Managing obesity in primary care practice: an overview with perspective from the POWER-UP study.

Primary care practitioners (PCPs) have been encouraged to screen all adults for obesity and to offer behavioral weight loss counseling to the affected individuals. However, there is limited research and guidance on how to provide such intervention in primary care settings. This led the National Heart, Lung and Blood Institute in 2005 to issue a request for applications to investigate the management of obesity in routine clinical care. Three institutions were funded under a cooperative agreement to undertake the practice-based opportunities for weight reduction (POWER) trials. The present article reviews selected randomized controlled trials, published before the initiation of POWER, and then provides a detailed overview of the rationale, methods and results of the POWER trial conducted at the University of Pennsylvania (POWER-UP). POWER-UP's findings are briefly compared with those from the two other POWER trials, conducted at Johns Hopkins University and Harvard University/Washington University. The methods of delivering behavioral weight loss counseling differed markedly across the three trials, as captured by an algorithm presented in the article. Delivery methods ranged from having medical assistants and PCPs from the practices provide counseling to using a commercially available call center, coordinated with an interactive website. Evaluation of the efficacy of primary care-based weight loss interventions must be considered in light of costs, as discussed in relation to the recent treatment model proposed by the Centers for Medicare and Medicaid Services.

Cost-effectiveness of a primary care intervention to treat obesity.

BACKGROUND: Data on the cost-effectiveness of the behavioral treatment of obesity are not conclusive. The cost-effectiveness of treatment in primary care settings is particularly relevant. METHODS: We conducted a within-trial cost-effectiveness analysis of a primary care-based obesity intervention. Study participants were randomized to: Usual Care (UC; quarterly visits with their primary care provider); Brief Lifestyle Counseling (BLC; quarterly provider visits plus monthly weight loss counseling visits) or Enhanced Brief Lifestyle Counseling (EBLC; all above interventions, plus choice of meal replacements or weight loss medication). A health-care payer perspective was used. Intervention costs were estimated from tracking data obtained prospectively. Quality-adjusted life years (QALYs) were estimated with the EuroQol-5D. We estimated cost per kilogram-year of weight loss and cost per QALY. RESULTS: Weight losses after 2 years were 1.7, 2.9 and 4.6 kg for UC, BLC and EBLC, respectively (P=0.003 for comparison of EBLC vs UC). The incremental cost per kilogram-year lost was $292 for EBLC compared with UC (95% confidence interval (CI): $219-$437). The short-term incremental cost per QALY was $115,397, but the 95% CI were undefined. Comparison of short-term cost per kg with published estimates of longer-term cost per QALY suggested that the intervention could be cost-effective over the long term (≥ 10 years). CONCLUSIONS: A primary care intervention that includes monthly counseling visits and a choice of meal replacements or weight loss medication could be a cost-effective treatment for obesity over the long term. However, additional studies are needed on the cost-effectiveness of behavioral treatment of obesity.

Relation of health-related quality of life to metabolic syndrome, obesity, depression and comorbid illnesses.

BACKGROUND: Metabolic syndrome has been associated with impaired health-related quality of life (HRQoL) in several studies. Many studies used only one HRQoL measure and failed to adjust for important confounding variables, including obesity, depression and comorbid conditions. OBJECTIVE: To investigate the relationship between metabolic syndrome and HRQoL using multiple measures. We also sought to determine whether increasing body mass index or diabetes status further modified this relationship. METHODS: This cross-sectional study included 390 obese participants with elevated waist circumference and at least one other criterion for metabolic syndrome. Of these 390 participants, 269 had metabolic syndrome (that is, they met 3 out of the 5 criteria specified by the NCEP (National Cholesterol Education Program)) and 121 did not. Participants were enrolled in a primary care-based weight-reduction trial. HRQoL was assessed using two generic instruments, the Medical Outcomes Study Short-Form 12 and the EuroQol-5D, as well as an obesity-specific measure, the Impact of Weight on Quality of Life. Differences in HRQoL were compared among participants with and without metabolic syndrome. Multivariable linear regression was used to determine how HRQoL varied according to metabolic syndrome status, and whether factors including weight, depression and burden of comorbid disease modified this relationship. RESULTS: Metabolic syndrome was not associated with HRQoL as assessed by any of the measures. In univariable analysis, depression, disease burden and employment status were significantly associated with worse HRQoL on all instruments. In multivariable models, only depression remained significantly associated with reduced HRQoL on all measures. Increasing obesity and diabetes status did not modify the relationship between metabolic syndrome and HRQoL. CONCLUSION: In contrast to previous studies, metabolic syndrome was not associated with impaired HRQoL as assessed by multiple measures. This suggests that metabolic syndrome in itself is not associated with decreased HRQoL, but other factors such as obesity, depression and greater disease burden may significantly influence the quality of life in this population.

Interpreting weight losses from lifestyle modification trials: using categorical data.

Although studies in obese subjects using weight loss medications typically report mean and categorical weight loss, results from diet and exercise intervention trials typically only report mean weight change from baseline along with a level of significance. These data alone do not give clinicians or administrators the data needed to determine the probability that an individual will achieve clinically relevant weight loss. Thus, it is difficult to decide which patients, employees or health plan enrollee would benefit from the type and level of support used in a clinical trial. Our goal was to assess what fraction of subjects enrolled in lifestyle modification interventions achieved clinically significant weight loss. Thus, we requested categorical weight loss data from several investigators who had published results from studies involving either a high- or low-intensity lifestyle modification intervention arm. These categorical data indicate that a substantial fraction of subjects in each lifestyle modification intervention achieved clinically meaningful weight loss, even when the average weight loss is modest.

Evidence of a gap in understanding obesity among physicians.

Background: Experience suggests that some physicians view obesity as a purely lifestyle condition rather than a chronic metabolic disease. Physicians may not be aware of the role of biological factors in causing weight regain after an initial weight loss. Methods: A questionnaire was administered at continuing medical education conferences, both primary care and obesity-specific. The questionnaire included items about biological and behavioral factors that predispose to weight regain and general items about treatment of obesity. The sample was separated into primary care physicians (PCPs) and physicians preparing for the obesity medicine (OMs) exam. Results: Among all respondents, behavioral factors were given higher importance ratings, relative to biological factors in causing weight regain. Respondents rated behaviour modification as more effective, relative to medications or surgery to treat obesity. OMs gave higher importance ratings to biological factors, relative to PCPs. OMs also gave higher effectiveness ratings for medications and surgery, relative to PCPs. However, even OMs gave higher effectiveness ratings for behaviour modification, relative to medications or surgery. Respondents who reported a belief in the role of behavioral factors rated lifestyle modification as more effective. Respondents who reported a belief in both behavioral and biological factors rated medications as more effective. Conclusions: Physicians rate biological factors as less important, relative to behavioral factors in causing weight regain. Physicians rate medications and surgery as less effective, relative to lifestyle modification alone. Belief in the importance of behavioral factors correlated with a higher effectiveness rating for lifestyle modification. A better understanding of the biological basis for weight regain may help to increase comfort with the use of biological treatments for obesity.

Beneficial effects due to increasing blood and plasma viscosity.

Increased plasma and blood viscosity are usually associated with pathological conditions; however there are several situations in which the elevation of both parameters results in increased perfusion and the lowering of peripheral vascular resistance. In extreme hemodilution blood viscosity is too low and insufficient to maintain functional capillary density, a problem that in experimental studies is shown to be corrected by increasing plasma viscosity up to 2.2 cP. This effect is mediated by Nitric oxide (NO) production via restoration of shear stress at the endothelium as shown by microelectrode perivascular measurements of NO concentration. Moderate elevations of blood viscosity by increasing hematocrit (approximately 10% of baseline) result in reductions of blood pressure by 10 mmHg of baseline. This effect is also NO mediated since it is absent after N-nitro-L-arginine methyl ester (L-NAME) treatment and in endothelial NO synthase deficient mice. These results show that the rheological properties of plasma affect vessel diameter in the microcirculation leading to counterintuitive responses to the increase in viscosity.

High viscosity plasma expanders: Volume restitution fluids for lowering the transfusion trigger.

Hemorheological studies lead to the axiom that high plasma viscosity is detrimental and that it is beneficial to lower blood viscosity, a precept embodied in the practice of hemodilution, where improved perfusion is attributed to the lowering of blood viscosity. Hemodilution is limited by the transfusion trigger, hemoglobin content of blood of about 7-8 g/dl, which indicates when further volume replacements must restore oxygen carrying capacity with red blood cells (RBC). However, oxygen consumption and delivery are not compromised upon passing this landmark. The reduced blood viscosity does not transmit adequate pressure to the capillaries, causing functional capillary density (FCD) to decrease, jeopardizing organ function through the inadequate extraction of products of metabolism from the tissue by the capillaries. Studies in hemorrhagic shock show that survival is primarily determined by the maintenance of FCD and secondarily by tissue oxygenation. FCD is maintained as hematocrit is reduced beyond the transfusion trigger by increasing plasma viscosity, which transmits systemic pressure to the capillaries and induces vasodilatation through the increased shear stress dependent release of vasodilators. Consequently the transfusion trigger is also a "viscosity trigger" indicating when blood and plasma viscosity are too low. In this condition increasing plasma viscosity is beneficial and extends the transfusion trigger reducing the use of blood transfusions.

Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function.

BACKGROUND: Heparanase is the major enzyme involved in degradation of endothelial heparan sulfates, which is associated with impaired endothelial nitric oxide synthesis. However, the effect of heparan sulfate chain length in relation to endothelial function and nitric oxide availability has never been investigated. We studied the effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo. METHODS AND RESULT: Flow-mediated dilation, a marker of nitric oxide bioavailability, was studied in Ext1(+/-) and Ext2(+/-) mice versus controls (n=7 per group), as well as in human subjects with heterozygous loss of function mutations in EXT1 and EXT2 (n=13 hereditary multiple exostoses and n=13 controls). Endothelial function was measured in microvascular endothelial cells under laminar flow with or without siRNA targeting EXT1 or EXT2. Endothelial glycocalyx and maximal arteriolar dilatation were significantly altered in Ext1(+/-) and Ext2(+/-) mice compared to wild-type littermates (glycocalyx: wild-type 0.67±0.1 µm, Ext1(+/-) 0.28±0.1 µm and Ext2(+/-) 0.25±0.1 µm, P<0.01, maximal arteriolar dilation during reperfusion: wild-type 11.3±1.0%), Ext1(+/-) 15.2±1.4% and Ext2(+/-) 13.8±1.6% P<0.05). In humans, brachial artery flow-mediated dilation was significantly increased in hereditary multiple exostoses patients (hereditary multiple exostoses 8.1±0.8% versus control 5.6±0.7%, P<0.05). In line, silencing of microvascular endothelial cell EXT1 and EXT2 under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho-endothelial nitric oxide synthesis protein expression. CONCLUSIONS: Our data implicate that heparan sulfate elongation genes EXT1 and EXT2 are involved in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability.

Impact of enzymatic degradation of the endothelial glycocalyx on vascular permeability in an awake hamster model.

Background. The inside of the endothelium is covered by a glycocalyx layer, and enzymatic degradation of this layer induces vascular leakage ex vivo. We hypothesized that enzymatic degrading of the glycocalyx in an in vivo, whole body model, would induce plasma leakage and affect the microcirculation. Methods. Golden Syrian hamsters were divided into an enzyme (hyaluronidase) and a control group. Mean arterial pressure (MAP), heart rate (HR), hematocrit (Hct), base excess (BE), and plasma volume were obtained before, 45 and 120 min after enzyme/saline treatment. Plasma volume was evaluated by the distribution volume of indocyanine green and the microcirculation by functional capillary density (FCD). The enzymatic effect was determined by measuring plasma levels of hyaluronan (HA). Results. There were no differences in MAP, HR, Hct, and BE between the two groups. Enzyme treatment did not induce changes in plasma volume but reduced FCD. There was a 50-100-fold increase in plasma HA, but no relationship was found between HA levels and plasma volume or FCD. Conclusion. Vascular leakage was not confirmed in an in vivo, whole body model after degradation of the endothelial glycocalyx. The microcirculation was affected, but no relationship between plasma levels of HA and FCD was seen.

Direct medical cost of overweight and obesity in the USA: a quantitative systematic review.

To estimate per-person and aggregate direct medical costs of overweight and obesity and to examine the effect of study design factors. PubMed (1968-2009), EconLit (1969-2009) and Business Source Premier (1995-2009) were searched for original studies. Results were standardized to compute the incremental cost per overweight person and per obese person, and to compute the national aggregate cost. A total of 33 US studies met review criteria. Among the four highest-quality studies, the 2008 per-person direct medical cost of overweight was $266 and of obesity was $1723. The aggregate national cost of overweight and obesity combined was $113.9 billion. Study design factors that affected cost estimates included use of national samples vs. more selected populations, age groups examined, inclusion of all medical costs vs. obesity-related costs only, and body mass index cut-offs for defining overweight and obesity. Depending on the source of total national healthcare expenditures used, the direct medical cost of overweight and obesity combined is approximately 5.0% to 10% of US healthcare spending. Future studies should include nationally representative samples, evaluate adults of all ages, report all medical costs and use standard body mass index cut-offs.

Cardiovascular benefits in moderate increases of blood and plasma viscosity surpass those associated with lowering viscosity: Experimental and clinical evidence.

Decreasing blood viscosity has been proposed since the advent of hemodilution as a means for increasing perfusion in many pathological conditions, and increased plasma viscosity is associated with the presence of pathological conditions. However, experimental studies show that microvascular functions as represented by functional capillary density in conditions of significantly decreased viscosity is impaired, a problem corrected by increasing plasma and blood viscosity. Blood viscosity, primarily dependent on hematocrit (Hct) is a determinant of peripheral vascular resistance, and therefore blood pressure. In the healthy population Hct presents a variability, which is not reflected by the variability of blood pressure. This is due to a regulatory process at the level of the endothelium, whereby the increase of Hct (and therefore blood viscosity) leads to increased shear stress and the production of the vasodilator nitric oxide (NO), a finding supported by experimental studies showing that the acute increase of Hct lowers blood pressure. Studies that in the healthy population show that blood pressure and Hct have a weak positive correlation. However, when the effect of blood viscosity is factored out, blood pressure and Hct are negatively and significantly correlated, indicating that as blood viscosity increases, the circulation dilates. Conversely, lower Hct and blood viscosity conditions lead to a constricted circulation, associated with a condition of decreased NO bioavailability, and therefore a pro-inflammatory condition.

Microvascular benefits of increasing plasma viscosity and maintaining blood viscosity: counterintuitive experimental findings.

The circulation is adapted to specific levels of blood viscosity resulting in a balance that simultaneously sets peripheral vascular resistance, blood pressure and cardiac output, factors in part mediated by the production of nitric oxide by the endothelium. Although it is generally perceived that decreasing blood viscosity is beneficial for cardiovascular function, small increases of blood viscosity in normal healthy experimental subjects significantly improve cardiovascular function. These changes are within the normal variations of viscosity due to the variations of hematocrit in the healthy population. Hemodilution reduces blood viscosity, which is proposed to be physiologically beneficial. However, in extreme hemodilution, increased plasma viscosity via the use of viscogenic plasma expanders sustains microvascular and tissue function at significantly reduced levels of oxygen delivery. Studies in hemorrhagic shock resuscitation using oxygen carrying and non-carrying red blood cells show that restoration of blood viscosity is as important as restoration of oxygen carrying capacity. It is concluded that although hemodilution is indicated for reducing abnormally high blood viscosities, it is beneficial to increase plasma viscosity when hematocrit is reduced. Furthermore small increases in hematocrit may be beneficial due to the related increase in blood viscosity, independently of the increase of oxygen delivery capacity.

Lowered microvascular vessel wall oxygen consumption augments tissue pO2 during PgE1-induced vasodilation.

Continuous infusion of intravenous prostaglandin E1 (PgE1, 2.5 mug/kg/min) was used to determine how vasodilation affects oxygen consumption of the microvascular wall and tissue pO(2) in the hamster window chamber model. While systemic measurements (mean arterial pressure and heart rate) and central blood gas measurements were not affected, PgE1 treatment caused arteriolar (64.6 +/- 25.1 microm) and venular diameter (71.9 +/- 29.5 microm) to rise to 1.15 +/- 0.21 and 1.06 +/- 0.19, respectively, relative to baseline. Arteriolar (3.2 x 10(-2) +/- 4.3 x 10(-2) nl/s) and venular flow (7.8 x 10(-3) +/- 1.1 x 10(-2)/s) increased to 1.65 +/- 0.93 and 1.32 +/- 0.72 relative to baseline. Interstitial tissue pO(2) was increased significantly from baseline (21 +/- 8 to 28 +/- 7 mmHg; P < 0.001). The arteriolar vessel wall gradient, a measure of oxygen consumption by the microvascular wall decreased from 20 +/- 6 to 16 +/- 3 mmHg (P < 0.001). The arteriolar vessel wall gradient, a measure of oxygen consumption by the vascular wall, decreased from 20 +/- 6 to 16 +/- 3 mmHg (P < 0.001). This reduction reflects a 20% decrease in oxygen consumption by the vessel wall and up to 50% when cylindrical geometry is considered. The venular vessel wall gradient decreased from 12 +/- 4 to 9 +/- 4 mmHg (P < 0.001). Thus PgE1-mediated vasodilation has a positive microvascular effect: enhancement of tissue perfusion by increasing flow and then augmentation of tissue oxygenation by reducing oxygen consumption by the microvascular wall.

Mechanotransduction and the homeostatic significance of maintaining blood viscosity in hypotension, hypertension and haemorrhage.

The increase of plasma and blood viscosity is usually associated with pathological conditions; however, elevation of both parameters often results in increased perfusion and the lowering of peripheral vascular resistance. In extreme haemodilution, blood viscosity is too low and insufficient to maintain functional capillary density, a problem that in experimental studies is shown to be corrected by increasing plasma viscosity up to 2.2 cP. This effect is mediated by mechanotransduction-induced nitric oxide (NO) production via shear stress in the endothelium as shown by microelectrode perivascular measurements of NO concentration. Moderate elevations of blood viscosity by increasing haematocrit ( approximately 10%) result in comparable reductions of blood pressure and peripheral vascular resistance, an effect also NO-mediated as it is absent after Nomega-nitro-L-arginine methyl ester treatment and in endothelial nitric oxide synthase-deficient mice. These findings show that the rheological properties of plasma affect vessel diameter in the microcirculation leading to counterintuitive responses to the changes in blood and plasma viscosity. Application of these findings to haemorrhagic shock resuscitation leads to the concept of hyperosmotic-hyperviscous resuscitation as a modality for maintaining the recovery of microvascular function.

Influence of cell-free Hb on local tissue perfusion and oxygenation in acute anemia after isovolemic hemodilution.

BACKGROUND: Oxygen-carrying solutions are intended to eliminate the blood transfusion trigger. Their ability to maintain microvascular perfusion and to deliver oxygen to tissue when they replace the RBCs as oxygen carriers has not been directly measured. STUDY DESIGN AND METHODS: Microvascular response to exchange transfusion with a polymerized bovine cell-free Hb (PBH) solution after acute isovolemic hemodilution with a plasma expander was investigated by using the hamster window model. In vivo functional capillary density (FCD), blood flow, and high-resolution oxygen distribution in microvascular networks were measured by noninvasive methods. RESULTS: Exchange transfusion of PBH solution after a 60-percent isovolemic hemodilution with dextran 70 (MW, 70 kDa) resulted in a Hct of 11 percent and a Hb content of 6.7 g per dL. FCD was 0.37 of baseline. Interstitial pO2 was reduced from 21.0 mm Hg to 0.3 mmHg. Arteriolar and venular blood flows were ratios of 0.75 and 0.76 relative to baseline. In a previous study, tissue pO2 after hemodilution to 5.6 g of Hb per dL with dextran 70 was 23.0 mmHg. Hypervolemic injection of PBH solution increased blood pressure and caused vasoconstriction. CONCLUSION: Using PBH solution to replace RBC oxygen-carrying capacity during low Hb content conditions (<50%) causes abnormally low tissue oxygenation and FCD, while the same level of hemodilution with dextran maintains normal microvascular conditions.

Local tissue oxygenation by statistically distributed sources.

The effect of red blood cell separation on tissue oxygenation was analyzed using a previously developed model which accounts for the particulate nature of blood at the capillary level. Results show that an empirically based RBC pattern yields the same levels of oxygenation at 20% hematocrit as an even spacing pattern. Introduction of an empirically based RBC spacing pattern during hemodilution, where capillary hematocrit is reduced by half with concomitant doubling of velocity, results in a reduction of average tissue pO2 by 23% and volume of oxygenated tissue by 28%, whereas axial delivery of oxygen along the length of the capillary was unchanged. Tissue oxygenation levels are optimized with even RBC spacing pattern but not with an empirical pattern because the tissue does not effectively use the oxygen delivered by unevenly spaced RBCs despite an equivalent time-averaged flux. Model predictions for tissue oxygenation for statistically distributed spacing under normal and hemodilution conditions show trends consistent with previously obtained results using even spacing, namely, increased axial distance and volume oxygenated, with decreased average tissue pO2. During hemodilution, the volume of tissue oxygenated above 2 mm Hg decreased to 84%, while the volume above 1 mm Hg increased to 131% relative to control. This finding suggests a redistribution of oxygen within tissue during hemodilution, causing a greater amount of tissue to be exposed, but at a lower pO2.

Evidence of flowmotion induced changes in local tissue oxygenation.

The effect of cyclic blood flow velocity on local tissue oxygenation was studied by means of a mathematical simulation in the situation where red blood cells (RBC) act as discrete oxygen sources. Cyclic time varying fluctuations of capillary blood (flowmotion) are due to arteriolar vasomotion. This effect was introduced into the model as an oscillating RBC velocity with equal periods of high and low velocity regulated by a square wave function. Changes in RBC velocity coupled with a constant time-average capillary hematocrit lead to periods of high and low flux. Input parameters were flowmotion frequency and amplitude, capillary hematocrit, and mean RBC velocity. All results were related to baseline states where the velocity and hematocrit are steady. Our principle finding is that flowmotion alters the tissue oxygenation, whereby: 1) high amplitudes of flowmotion cause a modest increase in axial delivery of oxygen but with a decreased average tissue pO2; 2) decreasing flowmotion frequencies lead to increased radial penetration of oxygen; 3) the lower frequencies of flowmotion cause an increase in the volume of tissue that achieves at least a pO2 level of 5 mmHg. Isovolemic hemodilution was simulated and found to substantially increase the volume of oxygenated tissue as a function of flowmotion. These findings indicate that pO2 transients caused by flowmotion oxygenate tissue domains which under steady-state conditions would remain anoxic.

Local tissue oxygenation during constant red blood cell flux: a discrete source analysis of velocity and hematocrit changes.

Tissue oxygenation in the proximity of single capillaries was investigated mathematically, with the red blood cells (RBC) modeled as discrete oxygen sources separated by plasma gaps. The variables studied are the simultaneous change of capillary RBC flow velocity, and hematocrit (Hct), during constant flux (e.g., RBC velocity x Hct), with an oxygen tension-dependent tissue oxygen consumption rate. The model was used to analyze isovolemic hemodilution under the assumption that the decrease of capillary Hct is compensated by the increase of RBC velocity. The results show that during constant flux conditions, changes in the RBC velocity are directly related to the distance along the capillary to which oxygen is delivered and inversely related to the radial penetration of oxygen into the tissue. Therefore during isovolemic hemodilution, there is a redistribution of the volume of tissue oxygenated whereby a greater volume of tissue becomes oxygenated at an oxygen tension above the critical limit, but at a lower time averaged value. Hypothermia is stimulated and its added effect on constant flux assessed. Tissue oxygenation at low capillary hematocrit was found to be highly sensitive to capillary spacing, suggesting that one of the mechanisms for the maintenance of tissue oxygenation during hemodilution is the recruitment of capillaries.