CHAPTER 36 Systemic Disorders
Among patients who present special problems for anesthesiologists are children whose underlying conditions complicate anesthetic management and may be associated with an increased risk of morbidity. The number of rare diseases that may be encountered in infants and children is great, although only a few are mentioned here. Chosen for discussion are the diseases most commonly seen, those carrying an increased risk related to anesthetic management, and a few of unusual interest. Modifications to the understanding of mechanisms of coagulation are included, along with consideration of coagulopathic states, and there is a comprehensive review of the anesthetic implications of pediatric syndromes associated with genetic, metabolic, and dysmorphic features (Baum and O’Flaherty, 2006). A partial list of syndromes with possible anesthetic implications is included in Appendix D, which can be accessed online at www.expertconsult.com
Endocrine Disorders
Diabetes Mellitus
The endocrine condition most commonly dealt with in the perioperative period is the management of glucose homeostasis in children with diabetes mellitus. The prevalence of type 1 (insulin-dependent) diabetes in the United States has remained stable for the past 15 years at 1 in 400 to 600 school-aged children, whereas the incidence of type 2 diabetes is increasing, especially among American Indian, Black, and Hispanic children and adolescents (CDC, 2007c). 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. Insulin deficiency results in abnormalities of glucose transport and storage and 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.
Children with type 1 diabetes may be treated with various types of insulin on a daily basis to maintain tight glucose control with the aid of frequent blood-glucose monitoring. Since 1982, most newly approved insulin preparations have been produced using recombinant DNA technology with laboratory-cultivated bacteria or yeast. This process allows the bacteria or yeast cells to produce complete human insulin. Recombinant human insulin has mostly replaced animal-derived insulin (e.g., pork and beef insulin) in diabetes management (Plotnick and Henderson, 1998). Insulin products called insulin analogues are produced so that the structure differs slightly from human insulin (by one or two amino acids) to change onset and peak of action. An example of an analogue is human lispro, an ultra–short-acting insulin that is given only 15 minutes before a meal. Its peak and duration of action parallel the glucose rise that results from carbohydrate ingestion.
Another new insulin is glargine, which almost mimics an insulin pump, providing a continuous, 24-hour, low background level of insulin. The kinetics of some of the insulin preparations most commonly used in children are listed in Table 36-1. Some children’s diabetes may be managed with an external insulin pump, which provides a low, background, subcutaneous infusion of insulin and the ability to give small boluses before meals. Most children with diabetes administer insulin at least three times each day and check their blood sugar at least four times each day. Type 2 diabetes in children and adolescents may be controlled with diet and exercise, but these children also may be taking metformin. Metformin was recently shown to decrease gluconeogenesis by directly modulating copper-binding protein (CBP) in the liver much as insulin itself does, rather than by overcoming the liver’s decreased sensitivity to insulin (He et al., 2009).
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, in 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 speedy healing and metabolic homeostasis. 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 treatment regimen or delay of procedure if control is not optimal. Rhodes and colleagues (2005) published a comprehensive review of concerns and perioperative management of pediatric patients with diabetes; it features an extremely useful clinical practice guideline that incorporates both preoperative assessment and choice of preoperative insulin regimen.
Preoperative Evaluation
The preoperative evaluation should include measurements of the hematocrit, electrolyte levels, and glucose levels. A hemoglobin (Hb) A1c level (i.e., glycosylated Hb assay), although a useful index of long-term glucose control, is unlikely to affect the anesthetic plan and is not a necessary preoperative test (Nathan et al., 1984). If glycohemoglobin results are available, it is important to remember that different laboratories have different ranges for Hb A1c in normal subjects. Even in the same laboratory, the normal range may change from time to time. It is therefore important to know the laboratory’s normal range to interpret results in patients with diabetes. The normal range of Hb A1c is 4.5% to 6.1%, but the normal range also varies with age (Rhodes et al., 2005; Custer and Rau, 2009).
Several systemic abnormalities may be present in the child with diabetes. Nineteen percent of children with diabetes have a vital capacity two standard deviations below the predicted mean value, suggesting the presence of restrictive lung disease (Buckingham et al., 1986). No apparent association exists between decreased vital capacity and duration of diabetes or presence of other diabetic complications. Abnormal lung elasticity and thickening of the alveolar basal laminae have been reported in children with diabetes (Schuyler et al., 1976; Vracko et al., 1980). Routine preoperative pulmonary function tests are not indicated in the asymptomatic child who has diabetes.
Decreased atlantooccipital joint mobility, resulting in difficult intubation, may be present in a subset of adolescents with a syndrome of diabetes mellitus, short stature, and tightness of small joints of the fingers, wrists, ankles, and elbows (Salzarulo and Taylor, 1986). Abnormal cross-linking of collagen by nonenzymatic glycosylation is the postulated cause of this syndrome (Chang et al., 1980).
Perioperative Management
Various regimens for managing insulin therapy perioperatively have been proposed, three of which are discussed in the following sections and in Table 36-2: a classic regimen, the subcutaneous infusion insulin pump, and intravenous (IV) insulin infusion. Essential to optimal management, regardless of regimen, is the scheduling of elective surgery for the child with diabetes as early as possible in the day (first case) to minimize time that the patient must fast. The fasting interval should be the same as that recommended for patients who do not have diabetes: no solid food or milk for 8 hours, and clear liquids are permissible until 2 hours before the scheduled time of surgery (Schreiner et al., 1990). Children with diabetes should be encouraged to continue taking clear liquids until 2 hours before surgery. If this is not possible, an IV fluid infusion should be started (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) may be continued through the day before surgery.
TABLE 36-2 Protocols for Perioperative Insulin Therapy
| Regimen | Morning of Surgery Procedure |
| Classic regimen | Start IV infusion of 5% dextrose in 0.45% saline or Ringer’s lactate solution at 1500 mL/m2/day. Administer half of usual morning insulin dose as regular insulin. Check blood glucose before induction, during and after anesthesia |
| Continuous insulin infusion | Start IV infusion of 5% dextrose in 0.45% saline or Ringer’s lactate solution at 1500 mL/m2/day. Add 1-2 units of insulin per 100 mL of 5% dextrose Starting insulin dose = 0.02 units/kg/hr Check blood glucose before induction, and during and after anesthesia |
| Insulin- and glucose-free regimen (for operative procedures of short duration) | Withhold morning insulin dose If indicated for procedure, give glucose-free solution (e.g., Ringer’s lactate) at maintenance rate. Check blood glucose before induction, and during and after anesthesia. |
Based on the blood-glucose level determined on arrival to the preoperative facility and before implementation of the regimens discussed in the following sections, glucose or insulin should be administered according to the scheme outlined in Table 36-3.
TABLE 36-3 Preoperative Glucose and Insulin Management for Diabetic Patients
| Blood Glucose Level | Management |
| <80 mg/dL | 2 mL/kg D10W followed by glucose infusion |
| 80-250 mg/dL | D5/0.45 NS or D10/0.45 NS solution at maintenance if insulin is to be administered; 0.9 NS if short case; no insulin |
| >250 mg/dL | Administer rapid-acting (lispro) or short-acting (regular) insulin SC to reduce blood sugar; use correction factor from patient’s endocrine provider or 0.2 unit/kg SC |
| >350 mg/dL | Consider canceling or postponing surgery, especially if ketonuria |
NS, Normal saline; SC, subcutaneously.
Classic Regimen
On the morning of surgery, one half of the usual dose of long-acting insulin (e.g., Neutral Protamine Hagedorn [NPH]) is administered subcutaneously after establishing an IV infusion of 5% glucose-containing solution at a rate of 100 mg/kg per hour of glucose (Table 36-2). Plasma-glucose concentrations should be maintained between 100 and 180 mg/dL. This target range is chosen because mild to moderate hyperglycemia (without ketosis) usually does not present a serious problem to the child, whereas hypoglycemia has devastating consequences. Hyperglycemia greater than 250 mg/dL should be avoided because of associated mental status changes, diuresis, and subsequent dehydration, which can occur because of the hyperosmolar state. Hyperglycemia has been associated with poorer outcomes in patients at risk for central nervous system (CNS) ischemia, including those undergoing cardiopulmonary bypass (Lanier et al., 1987; Lanier, 1991). Hyperglycemia has also been shown to impair wound healing and has adverse effects on neutrophil function in vitro. (Marhoffer et al., 1992; Delamaire et al., 1997). When the classic regimen is employed, supplemental subcutaneous doses of short-acting insulin can be given on a sliding scale postoperatively to maintain the desired plasma glucose level. This regimen should be restricted to patients who are scheduled for short surgical procedures, after which they are expected to resume eating promptly.
Subcutaneous Infusion Insulin Pump
Increasing numbers of pediatric patients with type I diabetes are being managed with an external insulin pump that is 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. At this time, the proliferation of pumps from multiple manufacturers precludes the easy acquisition of knowledge and familiarity with their use in the perioperative setting. Some clinicians and institutions allow continued use of insulin pumps for short, uncomplicated procedures (e.g., less than 2 hours), whereas most recommend transition to a continuous insulin infusion, as described in the next section (Glister and Vigersky, 2003; Rhodes et al., 2005).
Intravenous Insulin Infusion
If a long procedure or a prolonged period of postoperative fasting is anticipated, the continuous IV infusion of glucose and insulin may provide the best control. On the morning of surgery, a glucose infusion is begun at a maintenance rate of 100 mg/kg per hour, with an insulin infusion of 0.02 to 0.05 unit/kg per hour “piggy-backed” into the glucose infusion. The glucose infusion can be D5 or D10 in half-normal saline with 10 to 20 mEq/L of potassium chloride. These infusions should be started 2 hours before surgery to minimize the duration of fasting and decrease the risk of the development of a catabolic state. Insulin is absorbed by IV bags and tubing. When the insulin solution is prepared, the first portion of the solution should be run through the tubing and discarded to saturate the sites in the tubing that bind insulin (Kaufman et al., 1996). Blood glucose levels should be checked hourly for the first few hours, and adjustments of 0.01 unit/kg per hour in the insulin rate should be made to keep the blood sugar in the acceptable range of 100 to 180 mg/dL. This continuous-infusion regimen has been shown to yield better control of glucose concentrations than the regimen in which intermittent subcutaneous insulin is administered (Kaufman et al., 1996). The administration of intermittent large IV-insulin doses has no role, as it can result in large swings in glucose concentration (high and low) and a greater chance of lipolysis and ketogenesis. Patients with insulin pumps should have them turned off in the perioperative period, and pumps should be replaced by the continuous-infusion regimen, as most anesthesiologists are not familiar with the details of operation of such pumps. Fifty-percent dextrose solution should be available for administration in case of the development of hypoglycemia; 0.1 g/kg of dextrose raises the blood-glucose level by approximately 30 mg/dL.
Alternative Procedure (Insulin- and Glucose-free Regimen)
For extremely brief procedures, after which prompt resumption of oral intake is expected, an alternative protocol involves the administration of no insulin or glucose before or during surgery. When oral intake is established postoperatively, 40% to 60% of the usual daily insulin dose is given (Stevens and Roizen, 1987). Myringotomy with tube placement is an example of a procedure for which this regimen would be appropriate. The surgical procedure should be performed as the first case on the morning schedule to avoid prolonged fasting and excessive delay in insulin administration.
The most serious perioperative complication that can occur in the diabetic child is hypoglycemia. Common signs of low blood-glucose levels include tachycardia, tearing, diaphoresis, and hypertension. In the anesthetized patient, these signs may be misinterpreted as the result of inadequate anesthesia. Because the clinical signs of hypoglycemia are masked by sedation or anesthesia, frequent (every hour) measurement of the serum-glucose level is critical for the prevention of hypoglycemia, independent of the glucose-insulin regimen chosen. Glucose test strips, with or without the use of a reflectance photometer, provide quick, convenient, and reliable bedside blood-sugar measurements to guide therapy. Blood-glucose determinations performed with reflectance photometers provide results that are generally within 10% of clinical laboratory glucose determinations done on the same specimen (Chen et al., 2003). Visual evaluation of blood-glucose strips is less accurate (Arslanian et al., 1994). Postoperative insulin administration is determined by the time of resumption of oral or enteral feeding and by the postoperative blood-glucose concentration. The endocrinologist and surgeon should be active partners in the choice of an appropriate insulin regimen, because they are responsible for monitoring glucose homeostasis after the patient leaves the recovery room. For day-surgery patients, contingency planning for insulin management and mechanisms for follow-up care and consultation should be clearly defined for members of the care team and family.
Perioperative Management of Diabetic Ketoacidosis
Occasionally, patients with diabetes require surgery for trauma or infection while they are in a state of ketoacidosis. Diabetic ketoacidosis includes hyperglycemia (plasma-glucose concentration greater than 300 mg/dL) with glucosuria, ketonemia (ketones strongly positive at greater than 1:2 dilution of serum), ketonuria, and acidemia (pH lower than 7.30, serum bicarbonate lower than 15 mEq/L, or both). It is common for intraabdominal catastrophes with infection (e.g., appendicitis) to precipitate ketoacidosis. Foster and McGarry (1983) have succinctly summarized the pathophysiology of diabetic ketoacidosis. The initiating event is usually cessation of insulin therapy or onset of stress that renders the usual dose of insulin inadequate. Glucagon, catecholamines, cortisol, and growth hormone levels increase. A catabolic state is produced as substrates are mobilized, resulting in hepatic production of glucose and ketone bodies, which causes hyperglycemia and ketoacidosis. Subclinical brain swelling nearly always occurs during diabetic ketoacidosis therapy, although most patients remain asymptomatic (Krane et al., 1985). Fatalities from cerebral edema do occur, and some studies suggest that high rates of fluid administration early in treatment (more than 50 mL/kg in the first 4 hours) greatly increase the risk of herniation (Mahoney et al., 1999). Studies using 4 L/m2 for the first 24 hours followed by 1 to 1.5 times maintenance resulted in clearance of ketoacidosis equal to that in patients who were given more fluid, but a low but persistent incidence (0.35% to 0.5%) of symptomatic cerebral edema remained (Felner and White, 2001). The best methods to prevent the development of this devastating complication are administration of isotonic fluid only and frequent monitoring of serum osmolality (by direct measurement or calculation) to ensure that elevated osmolality is reduced gradually. Insulin therapy should be tailored to decrease the blood glucose concentration at a rate not greater than 100 mg/dL per hour. To prevent a more rapid decrease in blood glucose concentration, 5% dextrose and if necessary, 10% dextrose, should be added to the rehydration solution to slow the rate of fall, rather than decreasing the rate of insulin infusion (Arslanian et al., 1994). Fortunately, the anesthesiologist is rarely called on to administer anesthesia during this severe metabolic derangement. If an anesthetic is required during diabetic ketoacidosis, preoperative attention should be directed toward the correction of hypovolemia and hypokalemia, along with beginning an insulin infusion. Invasive hemodynamic monitoring may be indicated preoperatively to optimize the patient’s fluid and electrolyte balance and to monitor the patient’s hemodynamic status accurately. Surgery should not be delayed inordinately because it may be impossible to correct the metabolic derangements before the underlying source of infection or organ dysfunction is corrected. For patients with signs of cerebral edema, monitoring of intracranial pressure may be necessary.
Diabetes Insipidus
Diabetes insipidus (DI) is a clinical syndrome of hypotonic polyuria in the face of elevated plasma osmolality that results from inadequate production of, or inadequate response to, antidiuretic hormone (ADH). Central DI results from inadequate production or release of ADH from the posterior pituitary gland. ADH is synonymous with arginine vasopressin. Nephrogenic DI (also referred to as vasopressin-resistant DI) is characterized by partial or complete renal tubular unresponsiveness to endogenous ADH or exogenously administered arginine vasopressin. Congenital nephrogenic DI is caused by mutations in either the vasopressin receptor or aquaporin-2 gene. Inheritance is X-linked in the former and autosomal recessive or dominant in the latter (Sasaki, 2004). A combination of hydrochlorothiazide and a nonsteroidal antiinflammatory drug (NSAID) has been effective for the treatment of nephrogenic DI. Both cyclooxygenase-1 (COX-1; i.e., tolmetin and indomethacin) and cyclooxygenase-2 (COX-2; i.e., rofecoxib) drugs have been effective (Jakobsson and Berg, 1994; Pattaragarn and Alon, 2003). Toxic drug effects may also lead to acquired nephrogenic DI. Anesthetic implications of nephrogenic DI have been reviewed by Cramolini (1993) and Malhotra and Roizen (1987).
The causes of DI are outlined in Box 36-1. This discussion focuses on central DI and its clinical manifestations, which are polyuria and polydipsia. The urine is hypotonic relative to the plasma. The urine osmolality is usually less than 200 mOsm/L, and urine specific gravity is less than 1.005 (Custer and Rau, 2009). When the patient has had inadequate access to water, severe dehydration and hypernatremia ensue, because a large volume of dilute urine is continually produced.
Box 36-1 Causes of Diabetes Insipidus
Patients with preexisting DI may need incidental surgery. They are usually taking maintenance doses of vasopressin, which for relatively short, uncomplicated, elective procedures, should be continued through the perioperative period (Wise-Faberowski et al., 2004). Desmopressin (1-desamino-8-d-arginine vasopressin, or DDAVP), a longer-acting (8 to 20 hours) vasopressin analogue, has a decreased vasopressor effect relative to its antidiuretic effect (Hays, 1990). DDAVP is usually given intranasally (2.5 to 10 mcg once or twice daily) or orally (25 to 200 mcg once or twice daily) to prevent diuresis (Lee et al., 1976). DDAVP also may be given subcutaneously or intravenously (1 to 2 mcg twice daily). An algorithm for the management of DI, whether preexisting or developing intraoperatively or postoperatively, is presented in Figure 36-1.
The most common situation encountered by the anesthesiologist, however, is the new onset of DI intraoperatively or postoperatively in patients who are having surgery for pituitary or hypothalamic tumors, most commonly craniopharyngiomas; 70% to 90% of these patients develop DI (Lehrnbecher et al., 1998; Ghirardello et al., 2006;). Perioperative DI may present in one of four ways:
If any degree of DI is going to occur, the onset is most commonly within 18 hours after the operation. Recommendations for therapy are reviewed by Wise-Faberowski and colleagues (2004).
The goal of perioperative management of DI is to maintain normal fluid and electrolyte balance, urine output, and hemodynamic stability. Urine output may be prodigious (10 to 20 mL/kg per hour). Care must be taken to differentiate polyuria caused by DI (urine specific gravity of less than 1.005) from diuresis caused by mannitol administration, hyperglycemia (urine specific gravity that is usually greater than 1.015), or simple excessive administration of crystalloid (urine specific gravity of greater than 1.005). Patients with partial ADH deficiency usually do not require supplemental aqueous vasopressin perioperatively, because large quantities of ADH are produced in response to surgical stress (Malhotra and Roizen, 1987). However, serum osmolality should be measured often, and aqueous vasopressin should be given if the plasma osmolality exceeds 300 mOsm/L (Wise-Faberowski et al., 2004).
If central DI is present preoperatively and the planned surgery is prolonged, an infusion of aqueous vasopressin is begun preoperatively and continued intraoperatively. The recommendations for adults include a bolus of 100 milliunits of aqueous vasopressin followed by a continuous infusion of 100 to 200 mU/hr. This should be accompanied by the intraoperative administration of isotonic saline at two thirds of the maintenance rate, with additional fluid given for blood loss replacement and for maintaining hemodynamic stability (Malhotra and Roizen, 1987). Hypotonic fluids should be avoided, as hyponatremia may result. For the pediatric population, an infusion is begun at 0.5 mU/kg per hour and increased in 0.5 mU/kg per hour increments until a urine osmolality twice that of plasma and a urine output of less than 2 mL/kg per hour are achieved. It is rarely necessary to use more than 10 mU/kg per hour (Weigle, 1987). Side effects from vasopressin administration are minimal at doses used for antidiuresis; at larger doses, generalized vasoconstriction can occur and has resulted in tissue ischemia and myocardial infarction.
DDAVP, rather than aqueous vasopressin, may also be used for treatment of perioperative DI because of its potent antidiuretic effect with minimal pressor activity or other side effects. In the perioperative period, it may be given intravenously until intranasal administration can be started or resumed. The suggested IV dose is 0.5 to 4 mcg, with a single dose having a duration of action of 8 to 12 hours (Muglia and Majzoub, 2008). It is important to note that this dose of DDAVP is one fortieth to one fourth of that used to prevent bleeding in patients with von Willebrand’s disease (vWD). The ease of intermittent dosing with DDAVP with low incidence of side effects must be balanced against the ability to titrate the continuous vasopressin infusion cited earlier. The long half-life of DDAVP (6 to 24 hours) in combination with intraoperative fluid administration may incur an increased chance of hyponatremia. In either case, careful monitoring of fluid balance is essential.
The anesthesiologist may occasionally encounter children who are receiving nightly nasal DDAVP for the treatment of enuresis. A review of its use reveals a negligible incidence of water intoxication (and no permanent effect on enuresis when treatment is stopped) (van Kerrebroeck, 2002). Given the known duration of action, DDAVP administered the night before outpatient surgery should not affect the urine output on the day of surgery.
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Just as central DI is caused by ADH deficiency, syndrome of inappropriate ADH secretion (SIADH) is caused by an excess production of ADH that is inappropriate with respect to the state of the intravascular volume. The most common causes of SIADH are listed in Box 36-2. The hallmark of SIADH is hyponatremia in the face of high urine osmolality and sodium levels. A comparison of the urine and serum electrolyte status seen in DI and SIADH is presented in Table 36-4. The treatment for mild cases of SIADH is fluid restriction (50% to 60% of maintenance fluid requirement) or insensible loss (400 mL/m2 per day), plus one half to three fourths of the urine output. If hyponatremia is severe enough to cause coma or seizures, treatment with hypertonic saline (3%) solution may be indicated, but caution should be employed because the administration of hypertonic saline may cause circulatory overload because the intravascular volume is already increased. A too-rapid rise of osmolarity (more than 20 mOsm/kg or more than 10 mmol/L of sodium in 24 hours) carries a risk of central pontine myelinolysis, a condition that can result in death (Laureno and Karp, 1997). This syndrome is thought to be caused by the sudden shrinkage of brain cells in response to rapidly increasing extracellular osmolality.
TABLE 36-4 Comparison of Diabetes Insipidus and SIADH
| Laboratory Test | Diabetes Insipidus | SIADH |
| Urine specific gravity | ≤1.005 | ≥1.005 |
| Urine osmolality | 50-200 mOsm/L | >200 mOsm/L |
| Serum osmolality | >280 mOsm/L | <280 mOsm/L |
| Serum sodium | High (usually >148 mEq/L) | Low (usually <132 mEq/L) |
| Urine sodium | <20 mmol/L | >20 mmol/L |
Adrenal Insufficiency
Adrenal Insufficiency as a Result of Primary Abnormalities of the Hypothalamic-Pituitary-Adrenal Axis
Adrenal insufficiency is an uncommon disease in children, but when it occurs it is associated with significant implications for the anesthesiologist. The causes of adrenal insufficiency are listed in Box 36-3. Adrenal insufficiency may include glucocorticoid deficiency with or without mineralocorticoid deficiency (Box 36-4). Isolated hypoaldosteronism is rare. In the perioperative period, children with congenital adrenal insufficiency require glucocorticoid and mineralocorticoid replacement.
Box 36-3 Causes of Adrenal Insufficiency
Box 36-4 Signs and Symptoms of Adrenal Insufficiency
Chronic deficits in adrenal function result in the classic findings of Addison disease, including hyperpigmentation, weakness, and hyponatremia. The hyperpigmentation results from high levels of adrenocorticotropic hormone (ACTH) and unopposed melanophore-stimulating hormone caused by cortisol insufficiency. The additional presence of aldosterone insufficiency may produce hyponatremia, hyperkalemia, hypotension, and a small cardiac silhouette that results from hypovolemia (Keon and Templeton, 1993).
Perioperative Steroid Management
The preoperative recognition of adrenal insufficiency and appropriate preoperative therapy minimize the likelihood of significant perioperative complications. Ninety percent of patients with congenital adrenal hyperplasia with adrenal insufficiency have 21-hydroxylase deficiency (Migeon and Donohoue, 1994). Virilization of the external genitalia occurs in female patients, and they often require surgical revision of their external genitalia. An abnormal genital pigmentation occurs in male patients, but this finding may be subtle. Infants with undiagnosed congenital adrenal hyperplasia may undergo exploratory laparotomy for acute abdomen because of nausea and vomiting. It is important to be attuned to the signs and symptoms in the history, physical examination, and laboratory evaluation that point to this diagnosis to prevent or treat shock, which may occur because of failure to administer steroid replacement.
Mineralocorticoid deficiency can be managed by administering saline solution and avoiding potassium in IV fluids. Mineralocorticoid secretion rates in children are similar to those in adults, and the replacement dose is independent of age and weight. Desoxycorticosterone acetate may be administered intramuscularly in a dose of 1 mg/day. The intramuscular injection may be replaced by a single daily oral dose of 9-fluorocortisol (Florinef, 0.05 to 0.1 mg) when it is clear that an oral medication can be tolerated and absorbed. When cortisol is administered perioperatively, it has sufficient mineralocorticoid activity to obviate the need for any other replacement; 20 mg of hydrocortisone has mineralocorticoid activity equivalent to 0.1 mg 9a-fluorocortisol (Miller et al., 2008).
Glucocorticoid deficiency is treated with cortisol (hydrocortisone) replacement. The importance of cortisol replacement for patients with known adrenal insufficiency should not be underestimated, although vastly excessive doses are unwarranted. In the normal individual, the adrenal gland secretes 12 ± 2 mg of cortisol per square meter of body surface area every 24 hours (Kenny and Preeyasombat, 1966). The normal replacement dose prescribed for unstressed children is 25 mg/m2 per day; the dose is double the normal production because of factors of bioavailability and half-life (Migeon and Donohoue, 1994). In response to stress (e.g., fever, acute illness, surgery, and anesthesia), the normal adrenal gland secretes 3 to 15 times this amount. Consequently, in the past, the recommendations for “stress” steroid coverage in the perioperative period ranged from 36 to 180 mg/m2 per day.
More important than just the dose of steroid to be given, consideration should be devoted to the type of glucocorticoid administered, its half-life, the route of administration, and the timing of doses. The equivalencies for steroid preparations in terms of their relative glucocorticoid and mineralocorticoid effects are presented in Table 36-5. The most commonly cited recommendation for perioperative steroid coverage is hydrocortisone hemisuccinate (Solu-Cortef), given intravenously as 2 mg/kg immediately preoperatively and every 6 hours on the day of surgery, with reductions in the postoperative period depending on the degree of stress. Some practitioners feel that the half-life of hydrocortisone is so short that a 6-hour dosing interval may lead to periods of inadequate “coverage.” These practitioners recommend a preinduction dose of 25 mg/m2 of hydrocortisone given intravenously, followed by a continuous infusion of 50 mg/m2 administered during the estimated period of anesthesia. Postoperatively, 50 mg/m2 by continuous infusion is administered over the remainder of the first 24 hours. The total dose for the first 24 hours is 125 mg/m2, or 10 times normal physiologic production (Migeon and Donohoue, 1994). The first bolus dose must be administered before induction of anesthesia rather than waiting for an IV cannula to be placed after inhalational induction because of the stress associated with anesthetic induction itself. In the postoperative period, the steroid dose is tapered to a level commensurate with the residual stress. It is replaced with the child’s usual oral preparation when the child clearly can tolerate and absorb oral medication.
Hypothalamic-Pituitary-Adrenal Axis Suppression Caused by Exogenous Steroid Therapy
In addition to the diseases discussed previously, suppression of the hypothalamic-pituitary-adrenal (HPA) axis can also occur after exogenous steroid usage, such as that administered for the treatment of inflammatory conditions (e.g., Crohn disease and asthma) or autoimmune disease (e.g., lupus and juvenile rheumatoid arthritis). Nearly 60 years ago, it was reported that two patients developed irreversible shock perioperatively after glucocorticoid administration was stopped preoperatively (Fraser et al., 1952; Lewis et al., 1953). Both patients were found to have adrenal atrophy and hemorrhage at autopsy. These two cases led to suggestions for “stress” steroid coverage in the perioperative period. HPA suppression places steroid-dependent children at increased risk for complications in the perioperative period, because they may be unable to respond to stress with an appropriate increase in the adrenal secretion of glucocorticoid. Dosages of cortisol or its equivalent that exceed 15 mg/m2 per day for more than 2 to 4 weeks invariably produce HPA suppression. A study in children with relatively short-term exposure to prednisolone or dexamethasone (5 and 3 weeks, respectively) for treatment of acute lymphoblastic leukemia showed that recovery of normal adrenal function (in response to ACTH stimulation) had a very wide range, occurring between 2 weeks and 8 months (Petersen et al., 2003).
Although high dosages, prolonged therapy, and short duration between discontinuance of therapy and the surgical procedure increase the likelihood of HPA suppression, no practical test is available that unequivocally identifies patients who will need intraoperative steroids. Metyrapone depresses the production of cortisol by the adrenal glands and can be used to test the capacity of the pituitary gland to respond to decreased plasma cortisol concentrations by increasing ACTH secretion (Haynes, 1990). However, this test takes 3 days, is expensive, and has the risk of inducing adrenal insufficiency. Similarly, an ACTH-stimulation test can be performed at great expense to test adrenal responsiveness. However, even if cost and time were not issues, a study has shown a poor correlation between tests that indicate normal HPA function and dose or duration of glucocorticoid therapy or basal cortisol levels (Schlaghecke et al., 1992). Clinically significant events rarely occur during the perioperative period in unsupplemented patients who were receiving steroid medications for diseases other than adrenal insufficiency. Nevertheless, the potential for symptomatic adrenal insufficiency, although rare, coupled with the low risk of steroid-induced complications for short-term administration, suggests that steroids should be given in uncertain cases. If steroid therapy has been discontinued within the previous year, Donohoue (2005) makes the following recommendations:
HPA suppression also can result from modes of steroid administration other than oral, including topical, nasal spray, and inhalers. Although adrenal suppression is rarely symptomatic with these modes of administration, some drugs, especially fluticasone propionate, in high doses have been associated with growth failure and adrenal suppression (Duplantier et al., 1998). With surgical stress, patients with adrenal suppression may become symptomatic, as has been reported for other kinds of stress. The patients reported by Drake et al. (2002) all had been taking fluticasone and had hypoglycemia at times of stress from intercurrent illness. Numerous cases of acute adrenal crisis have been reported in children receiving inhaled corticosteroids (ICS) for prolonged periods (Randell et al., 2003). Anesthesiologists should have a high index of suspicion of adrenal suppression if an asthmatic child on inhaled steroids develops hypotension or hypoglycemia in the perioperative period.
The dose administered should also be proportional to the perceived degree of surgical stress. For brief procedures, such as upper endoscopy, a single preoperative dose of steroids is suggested (50 mg/m2 of hydrocortisone); for more complicated cases, such as appendectomy or major intraabdominal operations, 100 mg/m2 is administered as a continuous infusion or divided into 4 doses per day. This dose is usually continued for 1 to 3 days after more complex surgical procedures (Krasner, 1999). The dose is tapered postoperatively and replaced with the patient’s usual oral steroid preparation and dose when the child is able to tolerate oral medications. The dose that these patients commonly take for the underlying disease often exceeds even maximum “stress” doses described for congenitally adrenal insufficient patients, and treatment required for the underlying disease may limit further tapering of the steroid dose. A small study of adults comparing “stress steroids” with saline showed no adverse effects in patients who continued their usual steroid dose for their underlying disease (Glowniak and Loriaux, 1997).
Thyroid Disorders
Hypothyroidism
Hypothyroidism occurs because of abnormally low production of thyroid hormone. It may be caused by primary thyroid dysfunction or result from pituitary failure with decreased production of thyroid-stimulating hormone (TSH). Normal values for routinely performed thyroid function tests are presented in Table 36-6, and the interpretation of these test results with regard to diagnosis is presented in Table 36-7.
TABLE 36-6 Thyroid Function Tests
| Test | Age | Normal |
| T4 RIA (mcg/dL) | 1-3 days | 11-21.5 |
| 1-4 weeks | 8.2-16.6 | |
| 1-12 months | 7.2-15.6 | |
| 1-5 years | 7.3-15 | |
| 6-10 years | 6.4-13.3 | |
| 11-15 years | 5.6-11.7 | |
| 16-20 years | 4.2-11.8 | |
| T3 RU | 25%-35%* | |
| T index | 1.25-4.20† | |
| Free T4 (ng/dL) | 1-10 days | 0.6-2 |
| >10 days | 0.7-1.7 | |
| T3 RIA (ng/dL) | 1-3 days | 100-380 |
| 1-4 weeks | 99-310 | |
| 1-12 months | 102-264 | |
| 1-5 years | 105-269 | |
| 6-10 years | 94-241 | |
| 11-15 years | 83-213 | |
| 16-20 years | 80-210 | |
| TSH RIA (mIU/mL) | 1-3 days | <2.5-13.3 |
| 1-4 weeks | 0.6-10 | |
| 1 month-15 years | 0.6-6.3 | |
| 16-20 years | 0.2-7.6 | |
| TBG (mg/dL) | 1-3 days | — |
| 1-4 weeks | 0.5-4.5 | |
| 1-12 months | 1.6-3.6 | |
| 1-5 years | 1.3-2.8 | |
| 6-20 years | 1.4-2.6 | |
| Reverse T3‡ (mg/dL) | Newborns | 90-250 |
| Adults | 10-50 |
RIA, Radioimmunoassay; RU, resin uptake; T3, triiodothyronine; T4, thyroxine; TBG, thyroid-binding globulin; TSH, thyroid-stimulating hormone.
* Measures thyroid hormone binding, not T3.
Modified from Johnson KB, editor: The Harriet Lane Handbook, St. Louis, 1993, Mosby.
Primary thyroid dysfunction may be congenital or acquired. Congenital hypothyroidism usually appears in infancy. Classic features in the infant include large fontanels, wide sutures, large tongue, umbilical hernia, and decreased deep tendon reflexes. In the older child, manifestations include slow heart rate, narrow pulse pressure, growth failure, hypothermia, and cold intolerance. Severe hypothyroidism is rare but may be associated with coma, cardiovascular collapse, hyponatremia, hypothermia, and respiratory failure. Keon and Templeton (1993) reviewed the anesthetic management of patients with hypothyroidism and stressed the importance of correcting hypothyroidism gradually over a 2-week period. Sudden death has been reported in children with myxedematous heart disease 2 to 3 weeks into therapy (LaFranchi, 1979). It is suggested that these children receive one fourth of the maintenance dose of thyroid hormone (6 to 8 mcg/kg per day for an infant), with gradual incremental increases over 2 to 4 weeks until a maintenance dose is reached (Custer and Rau, 2009). Patients who are adequately treated will have normal thyroid hormone and TSH levels. Patients who do not respond to oral thyroid replacement may be given IV triiodothyronine (T3; loading dose of 0.7 mcg/kg), followed by an infusion titrated to T3 and TSH levels. Severe cardiac dysfunction in such a patient improved with T3 therapy (Mason et al., 2001). Patients with incompletely restored thyroid hormone levels may require hemodynamic monitoring and support to maintain hemodynamic stability. Patients with severe hypothyroidism may have associated adrenal insufficiency, and if so, they should receive stress steroid coverage as outlined earlier.
The anesthetic care of the symptomatic patient with hypothyroidism can be problematic and requires caution when any depressant medications are given. Prolonged effects may result from decreased drug metabolism. Important considerations in the management of hypothyroidism as described by Keon and Templeton (1993) are outlined in Table 36-8. Invasive monitoring may be indicated when significant blood loss or fluid shifts occur. Care should be taken intraoperatively to minimize heat loss. Postoperative care should include monitoring of oxygen saturation, blood pressure, heart rate, and respiratory rate; postoperative ventilation may be necessary in the patient with delayed emergence from anesthesia.
TABLE 36-8 Anesthetic Implications of Hypothyroidism
| System | Anesthetic Considerations |
| Pharmacologic | Possible lower MAC value; prolonged recovery from opioid anesthesia |
| Cardiovascular | Decreased cardiac output, heart rate, and stroke volume; increased PVR and decreased intravascular volume; myocardial depression resulting from impaired cellular metabolism or myxedematous infiltration; baroreceptor dysfunction |
| Respiratory | Abnormal response to hypercapnia and hypoxia |
| Thermal regulation | Hypothermia resulting from reduced basal metabolic rate; reduced ability to increase core temperature |
| Endocrine | Increased incidence of adrenal insufficiency; consideration for stress steroid coverage |
| Metabolic | SIADH; hypoglycemia with prolonged fasting |
| Gastrointestinal | Delayed gastric emptying; consideration for full stomach precaution |
MAC, Minimum alveolar concentration; PVR, peripheral vascular resistance; SIADH, syndrome of inappropriate antidiuretic hormone.
Hyperthyroidism
Hyperthyroidism is a syndrome produced by excess levels of circulating thyroid hormone. The most common causes are congenital hyperthyroidism and Graves disease (i.e., toxic goiter). Less commonly, acute suppurative thyroiditis, hyperfunctioning thyroid carcinoma, thyrotoxicosis factitia (i.e., exogenous administration of thyroid hormone), and toxic uninodular goiter (i.e., Plummer disease) may produce this syndrome. McCune-Albright syndrome (i.e., precocious puberty with polyostotic fibrous dysplasia) is also commonly associated with hyperthyroidism (Jones, 1988).
Congenital Hyperthyroidism
Congenital hyperthyroidism is a transient phenomenon seen in newborns that results from the transplacental transfer of thyroid-stimulating antibody from mothers who commonly have a history of Graves disease. Most of these infants have a goiter and typically appear anxious and restless or irritable. Signs of hypermetabolism, including tachycardia, tachypnea, and elevated temperature, may be present. In the severely affected infant, symptoms may progress to weight loss, severe hypertension, and high-output cardiac failure with hepatomegaly (Smith et al., 2001). Appropriate medical therapy (methimazole) should be instituted early. Because maternal immunoglobulins have a short half-life in infants, the hyperthyroid state resolves in a few weeks to a few months, and it sometimes may be followed by a period of hypothyroidism (Higuchi et al., 2001).
