Module 11 - Notes - Diabetes: Insulin Therapy & Types

Diabetes Management: Insulin Therapy

• Human recombinant DNA insulin is now favored to minimize allergic reactions and immuno-resistance.
• Insulin needs increase with physiologic stress and trauma.
• Intravenous insulin clears quickly from the plasma.
• Subcutaneous insulin offers slow release for lasting effect and is often combined with IV insulin perioperatively.

Types of Insulin

• Lispro and Insulin Aspart:
  • Short-acting, mirroring physiologic insulin secretion.
  • Administered 30-60 minutes before meals.
  • Effective for 3-5 hours.
• NPH:
  • Intermediate-acting with delayed subcutaneous absorption because of protamine conjugation.
• Glargine and Detemir:
  • Long-acting basal replacements lasting 24 hours, typically given at bedtime.
• Regular insulin (Humulin R):
  • Fast-acting and short-acting.
  • Treats abrupt hyperglycemia and ketoacidosis.
  • Given IV (onset 10-15 min) or SC (onset 30-60 min).
  • Avoid SC administration in hemodynamic instability, hypothermia, or vasoconstriction because of poor perfusion.
  • Effective for 2-8 hours.
  • Can bind to IV tubing.
• U-500:
  • A more concentrated form with a longer duration, similar to intermediate-acting insulins.
  • U-100 (100 units/mL) is more commonly used.

Correctional Insulin

• Follow facility guidelines for perioperative glucose management.
• Target glucose is typically less than 180 mg/dL, ideally 110-180 mg/dL.
• Subcutaneous correction:
  • Suitable for surgeries under 4 hours with stable hemodynamics and minimal fluid shifts.
  • Do not dose more often than every 2 hours to avoid insulin stacking.
  • Monitor blood glucose at least every 2 hours.
  • Expect marked variability in blood glucose response.
  • Consider dose reduction in sensitive patients (age > 70, renal insufficiency, no DM history).
• Intravenous Infusion Correction:
  • Considered for longer surgeries, hemodynamic fluctuations, inotropes, major fluid shifts, temperature changes, and critically ill/cardiac surgery patients.
  • Half-life of 15 minutes allows for rapid dose adjustments.
  • Monitor blood glucose hourly, and consider potassium monitoring.
  • Do not stop abruptly; titrate down.

Insulin and Glucose Solutions

• Insulin and glucose solutions may be infused together to treat and prevent hypoglycemia.
• Common algorithm: infuse glucose (BG divided by 100) units/hour, and titrate insulin to target BG.
• Glucose-insulin-potassium (GIK) solutions exist in different concentrations.

Insulin Pumps

• More common in Type 1 DM, but increasing in Type 2 DM.
• Continue basal insulin infusion perioperatively if appropriate or consider IV replacement.
• Monitor blood glucose hourly.
• Consider turning off the pump if BG < 110 mg/dL.
• Consider correctional insulin for BG > 180 mg/dL.
• Postoperatively, alert patients may resume self-management but consult a DM specialist for critically ill/sedated patients.

Hypoglycemia

• Serum glucose < 70 mg/dL is associated with poor outcomes and increased mortality.
• Signs and symptoms may be masked under general anesthesia.
• Reduce risk with conservative BG targets, frequent monitoring, communication, and algorithms based on insulin sensitivity.
• Management:
  • IV Dextrose (2.5-70% solutions), dose 5-25 grams, onset < 10 minutes. Use a large peripheral IV or central line for hypertonic solutions and administer slowly.
  • IV Glucagon (insulin antagonist), dose 0.5-1 mg, dilute with sterile water. It also relaxes GI smooth muscle.

Insulin Side Effects

• Hypokalemia: monitor due to stimulation of the sodium-potassium pump.
• Treatment of Hyperkalemia: IV regular insulin (5-10 units) and dextrose (25-50 grams). Onset ~15 min, duration ~2+ hours, serum K+ decrease ~1.5 mEq/L. Adjust dextrose dose based on blood glucose levels.
• Allergic reactions, injection site reactions, and insulin resistance can occur.

Dextrose Concentration

• The concentration of D50 is 500 mg/mL.

Oral Hypoglycemic Drugs: Metformin

• First-line drug for Type 2 DM.
• Biguanide class.
• Rarely causes hypoglycemia.
• Lowers BG in fasting and postprandial states.
• Improves lipid profiles and can contribute to weight loss.
• Mechanisms: suppresses hepatic glucose production, decreases GI glucose absorption, increases insulin sensitivity, and increases GLP-1 synthesis.
• Side effects: GI disturbances (nausea, anorexia, diarrhea), Vitamin B12 deficiency, and lactic acidosis (rare but serious).
• Hold metformin in patients at risk for contrast-induced nephropathy or with hepatic/renal dysfunction.
• Ambulatory, minor surgery: continue perioperatively but hold on the day of surgery for renal dysfunction, contrast medium use, NSAIDs, ACEI, ARBs.
• Major surgery: hold on the day of surgery and restart after 24 hours with adequate renal function and PO intake.

Oral Hypoglycemic Drugs: Sulfonylureas

• Examples include glyburide, glipizide, glimepiride, chlorpropamide.
• Capable of drastically lowering BG and decreasing insulin resistance.
• Require beta cell function.
• High risk of therapy failure.
• Mechanism: inhibit K+-ATP channels on beta cells, leading to Ca2+ influx and exocytosis of insulin.
• Side effects: hypoglycemia, cardiovascular risks, GI disturbances, abnormal liver function tests.
• Higher risk of hypoglycemia with long elimination half-lives, malnutrition, age > 60, impaired renal function, and certain drug interactions.
• Ambulatory surgery: continue until the day before.
• Minor or major surgery: hold the morning of surgery.
• Restart once PO intake is resumed.

Oral Hypoglycemic Drugs: Thiazolidinediones (TZDs)

• Examples include rosiglitazone, pioglitazone.
• Mechanism: increase insulin sensitivity at skeletal muscle, hepatic, and adipose tissues, decrease insulin resistance, decrease hepatic glucose production, and increase glucose use by tissues.
• Beneficial effects on lipid profile (increase HDL, decrease triglycerides).
• Risks include increased extracellular fluid (edema, weight gain) and liver dysfunction.
• Continue perioperatively due to very low hypoglycemia risk.

Oral Hypoglycemic Drugs: Glucagon-like Peptide-1 (GLP-1) Receptor Agonists

• Examples include liraglutide, semaglutide, dulaglutide, tirzepatide, exenatide.
• Mechanisms: increase beta cell insulin secretion, decrease alpha cell glucagon production, decrease appetite, increase satiety, and slow gastric emptying.
• Administered via daily to weekly injections (oral formulations also exist).
• Beneficial effects: cardiovascular protection and reduced risk of diabetic nephropathy.
• Adverse effects: GI disturbances, hypoglycemia risk when combined with sulfonylureas or insulin, acute pancreatitis, gallbladder/biliary disease risk, acute renal insufficiency, injection site reactions.
• Perioperative ASA guidelines: Proceed with surgery if no GI symptoms or consider delaying surgery if GI symptoms are present.
• AANA considerations: hold daily dosing the day of surgery and weekly dosing one week before surgery.

Oral Hypoglycemic Drugs: Alpha-Glucosidase Inhibitors

• Examples include acarbose, miglitol.
• Mechanism: inhibit complex carbohydrate absorption from the small intestine by competitively inhibiting enzymes.
• Reduce postprandial glucose.
• Consider the risk of hypoglycemia during prolonged NPO periods.
• Hold the day of surgery and monitor FSBS.
• Adverse effects: GI disturbances.

Oral Hypoglycemic Drugs: Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

• Examples include canagliflozin, dapagliflozin, empagliflozin ('gliflozins').
• Mechanism: inhibit SGLT2 in the proximal tubule of the kidney, reducing glucose and sodium reabsorption. Requires normal renal function.
• Potential adverse effects: hypovolemia, hypotension, acute kidney injury, euglycemic ketoacidosis (rare), urinary tract/genital infections, reduced bone density.
• Hold the morning of surgery for minor/major procedures. Consider risk for ketoacidosis and dehydration.

Oral Hypoglycemic Drugs: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

• Examples include saxagliptin, sitagliptin, linagliptin, alogliptin.
• Mechanism: inhibit the DPP-4 enzyme, leading to increased insulin secretion and decreased glucagon secretion.
• Very low risk of hypoglycemia.
• Continue perioperatively.

Thyroid Disorders: Hypothyroidism

• Prevalence ~11.7% in the US (2019).
• Types: primary, secondary, and exogenous.
• Managed with thyroid hormone replacement therapy, typically monitoring TSH and free T4 levels.
• Levothyroxine (Synthroid) is synthetic thyroxine (T4).
• Liothyronine is synthetic triiodothyronine (T3).
• Anesthetic considerations for non-euthyroid patients: exaggerated response to anesthetics and opioids, sedation, delayed emergence, respiratory depression/muscle weakness, and vasopressor-resistant hypotension.

Thyroid Disorders: Hyperthyroidism

• Prevalence 1.3% in the US.
• Characterized by excess production and secretion of thyroid hormone.
• Common causes: Graves' disease, Hashitoxicosis, and toxic adenoma/goiter.
• Treatment includes anti-thyroid drugs, radioiodine, and surgery.
• Thyroid storm is a rare but high-mortality risk factor.
• Thionamides (methimazole, propylthiouracil - PTU, carbimazole) inhibit thyroid peroxidase, blocking the iodination of thyroid hormones and reducing TH formation.
• Potassium iodide (Lugol's solution) decreases iodine uptake by the thyroid, decreasing TH synthesis and release, and reduces thyroid size and vascularity.
• Radioactive iodine is definitive treatment for Graves' disease but carries a risk of hypothyroidism.
• Beta blockade is crucial for symptomatic control, with long-acting beta-blockers preferred
• Anesthetic considerations involve managing cardiovascular signs/symptoms of thyroid hormone excess (potential thyroid storm).

Adrenal Cortex: Mineralocorticoids

• Aldosterone is the primary mineralocorticoid.
• Main role is fluid and electrolyte balance, increasing Na+ reabsorption and K+ excretion in the kidneys.

Adrenal Cortex: Glucocorticoids

• Cortisol is the primary glucocorticoid.
• Involved in metabolism, fluid balance, and has anti-inflammatory and immunosuppressive effects.
• Cortisol release is episodic, following the sleep-wake cycle and stress-induced release.
• The surgery-induced stress response leads to increased pro-inflammatory cytokines, CRH, ACTH, and a 5-10x normal increase in cortisol.

Synthetic Corticosteroids

• Used to treat adrenal insufficiency.
• Mechanism: bind cytoplasmic receptors, forming a complex that affects DNA transcription and protein synthesis.
• Examples: prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, triamcinolone.
• Comparison of Steroid Potency (approximate):
  • Cortisol: Glucocorticoid potency 1, Mineralocorticoid potency 1, Equivalent dose 20 mg.
  • Prednisone: Glucocorticoid potency 4, Mineralocorticoid potency 0.8, Equivalent dose 5 mg.
  • Dexamethasone: Glucocorticoid potency 25, Mineralocorticoid potency < 0.1, Equivalent dose 0.75 mg.
  • Fludrocortisone: Glucocorticoid potency 10, Mineralocorticoid potency 125, Equivalent dose N/A.

Clinical Uses of Glucocorticoids

• Examples include adrenal insufficiency, allergic reactions, asthma, cerebral edema, aspiration pneumonitis, arthritis, shock states, organ transplantation, antiemesis, and analgesia.

Perioperative Steroid Administration

• Long-term steroid administration can lead to HPA axis suppression.
• Glucocorticoid supplementation in the perioperative period depends on the risk of HPA axis suppression.
  • Low-no suppression (prednisone ≤ 5 mg/day or therapy < 3 weeks): supplementation not required.
  • Assumption of HPA axis suppression (prednisone > 20 mg/day for > 3 weeks or Cushing's symptoms): supplementation required based on surgery invasiveness.
  • Unknown suppression (prednisone 5-20 mg/day or prolonged intermittent therapy, high-dose inhaled/topical/injected steroids): consider supplementation, especially for major surgery.
• Hydrocortisone (Solu-Cortef) is the 1st line for stress dose steroid replacement.
  • Doses for replacement therapy: Minor surgery 25 mg IV, Moderate stress 50-75 mg IV, Major surgery 100 mg IV.
• Dexamethasone (Decadron) is a potent glucocorticoid with minimal to no mineralocorticoid activity.
• Adverse effects of long-term/high-dose steroid use: HPA axis suppression, electrolyte/metabolic changes, osteoporosis, peptic ulcer disease, skeletal muscle myopathy, CNS dysfunction, cataracts, hematologic changes, and inhibition of growth.
• Other anesthetic considerations: large opioid doses may attenuate cortisol response to stress, volatile anesthetics may minimally suppress the endocrine response, etomidate inhibits cortisol synthesis, and regional anesthesia may decrease cortisol release.

MemoryMaster Knowledge Check Answers

• Insulin is secreted by Beta cells and Glucagon from Alpha cells.
• The pancreatic islet delta cells produce Somatostatin, which inhibits GI motility and secretions.
• Metformin discontinuation depends on the type of surgery, renal function, and risk factors for lactic acidosis.
• Alpha-glucosidase inhibitors work by inhibiting complex carbohydrate absorption from the small intestine.
• Betamethasone and Dexamethasone have no mineralocorticoid potency.
• 25 mg of hydrocortisone (Solu-Cortef) at induction of general anesthesia provides adequate steroid coverage for patients with suspected secondary adrenal insufficiency.