Changing concepts in hypertension management.

Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with anti-hypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. The recent trials SPRINT and HOPE-3 will lead to changes in the way we manage hypertension and impact on clinical practice guidelines. These studies also demonstrate the shift toward automated blood pressure measurements. We have reviewed these studies and others to put them in context with the guidelines that have come before and to describe how they will impact on hypertension treatment thresholds and targets, the treatment of hypertension in the elderly, and changing approaches to the management of hypertension including resistant hypertension.

Intraclass differences among antihypertensive drugs.

The four major classes of antihypertensive drugs­diuretics, ß-blockers, calcium channel blockers, and renin-angiotensin system inhibitors (including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers)­have significant qualitative and quantitative differences in the adverse effects they cause. Structural and chemical differences have been identified within these classes, especially among the calcium channel blockers and, to a lesser extent, among the thiazide/thiazide-like diuretics. However, it has been more difficult to demonstrate that these differences translate into differential effects with respect to either the surrogate endpoint of blood pressure reduction or, more importantly, hypertension-related cardiovascular complications. Based on a hierarchy-of-evidence approach, differences are apparent between hydrochlorothiazide and chlorthalidone based on evidence of moderate quality. Low-quality evidence suggests atenolol is less effective than other ß-blockers. However, no significant intraclass differences have been established among the other classes of antihypertensive drugs.

Hypertension management initiative prospective cohort study: comparison between immediate and delayed intervention groups.

The Heart and Stroke Foundation of Ontario's Hypertension Management Initiative (HMI) was a pragmatic implementation of clinical practice guidelines for hypertension management in primary care clinics. The HMI was a prospective delayed phase cohort study of 11 sites enrolling patients in two blocks starting 9 months apart in 2007. The intervention was an evidence-informed chronic disease management program consisting of an interprofessional educational intervention with practice tools to implement the Canadian Hypertension Education Program's clinical practice guidelines. This study compares the change in blood pressure (BP) from baseline to 9 months after the intervention between groups. In the immediate intervention group, the mean BP at baseline was 134.6/79.1 mm Hg (18.2/11.5) and in the delayed intervention group 134.2/77.1 mm Hg (18.9/11.8). The fall in BP in the immediate intervention group from baseline to 9 months after the intervention was 7.3/3.6 mm Hg (95% confidence interval (CI): 5.9-8.7/2.6-4.5) and in the delayed group 8.1/3.3 mm Hg (95% CI: 7.0-9.3/2.5-4.1) (all P<0.0001 were compared from baseline to the end of 9 months of the program in both groups). This study is the first to demonstrate that implementation of an interprofessional knowledge integration initiative for the control of hypertension can rapidly lead to lower BP levels.

Reporting on sex-based analysis in clinical trials of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker efficacy.

BACKGROUND: Clinical practice recommendations for hypertension do not make recommendations specific to men or women. However, the sex hormones appear to modulate differently the renin-angiotensin system (RAS), which plays a central role in the regulation of blood pressure. Today, little is known about the effects of sex on the efficacy of therapies that antagonize the RAS, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). OBJECTIVE: To identify randomized controlled trials evaluating the efficacy of ACEIs and ARBs in preventing major cardiovascular outcomes, determine what proportion of the trial participants were female, and evaluate whether there was any evidence of a sex difference in the efficacy of these agents. METHODS: A systematic review of the literature was conducted to identify randomized controlled trials that used either ACEIs or ARBs for the treatment of hypertension. RESULTS: Thirteen ACEI trials and nine ARB trials were identified. Sex-specific outcome data were available in six of the ACEI trials and three of the ARB trials. These trials enrolled 74,105 patients; 39.1% were women. Seven of the nine trials indicated that ACEIs or ARBs may be slightly more beneficial in men. The magnitude of these differences, in most trials, was small. CONCLUSIONS: Sex-specific data are reported in 43% of large hypertension clinical trials. Review of the trials reporting sex-specific effect sizes indicates that ACEIs and ARBs may be more effective in men.

Peritoneal dialysis: a clinical update congestive heart failure and PD.

BACKGROUND: There is a belief that peritoneal dialysis may be an important treatment modality for refractory heart failure, allowing at least an improvement in quality if not quantity of life during the last stage of this debilitating chronic disease. This paper examines the rationale behind this modality, critically appraises the available literature, calls for more research in the area and puts forward a framework for considering peritoneal dialysis in refractory heart failure. CONCLUSION: When faced with a patient with refractory heart failure admitted to hospital on multiple occasions because of complications of volume overload, the following approach to initiating peritoneal dialysis should be considered: subjects for dialysis must have a minimal blood pressure, and those whose hemodynamic status improves with diuresis, even though they develop a pre-renal picture, may be the best candidates.

Microalbuminuria screening for patients having type 2 diabetes mellitus: who wants to participate?

BACKGROUND AND OBJECTIVES: "Difficult-to-recruit" patients are sometimes less compliant with their care, are more reluctant to seek medical attention and less likely to survive than their "easy-to-recruit" counterparts. They also tend to be excluded from clinical trials. The aim of this paper was to evaluate whether such differences extend to patients' willingness to be screened for diabetic nephropathy in a family practice setting. DESIGN: A cross-sectional study. SETTING: A Canadian university family practice unit. PATIENTS: Two hundred and forty-seven patients with type 2 (adult-onset) diabetes mellitus as identified by computer searches of patient records of approximately 12,000 patients in the family practice unit. INTERVENTION: A cross-sectional secondary preventive screening program obtained urine samples from all patients with type 2 diabetes mellitus, regardless of patients' willingness to participate. MAIN OUTCOME MEASURE: The prevalence of micro- and macroalbuminuria. RESULTS: Of the 247 patients identified, 186 (75%) easy-to-recruit enrollees agreed to participate in screening and 61 (25%) difficult-to-recruit non-enrollees initially declined to be screened. The non-enrollees were subsequently evaluated by their own family physicians as part of routine clinical care and the results were captured for analysis. Overall rates of albuminuria were similar in the easy- and difficult-to-recruit groups (31% versus 38%, p = 0.151). The main predictors of albuminuria were female sex (odds ratio [OR] = 2.1, p = 0.021), duration of diabetes in years (OR = 1.05, p = 0.023), current use of angiotensin-converting enzyme inhibitor (OR = 2.26, p = 0.008) and number of diabetic complications (OR = 1.45, p = 0.028). CONCLUSIONS: There is little difference in the prevalence of albuminuria related to patients' willingness to participate in a screening program. Therefore, there are no disproportionate gains for family practice researchers who aggressively seek difficult-to-recruit patients in this set ting. In contrast, primary care doctors should make every effort to ensure optimal care to diabetic patients regardless of a patient's initial hesitancy.

Continuous veno-venous haemodialysis with a novel bicarbonate dialysis solution: prospective cross-over comparison with a lactate buffered solution.

OBJECTIVE: To compare acid-base balance, lactate concentration and haemodynamic parameters during continuous veno-venous haemodialysis (CVVHD) using bicarbonate or a lactate buffered dialysate. DESIGN: prospective randomized cross-over design; SETTING: Multicentre combined adult surgical and medical intensive care units. Patients; 26 critically ill patients starting CVVHD for acute renal failure. INTERVENTIONS: Each patient to receive 48 h of bicarbonate dialysate and 48 h of lactate dialysate with the order of the 48 h block randomized at trial entry. RESULTS: The serum bicarbonate increased from baseline in both the lactate and bicarbonate groups over the first 48 h of treatment (16.3+/-1.53 to 22.2+/-1.41 mmol/l and 18.9+/-2.02 to 22.2+/-1.18 mmol/l, respectively) and continued to rise towards normal over the next 48 h after cross-over to the other dialysate. The H+ and pCO2 only trended higher in the lactate group. Unlike the acid base parameters, serum lactate levels varied depending on the dialysate composition. The patients initially randomized to the lactate dialysate had higher serum lactate levels and these tended to increase further after 48 h of dialysis from 2.4+/-0.8 to 2.6+/-0.4 mmol/l. However, in the following 48 h the lactate levels fell to 1.8+/-0.6 (P = 0.039) while patients were being treated with the bicarbonate dialysate. Similar results were seen in the patients initially randomized to the bicarbonate dialysate. Serum lactate remained stable over the first 48h (1.4+/-0.2 to 1.5+/-0.1 mmol/l) but after cross-over to the lactate dialysate increased to 3.1+/-0.7 mmol/l (P = 0.051). Overall, lactate levels were significantly higher during dialysis with lactate buffered solution than bicarbonate buffered solution (2.92+/-0.45 vs. 1.61+/-0.25 mmol/l P = 0.01). Mean arterial pressure trended higher during bicarbonate dialysis but did not reach statistical significance (lactate vs. bicarbonate; 71.1+/-3.1 vs. 81.3+/-5.8 mm Hg). Subgroup analysis of the patients with abnormal liver indices or increased lactate levels at initiation of dialysis (n = 15) revealed only a trend toward better bicarbonate control (lactate vs. bicarbonate; 22.00+/-1.73 vs. 22.86+/-1.09, P = 0.2). However, in this group with hepatic insufficiency elevations in serum lactate were even greater during lactate compared to the bicarbonate dialysis (3.39+/-0.68 vs. 1.78+/-0.42 P = 0.036). Patients who had elevations of lactate during lactate dialysis had a high mortality (6 of 7). These patients had an even greater disparity in lactate levels (4.3+/-1.4 vs. 1.3 +/-0.3) and blood pressure (68.0+/- 7.7 vs. 87.2+/-17.1) between lactate and bicarbonate dialysis. Due to small patient numbers these comparisons did not achieve statistical significance. CONCLUSION: During continuous veno venous haemodialysis a bicarbonate buffered dialysis solution provided equal acid-base control but maintained more normal lactate levels than a lactate buffered dialysis solution.

A new sterile bicarbonate dialysis solution for use during cardiopulmonary bypass.

Adding a dialysis filter to the perfusion circuit at the end of cardiopulmonary bypass (CPB) has become an accepted means of reducing potassium rapidly and safely. Rapid removal of solute requires a dialysate for diffusion, and peritoneal dialysis solutions have been the standard because of availability, although occasionally normal saline or bicarb/ saline mixtures are used. Cardioplegia solution is high in glucose as well as potassium and, with many diabetic patients undergoing CPB, it is desirable to minimize glucose loads. In this prospective cohort study, six patients received a commercially available sterile bicarbonate dialysate prepared in a point of care fashion. From the cardiovascular data base, four control patients (receiving lactate based dialysis solution during CPB) were matched for age, surgery type, body surface area (BSA), and pump duration for each of the six patients receiving bicarbonate dialysate. All of the control patients were dialysed against lactate buffered peritoneal dialysis solution. Plasma levels of potassium, glucose, and bicarb were measured before and after dialysis for each dialysate. Plasma potassium, glucose, and bicarb were not significantly different at start of dialysis. The lactate dialysate (LD) group received a mean of 17.4+/-7.7 L of lactate containing dialysate versus 14.6+/-4.7 L of bicarbonate dialysate (BD) (p = 0.41). After dialysis, potassium had been reduced to a similar degree in both groups, but plasma glucose levels had increased during LD while they fell during BD, and bicarbonate levels fell during LD while they rose during BD. Use of a commercially available sterile bicarbonate dialysate can safely help to lower plasma potassium during CPB and preserve more physiologic levels of glucose and bicarbonate.

Determinants of left ventricular mass in early hypertension.

One hundred seventy-six unmedicated mildly hypertensive subjects (113 men, 63 women) underwent M-mode echocardiography to determine left ventricular mass (LVM) and relative wall thickness (RWT), 24-h ambulatory blood pressure monitoring, and completed standardized questionnaires measuring marital and job stress. Subjects were aged 46 +/- 9 years old; 45.4% had daytime diastolic blood pressure < 90 mm Hg; 96.1% of LVM results were in the normal range. We found that neither marital distress nor job strain was a determinant of LVM. However, a segmental regression approach revealed inflection points of 131 mm Hg systolic daytime blood pressure and 83 and 87 mm Hg nighttime diastolic blood pressure in the relation between LVM and RWT, respectively, and ambulatory BP. In addition, we found that the variability of LVM was best explained by indexing LVM by height, rather than body surface area.

Mass balance index: an index for adequacy of dialysis and nutrition.

Determining adequacy of dialysis has remained a problem for the nephrologist despite the results of the National Cooperative Dialysis Study published more than 20 years ago. Urea Kinetics Modelling (UKM) which requires computer data entry is time-consuming for the dialysis staff but is the only method that has been rigorously studied. Furthermore, it is unclear today what value of Kt/V represents ideal dialysis; the technique is subject to a number of errors associated with estimation of dialyser clearance (K) and volume of distribution of urea (V) but it is useful for calculating protein catabolic rate (PCR). Methods that use urea reduction ratios (URR) is widely used because it is simpler but not always accurate and suffer from an inability to calculate PCR. Direct dialysis quantification (DDQ) can overcome a number of these problems but it is too cumbersome for routine use. Simpler methods to determine dialysateside kinetics have the advantage of solving a number of these problems and also facilitate the calculation of PCR to determine the patient's nutritional state. In our study we have demonstrated that by taking two dialysate samples at the beginning and at the end of dialysis (2-DSM), it is possible to determine total urea removal (TUR) which is equivalent to DDQ. By taking blood samples after dialysis and before the next dialysis, it is possible to calculate the total urea generated (TUG). The ratio of TUR/TUG will provide an index of dialysis which places emphasis on removal of solute that has accumulated in the inter-dialytic interval thus re-establishing a state of equilibrium. We refer to this index as the Mass Balance Index (MBI). The MBI is also useful in helping to identify those patients whose PCR is inadequate since the mean MBI for patients with an nPCR <0.8 was 0.93 +/- 0.03 vs 1.08 +/- 0.02 in those with a PCR >0.8. In these two groups of patients the Kt/V was not significantly different, 1.49 +/- 0.07 vs 1.53 +/- 0.06, p -0.64. We suggest that the emphasis for adequacy of dialysis should shift away from Kt/V to maintaining a state of equilibrium by removing the solutes that accumulate between dialysis and by identifying those patients with an inadequate PCR.

Foregoing renal dialysis: a case study and review of ethical issues. The End-Stage Renal Disease Group.

End-stage renal disease is treated by long-term dialysis when renal transplantation is not feasible. At a late stage in the disease, for a variety of reasons, dialysis is frequently stopped. This is one of the most common causes of death in dialysis patients. Ethical issues related to withdrawal of dialysis are therefore commonly encountered in nephrology practices. A case study involving discussions to forego dialysis in an incompetent patient is presented, and the ethical issues raised by this case, particularly related to the concepts of medical futility, informed choice, and justice are discussed. Finally, procedural approaches are suggested that will help to address the ethical problems raised and to assist in decision making at the time that the discontinuation of dialysis is being considered.

Expression of the multiple drug resistance gene in human renal cell carcinoma depends on tumor histology, grade, and stage.

Levels of mRNA expressed by the multidrug resistance gene MDR1 were examined in 23 renal cell carcinoma samples and adjacent normal kidney cortex using reverse-transcription PCR. Comparison of MDR1 levels between histological types revealed that there was on average significantly more MDR1 in clear cell tumors than in oncocytomas (0. 89 +/- 0.10 versus 0.28 +/- 0.20, ratio of MDR1 in tumor cells to the drug-resistant cell line KB-8, P < 0.05). The mean MDR1 level of all of the non-oncocytoma tumors was not significantly different from the mean MDR1 level of normal adjacent kidney (0.89 +/- 0.10 versus 1.11 +/- 0.12, P = 0.07). However, the mean MDR1 level of the more undifferentiated clear cell tumors was significantly lower than the mean MDR1 level of adjacent normal kidney (0.74 +/- 0.10 versus 1.11 +/- 0.12, P < 0.05). MDR1 levels in early stage, clear cell tumors (n = 14) were lower than in tumors that had spread into perinephric tissue or had metastasized (n = 6) (0.77 +/- 0.08 versus 1.24 +/- 0.30, P < 0.05). In conclusion, MDR1 expression decreases in the more undifferentiated tumors, but still remains at levels high enough to be drug resistant. Higher MDR1 expression in the invasive tumors compared with noninvasive tumors suggests that MDR1 expression and invasiveness may be linked.

Phase I-II study of vinblastine and oral cyclosporin A in metastatic renal cell carcinoma.

A phase I-II clinical trial was conducted to determine the maximum-tolerated dose (MTD) of oral cyclosporine (CsA) and vinblastine in patients with metastatic renal cell cancer (RCC) as well as to estimate the response rate. Sixteen patients received a 5 mg/kg oral loading dose of CsA followed by 3 days of CsA in 4 divided daily doses escalating from 10 mg/kg per day up to 17 mg/kg per day. Vinblastine (Vbl) was administered as an intravenous bolus on the morning of the 3rd day with dose escalation from 6 to 10 mg/m2. Cycles were repeated every 4 weeks until tumor progression. Forty-nine cycles of CsA with vinblastine were administered. The maximum tolerated dose of Vbl was 10 mg/m2, with neutropenia as the dose-limiting toxicity resulting in one death. CsA could not be escalated above 17 mg/kg per day because of nausea and vomiting. Other toxicities included constipation (100%), malaise (100%), temporary increase in pain (36%), and one seizure that may have been drug-related. There were no clinically significant changes in renal function or serum bilirubin. Mean peak whole-blood CsA level at the highest CsA dose level was 919 ng/ml (range: 414-1,827) with a trough prior to Vbl injection of 451 ng/ml (range: 128-1,229). There were no tumor responses. The combination of oral CsA and Vbl is not nephrotoxic but is poorly tolerated. In most patients optimal blood levels of CsA for reversal of MDR cannot be reliably achieved, and vinblastine dose intensity must be compromised because of the significant toxicity of this regimen.

Vinblastine and erythromycin: an unrecognized serious drug interaction.

Vinblastine and erythromycin are among the most commonly used chemotherapeutic and antimicrobial agents, respectively. No interaction between the two has ever been reported. Towards the end of a phase I study of vinblastine plus oral cyclosporin (to reverse multidrug resistance), three patients also received erythromycin to raise their cyclosporin levels. All developed severe toxicity consistent with a much higher vinblastine dose than was actually given. This apparent potentiation of vinblastine toxicity has not been previously described.

Peritoneovenous shunting restores atrial natriuretic factor responsiveness in refractory hepatic ascites.

BACKGROUND: Sodium retention in cirrhosis has been attributed to an imbalance between vasoconstrictive, antinatriuretic forces such as the renin aldosterone angiotensin system and the sympathetic nervous system, and vasodilatory, natriuretic agents such as atrial natriuretic factor (ANF). Patients with diuretic resistant refractory ascites may require peritoneovenous shunting (PVS) to control ascites. METHODS: To study the factors responsible for the improvement in sodium homeostasis post-PVS, we compared the response to ANF infusion before and 1 month after PVS in 6 patients with massive ascites. RESULTS: Before PVS, sodium excretion at baseline and in response to ANF infusion was blunted but became more normal post-PVS. ANF infusion post-PVS induced a significant increase in the glomerular filtration rate and filtration fraction and also in distal delivery of sodium. ANF's distal effect of increasing the fractional excretion of distally delivered sodium was present pre-PVS and was not significantly increased post-PVS. Changes in sodium handling were accompanied by a significant decrease in antinatriuretic forces (baseline aldosterone, 2079 +/- 507 vs. 647 +/- 17 nmol/L; P < 0.04) post-PVS. CONCLUSIONS: The improvement in sodium homeostasis and response to ANF infusion post-PVS appears to be associated with the decrease in antinatriuretic forces with the loss of massive refractory ascites. Thus, PVS restores the balance toward ANF responsiveness.

Angiotensin II modulates atrial natriuretic factor-induced natriuresis in cirrhosis with ascites.

Resistance to the natriuretic action of atrial natriuretic factor (ANF) in cirrhosis with ascites has been correlated with rising levels of antinatriuretic factors, such as renin, angiotensin II (AII), and aldosterone, as well as increased sympathetic nerve activity. To determine whether AII can serve as a mediator rather than only as a marker of the antinatriuresis, a nonpressor dose of AII (5 ng/kg/min) was given during an ANF infusion in eight patients with cirrhosis and ascites who responded to ANF infusion with a natriuresis. Patients were maintained in metabolic balance and measurements of para-aminohippuric acid, inulin, and lithium clearance were taken before and during infusion of ANF with or without AII. Atrial natriuretic factor infusion was associated with a natriuretic response accompanied by an increase in glomerular filtration rate, filtration fraction, and lithium clearance compared with baseline. The addition of AII was associated with a return of the glomerular filtration rate to baseline, with no change in filtration fraction. This was reversible on withdrawal of AII infusion. Natriuresis induced by ANF occurred despite baseline elevations of the renin angiotensin aldosterone system and was associated with an increase in distal delivery of sodium and a decrease in fractional reabsorption of distally delivered sodium as estimated by lithium clearance parameters. Angiotensin II infusion exerted effects on both proximal and distal nephron sites to abrogate ANF-induced natriuresis. These results suggest that AII may serve as a mediator as well as a marker of resistance to the natriuretic effect of ANF in patients with cirrhosis and ascites.(ABSTRACT TRUNCATED AT 250 WORDS)

Refractory ascites: modulation of atrial natriuretic factor unresponsiveness by mannitol.

We have previously shown that unresponsiveness to atrial natriuretic factor is a marker of the severity of ascites. The tubular mechanisms are unknown, but it seems that increased reabsorption of sodium proximal to the main site of action of atrial natriuretic factor (i.e., the inner medullary collecting duct) plays an important role. We attempted to decrease the proximal reabsorption of sodium with mannitol in patients unresponsive to atrial natriuretic factor. The results of mannitol in such a group of patients has previously been conflicting. We studied 10 patients with massive, resistant ascites who were off diuretics and on a 20-mmol/day sodium diet for 7 days. Atrial natriuretic factor unresponsiveness was confirmed by failure of a 2-hr atrial natriuretic factor infusion to induce a natriuresis. The next day all patients received an infusion of 40 gm of mannitol and subsequently a combined infusion of mannitol and atrial natriuretic factor. Proximal reabsorption of sodium and water were evaluated by lithium clearance, and glomerular filtration rate and renal blood flow were evaluated by inulin clearance and p-aminohippurate clearances, respectively. Six patients responded to mannitol alone with an increased diuresis (from 39 +/- 7 to 148 +/- 35 ml/hr) and natriuresis (from 0.27 +/- 0.05 mmol/hr to 1.65 +/- 0.53 mmol/hr; p less than 0.05) (responders), whereas four did not (nonresponders). The combination of atrial natriuretic factor and mannitol induced a further significant increase in sodium excretion (3.28 +/- 0.68 mmol/hr) but not in urine excretion, compared with mannitol alone.(ABSTRACT TRUNCATED AT 250 WORDS)