Miles Weinberger

Exercise-induced hyperventilation : a pseudoasthma syndrome

BACKGROUNDnExercise-induced asthma is common and generally responds well to an inhaled beta2 agonist.nnnOBJECTIVEnWe examined the physiologic changes in airflow and gas exchange that occurred during standardized treadmill exercise in patients previously diagnosed with exercise-induced asthma whose histories appeared atypical or where conventional treatment, including an inhaled beta2 agonist, was ineffective.nnnMETHODSnDuring a 1-year period 32 patients, aged 8 to 18, met these criteria. All had been previously diagnosed as having exercise-induced asthma. Exercise consisted of treadmill running at a time when the patients had received no inhaled beta2 agonist, cromolyn, or nedocromil for at least 4 hours. Spirometry was done before and at 2, 5, 10, and 15 minutes after exercise; oxygen saturation was monitored by pulse oximetry; and end-tidal CO2 was monitored with nasal cannula.nnnRESULTSnDespite their previous diagnoses of exercise-induced asthma, 11 patients who described chest tightness during exercise had decreases in FEV1 less than 15% with all but one of those less than 10% (mean decrease 5.6%) but demonstrated decreases in end-tidal CO2 greater than in all of the other 21 patients (mean 23.2 versus 9.8%, P < .01). Only 4 patients had unequivocal evidence for bronchospasm with cough and wheezing accompanying chest tightness in association with decreases in FEV1 from 18 to 22%. Seventeen patients had neither their symptoms reproduced nor physiologic abnormalities.nnnCONCLUSIONSnThese data show that chest discomfort perceived as dyspnea during vigorous exercise may be associated with hypocapnia from hyperventilation without bronchospasm in children and adolescents previously misdiagnosed and treated as having exercise-induced asthma.

Evaluation of a program for the pharmacologic management of children with asthma

Abstract An evaluation of a program used for the pharmacologic management of asthma was conducted by a retrospective chart review of patients seen by the Pediatric Allergy and Pulmonary Service at the University of Iowa. A scheme for drug selection based on pharmacologic and physiologic principles had been used to determine the medication requirements needed to attain specified therapeutic goals. Explicit criteria, defined prior to the review, were used to confirm the diagnosis, characterize the patients as chronically or intermittently symptomatic, and grade the disease by severity prior to the initiation of therapy. Of the 25 patients with intermittent symptoms, none of the patients with the 2 least severe grades of asthma required more than as-needed bronchodilators for control of symptoms while 80% of the patients in the 2 more severe grades required corticosteroids (p = 0.002). Among the 172 patients with chronic symptoms, a single noncorticosteroid prophylactic drug (usually theophylline in optimal doses) was the final management requirement for nearly 90% of the 27 patients in the 2 least severe grades of chronic asthma, for 70% of 129 patients in grade III, and in only 30% of the 16 patients in grade IV, the most severe grade (p

Theophylline QID, TID, BID and Now QD?

Dosing intervals for slow‐release theophylline preparations depend on the rate of formulation absorption, the rate of patient elimination, and clinically acceptable fluctuations in serum concentration. Three products, two new to the United States market, have received approval by the Food and Drug Administration (FDA) for 24‐hour dosing claims. Data submitted to the FDA for Theo‐24 (Searle) suggest slow but incomplete absorption in single‐dose studies, and multiple‐dose studies confirm incomplete absorption relative to plain theophylline tablets. Fluctuations in serum concentration expressed as a percentage of the trough value at steady state with Theo‐24 given once daily in the morning ranged from 48 to 1371% among 18 subjects; 13 of the 18 had greater than 100% fluctuation, which is the upper limit for fluctuations that can stay within the 10‐ to 20‐μg/ml therapeutic range. Among another 18 subjects with somewhat slower and less variable rates of elimination, fluctuations ranged from 40–168% at steady state, with 4 of 18 greater than 100% during daily dosing with Theo‐24; all subjects had fluctuations less than 100% (39–92%) when they were given Theo‐durà tablets every 12 hours. Theo‐dur tablets have also received FDA approval for once daily administrations, but only 1 of 14 subjects in a submitted study had fluctuations less than 100% and thus was able to stay within the therapeutic range. No data were available on the absorption of Uniphyl, also approved for once‐daily dosing, but large fluctuations in serum concentration are apparent from advertisements for the European product Uniphyllin, and are also suggested by presentations on Uniphyl at a recent scientific meeting. Current standards for receiving FDA approval for 24‐hour dosing appear to be inconsistent with the pharmacodynamics and pharmacokinetics of theophylline and fail to consider the greater risks from variability in absorption when a single, large daily dose is taken.

Comparative effects of antacids, enteric coating, and bile salts on the efficacy of oral pancreatic enzyme therapy in cystic fibrosis

70% of the areas obtained when chloramphenicol was administered orally. Our experience confirms that of others 3. that the wide variation in chloramphenicol metabolism and excretion requires monitoring of serum concentrations periodically during therapy to ensure therapeutic concentrations and at the same time minimize the risk of dose-related toxicity. Dosage requirements may vary threefold in children of the same age. This variation is even greater in newborn and young infants, making monitoring of serum concentration even more imperative in this age group. We gratefully acknowledge the collaboration of Dr. Ronald Poland, Chief of Neonatology, Childrens Hospital of Michigan, in collecting data on some of the infants in this study.

Dose Dependency for Absorption and Elimination Rates of Theophylline Implications for Studies of Bioavailability

Dose dependency for absorption and elimination rates of theophylline were examined by administering 2‐mg/kg and 6‐mg/kg doses of a theophylline solution to 8 adult volunteers. The area under the concentration‐time curve extrapolated to infinity after the lower dose was 84% of that calculated after the higher dose. This is associated with a decrease in the slope of the terminal portion of the elimination curve to varying degrees after the higher dose in all 8 patients (p < 0.001). A significantly smaller fraction of the higher dose was absorbed at 15 minutes (0.46 vs. 0.77, p < 0.002), but the differences were trivial by 30 to 45 minutes. Dose dependency for elimination may cause changes in a steady‐state serum concentration during multiple dosing that is disproportionately larger than changes in dosage. In addition, the slower elimination at higher serum concentrations may confound the assessment of bioavailability of slow‐release formulations when the doses used result in a substantial disparity in the range of serum concentrations attained for the slow‐release formulation and the reference. The use of unequal doses adjusted to provide similar peak serum concentrations appears to minimize this potential error.

The challenge of treating preschool asthma

Children with preschool asthma characterized by repeated episodic lower airway symptoms with viral respiratory tract infections have had the highest rate of hospitalization for asthma of any age group. The June issue of the Journal contains a post hoc study concluding that oral corticosteroids do not reduce the severity of acute lower respiratory tract illness in preschool children with recurrent wheezing. The nihilistic conclusion of that report was reiterated in an accompanying editorial. Similar negative conclusions have been presented in 2 studies by Grigg and colleagues. However, it is time to bring some critical thinking, common sense, and the results of clinical experience to the issue of treating preschoolers with this asthma phenotype. Doses were relatively low in the studies showing no effect from oral corticosteroids. Moreover, the progression of symptoms in the placebo group was associated with self-limited symptoms rapidly improving spontaneously within a few days on placebo in the recent publication and within 12 hours in others. This bears little resemblance to patients referred to specialists. Preschool children with recurrent episodic lower respiratory tract symptomswho I see at a tertiary care referral center have generally had recurrent symptomatic periods either lasting forweeks after a viral respiratory tract infection or have progressed rapidly to require urgent care or hospitalization. Multiple physician and emergency department visits and frequent hospitalization often result. In fact, as many as 1 in 200 US children in the preschool age group have been hospitalizedwith a diagnosis of asthma (ie, viral respiratory tract infection-induced lower airway disease). Moreover, asthma has been the leading cause of hospitalization at most children’s hospitals in the United States. From 2 national databases, more than 5% of pediatric hospitalizations are for asthma and another 5% are for pneumonia, which, based on our clinical experience, includes a substantial number of young children with asthma misdiagnosed as pneumonia. In contrast, asthma is an uncommon pediatric admission at the University of Iowa Children’s Hospital. I attribute this to our practice of treating nonatopic preschool children with this asthma phenotype by teaching the parents of children who have experienced episodes of viral respiratory tract infection-induced wheezing and cough that do not rapidly resolve with occasional albuterol to start an oral corticosteroid the day before dyspnea and wheezing are prominent. This has been shown to be recognizable in these children based on progressive severity of coughing.

Drug clearance in patients with cystic fibrosis

Clinical Pharmacology and Therapeutics (1992) 52, 106–107; doi:10.1038/clpt.1992.111