Hypertension after kidney transplant is a frequent occurrence in pediatric patients. It is a risk factor for graft loss and contributes to the significant burden of cardiovascular disease (CVD) in this population. The etiology of posttransplant hypertension is multifactorial including donor factors, recipient factors, medications, and lifestyle factors similar to those prevalent in the general population. Ambulatory blood pressure monitoring has emerged as the most reliable method for measuring hypertension in pediatric transplant recipients, and many consider it to be essential in the care of these patients. Recent technological advances including measurement of carotid intima-media thickness, pulse wave velocity, and myocardial strain using specked echocardiography and cardiac magnetic resonance imaging have improved our ability to assess CVD burden. Since hypertension remains underrecognized and inadequately treated, an early diagnosis and an appropriate control should be the focus of therapy to help improve patient and graft survival. Hypertension after renal transplantation is a common phenomenon with an estimated prevalence of 70–90% in adults and 58–89% in children –3. Long-Cardiovascular disease (CVD) is much more common among children with chronic kidney disease (CKD) and end-stage renal disease (ESRD) compared to the general population. CVD accounts for a large proportion of morbidity and mortality in this population . Renal tThe etiology of posttransplant hypertension is multifactorial encompassing donor-associated factors, side effects of immunosuppressive medications, underlying recipient disease, and possibly genetic factors, as seen in Figure It has been well established that several independent donor risk factors predispose the transplant recipient to hypertension including deceased donor, older age, and donor hypertension , 14. It The kidney donor profile index (KDPI) scoring system, used to evaluate donor grafts, was recently introduced in the United States . Donors APOL1), ATP-Binding Cassette Subfamily B Member 1 (ABCB1), Caveolin 1 (CAV1), and ATP-Binding Cassette Subfamily C Member 2 (ABCC2) have been shown to affect graft survival, hypertension, and calcineurin-induced nephrotoxicity  and worse glomerular filtration rate (GFR) than children with normal body mass index prior to transplant . The incImmunosuppressive medications play a significant role in the development of posttransplant hypertension. It has been well established that corticosteroids induce hypertension by increasing renal salt and water reabsorption and increase in renal vascular resistance. Studies have shown that patients on steroid-minimization protocols and patients undergoing late-withdrawal of steroids showed reduction in hypertension and obesity and improved lipid and carbohydrate metabolism .The incidence of posttransplant hypertension significantly increased after calcineurin inhibitors (CNI) such as cyclosporine and tacrolimus became commercially available for use. A recent Greek cohort of pediatric transplant patients showed that there was an increased risk of hypertension for patients on a CNI-based immunosuppression protocol .The mechanism of CNI-induced hypertension is primarily mediated by glomerular afferent arteriolar constriction leading to increased salt and water retention, in part through upregulation of the thiazide-sensitive Na+-Cl− cotransporter , 31. AddPreviously, it has been shown that mammalian target of rapamycin (mTOR) inhibitors act synergistically with CNI to worsen hypertention . BrunkhoTransplant renal artery stenosis is the most common vascular complication after renal transplant, usually presenting 2 months–2 years after transplant . ClinicaMYH9) gene on TRAS. The product of this gene is heavily expressed in glomeruli, tubular, and renal capillaries as well as arteriolar endothelial cells. Donor organs found to carry the rs3752462 CC variant had a 10.9-fold increase in TRAS compared to the recipients carrying rs5756168 TT variant that had a 3.45-fold decrease in risk , atypical hemolytic uremic syndrome (aHUS), antiglomerular basement membrane disease, systemic lupus erythematosus nephritis, membranous glomerulonephritis (MGN), and membranoproliferative glomerulonephritis. Of these, the most common are aHUS and FSGS, the latter with a 30–50% recurrence risk in the first transplant and 80–100% in subsequent transplants . Some tr decline –51.Acute rejection can be T-cell and antibody mediated and is often associated with hypertension. Any transplant patient with sudden onset or worsening of hypertension should be assessed for AR. The hypertension in this case usually responds well to treatment of AR.Transplant glomerulopathy causes hypertension through progressive scarring and fibrosis. Recent data showed that non-HLA autoantibodies targeting the angiotensin II type-1 receptor have been linked to hypertension, and treatment with an angiotensin receptor blocker may be beneficial –54.While patients with ESRD have numerous additional risk factors compared to normal children for developing hypertension, common risk factors for hypertension present in the general population also prevail in kidney transplant recipients. These risk factors include tobacco smoking, illicit drug use, medications for attention deficit hyperactivity disorder, high-salt diet, physical inactivity, obesity, sleep disturbances including obstructive sleep apnea, and genetic determinants of hypertension –59. FiguDefinitive cardiovascular outcomes such as stroke, myocardial infarction, and death are uncommon in the pediatric age group. Pediatric studies have relied on the use of intermediate endpoints such as LVH as measured by left ventricular mass index (LVMI), carotid intima-media thickness (cIMT), and pulse wave velocity (PWV) for CVD risk stratification. It has been well described that pediatric patients with CKD and ESRD have significantly increased cardiovascular morbidity and mortality compared to their healthy peers , 61. CVDLong-standing hypertension has been shown to result in LVH and increased LVMI and cIMT, all known risk factors for CVD . LVH is Evidence suggests that hypertension itself, regardless of BP level, is associated with LVH. Specifically, Hamdani et al. showed that treated hypertensive individuals with a normal blood pressure had a greater prevalence of LVH than normotensive individuals not treated with antihypertensive medications. In this same study, a large pediatric cohort of 221 patients evaluated with ambulatory blood pressure monitoring (ABPM), it was noted that patients with normal blood pressure who did not require antihypertensive medications had less allograft dysfunction than patients taking antihypertensive medications and even in those whose BP was in normal range . This emMasked hypertension as determined by ABPM in both patients receiving and not receiving antihypertensive therapy has an estimated prevalence of 25–35% . While sP < 0.05) (A study aimed at assessing CVD risk factors in pediatric transplant patients found that there was a negative correlation between GFR and SBP ± diastolic blood pressure (DBP) on univariate analysis. There was a noted trend of worsening hypertension with increasingly poor graft function on multivariate analysis, but the study was underpowered to detect this effect . A Finni < 0.05) . As wellA Dutch cohort study looking at long-term CVD outcomes in kidney transplant recipients (with an average follow-up of 15. 5 years) who developed ESRD as children (0–14 years of age) found that ~50% of males and 40% of females had LVH, 13% had diastolic dysfunction, and aortic valve calcification was seen in 25% males and 12% female patients . DuratioIn conclusion, children with CKD/ESRD come to transplant with significant burden of hypertension and CVD. With transplantation, their CVD risk improves overall but may be negatively impacted by poor control of blood pressure, by decline in GFR overtime, and by the presence of hyperlipidemia, obesity, and hyperglycemia.Screening for hypertension can be achieved by several methods that include casual clinic blood pressure measurement, home and school blood pressure measurement, and 24-h ABPM. ABPM has been shown to be the most reliable method for measuring blood pressure. It also has the added benefit of determining BP load and predicting LVH –73. PediBefore widespread use of ABPM, we must recognize its current limitations. Primarily, controversy remains about how to best interpret ABPM results due to lack of diverse normative data. Currently available normative data are based on ABPM measurements of 949 healthy children published by the German Working Group of Pediatric Hypertension . All chiHigh-resolution ultrasonography provides a non-invasive method for measuring cIMT. Increased cIMT, a marker for the development and progression of vascular calcification, has been documented in children as young as 8 years and correlates with duration of CKD, time on dialysis, hyperhomocysteinemia, and increased calcium–phosphorus product , 78. A rHypertension has been shown to have a linear correlation with cIMT in adults . BalzanoArterial PWV is a sensitive marker of arterial stiffness, which makes it a good surrogate endpoint for CVD . IncreasChronic kidney disease patients have been shown to have increased PWV. The recent 4C Study looked at numerous cardiovascular endpoints including PWV and found that 20.1% of CKD patients in their cohort had elevated PWV. In their analysis, the rise in PWV was independent of eGFR and moderately correlated with cIMT . Sinha eThe majority of coronary artery disease in CKD patients is asymptomatic and may initially present with arrhythmia and sudden death. Assessing the degree of myocardial strain using ECHO or magnetic resonance (MR) imaging can detect more subtle changes of impaired cardiovascular function, thus offering an opportunity for early intervention.Echocardiographic strain imaging helps to objectively quantify myocardial function . An exteCardiac MR is a relatively newer imaging modality that can provide additional information about CV risks in the CKD population. Blood oxygen level-dependent cardiac MR can be used to assess myocardial tissue oxygenation. A recent study employing this technique found that patients with CKD and renal transplant without known coronary artery disease had impaired myocardial response to stress, independent of the presence of diabetes mellitus, LVH, and myocardial scar . An addiAs these technologies become more readily available and cost-effective in clinical practice, they will be able to offer more reliable tools to assess cardiovascular dysfunction in pediatric transplant recipients.There are no published guidelines or recommendations for the immediate postoperative management of kidney transplant recipients. We will describe our center’s practice based on our clinical experience in this section. In the immediate postoperative period (first week), the most likely etiology of hypertension is fluid overload, side effect of high-dose steroid therapy for induction, and native kidney disease. In the first few postoperative days, permissive hypertension is tolerated to ensure adequate graft perfusion especially in small children. Size discrepancy of the donor and recipient arteries and relatively lower blood pressure in the child can compromise early graft perfusion and predisposition to thrombus formation. This necessitates higher patient blood pressures and may require vasopressor support to achieve this.After a few days postoperatively, excess fluid begins to mobilize and move into the intravascular space, contributing to hypertension. Allowing gradual diuresis back to the patient’s dry weight will often result in decrease of the systemic blood pressure. However, patients frequently need to be restarted or initiated on antihypertensive medications during the postoperative period.A holistic approach to the long-term management of hypertension should be pursued in the pediatric transplant recipient. As the goal of hypertensive management is ultimately to prolong patient and graft survival and decrease CVD, this approach should include close monitoring and management of graft function as well as adherence to medications, diet, and exercise. Many review papers have been published on the pharmacologic management of hypertension , 98, 99.As with hypertension in patients without renal transplant, pharmacologic therapy should be aimed at addressing the underlying etiology. In patients on CNI-based immunosuppression, afferent arteriole vasoconstriction contributes to hypertension, and therefore, a use of CCBs is usually the first-line therapy due to its vasodilatory properties. CCBs have a very good safety profile and have been shown to be efficacious in this patient population for both blood pressure control and improvement of GFR compared to placebo treated patients . In non-While pharmacological interventions have an important role in the management of hypertension, dietary and exercise counseling need to be at the forefront of long-term management of transplant recipients.Diets high in sodium and low in potassium have been shown to aggravate hypertension. In a Belgian study of adult patients, dietary history and urinary sodium and potassium excretion were evaluated. While sodium intake did not differ between the two groups (~10 g/day), patients with controlled blood pressure consumed higher amounts of potassium by regularly eating more fruits and vegetables, which lowered their observed Na+/K+ ratio . Asai etIn accordance with these findings, published nutritional guidelines for renal transplant recipients include low-sodium diet and weight loss in obese individuals to optimize blood pressure management . CounselChanges and improvement in management of hypertension in the pediatric kidney transplant population can be approached using quality improvement methodology. Because this is a complex multifaceted problem that affects patients’ long-term outcomes and requires multidisciplinary cooperation, this can be addressed by employing the Chronic Care Model as suggested by Hooper and Mitsnefes . RecommeHypertension in the pediatric kidney transplant recipients is highly prevalent and often underrecognized and undertreated. This contributes to worse allograft function and long-term risk of CVD in early adulthood and partly accounts for the significantly increased mortality in this patient population. Hypertension is a modifiable risk factor that should be aggressively monitored and treated, as summarized in Figure There are many gaps in our knowledge in this field that would benefit from further research including but not limited to CVD outcomes based on the donor KDPI; genetic polymorphism of donors affecting posttransplant hypertension in transplant recipients; ABPM normative data of diverse ethnic populations; blood pressure percentile treatment goals for transplant recipients; effect of ACE-I on long-term graft survival, and finally, addressing barriers to adherence at both provider and patient level with adequate treatment plan.OC wrote the manuscript under guidance and supervision by AM. Both parties were directly involved and were the only contributors to the production of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Multiple prior studies have recommended 30 cmH2O as the maximum safe cuff inflation pressure. This study sought to evaluate the inflation pressures in ETT cuffs of patients presenting to HEMS.Endotracheal intubation is a common intervention in critical care patients undergoing helicopter emergency medical services (HEMS) transportation. Measurement of endotracheal tube (ETT) cuff pressures is not common practice in patients referred to our service. Animal studies have demonstrated an association between the pressure of the ETT cuff on the tracheal mucosa and decreased blood flow leading to mucosal ischemia and scarring. Cuff pressures greater than 30 cmHWe enrolled a convenience sample of patients presenting to UMass Memorial LifeFlight who were intubated by the sending facility or emergency medical services (EMS) agency. Flight crews measured the ETT cuff pressures using a commercially available device. Those patients intubated by the flight crew were excluded from this analysis as the cuff was inflated with the manometer to a standardized pressure. Crews logged the results on a research form, and we analyzed the data using Microsoft Excel and an online statistical analysis tool.2O. The mean lies 40 cmH2O above the maximum accepted value of 30 cmH2O (p<0.0001). Eighty-four percent (84%) of patients encountered had pressures above the recommended maximum. The most frequently recorded pressure was >120 cmH2O, the maximum pressure on the analog gauge.We analyzed data for 55 patients. There was a mean age of 57 years (range 18–90). The mean ETT cuff pressure was 70 (95% CI= [61–80]) cmHPatients presenting to HEMS after intubation by the referral agency  have ETT cuffs inflated to pressures that are, on average, more than double the recommended maximum. These patients are at risk for tracheal mucosal injury and scarring from decreased mucosal capillary blood flow. Hospital and EMS providers should use ETT cuff manometry to ensure that they inflate ETT cuffs to safe pressures. Endotracheal intubation is a common intervention in critical care patients undergoing helicopter emergency medical services (HEMS) transportation. A standard adult endotracheal tube (ETT) is secured at its distal end in the trachea using an inflatable cuff. This cuff serves to minimize aspiration risk and provides a seal to allow for delivery of a positive pressure gradient. The pressure in an ETT cuff must be high enough to occlude the lumen of the trachea in order to serve these primary functions.2O may cause decreased blood flow to the tracheal mucosa in as little as 25 minutes.7Excess pressure, however, may increase the risk of damage to the tracheal mucosa.We hypothesized that in patients intubated by referral EMS agencies or referral hospitals, the initial cuff pressure measured by the HEMS crew would be within the accepted safe range.Reduction in tracheal blood flow as a consequence of higher-than-recommended ETTCP has been associated with ischemic lesions to the trachea.We performed a prospective cohort study of patients intubated by referring agencies, both hospitals and EMS agencies, who presented for critical care transport by UMass Memorial Life Flight. The study was approved by the University of Massachusetts Medical School Institutional Review Board.This study was performed at UMass Memorial Life Flight, a critical care transport service based in Worcester, MA, between 2013 and 2014. Patients who were intubated by referring agencies  and transported by helicopter were consecutively included in the study. We excluded patients if they were prisoners at the time of transfer, or if they had been intubated with non-cuffed ETTs.2O, it was lowered to that pressure. Pressure measurements, inflation, and deflation of the ETT cuffs were performed using the Posey Cufflator™ endotracheal tube inflator and manometer , a commercially available device. The maximum measurement on this device is >120 cmH2O  as equal to 120 cmH2O.This study is an observational cohort of a series collected to analyze the change in pressure of ETT cuffs with altitudinal changes in flight. This paper represents a pre-planned subgroup analysis of the initial ETTCP of patients intubated prior to UMass Memorial Life Flight arrival. The original study was planned for 110 patients based on a pre-hoc power calculation. We analyzed the data analyzed at midpoint (55 patients) and found them to be significant for this cohort. The data was entered into and analyzed using Microsoft Excel 2013  and a Web-based statistical analysis tool for the one-sided T test. For the purposes of analysis of the data, we treated manometer readings at the maximum on this analog manometer . We excluded four additional records as the patients were not intubated prior to the Life Flight crew’s arrival and were intubated by the crew. The remaining 55 patients were analyzed see .The 2O to >120 cm cmH2O. The mean pressure measurement was 70 cmH2O, 40 cmH2O higher than the accepted maximum safe value of 30 cmH2O . The mode was >120cmH2O. Of the measurements, 8 (14.55%) were below the accepted maximum safe value of 30 cmH2O, 47 (85.45%) above that value. Initial ETTCP ranged from 15 cmHThe vast majority of endotracheal tubes transported by our critical care HEMS crew had a dangerous level of cuff over-inflation. Less than 15% of the measurements found pressures within acceptable ranges and the most common value was at the upper limit of the manometer’s range. Pressures such as this have been shown in animal studies to cause tissue ischemia to the tracheal mucosa.32O.2O was associated with an elevated tracheal ischemia score.Evidence for the harm of over-inflation of ETT cuffs is not limited to animal studies. A 1984 study by Seegobin found blanching of tracheal mucosa on tracheoscopy in patients whose ETTCP exceeded 40 cm HLess severe complications related to over-inflation of ETT cuffs include hoarseness, sore throat and hemoptysis.10The prevalence of over-inflated ETTCP has been reported several times and yet persists. The reports have covered clinical environments including the prehospital environment,17Many clinicians rely on pilot-balloon estimation of cuff pressures. The inaccuracy of this technique has been demonstrated many times.14Techniques for using various-sized syringes as pressure-relief valves have been published over the years.22In this study each of the abnormal pressures was normalized prior to flight. Had the pressures not been normalized the risk of tracheal injury might have been even higher. Several papers have demonstrated that ETTCP is affected by altitude changesThis dataset is limited by possible confounding variables that were not collected by the data collection forms. It is possible that identification of whether the intubation was performed by hospital staff or field EMS personnel may have identified a tendency toward over-inflation by one of those groups. Additionally, for those cases intubated in a hospital setting, delineating whether they were done in the ED, ICU, or operating room, may have also allowed for more stratification of the data. Finally, the question of who specifically inflated the cuff, be they physician, nurse, or respiratory therapist, may also have elucidated some associations that could potentially have suggested further research.The fact that these data were collected from a single HEMS system may tend to limit the degree to which they can be generalized. Possibly offsetting this limitation is the fact that the subjects included in the study originated from multiple EMS systems and multiple referral hospitals across a five-state area, providing a greater cross-section than may be inferred from the single HEMS service.In conclusion, we present additional evidence that current standard practice in EMS agencies and referral hospitals in our HEMS system leads to frequently elevated ETTCP. These pressures place the patient at risk for complications from the ETT. Clinicians should move to routine measurement of ETTCP in all intubated patients.


Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney.This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride.On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group.In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney.NCT02832973. Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016.Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: The online version of this article (doi:10.1186/s13063-017-2343-3) contains supplementary material, which is available to authorized users. Systemic hypertension is a multifactorial and complex disease that is characterized by constantly high blood pressure (BP). It is associated with functional and structural changes in target organs  , 2 and mHypertension is a major modifiable risk factor for cardiovascular disease and one of the most important public health problems. As the BP rises above 115/75 mmHg, the mortality rate due to cardiovascular disease increases linearly . The exaThere has been a rise in the prevalence of hypertension in recent years due to the epidemic of obesity, increased longevity and the higher incidence of kidney disease in the population . On averResistant hypertension (RH) is characterized by the BP remaining above the recommended goal after taking three antihypertensive drugs with synergistic actions at maximum recommended tolerated doses, preferably including a diuretic, for at least 6 months, or on using four or more antihypertensive drugs even if the BP is controlled . True RHThe true prevalence of hypertension is unknown. In controlled randomized studies with thousands of hypertensive patients, approximately 25 to 30% of participants did not achieve the BP goal recommended by guidelines despite receiving three or more antihypertensive drugs; these studies included careful assessments of patient adherence to therapy and even ambulatory BP monitoring (ABPM), which identifies patients with pseudoresistance .However, observational data from the North American National Health and Nutrition Examination Survey (NHANES) collected in 2003–2008 showed that the prevalence of RH among adults diagnosed with hypertension was 8.9% and among adults on antihypertensive treatment, it was 12.8% , 20, 25.RH is a difficult-to-manage clinical condition because of patients’ failure to adhere to treatment, the physician’s difficulty to adjust the medication due to genetic factors that hinder the effectiveness of treatment and due to medical inertia . The chaInterventions with three different classes of antihypertensive agents, including a diuretic at the ideal dose, are necessary to achieve target values of BP in resistant hypertensive patients , 27, 28.Regarding the recommendations on research priorities published by Professor Iain Chalmers,  we can sA systematic research has already been performed to assess the benefits and harms of adding a new drug to the current triple-drug regimen for management of RH in adults versus continuation of treatment with triple-drug therapy alone. Charan et al. reviewed the pharmacotherapy for RH in adults .Finally, academic literature projects with similar designs but using other drugs have been published; for example, “Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open, blinded-endpoint study” ; and “TrHowever, a study of a Brazilian population and the use of other drugs not tested in these studies reinforces the importance of our study.The mechanisms involved in the pathophysiology of RH are vascular smooth muscle tone and increased blood volume, intensified sympathetic system activity and hyperactivity of the renin-angiotensin-aldosterone system (RAAS) , 48, 49.Increased sensitivity to sodium appears to be the main factor in the pathophysiology of this syndrome, not only as it mediates the above mechanisms, but also as it explains, in part, the variability of therapeutic response in patients with RH . The RAAFrom the physiological point of view, both of normal subjects and hypertensive patients, BP is maintained by the continuous regulation of cardiac output and peripheral vascular resistance exerted at three anatomic sites: the arterioles, post-capillary venules (capacitance vessels) and the heart. A fourth anatomical site of control, the kidney, contributes to the maintenance of BP by regulating intravascular volume , 51. TheRegulation in hypertension differs from the regulation in healthy individuals as the baroreceptors and renal control systems of blood volume seem to set the BP at a higher level. Thus, identifying the contribution of blood volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of blood volume, the sodium balance, or by acting on the effects of the RAAS on the kidney , 35, 50.Sequential nephron blockade consists of progressive increases in sodium depletion. After the administration of a thiazide diuretic  and an aldosterone-receptor blocker, low doses of furosemide are administered and ultimately amiloride is prescribed to enhance the natriuretic effect .Blockade of the RAAS is to increase the effect of the angiotensin receptor-1 blocker (ARB). Therapy then requires sequentially adding an angiotensin-converting enzyme (ACE) inhibitor to reduce the levels of angiotensin (Ang) II by blocking its receptor and then administering a beta-blocker to decrease the elevated renin secretion due to both the ACE inhibitors and ARBs , 55.Does sequential nephron blockade and dual blockade of the RAAS plus bisoprolol constitute good therapeutic options in the reduction of peripheral BP of patients with RH?Which therapeutic option is able to reduce the central pressure in resistant hypertensive patients?Does non-inferiority testing demonstrate that sequential nephron blockade has the same therapeutic efficacy as dual blockade of the RAAS plus bisoprolol?The following research questions will be explored:This study will compare two antihypertensive treatment regimens in RH patients at the Medical School in Sao Jose do Rio Preto. It aims to demonstrate the therapeutic efficacy of sequential nephron blockade compared to the dual blockade of the renin-angiotensin system plus bisoprolol in RH patients, and to assess the side effects and adherence to treatment over 20 weeks.Allocation: randomized Intervention model: parallel assignmentMasking: none (open label)Primary purpose: treatmentThis is an open-label, prospective, randomized clinical trial . Two therapeutic regimens for RH will be compared: sequential nephron blockade and dual blockade of the RAAS plus bisoprolol. This study is being developed in the Medical School in Sao Jose do Rio Preto.All participants are required to give written informed consent. The study participants are randomly allocated either to the sequential nephron blockade group or to the dual blockade of the RAAS group. All participants receive complete basic treatment.Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist: recommended items to address in a clinical trial protocol and related documents, is available online for this manuscript , spironolactone 25 mg plus furosemide (20 mg), spironolactone plus furosemide (40 mg) and spironolactone (25 mg) plus furosemide (40 mg) plus amiloride (5 mg), sequentiallyForty patients will receive, in addition to the basal therapy, ramipril (5 mg), ramipril (10 mg), ramipril (10 mg) plus bisoprolol (5 mg) and ramipril (10 mg) plus bisoprolol (10 mg), sequentiallyEighty patients undergoing RH treatment with losartan (100-200 mg), chlorthalidone (25 mg) and amlodipine (5 mg) will be enrolled and randomly allocated to one of two groups:To achieve adequate participant enrollment to reach target sample size, we will use the written and spoken media to identify volunteers for the study.Both groups will be analyzed in five visits at 28-day intervals over 20 weeks. Figure V0: week − 4 to week 0. All patients will remain under treatment with losartan (100–200 mg), chlorthalidone (25 mg) and amlodipine (5 mg)V1: week 0 to week 4. Individuals with BP > 135/85 mmHg by ABPM will be randomized to one of the study groupsV2: week 4 to week 8. Patients randomized to one of the study groups will receive 25 mg of spironolactone (SNB group) or 5 mg of ramipril (DBB group)V3: week 8 to week 12. Individuals with BP < 135/85 mmHg by ABPM will continue using the same regimen. Subjects with BP > 135/85 mmHg by ABPM will receive, in addition to their existing regimen, furosemide (20 mg) for the SNB group and ramipril (10 mg) for the DBB groupV4: week 12 to week 16. Subjects with BP < 135/85 mmHg by ABPM will continue on the same regimen. Individuals with BP > 135/85 mmHg by ABPM will receive 40 mg furosemide for patients in the SNB group and 5 mg bisoprolol for patients in the DBB groupV5: week 16 to week 20. Subjects with BP < 135/85 mmHg by ABPM will continue using the same regimen. Individuals with BP > 135/85 mmHg by ABPM will receive an extra 5 mg amiloride for patients in the SNB group and 10 mg bisoprolol for patients in the DBB groupVEnd: week 20 to week 24. Blood samples will be drawn from all patients. Radial artery applanation tonometry and ABPM will be performedPatients will be analyzed in five sequential visits with 28 days between visits. Figure The BP will be measured by the indirect method following the VI Brazilian Guidelines for the Treatment of Hypertension .ABPM and home BP measurements (HBPM) will be carried out as additional tools to investigate hypertension. Whenever possible, the measurement of BP outside the office is recommended for a definite diagnosis because of white-coat and masked hypertension. ABPM is a method that allows the indirect and intermittent recording of BP for 24 h while patients perform their usual activities during the day. BPs equal to or greater than 130/80 (mean 24-h ABPM), 135/85 (daytime) and 120/70 mmHg (nighttime) are considered abnormal . ABPM wiMonitoring requires patients to maintain their normal daily activities with the BP being measured automatically at 30-min intervals for an entire 24-h period according to the technical norms of the 5th Guidelines on Ambulatory Blood Pressure Monitoring. The systolic BP (SBP) and diastolic BP (DBP) will be obtained by ABPM with the mean values for the 24-h period, daytime and nighttime being considered for analysis. Patients with mean BP values ≥ 130/80 mmHg over 24 h, ≥ 135/85 mmHg during wakefulness and ≥ 120/70 mmHg when asleep will be considered RH. Pulse pressure (PP) will be calculated during the periods  using the formula PP = SBP − DBP. The normal nocturnal dip will be defined as a drop of > 10% in SBP from wakefulness to the period of sleeping.HBPM, performed by the patient or other trained person, is an indirect record of the BP that involves three measurements using validated devices in the morning and three at night for 5 days at home or at work.2). BMIs of 18.5 to 24.9 kg/m2 are considered eutrophic values, while individuals with BMIs of 25.0 to 29.9 kg/m2 are overweight and ≥ 30 kg/m2 are obese. The abdominal circumference, measured at the midpoint between the iliac crest and the lower costal margin, is the most representative anthropometric index of intra-abdominal fat and the simplest reproducible measurement. Values equal to or below 80 cm and 94 cm are considered appropriate for women and men, respectively.Weight and height, measured by anthropometric scales, will be used to calculate the Body Mass Index (BMI) using the formula BMI = weight (kg)/height squared , low-density lipoprotein cholesterol (LDLc), very low-density lipoprotein cholesterol (VLDLc), triglycerides (TG), glucose, insulin, creatinine, sodium and potassium. The following values are considered the normal ranges: total cholesterol < 200 mg/dL, HDLc > 40 mg/dL for men and > 50 mg/dL for women, LDLc < 130 mg/dL and TG < 150 mg/dL. The LDLc fraction is calculated using the Friedewald formula (LDLc (mg/dL) = TC − HDLc − TG/5 (for TG < 400 mg/dL)). The diagnosis of diabetes is confirmed by two glycemic measurements ≥ 126 mg/dL after fasting for at least 8 h.All patients will undergo electrocardiography, echocardiography, carotid Doppler ultrasound, ultrasound with Doppler of the renal arteries, stress testing and radial artery applanation tonometry (AT). Table Office-measured SBP and DBP at week 20, an average of three measurements using an oscillometric device (Time frame: at week 20).Efficacy: office-measured mean blood pressure (MBP) at week 20, an average of three measurements using an oscillometric device (time frame: at week 20).Efficacy: office-measured pulse pressure (PP) at week 20, calculated from an average of three measurements using an oscillometric device (Time frame: at week 20).Efficacy: mean 24-h SBP and DBP at week 20 measured with an ABPM device (Time frame: at week 20).Safety and tolerability: (Time frame: during the study).During the study, BP will be evaluated every 4 weeks by office-measured BP measurement in order to detect hypotension) (Time frame: every 4 weeks).Blood pressure (mean of three measurements by an automatic electronic device Omron HEM-711 DLX) and hemodynamic parameters (by Omron HEM 9000 AI device) will be measured in the office during follow-up visits.In order to improve adherence to intervention protocols, we use drug tablet return and laboratory tests to monitor patient compliance.Analysis of safety-related data will be performed with respect to frequency of serious adverse events (SAEs) stratified by causality and intensity of morbidity in both treatment groups. Patients will be interviewed at each visit about the occurrence of any adverse events, including time of onset, duration and severity; all information will be recorded on a Case Report Form. The causal relation to the study drug and the intensity of adverse events will be evaluated by the investigators. SAEs must be reported to the Institutional Review Board and study sponsor by the principal investigator within 24 h after the SAE becomes known.Laboratory adverse events, such as metabolic changes and glomerular filtration rate, will be analyzed at the final visit of patients.Participants will be registered with a phone number and address for further contact in case they miss scheduled visits.Furthermore, all participants are requested to promptly report possible adverse events by telephone. Study participants receive telephone contact numbers from the study team at the time of inclusion (visit 0).Participants can withdraw from the trial at any time for any reason without their medical care being affected.Data already collected will continue to be used, and the patients will be asked if they are still willing to provide follow-up data. The reason for withdrawal will be documented whenever possible.No washout period will be used.Eighty eligible patients undergoing RH treatment with losartan (100–200 mg), chlorthalidone (25 mg) and amlodipine (5 mg) will be enrolled and randomly allocated into one of two groups.https://www.stata.com/features/power-and-sample-size/ and Stata 11 program were used to estimate the sample size. The sample size was calculated at 36 patients per group (SNB versus DBB) considering an alpha error of 5%, statistical power of 80%, standard deviation (SD) of 8 mmHg, and maximum acceptable absolute difference of 6 mmHg (diastolic BP). However, considering a potential 10–15% dropout or loss to follow-up rate, 40 patients will be enrolled in each group. The difference of 5 mmHg (diastolic) has been achieved, on average, in clinical trials that have demonstrated the advantage of a drug over placebo or other non-pharmacological treatments in the prevention of major cardiovascular outcomes.The site t test or Wilcoxon test for quantitative variables and the chi-square test and Fisher’s exact test for qualitative variables will be used in the comparative analysis of the clinical characteristics of RH patients. Data will be expressed as means ± 1 SD.The The sample size was estimated at 72 individuals for an expected zero difference with a SD of 12 mmHg to demonstrate the non-inferiority of the strategy of sequential nephron blockade compared to dual blockade of the RAAS plus bisoprolol assuming an absolute difference of ≤ mmHg for systolic BP.P values < 0.05 will be considered statistically significant.Non-inferiority will be evaluated for a one-sided 95% confidence interval (CI) estimated by a linear mixed model for repeated measures. To demonstrate that the pharmacological treatment with sequential nephron blockade has the same antihypertensive efficacy as dual blockade of the RAAS plus bisoprolol after 20 weeks of active treatment of patients with RH.To evaluate the clinical and biological safety of sequential nephron blockade compared to dual blockade of the RAAS plus bisoprolol over 20 weeks of active treatment.To assess the side effects and adherence of sequential nephron blockade compared to dual blockade of the RAAS plus bisoprolol over 20 weeks of active treatment.The aims of this study comparing two antihypertensive treatment regimens in patients with RH are:At the time of manuscript submission, 50% of participant recruitment had been completed.Estimated enrollment: 80 including estimated 10% loss to follow-up.Study start date: September 2014.Study completion date: December 2017.Work in progress, still recruiting, not finalized. To date we have 61 patients included.Additional file 1:Free and clear term-compliance for research project's participation. (JPG 75 kb)Additional file 2:Research Ethics Committee. Approval Nº 870 093. (PDF 180 kb)


In the congestive heart failure (CHF) setting, chronic hyponatremia is very common. The present review aims at addressing topics relevant to the pathophysiology of hyponatremia in the course of CHF as well as its optimal treatment, including the main advantages and the limitations resulting from the use of the available dietary and pharmacological measures approved for the treatment of this electrolytic trouble. A narrative review is carried out in order to represent the main modalities of therapy for chronic hyponatremia that frequently complicates CHF. The limits of usual therapies implemented for CHF-related chronic hyponatremia are outlined, while an original analysis of the main advancements achieved with the use of vasopressin receptor antagonists (VRAs) is also executed. The European regulatory restrictions that currently limit the use of VRAs in the management of CHF are substantially caused by financial concerns, i.e., the high costs of VRA therapy. A thoughtful reworking of current restrictions would be warranted in order to enable VRAs to be usefully associated to loop diuretics for decongestive treatment of CHF patients with hyponatremia. ECFV is elevated in hypervolemic hyponatremia, which is typically caused by excessive retention of water, usually due to increased secretion of arginine-vasopressin (AVP), which is also known as antidiuretic hormone, as in the setting of several edematous syndromes such as chronic heart failure and liver cirrhosis. Euvolemic hyponatremia, where AVP secretion is increased but ECFV is essentially normal, is most often associated with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Finally, hypovolemic hyponatremia reflects a lower ECFV and is associated with depletional disorders  or with drugs that substantially increase the urinary clearance of electrolytes .Hyponatremia treatment varies depending on the speed of onset and on the cause, severity, and status of the ECFV. Conventional treatments for hyponatremia include fluid restriction, administration of isotonic saline solution, the combined administration of hypertonic saline solution plus furosemide, demeclocycline, lithium, and urea, even though these options are limited by concerns regarding the efficacy, adverse events, and, particularly in the case of fluid restriction, the patient’s adherence to therapy. In addition, low levels of serum sodium should not be corrected too quickly, because this may lead to osmotic demyelination syndrome, which is associated with significant neurological sequelae. Recent introduction of vasopressin receptor antagonists (VRAs) into the clinical armamentarium has provided additional therapeutic options for treatment of patients with hyponatremia. In this brief review, some topics relevant to the pathophysiology of hyponatremia in the course of CHF, as well as to its real clinical significance, are examined. Moreover, some issues concerning optimal treatment of hyponatremia arising during CHF are also addressed. Finally, advantages and limitations resulting from the use of VRAs, namely, the drugs that have recently emerged as the best available resource against hyponatremia, are outlined.+ and total body water (TBW) (In chronic heart failure (CHF), hyponatremia typically develops in the presence of expansion of the extracellular fluid compartment ; thus, it is typically marked by an increase in both total body Naer (TBW) .In its pathogenesis, a key role seems to be played by a mechanism of hypothalamic nonosmotic stimulation . ActuallIn congestive CHF, the non-osmotic stimulation of AVP neuroendocrine secretion along with increased efferent sympathetic nervous traffic and stimulation of the renin-angiotensin-aldosterone system (RAAS) frequently ensues as a consequence of decreased activity (hypoperfusion-related) of baroreceptors in the carotid arteries, aortic arch, left ventricle, and afferent arterioles of the kidneys. Hyponatremia, when it is present, results from a hemodilution state consequent to the inhibition of free water excretion in the renal collecting ducts, triggered by increased serum AVP levels and, to a lesser extent, by the direct impairment of renal water excretion by angiotensin. In our opinion, the term “hypervolemic hyponatremia” applied to congestive CHF really is a warped or deceptive interpretation, since in this condition an increased blood volume is contained only in the venous system, thereby producing systemic venous hypertension causing chronic interstitial extravasation leading to peripheral edema, while the effective arterial circulating volume is significantly reduced due to low cardiac output and a slowing down in circulation time ,3.In the pathogenesis of hyponatremia, a controversial role is played by diuretic and vasodilator treatments since these drugs can improve cardiac performance and relieve the symptoms of cardiac overload but do not correct per se a preexisting condition of arterial underfilling . Indeed,+ concentration quickly drops below 125 mEq/L. Between 115 and 120 mEq/L, headache, lethargy, and dullness appear, even though many patients with chronic hyponatremia exhibit only mild symptoms. The most severe manifestations such as seizures and coma are not frequent until the serum sodium exceeds 110–115 mEqL/L. Focal neurological signs are uncommon, but they may occur in patients with previous brain damage, such as a prior cerebral infarction.The neurological symptoms associated with hyponatremia are similar to those present in other metabolic encephalopathies. Generally, the patient begins to suffer discomfort and nausea when the plasma Na+ and water [In the presence of volume depletion, patients may also develop typical symptoms of hypovolemia . In addition, signs of expansion of the extracellular volume such as edema are not found in patients with water retention due to SIADH or primary polydipsia because more than two thirds of the retained water is accumulated in the cells, and the persistent hypervolemia is prevented by the increase in renal excretion of Nand water .+ concentration. Although the danger related to severe acute hyponatremia is clear, several clinical and experimental studies suggest that even a rapid correction of hyponatremia can have the same dangerous potential and lead to demyelinating lesions of the central nervous system, within a few days, in particular involving the pons, a disorder called central pontine myelinolysis, or osmotic demyelination syndrome [There is an additional mechanism that can cause neurological symptoms in patients with hyponatremia: too rapid correction of serum Nasyndrome . These n+ may be sufficient. Similarly, if mild hyponatremia is due to an inappropriate or excessive administration of parenteral fluids in a patient suffering from impaired renal excretion of water, the mere suspension of the therapy with hypotonic fluids may be sufficient.Treatment of mild asymptomatic hyponatremia  aims at identifying and eliminating the underlying cause. Thus, in patients with hyponatremia induced by thiazides, diuretic discontinuation, and the correction of deficit of NaThe coexistence of hyponatremia, hyperkalemia, and hypotension should suggest the presence of adrenal insufficiency and may require the administration of intravenous (i.v.) glucocorticoids . When adrenal function is normal and instead hyponatremia is associated with depletion of ECF volume and hypotension, the administration of saline solution usually corrects both hyponatremia and hypotension.+ ≥ 125 mEq/L), and the symptoms are absent or rather veiled. However, dietary water restriction (not more than 500–1000 mL/24 h) together with the treatment of the underlying cause does not restore normal serum Na+ concentrations in the majority of cases. Moreover, the restriction of water intake is poorly tolerated by the patient for the bothersome sense of persistent thirst that it can induce.In patients with hypervolemic hyponatremia, detectable in CHF, liver cirrhosis, and nephrotic syndrome, there is typically mild hyponatremia , containing sodium 513 mEq/L, can be associated with slow i.v. infusion of furosemide . Because of the possibility of precipitating additional neurological sequelae , HSS should be used with extreme caution during hyponatremia control. Experts agree that over-correction of hyponatremia is dangerous; hypernatremia and even normonatriemia should be avoided.+ to more than 1 mEq/L/h; similarly, they suggest that the absolute increase has to be maintained at no higher than 8 mEq/L/24 h. The following algorithm is a reasonable compromise: 250 mL of 3% HSS should be administered as a slow i.v. infusion coupled with an i.v. drip of furosemide (80 mg at a rate of no more than 15 mg/h); thereafter, serum Na+ should be determined after no more than 10 h. If the values remain excessively low, the infusion may be repeated, keeping the increase in serum Na+ within the limit of 8 mEq/L/24 h.Therefore, several experts advise against raising serum Na+ losses induced by the diuretic [Furthermore, in hyponatremic CHF patients , the abovementioned combination therapy with i.v. HSS plus a loop diuretic such as furosemide should be complemented by the administration of KCl to replenish the Kdiuretic ,20. In aFor the treatment of hyponatremia during CHF, especially when judged unresponsive to the combination therapy of HSS plus furosemide, another major option is administration of a VRA.The vasopressin receptor antagonists (VRAs) are a class of drugs known to be efficacious and safe for hyponatremia treatment. In recent years, they, in particular tolvaptan, have assumed major importance compared with conventional therapeutic approaches  for the treatment of hyponatremia ,25,26,27Among the VRAs, only oral tolvaptan is marketed in Europe, with the indication for euvolemic hyponatremia caused by a syndrome of inappropriate antidiuretic hormone secretion (SIADH). On the contrary, in the USA and Japan, i.v. conivaptan (V1A/V2 receptors antagonist) and oral tolvaptan are available on the market for the treatment of both euvolemic and hypervolemic hyponatremia ,29. AsidHeart failure is a plausible indication for therapy with VRAs because, even in this condition, AVP plays an important role. In heart failure, the stimulation of the supraoptic and paraventricular nuclei of the hypothalamus, i.e., the neuronal sites of AVP synthesis and secretion, is realized by a nonosmotic mechanism . Indeed,Numerous studies confirm the association of hyponatremia with increased morbidity and mortality in patients hospitalized with acute decompensated heart failure or in outpatients with CHF ,33,34. TThe effects of tolvaptan were evaluated extensively in this patient population. The largest study is the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) , which iThese positive effects were achieved without adversely affecting heart rate, blood pressure, or serum electrolytes. Furthermore, no clinically significant changes in renal function parameters were recorded, although there was a slight increase in serum creatinine. However, the EVEREST program showed that treatment with tolvaptan did not have any effect on long-term mortality or morbidity related to heart failure during a median follow-up of 9.9 months , as alsoMoreover, the possibility of coupling a VRA with a loop diuretic in the treatment of CHF has been seriously considered by several researchers ,37. In pHyponatremia is the most common electrolyte disorder observed in hospitalized patients. It is associated with an increased risk of morbidity and mortality and an increased length of hospital stay. Even the conditions of mild chronic hyponatremia may have significant clinical consequences, such as attention deficit, gait disturbance, falls, increased risk of fractures, and reduction in bone mineral density.Awareness of the importance of an accurate diagnosis and appropriate treatment is not yet adequately widespread , althougIndeed, tolvaptan in particular proved to be a therapeutic weapon that is specific and effective not only for the treatment of SIADH but also for the conditions of hypervolemic hyponatremia such as CHF, where the primary cause of hyponatremia is increased ADH release .Increased attention to the problem of hyponatremia also raises a question: Can hyponatremia be regarded just as a marker of disease severity? Or alternatively should it be considered as a pathological alteration in itself that must be diagnosed and treated? In light of the many studies on this issue, the second approach is probably correct, that is, hyponatremia must be considered as a disorder to be dealt with adequately because in this way the patient's quality of life can be improved .There is convincing evidence that the use of VRAs is more efficacious than other measures (water restriction and HSS plus furosemide) in the restoration of normal levels of serum sodium in patients with CHF associated with chronic hyponatremia . In addi


However, there is little evidence that phenylephrine augments HPV in clinical situations. This study aimed to evaluate the clinical effects of phenylephrine infusion on oxygenation during one-lung ventilation (OLV) in patients undergoing thoracic surgery.Phenylephrine is an αP < 0.05 was considered statistically significant.This was a prospective, randomized, double-blind, cross-over study. Included patients were those undergoing elective thoracic surgery in the lateral decubitus position with OLV. Patients were randomly allocated to two groups. The N-P group initially had OLV with normal saline infusion for 30 minutes; after a 10 minute interval, OLV was then maintained with phenylephrine infusion for 30 minutes. The P-N group had the drug-infusion in the reverse order. The primary outcome was arterial partial pressure of oxygen. Secondary outcomes were mean arterial pressure, heart rate, pulse pressure variation, perfusion index, and difference between bladder and skin temperature. Statistical analysis was performed using the student t-test, Fisher's exact test, and ANOVA for Cross-over design. P < 0.001), arterial partial pressure of oxygen did not differ between the two timepoints (P = 0.19). There was no carryover effect in arterial partial pressure of oxygen (P = 0.14). Phenylephrine infusion significantly decreased heart rate (P = 0.02) and pulse pressure variation (P < 0.001).Twenty-nine patients were analyzed. Although phenylephrine infusion significantly increased mean arterial pressure (Phenylephrine infusion did not improve oxygenation during OLV. The present results indicate that phenylephrine does not have clinically meaningful effects on HPV.000024317University Hospital Medical Information Network  Hypoxemia during one-lung ventilation (OLV) occurs in 5–10% of patients, and may affect the patient safety. Perfusi1 adrenergic receptor agonist that causes pulmonary vasoconstriction. Phenylephrine administration may effectively enhance HPV[2) during OLV. The aim of the present study was to evaluate the clinical effects of phenylephrine infusion on oxygenation during OLV in patients undergoing thoracic surgery.Phenylephrine is an αhance HPV; howeverhance HPV, 5. To thance HPV, reportihance HPV. Our hypThis manuscript adheres to the applicable CONSORT guidelines. The supporting CONSORT checklist and protocol are available as Inclusion criteria were: patients with American Society of Anesthesiologists physical status I–III undergoing elective thoracic surgery in the lateral decubitus position with at least 70 minutes of OLV. The original exclusion criteria were: history of stroke, uncompensated cardiac disease, or bradycardic arrhythmia. However, as arrhythmia affects the measurement of pulse pressure variation (PPV)[2), end-tidal carbon dioxide tension (ETCO2), PPV, perfusion index (PI) derived from the pulse oximeter plethysmographic waveform, bladder temperature, and skin temperature of the hand were continuously monitored . Intravenous fluid therapy consisted of 6% hydroxyethyl starch in saline  at a rate of 80 ml/h, and 4.3% dextrose solution  at a rate of 20 ml/h. If the mean arterial pressure (MAP) was less than 50 mmHg, a bolus of ephedrine (4 mg) was administered.Before induction of general anesthesia, a thoracic epidural catheter  was placed at T4 to T7 according to the incision level, and 3 mL mepivacaine 1% without epinephrine was administered. General anesthesia was induced with target-controlled infusion of propofol (2–4 μg/mL), remifentanil (0.3 μg/kg/min), and rocuronium (0.6 mg/kg). Anesthesia was maintained with target-controlled infusion of propofol (2–4 μg/mL) and remifentanil (0.1–0.5 μg/kg/min), and intermittent bolus administration of rocuronium (10 mg). Bispectral index (BIS) values were monitored using a BIS Quatro sensor , and the propofol infusion rate was adjusted to maintain BIS values between 40 and 60. No volatile anesthetics were used. The rate of remifentanil infusion was tailored to control hemodynamic responses. Rocuronium was used to maintain a train-of-four ratio of 1 or less . Heart rate (HR), direct arterial blood pressure, electrocardiogram, BIS, peripheral oxygen saturation (SpO2) of 1.0, tidal volume of 5–7 mL/kg of ideal bodyweight, and respiratory rate of 12 breaths/min; this was adjusted to maintain an ETCO2 of 35–45 mm Hg and a positive end-expiratory pressure of 6 cmH2O. The patients were randomly allocated to one of two groups using internet-based software in a complete randomization manner . The allocation was blinded for the patients, anesthesiologists, and surgeons. In the N-P group, 10 minutes after each patient’s chest was opened, OLV was initially maintained with a normal saline infusion (20 mL/h) for 30 minutes; after a 10 minute interval, OLV was then maintained with a phenylephrine infusion (15 μg/min) for 30 minutes. In the P-N group, 10 minutes after each patient’s chest was opened, OLV was initially maintained with a phenylephrine infusion (15 μg/min) for 30 minutes; after a 10 minute interval, OLV was then maintained with a normal saline infusion (20 mL/h) for 30 minutes. At the end of each drug infusion, arterial blood analysis was performed with a blood gas analyzer , and the MAP, HR, PPV, and PI were recorded. These measurements were recorded before any major pulmonary vessel clipping. The anesthetic management after these measurements was at the discretion of the anesthesia care provider.The trachea was intubated with a left-sided double-lumen tube (DLT) . Positioning of the DLT was confirmed by fiberoptic bronchoscopy before and after placing the patient in the lateral decubitus position. Lung separation was confirmed by auscultation. During OLV, the lumen of the non-dependent lung was left open to air. The patients’ lungs were ventilated using an Aisys Pro anesthetic machine  with an inspired oxygen fraction . Originally, we calculated the required sample size as 35 patients using between-subject variation as follows. To detect a difference of 30 mmHg in PaO2 during OLV with a two-sided approximation accepting an α error of 5% and a β error of 20%, the required study size was calculated as 29 patients based on a previous study using Power and Sample Size Calculation version 3.1.2 [2 during OLV in 40 minutes was 33 mmHg in the present study. To detect a difference of 30 mmHg in PaO2 with a two-sided approximation accepting an α error of 5%, the power was calculated as 0.925. All data were expressed as means with standard deviations or with 95% confidence intervals. Statistical analysis was performed using the student t-test, Fisher's exact test, and ANOVA for Cross-over design . P < 0.05 was considered statistically significant. All data were deposited in the public repository (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000028009).The primary outcome was PaOille, TN). To accoThe CONSORT diagram is shown in Of 50 patients considered eligible for the study, 13 patients were excluded due to a history of stroke or presence of a current arrhythmia, and two patients declined to participate. A total of 35 patients were included in the study; however, only the data from 29 patients were analyzed, as six patients did not receive their allocated intervention due to protocol violations. P = 0.04), although this difference was only a mean of 6 beats/min. No patient was hypoxemic before the interventions.There was no significant difference between groups in the patient demographics and surgical characteristics. Most patients underwent lobectomy. No patient had severe respiratory dysfunction, received preoperative β-blocker medications, or was transfused perioperatively. The primary and secondary outcomes are shown in Tables 2 did not significantly differ between the two timepoints. Phenylephrine infusion significantly decreased HR and PPV. There was no difference in PI and ΔT between the two timepoints. There was no carryover effect in the primary and secondary outcomes. The period significantly affected the PaO2 and HR.No patient had difficulty with operated lung isolation using the DLT during OLV. There were no hypoxemic episodes or vasodilator administrations during the study period. Although phenylephrine infusion significantly increased the MAP by about 30%, the PaOThe hemodynamic and arterial blood gas data are shown in Tables 2. There was no period effect among the other hemodynamic and arterial blood gas parameters. There were some differences in peak inspiratory pressure and ETCO2 between the two timepoints. No patient had any surgical or other perioperative complications.Carryover effects were detected in pH and PaCO2 during OLV. However, phenylephrine infusion increased the MAP by about 30%, and decreased the HR and PPV. Phenylephrine infusion did not significantly change the PI and ΔT compared with saline infusion. To the best of our knowledge, the present study is the first to evaluate the clinical effects of phenylephrine infusion on oxygenation and other hemodynamic indices during OLV.Phenylephrine infusion at a rate of 15 μg/min did not have clinically meaningful effects on the PaO2. The first phase of HPV begins within 1 minute and reaches a plateau at 15 minutes, while the second phase of HPV begins after 40 minutes of hypoxia and peaks at 2 hours[2. We usually ventilate patients with an FIO2 of around 0.5 during OLV. We do not consider a difference in PaO2 of less than 10 mmHg to be clinically meaningful during positive ventilation in a patient with an FIO2 of 0.5. We determined the clinically significant difference in PaO2 as 30 mmHg during positive ventilation with an FIO2 of 1.0, which means a difference of 15 mmHg with an FIO2 of 0.5. We believe that using a difference of 30 mmHg in PaO2 is appropriate, as previous studies have used a difference of 40 mmHg[We designed the present study as a crossover trial. The crossover design can decrease the required sample size, as each subject serves as his or her own control. The short-lasting effects of phenylephrine make it suitable for use in a crossover trial. Phenylephrine is a short-acting drug that decreases blood pressure by 50% in 2–3 minutes. We chosf 40 mmHg, 11.2 from 94 ± 8 to 109 ± 12 mmHg in patients with acute respiratory distress syndrome[2 during OLV. Schloss et al.[2 in a 12-year-old female who underwent OLV for anterior-posterior supine fusion. Her SpO2 was only 90–92% with OLV applying continuous positive airway pressure to the non-dependent lung[2 to 96–98%[2 from 100 mmHg to 150 mmHg in a 59-year-old female who underwent general anesthesia with two-lung ventilation. It seems that the pulmonary vessels in these two previous patients still had the ability to constrict in response to phenylephrine, as there was oxygen in the lungs. It is plausible that phenylephrine infusion may be able to improve oxygenation only when the pulmonary arteries are not fully constricted. Phenylephrine infusion might be effective when the patients are hypoxemic under OLV with continuous positive airway pressure applied to the non-dependent lungs. However, further studies are needed to prove this hypothesis.The present results show that phenylephrine infusion did not enhance HPV during OLV. This differs from the results of Doering et al., who fou syndrome; phenyle syndrome. Doering syndrome speculat syndrome is that to 96–98% reportedWe selected the infusion rate of 15 μg/min based on a previous study and our own experiences. Allen e1 stimulation constricts the splanchnic capacitance vasculature, which is dilated under general anesthesia, and increases venous return and cardiac preload[2, and PaCO2 between the two timepoints. However, we consider these differences to be clinically irrelevant. The increase in ETCO2 might have resulted from increased cardiac output due to the aforementioned-increase in cardiac preload.Phenylephrine infusion decreased the PPV in the present study, which is similar to the results of a previous study. Rebet ec preload. Althougc preload, at leasc preload, 18. In Our study has several limitations. First, we did not measure cardiac output or intrapulmonary shunt fraction, because the ethics committee of Kagoshima University Hospital declined our request of the insertion of esophageal doppler device or transesophageal echocardiography. We were not able to analyze the effects of phenylephrine on cardiac output or intrapulmonary shunt fraction, although these parameters directly affect oxygenation . Second,Phenylephrine infusion does not have clinical effects on oxygenation in patients undergoing OLV. Phenylephrine infusion should be used to stabilize patients’ hemodynamic status, not to improve oxygenation during OLV.S1 Fig(DOC)Click here for additional data file.S1 FileStudy protocol in English.(DOCX)Click here for additional data file.S2 FileStudy protocol in Japanese.(PDF)Click here for additional data file.


Pharmacists can assist patients in managing their blood pressure levels. We assessed whether adherence to blood pressure medication improved among people who used community pharmacies in rural Montana after pharmacists initiated consultations and distributed educational materials developed for the Million Hearts Initiative’s “Team Up. Pressure Down.” (TUPD) program.From 2014 to 2016, the Cardiovascular Health Program at the Montana Department of Public Health and Human Services conducted a statewide project to evaluate an intervention for adherence to blood pressure medication administered through community pharmacies. After the year 1 pilot, we redesigned the program for year 2 and year 3 and measured the percentage of participating patients who adhered to blood pressure medication. We also conducted a statewide survey to assess pharmacy characteristics, computer-system capabilities, and types of consulting services provided by pharmacists.Twenty-five community pharmacies completed Montana’s TUPD program: 8 pharmacies in the pilot year, 11 pharmacies in year 2, and 6 pharmacies in year 3. For year 2 and year 3 combined, the percentage of participating patients who achieved blood pressure medication adherence improved preintervention to postintervention from 73% to 89%, and adherence improved in 15 of the 17 pharmacies. The pilot pharmacies identified 3 major barriers to project success: patient buy-in, staff burden in implementing the project, and funding. In the statewide assessment, TUPD-funded pharmacies were significantly more likely than non-TUPD–funded pharmacies to provide prescription synchronization and medication management with feedback to the patient’s physician.Community pharmacies in rural areas can effectively use brief consultations and standard educational materials to improve adherence to blood pressure medication. Medscape, LLC, is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit.In support of improving patient care, this activity has been planned and implemented by Medscape, LLC, and Preventing Chronic Disease. Medscape, LLC, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Medscape, LLC, designates this Journal-based CME activity for a maximum of 1.00 http://www.medscape.org/journal/pcd; (4) view/print certificate.All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at Release date: June 29, 2017; Expiration date: June 29, 2018Upon completion of this activity, participants will be able to:Assess the effectiveness of a pharmacy-based program to improve adherence to antihypertensive drugs in a rural stateDistinguish the most common barrier among pharmacies to an adherence program in a rural stateDistinguish barriers cited by patients to an adherence program in a rural stateEvaluate differences in rural pharmacy practice based on their participation in the antihypertensive adherence program in a rural stateEDITOREllen Taratus, MSPreventing Chronic DiseaseEditor, Disclosure: Ellen Taratus has disclosed no relevant financial relationships.CME AUTHORCharles P. Vega, MDHealth Sciences Clinical Professor, UC Irvine Department of Family Medicine; Associate Dean for Diversity and Inclusion, UC Irvine School of Medicine, Irvine, CaliforniaDisclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: McNeil Consumer Healthcare Served as a speaker or a member of a speakers bureau for: Shire PharmaceuticalsAUTHORSCarrie S. Oser, MPHCardiovascular Health Program, Montana Department of Public Health and Human Services, Helena, MontanaDisclosure: Carrie S. Oser, MPH, has disclosed no relevant financial relationships.Crystelle C. Fogle, MBA, MS, RDCardiovascular Health Program, Montana Department of Public Health and Human Services, Helena, MontanaDisclosure: Crystelle C. Fogle, MBA, MS, RD, has disclosed no relevant financial relationships.James A. Bennett, RPh, CDM, CDETransforming Chronic Care, Bozeman, MontanaDisclosure: James A. Bennett, RPh, CDM, CDE, has disclosed the following relevant financial relationships:Served as a speaker or a member of a speakers bureau for: Johnson & Johnson Diabetes InstituteEmployed by a commercial interest: Bennett Apothecary Powered by Walgreens in Corinth, Mississippi (part-time diabetes educator/pharmacist)High blood pressure is a controllable risk factor for cardiovascular diseases  . HoweverA meta-analysis of 7 randomized controlled trials showed that adherence to blood pressure medication increased more in the pharmacist-led interventions than in the control groups . In the Pharmacy-based interventions are also effective in improving medication adherence among people in racial/ethnic minority populations ,5. We foOnly 2 interventions that we reviewed ,8 providWe evaluated whether patients’ adherence to blood pressure medication improved in rural Montana when we used pharmacy consultations in combination with educational materials that were developed for the Million Hearts Initiative’s “Team Up. Pressure Down.” (TUPD) and were designed for community pharmacists and their patients . Our secThis study consisted of 2 components: 1) a 3-year (February 2014–June 2016) intervention to improve adherence to blood pressure medication among people using community pharmacies in rural Montana and 2) a statewide assessment (November 2015–February 2016) of pharmacy characteristics, computer-system capabilities, and types of consulting services provided.Montana is the fourth largest state geographically but is ranked 48th in the United States for population density, with only 6.8 persons per square mile . Much ofIn 2014, the Montana Cardiovascular Health (CVH) Program at the Department of Public Health and Human Services (DPHHS) initiated a project with 9 community pharmacies in Montana to conduct and evaluate a blood pressure medication adherence intervention. However, one funded pharmacy did not complete the project because of problems with business structure and staffing. The project used an implementation study design and 3 cohorts . The proFebruary–June 2014: Pilot project completed with 8 pharmaciesJune–August 2014: Formative evaluationAugust 2014–June 2015: Year 2 cohort — 11 pharmaciesAugust 2015–June 2016: Year 3 cohort — 6 pharmaciesNovember 2015–February 2016: Community pharmacy assessmentThe University of Montana’s Skaggs School of Pharmacy provided a list of 258 community pharmacies in Montana. A community pharmacy is designated by the Montana Department of Labor and Industry as a pharmacy that serves customers in a retail setting, such as a pharmacy chain or an independent pharmacy, rather than in an institutional setting, such as a hospital. To recruit pharmacies for the pilot project, the CVH Program mailed an application to all 258 community pharmacies listed, and the Montana Pharmacy Association emailed the announcement to its members. In addition, Montana’s Medicare Quality Innovation Network–Quality Improvement Organization helped recruit pharmacies and disseminate project materials.Montana DPHHS staff members reviewed 9 applications for the pilot year. The criteria for funding included providing an estimate of the number of patients in the pharmacy who were taking blood pressure medication and the number of patients to be tracked and providing an adequate description of a project plan, including selecting, tracking, and following up with patients. Applicants also were required to describe components that could be continued by the pharmacy without external funding. In the pilot year, all 9 applicants met the application criteria and were funded. Using a similar application and notification process, we funded 2 more cohorts: 11 pharmacies in year 2 and 7 pharmacies in year 3 (one of which did not complete the project because of a staffing shortage). Each pilot pharmacy was required to recruit at least 25 patients. Participants were required to meet the following minimum criteria: 1) being an adult aged 18 years or older, 2) having had at least one pharmaceutical claim during the previous calendar year , and 3) having had at least one current prescription for a medication to lower blood pressure. Pharmacies were permitted to customize approaches for identifying and recruiting participants .As part of the project, pharmacies conducted a brief consultation with each participating patient. During the consultation, the pharmacist discussed medication management and changes in lifestyle behavior to help improve the patient’s medication adherence and blood pressure control. We asked the pharmacies to disseminate TUPD’s patient-education materials and information on the Dietary Approaches to Stop Hypertension (DASH) program  and to rDuring the pilot program, pharmacies measured medication adherence by 1) calculating the number of days of refill for a blood pressure medication for each participating patient or 2) using another standard method, such as calculating the percentage of participating patients who achieved blood pressure medication adherence, measured as the proportion of days covered (PDC) by prescription claims as 80% or greater (based on prescription fill date and days of supply). We did not require pharmacies to adhere to a particular method of calculating adherence. Some pharmacies electronically tracked prescription fill dates, and others used an Excel (Microsoft Corp) spreadsheet.Although the pilot project was designed initially to be implemented during a 10-month period, it was implemented during a 4-month period because of a delay in budget approval. After the conclusion of the pilot program, we obtained feedback from the pilot pharmacies and modified the intervention for year 2 and year 3. We also sought federal guidance on a standard definition of medication adherence  and requIn year 2 and year 3, in addition to other program improvements , we requ• Standardized the definition of medication adherence • Expanded project time frame from 4 months to 10 months• Increased the minimum number of patients required to participate from 25 to 35 (year 3 only)• Doubled the funding award to pharmacies as an incentive for participation• Offered 2 training options for pharmacists: a home-study blood pressure curriculum and a 1-day hands-on hypertension workshop on accurate blood pressure measurements, current guidelines, lifestyle changes, and medication management• Provided additional resources to each participating pharmacy: blood pressure cuffs for on-site use and 7-day pill boxes for participating patients• Provided a sample letter that pharmacists could send to health care providers informing them of their patients’ participation in the project• Provided a sample press release that pharmacists could send to the local news media to inform their community of the project• Created an Excel (Microsoft Corp) tracking program for such patient interventions as medication therapy management and lifestyle counseling• Organized a conference call in which a previously participating pharmacist oriented newly participating pharmacists• Hired a consulting pharmacist, who owns a community pharmacy, to provide technical assistance and engage pharmacists on a peer-to-peer basisThe CVH Program collected data from reports filed one month after the project began and final reports. Pre-intervention and postintervention data were collected on medication adherence at the start and end of each of the 3 project periods. The CVH Program developed a final report template that community pharmacies completed at the end of each project period. The final report gave information on barriers, lessons learned, sustainable components, and suggestions for improvement. The final reports also provided data on types of counseling provided and pharmacists’ perceptions of the usefulness of TUPD materials and resources. Lastly, the final report provided aggregate data on the percentage (numerator and denominator) of participating patients who adhered to their blood pressure medication schedule. In addition, for year 2 and year 3, the CVH Program periodically requested interim feedback from the participating pharmacies on progress made and barriers encountered. A consulting pharmacist reviewed the feedback and made suggestions to address barriers as part of his technical assistance.From November 2015 through February 2016, the CVH Program conducted a statewide assessment of community pharmacies to collect data required by CDC to measure grant performance. In October 2015, the CVH Program and a community pharmacist reviewed and revised a survey instrument that the program had designed and used in a statewide assessment in 2013. In November 2015, the Montana Department of Labor and Industry provided a list of licensed community pharmacies. We merged this list and the TUPD recruitment list from the Skaggs School of Pharmacy and eliminated duplicate pharmacies by matching license number, business name, and city, which yielded 259 community pharmacies. The survey, which was mailed, collected information on pharmacy characteristics (the number of pharmacists and pharmacy technicians); computer-system capabilities ; provision of prescription synchronization ; reimbursement of medication therapy management from Mirixa or OutcomesMTM, 2 leading vendors of medication therapy management services in Montana; and the types of consulting services provided by pharmacists. Medication therapy management is a service provided by pharmacists to optimize drug therapy and improve health outcomes.For year 2 and year 3 of the intervention, we aggregated the data from the final reports for medication adherence  from each pharmacy. Details on the calculation of PDC, including definition of terms, unit of analysis, and determination of numerators and denominators, are available elsewhere . To gene2 tests to assess any differences in pharmacy and consultation services offered by pharmacists, such as consultation on blood pressure medication adherence, between pharmacies funded by TUPD and pharmacies not funded by TUPD. We also used the nonparametric Mann–Whitney U test to compare differences between pharmacies funded by TUPD and pharmacies not funded by TUPD in the number of pharmacists and pharmacy technicians. A P value of < .05 was considered significant.For the community pharmacy assessment, we analyzed data using IBM SPSS Statistics version 21 (IBM Corporation). We used χTwenty-five community pharmacies completed Montana’s TUPD project: 8 in the pilot year, 11 in year 2, and 6 in year 3. All 25 pharmacies submitted a final report. For year 2 and year 3 combined (17 pharmacies), 534 patients completed the TUPD project, with 360 in year 2 and 174 in year 3; the aggregated percentage of participating patients who achieved blood pressure medication adherence increased from 73% pre-intervention to 89% postintervention . Blood pThe pilot pharmacies identified 3 major barriers to project success: patient buy-in, staff burden in implementing the project, and funding. A lack of awareness of the importance of controlling blood pressure, a lack of willingness or interest in project participation, and lack of recognition of the benefits of participation were major obstacles among patients. Staff burden was the most common barrier reported by the pharmacies. Adding another program to a busy schedule was difficult. A lack of time limited the ability of the pharmacists to provide customer service and pharmacy counseling beyond the core task of dispensing medication. In the pilot project, the pharmacists’ suggestions for enhancing the project included developing a template for tracking patients, a notification letter to health care providers, and a checklist of topics to discuss with patients. These resources were added in year 2 and year 3. Other recommendations  will be added in year 4.Feedback from year 2 and year 3 indicated that involving the entire pharmacy team in the project helped reduce the burden of work on the pharmacists. For example, one pharmacy created a system in which TUPD materials were attached to a patient’s medication refill. When the patient picked up the refill, the pharmacy technician notified the patient that the pharmacist wanted to speak with him or her. Another pharmacy involved the pharmacy technicians in using an alert system (tracking sheet) when a study patient was in the pharmacy so that pharmacists could provide consultations.TUPD-funded pharmacies reported that TUPD materials and resources were useful. Although all participating pharmacies reported distributing TUPD materials, pharmacists reported only 75% of project participants received these materials because some patients refused them. Pharmacists noted that the wallet card and journal were helpful and of interest to patients, although they noted that some of the materials could be written more concisely. Additionally, 21 pharmacies reported their pharmacists provided lifestyle counseling and medication therapy management to their patients with hypertension.The pharmacists noted that most of their patients appreciated the extra attention they received during the consultations. Pharmacists adjusted the length of the consultation according to the interest level and needs of each patient. Three pharmacists suggested that the TUPD project may be most suitable for patients with a new diagnosis of hypertension because patients with long-term hypertension had already found ways to manage their condition. One pharmacy lost many project participants because of the participants’ transient employment (oil workers). In addition, 13 pharmacies noted difficulty tracking patients . Three pharmacies found opportunities to collaborate with patients’ providers to improve blood pressure control.Twenty pharmacies reported plans to sustain at least one project component to foster medication adherence .The response rate for the community pharmacy assessment conducted was 46% (120 of 259). The average number of pharmacists per pharmacy in Montana was fewer than 3 . We founOur findings indicate that it is feasible for community pharmacies in rural areas to provide their patients with brief consultations and TUPD educational materials on how to improve blood pressure medication adherence. Our results are similar to those reported in other studies, which found that pharmacist interventions could significantly improve medication adherence ,8,18,19.Our study differed from most other studies in that ours focused only on rural pharmacies. Although one study did examine rural Minnesota pharmacies, it was a biennial pharmacy workforce survey of outpatient pharmacies rather than an intervention . Also, wOur results suggest that the pharmacies were able to customize the project to fit their needs. In addition, our findings indicate that major components of the project can be integrated into the usual practice of community pharmacies in rural areas. Pharmacies that were already being reimbursed for medication therapy management or that synchronized refills may have been more willing to participate in this project because of their experience in patient consultations.This project has several limitations. First, our study did not include a control group; however, because this was a project evaluation and not a research project, a control group may not have been needed. Second, pharmacies were not required to collect data on patients’ blood pressure control. We did not institute this requirement because of limited pharmacist time, lack of adequate funding, and difficulty in bringing participants in for measurement. Since we did not require pharmacies to collect data on patients’ blood pressure, we could not conduct additional analyses. However, some participating pharmacies used a blood pressure cuff for on-site measurement, and some made the cuff available to nonparticipating patients. Third, because of the small sample of pharmacies, the results of our study may not be generalizable to all pharmacies. We expect to have a larger sample size for study when additional pharmacies are funded for 2 more years. Fourth, this project assessed only the perceptions of the pharmacists and not those of other stakeholders . Lastly, because of the annual funding cycle of the CDC grant, we did not investigate long-term medication adherence. Despite these limitations, our project results suggest that community pharmacies in rural areas can use brief consultations and TUPD materials to improve blood pressure medication adherence.The TUPD project could be expanded to other states that have community pharmacies in rural areas. In year 2, the DPHHS diabetes program broadened the TUPD project by conducting a similar project with 7 of the pilot pharmacies, targeting pharmacy patients taking blood pressure and diabetes medications. Also, in 2016 the state asthma control program recruited 2 of the pilot pharmacies to address asthma medication adherence. This expansion of the TUPD blood pressure approach indicates the willingness of community pharmacies to work on chronic disease management. Future research should evaluate whether the TUPD strategy also improves medication adherence for patients with other chronic conditions such as diabetes or asthma. In addition, research could assess blood pressure control and medication adherence in community pharmacies in rural areas.