Changes in insulin products should be made by experienced medical personnel. Changes in insulin species source (i.e., animal versus human, etc.), purity, or brand can necessitate dosage adjustments. The physiologic response resulting from the mixing of different insulins for subcutaneous administration together may differ from the response occurring when the insulins are administered separately. Treatment must be individualized. Diabetic patients must follow a regular, prescribed diet and exercise schedule to avoid either hypo- or hyperglycemia. The timing of meals and exercise with insulin doses is extremely important, and should remain consistent, unless prescribed otherwise. Fever, thyroid disease, infection, recent trauma or surgery, diarrhea secondary to malabsorption, vomiting, and certain medications can also affect insulin requirements, requiring dosage adjustments. Diabetic patients should be given a 'sick-day' plan to take appropriate action with blood glucose monitoring and insulin therapy when acute illness is present.
Hepatic disease, renal impairment, or renal failure may affect insulin dosage requirements. Some pharmacokinetic studies have shown increased circulating levels of insulin in patients with hepatic or renal failure. Insulin dosage adjustments may be needed in some patients.
Isophane insulin (NPH) is not appropriate for intravenous administration (IV). Intermediate or long-acting insulin preparations should not be used for diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), diabetic coma, or other emergencies requiring rapid onset of insulin action. Several types, routes, and frequencies of administration of insulin have been studied in patients with DKA and HHS; however, the American Diabetes Association recommends that regular insulin (versus the rapid-acting analogs) by continuous intravenous infusion be used to treat these conditions unless they are considered mild.[30430] Regular insulin is also preferred for those patients with poor tissue perfusion, shock, or cardiovascular collapse, or in patients requiring insulin for the treatment of hyperkalemia. Isophane insulin (NPH) should not be used for continuous subcutaneous insulin infusion (CSII) administration; only quick acting insulins (e.g., regular insulin, insulin lispro, insulin glulisine, and insulin aspart) should be used by this route of administration.
Hypoglycemia is the most common adverse effect of insulin therapy; hypoglycemia is the major barrier to achieving optimal glycemic control long term. Insulin is contraindicated in patients during episodes of hypoglycemia. Patients at risk for hypoglycemia are those who have brittle diabetes, have received an overdose of insulin, have a delayed or decreased food intake, or undergo an excessive amount of exercise relative to their usual insulin dose. Patients at risk for severe, iatrogenic hypoglycemia include those with insulin deficiency (i.e., type 1 diabetes mellitus and advanced type 2 diabetes mellitus), those with a history of severe hypoglycemia or hypoglycemia unawareness, and those undergoing intensive insulin therapy. Patient and family education regarding hypoglycemia management is crucial; the patient and patient's family should be instructed on how to recognize and manage the symptoms of hypoglycemia. Early warning signs of hypoglycemia may be less obvious in patients with hypoglycemia unawareness which can be due to a long history of diabetes (where deficiencies in the release or response to counterregulatory hormones exist), with autonomic neuropathy, or taking beta-blockers. Patients should be aware of the need to have a readily available source of glucose (dextrose, d-glucose) or other carbohydrate to treat hypoglycemic episodes. In patients who are currently taking an alpha-glucosidase inhibitor (i.e., acarbose or miglitol) along with their insulin, oral glucose (dextrose) should be used to treat hypoglycemia; sucrose (table sugar) is unsuitable. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Insulin injections should not be used by the family to treat those patients who are unconscious. Geriatric patients are especially at risk for hypoglycemic episodes when using insulin. The specific reasons identified include intensive insulin therapy, use of an excessive insulin dose, improper timing of insulin administration with regards to meals, injection of the wrong type of insulin, renal failure, severe liver disease, alcohol ingestion, defective counterregulatory hormone release, missing meals/fasting, and gastroparesis.[30444] Because hypoglycemic events may be difficult to recognize in some elderly patients, the initial dosing and dosing increments of any insulin product should be conservative. Severe or frequent hypoglycemia in any patient is an indication for the modification of treatment regimens, including setting higher glycemic goals.
In addition to hypoglycemia, hypokalemia may also occur as insulin facilitates the intracellular uptake of potassium. Patients at risk for hypokalemia (e.g., patients who are using potassium-lowering drugs or taking potassium concentration sensitive drugs) should be monitored closely for these effects.
Insulins are contraindicated for use in patients hypersensitive to the insulin or the excipients in the formulations. In general, beef insulin should not be used in patients with a history of bovine protein hypersensitivity unless these patients have been adequately desensitized. Beef insulin and beef-pork insulin combinations are no longer available in the US due to concerns over the transmission of bovine spongiform encephalopathy (i.e., 'mad-cow disease'). Under certain registration processes with the FDA, beef insulin may be imported by individuals from outside the US, but this approach is not recommended. Pork insulins are still available in the US currently, although because of decreased use, the manufacturers of porcine insulins are discontinuing their production in the US; supplies are expected to be exhausted by the end of 2005. Porcine insulins should not be used in patients with a history of porcine protein hypersensitivity unless these patients have been adequately desensitized. Isophane insulin (NPH) contains m-cresol and should be avoided in patients with m-cresol hypersensitivity; localized reactions and general myalgias have been reported with the use of cresol as an injectable excipient. Minor, local sensitivity characterized by redness, swelling, or itching at the site of injection does not usually contraindicate therapy. Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis. Severe cases, including anaphylactoid reactions, may be life threatening.
Most insulins (including isophane insulin, NPH) are classified in FDA pregnancy risk category B.[29532] Most experts recommend human insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with Type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes. Use caution when administering long-acting insulin products near the time of labor and/or obstetric delivery; insulin requirements may fluctuate and carbohydrate intake may be unpredictable. Fetal abnormalities in animal studies of insulin have not been reported when insulin is used at doses similar to those that would be used in humans. Optimizing glycemic control before conception and during pregnancy appears to improve fetal outcome; this should include the avoidance of episodes of hypoglycemia as the toxic effects of maternal hypoglycemia on the fetus have been well-documented. In general, insulin requirements decline during the first trimester and increase during the second and third trimesters. Careful monitoring is required throughout pregnancy and during the perinatal period. During the perinatal period, careful monitoring of neonates born to mothers with diabetes is recommended. Post-partum, maternal insulin requirements may need adjustment.
The extent of excretion of insulin into breast milk is unknown. Insulin is degraded in the gastrointestinal tract; therefore, any insulin secreted into breast milk would not be absorbed by a breast-feeding infant. The American Diabetes Association encourages breast-feeding in women with pre-existing diabetes mellitus or gestational diabetes [30434]; accordingly, women on insulin therapy should be encouraged to breast-feed if no other contraindications exist. Breast-feeding, however, may decrease insulin requirements, despite the need for increased caloric intake. Careful observation of increased maternal caloric needs and maternal blood glucose levels are needed.
Treatment of children and infants on insulin therapy requires special care. In general, special attention must be given to caloric intake, insulin dosage adjustments, and avoidance of low blood glucose concentrations. Because children < 5 years of age may not be able to identify symptoms of hypoglycemia, several pediatric textbooks recommend less stringent goals for fasting or preprandial blood glucose concentrations (100—200 mg/dL) and HbA1C (7.5—9). The majority of insulin preparations, including isophane insulin (NPH), have been studied in pediatric patients.
Monitor blood glucose concentrations for needed insulin dosage adjustments in insulin-dependent diabetic patients whenever a change in either nicotine intake or tobacco smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose or an increase the subcutaneous absorption of ins