Specific Considerations with Endocrine Disease

Becky Y. K. Tsui

Robert A. Peterfreund

Stephanie L. Lee

I. DIABETES MELLITUS

A. Diabetes mellitus (DM) is a chronic systemic disease characterized by an absolute or relative lack of insulin. DM is the most common endocrinopathy encountered in the perioperative period.

B. Physiology of DM. Insulin is synthesized in pancreatic β-cells. Glucose, β-adrenergic agonists, arginine, and acetylcholine stimulate insulin secretion; α-adrenergic agonists and somatostatin inhibit insulin secretion. Insulin facilitates glucose and potassium transport across cell membranes, increases glycogen synthesis, and inhibits lipolysis. Peripheral tissues resist the effects of insulin during times of stress (e.g., surgery, infection, and cardiopulmonary bypass). Normally, low-level insulin production continues during fasting periods, preventing catabolism and ketoacidosis.

C. Types of DM

1. DM type 1 is caused by autoimmune destruction of β-cells resulting in an absolute insulin deficiency. Patients are generally thin, diagnosed at a younger age, sensitive to small amounts of insulin, and prone to ketoacidosis. Management is with insulin.

2. DM type 2 is the diagnosis in 90% of all adult diabetics. Patients have peripheral resistance to insulin and require high insulin levels to maintain euglycemia. They are generally older, obese, ketosis resistant, and prone to hyperosmolar complications. Initial management is usually with diet and exercise alone. Oral hypoglycemic agents, insulin sensitizers, and/or insulin are added as needed. Type 2 diabetics frequently have metabolic syndrome, a combination of obesity, hyperlipidemia, hypertension (HTN), and insulin resistance. With the increasing prevalence of childhood obesity, DM type 2 is now encountered in teenagers

3. Gestational DM. Between 2% and 5% of pregnancies are complicated by gestational DM. More than 50% of parturients with gestational DM will develop DM type 2 later in life.

4. Secondary DM is due to other causes of absolute or relative insulin insufficiency. Insulin hyposecretion is seen with pancreatic destruction due to cystic fibrosis, pancreatitis, hemochromatosis, cancer, and after pancreatic surgery. Glucose intolerance may result from glucagonoma, pheochromocytoma, thyrotoxicosis, acromegaly, or glucocorticoid excess.

D. Terminology. The terms “juvenile-onset DM,” “adult-onset DM,” “insulin-treated DM,” and “Insulin-requiring DM” should be avoided. These terminologies fail to specify the actual type of DM and its implications.

E. Outpatient Therapy for DM

1. Oral hypoglycemic agents (Table 6.1)

a. Sulfonylureas increase pancreatic insulin release and may cause hypoglycemia. Glyburide and glimepiride, the two longest acting of
the currently used sulfonylurea agents, can induce hypoglycemia for more than 24 hours after administration. Sulfonylureas increase the effectiveness of thiazide diuretics, barbiturates, and anticoagulants by displacing these drugs from albumin.

TABLE 6.1 Noninsulin Agents Used to Treat DM

Agent		Onset (Hours)	Duration (Hours)
Sulfonylurea	Tolbutamide^a	≤0.25	6-12
	Tolazamide^a	1	10-24
	Chlorpropamide^a	1	60
	Glipizide (Glucotrol)	1	10-20
	Glipizide XL	1	20-24
	Gliclazide (glibenclamide)	1-2	12-24
	Glyburide (Micronase, Glynase, and Diabeta)	1	18-24
	Glimepiride (Amaryl)	1	24
α-Glucosidase inhibitor^b	Acarbose (Precose)	Immediate	<0.3
α-Glucosidase inhibitor^b	Miglitol (Glyset)	Immediate	<0.3
Biguanide^b	Metformin (Glucophage, Glumetza, Riomet, and Fortamet)	1	8-12
Thiazolidinedione^b	Pioglitazone (Actos)	1	24
	Rosiglitazone (Avandia)	1	24
Meglitinide	Repaglinide (Prandin)	1	3-4
D-Phenylalanine derivative	Nateglinide (Starlix)	1	4
GLP-1 receptor agonists^b,^c	Exenatide (Byetta)	<0.25	6-12
	Exenatide QW (Bydureon)^d	2-4 wk^e
	Liraglutide (Victoza)^d		24
	Albiglutide QW (Tanzeum)^d Dulaglutide (Trulicity)^d Lixisenatide (Lyxumia)^f
Amylin analog^b	Pramlintide (Symlin)	<0.25	2-4
DPP-IV inhibitor^b,^g	Sitagliptin (Januvia)	1	24
	Saxagliptin (Onglyza)	1-2	24
	Linagliptin (Tradjenta)^d	1.5
	Alogliptin (Nesina)^d
	Vildagliptin (Galvus)^d,^f
Dopamine agonist	Bromocriptine Mesylate (Cycloset and Parlodel)	1	8-12
SGLT2 inhibitor	Canagliflozin (Invokana) Empagliflozin (Jardiance) Dapagliflozin (Farxiga) Ipragliflozin (Suglat)^f	Within 24 (dose dependent)	24
^aHistorical agents that are no longer widely used. ^bWhen used as the sole agent for treatment, hypoglycemia while fasting (NPO) is unlikely. ^cGlucagon-like peptide 1. ^dOnset of action and/or duration of action are not reported. ^eSteady state achieved by week 7. ^fCurrently not FDA approved. ^gDipeptidyl peptidase IV.

b. Meglitinides and d-phenylalanine derivatives act via a nonsulfonylurea receptor pathway to rapidly increase insulin release from the pancreas. These drugs may also cause hypoglycemia.

c. Biguanides decrease insulin resistance, decrease hepatic glucose production, and inhibit intestinal glucose absorption. They will not produce hypoglycemia when used as single agent therapy for diabetes. Patients with congestive heart failure, shock, or renal or hepatic dysfunction are at risk for biguanide-induced lactic acidosis. In patients without these risk factors, the risk is close to zero. Diarrhea is a common side effect.

d. Thiazolidinediones decrease hepatic glucose production, enhance insulin’s action in the liver and skeletal muscle, and decrease insulin resistance. Side effects include abdominal obesity, fluid retention leading to edema or congestive heart failure, anemia, hepatotoxicity, and increased creatine phosphokinase. Thiazolidinediones will not produce hypoglycemia when used as single agent therapy.

e. α-Glucosidase inhibitors delay carbohydrate digestion and reduce postprandial hyperglycemia. Side effects include malabsorption, flatulence, and diarrhea. Drugs in this class will not produce hypoglycemia when used as single agent therapy.

f. Dipeptidyl peptidase IV (DPP-IV) inhibitors increase the level of endogenous glucagon-like peptide 1 (GLP-1), thereby enhancing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. They are not associated with significant gastrointestinal (GI) side effects or hypoglycemia. There is a potential increased risk of heart failure in susceptible patients.

g. Dopamine agonists improve glycemic control by resetting circadian activity in hypothalamic neurons. This reduces fasting and postprandial glucose, triglyceride, and free fatty acid levels. Side effects include fatigue, headache, and dizziness. Single agent therapy is not associated with hypoglycemia.

h. SGLT2 inhibitors reduce renal reabsorption of filtered glucose by inhibiting sodium-glucose cotransporter 2 (SGLT2). SGLT2 is located in the proximal renal tubules and is responsible for more than 90% of renal glucose reabsorption. By inhibiting this cotransporter, SGLT2 inhibitors increase urinary excretion of glucose and reduce plasma glucose in a glucose-dependent manner.

2. Injectable agents

a. Insulin (Table 6.2). Rapid-acting insulins are given just before meals to prevent postprandial hyperglycemia. Short- and intermediate-acting insulins are often given several times a day to provide basal and peaking levels. Long-acting insulins are given once daily to mimic basal insulin secretion. Regular and rapid-acting insulins can also be administered continuously via a pump. The liver and kidney metabolize insulin. As a result, renal insufficiency may produce clinically significant prolongation of insulin action and reduce insulin requirement.

b. Amylin analogs (Table 6.1) suppress postprandial glucose release from the liver, suppress glucagon secretion, and reduce appetite by delaying gastric emptying. Amylin analogs do not cause hypoglycemia when given alone but may cause hypoglycemia when given concurrently with insulin. The most common side effect is nausea.

c. GLP-1 analogs (Table 6.1) enhance glucose-stimulated insulin secretion, reduce glucagon levels, slow gastric emptying, and increase insulin biosynthesis. The most common adverse events include
nausea, vomiting, and diarrhea. GLP-1 analogs may also increase the risk of heart failure in susceptible patients. Patients receiving both a GLP-1 analog and a sulfonylurea are at increased risk for hypoglycemia.

TABLE 6.2 Subcutaneous (SC) Insulin Preparations Used to Treat DM

Class	Agent	Onset (Hours)	Peak Effect (Hours)	Duration (Hours)
Rapid Acting
	Lispro (Humalog)	0.1-0.25	1-2	2-4
	Aspart (NovoLog)	0.1-0.25	1-2	2-4
	Glulisine (Apidra)	0.1-0.25	1-2	2-4
Short Acting
	Regular (Humulin R, Novolin R)	0.5-1	2-4	6-10
Intermediate Acting
	NPH	2-4	6-12	12-18
Long Acting
	Glargine (Lantus)	1-3	No peak	20-24
	Detemir (Levemir)	1-3	No peak	20-24
Note:
1. When regular insulin is administered IV, the onset of action is immediate. The duration of action is ˜1 h.
2. Fixed combinations of insulin are used sometimes with potential consequences of having two drugs with different onset and duration profiles mixed together.
NPH, neutral protamine hagedorn.

F. Acute Complications of Diabetes. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS, previously known as hyperglycemic, hyperosmolar nonketotic state [HONK]) are the result of insulin deficiency, resistance to insulin during stress (e.g., infection, surgery, myocardial infarction [MI], dehydration, and trauma), or medications.

1. DKA occurs primarily in DM type 1. It may be the initial presentation of DM type 1.

a. DKA is associated with depressed myocardial contractility, decreased vascular tone, anion gap acidosis due to ketones, electrolyte abnormalities, hyperglycemia, and hyperosmolarity. Patients are often profoundly hypovolemic because of the forced diuresis of hyperglycemia, emesis, and reduced oral intake during illness. Total body K⁺ is depressed (3 to 10 mEq/kg of body weight), but serum levels are falsely normal or elevated because acidosis shifts K⁺ out of cells. Measured Na⁺ concentrations are artifactually lowered by 1.6 mEq/L for every 100 mg/dL that the glucose is elevated. Hypophosphatemia and hypomagnesemia from osmotic diuresis are common. Patients may present with nausea, vomiting, abdominal pain, polyuria, polydipsia, weakness, renal failure, shock, deep rhythmic (Kussmaul) breathing with a fruity odor, or mental status changes. Mortality of DKA is less than 5% when identified and treated early.

b. Treatment of DKA is with volume replacement, insulin, correction of electrolyte abnormalities, identification and treatment of underlying stressors or precipitants (MI, infection, etc.), and supportive care. The following outline pertains to management in the general
medical environment; management of the patient in the perioperative period may need to be more aggressive.

1. Begin the treatment with 15 to 20 mL/kg of intravenous normal saline (NS) in the first hour followed by NS at 5 to 15 mL/kg/h. If the corrected serum sodium is high or normal, ½ NS can be substituted at the same rate. Monitor the hemodynamics and urine output. Consider invasive monitoring.

2. Initiate potassium repletion once serum potassium levels fall below 5.5 mEq/L and the patient is making urine. For patients presenting with significant hypokalemia (<3.3 mEq/L), begin potassium repletion immediately with 40 mEq of potassium per hour. Delay insulin therapy briefly until potassium replacement has started.

3. Treat hyperglycemia and insulin deficiency with regular intravenous (IV) insulin. Give a first bolus of 0.1 to 0.15 U/kg IV and then start an infusion at approximately 0.1 U/kg/h. Monitoring should include hourly glucose and electrolyte determinations and frequent measures of pH, osmolarity, and ketones to guide adjustment of insulin dose and electrolyte replacement. If the serum glucose falls less than 50 mg/dL after 1 hour, double the insulin infusion rate every hour until a decline in glucose between 50 and 75 mg/hour is attained. Once glucose is less than 250 mg/dL, reduce the insulin infusion rate to 3 to 6 U/hour and add 5% dextrose to the IV fluids. Continue the insulin infusion until the anion gap and serum bicarbonate are normal. Premature cessation of the insulin infusion may result in recrudescence of DKA.

4. Replace magnesium and phosphate as needed once normal renal function and urine output have been verified. Consider bicarbonate therapy only for severe acidosis (pH <7), hemodynamic instability, or rhythm disturbances.

5. Identify and treat the underlying precipitants.

6. Patients with altered mental status may require intubation for airway protection.

2. HHS may be the initial presentation of DM type 2.

a. HHS is often associated with glucose levels exceeding 600 mg/dL, electrolyte abnormalities, central nervous system (CNS) dysfunction (depressed sensorium, seizure, and coma), and severe hyperosmolarity, hypovolemia, and hemoconcentration from osmotic diuresis. The typical water deficit may be 8 to 10 L. Patients may present with blurred vision, neurologic deficits, weight loss, leg cramps, polydipsia, or polyuria. Although insulin levels are inadequate to prevent hyperglycemia, they are sufficient to block lipolysis, ketogenesis, and ketoacidosis. Mortality due to HHS may be as high as 15%.

b. Treatment of HHS. The following outline pertains to management in the general medical environment; management of the patient in the perioperative period may need to be more aggressive.

1. Begin fluid therapy with 1 to 1.5 L (or 15 to 20 mL/kg) of NS in the first hour followed by 5 to 15 mL/kg/h of either NS or ½ NS, depending on whether the corrected serum sodium concentration is low or normal or high. Approximately 50% of the fluid deficit should be given over the first 12 hours, with the remainder administered more slowly over the following 24 to 36 hours. After the initial resuscitation, correct severe hyperglycemia and hyperosmolarity gradually over 24 hours to reduce the risk of
cerebral edema. The rate of fluid replacement may be adjusted in the elderly or in a patient with a history of congestive heart failure.

2. Start insulin administration after fluid therapy has begun. Glucose concentration can drop as much as 80 to 200 mg/dL/h with fluid therapy alone. Administer insulin as in the treatment of DKA. Begin with a 0.1 to 0.15 U/kg bolus followed by an infusion of 0.1 U/kg/h. The insulin infusion can be doubled hourly until an appropriate response is noted. Titrate insulin infusion rates to maintain glucose levels at less than 250 mg/dL until cardiovascular, electrolyte, and metabolic parameters are normal.

3. Measure glucose and electrolyte levels hourly. Potassium and electrolyte repletion is similar to that in the treatment of DKA. The absence of acidosis makes potassium deficiency generally less profound than observed with DKA.

4. It is important to search for and treat precipitants.

5. Patients with altered mental status may require intubation for airway protection.

6. Consider venous thrombosis prophylaxis as these patients are at high risk for thrombotic events.

G. Anesthetic considerations in the patient with DM focus on risk reduction, maintenance of euglycemia, avoidance or treatment of acute complications of DM, and prevention of perioperative complications related to chronic complications of DM.

1. DKA, HHS, and metabolic abnormalities should be treated before elective surgery and actively managed in the operating room if surgery is urgent. For blood glucose level greater than 350 mg/dL, surgery should be postponed if the glucose level can be further optimized. Of note, certain surgical conditions (such as sepsis) or perioperative steroid therapy maybe the cause of hyperglycemia and should be considered before postponing elective surgery.

2. Glycemic management. There is no consensus on the ideal blood glucose target. However, there is evidence that tight control of blood glucose may not be desirable as recent studies show an increased mortality rate attributed to hypoglycemia. However, perioperative hyperglycemia is undesirable. It decreases white blood cell chemotaxis and function, increases infection rates, impairs wound healing, leads to dehydration from osmotic diuresis, and promotes a hyperviscous and possibly thrombogenic state. Hyperglycemia is also associated with increased rates of renal allograft rejection and worse outcomes after MI, stroke, burn, traumatic brain injury, and spinal cord injury. The authors of this chapter recommend maintaining serum glucose levels between 120 and 180 mg/dL. However, for short procedures, management of baseline hyperglycemia in patients with poorly controlled diabetes should be deferred to the postoperative period and not be actively corrected intraoperatively as acute alterations may be harmful.

a. Oral hypoglycemic agents and insulin sensitizers that can cause hypoglycemia (sulfonylureas, meglitinides, and D-phenylalanine derivatives) should be held the day of surgery. Amylin analogs and GLP-1 analogs, which cause delayed gastric emptying, should also be held in order to reduce the likelihood of postoperative nausea and vomiting (PONV). Metformin should be held from the day of surgery until normal postoperative renal function has been confirmed because of its association with lactic acidosis. Thiazolidinediones and DPP-IV inhibitors do not cause hypoglycemia and may be given
the morning of surgery. α-Glucosidase inhibitors also do not produce hypoglycemia, but they are ineffective when patients are NPO (nothing by mouth [nil per os]). SGLT2 inhibitors may cause hypovolemia. This is also the newest class of diabetic medications with little experience in anesthetized patients; there may be unexpected side effects. Patients with well-controlled DM type 2, who are undergoing a minor surgery and have held their oral hypoglycemics, can often be managed without insulin. However, glucose levels should be monitored in all patients to detect hypoglycemia or hyperglycemia. Patients who have taken their oral hypoglycemic agents may require a glucose infusion, and poorly controlled patients or patients undergoing major surgery may require insulin treatment.

b. Insulin-treated type 2 diabetics. Insulin should be continued through the night before surgery. If the patient has a history of hypoglycemia, the dose should be reduced to ½ to 2/3 of the patient’s customary dose.

c. Patients should receive approximately half of their total normal morning dose of intermediate- or long-acting insulin in a subcutaneous dose. Rapid- and short-acting insulins should not be given. Start a glucose-containing infusion (5% dextrose, 1.5 mL/kg/h) as soon as possible (with the morning insulin dose for hospitalized patients and on arrival to the hospital for same-day admit patients). Patients scheduled for surgery later in the day should arrive early to facilitate glucose and insulin management while they are NPO. The blood glucose should be checked frequently (every 2 to 4 hours). If glucose drops below 120 mg/dL, the glucose infusion rate should be increased. If glucose rises above 180 mg/dL, an infusion of regular insulin should be started and continued throughout the perioperative period. Because of unreliable intraoperative subcutaneous absorption, IV insulin dosing is preferable during surgery, especially in the presence of hypothermia, hemodynamic instability, or a requirement for vasopressors. A guideline for managing intraoperative infusions of regular insulin is presented in Table 6.3. During
therapy with IV insulin, glucose should be checked at least every hour until stable and every 2 hours thereafter. Monitor potassium levels during insulin infusion. Decrease the insulin infusion rate and avoid potassium administration if renal insufficiency develops.

TABLE 6.3 Guidelines for Routine Regular IV Insulin Infusion

Begin regular insulin infusion at 0.5-1 unit/h (25 units/25 mL of saline). Check glucose at least hourly until stable and adjust infusion as appropriate. Then check glucose at least every 2 h.
Adjustment of Regular Insulin Infusion Rate, units/hour
Blood Glucose (mg/dL)	Infusion Change	Other Treatment
<70	Hold 30 min	Administer D50, 15-20 mL. Recheck glucose after 30 min. Repeat D50 administration until glucose >70 mg/dL.
70-120	-0.3 U/h
121-180	No change
181-240	+0.3 U/h
241-300	+0.6 U/h
>300	+1.0 U/h
Notes: Guidelines assume the patient is fasting and not in DKA or HHS. Dosing must be individually titrated based on frequent blood glucose monitoring. D50 is a solution of dextrose, 50% (weight/volume) in water.