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Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

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1 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Chapter 32 Antidiabetic Drugs Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

2 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Diabetes Mellitus Diabetes mellitus (DM) actually is not a single disease, but a group of progressive diseases. It is often regarded as a syndrome rather than a disease. Two types Type 1 Type 2 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

3 Diabetes Mellitus (cont’d)
Signs and symptoms Elevated fasting blood glucose (higher than 126 mg/dL) or a hemoglobin A1C (A1C) level greater than or equal to 6.5% Polyuria Polydipsia Polyphagia Glycosuria Unexplained weight loss Fatigue Blurred vision Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

4 Type 1 Diabetes Mellitus
Lack of insulin production or production of defective insulin Affected patients need exogenous insulin Fewer than 10% of all diabetes cases are type 1 Complications Diabetic ketoacidosis (DKA) Hyperosmolar nonketotic syndrome Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

5 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

6 Type 2 Diabetes Mellitus
Most common type: 90% of all cases Caused by insulin deficiency and insulin resistance Many tissues are resistant to insulin Reduced number of insulin receptors Insulin receptors less responsive Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

7 Type 2 Diabetes Mellitus (cont’d)
Several comorbid conditions Obesity Coronary heart disease Dyslipidemia Hypertension Microalbuminemia (protein in the urine) Increased risk for thrombotic (blood clotting) events These comorbidities are collectively referred to as metabolic syndrome or insulin-resistance syndrome or syndrome X Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

8 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Gestational Diabetes Hyperglycemia that develops during pregnancy Insulin must be given to prevent birth defects Usually subsides after delivery 30% of patients may develop Type 2 DM within 10 to 15 years Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

9 Classroom Response Question
A woman who has type II diabetes is now pregnant. She wants to know whether to take her oral antidiabetic medication. What instructions will she receive? She should continue the antidiabetic medication at the same dosage. The antidiabetic medication dosage will be increased gradually throughout her pregnancy. She will be switched to insulin therapy while she is pregnant. She will not receive any antidiabetic medication while pregnant and will need to monitor her dietary intake closely. Correct answer: C Rationale: Oral antidiabetic medications are generally not recommended for pregnant patients because of a lack of firm safety data. Insulin therapy is the currently recommended drug therapy for pregnant women. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

10 Major Long-Term Complications of DM (Both Types)
Macrovascular (atherosclerotic plaque) Coronary arteries Cerebral arteries Peripheral vessels Microvascular (capillary damage) Retinopathy Neuropathy Nephropathy Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

11 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Screening for DM Prediabetes Categories of increased risk for diabetes Hemoglobin A1C of 5.7% to 6.4% Fasting plasma glucose (FPG) levels higher than or equal to 100 mg/dL but less than 126 mg/dL Impaired glucose tolerance test (oral glucose challenge) Screening recommended every 3 years for all patients 45 years and older Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

12 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Treatment for DM Type 1 Insulin therapy Type 2 Lifestyle changes Oral drug therapy Insulin when the above no longer provide glycemic control Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

13 Types of Antidiabetic Drugs
Insulins Oral hypoglycemic drugs Both aim to produce normal blood glucose states Some new injectable hypoglycemic drugs may be used in addition to insulin or antidiabetic drugs Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

14 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins Function as a substitute for the endogenous hormone Effects are the same as normal endogenous insulin Restores the diabetic patient’s ability to: Metabolize carbohydrates, fats, and proteins Store glucose in the liver Convert glycogen to fat stores Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

15 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins (cont’d) Human insulin Derived using recombinant DNA technologies Recombinant insulin produced by bacteria and yeast Goal: tight glucose control To reduce the incidence of long-term complications Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

16 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins (cont’d) Rapid-acting Most rapid onset of action (5 to 15 minutes) Shorter duration Patient must eat a meal after injection Insulin lispro (Humalog) Similar action to endogenous insulin Insulin aspart (NovoLog) Insulin glulisine (Apidra) May be given subcutaneously or via continuous subcutaneous infusion pump (but not IV) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

17 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins (cont’d) Short-acting Regular insulin (Humulin R) Onset 30 to 60 minutes The only insulin product that can be given by IV bolus, IV infusion, or even IM Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

18 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins (cont’d) Intermediate-acting Insulin isophane suspension (also called NPH) Cloudy appearance Slower in onset and more prolonged in duration than endogenous insulin Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

19 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins (cont’d) Long-acting glargine (Lantus), detemir (Levemir) Clear, colorless solution Usually dosed once daily Referred to as basal insulin Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

20 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

21 Classroom Response Question
The nurse has just administered the morning dose of a patient’s lispro (Humalog) insulin. Just after the injection, the dietary department calls to inform the patient care unit that breakfast trays will be 45 minutes late. What will the nurse do next? Inform the patient of the delay. Check the patient’s blood glucose levels. Call the dietary department to send a tray immediately. Give the patient food, such as cereal and skim milk, and juice. Correct answer: D Rationale: Lispro insulin’s onset of action is 15 minutes. It is essential that a diabetic patient eat a meal after injection. Otherwise profound hypoglycemia may result. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

22 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins (cont’d) Fixed combinations Humulin 70/30 Humulin 50/50 Novolin 70/30 Humalog Mix 75/25 Humalog 50/50 NovoLog 70/30 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

23 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Insulins (cont’d) Insulin use in special populations Pediatrics Pregnant women Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

24 Sliding-Scale Insulin Dosing
Subcutaneous short-acting or regular insulin doses adjusted according to blood glucose test results Typically used in hospitalized diabetic patients or those on total parenteral nutrition (TPN) or enteral tube feedings Subcutaneous insulin is ordered in an amount that increases as the blood glucose increases Disadvantage: delays insulin administration until hyperglycemia occurs; results in large swings in glucose control Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

25 Basal-Bolus Insulin Dosing
Preferred method of treatment for hospitalized diabetic patients Mimics a healthy pancreas by delivering basal insulin constantly as a basal and then as needed as a bolus Basal insulin is a long-acting insulin (insulin glargine) Bolus insulin (insulin lispro or insulin aspart) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

26 Oral Antidiabetic Drugs
Used for type 2 diabetes Treatment for type 2 diabetes includes lifestyle modifications Diet, exercise, smoking cessation, weight loss Oral antidiabetic drugs may not be effective unless the patient also makes behavioral or lifestyle changes Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

27 Oral Antidiabetic Drugs (cont’d)
Biguanides metformin (Glucophage) Sulfonylureas Second generation: glimepiride (Amaryl), glipizide (Glucotrol), glyburide (DiaBeta, Micronase) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

28 Oral Antidiabetic Drugs (cont’d)
Glinides repaglinide (Prandin), nateglinide (Starlix) Thiazolidinediones pioglitazone (Actos) rosiglitazone (Avandia) Only available through specialized manufacturer programs Also known as glitazones Alpha-glucosidase inhibitors acarbose (Precose), miglitol (Glyset) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

29 Oral Antidiabetic Drugs (cont’d)
Dipeptidyl peptidase-IV (DPP-IV) inhibitors sitagliptin (Januvia) saxagliptin (Onglyza) linagliptin (Tradjenta) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

30 Oral Antidiabetic Drugs: Mechanism of Action
Biguanides Decrease production of glucose by the liver Decrease intestinal absorption of glucose Increase uptake of glucose by tissues Do not increase insulin secretion from the pancreas (does not cause hypoglycemia) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

31 Oral Antidiabetic Drugs: Mechanism of Action (cont’d)
Sulfonylureas Stimulate insulin secretion from the beta cells of the pancreas, thus increasing insulin levels Beta cell function must be present Improve sensitivity to insulin in tissues Result in lower blood glucose levels Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

32 Oral Antidiabetic Drugs: Mechanism of Action (cont’d)
Glinides Action similar to sulfonylureas Increase insulin secretion from the pancreas Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

33 Oral Antidiabetic Drugs: Mechanism of Action (cont’d)
Thiazolidinediones Decrease insulin resistance “Insulin sensitizing drugs” Increase glucose uptake and use in skeletal muscle Inhibit glucose and triglyceride production in the liver Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

34 Oral Antidiabetic Drugs: Mechanism of Action (cont’d)
Alpha-glucosidase inhibitors Reversibly inhibit the enzyme alpha-glucosidase in the small intestine Result in delayed absorption of glucose Must be taken with meals to prevent excessive postprandial blood glucose elevations (with the “first bite” of a meal) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

35 Oral Antidiabetic Drugs: Mechanism of Action (cont’d)
Dipeptidyl peptidase-IV (DPP-IV) inhibitors Delay breakdown of incretin hormones by inhibiting the enzyme DPP-IV Incretin hormones increase insulin synthesis and lower glucagon secretion Reduce fasting and postprandial glucose concentrations Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

36 Oral Antidiabetic Drugs: Indications
Used alone or in combination with other drugs and/or diet and lifestyle changes to lower the blood glucose levels in patients with type 2 diabetes Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

37 Oral Antidiabetic Drugs: Adverse Effects
Biguanides (metformin) Primarily affects GI tract: abdominal bloating, nausea, cramping, diarrhea, feeling of fullness May also cause metallic taste, reduced vitamin B12 levels Lactic acidosis is rare but lethal if it occurs Does not cause hypoglycemia Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

38 Oral Antidiabetic Drugs: Adverse Effects (cont’d)
Sulfonylureas Hypoglycemia, hematologic effects, nausea, epigastric fullness, heartburn, many others Glinides Headache, hypoglycemic effects, dizziness, weight gain, joint pain, upper respiratory infection or flulike symptoms Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

39 Oral Antidiabetic Drugs: Adverse Effects (cont’d)
Thiazolidinediones Moderate weight gain, edema, mild anemia Hepatic toxicity—monitor alanine aminotransferase (ALT) levels Alpha-glucosidase inhibitors Flatulence, diarrhea, abdominal pain Do not cause hypoglycemia, hyperinsulinemia, or weight gain Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

40 Oral Antidiabetic Drugs: Adverse Effects (cont’d)
Dipeptidyl peptidase-IV (DPP-IV) inhibitors Upper respiratory tract infection, headache, and diarrhea Hypoglycemia can occur and is more common if used in conjunction with a sulfonylurea Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

41 Injectable Antidiabetic Drugs
Amylin agonists pramlintide (Symlin) Incretin mimetics exenatide (Byetta) liraglutide (Victoza) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

42 Injectable Antidiabetic Drugs: Mechanism of Action (cont’d)
Amylin agonist Mimics the natural hormone amylin Slows gastric emptying Suppresses glucagon secretion, reducing hepatic glucose output Centrally modulates appetite and satiety Used when other drugs have not achieved adequate glucose control Subcutaneous injection Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

43 Injectable Antidiabetic Drugs: Mechanism of Action (cont’d)
Incretin mimetic Mimics the incretin hormones Enhances glucose-driven insulin secretion from beta cells of the pancreas Only used for type 2 diabetes Exenatide: Injection pen device Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

44 Injectable Antidiabetic Drugs: Adverse Effects
Amylin agonist Nausea, vomiting, anorexia, headache Incretin mimetics Nausea, vomiting, and diarrhea Rare cases of hemorrhagic or necrotizing pancreatitis Weight loss Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

45 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Hypoglycemia Abnormally low blood glucose level (below 50 mg/dL) Mild cases can be treated with diet—higher intake of protein and lower intake of carbohydrates—to prevent rebound postprandial hypoglycemia Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

46 Hypoglycemia Symptoms
Early Confusion, irritability, tremor, sweating Late Hypothermia, seizures Coma and death will occur if not treated Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

47 Glucose-Elevating Drugs
Oral forms of concentrated glucose Buccal tablets, semisolid gel 50% dextrose in water (D50W) Glucagon Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

48 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Nursing Implications Before giving drugs that alter glucose levels, obtain and document: A thorough history Vital signs Blood glucose level, A1C level Potential complications and drug interactions Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

49 Nursing Implications (cont’d)
Before giving drugs that alter glucose levels: Assess the patient’s ability to consume food Assess for nausea or vomiting Hypoglycemia may be a problem if antidiabetic drugs are given and the patient does not eat If a patient is NPO for a test or procedure, consult primary care provider to clarify orders for antidiabetic drug therapy Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

50 Nursing Implications (cont’d)
Keep in mind that overall concerns for any patient with diabetes increase when the patient: Is under stress Has an infection Has an illness or trauma Is pregnant or lactating Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

51 Classroom Response Question
A patient with type 1 diabetes is admitted to the medical unit with an acute exacerbation of chronic obstructive pulmonary disease (COPD). He is placed on IVPB antibiotics, nebulizer treatments with albuterol, and an IV corticosteroid, and he is also taking a proton pump inhibitor for gastrointestinal esophageal reflux disease (GERD). He takes a dose of glargine insulin every evening. That evening the nurse notes that his blood glucose level is 170 mg/dL. The next morning, his fasting glucose level is 202 mg/dL. What is the most likely cause of his elevated glucose levels? The albuterol The antibiotics The proton pump inhibitor The corticosteroid Correct answer: D Rationale: Corticosteroids antagonize the hypoglycemic effects of insulin, resulting in elevated blood glucose levels. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

52 Nursing Implications (cont’d)
Thorough patient education is essential regarding: Disease process Diet and exercise recommendations Self-administration of insulin or oral drugs Potential complications Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

53 Nursing Implications (cont’d)
When insulin is ordered, ensure: Correct route Correct type of insulin Timing of the dose Correct dosage Insulin order and prepared dosages are second-checked with another nurse Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

54 Nursing Implications (cont’d)
Insulin Check blood glucose level before giving insulin Roll vials between hands instead of shaking them to mix suspensions Ensure correct storage of insulin vials Only use insulin syringes, calibrated in units, to measure and give insulin Ensure correct timing of insulin dose with meals Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

55 Nursing Implications (cont’d)
Insulin (cont’d) When drawing up two types of insulin in one syringe, always withdraw the regular or rapid-acting insulin first Provide thorough patient education regarding self-administration of insulin injections, including timing of doses, monitoring blood glucose levels, and injection site rotations Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

56 Classroom Response Question
After the 0700 report, the day shift nurse notices that a patient has a 0730 dose of insulin due and goes to the automated dispensing machine to retrieve the insulin. The nurse sees that the night shift nurse had removed the 0730 dose of insulin, but the medication administration record (MAR) has not been signed by the nurse. The patient is confused and says “she thinks” the night nurse gave her the insulin. The patient’s blood glucose level is 142 mg/dL. What will the day shift nurse do? Give the insulin because it was not signed off. Hold the insulin because the patient thinks she received it and it is recorded in the machine. Ask the charge nurse to call the night nurse at home to clarify whether the insulin was given. Report this to the nursing supervisor. Correct answer: C Rationale: Never guess whether a drug was given. Taking the drug out of the machine does not mean it was given. The nurse should ask the night nurse what was done. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

57 Nursing Implications (cont’d)
Oral antidiabetic drugs Always check blood glucose levels before giving Usually given 30 minutes before meals Alpha-glucosidase inhibitors are given with the first bite of each main meal Metformin is taken with meals to reduce GI effects Metformin will need to be discontinued if the patient is to undergo studies with contrast dye because of possible renal effects—check with the prescriber Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

58 Nursing Implications (cont’d)
Assess for signs of hypoglycemia If hypoglycemia occurs: Administer oral form of glucose, if the patient is conscious Give the patient glucose tablets or gel, corn syrup, honey, fruit juice, or nondiet soft drink or have the patient eat a small snack, such as crackers or a half sandwich Deliver D50W or glucagon intravenously, if the patient is unconscious Monitor blood glucose levels Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

59 Nursing Implications (cont’d)
Monitor for therapeutic response Decrease in blood glucose levels to the level prescribed by physician Measure hemoglobin A1C to monitor long-term compliance with diet and drug therapy Monitor for hypoglycemia and hyperglycemia Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

60 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Case Study A male patient who has a history of type 2 diabetes mellitus is admitted to the medical unit with a diagnosis of pneumonia. The patient has many questions regarding his care and asks the nurse why everyone keeps telling him about hemoglobin A1C. The nurse will inform the patient that hemoglobin A1C provides information regarding: which type of diabetes the patient has. if he has an infection. patient compliance with treatment regimen for several months previously. current fasting blood glucose level. Correct answer: C Rationale: Hemoglobin A1C is a good indicator of the patient’s compliance with the therapy regimen for several months previously. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

61 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Case Study The patient was taking metformin before this hospitalization. To facilitate better glucose control, the patient has been switched to insulin therapy while hospitalized. The patient asks the nurse why it is so important to time meals with the insulin injection and to give him an example of a long-acting insulin. Which drug will the nurse tell the patient is a long-acting insulin? Insulin glulisine (Apidra) Insulin isophane suspension (NPH) Insulin detemir (Levemir) Regular insulin (Humulin R) Correct answer: C Rationale: The nurse should inform the patient that timing of meals with insulin and oral antidiabetic therapy is important to prevent hypoglycemia and to obtain the most optimal results from the antidiabetic therapy. Insulin detemir (Levemir) is a long-acting insulin while insulin glulisine (Apidra) is a rapid-acting insulin. Insulin isophane suspension (NPH) is an intermediate-acting insulin, and regular insulin (Humulin R) is a short-acting insulin. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

62 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Case Study The patient is being discharged home with insulin aspart (NovoLog) and insulin isophane suspension (NPH). Which information does the nurse include when providing discharge teaching to the patient? Store the insulins in the refrigerator Shake the insulins for 1 full minute before use. Administer the injection at a 30-degree angle to your skin. Draw up the insulin aspart (NovoLog) first, then the insulin isophane suspension (NPH) into the same syringe. Correct answer: D Rationale: The rapid-acting (clear) then the intermediate-acting (cloudy) insulins should be mixed in the syringe after the appropriate amount of air has been injected. Insulin is stored at room temperature when it will be used within the month. The injection should be administered at a 90-degree angle for patients who have adequate body fat and at a 45-degree angle for patients who are very thin. Insulins should be rolled prior to administration and not shaken. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

63 Copyright © 2014 by Mosby, an imprint of Elsevier Inc.
Case Study The nurse enters the patient’s room to complete the discharge process and finds the patient to be lying in bed unresponsive and breathing. The patient has a blood glucose reading of 48 mg/dL. What is the most appropriate response by the nurse? Place a packet of table sugar in the patient’s mouth. Start CPR. Roll the patient to the side and administer the ordered glucagon. Have the patient drink orange juice. Correct answer: C Rationale: Glucagon, a natural hormone secreted by the pancreas, is available as a subcutaneous injection to be given when a quick response to severe hypoglycemia is needed. Because glucagon injection may induce vomiting, roll an unconscious patient onto his or her side before injection. Glucagon is useful in the unconscious hypoglycemic patient without established intravenous access. The patient is at risk for aspiration so nothing should be administered by mouth. CPR is not indicated. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.


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