insulin--isophane and Anaphylaxis

Insulin allergy is a rare yet severe side effect of exogenous insulin use. Management typically involves use of alternative antihyperglycaemic agents, symptom control with antihistamines, use of different insulin formulations, and induction of tolerance with incremental doses of insulin. This treatment regimen is not always successful, and the use of omalizumab, an anti-IgE monoclonal antibody, has been used to induce tolerance to insulin.. G.M. is a 62-year-old man with Type 2 diabetes mellitus. His condition was not optimized on oral agents, and insulin therapy was required. G.M. had anaphylaxis to insulin NPH, and subsequent skin-prick testing was positive to insulin aspart, insulin NPH, insulin glulisine, insulin detemir, regular insulin, insulin glargine 100 units/ml and insulin glargine 300 units/ml. He received incremental doses of several insulin formulations; however, he experienced diffuse urticaria preventing optimal glycaemic control. Three successful cases have been described in the literature of omalizumab inducing tolerance to exogenous insulin; therefore, G.M. was started on omalizumab. He subsequently tolerated treatment doses of insulin glulisine and insulin detemir with no allergic reactions and with improvement in glycaemic control.. To our knowledge, this is the first described case of allergy to insulin glargine 300 units/ml and reiterates the potential use of omalizumab in insulin allergy. Further research is warranted to determine if omalizumab should be considered standard of care in difficult-to-treat insulin hypersensitivity.

Topics: Anaphylaxis; Anti-Allergic Agents; Diabetes Mellitus, Type 2; Drug Hypersensitivity; Humans; Insulin; Insulin Aspart; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Male; Middle Aged; Omalizumab

Protamine insulin use may immunologically sensitize patients to protamine, leading to anaphylactoid reactions upon subsequent exposure to protamine sulfate during cardiac catheterization or cardiovascular surgery. The risk of such reactions in protamine insulin-dependent patients is uncertain. One catheterization study reported a 50-fold greater risk while a second showed no increased risk! To clarify the risk, the records of 7,750 cardiac catheterization procedures between 1984 and 1987 were analyzed for presence of NPH or PZI insulin use, protamine administration, and any complications or adverse reactions. Protamine was administered in 3,341/7,750 procedures (43%), including 171 in diabetics receiving NPH insulin. Adverse reactions to protamine occurred in 2/3, 170 noninsulin patients, 0.06%, and adverse reactions due to probable NPH insulin sensitization occurred in 1/171, 0.6%, of NPH diabetics, p = .034. Meta-analysis of risk showed an odds ratio of 7.96 for the NPH diabetic patients, and combining these results with the other large series in the literature (269 NPH diabetics total) showed an odds ratio of 4.19 compared to a non-NPH insulin group. Meta-analysis of the surgical literature showed the risk in surgical patients to be 2.1% in NPH patients versus 0.12% with no NPH, with an odds ratio of 15.52. The greater incidence in surgical patients may be due to protamine sensitization at prior catheterization and to the larger dose of protamine administered to surgical patients.

Topics: Anaphylaxis; Cardiac Catheterization; Cardiac Surgical Procedures; Diabetes Mellitus, Type 1; Humans; Immunization; Incidence; Insulin, Isophane; Insulin, Long-Acting; Meta-Analysis as Topic; Odds Ratio; Protamines; Risk Factors

Despite the occurrence of a severe allergic reaction including an anaphylactic shock, a drug may remain essential and impossible to replace. This may be the case of insulin in a diabetic patient. We describe the case of an anaphylactic shock to human insulin in whom a desensitization protocol was successfully achieved.. A 50-year-old type 2 diabetic man presented one year after initiation of the insulin therapy an anaphylactic shock following the subcutaneous administration of a human insulin containing protamine (Insulatard®). A desensitization protocol to human insulin was performed and allowed to use two human insulin analogues containing no protamine (asparte and glargine), with a two-year event-free follow-up. Positive skin tests with insulin and protamine, and the presence of insulin specific IgE were evidenced of an IgE-mediated mechanism. Desensitization was monitored by skin tests, Maunsell's test, measurement of specific IgE and IgG4, and the basophil activation test. The decrease of basophil sensitivity to insulin is an early marker for tolerance induction.. The effectiveness of the desensitization to human insulin underlines the importance to define the modalities of such desensitization protocol and of the monitoring of the tolerance induction.

Topics: Anaphylaxis; Basophil Degranulation Test; Basophils; Biomarkers; Desensitization, Immunologic; Diabetes Mellitus, Type 2; Humans; Immunoglobulin E; Immunoglobulin G; Injections, Subcutaneous; Insulin, Isophane; Insulin, Long-Acting; Insulin, Regular, Human; Intradermal Tests; Isophane Insulin, Human; Male; Middle Aged; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Skin Tests; Treatment Outcome

Allergic reaction to insulin preparations seemed to have decreased since the introduction of contaminant-free, human preparations. The role of protamine sulfate in decreasing the prevalence of allergy is unclear. This study examines the causative components of insulin allergy along with the value of skin tests for diagnosis. Eleven patients with insulin allergy and 53 patients receiving insulin but without an insulin allergy were included as controls. Intradermal skin tests were conducted using preparations containing various concentrations of insulin [Neutral protamine Hagedorn (NPH) insulin, regular insulin (RI)] and protamine sulfate. Of the 11 patients studied, 3 had anaphylaxis and 8 displayed localized reactions. All of the patients reacted positively during skin testing. Five patients showed positive intradermal skin test reactions to protamine sulfate, and 4 reacted to insulin. Two patients that were not tested with protamine sulfate reacted positively to NPH insulin. In the case of protamine sulfate, 4 patients with localized symptoms displayed positive reactions at concentrations of 10 microg/ml, 3 microg/ml or 0.3 microg/ml. One patient with anaphylaxis reacted positively to a concentration as low as 0.03 ng/ml. In the case of insulin protein, 3 patients reacted positively to a 100-fold dilution (1 UI/ml). Eight of the 53 controls experienced pruritus and/or skin lesions. However, none of the controls reacted at a concentration of NPH insulin of less than 10 U/ml or to protamine sulfate at less than 30 microg/ml. Allergic reactions to protamine sulfate are common and should not be ignored. This study shows a good correlation between clinical manifestations and skin test reactions for insulin allergy.

Topics: Adult; Aged; Anaphylaxis; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Insulin; Insulin, Isophane; Intradermal Tests; Male; Middle Aged; Protamines

Administration of protamine might cause serious complications especially in patients treated preoperatively with NPH insulin.. A case report.. Administration of protamine sulphate caused fatal anaphylactic reaction to a diabetic patient undergoing femoropopliteal by-pass surgery. Care should be taken when administering protamine to a patient treated preoperatively with NPH insulin and the possibility of an anaphylactid reaction to protamine have to be kept in mind.

Topics: Anaphylaxis; Arterial Occlusive Diseases; Diabetes Mellitus, Type 1; Drug Interactions; Fatal Outcome; Femoral Artery; Heparin Antagonists; Humans; Hypoglycemic Agents; Insulin, Isophane; Intermittent Claudication; Male; Middle Aged; Postoperative Complications; Protamines

Topics: Anaphylaxis; Angioedema; Diabetes Mellitus; Drug Hypersensitivity; Female; Heparin Antagonists; Humans; Hypoglycemic Agents; Immunoglobulin E; Insulin, Isophane; Intraoperative Complications; Middle Aged; Protamines; Urticaria; Vascular Surgical Procedures

We report an insulin-treated diabetic patient who suffered, in a 2-month period, three severe anaphylactic reactions immediately after self-administered subcutaneous injections of neutral protamine Hagedorn (NPH) human recombinant-DNA insulin. These reactions consisted of local and systemic symptoms, including dyspnea and hypotension. A simultaneous sensitization to human insulin and to protamine was demonstrated, both by skin tests and by the determination of serum specific IgE. Suspecting protamine allergy, we performed a test dose to human lente insulin with perfect tolerance. After a 1-year follow-up with lente-insulin treatment, no reactions have occurred, despite treatment interruptions. Therefore, protamine IgE-mediated allergy probably caused our patient's reactions. In conclusion, protamine sensitization should be ruled out in any patient with a history of reactions to subcutaneous protamine-containing insulins, even if insulin sensitization is present.

Topics: Adult; Anaphylaxis; Diabetes Mellitus, Type 1; Drug Hypersensitivity; Humans; Hypoglycemic Agents; Immunoglobulin E; Insulin, Isophane; Insulin, Long-Acting; Male; Protamines; Skin Tests

We report the clinical and immunologic analysis of two patients with diabetes who had anaphylaxis to neutral protamine Hagedorn (NPH) human insulin in the absence of allergy to regular insulin. A 36-year-old woman without a recent history of local insulin reactions or interruption of insulin therapy experienced anaphylaxis within 15 minutes of her usual morning dose of subcutaneously administered NPH human insulin. A 62-year-old man with a history of generalized reactions to NPH human insulin and of anaphylaxis to intravenously administered protamine had generalized urticaria after injection of NPH human insulin. Both patients subsequently tolerated Lente human insulin. Skin test results in both patients were negative to regular and Lente insulin preparations but positive to NPH insulin and to protamine at concentrations tested. In vitro assays demonstrated that both patients had markedly elevated serum levels of IgE and IgG to protamine, but not to regular human insulin, and that their IgE antibodies to protamine recognized protamine antigenic determinants in NPH human insulin. We conclude that the anaphylactic reactions to NPH insulin in our patients were mediated by IgE to protamine, which should be a pathogenetic consideration in the evaluation of immediate-type reactions to protamine-containing insulins.

Topics: Adult; Anaphylaxis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin E; Immunoglobulin G; Insulin; Insulin, Isophane; Male; Middle Aged; Protamines; Radioallergosorbent Test; Skin Tests

The frequency of anaphylactoid reactions to protamine sulfate was examined by reviewing the records of diabetic patients undergoing cardiac catheterization over a 5-year period, and by prospectively monitoring diabetic patients receiving NPH insulin during the infusion of protamine sulfate. No anaphylactoid reactions were noted after protamine administration (48 +/- 5 mg) in the retrospective study in either patients with prior exposure to protamine (74 catheterizations) or in diabetics with no exposure to protamine (132 catheterizations). In the prospective study, no anaphylactoid reactions were seen in the 24 NPH insulin-dependent diabetics during the infusion of protamine sulfate (45 +/- 5 mg). Five of the 42 patients (12%) from the retrospective study who underwent vascular surgery developed severe reactions to much larger doses of protamine (380 +/- 118 mg). Diabetics with prior exposure to protamine sulfate do not appear to be at increased risk of anaphylactoid reaction after the administration of protamine sulfate in the dose range of less than 50 mg at the time of cardiac catheterization.

Topics: Anaphylaxis; Cardiac Catheterization; Diabetes Mellitus; Female; Humans; Insulin, Isophane; Male; Middle Aged; Prospective Studies; Protamines; Retrospective Studies; Risk Factors

Protamine is widely used for reversing systemic heparinization after cardiac catheterization. Although rare, major reactions to protamine that simulate anaphylaxis occasionally occur and have previously been associated only with an allergic reaction to fish. Because neutral protamine Hagedorn (NPH) insulin includes protamine, it might be anticipated that NPH insulin-dependent diabetic patients would develop sensitivity to protamine. Of 866 consecutive patients undergoing cardiac catheterization over a 20 month period, 651 received protamine for reversal of heparinization. Of these, 8.5% (56/651) were diabetics and 2.3% (15/651) were NPH insulin-dependent diabetics. During this period seven patients were observed immediately after administration of protamine to have major adverse reactions that required the administration of catecholamines. One death ensued. Of the seven major reactions, four occurred in NPH insulin-dependent diabetics and one occurred in a patient with an allergy to fish. The incidence of major protamine reactions was 27% (4/15) in the NPH insulin-dependent diabetics vs 0.5% (3/636) in those with no history of NPH insulin use (p less than .001). This represents a 50-fold increased risk of a major reaction to protamine if the patient was receiving NPH insulin. Accordingly, we recommend that diabetics on NPH insulin and patients with allergies to fish undergo cardiac catheterization without the use of protamine or, when necessary, that protamine be administered cautiously in anticipation of a major adverse reaction.

Topics: Anaphylaxis; Blood Pressure; Cardiac Catheterization; Diabetes Mellitus, Type 1; Drug Hypersensitivity; Epinephrine; Female; Humans; Injections, Intravenous; Insulin, Isophane; Male; Middle Aged; Prospective Studies; Protamines