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

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.

Quantification of busulfan in plasma by liquid chromatography-ion spray mass spectrometry. Application to pharmacokinetic studies in children.

Optimisation of busulfan dosage in patients undergoing bone marrow transplantation is recommended in order to reduce toxic effects associated with high drug exposure. A new method was developed coupling liquid chromatography with mass spectrometry (LC-MS) and was validated for the determination of busulfan concentrations in plasma. Recovery was 86.7%, the limit of detection was 2.5 ng/ml and linearity ranged from 5 to 2500 ng/ml. The correlation between the busulfan concentrations measured by our previously published HPLC-UV method and the new HPLC-MS method was highly significant (P<0.0001). Sample volume was reduced and the method was rapid, sensitive and less expensive than the methods previously used in our laboratory. This method was used to determine the pharmacokinetic parameters of busulfan after the first administration of 1 mg/kg orally, in 13 children receiving the drug as part of the preparative regimen for bone marrow transplantation. Our results were similar to previously reported data. They showed that the apparent oral clearance of busulfan was 0.299+/-0.08 l/h/kg, and that it was significantly higher (P=0.02) in patients below the age of 5 years than in older children.

Determination of the median effective concentration (EC50) of propofol during oesophagogastroduodenoscopy in children.

BACKGROUND: Propofol is commonly used to provide anaesthesia for children undergoing oesophagogastroduodenoscopy (OGD). Despite this, the plasma concentration-response relationships for propofol used in this setting have not been established. METHODS: In order to determine the EC50 of propofol during OGD, we studied 12 children aged 3-10 years. No premedication was given. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a paediatric pharmacokinetic model. The 'up-and-down' method described by Dixon was used to determine the EC50. Accordingly, the target plasma propofol concentration for each patient, beginning with the second subject, was determined by the response of the previous patient. A patient was considered a 'responder' if there was minimal movement and the heart rate (HR) and blood pressure (BP) remained < or = 120% of baseline during the procedure. Patients who moved excessively, i.e. requiring more than gentle restraint, or who manifest HR and BP >120% of baseline, were considered 'nonresponders'. RESULTS: The EC50 of propofol during OGD was 3.55 microg.ml(-1) in this study. CONCLUSIONS: The plasma propofol concentration associated with adequate anaesthesia for OGD in 50% of unpremedicated children is 3.55 microg.ml(-1). This concentration is higher than that required for OGD in adult patients.

Circulating levels of transforming growth factor-beta1 and lymphokines among children with hemolytic uremic syndrome.

Verotoxin-producing Escherichia coli (VTEC) cause hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). The aim of this study was to compare the circulating levels of transforming growth factor-beta 1 (TGF-beta1), T helper (T(H))1 (interferon [IFN]-gamma, interleukin [IL]-2), and T(H)2-associated lymphokines (IL-4, IL-13) in children with uncomplicated Escherichia coli O157:H7 HC and patients who developed HUS. Circulating levels of IL-2, IL-4, and IL-13 were undetectable, and those of IFN-gamma were low and comparable among groups. Concentrations of TGF-beta1 were higher in children with uncomplicated O157:H7 HC than among those who developed HUS (934 +/- 680 versus 514 +/- 497 pg/mL, respectively; P < 0.04). The circulating levels of TGF-beta1 were also higher among children who did not take antidiarrheal agents (P < 0.008) and those who have been immediately discharged from the emergency room (P < 0.03). Our results did not show an imbalanced T(H)1/T(H)2-associated lymphokine response during the development of HUS. Increased circulating levels of TGF-beta1 in children with milder O157:H7 or uncomplicated HC most likely reflect appropriate intestinal tissue repair mechanisms rather than a remote systemic endocrine effect on the kidneys.

Protected specimen brush or bronchoalveolar lavage to diagnose bacterial nosocomial pneumonia in ventilated adults: a meta-analysis.

OBJECTIVE: We conducted a meta-analysis by using summary receiver operating characteristic curves to compare the diagnostic value for bacterial nosocomial pneumonia of the following: a) quantitative culture (colony-forming units per milliliter or CFU/mL) of respiratory secretions collected with a bronchoscopic protected specimen brush (PSB); b) quantitative culture of a bronchoscopic bronchoalveolar lavage (BAL); and c) the percentage of infected cells (IC) in BAL. DATA SOURCES: All studies published in the English or the French language, through January 1, 1995, on the evaluation of PSB or BAL for the diagnosis of pneumonia were considered for analysis. The relevant literature was identified through computer and reference searching and by experts in the field. STUDY SELECTION: A study was included if at least two of three independent readers regarded its purpose as the evaluation of CFU-PSB, CFU-BAL, or IC-BAL for the diagnosis in human beings of bacterial nosocomial pneumonia in ventilated adults and if the study was prospective and published in a peer-reviewed journal. DATA EXTRACTION: Three readers reviewed all published articles and decided whether to include each study; consensus was defined as agreement by at least two readers. The authors of each original article included in the meta-analysis were asked to complete a questionnaire in which they were asked to check and to correct the data extracted by one of the independent readers. DATA SYNTHESIS: Summary receiver operating characteristic curves were used to compare the efficacy of three diagnostic tests. Eighteen studies on CFU-PSB (795 patients) were included, as well as 11 studies on CFU-BAL (435 patients) and 11 on IC-BAL (766 patients). The accuracy of these tests was not different. However, it seems that administration of previous antibiotics markedly decreased accuracy of CFU-PSB (p = .0002) but not the accuracy of CFU-BAL and that of IC-BAL. CONCLUSION: Both PSB and BAL are reliable to diagnose bacterial nosocomial pneumonia. Because CFU-BAL and IC-BAL seemed more resistant to the effects of antibiotics, we recommend BAL rather than PSB if the patient is already receiving antibiotics.

Circulating inflammatory cytokine levels in hemolytic uremic syndrome.

Experimental data suggest that the host's inflammatory response is involved in the pathophysiology of verotoxin-producing Escherichia coli (VTEC)-associated hemolytic uremic syndrome (HUS). We compared the circulating levels of pro- [interleukin (IL)-6, IL-8] and anti-inflammatory [IL-10 and IL-1 receptor antagonist (Ra)] mediators on enrollment among children with HUS due to E. coli O157:H7, according to the severity of renal dysfunction. The latter was evaluated by the occurrence of oligoanuria, the requirement for dialysis, and a glomerular filtration rate (GFR)

Inflammatory mediators in Escherichia coli O157:H7 hemorrhagic colitis and hemolytic-uremic syndrome.

BACKGROUND: Recent experimental data suggest that the inflammatory response of the host to verotoxin and/or lipopolysaccharides of Escherichia coli is involved in the pathophysiology of verotoxin-producing E. coli (VTEC) infections. METHODS: We measured the circulating concentrations of cytokines [TNF-alpha, interleukin (IL)-1-beta, IL-1 receptor antagonist (Ra), IL-6, IL-8, IL-10] and soluble leukocyte adhesion molecules (L-selectin, P-selectin, E-selectin, intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1) by sandwich enzyme-linked immunosorbent assay among (1) normal controls (n = 12), (2) disease controls with hemorrhagic colitis (HC) not associated with VTEC infections (n = 57), (3) patients with uncomplicated HC caused by E. coli O157:H7 (n = 30), and (4) children with hemolytic-uremic syndrome (HUS) (n = 28). Patients with HUS were matched with children who presented an uncomplicated HC caused by E. coli O157:H7 for the time interval elapsed between the onset of HC and that of blood sample collection. RESULTS: Concentrations of TNF-alpha and IL-1-beta were undetectable. Children with HUS were characterized by increased amounts of IL-6 and IL-8, lower values of soluble L-selectin as well as increased levels of IL-10 and IL-1Ra. The circulating concentrations of IL-1Ra were higher among children with O157:H7 HC who subsequently developed HUS. CONCLUSIONS: Increased pro- and antiinflammatory cytokine responses are produced by the host during the development of HUS among children with VTEC infections. Further studies are needed to determine their relative contribution to the pathophysiology of classic HUS.