Epipen As an Alternative to Glucagon in the Treatment of Hypoglycemia in Children with Diabetes

Emerging Treatments and Technologies ORIGINAL ARTICLE

Epipen as an Alternative to Glucagon in the Treatment of Hypoglycemia in Children With Diabetes

TERESA P.C. MONSOD, MD MARY BRONSON, BSN, RN tracurricular activities for reasons of WILLIAM V. TAMBORLANE, MD TONY YONG-ZHAN MA safety. LUISA CORALUZZI, BSN, RN JO ANN AHERN, MSN, CDE, APRN Even though stimulation of epinephrine secretion is one of the main endogenous hormonal defenses against insulin- induced hypoglycemia in type 1 diabetes, use of epinephrine for treatment of severe OBJECTIVE — Fear of a severe hypoglycemic reaction is a major obstacle to achieving near- hypoglycemia in children has not been normal plasma glucose levels. Although parenteral glucagon is effective in treating these reac- tested. This is surprising because a pre- tions, it is cumbersome to use, causes severe nausea, and is impractical in the school setting. mixed and prefilled injection system for Epinephrine is available as a premixed injection (Epipen) that may be used by all care providers. Using Epipen to treat hypoglycemia may be an effective, safe, and easy-to-use alternative to parenteral epinephrine administration is glucagon. available for treatment of severe allergic reactions (Epipen; Dey Laboratories). RESEARCH DESIGN AND METHODS — Ten children (age 11.7 Ϯ 2.4 years) with Due to its ease of use and absence of se- type 1 diabetes were studied on two occasions. After an overnight equilibration period, hypo- vere side effects, teachers, administrators, glycemia was induced via an insulin pump (1 mU ⅐ kg–1 ⅐ min–1). At a blood glucose level of 2.8 and other school personnel are permitted mmol/l, either glucagon (1 mg) or epinephrine (0.3 mg), in random order, was administered to use the Epipen in emergency situa- intramuscularly and responses were monitored. tions. The present study was conse- quently undertaken to examine whether RESULTS — Plasma free insulin concentrations were similar in both studies. Plasma glucose parenteral injection of epinephrine using levels increased by 1.7 Ϯ 0.2 mmol/l (mean Ϯ SEM) in 10 min and by 2.6 Ϯ 0.2 mmol/l in 15 min with administration of glucagon and were not consistently increased with administration of the Epipen system could provide an effec- epinephrine (P Ͻ 0.01). Peak glucagon concentrations after administration of glucagon were tive alternative to injection of glucagon in Ͼ60-fold higher than basal concentrations. After administration of epinephrine, peak epineph- children with diabetes. rine levels were 20-fold higher than basal concentrations. RESEARCH DESIGN AND CONCLUSIONS — Epinephrine does not seem to be an adequate substitute for glucagon in METHODS the treatment of severe hypoglycemia. The effectiveness of glucagon in reversing hypoglycemia and its side effects of nausea and vomiting are likely related to the markedly supraphysiologic Study subjects plasma levels achieved with the standard intramuscular dose. Ten nonobese children (seven girls and three boys) with type 1 diabetes were Diabetes Care 24:701–704, 2001 studied. They had a mean (ϮSD) age of 11.7 Ϯ 2.4 years and duration of diabetes of 46 Ϯ 22 months. All of the patients evere hypoglycemia is the most fre- makes it difficult to use in an emergent were on a continuous subcutaneous insu- quent and feared acute complica- situation. In addition, the standard dose lin infusion and had good glycemic con- S tion of treatment of type 1 diabetes of glucagon is often associated with severe trol with a mean glycosylated hemoglobin during childhood. In fact, fear of a severe nausea and occasionally with vomiting, of 6.8 Ϯ 0.5 (normal value Ͻ6.4). None hypoglycemic reaction has become a ma- which can complicate recovery from hy- had clinical evidence of autonomic neu- jor obstacle in achieving lower glycosy- poglycemia by limiting the patient’s in- ropathy or severe hypoglycemia within lated hemoglobin levels with intensive take of oral carbohydrate. Because the preceding three months, and none treatment. Parenteral injection of 1.0 mg glucagon can only be administered by a were receiving any medication other than glucagon is the standard treatment for a licensed health professional in many insulin. The study was approved by the severe insulin reaction (1,2), but the need school systems, diabetic children may be Yale Human Investigation Committee, to reconstitute the hormone with diluent precluded from field trips and other ex- and all of the subjects and their parents ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● gave written informed consent. From the Department of Pediatrics, Division of Pediatric Endocrinology, Yale University, New Haven, Connecticut. Experimental protocol Address correspondence and reprint requests to Teresa P. C. Monsod, MD, Division of Pediatric Endo- Each patient was studied on two occa- crinology, Yale University School of Medicine, P.O. Box 208064, New Haven, CT 06520. E-mail: teresa. sions separated by an interval of at least 4 [email protected]. Received for publication 7 September 2000 and accepted in revised form 30 November 2000. weeks. On each occasion, the patient was A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion admitted to the Yale Children’s Clinical factors for many substances. Research Center at 8:00 P.M. on the night

DIABETES CARE, VOLUME 24, NUMBER 4, APRIL 2001 701 Epipen as an alternative to glucagon before the study. Each patient had eaten Table 1—Baseline and peak insulin levels during the two studies dinner before admission and had received the usual bolus of lispro insulin (Eli Lilly, Baseline Peak insulin levels Indianapolis, IN) for the meal. On admission, an intravenous cannula was inserted Insulin dose Insulin dose Ϫ1 Ϫ1 in an antecubital vein for blood sampling (mU ⅐ kg ⅐ Insulin level (mU ⅐ kg ⅐ Insulin level Ϫ1 Ϫ1 and the patients were maintained on their min ) (pmol/l) min ) (pmol/l) usual overnight subcutaneous basal infu- Glucagon 0.3 Ϯ 0.14 73 Ϯ 3 1.0 152 Ϯ 8 sion of lispro insulin. Blood glucose levels Epipen 0.3 Ϯ 0.15 75 Ϯ 7 1.0 136 Ϯ 16 were measured hourly overnight and Data are means Ϯ SEM. Peak insulin levels were achieved at the time of hypoglycemia (0 min) and were maintained between 3.9 and 8.3 mmol/l maintained throughout the study. by giving an intravenous bolus of 20% dextrose if levels were Ͻ3.9 mmol/l and by increasing the subcutaneous infusion vestigators and the children were masked achieved and maintained in both studies. of insulin if levels were Ͼ8.3 mmol/l. to the drug that was being given. It took 101 Ϯ 11 min (range 45–170) to At 7:00 A.M. the following morning, induce hypoglycemia after the insulin in- blood samples were drawn for baseline Analytical methods fusion rate had been increased. The time hormone levels and the insulin infusion Plasma glucose levels were measured by needed to induce hypoglycemia was sim- –1 –1 was then increased to 1 mU ⅐ kg ⅐ min the glucose oxidase method with a Beck- ilar in both studies. and stayed at this rate for the duration of man glucose analyzer (Beckman Instru- Basal plasma glucagon levels were the study. During the following 60–120 ments, Brea, CA). Catecholamines were similar in the glucagon (45 Ϯ 0.2 ng/l) min, blood glucose levels were allowed to collected in ice tubes containing glutathi- and epinephrine (42 Ϯ 0.8 ng/l) studies decrease to 2.8 mmol/l. When the blood one and measured by high-performance (Fig. 1), and plasma glucagon concentra- glucose concentration was 2.8 mmol/l, ei- liquid chromatography assay. Plasma free tions did not change during induction of ther 1.0 mg glucagon or 0.3 mg epineph- insulin (measured after precipitation with hypoglycemia. Intramuscular injection of rine (via Epipen) was administered polyethylene glycol) and glucagon were glucagon resulted in a rapid and marked intramuscularly in the anterolateral as- measured by double-antibody radioim- increase in plasma glucagon concentra- pect of the thigh. The patients were then munoassays (Human Insulin and Gluca- tions to 3,032 Ϯ 420 ng/l with peak monitored for 1 h after administration of gon RIA kits; Linco Research, St. Charles, plasma glucagon values achieved 21 Ϯ 3 the drug. Blood samples were taken at 20- MO). All samples from each subject were min after administration of glucagon. In to 30-min intervals during the prehypo- measured in a single assay. The intra-assay contrast, no change in plasma glucagon glycemic period and at 5- to 10-min in- coefficients of variation for free insulin, values was observed after administration tervals during the hypoglycemia period glucagon, epinephrine, and norepineph- of epinephrine (P Ͻ 0.01 for comparison for measurement of insulin, glucagon, rine were 11, 7, 6.5, and 4%, respectively. between the two groups). epinephrine, and norepinephrine levels. As shown in Fig. 1, basal concentra- Blood glucose levels were measured at the Statistical analysis tions and the increase in the plasma epi- bedside at 5- to 10-min intervals through- Data in text and figures are presented as nephrine levels that were observed during out the study. means Ϯ SEM. The plasma glucose con- induction of hypoglycemia were similar Symptoms of hypoglycemia were as- centrations, hormone responses, and in both studies (from 189 Ϯ 26 to 595 Ϯ sessed at 15-min intervals with a ques- symptom responses in the two studies 120 pmol/l and from 174 Ϯ 11 to 644 Ϯ tionnaire in which subjects were asked to were compared by analysis of variance rate a set of symptoms on a scale of 0 with repeated-measures design. When 322 pmol/l in the glucagon and epineph- (nonexistent) to 6 (extreme). The symp- there was a significant group-time inter- rine studies, respectively). After intra- toms were difficulty concentrating, head- action, two-tailed paired Student’s t test muscular injection of epinephrine, ache, thinking slow, sweaty, anxious, plasma epinephrine levels increased to was used to localize the effects. Baseline Ϯ shaky, and pounding heart. The scores plasma concentrations were defined as peak values that averaged 4,538 578 were added to give a total hypoglycemic the means of the values at –120 to –30 pmol/l, and the time to peak varied be- score (possible range 0–36). Families min during the induction of hypoglyce- tween 5 and 50 min (mean 18 min). After were instructed to call the principal inves- mia; 0 min is defined as the moment the administration of glucagon, plasma epi- tigators (T.P.C.M./J.A.A.) if there was any blood glucose concentration was 2.8 nephrine levels returned to baseline con- Ͻ problem after discharge from the research mmol/l and the epinephrine or glucagon centrations (P 0.01 for comparison center. Heart rate and blood pressure was given. between the two groups) (Fig. 1). There were measured at 5- to 15-min intervals, were no differences in plasma norepi- and the electrocardiogram was monitored RESULTS — As shown in Table 1, nephrine concentration between the two throughout the study. The order of the basal free insulin levels before the increase studies (data not shown). studies for each subject was random (ran- in insulin infusion rate were nearly iden- Baseline plasma glucose levels were domization performed by the Investiga- tical during the glucagon and epinephrine slightly higher during the epinephrine tional Pharmacy), and a Yale Children’s studies. In addition, when the insulin study than during the glucagon study (Fig. Clinical Research Center study nurse ad- infusion rate was increased to 1.0 mU ⅐ 1). Nevertheless, increasing the insulin Ϫ ministered the drug so that both the in- kg 1 ⅐ min–1, similar plateau values were infusion rate lead to a gradual decrease in

702 DIABETES CARE, VOLUME 24, NUMBER 4, APRIL 2001 Monsod and Associates

plasma glucose levels began to decline again after 30 min. Four patients did show responses when given epinephrine by increases in plasma glucose levels of at least 1.1 mmol/l in 15 min. When taken sepa- rately, their plasma glucose levels were 4.3 Ϯ 0.2 mmol/l at 15 min. In only one patient was this response sustained for 60 min. The basal and peak hormonal levels of these four patients were not signiﬁ- cantly different within and among groups. Of note, in 4 of the 10 children, maximum plasma epinephrine concentrations were achieved by 5 min. Of these four patients, three responded to the epinephrine by an increment in plasma blood glucose levels of at least 1.1 mmol/l by 15 min. Hypoglycemic symptom scores were higher in the patients who received the epinephrine injection (peak scores 10 Ϯ 5 vs. 6 Ϯ 3 for epinephrine versus glucagon, respectively; P Ͻ 0.01), although both groups had relatively mild symptoms (total score possible ϭ 36). None of the patients complained of nausea imme- diately after receiving glucagon. How- ever, 2–6 h after receiving the glucagon injection, 9 of the 10 patients complained of severe nausea that continued for up to 12 h. The mean heart rates increased only transiently after receiving epinephrine and peak values were within the wide range of normal values. No serious ad- verse effects were reported in either treatment group.

CONCLUSIONS — The present study was undertaken to determine whether a ﬁxed dose of epinephrine using the Epipen system might serve as an alternative to glucagon in the treatment of hypoglycemia. Although the severe hypoglycemia Figure 1—Plasma glucagon, epinephrine, and glucose concentrations after administration of that occurs when the endogenous gluca- glucagon (F) and epinephrine (E). After hormone administration (0 min), hormone levels be- gon response is impaired suggests that in- tween the two studies differed signiﬁcantly after 5 min (P Ͻ 0.01), and plasma glucose levels creased catecholamine secretion does not differed (P Ͻ 0.01) after 10 min. fully compensate for defective glucagon responses (3), the hypothesis that we tested was whether administration of plasma glucose over ϳ2 h in both studies. 8.5 Ϯ 1.1 mmol/l by the end of the study. pharmacologic doses of epinephrine As illustrated in the bottom panel of Fig. In comparison to the response to the glu- would cause recovery from hypoglycemia 1, parenteral administration of gluca- cagon injection, the plasma glucose re- with only minimal side effects. gon was able to rapidly reverse the de- sponse to epinephrine was disappointing. Hypoglycemia was induced in the crease in plasma glucose, even in the face In the group as a whole, epinephrine was study by a subcutaneous infusion of insu- of ongoing insulin infusion. Plasma glu- able to raise plasma glucose by only 0.4 Ϯ lin in a dose that raised plasma free insulin cose levels, which had increased by 1.7 Ϯ 0.3 mmol/l at 10 min and by 0.5 Ϯ 0.3 levels by only about twice basal concen- 0.2 mmol/l by 10 min and by 2.6 Ϯ 0.2 mmol/l at 15 min (P Ͻ 0.01 for compar- trations, levels that might be expected to mmol/l by 15 min, were increased to ison between the two groups). Moreover, be observed during a hypoglycemic epi-

DIABETES CARE, VOLUME 24, NUMBER 4, APRIL 2001 703 Epipen as an alternative to glucagon sode. Similarly, the infusion rate was con- plasma glucose increased by only 1.4–1.9 References tinued throughout the study to prevent mmol/l, an increment that might be insuf- 1. Carson MJ, Koch R: Clinical studies with the potentially confounding effects of ﬁcient to correct more severe hypoglyce- glucagon in children. J Pediatr 47:161– waning plasma insulin levels on the re- mia seen in clinical practice. Thus, use of 170, 1955 sponse to the two anti-insulin hormones. the Epipen in the single-dose form that is 2. Aman J, Wranne L: Hypoglycemia in This approach was also designed to sim- presently available does not seem to be an childhood diabetes. II. Effect of subcuta- ulate the persistent hyperinsulinemia that adequate alternative to glucagon in the neous or intramuscular injection of differ- occurs during clinical hypoglycemic epi- treatment of severe hypoglycemia. ent doses of glucagon. Act Pediatr Scand sodes in insulin-treated diabetic patients. The symptomatic effects of increased 77:548–553, 1988 3. De Feo P, Perriello G, Torlone E, Fanelli As expected, administration of the sympathoadrenal activity provide an early C, Ventura MM, Santeusanio F, Brunetti standard 1.0-mg dose of glucagon intra- warning of hypoglycemia and facilitate P, Gerich JE, Bolli GB: Contribution of muscularly resulted in a prompt and sub- the ingestion of carbohydrate (6). Cat- adrenergic mechanisms to glucose coun- stantial increase in plasma glucose from echolamines also have very powerful anti- terregulation in humans. Am J Physiol 261: 2.8 to 8.3 mmol/l. This increase in glu- insulin effects, including suppression of E725–E736, 1991 cose represents a pharmacologic rather endogenous insulin secretion, inhibition 4. De Feo P, Perriello G, de Cosmo S, Ven- than a physiologic response to glucagon, of glucose consumption in extraneural tura M, Campbell P, Brunetti P, Gerich JE, in that plasma glucagon levels that were tissues, generation of alternate fuels by Bolli GB: Comparison of glucose counter- regulation during short-term and pro- achieved were more than 60-fold higher stimulation of lipolysis, and generation of longed hypoglycemia in normal humans. than basal concentrations and 15- to 20- gluconeogenic precursors from periph- Diabetes 35:563–569, 1986 fold higher than the endogenous glucagon eral energy stores (6). Therefore, the weak 5. Haymond MW, Schreiner B, Study Group– response to insulin-induced hypoglyce- plasma glucose response to epinephrine TCH Diabetes Care Center: Mini-dose mia in nondiabetic subjects (4). It is not in our patients was surprising. The Epi- glucagon rescue of impending hypogly- surprising, however, that such marked pen injection failed to reverse hypoglyce- cemia in children and adolescents with hyperglucagonemias lead to severe and mia, even though the increase in plasma diabetes during episodes of gastroenteri- prolonged nausea in many of the children epinephrine levels was very rapid and tis and/or poor oral intake (Abstract). Di- Ͼ abetes 49 (Suppl. 1):A134, 2000 in this study. Smaller doses of glucagon peak concentrations (i.e., 4,366 pmol/l) 6. Maggs DG, Sherwin RS: Mechanisms of have been used to prevent hypoglycemia exceeded those seen during hypoglyce- sympathoadrenal response to hypoglyce- during sick days with apparent success mic clamp studies in diabetic and nondi- mia. Adv Pharmacol 42:622–626, 1998 and no reported nausea (5). It remains to abetic subjects (4,7). It should be noted 7. Jones TW, Porter P, Sherwin RS, Davis be determined whether smaller doses of that most of our subjects were prepuber- EA, O’Leary P, Frazer F, Byrne G, Stick S, glucagon would also be equally effective tal and all were very well controlled us- Tamborlane WV: Decreased epinephrine and better tolerated in young patients ing insulin pump therapy. Both of these responses to hypoglycemia during sleep. during severe hypoglycemic episodes. factors may have served to increase sensi- N Engl J Med 338:1657–1662, 1998 8. Amiel SA, Sherwin RS, Simonson DC, Compared with glucagon, intramus- tivity to insulin (8) and decrease respon- Tamborlane WV: Effect of intensive insu- cular injection of epinephrine via Epipen siveness to epinephrine. It is intriguing to lin therapy in glycemic thresholds for was much better tolerated by the children speculate that decreased responsiveness counterregulatory hormone release. Dia- in this study. The patients reported mild to epinephrine may explain, in part, why betes 37:901–907, 1988 adrenergic symptoms and heart rate in- younger age is an independent risk factor 9. Davis EA, Keating B, Byrne GC, Russell M, creased only slightly. Unfortunately, the for severe hypoglycemia in clinical epide- Jones TW: Hypoglycemia: incidence and Epipen injection was also much less effec- miological studies of children with diabe- clinical predictors in a large population- tive than glucagon in reversing insulin- tes (9,10). based sample of children and adolescents induced hypoglycemia. In this study, the with IDDM. Diabetes Care 20:22–25, 1997 10. Porter P, Keating B, Byrne G, Jones TW: Epipen injection counteracted the de- Incidence and predictive criteria of noc- crease in plasma glucose levels but did not Acknowledgments— We thank Dey Labora- turnal hypoglycemia in young children reverse hypoglycemia. Even in the sub- tories, Napa, California, for supplying the with insulin-dependent diabetes mellitus. jects who showed the best responses, Epipens used in the study. J Pediatr 131:2–4, 1997

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