EMERGENCY MANAGEMENT OF DISORDERS OF CARBOHYDRATE METABOLISM

Disorders of carbohydrate metabolism represent a broad category of emergent and potentially emergent conditions. Most are related to diabetes and associated complications. They may also occur as a result of or be mimicked by drug or alcohol toxicity, multisystem trauma, head injury, cardiovascular disease, cerebrovascular disease, and infection. Patients may present with coma or altered mental status or look remarkably well clinically yet be on the brink of metabolic decompensation. These disorders may be a challenge not only to diagnose early but also to treat in the most severe cases. Often they are precipitated by underlying illness or injury. Early diagnosis and effective treatment of these underlying entities is a crucial element in resolving the metabolic decompensation.

DIABETIC KETOACIDOSIS

Essentials of Diagnosis

Signs and symptoms include fatigue, tachypnea (Kussmaul respiration), tachycardia, altered mental status, abdominal pain, vomiting, polyuria, and polydipsia.

Arterial pH < 7.3, serum glucose = 250 mg/dL, and serum bicarbonate = 15 mEq/L.

General Considerations

Diabetic ketoacidosis (DKA) is the most common acute life-threatening complication of diabetes. It is more commonly seen in type 1 diabetes but may occur rarely in type 2 diabetes. It is a result of insulin-producing cell failure in the islets of Langerhans located in the pancreas. This results in insulin deficiency, which then shifts the normal metabolic processes from using glucose for fuel to using lipids for fuel. Metabolic stress, most commonly from trauma or infection, may accelerate this process. The result is osmotic diuresis from severe hyperglycemia leading to dehydration, electrolyte loss, and metabolic acidosis, which results from a combination of dehydration and the overproduction of ketone bodies from fat metabolism, primarily -hydroxybutyrate and acetoacetate, which further acidify the blood. Eventually, hypovolemia leads to inadequate blood flow to the kidneys and limits renal excretion of glucose. As serum osmolality rises above 320 mOsm/L, lethargy and coma may ensue. If left untreated, severe metabolic acidosis from DKA can lead to depression of cardiovascular function, severe hyperkalemia, and potentially lethal cardiac dysrhythmias.

Clinical Findings

A. History

Determine if the patient has diabetes. Direct the history to ascertain potential precipitating causes of DKA:

Recent or current infection of any type (most common)

Injury or trauma

Acute coronary syndrome or myocardial infarction

Transient ischemic attack or stroke

Medications (corticosteroids, thiazides, or sympathomimetics)

Acute or acute-on-chronic pancreatitis

Alcohol or drug abuse

Psychosocial factors, such as depression or inability to afford medications, limiting compliance

Noncompliance with insulin regimen

B. Symptoms and Signs

Symptoms and signs include general fatigue and weakness, abdominal pain (be aware of precipitating causes such as appendicitis, cholecystitis, pancreatitis, and pregnancy), and Kussmaul respirations (rapid deep respirations attempting to compensate for acidosis). Patients may have a fruity or acetone-like smell to the breath. Other findings include polyuria, polydipsia, and polyphagia (the body's attempt to compensate for inefficient use of fuel and water loss in excreting glucose); nausea and vomiting (hemorrhagic gastritis occurs in 25% of patients); altered mental status ranging from agitation to coma; hypothermia (may be fever equivalent; if present, prognosis is poor).

C. Laboratory Findings

1. Key findingsKey laboratory features include serum glucose = 250 mg/dL, ketonuria (ketonemia is unreliable unless -hydroxybutyrate is measured), serum bicarbonate = 15 mEq/L, and arterial pH < 7.3 (venous pH has been shown to be a consistent, acceptable substitute for arterial pH). Limit arterial blood gas analysis to patients in whom oxygenation or ventilation is a concern or when diagnosis may be uncertain.

2. Serum potassiumSerum potassium is often elevated initially despite total body deficits estimated at 3-5 mEq/kg body weight. Additionally, potassium may be lost through vomiting or urinary losses. Metabolic acidosis shifts potassium out of the cells and into the extracellular fluid space. Because insulin therapy drives potassium back into the cells, serum potassium should be monitored every 2 hours during the first 8 hours of treatment. Low initial serum potassium (< 3.2 mEq/L) represents a severe total body potassium deficit, and emergent repletion of potassium is essential to prevent life-threatening cardiac dysrhythmias.

3. Serum sodiumSerum sodium is usually low from losses in the urine and vomitus coupled with dilution effects of water being drawn out of the cells into the extracellular compartment by hyperglycemia. This effect can be corrected by adding 1.8 mEq/L to the serum sodium concentration for each 100 mg/dL the serum glucose concentration is above normal. Serum sodium may also be artificially lowered by severe hypertriglyceridemia. Although sodium deficits may approach 7-10 mEq/kg, sodium repletion must proceed gradually to avoid cerebral edema, especially in children.

4. Serum phosphateSerum phosphate is usually normal or elevated despite deficits approaching 1 mmol/kg body weight. Routine phosphate repletion has not been shown to improve clinical outcomes in DKA and is not indicated. There is significant potential to cause severe hypocalcemia, which may manifest without the typical finding of tetany. Severe hypophosphatemia (< 1 mg/dL) may cause skeletal, cardiac, and respiratory muscle depression; phosphate should be replaced in this circumstance.

5. Other important laboratory findings

a. Anion gapAnion gap is useful to assess severity of acidosis and to follow progress of therapy. The anion gap is obtained from the following formula:

Normal values are = 10. Effective serum osmolality may be estimated from the following formula:

Values of at least 320 mOsm/kg are associated with central nervous system involvement, usually lethargy or coma. Below this value, other causes for lethargy or coma such as head injury, subarachnoid hemorrhage, or cerebrovascular accident should be investigated. This value may also be used to diagnose hyperglycemic hyperosmolar nonketotic syndrome (HHNS) or ingestions of ethanol or other osmotically active substances such as ethylene glycol or other alcohols.

b. Serum ketonesStandard laboratory tests measure only acetoacetate. The primary ketone body formed in DKA initially is -hydroxybutyrate, which is broken down into acetoacetate in the presence of insulin. Serum ketones are not reliable as a diagnostic test because initially they may be reassuringly negative even in a severely ill DKA patient. They are not useful to track therapy because in most cases they will increase as the patient improves.

c. Blood urea nitrogen (BUN) and creatinineThese levels may be elevated because of severe dehydration, even to the point at which acute tubular necrosis and renal failure occur. If these levels are elevated on initial chemistries, be sure to establish urine output prior to initiating potassium repletion.

d. ElectrocardiogramThe electrocardiogram (ECG) may reveal severe electrolyte disturbances or diagnose cardiac ischemia or myocardial infarction, a common precipitating cause of DKA or HHNS in older patients. History and physical examination should dictate whether to order cardiac enzymes.

Treatment & Disposition

Given the similar nature of treatment for DKA and HHNS, treatment and patient disposition for these two entities are presented together in the discussion of HHNS, below.

HYPERGLYCEMIC HYPEROSMOLAR NONKETOTIC SYNDROME

Essentials of Diagnosis

Most symptoms relate to severe dehydration.

Kussmaul respirations and abdominal pain are unusual findings.

Absence of acidosis, small or absent serum ketones, and hyperglycemia usually = 600 mg/dL.

General Considerations

HHNS, formerly called hyperglycemic hyperosmolar nonketotic coma or hyperosmolar coma, is differentiated from DKA in that patients with HHNS have enough insulin activity to prevent lipolysis and ketogenesis. DKA often manifests suddenly over hours to a few days, whereas HHNS is more insidious, developing over several days to weeks. Also, in mild or early DKA, mental status is normal, whereas in HHNS, mental status is nearly always abnormal, ranging from confusion to stupor or coma. HHNS occurs most commonly in older (> 65 years) patients who may or may not have diagnosed diabetes and who are often residents in chronic care facilities. Symptoms of hyperglycemia such as frequent urination may be attributed to aging, and the thirst response may be depressed as normal physiology of aging or unrecognized secondary to dementia. Patients also may not have or be given proper access to fluids.

Usually, a severe physiologic stressor, most commonly infection, is a precipitating cause. Myocardial infarction, cerebrovascular accident, trauma, and drug effects or interactions may also precipitate HHNS. Electrolyte deficits are similar in DKA and HHNS, and the free water loss is on the order of 9 L in HHNS compared with an average water loss of 6 L in DKA.

Clinical Findings

A. History

Risk factors for HHNS include age of 65 years or older, residence in a chronic care facility or nursing home, change in diabetes regimen, addition of medications that may elevate glucose levels (eg, corticosteroids, thiazides, anticonvulsants, sympathomimetics), recent or current infection, and dementia.

B. Symptoms and Signs

Symptoms and signs include polydipsia, polyuria, or polyphagia; generalized weakness; altered mental status (clouded thinking to confusion to lethargy or coma); dry mucous membranes; poor skin turgor; and delayed capillary refill. Kussmaul respiration is usually not present unless metabolic acidosis from sepsis or hypoperfusion occurs.

Abdominal pain is not a typical finding in HHNS (in contrast to DKA); its presence merits aggressive investigation for precipitating causes. Acute cholecystitis and appendicitis may be insidious and occur atypically in elderly patients.

C. Laboratory Findings

1. Key laboratory findingsKey findings to diagnose HHNS and differentiate it from DKA include the following:

Serum glucose is usually = 600 mg/dL.

Urine or serum ketones are small or absent (a small amount of ketone may be detected secondary to starvation). Glucosuria is prominent. Serum bicarbonate is usually > 15 mEq/L.

pH is usually > 7.30.

The anion gap may be variable depending on precipitating cause but is usually = 10

Effective serum osmolality is = 320 mOsm/kg.

2. Serum sodiumIn the early stages of HHNS, serum sodium findings are similar to those in patients with DKA. Urinary losses and fluid shifts out of the cell and into the extracellular compartment create hyponatremia usually in the 125-130 mg/dL range (remember to correct by adding 1.8 mg/dL for every 100 mg/dL glucose above normal). As water losses worsen, hypernatremia ensues and osmolality rises, leading to progressive lethargy and coma.

3. Serum potassiumPotassium levels will most commonly be normal or low, unless renal failure is present. An associated metabolic acidosis driving potassium out of the cells is usually not present in HHNS.

4. Blood urea nitrogen and creatinineBUN is often markedly elevated. Gastrointestinal bleeding may also elevate BUN, and this is a possible precipitating cause of HHNS in elderly patients.

5. Other studiesOther studies should be dictated by the history and physical examination findings, but have a low threshold to obtain serial ECGs and cardiac enzymes to rule out cardiac ischemia or myocardial infarction, computed tomography (CT) scan of the head to rule out cerebrovascular accident or subdural hematoma, and rectal exam and nasogastric tube to look for gastrointestinal hemorrhage. Order an abdominal CT scan or ultrasound to work up abdominal pain if the patient is stable enough to leave the emergency department.

Treatment

Initial treatment for DKA and HHNS is similar. The various aspects of therapy should be initiated concurrently whenever possible. Differences in therapy of DKA and HHNS are noted when appropriate. Frequent reassessment of vital signs, mental status, and laboratory parameters are essential to successful therapy of DKA and HHNS.

A. Resuscitation Issues

Assess the airway and consider obtaining arterial blood gases for any patient who appears not to be oxygenating or ventilating properly or who is obtunded or comatose. Consider proceeding directly to rapid-sequence intubation in patients who are unresponsive or who have depressed gag or swallow reflexes. Avoid succinyl choline if hyperkalemia is suspected based on peaked T waves on ECG or rhythm strip.

Oxygen therapy is indicated for all DKA or HHNS patients at flow rates adequate to maintain oxygen saturation above 96% or PO2 = 70 mm Hg. Hypoxia should trigger an investigation for aspiration, pneumonia, or pulmonary edema in the differential diagnosis of precipitating causes.

B. Fluid Therapy

Fluid therapy is dictated by 3 parameters: vital signs, corrected serum sodium, and serum glucose. Overall fluid deficits approach 6-10 L in most patients, and daily maintenance fluid requirements must also be considered. Multiple, preferably large-bore (= 18-gauge), intravenous lines are essential. Central venous access should be strongly considered.

Hypotension should prompt a bolus of 1 L of 0.9% NaCl solution to restore blood pressure to at least 90 mm Hg.

Caution: Assess patients for cardiogenic shock and renal failure before giving large volumes of intravenous fluids. Reassess patients frequently for adequate urine output and absence of pulmonary edema or congestive heart failure. Hemodynamic monitoring (Swan-Ganz) is indicated to facilitate fluid management if cardiogenic shock is present. In the absence of hypotension, administer 1-1.5 L (~ 15-20 mL/kg) normal saline in the first hour of therapy.

Using the serum sodium corrected for excess glucose:

If serum sodium is high or normal, give 0.45% NaCl or half normal saline at a rate of 5-15 mL/kg for the next liter of fluids.

If serum sodium is low, give 0.9% NaCl or normal saline for next liter of fluids at a rate of 5-15 mL/kg.

Once serum glucose reaches approximately 250 mg/dL, 5% dextrose in 0.45% NaCl is the fluid of choice at a rate of 250 mL/h; or use 5% dextrose in normal saline if the corrected serum sodium remains low.

Follow serum electrolytes, venous pH, BUN and creatinine, and glucose, and calculate the osmolality frequently (every 2 hours in the first 8 hours) as measures of progress in therapy. The aim is a decrease in serum osmolality of no more than ~ 3 mOsm/kg/h. Urine output may be unreliable while glucose levels remain high secondary to osmotic diuresis. Once glucose levels approach normal, urine output may be used to guide therapy; 30-50 cc/h is considered adequate.

C. Electrolyte Replacement

1. PotassiumPotassium repletion may commence once urine output is confirmed and should be accomplished according to the following algorithm, with target levels of 4.0-5.0 mEq/L:

If serum potassium is 3.3 mEq/L or less, hold insulin therapy and give 40 mEq/h intravenously as potassium chloride or as a mixture of two-thirds potassium chloride and one-third potassium phosphate (~ 5 mmol) if serum phosphate is less than 1 mmol/L. If patient is not vomiting, potassium chloride, 20-40 mEq, may also be given orally or by nasogastric tube. Assume a deficit of about 100 mEq potassium for each 1 mEq/L below normal.

If serum potassium is 3.3-5.0 mEq/L, give 20-30 mEq potassium chloride in each liter of intravenous fluid.

If serum potassium is 5.0 mEq/L or more, hold potassium repletion and recheck serum potassium in 2 hours.

Follow serum potassium every 2 hours during the first 8 hours of therapy.

D. Insulin Therapy

Insulin therapy for DKA and HHNS is generally accomplished intravenously using regular human insulin. Subcutaneous insulin may be absorbed erratically in severely volume-depleted patients. Begin therapy with a bolus of 0.1-0.15 U/kg body weight. In DKA this dose rapidly halts lipolysis and further ketogenesis. In HHNS it helps in rapidly lowering very high serum glucose and halting further water loss to osmotic diuresis. Start a continuous infusion at 0.1 U/kg body weight per hour, and monitor capillary blood glucose hourly. If glucose is not decreasing at least 50-70 mg/dL/h, insulin dosage may be doubled hourly until this rate of decline is achieved. Hold insulin therapy for any potassium level less than 3.3 mEq/L until repletion is undertaken and the level has risen on recheck in 2 hours.

E. Sodium Bicarbonate Therapy

Sodium bicarbonate therapy is generally indicated only for severe cases of DKA (arterial pH < 6.9). Bicarbonate therapy will seldom if ever be indicated for HHNS. At pH higher than 6.9, no benefit has been proved in controlled trials on DKA outcomes, whereas studies have shown aggressive bicarbonate therapy leading to increased rates of cerebral edema, especially in children. No controlled data exist on bicarbonate therapy when pH is less than 6.9. Given the catastrophic potential of such severe acidosis on cellular metabolism, bicarbonate therapy is indicated in these patients and is accomplished by giving 100 mmol of NaHCO3 diluted in a 500-cc bag of 5% dextrose in water given over 2 hours. This may be repeated every 2 hours until venous pH is greater than 7.0

F. Treatment of Suspected or Known Precipitating Causes

Infection is the most common precipitating cause of DKA and HHNS. Be sure to examine the patient's entire skin surface for wounds and cellulitis. Obtain a urine pregnancy test and conduct a pelvic examination in women of child-bearing age who have DKA to rule out pelvic inflammatory disease or pregnancy as sources of physiologic stress. Analysis and cultures of all appropriate body fluids (blood, sputum, urine, cerebrospinal fluid) should be obtained as dictated by the history and physical examination or broadly in obtunded or comatose patients. Consider empiric administration of broad-spectrum antibiotics until culture results are available. Treat other precipitating causes as they become known, for example, cardiac catheterization and percutaneous transluminal coronary angioplasty for myocardial infarction.

G. Flow Sheet

It is a good idea to organize vital signs, mental status findings, monitored laboratory values, intravenous fluid therapy types and rates, insulin dosages, electrolyte repletion, urine output, and bicarbonate administration (if any) into a flow sheet that can be included in the patient's chart.

Disposition

Patients with all but the mildest cases of DKA and all patients with HHNS should have cardiac monitoring and a higher level of nursing care for at least 24 hours. Whether the patient goes to an intermediate care or telemetry unit or the intensive care unit is based on severity of the case and response to initial therapy as judged by the treating physician.

Kitabchi AE et al: Management of hyperglycemic crises in patients with diabetes mellitus. (Technical Review). Diabetes Care 2001;24:131. [PMID: 11194218] (Definitive and extremely comprehensive review on diagnosis and therapy of DKA and HHNS by the foremost authorities in these aspects of endocrinology and diabetes care. Contains helpful therapeutic algorithms.)

HYPERGLYCEMIA WITHOUT KETOACIDOSIS OR UNRECOGNIZED TYPE 2 DIABETES Hyperglycemia in the absence of metabolic decompensation (DKA or HHNS) is an increasingly common finding in the emergency department. Obesity, pre-diabetes, and diabetes are epidemic in the United States. Sedentary lifestyles and high-carbohydrate and high-fat diets have contributed to the epidemic. Patients with diabetes may present with hyperglycemia from self-monitored blood glucose, or they may have no history of diabetes. Patients without diabetes may present with symptoms of hyperglycemia, most typically polydipsia, polyuria, fatigue, and blurred vision, or they may present with one or more complications of unrecognized diabetes, such as ischemic heart disease, cerebral or peripheral vascular disease, nonhealing wounds, or persistent or recurrent infections (especially of the skin and genitourinary tract). Some patients present with unrelated complaints, and diabetes and hyperglycemia are found incidentally. The astute emergency clinician should know the risk factors for type 2 diabetes and recognize any of these symptomatic presentations as an indication to investigate the possibility of hyperglycemia or unrecognized diabetes.

Clinical Findings

A. History

Risk factors for hyperglycemia and unrecognized type 2 diabetes are listed in Table 41-1.

B. Symptoms and Signs

Symptoms of hyperglycemia may include polydipsia, polyuria, polyphagia, weakness, fatigue, headache, blurred vision, lightheadedness, or dizziness. When present, symptoms are generally mild to moderate.

Superficial skin and skin structure infections (cellulitis, furuncles, abscesses, nonhealing wounds or ulcers), urinary tract infections, candidal genital infections, malignant otitis externa, and rhinocerebral mucormycosis all have epidemiologic associations to hyperglycemia and diabetes. Chronic hyperglycemia impairs neutrophil function and other cellular immune responses. Glycosuria is thought to contribute directly to urine bacterial colonization.

To excrete excess glucose, large volumes of water are lost, and the patient rapidly becomes dehydrated if fluid intake is not keeping up. Symptoms may include weakness, dizziness, near-syncope, and headache. Signs are sunken eyes, poor skin turgor, and poor capillary refill.

C. Laboratory Findings

Random serum glucose of greater than 200 mg/dL in the setting of symptoms of hyperglycemia or metabolic decompensation (DKA or HHNS) or fasting serum glucose of greater than 126 mg/dL on repeat occasions are both diagnostic of diabetes. Impaired fasting glucose is defined as a fasting plasma glucose of 110- 126 mg/dL.

Glycosylated hemoglobin, or A1C, is increasingly available as a rapid assay, and the role of A1C in diagnosing diabetes is evolving. Levels of 6.1% or more are about 80% sensitive in diagnosing diabetes; levels of 7.0% or more are nearly always consistent with diabetes.

It is always prudent to assume that severe hyperglycemia (= 400 mg/dL) represents impending decompensation. An underlying cause should be sought aggressively, most commonly infection, but cardiac ischemia or myocardial infarction sometimes occur and an ECG plus cardiac enzymes may be helpful. Lack of compliance with antidiabetic regimen or diet should always be exclusionary. Have a low threshold in this setting to check electrolytes and BUN and creatinine to screen for metabolic decompensation, severe electrolyte imbalance, and renal insufficiency.

Treatment

A growing body of literature suggests that hyperglycemia is a risk factor for adverse outcomes and that tight glucose control is a strong component of therapy for nearly every acute illness or injury experienced by diabetes patients. If hyperglycemia is mild (< 300 mg/dL), patients are not significantly volume-depleted, no specific cause is identified, and medical follow-up is readily available, no specific treatment is required other than to refer patients to primary care for diabetes testing (fasting plasma glucose is preferred over oral glucose tolerance test) or for adjustment of antidiabetic regimen in patients with known diabetes. When serum glucose is greater than 300 mg/dL, treatment is as follows:

A. Fluids

Normal saline or lactated Ringer's solution, 1 L given over 1 hour, may be adequate monotherapy for hyperglycemia.

B. Insulin

Mildly volume-depleted patients may be given 0.1 U/kg regular human insulin or insulin lispro (Humalog) or insulin aspart (Novolog) subcutaneously. Regular insulin at a dose of 0.1-0.15 U/kg should be given intravenously to dehydrated patients because subcutaneous insulin absorption may be erratic in these patients. Insulin may be rebolused intravenously if glucose does not decline by 50-75 mg/dL in the first hour.

C. Oral Hypoglycemic Agents

Oral hypoglycemic agents are generally not indicated for acute therapy of severe hyperglycemia, but if a patient is newly diagnosed with diabetes, the emergency physician may wish to prescribe an oral agent on discharge. Metformin, which inhibits fasting hepatic glucose production and promotes weight loss, is the oral agent least likely to cause hypoglycemia. Metformin can be safely started at 500 mg orally once per day; the dosage can be increased by 500 mg/d each week until 500 mg 4 times a day is reached. Metformin therapy may be initiated if serum creatinine levels are 1.4 mg/dL or lower. Above this level, the patient is at risk for developing lactic acidosis. Sulfonylurea or insulin therapy is best undertaken after the patient has received diabetes education and knows the symptoms of hypoglycemia, how to treat them, and when to call for help. If adjusting an existing oral agent or insulin dosage, it is a good rule of thumb not to increase insulin dosages by more than 10% or sulfonylurea dosage by more than about 20%. Patients may also be taking insulin resistance-reduction agents such as thiazolidinediones or agents that inhibit breakdown of complex carbohydrates in the small intestine, such as a glucosidase inhibitors.

D. Treatment of Underlying Causes

Treat any underlying causes for hyperglycemia appropriately as they are discovered (eg, antibiotics for urinary tract infection).

Disposition

Most patients with hyperglycemia in the absence of metabolic decompensation can be safely discharged after thorough evaluation for underlying causes and therapy has reduced blood glucose to less than 250-300 mg/dL. Patients with serious underlying causes or in whom hyperglycemia is resistant to treatment should be hospitalized for further workup and treatment.

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26(Suppl. 1):S5. [PMID:12502614] (Defines the various types of diabetes, their presentation, and diagnostic criteria.)

Montori VM, Bistrian BR, McMahon MM: Hyperglycemia in acutely ill patients. JAMA 2002;288:2167. [PMID: 12413377] (Outstanding brief review of the pathophysiology of hyperglycemia, its causes, and the rationale and literature supporting aggressive blood glucose control in acutely ill patients.)

HYPOGLYCEMIA

Essentials of Diagnosis

Common signs and symptoms include irritability, diaphoresis, and tachycardia related to increased circulating catecholamines.

As hypoglycemia progresses, neuroglycopenic effects range from focal neurologic deficits such as diplopia and paresthesias to coma.

Always remember to check the fingerstick blood glucose on every patient presenting with altered mental status or who appears to be acutely ill.

Causes

Hypoglycemia may occur for many reasons. Most commonly hypoglycemia results from an excess of endogenous or exogenous insulin or oral hypoglycemic agents, such as sulfonylureas. Failure of other organs that either produce glucose or mediate the production of glucose and glucose homeostasis may also precipitate hypoglycemia.

A. Exogenous Insulin

In patients with known diabetes, hypoglycemia may occur as a result of the following:

Delay in eating after taking insulin, or general malnutrition or inadequate caloric intake from acute nausea and vomiting or gastroparesis

Increased or unusual physical exertion

Increased physiologic stress resulting from illness (most commonly infection or sepsis), injury, or emotional upset

Excessive dose of exogenous insulin (Note: Remember to check the patient's vision and confirm that he or she can read the syringe appropriately.)

Variable absorption from injection site

Impaired counter-regulatory hormone axis (glucagon and epinephrine) secondary to autonomic failure caused by iatrogenic (insulin therapy-related) hypoglycemia

Excessive insulin release produced by sulfonylurea drugs, especially in the presence of renal insufficiency

Alterations in therapeutic regimen, particularly increases in insulin or oral agent dosages or the addition of new oral agents such as thiazolidinediones, which may reduce insulin resistance and improve therapeutic action of endogenous or exogenous insulin

Rarely, insulin or sulfonylurea drugs have been given to nondiabetics with the intent to harm. Comprehensive toxicology, insulin, and C-peptide levels can help diagnose these problems. C-peptide is not present in manufactured insulin; therefore, a high insulin level without a correspondingly high C-peptide level is diagnostic of insulin overdose.

B. Pancreatic Cell Tumor

Tumor of the insulin-secreting cells in the islets of Langerhans may cause refractory hypoglycemia and even coma. C-peptide levels will elevate concurrently with insulin levels.

C. Alcohol

Excessive ethanol intake, especially without adequate caloric intake, may cause severe hypoglycemia. Alcohol abuse depletes hepatic glycogen production and storage and also reduces NADH-mediated gluconeogenesis. Caution: Administer thiamine, 100 mg, prior to giving large amounts of glucose to alcoholic patients with hypoglycemia to avoid Wernicke encephalopathy.

D. Postprandial or Reactive Hypoglycemia

The intake of large amounts of calories in nondiabetics may produce enough excess insulin to induce mildly symptomatic hypoglycemia. Seldom is the hypoglycemia severe enough or persistent enough to cause decreased level of consciousness or coma.

Clinical Findings

A. History

Try to obtain history of diabetes from emergency medical services; family; or Medic Alert bracelet, necklace, or wallet card. Emergency medical services or family may also be helpful in disclosing alcohol use, recent caloric intake, alterations of medication regimen, and recent illness or injury.

B. Symptoms and Signs

Most early symptoms and signs are the result of increased catecholamine release (glucose usually 30-50 mg/dL): tachycardia, irritability, diaphoresis, paresthesias, hunger, decreased concentration. Later or more severe symptoms and signs of neuroglycopenia (glucose usually < 30 mg/dL) include confusion or bizarre behavior; visual disturbances (blurred vision, diplopia, hallucinations); hypothermia; seizurelike activity (myoclonus, tremor) and even seizures; focal neurologic deficits similar to Todd paralysis that resolve with glucose administration or remain transiently; and lethargy, syncope, or coma.

C. Laboratory Findings

The capillary or fingerstick glucose test is the most rapid diagnostic method to test blood glucose levels. Because glucometers can become unreliable at readings less than 40 mg/dL, always try to draw a serum or plasma sample for glucose before administration of glucose.

Search for ancillary causes of hypoglycemia such as infection or sepsis, myocardial infarction, cerebrovascular accident, alcohol use, pregnancy, drug use (particularly stimulants), occult trauma, depression (poor caloric intake or insulin or oral agent overdose), other endocrinopathies (Addison disease, myxedema, thyrotoxicosis, pituitary insufficiency) as dictated by history and physical examination, and, when appropriate or if history is not available, laboratory studies.

Treatment

A. Airway

Make sure the patient's tongue is not obstructing the airway and that the gag reflex and preferably the ability to phonate and swallow are present.

B. Emergency Therapeutic Measures

1. Intravenous glucoseIf intravenous access is readily obtainable, administer 50 cc of 50% dextrose in water (containing approximately 25 g of glucose, which is enough to resolve most hypoglycemic episodes). Caution: Remember to give thiamine, 100 mg intravenously or intramuscularly, to alcoholic patients prior to administration of glucose to prevent Wernicke encephalopathy. Monitor the patient's mental status and recheck capillary blood glucose 30 minutes after glucose administration. Repeat dosages of 50% glucose or even infusion of glucose glucose-containing intravenous fluids (5-10%) may be necessary to maintain adequate blood glucose levels. Neuroglycopenia (altered level of consciousness, seizurelike activity, focal neurologic deficits) may take time to resolve completely; however, if abnormalities persist longer than 30 minutes after glucose administration and hypoglycemia has not recurred, other causes should be investigated with a head CT scan and appropriate laboratory studies.

2. Oral feedingAs soon as the patient regains consciousness, clear fruit juice (eg, apple, grape; 6 oz = ~ 15 g glucose) is a good choice to maintain glucose levels, and if the patient has not eaten, a snack or meal is appropriate.

3. GlucagonIf intravenous access is not readily available, 1 mg of glucagon may be given intramuscularly. The response time is typically 10-15 minutes, and nausea and vomiting along with overcorrection of glucose levels are common. Given that glucagon can be given intramuscularly, all patients with insulin-treated diabetes (or their families) should carry and be familiar with the use of glucagon emergency kits, which come with syringe, lyophilized glucagon, and diluent.

4. MonitoringConsider the duration of action of the insulin and/or oral agents taken by the patient. Hourly capillary glucose checks should be taken until glucose levels are stable. Generally the patient should be observed through the peak time of the longest-acting insulin, typically 30 minutes to 1 hour after the dose with insulin lispro or insulin aspart, 2 hours with regular insulin, or 6 hours with NPH. Insulin glargine has no peak activity and does not generally cause hypoglycemia by itself. Patients taking long-acting insulins with peak activity, such as lente or ultralente, and patients taking sulfonylurea oral agents should generally be observed for a day in the hospital.

Disposition

Indications for admission include persistent or recurrent hypoglycemia despite appropriate therapy, hypoglycemia related to an oral agent or long-acting insulin, or serious ancillary cause (eg, severe infection, persistent nausea and vomiting).

Conditions for discharge include availability of responsible adult to be with the patient for next 8-12 hours; ability to take oral fluids and food; medical follow-up available within 24-48 hours; and ability to (and understanding of the need to) perform blood glucose checks, especially if changes are made in the therapeutic regimen.

American Diabetes Association: Position Statement: Hospital admission guidelines for diabetes mellitus. Diabetes Care 2003;26(Suppl. 1):S118. [PMID: 12502634] (American Diabetes Association recommendations on when to admit patients with hypoglycemia.)

Cryer PE: Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 2002;45:937. [PMID: 12136392] (An excellent review of therapeutic hypoglycemia and the counter-regulatory response, both normal and pathologic.)

McAulay V, Deary IJ, Frier BM: Symptoms of hypoglycaemia in people with diabetes. Diabet Med 2001;18:690. [PMID: 11606166] (Extensive review of literature on clinical presentation and symptomatology in diabetes-related hypoglycemia.)

LACTIC ACIDOSIS

General Considerations

Lactic acidosis is a common complication of critical illness. It is defined as serum lactic acid concentration greater than 5 mmol/L and arterial pH less than 7.35. Typically lactic acidosis results from the metabolism of glucose in the presence of inadequate tissue oxygenation or inadequate disposal of lactic acid by the liver. Severe acidosis can lead to impairment of cardiac contractility, increased pulmonary vascular resistance, sensitization of the myocardium to dysrhythmias, hyperkalemia, and inhibition of metabolism at the cellular or molecular level. The mortality rate is high, approaching 40-60%.

Causes

Lactic acidosis may occur in any severe illness in which the combination of inadequate tissue oxygenation, inadequate tissue perfusion, and inadequate lactic acid disposal is present. Common underlying causes include the following:

Respiratory, hepatic, renal, or heart failure

Sepsis

Shock

Cancer, especially leukemias

Acute infarction of lung, bowel, or extremities

Severe abdominal or multisystem trauma

Alcohol, methanol, or ethylene glycol poisoning

Drugs: cocaine, metformin, isoniazid

Clinical Findings

Diagnostic efforts should focus on finding the underlying cause of the lactic acidosis. Treatment of the underlying cause is crucial to recovery.

A. Symptoms and Signs

The clinical presentation varies according to the underlying illness or injury. Symptoms may include hyperventilation, generalized weakness, abdominal pain, or hypotension. Often there is a general lack of symptoms, especially in the early stages of the underlying pathology. As a result, diagnosis is frequently difficult in the period when the underlying illness and the acidosis itself are most treatable. A high index of suspicion is essential in older patients and in patients with the underlying illnesses identified above.

B. Laboratory Findings

Laboratory findings include pH less than 7.35 and often less than 7.2; anion gap greater than 15 mEq/L; and lack of explanation of acidosis by other causessuch as salicylates; alcohol, methanol, or ethylene glycol poisoning; or diabetic or alcoholic ketoacidosis. Hyperphosphatemia is a common finding secondary to anaerobic glycolysis or cellular disruption. Samples collected for lactate should be chilled immediately and centrifuged promptly to avoid continued lactic acid production by red and white blood cells, which can distort results.

Treatment

Detailed attention to resuscitation issues is essential in improving outcome. Improving tissue oxygenation through delivery of adequate oxygen through the lungs and adequate perfusion to carry the oxygen to the tissues via the circulatory system is critical.

A. Oxygen

High flow rates are indicated. Consider rapid-sequence intubation, mechanical ventilation, or noninvasive ventilation (eg, bilevel positive airway pressure) when arterial blood gas analysis indicates that oxygenation or ventilation is inadequate.

B. Fluids BR>Rapid infusion of 1 L of 0.9% saline is indicated to restore intravascular volume. Reassess the patient frequently to avoid volume overload in the setting of acute renal failure or cardiogenic shock and circulatory failure.

C. Pressors

Avoid vasoconstrictive pressors such as norepinephrine and higher doses of active pressors such as dopamine and dobutamine because they tend only to worsen tissue hypoxia. Low doses of dopamine and dobutamine may improve cardiac output and renal blood flow and are worth trying.

D. Sodium Bicarbonate

The use of sodium bicarbonate is one of the most controversial issues in the treatment of metabolic acidosis. The majority of data available suggest that at pH levels greater than 6.9, no benefit has been shown supporting the administration of sodium bicarbonate, at least in the clinical settings of severe metabolic acidosis resulting from DKA and sepsis. Significant risks of administering bicarbonate include hypernatremia and hyperosmolality, volume overload, paradoxical increase of intracellular acidosis secondary to excess carbon dioxide as a result of bicarbonate metabolism, and cerebral edema. If pH is less than 6.9, especially if the patient is exhibiting one or more complications of severe acidosis as listed above, consider administering 1-2 amps (~ 44 mEq/amp) diluted in 1 L of 5% dextrose in water or 0.2% saline infused over 2 hours. Reassess pH after allowing at least 2 hours for equilibration.

E. Treatment of Underlying Causes

Treatment of underlying causes may include revascularization therapy or balloon pump support in patients with cardiogenic shock, antibiotics for suspected sepsis after appropriate culture material is obtained, amputation or revascularization of ischemic extremities, removal or revascularization of ischemic bowel, hemodialysis for renal failure, or removal of toxic components such as ethylene glycol or methanol.

Disposition

The prognosis is grim, and mortality is high. Prompt identification and treatment of the underlying root cause of lactic acidosis remains the best hope for a positive outcome.

Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. N Engl J Med 1998;338:26. [PMID: 9414329] (Excellent overview of pathophysiology of severe acidosis and the management of several common causes.)

Forsythe SM, Schmidt GA: Sodium bicarbonate for the treatment of lactic acidosis. Chest 2000;117:260. [PMID: 10631227] (An intelligent debate on the rationale, or more accurately lack thereof, for giving sodium bicarbonate as therapy for severe metabolic acidosis.)