Application of dopamine combined with dobutamine in children with pneumonia and heart failure.

Pediatric pneumonia and heart failure is a common critical illness in pediatrics. This article observes the clinical effects of dopamine and dobutamine in the treatment of pneumonia and heart failure. As a key neurotransmitter in the hypothalamus and pituitary gland, dopamine plays a very important role in the central nervous excitement of the human body. Dopamine could also promote excitement in the respiratory center and reduces oxygen consumption in the breath, thereby improving the symptoms of respiratory failure in children. Observe and compare the clinical efficacy of the two groups of children, the disappearance of lung rales, the time to correct heart failure and the length of hospital stay. The total effective rate in the observation group was 91%; the total effective rate in the control group was 65.4%. There was a significant difference in the total effective rate between the two groups of children. The time of disappearance of lung rales, the time of correction of heart failure and the length of hospital stay in the observation group were significantly shorter than those in the control group (P <0.05). The clinical effects of dopamine and dobutamine on pneumonia and heart failure are significant.

Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma.

BACKGROUND: Long-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children. METHODS: We randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis. RESULTS: Among the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01). CONCLUSIONS: In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

Low STAT3 expression sensitizes to toxic effects of ß-adrenergic receptor stimulation in peripartum cardiomyopathy.

Aims: The benefit of the ß1-adrenergic receptor (ß1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to ß-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice. Methods and Results: Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The ß-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the ß1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir. Conclusions: Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via ß1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.

Nebivolol versus Carvedilol or Metoprolol in Patients Presenting with Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction.

OBJECTIVE: The aim of this study was to evaluate the efficacy of nebivolol, carvedilol or metoprolol succinate on the outcome of patients presenting with acute myocardial infarction (AMI) complicated by left ventricular dysfunction. SUBJECTS AND METHODS: Patients (n = 172, aged 28-87 years) with AMI and left ventricular ejection fraction ≤0.45 were randomized to the nebivolol (n = 55), carvedilol (n = 60) and metoprolol succinate (n = 57) groups. Baseline demographic and clinical characteristics and composite event rates of nonfatal MI, cardiovascular mortality, hospitalization due to unstable angina pectoris or heart failure, stroke or revascularization during the 12-month follow-up were compared among the groups using the x03C7;2 test, t test or log-rank test as appropriate. RESULTS: Baseline demographic and clinical characteristics were similar in the three groups. The composite end point during follow-up was lower in the patients treated with nebivolol than those treated with metoprolol (14.5 vs. 31.5%; p = 0.03). However, event rates were similar between the patients treated with carvedilol and those treated with the metoprolol (20.3 vs. 31.5%, p > 0.05) and between the patients treated with nebivolol and carvedilol (14.5 vs. 20.3%, p > 0.05). CONCLUSION: The patients treated with nebivolol experienced 12-month cardiovascular events at a lower rate than those treated with metoprolol succinate. However, event rates were similar between the carvedilol and the metoprolol succinate groups and between the nebivolol and the carvedilol groups.

Advances in acute asthma.

PURPOSE OF REVIEW: The purpose of this study is to highlight some of the recent findings related with the management of acute exacerbations in the context of the emergency department setting. RECENT FINDINGS: ß2-agonist heliox-driven nebulization significantly increased by 17% [95% confidence interval (CI) 5.2-29.4] peak expiratory flow, and decreased the rate of hospital admissions (risk ratio 0.77, 95% CI 0.62-0.98), compared with oxygen-driven nebulization. Other findings indicate that there is no robust evidence to support the use of intravenous or nebulized magnesium sulphate in adults with severe acute asthma, and that levalbuterol was not superior to albuterol regarding efficacy and safety in individuals with acute asthma. Finally, hyperlactatemia developed during the first hours of acute asthma treatment has a high prevalence, is related with the use of ß2-agonists and had no clinical consequences. SUMMARY: After a comprehensive review of the best quality pieces of literature published in the last year, it is possible to conclude that the goals of acute asthma management remain almost unchanged.

Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled ß2-adrenergic signaling.

Xamoterol, a partial ß(1)-adrenergic receptor agonist, has been reported to impair the retrieval of hippocampus-dependent spatial reference memory in rats. In contrast, xamoterol restores memory retrieval in gene-targeted mice lacking norepinephrine (NE) and in a transgenic mouse model of Down syndrome in which NE levels are reduced. Restoration of retrieval by xamoterol in these two models complements the observation that NE and ß(1) signaling are required for hippocampus-dependent retrieval of contextual and spatial reference memory in wild-type mice and rats. Additional evidence indicates that cAMP-mediated PKA and Epac signaling are required for the retrieval of hippocampus-dependent memory. As a result, we hypothesized that xamoterol has effects in addition to the stimulation of ß(1) receptors that, at higher doses, act to counter the effects of ß(1) signaling. Here we report that xamoterol-induced disruption of memory retrieval depends on ß(2)-adrenergic receptor signaling. Interestingly, the impairment of memory retrieval by xamoterol is blocked by pretreatment with pertussis toxin, an uncoupling agent for G(i/o) signaling, suggesting that ß(2) signaling opposes ß(1) signaling during memory retrieval at the level of G protein and cAMP signaling. Finally, similar to the time-dependent roles for NE, ß(1), and cAMP signaling in hippocampus-dependent memory retrieval, xamoterol only impairs retrieval for several days after training, indicating that its effects are also limited by the age of the memory. We conclude that the disruption of memory retrieval by xamoterol is mediated by G(i/o)-coupled ß(2) signaling, which opposes the G(s)-coupled ß(1) signaling that is transiently required for hippocampus-dependent emotional memory retrieval.

The 20 year evolution of dobutamine stress cardiovascular magnetic resonance.

Over the past 20 years, investigators world-wide have developed and utilized dobutamine magnetic resonance stress testing procedures for the purpose of identifying ischemia, viability, and cardiac prognosis. This article traces these developments and reviews the data utilized to substantiate this relatively new noninvasive imaging procedure.

Effective dose of dobutamine in augmenting free flap blood flow during reconstructive surgery of the lower extremity.

Success of surgical free flap transfer depends on achieving and maintaining adequate perfusion across the microvascular anastomosis. The purpose of this prospective study was to determine the optimal infusion rate of dobutamine to augment duplex ultrasound measured blood flow to the tissue flap during surgery.Twenty-one patients undergoing general anesthesia for lower limb reconstructive surgery were recruited. The optimal dobutamine dose was evaluated using the modified Dixon's up-and-down method, starting at 6 µg·kg·min, and then titrated in increments of 1 µg·kg·min.The optimal dose of dobutamine for improving blood flow to the tissue flap was 3.50 ±â€Š0.57 µg·kg·min in 50% of patients. The 95% effective dose of dobutamine calculated by probit analysis was 4.46 µg·kg·min (95% confidence interval: 3.99-7.00 µg·kg·min).The results of our study suggest that a dobutamine infusion rate less than 5 µg·kg·minprovides significant improvement of blood flow to the tissue flap, while minimizing cardiovascular side effects.

Safety and utility of dobutamine and pressure wire use in the hemodynamic assessment of low-flow, low-gradient aortic stenosis with reduced left ventricular ejection fraction.

BACKGROUND: The ACC/AHA guidelines recommend low-dose dobutamine challenge for hemodynamic assessment of the severity of AS in patients with low flow, low gradient aortic stenosis with reduced ejection fraction (EF) (LFLG-AS; stage D2). Inherent pitfalls of echocardiography could result in inaccurate aortic valve areas (AVA), which have downstream prognostic implications. Data on the safety and efficacy of coronary pressure wire and fluid-filled catheter use for low dose dobutamine infusion is sparse. METHODS: We retrospectively analyzed 39 consecutive patients with EF<50%, AVA<1cm2 and SVI<35ml/m2 on echocardiography who underwent simultaneous right and left heart catheterization. Hemodynamic assessments were performed at baseline and at every increment in the dobutamine infusion rate (The infusion was continued until maximal dose of dobutamine or a mean AV gradient>40mmHg was attained. The occurrence of sustained ventricular arrhythmias, symptomatic hypotension or intolerable symptoms leading to cessation of infusion was recorded. Transient ischemic attacks (TIAs) or clinically apparent strokes periprocedurally or up to 30days after the procedure were recorded. RESULTS: Dobutamine challenge confirmed true AS in 26 patients (67%) and pseudosevere AS in 34%. No sustained arrhythmias, hypotension or cessation of infusion from intolerable symptoms were observed. No clinical strokes or TIAs were observed up to 30days after procedure in any of these patients. CONCLUSIONS: Hemodynamic assessment of AS using a pressure wire with dobutamine challenge is a safe and effective tool in identifying truly severe AS in patients with LFLG-AS with reduced EF.

Additivity of nebivolol/valsartan single-pill combinations versus other single-pill combinations for hypertension.

The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory ß1 -selective antagonist/ß3 -agonist, and valsartan (80 mg), a renin-angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved ß-blocker/renin-angiotensin-aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration-approved non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo-adjusted SPC blood pressure (BP) reduction to the placebo-adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735-0.866; systolic BP range: 0.717-0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable.

Frequency, Predictors, and Implications of Abnormal Blood Pressure Responses During Dobutamine Stress Echocardiography.

BACKGROUND: It is not known whether abnormal blood pressure (BP) responses during dobutamine stress echocardiography (DSE) are associated with abnormal test results, nor if such results indicate obstructive coronary artery disease (CAD). We sought to define the frequency of abnormal BP responses during DSE and their impact on accuracy of test results. METHODS AND RESULTS: We studied 21 949 patients who underwent DSE at Mayo Clinic, Rochester, MN, grouped by peak systolic BP achieved during the test. We also analyzed a subgroup who underwent coronary angiography within 30 days after positive DSE. The positive predictive value of DSE was calculated for each BP group. Patients with hypertensive response (n=1905; 9%) were more likely to have positive DSE than those with normal (n=19 770; 90%) or hypotensive (n=274; 1%) BP responses (32% versus 21% versus 23%, respectively; P<0.0001). Angiography, performed in 1126 patients, showed obstructive CAD (≥50% stenosis) in 814 patients and severe CAD (≥70% stenosis) in 708 patients. Positive predictive value of DSE was similar for patients who had hypertensive and normal BP responses (69% versus 73%; P=0.3), considering 50% stenosis cut point. The proportion of severe CAD (≥70% stenosis) was lower in patients who had hypertensive response compared with those who had normal BP response (54% versus 65%; P=0.005). CONCLUSIONS: Patients with hypertensive response during DSE are more likely to have stress-induced myocardial ischemia compared with those with normal or hypotensive BP responses but are not more likely to have false-positive DSE results. They are, however, less likely to have higher grade or multivessel CAD.

Nebivolol/valsartan: Fixed-dose combination for treatment of hypertension.

Clinical trials demonstrated that a fixed-dose combination (FDC) of the beta-blocker nebivolol (5 mg) and the angiotensin II antagonist valsartan (80 mg) produced a significant reduction of both diastolic and systolic blood pressure in patients with hypertension. Both nebivolol and valsartan contributed to this effect, partial additivity of 86.6% and 82.2% being observed for diastolic and systolic blood pressure, respectively. These values are very similar to the additivity ratios of other recently approved FDCs for hypertension. Use of the FDC nebivolol 5 mg/valsartan 80 mg formulation was associated with a low incidence of treatment-related adverse effects and of serious adverse effects. There was no evidence of adverse effects due to beta2-adrenoceptor blockade. The FDC (Byvalson) was approved and launched in 2016 in the U.S. for the treatment of hypertension.

Dobutamine stress echocardiography resulting in acute gastric dilatation and pneumoporta.

Acute gastric dilatation is a rare cause of gas within the hepatic portal vein, but one that is important to recognise as prompt decompression via a nasogastric tube is usually successful in resolving the situation. We report the rare case of a 68-year-old man with spontaneous acute gastric dilatation 50 minutes after a dobutamine stress echo that resulted in pneumoporta. The patient had a Nissen's fundoplication 18 months previously; patients with previous antireflux surgery or who have a degree of gastric outlet obstruction may be at increased risk of this unusual condition. Conservative management, with placement of a nasogastric tube was successful in resolving his symptoms.

Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function.

PURPOSE: In two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled ß2-agonist for treatment of COPD, were investigated. SUBJECTS AND METHODS: The first trial included eight subjects with mild hepatic function impairment (Child-Pugh A), eight subjects with moderate impairment (Child-Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min(-1)) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 µg olodaterol administered with the Respimat Soft Mist inhaler. RESULTS: Olodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0-4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%-125%) and 105% (79%-140%), respectively. Corresponding values for dose-normalized maximum concentration (C max) were 112% (84%-151%) (mild impairment) and 99% (73%-135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0-4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%-195%), and for C max was 137% (84%-222%). There was no significant relationship between creatinine clearance and AUC0-4 or C max. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment. CONCLUSION: Mild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose.

Dobutamine induced eosinophilic myocarditis and right heart failure requiring emergent biventricular assist device implantation.

Dobutamine is a rare and unrecognized cause of eosinophilic myocarditis (EM). It is even more unique for it to cause significant clinical deterioration. Patients with end stage cardiomyopathy have very little cardiac reserve and dobutamine induced myocarditis may cause enough harm to require urgent mechanical circulatory support. We describe a man with dilated cardiomyopathy that developed accelerated clinical deterioration from dobutamine induced EM. He had a predominance of right heart failure, requiring an urgent biventricular assist device and acutely responded to withdrawal of dobutamine.

A Review of Nebivolol Pharmacology and Clinical Evidence.

Nebivolol is a highly selective ß1-adrenergic receptor antagonist with a pharmacologic profile that differs from those of other drugs in its class. In addition to cardioselectivity mediated via ß1 receptor blockade, nebivolol induces nitric oxide-mediated vasodilation by stimulating endothelial nitric oxide synthase via ß3 agonism. This vasodilatory mechanism is distinct from those of other vasodilatory ß-blockers (carvedilol, labetalol), which are mediated via α-adrenergic receptor blockade. Nebivolol is approved for the treatment of hypertension in the US, and for hypertension and heart failure in Europe. While ß-blockers are not recommended within the current US guidelines as first-line therapy for treatment of essential hypertension, nebivolol has shown comparable efficacy to currently recommended therapies in lowering peripheral blood pressure in adults with hypertension with a very low rate of side effects. Nebivolol also has beneficial effects on central blood pressure compared with other ß-blockers. Clinical data also suggest that nebivolol may be useful in patients who have experienced erectile dysfunction while on other ß-blockers. Here we review the pharmacological profile of nebivolol, the clinical evidence supporting its use in hypertension as monotherapy, add-on, and combination therapy, and the data demonstrating its positive effects on heart failure and endothelial dysfunction.

Dobutamine in paediatric population: a systematic review in juvenile animal models.

OBJECTIVE: Although dobutamine is widely used in neonatal clinical practice, the evidence for its use in this specific population is not clear. We conducted a systematic review of the use of dobutamine in juvenile animals to determine whether the evidence from juvenile animal experiments with dobutamine supported the design of clinical trials in neonatal/paediatric population. METHODS: Studies were identified by searching MEDLINE (1946-2012) and EMBASE (1974-2012). Articles retrieved were independently reviewed by three authors and only those concerning efficacy and safety of the drug in juvenile animals were included. Only original articles published in English and Spanish were included. RESULTS: Following our literature search, 265 articles were retrieved and 24 studies were included in the review: 17 focused on neonatal models and 7 on young animal models. Although the aims and design of these studies, as well as the doses and ages analysed, were quite heterogeneous, the majority of authors agree that dobutamine infusion improves cardiac output in a dose dependent manner. Moreover, the cardiovascular effects of dobutamine are influenced by postnatal age, as well as by the dose used and the duration of the therapy. There is inadequate information about the effects of dobutamine on cerebral perfusion to draw conclusions. CONCLUSION: There is enough preclinical evidence to ensure that dobutamine improves cardiac output, however to better understand its effects in peripheral organs, such as the brain, more specific and well designed studies are required to provide additional data to support the design of clinical trials in a paediatric population.