Usefulness of the serum lactate concentration for predicting mortality in acute beta-blocker poisoning

Context.?Serum lactate measured in the emergency department was recently assessed as an excellent prognosticator of drug-overdose fatality, with the optimal lactate cutoff point being 3.0 mmol/L. However, lactate's role has never been specifically studied in beta-blocker poisonings. Objective.?We aimed to evaluate the ability of lactate concentrations to predict outcome (survival versus death) in beta-blocker poisoning. Methods.?We conducted an 8-year retrospective study for all symptomatic beta-blocker poisonings admitted to our toxicological intensive care unit (ICU). Serum lactate concentrations were measured in 110 patients and final outcomes of survival or death recorded. Results.?Lactate concentrations were 1.79 mmol/L [0.8–5.6] (median, 10–90% percentiles) and peak values of 1.9?mmol/L [0.9–9.5] (p?<?0.0001). Nine patients (8%) died in the ICU. Admission serum lactate concentrations differed significantly between survivors and fatalities (p?=?0.0008). Four patients (44% of the non-survivors) died in the ICU despite lactate concentrations lower than 3.0?mmol/L. The diagnostic characteristics of the 3.0?mmol/L selected lactate cutoff point were 55% sensitivity and 80% specificity. Conclusion.?Serum lactate elevation in beta-blocker poisoning is relatively mild on admission despite the presence of significant cardiovascular symptoms. Even if raised in severe poisonings and alone correlate well with prognosis, lactate concentration is not an absolute predictor of beta-blocker-overdose fatality.     

Prognostic benefit of beta-blockers in patients not receiving ACE-Inhibitors.

AIMS: Beta-blockers (BBs) confer significant prognostic benefit in patients (pts) with systolic chronic heart failure (CHF). However, major trials have thus far studied BBs mainly in addition to ACE-Inhibitors or angiotensin receptor blockers (ARBs) as background therapy. The magnitude of the prognostic benefit of BBs in the absence of ACE-I or ARB has not as yet been determined. METHODS AND RESULTS: We performed a meta-analysis of all placebo-controlled BB studies in patients with CHF (n>200). Trials were identified via Medline literature searches, meeting abstracts, and contact with study organizations. Results for all-cause mortality and death or heart failure hospitalization were pooled using the Mantel-Haenszel (fixed effects) method. The impact of BB therapy on all-cause mortality in CHF, in the absence (4.8%) and presence (95.2%) of ACE-I (or ARB), was determined from six trials of 13 370 patients. The risk ratio (RR) for BBs vs. placebo was 0.73 [95% confidence interval (CI) 0.53-1.02] in the absence of ACE-I or ARB at baseline, compared with a RR of 0.76 (95% CI 0.71-0.83) in the presence of these agents. When ACE-Inhibitors were analysed in the same way (pre-BB), a RR of 0.89 (0.80-0.99) vs. placebo was observed in studies of >90 days. The impact of BB therapy on death or HF hospitalization in systolic CHF, in the absence and presence of ACE-I, was determined from three trials of 8988 patients. The RR for BBs vs. placebo was 0.81 (95% CI 0.61-1.08) in the absence of ACE-I or ARB at baseline, compared with a RR of 0.78 (95% CI 0.74-0.83) in the presence of these agents. When ACE-Is were analysed in the same way (pre-BB), a RR of 0.85 (95% CI 0.78-0.93) vs. placebo was observed in studies of >90 days. CONCLUSION: The magnitude of the prognostic benefit conferred by BBs in the absence of ACE-I appears to be similar to those of ACE-Is in systolic CHF. These data therefore suggest that either ACE-Is or BBs could be used as first-line neurohormonal therapy in patients with systolic CHF. Prospective studies directly comparing these agents are required to definitively address this issue.     

Beta-blocker treatment of chronic systolic heart failure improves prognosis even in patients meeting one or more exclusion criteria of the MERIT-HF study.

AIMS: Improved prognosis of patients with chronic systolic heart failure by treatment with beta-blockers has been shown in several randomized controlled multicentre trials. However, in clinical practice only a part of heart failure patients meet the inclusion criteria of these trials. The present study evaluates whether reduction of mortality by beta-blockers also can be achieved in patients presenting one or more exclusion criteria of the MERIT-HF trial. METHODS AND RESULTS: From the Ludwigshafen Heart Failure Registry 675 patients with chronic systolic heart failure consecutively enrolled between January 1995 and June 2004 were divided in two groups either meeting the inclusion criteria of the MERIT-HF trial ('trial patients': n = 278, 60% treated with beta-blockers) or not ('non-trial patients': n = 397; 51% treated with beta-blockers). The distribution of the MERIT-HF exclusion criteria in the group of 'non-trial patients' was as follows: acute myocardial infarction 9.6%; systolic blood pressure <100 mmHg 7.5%; chronic obstructive lung disease 33.2%; other serious diseases potentially limiting prognosis 16.9%; acutely performed or planned ICD, bypass surgery, PCI, heart transplantation: 17.1, 15.9, 7.8, and 4.8%, respectively. Median follow-up was 31.3 months (upper/lower quartile 16.3/50.0 months). All-cause mortality was significantly reduced by beta-blocker treatment not only in 'trial patients' (adjusted hazard ratio 0.57, 95% CI 0.38-0.86) but also in 'non-trial patients' (adjusted hazard ratio 0.72, 95% CI 0.53-0.97). CONCLUSION: In clinical practice only the smaller part of the population to be treated for chronic systolic heart failure meets the inclusion criteria of the MERIT-HF study. However, beta-blocker treatment is associated with a significantly reduced long-term mortality even in patients meeting one or more exclusion criteria of the MERIT-HF study.     

Combining neuroendocrine inhibitors in heart failure: reflections on safety and efficacy

Neuroendocrine activation in heart failure has become the major target of pharmacotherapy for this growing epidemic. Agents targeting the renin-angiotensin-aldosterone and sympathetic nervous systems have shown cardiovascular and survival benefits in clinical trials. Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors remain the mainstream initial therapy. The benefits of aldosterone antagonists have been demonstrated in advanced heart failure (spironolactone) and after myocardial infarction complicated by left ventricular dysfunction and heart failure (eplerenone). Emerging clinical evidence demonstrated that angiotensin receptor blockers may be a reasonable alternative to ACE inhibitors in patients with heart failure (candesartan) and following myocardial infarction complicated by heart failure or left ventricular dysfunction (valsartan). Angiotensin receptor blockers (candesartan) also provided incremental benefits when added to ACE inhibitors in chronic heart failure. Thus, combining neuroendocrine inhibitors in heart failure appears both biologically plausible and evidence-based. However, this approach raised concerns about side effects, such as hypotension, renal insufficiency, hyperkalemia, and others. Close follow-up and implementation of evidence-based medicine (ie, using agents and doses proven beneficial in clinical trials) should therefore be undertaken when combining neuroendocrine inhibitors.     

Topical timolol 0.5% as the primary treatment of ophthalmic pyogenic granuloma: A prospective,single-arm study

Purpose:To study topical timolol (0.5%) as a first-line treatment in ophthalmic pyogenic granuloma (PG) in terms of safety and efficacy.Methods:This was a prospective, interventional, single-arm study conducted at a tertiary eye care hospital in central India. Only new cases of PG were counseled to get enrolled in the study. A total of 40 patients were analyzed in the study. Topical timolol eye drop (0.5%) was started in each patient twice daily for 4–6 weeks duration. The patients were divided into five categories according to the percentage reduction in the size of PG as follows: i) 80–100% reduction - excellent responders, ii) 60–80% – good, iii) 40–60% – satisfactory, iv) 20–40% – poor, and v) <20% – very poor/nonresponder. After 6 months of starting treatment final evaluation was done.Results:The mean age of the patients was 23.5 ± 13.3 years. Etiology of the disease included chalazion (n = 11, 27.5%), trauma (n = 2, 5%), surgery (n = 7, 17.5%), foreign body (n = 2, 5%), and idiopathic (n = 18, 45%). An excellent response was achieved in 31 (77.5%) patients. Twenty-seven (67.5%) patients had complete resolution of lesions within 6 weeks. Recurrence of the lesion was not noticed in any patients.Conclusion:Timolol 0.5% in topical form is a good treatment option for ophthalmic PG in all age groups. The treatment has no adverse effects when given to suitable individuals for a limited period.     

Combination Therapy Versus Monotherapy in Reducing Blood Pressure: Meta-analysis on 11,000 Participants from 42 Trials

Objective

To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose.

Methods

Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo.

Results

We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]).

Conclusion

Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.     

Effects of metoprolol therapy on cardiac troponin-I levels after elective percutaneous coronary interventions.

AIMS: Beta-blockers (BBs) have been shown to improve survival and reduce the risk of re-infarction in patients following myocardial infarction. There are conflicting data about the effects of BB therapy on cardiac biomarkers after percutaneous coronary interventions (PCIs). The aim of the study was to investigate the effects of BB use on cardiac troponin-I (cTnI) levels in patients who had undergone elective PCI. METHODS AND RESULTS: In this prospective study, 287 patients with coronary artery disease were included. Patients were randomized either to BB or control groups prior to the intervention. Blood samples for cTnI were obtained before and at 6, 24, and 36 h after the procedure. Of the 287 patients included, 143 received metoprolol succinate 100 mg/day, and 144 received no BB and served as the control group. Baseline clinical characteristics of both groups, except for history of coronary artery bypass graft surgery, were similar. We observed no significant difference in the elevation of cTnI levels between the two groups after PCI (BB group, 17 patients, 11.9%; control group, 10 patients, 6.9%; P=0.2). CONCLUSION: Metoprolol succinate therapy seems to have no cardioprotective effect in limiting troponin-I rise after PCI.     

Physiologic and cardiac roles of β-arrestins

β-arrestin1 and β-arrestin2 were initially identified by sequence homology to visual arrestins and by their ability to bind to and inactivate signaling of the beta-2-adrenergic receptor in a process known as desensitization. While the role of β-arrestins in desensitization has been known for some time, more recent evidence has revealed that β-arrestins are multifunctional scaffolding proteins that are involved in numerous aspects of G protein-coupled receptor (GPCR) signaling. Interestingly, exciting new data shows that β-arrestins can mediate signaling in their own right independent of classical second messenger mediated signaling, and that this β-arrestin-mediated signaling may be cardioprotective. Identifying novel ligands for GPCRs that can block G protein-mediated signaling while simultaneously promoting β-arrestin-mediated signaling could provide powerful new therapies for cardiac disease.     

The influence of penbutolol and placebo on blood sugar levels and insulin consumption in the glucose-controlled insulin infusion system (“Artificial endocrine pancreas”)

Summary The aim of the study was to investigate the influence of 40 mg of the beta-blocker penbutolol (BetapressinTM; Hoechst Ltd., Frankfurt/ Main) in comparison to placebo on the insulin consumption on the blood sugar profile in twelve insulin-dependent diabetes (IDDM) patients. The patients were treated with penbutolol and placebo for a period of three days, and then were examined with the help of the glucose-controlled insulin infusion system.The blood sugar profile and insulin consumption over a 24 hour period was not affected by either penbutolol or placebo, nor could any changes be measured in these parameters when measured after food intake.After a submaximal exercise load on the bicycle ergometer (1 watt per kg body weight) following an evening meal, no difference could be observed between penbutolol and placebo in the above-mentioned parameters. The same was also true for hormonal parameters as STH, ACTH, cortisol, and catecholamines.These findings demonstrated that medication of penbutolol over a three-day period has no influence on the baseline blood sugar profile and insulin consumption or on insulin consumption after food intake during rest and physical exercise.Abbreviations IDDM insulin-dependent diabetes - STH somatotropic hormone - GH growth hormone - ACTH adrenocorticotropic hormone - HbA1 glycosylated hemoglobin A1 - mE milli-units - SEM standard error of the mean     

Beta-blockers for the treatment of problematic hemangiomas

OBJECTIVE:

To examine treatment indications, efficacy and side effects of oral beta-blockers for the treatment of problematic hemangiomas.

METHODS:

A retrospective review of patients with hemangiomas presenting to the Alberta Children’s Hospital Vascular Birthmark Clinic (Calgary, Alberta) between 2009 and 2011 was conducted. The subset of patients treated with oral beta-blockers was further characterized, investigating indication for treatment, response to treatment, time to resolution of indication, duration of treatment, occurrence of rebound growth and side effects of therapy.

RESULTS:

Between 2009 and 2011, 311 new patients with hemangiomas were seen, of whom 105 were treated with oral beta-blockers. Forty-five patients completed beta-blocker treatment while the remainder continue to receive therapy. Indications for treatment were either functional concerns (68.6%) or disfigurement (31.4%). Functional concerns included ulceration (29.5%), periocular location with potential for visual interference (28.6%), airway interference (4.8%), PHACES syndrome (3.8%), auditory interference (0.95%) and visceral location with congestive heart failure (0.95%). The median age at beta-blocker initiation was 3.3 months; median duration of therapy was 10.6 months; and median maximal treatment dose was 1.5 mg/kg/day for propranolol and 1.6 mg/kg/day for atenolol. Ninety-nine patients (94.3%) responded to therapy with size reduction, colour changes, softened texture and/or healing of ulceration. Rebound growth requiring an additional course of therapy was observed in 23 patients. Side effects from beta-blockers included cool extremities (26.7%), irritability (17.1%), lower gastrointestinal upset (14.3%), emesis (11.4%), hypotension (10.5%), poor feeding (7.6%), lethargy (4.8%), bronchospasm (0.95%) and rash (0.95%). Side effects did not result in complete discontinuation of beta-blocker treatment in any case; however, they prompted a switch to a different beta-blocker preparation in some cases. Resolution of the primary indication, requiring a median time of three months, occurred in 87 individuals (82.9%).

CONCLUSIONS:

Treatment of infantile hemangiomas with oral beta-blocker therapy is highly effective and well tolerated, with more than 94% of patients demonstrating a response to treatment and 90% showing resolution of the primary functional indication for treatment.