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
Pulse rate
Respirations
90/40
130/min
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)
8 mEq/L (normal, 24 mEq/L)
HCO3
Ketones
(normal, none)
Arterial blood
P 02
112 mm Hg (normal, 100 mm Hg)
P co220 mm Hg (normal, 40 mm Hg)
7.22 (normal, 7.4)
pH
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.
Oj QUESTIONS
r
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?
RENAL AND ACID-BASE PHYSIOLOGY 199
5. 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?
200 PHYSIOLOGY CASES AND PROBLEMS
P Al
r
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
Respiratory
Compensation
Disorder
CO2 + H20
Metabolic
acidosis
,I, (respiratory
compensation)
Hyperventilation
Metabolic
alkalosis
T (respiratory
compensation)
Hypoventilation
<-> 11++ HCO3-
Renal
Compensation
Respiratory
acidosis
T excretion
T HCO 3- reabsorption
Respiratory
alkalosis
.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 = 6.1 + log HCO
co,
3-
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 CO2 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 Pc 02 (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
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 - 20.8 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 HCO3concentration 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 1
Unmeasured 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.)
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 HCO3- 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 HCO3was 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
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 4-11. 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
Causes of Shift of K' Into
Cells --> Hypokalemia
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
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
Low-K' diet
Hypoaldosteronism
Acidosis
K'-sparing diuretics
Thiazide diuretics
Loop diuretics
Lumina' anions
(Reprinted with permission from Costanzo LS:
2003, p 181.)
FIRS Physiology,
3rd ed. Baltimore, Lippincott Williams & Wilkins,
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