Diabetes Mellitus

Mark E. Nunnally

Vinod Malhotra

A 59-year-old woman presents for vaginal hysterectomy for cervical cancer. She is obese (body mass index 32 kg per m²) and has had diabetes mellitus (DM) type 2, hypertension, and dyslipidemia for 20 years. She takes enalapril, metoprolol, atorvastatin, metformin, sitagliptin, and recently, insulin glargine, 20 units subcuta-neous, daily for refractory hyperglycemia. She measures her serum glucose inter-mittently at home. Values are generally 150 to 220 mg per dL. She experiences an early and prolonged sense of fullness after meals and an unpleasant sour taste at night two or three times per week. Laboratory values are notable for a serum creatinine of 2.2 mg per dL and a serum glucose of 206 mg per dL. She has not taken any medications today and has had nothing to eat since midnight.

A. Medical Disease and Differential Diagnosis

What is the epidemiology of DM in the general population?
What are the factors in the etiology of the disease?
How is DM classified?
What are the complications of DM?
How are the different forms of this illness treated?
How is control of the disease adequately monitored?
What are some of the factors that alter insulin requirements?
What are the principles of management of diabetic ketoacidosis (DKA)?
What is a hyperglycemic hyperosmolar state?

B. Preoperative Evaluation and Preparation

How should this patient be evaluated?
How would the stiff joint syndrome affect her airway management?
What are the signs and implications of autonomic neuropathy in the diabetic patient?
How should this patient be prepared for anesthesia and surgery?
For elective surgery, how are insulin and glucose requirements managed on the day of surgery?
How should this patient be premedicated?

C. Intraoperative Management

What are the effects of anesthesia and surgery on insulin and glucose metabolism?
What anesthetic techniques should be considered?
How should this patient be monitored?
How is hyperglycemia treated intraoperatively?
How is hypoglycemic shock recognized and treated intraoperatively?

D. Postoperative Management

How is diabetes controlled in this patient postoperatively?
Does diabetes increase perioperative risk?
What are the common postoperative complications to be expected in a diabetic patient?
Is it necessary to achieve tight perioperative control of glucose?

A. Medical Disease and Differential Diagnosis

A.1. What is the epidemiology of DM in the general population?

DM, literally “sweet urine,” is a group of metabolic disorders defined by elevated serum glucose. Data from the National Health and Nutrition Examination Survey from 2007 to 2010 suggest a prevalence of DM in the adult population of 11.4%, with more than a quarter of those undiagnosed. For patients 65 years or older, the prevalence is 25.7%. National Health Interview Survey (NHIS) data suggest a doubling of prevalence between 1990 and 2008, but no significant change between 2008 and 2012.

A majority of patients with diabetes (approximately 90%) have type 2 diabetes (DM2); a minority (approximately 10%) have type 1 diabetes (DM1). Finally, 1% to 14% of pregnant women develop gestational diabetes. DM1 and DM2 are very different diseases. In DM1, ex-ogenous insulin is essential for cellular metabolism. Untreated, DM1 is a wasting disease associated with ketoacidosis and severe cumulative organ failure. DM2 is a metabolic disorder associated with resistance to insulin effects. Because of the presence of circulating insulin, ketoacidosis is rare in DM2. However, a hyperglycemic hyperosmolar state is a risk in the inadequately treated patient.

Diabetes prevalence and glycemic control among adults aged 20 and over, by sex, age, and race and Hispanic origin: United States, selected years 1988-1994 through 2007-2010. http://www.cdc.gov/nchs/data/hus/2013/046.pdf. Accessed September 15, 2015.

Geiss LS, Wang J, Cheng YJ, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980-2012. JAMA. 2014;312(12):1218-1226.

Hillier TA, Vesco KK, Pedula KL, et al. Screening for gestational diabetes mellitus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;148:766-775.

A.2. What are the factors in the etiology of the disease?

Because hyperglycemia defines DM, it is too easy to focus on elevations in serum glucose, ignoring other effects. Lipid and protein metabolism are deranged in both varieties of DM. Tissue growth, signaling, and function are likewise impaired. Simple control of blood sugar may not adequately treat the complex hormonal and metabolic derangements of DM. Inflammation and immune dysfunction are also components of the disease.

In DM1, the immune system destroys insulin-secreting pancreatic beta cells. The diagnosis of DM1 is frequently made in childhood. DM2 manifests in a variety of conditions that decrease the hypoglycemic effects of insulin. Among these are obesity and endocrine and inflammatory conditions. In both cases, genetic association is incomplete and there is association with other diseases, including autoimmune disorders, hypertension, and dyslipidemias. Gestational diabetes reflects insulin resistance exacerbated by the effects of pregnancy. It likely signals patients who are at risk of developing DM2.

Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health and Nutrition Examination Survey 1999-2002. Diabetes Care. 2006;29(6):1263-1268.

McDonald M, Hertz RP, Unger AN, et al. Prevalence, awareness, and management of hypertension, dyslipidemia, and diabetes among United States adults aged 65 and older. J Gerontol A Biol Sci Med Sci. 2009;64(2):256-263.

A.3. How is DM classified?

Table 23.1 lists the criteria for the diagnosis of DM1, DM2, and gestational diabetes. Elevated (≥6.5%) hemoglobin (Hgb) A₁C or fasting hyperglycemia (≥126 mg per dL) are useful means
to confirm metabolic derangement, but random hyperglycemia accompanied by classic symptoms (such as polyuria and polydipsia), or the inability to manage a glucose load, are sufficient to make the diagnosis. Ketoacidosis and the need for insulin reflect DM1, whereas obesity, gradual onset (usually at an older age), and hyperosmolality without ketosis suggest DM2. Gestational diabetes resembles DM2 only in the setting of pregnancy.

TABLE 23.1 American Diabetes Association Diagnostic Criteria for Diabetes Mellitus

1. Symptoms of diabetes plus random plasma glucose level >200 mg/dL (11.1 mmol/L)

2. Hemoglobin A₁C ≥6.5%

3. Fasting plasma glucose level ≥126 mg/dL (7.0 mmol/L)

4. Two-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L) during oral glucose tolerance test

From American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(suppl 1): S62-S69.

Therapy for DM varies by type. Insulin is essential in DM1. In DM2 and gestational diabetes, diet, exercise, and drugs that modify insulin secretion or sensitivity can help correct hyperglycemia, although exogenous insulin may be necessary.

American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36 (suppl 1): S11-S66.

A.4. What are the complications of DM?

Acute complications of DM include DKA and a hyperglycemic hyperosmolar state. Both are associated with severe systemic illness and a high mortality and will be discussed separately. Hypoglycemia is a serious risk of several diabetes therapies.

Chronically, DM impacts virtually every organ system. Of most concern to the anesthetist are macrovascular disease, including accelerated atherosclerosis, and microvascular nephropathy, neuropathy, and cardiomyopathy. Tissues fail from a combination of advanced glycation end products, inflammation, connective tissue proliferation, and impaired perfusion. Renal failure, neuropathy, and accelerated coronary, cerebral, and peripheral vascular disease are common. Autonomic neuropathy and the stiff joint syndrome are both factors for preoperative evaluation (see later discussion). Hypertension frequently accompanies DM, exacerbating organ failure. Impaired immune function predisposes to infection. Hypercoagulability exacerbates macrovascular disease. Dyslipidemias accelerate atherosclerotic lesions and may directly contribute to metabolic toxicities.

Cumulatively, the systemic lesions caused or exacerbated by DM reduce life expectancy. When diagnosed before the age of 35 years, DM causes an estimated mean of 25.9 years of lost life. Because complications worsen with time, this effect decreases. About 50% of mortality in diabetic patients comes from cardiovascular disease.

Although it would be helpful to stratify diabetic patients according to their risk of complications, the complexity of the disease and its management makes risk stratification difficult. The safest assumption is that a diabetic is at high risk for coronary and other macrovascular disease, congestive heart failure, and renal insufficiency.

Ford ES, Zhao G, Li C. Pre-diabetes and the risk for cardiovascular disease: a systematic review of evidence. J Am Coll Cardiol. 2010;55:1310-1317. Stolar M. Glycemic control and complications in type 2 diabetes mellitus. Am J Med. 2010;123:S3-S11.

A.5. How are the different forms of this illness treated?

Diabetes care is different in chronic and acute settings. It is essential to differentiate between the agents used chronically and during acute perioperative stress.

Care of DM1 requires exogenous insulin. Figure 23.1 illustrates the pharmacodynamics of several insulin preparations. A combination of a short- and a long-acting insulin preparation can help achieve the goals of resting and postprandial glycemic control. In contrast, DM2
responds to insulin, oral insulin secretagogues, insulin sensitizers, glucose uptake inhibitors, gastrointestinal hormones, weight loss, dietary management, and exercise. Table 23.2 lists the major classes of drugs for the treatment of DM2, their mechanisms of action, pharmacokinetics, and particular concerns for the anesthetist.

FIGURE 23.1 Onset and duration of action graphic for common subcutaneous insulin preparations. Regular insulin given intravenously fits the best profile for a titratable drug in the operating room, as onset peak and offset all occur within an hour. NPH, neutral protein hagedorn.

Certain medications have adverse effects that deserve consideration. Biguanides, such as metformin, increase peripheral glucose uptake but also predispose patients to greater production of lactic acid and acidosis. The significance of this finding is not clear, but many recommend discontinuing these drugs perioperatively because they might increase the risk of lactic acidosis with hypoperfusion during surgery. Because of its long half-life, metformin may take up to 72 hours to clear from the bloodstream, so discontinuation on the day of surgery does not minimize the risk of acidosis. Thiazolidinediones have been associated with hepatic injury and congestive heart failure. Exenatide is associated with reports of kidney dysfunction. Sulfonylureas, pramlintide, and sitagliptin may be associated with hypoglycemia. Glucose transporter type 2 inhibitors, such as dapagliflozin, may be associated with urogenital infections. Long-term risks remain poorly characterized for this and other new agents, such as glucagon-like peptide agonists and inhaled insulin preparations.

For these reasons, as well as unreliable pharmacokinetics, the best option for acute treatment of all types of diabetic hyperglycemia is insulin. Although subcutaneous dosing is often used in the hospital setting, intravenous insulin best meets the profile of an ideal titratable agent. It has a short time to onset (10 to 15 minutes), peak effect (less than 30 minutes), and duration of action (45 minutes). Frequent glucose monitoring is essential to titrate the therapy.

Although serum glucose or other markers of chronic hyperglycemia, such as Hgb A₁C are currently standard end points for chronic therapy, other factors such as serum lipid and blood pressure management may be just as important. Anesthesiologists should inquire about agents treating these conditions during preoperative evaluation.

Bagry HS, Raghavendran S, Carli F. Metabolic syndrome and insulin resistance: perioperative considerations. Anesthesiology. 2008;108:506-523.

Chen D, Lee SL, Peterfreund RA. New therapeutic agents for diabetes mellitus: implications for anesthetic management. Anesth Analg. 2009;108:1803-1810.

Jung CH, Chung EJ, Park JY. A novel therapeutic agent for type 2 diabetes mellitus: SGLT2 inhibitor. Diabetes Metab J. 2014;38:261-273.

A.6. How is control of the disease adequately monitored?

Self-monitoring of blood glucose is possible in all forms of diabetes, usually by using fingerstick blood samples and portable monitors. This method is the established standard of care in DM1 for carefully titrated control to prevent hypoglycemia and ketoacidosis. Many advocate

self-monitoring for patients with DM2, especially if they take insulin, but compliance varies, and self-monitoring may not be beneficial in all patients. Hgb A₁C, the product of hemoglobin exposure to hyperglycemic conditions, is a marker of long-term glycemic control. It may help identify subgroups of patients for whom the risk for complications is higher and can be a marker of disease control. The relationship between levels of glycemic control and Hgb A₁C is not linear, so a single laboratory value does not completely reveal the glycemic profile over time. Patients with DM have blood pressure and serum lipid profiles monitored as part of their long-term care because these factors increase the risk of lifetime complications.

TABLE 23.2 Common Therapies for Type 2 Diabetes^a

DRUG NAME/CLASS		MECHANISM	ROUTE	ONSET	DURATION	IMPORTANT CONSIDERATIONS
First-Generation Sulfonylureas		↑ Beta cell insulin secretion	PO			Hypoglycemia risk
	Tolbutamide			1 hr	12 hr
	Acetohexamide			3 hr	24 hr
	Tolazamide			4 hr	16 hr
	Chlorpropamide			2 hr	24 hr
Second-Generation Sulfonylureas		↑ Beta cell insulin secretion	PO			Hypoglycemia risk
	Glyburide (Micronase)			30 min	24 hr
	Glipizide IR (Glucotrol)			30 min	24 hr
	Glipizide ER (Glucotrol XL)			2-4 hr	24 hr
	Glimepiride (Amaryl)			2-3 hr	24 hr
Biguanides		↑ Peripheral glucose uptake in response to insulin	PO			Lactic acidosis risk may extend up to 72 hr after administration
	Metformin (Glucophage)			1-3 hr	17 hr
α-Glucosidase Inhibitors		↓ Digestive carbohydrate breakdown	PO			No known adverse effects
	Acarbose (Precose)			2 hr	NA
	Miglitol (Glyset)			2-3 hr	NA
Thiazolidinediones (PPAR-γ mediators)		↑ Peripheral glucose uptake	PO			Risk for hepatic injury, fluid retention; ongoing concerns about myocardial ischemia
	Pioglitazone (Actos)			hours	T_1/2 3-7 hr
	Rosiglitazone (Avandia)			hours	T_1/2 3-4 hr
Glinides		↑ Beta cell insulin secretion	PO			Hypoglycemia risk
	Repaglinide (Prandin)			15-60 min	4-6 hr
	Nateglinide (Starlix)			20 min	T_1/2 1.5 hr
Incretin-Mimetics		↑ Insulin, ↓ glucagon, hepatic glucose production, gastric emptying, and appetite	SC			Observational data associate with renal failure
	Exenatide (Byetta)			10 min	6-8 hr
	Liraglutide (Victoza)			minutes	T_1/2 13 hr
DPP-IV Inhibitors		Inhibits incretin breakdown	PO			May have effects on immune function
	Sitagliptin (Januvia)			hours	days
	Saxagliptin (Onglyza)			hours	24 hr
Amylin Analogues		↑ Satiety, ↓ glucagon, and appetite	SC			No confirmed hypoglycemia risk
	Pramlintide (Symlin)			minutes	hours
^aOnset and duration data are approximate only and subject to variability.
PO, per os (by mouth); PPAR, peroxisome proliferator-activated receptor; SC, subcutaneous; DPP-IV, dipeptidyl peptidase – 4.