[An unusual case of acute aminophylline intoxication]. / Un caso inusuale di intossicazione acuta da aminofillina.

Theophylline/aminophylline use for asthma and chronic obstructive pulmonary disease has declined over time, as new and safer therapies developed. However, theophylline/aminophylline overdose can occur. Hereby it is described an unusual case of severe aminophylline intoxication due to mesodermic injections treated with CVVHDF session.

Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs.

PURPOSE: To examine the effect of landiolol (ONO-1101), a new ultra-short acting, highly selective beta1 blocker, on hemodynamic response to acute theophylline intoxication in anesthetized dogs. METHODS: Thirty-four dogs were studied during halothane anesthesia. Aminophylline (50 mg x kg(-1) over 20 min followed by infusion at 1.75 mg x kg(-1) x hr(-1)) was administered as a model of acute theophylline intoxication. Dogs were randomly enrolled into four landiolol groups (0, 1, 10, 100 microg x kg(-1) x min(-1)) to treat tachyarrhythmias. Hemodynamic variables, heart rate (HR), systemic blood pressure (SBP), pulmonary artery pressure, pulmonary artery occlusion pressure, and cardiac output (CO) were measured along with plasma concentrations of theophylline, epinephrine, and norepinephrine. RESULTS: After 60 min, plasma concentration of theophylline reached 46.6+/-4.0 (mean +/- SD) microg x ml(-1), HR increased from 129+/-21 to 193+/-27 bpm (P<0.0001) and CO increased from 1.6+/-0.5 l x min(-1) to 2.1+/-0.4 l x min(-1) (P<0.0001), whereas SBP decreased from 139+/-25 to 121+/-25 mm Hg (P<0.0001), with decreasing systemic vascular resistance. After intoxication, plasma epinephrine concentration increased from 125 +/-112 to 325+/-239 pg x ml(-1) (P<0.0001), and norepinephrine concentration from 103+/-61 to 133+/-61 pg x ml(-1) (P<0.0011). Landiolol 10 microg x kg(-1) x min(-1) decreased HR to pre-intoxication level, whereas HR returned to the intoxication baseline by 30 min after cessation of landiolol infusion. CONCLUSIONS: Landiolol controlled tachyarrhythmias associated with theophylline toxicity. The optimal effective dose of landiolol was 10 microg x kg(-1) x min(-1).

Aspects of theophylline clearance in children.

Michaelis-Menten pharmacokinetic parameters for theophylline were estimated in a three-month infant following an accidental overdose of intravenous aminophylline. Fitting of time-concentration data was performed using nonlinear regression with MKMODEL. A mixed order elimination model was superior to a first order model. Parameter estimates were standardized to a 70 kg human using an allometric power model. Parameter estimates (SE) were: maximum rate of metabolism (Vmax) 71 (42) mg.h-1, Michaelis-Menten constant (Km) 32.3 (33.5) mg.l-1, volume of distribution (Vd) 46.9 (2.6)l. This Michaelis-Menten constant is lower than that reported for adults and consequently non-linear elimination will occur at lower plasma concentrations in infants than in adults. Theophylline clearance has traditionally been reported as directly proportional to body weight. This per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates in the first one to two years of life.

Aminophylline toxicity--how many hospital asthma deaths does it cause?

Aminophylline administration was compared in 43 patients who died from asthma and 43 matched controls who were admitted, suffering from acute asthma, to hospitals in the North East Thames Region. A computer program, which used information about individual characteristics, medical history and drug intake, was employed to calculate the serum theophylline levels which were likely to have resulted from the hospital treatment each patient received. Toxic theophylline levels were estimated to have occurred in 21% (9/43) of fatal cases and 7% (3/43) controls. Details of four patients who died when their serum theophylline levels were likely to have been very high are presented. Six fatal cases suffered gastro-intestinal bleeds during their final illness: four of these had theophylline levels which were calculated to have been toxic at the time of bleeding.

Multiple dose activated charcoal for theophylline poisoning in young infants.

Five cases are presented in which multiple doses of activated charcoal were given to infants 6 months of age or less, as treatment of theophylline overdose. This therapy was tolerated in all cases with apparent enhancement of theophylline elimination. Use of multiple dose activated charcoal appears to be a viable option in the treatment of young infants with theophylline poisoning.

Self-poisoning with sustained-release aminophylline: a mechanism for observed secondary rise in serum theophylline.

It has been known for some time that after the ingestion of a large quantity of sustained-release aminophylline tablets, a secondary rise in theophylline concentration may occur (Connell et al., 1982). This has, in the past, been ascribed variously to continued absorption from the sustained release formulation (Struthers et al., 1982) or to redistribution of the drug after charcoal haemoperfusion (Connell et al., 1982). This case demonstrates that Phyllocontin S-R tablets may cause a compacted mass in the stomach, which may become resistant to gastric lavage, and thus become a potential source of a sudden secondary rise in theophylline concentration.

Theophylline toxicity and the beta-adrenergic system.

After ingestion of 12 g of theophylline caused severe toxicity in a young woman, we developed an experimental canine model to study human theophylline toxicity. Our study involved four anesthetized dogs given theophylline in a continuous intravenous drip for 180 minutes in one of four protocols. The protocols included a low-dose infusion (400 mg/h), a high-dose infusion (1000 mg/h), a high-dose infusion with beta-blockade induced by propranolol at 125 minutes after infusion, and a high-dose infusion while maintaining beta-blockade with propranolol throughout the experiment. Toxic levels of theophylline were associated with hypokalemia, hypophosphatemia, hyperglycemia, metabolic acidosis, and hypotension in both the patient and the experimental series. These effects were either prevented or partially reversed after induction of beta-blockade with propranolol. Very high levels of theophylline were associated with elevated levels of norepinephrine and epinephrine in the animals.

Clinical experience with the use of charcoal haemoperfusion: is prostacyclin required?

Twenty patients have undergone a total of 47 charcoal haemoperfusions without the use of prostacyclin. A fall in platelet numbers and evidence of platelet activation have been found during haemoperfusion but few clinical complications have been observed. Therefore, we believe that the clinical value of the addition of prostacyclin during charcoal haemoperfusion has not been proven. Nevertheless, its apparent protective effect on platelet numbers and activation indicates that further controlled trials of the use of prostacyclin during charcoal haemoperfusion are required.

A difficult monitoring situation: theophylline toxicity.

The author discusses the mishandling of drugs as one of the difficulties of monitoring serum theophylline levels, citing the case of a 68-year-old woman with long-standing chronic obstructive pulmonary disease, in whom the first three days of aminophylline therapy were prescribed and administered in a manner inconsistent with policy and procedure. The need for pharmacists to participate actively in clinical practice and patient care is stressed.