Theophylline versus terbutaline in treating critically ill children with status asthmaticus: a prospective, randomized, controlled trial.

OBJECTIVE: To compare the efficacy of theophylline, terbutaline, or theophylline combined with terbutaline treatment in critically ill children with status asthmaticus who are already receiving continuous nebulized albuterol and intravenous corticosteroids. DESIGN: Randomized, prospective, controlled, double-blind trial. SETTING: Pediatric intensive care unit of a tertiary-care children's medical center. PATIENTS: Forty critically ill children between the ages of 3 and 15 yrs with impending respiratory failure secondary to status asthmaticus. INTERVENTIONS: All patients received intravenous methylprednisolone and continuous nebulized albuterol. The three study groups received theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). MEASUREMENTS AND MAIN RESULTS: Differences in baseline characteristics, change in clinical asthma score over time, length of pediatric intensive care unit stay, and incidence of adverse events were determined. The three study groups were similar in age, gender, race, asthma severity, and treatment. There were no differences in clinical asthma score over time, length of pediatric intensive care unit stay, or incidence of adverse events between the three groups, with the exception of a higher incidence of nausea in children in group 3. The median hospital cost of medication and theophylline blood levels was significantly lower in group 1 compared with groups 2 and 3 (280 US dollars vs. 3,908 US dollars vs. 4,045 US dollars, respectively, p < .0001). CONCLUSIONS: Theophylline, when added to continuous nebulized albuterol therapy and intravenous corticosteroids, is as effective as terbutaline in treating critically ill children with status asthmaticus. The addition of theophylline to baseline therapy is more cost-effective when compared with terbutaline alone or terbutaline and theophylline together. Theophylline should be considered for use early in the management of critically ill asthmatic children.     

Individually-adjusted dosages of aminophylline in children with bronchial asthma

Theophylline concentrations in serum between 10 to 20 micrograms/ml cannot be obtained with usual dosage of theophylline in children with individual very short elimination half time of theophylline. Multiple corrections of dosage and repeated controls of theophylline concentrations in serum are necessary for empirical adjustment of individual optimal dosage. Pharmacokinetic investigations were made to shorten this management. 12 patients with bronchial asthma, 6 to 18 years of age, received 1.5 to 3 tablets of Aminophyllin under conditions of steady state. Blood samples were taken up to 6 hours after oral application. As a result of statistical analysis we found that the biological half time of theophylline could be determined from 2 to 3 blood samples. Estimation of optimal individual dosage is possible by simple mathematical pharmacokinetic formulas.     

Theophylline toxicity in children

Sixty-five cases of theophylline toxicity in children were reviewed. Vomiting, tachycardia, and central nervous system excitation were the most common manifestations. Seizure activity occurred in four acutely intoxicated children whose serum theophylline concentrations were less than 70 micrograms/ml. Two patients experienced visual hallucinations in association with high serum theophylline levels. Dosing errors accounted for the majority of cases. Most instances of toxicity could have been avoided by more careful consideration of the patient's medication history and more diligent monitoring of serum theophylline concentrations.     

Theophylline poisoning in childhood: depurative therapy using a combination of activated charcoal and a saline cathartic

The Authors describe two cases of theophylline poisoning and discuss advantages of activated charcoal and magnesium hydroxide therapy. This treatment seems to be better in patients for whom hemoperfusion could be delayed. In fact, activated charcoal can determine a real decrease in serum theophylline as experimental data show. Patients who overdose with slow release theophylline preparation should receive multiple oral doses of activated charcoal; they should also receive multiple oral doses of cathartic, both saline or sorbitol like. There is a lack of references about the activated charcoal plus magnesium hydroxide regimen particularly in childhood. The Authors discuss their own experience.     

A comparative study about the therapeutic effect of theophylline and doxapram in apnoeic disorders]

The objective of this study was to prove the superiority of doxapram compared to theophylline therapy in apneas of prematurity in very low birth weight infants. Therefore all VLBW infants (gestational age < 35 weeks) were randomized if they had in a 2 hours-interval more than 2 apneas, 4 bradycardias or 4 oxygen desaturations. They received either theophylline (loading dose 5 mg/kg b. w., 3 mg/kg b. w. bid) or doxapram by continuous infusion of 0.5 mg/kg/h. Apneas, bradycardias and desaturations were recorded from the trend analysis of our monitoring system over the first 3-days and a 7 days period and compared statistically (Mann-Whitney U-test). Plasma levels of both drugs and a polysomnographic recording were obtained during steady state conditions in parallel to a behavioral observation according to Prechtl. The recorded events were again compared using the Mann-Whitney U-test. Twenty patients were treated with theophylline, 14 with doxapram. In 9 patients of each group we could perform a polysomnography and behavioral observation. The incidence of apneas, bradycardias and desaturations in a 7 days-interval was not significantly different between both groups. Analyzing the first 3 days of treatment, however, we could detect a significantly lower rate of apneas in the doxapram group (2.5 apneas compared to 7 in the theophylline group, p < 0.037). In the polysomnographic recording and in our behavioral observations we could not record any significant differences between both groups. Therefore we can conclude that theophylline and doxapram are comparable in the treatment of apneas of prematurity, however, doxapram is superior to theophylline in reducing the rate of apneas in the first 3 days of treatment.     

Altered theophylline clearance during an influenza B outbreak

During the 1980 influenza B outbreak in King County, Washington, 11 children whose asthma had previously been controlled with a stable theophylline dose, developed theophylline toxicity on this same dose. Two had seizures, eight had nausea and vomiting, and three had headaches. All had clinical evidence of a febrile viral illness. The toxicity appeared to be related to decreased theophylline clearance, which gradually returned to preillness levels over a period of one to three months. Six of ten children had serologic evidence of influenza B, which is presumed to be the cause of the altered clearance. In children receiving chronic theophylline therapy, symptoms of vomiting, headaches, or seizures during a viral illness may be due to theophylline toxicity rather than the virus. Such patients should have an immediate serum theophylline determination, even if previous levels have been in the therapeutic range.     

Monitoring long-term therapy with theophylline preparations in children with asthma

In 78 children (4 to 17 years of age) with moderate or severe asthma who were additionally treated with sustained-release theophylline preparations, different ways of drug monitoring were examined. Analysis of plasma and saliva theophylline was performed by means of high performance liquid chromatography. Saliva theophylline turned out to permit a reliable prediction of plasma theophylline, if an individual regression is calculated for each patient, basing on 3 simultaneously performed measurements of theophylline levels in saliva and plasma within the therapeutic range of 8 to 20 mg/l. In 25 patients theophylline levels were determined in venous and capillary blood. There was an excellent agreement (r = 0.97). Thus, a convenient monitoring of theophylline treatment in children is possible.     

Theophylline in treatment of apnoea of prematurity

ABSTRACT. In order to determine the usefulness of theophylline in the management of apnoea of prematurity, a double blind trial was carried out by using six bottles of solution, three of which contained theophylline and the other three contained a placebo in the same base as theophylline. The incidence of apnoeic episodes diminished within 6–12 hours of commencement of therapy in 10 of 15 patients in the theophylline group with no further episodes over the next 48 hours in contrast to no response in 11 of 14 patients in the placebo group (P < 0.01). Treatment with a known solution of theophylline (following failure in the trial) resulted in termination of apnoeic spells in 8 of 11 patients in the placebo group and in 1 of 4 patients in the theophylline group. Three of the 14 patients in the placebo group and one of the 15 patients in the theophylline group have been excluded from the statistical analysis as they suffered from apnoea associated with fatal conditions     

Comparison of New Sustained-Release Theophylline (E-0686) and Theo-Dur

New sustained-release theophylline (E-0686) was administered to asthmatic children to study changes in serum theophylline level and its reproducibility. Results are as follows:

• 1) t-Max. of E-0686 was shorter than that of Theo-Dur, however, E-0686 could maintain a satisfactory serum theophylline level at 12 hours on a single dose.
• 2) A steady state was reached after three days on a multiple dose of E-0686. P-T difference of E-06 was 5.17 μg/ml, which could be sufficient for sustained-release theophylline.
• 3) Changes in serum theophylline level of E-0686 was highly reproducible.

     

Adenosine analogues depress ventilation in rabbit neonates. Theophylline stimulation of respiration via adenosine receptors?

The effect of the adenosine analogue L-N-phenyl-isopropyl-adenosine (L-PIA) and theophylline on the respiration of rabbit pups was studied. L-PIA (5 mumol/kg) administered intraperitoneally caused a marked respiratory depression in urethane-anaesthetized decerebrate pups and unanaesthetized intact animals during natural sleep. The effect could often be reversed with theophylline. When L-PIA was given after theophylline (20 mg/kg), the effect of L-PIA was considerably lower. L-PIA also caused respiratory depression when administered onto the exposed surface of the fourth ventricle. The effect of the adenosine analogue was more pronounced in younger than in older animals. We conclude that adenosine strongly inhibits respiration and that effect is antagonized by theophylline. The hypothesis is put forward that the therapeutic effect of theophylline on neonatal apnea might be exerted via adenosine antagonism rather than via inhibition of phosphodiesterase. Apnea in infants is often triggered by hypoxemia. It is possible that adenosine, which is released during hypoxia, mediates this effect.     

Phenobarbital increases the theophylline requirement of premature infants being treated for apnea

To determine the effect of phenobarbital sodium therapy and subependymal intraventricular hemorrhage (SEp-IVH) on the theophylline requirement of premature infants suffering with apnea and seizure activity, we compared three groups of patients as follows: group 1, those with apnea of prematurity (ten patients); group 2, those with apnea and SEp-IVH (ten patients); and group 3, those with apnea, SEp-IVH, and seizure activity for which they were receiving phenobarbital therapy (nine patients). Patients in groups 1 and 2 required lower dosages and blood levels of theophylline to control their apnea than did those in group 3, who required higher dosages and blood levels of methylxanthines. Theophylline dosages and blood levels did not significantly differ between groups 1 and 2. In group 3, the theophylline requirement for control of apnea was significantly increased after initiation of phenobarbital therapy. There seems to be a direct correlation between the increased requirement for theophylline and concomitant phenobarbital administration. The data suggest that phenobarbital increases theophylline requirement when treating neonatal apnea.     

Low-dose theophylline in childhood asthma: a placebo-controlled, double-blind study

Regular anti-inflammatory treatment is essential in treating persistent asthma. Most commonly, inhaled corticosteroids (ICS) are used. However, especially in children, there is concern about the long-term safety of ICS such that doses should be kept to a minimum. The use of theophylline has decreased because of frequent side-effects in therapeutic doses. In adults, there have been reports about an immunomodulatory effect of low-dose theophylline. To study the clinical and immunomodulatory effect in children, 36 patients (mean age 12.5 SD 2.4 years) with moderate, persistent asthma on regular ICS were recruited into a placebo-controlled, double-blind study. After a 6-week run-in period, patients received either theophylline 10 mg/kg bodyweight or placebo for 12 weeks. Diary cards, lung function, peripheral blood lymphocyte subpopulations and serum eosinophil cationic protein (sECP) were assessed. In the treatment group, mean serum theophylline was 7.1 mg/l. There was no change in symptoms or use of rescue medication. Mean (SD) peak expiratory flow (PEF) increased from 86% (24) to 95% (18) predicted. sECP decreased from 43.2 μg/l (32.5) to 26.5 μg/l (16.9) (p = 0.02). Lymphocyte subpopulations did not change. The study failed to show a beneficial clinical or an immunomodulatory effect of theophylline when used in low doses. These results do not support a more important role of theophylline in the long-term treatment of moderate childhood asthma.     

Compliance of chronic asthmatics with oral administration of theophylline as measured by serum and salivary levels.

A group of ambulatory asthmatic children was studied with serum and salivary theophylline levels following a prescribed dose of a hydroalcoholic solution of theophylline to determine compliance. The gas chromatographic procedure used was both selective and sensitive for theophylline without the necessity of withholding coffee, tea, chocolate, or cocoa. In the first group of patients, only 11% achieved therapeutic levels, 65% had less than therapeutic levels, and 23% had no measurable drug in saliva. With more directive and supervised drug administration in a second group of patients, 42% achieved therapeutic levels, 51% were below therapeutic levels, and only 6% had no measurable drug. Monitoring patients with salivary theophylline levels proved an effective way of improving compliance and also alerted physicians to noncompliance as a possible explanation of "treatment failure". Salivary specimens are readily obtained and noninvasive so that the technique is readily adaptable for use in the office of clinic setting.     

Inconsistent absorption from a sustained-release theophylline preparation during continuous therapy in asthmatic children

During routine monitoring of hospitalized children with asthma receiving a sustained-release theophylline formulation, we frequently observe unpredictable fluctuations in serum theophylline concentration (STC). We evaluated eight asthmatic patients (ages 4 to 17 years) with inconsistent STCs to determine the cause of this phenomenon. Only minimal variation in STC and therefore theophylline clearance was noted during a 24-hour period of continuous intravenous aminophylline infusion. However, marked variability in STC was observed when measured every 2 hours for 48 hours after 6 days of continuous therapy orally. In addition, the time required to reach peak and trough STCs varied from dose to dose. Inasmuch as clearance was shown to be constant, the variability was attributed to inconsistent theophylline absorption. Unpredictable fluctuations of STC secondary to variable absorption from this sustained-release theophylline preparation may occur in certain patients. Appreciation of this potential variability is necessary for the proper interpretation of STC measurements and subsequent dosage adjustment.     

Apparent inconsistent theophylline absorption from sustained release capsules

Sustained release theophylline products can improve compliance and symptom control in children with asthma. This study examines theophylline serum concentration monitoring in pediatric patients. Fifteen children with documented asthma were randomized to receive either Slo-bid Gyrocaps or Theo-dur Sprinkle for 1 month, and then crossed over to the other product. On the last day of each study period, theophylline serum concentrations were obtained prior to the morning dose and 4 hours later. In two patients receiving Theo-dur Sprinkle and six with Slo-bid Gyrocaps, the 4-hour serum concentration was lower than the pre-dose concentration. The change between the pre-dose and post-dose serum concentrations for Theo-dur Sprinkle ranged from a decrease of 2.8 mg/L to an increase of 4.9 mg/L, and, for Slo-bid Gyrocaps, from a decrease of 4.6 mg/L to an increase of 10.5 mg/L. The inconsistent theophylline absorption with each product makes dosage adjustment difficult.     

A double-blind study comparing the effectiveness of cromolyn sodium and sustained-release theophylline in childhood asthma

The effectiveness of cromolyn sodium and theophylline on asthma in children was compared during a 3-month trial. Forty-six children (aged 5 to 15 years) with asthma were assigned at random to cromolyn or theophylline (Theo-Dur) treatment groups. Each subject received theophylline placebo or cromolyn placebo in addition to the active drugs. A methacholine challenge test was done at the start of the study to document asthma and was repeated during the third month. The theophylline dosage was regulated to obtain serum levels of 10 to 15 micrograms/mL by a physician not involved directly with patient care. Forty patients completed the study. Both theophylline and cromolyn treatment groups showed improvement from base-line status in terms of symptom scores, pulmonary function, and decreased use of inhaled albuterol. Patients treated with theophylline had more side effects and required more frequent office visits than those treated with cromolyn. Both groups had decreased sensitivity to methacholine, and for one statistical test patients treated with cromolyn improved significantly. These results indicate that cromolyn is as effective as theophylline in treating mild to moderate asthma in children; additional benefits were fewer side effects and a possible decrease in bronchial hyperactivity.     

Cerebrovascular circulation in premature infants in relation to theophylline therapy

The impact of 6 mg/kg resp. 1.5 mg/kg i.v. administered Euphyllin (containing ca. 80% theophylline and ca. 20% ethylenediamine) on intracerebral circulation was investigated in 20 (gestational age 25-37 weeks) resp. 10 preterms (26-33 weeks). For that purpose blood flow velocity was measured in three intracerebral vessels (Internal carotid artery, internal jugular vein, and anterior cerebral artery) by transfontanellar pulsed Doppler ultrasonography before, 2 min after and 6 min after the drug was given. Vmax (mean peak velocity) decreased by 25% in the internal carotid artery, by 26% in the internal jugular vein, and by 17% in the anterior cerebral artery. With 1.5 mg/kg a decrease could only be evaluated in the internal carotid artery (by 10%). The reduction of cerebral blood flow induced by theophylline is due to both the simultaneous decrease of pCO2 (by 3 mmHg in our study) and a direct vasoconstrictive effect of the drug on the cerebral resistance vessels. Effects of theophylline on systemic circulation are not responsible for its influence on cerebral circulation. Regarding the physiological variability and ischemic threshold of the human brain the impact of theophylline on neonatal cerebral circulation must be estimated as a tolerable risk.     

"Clear for surgery": current attitudes and practices of pediatricians

Two thousand five hundred pediatricians, constituting 10% of active, US-based members of the American Academy of Pediatrics, were randomly selected to receive a survey of attitudes and practices in the preoperative evaluation of children, and communication with anesthesiologists. Of the 790 respondents, 30% routinely examine children prior to elective surgery at present, although 60% felt they should ideally do so. Only 7.6% had training contacts with anesthesia during residency, and only 17% felt their expertise was appreciated by the operating team in preparing children for surgery. In clinical management situations, most agreed on the anesthetic risks of a recent-onset upper respiratory infection, but varied in assessing the risks to a growing premature infant, of a patient with Trisomy 21, or of an asthmatic on chronic theophylline. The results suggest that pediatricians see their role as important in preoperative preparation of children, but lack appropriate training and experience. If "clear for surgery" is to be a meaningful activity, greater communication between anesthesiologists and pediatricians must be developed.     

Provoked augmented inspirations in ventilated premature babies

The stimulating and moderating factors of augmented inspirations provoked by artificial ventilation have been studied in 40 preterm babies on 182 different occasions. Provoked augmented inspirations were demonstrated by recording spontaneous respiratory activity during artificial ventilation by means of an oesophageal balloon and a pneumotachograph. Augmented inspirations were only seen during 18% of the study occasions. The frequency of this reflex was inversely related to the lung compliance as was the ventilator pressure necessary to provoke the augmented inspiration. The inflating volume which stimulated the reflex, when related to body weight, was similar in all the babies. Augmented inspirations were always provoked during the rapid rise in ventilator pressure at the onset of each inflation. Neonates who were recovering from paralysis by pancuronium and others being treated with theophylline both showed an increased frequency of augmented inspirations. It is possible that theophylline could be used to harness this advantageous reflex for the benefit of the ventilated preterm neonate.     

Theophylline for treatment of asthma.

Theophylline has become useful not just as an acute bronchodilator, but also as a major prophylactic agent for the suppression of symptoms of chronic asthma. Efficacy and toxicity both relate closely to serum concentration. Variable elimination rates for the drug among individuals require careful individualization of dosage guided by measurement of serum theophylline concentration to maintain safe and effective serum theophylline concentrations. Fixed-dose combinations with ephedrine are more likely to add toxicity than benefit compared with theophylline alone if the latter is used in an adequate dose. Choices among the vase array of products available can be further simplified by considering cost and convenience of the various formulations. When used appropriately, theophylline has been successful in the essential elimination of asthmatic symptoms in over 70% of asthmatic children seen at a tertiary care referral center.