STUDIES ON EXPERIMENTAL AND CLINICAL HYPOCHLOREMIA IN MAN

Joseph B. Kirsner, … , Walter Lincoln Palmer, Kathryn Knowlton

J Clin Invest. 1943;22(1):95-102. https://doi.org/10.1172/JCI101373.

Research Article

Find the latest version: https://jci.me/101373/pdf STUDIES ON EXPERIMENTAL AND CLINICAL HYPOCHLOREMIA IN MAN1 By JOSEPH B. KIRSNER, WALTER LINCOLN PALMER, AND KATHRYN KNOWLTON (From the Frank Billings Clinic, Department of Medicine, University of Chicago, Chicago) (Received for publication July 21, 1942)

INTRODUCTION base was measured by a modification of the Stadie-Ross technique (13); the serum was ashed as for the In a recent study (1), it was demonstrated that analysis; the ash was taken up in 45 cc. of water, the severe hypochloremia and could be in- bases precipitated with benzidine hydrochloride, and the duced gradually in the dog, by means of continued difference between the titration of the acidity of this loss of chloride, without the development of a filtrate and that of the original reagents used as a meas- ure of the total base. marked azotemia or detectable renal injury. The patients' body weights were checked frequently. Kerpel-Fronius (2), Kerpel-Fronius and Butler The fluid intake and output were recorded daily. The (3), Ambard (4), and Hiatt (5) had previously pH of the urine was determined with a Beckman pH made similar observations in the dog and rabbit. itheter; the chloride content of the urine was measured The purpose of the present investigation was to by the Van Slyke-Sendroy method (14); and the am- monia plus ammonium salts determined by the technique determine whether or not the same situation could of Henriques and S6rensen (15). The volume, pH, and be induced in man. chloride content of the aspirated gastric secretions were measured similarly. METHOD OF STUDY Aspiration of the stomach was discontinued after a severe but safely obtainable state of chloride depletion I. Experimental hypochloremia had been achieved. The body chloride was then replaced Chloride deprivation was produced rather slowly by gradually in case M. S., over a period of 26 days, by the Wangensteen aspiration of the gastric contents, for vary- addition of increasing amounts of salt. The body chlo- ing lengths of time in 2 adult men (Cages M. S. and ride was replaced more rapidly in case W. L. (within 6 W. L.) with pyloric obstruction secondary to duodenal days) by the parenteral administration of saline solution. ulcer. The patients received no food or fluid by mouth during II. Hypochloremia incidental to ulcer therapy the period of chloride withdrawal; 3000 to 4500 cc. of 5 The problem was in 10 per cent glucose in distilled water were administered studied further patients with intravenously each day. The serum chloride, carbon alkalosis and chloropenia complicating the treatment of peptic ulcer. While two factors were operative in this dioxide, pH, and blood urea nitrogen were measured fre- latter quently (6). Renal function in case M. S. was deter- group, i.e., chloride loss and alkali ingestion, these mined by the urea clearance test cases are included because of the absence of nitrogen (7). Measurements retention and because the evidence indicated that the were made also of the serum calcium (8), phosphorus if (9), and (10). The cell volume was deter- major, indeed, not the only, factor in the acid-base mined frequently by hematocrit readings. The plasma disturbance was the hypochloremia. proteins were determined by the Hanna-Campbell method (11), a modified macro-Kjeldahl technique being em- RESULTS ployed for the nitrogen analysis; 4 per cent boric acid I. Experimental hypochloremia was used to absorb the ammonia released. The blood sodium was measured by a modification of the Butler- Case M. S. (Unit no. 204878 (Figures 1 and Tuthill method (12); the phosphate of the serum was 2). A 38-year-old salesman had taken alkalis removed by ignition with ferric sulfate and the sodium intermittently for 5 years for the relief of symp- determined on an aliquot from which the insoluble iron a salt had been removed by centrifugation. The urinary toms from stenosing duodenal ulcer. He had sodium was determined in case M. S. by the same tech- been for 5 days prior to hospitalization. nique as that used for the serum sodium, modified as to Five per cent glucose in both normal saline and the volume used; ferric salt was added in amounts suf- distilled water was administered intravenously ficient to prevent interference by phosphates. The total during the first 4 days. Continuous Wangensteen 'This study was supported in part by a grant from aspiration of the gastric contents was begun on John Wyeth and Bro., Inc., Philadelphia, Pennsylvania. the 5th day and continued for 96 hours. The 95 96 JOSEPH B. KIRSNER, WALTER LINCOLN PALMER, AND KATHRYN KNOWLTON

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FIG. 1. EXPERIMENT 1. THE EFFECT OF A GRADUALLY INDUCED HYPOCHLOREMIA ON THE SERUM ELECTROLYTES IN MAN gastric contents removed each day were acid, the hospital on the 39th day, at which time the pa- pH ranging from 1.84 to 2.70; the amounts varied tient was receiving 3.7 grams of chloride daily. daily from 1100 to 3090 cc. Wangensteen suction This amount was increased to 5.3 grams daily one was then limited to a period of 10 hours daily, week later, and the chloride intake was main- the amounts withdrawn ranging from 440 to 1200 tained at this level until the experiment had been cc. The intravenous intake of fluid during the concluded. period of gastric aspiration consisted of 5 per cent The lowest serum chloride of 53.8 mM./L. was glucose in distilled water, except for 1500 cc. nor- obtained on the 11th day. The maximum blood mal saline given on the 12th day. This repre- urea nitrogen of 30 mgm. per cent was obtained sented the only chloride (8.1 grams) taken by the at a time when the serum chloride measured 63.6 patient during the interval from the 4th to the mM./L.; the values ranged usually from 14.2 to 16th hospital days. The salt intake was then in- 19.6 mgm. per cent. The blood sodium decreased creased very gradually until discharge from the to 115.2 m.eq./L. and the total base to 133.3 EXPERIMENTAL AND CLINICAL HYPOCHLOREMIA 97 m.eq./L. The serum calcium and potassium were on 5 days. Sodium excretion paralleled the values normal. The urea clearance was not lowered sig- found for chloride ion. Ammonia excretion in nificantly. The patient lost 23 pounds in weight; the urine, as was to be expected, was diminished. the presence of dehydration was further indicated A histamine test performed on the 19th day by the increased hematocrit readings and the high (serum chloride between 65.5 and 68.8 mM./L.) plasma protein values. revealed normal gastric secretion; the pH of the The serum electrolytes, hematocrit, and plasma various samples of gastric juice ranged from 1.31 proteins gradually returned to normal during the to 1.71. An examination of the spinal fluid on period of chloride replacement. The blood urea the 25th day (serum chloride between 68.5 and nitrogen ranged from 8.1 to 14.3 mgm. per cent. 78.8 mM./L.) revealed a clear fluid under normal At the conclusion of the experiment, the patient's pressure. The chloride measured 100.4 mM./L. body weight had returned to its original level. and the total base 141.5 mM./L. (both values mod- The daily volume of urine varied from 775 to 1920 erately reduced). The calcium was 4.8 mgm. per cc., usually exceeding 1000 cc.; the pH ranged cent and the urea nitrogen 16.7 mgm. per cent from 5.9 to 6.85. Its chloride content was mark- (both values normal). edly reduced; no chloride was found in the urine The patient was very weak and listless during

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FIG. 2. EXPERMENT 1. ADDITIONAL DATA. HYPOCHLOREMIA IN MAN 98 JOSEPH B. KIRSNER, WALTER LINCOLN PALMER, AND KATHRYN KNOWLTON

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I I . I I I . I f 26 31 5 10 15 20 25 30 DEC. JAN FIG. 3. EXPERIMENT 2. THE EFFECT OF A GRADUALLY INDUCED HYPOCHLOREMIA ON THE SERUM ELECTROLYTES IN MAN the period of chloride depletion. He had no appe- marked pyloric obstruction. Therapy consisted of tite and complained of a loss of the sense of taste. Wangensteen aspiration of the gastric contents, Mild muscular twitchings appeared on the 12th day 3 blood transfusions, and, for the first week, 1500 (serum chloride 53.8 mM./L.) at which time the to 3000 cc. of 5 per cent glucose in normal saline patient received the 1500 cc. normal saline intra- each day. On the 8th day and for the next 5 venously, as noted above. The blood pressure, days, the patient received 5 per cent glucose in originally 130/95, decreased during the period of distilled water. An average of 1860 cc. of gastric hypochloremia; the systolic values ranged from contents were aspirated daily; the pH of the as- 90 to 110 and the diastolic from 60 to .72. The pirates ranged from 1.94 to 2.58. Wangensteen blood pressure at the completion of the experiment suction then was discontinued; the patient, how- was 126/84. The patient's clinical course during ever, vomited large amounts of gastric contents on the period of gradual chloride replacement was several occasions. Saline therapy was resumed on characterized by a steady gain in strength and the 14th hospital day and the patient was given improvement in appetite. from 3000 to 4500 cc. of 5 per cent glucose in Case W. L. (Unit no. 254018) (Figures 3 and normal saline and distilled water daily. Aspira- 4). A 39-year-old male had experienced ulcer tion of the stomach was resumed on the 20th day symptoms for several years. He entered the hos- but the electrolyte loss now was replaced by the pital because of a recent massive hemorrhage and use of parenteral fluids. EXPERIMENTAL AND CLINICAL HYPOCHLOREMIA 99

The serum chloride decreased to 58.9 mM./L. the pH ranged from 6.41 to 7.48. The chloride The maximum blood urea nitrogen was 23.1 mgm. content of the urine was markedly reduced. per cent, with the values ranging usually frqm The patient gradually became very weak and 13.1 to 21.2 mgm. per cent. The lowest blood listless during the period of chloride depletion. sodium was 129.2 m.eq./L., obtained on the day His blood pressure, originally 125/92, decreased of the lowest serum chloride. The serum cal- slightly; the systolic ranged from 90 to 116 and cium, phosphorus, and potassium were normal. the diastolic, from 68 to 90. These manifesta- Adequate urea clearance studies were not obtained tions disappeared rapidly, however, as the acid- in this case. The patient lost 8 pounds in weight. base balance was restored. The plasma protein and hematocrit values were Comment. The maximum blood urea nitrogen elevated. The volume of urine varied from 660 values of 30.0 and 23.3 mgm. per cent noted in to 4000 cc. daily, usually approximating 3000 cc.; these 2 cases are in sharp contrast to the severe

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FIG. 4. EXPERIMENT 2. ADDITIONAL DATA. HYPOCHLOREMIA IN MAN 100 JOSEPH B. KISNER, WALTER LINCOLN PALMER, AND KATHRYN KNOWLTON nitrogen retention observed by other workers in of Kerpel-Fronius (2) and Kerpel-Fronius and patients with hypochloremia and alkalosis sec- Butler (3). Dehydration was present in both pa- ondary to pyloric obstruction, or during experi- tients as evidenced by the significant weight loss mental salt deficiency produced by diet and sweat- and the high hematocrit and plasma protein values. ing (16), but are in agreement with the findings Since large quantities of glucose in distilled

TABLE I HypochJoremia withot asotemia during alkalosis (10 Patients)

Add-base balance Gaspiration

Cage | Semm CO pH | BuN Urea Day of treatment Therapy Sex-Age Serm Se pHmclearance Average Num- p daily ber of ci cot amount days

mM./L. mM./L. e man.cc. J. S. 65.9 38.0 7.52 18.4 90 2nd 622 4 Calcium carbonate; parenteral 264531 92.1 32.0 7.47 3rd fluids; gastroenterostomy on 8th M-26 92.2 35.1 7.56 16.9 110 5th day. J. C. 79.0 38.6 7.62 21.2 113 4th 393 11 Sippy powders; NaCI (4 to 6 185870 67.6 38.2 7.63 14.6 200 7th grams) started on 6th day. M-29 85.2 32.4 7.50 8.8 91 D. H. 98.4 26.3 7.47 3rd 217 16 Calcium carbonate; NaCI (5 112315 80.4 36.9 7.62 10A 85 11th grams) started on 14th day. M-45 92.8 35.2 7.47 7.9 15th J. K. 90.0 29.9 7.39 15.0 41 4th 207 20 Calciukn carbonate; no NaCl. 198489 86.2 35.0 7.46 9.1 67 12th F-55 89.2 34.9 7.50 13.7 53 16th T. S. 94.8 32.8 7.48 14.5 6th 148 16 Calcium carbonate; no NaCI. 212524 81.8 7.54 19.6 12th M-49 84.8 36.4 7.49 15.2 18th 97.6 31.5 7.47 10.4 29th 99.0 28.8 7.48 8.1 33rd F. W. 96.7 31.7 7.56 12.9 143 2nd 177 17 Sippy powders NH4CI (4 to 6 194370 82.8 37.3 7.55 12.4 9th grams) 15th to 22nd days. M-43 82.6 37.5 7.53 12.2 93 14th 98.8 29.5 7.38 11.4 200 18th 96.6 31.2 7.44 22nd W. B. 31.8 7.48 18.7 96 7th 354 43 Calcium carbonate; NaCI (10 211777 80.6 47.4 7.73 20.6 13th grams) 8th to 22nd days; vari- M-51 85.6 41.1 7.62 18.7 16th ous alkalis from 25th to 38th 98.1 28.0 7.49 8.8 128 28th days; calcium carbonate then 96.8 32.4 7.49 16.9 54 40th resumed. 97.2 34.2 7.45 18.3 69 47th 15.3 148 1 year later H. B. 90.4 30.6 7.50 23.2 4th 356 17 Calcium carbonate; NaCI started 225751 83.0 39.4 7.62 18.7 9th on 10th day; 200 cc. 5 per cent M-49 97.0 35.0 7.47 15.7 85 13th saline intravenously on 10th 101.8 31.0 7.47 11.7 76 17th day. 12.0 102 4 months later S. S. 84.3 42.9 7.71 17.3 83 15th 85 20 Sippy powders; NH4CI (2 to 6 101209 30.9 7.51 15.0 18th grams) from 16th to 20th days. M-37 95.2 36.0 7.53 22nd 100.2 32.9 7.50 24th 11.1 112 1 week later A. G. 96.0 31.1 7.54 11.7 2nd 100 15 Calcium carbonate; NaCl (3 232838 89.4 34.4 7.47 4th grams) started on 12th day. M-52 87.8 35.6 7.48 22.4 8th 87.4 36.7 7.49 14.2 10th 91.9 35.1 7.52 11.7 80 13th EXPERIMENTAL AND CLINICAL HYPOCHLOREMIA 101 water were administered daily, it would appear the chloride loss is induced, and the degree and that, as in the dog experiments, dehydration did rapidity of the dehydration associated with the not exist in the sense of deprivation of water but chloropenia. An abrupt depletion of chloride is was present in the sense that fluid could not be associated with an equally abrupt and marked loss retained in the body due to the marked depletion of sodium and, therefore, of body water, as shown of electrolytes. The volume of urine excreted by by Gamble and others (19). Loss of fluid de- both patients during the period of hypochloremia creases the circulating blood volume which, by was large; the daily output averaged 1340 cc. in reducing the venous return to the heart, pre- case M. S., and 1317 cc. in case W. L. The urea sumably lowers the cardiac output. This course clearance in case M. S. was not altered signifi- of events may actually lead to peripheral circula- cantly, and the absence of a marked elevation of tory failure. The blood flow through the kidney the blood urea nitrogen is further evidence of and the effective glomerular filtration pressure are satisfactory renal function. Despite the severe consequently lowered. The severe nitrogen reten- chloropenia, the pH and chloride content of the tion and decreased renal function, noted under gastric aspirations were reduced only slightly; and these conditions by other workers, evidently repre- the pH values of the histamine-stimulated gastric sent a decreased renal circulation rather than in- juice in case M. S. were as low as one finds in the trinsic renal disease. The absence of azotemia histamine-stimulated gastric secretion of indi- during hypochloremia in the present experiments viduals with a normal acid-base balance. This may be attributed to two factors: (a) the gradual finding is in accord with the observations made in deprivation of chloride, allowing the patients to dogs (1). The decrease in the spinal fluid chlo- make fairly satisfactory adjustments to the severe ride and total base noted is, of course, to be ex- electrolyte changes, and (b) the daily administra- pected; McCance (17) and Agar and MacPherson tion of large quantities of water which tended to (18) have reported similar findings. It is of "wash out" the urea nitrogen and apparently main- the interest that these values were not lower than tained an adequate blood flow through kidney. they were, in view of the severe hypochloremia and . The explanation for this discrep- CONCLUSIONS ancy is not apparent. 1. Severe alkalosis without marked nitrogen re- tention may be induced in man by the gradual II. Hypochloremia incidental to ulcer therapy withdrawal of gastric secretion. 2. Such hypochloremia and alkalosis are not In Table I are recorded the acid-base balance associated with decreased renal function, as meas- and other data in 10 patients with alkalosis and ured by the urea clearance test, when adequate hypochloremia, complicating the antacid treatment quantities of fluid are administered daily. of peptic ulcer. Large amounts of gastric content 3. Gastric secretion in man is not altered signifi- had been aspirated in 8 of this group. In no in- cantly by severe hypochloremia. stance was there any significant azotemia. Hypo- chloremia apparently had occurred gradually in all The authors wish to acknowledge the valuable technical 10 patients. assistance of Miss Jacqueline Front.

GENERAL DISCUSSION BIBLIOGRAPHY This study confirms the results of the animal 1. Kirsner, J. B., and Knowlton, K., Acid base balance, renal function, and gastric secretion during hypo- experiments referred to earlier, as well as the work chloremia in the dog. J. Clin. Invest., 1941, 20, of Kerpel-Fronius, and Kerpel-Fronius and But- 303. ler, and demonstrates that, in man also, a severe 2. a. Kerpel-Fronius, E., Zur pathogenese der "hypo- hypochloremia is not necessarily accompanied by chloramischen" Azotamie. Ztschr. f. d. ges exper. azotemia. The important factors which determine Med., 1936, 97, 733. b. Idem, Salzmangelzustande und chloroprive Azo- the extent of urea nitrogen elevation during hypo- tamie. Ergebn. d. inn. Med. u. Kinderh., 1936, 51, chloremia, apparently, are the speed with which 623. 102 JOSEPH B. KIRSNER, WALTER LINCOLN PALMER, AND KATHRYN KNOWLTON 3. Kerpel-Fronius, E., and Butler, A. M., Salt and water 12. Butler, A. M., and Tuthill, E., An application of the losses in diuretin diuresis and their relation to uranyl zinc acetate method for the determination serum non-protein nitrogen and electrolyte concen- of sodium in biological material. J. Biol. Chem., trations. J. Exper. Med., 1935, 61, 157. 1931, 93, 171. 4. Ambard, L., Stahl, J., and Kuhlmann, D., Azotemie 13. Stadie, W. C., and Ross, E. C., A micro method for et chloropenie. Arch. d. mal. d. reins, 1933, 7, 465. the determination of base in blood, serum, and other 5. Hiatt, E. P., Extreme hypochloremia in dogs induced biological materials. J. Biol. Chem., 1925, 65, 735. by nitrate administration. Am. J. Physiol., 1940, 14. Peters, J. P., and Van Slyke, D. D., Quantitative 129, 597. Clinical Chemistry, Vol. 2, Methods, Williams and 6. Peters, J. P., and Van Slyke, D. D., Quantitative Wilkins Company, Baltimore, 1931, page 367. Clinical Chemistry, Vol. 2, Methods. Williams and 15. Henriques, V., and S6rensen, S. P. L., Ueber die Wilkins Company, Baltimore, 1931. Serum CO2, quantitative Bestimmung der Aminosauren, Poly- p. 283. pH (Colorimetric), p. 796. Chloride, p. peptide und der Hippursaure im Harne durch 835. Blood urea nitrogen, p. 554. Formoltitration. Ztschr. f. physiol. Chem., 1909, 7. Van Slyke, D. D., and others, Observations on the 63, 27. courses of different types of Bright's disease and 16. McCance, R. A., and Widdowson, E.. M., The secre- on resultant changes in renal anatomy. Medicine, tion of urine in man during experimental salt de- 1930, 9, 257. ficiency. J. Physiol., 1937, 91, 222. 8. Clark, E. P., and Collip, J. B., A study of the Tisdall 17. McCance, R. A., The effect of salt deficiency in man method for the determination of blood serum cal- on the volume of extra-cellular fluids and on the cium with a suggested modification. J. Biol. Chem., composition of sweat, saliva, gastric juice, and 1925, 63, 461. cerebrospinal fluid. J. Physiol., 1938, 92, 208. 9. Fiske, C. H., and Subbarow, Y., The colorimetric 18. Agar, H., and MacPherson, I., The cerebrospinal fluid determination of phosphorus. J. Biol. Chem., 1925, in alkalosis. Lancet, 1940, 1, 171. 66, 375. 19. Gamble, J. L., and Ross, S. G., The factors in the 10. Shohl, A. T., and Bennett, H. B., A micro method for dehydration following pyloric obstruction. J. Clin. the determination of potassium as iodoplatinate. J. Invest., 1925, 1, 403. Biol. Chem., 1928, 78, 643. and McIver, M. A., Acid base composition of gastric 11. Campbell, W. R., and Hanna, M. I., The albumin, secretions. J. Exp. Med., 1928, 48, 837. globulins, and fibrinogen of serum and plasma. , Extracellular fluid. Bull Johns Hopkins Hosp., J. Biol. Chem., 1937, 119, 15. 1937, 61, 151.