Metabolic Acidosis: Diabetic Ketoacidosis

Transcription

1 1 98 PHYSIOLOGY CASES AND PROBLEMS Case 34 Metabolic Acidosis: Diabetic Ketoacidosis David Mandel, who was diagnosed with type I diabetes mellitus when he was 12 years old (see Case 30), is now a third-year medical student. David's diabetes remained in control throughout middle and high school, college, and the first 2 years of medical school. However, when David started his surgery clerkship, his regular schedule of meals and insulin injections was completely disrupted. One morning, after a very late night in trauma surgery, David completely forgot to take his insulin! At 5 A.M., before rounds, he drank orange juice and ate two doughnuts. At 7 A.M., he drank more juice because he was very thirsty. He mentioned to the student next to him that he felt "strange" and that his heart was racing. At 9 A.M., he excused himself from the operating room because he thought he was going to faint. Later that morning, he was found unconscious in the call room. He was transferred immediately to the emergency department, where the information shown in Table 4-9 was obtained. TABLE 4-9 David's Physical Examination and Laboratory Values Blood pressure 90/40 Pulse rate 130/min Respirations 32/min, deep and rapid Plasma concentration Glucose 560 mg/dl Na.132 meq/l (normal, 140 meq/l) 5.8 mhq/l (normal, 4.5 meq/l) Cl- 96 meq/l (normal, 105 meq/l) HCO3 8 meq/l (normal, 24 meq/l) Ketones (normal, none) Arterial blood P mm Hg (normal, 100 mm Hg) Pco220 mm Hg (normal, 40 mm Hg) ph 7.22 (normal, 7.4) Based on the information shown in Table 4-9, it was determined that David was in diabetic ketoacidosis. He was given an intravenous infusion of saline and insulin. Later, after his blood glucose had decreased to 175 mg/dl and his plasma K' had decreased to 4 meq/l, glucose and were added to the infusion. David stayed in the hospital overnight. By the next morning, his blood glucose, electrolytes, and blood gas values were normal. roj QUESTIONS 1. What acid-base disorder did David have? What was its etiology? 2. Did David's lungs provide the expected degree of "respiratory compensation"? 3. Why was his breathing rate so rapid and deep? What is this type of breathing called? 4. How did David's failure to take insulin cause his acid-base disorder?

2 RENAL AND ACID-BASE PHYSIOLOGY What was David's serum anion gap, and what is its significance? 6. Why was David so thirsty at 7 A.M.? 7. Why was his pulse rate increased? 8. What factors contributed to David's elevated plasma IQ- concentration (hyperkalemia)? Was his K. balance positive, negative, or normal? 9. How did the initial treatment with insulin and saline help to correct David's fluid and electrolyte disturbances? 10. Why were glucose and K. added to the infusion after his plasma glucose and K' levels were corrected to normal?

3 200 PHYSIOLOGY CASES AND PROBLEMS PrAl ANSWERS AND EXPLANATIONS 1. David's ph, HCO3, and Pc 0, values are consistent with metabolic acidosis: decreased ph, decreased HCO 3-, and decreased Pc02 (Table 4-10). TABLE 4-10 Sutmnaiy of Acid-Base Disorders Disorder CO2 + H 20 <-> HCO 3- Metabolic,I, (respiratory acidosis compensation) Metabolic T (respiratory alkalosis compensation) Respiratory acidosis Respiratory alkalosis Respiratory Compensation Hyperventilation Hypoventilation Renal Compensation T excretion T HCO 3- reabsorption.1,11+excretion.1, HCO3- reabsorption Heavy arrows indicate primary disturbance. (Reprinted with permission from Costanzo LS: BRS Physiology, 3rd ed. Baltimore, Lippincott Williams & Wilkins, 2003, p 195.) David had metabolic acidosis [diabetic ketoacidosis (DKA)] secondary to overproduction of the ketoacids 13-OH-butyric acid and acetoacetic acid. Metabolic acidosis is usually caused by an increase in the amount of fixed acid in the body, as a result of either ingestion or overproduction of acid. The excess fixed acid is buffered by extracellular HCO3 and, as a result, the HCO3 concentration in blood decreases. This decrease in blood HCO3 concentration causes the ph of the blood to decrease (acidemia), as described by the Henderson-Hasselbalch equation (see Case 29): ph = log HCO 3 - co, The acidemia then causes an increase in breathing rate, or hyperventilation, by stimulating peripheral chemoreceptors. As a result, arterial Pc 02 decreases. This decrease in arterial Pco, is the respiratory compensation for metabolic acidosis. Essentially, the lungs are attempting to decrease the denominator (CO 2) of the Henderson-Hasselbalch equation as much as the numerator (HCO 3) is decreased, which tends to normalize the ratio of HCO 3 to CO 2 and to normalize the ph. 2. The expected degree of respiratory compensation can be calculated from the "renal rules." These rules predict the appropriate compensatory responses for simple acid-base disorders (see Appendix). For example, in simple metabolic acidosis, the renal rules can determine whether the lungs are hyperventilating to the extent expected for a given decrease in HCO3- concentration. David's HCO3 concentration is decreased to 8 meq/l (normal, 24 meq/l). The rules can be used to predict the expected decrease in Pco, for this decrease in HCO3. If David's actual Pc 02 is the same as the predicted Pm,, the respiratory compensation is considered to be appropriate, and no other acid-base abnormality is present. If David's actual Pc02 is different from the predicted value, then another acid-base disorder is present (in addition to the metabolic acidosis). 'The renal rules shown in the Appendix tell us that in simple metabolic acidosis, the expected change in Pc02 (from the normal value of 40 mm Hg) is 1.3 times the change in HCO3 concentration (from the normal value of 24 meq/l). Thus, in David's case: Decrease in HCO 3- (from normal) = 24 meq/l - 8 ineq/l = 16 meq/l

4 RENAL AND ACID BASE PHYSIOLOGY 201 Predicted decrease in Pc 02 (from normal) = 1.3 x 16 meq/l = 20.8 mm Hg Predicted Pop, = 40 mm Hg mm Hg = 19.2 mm Hg The predicted Pc02 is 19.2 mm Hg. David's actual Pco 2 was 20 mm Hg. Thus, his degree of respiratory compensation was both appropriate and expected for a person with an HCO3- concentration of 8 meq/l; no additional acid-base disorders were present. 3. David's rapid, deep breathing is the respiratory compensation for his metabolic acidosis. This hyperventilation, typically seen in diabetic ketoacidosis, is called Kussmaul respiration. 4. David has type I diabetes mellitus. The beta cells of his endocrine pancreas do not secrete enough insulin, which is absolutely required for storage of ingested nutrients (see below). Even since David developed type I diabetes mellitus in middle school, he has depended on injections of exogenous insulin to store the nutrients he ingests. When David forgot to take his insulin in the morning and then ate a high-carbohydrate meal (orange juice and doughnuts), he was in trouble! If you have not yet studied endocrine physiology, briefly, the major actions of insulin are coordinated for storage of nutrients. They include uptake of glucose into cells and increased synthesis of glycogen, protein, and fat. Therefore, insulin deficiency has the following effects: (1) decreased glucose uptake into cells, resulting in hyperglycemia; (2) increased protein catabolism, resulting in increased blood levels of amino acids, which serve as gluconeogenic substrates; (3) increased lipolysis, resulting in increased blood levels of free fatty acids; and (4) increased hepatic ketogenesis from the fatty acid substrates. The resulting ketoacids are the fixed acids ft-oh-butyric acid and acetoacetic acid. Overproduction of these fixed acids causes diabetic ketoacidosis (discussed in Question 1). 5. The serum anion gap is "about" electroneutrality, which is an absolute requirement for every body fluid compartment (e.g., serum). That is, in every compartment, the concentration of cations must be exactly balanced by an equal concentration of anions. In the serum compartment, we usually measure Na' (a cation) and Cl and HCO 3- (anions). When the concentration of Ne is compared with the sum of the concentrations of Cl and HCO 3-, there is a "gap." This gap, the anion gap, is comprised of unmeasured anions and includes plasma albumin, phosphate, sulfate, citrate, and lactate (Figure 4-11). Anion gap 1Unmeasured anions = protein, phosphate, citrate, sulfate HCO3- Cations Anions Figure 4-11 Serum anion gap. (Reprinted with permission from Costanzo LS: BRS Physiology, 3rd ed. Baltimore, Lippincott Williams & Wilkins, 2003, p 198.)

5 202 PHYSIOLOGY CASES AND PROBLEMS The anion gap is calculated as follows: Anion gap = [Na l ] - ([C1-] + [HCO31) where Anion gap = unmeasured anions in serum or plasma [Nal = plasma Na+ concentration (meq/l) [C1-] = plasma Cl- concentration (meq/l) [FICO3] = plasma HCO 3- concentration (meq/l) The normal range for the serum anion gap is 8-16 meq/l, (average value, 12 meq/l). David's serum anion gap is: Anion gap = 132 meq/l - (96 m Eq/L + 8 meq/l) = 28 meq/l A calculated anion gap of 28 meq/l is much higher than the normal value of 12 meq/l. Why would the anion gap be increased? Since the anion gap represents unmeasured anions, a logical conclusion is that the concentration of unmeasured anions in David's plasma was increased because of the presence of ketoanions, Thus, David had metabolic acidosis with an increased anion gap. To maintain electroneutrality, the decrease in HCO 3- concentration (a measured anion) was offset by the increase in ketoanions (unmeasured anions). Did you notice that the anion gap was increased exactly to the same extent that the HCO3- was decreased? In other words, the anion gap of 28 meq/i, was 16 rneq/l above the normal value of 12 meq/l, and the HCO 3- of 8 meq/l was 16 meq/l below the normal value of 24 meq/l. This comparison, called "A/A" (A anion gap/a HCO 3), is used when metabolic acidosis is associated with an increased anion gap. A/A is used to determine whether metabolic acidosis is the only acid-base disorder that is affecting the HCO3 concentration. In David's case, we can conclude that was true to preserve electroneutrality, the decrease in HCO 3- was offset exactly by the increase in unmeasured anions. Therefore, no process, other than the increased anion gap metabolic acidosis, was affecting David's HCO 3- concentration. 6. David was extremely thirsty at 7 A.M. because he was hyperglycemic. He forgot to take his insulin, but ate a high-carbohydrate meal. Without insulin, the glucose he ingested could not be taken up into his cells, and his blood glucose concentration became elevated. At its normal plasma concentration, glucose contributes little to total plasma osmolarity. However, in hyperglycemia, the contribution of glucose to the total plasma osmolarity becomes more significant. Thus, David's plasma osmolarity was probably elevated secondary to hyperglycemia, and this hyperosmolarity stimulated thirst centers in the hypothalamus. In addition, David lost Na + and water from his body secondary to the osmotic diuresis that was caused by un-reabsorbed glucose (see Case 30). Extracellular fluid (ECF) volume contraction stimulates the renin-angiotensin II-aldosterone system (through decreases in renal perfusion pressure); angiotensin II is a powerful thirst stimulant (dypsogen). Other evidence for ECF volume contraction was David's hypotension in the emergency room (blood pressure of 90/40). 7. David's pulse rate was increased secondary to his decreased blood pressure. Recall from cardiovascular physiology that decreased arterial pressure activates baroreceptors in the carotid sinus (baroreceptor reflex), which relay this information to cardiovascular centers in the brain stem. These centers increase sympathetic outflow to the heart and blood vessels in an attempt to increase blood pressure toward normal, An increase in heart rate is one of these sympathetic responses. 8. To determine the factors that contributed to David's hyperkalemia, we must consider both internal K. balance (shifts of K* between extracellular and intracellular fluid) and external Kt

6 RENAL AND ACID-BASF. PHYSIOLOGY 203 balance (e.g., renal mechanisms). Thus, hyperkalemia can be caused by a shift of K' from intracellular to extracellular fluid, by a decrease in K' excretion, or by a combination of the two. The major factors that cause a K + shift from intracellular to extracellular fluid are shown in Table They include insulin deficiency, j3-adrenergic antagonists, acidosis (in which extracellular H + exchanges for intracellular hyperosmolarity, exercise, and cell lysis. In David's case, the likely contributors were insulin deficiency (surely!) and hyperosmolarity (secondary to hyperglycemia). It might seem that acidosis would also cause a K- shift, but this effect is less likely in ketoacidosis. The ketoanions (with their negative charge) accompany H` (with its positive charge) into the cells, thereby preserving electroneutra]ity. Thus, when an organic anion such as the ketoanion is available to enter cells with H', an I-1.-K- shift is not needed (see Table 4-11). TABLE 4-11 Shifts of K* Between Extratellular Fluid and Intracellular Fluid Causes of Shift of K. Out of Cells > Hyperkalemia Insulin deficiency p-adrenergic antagonists Acidosis (exchange of extracellular H+ for intracellular K') Hyperosmolarity (11 20 flows out of the cell; K' diffuses out with H20) Inhibitors of Na--K' pump (e.g., digitalis) [when pump is blocked, K' is not taken up into cells] Exercise Cell lysis Causes of Shift of K' Into Cells --> Hypokalemia Insulin p-adrenergic agonists Alkalosis (exchange of intracellular Fl" for extracellular K') Hypoosmolarity (H 20 flows into the cell; K. diffuses in with H20) (Reprinted with permission from Costanzo LS: BRS Physiology, 3rd ed. Baltimore, Lippinocott Williams & Wilkins, 2003, p 179.) Recall that the major mechanism for K' excretion by the kidney involves K + secretion by the principal cells of the late distal tubule and collecting ducts. Table 4-12 shows the factors that decrease K' secretion by the principal cells. Other than acidosis (which is probably not a factor, for the reason discussed earlier for K' shifts), nothing stands out as a possibility. In other words, decreased K- secretion does not seem to be contributing to David's hyperkalemia. In fact, there are reasons to believe that David had increased K- secretion, which brings us to the question of whether David's K' balance was positive, negative, or normal. TABLE 4-12 Changes in Distal K. Secretion Causes of Increased Distal K' Secretion Causes of Decreased Distal K' Secretion High-K' diet Hyperaldosteronism Alkalosis Thiazide diuretics Loop diuretics Lumina' anions Low-K' diet Hypoaldosteronism Acidosis K'-sparing diuretics (Reprinted with permission from Costanzo LS: FIRS Physiology, 3rd ed. Baltimore, Lippincott Williams & Wilkins, 2003, p 181.)

7 204 PHYSIOLOGY CASES AND PROBLEMS K+ balance refers to whether the renal excretion of K + exactly matches IC' intake. Perfect K+ balance occurs when excretion equals intake. If excretion is less than intake, K- balance is positive. If excretion is greater than intake, K- balance is negative. It is likely that David was in negative K+ balance for two reasons: (1) increased flow rate to the distal tubule (secondary to osmotic diuresis) and (2) hyperaldosteronism secondary to ECF volume contraction. Both increased urine flow rate and hyperaldosteronism increase K + secretion by the principal cells and may lead to negative K + balance. If you're feeling confused, join the crowd! Yes, hyperkalemia can coexist with negative K+ balance. While David had a net loss of IQ- in the urine (which caused negative K' balance), he simultaneously had a shift of K- from his cells (which caused hyperkalemia). In his case, the cellular shift "won" it had a larger overall effect on plasma I(' concentration. 9. The initial treatment with insulin and saline was intended to correct the insulin deficiency (which caused hyperglycemia, diabetic ketoacidosis, and hyperkalemia) and the volume contraction (which occurred secondary to osmotic diuresis). 10. Once the blood glucose and K- concentrations were in the normal range, glucose and IC' were added to the infusion to prevent David from becoming hypoglycemic and hypokalemic. Without the addition of glucose to the infusion, David would have become hypoglycemic as insulin shifted glucose into his cells. And, without the addition of K+ to the infusion, he would have become hypokalemic as insulin shifted K + into his cells. Remember, because David was in negative K+ balance, he needed exogenous K+ repletion. POW Key topics Acidemia Anion gap Baroreceptor mechanism Central chemoreceptors Control of breathing External K- balance Henderson-Hasselbalch equation Insulin Internal K* balance secretion K- shifts Ketoacids 43-OH butyric acid and acetoacetic acid) Kussmaul respiration Metabolic acidosis Principal cells Renin-angiotensin II-aldosterone system Respiratory compensation Type I diabetes mellitus Volume contraction, or extracellular volume contraction