Intravenous infusion of diazoxide in the treatment of chlorpropamide-induced hypoglycemia

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Brief clinical and laboratory observations

3. Lewis R, and Gorbach S: Actinomyces viscosus in man, Lancet 1:641, 1972. 4. Adeniyi-Jones C, Menielly JA, and Matthews WR: Actinomyces viscosus in a branchial cyst, J Clin Pathol 60:711, 1973. 5. Gutschik E: Endocarditis caused by Actinomyces viscosus, Scand J Infect Dis 8:271, 1976. 6. Leers WD, Dussault J, Mullens JE, and Volpe R: Suppurative thyroiditis: An unusual case caused by Actinomyces naeslundi, Can Med Assoc J 101:56, 1969. 7. Georg LK, Pine L, and Gerencser MA: Actinomyces visco-

80 1

sus, comb. nov., a catalase positive, facultative member of the genus Actinomyces, Int J Syst Bacteriol 19:291, 1969. 8. Gerencser MA, and Slacik JM: Identification Of human strains of Actinomyces viscosus, Appl Microbiol 18:80, 1969. 9. Turner OW, Robertson BS, and Langton RW: Cellmediated immune response to products of Actinomyces viscosus cultures, Infect Immun 14:372, 1976. 10. Engel D, VanEpps D, and Clagett J: In vivo and in vitro studies on possible pathogenic mechanism of Actinomyces viscosus, Infect Immun 14:548, 1976.

Intravenous infusion of diazoxide in the treatment of

chlorpropamide-inducedhypoglycemia Richard F. Jacobs, M.D.,* Richard A. Nix, M.D., Thomas E. Paulus, M.D., Ernest A. Kiel, M.D., and Robert H. Fiser, Jr., M.D., Little Rock, Ark.

CHLORPROPAMIDE OVERDOSE may cause prolonged and even fatal hypoglycemia with cardiac arrhythmias, seizures, and coma? Chlorpropamide produces the most prolonged hypoglycemia of the oral agents that stimulate insulin release. ~ The peak plasma concentration is observed at 39 hours, with a half-life of approximately 72 hours. Because of such a long half-life, close monitoring of blood glucose, electrolyte values, and cardiac function for a m i n i m u m of five days is suggested following ingestion of chlorpropamide? The intravenous use of glucose solution may not be sufficient to resolve symptoms and establish normal blood sugar concentrations. Other treatment may be needed to (1) block peripheral insulin effects on glucose utilization, (2) inhibit insulin secretion, or (3) increase endogenous glucose production. An optimal treatment would be to block pancreatic insulin secretion with an "insulin antagonist," the effect of which would not be overcome by glucose stimulation of a "sulfonylurea-primed pancreatic beta cell. ''~ Diazoxide is known to have hyperglycemic properties and has been used in children with insulin-secreting tumors? The pharmacologic effects are felt to be due to blockage of insulin secretion and possibly to an extrapancreatic metabolite that stimulates hyperglycemia. Because diazoxide has been reported to be of use in adults, 2 we From the Department of Pediatrics, University of Arkansas for Medical Sciences. *Reprint address: Department of Pediatrics, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72201.

0022-3476/78/110801 +03500.30/0 © 1978 The C. V. Mosby Co.

used it in the treatment of a child who had ingested chlorpropamide. CASE R E P O R T

A 9-year-old black boy was admitted to the University Hospital in a comatose state secondarY to chlorpropamide intoxication. Approximately 36 hours prior to admission he had ingested a total of 5 gm of chlorpropamide (Diabinese) and 5 gm of alphamethyldopa with 3 gm of chlorthiazide (Aldochlor). Twenty-four hours prior to admission he was found in a comatose state and was admitted to a local hospital. During the first 12 hours of that admission he would awaken and respond appropriately following intravenous administration of 50% dextrose in water (DsoW). Shortly after eating dinner that evening, the patient had a grand mal seizure and lapsed into a coma, from which he did not respond in spite of repeated doses of the glucose solution. He was then transferred to the University Hospital. The patient arrived at the University Hospital emergency room in a comatose state and was responsive only to painful stimuli (36 hours post-ingestion). On admission the blood glucose concentration was 30 mg/dl and serum potassium was 3.0 mEq/1. An initial intravenous dose of DsoW elevated the blood glucose level tO 156 mg/dl without improving the patient's sensorium. Arterial blood gas values, skull and chest radiographs were normal, as were serum electrolytes with the exception of potassium. An electrocardiogram revealed prominent U-waves without evidence of arrhythmias. Intravenous treatment was begun with 10% dextrose, 0.45% saline (D~o½NS)at 5 mg glucose/kg/minute via a Holter pump with KC1 supplement. Two hours after admission his serum potassium concentration was 2.9 mEq/1 and glucose was 20 mg/dl (Figure). Blood sugar levels were checked hourly (by Dextrostix), and plasma glucose, BUN, and electrolyte values were evaluated everY six hours. The blood glucose levels were very labile during

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Brief clinical and laboratory observations

I.V Glucose Infusion 104

The Journal of Pediatrics November 1978

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Figure. Graph illustrating plasma glucose and insulin values in relation to intravenous infusion and diazoxide administration.

the first i0 hours at this hospital. Seveh intravenous doses of DsoW (0.75 io 1.0 ml/kg) were required during that period, in addition to a continuous infusion of DIo%NS via a subclavian catheter. Ten hours after admission treatment was begun with diazoxide intravenously (Hyperstat) at a dose of 5 mg/kg/day, divided into four doses and given over a one-hour period (Figure). Blood pressure was monitored every 10 minutes during both the infusion and the first hour post-infusion. No systolic or diastolic pressure decreases greater than 10 mm Hg were observed. As depicted in the Figure, the patient required only one further dose of DsoW after diazoxide infusion was begun, since all blood sug~ir levels remined above 60 mg/dl. Three to four hours of glucose infusions at 10 mg/kg/minute were employed with the diazoxide infusion, making further IV doses of DsoWunnecessary. Plasma insulin level prior to administration of diazoxide was 133 ~U/ml, well above normal values. Eighteen 15ours after diazoxide was started the insulin value was 80.0 /~U/ml, subsequent levels were 131.7, 69.5, and 80.2 /~U/ml (Figure). (We feel that the subsequent value of 131.7 ~U/ml reflected the increase in glucose being !nfused.) The following day insulin levels were in the range of 60 to 80 ~U/ml. The patient's sensorium bleared during the second hospital day and he was fully alert and oriented thereafter• After 28 hours of diazoxide therapy, the patient was gradually weaned to a glucose infusion rate of 1.8 mg glucose/kg/minute. After 54 hours of intravenous therapy, diazoxide was discontinued and serum glucose levels were well maintained. Neuropsychiatric evaluation revealed no apparent sequelae from the hypoglycemic episodes. The child was discharged on the eighth hospital day in good condition. DISCUSSION Chlorpropamide is believed to exert its hypoglycemic effect by the stimulation of pancreatic synthesis and releaSe of insulin? Therefore, in chlorpropamide inges-

tion, the problem is primarily hyperinsulinemia, and not simply hypoglycemia. Thus, we directed the therapy toward the hyperinsulinemic state. Dialysis, in theory, is not effective in removing the drug since chlorpropamide is 90% bound to plasma proteins and 80% metabolized by the liver? Glucagon is not used for se~eeral reasons. (1) Glucagon exerts its hyperglycemic effect by mobilizing liver glycogen. Since our patient was 36 hours postingestion when he was referred to us, he most likely had depleted his liver glycogen reserves. Even if the patient were treated acutely with glucagon, the prolonged half-life of chlorpropamide would far outlast the 12- to 24-hour period of functional glyc0genolysis in the liver. (2i Glucagon has a potent effect on the release of insulin. 2 Induced hyperglycemia via glucagon or intravenous doses of DsoW lead to further stimulation of insulin production by the pancreatic beta cell. A more appropriate therapy for chlorpropamide overdose, therefore, would be to block insulin release in the pancreas. 2 Diazoxide, a nondiuretic thiazide, effectively lowers arterial pressure in hypertensive patients by decreasing peripheral resistance. This hypotensive response is dependent on the rate of injection, requiring rapid intravenous administration. ° The slow intravenous administration of diazoxide over one hour caused no significant decrease in our patient's blood pressure. The mechanism of diazoxide's hyperglycemic effect has not been completely delineated, but there is a direct effect on islet tissue blocking insulin release. 47 Based on animal studies, this blockage of insulin appears to occur without histologic damage to the islet cells? Diazoxide also stimulates the release of catecholamines from the adrenal medulla (mainly epinephrine) and from the extra-adrenal tissue reserves

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Brief clinical and laboratory observations

(mainly norepinephrine). This release is at least partly responsible for the peripheral hyperglycemia caused by diazoxide. 7 The necessity for close monitoring of electrolyte status throughout the course of therapy cannot be overemphasized. With the elevated endogenous insulin levels and the administration of concentrated glucose solutions, the patient can become a "potassium sink," with extracellular potassium being rapidly displaced into the intracellular space. During this period, supplemental potassium is necessary and close monitoring essential. However, as the need for diazoxide diminishes and insulin levels are lowered, intracellular potassium slowly leaks out of the intracellular space. Throughout therapy, potassium supplement Should be adjusted as indicated. Diazoxide may also cause sodium retention, so hypernatremia and edema should be watched for and treated with diuretics as necessary.'

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REFERENCES

1. Pruitt AW, Dayton PG, and Patterson J: Disposition of diazoxide in children, Clin Pharmacol Ther 14:73, 1972. 2. Johnson SF, et al: Chlorpropamide-induced hypoglycemia, Am J-Med 63:799, 1977. 3. Forrest JA: Chlorpropamide overdosage-delayed and prolonged hypoglycemia, Clin Tox 7:19, 1974. 4. Drash A, et al: The therapeutic application of diazoxide in pediatric hypoglycemis states, Ann NY Acad Sci 150:33;7, 1968. 5. DowellRC, Imrie AH: Chlorpropamide poisoning in nondiabetics, Scot Med J 17:305, 1972. 6. Sellars EM, et al: Protein binding and vascular activity of diazoxide, N Engl J Med 281:1141, 1969. 7. Loubatieres A, et al: The action of diazoxide on insulin secretion medullo-adrenal secretion and the liberation of cathecholamines, Ann NY Acad Sci 150:226, 1968. 8. Wolff FW, Parmley WW: Drug-induced hyperglycemia, Diabetes 13:115, 1964. 9. Physician's desk reference, ed 31, Oradell, N. J., 1977, Medical Economics Company.

We are indebted to Dr. Don E. Hill and Dr. Heinrich Schedewie for assistance and encouragement in this study.

Thyroxine, tri-iodothyronine, and reverse tri-iodothyronine concentrations in human milk S. K. Varma, M.D.,* M. Collins,** A. Row,** W. S. Hailer, Ph.D., and K. Varma, M.D., Lubbock, Texas

HUMAN MILK and colostrum are rich in inorganic iodine, but thyroxine-like iodine compound concentrations in colostrum or milk have been found in trace quantitie s not significantly higher than errors of the methods. 1 Although secretion of thyroid hormone in human milk has not been well studied, recently i t was suggested that thyroid hormones are secreted in significant amounts. 2, 3 In one athyreotic infant it was suggested that breast feeding prevented the detrimental effects of From the Departments of Pediatrics, Biochemistry, and Obstetrics and Gynecology, Texas Tech University School of Medicine. Part of the paper presented to Western Society for Pediatric Research meeting, Carmel, Calif., February, 1978. *Reprint address: Department of Pediatrics, Texas Tech University School of Medicine, PO Box 4569, Lubbock, TX 79409. **Supported by Summer Science Research Grant Program for Medical Students, 1976 The National Foundation-March of Dimes

0022-3476/78/110803 + 04500.40/0 © 1978 The C. V. Mosby Co.

congenital hypothyroidism by providing significant quantities of thyroid hormones in the milk.' However, in none of these studies were all of the thyroid hormones measured. The present study was undertaken to measure the concentrations of thyroxine, tri-iodothyronine, and reverse tri-iodothYronine in normal human milk. Abbreviations used T,: thyroxine T~: tri-iodothyronine rT~: reversetri-iodothyronine L-T~: levo tri-iodothyronine D-T~: dextro tri-iodothyronine L-T,: levothyroxine D-T,: dextro thyroxine MATERIALS

AND METHODS

Milk was obtained from 77 euthyroid healthy mothers from the day of delivery to 148 days postpartum except in three instances when the specimens were obtained at 1 year 4 months, 1 year 8 months, and 3 years 7 months,