A12: Antidotes in Depth

Hypoglycemia is a common cause of altered mental status. Although classically associated with tachycardia, tremor, and diaphoresis, the predictive value of these manifestations is too low to be relied upon. As a result, all patients with altered consciousness require either rapid point-of-care testing of their glucose concentrations or empiric treatment for presumed hypoglycemia. When rapidly diagnosed and treated, hypoglycemic patients typically recover without sequelae. However, delayed or incomplete therapy may lead to permanent neurologic dysfunction (Chap. 53).

In 1891, Fisher performed the unbelievable feat of identifying the 16 possible different spatial configurations of aldohexose (C₆H₁₂O₆), the most prominent member being dextrose or d-glucose.³⁸ This discovery won him the 1902 Nobel Prize in chemistry. The diverse manifestations of hypoglycemia and the treatment of severe cases with intravenous (IV) dextrose have been appreciated for decades.⁶⁸

Chemistry

Sugar is the general term used for sweet carbohydrates that are used as food. Simple sugars are called monosaccharides and include glucose (also known as dextrose, or d-glucose, as the l-isomer is hardly found in nature), fructose (also known as fruit sugar, the sweetest), and galactose. The disaccharides include maltose, lactose, and sucrose (sucrose is also known as table or granulated sugar).

Sugars are found in the tissues of most plants, but are only present in sufficient concentrations for efficient extraction in sugarcane and sugar beet. Commercially, glucose is produced from the hydrolysis of starch. Several crops serve as the starch source, with maize being the most common in the United States.

In humans, carbohydrates are absorbed and transported via two main systems. Sodium-dependent glucose transporters (SGLT1-6) are responsible for the intestinal glucose absorption.¹³ Their discovery represented the first description of the mechanism of “flux coupling” or cotransporting, in which transporting one substrate down its concentration gradient creates energy that can then be used to transport a second substrate against a concentration gradient. Other facilitative sugar transporters include GLUT1 to GLUT14 and HMIT.¹⁰⁷ GLUT4 is expressed in insulin-sensitive tissues and regulates whole-body glucose homeostasis.⁷⁸ GLUT3 is found in neurons and in the placenta and has a high affinity for glucose, allowing for transport even in low substrate conditions.⁷ GLUT5 is responsible for the absorption of fructose in the small intestine.⁹ The GLUT5 transporter has wide variability and is dependent on the amount of glucose ingested relative to the fructose. Decreased fructose absorption can lead to abdominal bloating and osmotic diarrhea in susceptible individuals.⁵⁵ Binding of glucose to one of the GLUT receptors causes a conformational change that results in glucose translocation across the membrane.⁵⁴

Related Xenobiotics

Besides the mono and disaccharides mentioned above, sugars are also found in polymer forms. Maltodextrins are oligosaccharides of d-glucose used as food additives. Starch and cellulose are the polymers of glucose found in plants. Glycogen and chitin are found in animals. Some of the polymers are used to store energy (starch and glycogen) and some are used for structural support (chitin and cellulose).

Mechanism of Action

Glucose reaching the liver, adipose tissue, and muscle cells is absorbed and stored as glycogen (under the influence of insulin) or used by all cells to produce adenosine triphosphate (ATP) and pyruvate via glycolysis. Hepatic glycogen can later be converted to glucose and returned to the blood when insulin is low or absent. In contrast, glycogen found in muscle and adipose cells is utilized internally and not released into the systemic circulation. Some glucose is converted to lactic acid by astrocytes and then utilized as an energy source. The brain can use both exogenous and endogenous lactate as an alternative energy source.^94,105,112 Finally, glucose is also directly used by intestinal cells and red blood cells.

Pharmacokinetics

Accurate prediction of the amount of dextrose required to effectively treat patients with hypoglycemia is difficult. At equilibrium, 25 g of dextrose distributed in total body water in a 70 kg adult is calculated to increase the serum glucose concentration by about 60 mg/dL.⁵¹ In the few clinical studies performed, the magnitude of glucose elevation after oral or IV dextrose loading was unpredictable. In one study, 25 g (50 mL) of D₅₀W administered to adults (both diabetics and nondiabetics) resulted in a mean blood glucose elevation of 166 mg/dL when measured in the opposite extremity 3 to 5 minutes after the bolus; however, the range of this elevation was 37 to 370 mg/dL above baseline.¹ In a human model of insulin-induced hypoglycemia, oral administration of 10 or 20 g of dextrose increased the serum glucose concentration from 60 to 120 mg/dL over one hour.¹¹⁹ Another study used 25 volunteers and administered 25 g of IV dextrose as D₅₀W. Glucose concentrations were measured at 5, 15, 30, and 60 minutes. Volume of distribution formulas could not accurately predict postinfusion glucose concentrations. The serum glucose elevation was statistically significant from baseline at 5 and 15 minutes, and glucose concentrations returned to baseline at 30 minutes postinfusion.⁵

Pharmacodynamics

ATP provides the metabolic energy that fuels all critical cellular processes in all organs. In the adult brain, the anaerobic and aerobic metabolism of glucose through glycolysis and the citric acid cycle, respectively, are the primary sources of ATP (Chap. 13). Although the adult brain can use fatty acids, amino acids, lactate, and ketones as alternate substrates for ATP synthesis, these are not adequate to sustain normal cerebral function in the setting of glucose deprivation. In contrast, in fetal and neonatal brains, glucose is the only substrate for ATP production.^88,113

Hypoglycemia cannot be defined by strict numerical values. Rather, it is best defined by organ dysfunction in the setting of inadequate glucose concentrations. The onset of hypoglycemia in both adults and children is followed rapidly by global cerebral dysfunction. In individuals with diabetes, the density and sensitivity of neuronal insulin receptors vary as a function of glycemic control, so that diabetic patients with poor glycemic control have fewer and less sensitive neuronal insulin receptors and may experience hypoglycemic symptoms at much higher concentrations of glucose than those who are normally euglycemic. An important study of diabetic patients demonstrated that the mean blood glucose concentration for symptomatic hypoglycemia in poorly controlled patients was 78 ± 5 mg/dL compared with 53 ± mg/dL in well-controlled patients.⁸ This differential response to hypoglycemia is also described at higher glucose concentrations in poorly controlled versus intensely controlled diabetic patients.⁵⁷ Thus, neuroglycopenia may occur despite “normal” peripheral blood glucose concentrations.¹¹⁵ In rare cases, glucose-consuming cancer cells can produce large amounts of lactate (Warburg effect), which can be used by the brain as an alternate source of energy. Even in the presence of profound hypoglycemia, such patients remain asymptomatic.³²

Hypoglycemia may cause a myriad of neuropsychiatric sequelae that are clinically indistinguishable from those of other toxic-metabolicand structural brain injuries.^{19,27,72,76,97,114,121} In a case series, preenting signs and symptoms included dizziness and tremulousness (8%); focal stroke syndromes (2%), movement disorders or seizures (7%), irritability, confusion, or bizarre behavior (30%), delirium, stupor, or coma (52%); and irreversible encephalopathy.⁷² These numbers are similar to those in a case series of patients with insulinomas.¹⁸ In cases of undifferentiated coma, both the absence of pupillary light reflex (sensitivity 83% and specificity 77%, positive predictive value {PPV} 70 and negative predictive value {NPV} 87, likelihood ratio {LR} 3.56) and the presence of anisocoria (sensitivity 39% and specificity 96%, PPV 86 and NPV 70, LR 9) are helpful in distinguishing structural from metabolic causes.¹¹⁰ Hypoglycemic hemiplegia is a well-recognized, although rare entity, and therein lies the relevance of a serum glucose measurement in patients with focal neurologic symptoms.⁷²

The heart is partially dependent on glucose as an energy substrate. Hypoglycemia causes myocardial stress that may manifest as angina and or dysrhythmias. There are two mechanisms postulated for hypoglycemia induced dysrhythmias. First, it causes K⁺ current inhibition, which results in QT prolongation.⁸⁰ This is aggravated by the systemic catecholamine response to hypoglycemia, which results in increased intracellular calcium, another dysrhythmogenic stimulus.^{29,67,75,79, 80, and 81} Nocturnal hypoglycemia is associated with the “dead in bed” syndrome. The postulated mechanisms are hypotonia of the respiratory muscles with an impaired awakening, mediated by orexin-A neurons, and QT prolongation and other dysrhythmogenic effects of hypoglycemia.^42,82 Counterregulatory hormone responses to hypoglycemia are also impaired by sleep.^26,58

Table A12–1 summarizes some causes of hypoglycemia.

Empiric Treatment Considerations

The history and physical examination do not reliably detect patients who are hypoglycemic.⁵⁰ Tachycardia, diaphoresis, pallor, hypertension, tremors, hunger, and restlessness tend to predominate when the decline in serum glucose concentration is rapid. However, neuroglycopenia, even when severe, may not trigger autonomic responses.¹⁹ Signs and symptoms may be further blunted or absent in the setting of concurrent use of β-adrenergic antagonists. Central nervous system signs of neuroglycopenia are also nonspecific. They may include visual disturbances, psychiatric disturbances, confusion, stupor, coma, seizures, and focal neurologic findings.^72,98 In children, the only sign of neuroglycopenia may be lethargy or irritability.¹²³

The bedside diagnosis of hypoglycemia is limited by the sensitivity and specificity of reagent strips, which do not have the reliability and accuracy of laboratory analysis.⁸⁴ Sensitivities of commonly available reagent strips for detection of hypoglycemia range between 92% and 97% in various studies.^{11,12,56,66,71,96} The accuracy of these point-of-care testing methods is affected by the source of blood, whether arterial, venous, or capillary, and by the poor perfusion associated with shock and cardiac arrest.^{4,14,28,41,59,62,64,70,106}

False-positive capillary hypoglycemia occurs in shock and cardiac arrest. Hypoglycemia was identified by capillary samples in 8 of 50 patients with cardiac arrest. Only three of these were confirmed to be hypoglycemic by laboratory determination of serum glucose. Reagent strip testing of venous blood correctly classified these patients. There were no false negative results.¹⁰⁶ A critical care unit study that evaluated patients in shock showed that 32% were incorrectly diagnosed as hypoglycemic when capillary blood was used. All these patients were either normoglycemic or hyperglycemic. Results of reagent strip tests of venous blood correlated well with laboratory results, correctly classifying all patients. No cases of hypoglycemia were missed.⁴ Therefore, capillary determinations of glucose should be used with caution in the critically ill population, recognizing that false positive detections of hypoglycemia are common.⁷⁰ When feasible, laboratory measurements should be obtained in these populations. A second best alternative is reagent strip testing of venous blood rather than capillary samples. However, it is important to know the specific test being used at a particular institution, as more recent reports have shown improved correlation between point-of-care testing and laboratory glucose measurements.^60,64,117

Several studies have compared the accuracy of standard reagent strips for the detection of hypoglycemia from capillary and venous blood compared with the gold standard of the laboratory. Two studies, one with 97 subjects⁴¹ and one with 270 subjects,⁶² evaluated the agreement between reagent strip determinations of capillary and venous blood glucose in healthy normoglycemic volunteers. In the larger study, 18% of subjects had a more than 15 mg/dL difference between capillary and venous reagent strip tests. In this study, capillary measurements were better correlated with the laboratory values. Whether these results have any clinical significance is not clear because none of the subjects were outside of the euglycemic range. However, the results suggest that the capillary blood glucose test has greater accuracy in the euglycemic range and in healthy individuals.

The “safe” number at which no cases of symptomatic hypoglycemia are missed by reagent strip testing is a subject of debate, because of the inherent risk of error from lack of sensitivity. In one study in which hypoglycemia was defined as a blood glucose concentration below 60 mg/dL, 2 of 33 hypoglycemic patients were not detected at the bedside. A cutoff of 90 mg/dL would have detected 100% of numerically hypoglycemic patients.⁶⁶ Based on these studies, it can be argued that a bedside reagent measurement of 90 mg/dL is a conservative cutoff for assurance of clinical euglycemia in all patients.

With reagent strip testing, variations in hematocrit and the presence of isopropyl alcohol in the sample may alter the accuracy of the test.^6,46 In some specific tests, such as the one using glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ), accuracy may be affected by a number of interfering xenobiotics, such as serum acetaminophen concentrations greater than 80 mg/dL, a serum bilirubin concentration greater than 20 mg/dL, a serum galactose concentration greater than 10 mg/dL, a maltose concentration greater than 16 mg/dL, a serum uric acid greater than 10 to 16 mg/dL, serum triglycerides greater than 5000 mg/dL, and the presence of d-xylose in the sample. All of these result in falsely elevated glucose measurements.³¹ There are reports of interference with the use of IV fat emulsion therapy as an antidote.⁴⁷ Notably, icodextrin, an ingredient in peritoneal dialysis fluids, may result in overestimation of glucose measurements because it is metabolized to maltose. In several case reports and at least 18 cases reported in a review, this overestimation resulted in excess insulin administration and subsequent hypoglycemia.^31,39,61,90 Glucose monitoring systems that use the GDH-PQQ method should not be used in patients using icodextrin in the peritoneal dialysis fluid.¹¹¹ Maltose is also contained in some immunoglobulin solutions, and the same interference can be expected.^34,104 Glucose measurements by the GDH-PQQ and the amperometric methods are also affected by the hematocrit.^103,117 Whereas hematocrits lower than 20% may result in falsely elevated glucose measurements, hematocrits higher than 55% may result in falsely low measured glucose concentrations.³¹ In a retrospective review of patients admitted to a hospital over a 12-month period, 1.2% were identified as having interfering substances. Of these, 36% had active orders for insulin. In this review, the most common interferences identified were a low hematocrit (44% of patients) and a high serum uric acid (29% of patients).³¹

One final consideration is in patients with salicylate toxicity (Chap. 39), in which serum glucose is not an accurate reflection of tissue glucose concentrations.¹⁰⁸ Salicylate poisoning is a relatively uncommon cause for drug-induced hypoglycemia.¹⁰² Salicylates uncouple oxidative phosphorylation, which results in increased intracellular glucose demands. Patients may demonstrate symptoms of neuroglycopenia despite normal serum glucose concentrations. Dextrose administration reverses the signs and symptoms,⁶³ and can improve survival.¹⁰⁸

Advances in monitoring technology include continuous glucose monitoring, which uses a sensor placed under the skin that measures interstitial fluid glucose.⁸⁹ These sensors are generally accurate at normal glucose concentrations. However, in situations where the serum glucose is fluctuating, changes in the interstitial glucose concentration may lag for up to 15 minutes. Patients are encouraged to measure the capillary blood glucose before making treatment decisions.¹²⁰ A noninvasive device that also measures interstitial glucose concentrations has been approved by the US Food and Drug Administration.²⁵

Patients with asymptomatic or minimally symptomatic hypoglycemia should be treated with oral carbohydrates (juice, milk, candy, or glucose tablets). For adults, the recommended dose of 20 g should result in symptom improvement in 15 to 20 minutes.¹⁵ Since this improvement may be transient, it is recommended that the initial glucose intake should be followed by a more substantial meal. For the patient unable (coma, seizures) or unwilling (from neuroglycopenia) to receive oral glucose, the IV route must be used. In an adult a bolus dose of 0.5 to 1.0 g/kg of IV dextrose is recommended. The subsequent improvement in glucose concentration is transient and the patient should be monitored closely for recurrence.¹⁵ Generally, a dextrose infusion should follow the initial dextrose bolus,¹⁵ with the recognition that this supplies very little caloric content.

Rapid increases in serum glucose are sufficient to stimulate insulin release from the pancreas and may result in reactive (or rebound) hypoglycemia. Therefore, glucose concentrations must be closely followed after a bolus of concentrated glucose solutions. This effect is exaggerated in the patients who have ingested sulfonylureas.^44,48

Alcoholic ketoacidosis (AKA) is a metabolic emergency. It occurs when drinkers cease or significantly decrease their food intake and have some degree of vomiting. The result is salt and water depletion with an anion gap metabolic acidosis that is typically accompanied by a normal to low serum glucose (unlike diabetic ketoacidosis). In children, hypoglycemia may occasionally ensue after exposure to ethanol and ethanol-containing household products.^35,87 Newborns and young infants, in contrast to adults, may present with irritability, feeding problems, lethargy, cyanosis, tachypnea, and/or hypothermia.⁴⁹

The management of AKA consists of rehydration using isotonic crystalloids, parenteral thiamine administration, dextrose infusion using D₅W or D₁₀W, potassium replacement, and addressing the underlying medical problem that led to AKA.⁴⁰

Chapter 80 has an in-depth discussion of AKA.

As discussed in the previous section, salicylates uncouple oxidative phosphorylation, which results in increased intracellular glucose demands.¹⁰⁹ Patients with salicylate toxicity may demonstrate symptoms of neuroglycopenia despite normal serum glucose concentrations. Dextrose administration has been shown to reverse these signs and symptoms of neuroglycopenia.⁶³

Chapter 39 provides an in-depth discussion of salicylate toxicity and its management.

Hyperinsulinemia/euglycemia is one of the cornerstones of management of patients with drug induced cardiovascular toxicity. Insulin improves carbohydrate utilization by the cells and restores calcium fluxes. This improves cardiac contractility and allows for improved vascular tone.⁷⁴ The available data strongly support this approach in patients with calcium channel blocker ­toxicity, and there are also reports that describe benefit in cases of β-adrenergic antagonist toxicity.^69,124 The initial bolus of 1 unit/kg and subsequent 1 unit/kg/h of regular insulin must be supplemented with sufficient dextrose to maintain euglycemia. The use of continuous dextrose infusions with insulin (insulin–euglycemia) as antidotal therapy for cardiovascular toxicity is reviewed in Antidotes in Depth: A17.

Hyperkalemia occurs commonly in the emergency department, most often as a result of end stage kidney disease. It can represent an adverse medication reaction. IV insulin is used to redistribute potassium inside the cell. A dose of 10 units of regular insulin is usually followed by 25 g of IV 50% dextrose.¹¹⁸ The initial dextrose dose should be followed by a dextrose infusion, as a single bolus is not sufficient to prevent hypoglycemia at one hour.² The onset of action is less than 15 minutes and peaks at 30 to 60 minutes.¹¹⁸ This regimen results in an average serum potassium decrease of about 0.6 mEq/L.¹¹⁸

The most serious complications associated with hypoglycemia are directly attributable to the failure to recognize and treat it. Most complications due to the administration of concentrated IV dextrose are either clinically insignificant or exceedingly rare. Phlebitis and sclerosis of veins may occur. Tissue necrosis may occur after soft tissue extravasation of D₅₀W and after inadvertent intraarterial injection.^3,24 Inappropriately large boluses of D₅₀W in children are associated with seizures, brain hemorrhage, and hyperosmolar coma.⁹⁹ Anaphylactoid reactions are also rarely reported after the administration of D₅₀W.¹⁶

While prolonged glucose infusions without thiamine supplementation are associated with Wernicke encephalopathy in at-risk patients, this does not occur if thiamine is administered proximate to the time of ­dextrose administration. Correction of hypoglycemia should not be delayed in order to administer thiamine (Antidotes in Depth: A24).⁹²

Dilute dextrose solutions should not be administered with blood as they can cause pseudoagglutination of erythrocytes. These solutions can also result in electrolyte dilution and excess intravascular volume. Most ­dextrose products are derived from corn, so they should not be used in patients with of severe corn allergy.

One final important consideration is the development of rebound hypoglycemia when dextrose is used to treat sulfonylurea-induced hypoglycemia (Chap. 53). In these cases, serial measurements of glucose and close patient monitoring should follow any dextrose boluses.⁷³

Concerns Regarding Elevated Blood Glucose Concentrations in Patients with Cerebral Ischemia

Studies of ischemic brain injury in a variety of animal models consistently demonstrate that higher blood glucose concentrations are associated with more extensive cerebral injury and worse outcomes.^{17,20, 21, and 22,43,52,65,86,100,101} The clinical literature also demonstrates that the presence of hyperglycemia upon admission is associated with poorer outcomes in patients with acute ischemic stroke.^{23,33,53,83,85,116,122,125}

While concerns previously existed regarding provision of dextrose in the clinical scenario of potential cerebral ischemia, rapid bedside testing has essentially eliminated this consideration. Although underpowered, the Glucose Insulin in Stroke Trial—United Kingdom (GIST-UK) failed to show any mortality benefit from treatment of hyperglycemia in acute stroke patients.^45,95 Additionally, it is now clear that attempts at intensive glucose control are associated with higher rates of hypoglycemia, which is related to increased mortality.^36,37,91,93

Dextrose is a pregnancy category C (IV) and A (oral); studies have not been conducted regarding its safety to the fetus. Hypoglycemia is a serious concern for fetal well being, and the best evidence suggests that hypoglycemia in a pregnant woman should be approached in the same manner as in any nonpregnant patient. Although there are no data regarding the use of hypertonic dextrose in lactation, it is unlikely to be a concern, because even if the concentration of glucose in subsequent breast milk is a significantly increased, the effect will be transient.

In most cases, the rapid correction of hypoglycemia by the administration of 0.5 to 1 g/kg of concentrated IV dextrose (Table A12–2) immediately reverses neurologic and cardiac effects. However, prolonged or severe hypoglycemia may result in permanent brain injury, myocardial infarction, and death.^10,30,77 Glucose should be monitored after concentrated dextrose administration. This is usually done within an hour after administration or if there is a change in the patient’s condition.

Dextrose is available as a 5%, 10%, 20%, or 50% solution for IV use. Concentrations greater than 10% should be infused via a central venous catheter, except in emergencies. Table A12–3 summarizes the most commonly available intravenous and oral preparations.

• Dextrose is an effective antidote for patients with hypoglycemia and has additional indications in those with alcoholic ketoacidosis and as an adjunct to high-dose insulin therapy for cardiovascular drug ­toxicity.

• Hypoglycemia can mimic many syndromes, producing any alteration in consciousness, including focal neurologic syndromes.

• The currently available reagent strips reliably demonstrate the absence of significant hypoglycemia at readings greater than 90 mg/dL. Profound neurologic impairment likely is not the result of hypoglycemia with such concentrations, even in diabetic patients.

• Dextrose should be administered to all patients with altered levels of consciousness and numerical hypoglycemia (glucose concentration <90 mg/dL).

• Dextrose should be empirically administered to patients with altered levels of consciousness in the rare cases where bedside reagent strips are not readily available.

References