The underlying pathophysiologic disturbances in DKA need to be assessed carefully throughout the course of treatment. Careful trending of clinical and laboratory data allows for optimal and timely treatment of underlying acidemia and hyperglycemia and prevents potentially lethal complications, such as severe hyponatremia and hypokalemia.

Pathophysiologic changes associated with DKA are depicted in Figure 10-1.¹⁰ Overall, a shift from the normal carbohydrate metabolism of the fed state to one of primarily fat metabolism typical of the fasting state initiates the process. When carbohydrates are not available, caused either by a lack of insulin or insulin utilization at the cellular level, the body is unable to transport glucose into cells, a process that is necessary for the maintenance of normal, aerobic metabolism. With an obligatory alternate shift to fat oxidation, free fatty acids (FFAs) are produced in adipocytes and transported to the liver bound to albumin. There they are
broken down into acetate, and then turned into ketoacids (e.g., acetic acid, β-hydroxybutyrate, and acetone).¹² In the absence of insulin, the liver maximally initiates this ketogenic pathway such that the supply of these moderately strong acids exceeds peripheral utilization and maternal buffering capacity in the circulation. The presence of excessive ketone bodies, combined with increased lactic acid caused by decreased peripheral uptake of glucose, results in metabolic acidosis.¹³

As glucagon levels rise, the combination of excess glucagon and insufficient insulin inhibits glycolysis and stimulates gluconeogenesis, which worsens hyperglycemia. As the degree of hyperglycemia and ketonemia increases, there is a rise in serum osmolarity. As a result, hyperglycemia and ketones serve as an osmotic reservoir, leading to diuresis, profound hypovolemia, and hypotension. Hypovolemia then stimulates other counter-regulatory stress hormones (e.g., catecholamines, growth hormone, and cortisol), which further enhance the release of glucagon. This sequence of events contributes to the continued cycle of dehydration, increased serum osmolarity, and increased release of insulin counter-regulatory stress hormones, therefore worsening acidemia that subsequently leads to acidosis.

As a result of osmotic diuresis, the loss of free water can be significant and may approach 100 to 150 mL/kg body weight. For example, a woman who weighs 165 lb (75 kg) may lose over 11 liters of free water from osmotic diuresis. The increased production of urine is accompanied by depletion of electrolytes, especially sodium, potassium, and phosphorus.

Significant dehydration secondary to DKA leads to a significantly depleted potassium level (as much as 5 mEq/kg of body weight). Consequently, low serum potassium levels may be a sign of severe hypokalemia, since potassium is lost not only at the intracellular level but also from within the circulation. Further, sodium levels may be normal, high, or low, and are proportionate to the degree of hydration and hyperglycemia. For example, for each 100 mg/dL of glucose above 100 mg/dL, serum sodium is decreased by approximately 1.6 mEq. Conversely, when glucose falls, serum sodium levels rise by a corresponding amount.

Select physiologic changes of pregnancy contribute to an increased predisposition for the development of DKA during pregnancy. An increase in pulmonary minute ventilation is a result of an increased tidal volume. This relative hyperventilation causes a state of respiratory alkalemia which results in a compensatory renal excretion of bicarbonate. The net effect is decreased total buffering capacity, which makes the pregnant diabetic more susceptible to development of metabolic acidemia and subsequently DKA.¹³ In addition, emesis, commonly present during the first trimester, may result in dehydration significant enough to predispose to the development of DKA. Predisposing factors and events associated with the development of DKA are listed in Table 10-1.¹³

Norbert Freinkel described pregnancy as a state of “accelerated starvation.” He noted that, when pregnant women skipped breakfast and had a prolonged period of fasting, lipolysis was enhanced. Measured plasma glucose concentrations in pregnant women after fasting longer than 14 hours demonstrated that final FFA and β-hydroxybutyrate levels were strongly correlated and inversely related to final plasma glucose levels. These results show why the common practice of meal skipping by personal preference or for medical testing should be avoided in pregnant women.¹⁴

Insulin sensitivity has been shown to decrease as gestation advances, particularly in the third trimester with decreased hepatic sensitivity to insulin, postprandial hyperglycemia, and an increased risk for ketoacidosis.⁹ Increased insulin antagonists from the placenta such as human placental lactogen (HPL), prolactin, cortisol, and tumor necrosis factor (TNF) alpha act on insulin-sensitive tissues to produce alternate substrate for energy use during DKA. A concomitant rise in levels
of stress hormones (e.g., glucagon, corticosteroids, catecholamines and growth hormone) further enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis and contributes to the diabetogenic state.¹³

In addition to predisposing factors to DKA, there are also recognized precipitating events to DKA in pregnancy (see Table 10-1) including poor compliance with insulin regimens or meal plans, viral or bacterial infection, obstetrical use of steroids and/or administration of beta-mimetics, insulin administration failures, poor management, diabetic gastroparesis, and newly diagnosed diabetes.¹³

It is important to emphasize that pregnant women with diabetes are susceptible to the development of DKA at lower glycemic levels than non-pregnant individuals with diabetes. A study reported by Cullen showed that in pregnancies complicated by diabetes, 2 percent of patients demonstrated classic symptoms of DKA during the 10-year study period.⁴ Ten of 11 patients presenting with DKA (90 percent) demonstrated nausea, vomiting, and decreased caloric intake. Plasma glucose levels of less than 200 mg/dL were present in 4 of the 11 patients (36 percent). Despite contemporary methods of diabetes care, near-normal plasma glucose levels do not preclude DKA. Nausea, vomiting, and decreased caloric intake in an otherwise normal pregnant woman with diabetes requires evaluation to exclude ketosis.⁴ This has been demonstrated in women with type 1 diabetes who have had insulin withheld due to seemingly normal BG values. Therefore, insulin should not be withheld for more than a few hours in a patient with type 1 diabetes, even with a normal BG value.⁷

DKA in pregnancy occurs more often in women with type 1 diabetes rather than type 2 diabetes, and it is rare in GDM. Some ethnic groups have ketosis-prone type 2 diabetes, such as African Americans and Hispanics, and development is usually associated with the cessation of medication, infection, pancreatitis, or obesity.¹⁵ Overall, the prevalence of DKA during pregnancy has declined from 16.7 percent before 1960, to 7.8 percent from 1965 to 1985, and to 1.2 to 4.1 percent from the 1990s to 2003.¹⁶

DKA profoundly affects both the mother and the fetus. Literature from the last decade supports a fetal loss rate of approximately 9 percent in pregnancies in which DKA occurred.⁴ Maternal volume depletion and acidosis leading to decreased uterine blood flow may cause a relative fetal hypoxemia.¹⁷ Glucose and ketones readily cross the placenta, at maternal levels.¹³

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