The incidence of both type 1 and type 2 diabetes mellitus in children is increasing worldwide.¹^–⁶ The use of insulin pumps and various multicomponent insulin regimens has increased the complexity of perioperative management of children with diabetes. Anesthesiologists must carefully consider the pathophysiology of the disease, as well as each child’s specific diabetes treatment regimen, glycemic control, intended surgery, and anticipated postoperative course, when devising an appropriate perioperative management plan. Standardized algorithms for perioperative diabetes management improve care⁷^–⁹ without significantly increasing costs⁹; several guidelines and studies of perioperative management of children with diabetes are available in the literature and examples are included.¹⁰^–¹⁵

Classification and Epidemiology in Children

Type 1 and type 2 are the most common forms of diabetes.^16,¹⁷ Type 1 diabetes is characterized by absolute deficiency of insulin, which usually results from immune-mediated destruction of pancreatic beta cells.¹⁷ In contrast, type 2 diabetes results from a combination of insulin resistance and a relative deficiency of insulin.^16,¹⁷ Children with type 2 diabetes typically are overweight and frequently have a first- or second-degree relative with type 2 diabetes.¹⁶ However, the increasing prevalence of obesity in children¹⁸ has made distinction between type 1 and type 2 diabetes, at times, rather difficult. Children with phenotypic characteristics of type 2 diabetes may have pancreatic autoimmunity,¹⁹^–²¹ and approximately 35% of children with diabetes who require exogenous insulin at diagnosis are overweight or obese,^22,²³ consistent with the prevalence of childhood overweight and obesity in the general U.S. pediatric population.²⁴ Other forms of diabetes may be less commonly encountered (Table 25-1). Additional modifications to the perioperative treatment regimen may be necessary when diabetes is associated with genetic syndromes and/or other endocrinopathies, such as adrenal insufficiency (see later discussion).

TABLE 25-1 Classification of Less Common Forms of Diabetes Mellitus

Genetic Defects of Beta Cell Function

Monogenic diabetes (formerly referred to as maturity-onset diabetes of the young [MODY])

Permanent neonatal diabetes

Mitochondrial disorders

Disease of the Exocrine Pancreas

Cystic fibrosis–related diabetes

Drug-Induced Diabetes

Steroids

Chemotherapeutic agents

Genetic Syndromes

Prader-Willi syndrome

Down syndrome

Turner syndrome

Wolfram syndrome

Endocrinopathies

Autoimmune polyglandular syndrome

Cushing syndrome

Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.

Although the worldwide incidence of type 1 diabetes is quite variable,²⁵ the incidence is increasing in almost all populations throughout the world.⁴ In the United States, the SEARCH for Diabetes in Youth Study, which began in 2000, provides the most comprehensive estimates of the prevalence and incidence of type 1 and type 2 diabetes among youth less than 20 years of age in the United States.²⁶^–³⁰ Type 1 diabetes remains the most common form of diabetes observed among youth in the United States, with the greatest prevalence (2 per 1000) among non-Hispanic Caucasians.²⁹ The epidemic of obesity has also contributed to a progressive increase in the incidence and prevalence of type 2 diabetes in U.S. children.¹ In the SEARCH study, the prevalence of type 2 diabetes in 10- to 19-year-old youth ranged from 0.18 per 1000 among non-Hispanic Caucasian youth to 1.45 per 1000 among Navajo youth, and the incidence ranged from 3.7 per 100,000 per year among non-Hispanic Caucasian youth to 27.7 per 100,000 per year among Navajo youth.^29,³⁰ Increases in the incidence and prevalence of type 2 diabetes have been noted in other parts of the world.^2,^3,^5,^6,³¹^–³⁴

General Management Principles

Understanding both the pharmacokinetic and pharmacodynamic properties of different insulin preparations and antihyperglycemic medications is critical to developing an appropriate perioperative plan.

Type 1 diabetes always requires treatment with insulin. However, an increasing number of insulin preparations (Table 25-2) and delivery systems are available. The least complex insulin regimens consist of two or three insulin injections per day. They incorporate a combination of an intermediate-acting insulin (e.g., neutral protamine Hagedorn [NPH]) and/or a long-acting insulin (e.g., insulin detemir [Levemir] or insulin glargine [Lantus]) for basal coverage with a short- or rapid-acting insulin (e.g., regular, insulin aspart [NovoLog], insulin lispro [Humalog], or insulin glulisine [Apidra]) to provide prandial glycemic coverage. More intensive insulin regimens are being used with greater frequency and typically consist of insulin glargine, a long-acting insulin, which provides a relatively constant 24-hour basal concentration of circulating insulin without a pronounced peak, to simulate basal insulin secretion,³⁵ in conjunction with rapid-acting insulin administered with food. Some studies have demonstrated superior glycemic control with such regimens as compared with regimens using NPH insulin and regular insulin,³⁶ although the ideal insulin regimen for children with type 1 diabetes remains controversial.³⁷ Another long-acting insulin, insulin detemir, may also be used in intensive insulin regimens and has demonstrated more predictable glucose-reducing effects than both NPH insulin³⁸^–⁴⁰ and insulin glargine.³⁸

TABLE 25-2 Insulin Preparations Classified according to Their Pharmacokinetic Profiles^*

Many children with type 1 diabetes are managed with an insulin pump,^41,⁴² a device that administers a continuous subcutaneous infusion of insulin (typically a rapid-acting insulin, see Table 25-2) at a basal rate that is supplemented by bolus doses of insulin given with meals and snacks and to correct hyperglycemia. In appropriately selected children, pump therapy has shown superiority over injection regimens.⁴³^–⁴⁶ Standard insulin preparations are U100, meaning that there are 100 units of insulin per milliliter. However, very young patients with type 1 diabetes may require diluted insulin (e.g., U10) to achieve accurate dosing.⁴⁷ Parents of toddlers with type 1 diabetes should be specifically questioned about their use of diluted insulin.

Most children with type 2 diabetes are managed with insulin and/or oral metformin, the only oral agent approved for use in children with diabetes in the United States.⁴⁸^–⁵⁰ Metformin’s primary action is to decrease hepatic glucose production and, secondarily, to increase insulin sensitivity in peripheral tissues. Occasionally, other oral agents, including sulfonylureas, which promote insulin secretion, and thiazolidinediones, which increase insulin sensitivity in muscle and adipose tissue, are used in adolescents.^48,⁵¹ Nutritional therapy is always included in the management of children with type 2 diabetes. Studies, such as the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial,^52,⁵³ are evaluating the optimal treatment for type 2 diabetes. Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone.

New medications introduced to manage adults with diabetes may eventually become available for use in children. Incretins, including glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), are gastrointestinal hormones released after eating that stimulate insulin secretion and are necessary for normal glucose tolerance.^54,⁵⁵ GLP-1 acts through a G protein–coupled receptor to promote glucose-dependent insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, and reduction in food intake.⁵⁴ Exenatide (Byetta) is a GLP-1 receptor agonist widely used in adults with type 2 diabetes as an adjunctive therapy for those taking metformin and/or a sulfonylurea.⁵⁶ Inhibitors of dipeptidyl peptidase-IV,⁵⁷ the enzyme that degrades GLP-1, are also increasingly being used for the treatment of type 2 diabetes in adults, but have not been approved for use in children. Pramlintide acetate (Symlin) is a synthetic amylin receptor agonist that can be used as an adjunct to insulin therapy in adults with type 1 or type 2 diabetes.⁵⁸^–⁶¹ Amylin, a 37-amino acid polypeptide islet hormone cosecreted with insulin from beta islet cells,⁵⁴ has three effects: delays gastric emptying, inhibits glucagon secretion, and modulates satiety.⁵⁴

Metabolic Response to Surgery

Trauma of any kind, and surgery in particular, causes a complex neuroendocrine stress response, including suppression of insulin secretion and increased production of counter-regulatory hormones (frequently called “stress hormones” in the anesthesiology literature), particularly cortisol and catecholamines.^62,⁶³ Insulin is the primary anabolic hormone that promotes glucose uptake in muscle and adipose tissue while suppressing glucose production (glycogenolysis and gluconeogenesis) by the liver.⁶⁴ The counter-regulatory hormones, which include epinephrine, glucagon, cortisol, and growth hormone, exert the opposite effects, resulting in resistance to insulin action⁶⁵^–⁶⁷ and an increase in blood glucose concentration by: (1) stimulating glycogenolysis and gluconeogenesis in the liver, (2) increasing lipolysis and ketogenesis, and (3) inhibiting glucose uptake and utilization in muscle and fat. Glucagon, secreted by alpha cells in the pancreatic islets, suppresses insulin secretion while stimulating hepatic glycogenolysis, gluconeogenesis, and ketogenesis.^64,⁶⁵ Epinephrine, which acts via β₂– and α₂-adrenergic receptors, stimulates glucagon production, increases glycogenolysis and gluconeogenesis, stimulates lipolysis, decreases insulin secretion, and decreases glucose utilization in insulin-sensitive tissues.⁶⁴ Cortisol stimulates gluconeogenesis, proteolysis, and lipolysis, and decreases glucose utilization.^65,⁶⁸ Growth hormone augments glucose production, decreases glucose utilization, and accelerates lipolysis.⁶⁹ Pro-inflammatory cytokines may further stimulate secretion of counter-regulatory hormones and alter insulin receptor signaling.⁶⁷ These changes increase catabolism, as evidenced by increased hepatic glucose production and breakdown of protein and fat. In the diabetic patient with absolute or relative insulin deficiency, the enhanced catabolism resulting from surgical trauma can lead to marked hyperglycemia and even diabetic ketoacidosis.⁷⁰ These metabolic effects may be exacerbated by a prolonged fast before and during surgery.

Metabolic Response to Anesthesia

Although adequate analgesia is essential to minimize the neuroendocrine stress response to surgery, some anesthetics may also independently contribute to perioperative hyperglycemia.^10,⁷¹ Inhalation anesthetics, such as isoflurane, may cause hyperglycemia by inhibiting insulin secretion^72,⁷³; the hyperglycemia results from both impaired glucose uptake and increased glucose production.⁷¹ In contrast, epidural analgesia with local anesthetics prevents this hyperglycemic effect^74,⁷⁵ through an inhibitory effect on endogenous glucose production.⁷¹ Similarly, intravenous (IV) anesthesia with opioids mitigates the hyperglycemic response of surgery^71,^76,⁷⁷ through its apparent neutral effect on endogenous glucose production but decrease in glucose clearance.⁷¹ Although these differences are important to consider, the metabolic effects of anesthesia are relatively minor compared with the direct effects of surgery.¹⁰

Adverse Consequences of Hyperglycemia

Hyperglycemia can impair wound healing by hindering collagen production, which may decrease the tensile strength of the surgical wound.⁷⁸ Hyperglycemia may also have adverse effects on neutrophil function, including decreased chemotaxis, phagocytosis, and bactericidal killing.⁷⁹^–⁸² Evidence from controlled experimental studies in rabbits demonstrated that these effects may be reversed, in part, by glycemia-independent effects of insulin.⁸³ However, the overall benefits of intensive insulin therapy, including a reduction in mortality, were derived mainly from maintenance of normoglycemia, whereas glycemia-independent actions of insulin exert only minor, organ-specific effects.⁸³

Clinical studies in humans have not consistently supported the relationship between perioperative glycemic control and short-term risk of infection or morbidity.^84,⁸⁵ However, several studies in diabetic adults undergoing surgery have shown an association between postoperative hyperglycemia and infectious complications.^86,⁸⁷ A meta-analysis showed that patients in surgical intensive care units (ICUs) appear to benefit from intensive insulin therapy, whereas patients in other ICU settings do not.⁸⁸ These outcomes have contributed to confusion regarding specific glycemic targets and the means for achieving them in both critically and noncritically ill patients. A recent consensus statement⁸⁹ recommended that an insulin infusion should be used to control hyperglycemia in the majority of critically ill patients in the ICU setting, with a starting threshold of no greater than 180 mg/dL. Once IV insulin therapy has been initiated, the glucose level should be maintained between 140 and 180 mg/dL. With no prospective, randomized controlled trial data for establishing specific guidelines in noncritically ill patients treated with insulin, pre-meal glucose targets should generally be less than 140 mg/dL and random blood glucose values less than 180 mg/dL, as long as these targets can be safely achieved. To avoid hypoglycemia, one should reassess the insulin regimen if blood glucose levels decline below 100 mg/dL. Modification of the insulin regimen is necessary when blood glucose values are less than 70 mg/dL, unless the event is easily explained by other factors (such as a missed meal).⁸⁹

The single pediatric trial to date demonstrated shorter length of stay, attenuated inflammatory response, and decreased mortality in patients randomized to targeting of age-adjusted normoglycemia.⁹⁰ However, the rate of severe hypoglycemia (less than 40 mg/dL) in that study was too frequent, at 25% of the total cohort, making the implementation of this approach ill-advised without further evidence from ongoing multicenter pediatric trials. Other retrospective studies of critically ill children managed in pediatric ICUs have also demonstrated associations of hyperglycemia with morbidity and mortality.⁹¹^–⁹⁴ In the 1980s and 1990s the dogma of tight glucose control replaced an era in which the mantra of caring for diabetic surgical patients was “keep them sweet,” but in more recent years glucose control has become controversial and is unresolved, with conflicting evidence; a systematic review of the literature concluded that there are insufficient data regarding the best strategy or regimen to attain target blood glucose levels in ambulatory surgical patients with diabetes mellitus.⁹⁵ The recommended practice for subspecialties, such as cardiac, neurosurgical, and solid organ transplant surgical patients, requires still more study, and it must be highlighted that few of the published investigations and meta-analyses have focused specifically on the pediatric age group.

Preoperative Assessment

When feasible, children with diabetes should not undergo elective surgery until they are metabolically stable (Fig. 25-1, box 4); that is, there is no ketosis, serum electrolytes are normal, and the glycated hemoglobin (HbA1c) value is close to or within the ideal range for the child’s age. Although there is no consensus regarding the ideal metabolic targets for control of diabetes in children,⁹⁶ the American Diabetes Association recommends an HbA1c less than or equal to 8.5% for children younger than 6 years of age; less than 8% for children 6 to 12 years of age; and less than 7.5% for 13 years of age or older, with a more stringent target of less than 7% to be considered in this last age group, for children in whom this can be achieved without excessive hypoglycemia,⁹⁶ as well as for those with type 2 diabetes.¹⁶ The preoperative consultation to assess the adequacy of metabolic control should be scheduled at least 10 days before the procedure (see Fig. 25-1, box 3). If metabolic control is poor, surgery should be delayed if possible. Both the endocrinology and anesthesiology services should participate in this assessment. Whenever possible, surgery for children with diabetes should be scheduled as the first case in the morning so that prolonged fasting is avoided and diabetes treatment regimens may be most easily adjusted.

FIGURE 25-1 Clinical practice guideline for perioperative management of diabetes mellitus. Split-mixed insulin regimen refers to a regimen combining multiple daily injections of intermediate- or long-acting insulins (e.g., neutral protamine Hagedorn [NPH] or insulin detemir [Levemir]) and multiple injections of rapid- or short-acting insulins (regular, insulin lispro [Humalog], insulin aspart [NovoLog], or insulin glulisine [Apidra]). ECG, Electrocardiogram.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

Children who present for emergent surgery, for example, because of trauma or acute surgical conditions, require a multidisciplinary preoperative assessment with collaborative involvement of both the endocrinology and anesthesiology services. In these situations, surgery often cannot be delayed even if metabolic control is poor, as in the case of a child requiring emergent surgery who presents in diabetic ketoacidosis. This has implications for the intraoperative management of such children, as described later under “Special Surgical Situations.”

Preoperative Management

The regimen for managing diabetes before, during, and after a surgical or diagnostic procedure that requires the child to fast should aim to maintain near-normoglycemia, that is, blood glucose levels of 100 to 200 mg/dL. In this blood glucose range there will be a reduced risk of osmotic diuresis, dehydration, electrolyte imbalance, metabolic acidosis, infection, and hypoglycemia in the sedated child who may be unaware of hypoglycemia or unable to communicate with staff.⁹⁷ The child need not be admitted before the day of surgery, but rather early on the same morning as the surgery or procedure. Parents should receive explicit written instructions regarding appropriate modifications of their child’s diabetes regimen before and for the day of surgery. On admission to the hospital, metabolic control should be assessed, including a preoperative determination of glucose concentration. On the morning of surgery, no rapid- or short-acting acting insulin should be administered unless the blood glucose level exceeds 250 mg/dL. However, admission to the hospital before major surgical procedures in children¹⁰ and adults has been recommended if the metabolic status needs to be optimized preoperatively.⁶⁵ If the surgery must be delayed for any reason, frequent blood glucose monitoring is mandatory to prevent perioperative hypoglycemia or hyperglycemia.

If the blood glucose exceeds 250 mg/dL, a conservative dose of rapid-acting insulin (e.g., insulin lispro or insulin aspart) or short-acting insulin (regular) is administered to restore near-normoglycemia. This is achieved using the child’s usual sliding scale or a “correction factor.” The insulin “correction factor” is the decrease in the blood glucose concentration expected after administering 1 unit of rapid- or short-acting insulin. This can be calculated using the “1500 rule”: divide 1500 by the child’s usual total daily dose (TDD) of insulin. For example, if a child typically receives 30 units of insulin daily, this child’s “correction factor” would be 1500 ÷ 30 = 50. Therefore 1 unit of rapid- or short-acting insulin would be expected to decrease the child’s blood glucose concentration by approximately 50 mg/dL. Various correction factors have been described, including a “1500 rule” for short-acting insulin (regular) and an “1800 rule” for rapid-acting insulin, such as insulin lispro.^91,⁹⁸ For simplicity and because of insulin resistance stimulated by surgical stress, the “1500 rule” is appropriate in this setting, even with the use of a rapid-acting insulin. To then calculate an appropriate corrective dose of insulin to restore near-normoglycemia, the anesthesiologist should aim for a target blood glucose concentration of 150 mg/dL.

The “correction factor” rather than a sliding scale is used to manage a child with hyperglycemia and restore the blood glucose concentration to 150 mg/dL. For example, if the child has a correction factor of 1 unit of rapid- or short-acting insulin to reduce the blood glucose concentration by about 50 mg/dL, and the current blood glucose value is 300 mg/dL, to reduce the blood glucose concentration from 300 mg/dL to 150 mg/dL, a total dose of (300 − 150)/50 or 3 units of insulin would be required. At the start of the procedure, the “correction” dose may be administered subcutaneously (using rapid-acting insulin) or IV using short-acting (regular) insulin in those children who will be managed with an intravenous insulin infusion during the procedure. For children with type 2 diabetes who do not require insulin (but who are, by definition, insulin resistant), an insulin dose of 0.1 unit/kg of rapid-acting insulin may be administered subcutaneously to correct a blood glucose concentration greater than 250 mg/dL.

More detailed preoperative recommendations must be based on the individual child’s usual treatment regimen. For most children with diabetes undergoing minor outpatient surgical procedures, insulin can be provided perioperatively with subcutaneous injections. In adults, especially those with type 2 diabetes, this practice is commonly,⁹⁷ although not universally, preferred.⁹⁹ Others routinely recommend insulin infusions even for minor outpatient surgical procedures in children.¹⁰ Several reports suggest that better glycemic control can be achieved in the perioperative period with a continuous intravenous infusion rather than subcutaneous insulin administration.^12,^100,¹⁰¹ However, these studies were conducted before the availability of rapid-acting insulins whose rapid and reproducible effects after subcutaneous administration¹⁰² may more closely match the ability to titrate IV-administered short-acting insulin. Subcutaneous insulin lispro has been shown to be as efficacious as regular IV insulin for treatment of uncomplicated diabetic ketoacidosis in children.¹⁰³ Whatever the management strategy for the diabetes, it is most important that it is coordinated between the anesthesiology and endocrinology services, and the modifications to the child’s diabetic regimen at home needs to be communicated clearly and in a timely manner to the family.

Split-mixed insulin regimens involve two to three injections per day with a combination of NPH or insulin detemir plus a rapid- or short-acting insulin. For children who use such a regimen, 50% of the usual morning dose of NPH or the full usual dose of insulin detemir should be administered on the morning of the procedure (Fig. 25-2). For the child whose basal insulin is once-daily insulin glargine or insulin detemir, no additional insulin is given on the morning of the surgery if the child received a dose in the evening of the previous day (Fig. 25-3). However, if insulin glargine or detemir is typically administered in the morning, the full dose should be administered on the morning of the procedure to prevent ketosis.

FIGURE 25-2 Preoperative management for children with diabetes mellitus on split-mixed insulin regimens. The calculation for insulin “correction factor” is as follows:

1. Divide 1500 by child’s total daily dose (TDD).

2. If daily dose varies (i.e., use of sliding scales), use the average daily dose in the past week to determine TDD.

3. Example: if TDD = 50 units, then insulin correction factor is 1 unit insulin lispro (Humalog) to reduce blood glucose by 30 mg/dL.

NPH, Neutral protamine Hagedorn; SC, subcutaneous.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

FIGURE 25-3 Preoperative management for children with diabetes mellitus on once-daily insulin glargine (Lantus) or insulin detemir (Levemir) regimens. Note that insulin glargine and insulin detemir should not be mixed with any other insulin. SC, Subcutaneous.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

Management of the child on an insulin pump depends on the duration of the surgical procedure (Fig. 25-4). Those undergoing minor procedures expected to last less than 2 hours can continue to receive their usual basal rate via their insulin pump. However, this approach requires that the anesthesiologist is familiar and comfortable with the use of the pump in the operating room. Other protocols include transitioning patients who use an insulin pump to IV insulin infusion or subcutaneous insulin glargine.⁶⁵ For procedures longer than 2 hours, children should be transitioned to an IV insulin infusion, as described in the next section.

FIGURE 25-4 Preoperative management for children with diabetes mellitus who are using an insulin pump. SC, Subcutaneous.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

Major Surgery and Intravenous Insulin Infusions

For children who require major surgery, especially procedures anticipated to last more than 2 hours, an IV insulin infusion is the preferred perioperative diabetes management plan (Fig. 25-5). Studies in children¹² and adults⁷ have demonstrated that glycemic control is superior with infusions of IV insulin compared with subcutaneous injections. These children should receive their usual doses of insulin on the day before the procedure. On the morning of the procedure, an IV infusion of 5% dextrose in half-normal saline should be started at a maintenance rate, and an IV insulin infusion should also be provided to accommodate the dextrose infusion to maintain blood glucose in the target range of 100 to 200 mg/dL (see Fig. 25-5). The maintenance rate for IV fluids in a child depends on body size and can be calculated either based on body weight (4 mL/kg/hr for the first 10 kg body weight, 2 mL/kg/hr for 11 to 20 kg, and then 1 mL/kg/hr for each kg over 20 kg) or body surface area (1.5 L/m²/day). The insulin dose varies with the child’s pubertal status; prepubertal children are relatively more sensitive to insulin than pubertal adolescents.¹⁰⁴ In prepubertal children with type 1 diabetes, after the remission (honeymoon) period, the insulin requirement is typically 0.6 to 0.8 unit/kg/day, whereas in adolescents, the requirement is 1 to 1.5 units/kg/day.^105,¹⁰⁶ Children with type 2 diabetes may require even greater doses of insulin because of their insulin resistance. With IV insulin, a suitable initial ratio of insulin to dextrose may be estimated from the child’s usual or average total daily insulin dose (TDD) using the formula 500 ÷ TDD. For example, if the child typically receives 50 units of insulin daily, then 500 ÷ 50 = 10. Therefore, in this example, 1 unit of insulin would be administered via a “piggyback infusion” for each 10 g of dextrose contained in the maintenance IV infusion to prevent hyperglycemia. Note that a maintenance IV solution of 5% dextrose contains 10 g of dextrose in every 200 mL. Only regular insulin should be used for IV infusions.

FIGURE 25-5 Preoperative management for children with diabetes mellitus who require insulin infusions during surgery. IV, Intravenous; NS, normal saline; SC, subcutaneous.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

Special Considerations for Preoperative Management of Type 2 Diabetes

Children with type 2 diabetes may require insulin or one of several oral antihyperglycemic agents (Fig. 25-6). Metformin should be discontinued 24 hours before a procedure because of its long half-life and the risk of lactic acidosis in the presence of dehydration, hypoxemia, or poor tissue perfusion.¹⁰⁷ Other oral agents, such as sulfonylureas and thiazolidinediones, may be discontinued on the morning of the procedure. Figure 25-6 outlines additional recommendations for children with type 2 diabetes who use a split-mixed or basal-bolus insulin regimen. Adjustments for other insulin regimens or oral hypoglycemic agents in type 2 diabetes should be determined in consultation with an endocrinologist or diabetologist.

FIGURE 25-6 Preoperative management for children with type 2 diabetes who are using oral agents and/or insulin. NPH, Neutral protamine Hagedorn; SC, subcutaneous.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

Intraoperative Management

The insulin and fluid regimen during and after surgery depends on the duration of the procedure. If the procedure is likely to be brief (e.g., ≤1 hour) and one can reasonably anticipate that the child will be able to drink soon after the procedure, it may not be necessary to start a glucose-containing IV infusion. If the duration of fasting is likely to be more prolonged, an IV infusion should be started at a maintenance rate as described earlier (Fig. 25-7). Intraoperative maintenance fluid should then be replaced with a comparable glucose-containing solution. Replacement of insensible losses and intravascular volume owing to blood or other body fluid losses should be with an appropriate isotonic solution (e.g., lactated Ringer’s solution or normal saline).

FIGURE 25-7 Intraoperative management of children with diabetes mellitus. The management goal for the child with diabetes is near-normoglycemia (100-200 mg/dL). Maintenance fluid rate calculation is 4 mL/kg/hr for the first 10 kg of body weight, 2 mL/kg/hr for body weight between 11 and 20 kg, and 1 mL/kg/hr for every kg of body weight over 20 kg. IV, Intravenous; NS, normal saline; SC, subcutaneous; UA, urinanalysis.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

Although some protocols include potassium chloride in the maintenance IV fluid solution,^10,^65,⁹⁷ this practice should generally be avoided because of the danger of inadvertent intraoperative administration of large quantities of potassium during fluid resuscitation. Children undergoing a brief procedure with a baseline normal serum potassium concentration and well-controlled diabetes have a small risk of hypokalemia. Those undergoing more prolonged surgeries or emergent surgeries during which metabolic decompensation is more likely, require intraoperative assessment of electrolytes and appropriate adjustment of the electrolyte composition of their IV solution. In all cases, blood glucose concentrations should be measured hourly and either insulin or dextrose adjusted, as necessary, to maintain blood glucose in the target range of 100 to 200 mg/dL. If the blood glucose exceeds 250 mg/dL, urine or blood ketones should also be measured (see Fig. 25-7). Either an increase in the rate of continuous insulin infusion or subcutaneous administration of a rapid-acting insulin analog is used to correct intraoperative hyperglycemia. Intraoperative IV bolus of regular insulin is not recommended because this causes a rapid supraphysiologic increase in serum insulin concentration, which, owing to insulin’s short half-life (approximately 5 minutes), will have a short-lived effect on blood glucose levels. In contrast, subcutaneously administered rapid-acting insulin analogs have a typical and reproducible pharmacologic profile.

Postoperative Management

As soon as the child is able to resume drinking and eating normally, the usual diabetes regimen, including insulin and/or oral agents, may be reinstituted and the dextrose infusion discontinued, if applicable (Fig. 25-8). One exception to this approach is for children with type 2 diabetes who take metformin; metformin should be held for 48 hours and renal function must be within normal limits before its resumption. For children who are unable to eat or drink, IV dextrose and electrolyte solution should be continued until oral intake is restored. An infusion of IV short-acting insulin (regular) or intermittent subcutaneous rapid-acting insulin should be administered, not more than every 3 hours, to maintain blood glucose in the target range of 100 to 200 mg/dL. Frequent blood glucose monitoring and monitoring blood or urine ketones is essential because of the variable effects of surgical trauma, inactivity, pain, anxiety, nausea and/or vomiting with poor oral intake, medications, and postoperative infection. At the time of discharge from the hospital, children and their parents or care providers should be given appropriate guidelines regarding these issues. Those who are admitted to the hospital overnight after surgery should be managed in consultation with the endocrinology service, if possible, to coordinate appropriate scheduling and subsequent dosing of insulin.

FIGURE 25-8 Postoperative management of children with diabetes mellitus. IV, Intravenous; PO, postoperative; SC, subcutaneous.

(Modified from Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg 2005;101:986-99.)

Special Surgical Situations

Children with diabetes who need urgent surgery must have a full clinical and biochemical assessment. Frequently, the problem necessitating surgery may have led to metabolic decompensation that must first be corrected and stabilized, unless the need for surgery is immediate. These children are often dehydrated; in addition to administering insulin, rehydration and electrolyte replacement is critical to address their metabolic derangements and restore normal glomerular filtration rate and renal function. In most cases, these children require emergent surgery that should be managed with an IV infusion of insulin as described earlier (see Fig. 25-5). Children with diabetic ketoacidosis require close collaboration between the anesthesiology and endocrinology services.

Diabetes Insipidus

Children undergoing neurosurgical procedures for tumors in or near the pituitary gland, especially craniopharyngioma, often require management of diabetes insipidus (DI), as do children with known DI who require anesthesia for surgical or radiologic procedures. The perioperative management of these children is frequently complicated by either overhydration or underhydration and electrolyte disturbances.

DI is caused by a deficiency of the antidiuretic hormone arginine vasopressin, which acts on the distal tubule and collecting duct of the kidney to promote reabsorption of water. Central (hypothalamic, neurogenic, or vasopressin-sensitive) DI can be caused by disorders of vasopressin gene structure; accidental or surgical trauma to vasopressin neurons; congenital anatomic hypothalamic or pituitary defects; neoplasms; infiltrative, autoimmune, and infectious diseases affecting vasopressin neurons or fiber tracts; and increased metabolism of vasopressin. The etiology is unknown in approximately 50% of children with central DI.

Diagnosis of Neurosurgical Diabetes Insipidus: The Triple-Phase Response

It is important to distinguish polyuria caused by the onset of acute postsurgical central DI from polyuria resulting from diuresis of fluids given during surgery. In both cases, children may have a large volume (exceeding 200 mL/m²/hr) of dilute urine. Serum osmolality will be increased in DI but will be normal in the child excreting excess salt and water. The normal child who excretes excess salt and water has a markedly increased urine osmolality. A meticulous examination of the intraoperative and postoperative records and careful bedside assessment of volume status (jugular venous distention, capillary refill) will help to distinguish between these two entities.

Of special interest is the triphasic pattern of vasopressin secretion, often, but not always, observed after neurosurgical procedures that interfere with the supraoptic-hypophyseal tract.¹⁰⁸ After surgery, an initial phase of transient DI may be observed, lasting between 12 hours and 2 days. This may be explained by local edema that interferes with normal vasopressin secretion. If significant vasopressin-secreting cell damage has occurred, release of stored vasopressin from damaged neurons leads to a second phase that involves water retention. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may last up to 10 days. Finally, a third phase, permanent neurogenic DI, may follow if more than 90% of vasopressin cells are destroyed. Pronounced SIADH in the second phase generally portends permanent DI in the final phase of the triple response. In children with vasopressin and cortisol deficiency (e.g., in combined anterior and posterior hypopituitarism after neurosurgical treatment of craniopharyngioma), symptoms of DI may be masked because cortisol deficiency impairs renal free water clearance. Institution of glucocorticoid therapy may precipitate polyuria, leading to the diagnosis of DI (Fig. 25-9).

FIGURE 25-9 Perioperative management of diabetes insipidus.

Perioperative Management of Minor Procedures

Children with preexisting DI who are scheduled for a minor procedure, i.e., a procedure without significant blood loss and not followed by a period of further fasting or fluid shifts (e.g., myringotomy, radiologic imaging, peripheral orthopedic procedures) are treated differently from those undergoing a more major procedure associated with blood loss or fluid shifts and delayed postoperative resumption of fluid intake (see Fig. 25-9).

Children undergoing minor procedures under anesthesia should receive their usual morning dose of desmopressin (DDAVP) (Table 25-3). The anesthetic technique is tailored to the procedure (e.g., IV sedation for MRI, general endotracheal anesthesia for tonsillectomy). Arterial and urinary catheters are not required, and recovery takes place in the postanesthesia care unit (PACU). Once the morning dose of desmopressin has been administered, intraoperative and postoperative fluids should be restricted to the rate of 1 L/m²/24 hours, i.e., to match insensible free water losses and obligatory urine output. Oral fluids may be offered once the child is awake. Although modern PACU policies often no longer require successful fluid intake before discharging the ambulatory patient, discharging the child with DI should be delayed until the child is able to freely take oral fluids without vomiting. Subsequent doses of desmopressin should be administered according to the child’s usual preoperative schedule.

TABLE 25-3 Medications for Management of Central Diabetes Insipidus

Desmopressin acetate (100-, 200-µg tablets; nasal tube 10 µg/0.1 mL; nasal spray 10 µg/0.1 mL: delivers 0.1 mL/spray)
Oral	Dose: 100-400 µg q12h
	Oral doses are 10-20 times intranasal doses of desmopressin
	Onset of action: ~15-30 minutes
	Duration: 8-12 hours
	May develop tachyphylaxis
Intranasal	Dose: ~10-20 µg/dose q12-24h
	Onset of action: 5-15 minutes
	Duration: 8-12 hours
Vasopressin (Pitressin) (20 units/mL; 0.5-mL, 1-mL, and 10-mL vials; conversion: 1 unit = 2.5 µg)
Intravenous	Dose: 1.5 milliunits/kg/hr
	Onset of action: minutes
	Half life: 5-10 minutes

Perioperative Management of Major Procedures

A major surgical procedure is defined as an operation associated with the potential for significant blood loss; intraoperative or postoperative hemodynamic, neurologic, or respiratory instability; entry into a body cavity (e.g., craniotomy, abdominal surgery, thoracic surgery); craniofacial or airway surgery; major orthopedic surgery (e.g., spine surgery, tumor resection or amputation, major osteotomies); and/or surgery followed by delayed resumption of unrestricted fluid intake. The child with DI should be scheduled as the first case of the day. On the day before the procedure, the child treated with desmopressin should receive the usual morning dose, but only 50% of the usual evening or bedtime dose (see Fig. 25-9). On the morning of the procedure, desmopressin is withheld. The child undergoing a major procedure should receive general anesthesia with conventional monitoring, as well as insertion of arterial and urinary catheters, and after surgery is admitted to the ICU. A central venous catheter for monitoring central venous pressure, although not indicated solely for the management of DI, is useful in the postoperative period.

At the start of the procedure, an infusion of aqueous vasopressin (20 units/1000 mL to yield a final concentration of 20 milliunits/mL) should be started at 1.5 milliunits/kg/hr (0.0015 unit/kg/hr). IV fluids, using normal saline with 5% dextrose, should total 1 L/m²/24 hours to approximate insensible losses and obligate urine output. Additional IV saline, isotonic fluid, or blood products may be given, as needed, to correct blood and surgical fluid loss, to correct third space fluid loss, and to maintain hemodynamic stability. Urine output should not routinely be replaced in the child receiving a vasopressin infusion.

New Perioperative Diagnosis

The new diagnosis of intraoperative or postoperative DI is based on clinical and laboratory findings, including serum sodium level greater than 145 mmol/L, polyuria (greater than 4 mL/kg/hr) for 30 minutes or more, increased plasma osmolality (greater than 300 mOsm/kg) in association with hypotonic urine (less than 300 mOsm/kg), and after excluding the presence of glycosuria and diuretic or mannitol administration as possible causes of polyuria.

When DI occurs, an infusion of aqueous vasopressin (20 units/1000 mL) is initiated at 1.5 milliunits/kg/hr (0.0015 unit/kg/hr) and the dose is doubled after 15 to 30 minutes if the child does not respond, until urine output decreases to less than 2 mL/kg/hr. Once a urine output of less than 2 mL/kg/hr is achieved, the vasopressin infusion is maintained at a constant rate.

IV desmopressin should not be used in the acute management of postoperative central DI because it offers no advantage over aqueous vasopressin and because its long half-life (8 to 12 hours) compared with that of vasopressin (5 to 10 minutes) increases the risk of water intoxication and precludes dose titration.

Postoperative Management

The child with DI should be cared for in an ICU after major surgery. Fluid input and output, serum electrolytes and osmolality are monitored closely (hourly if necessary) in the intraoperative and postoperative periods. Until stability is achieved, it is important to have a urinary catheter in place to distinguish postoperative urinary retention from oliguria. The vasopressin infusion initiated intraoperatively is continued in the ICU. Fluid administration is not adjusted according to urine output; however, fluid deficits are replaced and blood pressure supported until antidiuresis (urine output of less than 2 mL/kg/hr) is clearly established. Total (oral and IV) maintenance fluids should not exceed insensible plus obligatory urinary losses of 1 L/m²/24 hours. In the postoperative period, appropriate maintenance fluid is generally 5% dextrose in half-normal saline with 0 to 40 mEq/L of potassium chloride (depending on the serum potassium concentration). Blood loss should be replaced with normal saline, 5% albumin, or blood products, as appropriate.

Aqueous vasopressin at a dose of 1.5 milliunits/kg/hr results in a supranormal blood vasopressin concentration of approximately 10 pg/mL, twice that needed for full antidiuretic activity.¹⁰⁹ The effect of vasopressin is maximal within 2 hours after starting an infusion.¹⁰⁹

After hypothalamic, but not trans-sphenoidal surgery, greater initial concentrations of vasopressin are occasionally required to treat acute DI. This may be attributed to the release of a substance related to vasopressin from the damaged hypothalamo-neurohypophyseal system, which acts as an antagonist to normal vasopressin activity.¹¹⁰ Much greater rates of vasopressin infusions, resulting in plasma concentrations greater than 1000 pg/mL, should be avoided because they may cause cutaneous necrosis,¹¹¹ rhabdomyolysis,^111,¹¹² and cardiac rhythm disturbances.¹¹²

Post–intensive Care Unit Management

Children treated with vasopressin for postneurosurgical DI should be switched from IV to oral fluid intake at the earliest opportunity. With an intact thirst mechanism and access to free water, the patient will better regulate blood osmolality. Once oral intake has been resumed without nausea and vomiting (often by the morning of the day after surgery), the vasopressin infusion should be stopped; all IV infusions should be stopped to avoid iatrogenic fluid overload, and oral fluids are permitted freely. Desmopressin is reinstituted (nasally or orally) in the child with preexisting DI or begun in the child who has new-onset DI (see Table 25-3).

Syndrome of Inappropriate Antidiuretic Hormone Secretion

SIADH is characterized by hypotonic hyponatremia, urine osmolality in excess of plasma osmolality, natriuresis in the absence of edema and volume depletion, and normal renal and adrenal function.¹¹³ The dilutional hyponatremia of SIADH develops because of persistent detectable or increased plasma arginine vasopressin (AVP; also known as antidiuretic hormone [ADH]) concentrations in the presence of continued fluid intake. Chronic hyponatremia, however, is the result of a combination of water retention and sodium excretion.¹¹⁴ The major causes of SIADH are neurologic diseases, neoplasia, lung diseases, and medications (Table 25-4).¹¹⁵ Inappropriate infusion of hypotonic fluids in the postoperative period is among the most common causes.¹¹⁶ The clinical manifestations are principally neuromuscular (headache, nausea, vomiting, muscle cramps, lethargy, restlessness, disorientation, and depressed reflexes). The severity of symptoms is related to both the absolute serum sodium concentration (most patients with serum sodium greater than 125 mEq/L are asymptomatic) and its rate of decrease, especially if greater than 0.5 mEq/L/hr.

TABLE 25-4 Causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Central Nervous System Disturbances

Head injury

Brain tumor

Subarachnoid hemorrhage

Stroke

Infection (meningitis, encephalitis)

Acute psychosis

Drugs

Major Surgery

Major abdominal or thoracic surgery

Pituitary surgery

Pain

Severe nausea

Pulmonary Disease

Pneumonia, tuberculosis

Asthma

Atelectasis

Pneumothorax

Positive-pressure ventilation

Neoplasia

Carcinoma of lung (e.g., small cell carcinoma)

Infection

Human immunodeficiency virus

Hereditary SIADH

Functional mutations in the gene for vasopressin-2 receptor

Although ADH secretion impairs water excretion, the mechanisms that regulate volume (renin-angiotensin-aldosterone system and atrial natriuretic peptide) are intact. Volume expansion activates natriuretic mechanisms (decreased proximal sodium reabsorption and decreased aldosterone production), resulting in sodium and water excretion and the restoration of near-euvolemia. With chronic SIADH, sodium loss is a more prominent feature than is water retention. Severe hyponatremia increases cell size because of entry of water into the cell along its osmotic gradient, and may be associated with loss of intracellular potassium and other solutes in an attempt to restore cell volume.

Perioperative Management

Many of the causes of SIADH are transient and resolve as the underlying condition is corrected. Treatment of chronic SIADH consists of water restriction; that is, fluid intake is restricted to less than or equal to 1 L/m²/24 hours. Unless sodium intake is adequate, water restriction can lead to volume depletion in children with a sodium deficit. In asymptomatic chronic (more than 3 days) dilutional hyponatremia and in chronic SIADH, specific therapy may not be required.

Hypertonic (3%) saline should be used with caution in children. Rapid correction of chronic hyponatremia can lead to serious, permanent, and even fatal neurologic complications from osmotic demyelination (central pontine myelinolysis).¹¹⁷ Only children with neurologic symptoms (e.g., altered level of consciousness, coma, or seizures) attributable to acute hyponatremia of less than 3 days’ duration require rapid initial correction of the sodium deficit (use 3% hypertonic saline to deliver 5 mEq/kg per hour). The rate of increase of serum sodium concentration in states of chronic hyponatremia should not exceed 0.5 mEq/L/hr (or 8 to 10 mEq/L/24 hours).^118,¹¹⁹ The saline infusion should stop when the absolute concentration of serum sodium reaches 120 to 125 mEq/L. Hypertonic saline is usually combined with furosemide to limit treatment-induced expansion of the extracellular fluid volume.¹¹⁹ Thereafter, treatment should consist of fluid restriction.

Thyroid Disorders

Thyroid hormones play an important role in metabolic processes, growth, and development in children.¹²⁰ The thyroid gland develops from the embryonic pharyngeal floor and descends along the thyroglossal duct to its final position in the anterior neck. Thyroid hormone production is controlled by the hypothalamic-pituitary-thyroid axis. Two principal thyroid hormones are produced. Although thyroxine (T₄) is the predominant circulating thyroid hormone, triiodothyronine (T₃), primarily formed by peripheral conversion from T₄ by a family of deiodinases, is the major physiologically active thyroid hormone. Serum T₃ and T₄ concentrations in turn regulate hypothalamic thyrotropin-releasing hormone (TRH) and pituitary thyroid stimulating hormone (TSH) secretion via negative feedback. Thyroid hormones are transported in the blood by carrier proteins, including thyroxine-binding globulin (TBG), prealbumin, and albumin. Protein-bound T₄ and T₃ are not biologically active. Only 0.03% of circulating T₄ and 0.3% of T₃ are unbound and active.^121,¹²²

Hypothyroidism

Classification and Epidemiology

Hypothyroidism, the most common thyroid disorder in children, can range from subclinical to overt disease. In subclinical hypothyroidism, children maintain a normal T₄ level by increasing TSH release. Over time, however, thyroid function can decompensate despite increased TSH stimulation and progress to overt thyroid hormone deficiency.¹²³^–¹²⁵ Iodine deficiency continues to be the foremost cause of hypothyroidism worldwide.¹²⁶ However, in the United States and other regions in which the intake of iodine is adequate, autoimmune thyroid disease is the most common cause of hypothyroidism.¹²⁴ Other less frequent causes of hypothyroidism include secondary and tertiary processes resulting from pituitary or hypothalamic insufficiency, respectively, which are relevant in many surgical situations, especially tumors of the central nervous system (CNS).

Biochemical Tests of Thyroid Function

In general, measurement of serum TSH and either total T₄ or free T₄ suffices for assessment of thyroid function. However, several conditions exist in which thyroid hormone levels appear abnormal yet the individual is clinically euthyroid. These conditions may lead to erroneous diagnosis and inappropriate treatment for hypothyroidism or hyperthyroidism. TSH is the most sensitive test for diagnosing primary thyroid disorders and generally precedes noticeable changes in total T₄ and T₃ levels. Thyroid function can also be assessed by measurement of unbound or free T₄. When the total T₄ level is reduced but free T₄ and TSH values are normal, TBG deficiency is the most likely diagnosis. No treatment is required for TBG deficiency because these individuals have normal concentrations of free T4 and are euthyroid. Likewise, medical intervention is unnecessary for familial dysalbuminemic hyperthyroxinemia, which manifests with increased total T₄ levels but normal free T₄ and TSH values.¹²⁷

Importantly, if the hypothalamic-pituitary axis is not intact, TSH becomes a useless measurement of thyroid function. Therefore, in cases of secondary or tertiary (central) thyroid disorders, diagnosis and treatment is based solely on serum T₄ levels and clinical signs. During times of stress or acute illness, increased conversion of T₃ to a metabolically inactive form (reverse T₃) occurs. In addition, T₄ and TSH values may both be reduced, reflecting a decreased metabolic state. Individuals are considered euthyroid based on non-elevated TSH values but the differential diagnosis includes central hypothyroidism, a distinction that often cannot be made by laboratory evaluation. Controversy still exists regarding possible benefits of using T₄ or T₃ to treat euthyroid sick syndrome, in which there are abnormal thyroid tests in the setting of a nonthyroid illness, such as a critical illness. Typically, children with euthyroid sick syndrome have a reduced T₄ level with a normal or low-normal TSH level, indicating a decreased metabolic state.¹²⁸^–¹³¹

Clinical Manifestations

Because thyroid hormone affects all metabolically active cells, hormone deficiency leads to a wide array of systemic abnormalities. Classic signs and symptoms of hypothyroidism in children include short stature resulting from a decline in growth rate, fatigue, cold intolerance, weight gain, dry skin, hair loss, constipation, hoarse voice, and coarse facial features. Myxedema coma is a severe manifestation of hypothyroidism that can occur in profoundly hypothyroid individuals exposed to an external stress, such as infection, surgery, hypnotics, or cold temperature. Myxedema coma can result in severe life-threatening heart failure or coma ^132,¹³³ and should be considered in any postoperative child with unexplained cardiovascular dysfunction, difficulty weaning from ventilator support, or delirium.⁹⁷ Other medical conditions associated with hypothyroidism include anemia, hyperlipidemia, and pubertal disorders.

Neonatal Hypothyroidism

Congenital hypothyroidism remains the most frequent cause of preventable mental developmental delay. Thyroid dysgenesis or agenesis accounts for the majority of cases, whereas a smaller percentage results from thyroid dyshormonogenesis and secondary or tertiary hypothyroidism.¹³⁴ Because neonates do not exhibit the classic signs or symptoms of hypothyroidism, testing for congenital hypothyroidism occurs with the neonatal screen. Newborn screening programs that employ a strategy based on TSH thresholds detect only primary thyroid deficiency and not the central hypothyroidism that accompanies hypopituitarism or CNS anomalies, such as septo-optic dysplasia. Early detection and implementation of thyroid replacement are essential to avoid permanent neurologic sequelae. The classic syndrome includes macroglossia, umbilical hernia, constipation, hypothermia, a low hoarse cry, and neonatal jaundice (Fig. 25-10). In general, affected children who receive adequate thyroid replacement starting early in the neonatal period lead normal lives.

FIGURE 25-10 An infant with congenital hypothyroidism.

(“Congenital hypothyroidism,” Wikipedia: The Free Encyclopedia. Wikimedia Foundation, Inc. 24 Feb 2012, as of 31 Mar. 2012. http://en.wikipedia.org/wiki/Congenital_hypothyroidism.)

Treatment

The goal of thyroid replacement is to normalize T₄ within 1-2 weeks and TSH within 4 weeks, and consequently reverse the metabolic derangements caused by hypothyroidism. In general, daily levothyroxine (LT₄) replacement leads to normalization in T₄ levels within a week but equilibration of TSH occurs more slowly, over 4 to 6 weeks.¹³⁵ The appropriate starting LT₄ dose varies with age and disease state. For neonates, the starting dose is 10 to 15 µg/kg/day, which is much greater than the conventional replacement dose of 2 to 4 µg/kg/day in older children and adolescents.¹³⁶ In healthy children with acute hypothyroidism (e.g., post thyroidectomy), full LT₄ replacement can be started immediately. However, symptomatic children with chronic hypothyroidism may develop pseudotumor cerebri or slipped capital femoral epiphysis if they are started on full LT₄ doses. Therefore treatment should begin at one-fourth of the expected dose, with slow titration every 4 to 6 weeks.^137,¹³⁸ After dose stabilization, children and adolescents should continue to have regular clinical examinations and TSH monitoring owing to increased dose requirements during puberty and pregnancy.^139,¹⁴⁰ Thyroid replacement can be given parenterally if needed. The IV dose of LT₄ is approximately half of the oral dose and should be given once daily.

Preoperative Management

Because thyroid hormones play a critical role in regulating metabolism, children should be clinically and biochemically euthyroid before any type of elective surgery. Several case studies have shown decreased cardiac function, diminished breathing capacity, and increased sensitivity to anesthetic agents with moderate to severe hypothyroidism.¹⁴¹^–¹⁴³ Children with known hypothyroidism should have documented normal thyroid function tests before surgery. For those with undiagnosed hypothyroidism, a detailed history should be obtained regarding previous thyroid disorders, head and neck radiation, radioiodine therapy, thyroid surgery, and family history of thyroid disease.¹⁴⁴ In addition, children with autoimmune disorders, type 1 diabetes mellitus, celiac disease, and children with genetic syndromes such as trisomy 21 and Turner syndrome are at increased risk for developing autoimmune thyroiditis and should be screened if symptomatic.¹⁴⁵^–¹⁴⁷

Children with subclinical or mild hypothyroidism often must undergo urgent surgery without delay. Thyroid replacement can be started and continued with the same regimen as described in the outpatient setting. For children with moderate to severe hypothyroidism, however, surgery should be postponed, if possible, until thyroid hormone levels normalize on replacement therapy. However, if urgent surgery is required, perioperative treatment with IV LT₄ with or without glucocorticoids should be given to prevent myxedema coma.^97,¹⁴⁴ An exception to this strategy applies to the child who is scheduled for cardiovascular surgery or cardiac catheterization in which thyroid replacement could precipitate or worsen unstable coronary syndromes. Several studies in adults reported no adverse outcomes in cardiac patients undergoing surgery without thyroid replacement.^97,^144,¹⁴⁸ Therefore thyroid replacement could be initiated postoperatively in children with cardiovascular disease undergoing cardiac surgery or cardiac evaluation.

Hyperthyroidism

(With permission of author and publisher, HealthInfoTimes, Symptoms of Graves disease, 14 Feb 2012, http://healthinfotimes.com/symptoms-of-graves-disease-in-children-14945.html.)

Treatment

Antithyroid medications remain the first line of treatment for many physicians, because one-third of children enter remission after several years of drug therapy.^155,¹⁶⁵ Long-term remission rates are greater in pubertal than prepubertal children. Other favorable prognostic indicators include a small thyroid gland and normal levels of TSH receptor antibodies at the time of diagnosis.^166,¹⁶⁷ Methimazole (a thioamide) is the mainstay of antithyroid therapy. Minor adverse effects occur in 25% of children treated with thioamides and include increases in liver enzymes, neutropenia, rash, and lymphadenopathy. Serious adverse effects, such as agranulocytosis and liver failure, are rare, occurring in up to 1% of individuals.¹⁶⁸

Perioperative Management

For children who relapse after antithyroid drug therapy or who require immediate definitive therapy, radioiodine is a safe and effective alternative to thyroidectomy. Treatment consists of iodine-131 uptake in the thyroid gland, which leads to cell destruction by internal radiation. Several longitudinal studies have shown that children are not at increased risk for developing thyroid cancer if appropriate ablative doses of radioiodine are used.^169,¹⁷⁰ In cases in which radioiodine is contraindicated, surgical removal of the entire thyroid gland can also cure the hyperthyroid state. Children should be euthyroid or slightly hypothyroid before surgery to avoid precipitation of thyroid storm. In addition, because of potential serious complications from neck surgery, only surgeons with expertise in performing thyroidectomies in children should perform the surgery.¹⁷¹

In special circumstances, perioperative rapid control of hyperthyroidism can be achieved by using large doses of oral iodine (Lugol solution or saturated potassium iodine), which inhibit thyroid hormone synthesis. The effect is short-lived (several days) because of eventual escape from the Wolff-Chaikoff effect (iodine inhibition of thyroid hormone release); therefore, the addition of a thioamide is necessary for long-term treatment. Rarely, untreated or undertreated hyperthyroidism can lead to thyroid storm (approximately 1 in 1,000,000 young children), a potentially lethal complication.¹⁷² Thyroid storm may be difficult to differentiate from an acute malignant hyperthermia (MH) reaction.^173,¹⁷⁴ However, in contrast to MH, thyroid storm has a varied onset (usually an insidious onset 6 to 18 hours postoperatively, although it may develop precipitously during surgery), it induces a less severe acidosis than MH, and the serum creatine phosphokinase remains unchanged. Because the serum creatine phosphokinase peaks at 12 to 18 hours after an MH reaction, it is a late sign to differentiate from MH. Interestingly, IV dantrolene will ameliorate some of the clinical manifestations of thyroid storm, including rigidity and hyperthermia.^174,¹⁷⁵ Thyroid storm usually responds to symptomatic treatment, including parenteral β-blockers, large doses of glucocorticoids (block conversion of T4 to T3 and prevent relative adrenal insufficiency), and propylthiouracil, the last intervention administered with a nasogastric tube.¹⁷³ If left untreated, the mortality rate resulting from thyroid storm is 20% to 30%.¹⁷² Several factors may precipitate thyroid storm, including surgery, infection, and stress. Because of the dramatically increased metabolic state, acute management of hyperthyroidism and targeted symptomatic treatment is essential to avoid death.^132,^150,¹⁷³ If the presentation proves difficult to distinguish from MH (both diseases may present with tachycardia, rigidity, and fever), it would be prudent to administer dantrolene 2.5 mg/kg IV in case the presumptive diagnosis of thyroid storm is incorrect.¹⁷⁵ However, if the hypermetabolic signs abate after dantrolene, one cannot conclude that the reaction was MH, as dantrolene does attenuate the hypermetabolic signs of thyroid storm.¹⁷⁴ The specific treatment for thyroid storm, however, remains a multidrug approach to (1) halt production and release of thyroid hormone, (2) prevent conversion of T₄ to T₃, (3) antagonize the peripheral (adrenergic) effects of thyroid hormone, and (4) control systemic disturbances with supportive therapy (Table 25-5).^133,^153,^168,¹⁷⁶^–¹⁷⁹

TABLE 25-5 Management of Hyperthyroid Crisis

Parathyroid and Calcium Disorders

Physiology of Calcium Homeostasis

The four parathyroid glands are usually present in pairs on the posterior aspect of the superior and inferior poles of the thyroid gland, with the inferior pair occasionally ectopic elsewhere in the neck or chest. Parathyroid hormone (PTH) is released from secretory granules in response to a decrease in serum ionized calcium; its secretion is inhibited by hyperphosphatemia, profound hypomagnesemia or hypermagnesemia, or increased 1,25-dihydroxyvitamin D (calcitriol). The calcium-sensing receptor in the parathyroid mediates PTH release and also directly regulates calcium reabsorption in the distal tubule. Inactivating mutations in the calcium-sensing receptor gene result in a greater serum calcium set point in familial hypocalciuric hypercalcemia, now a relatively common and incidental diagnosis that is benign unless homozygotic, whereas activating mutations result in autosomal dominant hypocalcemia with hypercalciuria.^180,¹⁸¹ PTH has three primary modes of increasing serum calcium: (1) calcium reabsorption in the proximal convoluted tubule, and concomitant phosphaturia in the proximal tubule; (2) upregulation of osteoclast-mediated calcium and phosphate release from bone; and (3) renal conversion of 25-hydroxyvitamin D to the active metabolite, calcitriol. In turn, calcitriol increases absorption of calcium and phosphate from the gut and has direct calcium-releasing effects on bone. Calcitonin is secreted by the thyroid C cells and has calcium-reducing properties via its own G protein–coupled receptor. It has no known physiologic role at this time.

Hypocalcemia

Neonatal Hypocalcemia

Neonatal hypocalcemia owing to prematurity and maternal diabetes is common but is typically transient. Rare causes include maternal hyperparathyroidism, excessive diuretic use or phosphate load, and transient neonatal hypoparathyroidism.¹⁸² Neonatal hypocalcemia requires exclusion of 22q11.2 deletion syndrome (which includes DiGeorge syndrome, velocardiofacial syndrome [VCF], and other clinical manifestations) by genetic testing.¹⁸³^–¹⁸⁵ The hypocalcemia of VCF results from an incomplete hypoparathyroidism that tends to normalize eventually but may recur. Reduced PTH or PTH resistance (pseudohypoparathyroidism) cause hyperphosphatemia beyond the already increased normal range in neonates, whereas vitamin D deficiency or resistance is associated with low to normal serum phosphate levels. Maternal 25-hydroxyvitamin D deficiency is another common cause of early or late infantile hypocalcemia in the United States, regardless of the infant’s dietary intake.^186,¹⁸⁷ Childhood hypocalcemia with reduced PTH may be the first endocrine sign of polyglandular autoimmune disease type I, now called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).¹⁸⁸

Childhood Hypocalcemia

Persistent hypocalcemia in infants and children can have many manifestations, including poor feeding, tetany, seizures, laryngospasm, paresthesias, and muscle cramping. Initial evaluation of hypocalcemia, regardless of age, includes measurement of serum calcium, phosphate, magnesium, alkaline phosphatase, creatinine, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, plus urine calcium, phosphate, and creatinine. Therapy for acute hypocalcemia includes parenteral calcium, followed by oral calcium supplementation and 25-hydroxyvitamin D if reduced,¹⁸⁷ and calcitriol as a substitute for PTH, because PTH itself, an anabolic bone agent in adults,¹⁸⁹ is contraindicated in children owing to concerns about its possible role in osteosarcoma.

Perioperative Management

Hypocalcemia is most frequently managed by IV infusion of calcium in the form of calcium chloride or calcium gluconate, with frequent measurement of serum ionized calcium levels to guide therapy (see Chapter 10). Calcium salts release free calcium ions and should be given via a central venous catheter because their hypertonicity and the increase concentration of ionized calcium causes intense local vasoconstriction that may lead to necrosis of the skin and subcutaneous tissues and possible gangrene of the affected limb if administered via a peripheral IV cannula that becomes interstitial. In the postoperative period after the child is tolerating oral intake, IV calcium supplementation may be converted to oral supplementation.

Hypercalcemia

Hyperparathyroidism (HPT) is much less common in children than in adults.¹⁹⁰ In most cases of HPT in children, an adenoma is present that is unresponsive to the increased serum calcium level. Other uncommon causes of HPT in children include generalized parathyroid hyperplasia and, rarely, parathyroid carcinoma.¹⁹¹

Parathyroid hyperplasia occurs in familial forms of HPT, including multiple endocrine neoplasia type 1 (MEN 1), in which HPT is a nearly universal manifestation of the mutation of the menin gene; the hyperparathyroid abnormality occurs more commonly and earlier in presentation than the associated pancreatic, pituitary, and gastrointestinal neuroendocrine tumors associated with MEN 1.^192,¹⁹³ HPT is a less common manifestation of MEN 2A, in which medullary thyroid carcinoma and pheochromocytoma occur as a result of the proto-oncogene mutation.¹⁹⁴ Secondary HPT with relatively normal calcium levels is a common pediatric phenomenon that accompanies renal failure, renal tubular acidosis, and hypophosphatemic rickets.¹⁹⁵ When hypercalcemia is present, the differential diagnosis includes Williams syndrome, vitamin A intoxication, vitamin D excess and conversion to 1,25-dihydroxyvitamin D in granulomatous disorders, and infantile subcutaneous fat necrosis.¹⁹⁶ Solid tumors may secrete increased concentrations of parathyroid hormone–related protein (PTHrP). Tumors, such as leukemias, lymphomas, and others, may release excess cytokines and osteoclast-activating factors, with the hypercalcemia leading to the tumor diagnosis.^197,¹⁹⁸

Signs and symptoms of hypercalcemia are usually nonspecific, such as nausea and vomiting, polyuria, and fatigue. Initial laboratory evaluation of hypercalcemia matches the list for hypocalcemia given earlier.¹⁹⁹

Evaluation of unexplained hypercalcemia includes measurement of PTHrP for malignancy, and of parental calcium levels for familial hypocalciuric hypercalcemia, additional hormones or genetic testing for MEN syndromes, tumor markers, bone marrow biopsy, and relevant imaging. When HPT is found, ultrasonography is helpful to assess the parathyroid glands, but MRI or technetium-sestamibi scan is more precise, and intraoperative measurement of PTH levels can be provided for tumor localization.

Perioperative Management

Management of acute hypercalcemia begins with isotonic rehydration and administration of furosemide to induce calciuria. Treatment then proceeds to administration of calcitonin, to which tachyphylaxis may occur within 1 or 2 days, or to glucocorticoids. In the absence of a definitive therapy, such as surgical excision of the pathologic source of PTH, chronic hypercalcemia is responsive to bisphosphonates, such as pamidronate, which can be given by infusion every 3 months.^200,²⁰¹ Acute management after parathyroidectomy requires careful monitoring and replacement of calcium and possibly the use of calcitriol for persistent hypocalcemia. In isolated parathyroid hyperplasia, MEN, or secondary HPT, surgeons may elect to leave a portion of one gland in the forearm to avoid permanent hypoparathyroidism, which is challenging to manage.

Adrenal Endocrinopathies

Physiology

Adrenal steroidogenesis begins with cholesterol as precursor and results in three types of steroids: mineralocorticoids, glucocorticoids, and sex steroids (androgen precursors).²⁰² Most of the enzymes involved in adrenal (or gonadal) steroidogenesis are cytochrome P450s. The adrenal cortex comprises three zones: the outer zona glomerulosa exclusively synthesizes mineralocorticoids owing to localized expression of CYP11B2, whereas the zona fasciculata and reticularis synthesize glucocorticoid and androgens owing to localized expression of CYP17.²⁰³ Cortisol, the end-product of the glucocorticoid pathway, is the primary regulator of the hypothalamic-pituitary-adrenal (HPA) axis, in which hypothalamic corticotropin-releasing hormone regulates pituitary adrenocorticotropic hormone (ACTH) secretion and downstream adrenal production of all three categories of steroid. ACTH release follows a diurnal pattern with a peak at 0400 to 0800 hours and, most importantly, markedly increases in response to trauma, acute illness, high fever, and hypoglycemia.

Mineralocorticoid production is primarily controlled by the renin-angiotensin system, in which angiotensinogen secreted by the liver is cleaved by renin to angiotensin I, which is then converted to angiotensin II.²⁰⁴ The mineralocorticoid pathway is also responsive to ACTH, as demonstrated by a rise in all mineralocorticoid precursors and the end-product aldosterone within minutes of exogenous ACTH stimulation. However, hypopituitarism does not lead to mineralocorticoid deficiency because an intact renin-angiotensin system independently stimulates aldosterone synthesis. Nevertheless, patients with ACTH deficiency may present with hyponatremia (glucocorticoids are required for free water excretion) and hypotension. The latter consequence of failure of the adrenal to release an adequate amount of glucocorticoid may be attributable to the role of cortisol in enhancing vascular responsiveness to catecholamines and inotropic activity.²⁰⁵ This essential aspect of glucocorticoid activity is the most lethal potential consequence of both primary adrenal insufficiency and hypothalamic-pituitary deficiency and requires the utmost caution on the part of pediatrician, endocrinologist, surgeon, or anesthesiologist. When any question regarding adequacy of the HPA arises, it is prudent to provide exogenous glucocorticoid, particularly perioperatively.²⁰⁶

Causes of Adrenal Insufficiency

Primary adrenal insufficiency is suspected from features such as weight loss, nausea and vomiting, poor appetite, and, specifically, the characteristic skin hyperpigmentation that is secondary to melanocyte-stimulating hormone receptor cross-stimulation by ACTH (which is present in extraordinarily large concentrations).²⁰⁷ Primary adrenal insufficiency is uncommon in countries with advanced health care systems now that infectious diseases, such as tuberculosis, are less prevalent, but adrenal hemorrhage still causes adrenal failure.²⁰⁸ Autoimmune adrenal insufficiency, sometimes as part of a polyendocrinopathy syndrome, is now the most common cause and includes both glucocorticoid and mineralocorticoid deficiency. Glucocorticoid deficiency with or without mineralocorticoid loss is characteristic of congenital adrenal hyperplasia.²⁰⁹ Rare disorders causing adrenal insufficiency include adrenoleukodystrophy,²¹⁰ congenital adrenal hypoplasia, X-linked adrenal hypoplasia congenita, and ACTH receptor defects.²¹¹

Congenital or acquired lesions of the hypothalamus or pituitary may lead to ACTH deficiency. In general, these lesions cause other pituitary deficiencies, particularly growth hormone or TSH deficiency; isolated ACTH deficiency is rare. Both growth hormone and ACTH deficiency may cause hypoglycemia in infancy. CNS malformations leading to ACTH deficiency are usually detectable by MRI. A notable CNS anomaly with hypopituitarism is septo-optic dysplasia,^29,²¹²^–²¹⁴ which may be associated with an assortment of midline defects, such as an absent or underdeveloped septum pellucidum and optic nerve hypoplasia, but isolated pituitary agenesis or hypoplasia is more common. Acquired lesions leading to hypopituitarism include hydrocephalus, meningitis, infiltrative disorders,²¹⁵ and tumors such as craniopharyngioma or histiocytosis X.²¹⁶ Tumor resection, especially craniopharyngioma, cranial irradiation, and chemotherapy, can lead to multiple pituitary deficiencies, often evolving over many years.²¹⁷

Testing for Adrenal Insufficiency

Cortisol levels follow a diurnal pattern, with peak levels resulting from an ACTH surge in the early morning and trough levels later in the day. Although a morning serum cortisol level of less than 5 µg/dL is less than normal and suggestive of adrenal insufficiency, it may be difficult to interpret the significance of a random cortisol concentration. A reduced concentration at any other time of day is uninformative and should not be used to test for adrenal function. In contrast, laboratory confirmation of primary mineralocorticoid deficiency by obtaining a random serum sample will show a low aldosterone concentration despite markedly increased plasma renin activity.

Primary adrenal insufficiency may be effectively assessed in two ways,²¹⁸ either by simultaneous measurement of serum cortisol and plasma ACTH concentrations or by stimulating the adrenal with exogenous ACTH (cosyntropin [Cortrosyn], the biologically active fragment of ACTH containing the first 24 amino acids). A markedly increased random plasma ACTH concentration is definitive evidence of primary adrenal insufficiency, but levels can be moderately increased by the stress of phlebotomy itself. Therefore blood for plasma ACTH levels should be obtained from an indwelling catheter to avoid false-positive values.

Hypothalamic-pituitary insufficiency is more difficult to assess. The complete absence of ACTH levels, as in the obvious case of pituitary ablation or destruction, leads eventually to adrenal atrophy and complete unresponsiveness to cosyntropin stimulation, a finding that necessitates maintenance glucocorticoid replacement. However, an “adequate” response to cosyntropin implies only tonic ACTH secretion and does not guarantee the ability to generate a normal surge of ACTH during stress. As a consequence, any patient with a CNS lesion that might cause HPA deficiency should receive stress doses of glucocorticoid (see later discussion). In practical terms, a post–cosyntropin-treatment cortisol value of 10 to 20 µg/dL in an at-risk child suggests the need for stress coverage, whereas a value less than 10 µg/dL indicates long-term replacement.^218,²¹⁹

Perioperative Management of Adrenal Insufficiency

Glucocorticoid Dosing

Endogenous cortisol secretion is 6 to 8 mg/m²/day. Because a fraction of oral cortisol is degraded by the liver, the typical oral replacement dose is 10 to 12 mg/m²/day. A replacement dose of hydrocortisone depends on age and body size but might be 5.0 to 7.5 mg two to three times a day orally for an adolescent with chronic adrenal insufficiency. No dose monitoring is required, but the child’s growth rate should be tracked according to age. With concomitant or isolated mineralocorticoid deficiency, replacement uses fludrocortisone (Florinef) at an approximate dose of 0.1 mg orally per day, independent of body size, with intermittent monitoring of blood pressure and plasma renin activity. When the primary goal of glucocorticoid therapy is not replacement but suppression of ACTH secretion, as in congenital adrenal hyperplasia, the daily hydrocortisone dose is generally 15 to 20 mg/m², guided by monitoring of serum levels of 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulfate, and testosterone. Alternatives to hydrocortisone include prednisone, which is four to five times more potent than hydrocortisone. Dexamethasone is 30 to 40 times more potent than hydrocortisone, but has no mineralocorticoid activity and carries much more significant risk of adverse effects, such as osteopenia and aseptic necrosis of the femoral head, and so should not be used for chronic routine replacement therapy. Single-dose use of dexamethasone has not been associated with aseptic necrosis of the femoral head.

Conventional stress glucocorticoid coverage is 3 to 10 times the patient’s usual replacement dose, depending on the severity of illness or trauma, although this practice is not evidence based.²²⁰ Therefore, with little risk associated with the transient use of excess glucocorticoid, for children who are on oral replacement therapy we recommend exogenous glucocorticoid replacement using three to five times the patient’s usual oral maintenance dose for intercurrent illness or fever (greater than 101° F) and five to ten times the oral maintenance dose for major surgery, during critical illness, or in major emergencies. For children who require stress glucocorticoid coverage but who do not take outpatient steroids, or who are unable to take medications by mouth, we recommend using parenteral cortisol (Solu-Cortef) at a dose of 0.5 mg/kg/day every 12 hours for illness associated with nausea, vomiting, diarrhea, or fever (greater than 101° F) and 0.5 to 1 mg/kg every 6 hours for perioperative, intensive care, or emergency department indications for up to 72 hours.²²¹

Iatrogenic Adrenal Suppression and Tapering

Increased doses of exogenous glucocorticoids are used chronically for control of autoimmune disorders, suppression of transplant rejection, and control of inflammatory processes. Iatrogenic adrenal suppression depends on the duration and dose of glucocorticoid used. Periods of high-dose steroids up to 7 to 10 days do not suppress the HPA axis. Adrenal suppressive treatments lasting 3 to 6 weeks require a taper over 1 to 2 weeks to allow recovery of the HPA axis. Long-term high-dose treatment may require up to 6 to 9 months for complete return of HPA function and necessitates a taper during that period. At the termination of the taper, a repeat cosyntropin stimulation test should be performed to confirm recovery of function, and any repeat trauma or illness during the period of taper requires short-term stress coverage.

The glucocorticoid taper has two meanings. The tempo of therapeutic tapers of prednisone by gastroenterologists, rheumatologists, nephrologists, and oncologists, and of dexamethasone by surgeons, is entirely dependent on their assessment of the immune or inflammatory process. As long as the glucocorticoid dose is in excess of the replacement dose, and regardless of the dose, the HPA axis continues to be suppressed. It is only when the steroid dose is tapered down to the daily replacement dose (approximately 10 mg/m² hydrocortisone, 2 mg/m² prednisone, or less than 0.5 mg/m² dexamethasone) that the endocrine taper begins. At that point, the prednisone should be switched to hydrocortisone for ease of starting a gradual taper from replacement therapy to reduced doses while function of the HPA axis is reestablished. In the perioperative period, steroid coverage should be administered if there is any concern about the integrity of the HPA axis during a steroid taper (Table 25-6).

TABLE 25-6 Steroid Equivalency Ratios and Doses

Hypercortisolism (Cushing Syndrome)

Excess cortisol, whether exogenous or endogenous, results in muscle wasting, truncal obesity, moon facies, hypertension, hyperglycemia, osteopenia, and growth deceleration.^222,²²³ Iatrogenic hypercortisolism is common in pediatrics,²²⁴ whereas Cushing disease or syndrome is rare.²²⁵ Cushing disease refers to an ACTH-secreting pituitary adenoma. Cushing syndrome refers to other conditions of excess glucocorticoid, including ectopic ACTH-secreting tumors²²⁶ and adrenal tumors that secrete cortisol.²²⁷ An adrenal tumor (adenoma or carcinoma) is the most likely cause of hypercortisolism in a young child. These tumors can secrete any combination of steroids and commonly cosecrete androgens, resulting in virilization.²²⁸ A unilateral glucocorticoid-secreting tumor typically causes HPA axis suppression, requiring careful tapering of hydrocortisone replacement after resection to reestablish normal cortisol production in the contralateral adrenal gland.²²⁹

In a child with signs of hypercortisolism (and not simply obesity), screening tests include an overnight small dose dexamethasone suppression test, measurement of 24-hour urinary free cortisol and creatinine, and measurement of nocturnal salivary cortisol concentrations.²³⁰ If screening tests suggest a diagnosis of hypercortisolism, additional adrenal steroids should be measured and an adrenal computed tomographic scan or magnetic resonance image obtained. In an adolescent with pure glucocorticoid effects and suspicious results of a corticotropin-releasing hormone stimulation test or longer dexamethasone suppression test²³¹ suggestive of a pituitary ACTH-secreting adenoma (Cushing disease), pituitary magnetic resonance imaging is warranted.²³² Because pituitary adenomas can be very small, bilateral inferior petrosal sinus sampling may be necessary to locate the adenoma.²³³

Perioperative Management of Hypercortisolism

Therapy for Cushing disease and Cushing syndrome is surgical.^234,²³⁵ There are no specific anesthetic considerations except the supportive management of secondary manifestations, such as obesity and its attendant airway concerns, hypertension, and skin and bone fragility.

Annotated References

2000 Type 2 diabetes in children and adolescents. American Diabetes Association. [No authors listed]. Diabetes Care. 2000;23:381–389.

This consensus statement from the American Diabetes Association reviews the classification of diabetes in children, epidemiology of type 2 diabetes in U.S. children, along with recommendations for screening, treatment, and prevention of type 2 diabetes in children and adolescents.

Andersen LJ, Andersen JL, Schutten HJ, et al. Antidiuretic effect of subnormal levels of arginine vasopressin in normal humans. Am J Physiol. 1990;259:R53–R60.

The renal response to 120-minute infusions of arginine vasopressin (AVP) was investigated in healthy volunteers undergoing water diuresis induced by an oral water load. The human kidney is sensitive to changes in the rate of secretion of AVP of less than 1 pg/min/kg and maximal change occurs after 1 to 2 hours of constant infusion. It is estimated that the rate of infusion of AVP required to produce isosmolar urine during overhydration is approximately 3 pg/min/kg.

Baylis PH. The syndrome of inappropriate antidiuretic hormone secretion. Int J Biochem Cell Biol. 2003;35:1495–1499.

The author reviews the cardinal diagnostic criteria, clinical features, and pathophysiology of SIADH, which develops because of persistent detectable or elevated plasma arginine vasopressin concentrations in the presence of continued fluid intake. Inappropriate infusion of hypotonic fluids in the postoperative state is a common cause. For symptomatic patients with chronic SIADH, the mainstay of therapy is fluid restriction.

LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid. 1999;9:735–740.

LaFranchi thoroughly reviews and discusses thyroid development and hypothyroidism in this article. He includes both embryologic and molecular defects of hypothyroidism.

Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of pediatric surgical patients with diabetes mellitus. Anesth Analg. 2005;101:986–999.

The authors review the fundamental pathophysiology and perioperative management of type 1 and type 2 diabetes mellitus in children who are surgical patients.

Rivkees SA. The treatment of Graves’ disease in children. J Pediatr Endocrinol Metab. 2006;19:1095–1111.