Kids are different: developmental variability in toxicology.

Data on the impact of many environmental compounds to human health is often lacking, particularly when considering the risk to the unborn and developing child. The stage of development of the individual at the time of exposure to a toxicant has not always been considered. For example, a higher percentage of ingested lead is absorbed from the gastrointestinal tract of infants than adults. Renal elimination also follows a developmental pattern, being very limited during the newborn period, increasing during infancy and childhood, and declining gradually after puberty. Genetic polymorphisms in metabolic enzyme activity add another dimension of variability. Depending on the particular chemical, this may serve as a protective factor or increase susceptibility to toxic effects (e.g. epoxide hydrolase and fetal hydantoin syndrome). Children also have distinctive behaviors and target organ susceptibilities that warrant special consideration. The consequences of developmental changes are well-known in medical practice, and many drug doses are modified based on age, liver, and renal function, and other factors that may influence pharmacokinetic behavior of drugs. There is a sizable body of such information available, in part, in the pediatric and clinical pharmacology and toxicology literature. The concept of the significance of developmental stage is becoming increasingly important in toxicological risk assessment as well.

Acute and chronic neuropsychological consequences of mercury vapor poisoning in two early adolescents.

Mercury is an extremely toxic heavy metal that can devastate the central nervous system. The neuropsychological consequences of mercury vapor intoxication have been studied primarily in adults. We present two adolescent half-siblings, ages 13 and 15, who were unintentionally exposed to concentrated mercury vapor for 3 months. Both children participated in neuropsychological evaluations shortly after being diagnosed with mercury toxicity, and again 1 year later. Results from the initial assessments documented functional deficits consistent with diffuse encephalopathy. Upon follow-up, neuropsychological functioning had improved, but deficits remained in visuoperceptual and constructional skills, nonverbal memory, and conceptual abstraction. The deficits persisted despite removal from exposure, return of urinary and blood mercury to acceptable levels, and resolution of neuropsychiatric symptoms. The deficits were similar to, but more severe than, those found in adults suffering from mercury vapor intoxication. The results suggest that the developing brain may be especially vulnerable to mercury vapor toxicity.

Comparison of the pharmacokinetics of naproxen tablets and suspension in children.

Twenty-three children, aged 8 to 14 years, with postoperative pain, were randomly assigned to receive a fixed 250-mg dose (4.66-7.58 mg/kg) of naproxen as either a liquid suspension or tablet. After an overnight fast, the serum concentrations were measured before and at 0.5, 1, 2, 3, 4, 8, 12, 18, and 24 hours after administration of naproxen. The concentration versus time data were best fit to a one-compartment open model. The area under the concentration versus time curve, apparent volume of distribution (VDss/F), and elimination parameters (CL/F, Ke, elimination half-life) were similar in children who received suspension or tablets. Although the apparent maximum peak plasma concentration (Cmax) was greater in children who received tablets compared with those who received the suspension, Cmax/area under the curve (AUC), apparent time to maximum peak concentration (tmax), Ka, and estimated time to 10%, 50%, and 90% absorption (T10, T50, T90) were not different. The dose range was relatively narrow; hence, direct relationships between dose and elimination parameters, VDss/F, apparent tmax, Ka, T10, T50 or T90 were not observed. Neither VDss/F or CL/F were age related over the relatively narrow range of ages that were studied. Elimination of naproxen in our patients was more rapid than has previously been reported in children or adults, however. From a practical standpoint, naproxen tablets and suspension seem to be bioequivalent in fasting children ages 8 to 14 years.

Safety of vancomycin with or without gentamicin in neonates.

Short- and long-term side effects of vancomycin, or the combination of vancomycin and gentamicin, were retrospectively evaluated for 65 treatment courses in 47 premature infants who were exposed to high vancomycin serum concentrations. Thirty-five treatment courses involved treatment with the combination; 30 courses involved treatment with vancomycin alone. No immediate side effects were noted. Nephrotoxicity, defined as an increase in serum creatinine 0.5 mg/dl or more above baseline, was found in only 1 patient receiving vancomycin as the only antibiotic; that patient had pre-existing renal dysfunction. Three treatment courses involving the vancomycin-gentamicin combination resulted in nephrotoxicity; renal function returned to normal by 14 days after treatment. Thrombocytopenia was noted in 5 patients, but none exhibited clinical bleeding. Low platelet counts persisted throughout treatment, but by two weeks after treatment, this was resolved. In conclusion, the use of vancomycin or the combination of vancomycin and gentamicin in seriously ill premature infants is usually safe. The adverse effects noted were reversible, and monitoring creatinine and platelet counts during treatment is recommended.

Cardiac toxicity in an adolescent following chronic lithium and imipramine therapy.

A case report is presented of an adolescent male who developed hypothyroidism and cardiomyopathy 6 months after he began taking lithium and imipramine for a severe conduct disorder. After discontinuation of psychiatric medications and institution of thyroid hormone replacement therapy, he developed asymptomatic but potentially serious dysrhythmias. Evidence for potential cardiac toxicity of combined lithium and tricyclic antidepressant therapy is reviewed. Repeated assessment of cardiac function during such therapy is advised.

Fatal ingestion of boric acid in an adult.

A 45-year-old white man ingested approximately two cups of boric acid crystals dissolved in water in a suicide attempt. Nausea, vomiting, greenish diarrhea, and dehydration occurred shortly thereafter. Two days later, he presented to the hospital with hypotension, metabolic acidosis, oliguric renal failure, a generalized erythematous rash, and several superficial skin abrasions. His condition failed to improve despite intravenous fluids and vasopressors. He later developed atrial fibrillation with a rapid ventricular response and could not be converted to a sinus rhythm. This rhythm deteriorated to electromechanical dissociation, and the patient died 17 hours after admission. The urine and whole blood boric acid concentrations approximately 52 hours after ingestion were 160 and 42 mg/dL, respectively. These results are equivalent to urine and blood boron concentrations of 28 and 7 mg/dL, respectively. A postmortem urine boron concentration was 29.4 mg/dL. The autopsy report listed boron toxicity as the cause of death. This is the only adult reported to die from acute boric acid ingestion in recent years and may be atypical since the patient was untreated for 3 days and presented with dehydration and renal function impairment. This case suggests that lack of adequate urine flow and dehydration increases the risk of boron toxicity.

Encainide overdose in an infant.

Ingestion of as little as a single tablet of encainide resulted in life-threatening ventricular arrhythmias in a child. Insertion of an intraosseous line permitted prompt delivery of medications and fluids. Prehospital care providers must be aware that apparently trivial amounts of some adult dosage forms can be toxic to small children.

Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children.

The pharmacokinetics of racemic ibuprofen and its stereoisomers have been described in adults, but little has been reported for children. The pharmacodynamics of acetaminophen and ibuprofen have not been well described in either adults or children. Children (N = 39; age range, 11 months to 11 1/2 years) were randomly selected to receive a single dose of either 6 mg/kg of liquid ibuprofen or 10 to 15 mg/kg of liquid acetaminophen (mean +/- dose given, 11.6 +/- 0.7). Pharmacokinetic and pharmacodynamic analyses were performed with temperature as the effect parameter and mean acetaminophen, total ibuprofen, and ibuprofen stereoisomer concentrations over time. Time of maximum serum concentrations for ibuprofen was 54.05 minutes versus 27.0 minutes for acetaminophen, time to maximum temperature decrease was 183 minutes for ibuprofen and 133 minutes for acetaminophen. Temperature reduction for the ibuprofen dose was significantly different than that of the acetaminophen dose at later time points (240, 300, 360, 420, and 480 minutes). Further pharmacokinetic-pharmacodynamic studies with use of individual ibuprofen stereoisomers and other dosing regimens are indicated.

Patient-controlled versus conventional analgesia for postsurgical pain relief in adolescents.

We performed a randomized nonblinded, cross-over comparison of patient-controlled analgesia (PCA) with conventional intramuscular analgesia in 10 adolescents (13-18 years) undergoing spinal fusion for idiopathic scoliosis. PCA use afforded more effective pain control (p < 0.02) on a 10-point linear pain intensity scale than did intramuscular injections, while causing an equal amount of sedation and no side effects. PCA appears to be a promising technique for providing postoperative pain relief in this group of adolescents. Further studies are needed to define its role for other pediatric conditions.

Inadvertent intrathecal injection of daunorubicin with fatal outcome.

We report the first known case of daunorubicin administered directly into the human central nervous system. A 3 1/2-year-old female with pneumonia and otitis media was diagnosed with acute lymphoblastic leukemia and was admitted for antibiotics and chemotherapy. On the first day she inadvertently received a 17 mg intrathecal (IT) injection of daunorubicin. When the error was recognized about 1 hour later, her cerebrospinal fluid (CSF) was exchanged with sterile saline by barbotage, IT hydrocortisone was given, a subarachnoid catheter was inserted, and the CSF was allowed to drain for 36 hours. Only 5.6 mg (33%) of the dose was recovered from CSF, 2.7 mg as daunorubicin and 2.9 mg as the metabolite, daunorubicinol. Initially she was asymptomatic and induction therapy continued with vincristine, 1-asparaginase, prednisone, and IT methotrexate. One week after the daunorubicin injection she developed headache and irritability; CSF protein was 3.2 gm/dl. On the 12th day, she developed fungal sepsis and worsening pneumonia. On the 15th day, she became comatose with a flacid paraparesis, areflexia, and an ascending progressive bulbar palsy. A series of computerized tomography scans over 6 weeks showed increasing diffuse cerebral atrophy. Nerve conduction velocity studies were consistent with an axonal neuropathy. Despite her multiple concurrent medical problems, the timing and characteristics of neurologic damage suggest that IT daunorubicin caused progressive destruction of the nervous system.

Presentation and management of an acute caffeine overdose.

A one-year-old white female ingested approximately two to three grams of caffeine (200-300 mg/kg). The patient survived the ingestion with a maximum caffeine concentration of 385 micrograms/ml four hours postingestion. The child developed ventricular arrhythmias, seizures, metabolic disturbances, and severe pulmonary edema. She survived without apparent long-term sequelae despite having reached a serum caffeine concentration that is the second highest reported level in a survivor.

Clinical pharmacology and use of nonsteroidal anti-inflammatory drugs.

This review informs clinicians about current clinical usage and pharmacokinetics of newer NSAIDs and aspirin. To understand the effects of these drugs, a review of prostaglandin synthesis and actions is provided.

Pharmacokinetics of common analgesics, anti-inflammatories and antipyretics in children.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a major component of paediatric therapeutics. This paper summarises the clinical pharmacology and pharmacokinetics of some commonly used NSAIDs as well as paracetamol (acetaminophen), which has very weak anti-inflammatory activity. Available information is reviewed in an attempt to evaluate the basis for paediatric dosing recommendations and to underline known or likely differences in drug disposition that result from diseases and changes in developmental physiology. Clinically important general considerations are stressed, including areas in which age-appropriate pharmacological information is needed but unavailable. The review is not exhaustive, as only the following selected drugs are surveyed: paracetamol, ibuprofen, indomethacin, diclofenac, naproxen and sulindac. Some compounds of interest, including salicylates (e.g. aspirin, salsalate), recently introduced drugs (e.g. ketoprofen, nimesulide) and those withdrawn (e.g. zomepirac, benoxaprofen), are not included. Non-NSAID analgesics (e.g. dextropropoxyphene, narcotics) are also not included.