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Author(s): AubreySamost-Williams, JenniferCottral

  1. Diabetes mellitus (DM) is a chronic systemic disease characterized by an absolute or relative lack of insulin. As of 2020, approximately 10.5% of the US population has DM, 90% to 95% of which is DM type 2. DM is the most common endocrinopathy encountered in the perioperative period.
  2. Types of DM
    1. DM type 1 (DM1) is caused by autoimmune destruction of pancreatic β-cells resulting in an absolute insulin deficiency. Patients are usually diagnosed at a young age, not obese, and prone to ketoacidosis. Management is with insulin.
    2. DM type 2 (DM2) is characterized by impaired insulin secretion and peripheral insulin resistance. Patients are typically diagnosed in adulthood and prone to hyperosmolar complications. Common comorbidities include hypertension (HTN), obesity, cerebrovascular disease, cardiovascular disease, and peripheral vascular disease. Common complications of DM2 include retinopathy, nephropathy, and neuropathy. With the increasing prevalence of childhood obesity, DM2 is now encountered in children and adolescents. Initial management is usually with diet and exercise. Oral hypoglycemic agents, insulin sensitizers, and/or insulin are added as needed.
    3. Gestational DM. Between 6% and 9% of pregnancies are complicated by gestational DM. Parturients with gestational DM have a 3 to 7 times increased risk of developing DM2 within 5 to 10 years and a lifetime risk of up to 60%.
    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 a glucagonoma or pheochromocytoma, thyrotoxicosis, acromegaly, or glucocorticoid excess.
  3. 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 (eg, surgery, infection, cardiopulmonary bypass). Normally, low-level insulin production continues during fasting periods, preventing catabolism and ketoacidosis.
  4. Obsolete 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. Instead use the terms listed above.
  5. Outpatient therapy for DM
    1. Oral hypoglycemic agents (Table 7.1)
      1. Sulfonylureas (SFUs) increase pancreatic insulin release, thereby lowering blood glucose. There is an increased risk of hypoglycemia with these agents because circulating blood glucose levels do not influence the effect of SFUs. Glyburide and glimepiride, the two longest acting of the currently used SFUs, can induce hypoglycemia for more than 24 hours after administration. SFUs increase the effectiveness of thiazide diuretics, barbiturates, and anticoagulants by displacing these drugs from albumin.

        Table 7-1 Noninsulin Agents Used to Treat DM

        AgentOnset (Hours)Duration (Hours)
        SulfonylureaTolbutamidea≤0.256-12
        Tolazamidea110-24
        Chlorpropamidea160
        Glipizide (Glucotrol)110-20
        Glipizide XL120-24
        Gliclazide (glibenclamide)1-212-24
        Glyburide (Micronase, Glynase, and Diabeta)118-24
        Glimepiride (Amaryl)124
        α-Glucosidase inhibitorbAcarbose (Precose)Immediate<0.3
        Miglitol (Glyset)Immediate<0.3
        BiguanidebMetformin (Glucophage, Glumetza, Riomet, and Fortamet)18-12
        ThiazolidinedionebPioglitazone (Actos)124
        Rosiglitazone (Avandia)124
        MeglitinideRepaglinide (Prandin)13-4
        D-Phenylalanine derivativeNateglinide (Starlix)14
        GLP-1 receptor agonistsb,cExenatide (Byetta)<0.256-12
        Exenatide QW (Bydureon)d2-4 wke
        Liraglutide (Victoza)d24
        Albiglutide QW (Tanzeum)d
        Dulaglutide (Trulicity)d
        Lixisenatide (Lyxumia)
        Amylin analoguebPramlintide (Symlin)<0.252-4
        DPP-IV inhibitorb,gSitagliptin (Januvia)124
        Saxagliptin (Onglyza)1-224
        Linagliptin (Tradjenta)d1.5
        Alogliptin (Nesina)d
        Vildagliptin (Galvus)d,f
        Dopamine agonistBromocriptine Mesylate (Cycloset and Parlodel)18-12
        SGLT2 inhibitorCanagliflozin (Invokana)
        Empagliflozin (Jardiance)
        Dapagliflozin (Farxiga)
        Ipragliflozin (Suglat)f        		Within 24 (dose dependent)24

        a Historical agents that are no longer widely used.

        b When used as the sole agent for treatment, hypoglycemia while fasting is unlikely.

        c Glucagon-like peptide 1.

        d Onset of action and/or duration of action are not reported.

        e Steady state achieved by week 7.

        f Currently not FDA approved.

        g Dipeptidyl peptidase IV.

      2. Meglitinides andD-phenylalanine derivatives act via a nonsulfonylurea receptor pathway to rapidly increase insulin release from the pancreas. These drugs may also cause hypoglycemia but are more rapid and short acting than SFUs.
      3. Biguanides decrease hepatic glucose production, inhibit intestinal glucose absorption, and increase peripheral glucose uptake and utilization. Metformin is the only currently marketed drug in this class and when used as monotherapy, is associated with a very low risk of hypoglycemia. Medical conditions leading to increased plasma metformin levels may predispose patients to lactic acidosis, such as renal dysfunction (reduced drug clearance), hepatic dysfunction (reduced lactate clearance), or heart failure. Diarrhea is a common side effect.
      4. Thiazolidinediones increase insulin sensitivity and decrease hepatic glucose production. Side effects include weight gain, fluid retention leading to edema or heart failure, and upper respiratory tract infection. Risk of hypoglycemia is low when used as monotherapy. As of 2020, rosiglitazone remains available in the United States despite an associated increased risk of heart attack, heart failure, and death.
      5. α-Glucosidase inhibitors decrease the rise in postprandial glucose by preventing intestinal absorption of glucose. There is a low risk of hypoglycemia, and side effects include abdominal pain, flatulence, and diarrhea.
      6. Dipeptidyl peptidase IV (DPP-4) inhibitors prevent the breakdown 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, and there is a low risk of hypoglycemia. There is a potential increased risk of heart failure with some DPP-4 agents in susceptible patients.
      7. Dopamine (D2) agonists improve glycemic control by increasing hypothalamic dopamine levels and decreasing excessive sympathetic tone within the central nervous system (CNS). This reduces fasting and postprandial glucose, triglyceride, and free fatty acid levels. Side effects include nausea, asthenia, constipation, and dizziness. Single-agent therapy is not associated with hypoglycemia.
      8. SGLT2 inhibitors decrease renal glucose reabsorption by inhibiting sodium-glucose cotransporter 2 (SGLT2) in the nephron, which is responsible for more than 90% of renal glucose reabsorption. SGLT2 inhibitors do not usually cause hypoglycemia because they increase urinary excretion of glucose in a plasma glucose-dependent manner. Adverse effects include an increased risk of genitourinary infection, osmotic diuresis leading to volume depletion and orthostatic hypotension, euglycemic diabetic ketoacidosis, bone fractures, and lower limb amputations.
    2. Injectable agents
      1. Insulin (Table 7.2). Rapid and short-acting insulins are given just before meals to prevent postprandial hyperglycemia. Intermediate and long-acting insulins are given 1 to 2 times a day to mimic basal insulin secretion needed to meet baseline metabolic requirements. Rapid and short-acting insulins can also be administered continuously via a subcutaneous pump. The liver and kidney metabolize insulin. As a result, renal insufficiency and hepatic impairment may produce clinically significant prolongation of insulin action and reduce insulin requirements. Adverse reactions associated with insulin analogues are vast, but the most relevant risk is severe hypoglycemia.

        Table 7-2 Subcutaneous Insulin Preparations Used to Treat DM

        ClassAgentOnset (Hours)Peak Effect (Hours)Duration (Hours)
        Rapid Acting
        Lispro (Humalog)0.1-0.251-22-4
        Aspart (NovoLog)0.1-0.251-22-4
        Glulisine (Apidra)0.1-0.251-22-4
        Short Acting
        Regular (Humulin R, Novolin R)0.5-12-46-10
        Intermediate Acting
        NPH2-46-1212-18
        Long Acting
        Glargine (Lantus)1-3No peak20-24
        Detemir (Levemir)1-3No peak20-24

        When regular insulin is administered IV, the onset of action is immediate. The duration of action is ~1 h.

      2. Amylin analogues (Table 7.1) suppress inappropriate postprandial glucagon secretion seen in DM (glucagon stimulates hepatic release of glucose) and reduce appetite by delaying gastric emptying. Amylin analogues do not cause hypoglycemia as monotherapy but may cause hypoglycemia when given concurrently with insulin. Common side effects include nausea and headache.
      3. GLP-1 analogues (Table 7.1) enhance glucose-dependent insulin secretion, reduce inappropriate postprandial glucagon secretion seen in DM, and reduce appetite by delaying gastric emptying. Hypoglycemia is a risk only when GLP-1 analogues are taken with other agents known to cause hypoglycemia. The most common adverse events include nausea, vomiting, and diarrhea.
  6. Acute complications of diabetes.Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) are the result of insulin deficiency, resistance to insulin during stress (eg, infection, surgery, myocardial infarction, intoxication [alcohol, cocaine], dehydration, and trauma), and/or medications.
    1. DKA occurs primarily in DM1.
      1. Pathophysiology of DKA is related to an absolute low level of insulin leading to extracellular hyperglycemia and intracellular hypoglycemia. This shifts metabolism from glucose-based to ketogenic, leading to the uncontrolled production of ketone bodies and subsequent high anion gap metabolic acidosis. Extracellular hyperglycemia leads to fluid shifts, osmotic diuresis, and subsequent electrolyte abnormalities.
      2. Clinical manifestations of DKA include nausea, vomiting, abdominal pain, polyuria, polydipsia, weakness, renal failure, shock, deep rhythmic (Kussmaul) breathing with a fruity odor, and mental status changes. It is associated with depressed myocardial contractility, decreased vascular tone, high anion gap metabolic acidosis, electrolyte abnormalities, hyperglycemia, and hyperosmolarity. Patients are often profoundly hypovolemic owing to hyperglycemia-related osmotic diuresis, emesis, and reduced oral intake. Total body potassium (K+) is depressed, but serum levels are spuriously normal or elevated because acidemia shifts K+ out of cells via transcellular hydrogen (H+)-K+ exchange. Serum sodium (Na+) concentrations may be spuriously low because hyperglycemia causes osmotic shifts of water from the intracellular to the extracellular space, leading to a relative dilutional hyponatremia. Hypophosphatemia and hypomagnesemia from osmotic diuresis are common.
      3. Treatment of DKA is based on the principles of volume replacement (fluid deficit in adult DKA averages 6-9 L), insulin therapy, correction of electrolyte abnormalities, identification and treatment of underlying stressors or precipitants, and supportive care. DKA management algorithms often vary by institution.
    2. HHS is primarily a presentation of DM2.
      1. Pathophysiology of HHS is related to severe hyperglycemia owing to a relative insulin deficiency and increase in counterregulatory hormones (glucagon, catecholamines, cortisol) leading to osmotic diuresis and profound hypovolemia. Insulin levels are inadequate to prevent hyperglycemia but are sufficient to block ketogenesis and ketoacidosis.
      2. Clinical manifestations of HHS are often associated with serum glucose levels exceeding 600 mg/dL. They include electrolyte abnormalities, CNS dysfunction (depressed sensorium, seizure, coma), blurred vision, neurologic deficits, weight loss, leg cramps, polydipsia, and polyuria. Mortality in HHS may be as high as 20%.
      3. Treatment of HHS is similar to the treatment of DKA, with an emphasis on volume repletion, insulin therapy, correction of electrolyte abnormalities, and diagnosis and treatment of underlying precipitants. Intubation should be considered if there is a concern for lack of airway protection owing to altered mental status. Volume repletion is generally more aggressive in HHS owing to a higher fluid deficit (8-10 L in the average size adult), and initial target glucose level is higher than DKA (250-300 mg/dL in HHS, 200 mg/dL in DKA). The target glucose level in HHS is higher to prevent rapid correction of serum osmolality and subsequent cerebral edema.
  7. 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. Perioperative glycemic targets. Both hyperglycemia and hypoglycemia have been associated with increased morbidity and mortality in the preoperative period. However, the optimal target blood glucose range remains unclear and no consensus has been reached among affiliated professional societies. In addition, there is a growing body of evidence suggesting that the link between hyperglycemia and adverse outcomes in cardiac and noncardiac surgery may not be as strong in diabetic patients as compared with their nondiabetic counterparts. A consistent finding is that tighter glucose control leads to more frequent hypoglycemic events, which may be associated with increased morbidity and mortality. Most professional societies agree that treatment with insulin therapy should be initiated at blood glucose levels >180 mg/dL.
    2. Perioperative glycemic management depends on anesthetic technique, duration and invasiveness of surgery, and anticipated time to resumption of oral intake.
      1. Oral hypoglycemic agents and insulin sensitizers that can cause hypoglycemia should be held the day of surgery.
        1. Amylin analogues and GLP-1 analogues, which cause delayed gastric emptying, should also be held in order to reduce the likelihood of postoperative nausea and vomiting.
        2. Metformin should be held from the day of surgery until normal postoperative renal function has been confirmed.
        3. Thiazolidinediones and DPP-IV inhibitors do not cause hypoglycemia and may be given the morning of surgery.
        4. α-Glucosidase inhibitors also do not produce hypoglycemia, but they are ineffective when patients are NPO (nothing by mouth). SGLT2 inhibitors should be continued if ambulatory surgery, and should be stopped the morning of any minor or major nonambulatory surgery.
      2. Insulin
        1. Insulin-dependent DM2.
          1. Insulin should be continued through the night before surgery. If the patient has a history of hypoglycemia, the dose should be reduced to half to two-thirds of the patient’s customary dose.
          2. 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.
          3. If glucose drops below 120 mg/dL, consider starting a glucose infusion. If glucose rises above 180 mg/dL consider starting insulin.
            1. IV insulin should be used if the patient is (1) expected to be hemodynamically unstable, (2) expected to have fluid shifts or temperature changes, (3) has an operative duration > 4 hours, (4) is critically ill, or (5) is poorly controlled at home. See Table 7.3 for an example infusion regimen.

              Table 7-3 Guidelines for Routine Regular IV Insulin Infusion

              If blood glucose (BG) >180: Start IV insulin bolus dose (blood sugar/40) units. Start IV insulin infusion (blood sugar/100) units/h. Check glucose at least hourly until stable and adjust infusion as appropriate. Then check glucose at least every 2 hours.
              Adjustment of Regular Insulin Infusion Rate, units/hour
              Blood Glucose (mg/dL)Infusion change if BG has increased since last checkInfusion change if BG has decreased less than 30 mg/dLInfusion change if BG has decreased more than 30 mg/dL
              <70Treat hypoglycemia with D50 boluses. Recheck and repeat as needed.
              71-109Hold infusion and check blood sugars at least hourly. Restart infusion at half previous rate if BG >180 mg/dL.
              110-140No changeDecrease rate by 0.5 U/hHold infusion
              141-180No changeNo changeNo change
              181-210Increase rate by 1 U/hrIncrease rate by 1 U/hNo change
              211-240Increase rate by 2 U/hIncrease rate by 2 U/hNo change
              >241Increase rate by 3 U/hIncrease rate by 3 U/hNo change

              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.

              Adapted with permission from Duggan EW, CarlsonK, UmpierrezGE. Perioperative hyperglycemia management: an update. Anesthesiology. 2017;126(3):547-560. Copyright © 2017 the American Society of Anesthesiologists, Inc.

            2. If the patient meets none of the above criteria, can consider subcutaneous insulin instead.
            3. If insulin is started, check blood sugars at least every 2 hours. In addition, monitor potassium levels if using an insulin infusion.
        2. DM1. These patients must always receive insulin to prevent ketoacidosis, even in the setting of low or normal glucose levels. Simultaneous infusion of a glucose-containing solution may be necessary to prevent hypoglycemia.
          1. Perioperative insulin management for patients with DM1receiving newer intensive regimens of three or more daily insulin injections should be discussed in advance with the physician responsible for managing the patient’s diabetes.
          2. For the patient with an insulin pump, the following information should be obtained preoperatively: pump identification information, programmed settings information, insertion site, blood sugar measurements, plans for correction dosing, pump failure plan, and diabetes provider contact information. The anesthesia provider needs to know how to use the pump in case settings need to be changed intraoperatively.
            1. The usual basal rates can be reduced by 10% to 20% while the patient is NPO to avoid hypoglycemia.
            2. Only use if (1) the site does not interfere with the surgery, (2) there is no plan for MRI or other radiation, (3) the pump is out of the path of the electrocautery return circuit, and (4) there is minimal risk of needing defibrillation.
            3. Blood glucose levels should be checked frequently with target glucose level of 120 to 180 mg/dL, which is typically more liberal than home management. This may require turning basal rate down to 80% of normal.
      3. Fixed ratio insulin combinations are prescribed for the outpatient management of some diabetics. In consultation with the physician managing the diabetes, these patients should be switched to preparations of individual insulins in the immediate preoperative period. An appropriately reduced dose (approximately 50%) of only the long-acting insulin can then be taken on the morning of surgery as described above.
    3. DKA, HHS, and metabolic abnormalities should be treated before elective surgery and actively managed in the operating room if surgery cannot be postponed until the patient is medically stabilized.
    4. Vascular disease. Diabetic patients have a strong predisposition to all types of vascular diseases. Macrovascular disease (coronary artery, cerebrovascular, and peripheral vascular) and microvascular disease (retinopathy, neuropathy, and nephropathy) occur more frequently, more extensively, and at an earlier age than in the general population. Insulin-dependent DM is a known independent risk factor for perioperative major adverse cardiac events. Diabetic patients with ischemic heart disease are more likely to be asymptomatic or have atypical anginal symptoms. Continuation of aspirin and β-blockade and a high index of suspicion for ischemic heart disease are mainstays of management. DM is the most common cause of chronic and end-stage renal disease. Avoid nephrotoxins and consider renal protective treatments in patients exposed to IV contrast.
    5. Neuropathy. Diabetic autonomic neuropathy (DAN) can be present even in patients with well-controlled DM. It has widespread effects, including decreased lower esophageal sphincter tone, gastroesophageal reflux disease, gastroparesis, bladder atony, sexual dysfunction, orthostatic hypotension, and labile blood pressure. DAN is associated with an increased risk for silent myocardial ischemia, renal failure, stroke, obstructive sleep apnea (OSA), and overall mortality among patients with DM. Patients with DAN may be at higher risk for intraoperative hypothermia, be more susceptible to aspiration owing to higher residual gastric volumes, and be less able to compensate for the sympathectomy of neuraxial anesthesia. Signs of cardiac autonomic neuropathy include resting tachycardia, orthostatic hypotension, and decreased beat-to-beat variability with deep breathing. Peripheral neuropathies may cause pain and/or numbness. Patients with peripheral neuropathy may be more vulnerable to positioning injuries and should be padded carefully. Document neuropathies in the anesthesia preoperative evaluation and before initiating regional anesthesia.
    6. Airway management
      1. DM has been associated with difficult laryngoscopy. Postulated mechanisms include obesity (excess pretracheal and occipital tissue, large neck circumference) and DM-related decrease in temporomandibular joint and cervical spine mobility. This may be predicted by signs of other joint stiffness, such as incomplete approximation of one or more digits when attempting to approximate palmar surfaces (prayer sign).
      2. Obesity, sleep apnea, and redundant pharyngeal tissue are common in patients with metabolic syndrome and DM2.
    7. Protamine. Diabetic patients receiving NPH or NPL (Humalog mix) insulin are at increased risk for protamine reactions owing to the structural similarities between the drugs.