Should beta-blockers be used for the treatment of pediatric patients with chronic heart failure?

In multiple clinical trials, beta-blockers have been shown to significantly improve morbidity and mortality in adults with chronic congestive heart failure, but there is little reported experience with their use in children. Heart failure involves activation of the adrenergic nervous system and other neurohumoral systems in order to maintain cardiovascular homeostasis. These compensatory mechanisms have been shown to cause myocardial damage with chronic activation, which has been hypothesized to be a major contributing factor to the clinical deterioration of adults with heart failure. Studies have demonstrated inhibition of this neurohumoral response and concomitant clinical benefits with beta-blockers. Consequently, beta-blockers have evolved to become an important part of comprehensive medical therapy for congestive heart failure in adults. Pediatric heart failure represents an entirely different spectrum of disease, caused more commonly by congenital heart disease than cardiomyopathy. Surgical palliation and correction are important components of pediatric heart failure therapy, and residual, postsurgical cardiac lesions can lead to chronic heart failure. Although neurohumoral activation in children is similar to that in adults with heart failure, there are important differences from adults in physiology and developmental changes that are especially observed in infants. Current published clinical experience with beta-blocker use in children with heart failure is limited to case series with relatively small numbers of patients. Nevertheless, these series show consistent symptomatic improvement, and improvement in ventricular systolic function in patients with cardiomyopathies and congenital heart disease, similar to findings in adults. Adverse effects were common and many patients in these studies had adverse outcomes (death and/or need for transplantation). One study has noted differences in pharmacokinetics in children compared with adults. However, a multicenter, randomized controlled trial to evaluate carvedilol in pediatric heart failure from systolic ventricular dysfunction is currently ongoing and should help to clarify the efficacy and tolerability of carvedilol in children.     

Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris? A critical appraisal

Introduction: Ranolazine is a novel antianginal and anti-ischemic agent, that, unlike other available antianginal drugs in the United States (beta-blockers, organic nitrates, and calcium channel blockers), has no significant effect on either heart rate or blood pressure. Its exact mechanism of action is unknown. Ranolazine does increase electrocardiographic QTc interval in a dose-related manner, but at therapeutic doses it has no proarrhythmic effects. Ranolazine (ER) at doses of 500 and 1,000 mg twice daily is currently approved for the treatment of angina pectoris either as monotherapy or added to beta-blockers, nitrates, and calcium channel blockers. Ranolazine (ER) is currently not approved for the treatment of unstable angina, silent ischemia, or cardiac arrhythmias. The most common adverse effects reported in clinical trials during ranolazine (ER) treatment are dizziness, headaches, constipation, and nausea.

Areas covered: Recent changes in ranolazine (ER) labeling have led to its increased use for treating patients with ischemic heart disease. This review addresses its appropriate use. All publications were reviewed and those relevant were included.

Expert opinion: Ranolazine (ER) is an effective antianginal and anti-ischemic agent, but I restrict its use to treat patients with stable angina pectoris.     

Should antiepileptic drugs be withdrawn in seizure-free patients?

Discontinuation of antiepileptic drug (AED) treatment is a valuable option in patients with epilepsy who have been seizure free for 2 years or longer. However, the decision to withdraw AEDs must be based on a balanced view of the overall risk of seizure relapse, the factors most likely to affect that risk, and the medical, emotional and social implications of treatment continuation versus treatment withdrawal. In a critical review of 28 studies accounting for 4571 patients (2758 children, 1020 adults and a combined group of 793), most with at least 2 years of seizure remission, the proportion of patients with relapses during or after AED withdrawal ranged from 12 to 66%. Using life-table analysis, the cumulative probability of remaining seizure-free in children was 66-96% at 1 year and 61-91% at 2 years after withdrawal of AEDs. The corresponding values in adults were 39-74% and 35-57%, respectively. The relapse rate was highest in the first 12 months (especially in the first 6 months) after withdrawal and tended to decrease thereafter. Based on a previously published meta-analysis of data published up to 1992, the pooled relapse risk was 25% (95% CI 21, 30%) at 1 year and 29% (95% CI 24, 34%) at 2 years after AED withdrawal. The factors associated with a higher-than-average risk of seizure relapse included adolescent-onset epilepsy, partial seizures, the presence of an underlying neurological condition, and abnormal EEG findings at the time of AED withdrawal in children. Factors associated with a lower-than-average risk were childhood-onset epilepsy, idiopathic generalised epilepsy and - for children - a normal EEG. Selected epilepsy syndromes (e.g. benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) may be associated with significantly different outcomes after AED withdrawal.All these factors and their combinations may contribute to the development of guidelines for practising physicians to help them in making the best decision related to treatment discontinuation. The decision plan should also take into account social factors (driving license, job and leisure activities) as well as emotional and personal factors, and must be tailored to and discussed with the individual patient and his/her family.     

Are free radicals involved in lead poisoning?

1. The enolamine form of 5-aminolaevulinic acid (ALA), a haem precursor that accumulates in lead poisoning and in acute intermittent porphyria (AIP), undergoes fast autoxidation at slightly alkaline pH with concomitant generation of reactive oxygen species.

2. The transmembrane potential, Ca²⁺ ion fluxes and state-4 respiratory rate, of isolated rat liver mitochondria are severely affected by mM addition of ALA; the toxic role of ALA-produced oxygen radicals was demonstrated by use of appropriate scavengers.

3. Induction of superoxide dismutase biosynthesis in lead-exposed workers, in AIP carriers and in ALA-treated rats, is viewed as a protective response against oxygen radical toxicity.

4. 5-Aminolaevulinic acid-generated oxygen radicals, together with Pb-stimulated Fe-dependent lipid peroxidation, might be involved in the aetiology of the neuropsychiatric manifestations of both plumbism and acute intermittent porphyria.     

Should pediatric patients with hyperlipidemia receive drug therapy?

Hyperlipidemia is now established as a major risk factor for causation of coronary heart disease (CHD) in adults; however, there is much debate on the level of coronary risk at which lipid-lowering drugs should be used. These issues of possible harm or lack of benefit from long-term use of lipid-lowering therapy, and cost effectiveness, are also pertinent in the pediatric setting. Evidence from several countries indicates that children have an increasing prevalence of obesity, hyperlipidemia and type 2 diabetes mellitus. Children who have high serum lipids 'track' these increased levels into adulthood. In some countries there is a trend to screen children for hypercholesterolemia. Family history itself is a poor discriminator in determining which children need to be screened and treated. Estimation of apolipoprotein B and/or apolipoprotein E genotype can improve prediction. Measuring high density lipoprotein cholesterol also helps, but obesity appears to be the best marker for screening children at high risk. These considerations should not cloud the need for case finding and treatment of children with genetic disorders. Low fat diets have been shown to be well tolerated and effective in children; however, there are no major long-term studies demonstrating harm or benefit in those on lipid-lowering drugs. Nevertheless, concerns regarding the psychological effect and the theoretical metabolic effects of long-term lipid lowering remain. Lipid-lowering drugs should be generally restricted to children with genetic disorders of lipid metabolism. Children with diabetes mellitus, hypertension or nonlipid-related inherited disorders leading to premature CHD in adults should be treated with diet, and with lipid-lowering drugs when they reach adulthood. Children with secondary hyperlipidemia should be assessed individually. A number of drugs and nutriceuticals are available for use in children, but only a few drugs are licensed for use in children.     

Treatment of central sensitization in patients with chronic pain: time for change?

ABSTRACT

Introduction: Given our improved understanding of the role of central sensitization (CS) in many patients with chronic pain, it seems rational to account for CS during treatment.

Areas covered: First, the treatment rationale based on the complex mechanisms underlying CS in patients having chronic pain is presented. Second, emphasis is given to explaining the concept of CS when providing treatment, as well as why patients and clinicians should focus on long-term rather than short-term treatment effects. Third, possible pharmacological and non-pharmacological treatment options are discussed.

Expert opinion: Centrally acting drugs such as tricyclic compounds, serotonin-norepinephrine reuptake inhibitors, and α₂δ ligands each target mechanisms that are often dysfunctional in patients having chronic pain and CS, but decades of clinical practice and clinical trials have not resulted in satisfactory outcomes. This comes as no surprise; CS comprises complex psycho-neuro-immunological interactions, while each of the tested drugs targets one or two of those mechanisms from a purely biomedical viewpoint. Clinicians willing to take CS into account should design an individually tailored multimodal treatment plan comprising pain neuroscience education, cognition-targeted exercise therapy, sleep management, stress management, and/or dietary intervention.     

Should patients in need be given access to experimental drugs?

Patient access to experimental drugs outside of clinical trials is called compassionate use or expanded access. Compassionate use/expanded access presents a powerful ethical dilemma in that it involves competing claims that both have moral weight: specifically, an individual patient’s very understandable desire to try to extend his or her life versus the orderly and efficient functioning of a drug development and clinical trial system that benefits much larger numbers of patients. Patient advocates, the FDA, pharmaceutical trade groups, and state and national legislators in the US are all currently weighing in on patient access to experimental drugs, and new guidelines and rules are being introduced. In this editorial, we discuss the impulse to rescue individual patients facing dire diseases and underscore the ethical questions that such rescue efforts raise.     

Should patients be given an initial low test dose of sildenafil?

Sildenafil is highly effective for treating erectile dysfunction (ED). However, its use has been associated with serious adverse events including myocardial infarctions and strokes, and 130 verifiable plus 112 unverified deaths reported to the US Food and Drug Administration during the 8 months after sildenafil was introduced in the US, and 522 reported deaths during the 13.5 months after its introduction. Moreover, some events have occurred in men taking their first dose of the agent, suggesting that sildenafil, like some drugs that affect blood pressure, may provoke a first-dose reaction. This possibility warrants extra caution to be used when initiating treatment with sildenafil. Such caution is not currently provided by the current dosage guidelines that, for example, recommend the use of sildenafil 50 mg initially for most men between the ages of 18 and 65 years, despite wide differences in bodyweight, age, drug metabolism, health status and usage of other medications. It can be difficult to identify the patient who may be unusually sensitive to the effects of sildenafil. Exercise stress tests have been recommended, but serious adverse events have occurred in men with normal stress tests following the ingestion of sildenafil. Blood pressure monitoring following sildenafil administration will not prevent a serious adverse drug event already in progress. This article discusses the advantages and disadvantages of initiating treatment with a low test dose of sildenafil, performed at home or in the doctor's office. The advantages of this approach include: (i) identifying patients who are highly sensitive to the effects of sildenafil and who may need no higher dose; (ii) minimising adverse effects such as flushing and dizziness that often frighten patients and may affect adherence; (iii) avoidance of major adverse events; and (iv) reassuring patients with ED who remain wary about trying sildenafil therapy.