Nonsteroidal anti-inflammatory drugs (NSAIDs) possess antipyretic, analgesic and anti-inflammatory effects. They are frequently used in children and have numerous therapeutic indications, the most common ones being fever, postoperative pain and inflammatory disorders, such as juvenile idiopathic arthritis (JIA) and Kawasaki disease. Their major mechanism of action is through inhibition of prostaglandin biosynthesis by blockade of cyclo-oxygenase (COX). The disposition of most NSAIDs has been mainly studied in infants > or = 2 years of age. Compared with adults, the volume of distribution and clearance of NSAIDs such as diclofenac, ibuprofen (infants aged between 3 months and 2.5 years), ketorolac and nimesulide were increased in children. The elimination half-life was similar in children to that in adults. These pharmacokinetic differences might be clinically significant with the need for higher loading and/or maintenance doses in children. Ibuprofen, acetylsalicylic acid (ASA) and acetaminophen are the most frequently used agents for fever reduction in children. Over the past 20 years, because of the association between ASA use and Reye's syndrome, most of the interest has been directed toward ibuprofen and acetaminophen. In view of its comparable antipyretic efficacy, but superior tolerability profile, acetaminophen, when used appropriately with age-adapted formulations, should remain the first-line therapy in the treatment of childhood fever. At the moment, there is no scientific evidence to recommend simultaneous use of these two antipyretic drugs. Most NSAIDs provide mild to moderate analgesia, with the exception of ketorolac which has a strong analgesic activity. The analgesic efficacy of ketorolac, ketoprofen, diclofenac and ibuprofen in the treatment of postoperative pain has been mainly studied following a single dose, in children of > or = 1 year of age undergoing minor surgeries. In this setting, when used either alone or in adjunct to caudal or epidural anaesthesia, they were associated with an opioid-sparing effect and were well tolerated. With the exception of ketorolac use in children undergoing tonsillectomy, where controversy exists regarding the risk of postoperative haemorrhage, NSAIDs have not been associated with an increased risk of perioperative bleeding. NSAIDs are the first-line therapy in JIA. They appear to be equally effective and tolerated, with the exception of ASA which is associated with more adverse effects. ASA has been used for many years in the treatment of Kawasaki disease and is part of the standard modality of treatment in combination with intravenous gammaglobulins. More recently, lung inflammation associated with cystic fibrosis (CF) has become a new target for NSAIDs. Despite promising preliminary results with ibuprofen, numerous questions need to be answered before this new strategy becomes part of the conventional treatment of patients with CF. In summary, NSAIDs are effective in reducing fever, alleviating pain and reducing inflammation in children, with a good tolerance profile. Pharmacokinetic studies are needed to characterise the disposition of NSAIDs in very young infants in order to use them rationally. To date, no studies have been published on the disposition, tolerability and efficacy of specific COX-2 inhibitors in children. Further clinical experience with these agents in adults is warranted before undergoing trials with specific COX-2 inhibitors in children.

Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol.

Background
Kawasaki disease is the most common cause of acquired heart disease in children in developed countries. The coronary arteries supplying the heart can be damaged in Kawasaki disease. The principal advantage of timely diagnosis is the potential to prevent this complication with early treatment. Salicylate (acetyl salicylate acid (ASA), aspirin) and intravenous immunoglobulin (IVIG) are widely used for this purpose. Salicylate is largely otherwise avoided in children because of concerns about serious side effects, particularly the risk of Reyes syndrome.

Objectives
The objective of this review was to evaluate the effectiveness of salicylate in treating and preventing cardiac consequences of Kawasaki disease in children.

Search methods
For this update the Cochrane Peripheral Vascular Diseases Group searched their trials register (last searched January 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 1, 2009). The authors searched MEDLINE (January 1966 to July 2006), EMBASE (January 1980 to July 2006), and CINAHL (1982 to July 2006), and reference list of articles. In addition, we contacted experts in the field.

Selection criteria
Randomised controlled trials (RCTs) of salicylate to treat Kawasaki disease in children were eligible for inclusion.

Data collection and analysis
Two authors independently assessed trial quality and extracted data. Study authors were contacted for additional information.

Main results
We found one trial involving 102 children which was described as randomised, but it was not possible to confirm the method of treatment allocation. A second comparative study, possibly with a randomised treatment allocation, was also identified. The one randomised trial reported no association between the addition of ASA to IVIG treatment on the rate of coronary artery abnormalities at follow up, but with wide confidence limits. The second, possibly randomised trial did demonstrate a reduction in duration of fever with high dose ASA compared with low dose ASA, but was insufficiently powered to establish the effect on coronary artery abnormalities at follow up.

Authors' conclusions
Until good quality RCTs are carried out, there is insufficient evidence to indicate whether children with Kawasaki disease should continue to receive salicylate as part of their treatment regimen.

Salicylate for the treatment of Kawasaki disease in children.

Background and Objectives
We sought to determine whether high-dose aspirin is necessary for the acute therapy of Kawasaki disease (KD) in the intravenous immunoglobulin (IVIG) era.

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Is High-Dose Aspirin Necessary in the Acute Phase of Kawasaki Disease?

Decreased protein binding of salicylates in Kawasaki disease

While there is a generally accepted standard approach to the management of Kawasaki disease (KD) in North America, controversy still exists regarding certain aspects of treatment. Do all patients require treatment with intravenous immunoglobulin (IVIG)? What is the appropriate dose of aspirin (ASA) during the acute phase of the disease? Is there a role for corticosteroids in those who fail IVIG? How should patients with atypical, incomplete or late presentations of KD be managed? What is the appropriate long-term management and follow-up, particularly for those without coronary artery abnormalities (CAA)? Is there a role for surgical intervention, particularly transplantation? These questions, among others, are explored with reference to the pertinent literature.IVIG has been well studied and shown to be efficacious in a number of studies and in two meta-analyses, with clear evidence to support the use of 2g/kg in a single dose. The appropriate dose of ASA during the acute phase is less clear but, increasingly, data suggest that lower doses of ASA are adequate and perhaps more appropriate. Corticosteroids appear to have a role in those who have failed IVIG but this requires further study before being embraced as accepted treatment. The management of less typical presentations of KD remains controversial, with inadequate data to direct us, although there is a general trend towards treating such patients with IVIG. Careful follow-up of all patients is recommended and, while there are guidelines for this, there is no clear consensus on the most appropriate monitoring investigations for those with and without CAA. There is an expanding role for transplantation, with clearly defined indications for this intervention.

Suzan Schue

Papers

Determinants of low serum concentrations of salicylates in patients with Kawasaki disease