Continuous Subcutaneous Insulin Infusion. Short-acting insulins are the only form of the hormone used in subcutaneous infusion pumps. A number of pumps are available for continuous subcutaneous insulin infusion (CSII) therapy. CSII, or pump, therapy is not suitable for all patients because it demands considerable attention. However, for patients interested in intensive insulin therapy, a pump may be an attractive alternative to several daily injections. Insulin pumps provide a constant basal infusion of insulin and have the option of different infusion rates during the day and night to help avoid the dawn phenomenon (rise in blood glucose that occurs just prior to awakening from sleep) and bolus injections that are programmed according to the size and nature of a meal.
Glucose sensors that measure the interstitial glucose are now available and may be helpful in patients with labile blood glucose and frequent hypoglycemia (Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, 2008). Although patients can use both a pump and a sensor, these devices are not yet integrated into a closed-loop system. Similar to the collected evidence with CSII, the benefits of continuous glucose monitoring have not been conclusively demonstrated, nor have clear selection criteria for appropriate patient groups been developed. However, the results from recent studies suggest that real-time glucose monitoring may lead to modest improvements in glycemic control and improved patient/family quality of life.
Pump therapy presents some unique problems. Because all the insulin used is short acting and there is a minimal amount of insulin in the subcutaneous pool at any given time, insulin deficiency and ketoacidosis may develop rapidly if therapy is interrupted accidentally. Although modern pumps have warning devices that detect changes in line pressure, mechanical problems such as pump failure, dislodgement of the needle, aggregation of insulin in the infusion line, or accidental kinking of the infusion catheter may occur. There also is a possibility of subcutaneous abscesses and cellulitis. Selection of the most appropriate patients is extremely important for success with pump therapy. Offsetting these potential problems, pump therapy is capable of producing a more physiological profile of insulin replacement during exercise (where insulin production is decreased) and therefore less hypoglycemia than do traditional subcutaneous insulin injections.
Factors That Affect Insulin Absorption. Factors that determine the rate of absorption of insulin after subcutaneous administration include the site of injection, the type of insulin, subcutaneous blood flow, smoking, regional muscular activity at the site of the injection, the volume and concentration of the injected insulin, and depth of injection (insulin has a more rapid onset of action if delivered intramuscularly rather than subcutaneously). Increased subcutaneous blood flow (brought about by massage, hot baths, or exercise) increases the rate of absorption.
Insulin usually is injected into the subcutaneous tissues of the abdomen, buttock, anterior thigh, or dorsal arm. Absorption is usually most rapid from the abdominal wall, followed by the arm, buttock, and thigh. If a patient is willing to inject into the abdomen, injections can be rotated throughout the entire area, thereby eliminating the injection site as a cause of variability in the rate of absorption. The abdomen currently is the preferred site of injection in the morning because insulin is absorbed 20-30% faster from that site than from the arm. If the patient refuses to inject into the abdominal area, it is preferable to select a consistent injection site for each component of insulin treatment (e.g., before-breakfast dose into the thigh, evening dose into the arm). Rotation of insulin injection sites traditionally has been advocated to avoid lipohypertrophy or lipoatrophy, although these conditions are infrequent with current preparations of insulin. In a small group of patients, subcutaneous degradation of insulin has been observed, and this has necessitated the injection of large amounts of insulin for adequate metabolic control.
Insulin Dosing and Regimens. In most patients, insulin-replacement therapy includes long-acting insulin (basal) and a short-acting insulin to provide postprandial needs. In a mixed population of type 1 diabetes patients, the average dose of insulin is usually 0.6-0.7 units/kg body weight per day, with a range of 0.2-1 units/kg per day. Obese patients generally and pubertal adolescents require more (~1-2 units/kg per day) because of resistance of peripheral tissues to insulin. Patients who require less insulin than 0.5 units/kg per day may have some endogenous production of insulin or may be more sensitive to the hormone because of good physical conditioning. The basal dose suppresses lipolysis, proteolysis, and hepatic glucose production; it is usually 40-50% of the total daily dose with the remainder as prandial or pre-meal insulin. The insulin dose at meal time should reflect the anticipated carbohydrate intake (many patients with type 1 diabetes calculate a ratio of the insulin dose to the number of grams of carbohydrate). A supplemental scale of short-acting insulin is added to the prandial insulin dose to allow correction of the BG. With all insulin dosing, the provider should consider the insulin sensitivity of the patient and adjust the insulin dosing accordingly. Insulin administered as a single daily dose of long-acting insulin, alone or in combination with short-acting insulin, is rarely sufficient to achieve euglycemia. More complex regimens that include multiple injections of long-acting or short-acting insulin are needed to reach this goal. In all patients, careful monitoring of therapeutic end points directs the insulin dose used. This approach is facilitated by self-glucose monitoring and measurements of A1C.
A number of commonly used dosage regimens that include mixtures of insulin given in two or more daily injections are depicted in Figure 43–8. An effective regimen involving multiple daily injections consisting of basal administration of long-acting insulin (e.g., insulin glargine or determir) either before breakfast or at bedtime and preprandial injections of a short-acting insulin (Weng et al., 2008). This method is called basal/bolus and is very similar to the pattern of insulin administration achieved with a subcutaneous infusion pump. Another regimen used is the split-mixed regimen involving the pre-breakfast and pre-supper injection of a mixture of short- and long-acting insulins. When the pre-supper NPH insulin is not sufficient to control hyperglycemia throughout the night, the evening dose may be divided into a pre-supper dose of regular insulin followed by NPH insulin at bedtime.
Individuals with diabetes may sometimes consume smaller amounts of food than originally planned. This, in the presence of a previously injected dose of insulin that was based on anticipation of a larger meal, could result in postprandial hypoglycemia. Thus, in patients who have gastroparesis or loss of appetite, injection of a short-acting analog postprandially, based on the amount of food actually consumed, may provide smoother glycemic control.
Adverse Events. The most common adverse reaction during insulin therapy is hypoglycemia. Hypoglycemia is the major risk that must be weighed against benefits of efforts to normalize glucose control. Additional information about hypoglycemia and its treatment is provided later in this chapter. Insulin is an anabolic hormone, and insulin treatment of both type 1 and type 2 diabetes is associated with modest weight gain. Paradoxically, improved glycemic control may initially lead to the deterioration of retinopathy in rare patients, but this is followed by a long-term reduction in diabetes-related complications. There has been a dramatic decrease in the incidence of allergic reactions to insulin with the transition to recombinant human insulin; these may still occur as a result of reaction to the small amounts of aggregated or denatured insulin in preparations, to minor contaminants, or because of sensitivity to one of the components added to insulin in its formulation (protamine, Zn2+, etc.). Human insulin, as delivered to patients with diabetes, is immunogenic as reflected by the observation that many patients have circulating anti-insulin antibodies, but these do not alter insulin pharmacokinetics or action. Atrophy of subcutaneous fat at the site of insulin injection (lipoatrophy) was a rare side effect of older insulin preparations. Lipohypertrophy (enlargement of subcutaneous fat depots) has been ascribed to the lipogenic action of high local concentrations of insulin.
Insulin Treatment of Ketoacidosis and Other Special Situations. Acutely ill diabetic patients may have metabolic disturbances that are sufficiently severe or labile to justify intravenous administration of insulin (Kitabchi et al., 2009). Such treatment is most appropriate in patients with ketoacidosis or severe hyperglycemia with a hyperosmolar state. Insulin infusion inhibits lipolysis and gluconeogenesis completely and produces near-maximal stimulation of glucose uptake. In most patients with diabetic ketoacidosis, blood glucose concentrations will fall by ~10% per hour; the acidosis is corrected more slowly. As treatment proceeds, it often is necessary to administer glucose along with the insulin to prevent hypoglycemia but to allow clearance of all ketones. Some physicians prefer to initiate therapy with a loading dose of insulin, but this tactic appears unnecessary because steady-state concentrations of the hormone are achieved within 30 minutes with a constant infusion. Patients with nonketotic hyperglycemic hyperosmolar state may be more sensitive to insulin than are those with ketoacidosis. Appropriate replacement of fluid and electrolytes is an integral part of the therapy in both situations because there is always a major deficit. Regardless of the insulin regimen, the key to effective therapy is careful and frequent monitoring of the patient's clinical status, glucose, and electrolytes. A frequent error in the management of such patients is the failure to administer long-acting insulin subcutaneously before the insulin infusion is discontinued.
Treatment of Diabetes in Children or Adolescents. Diabetes is one of the most common chronic diseases of childhood, and rates of type 1 diabetes in American youth are estimated at 1 in 300, with an increasing incidence over the past 20 years. One of the unfortunate corollaries of the growing rates of obesity over the past three decades is an increase in the numbers of children and adolescents with nonautoimmune, or type 2, diabetes. Current estimates are that 15-20% of new cases of pediatric diabetes may in fact be type 2 diabetes; rates vary by ethnicity, with disproportionately high rates in Native Americans, African Americans, and Latinos. Because of a paucity of clinical trials performed in children, there is only limited information on which to base decisions for appropriate therapy. Thus the results in the Diabetes Control and Complications Trial with young and middle-aged adults have been extrapolated to the pediatric population such that current practice is for more intensive, physiologically based insulin replacement with a goal of tight glucose control (Diabetes Control Complications Trial Research Group, 1993). This is achieved with combinations of basal and prandial insulin replacement. The primary limiting factor of more aggressive insulin therapy is hypoglycemia, a problem with special concerns in young children. Diabetic patients <5 years old are at greater risk for hypoglycemia, have increased rates of severe hypoglycemia with seizures and coma, and may suffer permanent cognitive dysfunction as a result of repeated episodes of low blood glucose. Older children and adolescents do not seem to have demonstrable cognitive impairment related to hypoglycemia; good glycemic control is associated with better mental function (Kodl and Seaquist, 2008).
The treatment of type 1 diabetes in children and adolescents has changed with the availability of newer technologies. The standard for insulin treatment now includes multiple dose regimens with three to five injections per day or CSII. Split/mixed regimens using NPH and regular insulin have been increasingly supplanted by regimens using insulin analogs because they offer more flexibility in dosing and meal patterns. Similarly, CSII is used with increasing frequency in the pediatric diabetic population. Moreover, recent studies show that this approach is applicable to young children as well as older children and adolescents.
Because of the nearly uniform association of type 2 diabetes with obesity in the pediatric age group, lifestyle management is the recommended first step in therapy. Goals of reducing body weight while maintaining normal linear growth, and increasing physical activity, are broadly recommended and can be effective when patients are compliant. There have been few clinical trials of glucose lowering therapy in pediatric type 2 diabetes. The only medication currently approved by the FDA specifically for medical treatment of type 2 diabetes is metformin. Metformin is approved for children as young as 10 years of age and is available in a liquid formulation (100 mg/mL). Results from clinical trials have shown that both metformin and glimepiride effectively lower blood glucose in affected patients. Insulin is the typical second line of therapy after metformin; basal insulin can be added to oral agent therapy or multiple daily injections can be used when simpler regimens are not successful. Weight gain is a more significant problem than hypoglycemia with insulin treatment in pediatric type 2 diabetes. Other diabetes medications, such as thiazolidinediones, α-glucosidase inhibitors, DPP-4 inhibitors, and exenatide, have been tried empirically in type 2 diabetic adolescents, but there is no systematically collected data on efficacy or safety of these agents in the pediatric population.
Management of Diabetes in Hospitalized Patients. Hyperglycemia is common in hospitalized patients. Depending on how hyperglycemia is defined, prevalence estimates of elevated blood glucose among inpatients with and without a prior diagnosis of diabetes range between 20% and 100% for patients treated in intensive care units (ICUs) and 30% and 83% outside the ICU. Although most of these individuals will have known diabetes, ~30% of hospitalized patients will have elevated blood glucose levels without a prior diagnosis of diabetes (Falciglia, 2007). Patients admitted to the hospital often have a number of challenges to glucose regulation in addition to those faced by diabetic outpatients (Donner and Flammer, 2008). Stress of illness has been associated with insulin resistance, possibly the result of counterregulatory hormone secretion, cytokines, and other inflammatory mediators. Food intake is often variable due to concurrent illness or preparation for diagnostic testing. Medications used in the hospital, such as glucocorticoids or dextrose-containing intravenous solutions, can exacerbate tendencies toward hyperglycemia. Finally fluid balance and tissue perfusion can affect the absorbance of subcutaneous insulin and the clearance of glucose. Therapy of hyperglycemia in hospitalized patients needs to be adjusted for these variables.
There is an emerging body of information indicating that hyperglycemia portends poor outcomes in hospitalized patients, most notably in the critically ill, and that this effect is independent of severity of illness (Finfer et al., 2009; van den Berghe et al., 2001). The mechanisms for this association have not been fully explained, and controversy persists about the optimal level of glycemia in hospitalized patients. The ADA currently suggests these blood glucose targets: 140-180 m/dL (7.8-10.0 mM) in critically ill patients and random glucose of 180 mg/dL (10 mM) or pre-meal glucose of 140 mg/dL (7.8 mM) in noncritically ill patients. Great emphasis should be placed on steps taken to minimize hypoglycemia in both settings.
Insulin is the cornerstone of treatment of hyperglycemia in hospitalized patients (Moghissi et al., 2009). For critically ill patients and those with variable blood pressure, edema, and tissue perfusion, intravenous insulin is the treatment of choice. This method of insulin administration has been firmly established in the care of critically ill patients with elevated blood glucose and provides the most flexible and precise means of treatment. A number of algorithms have been adapted to allow rapid titration with adjustments to maintain blood glucose in a target range. For patients who are more stable, subcutaneous insulin regimens using combinations of basal and prandial insulin is the standard. There is considerable evidence that reactive treatment, using sliding scale regimens, is inferior and associated with wider fluctuations in blood glucose and greater rates of both hyper- and hypoglycemia. Oral agents have a limited place in treatment of hyperglycemic patients in the hospital because of slow onset of action, insufficient potency, need for intact GI function, and side effects. In general, oral glucose-lowering medications should be discontinued on hospital admission and can be restarted at discharge.
Intravenous administration of insulin also is well suited to the treatment of diabetic patients during the perioperative period and during childbirth. There is debate, however, about the optimal route of insulin administration during surgery. Although some clinicians advocate subcutaneous insulin administration, most recommend intravenous insulin infusion. Some physicians give patients half their normal daily dose of insulin as long-acting insulin subcutaneously on the morning of an operation and then administer 5% dextrose infusions during surgery to maintain glucose concentrations. This approach provides less minute-to-minute control than is possible with intravenous regimens and also may increase the likelihood of hypoglycemia. For patients with type 1 diabetes, failure to provide some basal insulin at all times can precipitate diabetic ketoacidosis.