I

CLIN. CHEM, 31/2, 309-313 (1985)

Normal Anion Gap (Hyperchloremic) Acidosis

R. N. Walmsley and G. H. White
Hyperchloremic metabolic acidosis in which the anion gap is within normal limits is a common condition in the hospital population, and often presents a difficult diagnostic problem. We describe nine typical cases of this disorder and suggest a logical approach to its evaluation. A low plasma bicarbonate concentration represents, by definition, a metabolic acidosis, which may be primary or can be secondary to a respiratory alkalosis. Further division of metabolic acidoses into those with a high or a normal anion gap facilitates the etiological diagnosis of this disorder. An increased gap is associated with renal failure, ketoacidosis, lactic acidosis, and ingestion of various toxins (Table 1). Unlike an increased-anion-gap metabolic acidosis, the cause of which can usually be easily identified by inspection of the routine chemical results for plasma and the clinical picture, the etiological diagnosis of the normal-anion-gap type may in some cases require further laboratory investigations. Patients with the latter type of metabolic acidosis (a low bicarbonate concentration and a normal anion gap in plasma) may have either a primary respiratory alkalosis (with a secondary metabolic acidosis) or a primary metabolic acidosis, and the latter can be due to a variety of causes (Table 1). Here, we describe nine cases of normal anion gap acidosis recently encountered in our hospital. Some of the cases presented a diagnostic problem, and we suggest a simple investigative scheme that has proved helpful to us in evaluation of this biochemical abnormality. Note: A normal-anion-gap acidosis is often referred to as hyperchloremic metabolic acidosis, because so many patients with the disorder have hyperchloremia. However, the latter disturbance only occurs if the plasma sodium concentration is normal. If there is an associated hyponatremia, the chloride concentration may be normal or even low; thus, we prefer the term normal-anion-gap acidosis. The plasma anion gap (AG) in the following cases has been calculated from the concentrations of sodium, potassium, chloride, formula (1): and bicarbonate in plasma
+

Table 1. Causes of Metabolic Acidosis

High-anIon-gap metabolIc acldosls

Renal failure:acute, chronic Ketoacidosis Lactic acidosis:L-lactate,D-lactate

Drugs/toxins:

salicylate methanol

ethanol ethyleneglycol paraldehyde

Normal-anion-gap (hyperchloremlc) Hyperkalemic Early uremic acidosis
Obstructive uropathy

by the widely

used

metabolIc acidosis

AG, mmol/L

([Na]
-

mmolJL

([HC03]

[KI mmolIL) mmol/L + [Cl]

mmol/L)

Renal tubular acidosis type 4: mineralocorticoid deficiency primary, secondary

Case Presentation
Case 1
A 45-year-old malaise, nausea, headaches and
taking

tubule unresponsive
potassium-sparing diuretics

interstitial nephntis
lupus erythematosus

sicklecell anemia renal transplant

amyloidosis pseudohypoaldosteronism Ingestions/infusion: HCI, NH4CI, lysine-, arginine-HCI
Diabetic ketoacidosis: post-therapy

woman presented with a long history of and loss of energy. She also complained of rheumatism, for which she had been
preparations. are shown Her plasma electro-

lyte values

various analgesic on admission

in Table 2.
Reference Intervals

Table 2. Plasma Analyte Values In Case 1

Units Plasma

Hypokalemic

Renal tubularacidosis:type 1, type 2 Carbonic anhydraseinhibition: acetazolamide Acutediarrhea Urinediversions: ureterosigmoidostomy vesico-colic fistula
obstructed ileal bladder Post-hypocapnic acidosis

Na HC03 Urea

141
5.7 115 17 21 0.21 15

mmol/L
mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L

(132-144)
(3.2-4.8)

Clinical Biochemistry, Flinders Medical Centre, Bedford Park, South Australia 5042.
Received August 10,1984; accepted November 5, 1984.

Creatinine Anion gap Blood gases (7.35-7.45) 7.29 pH (35-45) mmHg 37 Pco2 In the tablesthat follow, the units and referenceintervals are as above.

(98-108) (23-33) (3.0-8.0) (0.06-0.12) (7-17)

CLINICALCHEMISTRY,Vol. 31, No. 2, 1985 309

The urinary pH on admission was 4.5, her creatinine clearance 26 mL/min (reference interval 90-130 mL/min). Final diagnosis: Chronic renal insufficiency owing to
analgesic nephropathy, Comnient: A characteristic biochemical feature of ad-

vanced renal failure is a high-anion-gap metabolic acidosis consequent to tubular dysfunction (retention of H f) and decreased glomerular filtration rate (retention of acid anions). However, H is not retained by the kidneys in uncomplicated renal insufficiency until late in the disease process, and usually not before the glomerular filtration rate (GFR) declines to less than about 20 mL/min (2) or the plasma creatinine concentration increases above about 0.35 mmol/L (--4.0 mg/dL). In diseases that predominantly affect the renal medulla such as interstitial nephritis, pyelonephritis, cystic disease,
and analgesic nephropathy, distal nephron function is compromised early in the disease process. In these cases H excretion may be sufficiently decreased as to result in a metabolic acidosis long before the diminishing glomerular function is decreased enough to produce a plasma creatinine concentration >0.35 mmolIL. Indeed, there is often sufficient glomerular function to clear the plasma of endogenously produced acid anions (phosphate, sulfate, etc.) normally and thus result in a normal-anion-gap metabolic acidosis.

high (e.g., >0.35 mmol/L), indicating a severe drop in the GFR, they often have a normal plasma anion gap, which suggests adequate clearance of plasma acid anions. In severe prolonged obstruction, however, the plasma anion gap is usually increased and may be associated with a
quite normal-or occasionally a high-chloride concentration in plasma. This plasma electrolyte disorder has been termed a mixed hyperchloremic high-anion-gap metabolic acidosis (5). As shown in the above case the abnormal plasma biochemistry of obstructive uropathy usually starts to resolve

when the obstruction weeks to normalize.

is relieved,

but may take

several

Case 3 A 67-year-old man was admitted to hospital for investigation of general malaise and hyperkalemia (plasma [KJ of 7,0 mmolIL), which was noted on a biochemical screen. The values at admission for plasma are shown in Table 4. A plasma cortisol value before adrenocortical stimulation was 229 nmol/L (reference interval 170-690); 30 mm after stimulation with Synacthen it was 224 nmolJL (normal response is a rise exceeding 200 nmoltL over basal level). Final diagnosis: Primary adrenal failure (Addisons disease). Comment: The mineralocorticoid aldosterone not only increases reabsorption of Na + and secretion of K by the distal renal tubule, it is also associated with W secretion in this portion of the nephron (6). Aldosterone increases H secretion (and excretion) by the following mechanisms: (a) increases conductance of protons by the distal nephron (mainly collecting-duct) cell proton pump; (b) increases the negative potential in the tubular lumen, necessary for efficient secretion of H and K, by increasing Na reabsorption; and (c) increases ammonia synthesis directly, and
also indirectly by increasing K excretion (hypokalemia is a potent stimulus for ammonia synthesis). Hypoaldosteronism is therefore associated with renal retention of both H and K and can result in hyperkalemic metabolic acidosis. The GFR in hypoaldosteronism may be decreased to some extent, owing to dehydration secondary to sodium depletion, but it is usually sufficient to clear the plasma of the endogenous acid anions; thus the metabolic acidosis of primary adrenal failure is usually of the normal-anion-gap

Potassium homeostasis in progressive renal failure follows a similar pattern to that of H i.e., K retention tends not to occur until the GFR falls below about 20 mL/min, and so hyperkalemia is rare in renal failure patients with a plasma creatinine concentration <0.35 mmol/L. Hyperkalemia at creatinine concentrations less than this suggests either severe tubular damage or other disorders of potassium homeostasis such as hyporeninemic hypoaldosteronism, potassium-sparing diuretics, and the like (3).
,

Case 2
An 80-year-old man presented with intermittent urinary obstruction secondary to benign prostatic hypertrophy. Table 3 shows the plasma analyte values on admission, one day later, and seven days later. Final diagnosis: Obstructive uropathy. Comment: The occurrence of hyperkalemic normal-aniongap (hyperchloremic) metabolic acidosis in obstructive uropathy has been well documented (3). The exact mechanism of the K4 and H4 retention is yet to be clarified, but is most likely to be associated with distal nephron dysfunction due to back-pressure of the urine. In a recent study (4) it was shown that some of these patients had hypoaldosteronism (etiology uncertain), others had evidence of a distal renal tubular lesion similar to that of classical distal renal tubular acidosis, and still others had a combination of these two conditions. A curious feature of many patients with this disorder is that, although the plasma creatinine concentration may be

variety.
Although these patientshave a defectin the renal excre-

tion of IF , they still nism and are thus decrease the urinary i.e., hyperkalemic with the ability to been termed type 4

have an intact proton-secreting mechaable to secrete sufficient H so as to pH to <5.3. This type of renal acidosis, normal-anion-gap acidosis associated acidifr the urine to below pH 5.3, has
renal tubular acidosis (7).

Table 3. Plasma Analyte Values in Case 2

AdmIssion Plasma Na K
137

+1 day
142

Table 4. Plasma and Urinary Analyte Values in Case3

days
Plasma Na 127

135

K
Cl HC03 Urea
Creatinine

CI
HCO3

Urea

5.4 111 19 20.7

0.61

5.0 114 18 15.5

0.29

4.8 103 24
9.0

74 100
19 18.7
0.22

Creatinine
Anion gap Blood gases pH Pco2

12 7.33 36

15

0.15 13
-

Anion gap Blood gases pH

PCO2

15 7.36
4.7

-.

Urinary pH

310

CLINICAL CHEMISTRY, Vol. 31, No. 2, 1985

Case 4
A man, 38 years of age, was having
suction persistent because of a small-bowel obstruction

Table 6. Plasma Analyte Values In Case 5

continuous
related gastric to acute Seti Plasma Set2

pancreatitis.

juice resulted in a severe alkalosis (first set of values, Table 5), which was difficult to control. To relieve this alkalosis he was given an infusion of HC1 (set 2, Table 5), which unfortunately was made 1.0 mol/L rather than 0.1 mol/L. Comment: Infusion (or ingestion) of HC1 or compounds that are metabolized to HC1 (e.g., NH4C1, arginine HC1, and lysine HC1), if given in sufficient quantities will result in a hyperchloremic metabolic acidosis, i.e., consumption of extracellular HCO by H and its replacement by C. Acidemia affects potassium metabolism in two ways: (a) it releases intracellular potassium ions, which are exchanged for extracellular hydrogen ions, and this can result in hyperkalemia; and (b) it increases renal potassium excretion, which can result in potassium depletion. The acidemia-induced release of cellular potassium depends on the nature of the acid anions. If the anion is C1 (e.g., hyperchloremic acidosis) H is exchanged across the cell membrane for K because C1 is not easily taken up by cells. On the other hand, if the acid anions are organic in nature (e.g., lactate or acetate) the hydrogen ions are taken up by the cell in association with their corresponding anions, which readily cross cell membranes, and there is no extracellular movement of potassium ions (3). Thus hyperkalemia can be associated with HC1-induced acidemia, but is unusual with organic acid-induced acidemia. In the early stages of acidemia (metabolic or respiratory) there is decreased renal K excretion, possibly because of a decreased cell concentration of this ion (exchange with extracellular H) in the renal tubular cell. However, in prolonged acidemia there is increased renal potassium excretion, owing to increased distal renal tubular flow rate. This increased flow rate results from decreased reabsorption of Na in the proximal renal tubule (8).
hypokalemic metabolic

The loss of gastric

Na
CL

130
5.3 110 4 6.0

129
4.9

114
6 3.7

HC03
Urea

Creatinine Anion gap Glucose

Blood gases

0.18
21

0.16
14

19.2
7.03 15

13.Oa
7.10 20

pH
Pco2
Ref. interval 3.0-5.5 mmol/L.

If the patient is severely dehydrated there is avid proximal renal tubular reabsorption of sodium ions. This encourages-in the interest of electroneutrality-reabsorption of keto-anions and thus maintenance of the high anion gap in plasma. During therapy with saline and insulin there is retention of NaCl so that the expanding extracellular volume decreases the proximal tubule reabsorption of sodium and keto-anions, which are then lost in the urine. In summary, Na and keto-anions are lost from the body and replaced with Na and Cl, resulting in hyperchloremia. Recovery from this type of acidosis is slower than from the high-anion-gap variety, because in the latter situation the retained keto-anions are taken up by the cells along with H, under the influence of insulin, resulting in the generation of extracellular bicarbonate. In the former case, because the keto-anions are lost in the urine, bicarbonate can be generated only by the kidney. This can take considerable time, and the patient will often require intravenous bicarbonate supplementation in order to normalize his acid-base status (9).

Case 6
The first set of values shown in Table 7 were those for a 70-year-old man with a vesico-colic fistula secondary to an adenocarcinoma of the colon. Comment: When urine is diverted into the large gut (ureterosigmoidostomy, vesico-colic fistula), and remains in prolonged contact with the mucosae, there is reabsorption of water and chloride and secretion of bicarbonate and potassium (10). The result is a hypokalemic normal-anion-gap metabolic acidosis. The ureterosigmoidostomy procedure is rarely performed these days; rather, the ureters, if they require diversion, are implanted into an exteriorized ileal loop. Obstruction of this ileal bladder will also result in biochemical abnormalities similar to those in case 6.

Case 5
The clinical chemical results for plasma shown in Table 6 are those of a 36-year-old female diabetic. The first set of results are the admission values; the second set are those after 8 h of intravenous therapy, which included saline, insulin (-2 mt. units per hour), and potassium supplements. Comment: Diabetic ketoacidosis usually presents with a high-anion-gap metabolic acidosis, the increased gap being ascribable to the anions acetoacetate and hydroxybutyrate (ketone bodies). Occasionally this disorder may present with a normal-anion-gap (hyperchloremic) metabolic acidosis, and this type of acidosis may also occur during therapy with fluids and insulin. The mechanism of the hyperchloremia is related to the patients hydration status, in particular to the reabsorption of sodium in the proximal renal tubule.

Case 7
A woman, 66 years old, was treated with oral mide (250 mg twice daily) and epinephrine eye acute glaucoma. Blood sampled three days later showed a hypokalemic normal-anion-gap metabolic acetazoladrops for (Table 7) acidosis.

Table 5. Plasma Analyte Values in Case 4

Sefl Plasma Na C1 151 2.8 92 52 7.5 2 152 6.0 134 12
12.9

Comment: Acetazolamide inhibits carbonate dehydratase (EC 4.2.1.1) activity both within the proximal renal tubular

HCO Urea Creatinine Anion gap

Blood gases

0.14
10 7.56 59

0.18 12
7.18

cell and at its brush border. This has the effect of suppressH secretion. Thus reabsorption of HCO is inhibited and it is lost in the urine as NaHCO3 (10). The consequent hypovolemia (sodium depletion) causes increased renal tubular reabsorption of Na and Cl and this results in a hyperchloremic metabolic acidosis-i.e., Na and HCO are lost in the urine and replaced in the extracellular fluid by
ing

pH Pco,

NaCl (dietaryNaCl and that reabsorbed by the kidney). This acidosis, which is similar in nature to primary proximal renal tubular acidosis, is self-limiting: when the CLINICALCHEMISTRY,Vol. 31, No. 2, 1985 311

plasma bicarbonate declines to a certain concentration (-14-15 mmollL) the tubules can then reabsorb all that is presented by the glomeruli. Distal tubular function remains intact in these cases, and if the patient is challenged by an acid load (e.g., NH4C1) he is able to acidify his urine to below pH 5.3 (cf. Case 9). The hypokalemia seen in these patients is attributable to increased renal potassium loss consequent to the increased distal renal tubular urine flow rate induced by the high load of NaHCO3 in the tubules. Case 8 A 44-year-old man presented with a two-day history of acute severe diarrhea. He was moderately dehydrated and had a hypokalemic normal-anion-gap metabolic acidosis (Table 7). Comment: During acute diarrhea there is loss of water, sodium, bicarbonate, and potassium in the fecalfluid. This resultsin (a)dehydration and contraction of the extracellular fluid around the remaining sodium and chloride producing hyperchloremia, (b) hypobicarbonatemia (metabolic acidosis), and (c) potassium depletion. The dehydration (hypovolemia) also results in increased renal reabsorption of NaCI and retention of any NaCl ingested (the sodium lost as NaHCO3 in the diarrhea fluid is replaced by NaC1 and this further accentuates the hyperchloremia) and in secondary hyperaldosteronism, which increases K excretion by the kidney and thus worsens the potassium depletion. Patients with HC03 depletion due to diarrhea are able to replete it in their plasma only by renal generation of new bicarbonate. This may take several days, and thus such patients will usually require intravenous therapy with bicarbonate if their acidosis is severe.

NaCl). Thus hyperchioremia develops in associationwith the abnormal plasma bicarbonate concentration.

Patients with this type of renal tubular acidosis, unlike those with the proximal-tubular variety, are unable to maintain a high hydrogen ion gradient across the renal tubule cell membranes and therefore will not be able to lower their urinary pH to <5.3 when made acidemic by ingestion of NH4C1 (cf Case 7). The hypokalemia in the above patient reflects potassium depletion due to loss of this ion in the urine as a result of increased renal distal tubular urine flow rate (sodium diuresis) and secondary hyperaldosteromsm consequent to hypovolemia.

Discussion
A low plasma bicarbonate concentration (metabolic acidosis) is common in the hospital population-it is found in about 8% of patients in our institution-and is due to either primary respiratory alkalosis (thus a compensatory metabolic acidosis) or primary metabolic acidosis. The former is the commoner cause (11). In most cases the etiology is clearly apparent from the patients clinical presentation or from the patients other clinical chemical values for plasma. Yet in some instances the low bicarbonate concentration in plasma may be unexpected, with no clinical indications of the cause. In these cases the evaluation of the abnormality can be approached in the manner suggested in Figure 1 and Table 1. The values for routine plasma biochemistry-Na , K, Cl, HC03, creatinine, and glucose-usually provide sufficient information for a diagnosis to be made, or at least to narrow the possibilities (Figure 1). What further laboratory investigations are done will depend on the results of these
tests, considered together with the clinical picture.

Case 9
A 60-year-old man was admitted to hospital with a fourweek history of increasing muscle weakness and lethargy. His plasma and urinary biochemistry values (Table 7) suggested a distal renal tubular acidosis, which was later confirmed by further investigations. Comment: In classical distal renal tubular acidosis there is an inability of the distal nephron (mainly the collecting ducts) to secrete H; thus regeneration of the HC03 consumed during the normal buffering of endogenously produced acids does not occur and hypobicarbonatemia results (7). The decreased renal tubular H secretion also induces increased renal sodium loss (decreased Na-H exchange), which will result in water loss and hypovolemia. The hypovolemia causes increased NaCl reabsorption in the proximal nephron (as well as retention of any ingested

Table 7. Plasma Analyte Values in Cases 6-9

Case Plasma Na K*
CL

6
145

7
139

8
134

9 137

2.9
126 13

2.8
112

2.9
113

1.7

120
11 8.4
0.18

HC03 Urea
Creatinine

Anion gap
Blood gases
pH

13.6 0.09 9
7.31

19 6.5
0.11

16 12.3
0.30

11
7.31

8
7.31

8
7.21

Pco UrMe Na K pH

26
-

38
5.7

33
4.4

27
42 mmoIfL 24 mmol/L 7.0

to the preceding routine laboratory tests the most useful tests for further evaluating these patients are blood gases, plasma lactate concentrations, plasma ketone bodies (qualitative or quantitative), a urinary acidification test (e.g., ammonium chloride loading), and tests to evaluate mineralocorticoid status (e.g., assay of cortisol, aldosterone, and/or renin activity in plasma). Blood gases: All patients with a low plasma bicarbonate in whom the diagnosis is equivocal, or the hypobicarbonatemia is severe (e.g., <15 mmolIL), should have an estimation of their blood-gas values, to define the blood H activity and the severity of the disorder. A metabolic acidosis secondary to respiratory alkalosis (low blood pco2) is characterized by alklemia (pH >7.45; [HJ <35 nmollL). However, patients with chronic respiratory alkalosis can fully compensate by lowering their plasma [HCO3I so much that the blood pH becomes normal. This is the only acid-base disorder for which the body can completely compensate (10). Primary metabolic acidosis never shows complete compensation and thus always presents with an acidemia (pH <735; [HI >45 nmollL). However, mixed acid-base disturbances are not unusual, and a low plasma bicarbonate concentration associated with a low Pco, and a normal pH (7.35-7.45) may indicate a mixed metabolic acidosis and respiratory alkalosis (e.g., salicylate intoxication) as well as a chronic respiratory alkalosis (5). The distinction between these two disorders can only be made on clinical grounds, or after commencing treatment of one or other of the disorders. The blood po2 value is a useful but unreliable indicator of tissue oxygenation. Adequate evaluation requires a measure of hemoglobin oxygen saturation; a low value suggests anoxia and may indicate the possibility of lactic acidosis due to tissue hypoxia. As a rule of thumb, anoxia sufficient to produce an increase in the blood lactate concentration is rarely associated with a blood Po, exceeding 50 mmHg (12). In addition

312

CLINICAL

CHEMISTRY,

Vol. 31, No. 2, 1985

+ PLASMA IHCOI

$ pH

ANION GAP

ii
EXCLUDE
Respiratory

Renal failure Ketoacidosis Lactic acidosis Ingestions (Table 1)

I
$

alkalosis

(clinical + blood gases)

PLASMA

IKI

N-.-4

acidification test: The definitive diagnosis of tubular acidosis requires investigation of the renal response to acidemia, e.g., estimation of H and ammonium ion excretion after an ammonium chloride load. However, if the patient is already acidemic (pH <7.35) an estimation of the urinary pH suffices to categorize the disorder. A pH >5.3 indicates classical distal renal tubular acidosis (type 1). A pH <5.3 may be associated with type 2 renal tubular acidosis, or type 4, or the acidosis of renal insufficiency (7); it excludes type 1. Mineralocorticoid status: A hyperkalemic normal-aniongap acidosis in the absence of moderate to severe renal insufficiency and ingestion of HC1-producing substances indicates a type 4 renal tubular acidosis (7). This may be due to primary adrenal failure, selective deficiency of aldosterone synthesis, or renal tubular unresponsiveness to aldosterone. Full investigation of these disorders may require evaluation of cortisol status, aldosterone status, and plasma renin activity. These disorders, and their investigation, are discussed in detail elsewhere (6, 7, 13). Urinary

renal

Early uremic acidosis

Obstructive uropathy

EXCLUDE Vesico-colic fistula

References
Brackett NC, Cohen JJ, Schwartz WR. Carbon dioxide titration curve of normal man: Effect of increasing degrees of acute hypercapala on acid-base equilibrium. N Engi J Med 272, 6-12 (1965). 2. Narins RG. The renal acidoses. In Contemporary Issues in Nephrology: Acid-Base and Potassium Homeostasis, BM Brenner, JH Stein, Eds., Churchill Livingstone, New York, NY, 1978, pp 3060. 3. DeFronzo RA, Bia M, Smith D. Clinical disorders of hyperkalemia. Ann Rev Med 33, 521-554 (1982). 4. Batlle DC, Arruda JAL, Kurtzman NA. Hyperkalemic distal
1.

Diabetic ketoacidosis Mineralocorticoid deficiency Ingestions/infusions (Table 2)

F <5.3

Ureterosigmoidostomy Obstructed ileal bladder

URINE pH during acidemia

>5.3 Proximal RTA Acute diarrhea Post-hypocapnic Carbonic anhydrase acidosis inhibition Distal RTA

renal tubular acidosis associated with obstructive uropathy. NEngi J Med 304, 373-380 (1981). 5. Narins RG, Emmett M. Simple and mixed acid-base disorders: A practical approach. Medicine 59, 161-187 (1980). 6. Bathe DC, Kurtzman NA. Syndromes of aldosterone deficiency and excess. Med Clin North Am 67, 879-902 (1983). 7. Sebastian A, Morris RC. Renal tubular acidosis. Gun Nephrol 7,

216-230 (1977). 8. Gennari FJ, Cohen JJ. Role of the kidney in potassium homeostasis: Lessons from acid-base disturbances. Kidney ml 8, 1-S
(1975).

Figure 1. Suggested scheme for the evaluation of a normal anion gap

metabolic acidosis RTA:renaltubular acidosis

Plasma lactate and ketones: In the absence of severe renal failure (plasma creatinine concentration >0.4 mmol/L) a

high-anion-gap acidosis indicates ketoacidosis, lactic acidosis, or an acidosis due to ingestion of some toxin (Table 1). Estimation of plasma lactate or kethnes, or both, aids in evaluation of these cases if the pathophysiology is unclear.

lid, Wilson H, Boyd A, etal. Plasma acid-base patterns ketoacidosis. N Engi J Med 307, 1603-1610 (1982). RG, Gardner LB. Simple acid-base disturbances. Med Am 65, 321-346 (1981). 11. Mazzara JT, Ayres SM, Grace WJ. Extreme hypocapnia inthe critically ill patient. Am J Med 56, 450-456 (1974). 12. McCurdy DK. Mixed metabolic and respiratory acid-base disturbances: Diagnosis and treatment. Chest 62, 35S-44S (1972). 13. Bathe DC. Hyperkalemic hyperchloremic metabolic acidosis associated with selective aldosterone deficiency and distal renal tubular acidosis. Semin Nephrol 1, 260-273 (1981). 9. Adrogue in diabetic 10. Narins Clin North

CLINICAL

CHEMISTRY,

Vol. 31, No. 2, 1985

313