Antipyretic effect of oral dipyrone (Metamizole) compared to oral ibuprofen in febrile children: a systematic review and meta-analysis.

BACKGROUND: Dipyrone (Metamizole) is a potent pain reliever and fever reducer with muscle relaxant properties, most commonly used as an analgesic and antipyretic agent. Despite the fact that it has been banned in many high-income countries following confirmed studies of fatal agranulocytosis and adverse drug reactions, it is still widely used in various countries of the world. However, the antipyretic therapeutic indications of dipyrone in febrile children are currently unknown, and there is little information on the advantages and disadvantages of using dipyrone in febrile children. In febrile children, we expected that dipyrone's antipyretic effectiveness wouldn't be any more effective than ibuprofen. Therefore, the purpose of this research is to evaluate the effectiveness of oral dipyrone and oral ibuprofen as antipyretics in febrile children. METHODS: Several databases, including PubMed, Scopus, Web of Science, and Cochrane Library, were searched thoroughly using a pre-established search strategy for potential research. The studies included in this analysis comprised randomized controlled trials that compared the antipyretic effects of oral ibuprofen and oral dipyrone in febrile children. Data analysis was carried out using RevMan 5.4 software. RESULTS: Three studies were selected among the 27 publications we discovered to be applicable, and they underwent qualitative and quantitative analysis. The pooled analysis revealed no discernible difference between oral dipyrone and oral ibuprofen in terms of their antipyretic effects (Mean difference (MD) = 0.06; 95% confidence interval (CI): -0.08, 0.20). CONCLUSION: Both oral dipyrone and ibuprofen are effective in reducing high-temperature levels in febrile children without any significant difference.

Rectal versus intravenous administration of acetaminophen; Clinical investigation of plasma level, analgesic, and antipyretic effects on 6-month to 6-year-old children in Zabol city, Iran.

OBJECTIVES: Acetaminophen is the most widely antipyretic analgesic medicine used in adults and children worldwide. Rectal acetaminophen is widely used in children who resist or cannot take oral medications. This study was designed to compare the efficacy of rectal and IV acetaminophen in children with fever and mild to moderate pain. PATIENTS AND METHODS: Total 60 children aged six months to 6 years, with fever and pain, that were treated with rectal or intravenous acetaminophen were selected and assigned in two groups. The IV group received 10mg/kg paracetamol as an IV infusion, and the rectal group received a 15mg/kg dose immediately after admission. Pain score was calculated using the FLACC method, and the axillary temperature was recorded at baseline and then 0.5, 1, 2, 4, and 6hours after drug administration. Blood samples were collected at baseline and then at 30min-intervals for the first 90minutes. RESULTS: The trend of changes in mean pain score at different time intervals was significantly different between the two groups. Body temperature decrease was more prominent in the IV group. The plasma concentration increased in both groups significantly with time. This increase was sharper in the IV group, just in the first 60minutes after drug administration. CONCLUSIONS: IV acetaminophen has more rapid onset of action, while rectal dosage form control fever and pain for longer duration. Considering its favorable effects with ease of administration and lower cost, rectal acetaminophen can be a reasonable option in selected patients with pain or fever.

Passive antipyretic therapy is not as effective as invasive hypothermia for maintaining normothermia after cardiac arrest.

AIM OF THE STUDY: Targeted temperature management is a class I indication in comatose patients after a cardiac arrest. While the literature has primarily focused on innovative methods to achieve target temperatures, pharmacologic therapy has received little attention. We sought to examine whether pharmacologic therapy using antipyretics is effective in maintaining normothermia in post cardiac arrest patients. MATERIALS AND METHODS: Patients ≥18 years who were resuscitated after an in-hospital or out-of-hospital cardiac arrest and admitted at our institution from January 2012 to September 2015 were retrospectively included. Patients were divided into groups based on the method of temperature control that was utilized. The primary outcome was temperature control <38 °C during the first 48 h after the cardiac arrest. RESULTS: 671 patients were identified in Group 1 (no hypothermia), 647 in Group 2 (antipyretics), 44 in Group 3 (invasive hypothermia), and 51 in Group 4 (invasive hypothermia and antipyretics). Mean patient age was 59 (SD ±15.7) years with 40.6% being female. Using Group 1 as the control arm, 57.7% of patients maintained target temperature with antipyretics alone (p < 0.001), compared to 69.3% in the control group and 82.1% in the combined hypothermia groups 3&4 (p = 0.01). Patients receiving both invasive hypothermia and antipyretics (Group 4), had the greatest mean temperature decrease of 5.2 °C. CONCLUSIONS: Among patients undergoing targeted temperature management, relying solely on as needed use of antipyretics is not sufficient to maintain temperatures <38 °C. However, antipyretics could be used as an initial strategy if given regularly and/or in conjunction with more aggressive cooling techniques.

Comparison of intravenous ibuprofen and paracetamol in the treatment of fever: A randomized double-blind study.

OBJECTIVE: Fever is one of the frequent reasons for admission to the emergency department. Studies comparing oral forms of non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol with intravenous (IV) forms for fever are common in the literature. Our study is the first emergency department study comparing IV forms of ibuprofen and paracetamol in the treatment of febrile patients. METHODS: A randomized, double-blind study was conducted in a tertiary university emergency department for a six-month period. Patients aged 18-65 years who had a fever of ≥38.0 °C were included. Patients were administered 400 mg of IV ibuprofen and 1000 mg of IV paracetamol. The primary aim of the study was to determine whether there was a difference in the effect of the two drugs on fever. The secondary aim was to investigate whether there was a difference in terms of numeric rating scale (NRS) measurements and the need for additional antipyretic therapy. RESULTS: A total of 200 people, 100 of whom were female, were included in the study. The mean age was 30.77 ± 10.61 years. The mean initial temperature for ibuprofen and paracetamol was 38.79 ± 0.470 °C and 38.70 ± 0.520 °C, respectively, with no difference noted between the groups (p = 0.380). It was found that both drugs significantly provided fever control in the first 30 min (p < 0.001), with no difference between them in terms of fever reduction (p = 0.980). Both drugs significantly improved in accompanying symptoms, although both drugs did not show superiority to each other (p = 0.0226). When evaluated in terms of a need for rescue medication, no significant difference was found between the two drugs (p = 0.404). No side effects were encountered during the study. CONCLUSION: In adult age group patients admitted to the emergency department with high fever, the IV forms of 1000 mg paracetamol and 400 mg ibuprofen effectively and equally reduce complaints, such as fever and accompanying pain. They can be effectively used as each other's rescue medicine and as an alternative to each other in patients with comorbid diseases.

Interventions to reduce body temperature to 35 °C to 37 °C in adults and children with traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated 5.5 million people experiencing severe TBI worldwide every year. Observational clinical studies of people with TBI suggest an association between raised body temperature and unfavourable outcome, although this relationship is inconsistent. Additionally, preclinical models suggest that reducing temperature to 35 °C to 37.5 °C improves biochemical and histopathological outcomes compared to reducing temperature to a lower threshold of 33 °C to 35 °C. It is unknown whether reducing body temperature to 35 °C to 37.5 °C in people admitted to hospital with TBI is beneficial, has no effect, or causes harm. This is an update of a review last published in 2014. OBJECTIVES: To assess the effects of pharmacological interventions or physical interventions given with the intention of reducing body temperature to 35 °C to 37.5 °C in adults and children admitted to hospital after TBI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and PubMed on 28 November 2019. We searched clinical trials registers, grey literature and references lists of reviews, and we carried out forward citation searches of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with participants of any age admitted to hospital following TBI. We included interventions that aimed to reduce body temperature to 35 °C to 37.5 °C: these included pharmacological interventions (such as paracetamol, or non-steroidal anti-inflammatory drugs), or physical interventions (such as surface cooling devices, bedside fans, or cooled intravenous fluids). Eligible comparators were placebo or usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of the evidence with GRADE. MAIN RESULTS: We included one RCT with 41 participants. This study recruited adult participants admitted to two intensive care units in Australia, and evaluated a pharmacological intervention. Researchers gave participants 1 g paracetamol or a placebo intravenously at four-hourly intervals for 72 hours. We could not be certain whether intravenous paracetamol influenced mortality at 28 days (risk ratio 2.86, 95% confidence interval 0.32 to 25.24). We judged the evidence for this outcome to be very low certainty, meaning we have very little confidence in this effect estimate, and the true result may be substantially different to this effect. We downgraded the certainty for imprecision (because the evidence was from a single study with very few participants), and study limitations (because we noted a high risk of selective reporting bias). This study was otherwise at low risk of bias. The included study did not report the primary outcome for this review, which was the number of people with a poor outcome at the end of follow-up (defined as death or dependency, as measured on a scale such as the Glasgow Outcome Score), or any of our secondary outcomes, which included the number of people with further intracranial haemorrhage, extracranial haemorrhage, abnormal intracranial pressure, or pneumonia or other serious infections. The only other completed trial that we found was of a physical intervention that compared advanced fever control (using a surface cooling device) versus conventional fever control in 12 participants. The trial was published as an abstract only, with insufficient details to allow inclusion, so we have added this to the 'studies awaiting classification' section, pending further information from the study authors or publication of the full study report. We identified four ongoing studies that will contribute evidence to future updates of the review if they measure relevant outcomes and, in studies with a mixed population, report data separately for participants with TBI. AUTHORS' CONCLUSIONS: One small study contributed very low-certainty evidence for mortality to this review. The uncertainty is largely driven by limited research into reduction of body temperature to 35 °C to 37.5 °C in people with TBI. Further research that evaluates pharmacological or physical interventions, or both, may increase certainty in this field. We propose that future updates of the review, and ongoing and future research in this field, incorporate outcomes that are important to the people receiving the interventions, including side effects of any pharmacological agent (e.g. nausea or vomiting), and discomfort caused by physical therapies.

The efficacy of Antipyretic Analgesics administration intravenously for Preventing Rocuronium-Associated Pain/Withdrawal Response: a systematic review and meta-analysis.

BACKGROUND: Rocuronium-associated injection pain/withdrawal response (RAIPWR) was non-ideal but occurred frequently when injection intravenously during anesthesia induction. Many studies had reported that pretreating with antipyretic analgesics (AAs) could reduce the occurrence of RAIPWR, but there was no consensus yet. Therefore, this meta-analysis was designed to systematically evaluate the benefits of AAs on RAIPWR in patients. METHODS: PubMed, Cochrane Library, Ovid, EMbase, Chinese National Knowledge Infrastructure (CNKI), Wan Fang Data were searched by January 1st 2019 for randomized controlled trials (RCTs) applying AAs to alleviate RAIPWR in patients who underwent elective surgery under general anesthesia. Two investigators assessed quality of RCTs and extracted data respectively and the meta-analysis was carried on Revman 5.3 software. Moreover, we compared AAs in pros and cons directly with lidocaine, the most reported medicine to prevent RAIPWR. RESULTS: Data were analyzed from 9 RCTs totaling 819 patients. The results of Meta-analysis showed that compared to the control group, pretreating with AAs could prevent the total occurrence of RAIPWR [Risk ratio (RR), 0.52; 95% confidence interval (CI), 0.42 to 0.66; P < 0.0001], and took effect on moderate (RR, 0.56; 95%CI, 0.43 to 0.73; P < 0.0001) and severe RAIPWR (RR = 0.14; 95%CI, 0.08 to 0.24; P < 0.00001). When compared to lidocaine, the preventive effect was not so excellent as the latter but injection pain induced by prophylactic occurred less. CONCLUSION: The currently available evidence suggested that pretreating with AAs intravenously could alleviate RAIPWR. TRIAL REGISTRATION: PROSPERO CRD42019129776.

Antipyretic Efficacy of Acetaminophen and Ibuprofen in Critically Ill Pediatric Patients.

OBJECTIVES: To determine the antipyretic efficacy of acetaminophen (IV, enteral, rectal) and ibuprofen (enteral) in critically ill febrile pediatric patients. DESIGN: Retrospective cohort study. SETTING: Quaternary care pediatric hospital ICUs. PATIENTS: Pediatric patients less than 19 years old who were febrile (≥ 38.0°C), received a dose of IV acetaminophen, enteral acetaminophen, rectal acetaminophen, or enteral ibuprofen and had at least one temperature measurement in the following 6 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 3,341 patients (55.8% male, median age 2.5 yr [interquartile range, 0.63-9.2 yr]) met study criteria. Baseline temperature was median 38.6°C (interquartile range, 38.3-38.9°C) measured via axillary (76.9%) route. Patients became afebrile (87.5%) at median 1.4 hours (interquartile range, 0.77-2.3 hr) after the first dose of medication, a -2.9 ± 1.6% change in temperature. Antipyretic medications included as follows: enteral acetaminophen (n = 1,664), IV acetaminophen (n = 682), rectal acetaminophen (n = 637), and enteral ibuprofen (n = 358). Enteral ibuprofen had a significantly greater odds of defervescence on multivariable logistic regression analysis (p = 0.04) with a decrease of -1.97 ± 0.89°C while IV acetaminophen was significant for a decreased time to defervescence at median 1.5 hours (interquartile range 0.8-2.3 hr) after a dose (p = 0.03). Patient age, presence of obesity, and baseline temperature were significant for decreased antipyretic efficacy (p < 0.05). CONCLUSIONS: Enteral ibuprofen was the most efficacious antipyretic and IV acetaminophen had the shortest time to defervescence.

Extract from Coriolus versicolor fungus partially prevents endotoxin tolerance development by maintaining febrile response and increasing IL-6 generation.

Endotoxin tolerance is defined as a reduced endotoxin-induced fever following repeated injections of lipopolysaccharide (LPS). Clinical examples of endotoxin tolerance include sepsis or cystic fibrosis. This state is characterized by inhibition of pro-inflammatory cytokines production and decrease in nuclear factor-kappa B (NF-κB) activation. Extract from Coriolus versicolor (CV) fungus is classified as a biological response modifier, which exhibits various biological activities, including immunopotentiating properties. The aim of study was to examine the effect of CV extract injection on body core temperature of Wistar rats during LPS-induced endotoxin tolerance. Body temperature was measured using biotelemetry. CV extract was injected intraperitoneally (100 mg kg-1) 2 h prior to the first LPS peritoneal administration (50 µg/kg). Endotoxin tolerance was induced by three consecutive daily injections of LPS at the same dose. We also investigated the influence of CV extract pre-injection on the properties of peripheral blood mononuclear cells (PBMCs) isolated from LPS-treated rats in response to LPS stimulation ex vivo. PBMCs were isolated 2 h after the first LPS injection. After 24 h pre-incubation, the cells were stimulated with LPS (1 µg ml-1) for 4 h. Our results revealed that CV extract partially prevents endotoxin tolerance through maintaining febrile response in rats following consecutive exposure to LPS. This state was accompanied by the ability of PBMCs isolated from rats injected with CV extract and LPS to release larger amounts of interleukin 6 and greater NF-κB activation in response to LPS stimulation ex vivo compared with the cells derived from rats injected only with LPS. Data also showed that CV extract augmented mitogenic effect of LPS on PBMCs and caused increase in reactive oxygen species generation. We concluded that CV extract, by a modifying effect on body temperature during endotoxin tolerance, can be consider as the immunostimulating agent, which prevents the non-specific refractoriness described in patients with sepsis or ischemia.

Specific association of the rs6500265 and rs9933632 single-nucleotide polymorphisms in Japanese patients with antipyretic analgesic-related Stevens-Johnson syndrome and toxic epidermal necrolysis with severe ocular involvements.

A recent study using the microarray for single-nucleotide polymorphisms (SNPs) genotyping specifically designed for the Japanese population in combination with genome-wide imputation showed the association of several SNPs with cold medicine-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications. However, it remains to be determined whether these polymorphisms are associated with the onset of antipyretic analgesic (AA)-related SJS/TEN, the progression of severe ocular involvements (SOIs), or both AA-related SJS/TEN and SOI phenotypes. To gain a better understanding of the features of these genetic markers, we compared the allele and carrier frequencies of these SNPs among our original SJS/TEN patient groups: (a) AA-related SJS/TEN with SOIs, (b) AA-related SJS/TEN without SOIs, and (c) AA-unrelated SJS/TEN with SOIs. AA-related SJS/TEN with SOIs were found to be associated significantly with both rs6500265 [allele frequency: odds ratio (OR): 2.18; 95% confidence interval (CI): 1.30-3.65; P=0.0052; carrier frequency: OR: 2.52; 95% CI: 1.33-4.78; P=0.058] and rs9933632 (allele frequency: OR: 2.28: 95% CI: 1.37-3.79; P=0.0032; carrier frequency: OR: 2.76; 95% CI: 1.46-5.22; P=0.0031). In contrast, allele and carrier frequencies of these SNPs in patients with AA-related SJS/TEN without SOIs or with SOIs not treated with any AAs were comparable with those in healthy Japanese controls. Collectively, our findings indicate that the rs6500265 and rs9933632 SNPs could be specific markers for AA-related SJS/TEN with SOIs, suggesting that certain genetic backgrounds contribute toward the etiology of this complex syndrome.

Knowledge, attitudes and misconceptions of Italian healthcare professionals regarding fever management in children.

BACKGROUND: Fever phobia is still a major issue in paediatrics. We report knowledge of a sample of Italian paediatricians performed six years after the release of the Italian guidelines for the management of fever in children (IFG). METHODS: A questionnaire, developed following the IFG recommendations and previously administered to 300 paediatricians in 2012, was proposed to all the paediatricians attending the 2015 National Congress of Practice Paediatrics, held in Florence, Italy. Changes in answers over time were analyzed. RESULTS: 70.2% (562/800) paediatricians returned the questionnaire. The recommended site and device for body temperature measurement in children > 1 year was correctly chosen by 89.3% of participants (vs. 80.7% of 2012 participants; P < 0.001), but with children aged less than 1 year the correct answer was selected only by the 50.3% (vs. 39.3% of 2012 participants: P < 0.001). Use of physical methods was still incorrectly recommended by 51.6% of paediatricians (vs. 63.6% in 2012; P < 0.001). Use of antipyretics according to discomfort was adopted only by 38.2% of participants, while 12.2% of them recommended alternate use of antipyretics. These proportions were substantially stable since 2012 (45 and 11% respectively), rectal administration of antipyretics only in case of vomiting was correctly recommended by 86.8% of paediatricians vs. 74.7% in 2012 (P < 0.001). CONCLUSION: Improvements in some pediatricians' misconceptions were observed over time. However, some incorrect habits persist. Further studies are needed to better understand the "weak points" of the communication between Scientific Societies and paediatricians in order to impact everyday clinical practice.

Effectiveness of intravenous immunoglobulin alone and intravenous immunoglobulin combined with high-dose aspirin in the acute stage of Kawasaki disease: study protocol for a randomized controlled trial.

BACKGROUND: Kawasaki disease (KD) is an acute febrile systemic vasculitis most commonly seen in children under 5 years old. High-dose aspirin is often administered, but the duration of such treatment varies. Many centers reduce the aspirin dose once the patient is afebrile, even before treating said patient with intravenous immunoglobulin (IVIG). However, a randomized controlled trial regarding high-dose aspirin in the acute stage of KD has not previously been carried out. METHODS/DESIGN: This trial has been designed as a multi-center, prospective, randomized controlled, evaluator-blinded trial with two parallel groups to determine whether IVIG alone as the primary therapy in acute-stage KD is as effective as IVIG combined with high-dose aspirin therapy. The primary endpoint is defined as coronary artery lesion (CAL) formation at 6-8 weeks. Patients meeting the eligibility criteria are randomly assigned (1:1) to a test group (that receives only IVIG) or a standard group (that receives IVIG plus high-dose aspirin). This clinical trial is conducted at three medical centers in Taiwan. DISCUSSION: Since high-dose aspirin has significant anti-inflammatory and anti-platelet functions, it does not appear to affect disease outcomes. Furthermore, it can decrease hemoglobin levels. Therefore, we have initiated this randomized controlled trial to evaluate the necessity of high-dose aspirin in the acute stage of KD. TRIAL REGISTRATION: Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Taiwan. ClinicalTrials.gov Identifier: NCT02951234. Release Date: November 3, 2016.

Croup: Diagnosis and Management.

Croup is a common respiratory illness affecting 3% of children six months to three years of age. It accounts for 7% of hospitalizations annually for fever and/or acute respiratory illness in children younger than five years. Croup is a manifestation of upper airway obstruction resulting from swelling of the larynx, trachea, and bronchi, leading to inspiratory stridor and a barking cough. Many patients experience low-grade fevers, but fever is not necessary for diagnosis. Less commonly, stridor can be associated with acute epiglottitis, bacterial tracheitis, and foreign body airway obstruction. Laboratory studies are seldom needed for diagnosis of croup. Viral cultures and rapid antigen testing have minimal impact on management and are not routinely recommended. Radiography and laryngoscopy should be reserved for patients in whom alternative diagnoses are suspected. Randomized controlled trials have demonstrated that a single dose of oral, intramuscular, or intravenous dexamethasone improves symptoms and reduces return visits and length of hospitalization in children with croup of any severity. In patients with moderate to severe croup, the addition of nebulized epinephrine improves symptoms and reduces length of hospitalization.

Oxaprozin prodrug as safer nonsteroidal anti-inflammatory drug: Synthesis and pharmacological evaluation.

Oxaprozin is a popular non-steroidal anti-inflammatory drug (NSAID) and its chronic oral use is clinically restricted due to its gastrointestinal (GI) complications. In order to circumvent the GI complications, oxaprozin was amended as a prodrug in a one-pot reaction using N,N-carbonyldiimidazole as an activating agent. Dextran of average molecular weight (60,000-90,000 Da) was exploited as a carrier in the process of oxaprozin prodrug production by esterification. The structural profiles of the synthesized oxaprozin prodrug were characterized by FT-IR and NMR spectroscopy. The oxaprozin prodrug possessed optimal molecular weight, lipophilicity, partition coefficient, protein binding, and degree of substitution of 52.4%. The release of oxaprozin upon hydrolysis of the prodrug in both simulated gastric fluid and simulated intestinal fluid followed first-order kinetics with 55.2 min of half-life. Varied ADME properties of the prodrug resulted upon Schrodinger's QikProp tool application. Oxaprozin prodrug displayed significant analgesic, antipyretic, and anti-inflammatory activities, with a remarkable decrease in the ulcer index and being devoid of antigenicity in experimental animals. Thus, it is evident that oxaprozin prodrug is a safer oral NSAID without causing any ulcerations.

Effect of early natal supplementation of paracetamol on attenuation of exotoxin/endotoxin induced pyrexia and precipitation of autistic like features in albino rats.

The present study was aimed to test the hypothesis that paracetamol (PCM) can precipitate autistic like features when used to counteract vaccine-induced fever using experimental rat pups. The pups were treated with measles mumps rubella (MMR) vaccine, diphtheria tetanus and pertussis (DPT) vaccines and lipopolysaccharide (LPS) with subsequent PCM treatment. The pups were evaluated for postnatal growth (weight gain, eye opening) and behavior alterations (swimming performance, olfactory discrimination, negative geotaxis, nociception, and locomotor activity) by performing battery of neurobehavioral test. Significant correlation was observed between social behavioral domains (nociception, anxiety and motor coordination) and pro-inflammatory load in the pups when treated with MMR/LPS along with PCM. A significant change in pro and anti-inflammatory (IL-4, IL-6, IL-10) markers were observed in rats treated with PCM, MMR, LPS, DPS alone or in combination with MMR, LPS and DPT (5128.6 ± 0.000, 15,488 ± 0.000***, 9661.1 ± 157.29***a, 15,312 ± 249.29***, 10,471 ± 0.00***a, 16,789 ± 273.34*** and 12,882 ± 0.00***a). Pups were also scrutinized for the markers of oxidative stress, inflammation and histopathologically. All the treatment groups showed significant alteration in the behavioral changes, oxidative markers (TBARS-in control-4.33 ± 0.02, PCM-9.42 ± 0.18***, MMR-5.27 ± 0.15***, MMR + PCM-8.57 ± 0.18*** a, LPS-6.84 ± 0.10***, LPS + PCM-4.51 ± 0.30***a, DPT-5.68 ± 0.12***, DPT + PCM-7.26 ± 0.18***a) and inflammatory markers without following any specific treatment. These observation could be accorded to variable phenotypes of autistic spectrum disorders (ASDs).

Inhibition of heat stress-related apoptosis of chicken myocardial cells through inducing Hsp90 expression by aspirin administration in vivo.

1. This experiment investigated the anti-apoptosis effects and the mechanism of aspirin action in the heat shock response of chicken myocardial cells in vivo, via changes in the heat stress (HS) protein Hsp90 and the rate of apoptosis. Broiler chickens were administered aspirin (1 mg/kg body weight) 2 h before exposure to HS, and then exposed to 40 ± 1°C for 0, 1, 2, 3, 5, 7, 10, 15 and 24 h. 2. The induction and consumption of the HS factor heat shock factor (HSF)-1, and reductions of HSF-2 and HSF-3 induced by HS led to a delay in Hsp90 expression. HSF-1, 2 and 3 regulation of hsp90 expression in turn inhibited the synthesis and activation of protein kinase ß (Akt), which resulted in a significant increase in caspase-3 at 2 and 10 h, caspase-9 from 1 to 7 h (except at 5 h), and the heat-stressed apoptosis of the myocardial cells. 3. Administration of aspirin changed the expression patterns of HSF-1, 2 and 3 such that the expression of Hsp90 protein was significantly upregulated (by 2.3-4.1 times compared with that of the non-treated cells). The resultant increase in Akt expression and activation, compared with the HS group, inhibited caspase-3 and caspase-9 activities and reduced the myocardial cells apoptosis rate (by 2.14-2.56 times). 4. Aspirin administration could inhibit heat-stressed apoptosis of myocardial cells in vivo and may be closely associated with its promotion of HS response of chicken hearts, especially Hsp90 expression.

National modulators of symptomatic fever management in children: comparative analysis of survey data.

BACKGROUND: In symptomatic fever management of children, cultural differences have been detected. We aimed at investigating the presence of national modulators of symptomatic fever management. METHODS: We analyzed the data collected in the context of the Swiss national survey on symptomatic fever management in children and of an adapted version of that survey performed in Lombardy (Northern Italy). RESULTS: Ibuprofen (P<0.001) and an alternation regimen with 2 drugs (P<0.001) are more often prescribed in Switzerland than in Lombardy. In front of a comfortable child whose fever has not responded to the first antipyretic, Swiss pediatricians are more aggressive than Italian colleagues (P<0.001). In an 18-month-old child, the rectal administration route of paracetamol is less often chosen in Lombardy than in Switzerland (P<0.025). Additionally, some previously identified cultural differences among linguistically different regions of Switzerland (role of reduced general appearance and perceived frequency of fever phobia) held true also beyond national borders. CONCLUSIONS: Several significant differences between Northern Italy and the different speaking regions of Switzerland were detected. This suggests the existence of national modulators of symptomatic fever management in children.

PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a Randomized, Double-Blind Placebo-Controlled Clinical Trial.

BACKGROUND AND PURPOSE: Subfebrile body temperature and fever in the first days after stroke are strongly associated with unfavorable outcome. A subgroup analysis of a previous trial suggested that early treatment with paracetamol may improve functional outcome in patients with acute stroke and a body temperature of ≥36.5°C. In the present trial, we aimed to confirm this finding. METHODS: PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2) was a multicenter, randomized, double-blind, placebo-controlled clinical trial. We aimed to include 1500 patients with acute ischemic stroke or intracerebral hemorrhage within 12 hours of symptom onset. Patients were treated with paracetamol in a daily dose of 6 g or matching placebo for 3 consecutive days. The primary outcome was functional outcome at 3 months, assessed with the modified Rankin Scale and analyzed with multivariable ordinal logistic regression. Because of slow recruitment and lack of funding, the study was stopped prematurely. RESULTS: Between December 2011 and October 2015, we included 256 patients, of whom 136 (53%) were allocated to paracetamol. In this small sample, paracetamol had no effect on functional outcome (adjusted common odds ratio, 1.15; 95% confidence interval, 0.74-1.79). There was no difference in the number of serious adverse events (paracetamol n=35 [26%] versus placebo n=28 [24%]). CONCLUSIONS: Treatment with high-dose paracetamol seemed to be safe. The effect of high-dose paracetamol on functional outcome remains uncertain. Therefore, a large trial of early treatment with high-dose paracetamol is still needed. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR2365.

Randomized, controlled, multicentre clinical trial of the antipyretic effect of intravenous paracetamol in patients admitted to hospital with infection.

AIM: No randomized study has been conducted to investigate the use of intravenous paracetamol (acetaminophen, APAP) for the management of fever due to infection. The present study evaluated a new ready-made infusion of paracetamol. METHODS: Eighty patients with a body temperature onset ≥38.5°C in the previous 24 h due to infection were randomized to a single administration of placebo (n = 39) or 1 g paracetamol (n = 41), and their temperature was recorded at standard intervals. Rescue medication with 1 g paracetamol was allowed. Serum samples were collected for the measurement of APAP and its metabolites. The primary endpoint was defervescence, defined as a core temperature ≤37.1°C. RESULTS: During the first 6 h, defervescence was achieved in 15 (38.5%) patients treated with placebo compared with 33 (80.5%) patients treated with paracetamol 1 g (P < 0.0001). The median time to defervescence with paracetamol 1 g was 3 h. Rescue medication was given to 15 (38.5%) and five (12.2%) patients allocated to placebo and paracetamol, respectively (P = 0.007); nine (60.0%) and two (40.0%) of these patients, respectively, experienced defervescence. No further antipyretic medication was needed for patients becoming afebrile with rescue medication. Serum glucuronide-APAP concentrations were significantly greater in the serum of patients who did not experience defervescence with paracetamol. The efficacy of paracetamol was not affected by serum creatinine. No drug-related adverse events were reported. CONCLUSIONS: The 1 g paracetamol formulation has a rapid and sustainable antipyretic effect on fever due to infection. Its efficacy is dependent on hepatic metabolism.

Association of Acetaminophen and Ibuprofen Use With Wheezing in Children With Acute Febrile Illness.

BACKGROUND: Many infants and children receive acetaminophen and/or ibuprofen during febrile illness. Previously, some studies have linked acetaminophen and ibuprofen use to wheezing and exacerbation of asthma symptoms in infants and children. OBJECTIVE: To assess whether acetaminophen or ibuprofen use are associated with wheezing in children presenting to the emergency department (ED) with febrile illness. METHODS: This was a cross-sectional study of children who presented with fever to the pediatric ED between 2009 and 2013. The data were collected from questionnaires and from the children's medical files. Patients with wheezing in the ED were compared with nonwheezing patients. Associations between medication use and wheezing were assessed using univariate and multivariate analyses. The multivariate analysis adjusted for potential confounding variables (ie, age, atopic dermatitis, allergies, smoking, antibiotics use, etc) via propensity scores. RESULTS: During the study period, 534 children admitted to the ED met our inclusion criteria, of whom 347 (65%) were included in the study. The use of acetaminophen was similar in children diagnosed with wheezing compared with those without wheezing (n = 39, 81.3%, vs n = 229, 82.7%, respectively). Ibuprofen use was significantly lower in children diagnosed with wheezing (n = 22, 52.4%, vs n = 168, 69.4%, respectively). In multivariate analysis, acetaminophen was not associated with a higher rate of wheezing during acute febrile illness (adjusted odds ratio [OR] = 0.76, 95% CI = 0.24- 2.39), whereas ibuprofen was associated with a lower risk of wheezing (adjusted OR = 0.36, 95% CI = 0.13-0.96). CONCLUSIONS: Our study suggests that acetaminophen and ibuprofen are not associated with increased risk for wheezing during acute febrile illness.