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Pronunciation
(IN soo lin REG yoo ler)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of type 1 diabetes mellitus (insulin dependent, IDDM) and type 2 diabetes mellitus (noninsulin dependent, NIDDM) to improve glycemic control
Use: Unlabeled
Hyperkalemia; gestational diabetes mellitus (GDM), diabetic ketoacidosis (DKA); hyperosmolar hyperglycemic state (HHS); adjunct of parenteral nutrition
Pregnancy Considerations
Insulin has not been found to cross the placenta, but insulin bound to anti-insulin antibodies has been detected in cord blood. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A1c is above the normal range. Insulin requirements tend to fall during the first trimester of pregnancy and increase in the later trimesters, peaking at 28-32 weeks of gestation. Following delivery, insulin requirements decrease rapidly. Diabetes can be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may in turn negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the fetus and the mother. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.
Lactation
Excretion in breast milk unknown/compatible
Breast-Feeding Considerations
Endogenous insulin can be found in breast milk. Plasma glucose concentrations in the mother affect glucose concentrations in breast milk. The gastrointestinal tract destroys insulin when administered orally; therefore, insulin is not expected to be absorbed intact by the breast-feeding infant. All types of insulin are safe for use while breast-feeding. Due to increased calorie expenditure, women with diabetes may require less insulin while nursing.
Contraindications
Hypersensitivity to regular insulin or any component of the formulation; during episodes of hypoglycemia
Warnings/Precautions
Concerns related to adverse effects:
• Hypoglycemia: The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (eg, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be altered during illness, emotional disturbances, or other stressors.
• Hypokalemia: Insulin (especially I.V. insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium frequently with I.V. use and supplement potassium when necessary.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage requirements may be reduced.
• Renal impairment: Use with caution in patients with renal impairment. Dosage requirements may be reduced.
Dosage form specific issues:
• Product variation: Human insulin differs from animal-source insulin. Any change of insulin should be made cautiously; changing manufacturers, type, and/or method of manufacture may result in the need for a change of dosage.
• U-500 regular insulin: U-500 regular insulin is a concentrated insulin formulation which contains 500 units of insulin per mL; for SubQ administration only using a U-100 insulin syringe or tuberculin syringe; not for I.V. administration. To avoid dosing errors when using a U-100 insulin syringe, the prescribed dose should be written in actual insulin units and as unit markings on the U-100 insulin syringe (eg, 50 units [10 units on a U-100 insulin syringe]). To avoid dosing errors when using a tuberculin syringe, the prescribed dose should be written in actual insulin units and as a volume (eg, 50 units [0.1 mL]). Mixing U-500 regular insulin with other insulin formulations is not recommended.
Other warnings/precautions:
• Appropriate use: Diabetes mellitus: The general objective of exogenous insulin therapy is to approximate the physiologic pattern of insulin secretion which is characterized by two distinct phases. Phase 1 insulin secretion suppresses hepatic glucose production and phase 2 insulin secretion occurs in response to carbohydrate ingestion; therefore, exogenous insulin therapy may consist of basal insulin (eg, intermediate- or long-acting insulin via continuous subcutaneous insulin infusion [CSII]) and/or preprandial insulin (eg, short- or rapid-acting insulin) (see Related Information: Insulin Products). Patients with type 1 diabetes do not produce endogenous insulin; therefore, these patients require both basal and preprandial insulin administration. Patients with type 2 diabetes retain some beta-cell function in the early stages of their disease; however, as the disease progresses, phase 1 insulin secretion may become completely impaired and phase 2 insulin secretion becomes delayed and/or inadequate in response to meals. Therefore, patients with type 2 diabetes may be treated with oral antidiabetic agents, basal insulin, and/or preprandial insulin depending on the stage of disease and current glycemic control. Since treatment regimens often consist of multiple agents, dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient's impaired glycemic control. Treatment and monitoring regimens must be individualized.
• I.M. administration: Regular insulin may be administered I.M. in selected clinical situations to control hyperglycemia (eg, DKA); close monitoring of blood glucose and serum potassium as well as medical supervision is required.
• I.V. administration: Regular insulin may be administered I.V. in selected clinical situations (eg, DKA, hyperkalemia); close monitoring of blood glucose and serum potassium as well as medical supervision is required.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
Adverse Reactions
Primarily symptoms of hypoglycemia
Cardiovascular: Pallor, palpitation, tachycardia
Central nervous system: Fatigue, headache, hypothermia, loss of consciousness, mental confusion
Dermatologic: Redness, urticaria
Endocrine & metabolic: Hypoglycemia, hypokalemia
Gastrointestinal: Hunger, nausea, numbness of mouth
Local: Atrophy or hypertrophy of SubQ fat tissue; edema, itching, pain or warmth at injection site; stinging
Neuromuscular & skeletal: Muscle weakness, paresthesia, tremor
Ocular: Transient presbyopia or blurred vision
Miscellaneous: Anaphylaxis, diaphoresis, local and/or systemic hypersensitivity reactions
Metabolism/Transport Effects
None known.
Drug Interactions
Antidiabetic Agents (Thiazolidinedione): Insulin may enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Beta-Blockers: May enhance the hypoglycemic effect of Insulin. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulin. Risk C: Monitor therapy
Edetate Disodium: May enhance the hypoglycemic effect of Insulin. Risk C: Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Quinolone Antibiotics: Insulin may enhance the hyperglycemic effect of Quinolone Antibiotics. Insulin may enhance the hypoglycemic effect of Quinolone Antibiotics. Risk C: Monitor therapy
Somatropin: May diminish the hypoglycemic effect of Antidiabetic Agents. Risk D: Consider therapy modification
Thiazide Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Use caution with ethanol; may increase risk of hypoglycemia.
Herb/Nutraceutical: Use caution with alfalfa, aloe, bilberry, bitter melon, burdock, celery, damiana, fenugreek, garcinia, garlic, ginger, ginseng (American), gymnema, marshmallow, stinging nettle; may increase risk of hypoglycemia.
Storage
Humulin® R, Humulin® R U-500: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F); do not freeze; keep away from heat and sunlight. Once punctured (in use), vials may be stored for up to 31 days in the refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature of ≤30°C (≤86°F).
Novolin® R: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F) until product expiration date or at room temperature ≤25°C (≤77°F) for up to 42 days; do not freeze; keep away from heat and sunlight. Once punctured (in use), store vials at room temperature ≤25°C (≤77°F) for up to 42 days (this includes any days stored at room temperature prior to opening vial); refrigeration of in-use vials is not recommended.
Canadian labeling (not in U.S. labeling): All products: Unopened vials, cartridges, and pens should be stored under refrigeration between 2°C and 8°C (36°F to 46°F) until the expiration date; do not freeze; keep away from heat and sunlight. Once punctured (in use), Humulin® vials, cartridges, and pens should be stored at room temperature <25°C (<77°F) for up to 4 weeks. Once punctured (in use), Novolin® ge vials, cartridges, and pens may be stored for up to 1 month at room temperature <25°C (<77°F) for vials or <30°C (<86°F) for pens/cartridges; do not refrigerate.
For SubQ administration:
Humulin® R: According to the manufacturer, diluted insulin should be stored at 30°C (86°F) and used within 14 days or at 5°C (41°F) and used within 28 days.
For I.V. infusion:
Humulin® R: Stable for 48 hours at room temperature or for 48 hours under refrigeration followed by 48 hours at room temperature.
Novolin® R: Stable for 24 hours at room temperature
Reconstitution
For SubQ administration:
Humulin® R: May be diluted with the universal diluent, Sterile Diluent for Humalog®, Humulin® N, Humulin® R, Humulin® 70/30, and Humulin® R U-500, to a concentration of 10 units/mL (U-10) or 50 units/mL (U-50).
Novolin® R: Insulin Diluting Medium for NovoLog® is not intended for use with Novolin® R or any insulin product other than insulin aspart.
For I.V. infusion:
Humulin® R: May be diluted in NS or D5W to concentrations of 0.1-1 unit/mL.
Novolin® R: May be diluted in NS, D5W, or D10W with 40 mEq/L potassium chloride at concentrations of 0.05-1 unit/mL.
Compatibility
Stable in D5W and NS. Note: A universal sterile diluent, Sterile Diluent for Humalog®, Humulin® N, Humulin® R, Humulin® 70/30, and Humulin® R U-500, is available from the manufacturer for SubQ administration.
Y-site administration: Compatible: Alcohol (ethyl), amiodarone, ampicillin, ampicillin/sulbactam, aztreonam, caspofungin, cefazolin, cefepime, cefotetan, ceftazidime, dobutamine, doripenem, esmolol, famotidine, gentamicin, heparin, heparin with hydrocortisone sodium succinate, imipenem/cilastatin, indomethacin, magnesium sulfate, meperidine, meropenem, midazolam, milrinone, morphine, nitroglycerin, nitroprusside, oxytocin, pancuronium, pentobarbital, potassium chloride, propofol, sodium bicarbonate, tacrolimus, terbutaline, ticarcillin/clavulanate, tobramycin, vancomycin, vasopressin, vecuronium, vitamin B complex with C. Incompatible: Dopamine, drotrecogin alfa, micafungin, nafcillin, nesiritide, ranitidine. Variable (consult detailed reference): Digoxin, diltiazem, doxapram, labetalol, levofloxacin, norepinephrine, pantoprazole.
Compatibility in syringe: Compatible: Insulin NPH, metoclopramide. Incompatible: Insulin aspart, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, pantoprazole. Variable (consult detailed reference): Lidocaine.
Mechanism of Action
Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.
Within the liver, insulin stimulates hepatic glycogen synthesis. Insulin promotes hepatic synthesis of fatty acids, which are released into the circulation as lipoproteins. Skeletal muscle effects of insulin include increased protein synthesis and increased glycogen synthesis. Within adipose tissue, insulin stimulates the processing of circulating lipoproteins to provide free fatty acids, facilitating triglyceride synthesis and storage by adipocytes; also directly inhibits the hydrolysis of triglycerides. In addition, insulin stimulates the cellular uptake of amino acids and increases cellular permeability to several ions, including potassium, magnesium, and phosphate. By activating sodium-potassium ATPases, insulin promotes the intracellular movement of potassium.
Normally secreted by the pancreas, insulin products are manufactured for pharmacologic use through recombinant DNA technology using either E. coli or Saccharomyces cerevisiae. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin).
Pharmacodynamics/Kinetics
Note: Rate of absorption, onset, and duration of activity may be affected by site of injection, exercise, presence of lipodystrophy, local blood supply, and/or temperature.
Onset of action: SubQ: 0.5 hours
Peak effect: SubQ: 2.5-5 hours
Duration: SubQ:
U-100: 4-12 hours (may increase with dose)
U-500: Up to 24 hours
Distribution: Vd: 0.26-0.36 L/kg
Bioavailability: SubQ: 55% to 77%
Half-life elimination: I.V.: ~0.5-1 hour (dose-dependent); SubQ: 1.5 hours
Time to peak, plasma: SubQ: 0.8-2 hours
Excretion: Urine
Dosage
Diabetes mellitus: SubQ: Note: Insulin requirements vary dramatically between patients and therapy requires dosage adjustments with careful medical supervision. Specific formulations may require distinct administration procedures; please see individual agents.
Type 1:
Children and Adults: Note: Multiple daily injections (MDI) guided by blood glucose monitoring or the use of continuous subcutaneous insulin infusions (CSII) is the standard of care for patients with type 1 diabetes. Combinations of insulin formulations are commonly used.
Initial dose: 0.5-1.0 units/kg/day in divided doses. Conservative initial doses of 0.2-0.4 units/kg/day may be recommended to avoid the potential for hypoglycemia.
Division of daily insulin requirement: Generally, 50% to 75% of the total daily dose (TDD) is given as an intermediate- or long-acting form of insulin (in 1-2 daily injections). The remaining portion of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting or short-acting form of insulin. Premixed combinations are available that deliver the rapid- or short-acting component at the same time as the intermediate- or long-acting component. Some patients may benefit from the use of CSII which delivers rapid-acting insulin as a continuous infusion throughout the day and as boluses at mealtimes via an external pump device.
Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain preprandial plasma glucose between 70-130 mg/dL for most patients. Since treatment regimens often consist of multiple formulations, dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient's impaired glycemic control. Treatment and monitoring regimens must be individualized. Also see Additional Information or Pharmacotherapy Pearls.
Usual maintenance range: 0.5-1.2 units/kg/day in divided doses. Insulin requirements are patient-specific and may vary based on age, body weight, and/or activity factors:
Adolescents: May require as much as 1.5 units/kg/day during puberty (Silverstein, 2005)
Prepuberty: 0.7-1 unit/kg/day
Type 2:
Children and Adults: The goal of therapy is to achieve an Hb A1c <7% as quickly as possible using the safe titration of medications. According to a consensus statement by the ADA and European Association for the Study of Diabetes (EASD), basal insulin therapy (eg, intermediate- or long-acting insulin) should be considered in patients with type 2 diabetes who fail to achieve glycemic goals with lifestyle interventions and metformin ± a sulfonylurea. Pioglitazone or a GLP-1 agonist may also be considered prior to initiation of basal insulin therapy. In patients who continue to fail to achieve glycemic goals despite the addition of basal insulin, intensification of insulin therapy should be considered; this generally consists of multiple daily injections with a combination of insulin formulations (Nathan, 2009).
Initial basal insulin dose: 0.2 units/kg or 10 units/day (Nathan, 2009). Note: Current guidelines recommend that insulin therapy begin with intermediate- or long-acting insulin given at bedtime or long-acting insulin given in the morning (Nathan, 2009).
Adjustment of basal insulin dose: Increase dose by 2 units/day every 3 days until fasting glucose levels are consistently within target range (70-130 mg/dL); may increase dose in larger increments (eg, 4 units/day) if fasting glucose levels are >180 mg/dL (Nathan, 2009)
Note: If the patient experiences hypoglycemia following adjustment, reduce dose by 4 units/day or 10% of total daily dose, whichever is greater (Nathan, 2009). Additional algorithms, such as the “1-1-100”, “2-4-6-8”, “3-0-3”, and “3-2-1” algorithms, exist to aid in the titration of basal insulin (Davies, 2005; Gerstein, 2006; Meneghini, 2007; Riddle, 2003); therapy should be individualized and based on patient-specific details.
Intensification of therapy: Add a second injection of a short-, rapid-, or intermediate-acting insulin as needed based on blood glucose monitoring; the timing of administration and type of insulin added for intensification of therapy depends on the blood glucose level that is consistently out of the target range (eg, preprandial glucose levels before lunch or dinner, postprandial glucose levels, and/or bedtime glucose levels). Additional injections and subsequent dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient's impaired glycemic control. Intensification of therapy can usually begin with a second injection of ~4 units/day followed by adjustments of ~2 units/day every 3 days until the targeted blood glucose is within range (Nathan, 2009).
In the setting of glucose toxicity (loss of beta-cell sensitivity to glucose concentrations), insulin therapy may be used for short-term management to restore sensitivity of beta-cells; in these cases, the dose may need to be rapidly reduced/withdrawn when sensitivity is re-established.
Diabetic ketoacidosis (DKA) (unlabeled use): Only I.V. regular insulin should be used for severe DKA; use of SubQ rapid-acting insulin analogs (eg, aspart, lispro) may be appropriate for mild-moderate DKA (Kitabchi, 2009). Treatment should continue until reversal of acid-base derangement/ketonemia. Serum glucose is not a direct indicator of these abnormalities, and may decrease more rapidly than correction of the metabolic abnormalities. Also, refer to institution-specific protocols where appropriate.
Children and Adults <20 years (Kitabchi, 2004):
I.V.:
Infusion: 0.1 units/kg/hour
Adjustment: If serum glucose does not fall by 50 mg/dL in the first hour, check hydration status; if acceptable, double insulin dose hourly until glucose levels fall at rate of 50-75 mg/dL per hour. Once serum glucose reaches 250 mg/dL, decrease dose to 0.05-0.1 units/kg/hour; dextrose-containing I.V. fluids should be administered to maintain serum glucose between 150-250 mg/dL until the acidosis clears. After resolution of DKA, supplement I.V. insulin with SubQ insulin as needed until the patient is able to eat and transition fully to a SubQ insulin regimen. An overlap of ~1-2 hours between discontinuation of I.V. insulin and administration of SubQ insulin is recommended to ensure adequate plasma insulin levels.
SubQ, I.M. (Note: Only use the SubQ and I.M route if I.V. infusion access is unavailable): 0.1-0.3 units/kg SubQ bolus, followed by 0.1 units/kg given every hour SubQ or I.M. or 0.15-0.2 units/kg every 2 hours SubQ; continue until acidosis clears, then decrease to 0.05 units/kg given every hour until SubQ replacement dosing can be initiated (Kitabchi, 2004; Wolfsdorf, 2007)
Adults ≥20 years (Kitabchi, 2009):
I.V.:
Bolus: 0.1 units/kg (optional)
Infusion: 0.1-0.14 units/kg/hour. Note: If no I.V. bolus was administered, patients should receive a continuous infusion of 0.14 units/kg/hour; lower doses may not achieve adequate insulin concentrations to suppress hepatic ketone body production.
Adjustment: If serum glucose does not fall by at least 10% in the first hour, give an I.V. bolus of 0.14 units/kg and continue previous regimen. In addition, if serum glucose does not fall by 50-70 mg/dL in the first hour, the insulin infusion dose should be increased hourly until a steady glucose decline is achieved Once serum glucose reaches 200 mg/dL, decrease infusion dose to 0.02-0.05 units/kg/hour or switch to SubQ rapid-acting insulin (eg, aspart, lispro) at 0.1 units/kg every 2 hours; dextrose-containing I.V. fluids should be administered to maintain serum glucose between 150-250 mg/dL until the acidosis clears. After resolution of DKA, supplement I.V. insulin with SubQ insulin as needed until the patient is able to eat and transition fully to a SubQ insulin regimen. An overlap of ~1-2 hours between discontinuation of I.V. insulin and administration of SubQ insulin is recommended to ensure adequate plasma insulin levels.
SubQ, I.M.: According to the 2009 ADA consensus statement on hyperglycemic crises, a rapid-acting insulin analog (eg, aspart, lispro) given every 1-2 hours via the SubQ route may be appropriate for mild-moderate DKA; however, specific dosing recommendations are not provided (Kitabchi, 2009). If using the I.V. route for severe DKA, consider switching to SubQ rapid-acting insulin once serum glucose reaches 200 mg/dL (Kitabchi, 2009). The following dosing regimen from the 2004 ADA position statement recommends regular insulin (Kitabchi, 2004):
Bolus: 0.4 units/kg; Note: Give half of the dose (0.2 units/kg) as an I.V. bolus and half of the dose (0.2 units/kg) as SubQ or I.M.
Intermittent: 0.1 units/kg given every hour SubQ or I.M.
Adjustment: If serum glucose does not fall by 50-70 mg/dL in the first hour, administer 10 units hourly by I.V. bolus until glucose levels fall at a rate of 50-70 mg/dL per hour. Once serum glucose reaches 250 mg/dL, decrease dose to 5-10 units SubQ every 2 hours; dextrose-containing I.V. fluids should be administered to maintain serum glucose between 150-250 mg/dL until the acidosis clears.
Gestational diabetes mellitus (unlabeled use): Insulin therapy should be considered when medical nutrition therapy has not achieved GDM glycemic goals (fasting plasma glucose: <95 mg/dL; 1-hour postprandial levels: <130-140 mg/dL; 2-hour postprandial levels: <120 mg/dL); dose and timing of administration should be based on frequent monitoring of plasma glucose levels (ACOG, 2001; ADA, 2004). Human insulin may be preferred (ADA, 2004); however, rapid-acting insulin analogues may also be considered (ACOG, 2001).
Hyperkalemia, moderate-to-severe (unlabeled use): I.V.:
Children: 0.1 units/kg regular insulin with dextrose 400 mg/kg infused over 15-30 minutes; ratio of ~1 unit of insulin to every 4 g of dextrose (Hegenbarth, 2008). Note: Dextrose monotherapy may be sufficient to correct hyperkalemia.
Adults: 10 units regular insulin mixed with 25 g dextrose (50 mL D50W) given over 15-30 minutes (ACLS, 2010); alternatively, 50 mL D50W over 5 minutes followed by 10 units regular insulin I.V. push over seconds may be administered in the setting of imminent cardiac arrest. In patients with ongoing cardiac arrest (eg, PEA with presumed hyperkalemia), administration of D50W over <5 minutes is routine. Effects on potassium are temporary. As appropriate, consider methods of enhancing potassium removal/excretion.
Hyperosmolar hyperglycemic state (HHS) (unlabeled use): Only regular insulin should be used. Infusion should continue until reversal of mental status changes and hyperosmolality. Serum glucose is not a direct indicator of these abnormalities, and may decrease more rapidly than correction of the metabolic abnormalities. Also, refer to institution-specific protocols where appropriate.
Children and Adults <20 years (Kitabchi, 2004):
I.V.:
Infusion: 0.1 units/kg/hour
Adjustment: If serum glucose does not fall by 50 mg/dL in the first hour, check hydration status; if acceptable, double insulin dose hourly until glucose levels fall at rate of 50-75 mg/dL per hour. Once serum glucose reaches 300 mg/dL, decrease dose to 0.05-0.1 units/kg/hour; dextrose-containing I.V. fluids should be administered to maintain serum glucose between 250-300 mg/dL until hyperosmolality clears and mental status returns to normal. After resolution of HHS, supplement I.V. insulin with SubQ insulin as needed until the patient is able to eat and transition fully to a SubQ insulin regimen. An overlap of ~1-2 hours between discontinuation of I.V. insulin and administration of SubQ insulin is recommended to ensure adequate plasma insulin levels.
SubQ, I.M. (Note: Only use the SubQ and I.M route if I.V. infusion access is unavailable): 0.1-0.3 units/kg SubQ bolus, followed by 0.1 units/kg given every hour SubQ or I.M. or 0.15-0.2 units/kg every 2 hours SubQ; continue until resolution of hyperosmolality, then decrease to 0.05 units/kg given every hour until SubQ replacement dosing can be initiated (Kitabchi, 2004; Wolfsdorf, 2007)
Adults ≥20 years (Kitabchi, 2009):
I.V.:
Bolus: 0.1 units/kg bolus (optional)
Infusion: 0.1-0.14 units/kg/hour. Note: If no I.V. bolus was administered, patients should receive a continuous infusion of 0.14 units/kg/hour.
Adjustment: If serum glucose does not fall by at least 10% in the first hour, give an I.V. bolus of 0.14 units/kg and continue previous regimen. In addition, if serum glucose does not fall by 50-70 mg/dL in the first hour, the insulin infusion dose should be increased hourly until a steady glucose decline is achieved. Once serum glucose reaches 300 mg/dL, decrease dose to 0.02-0.05 units/kg/hour; dextrose-containing I.V. fluids should be administered to maintain serum glucose between 200-300 mg/dL until the patient is mentally alert. After resolution of HHS, supplement I.V. insulin with SubQ insulin as needed until the patient is able to eat and transition fully to a SubQ insulin regimen. An overlap of ~1-2 hours between discontinuation of I.V. insulin and administration of SubQ insulin is recommended to ensure adequate plasma insulin levels.
Dosing adjustment in renal impairment: Insulin requirements are reduced due to changes in insulin clearance or metabolism. Close monitoring of blood glucose and adjustment of therapy is required in renal impairment.
Clcr 10-50 mL/minute: Administer at 75% of normal dose and monitor glucose closely
Clcr <10 mL/minute: Administer at 25% to 50% of normal dose and monitor glucose closely
Hemodialysis: Because of a large molecular weight (6000 daltons), insulin is not significantly removed by hemodialysis; supplemental dose is not necessary
Peritoneal dialysis: Because of a large molecular weight (6000 daltons), insulin is not significantly removed by peritoneal dialysis; supplemental dose is not necessary
Continuous renal replacement therapy: Administer 75% of normal dose and monitor glucose closely; supplemental dose is not necessary
Dosing adjustment in hepatic impairment: Insulin requirements may be reduced. Close monitoring of blood glucose and adjustment of therapy is required in hepatic impairment.
Administration: I.M.
Do not use if solution is viscous or cloudy; use only if clear and colorless. May be administered I.M. in selected clinical situations; close monitoring of blood glucose and serum potassium as well as medical supervision is required.
Administration: I.V.
Do not use if solution is viscous or cloudy; use only if clear and colorless. May be administered I.V. with close monitoring of blood glucose and serum potassium; appropriate medical supervision is required. If possible, avoid I.V. bolus administration in pediatric patients with DKA; may increase risk of cerebral edema. Do not administer mixtures of insulin formulations intravenously. I.V. administration of U-500 regular insulin is not recommended.
Administration: Other
SubQ administration: Do not use if solution is viscous or cloudy; use only if clear and colorless. Regular insulin should be administered within 30-60 minutes before a meal. Cold injections should be avoided. SubQ administration is usually made into the thighs, arms, buttocks, or abdomen; rotate injection sites. When mixing regular insulin with other preparations of insulin, regular insulin should be drawn into syringe first. Regular insulin is not recommended for use in external SubQ insulin infusion pump.
Administration: I.V. Detail
I.V. infusions: To minimize adsorption to I.V. solution bag (Note: Refer to institution-specific protocols where appropriate):
If new tubing is
not
needed: Wait a minimum of 30 minutes between the preparation of the solution and the initiation of the infusion.
If new tubing is needed: After receiving the insulin drip solution, the administration set should be attached to the I.V. container and the entire line should be flushed with a priming infusion of 20-50 mL of the insulin solution (Goldberg, 2006; Hirsch, 2006). Wait 30 minutes, then flush the line again with the insulin solution prior to initiating the infusion.
If insulin is required prior to the availability of the insulin drip, regular insulin should be administered by I.V. push injection.
Because of adsorption, the actual amount of insulin being administered via I.V. infusion could be substantially less than the apparent amount. Therefore, adjustment of the I.V. infusion rate should be based on effect and not solely on the apparent insulin dose. The apparent dose may be used as a starting point for determining the subsequent SubQ dosing regimen (Moghissi, 2009); however, the transition to SubQ administration requires continuous medical supervision, frequent monitoring of blood glucose, and careful adjustment of therapy. In addition, SubQ insulin should be given 1-4 hours prior to the discontinuation of I.V. insulin to prevent hyperglycemia (Moghissi, 2009).
pH: 7.0-7.8
Monitoring Parameters
Diabetes mellitus: Plasma glucose, electrolytes, Hb A1c
DKA/HHS: Serum electrolytes, glucose, BUN, creatinine, osmolality, venous pH (repeat arterial blood gases are generally unnecessary), anion gap, urine output, urinalysis, mental status
Hyperkalemia: Serum potassium and glucose must be closely monitored to avoid hypokalemia, rebound hyperkalemia, and hypoglycemia.
Reference Range
Therapeutic, serum insulin (fasting): 5-20 μIU/mL (SI: 35-145 pmol/L)
Glucose, fasting:
Newborns: 60-110 mg/dL
Adults: 60-110 mg/dL
Elderly: 100-180 mg/dL
Recommendations for glycemic control in adults with diabetes mellitus:
Hb A1c: <7%
Preprandial capillary plasma glucose: 70-130 mg/dL
Peak postprandial capillary plasma glucose: <180 mg/dL
Dietary Considerations
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Patient Education
Do not share pens, cartridges, or needles with others. This medication is used to control diabetes; it is not a cure. It is imperative to follow other components of prescribed treatment (eg, diet and exercise regimen). If you experience hypoglycemic reaction, contact prescriber immediately. Always carry quick source of sugar with you. Monitor glucose levels as directed by prescriber. Report adverse side effects, including chest pain or palpitations; persistent fatigue, confusion, headache; skin rash or redness; numbness of mouth, lips, or tongue; muscle weakness or tremors; vision changes; respiratory difficulty; or nausea, vomiting, or flu-like symptoms.
Geriatric Considerations
Intensive glucose control (HbA1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. Patients who are unable to accurately draw up their dose will need assistance, such as prefilled syringes. Initial doses may require considerations for renal function in the elderly with dosing adjusted subsequently based on blood glucose monitoring. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.
Additional Information
Split-mixed or basal-bolus regimens: Combination regimens which optimize differences in the onset and duration of different insulin products are commonly used to approximate physiologic secretion. In split-mixed regimens, an intermediate-acting insulin (eg, NPH insulin) is administered once or twice daily and supplemented by short-acting (regular) or rapid-acting (lispro, aspart, or glulisine) insulin. Blood glucose measurements are completed several times daily. Dosages are adjusted emphasizing the individual component of the regimen which most directly influences the blood sugar in question (either the intermediate-acting component or the shorter-acting component). Fixed-ratio formulations (eg, 70/30 mix) may be used as twice daily injections in this scenario; however, the ability to titrate the dosage of an individual component is limited. An example of a “split-mixed” regimen would be 21 units of NPH plus 9 units of regular insulin in the morning and an evening meal dose consisting of 14 units of NPH plus 6 units of regular insulin.
Basal-bolus regimens are designed to more closely mimic physiologic secretion. These regimens employ a long-acting insulin (eg, glargine) to simulate basal insulin secretion. The basal component is frequently administered at bedtime or in the early morning. This is supplemented by multiple daily injections of rapid-acting products (lispro, aspart, or glulisine) immediately prior to a meal, which provides insulin at the time when nutrients are absorbed. An example of a basal-bolus regimen would be 30 units of glargine at bedtime and 12 units of lispro insulin prior to each meal.
Estimation of the effect per unit: A “Rule of 1500” has been frequently used as a means to estimate the change in blood sugar relative to each unit of insulin administered. In fact, the recommended values used in these calculations may vary from 1500-2200 (a value of 1500 is generally recommended for regular insulin while 1800 is recommended for "rapid-acting insulins"). The higher values lead to more conservative estimates of the effect per unit of insulin, and therefore lead to more cautious adjustments. The effect per unit of insulin is approximated by dividing the selected numerical value (eg, 1500-2200) by the number of units/day received by the patient. This may be used as a crude approximation of the patient's insulin sensitivity as adjustments to individual components of the regimen are made. Each additional unit of insulin added to the corresponding insulin dose may be expected to lower the blood glucose by this amount.
To illustrate, in the “basal-bolus” regimen example presented above, the rule of 1800 would indicate an expected change of 27 mg/dL per unit of lispro insulin (the total daily insulin dose is 66 units; using the formula: 1800/66 = 27). A patient may be instructed to add additional insulin if the preprandial glucose is >125 mg/dL. For a prelunch glucose of 195 mg/dL, this would mean the patient would administer the scheduled 12 units of lispro along with an additional “correctional” 3 units for a total of 15 units prior to the meal. If correctional doses are required on a consistent basis, an adjustment of the patients diet and/or scheduled insulin dose may be necessary.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information:
Intensive Insulin Therapy in the Critically Ill: Guidelines:
The 2008 Surviving Sepsis Campaign guidelines (Dellinger, 2008) have suggested targeting blood glucose levels <150 mg/dL by using a validated protocol for insulin adjustments (Grade 2C) and that all patients receiving I.V. insulin should receive a glucose calorie source. Concurrently blood glucose values should be monitored every 1-2 hours until glucose values and insulin infusion rates are stable, then monitored every 4 hours thereafter (Grade 1C).
As a result of a meta-analysis (Wiener, 2008) and the NICE-SUGAR study (2009), the American College of Endocrinology and the American Diabetes Association (Moghissi, 2009) recommended initiation of a continuous I.V. insulin infusion for the critically ill patient with persistent hyperglycemia (≥180 mg/dL) to maintain serum glucose levels between 140-180 mg/dL. Target serum glucose levels ≤110 mg/dL are no longer recommended. Frequent blood glucose monitoring (ie, every 0.5-2 hours) is necessary to reduce the incidence of hypoglycemia and achieve optimal glycemic control.
The 2011 ACP clinical practice guideline for the management of glycemic control in hospitalized patients strongly recommends avoiding intensive insulin therapy in SICU/MICU patients, because combined evidence does not show mortality benefit with blood glucose levels of 80-110 mg/dL compared to higher blood glucose ranges. Target blood glucose levels of 140-200 mg/dL are recommended if insulin therapy is used in SICU/MICU patients given the lower risk of hypoglycemia. There is inconclusive evidence associating the use of intensive insulin therapy to reductions in length of stay in the SICU/MICU (Qaseem, 2011).
Cardiovascular Considerations
Acute Coronary Syndromes (ACS): The 2004 ACC/AHA STEMI guidelines (Antman, 2004) recommended an insulin infusion to normalize blood glucose in patients with STEMI and complicated courses; however, no study has shown whether treatment of hyperglycemia has benefit in patients with ACS. The 2009 ACCF/AHA STEMI guidelines modified this statement to say that it is reasonable to use an insulin-based regimen to achieve and maintain glucose levels <180 mg/dL while avoiding hypoglycemia (Class IIa recommendation). There is uncertainty about the ideal glucose target range in STEMI patients. The target glucose range of the conventional-control group in the NICE-SUGAR study which enrolled 6104 critically ill medical and surgical patients was 144 -180 mg/dL. The NICE-SUGAR study demonstrated an increase in the risk of death, predominantly due to cardiovascular causes, in the intensive glucose control group (target range: 81-108 mg/dL) compared to the conventional-control group (NICE-SUGAR study investigators, 2009).
The 2011 ACP clinical practice guideline for the management of glycemic control in hospitalized patients recommends against the use of intensive insulin therapy in non-SICU/MICU patients which includes patients suffering a myocardial infarction (Qaseem, 2011).
Dental Health: Effects on Dental Treatment
Patients with type 1 diabetes (insulin dependent) should be appointed for dental treatment in the morning in order to minimize chance of stress-induced hypoglycemia.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness or confusion
Mental Health: Effects on Psychiatric Treatment
MAO inhibitors may enhance the hypoglycemic effects of insulin; TCAs may antagonize the effects of insulin
Nursing: Physical Assessment/Monitoring
Monitor for hypoglycemia at regular intervals during therapy. Teach patient proper use, including appropriate injection technique and syringe/needle disposal, and monitoring requirements.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution:
HumuLIN® R: 100 units/mL (3 mL, 10 mL)
NovoLIN® R: 100 units/mL (10 mL)
Injection, solution [concentrate]:
HumuLIN® R U-500: 500 units/mL (20 mL)
Pricing: U.S. (www.drugstore.com)
Solution (HumuLIN R)
100 units/mL (10): $73.99
Solution (HumuLIN R U-500 (Concentrated))
500 units/mL (20): $443.01
Solution (NovoLIN R)
100 units/mL (10): $75.99
References
American College of Obstetricians and Gynecologists Committee on Practice Bulletins, “ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 30, September 2001 (Replaces Technical Bulletin Number 200, December 1994). Gestational Diabetes,” Obstet Gynecol, 2001, 98(3):525-38.
American Diabetes Association, “Gestational Diabetes Mellitus,”Diabetes Care, 2004, 27(Suppl 1):88-90.
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2012,” Diabetes Care, 2012, 35(Suppl ):11-63.
American Diabetes Association, “Type 2 Diabetes in Children and Adolescents,” Diabetes Care, 2000, 23(3):381-9.
Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636.
Brown G and Dodek P, “Intravenous Insulin Nomogram Improves Blood Glucose Control in the Critically Ill,” Crit Care Med, 2001, 29(9):1714-9.
Brunkhorst FM, Engel C, Bloos F, et al, “Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis,” N Engl J Med, 2008, 358(2):125-39.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, "Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada," Can J Diabetes, 20078, 32(suppl 1):1-201.
Dailey G, “New Strategies for Basal Insulin Treatment in Type 2 Diabetes Mellitus,” Clin Ther, 2004, 26(6):889-901.
Davies M, Storms F, Shutler S, et al, “Improvement of Glycemic Control in Subjects With Poorly Controlled Type 2 Diabetes,” Diabetes Care, 2005, 28(6):1282-8.
Deedwania P, Kosiborod M, Barrett E, et al, “Hyperglycemia and Acute Coronary Syndrome: A Scientific Statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism,” Circulation, 2008, 117(12):1610-9.
Dellinger RP, Levy MM, Carlet JM, et al, “Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008,” [published correction appears in Crit Care Med, 2008, 36(4):1394-6], Crit Care Med, 2008, 36(1):296-327.
Field JM, Hazinski MF, Sayre MR, et al, “Part 1: Executive Summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” Circulation, 2010, 122 (18 Suppl 3):640-56.
Gerstein HC, Yale JF, Harrist SB, et al, “A Randomized Trial of Adding Insulin Glargine vs. Avoidance of Insulin in People with Type 2 Diabetes on Either No Oral Glucose-Lowering Agents or Submaximal Doses of Metformin and/or Sulphonylureas: The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study,” Diabet Med, 2006, 23(7):736-42.
Goldberg PA, Kedves A, Walter K, et al, “'Waste Not, Want Not': Determining Optimal Priming Volume for Intravenous Insulin Infusions,” Diabetes Technol Ther, 2006, 8(5):598-601.
Handelsman Y, Mechanick JI, Blonde L, et al, “American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan,” Endocr Pract, 2011, 17(Suppl 2):1-53.
Hegenbarth MA and American Academy of Pediatrics Committee on Drugs, “Preparing for Pediatric Emergencies: Drugs to Consider,” Pediatrics, 2008, 121(2):433-43.
Hillis LD, Smith PK, Anderson JL, et al, “2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 124(23):2610-42.
Hirsch IB, “Evidence-Based Priming,” Diabetes Technol Ther, 2006, 8(5):521-2.
Holman RR and Turner RC, “Insulin Therapy in Type II Diabetes,” Diabetes Res Clin Pract, 1995, (28 Suppl):179-84.
Hopkins DF, Cotton SJ, and Williams G, “Effective Treatment of Insulin-Induced Edema Using Ephedrine,” Diabetes Care, 1993, 16(7):1026-8.
Joint Commission on Accreditation of Healthcare Organizations, “2005 National Patient Safety Goals.” Available at http://www.jointcommission.org/PatientSafety/NationalPatientSafetyGoals/05_npsgs.htm
Kitabchi AE, Umpierrez GE, Miles JM, et al, “Hyperglycemic Crises in Adult Patients With Diabetes,” Diabetes Care, 2009, 32(7):1335-43.
Kitabchi AE, Umpierrez GE, Murphy MB, et al, "Hyperglycemic Crises in Diabetes,” Diabetes Care, 2004, 27(Suppl 1): 94-102.
Kushner FG, Hand M, Smith SC, et al, “2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2009, 54(23):2205-41.
Lazar HL, Philippides G, Fitzgerald C, et al, “Glucose-Insulin-Potassium Solutions Enhance Recovery After Urgent Coronary Artery Bypass Grafting,” J Thorac Cardiovasc Surg, 1997, 113(2):354-60.
Malhotra A, “Intensive Insulin in Intensive Care,” N Engl J Med, 2006, 354(5):516-8.
Malmberg K, “Prospective Randomised Study of Intensive Insulin Treatment on Long Term Survival After Acute Myocardial Infarction in Patients With Diabetes Mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group,” BMJ, 1997, 314(7093):1512-5.
Meneghini L, Koenen C, Rojas P, et al, “Efficacy and Safety of Insulin Detemir in a Large Cohort of Patients With Type 2 Diabetes Using a Simplified Self-Adjusted Dosing Guideline -- Results of the Predictive 303 Study,” Presented at: 67th Scientific Sessions of the American Diabetes Association; June 22-25, 2007; Chicago, Ill.
Moghissi ES, Korytkowski MT, DiNardo M, et al, “American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control,” Endocr Pract, 2009, 15(4):353-69.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Morley JE and Perry HM 3d, “The Management of Diabetes Mellitus in Older Individuals,” Drugs, 1991, 41(4):548-65.
Mueller-Schoop J, “Accidental Intravenous Self-Injection With Insulin Pen,” Lancet, 1993, 341(8849):894.
Nathan DM, Buse, JB, Davidson MB, et al, “Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy,” Diabetes Care, 2009, 32(1):193-203.
Nathan DM, “Insulin Treatment in the Elderly Diabetic Patient,” Clin Geriatr Med, 1990, 6(4):923-31.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al, “Intensive Versus Conventional Glucose Control in Critically Ill Patients,” N Engl J Med, 2009, 360(13):1283-97.
Oiknine R, Bernbaum M, and Mooradian AD, “A Critical Appraisal of the Role of Insulin Analogues in the Management of Diabetes Mellitus,” Drugs, 2005, 65(3):325-40.
“Proceedings of the American College of Endocrinology Task Force on Inpatient Diabetes and Metabolic Control Consensus Conference, Washington, DC, USA, December 2003,” Endocr Pract, 2004, (10 Suppl 2):3-108.
Qaseem A, Humphrey LL, Chou R, et al, "Use of Intensive Insulin Therapy for the Management of Glycemic Control in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians," Ann Intern Med, 2011, 154(4):260-7.
Riddle MC, Rosenstock J, Gerich J, et al, “The Treat-to-Target Trial: Randomized Addition of Glargine or Human NPH Insulin to Oral Therapy of Type 2 Diabetic Patients,” Diabetes Care, 2003, 26(11):3080-6.
Rodbard HW, Jellinger PS, Davidson JA, et al, “Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control,” Endocr Pract, 2009, 15(6):540-59.
Silverstein J, Klingensmith G, Copeland K, et al, “Care of Children and Adolescents With Type 1 Diabetes: A Statement of the American Diabetes Association,” Diabetes Care, 2005, 28(1):186-212.
Simeon PS, Geffner ME, Levin SR, et al, “Continuous Insulin Infusions in Neonates: Pharmacologic Availability of Insulin in Intravenous Solutions,” J Pediatr, 1994, 124(5 Pt 1):818-20.
Van den Berghe G, Wilmer A, Hermans G, et al, “Intensive Insulin Therapy in the Medical ICU,” N Engl J Med, 2006, 354(5):449-6.
Van den Berghe G, Wouters P, Weekers F, et al, “Intensive Insulin Therapy in the Critically Ill Patients,” N Engl J Med, 2001, 345(19):1359-67.
Vanden Hoek TL, Morrison LJ, Shuster M, et al, “Part 12: Cardiac Arrest in Special Situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” Circulation, 2010, 122(18 Suppl 3):829-61.
Wiener RS, Wiener DC, and Larson RJ, “Benefits and Risks of Tight Glucose Control in Critically Ill Adults: A Meta-Analysis,” JAMA, 2008, 300(8):933-44.
Wolfsdorf J, Craig ME, Daneman D, et al, “Diabetic Ketoacidosis,” Pediatr Diabetes, 2007, 8(1):28-43. Available at http://www.ispad.org/FileCenter/10-Wolfsdorf_Ped_Diab_2007,8.28-43.pdf
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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