Chapter 50 Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State
1 What is diabetic ketoacidosis (DKA)?
DKA is a serious acute metabolic decompensation in persons with known or newly presenting diabetes. It is a consequence of a relative or an absolute insulin deficiency in combination with an excess of counterregulatory hormones (primarily glucagon and catecholamines, but also cortisol and growth hormone). The classic triad of features is hyperglycemia (typically > 250 mg/dL), anion gap metabolic acidosis, and ketosis.
2 Describe the tissue actions of insulin
The major action of endogenously secreted or injected insulin is to lower blood glucose level by increasing glucose uptake into peripheral tissues such as skeletal muscle and adipose and by promoting glycogen production and stopping gluconeogenesis in the liver. Additionally its anabolic effects inhibit adipose breakdown to free fatty acids and muscle breakdown to amino acids. The sensitivity of these actions differs in the various target tissues, with small amounts of insulin fully preventing triglyceride metabolism and release of free fatty acids from adipose tissue whereas larger amounts are needed for suppression of hepatic glucose production and to promote glucose clearance into peripheral tissues.
3 What is the pathogenesis of DKA?
DKA starts withabsolute insulin deficiencybecause of a broken or clogged insulin pump, missed injections, or progression of an unknown illness to overt insulin deficiency or withrelative insulin deficiencyfrom a rise in tissue insulin requirements from infection, trauma, or other stresses. Glucose production from the liver increases, and glucose clearance into peripheral tissues is impaired, causing the blood glucose level to rise. Stress-related increases in counterregulatory hormones exacerbate these effects. As the renal glucose threshold is passed, an osmotic diuresis occurs causing urinary losses of water and electrolytes. The ensuing dehydration further increases the level of catecholamines. Also, because glucagon and insulin levels are normally inversely related, the insulin deficiency causes hyperglucagonemia. The increased catecholamines and glucagon and the insulin deficiency promote excess release of fatty acids from the adipose tissue that further impairs insulin-mediated glucose uptake into peripheral tissues. The capacity of the liver for β-oxidation of the fatty acids is exceeded, resulting in ketone production. This ketonemia and the resulting acidosis often cause nausea and vomiting; the patient’s polydipsia therefore stops, worsening the dehydration. The patient is now in DKA with this whole process occurring over a 12- to 48-hour period. This sequence of events is depicted inFigure 50-1.
4 How does DKA cause an anion gap metabolic acidosis?
The insulin deficiency and increased glucagon and catecholamines cause excess release of fatty acids from the adipose tissue and activation of metabolic pathways in the liver for conversion to ketoacids: acetoacetate, acetone, and β-hydroxybutyrate. Their accumulation results in the anion gap metabolic acidosis that is characteristic of DKA. Theanion gapis calculated by subtracting the serum concentration of the major anions (chloride and bicarbonate)from the main cation (sodium). A difference of greater than 12 mEq/L along with a lowered bicarbonate level (<15 mEq/L) shows the presence of anions that are not identified in this calculation, thus the anion gap (in this case the ketoacids).
5 How is type 1 diabetes diagnosed?
Type 1 diabetes results from autoimmune-mediated destruction of islet beta cells. Most patients therefore present with signs and symptoms of insulin deficiency: exhaustion, weight loss, nocturia, thepolys(polyuria and polydipsia), and sometimes DKA. It is usually diagnosed because of a typical clinical presentation and can be confirmed with use of specific markers for the autoimmune beta cell destruction. The best known is glutamic acid decarboxylase-65 (GAD-65) antibody, which is directed against a beta cell enzyme called glutamic acid decarboxylase. A positive test confirms type 1 diabetes, but a negative test does not rule it out. It is not necessary to perform GAD-65 antibody testing in all patients with newly identified type 1 diabetes, but it is most useful in those with elements of both type 1 and type 2 diabetes. In contrast, insulin or C peptide testing is not recommended, because insulin secretion is driven by glycemia, and the patient’s hyperglycemia and short duration of diabetes mean that these measures are rarely absent in patients with new-onset type 1 diabetes.
6 Does DKA develop in persons with type 2 diabetes?
Most series of persons with DKA show a 10% to 30% incidence of type 2 diabetes usually in association with an accompanying severe medical illness. The concept is that the added stress of the associated illness allows ketoacidosis to occur, in part because catecholamines are potent inhibitors of insulin secretion from the beta cell. This accompanying illness also impacts the course. Mortality rates are much higher in persons with DKA who are older than 50 years of age versus younger patients, with the older group dying of sepsis, adult respiratory distress syndrome, shock, or cardiovascular collapse.
A form of type 2 diabetes also exists that is ketosis prone, so-calledFlatbush diabetesorketosis-prone type 2 diabetes. These patients are mostly from minority populations (most studied are black and Latino) who have ketosis and sometimes DKA, often with obesity, but test negative for markers of type 1 diabetes. The defining clinical feature is being able to stop insulin months later, sometimes permanently. The pathogenesis is thought to be a heightened sensitivity for suppression of insulin secretion during stress that partially reverses with time.
7 What are the common precipitating events for DKA?
The most frequent initiating events for DKA are infection, insulin underdelivery, and newly presenting type 1 diabetes. Cardiovascular events and cerebrovascular accidents also occur, mostly in older patients. Insulin omission used to be most common in teenagers and young adults, although the growing use of insulin pumps in all ages means DKA from pump failure or catheter occlusion is age independent. Among infections pneumonias, gastrointestinal tract viral infections, and urinary tract infections are most common. Other causes are pancreatitis, drug abuse, or severe medical illness of any type. Even with all of the known causes, failure to identify a precipitating event is relatively common.
8 Describe the common signs and symptoms of DKA
Patients typically describe 1 to 3 days of polyuria, nocturia, and thirst. Fatigue also occurs, and often a rapid weight loss reflects the catabolic effect of the insulin deficiency and volume depletion. As the ketonemia and metabolic acidosis progress, nausea and repeated vomiting may occur, exacerbating the dehydration. Abdominal pain is also common related to gastric distention from the metabolic acidosis or irritation from repeated vomiting. Patients may report shortness of breath from their Kussmaul respirations that can be mistaken for a pulmonary infection or cardiac event. What is not usually reported is confusion or coma; fewer than 20% of patients are stuporous or show any confusion.
On examination, patients often show the Kussmaul breathing pattern of deep, sighing breaths as they attempt to compensate for the metabolic acidosis by lowering their PCO2. Tachycardia is common. In contrast the systolic blood pressure is rarely less than 100 mm Hg because of the osmotic effect of the hyperglycemia keeping fluid in the vascular space. Body temperature is usually normal even when an infection is present because the metabolic acidosis blunts the fever response. A distinguishing feature of DKA is the fruity sweet smell of the patient’s breath from their exhaling the ketone acetone. The remainder of the physical examination is typically unremarkable except for a generalized abdominal tenderness.
9 How does the hyperosmolar hyperglycemic state (HHS) differ from DKA?
HHS also is characterized by profound hyperglycemia but without ketoacidosis. The distinguishing clinical features of HHS are as follows:
Occurs most often in the elderly and those with known type 2 diabetes
Very high blood glucose levels of 600 mg/dL or greater
Markedly elevated serum osmolarity of 320 mOsm/kg or greater
Frequent occurrence of altered mental state or coma
More serious hypotension and overt dehydration including substantially larger electrolyte losses than DKA
High mortality rate that averages 15% versus less than 2% in uncomplicated DKA
10 What is the pathogenesis of HHS?
The major difference from DKA is a modestly higher circulating insulin level that prevents much of a rise in free fatty acids and thus blocks ketone production from the liver but is not enough to suppress hepatic glucose production or promote glucose clearance into peripheral tissues. Therefore the main feature is hyperglycemia without ketoacidosis, although small amounts of urinary ketones and a modest widening of the anion gap can be seen. As such the metabolic acidosis–induced vomiting and abdominal pain that are common in DKA, and often are what gets the patient to seek medical help, are lacking. Instead the worsening hyperglycemia and osmotic diuresis go on for much longer, typically many days or a couple of weeks, and the presentation is often insidious, manifesting in symptoms such as bed-wetting or modest confusion that may be unnoticed in the elderly. Thus the dehydration and urinary electrolyte losses are considerably worse than in DKA, and it is this dehydration that is the key feature leading to HHS by causing a fall in urine output and with it glycosuria. The blood glucose level now rises above the renal threshold to values that can exceed 1000 mg/dL. Serum osmolarityrises in parallel, and the resulting confusion or coma is usually why the patient is brought for medical attention.
11 What are the common precipitating events in HHS?
HHS occurs most often in patients with known type 2 diabetes although it is the first evidence of diabetes in 30% to 40% of patients. The most common cause is a medical crisis such as infection or sepsis, cardiovascular event, cerebrovascular accident, pancreatitis, or acute abdomen. Pharmaceuticals that raise glycemia also are sometimes at fault, with the best known high-dose thiazides, corticosteroids, sympathomimetic agents, atypical antipsychotics, and β-blockers. Another common feature is caregivers having restricted the patient’s access to water because of incontinence or bed-wetting.
12 Describe the common signs and symptoms of HHS
Patients are usually brought for medical evaluation because of a mood change, fall-off in appetite, confusion, or coma. Particularly common are subtle behavior changes over several weeks such as lethargy or less interaction with the family. Also hints to the precipitating cause or illness may be elicited. Useful history is a worsening of bed-wetting or incontinence to gauge the duration of the osmotic diuresis.
On examination, patients typically show some mental alteration from slow answers to questions or searching for words to obtundation or coma. Because of the advanced age of many of these patients and the potential for underlying central nervous system (CNS) pathologic conditions, they may have focal findings that mimic a stroke. In addition, these patients usually are seen with signs of severe volume depletion such as marked hypotension, dry mucous membranes, and skin tenting. As with DKA, the absence of a fever does not exclude infection especially because of the blunted fever response in elderly patients.
13 Which initial laboratory tests are obtained in DKA and HHS?
Laboratory testing at presentation includes a complete blood cell count, serum electrolytes, arterial blood gases, serum creatinine, serum ketones including β-hydroxybutyrate when available, a Chem 12 panel, and urinalysis for signs of infection. In DKA, radiographs or scans, pan-cultures, drug screens, and serum brain natriuretic peptide, lactate, lipase, or markers of ischemic cardiac damage are not usually obtained without suggestive history or physical findings. In HHS because of the advanced age of many patients and the insidious nature of the presentation, pan-testing is common particularly in patients who are confused or comatose: urine and blood cultures, electrocardiogram, cardiac enzymes, and CNS imaging, especially if there are focal neurologic findings. Hemoglobin A1ctesting is very helpful to determine the patient’s diabetes control before the acute hyperglycemic event or the chronicity of hyperglycemia in patients with new-onset diabetes.
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