Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics.

BACKGROUND AND AIMS: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. METHODS AND RESULTS: A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. CONCLUSION: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04860011.

Comparing the sodium excreting efficacy of furosemide and indapamide combination against furosemide and metolazone combination in congestive heart failure patients: A randomized control trial.

OBJECTIVE: To compare efficacy and safety of indapamide-furosemide combination against metolazone-furosemide combination in refractory heart failure patients. METHODS: The randomised controlled trial was conducted at Rehman Medical Institute, Peshawar, Pakistan, from January 1 to June 30, 2018, and comprised refractory heart failure patients who were randomised into two groups using lottery method Group 1 received intravenous furosemide 40mg Q12hr with metolazone 5mg Q24hr, while group 2 received intravenous furosemide 40mg Q12hr with indapamide 2.5mg Q24hr. Both groups were assessed for urinary sodium excretion, total urine output and decrease in weight on day one, day three and day five of admission. SPSS 22 was used for data analysis. RESULTS: Of the 150 patients, there were 75(50%) in each of the two groups. Mean age in group 1 was 64.8}11.2 years, while it was 66.3}12.9 years in group 2. Both groups showed increased urinary sodium excretion and total urine output (p>0.05). Hypokalaemia was the most common adverse event 66%. Mean hospital stay was not significantly different between the groups (p>0.05). CONCLUSIONS: There was no significant differences between adverse events and efficacy between patients receiving either indapamide-furosemide combination or metolazone-furosemide combination.

Intravenous Chlorothiazide Versus Enteral Metolazone to Augment Loop Diuretic Therapy in the Intensive Care Unit.

BACKGROUND: In cases of loop diuretic resistance in the intensive care unit (ICU), recommendations for a specific second-line thiazide agent are lacking. OBJECTIVE: To compare the effects of intravenous chlorothiazide (CTZ) and enteral metolazone (MET) on urine output (UOP) when added to furosemide monotherapy therapy in critically ill adults. METHODS: This was a retrospective cohort study conducted in the medical, surgical, and cardiothoracic ICUs of a quaternary medical center. The primary outcome was change in UOP induced by the study interventions compared with furosemide alone. Secondary outcomes included onset of diuresis, eventual need for hemodialysis, and incidence of adverse events. RESULTS: A total of 122 patients (58 in CTZ, 64 in MET) were included. When added to furosemide monotherapy, CTZ induced a greater change in UOP at 24 hours compared with MET (2405 vs 1646 mL, respectively; P = 0.01). CTZ also caused a more rapid dieresis: 1463 mL total UOP in the first 6 hours compared with 796 mL in the MET group ( P < 0.01). There were no differences found regarding ICU length of stay, need for renal replacement therapy, or survival to discharge. The CTZ arm required more potassium supplementation to maintain normokalemia (median 100 vs 57 mEq in MET; P = 0.02) and carried a higher cost (mean $97 vs $8, P < 0.01). CONCLUSION: Both CTZ and MET induced significant increases in UOP. CTZ induced a greater and more rapid change and was associated with higher cost and greater need for potassium replacement. Randomized controlled trials are needed to establish whether a preferable thiazide diuretic exists in this setting.

Design and rationale for the Acute Congestive Heart Failure Urgent Care Evaluation: The ACUTE Study.

BACKGROUND: Heart failure (HF) is one of the leading reasons for emergency department (ED) visits and hospitalization. However, externally validated risk algorithms for acute prognostication of heart failure patients are not available. Thus, many low-risk patients are hospitalized and some high-risk patients are discharged home, which, in some cases, may lead to death. OBJECTIVES: The first objective of the ACUTE study is to perform a prospective validation of the Emergency Heart failure Mortality Risk Grade (EHMRG), which is a risk score derived to predict 7-day mortality in the ED setting. The second objective is to independently validate the 30-day model extension of the risk score (EHMRG30-ST) in the same cohort. STUDY DESIGN: Patients with HF presenting to the ED will be recruited with a waiver of informed consent as a minimal risk study. The ED physician will calculate the EHMRG 7-day risk score, but treatment decisions will not be influenced by the predictive models. Follow-up will be obtained using probabilistic linkage with the Registered Persons Database of vital statistics, whereby deaths will be ascertained. We will examine mortality rates according to EHMRG and EHMRG30-ST algorithms. We will also compare physician-judged risk estimates, based on clinical judgment alone, with the EHMRG score. CONCLUSION: The ACUTE study will determine if a retrospectively derived algorithm for simultaneous estimation of 7-day and 30-day mortality risk can accurately identify low- and high-risk patients with acute HF and improve upon physician-judged risk estimation.

Diuretic exposure in premature infants from 1997 to 2011.

OBJECTIVE: Diuretics are often prescribed off-label to premature infants, particularly to prevent or treat bronchopulmonary dysplasia. We examined their use and safety in this group. STUDY DESIGN: Retrospective cohort study of infants < 32 weeks gestation and < 1,500 g birth weight exposed to diuretics in 333 neonatal intensive care units from 1997 to 2011. We examined use of acetazolamide, amiloride, bumetanide, chlorothiazide, diazoxide, ethacrynic acid, furosemide, hydrochlorothiazide, mannitol, metolazone, or spironolactone combination. Respiratory support and fraction of inspired oxygen on the first day of each course of diuretic use were identified. RESULTS: About 37% (39,357/107,542) infants were exposed to at least one diuretic; furosemide was the most commonly used (93% with ≥ 1 recorded dose), followed by spironolactone, chlorothiazide, hydrochlorothiazide, bumetanide, and acetazolamide. About 74% patients were exposed to one diuretic at a time, 19% to two diuretics simultaneously, and 6% to three diuretics simultaneously. The most common combination was furosemide/spironolactone, followed by furosemide/chlorothiazide and chlorothiazide/spironolactone. Many infants were not receiving mechanical ventilation on the first day of each new course of furosemide (47%), spironolactone (69%), chlorothiazide (61%), and hydrochlorothiazide (68%). Any adverse event occurred on 42 per 1,000 infant-days for any diuretic and 35 per 1,000 infant-days for furosemide. Any serious adverse event occurred in 3.8 for any diuretic and 3.2 per 1,000 infant-days for furosemide. The most common laboratory abnormality associated with diuretic exposure was thrombocytopenia. CONCLUSION: Despite no Food and Drug Administration (FDA) indication and little safety data, over one-third of premature infants in our population were exposed to a diuretic, many with minimal respiratory support.

Formulation, Characterization, and the Diuretic Effects of a New Intravenous Metolazone Emulsion.

OBJECTIVE: Acute decompensated heart failure is often treated with a combination of loop and thiazide-like diuretics. Of these thiazide-like diuretics, two common choices are intravenous chlorothiazide or oral metolazone. Metolazone is more potent and has a longer duration of action, but since it is an oral formulation, it has a longer on-set time as compared to chlorothiazide. In addition, metolazone is poorly water-soluble, thereby rendering intravenous formulation more challenging. To address these issues, we proposed the formulation of a solvent-free metolazone emulsion for intravenous administration. METHODS: An oil-in-water emulsion containing 1 mg/mL of metolazone was formulated by homogenizing soybean oil and l-lecithin in water in the presence of optimized concentrations of glycerin with tween 80 or poloxamer 188 as surfactant. The emulsion was characterized on the basis of particle size, zeta potential, morphology and metolazone release kinetics. The diuretic effect of the metolazone emulsion was evaluated in rats. RESULTS: The 1 mg/mL metolazone emulsion prepared with 5% tween 80 displayed the best physical stability. The emulsion exhibited a hydrodynamic diameter of 157.13±1.52 nm. About 93% of metolazone was released from the formulation within 2 h. The 2 mg/kg and 4 mg/kg dose of the metolazone emulsion increased urine output in the rats by 68.9 and 134%, respectively, as compared to control rats. Furthermore, the 4 mg/kg dose exhibited a 168.8%, 25.8%, and 150.9% increase in sodium, potassium, and chloride, respectively. CONCLUSION: This metolazone emulsion was capable of increasing urine volume output and demonstrated both natriuretic and kaliuretic properties.

A Systematic Review and Meta-Analysis of Metolazone Compared to Chlorothiazide for Treatment of Acute Decompensated Heart Failure.

Treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is typically achieved through the use of loop diuretics. While they are highly effective, some patients may develop loop diuretic resistance. One strategy to overcome this scenario includes sequential nephron blockade with a thiazide-type diuretic; however, it is unknown which thiazide-type diuretic used in this setting is most effective. A systematic review and meta-analysis were performed to compare the efficacy and safety of chlorothiazide with metolazone as add-on therapy in the setting of loop diuretic resistance for the treatment of ADHF. Literature searches were conducted through PubMed, Google Scholar, and Science Direct from inception through February 2020 using the following search terms alone or in combination: metolazone, chlorothiazide, acute decompensated heart failure, loop diuretic, and urine output. All English-language prospective and retrospective trials and abstracts comparing metolazone to chlorothiazide for the treatment of ADHF were evaluated. Studies were included if they analyzed urine output for at least 24 hours in patients with ADHF. Meta-analysis was conducted to evaluate pooled effect size by using a random-effect model. Primary outcomes included net and total urine output. Secondary outcomes included commonly reported safety outcomes. Four studies comparing the use of metolazone to chlorothiazide as an adjunct to loop diuretics to treat ADHF were included in the evaluation. Metolazone was as effective as chlorothiazide to augment loop diuretic therapy in ADHF in most studies with no pooled difference in net or total urine output. However, there were notable differences in baseline loop diuretic dosing, ejection fraction, renal function, race, and endpoint timing across studies. Adverse effects were commonly observed and included electrolyte abnormalities, change in renal function, and hypotension but were comparable between groups. Metolazone is as effective as chlorothiazide as add-on to loop diuretics in treating ADHF without an increase in safety concerns.

Hydroxychloroquine-induced hyperpigmentation: the staining pattern.

We report two cases of hydroxychloroquine-induced hyperpigmentation presenting in a 50-year-old Caucasian female (case 1) and a 78-year-old female (case 2), both receiving 400 mg per day. Case 1 had an arthritis predominant undifferentiated connective tissue disease, which was treated with hydroxychloroquine for 4-5 years. She presented with a mottled, reticulated macular gray pigmentation involving the upper back and shoulders. Case 2 had a history of systemic lupus erythematosus and rheumatoid arthritis, treated with hydroxychloroquine for 1.5 years. She presented to the hospital for treatment of constrictive cardiomyopathy and was noted to have a blue macular pigmentation involving the right temple. The biopsies from both patients showed superficial dermal, yellow-brown, non-refractile and coarsely granular pigment deposition. A Fontana-Masson stain highlighted some of these granules, while the Perl's iron stain was negative. Rare, previous reports of hyperpigmentation indicate the presence of both melanin and hemosiderin in patients being treated with antimalarial medication. To our knowledge, this staining pattern for hydroxychloroquine has not been previously reported in the literature and supports that hydroxychloroquine, in addition to chloroquine, binds to melanin.

Efficacy of Intravenous Chlorothiazide for Refractory Acute Decompensated Heart Failure Unresponsive to Adjunct Metolazone.

STUDY OBJECTIVE: To assess the efficacy of intravenous chlorothiazide in patients with acute decompensated heart failure (ADHF) who were determined to be loop diuretic resistant and refractory to metolazone. DESIGN: Retrospective cohort study with patients serving as their own controls. SETTING: Large, academic, tertiary care hospital. PATIENTS: Forty-five patients with ADHF who had an inadequate response to high-dose loop diuretics and then received at least one dose of oral metolazone 5 mg or greater (metolazone index dose) followed by at least one dose of intravenous chlorothiazide 500 mg (chlorothiazide index dose) if the response to metolazone was considered inadequate, according to the institutional protocol, between February 4, 2013, and February 28, 2015, were included. If multiple doses of metolazone were administered, the last dose given before the chlorothiazide index dose was considered the index dose; the metolazone index dose had to have been administered more than 2 hours before the chlorothiazide index dose. MEASUREMENTS AND MAIN RESULTS: Data for a total of 90 diuretic doses (45 metolazone, 45 chlorothiazide) were included in the analysis. The median dose of loop diuretic in intravenous furosemide equivalents given over the 24-hour period before the metolazone index dose was 400 mg. The average length of stay was 34.7 days, and in-hospital mortality was 35.6% (16/45 patients). The primary end point of a net-negative urine output of 500 ml or greater during the 12 hours after the index dose occurred in 42.2% (19/45 patients) and 35.5% (16/45 patients) for the chlorothiazide and metolazone doses, respectively (p=0.581). The median 12-hour urine output following administration of metolazone was 810 ml (interquartile range [IQR] 866 ml) versus 1075 ml (IQR 940 ml) following administration of chlorothiazide (p=0.363). Compared with metolazone, the chlorothiazide doses did not result in an increase in urine output of at least 500 ml during the 12 hours following the dose relative to the 12 hours before the dose (31.1% vs 22.2%, p=0.754). No significant difference in achievement of net-negative urine output of 500 ml or greater during the 12 hours following the chlorothiazide or metolazone dose was noted (42.2% for chlorothiazide vs 35.5% for metolazone, p=0.581). CONCLUSION: The addition of intravenous chlorothiazide did not result in improved diuresis in patients with ADHF determined to be refractory to loop diuretics and adjunctive oral metolazone.

Efficacy and Safety of Intravenous Chlorothiazide versus Oral Metolazone in Patients with Acute Decompensated Heart Failure and Loop Diuretic Resistance.

STUDY OBJECTIVE: To assess the efficacy and safety of intravenous (IV) chlorothiazide versus oral metolazone when added to loop diuretics in patients with acute decompensated heart failure (ADHF) and loop diuretic resistance. DESIGN: Retrospective cohort study. SETTING: Large urban academic medical center. PATIENTS: Adults admitted with ADHF between 2005 and 2015 who had loop diuretic resistance, defined as administration of IV furosemide at a dose of 160 mg/day or higher (or an equivalent dose of IV bumetanide), during hospitalization, and who then received at least one dose of IV chlorothiazide (88 patients) or oral metolazone (89 patients) to augment diuresis. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end point was a change in 24-hour net urine output (UOP) from before to after thiazide-type diuretic administration, and the study was designed to test for the noninferiority of metolazone. Safety end points included changes in renal function and electrolyte concentrations. The mean dose of IV loop diuretic therapy (in IV furosemide equivalents) at baseline (before thiazide-type diuretic administration) was higher in the chlorothiazide group (mean ± SD 318.9 ± 127.7 vs 268.4 ± 97.6 mg/day in the metolazone group, p=0.004), but net UOP was similar (mean ± SD 877.0 ± 1189.0 ml in the chlorothiazide group vs 710.6 ± 1145.9 ml in the metolazone group, p=0.344). Mean doses of chlorothiazide and metolazone were 491 ± 282 mg and 5.8 ± 3.5 mg, respectively. Following thiazide-type diuretic administration, net UOP improved to a similar degree (2274.6 ± 1443.0 ml vs 2030.2 ± 1725.0 ml in the chlorothiazide and metolazone groups, respectively, p=0.308). For the primary efficacy end point, metolazone met the threshold for noninferiority by producing a net UOP of 1319.6 ± 1517.4 ml versus 1397.6 ± 1370.7 ml for chlorothiazide (p=0.026 for noninferiority). No significant differences in renal function were observed between the groups. Although hypokalemia was more frequent in the chlorothiazide group (75% with chlorothiazide vs 60.7% with metolazone, p=0.045), no significant differences in the rates of severe hypokalemia or other electrolyte abnormalities were observed between the groups. CONCLUSION: Oral metolazone was noninferior to IV chlorothiazide for enhancing net UOP in patients with ADHF and loop diuretic resistance and was similarly safe with regard to renal function and electrolyte abnormalities. Given the significant cost disparity between the two agents, these findings suggest that oral metolazone may be considered a first-line option in this patient population.

How much responsibility should heart failure nurses take?

This article examines the emerging role of the heart failure nurse and the responsibilities and educational and training requirements surrounding such a role. There may be variations in the role and its responsibilities in different health care settings. However the principles are similar and include: history taking, carrying out clinical assessment and making appropriate decisions about patient management within the context of practice. An example of this is nurse supervision of adjusting and titration of medication in a clinic setting or in the patient's own home. A major challenge to this role is defining the limitations and scope of practice. Patients with chronic heart failure (CHF) are generally a frail, elderly population, and often have significant other co-morbidities. They can be on multiple medications and are frequently prescribed sub-optimal doses of evidence-based medication. Many patients are not managed by specialists, thus creating a huge potential for improved management.

Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance.

AIMS: Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head studies are lacking and equipoise exists regarding the preferred thiazide-like diuretic in this setting. We thus compared the effectiveness of oral metolazone versus intravenous (IV) chlorothiazide as add-on therapy to loop diuretics in hospitalized patients with ADHF and renal dysfunction. METHODS: This retrospective cohort study evaluated the efficacy and safety of oral metolazone versus IV chlorothiazide as add-on therapy to loop diuretics in patients hospitalized with ADHF and renal dysfunction. The primary endpoint was net urine output (UOP) at 72 h after initiation of thiazide-like diuretics. Safety endpoints included worsening renal function, hypotension, and electrolyte abnormalities. RESULTS: Fifty-five patients were enrolled with 33 patients receiving metolazone and 22 patients receiving chlorothiazide. There was no difference in median net UOP at 72 h in those receiving metolazone (4828 mL, interquartile range [IQR] 2800-7209 mL) compared to chlorothiazide (3779 mL, IQR 1885-6535 mL) (P = 0.16). There was no difference in hypotension, worsening renal function, hyponatremia, or hypokalemia (P = NS for all comparisons). Hospital length of stay was shorter in the metolazone cohort (median 7 days) compared to chlorothiazide (median 15 days), suggesting the chlorothiazide cohort was likely sicker. CONCLUSION: Sequential nephron blockade with either metolazone or chlorothiazide appears to be efficacious and safe in ADHF, renal dysfunction, and diuretic resistance. Given the considerable cost difference favoring oral metolazone, larger randomized studies are warranted to confirm our findings and to exclude the possibility of confounding by indication.

Changes in calcium excretion after prolonged metolazone therapy in recurrent stone formers.

The handling of an acute oral calcium load in 22 men with recurrent calcium stone disease was studied before and after diuretic therapy. As a group, the patients had marginal hypercalciuria (150 mg calcium per gram of creatinine in a 24-hr urine collection). Metolazone, a diuretic with an action in the cortical thick ascending limb of Henle's loop, was given in oral daily doses of 5.0 mg for periods of 9 to 34 mo. An oral calcium load induced a rapid rise in urine calcium exeretion, which was blunted markedly by metolazone. Further analysis of the subjects revealed that one group (11 subjects) had higher baseline 24-hr calcium excretion levels and higher parathyroid hormone (PTH) than the others. The effect of metolazone in reducing the calciuric response was significant only in this group. Thus, while long-term treatment with metolazone inhibited the rise in urinary calcium excretion elicited by an oral calcium load, the effect was significant only in patients who had high baseline urinary calcium and PTH values. The reduction in calcium excretion in response to an acute calcium challenge may explain in part the beneficial effects of cortical diluting segment diuretics in recurrent stone formers.

Metolazone therapy of active calcium nephrolithiasis.

Metolazone, a nonthiazide diuretic with the hypocalciuric effect of the thiazides, was evaluated in patients with idiopathic calcium nephrolithiasis. During the mean 3-yr treatment period, there was a 77% decrease in stone incidence in 38 male patients (from 2.10 to 0.49 stones/patient/year). Urine calcium decreased 51% (from 231 +/- 19 to 114 +/- 7 mg/24 hr after 13 mo therapy). The treatment response was the same when these patients were divided into normocalciuric (n = 23), borderline hypercalciuric (n = 10), and hypercalciuric groups (n = 5). In six other patients with high sodium intake there was no decrease in urine calcium on stone formers regardless of the initial level of urine calcium excretion. High sodium intake may blunt and low intake potentiate the hypocalciuric effect of metolazone.

Metolazone and bendroflumethiazide in hypertension: physiologic and metabolic observations.

A double-blind crossover comparison was made in 18 nonedematous hypertensive subjects with glomerular filtration rates exceeding 70 ml/min/1.73 m2 of the effects of 5 mg metolazone and 5 mg bendroflumethiazide on blood pressure and metabolic parameters. After a 4-wk run-in placebo period, patients received either metolazone or bendroflumethiazide for 6 wk in a crossover fashion with an intervening washout period of 4 wk. Metolazone induced a more sustained and greater blood pressure response than bendroflumethiazide. Changes in plasma potassium, urate, bicarbonate, renin, and angiotensin II occurred during treatment with both metolazone and bendroflumethiazide; the only significant difference, however, was in changes in plasma bicarbonate. Total body potassium (TBK), measured by whole-body monitor, did not fall outside the normal range with either metolazone or bendroflumethiazide, although metolazone induced a greater reduction in TBK (6.2 gm, 5.5% of TBK) than bendroflumethiazide (1.2 gm, 1.1% of TBK, p < 0.05). Our results suggest that metolazone is a more effective antihypertensive and induces similar but greater metabolic changes than bendroflumethiazide. The results of our comparison suggest that although changes in plasma potassium and TBK are minor, they are greater with metolazone, and potassium supplements may not be necessary in nonedematous hypertensive patients with normal renal function.

Metolazone and spironolactone in cirrhosis and the nephrotic syndrome.

Eighteen patients with hepatic cirrhosis or nephrotic syndrome and having edema and/or ascites were treated during successive periods with metolazone 5 to 40 mg/day, spironolactone 100 mg/day, and with both diuretics concurrently. Metolazone alone produced a marked diuresis, natriuresis, and weight loss in 8 patients. Spironolactone alone had little effect, but the addition of metolazone renewed diuresis and natriuresis and resulted in additional substantial weight losses in all patients responsive to metolazone alone. Concurrent spironolactone and metolazone also induced moderate diuretic effects in some patients who failed to respond to either drug alone. The drugs were well tolerated; the administration of spironolactone with metolazone prevented decreases in serum potassium, which had occurred during treatment with metolazone alone.

Efficacy of medical therapy tailored for severe congestive heart failure in patients transferred for urgent cardiac transplantation.

Cardiac transplantation can only be performed in a few patients with severe congestive heart failure (CHF), due to the shortage of donor hearts. The efficacy of current medical therapy tailored for severe CHF, which has not previously been determined for transplant candidates, is of particular importance in patients considered for urgent cardiac transplantation. In this study, 50 consecutive in-patients transferred from other hospitals for urgent transplantation underwent intensive afterload reduction therapy, initially with intravenous and subsequently with oral vasodilators and diuretics tailored to hemodynamic goals. Oral regimens allowed hospital discharge without surgery for 40 of 50 patients. Nineteen of these patients had arrived on inotropic infusions and 32 had received oral vasodilators in the previous month. Cardiac index increased from 1.9 +/- 0.6 to 2.8 +/- 0.7 liters/min/m2, while pulmonary capillary wedge pressure decreased from 30 +/- 8 to 15 +/- 4 mm Hg and systemic vascular resistance decreased from 1,800 +/- 800 to 1,100 +/- 200 dynes-s-cm-5. Despite poor initial hemodynamics, ejection fraction 16 +/- 4%, serum sodium 131 +/- 6 mEq/liter, and apparent failure of previous medical therapy, actuarial survival for 24 discharged patients receiving sustained medical therapy alone was 67% at 1 year, with 67% of survivors employed full- or part-time, and 14 of 16 (88%) discharged transplant candidates survived until transplantation. By decreasing the need for transplantation to be performed urgently, increased emphasis on the design of medical therapy may allow more effective distribution of limited donor hearts.

Antihypertensive and renin angiotensin effects of metolazone with and without propranolol.

Renin angiotensin system parameters and blood pressure (B.P.) were followed monthly in patients with essential hypertension on metolazone, 5 mg daily for three months and with added propranolol, 40 to 160 mg, for the subsequent three months. On metolazone alone at three months, sitting B.P. declined from 166/108 +/- 14/11 mm Hg to 145/98 +/- 14/9 mm Hg (P less than 0.005). Plasma renin activity (PRA) increased from 3.9 +/- ng/ml/hr to 10.4 +/- 8.6 ng/ml/hr (P less than 0.005); plasma angiotensinogen did not change. Venous blood angiotensin I and II levels (pg/ml) rose initially but returned toward control values. A significant decline in plasma renin substrate reactivity (PRSr) in index occurred. Propranolol addition caused further lowering of only systolic B.P. and predominantly in the standing position, more marked at one month (40 mg) than at three months (160 mg). No significant further changes were observed in any of the measured parameters of renin angiotensin system, except for a rise in PRSr index concomitant with B.P. elevation at three months. Metolazone-induced changes in B.P. showed significant correlations at three months with changes in PRSr index. It is concluded that during chronic metolazone administration, the overall activity of the renin angiotensin system was diminished or unchanged. Propranolol did not inhibit metolazone stimulated PRA but did cause further decline in B.P. in the first two months, unrelated to renin angiotensin system.

The effect of triple drug therapy on renal function in patients with essential hypertension.

The effects of long-term triple drug therapy on renal function in patients with moderate to severe essential hypertension have not been evaluated systematically. We prospectively studied fifteen male patients with moderate to severe essential hypertension receiving triple drug therapy (metolazone, atenolol or betaxolol, and minoxidil) for 16 weeks. Supplemental potassium was prescribed in an attempt to maintain serum potassium above 3.5 mEq/liter. Systemic blood pressure was well controlled with this regimen. However, glomerular filtration rate (assessed by inulin clearance), effective renal plasma flow (assessed by paraaminohippurate clearance), and renal blood flow were reduced. Filtration fraction and renal vascular resistance were not significantly altered. Plasma renin activity remained stimulated throughout the protocol. Weight gain occurred, and serum potassium remained low. These results suggest that triple drug therapy employing a diuretic, beta-adrenergic antagonist, and a potent vasodilator is effective therapy for controlling moderate to severe systemic hypertension. However this antihypertensive regimen may be associated with a decrement in renal function.