Efficacy of a single dose of esmolol to prevent extubation-related complications during emergence from anesthesia: a randomized, double-blind, placebo-controlled trial

Abstract Background Few trials have examined the efficacy of esmolol to attenuate hemodynamic and respiratory responses during extubation. However, the most appropriate dose of esmolol and an optimal protocol for administering this beta-blocker are uncertain. Methods Ninety patients ASA physical status I, II, and III (aged 18-60 years) scheduled to procedures with general anesthesia and tracheal extubation were selected. Patients were randomized into esmolol and placebo group to evaluate the efficacy and safety of a single bolus dose of esmolol (2 mg.kg-1) on cardiorespiratory responses during the peri-extubation period. The primary outcome was the rate of tachycardia during extubation. Results The rate of tachycardia was significantly lower in esmolol-treated patients compared to placebo-treated patients (2.2% vs. 48.9%, relative risk (RR): 0.04, 95% confidence interval (95% CI) = 0.01 to 0.32, p= 0.002). The rate of hypertension was also significantly lower in the esmolol group (4.4% vs. 31.1%, RR: 0.14, 95% CI 0.03 to 0.6, p= 0.004). Esmolol-treated patients were associated with higher extubation quality compared to patients who received placebo (p< 0.001), with an approximately two-fold increase in the rate of patients without cough (91.1%) in the esmolol group compared to the placebo group (46.7%). The rate of bucking was approximately 5-fold lower in the esmolol group (8.9% vs. 44.5%, respectively, RR: 0.20 (95% CI, 0.1 to 0.5, p= 0.002, with an NNT of 2.8). Conclusion A single bolus dose of esmolol is an effective and safe therapeutic strategy to attenuate cardiorespiratory responses during the peri-extubation period.

A nonsense variant in FBN1 caused autosomal dominant Marfan syndrome in a Chinese family: a case report.

BACKGROUND: Marfan syndrome (MFS) is a common autosomal dominant inherited disease, and the occurrence rate is around 0.1-0.2‰. The causative variant of FNB1 gene accounts for approximately 70-80% of all MFS cases. In this study, we found a heterozygous c.3217G > T (p.Glu1073*) nonsense variant in the FBN1 gene. This finding extended the variant spectrum of the FBN1 gene and will provide a solution for patients to bear healthy offspring by preimplantation genetic testing or prenatal diagnosis. CASE PRESENTATION: The patient was treated due to tachycardia during excitement in a hospital. Echocardiography showed dilatation of the ascending aorta and main pulmonary artery, mitral regurgitation (mild), tricuspid regurgitation (mild), and abnormal left ventricular filling. Electrocardiograph showed sinus rhythm. In addition, flutters of shadows in front of his eyes and vitreous opacity were present in the patient. Genomic DNA was extracted from peripheral blood samples from members of the family and 100 unrelated controls. Potential variants were screened out by next-generation sequencing and confirmed by MLPA & Sanger sequencing. Real-time fluorescence quantitative PCR (RT-qPCR) was performed to detect the relative mRNA quantitation in the patient. A heterozygous nonsense variant c.3217G > T of the FBN1 gene, which resulted in p. Glu1073Term, was identified in both patients. Only wild type bases were found in the cDNA sequence of the patient. Real-time fluorogenic quantitative PCR results showed that the relative expression level of FBN1 cDNA in the patient was only about 21% compared to that of normal individuals. This variant c.3217G > T of the FBN1 gene introduces a Stop codon in the cb-EGF12 domain. We speculated that a premature translational-termination codon (PTC) was located in the mRNA and the target mRNA was disintegrated through a process known as nonsense-mediated mRNA decay (NMD), which led to a significant decrease of the fibrillin-1 protein, eventually causing clinical symptoms in the patient. CONCLUSIONS: In this study, we found a heterozygous c.3217G > T (p.Glu1073*) nonsense variant in the FBN1 gene, which eventually led to Marfan syndrome in a Chinese family.

Masked tachycardia. A predictor of adverse outcome in hypertension.

OBJECTIVE: The relative role of office heart rate (HR) and ambulatory HR for predicting major adverse cardiovascular events (MACEs) and mortality is not well known. Aim of this study was to investigate the association of white-coat tachycardia and masked tachycardia with MACE and mortality in hypertensive patients. METHODS: We performed 24-h ambulatory blood pressure and HR monitoring in 7602 hypertensive patients (4165 men) aged 52 ±â€Š16 years enrolled in six prospective studies in Italy, Japan, and Australia. Participants were divided into four groups: normal office and normal night-time HRs (N = 5238), white-coat tachycardia (N = 998), masked tachycardia (N = 796), and sustained tachycardia (N = 570). Median follow-up was 5.0 years. RESULTS: In age-and-sex-adjusted Cox model, using the normal HRs group as a reference, white-coat tachycardia was not a significant predictor of excess MACEs or all-cause death. In contrast, both masked tachycardia [hazard ratio, 95% confidence interval (CI); 1.40, 1.11-1.77] and sustained tachycardia (1.86, 1.44-2.40) were associated with risk of excess MACE. In addition, masked tachycardia (hazard ratio, 95% CI; 1.62, 1.14-2.29) but not sustained tachycardia (1.35, 0.83-2.19) was a significant predictor of excess mortality. These relationships held true in multivariable parsimonious Cox models including major risk factors. In these models, masked tachycardia remained an independent predictor of excess MACE (hazard ratio, 95% CI; 1.34, 1.06-1.71) and all-cause mortality (1.68, 1.18-2.41). CONCLUSION: The current study confirms that measurement of HR adds to the risk stratification for MACE and mortality and shows that an elevated night-time HR confers an increased mortality risk to hypertensive patients who have normal office HR.

Clinical characteristics and risk factors of pericardial effusion complicating radiofrequency catheter ablation in Chinese Han patients with tachyarrhythmias.

BACKGROUND: The clinical features and risk factors of pericardial effusion complicating radiofrequency catheter ablation (RFCA) in a large sample of Chinese Han patients with tachyarrhythmias have rarely been reported. METHODS: We summarized the clinical characteristics and analyzed the risk factors of pericardial effusion complicating RFCA in 1,756 Chinese Han patients with tachyarrhythmias. RESULTS: There were 27 patients with pericardial effusion after RFCA. Of these patients, 10 developed cardiac tamponade; the symptoms of 9 patients were relieved after pericardiocentesis and drainage, while 1 patient was discharged after emergency surgical repair. The rate of pericardial effusion in patients with atrial fibrillation was significantly higher than in those with other tachyarrhythmias (P < 0.001). The proportion of female patients, hypertension, diabetes mellitus, coronary heart disease, age, left atrial size, and length of hospitalization in the pericardial effusion group was significantly increased compared with the non-pericardial effusion group (P < 0.01). Multivariate logistic regression analysis showed that female sex and atrial fibrillation were independent risk factors of complications by pericardial effusion after RFCA in patients with tachyarrhythmias. Age and left atrial size in female patients and those with atrial fibrillation were significantly higher than in male patients and patients without atrial fibrillation. CONCLUSION: Pericardial effusion complicating RFCA is not rare in patients with tachyarrhythmias, and it tends to develop into cardiac tamponade. Emergency pericardiocentesis and drainage are the most effective therapy. Female sex and atrial fibrillation may be independent risk factors of pericardial effusion after RFCA in patients with tachyarrhythmias.

Fine-mapping and initial characterization of QT interval loci in African Americans.

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

GRK5 Gln41Leu polymorphism is not associated with sensitivity to beta(1)-adrenergic blockade in humans.

AIMS: A common, functionally significant polymorphism in GRK5 (Gln41Leu) encodes a gain-of-function enzyme that enhances desensitization of the beta(1)-adrenergic receptor. GRK5 Leu41 has been postulated to confer endogenous 'genetic beta-blockade' and contribute to an attenuated response to beta-blockers in black subjects. The effects of this GRK5 variant on sensitivity to a beta-blocker have not been studied in humans. We hypothesized that the GRK5 Gln41Leu variant contributes to interindividual variability in response to beta-blockade and to the ethnic difference in sensitivity between black and Caucasian individuals. MATERIALS & METHODS: We measured the heart rate at rest and during a graded incremental exercise in 154 healthy subjects (85 white and 69 black) before and after an oral administration of 25 mg atenolol. We determined the genotypes of GRK5 (Gln41Leu), beta(1)-adrenergic receptor (ADRB1 Ser49Gly and Arg389Gly) genotypes and plasma atenolol concentrations. The effects of genotype and covariates on sensitivity to atenolol, measured as the reduction in exercise-induced tachycardia, were determined using multiple regression analyses. RESULTS: The minor allele frequency of GRK5 Leu41 was 32.6% in blacks and 0% in whites. Black individuals were less sensitive to atenolol than white individuals (p < or = 0.011) but this was not explained by the GRK5 genotype. The GRK5 genotype had no effect on resting heart rate before (p = 0.61) and after adjustment for age, sex, ethnicity, atenolol concentrations, BMI and ADRB1 genotypes (p = 0.81). The decrease in heart rate after atenolol administration did not differ significantly according to the GRK5 genotype at rest or after exercise, before (all p > 0.14) and after statistical adjustment for covariates (all p > 0.17). CONCLUSION: The GRK5 Gln41Leu polymorphism does not affect sensitivity to the beta(1)-adrenergic blocker, atenolol, during acute physiological adrenergic stimulation, nor does it contribute to the ethnic differences in sensitivity to atenolol among black and Caucasian individuals.

Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade.

OBJECTIVES: Black patients may be less responsive to beta-blockers than whites. Genetic variants in the beta1-adrenergic receptor (beta1-AR) associated with lesser response to beta-blockers are more common in blacks than in whites. The purpose of this study was to determine whether ethnic differences in response to beta-blockade can be explained by differing distributions of functional genetic variants in the beta1-AR. METHODS: We measured sensitivity to beta-blockade by the attenuation of exercise-induced tachycardia in 165 patients (92 whites), who performed a graded bicycle exercise test before and 2.5 h after oral atenolol (25 mg). We determined heart rate at rest and at three exercise levels from continuous ECG recordings and calculated the area under the curve. We also measured plasma atenolol concentrations and determined genotypes for variants of the beta1-AR (Ser49Gly, Arg389Gly) and alpha2C-AR (del322-325). The effects of ethnicity, genotype, and other covariates on the heart rate reduction after atenolol were estimated in multiple regression analyses. RESULTS: Atenolol resulted in a greater reduction in exercise heart rate in whites than in blacks (P=0.006). beta1-AR Arg389 (P=0.003), but not the alpha2C-AR 322-325 insertion allele (P=0.31), was independently associated with a greater reduction in heart rate area under the curve. Ethnic differences in sensitivity to atenolol remained significant (P=0.006) after adjustment for beta1-AR and alpha2C-AR genotypes. CONCLUSION: Ethnic differences in sensitivity to the beta1-blocker atenolol persist even after accounting for different distributions of functional genetic beta1-AR variants, suggesting that additional, as yet unidentified factors contribute to such ethnic differences.

Racial differences in sensitivity to the negative chronotropic effects of propranolol in healthy men.

OBJECTIVE: Dose-response studies in patients with hypertension have shown that black subjects are less responsive to beta-blocker therapy than white subjects, whereas studies in healthy volunteers suggest marginal or no racial differences in response. No concentration-response studies have been conducted in black subjects and white subjects. The purpose of this study was to characterize beta-blocker pharmacodynamics in healthy black and white men. METHODS: Thirteen black and 13 white healthy men took 80 mg oral propranolol three times daily, for a total of 16 doses. Heart rate response to treadmill exercise was measured at various times over 24 hours. Serum propranolol samples were collected during the same 24-hour time period and were measured by chiral HPLC. The sigmoid maximal effect (Emax), Emax, and linear models were fitted to percentage reductions in exercise heart rate and S-propranolol concentrations. RESULTS: Black subjects had significantly lower values for serum concentration producing one-half the maximal effect (EC50) and unbound EC50 than white subjects (EC50: 10.2 ng/ml (4.4 to 28.0 ng/ml) versus 24.4 ng/ml (14.3 to 64.1 ng/ml), blacks versus whites; unbound EC50: 1.29 ng/ml (0.686 to 4.91 ng/ml) versus 2.77 ng/ml (1.70 to 8.11 ng/ml), blacks versus whites). There was no statistical difference in Emax (33.3% [22.2% to 39.7%] versus 38.3% [30.7% to 45.1%], blacks versus whites). CONCLUSIONS: Healthy black men were more sensitive to beta-blockade than healthy white men. The results of this study in healthy volunteers suggest that the racial differences in response observed in patients with hypertension are related to hypertensive pathophysiology rather than normal physiology.