Severe hypoglycemia in children treated with nadolol: A case report and FDA adverse event reporting system (FAERS) database analysis.

OBJECTIVE: We describe a case of severe hypoglycemia in a 14-month-old child as a suspected adverse drug reaction (ADR) to nadolol, and we performed an analysis of the FDA Adverse Event Reporting System (FAERS) database. Although previous reports have identified the risk of severe hypoglycemia in children during treatment with ß-blockers, little is known about hypoglycemia as an ADR in infants treated with nadolol. Moreover, the pharmacodynamic and pharmacokinetic profiles of nadolol in children aged less than 1 year old are still not fully known. MATERIALS AND METHODS: We extracted all ADR reports involving nadolol from the FAERS database; in order to reduce the risk of bias, we only considered cases that exclusively reported nadolol as the suspect drug. We then selected cases of hypoglycemia in the pediatric population and conducted a manual deduplication. RESULTS: Upon FAERS database analysis, a total of 2,674 suspected ADR reports to nadolol were found. Of these, 1,950 (73%) were solely attributed to nadolol, and 63 of them were hypoglycemic events. A total of 47 reports included the relevant pediatric age (74.6%). After deduplication, we identified 25 cases (mean age: 3.65 years old); all of these reports were categorized as serious, and hospitalization was required in 15 cases. CONCLUSION: Hypoglycemia is a reported life-threatening ADR associated with nadolol, especially in infants, in whom this drug should be used with caution.

Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices.

BACKGROUND: Non-selective beta-blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non-selective beta-blocker with additional intrinsic alpha1-blocking effects, which may be superior to traditional, non-selective beta-blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of carvedilol compared with traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato-Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. SELECTION CRITERIA: We included randomised clinical trials comparing carvedilol versus traditional, non-selective beta-blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. DATA COLLECTION AND ANALYSIS: Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the quality of the evidence with GRADE. MAIN RESULTS: Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low-quality evidence). There appeared to be no differences between carvedilol versus traditional, non-selective beta-blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low-quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low-quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long-term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non-selective beta-blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non-serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low-quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non-selective beta-blockers both in absolute (MD -1.75 mmHg, 95% CI -2.60 to -0.89; 368 participants; 6 trials; I2 = 0%; low-quality evidence) and percentage terms (MD -8.02%, 95% CI -11.49% to -4.55%; 368 participants; 6 trials; I2 = 0%; low-quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low-quality evidence) or in clinical outcomes. AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effects of carvedilol versus traditional, non-selective beta-blockers on mortality, upper gastrointestinal bleeding, serious or non-serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

Nadolol reduces insulin sensitivity in liver cirrhosis: a randomized double-blind crossover trial.

BACKGROUND: Liver cirrhosis is frequently complicated by portal hypertension leading to increased mortality from variceal bleeding and hepatic decompensation. Noncardioselective ß-blockers not only reduce portal hypertension and prevent variceal bleeding in cirrhosis but also impair glucose tolerance and insulin sensitivity in other settings. This study aimed to determine whether nonselective ß-blockade with nadolol impairs glucose metabolism in liver cirrhosis. METHODS: A randomized, double-blind, placebo-controlled crossover trial of nadolol in cirrhotic patients examined insulin sensitivity, disposition index, and glucose tolerance. Stable cirrhotic patients of mixed etiology underwent an intravenous glucose tolerance test and hyperinsulinemic-euglycemic clamp for the measurement of insulin secretion and insulin sensitivity (n = 16) and a 75-g oral glucose tolerance test (n = 17). These measurements were conducted twice (after 3 months of treatment with nadolol or placebo and, after a 1-month washout period, after 3 months on the alternative treatment). Total body fat and plasma catecholamines were measured at the end of each 3-month treatment. RESULTS: Compared with placebo, nadolol treatment reduced insulin sensitivity (79.7 ± 10.1 vs 99.6 ± 10.3 µL/kg fat-free mass·min-1 ·(mU/L)-1 , P = .005). Insulin secretion was unchanged (P = .24), yielding a lower disposition index with nadolol (6083 ± 2007 vs 8692 ± 2036, P = .050). There was no change in total body fat or plasma catecholamines. A 2-hour plasma glucose concentration from the oral glucose tolerance test was higher on nadolol than placebo (10.8 ± 0.9 vs 9.9 ± 0.9 mmol/L, P = .035). CONCLUSIONS: Nadolol significantly worsened insulin sensitivity, glycemia, and disposition index in patients with liver cirrhosis. These findings may have significant clinical implications because cirrhosis is already associated with an increased prevalence of diabetes.

Nadolol for Treatment of Supraventricular Tachycardia in Infants and Young Children.

Supraventricular tachycardia (SVT) is a common infant arrhythmia, for which beta-blockers are frequently chosen as therapy. Propranolol is a common choice though it is dosed every 6-8 h. We reviewed the clinical results of treating infant SVT with an extemporaneous preparation of nadolol. Retrospective cohort study of patients under 2 years old receiving nadolol for SVT at a single center. Patients were ascertained by patient and pharmacy databases. Twenty-eight infants received nadolol, of whom 25 had regular narrow complex tachycardia, 2 atrial flutter, and 1 focal atrial tachycardia. Patient age at initiation was a median 54 days (range 10-720). The final dose was 1 mg/kg/day in 22/28 patients (range 0.5-2). Once-daily dosing was used in 20 patients (71.4%); dosing was BID in 7, TID in 1. Among regular narrow complex tachycardia patients, 18/25 received nadolol monotherapy and 7 required additional agents; flecainide in 6, digoxin in 1. The median age of tachyarrhythmia onset was 18 days (range 1-180) with a median age of nadolol initiation of 30 days (range 11-390). Of the 20 regular narrow complex tachycardia patients initiated on nadolol monotherapy, 85% had no recurrences as of 1-year follow-up. Side effects were suspected in 3 of 28 (10.7%), including wheezing (n = 1, 3.5%), irritability and diarrhea (n = 1, 3.5%), and bradycardia (n = 1, 3.5%). Oral nadolol suspension was a successful treatment for SVT in 85% of patients with minimal adverse effects. Single daily dosing was used in the majority of patients.

Oral Nadolol for the Treatment of Infantile Hemangiomas: A Single-Institution Retrospective Cohort Study.

BACKGROUND: Beta-blockers have become the treatment of choice for problematic infantile hemangiomas (IHs). Nadolol, a nonselective beta-blocker with potential dosing advantages and a better safety profile than that of other beta-blockers, has been studied as an alternative therapeutic option. Our objective was to characterize the efficacy and safety of oral nadolol in the treatment of proliferating IHs. METHODS: A retrospective cohort study was conducted at the Hospital for Sick Children between February 2010 and April 2012 in patients treated with nadolol for proliferating IHs causing functional impairment or cosmetic disfigurement. The primary outcome was the percentage involution measured independently by two assessors who scored changes in the extent of IHs by comparing serial photographs using a 100-mm visual analogue scale (VAS), on which 5 mm represented 10% change. RESULTS: Forty-four patients treated with nadolol for IHs with adequate photographic documentation were identified. The median age at presentation was 4.5 months (interquartile range 1.5-7.9 mos). There was a mean improvement of 91.8 ± 11.1%. At least 50% improvement was noted in 42 (95%) patients and 75% improvement in 39 (89%) patients. The mean time to 50% and 75% improvement was 2.9 and 3.7 months, respectively. Analysis of variance showed that younger age at the time of treatment start was associated with a higher mean VAS score (% involution) (p < 0.05). Treatment duration (mean 9.5 ± 5.6 months) had no significant effect on VAS score. Test of interobserver correlation showed good agreement (intraclass correlation coefficient = 0.86, p = 0.001). CONCLUSIONS: Oral nadolol is efficacious in patients with problematic IHs. Further large-scale prospective comparative studies are warranted to compare nadolol with other beta-blockers.

Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding.

BACKGROUND AND AIM: Carvedilol has been shown to be more effective than propranolol in decreasing portal pressure. Sufficient data from controlled trials remains limited. This trial compared the relative safety and efficacy between carvedilol and nadolol plus isosorbide mononitrate in preventing variceal rebleeding. METHODS: After successful control of acute esophageal variceal bleeding, eligible patients were randomized to the carvedilol group, 61 patients, using carvedilol 6.25-12.5 mg daily or the N + I group, 60 patients, using nadolol 40-80 mg plus isorsorbide-5-mononitrate 20 mg daily. The end points were rebleeding from varices, adverse events or death. RESULTS: After a median follow up of 30 months, recurrent upper gastrointestinal bleeding developed in 37 patients (61%) in the carvedilol group and 37 patients (62%) in the N + I group (P = 0.90). Recurrent bleeding from esophageal varices occurred in 31 patients (51%) in the carvedilol group and in 26 patients (43%) in the N + I group (P = 0.46). Recurrent bleeding from gastric varices occurred in two patients (3%) in the carvedilol group and in eight patients (13%) in the N + I group (P = 0.05). Severe adverse events occurred in one patient in the carvedilol group and 17 patients in the N + I group (P < 0.0001). Fifteen patients of the carvedilol group and 17 patients in the N + I group died (P = 0.83). Two patients in the carvedilol group and three patients in the N + I group died of variceal bleeding. CONCLUSIONS: Carvedilol was as effective as nadolol plus isorsorbide-5 -mononitrate mononitrate in the prevention of gastroesophageal variceal rebleeding with fewer severe adverse events and similar survival.

Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile Hemangioma: A Randomized Clinical Trial.

Importance: Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic ß-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events. Objective: To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH. Design, Setting, and Participants: This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement. Interventions: Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d. Main Outcomes and Measure: Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale. Results: The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions. Conclusions and Relevance: Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required. Trial Registration: ClinicalTrials.gov Identifier: NCT02505971.

Propranolol versus nadolol for treatment of pediatric subglottic hemangioma.

PURPOSE: The beta-blocker propranolol is the standard medical therapy for subglottic hemangioma (SGH), but side effects and incomplete response rates require close monitoring. Nadolol has been identified as a potential alternative but its use has not been examined for SGH. METHODS: Single institution retrospective cohort study of pediatric SGH treated with propranolol or nadolol. RESULTS: Thirteen children (1 male, 12 female) with SGH were included: 6 were treated with propranolol (2.0-3.5 mg/kg/d) and 7 with nadolol (2.0-4.0 mg/kg/d). The most common presenting symptom was stridor (85%) and mean (SD) symptom duration prior to diagnosis was 4.6 (3.8) weeks. Cutaneous vascular lesions were present in 54%. There were 7 right-sided, 5 left-sided and 1 bilateral SGH. The mean (SD) percentage of airway obstruction was 60.6% (27.4). The response rate was 100% (6/6) for propranolol and 85.7% (6/7) for nadolol (p = 0.36). Mean (SD) time to symptomatic improvement was 2.6 (2.2) days with no difference across groups (p = 0.71). There was no hypotension, hypoglycemia, weight loss, or sleep disturbances in either group. One patient in the propranolol group experienced vomiting. Two patients in the nadolol group required dosage reduction due to asymptomatic bradycardia. The mean (SD) duration of admission was 14.4 (12.6) days and duration of treatment was 13.8 (11.2) days with no difference across groups (p = 0.23; p = 0.31, respectively). All patients had treatment initiated as inpatients and completed as outpatients. CONCLUSION: Children with SGH treated with propranolol or nadolol had similar response rates and side effect profiles.

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial.

BACKGROUND AND AIMS: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes METHODS: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4-6 weeks on medical therapy. RESULTS: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction >or=20% or

Death Associated With Nadolol for Infantile Hemangioma: A Case for Improving Safety.

Nadolol is a ß-adrenergic antagonist that has been shown to be efficacious in the treatment of infantile hemangioma. It has been suggested that this drug may have fewer side effects compared with the gold standard therapy, propranolol, because it does not exhibit membrane-stabilizing effects and has little ability to cross the blood-brain barrier. However, the pharmacokinetics and safety of nadolol in infants are not well understood, potentially making this therapy dangerous. ß-adrenergic antagonist toxicity causes bradycardia, hypotension, hypoglycemia, and even death. We report a case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity. Pharmacokinetics studies show a large fraction of oral nadolol either remains in the feces unchanged or is excreted into feces via the biliary system, allowing continued absorption over time in infants who stool infrequently. Propranolol may be a safer therapy overall. Not only does it have a shorter half-life, but propranolol is hepatically metabolized and renally eliminated, allowing for less drug accumulation in healthy infants with variable stooling patterns. We suggest that if nadolol is selected for therapy, pediatricians should instruct parents to monitor their infants' bowel movements closely and encourage early intervention in the event of decreased stooling. This intervention may greatly improve the safety of nadolol in this vulnerable patient population.

Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with ß1-selective ß-blockers in patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disease predisposing to malignant ventricular arrhythmias. OBJECTIVE: We aimed to explore the incidence and severity of ventricular arrhythmias in patients with CPVT before the initiation of ß-blocker treatment, when treated with ß1-selective ß-blockers, and when treated with nadolol. METHODS: In this study, 34 patients with CPVT were included (mean age 34 ± 19 years; 15 (44%) women; 30 (88%) ryanodine receptor 2 variant positive). We performed 3 bicycle exercise stress tests in each patient: (1) before the initiation of ß-blocker treatment, (2) after >6 weeks of treatment with ß1-selective ß-blockers and (3) after >6 weeks of treatment with nadolol. We recorded resting and maximum heart rates and the most severe ventricular arrhythmia occurring. Severity of arrhythmias was scored as 1 point for no arrhythmias or only single ventricular extrasystoles, 2 points for >10 ventricular extrasystoles per minute or bigeminy, 3 points for couplets, and 4 points for nonsustained ventricular tachycardia or sustained ventricular tachycardia. RESULTS: Resting heart rate was similar during treatment with nadolol and ß1-selective ß-blockers (54 ± 10 beats/min vs 56 ± 14 beats/min; P = .50), while maximum heart rate was lower during treatment with nadolol compared with ß1-selective ß-blockers (122 ± 21 beats/min vs 139 ± 24 beats/min; P = .001). Arrhythmias during exercise stress testing were less severe during treatment with nadolol compared with during treatment with ß1-selective ß-blockers (arrhythmic score 1.6 ± 0.9 vs 2.5 ± 0.8; P < .001) and before the initiation of ß-blocker treatment (arrhythmic score 1.6 ± 0.9 vs 2.7 ± 0.9; P = .001); however, no differences were observed during treatment with ß1-selective ß-blockers compared with before the initiation of ß-blocker treatment (arrhythmic score 2.5 ± 0.8 vs 2.7 ± 0.9; P = .46). CONCLUSION: The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with ß1-selective ß-blockers. ß1-Selective ß-blockers did not change the occurrence or severity of arrhythmias compared with no medication.

Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.

BACKGROUND: beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated. METHODS AND RESULTS: The study population comprised 869 LQTS patients treated with beta-blockers. Effectiveness of beta-blockers was analyzed during matched periods before and after starting beta-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed beta-blockers. After initiation of beta-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97+/-1.42 to 0.31+/-0.86 events per year) and in affected family members (0. 26+/-0.84 to 0.15+/-0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before beta-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during beta-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed beta-blockers. Patients with a history of aborted cardiac arrest before starting beta-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed beta-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on beta-blockers. CONCLUSIONS: beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy.

Predictive value of electrophysiologic studies during treatment of ventricular tachycardia with the beta-blocking agent nadolol. The Working Group on Arrhythmias of the French Society of Cardiology.

Sixty patients with recurrent inducible sustained ventricular tachycardia were prospectively treated with nadolol (40 or 80 mg/day). Old myocardial infarction was present in 43 patients and dilated cardiomyopathy in 12. In group I (n = 36), nadolol was given alone, whereas in group II (n = 24), previously ineffective treatment with amiodarone was continued in combination with nadolol. Left ventricular ejection fraction was higher in patients in group I (0.40 +/- 0.12) than in group II (0.30 +/- 0.10, p less than 0.01) patients. Electrophysiologic study was repeated after short-term treatment with nadolol, which was continued regardless of the results of this test, according to the scheme of the parallel approach. Recurrence of spontaneous tachycardia or sudden death occurred in 21 patients after 10 +/- 9.2 months; sustained tachycardia was inducible in 19 on nadolol therapy. The remaining 39 patients (of whom 21 had inducible tachycardia while taking the drug) have had no recurrence of tachycardia after 27.8 +/- 9.3 months of follow-up study. Sensitivity, specificity and predictive value of a positive and negative test were 90.5%, 46%, 47.5% and 90%, respectively. The results differ between group I and group II patients, the latter having a high percent of false positive responses. This difference is even more obvious with respect to left ventricular ejection fraction: the predictive value of a positive test was 86% when ejection fraction was greater than 0.40 and 39% when it was less than 0.40.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy.

OBJECTIVES: The aim of this study was to determine whether therapy with a beta-adrenergic or calcium channel blocking agent can improve the functional capacity and quality of life of patients with mild or moderately symptomatic hypertrophic cardiomyopathy. BACKGROUND: Both beta-blockers and calcium channel blockers may alleviate symptoms in hypertrophic cardiomyopathy, but previous studies have been performed in hospitalized patients or have been open studies without control subjects. METHODS: A randomized, double-blind crossover trial of nadolol, verapamil and placebo, administered for periods of 4 weeks each, was performed in 18 patients with mild or moderately symptomatic hypertrophic cardiomyopathy (10 men, 8 women; mean age +/- SD 39 +/- 17 years). A detailed symptom assessment, bicycle exercise testing, echocardiography and Holter monitoring were performed in each period. RESULTS: Two patients withdrew from the study owing to symptomatic sinus bradycardia during nadolol therapy. Neither drug improved maximal oxygen consumption (placebo 26 +/- 8, verapamil 23 +/- 6, nadolol 21 +/- 7 ml/kg per min; p = 0.1). Peak exercise work load was reduced by > or = 10 W in 13 patients (81%) during nadolol therapy and in 4 patients (25%) during verapamil therapy (p = 0.005, nadolol vs. verapamil). Despite the effects on exercise capacity, 13 patients (81%) preferred drug treatment (8 verapamil, 5 nadolol) over placebo (p = 0.001). Verapamil improved reported performance at work compared with nadolol (p = 0.01) and tended to improve other measures of health-related behavior and symptoms compared with nadolol and placebo. CONCLUSIONS: In patients with mild or moderately symptomatic hypertrophic cardiomyopathy, exercise capacity was not improved by nadolol or verapamil, and individuals were more often impaired by nadolol than with verapamil. Nevertheless, many patients derived symptomatic benefit from drug therapy, especially with verapamil.

Efficacy and safety of intravenous and oral nadolol for supraventricular tachycardia in children.

The efficacy and safety of oral nadolol in supraventricular tachycardia were evaluated prospectively in 27 children (median age 5.5 years). Fifteen patients had an unsuccessful trial of digoxin therapy. Intravenous nadolol was given to seven patients during electrophysiologic study; five of these had an excellent response and two had a partial response (25% decrease in tachycardia rate). Six of these patients had a similar response to oral nadolol. Twelve patients received both propranolol and nadolol. Among six patients, intravenous propranolol was successful in four and unsuccessful in two; all six had a similar response to oral nadolol. With oral propranolol, tachycardia was well controlled in four patients and persistent in two; five of five patients had a similar response to oral nadolol. Twenty-six patients were treated with oral nadolol; the arrhythmia was well controlled in 23, 2 had recurrent tachycardia and 1 patient had tachycardia at a 25% slower rate. The effective dose of nadolol ranged between 0.5 and 2.5 mg/kg body weight once daily (median dose 1 mg/kg per day). During follow-up (3 to 36 months), compliance and tolerance were excellent; excluding 2 patients with reactive airway disease who developed wheezing, only 3 (12%) of 24 had side effects necessitating a change in drug therapy. Once a day nadolol is a safe and effective agent in the management of supraventricular tachycardia in children. Its long-term efficacy can be predicted by the short-term response to intravenous nadolol or propranolol during programmed electrophysiologic study.

Frequency and severity of hypoglycemia in children with beta-blocker-treated long QT syndrome.

BACKGROUND: Hypoglycemia is a potential side effect of beta-blockers; however, no cases have been reported in children with long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to determine the frequency and severity of hypoglycemia among children with beta-blocker-treated LQTS. METHODS: A retrospective study was performed to identify children with LQTS evaluated from 2000 to 2014 who developed symptomatic hypoglycemia while being treated with a beta-blocker. RESULTS: Nine children (3%; 7 boys; average corrected QT interval 486 ± 35 ms) developed 13 episodes (0.005 events per 100 treatment years) of beta-blocker-associated hypoglycemia (mean initial glucose 21 ± 7 mg/dL), including 3 of 157 patients with LQTS type 1 (LQT1; 1.9%) and 6 of 105 with LQTS type 2 (LQT2; 5.7%). The mean age at hypoglycemic event was 3.5 ± 2 years (range 7 months to 9 years), involving nadolol in 6 cases (mean dose 1.4 ± 0.2 mg/kg/d) and propranolol in 3 (mean dose 2.7±1 mg/kg/d). Hypoglycemic events were more frequent in patients with LQT2 than in those with LQT1 (10 vs. 3 events; P = .02). Hypoglycemia-triggered seizures were observed in 6 patients, fasting ketoacidosis in 5, and 7 patients required hospitalization (mean of 3 ± 2 days). Decreased caloric intake before the event was identified in all patients and a concomitant viral infection in 3. CONCLUSION: This is the largest single-center case series of beta-blocker-induced hypoglycemia. Clinicians should be cognizant of hypoglycemia symptoms in younger children during periods of poor appetite and during viral illness, and parents of these children should be educated about the signs and symptoms of hypoglycemia. A potential LQT2-hypoglycemia genotype-phenotype relationship warrants further investigation.

Beta-blockade disappearance rate predicts beta-adrenergic hypersensitivity.

We determined whether the beta-blockade disappearance rate would determine the degree of subsequent transient beta-adrenoceptor hyperresponsiveness after abrupt withdrawal of a beta-adrenoceptor drug. In a single-blind randomized study, 10 healthy men took a placebo for 1 week and then took nadolol one time a day (t1/2, 18 to 24 hours) or propranolol three times a day (t1/2, 4 to 6 hours) in doses that were increased weekly for 4 weeks to reach 240 mg per day. beta-Receptor responsiveness was assessed before and repeatedly after abrupt drug withdrawal by infusion of isoproterenol and epinephrine and by ergometer exercise. In the 13 days after drug discontinuation, peak beta-receptor sensitivity correlated (p less than 0.05) with the disappearance rate of beta-blockade as assessed by heart rate responses to isoproterenol (r = 0.68) and to submaximal exercise (r = 0.62) and by diastolic blood pressure responses to isoproterenol (r = 0.86) and epinephrine (r = 0.86). Plasma catecholamine levels and renin activity showed no overshoot. beta-Blockers with long plasma t1/2 values may prevent beta-blocker withdrawal syndromes by means of "self-tapering."

Combined beta-adrenergic and cholinergic antagonism produces behavioral and cognitive impairments in the water maze: implications for Alzheimer disease and pharmacotherapy with beta-adrenergic antagonists.

This study examined the effects of beta-adrenergic and muscarinic blockade on spatial learning and strategy use in the water maze. Male Long-Evans rats received systemic injections of propranolol (PRO; 10 or 20 mg/kg) or scopolamine (SCO; 0.3 or 1.0 mg/kg) either singly or in combination. To separate strategies learning from spatial learning approximately half of the rats underwent water maze strategies pretraining prior to drug administration and spatial training. PRO did not impair performance in any group. SCO impaired naive but not pretrained rats. PRO and SCO given together in high doses impaired all aspects of behavior in both naive and pretrained rats, and caused sensorimotor disturbances in some groups. PRO (10 mg/kg) and SCO (0.3 mg/kg) together caused a specific spatial reversal learning impairment in pretrained rats without causing strategies impairments or sensorimotor disturbances. Nadolol administered with SCO failed to produce the same impairments as PRO, suggesting that PRO produced its effects by acting on central nervous system sites. These results point to a greater than additive impairing effect of PRO and SCO on adaptive behavior, and a specific role for beta-adrenergic and cholinergic systems working in conjunction in spatial learning. They also suggest that some of the behavioral and cognitive impairments seen in Alzheimer patients or patients receiving pharmacotherapy with beta-adrenergic antagonists in which cholinergic activity is also compromised may result from the combined impairment of beta-adrenergic and cholinergic systems.