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ACUTE HYPERGLYCEMIC COMPLICATIONS
Dr. S.M.Sadikot.
Hon. Endocrinologist,
Jaslok Hospital and Research Centre,
Mumbai 400026

Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar Nonketotic state (HONK or HHS) are the two most serious acute hyperglycemic complications of diabetes. They continue to be important causes of morbidity and mortality among patients with diabetes in spite of major advances in the understanding of their pathogenesis and more uniform agreement about their diagnosis and treatment.

Although DKA is usually associated with people with Type 1 DM, it is also often seen in people with Type 2 DM. HONK is more typically seen in the older Type 2 patient.

Although for the purpose of discussion, these are considered separately as two entities, DKA and HONK should be thought of as a continuum of disease. At one extreme is pure DKA without hyperosmolarity of significant amount. As noted above these patients may present with more modest degrees of glucose elevation. At the other extreme is HONK with extreme elevations of glucose, and hyperosmolarity, but without significant ketosis. Finally, there are a range of patients who will have features of both.

It is due to this continuum, that I have dealt with various aspects of HONK along with DKA.

Diabetic Ketoacidosis (DKA) DKA is a metabolic disorder consisting of three major abnormalities: elevated blood glucose level, high ketone bodies, and a metabolic acidosis with an elevated anion gap. Dehydration and hyperosmolarity may be present as well. There is no "typical" presentation and individual patients may present with a range of clinical findings not clearly meeting the above criteria.

Precipitating Factors For the Development of DKA

When considering the precipitating factors for the development of DKA it is important to remember that DKA develops due to either an absolute or a relative absence of insulin. An absolute insulin deficiency is the major precipitant for those patients presenting in DKA who have new onset type I diabetes. It is estimated that 10-20% of patients with new onset diabetes will present in DKA as their initial presentation. Another major cause of absolute insulin deficiency is omission of normal insulin in a patient with know type I diabetes.

In those patients with known diabetes the precipitating factor for DKA can be identified in greater than 80% of the cases. Except in the case where the patient stops taking their insulin, the usual cause of the DKA is a relative lack of insulin. Relative insulin deficiency occurs when there is an increased requirement for insulin due to an increased physiologic stress such as seen with an infection, trauma, or other process. Infection is the most frequent identifiable cause of DKA with pneumonia and urinary tract infections being two of the most common causes. Myocardial infarction should always be considered in the list of precipitating factors of DKA, particularly in older patients, as the condition is associated with elevations of epinephrine which may stimulate a pathologic process that results in DKA.

Other precipitating causes are noted in the table below.

Precipitating Factors of DKA:

Absolute lack of insulin

Relative lack of Insulin

Acute Illness

Infection or other inflammatory process

Myocardial Infarction

Stroke

Trauma

Endocrine Disorders

Drugs: Steroids, Calcium channel blockers, Pentamidine, Beta-blocking agents, Dilantin, Alcohol, HCTZ

DIAGNOSIS

History and physical examination

The evolution of the acute DKA episode in type 1 Diabetes or even in type 2 diabetes tends to have a much shorter time span as compared to HHS. Although the symptoms of poorly controlled diabetes may be present for several days, the metabolic alterations typical of ketoacidosis usually evolve within a short time frame (typically <24 h). Occasionally, the entire symptomatic presentation may evolve or develop more acutely, and the patient may present in DKA with no prior clues or symptoms.

The classical clinical picture includes a history of polyuria, polydipsia, polyphagia, weight loss, vomiting, abdominal pain, dehydration, weakness, clouding of sensorium, and finally coma. Patients with DKA usually present with complaint of fatigue, malaise, thirst, and polyuria. Depending on the length of symptoms the patient may be able to report weight loss. As the patient becomes increasingly ill they may begin to vomit and complain of abdominal pain.

Physical findings may include poor skin turgor, Kussmaul respirations , tachycardia, hypotension, alteration in mental status, shock, and ultimately coma. Up to 25% of DKA patients have emesis, which may be coffee-ground in appearance and guaiac positive. Endoscopy has related this finding to the presence of hemorrhagic gastritis. Mental status can vary from full alertness to profound lethargy or coma, with the latter more frequent in HHS. Although infection is a common precipitating factor for both DKA and HHS, patients can be normothermic or even hypothermic primarily because of peripheral vasodilation. Hypothermia, if present, is a poor prognostic sign.

The physical signs of DKA can be variable. Most patients will have some degree of tachycardia, but the blood pressure is often normal. Evidence of dehydration, such as loss of skin turgor, and dry mucus membranes may be present. The patient may be febrile, and extreme elevations of temperature should not be assumed to be the result of dehydration. Hypothermia may also be seen. The respiratory rate may be normal or somewhat rapid, but if the patient is examined closely the deep breathing typical of "Kussmaul" respirations may be noted. Caution needs to be taken with patients who complain of abdominal pain on presentation. The exact cause of abdominal pain that is associated with DKA is not known. The abdominal pain is disturbing since it may be secondary to the DKA, or be from the pathologic process that initiated the crisis, such as pyelonephritis, pancreatitis, etc. Usually, abdominal pain secondary to DKA will begin to resolve with treatment. Further evaluation is necessary if this complaint does not resolve with resolution of dehydration and metabolic acidosis.

Physical examination reveals other findings, such as a fruity breath odor (similar to the odor of nail polish remover) as the result of volatile acetone and signs of dehydration, including loss of skin turgor, dry mucous membranes, tachycardia, and hypotension. Mental status can vary from full alertness to profound lethargy; however, <20% of patients with DKA or HHS are hospitalized with loss of consciousness. In HHS, mental obtundation and coma are more frequent because the majority of patients, by definition, are hyperosmolar. In some patients with HHS, focal neurological signs (hemiparesis or hemianopsia) and seizures may be the dominant clinical features. Although the most common precipitating event is infection, most patients are normothermic or even hypothermic at presentation, because of either skin vasodilation or low fuel-substrate availability.

Although usually straightforward, the diagnosis of diabetic ketoacidosis is occasionally missed in unusual situations, such as when it is the initial presentation of diabetes in infants or elderly patients or when patients present with sepsis or infarction of the brain, bowel or myocardium. These presentations can distract the physician from the underlying diagnosis of diabetic ketoacidosis.

Laboratory Abnormalities

In general, the laboratory diagnosis of DKA is based on an elevated blood glucose (usually above 250mg/dl), a low serum bicarbonate level (usually below 15 mEq/L), and elevated anion gap, and demonstrable ketonemia. Individually, all of these values may vary considerably, but taken together they help make the diagnosis of DKA. In addition to the above there are several calculations that are important in the evaluation and therapy of the patient with DKA.

Serum Osmolality:

Mental status changes can occur in DKA and may be the result of DKA, or some underlying process that may have caused the patient to develop DKA. Obviously, it is critical to determine the cause of the patient's altered mental status. It has been well documented that mental status changes in DKA correlate with the effective serum osmolality. Thus, a patient with mental status changes can only have this decompensation explained by the elevated glucose level if the serum osmolality is significantly elevated.

The effective serum osmolality is calculated as follows:

Serum Osmolality = 2(Na+K) + glu/18 + BUN/2.8

Calculated total osmolalities of greater than 340 mOsm/kg H2O are associated with stupor and coma. Calculated values below this level would not explain a patient with coma and an additional cause such as meningitis, or stroke should be considered. Corrected Serum Sodium Levels:

Despite volume depletion, serum sodium may be low, normal, or elevated. This variation has several causes. First, dehydration from an osmotic diuresis may result in excess loss of water compared to sodium, this may give increased values of serum sodium despite total body sodium depletion. On the other hand, serum sodium level frequently "appears" low. Insulin deficiency results in reduced clearance of triglycerides. The presence of triglycerides displaces plasma water and cause a low reading for the sodium concentration (this is pseudohyponatremia). It is possible to recognize this clinically by noting that the plasma is milky or cloudy appearing. Finally, Sodium levels often appear artificially low due to the osmotic pull of the elevated serum glucose levels. The presence of the increased glucose causes water to shift into the extracellular space resulting in a dilutional reduction on the serum sodium. When trying to determine the degree of dehydration in a patient it is best to use corrected serum sodium level.

To assess the severity of sodium and water deficits, serum sodium may be corrected by adding 1.6 mEq to the measured serum sodium for each 100 mg/dl of glucose above 100 mg/dl

This can be calculated using the following formula:


Corrected Na = [Na+] + 1.6 x [glu in mg/dl] - 100
100

Often, the initial serum sodium appears low, but when the above calculation in performed, the final value is elevated. This indicates a marked intracellular dehydration.

Anion Gap:

The ketoacids produced during DKA are buffered by the serum bicarbonate and then excreted in the urine. This causes a loss of bicarbonate which is a measured anion. As the bicarbonate is lost the anion gap increases.

The three ketone bodies are beta- hydroxybutyrate, acetoacetate, and acetone. Only acetoacetate and acetone are measured in the nitroprusside reaction, but the formation of these ketone bodies favors the development of beta-hydroxybutyrate. Thus, the test for ketone bodies may be only weakly positive even when large amounts of total ketones are present. Acetone does not contribute to the anion gap, but it is measured in the nitroprusside reaction and is a precursor for the regeneration of bicarbonate. It is not uncommon for the patient to be improving clinically, but to have the nitroprusside test become more strongly positive since acetone is being produced. At this point, the anion gap should be narrowing, even as the nitroprusside test is getting stronger.

Additional Laboratory Evaluation:

Other tests should be varied out initially. Many of these common tests will give the data needed to do the above important calculations. A tube should be sent for exact glucose determination, but a bedside test can me used to determine gross blood sugar levels. To determine the degree of acidosis and bicarbonate loss, an ABG should be sent early in the evaluation of a patient considered to have DKA.

The complete blood count often shows an elevation of the white blood cells. This may be, in part, due to hemoconcentration secondary to dehydration. Thus, WBC's of 20,000 occur commonly. Those patients with WBC's greater than 30,000 who have a bandemia on peripheral smear should be assumed to have an infectious process.

Additional evaluation should take into consideration the best tests to help determine the potential cause of the patient's decompensation into DKA. Urinalysis, chest radiograph, and electrocardiogram should be done on most patients.

Pitfalls of Laboratory Diagnosis

In assessment of blood glucose and electrolytes in DKA, certain precautions need to be taken in interpreting results. Severe hyperlipidemia, which is occasionally seen in DKA, could reduce serum glucose and sodium levels, factitiously leading to pseudohypo- or normoglycemia and pseudohyponatremia, respectively, in laboratories still using volumetric testing or dilution of samples with ion-specific electrodes. This should be rectified by clearing lipemic blood before measuring glucose or sodium or by using undiluted samples with ion-specific electrodes. Creatinine, which is measured by a colormetric method, may be falsely elevated as a result of acetoacetate interference with the method. Hyperamylasemia, which is frequently seen in DKA, may be the result of extrapancreatic secretion and should be interpreted cautiously as a sign of pancreatitis. The usefulness of urinalysis is only in the initial diagnosis for glycosuria and ketonuria and detection of urinary tract infection. For quantitative assessment of glucose or ketones, the urine test is unreliable, because urine glucose concentration has poor correlation with blood glucose levels and the major urine ketone, -hydroxybutyrate, cannot be measured by the standard nitroprusside method. Treatment

Therapeutic Goals

The therapeutic goals for treatment of hyperglycemic crises in diabetes consist of 1) improving circulatory volume and tissue perfusion, 2) decreasing serum glucose and plasma osmolality toward normal levels, 3) clearing the serum and urine of ketones at a steady rate, 4) correcting electrolyte imbalances, and 5) identifying and treating precipitating events.

Fluid Replacement

The severity of fluid and sodium deficits is determined primarily by the duration of hyperglycemia, the level of renal function and the patient's fluid intake. Dehydration can be estimated by clinical examination and by calculating total serum osmolality and the corrected serum sodium concentration.

The severity of dehydration and volume depletion can be estimated by clinical examination using the following guidelines, with the caveat that these criteria are less reliable in patients with neuropathy and impaired cardiovascular reflexes:

1. An orthostatic increase in pulse without change in blood pressure indicates ~10% decrease in extracellular volume (i.e., ~2 liters isotonic saline).

2. An orthostatic drop in blood pressure (>15/10 mmHg) indicates a 15-20% decrease in extracellular volume (i.e., 3-4 liters).

3. Supine hypotension indicates a decrease of >20% in extracellular fluid volume (i.e., >4 liters).

The measured serum sodium concentration must be corrected for the changes related to hyperglycemia. Corrected serum sodium concentrations of greater than 140 mEq per L (140 mmol per L) and calculated total osmolalities of greater than 330 mOsm per kg of water are associated with large fluid deficits. Calculated total osmolalities are correlated with mental status, in that stupor and coma typically occur with an osmolality of greater than 330 mOsm per kg of water.

The initial priority in the treatment of diabetic ketoacidosis is the restoration of extracellular fluid volume through the intravenous administration of a normal saline (0.9 percent sodium chloride) solution. This step will restore intravascular volume, decrease counterregulatory hormones and lower the blood glucose level. As a result, insulin sensitivity may be augmented. The initial treatment is typically with a 0.9 percent saline solution administered at a rate of 7 to 14 mL per kg per hour. In patients with mild to moderate volume depletion, infusion rates of 7 mL per kg per hour have been as efficacious as infusion rates of 14 mL per kg per hour. The subsequent administration of a hypotonic saline (0.45 percent sodium chloride) solution, which is similar in composition to the fluid lost during osmotic diuresis, leads to gradual replacement of deficits in both intracellular and extracellular compartments.

When the blood glucose concentration is approximately 250 mg%, glucose should be added to the hydration fluid (i.e., 5 percent dextrose in hypotonic saline solution). This allows continued insulin administration until ketonemia is controlled and also helps to avoid iatrogenic hypoglycemia. Another important aspect of rehydration therapy in patients with diabetic ketoacidosis is the replacement of ongoing urinary losses.

The use of isotonic versus hypotonic saline in treatment of DKA and HHS is still controversial, but there is uniform agreement that in both DKA and HHS, the first liter of hydrating solution should be normal saline (0.9% NaCl), given as quickly as possible within the 1st hour and followed by 500-1,000 ml/h of 0.45 or 0.9% NaCl (depending on the state of hydration and serum sodium) during the next 2 h. State of hydration can also be estimated by calculating total and effective plasma osmolality and by calculating corrected serum sodium concentration.

Dextrose should be added to replacement fluids when blood glucose concentrations are <250 mg/dl in DKA or <300 mg/dl in HHS. This can usually be accomplished with the administration of 5% dextrose; however, in rare cases, a 10% dextrose solution may be needed to maintain plasma glucose levels and clear ketonemia. This allows continued insulin administration until ketogenesis is controlled in DKA and avoids too rapid correction of hyperglycemia, which may be associated with development of cerebral edema (especially in children).

An additional important aspect of fluid replacement therapy in both DKA and HHS is the replacement of ongoing urinary losses. Failure to adjust fluid replacement for urinary losses leads to a delay in repair of sodium, potassium, and water deficits. Overhydration is a concern when treating children with DKA, adults with compromised renal or cardiac function, and elderly patients with incipient congestive heart failure. Once blood pressure stability is achieved with the use of 10-20 ml · kg-1 · h-1 0.9% NaCl for 1-2 h, one should become more conservative with hydrating fluid.

Reduction in glucose and ketone concentrations should result in concomitant resolution in osmotic diuresis of DKA. The resulting decrease in urine volume should lead to a reduction in the rate of intravenous fluid replacement. This reduces the risk of retention of excess free water, which contributes to brain swelling and cerebral edema, particularly in children. The duration of intravenous fluid replacement in adults and children is ~48 h depending on the clinical response to therapy. However, in a child, once cardiovascular stability is achieved and vomiting has stopped, it is safer and as effective to pursue oral rehydration.