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Diabetes Research and Clinical Practice 34 (1996) 23-27

Acid-base and disturbances in patients with diabetic

Moses S. Elisaf, Agathoklis A. Tsatsoulis, Kostas P. Katopodis, Kostas C. Siamopoulos*

Department of Internal Medicine, University of Ioannina Medical School, GR 451 10 loannina, Greece

Received 2 April 1996; revised 22 July 1996; accepted 9 September 1996

Abstract

We undertook the present study to examine the acid-base and electrolyte disturbances in relation to hydration status in patients with (DKA). A total of 40 insulin-dependent diabetes mellitus patients (22 male, 18 female), aged 18-61 years with DKA admitted to our hospital during the last 2 years, were studied. The duration of diabetes averaged 9 + 2 years. In all casesa detailed investigation of the acid-base status and electrolyte parameters was performed. Twenty-one patients had a pure metabolic with an increased serum , seven had DKA combined with hyperchloremic , nine had DKA coexisting with metabolic , while three had DKA with a concurrent . Hydration status as evidenced by the ratio of urea/creatinine seems to play an important role in the development of mixed acid-base disorders (detected by changes in the ratios A anion gap/A (AAG/AHCO,) and sodium/chloride (Na/Cl)). In fact, hyper- chloremic acidosis developed in the patients with the better hydration status. However, contradictorily, the severely dehydrated patients who experienced recurrent episodes of developed DKA with a concurrent . Finally, patients with pneumonia or gram-negative septicemia exhibited DKA combined with a primary respiratory alkalosis. We conclude that patients with DKA commonly develop mixed acid-base disorders, which are partly dependent on patients’ hydration status.

Keywords: A anion gap/A bicarbonate (AAG/AHCO,) ratio; Diabetic ketoacidosis; Serum anion gap; Sodium/Chlo- ride concentration ratio (Na/Cl)

1. Introduction

Patients with diabetic ketoacidosis (DKA) com- * Corresponding author. Tel.: + 30 65 146728;fax: + 30 65 monly develop mixed acid-base disorders which 145944. are possible to be diagnosed only when a careful

016%8227/96/$15.000 1996 Elsevier Science Ireland Ltd. All rights reserved PII SO168-8227(96)01332-O 24 M.S. Elisqf’ et al. / Diabetes Research and Clinical Practice 34 (1996) 23-27

search of acid-base balance and electrolyte blood gasesmeasurement. SAG was computed as: parameters is performed [l-6]. It has been stated SAG = Nat - (Cl- + HCO,) [8]. A decrease in that hydration status can modify the appearance of serum bicarbonate (AHCO,) was calculated as the mixed acid-base disorders as well as the values of normal serum bicarbonate (24 mmol/l) minus the these parameters [4,6,7]. In the present paper, a measured serum bicarbonate. The excessanion gap careful approach of the acid-base and electrolyte (AAG) was estimated as the calculated anion gap abnormalities in relation to hydration status is minus the normal anion gap (12 mmol/l). attempted in patients with DKA. The diagnosis of pure DKA was established when no conditions that could have caused mixed acid-base disorders were present and the decrease 2. Material and methods in serum bicarbonate was approximately equal to the increase in serum anion gap (AAG/AHCO, We studied a total of 40 insulin-dependent dia- ratio between 0.8 and 1.2). The presence of mixed betes mellitus patients (22 male, 18 female) aged acid-base disorders was defined as follows: a hyper- 18-61 years with DKA, who were hospitalized chloremic acidosis component was diagnosed when during the last 2 years in our University Hospital the reduction in serum bicarbonate was signifi- (600 beds) This hospital is one of the two tetriary cantly greater than the increase in anion gap in the hospitals which care for the whole region of North- absence of respiratory alkalosis, resulting in a western Greece (0.5 million people). The duration AAG/AHCO, ratio less than 0.8. The coexistence of diabetes averaged 9 f 2 years (range 1- 17 of DKA with a primary metabolic alkalosis was years). The diagnosis of DKA was based on the present when the decrease in serum bicarbonate presenceof a high ( > 20 mmol/l) serum anion gap was significantly less than the increase in anion gap (SAG) metabolic acidosis with hyperglycemia resulting in a AAG/AHCO, ratio more than 1.2. (serum glucose more than 250 mg/dl) and was Finally, the combination of DKA with a primary confirmed by the demonstration of ketonemia, respiratory alkalosis was diagnosed when the mea- defined as serum acetest reaction of 4 + in a sured PCO, was less than that predicted by the dilution greater than 1:2. In 24 patients, insufficient formula of Albert et al [9] (expected arterial carbon insulin was the primary cause of ketoacidosis, dioxide tension = 1.5 (serum bicarbonate) + 8 &- while in the remaining 16 patients DKA was 2). ascribed to a superimposed infection of the urinary Hydration status was evaluated by the serum tract or the (11 patients), to acute primary urea/creatinine ratio, which has been suggested to trauma (2 patients), to severe emotional stress (2 be especially helpful in the evaluation of hypov- patients), and to acute myocardial infarction (1 olemic states, even though it is affected to some patient). Patients with chronic renal failure (serum degree by the rate of urea production. creatinine > 1.6 mg/dl after rehydration), liver The results were expressed as means _+SD. failure, hypoalbuminemia of any cause, chronic Statistical analysis was performed by one-way obstructive disease, , as well as analysis of variance (ANOVA) followed by stu- alcoholic patients, or patients consuming drugs dent’s t-test to assessdifferences between groups. affecting acid-base status and electrolyte parame- Linear regression analysis was performed for the ters, were excluded from the study. Fifty-one ran- correlation between parameters. Comparisons with domly selectedpatients aged 19-62 years who had P values less than 0.05 were considered statistically no conditions that could cause acid-base disorders significant. and were admitted for elective procedures were used as controls. In all casesadmission serum was available before treatment for the determination of 3. Results serum glucose, urea; creatinine, total proteins and (potassium, sodium, chloride, and bi- Laboratory parameters based on the type of carbonate). Arterial blood was also obtained for acid-base disturbances are shown in Table 1. Table 1 Laboratory parameters of patients and controls

Parameters Control population Pure DKA DKA + hyperchloremic DKA + metabolic DKA + respiratory P* (n = 51) (n = 21) acidosis (n = 7) alkalosis (n = 9) alkalosis (n = 3)

Serum glucose (mg/dl) 90 * 9 385 & 49 340 L- 44 408 & 62 376k44 Serum urea (mg/dl) 25 + 5 68 f 16 43& 12 88&11 66f 12 Serum creatinine (mg/dl) 1.1 +0.3 1.9 * 0.5 I .6 k 0.4 2.1 * 0.2 1.8 kO.4 Serum urea/creatinine 21 16 36i7 21 i 6 42 h 8 35 i 6 Total serum proteins (g/dl) 7.9 _+0.5 8.6 f 0.5 7.6 f 0.5 9.5 f 0.5 8.5 k 0.6 Serum potassium (mmol/L) 4.2 + 0.5 4.2 f 0.5 4.1 +0.6 3.5 & 0.6 4 * 0.5 Serum sodium (mmol/L) 140 + 4 141+9 141 f 8 137f7 139_+9 Serum chloride (mmol/L) 101+ 3 101 * 5 109+4 95 +6 105*5 Serum Na/Cl 1.4 &-0.02 1.4 f 0.03 1.29 + 0.07 1.5 f 0.06 1.34 * 0.03 Serum bicarbonate (mmol/L) 23.5 + 2 8&5 8&4 16*4 8+5 Serum anion gap (mmol/L) 12 + 2.4 3Ok6 24k4 25&4 26*4 AAGIAHCO, 1.Ol k 0.06 0.76 f 0.03 1.7 * 0.2 0.82 k 0.06 Arterial pH 7.39 & 0.02 7.22 f 0.08 7.20 + 0.06 7.28 k 0.05 7.30 i- 0.06 PCO, (mmHg) 39.5 + 2 23.5 + 6 22.5 k 5 26.5 + 4 16&8

Data: means k SD DKA: diabetic ketoacidosis * ANOVA 26 MS. Elisaj” et al. 1 Diabetes Research and Clinical Practice 34 (1996) 23-27

In 21 cases no evidence of mixed acid-base No correlation was found between SAG and disorders was found. In these patients, the serum urea or the ratio of urea/creatinine in the sodium/chloride concentration ratio (Na/Cl) was whole group of patients. However, a very good found to be within the range obtained in the control correlation was found between the ratio population (1.37- 1.44). Seven patients had DKA urea/creatinine and both the ratios AAG/AHCO, combined with hyperchloremic metabolic acidosis. (r = 0.72, P-c 0.001) and Na/Cl (Y= 0.68, In thesecases the ratio Na/Cl was found to be lower P < 0.001). Moreover, serum glucose levels were than 1.37 (the lowest value observed in the normal well correlated with serum urea (r = 0.31, controls). Compared with patients developing pure P < O.Ol), as well as with the ratio of DKA, the group of patients demonstrating DKA urea/creatinine (Y = 0.61, P < 0.001). combined with hyperchloremic metabolic acidosis In all patients the restoration of intravascular had significantly decreased serum glucose, urea, volume, the appropriate electrolyte management, creatinine, urea/creatinine, total proteins, and the insulin administration, and the treatment of the anion gap levels, as well as significantly increased precipitating conditions leading to DKA was serum chloride levels. In two out of these patients followed by the reversal of acid-base abnormalities a chronic diarrhea1 syndrome was present, while irrespective of the type of DKA. another patient had increased serum potassium levels. In this patient laboratory investigation after treatment of acidemia confirmed the diagnosis of 4. Discussion hyporeninemic hypoaldosteronism. Nine patients had DKA coexisting with metabolic alkalosis. In our study the positive correlation between These patients exhibited an increased Na/Cl ratio the ratio of urea/creatinine and both the ratios of higher than the upper normal limit (1.44). They also AAG/AHCO, and Na/Cl in the whole group of had significantly increased serum glucose, urea, patients suggeststhat the hydration status plays a creatinine, urea/creatinine, total proteins, prominent role in the development of mixed acid- bicarbonate, anion gap, arterial pH and PCO, base disorders, evidenced by changes in the ratios levels, as well as decreased serum potassium, AAGIAHCO, and Na/Cl. In fact, hyperchloremic sodium and chloride levels compared to patients acidosis occurred in patients with the better hy- with pure DKA or DKA combined with dration status. These patients can excrete ketones hyperchloremic metabolic acidosis. These patients in the urine so efficiently that the anion gap is experienced recurrent bouts of vomiting due to relatively normal before any therapy has been DKA. Finally, three patients had DKA coexisting instituted resulting in a low ( < 0.8) AAG/AHCO, with respiratory alkalosis. This small group of ratio [2,4,6,10]. This ketoacid loss, which tends to patients had significantly decreased serum Na/Cl, lower the anion gap, is responsible for the con- anion gap, AAGIAHCO, and PCO, levels, as well comitant hyperchloremic metabolic acidosis, as as increased serum chloride and arterial pH levels these ketoacid anions, if retained, could have been compared with patients exhibiting pure DKA. converted back into bicarbonate. In this setting, Primary was due to gram-negative is due to the retention of sodium septicemia (two patients) or to pneumonia (one chloride by the kidneys in an effort to preserve the patient). The last patient, who also exhibited extracellular volume. Moreover, the loss of the chronic obstructive lung disease,had a PCO, of 27 sodium salt of b-hydroxybutyrate and acetoac- mmHg, a value which is relatively high, possibly etate, together with water, leaves a fixed quantity owing to a concomitant of chloride to be distributed in a smaller volume, component. thereby increasing its concentration [2,4,6]. Fur- It should be mentioned that no difference in the thermore, diarrhea as well as hyporeninemic hy- frequency of the various forms of DKA was found poaldosteronism observed in some of these between younger ( < 40 years) and older ( > 40 patients could have contributed to the develop- years) patients. ment of hyperchloremic acidosis [ll]. On the MS. Elisaf et al. / Diabetes Research and Clinical Practice 34 (1996) 23-27 21

other hand, patients with DKA combined with Acknowledgements a metabolic alkalosis had the most severe degree of hypovolemia. The coexistent metabolic alka- We are indebted to C. Hatzigianni for her losis was due to vomiting, frequently complicat- assistance in the preparation of the manuscript. ing ketoacidosis, which raised the serum bicarbonate concentration (and therefore the ar- terial pH) without significantly affecting the an- References ion gap, thus leading to an increase in the AAG/AHCO, ratio [ 111. Moreover, hypovolemia 111Oster, J.R. and Epstein, M. (1984) Acid-base aspects of resulted from both vomiting and osmotic diure- ketoacidosis. Am. J. Nephrol. 4, 137-151. PI Oh, M.S., Carroll, H.J. and Uribarri, J. (1990) Mecha- sis and contributed to the pathogenesis of nism of normochloremic and hyperchloremic acidosis in metabolic alkalosis () [12]. diabetic ketoacidosis. . 54, l-6. Additionally, this group of patients had lower 131 Cronin, J.W., Kroop, S.F., Diamond, J. and Rolla, A.R. serum levels of potassium, sodium and chloride (1984) Alkalemia in diabetic ketoacidosis. Am. J. Med. compared with the other groups of DKA pa- 77, 192-194. 141 Adrogue, H.J., Wilson, H., Boyd, A.E. III, Suki, W.N. tients reflecting the greater volume and elec- and Eknoyan, G. (1982) Plasma acid-base patterns in trolytes losses observed. Finally, few patients diabetic ketoacidosis. N. Engl. J. Med. 307, 160331610. had DKA coexisting with a primary respiratory [51 Paulson, W.D. and Gadallah, M.F. (1993) Diagnosis of alkalosis due to primary hyperventilation. In mixed acid-base disorders in diabetic ketoacidosis. Am. J. these patients, the ratio AAG/AHCO, was de- Med. Sci. 306, 2955300. VI Adrogue, H.J., Eknoyan, G. and Suki, W.K. (1984) Dia- creased because the degree of reduction in betic ketoacidosis: role of the kidney in the acid-base serum bicarbonate was exaggerated by the addi- re-evaluated. Kidney Int. 25, 591-598. tive effects of accumulated acid (as reflected by 171 Paulson, W.D. (1986) Anion gap-bicarbonate relation in the AAG) and the metabolic compensation for diabetic ketoacidosis. Am. J. Med. 81, 9955 1000. PI Emmett, M. and Narins, R.G. (1977) Clinical use of the respiratory alkalosis [ 111. The observed worsen- anion gap. Medicine 56, 38-54. ing of hypocarbonatremia in the face of virtual [91 Albert, MS., Dell, R.B. and Winters, R.W. (1967) Quan- normalization of arterial pH emphasizes the fact titative displacement of acid-base equilibrium in that the serum bicarbonate concentration by it- metabolic acidosis. Ann. Intern. Med. 66, 312-322. self does not give enough information to appro- 1101Gambhn, G.T., Ashburn, R.W., Kemp, D.G. and Beuttel, evaluate acid-base disorders. S.C. (1986) Diabetic ketoacidosis presenting with a nor- priately mal anion gap. Am. J. Med. 80, 7588760. Furthermore, a decrease of the ratio Na/Cl was illI Goodkin, D.A., Krishna, G.G. and Narins, R.G. (1984) evident, due to respiratory alkalosis-induced hy- The role of the anion gap in detecting and managing perchloremia [ 131. mixed metabolic acid-base disorders. Clin. Endocrinol. Interestingly, a positive correlation between Metab. 13, 333-349. 1121Garella, S., Chang, B.S. and Kahon, S.I. (1975) Dilution serum glucose levels and the urea/creatinine ra- acidosis and contraction alkalosis: Review of a concept. tio was noticed in the whole group of patients Kidney Int. 8, 279-283. implying that the hydration status can influence v31 Gennari, F.J., Goldstein, M.B. and Schwartz, W.B. glucose control, since volume depletion tends to (1972) The nature of the renal adaptation to chronic increase hyperglycemia [7,14]. hypocapnia. J. Clin. Invest. 51, 1722-1730. 1141 Halperin, M.L., Goldstein, M.B., Bear, R.A. and Josse, In conclusion, patients with DKA commonly R.G. (1985) Diabetic . In: A.I. Arieff, R.A. De- develop mixed acid-base disorders, which are Fronzo (Eds.), Fluids, Electrolyte and Acid-base Disor- partly dependent on patients’ hydration status. ders, Churchill Livingstone, New York, pp. 9333967.