Henry C. Farrar

Clinical Report—Fever and Antipyretic Use in Children

Fever in a child is one of the most common clinical symptoms managed by pediatricians and other health care providers and a frequent cause of parental concern. Many parents administer antipyretics even when there is minimal or no fever, because they are concerned that the child must maintain a “normal” temperature. Fever, however, is not the primary illness but is a physiologic mechanism that has beneficial effects in fighting infection. There is no evidence that fever itself worsens the course of an illness or that it causes long-term neurologic complications. Thus, the primary goal of treating the febrile child should be to improve the childs overall comfort rather than focus on the normalization of body temperature. When counseling the parents or caregivers of a febrile child, the general well-being of the child, the importance of monitoring activity, observing for signs of serious illness, encouraging appropriate fluid intake, and the safe storage of antipyretics should be emphasized. Current evidence suggests that there is no substantial difference in the safety and effectiveness of acetaminophen and ibuprofen in the care of a generally healthy child with fever. There is evidence that combining these 2 products is more effective than the use of a single agent alone; however, there are concerns that combined treatment may be more complicated and contribute to the unsafe use of these drugs. Pediatricians should also promote patient safety by advocating for simplified formulations, dosing instructions, and dosing devices.

Cytokines and Toxicity in Acetaminophen Overdose

Several cytokines have been reported to have hepatoprotective properties in animal models of acetaminophen toxicity. To investigate the relationships of cytokines and toxicity in acetaminophen overdose, blood samples were collected from patients following acute ingestions of acetaminophen. Samples for cytokine analysis were collected at the time of routine clinical monitoring in 111 patients (90 females; mean age 13.6 years). Plasma concentrations of interleukin 6, interleukin 8, interleukin 10, and monocyte chemoattractant protein 1 were analyzed by enzyme‐linked immunosorbent assay. Patients were stratified by toxicity severity, defined by the maximal values of hepatic transaminase elevation. Levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 were higher in patients with serum alanine aminotransferase > 1000 IU/L, and monocyte chemoattractant protein 1 had the strongest association with toxicity. Monocyte chemoattractant protein 1 values were higher in patients with greater delays in N‐acetylcysteine treatment and in patients with higher values of prothrombin time. Monocyte chemoattractant protein 1 elevation in acetaminophen overdose may represent an innate, immunomodulary response of the liver to earlier events in the toxicity. An understanding of the role of cytokine responses in acetaminophen overdose may be relevant to the future development of new therapies for acetaminophen toxicity.

Validation of a liquid chromatographic method for the determination of ibuprofen in human plasma.

A simple, rapid method of determining the ibuprofen concentration in small volumes of human plasma (50 microl) by HPLC was developed. The sample was prepared for injection using a solid-phase extraction method, with naproxen as the internal standard. A 96-well extraction plate was used, easing sample preparation and allowing the simultaneous extraction of multiple plasma samples directly into the HPLC injection vials. Samples were stable at room temperature for at least 48 h prior to injection. The HPLC method used an ultraviolet detector with a 5-min run time and measured concentrations across the range typically seen with the clinical use of this drug. The calibration curve was linear across the concentration range of 0.78-100 microg/ml with a limit of quantitation (LOQ) of 1.56 microg/ml. The coefficient of variation for intra-day and inter-day precision was 6% or less with accuracies within 2% of the nominal values for low (4.5 microg/ml), medium (40 microg/ml) and high (85 microg/ml) ibuprofen concentrations. For ibuprofen concentrations at the LOQ, the intra-day and inter-day precision and accuracy were within 10 and 15%, respectively. Recovery was 87% or greater for ibuprofen. This method was used to analyze plasma samples for unknown ibuprofen concentrations in bioequivalence and limited food effect studies of different formulations of ibuprofen. Thus, this method has been fully validated and used in the analysis of unknown plasma samples for ibuprofen.

The pharmacokinetics of continuous infusion pralidoxime in children with organophosphate poisoning

OBJECTIVE To define the pharmacokinetics of continuous infusion pralidoxime in organophosphate-poisoned children. STUDY DESIGN Open-label study in 11 children and adolescents poisoned with organophosphates or carbamates. Serial blood samples were obtained during continuous pralidoxime infusion and after the drug was stopped. RESULTS Patients were treated for 12-43 hours. Steady-state concentrations were (mean +/- SD) 22.2 +/- 12.3 mg/L. Volume of distribution ranged from 1.7 to 13.8 L/kg and was significantly higher in the more severely poisoned subjects. Elimination half-life was 3.6 +/- 0.8 hours, and clearance was 0.88 +/- 0.55 L/h/kg. After initiation of continuous infusion pralidoxime, only 1 patient required any additional atropine to control recurrent muscarinic symptoms. All patients exhibited complete clinical recovery. CONCLUSIONS The pharmacokinetics of pralidoxime in poisoned children following continuous intravenous infusion are widely variable and differ from those previously reported in both healthy and poisoned adults. A loading dose of 25-50 mg/kg is recommended followed by a continuous infusion of 10-20 mg/kg/h. A loading dose of 50 mg/kg may be appropriate in more severely poisoned patients.

Measurement of Acetaminophen‐Protein Adducts in Children and Adolescents with Acetaminophen Overdoses

Acetaminophen‐protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen‐induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen‐protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time ofrou‐ tine blood sampling for clinical monitoring. Six subjects developed “severe” hepatotoxicity (transaminase elevation > 1000IU/L), and 6 subjects had transaminase elevation of 100 to 1000 IU/L. Acetaminophen‐protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6000 IU/L) and high riskforthe development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen‐protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.

Acute mental status changes and hyperchloremic metabolic acidosis with long-term topiramate therapy.

Mental status changes and metabolic acidosis may occur with topiramate therapy. These adverse events were reported during dosage titration and with high dosages of the drug. A 20‐year‐old man receiving topiramate, valproic acid, and phenytoin experienced acute‐onset mental status changes with hyperchloremic metabolic acidosis. He had been receiving a modest dose of topiramate for 9 months. He was weaned off topiramate over 5 days, and his mental status returned to baseline within 48 hours of discontinuing the agent. This case illustrates the need for close evaluation of patients who experience acute‐onset mental status changes during topiramate therapy.

Pharmacokinetics and Pharmacodynamics of Famotidine in Infants

The pharmacokinetics and pharmacodynamics of intravenous famotidine were evaluated in 10 infants ranging from 5 to 19 days of age who had a therapeutic indication for the prophylactic treatment of stress ulceration. After a 0.5‐mg/kg infusion of famotidine, timed serum (n = 6), urine (24‐hour collection), and repeated measurements of gastric pH were obtained. The mean ± standard deviation maximum plasma concentration (Cmax) was 640.66 ± 250.66 ng/mL, the elimination half‐life (t1/2β) was 10.51 ± 5.43 hours, and the apparent volume of distribution at steady state (Vdss) was 0.82 ± 0.29 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.132 ± 0.061 L/hr/kg and 0.093 ± 0.056 L/hr/kg, respectively. No significant correlations were found between t1/2β, Vdss, Cl, and ClR and age. Six of the nine infants who had intragastric pH monitoring maintained a gastric pH > 4 until the final 24‐hour sampling point. In this study, the t1/2β of famotidine was prolonged and the Vdss, Cl, ClR were reduced compared with corresponding parameters in previously reported studies of children older than one year of age and adults.

Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents

Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin‐associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity.

Incorporating the ACGME Educational Competencies Into Morbidity and Mortality Review Conferences

Background: The Accreditation Council for Graduate Medical Education (ACGME) mandates that residents be trained in six core educational competencies. Practice-based learning and improvement (PBLI), one of the six competencies, is defined as the investigation and evaluation of ones own patient care. Morbidity and Mortality Conference, a frequently used venue to review the clinical outcome of hospitalized patients, provides the opportunity to teach and assess PBLI. Description: We report an approach to Morbidity and Mortality Conference that includes a systematic analysis of the ACGME core competencies and their application to a clinical case, a regular review of the factors that defines high-quality patient care, and a focused discussion of the PBLI competency. Evaluation: Preliminary data indicate that our residents preferred this revised method for conducting Morbidity and Mortality Conference. Conclusion: Our adaptation to Morbidity and Mortality Conference provides a systematic review of the core competencies and their relevance to clinical decision making, with the ultimate goal of improving patient care.

Life-Threatening Respiratory Failure Following Accidental Infusion of Polyethylene Glycol Electrolyte Solution into the Lung

Functional fecal retention is the most common cause of encopresis in children. Hospitalization may be required to clear the bowel following failure of outpatient management. Although the safety and efficacy of polyethylene glycol electrolyte solution is well established in children older than 6 months , its use should be carefully monitored in patients with altered mental status or impaired airway protective reflexes. We report the accidental infusion of NuLytely® into the lungs of an 11-year-old female patient who consequently developed life-threatening acute lung injury. She rapidly developed respiratory failure requiring emergent tracheal intubation and suctioning, followed by mechanical ventilation. Careful monitoring is needed to avoid this potential complication if polyethylene glycol solution is infused via a nasogastric tube.