Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey.

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence.

Suboptimal care in the initial management of children who died from severe bacterial infection: a population-based confidential inquiry.

OBJECTIVES: To study the frequency and types of suboptimal care and medical errors in children who died of severe bacterial infection as the first-stage procedure intended to improve quality of care. DESIGN: Population-based confidential inquiry. SETTING: Two adjoining administrative districts in France. PATIENTS: Children older than 3 months dead from severe bacterial infection from 2000 through 2006. INTERVENTIONS: The medical files were summarized on standardized forms and then evaluated independently by two experts, who determined whether the initial management before the patients' arrival in intensive care was or was not optimal, in comparison with current guidelines. MEASUREMENTS AND MAIN RESULTS: Of 23 deaths from severe bacterial infection, 21 could be analyzed; management was considered suboptimal in 76%. The coefficient of agreement between the experts was high, with a weighted kappa of 0.73. The types of errors identified included parental delay in seeking medical care (33%; 95% confidence interval, [12-54]), physicians' delay in administering appropriate treatment (antibiotic therapy in the case of purpura; 38%; 95% confidence interval, 16-60), insufficient doses of or failure to repeat fluid resuscitation (24%; 95% confidence interval, [9 -35]), and overall underestimation of disease severity (38%; 95% confidence interval, [16-60]). CONCLUSION: This study found a high frequency of suboptimal care in the initial management of children who died of severe bacterial infection, with four separate types of errors. Other studies are needed to assess the potential avoidability of this type of death.

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease.

BACKGROUND: Acetylcysteine and carbocysteine are the most commonly prescribed mucolytic drugs in many European countries. To our knowledge, no systematic review has been published on their efficacy and safety for acute upper and lower respiratory tract infections (ARTIs) in children without chronic broncho-pulmonary disease. OBJECTIVES: The objective was to assess the efficacy and safety and to establish a benefit-risk ratio of acetylcysteine and carbocysteine as symptomatic treatments for ARTIs in children without chronic broncho-pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 4) which contains the Acute Respiratory Infections (ARI) Group's Specialized Register, MEDLINE (1966 to 2008), EMBASE (1980 to 2008); Micromedex (2008), Pascal (1987 to 2004), and Science Citation Index (1974 to 2008). SELECTION CRITERIA: To study efficacy, we used randomised controlled trials (RCTs) comparing the use of acetylcysteine or carbocysteine versus placebo either alone or as an add-on therapy.To study safety, we also used trials comparing the use of acetylcysteine or carbocysteine versus active treatment or no treatment and case reports. DATA COLLECTION AND ANALYSIS: At least two review authors extracted data and assessed trial quality. We performed a subgroup analysis of children younger than two years of age. MAIN RESULTS: Six trials involving 497 participants were included to study efficacy. They showed some benefit from mucolytic agents, although differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because the data were unavailable. Thirty-four studies including the previous six trials involving 2064 children were eligible to study safety. Overall safety was good but very few data were available to evaluate safety in infants younger than two years. However, 48 cases of paradoxically increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system. AUTHORS' CONCLUSIONS: The results of this review have to be interpreted with caution because it was based on a limited number of participants included in studies whose methodological quality is questionable. Acetylcysteine and carbocysteine seem to have a limited efficacy and appear to be safe in children older than two years. These results should take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self-limiting diseases (for example, acute cough, bronchitis). Regarding children younger than two years, given concerns about safety, these drugs should only be used for ARTIs in the context of an RCT.