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

BACKGROUND: 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. METHODS: Serum levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peak cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. RESULTS: Five patients had aspartate aminotransferase or alanine aminotransferase levels >1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels > or =100 IU/L and < or =1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P <.001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at >15 hours, as compared with other patients (Mann-Whitney U test, P <.01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity. In addition, interleukin 8 concentrations of >20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P <.015). CONCLUSIONS: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults.

Protracted methemoglobinemia after phenazopyridine overdose in an infant.

Acquired methemoglobinemia may be produced by the ingestion or absorption of certain chemicals and xenobiotics. A case of methemoglobinemia in an 8.5-month old infant who ingested approximately 227 mg/kg of phenazopyridine is presented. Although this adverse event is often reversed with a single dose of methylene blue, this patient required three doses of methylene blue (1 mg/kg) over a 25-hour period. It is suggested that the need for repeated doses of methylene blue in this case was not only related to the large dose of phenazopyridine, but also its metabolites (i.e., aniline), which have the potential to produce methemoglobinemia. This case illustrates the need for close observation and serial monitoring of methemoglobin levels in patients who are at increased risk for the development of protracted methemoglobinemia. Integration of knowledge of developmental pharmacology, drug metabolism, and pharmacodynamic properties are critical determinants in the evaluation and treatment of patients with drug-induced methemoglobinemia.

The pharmacokinetics of oral ranitidine in children and adolescents with cystic fibrosis.

The pharmacokinetics of oral ranitidine were studied in 9 patients (ages 9.9 to 19.6 years) with cystic fibrosis (CF). Patients were evaluated at steady-state conditions, and the mean maximum serum concentration (Cmax) was 845.7 +/- 448.1 ng/mL. To adjust for the variable drug dosing used among study patients, both Cmax and area under the concentration curve (AUC) were standardized to dose (CmaxST and AUCST, respectively) and were 217.9 +/- 87.9 ng/mL and 1038.0 +/- 242.2 ng/mL.h. The elimination half-life (t1/2) was 2.7 +/- 1.4 hours, and the apparent steady-state volume of distribution (Vdss) was 4.6 +/- 1.7 L/kg. The plasma clearance was 1.022 +/- 0.290 L/kg/h. The Vdss in this study was greater than that previously reported in children with peptic ulcer disease. Statistically significant relationships between pharmacokinetic parameters and measures of disease severity were not observed in the study population. The pharmacokinetics of ranitidine in children and adolescents with CF may differ from those in children and adolescents without CF.

A comparison of two dosing regimens of succimer in children with chronic lead poisoning.

There is limited information defining the optimal dosing regimen of succimer in the treatment of children with chronic lead poisoning. It is typically administered as a five day course of high dose therapy (1,050 mg/m2/day) followed by 14 days of low dose therapy (700 mg/m2/day). This study compared the effect on blood lead concentrations (BPb) of treatment with this standard regimen and an alternate regimen consisting of two courses of high dose therapy separated by one week. There were significant reductions in the mean BPb in both the standard (n = 7) and alternate (n = 4) treatment groups but there was not a significant difference between the groups. In the standard group, the BPb decreased from 33 +/- 4 to 27 +/- 6 mcg/dL. The BPb decreased from 33 +/- 6 to 23 +/- 4 mcg/dL in those treated with alternate therapy. This study suggests that two short courses of high dose therapy may be an acceptable alternative to standard succimer therapy. Because of the small size of this study, other studies are warranted.

Pharmacokinetics of famotidine in patients with cystic fibrosis.

Famotidine pharmacokinetics were studied in 13 patients with severe cystic fibrosis (CF) ranging from 10 to 47 years of age and 25 to 72 kg in weight. Patients were randomized to first receive famotidine either 20 mg intravenously or 40 mg orally. Twelve patients were crossed over to the alternate treatment. Repeated blood samples were obtained over 12 hours after intravenous and oral administration and urine was collected over 24 hours for quantitation of famotidine by means of high-performance liquid chromatography (HPLC). A compartment model-dependent approach was used to characterize the disposition of famotidine. From the intravenous data, the mean +/- standard deviation elimination half-life (t1/2) was 2.11 +/- 0.75 hours, the total clearance (Cl) was 0.79 +/- 0.41 L/kg/hr, the renal clearance was 0.57 +/- 0.26 L/kg/hr, the fraction eliminated unchanged in the urine was 83% +/- 16%, and the apparent volume of distribution (Vdss) was 1.33 +/- 0.53 L/kg. The bioavailability determined from comparison of intravenous and oral area under the curve data was 71% +/- 27%. Results of this study support an initial famotidine dose of 20 mg intravenously or 40 mg orally every 12 hours in patients with CF who are older than 9 years of age.

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 (t1/2 beta) 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 t1/2 beta, 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 t1/2 beta 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.

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 of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the 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.

Evaluation of occult acetaminophen hepatotoxicity in hospitalized children receiving acetaminophen. Pediatric Pharmacology Research Unit Network.

The safety of repeated doses of acetaminophen in ill children with the potential of reduced glutathione stores has been questioned. This study measured hepatic transaminases in children and adolescents (n=100) who received > or = 6 therapeutic doses of acetaminophen over a 48-hour period of hospitalization. Acetaminophen-protein adducts were measured in a cohort of subjects with hepatic transaminase elevation (n=8) and in those (n=10) receiving concurrent drug therapy with agents that induce the cytochrome P450 enzymes involved in acetaminophen metabolism. Acetaminophen-protein adducts were not detected in this cohort of 18 subjects. Based on this pilot study, the routine use of acetaminophen at therapeutic doses in ill, hospitalized children and adolescents appears safe.

Diarrhea associated with enteral benzodiazepine solutions.

Diarrhea occurred in an infant given large enteral doses of benzodiazepine solutions that contained the carriers propylene glycol and polyethylene glycol. This adverse drug effect may be avoided by prescribing the tablet formulations appropriately prepared for enteral administration.

Hypokalemia in an asthmatic child from abuse of albuterol metered dose inhaler.

A case of albuterol abuse by a pediatric patient with the development of hypokalemia with electrocardiographic changes is presented. The hypokalemic effects of beta2-agonists are discussed in regard to the production of significant cardiac symptoms. Additionally, guidance regarding the evaluation of similar patients presenting in the emergency department is provided.

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 (1), 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.

Bromism: intoxication from a rare anticonvulsant therapy.

Bromide, the first effective therapy for epilepsy, is not commonly prescribed today but has been advocated by some pediatric neurologists for the treatment of intractable seizures in children. We report a 17-year-old female patient with intractable epilepsy who insidiously developed bromism while on treatment with triple bromide elixir. We review the clinical presentation, diagnosis, pathophysiology, and management of bromism.

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.

Hyponatremia as the cause of seizures in infants: a retrospective analysis of incidence, severity, and clinical predictors.

STUDY OBJECTIVES: (1) To determine the incidence of hyponatremic seizures in infants, (2) to compare the severity and outcome of seizures in hyponatremic and normonatremic patients, and (3) to evaluate the utility of clinical predictors of hyponatremia. DESIGN: Retrospective chart review of infants who presented to an urban pediatric emergency department from 1988 through 1993. PARTICIPANTS: Patients who experienced seizures while in the ED. These patients were divided into hyponatremic and normonatremic groups. RESULTS: Hyponatremia was the cause of seizures in 70% of 47 infants younger than 6 months who lacked other findings suggesting a cause. Median seizure duration was longer in hyponatremic patients (30 versus 17 minutes; P = .007), with a greater incidence of status epilepticus (73% versus 36%; P = .02) and fewer patients with seizures lasting less than 10 minutes (9% versus 36%; P = .04). Emergency intubation was performed more often in hyponatremic patients (12% versus 0%; P = .009). The median temperature was lower in hyponatremic infants than in normonatremic patients (35.5 degrees C versus 37.2 degrees C; P = .0001). Exact logistic-regression methods identified temperature of 36.5 degrees C or less as the best predictor of hyponatremic seizures, with an OR of 64 (95% CI, 8 to 1,026). CONCLUSION: Hyponatremia should be strongly suspected in an infant less than 6 months old with seizures and a temperature of 36.5 degrees C or less.

Sympathomimetic drug use in adolescents presenting to a pediatric emergency department with chest pain.

BACKGROUND: Drug use has been associated with chest pain in adults presenting for emergency care. The association of drug use and chest pain in adolescents presenting to a pediatric emergency department has not been evaluated. METHODS: Urine drug testing was conducted in a convenience sample of healthy adolescents with chest pain (cases) and compared to a control group of adolescents presenting with other complaints to a pediatric emergency department. Exclusion criteria were known diagnoses associated with chest pain (e.g., cardiac disease, sickle cell disease) and major trauma (due to its association with drug use). Urine drug testing consisted of 2 screening tests and gas chromatography-mass spectrometry confirmation of all positive or indeterminate results. All patients completed a questionnaire regarding recently prescribed, over-the-counter, and illicit drug use. RESULTS: Twenty-eight cases and 26 controls completed the study over an 11-month study period. No cases or controls were positive for cocaine whereas marijuana was detected in 7 (25.0%) cases and in 7 (26.7%) controls. Five (17.8%) of the cases but none of the controls were positive for ephedrine (p = 0.05). CONCLUSIONS: Ephedrine exposure appeared to be associated with chest pain in adolescents presenting for emergency care and marijuana was the most common drug of abuse, regardless of presenting complaint.