A half doubling dose change in bronchial hyperresponsiveness in a population represents an important difference.

BACKGROUND: The prevalence of asthma has increased over recent decades and the reasons for this are poorly understood. A sensitive tool that can evaluate potential risk factors for asthma is bronchial hyperresponsiveness (BHR), a key physiological characteristic of asthma. However, although the minimum clinically important difference in BHR for an individual is accepted to be around one doubling dose, the minimum important change in a population is not defined. As with surrogate measures of cardiovascular disease risk such as blood pressure and cholesterol, a change that is not clinically important in an individual may be extremely important in public health terms. FINDINGS: To assess the potential impact of a small absolute change in BHR across a population, we modelled the effect of different changes in BHR on the prevalence rates of moderate and severe BHR in an asthmatic population. We calculate that a one half doubling dose increase in BHR increases the prevalence of moderate and severe BHR by 30%. If this was accompanied by an equivalent increase in the population prevalence of moderate and severe asthma, this would be highly significant in public health terms. CONCLUSIONS: We propose that a one half doubling dose worsening in BHR across a population may represent an important change.

Proposed MHRA changes to UK children's paracetamol dosing recommendations: modelling study.

OBJECTIVES: Paracetamol is the most commonly administered medicine to children. A recent study highlighted the risk of overdose of paracetamol using British National Formulary for Children (BNFC) age-based dosing guidelines. This current study assesses the safety of changes to the UK paracetamol product dosing system proposed by the Medicines and Healthcare products Regulatory Authority (MHRA) which include a larger number of narrower age bands and a single dose per age band. DESIGN: Theoretical comparison of the proposed MHRA dosing system with the product dosing instructions of a commonly prescribed form of paracetamol in the UK. SETTING: United Kingdom Participants Proposed MHRA dosing recommendations and current product dosing instructions were compared using a previously validated model. MAIN OUTCOME MEASURES: For both dosing recommendations, single and cumulative daily doses of paracetamol for boys and girls at the 9th, 50th and 91st centiles for weight were calculated for 3 month, 1 year, 6 year and 12 year age groups. RESULTS: With the current product dosing instructions, underweight children are at risk of receiving approximately two times the recommended single and cumulative daily dose of paracetamol, particularly at age 1 year and 6 years. This risk is negligible when the same model is applied to the proposed MHRA dosing system, whereby underweight, average weight and overweight children at all ages receive doses marginally above or within the recommended dose range or limit. CONCLUSION: The proposed MHRA dosing recommendations for paracetamol use in children are effective at reducing the risk of paracetamol overdose in children of all ages, when compared with current product dosing instructions.

British National Formulary for Children: the risk of inappropriate paracetamol prescribing.

BACKGROUND: Paracetamol is the most commonly prescribed medicine for children. Age-based dosing guidelines can lead to inappropriate dosing. METHODS: A review of age-based guidelines for paracetamol in the British National Formulary for Children (BNFC) 2011-2012 was undertaken. Single and cumulative daily doses of paracetamol for boys and girls at 9th, 50th and 91st centiles for weight were calculated for the age groups 1-3 months, 3-12 months, 1-6 years and 6-12 years. RESULTS: For children at the 9th centile, aged 3 months and above, doses were above recommended single and cumulative daily dose therapeutic limits when given the highest dose specified for their age. For children at the 91st centile at all ages, doses were below recommended single and cumulative daily dose therapeutic limits when given the lowest dose specified for their age. CONCLUSIONS: Underweight and overweight children are at risk of inappropriate paracetamol administration based on BNFC age-based dosing instructions.

Systematic review and meta-analysis of the effects of antipyretic medications on mortality in Streptococcus pneumoniae infections.

AIM: To determine whether the use of antipyretic medications in the treatment of Streptococcus pneumoniae infection affects mortality in humans or animal models. DESIGN: A systematic search of Medline, Embase, and The Cochrane Register of Controlled Trials was undertaken to identify in vivo animal experiments or randomised, controlled trials in humans of antipyretic medication in S pneumoniae infection which reported mortality data. Meta-analysis was by inverse variance weighted method for odds ratios. SETTING: Antipyretics are recommended for the symptomatic treatment of various diseases caused by S pneumoniae. However, there is evidence that fever is a protective physiological response to infection, that treating fever secondary to infection may be harmful, and that some strains of S pneumoniae are temperature sensitive. MAIN OUTCOME MEASURES: Mortality associated with antipyretic use in S pneumoniae infection. RESULTS: Four studies from two publications met the inclusion criteria and investigated the use of aspirin in animal models. The pooled estimate of mortality was an OR with aspirin treatment of 1.97 (95% CI 1.22 to 3.19). There were no suitable human studies identified. CONCLUSIONS: A twofold increased risk of mortality was found with aspirin treatment in animal models of S pneumoniae infection. No relevant human studies were identified. It is difficult to generalise from animal models to clinical medicine, but based on these findings and the prevalence and severity of S pneumoniae infections worldwide, future study of the effects of antipyretic therapy in S pneumoniae infection in humans is recommended.

The effect of antipyretic medications on mortality in critically ill patients with infection: a systematic review and meta-analysis.

BACKGROUND: Antipyretic medications are widely used in critically ill patients with infection despite evidence supporting a protective, adaptive role of fever. OBJECTIVE: To assess the mortality risk of antipyretic medications among critically ill patients with infection. METHODS: A systematic search of MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and PubMed was undertaken to identify randomised controlled trials (RCTs) of antipyretic use among critically ill patients with suspected or confirmed infection that reported mortality. A quantitative meta-analysis of the risk of death was carried out with calculation of the pooled risk of death and standard evaluation of heterogeneity. RESULTS: Six RCTs investigating the use of paracetamol (1) and non-steroidal anti-inflammatory medications (5) met the inclusion criteria for meta-analysis. The trials were heterogeneous in terms of study populations and interventions, were not primarily designed to evaluate antipyretic effect on mortality risk, and significant confounding was present from the use of other concomitant antipyretic strategies. The pooled estimates of odds ratios for mortality with antipyretic treatment were 0.96 (95% CI, 0.68-1.34) and 1.08 (95% CI, 0.60-1.96) for fixed effects and random effects, respectively, and the I-squared value was 34.9 (95% CI, 0.0-73.9). CONCLUSION: The studies included in this review were insufficient to allow a robust estimate of the effect of pharmacological antipyresis on mortality in critically ill patients with suspected infection. Further RCTs are required to resolve this important area of clinical uncertainty.

The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis.

OBJECTIVE: To determine whether antipyretic treatment for influenza infection influences the risk of mortality in animal models and humans. DESIGN: A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials was undertaken to identify randomized placebo-controlled trials of antipyretic use in influenza infection in animal models or humans that reported mortality. A quantitative meta-analysis of the risk of death using Peto's one step odds ratio with calculation of the pooled risk of death and standard evaluation of heterogeneity was undertaken. SETTING: Not applicable. PARTICIPANTS: Not applicable. MAIN OUTCOME MEASURES: Risk of mortality associated with antipyretic use in influenza infection. RESULTS: Eight studies from three publications met the inclusion criteria. No human studies were identified. The risk of mortality was increased by antipyretic use in influenza-infected animals with a fixed effects pooled odds ratio of 1.34 (95% CI 1.04-1.73). An increased risk was observed with aspirin, paracetamol and diclofenac. CONCLUSION: In animal models, treatment with antipyretics for influenza infection increases the risk of mortality. There are no randomized placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy. We suggest that randomized placebo-controlled trials of antipyretic use in human influenza infection are urgently required, and that these are sufficiently powered to investigate a potential effect on mortality.