The association between admission systolic blood pressure and mortality in significant traumatic brain injury: A multi-centre cohort study

INTRODUCTION Low systolic blood pressure (SBP) is an important secondary insult following traumatic brain injury (TBI), but its exact relationship with outcome is not well characterised. Although a SBP of <90mmHg represents the threshold for hypotension in consensus TBI treatment guidelines, recent studies suggest redefining hypotension at higher levels. This study therefore aimed to fully characterise the association between admission SBP and mortality to further inform resuscitation endpoints. METHODS We conducted a multicentre cohort study using data from the largest European trauma registry. Consecutive adult patients with AIS head scores >2 admitted directly to specialist neuroscience centres between 2005 and July 2012 were studied. Multilevel logistic regression models were developed to examine the association between admission SBP and 30 day inpatient mortality. Models were adjusted for confounders including age, severity of injury, and to account for differential quality of hospital care. RESULTS 5057 patients were included in complete case analyses. Admission SBP demonstrated a smooth u-shaped association with outcome in a bivariate analysis, with increasing mortality at both lower and higher values, and no evidence of any threshold effect. Adjusting for confounding slightly attenuated the association between mortality and SBP at levels <120mmHg, and abolished the relationship for higher SBP values. Case-mix adjusted odds of death were 1.5 times greater at <120mmHg, doubled at <100mmHg, tripled at <90mmHg, and six times greater at SBP<70mmHg, p<0.01. CONCLUSIONS These findings indicate that TBI studies should model SBP as a continuous variable and may suggest that current TBI treatment guidelines, using a cut-off for hypotension at SBP<90mmHg, should be reconsidered.

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

Ubiquitylation plays an important role in the control of Na⁺ homeostasis by the kidney. It is well established that the epithelial Na⁺ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney and is also a circadian output gene. In heterologous expression systems, USP2-45 binds to ENaC, deubiquitylates it, and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na⁺ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences from wild-type littermates with respect to the diurnal control of Na⁺ or K⁺ urinary excretion and plasma levels either on a standard diet or after acute and chronic changes to low- and high-Na⁺ diets, respectively. Moreover, they had similar aldosterone levels on either a low- or high-Na⁺ diet. Blood pressure measurements using telemetry did not reveal variations compared with control mice. Usp2-KO mice did not display alterations in expression of genes involved in sodium homeostasis or the ubiquitin system, as evidenced by transcriptome analysis in the kidney. Our data suggest that USP2 does not play a primary role in the control of Na⁺ balance or blood pressure.

Risk of Cardiovascular Events and Blood Pressure Control in Hypertensive HIV-Infected Patients: HIV Cohort Study (SHCS)

Background: Prevalence of hypertension in HIV infection is high, and information on blood pressure control in HIV-infected individuals is insufficient. We modeled blood pressure over time and the risk of cardiovascular events in hypertensive HIV-infected individuals. Methods: All patients from the Swiss HIV Cohort Study with confirmed hypertension (systolic or diastolic blood pressure above 139 or 89 mm Hg on 2 consecutive visits and presence of at least 1 additional cardiovascular risk factor) between April 1, 2000 and March 31, 2011 were included. Patients with previous cardiovascular events, already on antihypertensive drugs, and pregnant women were excluded. Change in blood pressure over time was modeled using linear mixed models with repeated measurement. Results: Hypertension was diagnosed in 2595 of 10,361 eligible patients. Of those, 869 initiated antihypertensive treatment. For patients treated for hypertension, we found a mean (95% confidence interval) decrease in systolic and diastolic blood pressure of −0.82 (−1.06 to −0.58) mm Hg and −0.89 (−1.05 to −0.73) mm Hg/yr, respectively. Factors associated with a decline in systolic blood pressure were baseline blood pressure, presence of chronic kidney disease, cardiovascular events, and the typical risk factors for cardiovascular disease. In patients with hypertension, increase in systolic blood pressure [(hazard ratio 1.18 (1.06 to 1.32) per 10 mm Hg increase], total cholesterol, smoking, age, and cumulative exposure to protease inhibitor–based and triple nucleoside regimens were associated with cardiovascular events. Conclusions: Insufficient control of hypertension was associated with increased risk of cardiovascular events indicating the need for improved management of hypertension in HIV-infected individuals.

Effects of weight on blood pressure at rest and during exercise.

Body weight (BW) and blood pressure (BP) have a close relationship, which has been accounted for by hormonal changes. No previous study has evaluated the effect of wearing an external weight vest on BP to determine whether there is a simple mechanism between BW and BP. Seventeen healthy volunteers underwent weight reduction (WR) through caloric restriction. Before and after WR, BW, body fat percentage and BP at rest and during exercise were measured. Before and after WR, exercise testing was performed twice with the random allocation of a weight vest (10 kg) during one of the tests. Linear regression was used to detect independent associations between BP and the weight vest, BW and body fat percentage. BW decreased from 89.4 ± 15.4 kg to 79.1 ± 14.0 kg following WR (P<0.001). WR led to significant decreases in BP at rest (from 130.0/85.9 mm Hg to 112.5/77.8 mm Hg, P<0.001 for systolic and diastolic BPs) and during exercise. The weight vest significantly increased BP at rest (to 136.1/90.7 mm Hg before and 125.8/84.6 mm Hg after WR) and during exercise. Linear regression analysis identified an independent association between the weight vest and BP (P=0.006 for systolic BP and P=0.009 for diastolic BP at rest). This study demonstrates that wearing an external weight vest has immediate effects on BP at rest and during exercise independent of BW or body fat. More research is needed to understand the physiological mechanisms between weight and BP.

Genes to blood pressure: The effects of variation in genes of the renin-angiotensin system on the hormonal and renal control of blood pressure

Objective. Essential hypertension affects 25% of the US adult population and is a leading contributor to morbidity and mortality. Because BP is a multifactorial phenotype that resists simple genetic analysis, intermediate phenotypes within the complex network of BP regulatory systems may be more accessible to genetic dissection. The Renin-Angiotensin System (RAS) is known to influence intermediate and long-term blood pressure regulation through alterations in vascular tone and renal sodium and fluid resorption. This dissertation examines associations between renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1) gene variation and interindividual differences in plasma hormone levels, renal hemodynamics, and BP homeostasis.^ Methods. A total of 150 unrelated men and 150 unrelated women, between 20.0 and 49.9 years of age and free of acute or chronic illness except for a history of hypertension (11 men and 7 women, all off medications), were studied after one week on a controlled sodium diet. RAS plasma hormone levels, renal hemodynamics and BP were determined prior to and during angiotensin II (Ang II) infusion. Individuals were genotyped by PCR for a variable number tandem repeat (VNTR) polymorphism in REN, and for the following restriction fragment length polymorphisms (RFLP): AGT M235T, ACE I/D, and AT1 A1166C. Associations between clinical measurements and allelic variation were examined using multiple linear regression statistical models.^ Results. Women homozygous for the AT1 1166C allele demonstrated higher intracellular levels of sodium (p = 0.044). Men homozygous for the AGT T235 allele demonstrated a blunted decrement in renal plasma flow in response to Ang II infusion (p = 0.0002). There were no significant associations between RAS gene variation and interindividual variation in RAS plasma hormone levels or BP.^ Conclusions. Rather than identifying new BP controlling genes or alleles, the study paradigm employed in this thesis (i.e., measured genes, controlled environments and interventions) may provide mechanistic insight into how candidate genes affect BP homeostasis. ^

Contribution of the genes of the renin-angiotensin system to interindividual differences in blood pressure levels in Caucasians from Rochester, Minnesota

The Renin-Angiotensin system (RAS) regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. The genes encoding the four major components of the RAS, angiotensinogen, renin, angiotensin I-converting enzyme (ACE), and angiotensin II receptor type 1 (AT1), have been investigated as candidate genes in the pathogenesis of essential hypertension. However, studies have primarily focused on small samples of diseased individuals, and, therefore, have provided little information about the determinants of interindividual variation in blood pressure (BP) in the general population.^ Using data from a large population-based sample from Rochester, MN, I have evaluated the contribution of variation in the region of the RAS genes to interindividual variation in systolic, diastolic, and mean arterial pressure in the population-at-large. Marker genotype data from four polymorphisms located within or very near these genes were first collected on 3,974 individuals from 583 randomly ascertained three-generation pedigrees. Haseman-Elston regression and variance component methods of linkage analysis were then carried out to estimate the proportion of interindividual variance in BP attributable to the effects of variation at these four measured loci.^ A significant effect of the ACE locus on interindividual variation in mean arterial pressure (MAP) was detected in a sample of siblings belonging to the youngest generation. After allowing for measured covariates, this effect accounted for 15-25% of the interindividual variance in MAP, and was even greater in a subset with a positive family history of hypertension. When gender-specific analyses were carried out, this effect was significant in males but not in females. Extended pedigree analyses also provided evidence for an effect of the ACE locus on interindividual variation in MAP, but no difference between males and females was observed. Circumstantial evidence suggests that the ACE gene itself may be responsible for the observed effects on BP, although the possibility that other genes in the region may be at play cannot be excluded.^ No definitive evidence for an effect of the renin, angiotensinogen, or AT1 loci on interindividual variation in BP was obtained in this study, suggesting that the impact of these genes on BP may not be great in the Caucasian population-at-large. However, this does not preclude a larger effect of these genes in some subsets of individuals, especially among those with clinically manifest hypertension or coronary heart disease, or in other populations. ^

Evaluation of androgenicity, abdominal adiposity, blood pressure and types of ovulatory patterns in a sample of women with menstrual irregularities

Objective: To determine the prevalence of and the relationships between the degree and source of hyperandrogenemia, ovulatory patterns and cardiovascular disease risk indicators (blood pressure, indices or amount of obesity and fat distribution) in women with menstrual irregularities seen at endocrinologists' clinic. Design: A cross-sectional study design. Participants: A sample of 159 women with menstrual irregularities, aged 15-44, seen at endocrinologists' clinic. Main Outcome Measures: androgen levels, body mass index (BMI), waist-hip ratio (WHR), systolic and diastolic blood pressure (SBP & DBP), source of androgens, ovulatory activity. Results: The prevalence of hyperandrogenemia was 54.7% in this study sample. As expected, women with acne or hirsutism had an odds ratio 12.5 (95%CI = 5.2-25.5) times and 36 (95%CI = 12.9-99.5) times more likely to have hyperandrogenemia than those without acne or hirsutism. The main findings of this study were the following: Hyperandrogenemic women were more likely to have oligomenorrheic cycles (OR = 3.8, 95%CI = 1.5-9.9), anovulatory cycles (OR = 6.6, 95%CI = 2.8-15.4), general obesity (BMI $\ge$ 27) (OR = 6.8, 95%CI = 2.2-27.2) and central obesity (WHR $\ge$ 127) (OR = 14.5, 95%CI = 6.1-38.7) than euandrogenemic women. Hyperandrogenemic women with non-suppressible androgens had a higher mean BMI (29.3 $\pm$ 8.9) than those with suppressible androgens (27.9 $\pm$ 7.9); the converse was true for abdominal adiposity (WHR). Hyperandrogenemic women had a 2.4 odds ratio (95%CI = 1.0-6.2) for an elevated SBP and a 2.7 odds ratio (95%CI = 0.8-8.8) for elevated DBP. When age differences were accounted for, this relationship was strengthened and further strengthened when sources of androgens were controlled. When the differences in BMI were controlled, the odds ratio for elevated SBP in hyperandrogenemic women increased to 8.8 (95%CI = 1.1-69.9). When the age, the source of androgens, the amount of obesity and the type of obesity were controlled, hyperandrogenemic women had 13.5 (95%CI = 1.1-158.9) odds ratio for elevated SBP. Conclusions: In this study population, the presence of menstrual irregularities are highly predictive for the presence of elevated androgens. Women with elevated androgens have a high risk for obesity, more specifically for central obesity. The androgenemic status is an independent predictor of blood pressure elevation. It is probable that in the general population, the presence of menstrual irregularities are predictive of hyperandrogenemia. There is a great need for a population study of the prevalence of hyperandrogenemia and for longitudinal studies in hyperandrogenemic women (adrenarche to menopause) to investigate the evolution of these relationships. ^

Non-invasive and non-occlusive blood pressure estimation via a chest sensor

The clinical demand for a device to monitor Blood Pressure (BP) in ambulatory scenarios with minimal use of inflation cuffs is increasing. Based on the so-called Pulse Wave Velocity (PWV) principle, this paper introduces and evaluates a novel concept of BP monitor that can be fully integrated within a chest sensor. After a preliminary calibration, the sensor provides non-occlusive beat-by-beat estimations of Mean Arterial Pressure (MAP) by measuring the Pulse Transit Time (PTT) of arterial pressure pulses travelling from the ascending aorta towards the subcutaneous vasculature of the chest. In a cohort of 15 healthy male subjects, a total of 462 simultaneous readings consisting of reference MAP and chest PTT were acquired. Each subject was recorded at three different days: D, D+3 and D+14. Overall, the implemented protocol induced MAP values to range from 80 ± 6 mmHg in baseline, to 107 ± 9 mmHg during isometric handgrip maneuvers. Agreement between reference and chest-sensor MAP values was tested by using intraclass correlation coefficient (ICC = 0.78) and Bland-Altman analysis (mean error = 0.7 mmHg, standard deviation = 5.1 mmHg). The cumulative percentage of MAP values provided by the chest sensor falling within a range of ±5 mmHg compared to reference MAP readings was of 70%, within ±10 mmHg was of 91%, and within ±15mmHg was of 98%. These results point at the fact that the chest sensor complies with the British Hypertension Society (BHS) requirements of Grade A BP monitors, when applied to MAP readings. Grade A performance was maintained even two weeks after having performed the initial subject-dependent calibration. In conclusion, this paper introduces a sensor and a calibration strategy to perform MAP measurements at the chest. The encouraging performance of the presented technique paves the way towards an ambulatory-compliant, continuous and non-occlusive BP monitoring system.

Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function.

INTRODUCTION: The objective of this study was to evaluate the effects of two different mean arterial blood pressure (MAP) targets on needs for resuscitation, organ dysfunction, mitochondrial respiration and inflammatory response in a long-term model of fecal peritonitis. METHODS: Twenty-four anesthetized and mechanically ventilated pigs were randomly assigned (n = 8/group) to a septic control group (septic-CG) without resuscitation until death or one of two groups with resuscitation performed after 12 hours of untreated sepsis for 48 hours, targeting MAP 50-60 mmHg (low-MAP) or 75-85 mmHg (high-MAP). RESULTS: MAP at the end of resuscitation was 56 ± 13 mmHg (mean ± SD) and 76 ± 17 mmHg respectively, for low-MAP and high-MAP groups. One animal each in high- and low-MAP groups, and all animals in septic-CG died (median survival time: 21.8 hours, inter-quartile range: 16.3-27.5 hours). Norepinephrine was administered to all animals of the high-MAP group (0.38 (0.21-0.56) mcg/kg/min), and to three animals of the low-MAP group (0.00 (0.00-0.25) mcg/kg/min; P = 0.009). The high-MAP group had a more positive fluid balance (3.3 ± 1.0 mL/kg/h vs. 2.3 ± 0.7 mL/kg/h; P = 0.001). Inflammatory markers, skeletal muscle ATP content and hemodynamics other than MAP did not differ between low- and high-MAP groups. The incidence of acute kidney injury (AKI) after 12 hours of untreated sepsis was, respectively for low- and high-MAP groups, 50% (4/8) and 38% (3/8), and in the end of the study 57% (4/7) and 0% (P = 0.026). In septic-CG, maximal isolated skeletal muscle mitochondrial Complex I, State 3 respiration increased from 1357 ± 149 pmol/s/mg to 1822 ± 385 pmol/s/mg, (P = 0.020). In high- and low-MAP groups, permeabilized skeletal muscle fibers Complex IV-state 3 respiration increased during resuscitation (P = 0.003). CONCLUSIONS: The MAP targets during resuscitation did not alter the inflammatory response, nor affected skeletal muscle ATP content and mitochondrial respiration. While targeting a lower MAP was associated with increased incidence of AKI, targeting a higher MAP resulted in increased net positive fluid balance and vasopressor load during resuscitation. The long-term effects of different MAP targets need to be evaluated in further studies.

Re-thinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach

Definitions of shock and resuscitation endpoints traditionally focus on blood pressures and cardiac output. This carries a high risk of overemphasizing systemic hemodynamics at the cost of tissue perfusion. In line with novel shock definitions and evidence of the lack of a correlation between macro- and microcirculation in shock, we recommend that macrocirculatory resuscitation endpoints, particularly arterial and central venous pressure as well as cardiac output, be reconsidered. In this viewpoint article, we propose a three-step approach of resuscitation endpoints in shock of all origins. This approach targets only a minimum individual and context-sensitive mean arterial blood pressure (for example, 45 to 50 mm Hg) to preserve heart and brain perfusion. Further resuscitation is exclusively guided by endpoints of tissue perfusion irrespectively of the presence of arterial hypotension ('permissive hypotension'). Finally, optimization of individual tissue (for example, renal) perfusion is targeted. Prospective clinical studies are necessary to confirm the postulated benefits of targeting these resuscitation endpoints.

Response of day-to-day home blood pressure variability by antihypertensive drug class after transient ischemic attack or nondisabling stroke.

BACKGROUND AND PURPOSE Visit-to-visit variability in systolic blood pressure (SBP) is associated with an increased risk of stroke and was reduced in randomized trials by calcium channel blockers and diuretics but not by renin-angiotensin system inhibitors. However, time of day effects could not be determined. Day-to-day variability on home BP readings predicts stroke risk and potentially offers a practical method of monitoring response to variability-directed treatment. METHODS SBP mean, maximum, and variability (coefficient of variation=SD/mean) were determined in 500 consecutive transient ischemic attack or minor stroke patients on 1-month home BP monitoring (3 BPs, 3× daily). Hypertension was treated to a standard protocol. Differences in SBP variability from 3 to 10 days before to 8 to 15 days after starting or increasing calcium channel blockers/diuretics versus renin-angiotensin system inhibitors versus both were compared by general linear models, adjusted for risk factors and baseline BP. RESULTS Among 288 eligible interventions, variability in SBP was reduced after increased treatment with calcium channel blockers/diuretics versus both versus renin-angiotensin system inhibitors (-4.0 versus 6.9 versus 7.8%; P=0.015), primarily because of effects on maximum SBP (-4.6 versus -1.0 versus -1.0%; P=0.001), with no differences in effect on mean SBP. Class differences were greatest for early-morning SBP variability (3.6 versus 17.0 versus 38.3; P=0.002) and maximum (-4.8 versus -2.0 versus -0.7; P=0.001), with no effect on midmorning (P=0.29), evening (P=0.65), or diurnal variability (P=0.92). CONCLUSIONS After transient ischemic attack or minor stroke, calcium channel blockers and diuretics reduced variability and maximum home SBP, primarily because of effects on morning readings. Home BP readings enable monitoring of response to SBP variability-directed treatment in patients with recent cerebrovascular events.