Use of Low-Dose Continuous Corticosteroid Infusion to Facilitate Insulin Pump Use in Local Insulin Hypersensitivity

Hypersensitivity reactions may occur at the site of insulin injection and can cause painful local reactions, which complicate insulin therapy. Furthermore, hypersensitivity reactions to insulin continue to be reported despite the use of highly purified animal and human insulins. We report the results of investigation and management of a patient who had persistent local reactions at the sites of insulin injection with either intermittent or continuous subcutaneous insulin infusion (CSII) therapy. The patient's local reactions to insulin disappeared when low doses of corticosteroid were mixed with insulin administered by CSII. The patient is a 16-yr-old women who had type I diabetes mellitus diagnosed 6 yr before our evaluation. She was first placed on lente beef-pork insulin without complication but began to have frequent hospitalization for diabetic ketoacidosis at 14 yr of age. She was started on twice daily subcutaneous injections of Iletin II purified pork regular and NPH insulins, but continued to have unstable diabetes mellitus. Her control improved for ~6 mo with CSII of Iletin II purified pork regular insulin administered by an insulin pump (Autosyringe 6C, Travenol, Deerfield, Illinois). She objected to continued use of the insulin pump and was placed on multiple daily subcutaneous injections of Iletin II purified pork regular and NPH insulins, and later on beef-pork ultralente and regular insulins. After requiring five hospitalizations for diabetic ketoacidosis in a 7-mo period, she was again placed on CSII, using Lilly Humulin regular insulin. After ~1 mo on this routine, she began to develop reactions at the insulin infusion site. Observation of skin test sites injected with single doses of insulin revealed that persistent induration resulted from the fact that the dermal reactions were "biphasic" in type. That is, wheal-and-flare (hive) reactions developed at the site of CSII within 15 min, peaked during the ensuing 15 min and decreased in size without complete resolution over the remaining 1-2 h. During the 2to 6-h period after insulin injection, the site again became erythematous and pruritic and induration gradually developed. Reactions appeared fully developed by 6 h, at which time they were circumscribed, intensely pruritic, edematous, and painful to touch. These reactions frequently persisted for up to 24 h. Staphylococcus aureus was not cultured from the needle site used for CSII. Actrapid human insulin (Squibb-Novo, Princeton, NJ) was substituted for the Lilly preparation, but reactions still occurred. Reactions became progressively larger and more painful with continued insulin therapy. Attempts to block these local reactions with oral antihistamine therapy were unsuccessful. Also, changing the needle from the usual stainless steel needle to a plastic catheter failed to affect the size of the reaction. Reactions were especially large at the site of needle placement when it was left in place for >24 h. Further evaluation was initiated at that time. The patient was skin tested with a battery of 14 insulin preparations using 0.02 ml of a 50-U/ml insulin solution prepared from U 100 insulin by diluting insulin with equal volumes of buffered phenol saline. Appropriate control skin tests with phenol saline and histamine (1 mg/ml) were performed. Skin tests were positive at 20 min for all insulins tested, including zinc-free insulins, protamine-free insulins, and human insulins. No reactivity to zinc acetate or to the insulin diluents was noted. Reaction sites were observed at 6 h with local induration present at all insulin skin test sites. Insulin-specific IgE was measured (courtesy of Dr. Phillip Fireman) using a radioallergoabsorbent test. Results were expressed in RAST units calculated as percentage counts bound to total counts. Insulin-specific antibodies of the IgE class were detectable to beef (6.5 U/ml), pork (5.4 U/ml), and human (5.5 U/ml) insulins. Values for IgE-anti-insulin in nondiabetic individuals average <4 U/ml and those for insulin-requiring diabetic individuals without reactions average <5 U/ml in this system. Insulin-specific IgG was measured using I-labeled insulin in an insulin-antibody binding assay where results are reported as percent binding, and was detectable in the two regular insulins tested: beef (24-7%) and pork (16.5%). Control values for nondiabetic individuals are <3% binding in this system. Since previous reports have suggested that incorporation of small amounts of corticosteroids into insulin preparations are useful in patients with local insulin reactions who are receiving intermittent insulin therapy,' 0.22 mg methylprednisolone was added to each 5 U of human insulin placed in the pump (0.04 mg methylprednisolone/1 U insulin). The addition of this preparation resulted in immediate and complete resolution of the dermal reactions previously noted. Subsequently, lower doses of methylprednisolone (0.02 mg methylprednisolone/1 U insulin) were found to be equally effective. After several months, corticosteroid was gradually discontinued and reactions did not recur. Two types of local reactions have been reported in patients on continuous insulin infusion—local hypersensitivity reactions and cutaneous abscesses associated with Staphylococcus aureus infection at the needle site. The latter reactions are characterized by a pustule and on occasion may require incision, drainage, and antibiotic therapy. Four types of local hypersensitivity reactions to insulin have been reported. ' These include immediate wheal-and-flare reactions, biphasic reactions with a wheal and flare followed by a late reaction at 6 12 h, and delayed hypersensitivity reactions and Arthus reactions. The timing and appearance of the reactions that occurred in this patient were biphasic-type insulin reactions, the more common type of dermal hypersensitivity to insulin. * In general, biphasic reactions appear to be decreased in size by oral antihistamine therapy, although in our experience