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Diabetes & Metabolism
Vol 25, N° 6  - novembre 1999
p. 513
Doi : DM-11-1999-25-6-1262-3636-101019-ART51
Case report

Theophylline intoxication mimicking diabetic ketoacidosis in a child
 

M. Polak [1], M.A. Rolon [1], A. Chouchana [1], P. Czernichow [1]
[1] Service d'Endocrinologie Pédiatrique et Métabolique, Hôpital Robert Debré, 48, bd Sérurier, 75019 Paris, France.

Abstract

A 5-year-old boy presented with abdominal pain, nausea and vomiting of blood. Twelve hours after admission, "diabetic ketoacidosis" was diagnosed on the basis of elevated glycaemia, glycosuria, ketonuria and a low bicarbonate blood level, which led to treatment with fluids and regular insulin infusion. Over a 36-hour period, insulin was progressively decreased and finally stopped because of the rapid fall and normalisation of blood glucose concentration. Drug poisoning was suspected on the basis of persistent tachycardia in the absence of other signs of dehydration. Salicylate intoxication was excluded, and theophylline was finally incriminated. This compound, used by adults in the child's home, had caused accidental theophylline poisoning, mimicking diabetic ketoacidosis. Pre-diabetic immune markers were repeatedly negative, and no diabetes has developed after four years of follow-up. Thus, the transient increase in blood glucose was not related to a pre-diabetic status. A diagnosis of masked theophylline poisoning should be considered in similar situations involving a rapid decrease of insulin requirements.

Abstract
Un cas d'intoxication par la théophylline ayant « mimé » une acidocétose diabétique chez un enfant.

Un garçon âge de 5 ans a été vu aux urgences de l'hôpital pour douleurs abdominales, nausées et vomissements sanglant. Douze heures après son admission le diagnostic d'acidocétose diabétique a été pose du fait de l'augmentation de la glycémie, de l'apparition d'une glycosurie et d'une cétonurie et d'un taux abaissé de bicarbonates sanguins. La réhydratation et le traitement par perfusion d'insuline rapide ont été débutés. Sur une période de 36 heures, l'insuline a été progressivement diminuée en raison d'une chute rapide de la glycémie, et l'insuline a été finalement arrêtée. La glycémie est restée normale ensuite. La tachycardie persistante face à l'absence d'autres signes de déshydratation a mené à la suspicion d'une intoxication. Une intoxication à l'aspirine a été exclue. La notion de l'utilisation de théophylline par des adultes dans l'entourage de l'enfant a aidé au diagnostic. Le diagnostic a été finalement confirmé : il s'agissait d'une intoxication accidentelle par théophylline qui a « mimé » une acidocétose diabétique. Les marqueurs de pré-diabète étaient à plusieurs reprises négatifs et aucun diabète ne s'est développé pendant les quatre ans de suivi après l'épisode. Par conséquent cette augmentation passagère de la glycémie ne peut pas être considéré comme faisant partie d'un « état pré-diabétique ». Le diagnostic d'intoxication à la théophylline devra être évoqué dans une situation semblable avec diminution rapide des besoins d'insuline.


Mots clés : Intoxication par la théophylline. , cétoacidose diabétique. , diabète sucré transitoire.

Keywords: Theophylline intoxication. , diabetic ketoacidosis. , transient diabetes mellitus.


DISCUSSION

Although the use of theophylline in the treatment of asthma has been less common in recent years, instances of poisoning still occur. We report a case of suspected "diabetic ketoacidosis" in a child which proved to be due to accidental theophylline intoxication.

A 5-year-old boy was admitted to our emergency ward in April 1994 for abdominal pain, nausea and vomiting of blood. He had eaten a light meal 4 h prior to the onset of symptoms. Except for somnolence, his neurological examination was normal. Physical examination revealed apyrexia, normal blood pressure, sinus tachycardia with a heart rate of 163 bpm, and normal pulmonary auscultation. Laboratory studies showed haemoglobin 12.3 gr/100 ml, a normal coagulation profile, sodium 132 mmol/l, potassium 4.1 mmol/l, and glycaemia 7.2 mmol/l. An intravenous infusion of 5 % glucose solution and electrolytes was started. He underwent iced saline gastric lavage and anti-acid therapy. Upper endoscopy performed 12 h later showed a hiatal hernia, gastritis, and no focal bleeding source. Urinalysis revealed glycosuria 50 gr/dl and maximal ketonuria (+++, Ketodiabur, Boehringer). Blood chemical analyses showed normal electrolytes, elevated blood glucose (14.6 mmol/l) and low bicarbonate (11.6 mEq/l). Diabetic ketoacidosis was diagnosed, and the patient was transferred to our endocrinology unit. At this time, he had physical signs of moderate extracellular dehydration. Initial therapy consisted of an infusion of fluids plus intravenous regular insulin. Over a 36-h period, the insulin dose was progressively decreased because of a rapid fall in blood glucose concentration and finally stopped. As blood glucose was then within the normal range, further insulin treatment was considered unnecessary. In the absence of other signs of dehydration, drug poisoning was suspected 36 h after admission on the basis of persistent tachycardia. Salicylate intoxication was excluded as no blood acetylsalicylate level was detectable. Theophylline usage by asthmatic adults in the child's home was then considered as a possible source of the poisoning. This was confirmed the same day when theophylline blood level was found to be 16 &mgr;mol/l 36 h after admission. Extrapolation of this level to that at admission gave 1 024 &mgr;mol/l (based on a half-life of 6 h and linear pharmacokinetics [ [1]]) compared to a therapeutic range of 55-110 &mgr;mol/l. Finally, the child admitted having ingested the drug.

Thus, the final diagnosis during hospitalisation was hyperglycaemia, acidosis and ketonuria due to accidental theophylline ingestion. The vomiting and gastritis were caused by the intoxication.

We then investigated whether the child's transient hyperglycaemia was indicative of a pre-diabetic status. No past history of diabetes was apparent in the family. An extensive workup excluded pre-diabetic status (Table I)

. An oral glucose tolerance test performed 6 days later was normal, and insulin release evaluated by the intravenous glucose tolerance test was normal. Immune pre-diabetic markers (islet cell antibodies and insulin autoantibodies) were repeatedly negative. Class II HLA typing (DQ 0402/0301 with aspartic acid at position 57 of the B chain) showed no high-risk haplotypes. After four years of follow-up, glucose tolerance is still normal, indicating that the transient hyperglycaemia during initial hospitalisation was not related to a pre-diabetic status.

An overdose of theophylline can produce metabolic abnormalities and hyperglycaemia [ [2]]. Patients with acute poisoning (as in the present case) have a higher serum glucose level than children with chronic intoxication [ [3]], presumably because theophylline induces a rise in cyclic 3' 5' adenosine monophosphate levels, which may stimulate hepatic glucose production and increase plasma catecholamines [ [4]].

Both the fasting state of the child before endoscopy and his young age were factors in increased production of ketone bodies and ketonuria [ [5]] Moreover, the glucose infusion given during the fast before endoscopy and the stress created by the examination contributed to the increase in blood glucose in a manner similar to that of glucose intolerance when carbohydrate intake is not sufficient before an oral glucose tolerance test [ [6]]. The moderately elevated glucose level before endoscopy favoured this hypothesis. Thus, metabolic disturbances were probably due to the combined factors of theophylline poisoning, glucose infusion in a fasting condition, the young age of the child and the stress generated by endoscopy.

None of the immune markers in the episode of "stress"-related hyperglycaemia in our patient were indicative of the condition of pre-diabetes found in other patients with transient hyperglycaemia [ [7], [8]]. The transient increases in plasma glucose concentration apparently resulted from the action of theophylline.

In conclusion, theophylline poisoning remains a cause of concern because of a narrow therapeutic index. Though acute theophylline intoxication presenting as hyperglycaemia, acidosis and ketonuria (i.e. mimicking "diabetic ketoacidosis") has rarely been documented, it should be considered in similar situations characterised by a rapid decrease in insulin requirements.

Références

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Rosen JP, Danish M, Ragni MC, Saccar CL, Yaffe SJ, Lecks HI. Theophylline Pharmacokinetics in the Young Infant. Pediatrics, 1979, 64, 248-251.
[2]
Hall KW, Dobson KE, Dalton JG, Ghignone MC, Penner SB. Metabolic abnormalities associated with intentional theophylline overdose. Annals of Internal Medicine, 1984, 101, 457-462.
[3]
Shannon M, Lovejoy F. Effect of acute versus chronic intoxication on clinical features of theophylline poisoning in children. The Journal of Pediatrics, 1992, 121, 125-130.
[4]
Shannon M. Hypokalemia, hyperglycemia and plasma catecholamine activity after severe theophylline intoxication. Clinical Toxicology, 1994, 32, 41-47.
[5]
Bonnefont JP, Specola NB, Vassault A et al. The fasting test in pediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr, 1990, 150, 80-85.
[6]
Heinze E, Holl R. Test for (&bgr;-Cell Function in Childhood and Adolescence. In: Ranke M, ed. "Diagnostics of Endocrine Function in Children and Adolescents" , 2nd edn. Mannheim: J & J, 1996, 299-313.
[7]
Vardi P, Shehade N, Etzioni A et al. Stress hyperglycemia in childhood. A very high risk group for the development of type 1 diabetes. The Journal of Pediatrics, 1990, 117, 75-77.
[8]
Herskowitz-Dumont R, Wolfsdorf J, Jackson R, Eisenbarth G. Distinction between transient hyperglycemia and early insulin-dependent diabetes mellitus in childhood: A prospective study of incidence and prognostic factors. The Journal of Pediatrics, 1993, 123, 347-354.




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