Alternating antipyretics for fever reduction in children: an unfounded practice passed down to parents from pediatricians

A convenience sample of parents/caregivers completed a 10-question survey on their patterns of antipyretic therapy administration to determine if antipyretics were alternated, how often, who advised them to do this, and how they learned to dose the antipyretic. Of the 256 caregivers (93%) who completed the survey, 67% responded that they alternated acetaminophen and/or ibuprofen. The frequency varied: every 2 hours (9%), every 3 hours (16%), every 4 hours (43%), every 6 hours (23%) and other (8%). Of these, 81% stated that their health care provider/pediatrician advised them to alternate acetaminophen and/or ibuprofen; 8% stated that nobody advised them. Only 61% received written instructions on how to dose antipyretics from their health care provider. Most caregivers of young children reported alternating acetaminophen and ibuprofen for fever reduction in their children. There was a wide variability of the dosing interval. Most learned this practice from their pediatrician/health care provider.     

Late delirious behavior with 2009 H1N1 influenza: mild autoimmune-mediated encephalitis?

Delirious behavior associated with influenza usually has an onset within a few days after fever and lasts <24 hours. As we encountered several patients with 2009 H1N1 influenza who presented with late-onset and long-standing delirious behavior, we retrospectively evaluated the clinical, radiologic, and laboratory features to elucidate the possible pathophysiology. This information was collected on 5 previously healthy patients (2 boys and 3 girls, aged 10-15 years) with 2009 H1N1 influenza who presented with late onset (>3 days after fever) and long-standing (>48 hours) delirious behavior. Each exhibited mild to moderate drowsiness between the episodes of delirious behavior. Electroencephalography was normal except for 1 patient with high voltage and slow activity bilaterally in the occipital regions. Brain MRI was normal. The outcome was excellent with no neurologic sequel in 4 of the 5 patients. In all 5 patients, autoantibodies against N-methyl-D-aspartate type glutamate receptor were elevated or positive in cerebrospinal fluid or serum; the autoantibody levels normalized in the 3 patients who had follow-up studies. This study indicates that 2009 H1N1 influenza has a tendency to cause late-onset and long-standing delirious behavior, at least in Japanese children. Mild autoimmune-mediated encephalitis should be considered as an underlying cause.     

Familial use of ibuprofen in febrile children: a prospective study in the emergency room of an hospital in Lille]

AIM OF THE STUDY: To assess the place of ibuprofen in the treatment of fever in children. PATIENTS AND METHODS: An anonymous self-questionnaire was submitted to the parents of 156 children aged less than 15 years and 3 months consulting for a fever in a pediatric emergency care unit. Questions related antipyretic drugs availability at home and their administration modality to the febrile child. RESULTS: Acetaminophen (liquid or rectal) was the first drug owned by families (N = 149, 96%). Ibuprofen was owned by 79 families (51%). The antipyretic drug administered as a first intention treatment was acetaminophen in 131 children (77%), ibuprofen in 27 (17%) and aspirin in 6 children (4%). An antipyretic bi-therapy was received by 58 children (35%), nearly always acetaminophen and ibuprofen (N = 48, 87%). The use of a bi-therapy was more frequent when ibuprofen was the first drug used. Children who received an antipyretic bi-therapy as compared to those who received a monotherapy exhibited significantly a higher fever level and long lasting fever period. Antipyretic drugs given to the sick children were prescribed by a physician in more than 90% of cases. CONCLUSION: Ibuprofen was largely used in febrile children. This drug has almost always been prescribed by a physician. However, due to its side effects, ibuprofen should be used only in high and badly tolerated fever that is not altered by a well conducted acetaminophen monotherapy.     

Double blind comparison of ibuprofen and paracetamol for adjunctive treatment of uncomplicated typhoid fever

BACKGROUND: Antipyretics reduce the prolonged, high fever characteristic of typhoid fever. The benefits of nonsteroidal drugs in this role have not been quantified. There have been concerns about the safety of antipyretics in typhoid. METHODS: In a double blind randomized study, 80 Vietnamese children with uncomplicated typhoid fever were randomized to receive identical syrup preparations of ibuprofen (10 mg/kg) or paracetamol (12 mg/kg) every 6 h until 36 h after defervescence. Children with a nalidixic acid-susceptible (Na) isolate of Salmonella typhi were treated with ofloxacin (15 mg/kg/day) for 3 days and those with a nalidixic acid-resistant (Na) isolate were treated for 7 days. RESULTS: S. typhi was isolated from 36 of 40 children randomized to ibuprofen (11 isolates Na) and 37 of 40 randomized to paracetamol (13 isolates Na). The median (range) fever clearance time (hours) was shorter in the ibuprofen group than the paracetamol group (68, 4 to 260 vs. 104, 12 to 404; P = 0.055) as was the area under the temperature time curve above 37 degree C (74, 0 to 237 vs. 127, 0 to 573; P = 0.013). The differences occurred predominantly in the children infected with a NaS. typhi whose infections responded more slowly to antibiotic treatment. There were no major side effects associated with the use of either drug. There were no differences between the two treatment arms in the concentrations of circulating interleukin-6 and tumor necrosis factor alpha during the course of treatment. CONCLUSION: The antipyretic effect of ibuprofen is superior to that of paracetamol in children with typhoid fever, particularly those with prolonged fever. Both antipyretics appeared to be safe.     

Efficacy and safety of acetaminophen vs ibuprofen for treating children's pain or fever: a meta-analysis

OBJECTIVE: To summarize studies testing the efficacy and safety of single-dose acetaminophen and ibuprofen for treating children's pain or fever. DATA SOURCES: Reports were gathered by searching computerized databases (from their inception through May 2002) and registries, relevant journals, and bibliographies of key articles. STUDY SELECTION: Seventeen blinded, randomized controlled trials with children (<18 years) receiving either drug to treat fever or moderate to severe pain. DATA EXTRACTION: Under a fixed-effects model, outcome measures for an initial single dose of ibuprofen vs acetaminophen were the risk ratio for achieving more than 50% of maximum pain relief, effect size for febrile temperature reduction, and risk ratio for minor and major harm. DATA SYNTHESIS: Ibuprofen (4-10 mg/kg) and acetaminophen (7-15 mg/kg) showed comparable efficacy (3 pain relief trials; 186 children). The risk ratio point estimates was 1.14 (95%confidence interval [CI], 0.82-1.58) at 2 hours after receiving the dose, and 1.11 (95% CI, 0.89-1.38) at 4 hours. Ibuprofen (5-10 mg/kg) reduced temperature more than acetaminophen (10-15 mg/kg) at 2, 4, and 6 hours after treatment (respective weighted-effect sizes: 0.19 [95% CI, 0.05-0.33], 0.31 [95% CI, 0.19-0.44], and 0.33 [95% CI, 0.19-0.47]) (9 fever trials; 1078 children). For ibuprofen 10 mg/kg (acetaminophen, 10-15 mg/kg), corresponding effect sizes were 0.34 (95% CI, 0.12-0.56), 0.81 (95% CI, 0.56-1.03), and 0.66 (95% CI, 0.44-0.87). There was no evidence the drugs differed from each other (or placebo) in incidence of minor or major harm (17 safety trials; 1820 children). CONCLUSIONS: In children, single doses of ibuprofen (4-10 mg/kg) and acetaminophen (7-15 mg/kg) have similar efficacy for relieving moderate to severe pain, and similar safety as analgesics or antipyretics. Ibuprofen (5-10 mg/kg) was a more effective antipyretic than acetaminophen (10-15 mg/kg) at 2, 4, and 6 hours posttreatment.     

Risks of antipyretics in young children with fever due to infectious disease

The objective of this study was to determine whether paracetamol (acetaminophen) affects the outcome of children with fever due to bacterial infectious disease. A total of 208 outpatients aged 6 months to 15 years with pyrexia due to bacterial infection who had been examined at the Fujimoto Children's Hospital from March 1992 to May 1992. The number of antipyretic doses of paracetamol (10 mg/kg) a day received within 3 days of illness in the patients with acute fever (≥ = 38°C) was investigated. In this study, the patients were divided into two groups: (i) the pneumonia group, which consisted of 101 patients who were subsequently diagnosed as having pneumonia during their illness and (ii) the control group, which consisted of 107 patients who were subsequently diagnosed as having illness with fever that did not progress to pneumonia. The mean number of daily doses was significantly higher for the pneumonia group (2.52 ± 0.80) than for the control group (1.37 ± 0.72, P < 0.001). There was no significant difference between the pneumonia group and the control group in body temperature during acute fever (38.7 ± 0.65 vs 38.8 ± 0.54°C). The data suggest that frequent administration of antipyretics to children with infectious disease may lead to a worsening of their illness.     

Childhood fever: correlation of diagnosis with temperature response to acetaminophen

Many people believe that temperature response to antipyretics in febrile children varies according to diagnosis. To evaluate the validity of this premise, we prospectively studied the temperature response to acetaminophen of febrile children who came to an urban pediatric emergency and walk-in facility. The study group consisted of 1,559 patients between the ages of 8 weeks and 6 years whose temperatures when seen were greater than 38.4 degrees C and who had not received antipyretic treatment within the previous four hours. Acetaminophen (15 mg/kg) was administered to each child and repeat temperatures were taken one and two hours later. Patient management was unaffected by the study, and physicians were unaware of the repeat temperature measurements. Telephone follow-up was conducted with the parents of each child within five days of the initial visit. Children with cultures positive for bacterial disease or chest x-ray films positive for pneumonia had slightly greater one- and two-hour temperature decreases compared with children with other diagnoses. Although statistically significant, we do not consider these differences in response to be clinically useful. We conclude that fever response to acetaminophen is not a clinically useful indicator by which to differentiate the causes of febrile illnesses in young children.     

Newly approved IV acetaminophen in Canada: Switching from oral to IV acetaminophen. Is IV worth the price difference? A systematic review

ContextThe use of intravenous acetaminophen leads to meaningful health cost increases for paediatric institutions. Therefore, strict criteria for intravenous acetaminophen administration are needed.ObjectiveTo undertake a systematic review of available evidence comparing oral versus intravenous acetaminophen use in children.MethodA systematic literature search was conducted on five databases. All prospective interventional studies comparing intravenous to oral acetaminophen in patients <18 years old were included. Data collection and analysis were done according to PRISMA guidelines.ResultsAmong 6,417 retrieved abstracts, 29 full-text articles were assessed of which 3 were retained. (1) Pharmacokinetic: Oral bioavailability (72% with a high inter-individual variability) was reported in 47 stable patients in a paediatric intensive care unit. (2) Analgesia: In a double-blind randomized controlled trial of 45 children, no difference in analgesia was found between oral and intravenous administration after cleft palate repair. (3) Fever: In an open-label prospective observational study of 200 children, temperature decreased faster after intravenous than oral administration but was similar 4 hours later.ConclusionsAvailable data are insufficient to guide clinicians with a rational choice of route of administration. Oral bioavailability should be studied in paediatric populations outside the intensive care unit. Despite the widespread use of intravenous acetaminophen, there is little evidence to suggest that it improves analgesia compared to the oral formulation. Similarly, fever weans faster but whether this translates into any meaningful clinical outcome is unknown. The lack of data plus the significantly higher costs of intravenous acetaminophen should motivate further research.     

Comparison of multidose ibuprofen and acetaminophen therapy in febrile children.

OBJECTIVE--To determine whether febrile children receiving 2.5-, 5-, or 10-mg/kg ibuprofen therapy via a liquid or 15-mg/kg acetaminophen therapy via an elixir every 6 hours for 24 to 48 hours show equivalent fever reduction or suffer adverse effects of the drug administered. DESIGN--Randomized, double-blind, multidose, parallel-group, variable-duration (24 to 48 hours) clinical trial. SETTING--The academically affiliated Children's Hospital in Columbus, Ohio. PARTICIPANTS--64 febrile (defined as oral or rectal temperature of 39 degrees C to 40.5 degrees C) but otherwise healthy children aged 6 months to 11 years 7 months randomly assigned to one of the four drug regimens. INTERVENTIONS--Treatment with either ibuprofen or acetaminophen as described above. Administration of antibiotics or intravenous fluids was allowed only after at least 24 hours of treatment with the assigned drug. MEASUREMENTS/MAIN RESULTS--In 61 of the 64 evaluable patients, treatments were effective and well tolerated during the entire study. While the rates of temperature reduction and maximal reduction of fever after administration of the initial dose were equal for patients receiving 10-mg/kg ibuprofen therapy and 15-mg/kg acetaminophen therapy, and both regimens were more effective than smaller doses of ibuprofen in reducing fever, after the second dose (and continuing to the end of the study) there were no statistically significant differences in temperature response among the treatment groups. Six children were withdrawn from the study, two because of dosing errors, three because of hypothermia (temperature of less than 35.6 degrees C; all three patients were in the acetaminophen group), and one because of gastrointestinal distress (this child was in the group receiving 2.5-mg/kg ibuprofen therapy). No other significant symptoms or adverse laboratory or physical findings were noted. While further confirmatory studies are needed, ibuprofen liquid (10 mg/kg) and acetaminophen elixir (15 mg/kg) administered every 6 hours for 24 to 48 hours appeared to be most effective in reducing fever. These two regimens were equally effective and equally tolerated in febrile children. Lower ibuprofen doses (2.5 and 5 mg/kg) were less effective than acetaminophen and 10-mg/kg ibuprofen therapy after the initial dose but were at least equally effective as these two higher-dose regimens thereafter.     

The effect of prophylactic acetaminophen administration on reactions to DTP vaccination

To determine the effect of prophylactic acetaminophen on reactions after diphtheria and tetanus toxoids and pertussis vaccination, 282 children received either acetaminophen or placebo in a double-blind, randomized fashion before and 3, 7, 12, and 18 hours after vaccination. Fever and local and systemic reactions were monitored. Switching to known acetaminophen was permitted if the patient's temperature was 38.9 degrees C or higher or for moderate pain. Overall, the reaction score of acetaminophen recipients was significantly less than that of placebo recipients. The rates of occurrence of fever and fussiness and the degree of pain at the injection site were significantly reduced by acetaminophen administration. Children who received acetaminophen were less likely to be switched to "open" acetaminophen than placebo recipients. It is concluded that prophylactic acetaminophen as given in this study had a moderating effect on fever, pain, and fussiness after diphtheria and tetanus toxoids and pertussis immunization.     

Severity of disease correlated with fever reduction in febrile infants

A prospective study of the effects of fever reduction on the clinical appearance of infants at risk for occult bacteremia was undertaken to study the hypothesis that infants with bacteremic illness fail to improve clinically following defervescence compared with infants with benign viral illness. A total of 154 children were enrolled in the study, including 19 with bacteremia: 13 with occult Streptococcus pneumoniae bacteremia, two with occult Haemophilus influenzae, type b bacteremia, and four with Haemophilus meningitis and bacteremia. There were no differences in degree of temperature reduction with acetaminophen between the bacteremic and nonbacteremic groups of infants. Among infants with bacteremia but without meningitis, differences from nonbacteremic children were detected in clinical appearance prior to fever reduction but not following defervescence. All patients with meningitis appeared seriously ill before and after defervescence. It was concluded that clinical improvement with defervescence is not a reliable indicator of the presence of occult bacteremia. Lack of clinical improvement with defervescence may be a reliable indicator for the presence of meningitis. Because there were differences in clinical appearance prior to fever reduction, routine administration of acetaminophen may interfere with the clinical evaluation by the physician.     

Acetaminophen and ibuprofen dosing by parents

BACKGROUND: Acetaminophen and ibuprofen are two of the most commonly used medications in children. It is our experience that parents often misdose these medications. Misdosing may lead to unintended toxicity or inadequate symptomatic improvement. There are limited data on the extent of misdosing of these antipyretics. We sought to determine the prevalence of and risk factors for inaccurate dosing by parents seeking care for their children in the emergency department (ED). METHODS: A cross-sectional observational study was performed in an urban academic pediatric ED. Two hundred patients 10 years of age and younger who were given a known dose of acetaminophen or ibuprofen in the 24 hours prior to the ED visit were enrolled. The treating physician completed a questionnaire for each patient. Caregivers were asked about quantity and frequency of antipyretic use prior to the ED visit, the source of information used to determine dosage, and which factor (eg, age, sex, height, weight, height of fever, severity of illness) they considered most important in determining the correct dosage of medication. Doses of 10 to 15 mg/kg for acetaminophen and 5 to 10 mg/kg for ibuprofen were considered accurate. RESULTS: Overall, 51% of patients received an inaccurate dose of medication, including 62% of patients given acetaminophen and 26% of patients given ibuprofen. Infants < 1 year old were more likely to receive an inaccurate dose (RR 1.40, P < 0.04, 95% CI = 1.06-1.86). Caregivers who stated that medication dosage was based on weight were less likely to give an inaccurate dose of medication (RR 0.71, P < 0.03, 95% CI = 0.52-0.97). CONCLUSIONS: Over half of the caregivers surveyed gave an inaccurate dose of acetaminophen or ibuprofen, particularly to infants. Caregivers who reported that antipyretic dosage was based on weight were less likely to misdose medication, suggesting a valuable role for patient education.     

The association of acetaminophen and asthma prevalence and severity

The epidemiologic association between acetaminophen use and asthma prevalence and severity in children and adults is well established. A variety of observations suggest that acetaminophen use has contributed to the recent increase in asthma prevalence in children: (1) the strength of the association; (2) the consistency of the association across age, geography, and culture; (3) the dose-response relationship; (4) the timing of increased acetaminophen use and the asthma epidemic; (5) the relationship between per-capita sales of acetaminophen and asthma prevalence across countries; (6) the results of a double-blind trial of ibuprofen and acetaminophen for treatment of fever in asthmatic children; and (7) the biologically plausible mechanism of glutathione depletion in airway mucosa. Until future studies document the safety of this drug, children with asthma or at risk for asthma should avoid the use of acetaminophen.     

Treatment of fever in childhood

Although the need for routine antipyretic therapy in children has often been questioned, there are no data to contra-indicate this. Not all fevers need to be treated but many physicians do so to relieve parental concern. The most commonly used antipyretic drugs are acetylsalicylic acid (ASA), paracetamol (acetaminophen) and dipyrone (metamizol). Paracetamol and ASA have been extensively evaluated but there are few clinical trials on dipyrone. In the last decade a strong statistical association has been observed between salicylates and Reye syndrome. Paracetamol is the most common cause of acute hepatic failure. Dipyrone has been associated with agranulocytosis. In the light of these findings the extensive use of antipyretics drugs has been seriously questioned.     

Severe intrinsic acute kidney injury associated with therapeutic doses of acetaminophen

Acetaminophen is a commonly used medication to manage fever and pain in children and the drug is generally considered to be safe when used at appropriate therapeutic dosages. Recently, we encountered the case of a 3‐year‐old Japanese girl who suffered from severe intrinsic acute kidney injury (AKI) after therapeutic doses of acetaminophen for a fever due to viral infection. Renal biopsy indicated severe acute tubular necrosis with a significant striped interstitial fibrosis and mild interstitial inflammation. Unfortunately, she developed chronic kidney disease thereafter. This is the youngest case of biopsy‐proven severe intrinsic AKI associated with therapeutic doses of acetaminophen. Acetaminophen, even if administered at therapeutic dosages, may be dangerous in selected children, especially with possible pre‐existing volume depletion.