We will discuss some of the advances in the diagnosis, management, and treatment of early onset Type I diabetes mellitus (DM) and their implications in anesthesia.
DM is a disease characterized by disordered metabolism resulting in hyperglycemia resulting from either a deficiency of insulin production or a combination of insulin resistance with inadequate compensatory secretion (1). Before the age of 30 yr, patients are most often diagnosed with Type I DM (T1DM), which represents between 75% and 80% of all diabetics in this age group. T1DM affects genetically predisposed patients with altered Human Lymphocyte Antigen on the short arm of chromosome 6 (HLA-DR3, HLA-DR4, and HLA-DR3/DR4 phenotypes). This defect causes “insulitis,” an immune-mediated selective destruction of more than 90% of insulin secreting islet cells, characterized by the infiltration of T-lymphocytes, macrophages, and B lymphocytes but sparing the glucagon secreting alpha, somatostatin secreting delta, and pancreatic polypeptide secreting PP cells. Diabetes-associated autoantibodies, which may be distinguished at the time of diagnosis, may be undetectable years after onset. At diagnosis, patients with T1DM display the signs and symptoms of hyperglycemia, one third presenting with ketoacidosis (2). According to the American Diabetes Association (ADA), a fasting glucose level of 126 mg/dl (6.99 mmol/L or a random glucose level of > 200 mg/dl is diagnostic of DM (3). In the United States, the incidence of DM is approximately 15 per 100,000 population. Those of European descent are more susceptible to the disease.
Implications for Anesthesia
Physicians who know their patients are preparing for anesthesia should make every effort to optimize their blood glucose (BG) control. There are, of course, emergency situations when no advance management is possible but, in any case, anesthesiologists should become familiar with innovations in insulin types and delivery methods to provide the best care possible.
New Insulin Types
Insulins currently available are classified on the basis of onset of action, peak effect, and duration of action. (Table 1) Newly available insulin produced by recombinant technology, including Humulin (Eli Lilly) and Novolin (Novo Nordisk), are dispensed as short-acting, intermediate-acting, or long-acting preparations. Short-acting or regular insulin, administered IV, is a clear solution with a neutral pH and a small amount of zinc. Intermediate-acting insulin and ultralente are modified as turbid solutions with a neutral pH and contain either protamine with phosphate buffer (NPH) or vary the concentration of acetate in the buffer (ultralene and lente). Neither of these preparations can be given IV. Three analogs of human insulin are also currently in use: insulin lispro and aspart are rapid acting and glargine is long-acting when given subcutaneously. Glargine has an acid pH and cannot be mixed with other molecules or given IV. The rapid-acting analogs do not offer an advantage over regular insulin when given IV.
Insulin lispro was the first true rapidly acting insulin produced by recombinant DNA technology. In the insulin gene transfection to DNA, Escherichia coli, proline, and lysine are transposed at positions B-28 and B-29 on the C-terminus of the insulin β chain. Regular insulin, when injected subcutaneously, produces hexamers and dimers, slowing the absorption. This aggregation is diminished with lispro, so it is more rapidly absorbed and has a shorter duration of action (4). The effect peaks in 30 min to 1 h and lasts from 3 to 4 h. Thus, the critical time during which hypoglycemia may develop is 0.5 to 1.5 h after administration. When used with an external pump, insulin lispro provides better glycemic control than buffered regular insulin, less frequent hypoglycemia (5). Insulin aspart (Novolog) (5) has a single substitution of proline by aspartic acid at B-28; the kinetics are similar to lispro.
Insulin glargine is a long-acting recombinant human insulin analog. It may be compared to, and considered as, a replacement for NPH, Lente, and Ultralene. It has a longer duration of action with no pronounced peak (6,7). With once-daily use, it is similar to twice-daily human NPH insulin in tolerability and glycemic control. Results of trials have shown that insulin glargine can be used as a baseline in Type I and 2 DM in concert with other drugs, including short-acting insulin, insulin lispro, and oral hypoglycemic drugs in Type 2 patients. Glargine is not physically compatible with other insulin and therefore requires a separate injection.
New Monitoring Methods
Although home monitoring is not new, present technology allows the multiple, rapid, and accurate daily analysis that is crucial for optimum disease control. Technology allows for an almost painless collection of a blood sample. Home monitors require very small amounts of blood and yield results in seconds. BG readings help the patient to adjust his or her dose of insulin and allow the information necessary to program an insulin pump to be obtained. Home monitors use two methods to measure glucose levels: reflectance photometry, which reads the intensity of color change on a reagent strip, and an electrochemical method that uses light reflectance to detect the electrical conductance of the blood sample. The advances in monitoring are felt even more strongly in the operating room where, in times past, even a STAT BG level would be rendered useless because of the time lag between presenting the sample and getting the results. Perioperative monitors, like the i-STAT System, (Abbott Laboratories, North Chicago, IL) provide clinicians an on-site, portable, nearly instantaneous blood analysis that is reliable and accurate. When blood samples contact the sensors, glucose is measured amperometrically. The oxidation of glucose, catalyzed by the enzyme glucose oxidase, produces hydrogen peroxide. The liberated hydrogen peroxide is oxidized at an electrode to produce an electric current proportional to the glucose concentration.
Hb-A1c is a measure of the percent of hemoglobin (Hb) that has been non-enzymatically glycosylated by glucose on the β chain. A normal level is 4%–6%. The ADA recommends values of <7% to <8.5% depending on the age of the patient. Although not diagnostic, increased levels suggest existing diabetes or poor control of BG levels during the previous 1–3 months. Periodic measurements allow for the assessment of the long-range effectiveness of glucose control.
Commercially available reagent strips are used by patients if they develop symptoms of a cold, flu, vomiting, abdominal pain, polyuria, or on finding an unexpectedly high glucose level. Blood ketone testing is also available and is recommended for patients with persistent, rapid and marked fluctuations in their degree of hyperglycemia.
Methods of Medication Administration
As proven unequivocally by Diabetes Complications and Control Trial, the first objective of diabetes management is to maintain BG levels as close to normal as possible. The long-term complications of DM, such as atherosclerosis, neuropathy, nephropathy, and retinopathy, can be delayed or minimized by rigid BG control. Multiple methods of insulin administration have been suggested.
Multiple Subcutaneous Injections
Multiple subcutaneous injections involve the administration of 25% of the total dose as intermediate or long-acting insulin at bedtime with additional doses of a rapid-acting preparation before each meal (four dose regimens). Type I patients may require intermediate or long-acting insulin in the am, as well as the evening, for coverage throughout the day. They will also require rapid-acting insulin with each meal or snack. Patients adjust the dose in concert with recommendations of their provider by evaluating BG levels. Insulin is now available in multiple-dose insulin injection pens. These pens provide insulin in a variety of combinations, including lispro (Humalog), aspart (Novolog), NPH, and fixed mixtures of regular or rapid-acting analog and NPH (8–12). Pens may make multiple injection prescriptions more convenient for patients because they eliminate the need for carrying vials of insulin and syringes. The fixed mixtures are generally not used in T1DM.
It is now possible to use an external pump connected to a subcutaneous catheter to administer insulin continuously. (MiniMed, Insulin Pump (Medtronic MiniMed, Northridge, CA.) Delivery is through a specially developed 25-gauge catheter placed under the skin. The site is changed every 2–4 days to ensure adequate delivery: detachable catheters allow patients to bathe. Insulin pumps can program multiple different 24-h delivery rate patterns and are adjusted to achieve a normal or near-normal BG level. Usually rapid-acting insulin is used in these pumps and the requirement is dictated by the previous insulin regimen of the patient. There is a basal rate as well as a bolus mode for preprandial deliveries. They are programmable to give a variable basal insulin rate with the capability for boluses at appropriate times.
Implantable insulin pumps are not currently available. Mini-med pumps (in development) are disk-shaped, titanium-cased devices, and the infusion rate can be adjusted by a hand-held remote controlled programmer. They are placed subcutaneously and the catheter floats freely in the peritoneum. Refill is accomplished subcutaneously via injection. The proximal portion has a port through which the catheter can be flushed when blocked. The advantage is that the intraperitoneal insulin is completely absorbed into the portal circulation and 50% of the dose is extracted by the liver in the first pass effect. Absorption of insulin is more predictable intraperitoneally than subcutaneously. The higher portal circulation and lower systemic circulation mimics physiology and with hypoglycemia, lower systemic circulation inhibits the counter-regulatory hepatic glucose production less than would otherwise occur. The degrees of glycemic control and glycated Hb concentration achieved with peritoneal absorption are similar to those obtained with intensive subcutaneous insulin treatment but with less risk of hyperglycemia from subcutaneous catheter interruptions.
Continuous Subcutaneous Glucose Monitors
Still in development, these monitors can be used for short-term monitoring in the pediatric population. Although they are not sufficiently accurate to use for immediate insulin determination, they can identify glucose trends (8). Thus, changes in BG can be monitored very closely and changes in glucose dynamics can be detected early. These monitors document incidences of asymptomatic hypoglycemia of 30%–60%.
Inhaled insulin (Exubera™) is a method of insulin delivery currently being evaluated in clinical trials. Should the results be positive, it may become useful for interoperative administration to regulate BG.
For the patient using daily subcutaneous injections, a combination of one half the am dose of intermediate or very long-acting insulin with small doses of short-acting or rapid-acting insulin administered as needed may be used. Alternatively, or for longer procedures, a continuous IV insulin infusion of 0.05 U · kg−1 · h−1 may be administered with a maintenance glucose solution of 5% dextrose plus electrolytes to maintain target serum glucose levels. IV boluses of regular insulin for treatment of perioperative hyperglycemia can create dangerous swings of glucose levels, as regular insulin has a half-life of 4–5 min and the biologic half-life is 15–20 min, resulting in short but high levels of insulin.
Guidelines for perioperative BG management for patients on insulin pumps are listed in Figure 1. With frequent glucose determinations (hourly or more often), subcutaneous continuous insulin administration with an insulin pump is safe and provides more consistent BG levels. On arising, before surgery, the patient will have BG measured and be given clear liquids with or without sugar depending on the BG level. The basal insulin infusion continues as programmed. The pump can be used to administer subcutaneous insulin boluses if directed. The anesthesiologist should query the patient or parent who will know the amount of insulin that will decrease the BG 50 mg/dl (the correction factor, or sensitivity factor).
Regardless of the method chosen to administer insulin in the perioperative period, frequent BG monitoring is essential to guide management. Surgical stress may alter the expected BG requiring intraoperative adjustments in insulin or glucose administration to maintain the BG in the desired range. Obviously, a glucose infusion is indicated if the BG decreases to less than 80 mg/dl.
As always, it is far better for surgical patients to have somewhat higher, rather than hypoglycemic, glucose levels. Signs of low BG can be masked by anesthesia and may result in catastrophic neurologic complications. Although a mild degree of hyperglycemia can be tolerated, optimal perioperative BG levels should remain between 80 and 180 mg/dl.
Anesthesiologists can expect to see more patients using continuous subcutaneous insulin infusion pumps. Subcutaneous absorption of both insulin lispro and aspart are more rapid than regular insulin. For elective procedures, these patients most often present with well regulated glucose levels and in a relatively stable state. During emergencies, patients may not be stable before surgery, but the same guidelines for insulin, glucose, and electrolyte infusion and frequent monitoring should be followed to allow the required procedures to proceed. Unstable patients will require more intensive management and both young and very ill patients will continue to pose challenges.
Postoperative nausea and vomiting (PONV) with resultant delay in oral intake may disrupt normal patterns of insulin administration. Elective surgeries in children such as tonsillectomy, strabismus repair, and middle ear surgery are particularly likely to be associated with significant PONV. Vigorous and preemptive anti-PONV treatment should be initiated in the operating room with 5-hydroxytryptamine-3 antagonists such as ondansetron (Zofran; Glaxo/Smith/Kline, Research Triangle Park, NC) (13). Elective surgery for TIDM patients should usually be scheduled for the first case of the day. This allows the most predictable management of BG levels through knowledge of the patient's normal initial BG and development of an appropriate treatment plan.
Whether using new or old technology and drugs, the objective remains the same: maintaining a safe BG level in the diabetic patient during the perioperative period. New forms of insulin and new technology can make this task easier for the anesthesiologist with improved BG control for the patient.
1. Masharani U. Diabetes mellitus &hypoglycemia. In: Tiernet LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis &Treatment. New York: McGraw-Hill, 2004:1146–91.
2. Unger RH, Foster DW. Diabetes mellitus. In: Tiernet LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis &Treatment. New York: McGraw-Hill, 2004:1029–40.
3. Cryer PE, Polonsky KS. Glucose homeostasis and hypoglycemia. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia: WB Saunders, 1998:962–3.
4. Roper NA, Bilous RW. Resolution of lipohypertrophy following change of short-acting insulin to insulin lispro (Humalog). Diabet Med 1998;15:1063–4.
5. Lorenz RA. Modern insulin therapy for type 1 diabetes mellitus. Prim Care 1999;26:917–29.
6. Campbell RW, White JR, Levien T, Baker D. Insulin glargine. Clin Ther 2001;23:1938–57.
7. Levien TL, Baker DE, White JR Jr., Campbell RK. Insulin glargine: a new basal insulin. Ann Pharmacother 2002;36:1019–27.
8. Maniatis AK, Klingensmith GL, et al. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics 2001;107:351–6.
9. Meece JD, Campbell RK. Insulin lispro update. Diabetes Educ 2002;28:269–77.
10. Gerber RA, Cappelleri JC, Kourides IA, Gelfand RA. Treatment satisfaction with inhaled insulin in patients with type 1 diabetes: a randomized controlled trial. Diabetes Care 2001;24:1556–9.
11. Selam JL. Development of implantable insulin lumps: long is the road. Diabet Med 1988;5:724–33.
12. Chase HP, Kim LM, Owen SL, et al. Continuous subcutaneous glucose monitoring in children with type 1 diabetes. Pediatrics 2001;107:222–6.
13. Sun R, Klein KW, White PF. The effect of timing on ondansetron administration in outpatients undergoing otolaryngologic surgery. Anesth Analg 1997;84:331–6.