Endocrine disorders

Background

The endocrine condition most frequently encountered in the perioperative period in children is diabetes mellitus. Diabetes mellitus is the result of an absolute or functional deficiency of insulin production by the pancreas. In type 1 diabetes, this deficiency is caused by an autoimmune pathophysiologic process, mediated by autoantibodies, including anti-GAD (glutamic acid decarboxylase) and insulinoma-associated antibody. Insulin deficiency results in abnormalities of glucose transport and storage and abnormalities of lipid and protein synthesis. Over time, these metabolic derangements result in the vascular pathology that leads to end-stage complications of renal, cardiac, and eye disease—diseases that typically do not occur before adulthood. The anesthetic implications of type 1 diabetes in children differ from those in adults with the same disease, for whom the primary concern is the type and severity of end-organ disease. The adjusted annual incidence of type 1 diabetes in children and adolescents in the United States has increased by 1.8% per year between 2002 and 2012, and the incidence of type 2 diabetes (insulin resistance without evidence of autoimmunity) has increased by 4.8% per year in this age group ( ). These are staggering statistics, emphasizing the need for pediatric anesthesiologists to be well versed in perioperative management of this disease.

Insulin is an anabolic hormone that promotes glycogen and triglyceride storage and protein synthesis. Present in small amounts even in the fasting state, it decreases glycogenolysis, gluconeogenesis, and lipolysis, with resultant ketogenesis and protein breakdown. Its complete absence at the time of surgery puts the patient in a state of starvation during which caloric intake is greatly restricted and substrate demands (e.g., for healing) are at their highest. The risk of a catabolic state is increased by the release of stress hormones, including catecholamines, cortisol, and glucagon. Perioperative insulin administration is essential to control glucose and to promote an anabolic state, which is most conducive to proper healing and metabolic homeostasis.

Children with insulin-dependent diabetes may be treated with various types of insulin on a daily basis to maintain tight glucose control, with the aid of frequent or constant blood glucose monitoring. Currently, all Food and Drug Administration (FDA)-approved insulin preparations are produced using recombinant DNA technology with laboratory-cultivated bacteria or yeast. Animal-sourced insulin has not been produced in the United States since the manufacturers voluntarily discontinued production of beef insulin in 1998 and porcine insulin in 2006 ( ). Insulin products called insulin analogs are produced so the structure differs slightly from human insulin (by one or two amino acids) to change the onset and peak of action. Examples of analogs include lispro (Humalog), aspart (Novolog), and glulisine (Apidra). These are ultra-short-acting insulins that may be given 15 minutes before a meal or even within 20 minutes of beginning a meal. The peak and duration of action of these analogs parallel the glucose rise that results from carbohydrate ingestion.

The FDA approved glargine in 2000 for once-daily subcutaneous injection for management of type 1 and type 2 diabetes mellitus. Glargine (Lantus, Basaglar), which almost mimics an insulin pump’s basal infusion, provides a 24-hour, continuous low background level of insulin. Detemir (Levemir) is another long-acting insulin analog initially approved in 2005 and then for use in children 2 to 5 years of age in 2012. Both of these agents are used in combination with ultra-short-acting analogs to mimic endogenous insulin secretion in nondiabetics ( ). The kinetics of some insulin preparations most commonly used in children are listed in Table 46.1 .

An increasing number of children are being managed with continuous subcutaneous insulin infusion via an external insulin pump, which provides a background (basal) infusion of insulin and the ability to give boluses before meals and for correction of hyperglycemia. The newest insulin pumps incorporate feedback from continuous glucose monitoring systems (CGMSs) to adjust insulin delivery according to the patient’s blood sugar using a hybrid closed-loop system ( ). An update on the perioperative management of pediatric patients with type 1 diabetes was reported by .

Type 2 diabetes in children and adolescents may be controlled with diet and exercise, but these children also may be taking metformin (Glucophage). Metformin’s antihyperglycemic action is primarily the result of direct inhibition of mitochondrial complex I, which decreases hepatic gluconeogenesis in response to glucagon. Insulin-mediated glucose uptake by skeletal muscle may be increased by metformin as well ( ).

Preoperative optimization

Because of the effects of surgical stress on glucose homeostasis, insulin-dependent diabetic children are at risk for significant perioperative difficulties, even when their preoperative glucose control is good. Poorly controlled or noncompliant diabetic patients have additional problems, including an increased risk of perioperative hypoglycemia or hyperglycemia, osmotic diuresis with resultant hypovolemia, and altered mental status. The physician must document the child’s current insulin regimen, degree of compliance, preoperative glucose control, and risk of hypoglycemia from preoperative fasting. Much of this information can be obtained from the patient’s endocrinologist or by examination of the child’s blood glucose monitoring log. Coordination and cooperation among the patient, parents, pediatrician, endocrinologist, and anesthesiologist are essential if the goal of optimal perioperative glucose homeostasis is to be achieved.

Preoperative anesthesia evaluation for elective procedures, informed by contemporaneous endocrine assessment of adequacy of glucose control, should be completed 7 to 10 days before the scheduled date of surgery to allow adjustment of the treatment regimen or to delay the procedure if control is not optimal. The International Society for Pediatric and Adolescent Diabetes published a comprehensive review of concerns and perioperative management of pediatric diabetic patients; it features useful clinical practice guidelines, incorporating both preoperative assessment and perioperative insulin regimens ( ).

The preoperative evaluation should include a review of recent measurements of glucose levels over a period of days or weeks, because a single, isolated value does not indicate the adequacy or quality of glycemic control. A hemoglobin A _1c (HbA _1c ) level (i.e., glycosylated hemoglobin assay), although a useful index of long-term (i.e., over the preceding 2 to 3 months) glucose control ( ), is unlikely to affect the anesthetic plan and is not an essential preoperative test. With the rise of CGMSs, time in range (TIR) has become a useful and clinically meaningful metric and outcome measure. TIR has been defined as the percentage of blood glucose readings in the target range of 70 to 180 mg/dL per unit of time. The monitors are usually preset to a range of 70 to 150, and the goal is for 80% “time in range.”

Compared with HbA _1c , TIR captures all glucose levels, including hypoglycemia and hyperglycemia, over a given time frame and is more likely to reveal the impact of acute interventions and changes in diabetes management ( ).

Perioperative management

Various regimens for managing insulin therapy perioperatively have been proposed, including frequent blood sugar monitoring without altering the patient’s usual regimen and relying upon either a long-acting insulin analog or the patient’s subcutaneous infusion insulin pump to provide a basal level of insulin, intravenous (IV) insulin infusion, and the “classic” regimen (see later). Regardless of the regimen chosen, it is ideal to schedule elective surgery for the diabetic child as early as possible in the day (first case) to minimize time that the patient must fast and thus reduce the risk of hypoglycemia. The fasting interval should be the same as that recommended for nondiabetic patients: no solid food or milk for 6 hours (or 8 hours, depending on institutional practice and policy) and clear liquids permissible until 2 hours before the scheduled time of surgery ( ; ). Some institutions have relaxed their preoperative fasting guidelines and allow clear liquids up until 1 hour before the induction of anesthesia. Children with diabetes should be encouraged to continue to drink clear liquids up until the time allowed by institutional policy. If this is not possible, an IV fluid infusion should be considered (described later). As recommended in adult patients with type 2 diabetes, metformin should be stopped 48 hours before surgery, based on reports of lactic acidosis in patients who remain on the drug and are in a fasting state perioperatively. Other orally administered medications (e.g., thiazolidinediones or sulfonylureas) are rarely used in pediatric patients but may be continued through the day prior to surgery.

Although some investigators have recommended the withholding of preoperative sedation from diabetic patients to better monitor for signs of hypoglycemia, premedication is recommended in children. The use of agents such as benzodiazepines, opioids, or barbiturates does not alter glucose metabolism, and a mild rise in blood sugar (caused by the catecholamine response to anxiety) might actually occur with avoidance of these agents.

Based on blood glucose level determined on arrival to the preoperative facility and before implementation of the regimens discussed later, glucose and/or insulin should be administered according to the scheme outlined in Table 46.2 . With the proliferation of long-acting insulin analogs and subcutaneous insulin infusion pumps, perioperative insulin therapy often does not require major deviation from the patient’s usual regimen.

Long-acting insulin analogs and subcutaneous infusion insulin pumps

Patients who are maintained on a home regimen involving once- (or twice-) daily subcutaneous injections of a long-acting analog (e.g., glargine or detemir) can take their normal dose the night before and/or on the morning of surgery. Insulin pump basal infusions can be maintained at their normal rate. If morning hypoglycemia is an issue, the dose or basal rate can be reduced slightly (up to one-third of normal), but this carries the risk of hyperglycemia and ketosis that may be more problematic than mild hypoglycemia. Parents should be advised to check their child’s blood sugar upon arising that morning and correct hyperglycemia according to their usual routine, and blood sugar should be rechecked upon arrival to the hospital or surgical facility. Hypoglycemia should be treated with clear, glucose-containing fluids (e.g., apple juice, white grape juice, Pedialyte) to avoid delaying the anesthetic, because clear liquids are generally allowed up until 1 or 2 hours before the induction of anesthesia.

Increasing numbers of pediatric patients with type 1 diabetes are being managed with external insulin pumps capable of subcutaneous administration of both continuous and bolus doses of insulin. Such pumps afford excellent control, with changes in administration coordinated with eating, exercise, and stress ( ). The increasing adoption of continuous subcutaneous insulin infusion (CSII) technology is an indication of the added convenience and quality of glucose control for patients in the outpatient setting, and these benefits can be observed in the inpatient and hospital setting as well. The use of insulin pumps throughout the perioperative period, including intraoperatively, has become widely accepted as standard practice, regardless of the anticipated duration of the procedure or anesthetic ( ). The use of insulin pumps in the magnetic resonance imaging (MRI) suite or magnetoencephalography (MEG) is contraindicated, but for short studies (under 1 to 2 hours), the pump can be disconnected with little effect on blood sugars and reconnected immediately at the cessation of the study, and any hyperglycemia can be corrected at that time ( ). Most manufacturers recommend against the use of insulin pumps in the setting of ionizing radiation (e.g., x-rays, fluoroscopy, computed tomography [CT] scan), but many practitioners will use lead aprons to shield the pump in those cases ( ). In surgical cases requiring electrocautery, either bipolar cautery should be used or the grounding pad should be placed between the surgical site and the infusion set.

Despite the proliferation of pumps from multiple manufacturers, programming the delivery of a bolus for correction of hyperglycemia or suspending the basal infusion in the setting of hypoglycemia is a simple task that can be easily learned by the anesthesiologist. At the preoperative visit, basic pump information and settings should be obtained (including basal rate, correction factor, and carbohydrate sensitivity), and instructions should be provided to the parents regarding any alterations in normal regimen the night before and the morning of surgery.

Because of the rapid development and advances in technology, CGMSs and hybrid closed-loop systems (HCLSs) have not yet been studied extensively in the perioperative setting. Nevertheless, these systems likely will provide superior perioperative glucose management compared with intermittent finger sticks and/or fixed basal infusion rates, in conjunction with frequent monitoring of the CGM values and close attention to pump alarms. A caveat regarding CGMs is that they may not be accurate in the setting of profound hypotension or hypothermia. In addition, some medications may give false readings (e.g., acetaminophen) ( ; ; ).

The recommendations used at the Children’s Hospital of Philadelphia for perioperative management of patients maintained on either insulin pump or with intermittent insulin injections are provided in Boxes 46.e1 and 46.e2 .