Which is the most commonly administered agent for a patient in a hypoglycemia emergency?

Therapeutic indications

Hypoglycemic states secondary to diabetes mellitus or fasting hypoglycemia in the conscious patient (Chapter 17).

Side effects, contraindications, and precautions

Liquid or viscous oral carbohydrates should not be administered to a patient who does not have an active gag reflex or is unable to drink without assistance. Parenteral administration of antihypoglycemics is recommended in these situations. There are no side effects when oral carbohydrates are administered as directed.

Availability

Antihypoglycemics come in a variety of forms, including Glucola, Gluco-Stat, Insta-Glucose, nondiet cola beverages, fruit juices, granulated sugar, and tubes of decorative icing (Figure 3-14).

Suggested for emergency kit

Any of the previously mentioned sources may be included in the emergency drug kit.

Metformin

Metformin is an oral hyperglycemic agent in the biguanide class. Metformin acts by increasing peripheral glucose uptake by increasing the capacity of insulin to bind to its receptors and increasing the synthesis of glucose transporter. Metformin also inhibits gluconeogenesis, by way of non-competitively inhibiting the enzyme mitochondrial glycerophosphate dehydrogenase, resulting in a reduced conversion of lactate to glucose, ultimately resulting in metformin induced lactic acidosis.9 This occurs as a result of decreased conversion of pyruvate to glucose in the liver via inhibition of pyruvate carboxylase, responsible for the first step of gluconeogenesis. As a result of this inhibition, pyruvate is diverted into lactic acid formation, responsible for the anion gap metabolic acidosis. The lactic acidosis that forms as a result of metformin poisoning is different than the lactic acidosis that is well known in critical care. Lactic acidosis occurs as a result of hypoxia and hypoperfusion (type A) or elimination, clearance, liver dysfunction without clinical evidence of hypoxemia, or hypoperfusion (type B). Type B is associated with metformin poisoning resulting in gluconeogenesis inhibition and impairment of lactate metabolism.10 The most common factors that predispose a patient to metformin-induced lactic acidosis are renal insufficiency, drug-drug interaction, and liver injury.

Severe lactic acidosis associated with metformin is rare but can be serious and possibly fatal. It is characterized by generalized symptoms such as nausea, vomiting, abdominal pain, and malaise.11 Maintaining a high index of suspicion is of utmost importance. These patients may progress to a critically ill state with hypotension, altered mental status, respiratory failure, and hypothermia, which may mimic septic shock. These patients need aggressive symptomatic and supportive care with fluid resuscitation and vasopressor use. Hemodialysis with a bicarbonate buffer may provide some benefit to patients with severe metabolic acidosis.12

Hyperglycemic Agents

Glucagon is used as a hyperglycemic agent in insulin-treated patients who become hypoglycemic and are too obtunded to take oral carbohydrates; nonendocrine uses have included therapy of β-blocker overdose, cardiovascular emergencies, and relaxation of the gastrointestinal (GI) tract for diagnostic procedures. Its toxicity is limited; nausea and vomiting are frequent consequences of its use. The expected increase in glucose does not occur in patients who are depleted of glycogen stores; for example, patients with alcohol-related hypoglycemia show no response, and delaying more effective therapy (such as glucose administration) poses a risk in such a setting. In a patient with an insulinoma, the initial beneficial increase in glucose levels may be followed by a subsequent precipitous glucose drop due to stimulation of further insulin production by the glucagon.

Diazoxide, used infrequently as a parenteral agent in hypertensive crisis, is an inhibitor of insulin secretion and can be used as an oral agent in the therapy of patients with insulinomas. It causes sodium and fluid retention, with associated edema, and simultaneous use of a loop diuretic is a frequent need. In addition to being monitored for development of hyperglycemia related to excessive insulin suppression, patients should be monitored for complications that include GI distress, pancreatitis, thrombocytopenia or leukopenia, impairment of renal function, and proteinuria.

Glucagon — (GlucaGen [rDNA origin])

Crustacean hyperglycemic hormone

Eyestalk CHH controls crustacean hemolymph glucose levels as a hyperglycemic factor. Hyperglycemia is a result of the mobilization of glycogen in target tissues such as the hepatopancreas and abdominal muscles. Steady CHH hemolymph levels of C. maenas are 25 fmol/mL in the winter and 50–55 fmol/mL in the summer.11 Recent studies have revealed that eyestalk CHHs in many species have pleiotropic functions, such as MIH, MOIH, and VIH activities.7, 8, 11 Eyestalk CHH also has a role in osmo/ionoregulation at the gill in euryhaline crustacean species. CHH expressed in the gut, the aa sequence of which is identical with that of eyestalk CHH, contributes as an another osmoregulator in, for example, ion transport at the gills and water uptake for the purpose of enlarging the body size after molting. A few studies have showed that eyestalk CHH is probably involved with the inhibitory regulation of the androgenic gland (AG). The biological functions of long type CHH isoforms (noneyestalk type) have not yet been elucidated.

3.4 Glucagon

Shortly after the discovery of insulin, an antagonistic hyperglycaemic factor was postulated and named glucagon (Kimball & Murlin, 1923), though it was not purified until 1955 (Staub, Sinn, & Behrens, 1955). This 29-amino acid polypeptide is produced from the cleavage of proglucagon in the alpha cells of the islets of Langerhans. Glucagon acts on a class 2 G-protein-coupled receptor which is structurally related but distinct to those stimulated by the other products of proglucagon cleavage, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) (Mayo et al., 2003).

Glucagon opposes the effects of insulin by increasing hepatic glucose output via hepatic glycogenolysis or gluconeogenesis. Glucagon release is stimulated by hypoglycemia (Havel & Valverde, 1996), and also by amino acids (Rocha, Faloona, & Unger, 1972), though it is suppressed by fatty acids (Gerich et al., 1976).

Peripheral administration of glucagon reduces food intake in humans and rodents (Geary, Kissileff, Pi-Sunyer, & Hinton, 1992; Le Sauter & Geary, 1991; Martin & Novin, 1977; Schulman et al., 1957), while immunoneutralization of glucagon increases meal size in rats (Geary, Le Sauter, & Noh, 1993; Le Sauter, Noh, & Geary, 1991). Exogenously administered glucagon also increases energy expenditure (Tan et al., 2012). Glucagon-receptor knockout mice have reduced adiposity, though the effect on food intake and energy expenditure in such animals is variable (Conarello et al., 2007; Gelling et al., 2003). The anorectic effect of glucagon may appear counterintuitive for a hormone that normally acts to increase blood glucose, but it is compatible with glucagon's role as a stress hormone, where an anorectic effect might be advantageous as part of a “fight or flight” response (Jones, Tan, & Bloom, 2012).

The satiating effect of glucagon occurs both centrally and peripherally. Central administration of glucagon suppresses feeding to a greater degree than peripheral administration in rats, chicks, and sheep (Honda et al., 2007; Inokuchi, Oomura, & Nichimura, 1984; Kurose et al., 2009). The central site of glucagon action is the hypothalamus, where glucagon inhibits neurons within multiple hypothalamic nuclei (Inokuchi et al., 1986). In the periphery, glucagon acts on the liver: infusion of glucagon into the hepatic portal vein suppresses feeding at levels that fail to do so when infused into the inferior vena cava (Geary et al., 1993). The effect of peripheral glucagon is also conveyed centrally: vagotomy prevents the suppression of feeding caused by peripherally administered glucagon (Geary et al., 1993; Le Sauter & Geary, 1990; Martin, Novin, & Vanderweele, 1978), as do lesions to the area postrema and the NTS (Weatherford & Ritter, 1988). The vagus nerve also stimulates glucagon release through its innervation of the pancreas (Ahrén & Taborsky, 1986); the cephalic phase of glucagon release is lost from transplanted pancreata, due to loss of these innervations (Secchi et al., 1995).

Severe insulin resistance

Most of the endocrine causes of glucose intolerance are the result of circulating insulin antagonists causing insulin resistance. A variety of other medical conditions, although rare, may be associated with severe resistance to insulin.

Acanthosis nigricans is characterized by the presence of velvety brown hyperkeratotic lesions on the neck, axillae and groins. There is a well-recognized, but relatively rare association with malignancy. Acanthosis nigricans not associated with malignancy may be classified into two types, both associated with insulin resistance and obesity. Type A is a variant of polycystic ovarian syndrome where the skin changes are marked; additional features include hirsutism, polycystic ovaries, virilization, coarse features and early accelerated growth. The cause of the insulin resistance in this type has not yet been determined. Several factors may be involved: reductions in insulin binding, receptor number and receptor kinase activity, and post receptor defects have each been reported in some patients. Patients with type B acanthosis nigricans tend to be older and are usually female. They have markers of autoimmune disease including hypergammaglobulinaemia, proteinuria, hypocomplementaemic nephritis, leucopenia, arthralgia, alopecia, enlarged salivary glands and positive antinuclear and anti-DNA antibodies. They have reduced insulin binding to monocytes in vitro, owing to the presence of an autoantibody against the insulin receptor. Ataxia telangiectasia may show some overlap with the features of type B acanthosis nigricans.

Leprechaunism is a rare congenital condition with typical facies, lipodystrophy, cliteromegaly, hirsutism and acanthosis nigricans. It is usually fatal. Affected children are severely resistant to exogenous insulin. They produce large amounts of normal insulin endogenously. Several cellular defects have been described that produce the phenotype of leprechaunism. Most patients have defective kinase activity of the insulin receptor, although some show defective insulin receptor formation and others are unable to recycle insulin receptors back to cell membranes after insulin binding. The common features of acanthosis nigricans and virilism are probably an effect of stimulation of IGF receptors by high concentrations of insulin.

Lipodystrophy occurs in local and generalized forms; it is usually familial. There are several associated features but these vary from family to family. Acanthosis nigricans, hepatosplenomegaly, nephritis and hyperlipoproteinaemia have all been reported. Likewise, the cellular defect varies, with some families having reduced insulin binding and some having reduced receptor numbers. Lipodystrophy is also frequently seen as a complication of treatment of acquired immune deficiency syndrome (AIDS), particularly with protease inhibitors. This may be severe enough not only to be disfiguring, but also to cause severe hyperlipidaemia and diabetes mellitus. There is something of a paradox in the fact that type 2 diabetes is associated with increased visceral fat depots but also with lipodystrophy. This is probably explained by the role that adipose tissue has in storing fatty acids as triglycerides. In conditions where this process is impaired, circulating concentrations of NEFA are increased and may affect hepatic insulin sensitivity in much the same way that they do when there is excess visceral adipose tissue accumulation in obesity.

Injectable Drugs

A number of injectable drugs—anticonvulsant, analgesic, vasopressor, corticosteroid, antihypoglycemic, antihypertensive, and anticholinergic drugs—are recommended or required for inclusion in the emergency kit of dentists who have advanced training in emergency medicine and/or anesthesia (Table 33-2). Such persons include oral and maxillofacial surgeons; dentist anesthesiologists; pedodontic, periodontic, endodontic, and other dental specialists who have completed a hospital training program; and general practitioners who have completed a general practice residency.

The anticonvulsant of choice is a benzodiazepine, either midazolam or diazepam. Anticonvulsants are administered either intravenously or intranasally to terminate a tonic-clonic seizure, whether in a patient with a history of prior seizure disorders or in management of local anesthetic overdose. Other therapeutic indications for the emergency administration of a benzodiazepine include termination of febrile convulsions, hyperventilation (for sedation), and thyroid storm (for sedation). Suggested for the emergency kit is midazolam, 5 mg/ml in a 5- or 10-ml multidose vial. If administered intranasally, the 5-mg/ml concentration is recommended.

An analgesic drug will be valuable during situations in which acute pain or anxiety is present. Management of pain during acute myocardial infarction (AMI) represents an important indication for administration of analgesics. Other therapeutic indications include intense, prolonged pain or anxiety and as a sedative in the management of heart failure (HF). Opioid analgesics are the drugs of choice, with morphine sulfate recommended. In recent years, however, the use of nitrous oxide-oxygen (N2O-O2) in management of pain during myocardial infarction has increased in popularity.11 N2O-O2 is administered in a concentration of 35% N2O and 65% O2. If N2O is not available, morphine sulfate, 10 mg/ml (two to three 1-ml ampules), is recommended.

Vasopressors are administered to manage hypotension. One vasopressor, epinephrine, has already been included in the basic emergency kit; however, its administration in most cases of mild hypotension is not recommended. A vasopressor with less intense actions is usually desirable. Within this category, many drugs are available; methoxamine is selected because of its ability to increase blood pressure with little secondary effect on the workload of the myocardium. Indications for vasopressor administration include management of hypotension as seen in syncopal reactions, drug-overdose reactions, postseizure states, acute adrenal insufficiency, and allergy. Recommended for the emergency kit is 10 mg/ml of methoxamine (two to three 1-ml ampules).

Parenteral antihypoglycemics are administered in the definitive management of hypoglycemia and in the differential diagnosis of unexplained unconsciousness or seizures of unknown origin. A 50% dextrose (D50) solution is recommended, which because of its volume and viscosity must be administered intravenously. One vial (50 ml) of 50% dextrose is recommended for the emergency kit. An alternative is glucagon, available as 1 mg/ml in a 2-ml ampule. Glucagon may be administered either intravenously or intramuscularly. For pediatric patients, D25 is recommended.

Corticosteroids are administered in the management of the acute allergic reaction, but only after epinephrine and the histamine blockers have proven effective. Another indication for their administration is management of acute adrenal insufficiency. Recommended for the emergency kit is 50 mg/ml of hydrocortisone sodium succinate (one 2-ml vial).

The need to administer antihypertensive drugs to manage a hypertensive crisis (excessive elevations in blood pressure) is extremely rare. First, the incidence of extreme acute blood pressure elevations is quite uncommon, and second, other methods may be used to decrease blood pressure without the use of parenteral antihypertensive drugs. Oral drugs, such as nifedipine or nitroglycerin, may be administered in most situations to provide a slight depression of blood pressure. The inclusion of an antihypertensive drug is in response to state dental board requirements for general anesthesia permits (and in a few states also for parenteral sedation).

Esmolol (Brevibloc) is a β1-selective adrenergic receptor–blocking agent with a very short duration of action and is the recommended parenteral drug for acute hypertensive episodes. It is available as a 10-mg/ml formulation, and two ampules of 100 mg/ml (with diluent) are recommended.

Atropine, a parasympathetic anticholinergic blocking agent, is recommended for the management of symptomatic bradycardia (adult heart rate of <60 beats per minute). Atropine is also considered an essential drug in ACLS, in which it is employed in the management of hemodynamically significant bradydysrhythmias (significant heart block and asystole). It is available as 0.5 mg/mL in 1-mL vials and 1 mg in a 10-mL syringe, and two or three ampules of 0.5 mg/mL (for IM administration) and/or two 10-mL syringes of 1 mg per syringe (for IV administration) are recommended.

What should an emergency person take for hypoglycemia?

What medications are administered in the hospital for someone with hypoglycemia?

Which IV fluid is best for hypoglycemia?

What is the drug of choice for an unconscious patient with hypoglycemia?