Biomedical subjects
Publications and source records attributed to F E Simons.
In this prospective study, chest radiographs were obtained in 23 children during 33 acute asthmatic episodes. The degree of hyperinflation was assessed radiologically by three methods and compared to the clinical findings. There was no correlation between the radiologic impression of hyperinflation and the clinical severity of the asthmatic episode.
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Theophylline protein binding was 58-82% in serum from six normal adults and 42 asthmatic patients, 1-25 years old, who were given 5 mg of theophylline/kg. The binding range was greatest in young patients, but the proportion of protein-bound drug did not correlate with age. Theophylline protein binding was higher than previously reported. The effect of binding should be considered in patients who do not have optimal bronchodilation from theophylline despite total serum theophylline concentrations of 10-20 microgram/ml.
The pharmacokinetics and urinary excretion of a single dyphylline dose were studied in five normal volunteers. The mean dyphylline half-life was 1.8 +/- 0.2 hr; the mean total body clearance rate and mean renal clearance rate were 333 +/- 62 and 276 +/- 52 ml/min, respectively; and the mean volume of distribution was 0.8 +/- 0.2 liter/kg. In the urine, 83 +/- 5% of the dose was excreted as unchanged drug, and theophylline was not detected. Dyphylline doses of 19--27 mg/kg, resulting in peak serum dyphylline concentrations of 19.3--23.5 micrograms/ml, were tolerated well by four subjects. One subject had a severe headache following a 28-mg/kg dose, associated with a peak serum dyphylline concentration of 36.4 micrograms/ml. This study confirms speculation that dyphylline is not metabolized to theophylline in vivo.
High performance liquid chromatograhic (HPLC) and enzyme immunoassay (EMIT) methods for quantitating theophylline concentrations in serum were evaluated. For both methods, standard curves were linear over the therapeutic range of serum concentrations. Precision was acceptable, with coefficients of variation being less than 9%. The HPLC assay was slightly, but not significantly, more precise. No interference was noted in either method by caffeine, theobromine, diphylline, 8-chlorotheophylline, or by metabolites such as 1-methylxanthine, and 3-methylxanthine, or by potentially interfering compounds such as urea and uric acid. The two methods correlated well, with a correlation coefficient of 0.98%. The enzyme immunoassay was superior in terms of lower costs, greater ease of performance, and potential for automation.
In a double-blind, single-dose trial asthmatic children, ages two to six years, received 25, 50 or 100 ug/kg terbutaline and placebo on four consecutive days. After ingestion of all doses and placebo mean pulmonary index score and mean total respiratory resistance (Rrs), measured by forced oscillation decreased significantly at 0.5, 1, 2, 3 and 4 hours, with maximal decrease at two hours. A dose response was apparent but was significant only between doses of 25 ug/kg and 50 ug/kg at four hours. Adverse effects included elevation of heart rate two hours after the 100 ug/kg dose and tremor. In a subsequent nine-week, single-blind trial clinical wheezing was completely prevented by terbutaline 50 ug/kg tid in five of eight patients and by 75 or 100 ug/kg tid in two patients. Baseline Rrs did not decrease. No adverse ophthalmologic, hematologic or biochemical changes were observed.
The reliability of skin testing in the diagnosis of penicillin allergy was studied in 86 adults and 167 children with a history of possible hypersensitivity reactions to penicillin. Skin testing was done with the major antigenic determinant of benzylpenicillin and minor determinants of benzylpenicillin, ampicillin, cloxacillin, methicillin and cephalothin. The overall frequency of positive skin reactions was 11.5%. Among the patients with positive skin reactions about half had a history of immediate or accelerated reactions to penicillins, but 2 of 11 adults and 50% of the children in this group had a history of maculopapular rash of delayed onset. There was a low frequency of positive skin reactions when there was a long interval between the times of clinical reaction and skin testing. Of 169 patients reacting negatively to skin testing who received a specific drug challenge only 2 manifested mild urticaria; this indicates the reliability of the skin tests in predicting penicillin allergy. The major and minor determinants of benzylpenicillin were the most useful reagents. One fifth of the patients with penicillin hypersensitivity would have been missed if the major determinant of benzylpenicillin alone had been used for skin testing. The additional use of the minor determinants of other penicillin derivatives, however, did not increase substantially the clinical reliability of the skin testing procedure.
Theophylline clearance rates and half-life values were measured in 15 infants aged three to 23 months, after infusion of aminophylline by the intravenous route for at least 24 hours. The mean clearance rate was 1.07 +/- 0.55 ml/min-kg, which is comparable with values obtained by others in older children. There was some correlation of clearance rates with age. The mean half-life was 4.4 +/- 2.2 hours. There was a tenfold variability in half-life, suggesting that individualization of theophylline dose is especially important in infants if undertreatment and toxicity are to be avoided.
Ten preterm infants (birth weight 0.970 to 2.495 kg) with apnea due to periodic breathing (apneic interval = 5 to 10 seconds) or with "serious apnea" (greater than or equal to 20 seconds) were studied before and after the administration of theophylline. We determined the incidence of apnea, respiratory minute volume, alveolar gases, arterial gases and pH, "specific" compliance, functional residual capacity, and work of breathing. Theophylline decreased the incidence of apnea (P less than .05), increased respiratory minute volume (P less than 0.001), decreased (PACO2 (and PaCO2 P less than 0.001), increased the slope of the CO2 response curve (P less than 0.02) with a significant shift to the left (P less than 0.02). These findings suggest that the decreased incidence of apnea after theophylline is associated with an increase in alveolar ventilation and increased sensitivity to CO2 with a pronounced shift of the CO2 response curve to the left. These data are consistent with the idea that apnea is a reflection of a depressed respiratory system.
Serum theophylline concentrations were measured in 17 children and adolescents with acute asthma who received an aminophylline loading dose of 7 mg/kg and a constant infusion of 15 mg/kg/24 hours. The mean total theophylline clearance rate was 1.32 +/- S.D. 0.66 ml/min/kg. Hypoxia, and in two patients, acidosis, did not appear to significantly influence theophylline clearance rates. Inter-individual differences in clearance rates were great. No child experienced symptoms or signs of theophylline toxicity during the study. If serum theophylline concentrations cannot be monitored readily, an aminophylline infusion rate of 15 mg/kg/24 hours can be used safely in patients with acute asthma, but in most patients this infusion rate will not provide serum theophylline concentrations in the desired therapeutic range of 10-20 microgram/ml. Monitoring of serum theophylline concentrations during aminophylline infusion is desirable in order to individualize infusion rates, and achieve optimal bronchodilation without toxicity.
One hundred and seventy-eight admissions of 142 children with acute asthma were reviewed and graded for clinical severity. Abnormalities including consolidation (21%), atelectasis (3%) and pneumomediastinum (2%) were found on chest radiographs, most commonly in patients with clinically moderate or severe acute asthma. Hyperinflation proved difficult to assess, but was present in only 67% of admissions using the criteria described. The frequency of complications detected justifies the use of chest radiographs in assessing children admitted to hospital for acute asthma.
Thirteen of 356 children consecutively admitted for treatment of status asthmaticus in a 37-month period experienced 19 episodes of respiratory failure, an incidence of 5.3%. In this retrospective study, all children received similar pharmacologic therapy after admission, and all were treated with nasotracheal intubation and controlled ventilation with a volume-cycled ventilator. Mean duration of mechanical ventilation was 54 hours and mean duration of hospital stay was 7.5 days. Complications occurred in nine of 19 episodes and there was one death not directly related to acute asthma. It is possible that 12 of the 19 episodes of respiratory failure might have been prevented by more prompt or more appropriate treatment of the child with acute asthma.
This study compared two beta-adrenergic agents in the treatment of severe asthma of children and adolescents. Thirty patients admitted to Children's Orthopedic Hospital and Medical Center with acute asthma were treated with either isoproterenol 0.05% (iso) or metaproterenol 0.5% (meta) nebulized in physiologic saline and delivered with O2 in addition to intravenous hydration, aminophylline, and corticosteroids. Vital signs, blood gases, and pulmonary function were monitored frequently. No adverse reactions to the study drugs were encountered. Pulse rates increased similarly after treatments with both drugs. Patients treated with meta had somewhat higher rates than those treated with iso. Diastolic blood pressure decreased significantly from admission in the meta group compared to the iso group. For FVC and FEV1, the meta group had greater percentage increases from admission than the iso group at all times, with the difference being significant (p less than 0.05) at 1 and 12 hr. The same trend occurred for FEF 25%-75%. Though iso seemed to cause greater increases in flow immediately after administrations, these changes were transient compared to improvement caused by meta. Thus, meta seemed to be more effective than iso in reversing bronchospasm as measured by certain pulmonary function parameters.
The bioavailability of dyphylline from sustained-release tablets, studied in seven normal subjects given a single dose of the drug, was 67.8 per cent of that from conventional tablets. In three subjects given 40 mg/kg dyphylline as sustained-release tablets every 8 hours for four days, serum dyphylline concentrations were maintained above 7.88 microng/ml once steady state was achieved. No adverse effects were noted, though in one subject peak serum dyphylline concentrations reached 30 microng/ml after multiple doses.
Evaluation of a mentally deficient child should be individualized, using findings from an appropriate history and physical examination. Depending on these findings the patient may be assigned to one of four subcategories, as determined by clinical indications and the patient's age at onset of the problem. These categories are (1) prenatal problem of morphogenesis, (2) perinatal insult to brain, (3) postnatal onset of brain dysfunction, and (4) undecided age at onset. This subcategorization has revelance to the type of diagnostic studies that may be indicated. Using this approach, a retrospective study of the diagnostic evaluation of 98 mentally deficient children was performed. Ninety percent of these children were considered to have had "nonrational" laboratory tests, and of these, none contributed to elucidation of the basic diagnosis. The only tests that were valuable had been indicated by a specific historical or physical finding in addition to mental deficiency.
Dihydroxypropyltheophylline (dyphylline) was administered in a single dose on 7 different days to 7 normal subjects; 5 mg/kg was given by intramuscular injection and oral tablet; 10 mg/kg was given by these routes and also in 3 different liquid formulations. Dyphylline is rapidly absorbed, and bioavailability is independent of route of administration or formulation. The pharmacokinetics of dyphylline do not appear to be dose-dependent in the dosage range studied. The mean half-life of dyphylline is 2.11 +/- 0.36 hr; because of its short half-life and unproved efficacy, current dosage recommendations for dyphylline must be revised greatly. Further efficacy trials utilizing the pharmacokinetic data from this study are essential.
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