of Genetic Linkage” application (Copyright © 1988 J. Ott). We also performed linkage disequilibrium analysis of the analyzed polymorphisms of HNMT gene using free online software Haploview version 4.1 from the website: http://www.broadinstitute.org/haploview[HNMT polymorphisms: 10% for 1637, 82% for 314, 9.7% for 411, 23.8% for 1097 and 23.9% for ABP1 polymorphism.The Pearson’s chi-square  and ABP1 His645Asp polymorphism in the group of asthmatic patients (p = 0.046).Genotype distributions for all studied polymorphisms in the In the analysis of genotype distribution we observed significant differences for 314C/T polymorphism, with TT genotype significantly more frequent in the group of asthmatic children in comparison to the control group  and control children  of the same Caucasian origin and the association was confirmed .Comparison of allele frequencies revealed that T allele of 314C/T polymorphism was significantly more frequent in the group of asthmatic patients as compared to the control group (p = 0.048). This allele was also statistically more frequent in the group of asthmatic boys (p = 0.009), but not in the group of asthmatic girls in comparison to the control subjects, male and female, respectively. The OR (95%CI) for carriers of T allele (Ile) was 1.88 (1.09-3.25) for patients with asthma. For the other three polymorphisms of ABP1 gene His645Asp polymorphism, no significant differences were in genotype distribution (p = 0.530) or allele frequencies (p = 0.412) between the asthmatic patients and the control group. The OR (95%CI) for carriers of ABP1 G variant (Asp) was 1.16 (0.70-1.76) in patients with asthma. No gender-specific differences were observed in our sample for the studied ABP1 polymorphism. Data were shown in table For the HNMT and ABP1 SNPs in regard to asthma-related phenotypes such as asthma severity, total IgE level, FEV1 and exNO measurement, however, no significant associations with any of the studied polymorphisms were observed (data not shown).We have also performed analysis of the HNMT polymorphisms, we found suggestive evidence for linkage between -1637C/T and -411C/T polymorphisms . However, comparing haplotype frequencies in this block, no significant differences were observed between the asthmatic patients and the control subjects . When we compared haplotype frequencies within this block, we observed that CT haplotype  was significantly more frequent in the group of asthmatic patients in comparison to the control subjects (p = 0.0046). However, this linkage seems unlikely, considering the distance between those two markers (37 kb) and observed association of CT haplotype with asthma probably depends only on the association of 314C/T polymorphism in our group.In linkage disequilibrium analysis for HNMT and ABP1 enzymes are involved in histamine metabolism, we analyzed both functional variants together (Thr105Ile of HNMT gene and His645Asp of ABP1 gene) to check if the two allelic variants responsible for reduced activity of both enzymes are more frequently observed in asthmatic patients. We have not found any statistically significant differences in frequencies of HNMT and ABP1 allelic variants combinations between the asthmatic patients and the control subjects (data not presented).As both HNMT gene with asthma in the Polish population of pediatric patients which may confirm that impaired histamine metabolism caused by reduced activity of HNMT is involved in asthma pathogenesis.The main finding of this study is an association of 314C/T polymorphism of HNMT gene was also involved in other disorders associated with altered histamine metabolism such as inflammatory bowel disease, neuronal degeneration and alcoholism as summarized by Garcia-Martin et al. [This common polymorphism responsible for Thr105Ile substitution was discovered by Preuss et al.  and it wn et al. , presentn et al. -19,21 foHNMT gene have been also reported [The other SNPs from the 5’-flanking region  as well as 3’UTR (939A/G and 1097A/T) of reported , howeverreported . For theABP1 polymorphisms, one contributing to His645Asp substitution (rs1049793) was found to be functional and was associated with significant decrease in the serum enzyme activity in vivo [Among several ion rs104793 was f in vivo . It is a in vivo . HoweverHNMT gene) might have arisen from insufficient sample size and power which is further supported by our demonstration that increasing sample size by combining data from different samples may be useful in validating the existing results by increasing power.The main limitation of the present study was the small sample size of the analyzed group. Our group (n = 149 asthmatic patients) is comparable to the group reported by Garcia-Martin   may influence the risk of asthma development.In conclusion, we report here an association of The authors declare that they have no competing interests.AS –participated in the study design, recruited the control group, performed genotyping and statistical analysis, participated in interpretation of the results and drafted the manuscript; AB – participated in the study design, recruited patients, collected clinical data; PS – recruited the patients, collected clinical data; AP – recruited the patients, collected clinical data. All authors read and approved the final manuscript.


Mortality of severe acute respiratory distress syndrome in adults is still unacceptably high. Extracorporeal membrane oxygenation (ECMO) could represent an important treatment option, if complications were reduced by new technical developments.Efficiency, side effects and outcome of treatment with a new miniaturized device for veno-venous extracorporeal gas transfer were analysed in 60 consecutive patients with life-threatening respiratory failure.2/FiO2) from 64 (48 to 86) mmHg to 120 (84 to 171) mmHg and a decrease of PaCO2 from 63 (50 to 80) mmHg to 33 (29 to 39) mmHg were observed after start of the extracorporeal support (P < 0.001). Gas exchange capacity of the device averaged 155 (116 to 182) mL/min for oxygen and 210 (164 to 251) mL/min for carbon dioxide. Ventilatory parameters were reduced to a highly protective mode, allowing a fast reduction of tidal volume from 495 (401 to 570) mL to 336 (292 to 404) mL (P < 0.001) and of peak inspiratory pressure from 36 (32 to 40) cmH2O to 31 (28 to 35) cmH2O (P < 0.001). Transfusion requirements averaged 0.8 (0.4 to 1.8) units of red blood cells per day. Sixty-two percent of patients were weaned from the extracorporeal system, and 45% survived to discharge.A rapid increase of partial pressure of arterial oxygen/fraction of inspired oxygen (PaOVeno-venous extracorporeal membrane oxygenation with a new miniaturized device supports gas transfer effectively, allows for highly protective ventilation and is very reliable. Modern ECMO technology extends treatment opportunities in severe lung failure. The estimated annual number of deaths due to acute lung injury was calculated as 74,500 for the US in a population-based study in 2005 . MortaliExtracorporeal membrane oxygenation (ECMO) has been advocated as rescue therapy in severe ARDS with presumed improved survival in specialized centres -7. HistoRecently, a new miniaturized system for long-term extracorporeal gas exchange has been approved in Europe. The small size of this device with reduced foreign surface combined with heparin-coating, a plasma-resistant membrane and improved pump technology decreases the need for systemic anticoagulation. Encouraging results in the treatment of pediatric patients  and adul2/FiO2 ratio of <85 mmHg and/or severe respiratory acidosis with a pH of <7.25 persisted, extracorporeal lung support was considered. In 10 patients proving too instable for transport, our mobile team implanted the portable veno-venous ECMO in the referring hospital. Patient characteristics before inclusion are specified in Table From April 2006 to December 2008, 60 patients with severe lung failure were treated with the new device in a veno-venous mode. The leading cause of lung failure was pneumonia; all diagnoses are listed in Table D, Maquet-Cardiopulmonary-AG) is made of polymethylpentene, which avoids plasma-leakage and has a total gas exchange surface of 1.8 m2 with a very low inherent resistance. The filling volume of the complete device is between 400 and 500 mL, depending on the length of the tubing. The whole system is coated with heparin, hence a pronounced systemic anticoagulation is unnecessary and a partial thromboplastin time (aPTT) of 1.5 normal is sufficient. Usually 100 mg/day of acetylsalicylic acid were given to inhibit platelet aggregation. Oxygen was used as sweep-gas with a flow of 1 to 12 L/min. Blood gas analysis was done with Radiometer-700 .The extracorporeal system consists of two venous cannulae, a centrifugal pump and a membrane oxygenator Figure . For out2 and pH, was used for calculation of carbon dioxide removal, as CO2 measurement in exhaust-gas, the preferable method, was not available.The oxygen transfer capacity of the ECMO was calculated by multiplying the difference of oxygen content pre and post ECMO with the blood flow. The approximated carbon dioxide content, calculated by the blood gas analyser with consideration of the Henderson-Hasselbalch equation, plasma-PCO2 of 75 mmHg and PaCO2 was adjusted to achieve a normal pH level. Accordingly, tidal volume (TV), minute ventilation (MV), inspiratory pressure (PIP) and fraction of inspired oxygen (FiO2) were decreased. Positive end-expiratory pressure (PEEP) was initially not reduced to avoid atelectasis due to small TV. A recommendation for substitution was given for a hemoglobin level below 8 g/dl.After implementation of the ECMO, invasiveness of ventilation was reduced to diminish further ventilator-induced lung injury (VILI). Goals for oxygenation were a PaO2 < 0.5, PEEP <10 cmH2O, PIP <27 cmH2O), extracorporeal blood flow was stepwise reduced to 1.5 L/min. Thereafter, gas flow was tapered and finally shut off for 30 minutes. If blood gases remained stable, the ECMO system was removed and decannulation with manual compression was carried out.After successful treatment of the underlying disease and improvement of lung function .Variables are reported as median and interquartile ranges, if not told otherwise, after testing for normal distribution with the Kolmogorov-Smirnov test. Nonparametric test procedures were used for paired analysis (Wilcoxon signed-rank test) and unpaired analysis (Mann-Whitney test). A A total of 60 patients with severe respiratory insufficiency were treated with the new miniaturized device, all but two fulfilling the definition of ARDS . The mosThirty-seven patients (62%) were successfully weaned from ECMO. Of these, 10 patients died during their further course in the intensive care unit; 30-day survival was 52%, and 27 patients (45%) survived to discharge. A significant difference between non-survivors and survivors was demonstrated for age, sequential organ failure assessment (SOFA) score and acute renal failure.2/FiO2 increased from 64 (48 to 86) mmHg to 120 (84 to 171) mmHg (P < 0.001). In parallel, PaCO2 decreased from 63 (50 to 80) mmHg to 33 (29 to 39) mmHg (P < 0.001) , despite a notable reduction in norepinephrine dose (P < 0.001).Within two hours a fast rise in oxygenation occurred. PaO) Figure  and 2b. Oxygen transfer by the device was calculated with 155 (116 to 182) mL/min after two hours and remained stable until the end of treatment Table . The max2 of 0.6 (0.55 to 0.70), a PIP of 30 (27 to 34) cmH2O and a TV of 4.8 (3.6 to 6.1) mL/kg of predicted BW . For every patient 9 (3 to15) red blood cell (RBC) concentrates, 4 (0 to 14) units of fresh frozen plasma (FFP) and 0 (0 to 4) platelet concentrates were transfused during the period on ECMO. The number of substituted blood products per day is displayed in Table Laboratory values before, during and after extracorporeal assist are presented in Table Complications during ECMO treatment are summarized in Table The most common cause for death was intractable septic shock and multiple organ failure (81%), generally despite sufficient oxygenation with ECMO, as can be seen in Table The current study presents for the first time the use of a new miniaturized system for extracorporeal membrane oxygenation in a large adult study population with severe ARDS. Crucial technical innovations, easy application and a limited number of side effects support its employment as a highly effective method to secure vital gas exchange and to reduce further VILI also in patients with an increased risk of hemorrhage.Lately, a meta-analysis suggested that mortality from ARDS may not have decreased since 1994 . Hence, 2/FiO2 of 63 mmHg, a LIS of 3.75 and a SOFA-score of 12.5, the survival rate in our study was 79%. In a retrospective analysis, older age, acute renal failure before initiation of ECMO therapy and a higher SOFA-score were predictors of a higher mortality  cross-over to the ECMO group would be allowed. Several questions remain unanswered. As mentioned before, the ideal hemoglobin-content on ECMO-treatment is currently not known. As ECMO can activate inflammation and coagulation cascades, a continuing effort to optimise biocompatibility is desirable.The present study has limitations. It is a single centre experience without a randomised control group. Comparison of mortality with a historical control group is biased, as general treatment of ARDS has changed substantially in the last decade. In the past mortality rates of >80% have been reported in severe ARDS . A prosp2/FiO2 as well as a rapid decrease in PaCO2 and normalization of pH resulted in a clearly more protective ventilation. Therefore, a reduction of VILI can be assumed and time was gained for lung healing. Labour resources are low, and serious technical complications were not encountered. Miniaturization and improved biocompatibility of ECMO will extend the indication for its employment from a rescue therapy at present to an effective therapeutic intervention to avoid injurious ventilator settings in ARDS in the future.The current miniaturized system enables extracorporeal lung support with more than 50% of total gas exchange. Improved oxygenator, tubing and centrifugal pump allow less systemic anticoagulation compared to earlier trials. The rate of hemorrhagic complications is markedly reduced, which makes its implementation possible in patients with a risk of bleeding and older age, which had been traditionally contraindications for ECMO therapy. A fast and sustained rise in PaO• The new miniaturized system for extracorporeal membrane oxygenation supports gas transfer in severe acute lung failure very effectively.• Due to crucial technical developments the need for systemic anticoagulation is lowered, allowing application in patients with a risk of hemorrhage.• Injurious ventilatory settings can be reduced rapidly to a highly protective mode.• Interhospital transport is possible without major effort.• Despite a low probability for survival, 62% of patients were weaned from the extracorporeal system, and 45% survived to discharge.2: fraction of inspired oxygen; LDH: lactic dehydrogenase; LIS: lung injury score; MAP: mean arterial pressure; MV: minute ventilation; PaCO2: partial pressure of arterial carbon dioxide; PaO2: partial pressure of arterial oxygen; PC: platelet concentrate; PEEP: positive end-exspiratory pressure; PIP: plateau inspiratory pressure; RBC: red blood cell concentrate; SOFA: sequential organ failure assessment; TV: tidal volume; VILI: ventilator induced lung injury.ALI: acute lung injury; aPTT: activated partial thromboplastin time; ARDS: acute respiratory distress syndrome; BMI: body mass index; BW: body weight; CESAR: Conventional ventilation or ECMO for Severe Adult Respiratory Failure; DIC: disseminated intravascular coagulopathy; ECMO: extracorporeal membrane oxygenation; ELSO: Extracorporeal Life Support Organization; FFP: fresh frozen plasma; FiODr. Müller has received lecture honoraria from Maquet CardioPulmonary Care, Germany. Mr. Philipp is Chief Perfusionist at the University Hospital Regensburg and a member of the technical advisory board of Maquet CardioPulmonary Care. Prof. Schmid has no conflicts of interest to disclose, but participated in speaking activities about va-ECMO. The remaining authors declare that they have no competing interests.TM has made important and substantial contributions to design, acquisition of data, analysis and interpretation of data and drafted the manuscript. AP, AL, CK, TB, LR, JL and ML have made substantial contributions to treatment of patients, acquisition of data, interpretation of data and revised the manuscript critically. JW has made substantial contribution to acquisition of data and analysis of data. MH, MZ, MA, CS, GR and MP have made substantial contribution to conception and design and interpretation of data.All authors revised the submitted article critically for important intellectual content and approved the final version.


A series of 56 consecutive patients, referred for surgery to a specialized institute, had elective laparotomies with various surgical procedures aimed at curing locoregional colorectal cancer. Data defining patient and tumour-related preoperative, operative and postoperative variables, including costs, were collected. The study group was divided into two age groups (< 65 vs > or = 65 years), which were similar in terms of patient- and tumour-related variables. Differences were not statistically significant . There is no evidence to suggest that there are any total charge differences in treating the two age groups, as confirmed by the cost analysis.


Systematic reviews can often reveal much more than the original objective of the work. The objectives of this retrospective analysis were to answer three basic questions about blood pressure variability: 1) Does blood pressure entry criterion have an effect on baseline blood pressure variability? 2) Do thiazide diuretics have a significant effect on blood pressure variability? and 3) Does systolic blood pressure vary to the same degree as diastolic blood pressure? This analysis of blood pressure variability is based on resting standardized research setting BP readings from two systematic reviews evaluating blood pressure lowering efficacy of thiazide diuretics from double blind randomized controlled trials in 33,611 patients with primary hypertension. The standard deviation reported in trials was the focus of the research and the unit of analysis. When a threshold systolic or diastolic blood pressure value is used to determine entry into a trial, baseline variability is significantly decreased, systolic from 14.0 to 9.3 mmHg and diastolic from 8.4 to 5.3 mmHg. Thiazides do not change BP variability as the standard deviation and coefficient of variation of systolic blood pressure and diastolic blood pressure did not differ between thiazide and placebo groups at end of treatment. The coefficient of variation of systolic blood pressure was significantly greater than the coefficient of variation of diastolic blood pressure. Entry criterion decreases the baseline blood pressure variability. Treatment with a thiazide diuretic does not affect blood pressure variability. Systolic blood pressure varies to a greater degree than diastolic blood pressure. Blood pressure (BP) measurements are highly variable. This is a fact that is commonly not appreciated and variability of blood pressure in an individual could be as important as the magnitude of the blood pressure. Measured blood pressure varies due to a large number of factors such as measurement technique, accuracy of equipment, and multiple patient factors such as anxiety. Even if these factors are controlled, blood pressure is subject to biological variation from beat to beat, minute to minute, and day to day. Each blood pressure measurement is therefore analogous to a single sample from a population of blood pressures. However, it is a patient's mean blood pressure over months and years that are thought to determine his or her risk of cardiovascular disease. In order to increase the precision of the estimated blood pressure, clinical diagnosis is based on the average of 2 to 3 measurements taken after resting for 5 minutes in a non-stimulating environment. Despite such standardized procedures, BP remains highly variable both within and between individuals. However, both this accepted fact and the ease of describing such variability are not well appreciated. Understanding to what extent BP is variable is very important since the large variability of BP impacts diagnosis of hypertension, clinical management of elevated BP and number of drugs prescribed to achieve “BP control”.BP variability has been shown to increase with increasing blood pressure and correlate with target-organ damage, independent of absolute BP values We have used the availability of a large amount of resting research setting BP data from 33,611 patients, accumulated as part of two systematic reviews, to answer whether thiazides affect BP variability and describe some other characteristics of BP variability The objective of this study was to use standard deviation data available from trials meeting the inclusion criteria of two systematic reviews to answer the following three questions about BP variability:Does blood pressure entry criterion have an effect on baseline BP variability?Do thiazide diuretics have a significant effect on BP variability?Does systolic blood pressure (SBP) vary to the same degree as diastolic blood pressure (DBP)?Standard Cochrane Hypertension Review group search strategies was applied and the following databases were used - Medline, EMBASE, and the Cochrane Clinical Trial Register from 1966–2000 for systematic review 1 and up to 1998 for systematic review 2 to identify trials meeting the inclusion criteria. References of previously published systematic reviews and bibliographic citations of included studies were used to identify any additional trials Review 1 –compared thiazide monotherapy with placebo for 3–12 weeks duration and Review 2 – compared thiazide as first-line therapy with placebo or untreated controls for at least one year of therapy Both reviews included double blind randomized controlled trials (RCTs) in adult patients with primary hypertension (defined as SBP ≥140 mm Hg and/or DBP ≥90 mm Hg without an identifiable cause). A total of 33 trials included in Review 1  and 16 trials included in Review 2  met the inclusion criteria for the primary objectives of the two systematic reviews In review 1 the resting baseline BP (mean of 3 readings) was 159/97 mm Hg and thiazide diuretic monotherapy as compared to placebo reduced SBP by −6.8(−7.7 to −5.9) mmHg and DBP by −4.7(−5.8 to −3.5) mm Hg over a mean duration of 8.8 weeks Trial entry criteria affected BP variability at baseline. When a threshold SBP level is part of or the sole entry criterion, baseline SBP variability as assessed by SD is significantly decreased from 14.0 to 9.3 mmHg. see .Only review 1 data could be used to answer this question as in review 2 other drugs besides thiazides were added For this analysis we used all the unconfounded measures of systolic BP variability and diastolic BP variability from both reviews. Systolic blood pressure SD as expected is greater than diastolic blood pressure SD. Comparing the variability of the two using CV showed the CV of SBP (9.2%) was significantly greater than CV of DBP (8.3%). The results are shown in We have demonstrated in this retrospective analysis that one of the main factors that affect blood pressure variability in the research setting is whether systolic or diastolic BP is used to decide whether the patient is eligible for entry into a trial. When diastolic blood pressure is used, it artificially reduces the variability of diastolic blood pressure at baseline. Similarly, if systolic blood pressure is used, it artificially reduces the variability of systolic blood pressure at baseline. In this assessment the magnitude of this effect in absolute terms is quite large (4.7 mmHg for SBP and 3.1 mmHg for DBP). Some reduction in variability for measures used as entry criteria is not that surprising as the distribution of baseline BP values is truncated at the threshold level of BP required for entry into the trial. However, the large magnitude of the effect suggests that it also reflects clustering of BP measurements at the threshold entry criterion level, an effect that is likely to reflect measurement bias. For example patients with blood pressure slightly below the required entry level might have their measurement increased by the researcher so that they meet the entry level and can be recruited into the trial. The HOT trial, one of the largest hypertension trials, is a good example of this phenomenon In contrast to the HOT trial the ALLHAT trial randomized 33,357 patients most of whom were selected because they were previously treated The most important question addressed in this analysis is whether thiazides have an effect on BP variability. Thiazides have been shown to lower blood pressure in many trials, but as far as we are aware nobody has asked or tested whether they have an effect on BP variability. If thiazides (or other antihypertensive treatments) lower or raise BP variability, this could be clinically useful or harmful, respectively. The data we have accumulated suggests that thiazides do not have much effect on BP variability. However, the lack of significance of BP variability between treated and control groups could reflect the absence of any real difference, or lack of power to show a difference. The small increase in both systolic and diastolic CV in the end-of-treatment thiazide group though not statistically significant, makes it probable that thiazides do not decrease BP variability and possible that they could increase BP variability. This should be tested with other databases and preferably databases where individual patient data are available. If there is an increase in variability associated with thiazide treatment it would be important to determine whether it was an increase in interpatient or intrapatient variability. It is particularly the setting of an increase in intrapatient variability that an antihypertensive therapy could increase risk to patients.Systolic and diastolic BP measurements are dependent on each other; however, there are physiologic settings where systolic BP rises more than diastolic such as during exercise and as muscular arteries lose their elasticity as a part of normal aging. In clinical trials, resting blood pressure is measured in a standardized way. We are not aware of other settings where the variability of systolic and diastolic blood pressure has been directly compared using the coefficient of variation (the mean measurement divided by the SD). In this case we have used all the unconfounded estimates of systolic BP and compared them with all the unconfounded estimates of diastolic BP to increase the chance of showing a difference. In the event the systolic CV was statistically significantly greater than the diastolic CV. This may reflect a true physiological difference. However, it is more likely due to an artifact of the method of measurement. In this case measurements were auscultatory using a mercury manometer. This means that the systolic BP is measured first and the diastolic BP is measured after a short delay. Because of this difference in timing of the two measures patient factors could contribute to the difference in variability e.g. Patients are more relaxed as the pressure in the cuff decreases. Alternatively, it is easier to accurately measure systolic blood pressure (appearance of first Korotkoff sounds) than diastolic blood pressure (disappearance of Korotkoff sounds). Thus the difficulty in detecting the disappearance could lead to a greater likelihood of guessing, which would be expected to artificially lower the variability of diastolic blood pressure. It will be important to repeat this analysis with other data and in other settings. For example a study of blood pressures measured with automatic BP machines using an oscillometric technique may not show a difference in variability of systolic and diastolic blood pressure, thus providing evidence in favor of this being an artificial difference caused by the technique of measurement. Whatever the explanation for the statistically greater variability of systolic blood pressure the magnitude of the increase in variability is small and probably not clinically significant. We do not think that it is a reason to suggest that diastolic blood pressure is a more reliable measure.In conclusion, systematic reviews can often reveal much more than the original objective of the work. Blood pressure variability as estimated by SD is an important measure and researchers in the area should be familiar with the average magnitude of that variability, 14 mmHg for systolic and 8 mmHg for diastolic, and the factors that can affect it. The impact of the large variability of SBP/DBP needs to be taken in to account when hypertension is diagnosed and when considering what represents “BP control” under treatment.Most importantly, we need to learn more about the relationship between BP variability and cardiovascular outcomes plus the effect of specific drug treatments on blood pressure variability. We believe that BP variability is a neglected but important measure that deserves more attention.