Effect of Intragastric Glucose-Electrolyte Infusion Upon Water and Electrolyte Balance in Asiatic Cholera

Vol. 55, No.3 Printed in U.S .A.

GASTROENTEROLOGY

Copyright© 1968 by The Williams & Wilkins Co .

EFFECT OF INTRAGASTRIC GLUCOSE-ELECTROLYTE INFUSION UPON WATER AND ELECTROLYTE BALANCE IN ASIATIC CHOLERA NATHANIEL F. PIERCE, M.D., JoHN G. BANWELL, D.M., RuPAK C. MITRA, M.B. B.S., GEORGE J. CARANAsos, M.D., RoBERT I. KEIMOWITZ, M.D., ARABINDO MONDAL, M.B., CH.B., AND PHANINDRA M. MANJJ, M.B.B.S. The Johns Hopkins University Center for Medical Research and Tmining, the Infectious Diseases Ho spital, and the School of Tropical Medicine, Calcutta, India

In the norma l human small bowel glucose is rapidly and actively absorbed, absorption occurring predominantly in the duodenum and jejunum. 1 It has been demonstrated in man 2 • 3 and animals 4 that the absorption of glucose from a ll, or part, of the small bowel is accompanied by increased absorption of sodium and water. This phenomenon in man occurs predominantly in the jejunum, is dependent only upon active glucose absorption, and is unrelated to active sodium transport.5 The mechanism by which active glucose absorption enhances sodium absorption in the human jejunum is no t entirely clear; however, it appears to be a passive process.5 It ·would be of physiological and perhaps therapeutic interest to know whether glucose is absorbed by cholera patients and whether glucose absorption enhances absorption (or diminishes net losses) of water and sodium. The present study was designed to determine whether intestinal gluReceived January 13, 1968. Accepted April 9, 1968. Address requests for reprints to: Nathaniel F. Pierce, M.D ., The Johns Hopkins University CMRT, 4A Orient Row, Calcutta 17, India. This study was supported by Research Grants 5X4317, AI-07628-01, and 5R07TW00141-07CIC from the National Institutes of Health. The authors wish to acknowledge the valuable assistance of Doctor K. N. Neogy, Department of Bacteriology, Calcutta School of Tropical Medicine; Mr. Jacob Thomas, Statistician, and Miss Uma Ganguly, Biochemist, The Johns Hopkins University Center for Medical Research and Training, Calcutta; and Doctor C. K. Wallace, Department of Medicine, The Johns Hopkins Hospital in the planning and conduct of this study. 333

cose absorption occurs in cholera patients and, if so, whether an intragastric infusion of a glucose-electroly te solution would alter cholera stool production or composition. The efficacy of such solutions in maintaining water, electrolyte, and acid-base balance in cholera patients with severe diarrhea was a lso evaluated.

Method Fourteen adult males with severe "rice water" diarrhea and bacteriologically proven cholera (Vibrio choleme, biotype El Tor, Ogawa) who passed 367 to 792 ml of stool per hr during the first 7 to 18 hr after hospital admission were studied. Patients were selected from among the most severe cases of cholera admitted to the Infectious Diseases Hospital during 1967 and included only those with very high rates of stool production. No patient received antibiotics before or during the study. The study compared stool volume and composition during a period of intragastric infusion of a glucose-electrolyte solution with similar observations in control periods. Each patient was studied during four consecutive periods: (1) a control period of 7 to 18 hr (mean 12.0 hr), beginning at admission, during which rapid rehydration and replacement of subsequent stool losses was accomplished intravenously, the patient receiving nothing by mouth; (2) a study period during which the glucose-electrolyte solution was infused via a nasogastric tube by a Sigmamotor pump, and during which intravenous fluids were given only if water balance was not maintained; and (3) and (4) consecutive control periods identical to the first control period. Twelve-hour periods were chosen because prior observations had shown that during shorter periods the mean rate at which stool was passed varied unpredictably. Because the mean hourly rate of stool production for consecutive 12-hr pe-

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PIERCE ET AL.

334 T All L E

1. Intmga stric infusion fluid

composition

~o- IP~tas-1 slUm

dtum

Chlo- 1HCOa nde

mEq/liter

Group I. .. . 118 Group II ... 110 Group III .. 101

8.5 9.0 8.5

86.5 79.0 74.5

Osmolari ty

Glucose

mM/ mOsm/ liter liter

40 40 40 160 35 1 220

1

274 380 421

riods decreased steadily, the output during the study period was compared with both a precedin()" and a following control period. The patients"' were studied in three groups with a different o-lucose-electrolyte solution (table 1) beino- evaluated in each group. The solutions diffe~ed primarily in glucose concentration and osmolarity; as glucose concentration was increased t he electrolyte content was reduced slightly. The groups of patients were studied consecutively, efforts being made to choose subjects with disease of comparable seventy. The intravenous fluid used contained sodium (154 mEq per liter), chloride (134 mEq per liter), and lactate (51 mEq per liter) with KCl (20 mEq per liter) added after the 3rd liter. Patients were studied on metabolic beds permitting separate stool and urine collection. Stool and urine output and oral solution input were determined by weight to the nearest gram. In calculating t he mean hourly rate of stool production the outputs of the 2 hr immediately following the start and end of the intragastric infusion were omitted because any influence of intragastric infusion upon stool volume was assumed to be delayed by a period equal to the intestinal transit time. The stomach to anus transit time of T-1824 blue dye was determined in each patient at the beginning and end of the study period and was recorded as time elapsed after intragastric administration until first appearance in the stool; it averaged 61 min (range 20 to 100) at the start of the study period and 117 min (range 50 to 180) at the end. Stool continued to contain visible dye for about 60 min after first appearance. The intragastric infusion was initiated at a rate slightly in excess of the mean hourly rate of stool production in the preceding control period. The rate was altered once or twice during the study period to achieve a rate slightly in excess of stool output during the study period. When emesis occurred, its volume was subtracted from the volume of solution infused before determining the mean rate of oral infusion . Patients were weighed at the beginning

and end of the study period to confirm input and output balance data. Vital signs were recorded hourly during the study period and at 4-hr intervals during control periods. Abdominal girth was measured hourly in some patients during the study period. Femoral artery blood was obtained at admission, at the start of the study period, and at 4-hr intervals until its completion. Immediate determinations were made of pH with a Radiometer pH meter-27 with microelectrode ; CO, combining power with a Van Slyke volumetric apparatus; and plasma specific gravity with a temperature-corrected total solids meter (American Optical Company). Remaining plasma was frozen for later determination of sodium and potassium with a Patwin flame photometer with internal lithium standard, chloride with a Buchler-Cotlove chloridometer, total protein by the biuret method, and glucose by a glucose oxidase method. Specimens of stool were obtained via rectal catheter at similar intervals and at the end of each control period. Bicarbonate content and the presence or absence of reducing substances (with Clinitest tablets) were determined immediately and the remainder was frozen at once for analysis at a later date. Aliquots of each oral solution were analyzed to confirm the composition. All determinations were performed in duplicate.

Results The results are presented as a compariswn between the groups receiving the first, second , and third glucose-electrolyte solutions. The historica l, physical, and laboratory data for each group obtained at admission are compared in t a ble 2. Examination by analysis of variance indicates that groups did not differ significantly in regard to a ny of these observations.

Influence of intragastric infusion upon stool production and watm· and electrolyte balance. Oral inta ke and stool output data for the three groups during the four consecutive periods are presented in table 3. Water, sodium, potassium, bicarbonate, and chloride balances are each summarized. Figure 1 compares mean stool output rates of water and electrolytes of each study group during the study and control periods and indicates the rate of water or electrolyte administration during the study period. vVater balance was positive in

2. Compm·ison of study groups at admissiona

TABLE

Group I (n = 4)

. . . . . .. Age (years) ... . .. Duration of dia rrhea before entry (hr). ... . . .. ... .. Weight (kg) . . .. . . . . . .. . . .. .. . . .. . Systolic blood pressure (mm Hg) . . . . . . . . .. ... . . . . . . . Pulse rate per minute .. . . . . . . . . . . . . . . . . . . .. . Respiration rate per minute. . .. . . . . . .... . .. . . . . . .. P lasma specific gravity ... . . . . . . . . .. .. . ... . . . ... Arterial pH. . . . . . . . . . . . . . . . . . . . . . . .. . ... . . . . .. .. . . . Serum Na+ (mEq/liter). . . . . . .. . . . . . . . . . . . . . . . . . . . . Serum!{+ (mEq/liter). . . . . . . ... .. . . . . . . . . . .. . . Serum CJ- (mEq/liter) . . . . . ..... .. ..... . . .. . . . . . . Serum HCO, (mEq/liter) . . . •

•

•

•

•

•

•

•

•

•

•

•

•

•

0

•

•

•

•

•

•

0

•

•

•

•

•

•

43.8 10.8 47. 0 - 17. 5 132. 0 23.5 1.0438 7.128 137 .8 5 . 23 104.3 11. 2

± ± ± ± ± ± ± ± ± ± ± ±

Group II (n = 5)

9.5 33 .4 3.2 8 .8 3. 7 50. 6 35 . 5b - 21. 0 17. 6 142.6 3.4 44 .0 .0031 1. 0448 . 009 7. 122 5 .7 139 .8 .89 5.43 8.1 108.3 7.6 4. 1

± ± ± ± ± ± ± ± ± ± ± ±

Group III (n = 5)

17. 0 36.2 4. 3 5.9 7.8 41. 9 30 . 1b - 38.0 20.4 127.8 17.9 42.4 0.031 1.0422 .120 7. 175 2. 9 141.8 .91 5.45 4 .1 106.3 3. 1 8 .0

± ± ± ± ± ± ± ± ± ± ± ±

18 . 3 1.7 5.4 37 .7b 19.9 12. 2 . 0026 . 161 2.8 . 75 3 .9 3. 5

a T he mean figures and standard deviations for each group are p resented . In all instances the means of each group did not d iffer significantly when examined by analysis of variance . n, number of patients in each gro up. b Mean figures in each group include 2 or 3 patients in whom blood pressure was u nobtainable and given a value of zero.

TABLE

3. Balance data during study and control periodsa Study period

Group

Control period !, stool outpu t

Control period Stool output

-

Water (ml/hr)

II

III I II III Potassium (mEq/hr)

I

II III Bica rbon ate (mEq/hr)

I II III

Chloride (mEq / hr)

I II

III

I

2, stool outpu t

Control period 3, stool output

237. 0 (166- 317 ) 307 .8 (106- 477) 219 .0 (188- 256) 32 . 5 (24-46) 42.4 (14-67) 29.6 (25- 33) 2. 90 (2.1-4 .1 ) 2. 98 (0 . 7-5 . 5) 1. 86 (1. 2-2. 9) 13. 1 (8-16) 17.8 (9-24) 15 . 2 (12-17) 22.0 (15- 34) 25.9 (7-40) 16. 4 (14-19)

149.3 (125-183) 271.8 (97- 413) 172 .8 (102-278) 20. 5 (16- 26) 37 . 4 (13-58) 23 . 4 (14- 39) 1.85 (1. 6-2.4 ) 2. 64 (0. 6- 4. 4) 1. 78 (0.6-3. 1) 9.0 (6- 13) 15.8 (8-21) 12.4 (6- 20 ) 13. 0 (9- 20) 22 . 7 (7-36) 12.8 (6-22)

Net balance

--

I

Sodium (mEq/hr)

Intragastric intake

591.8 1236.3 1309.3 (367- 783) (1055-1490 ) (1107-1450) 743 .0 871 .8 666 .6 (447-792) (342-1023) (567-1158) 555.4 692.4 507. 0 (373- 683) (468- 875) (366-757) 171.0 154 . 5 86.3 (141-223) (131- 171) (46- 128) 98.4 93 . 2 94.4 (62-126) (46-143) (62-118) 79.8 70 .2 70.8 (46-120 ) (47-89) (45-104) 11.03 7.00 12.53 (5.2- 9. 0) (9.8-18 . 0 ) (9. 4-12. 0) 7 . 52 7.86 7.36 (4 . 9- 11. 9) (3.4-10 .3) (5 . 1-10 .4) 5.88 7.72 5 . 54 (4.5- 15.3) (2.9-15 .3 ) (4 . 0-7.4) 52 . 3 26 . 2 54.5 (44-58) (18- 38) (45-61) 34 . 2 42 .4 34.8 ( 28-59) (23-46) (26-60) 24.2 24 . 4 33 .0 (20-44) (16-31) (14- 47) 67 .8 130 .3 113.0 (108- 180 ) (96-125) (35- 108) 66 . 4 67.6 69 . 0 (23-98) (38-85) (45- 92) 52 . 6 49.4 51. 6 (39- 67) (33-60) (35-65)

+ 73. 0 ( - 40 to + 177) + 128 .8 (+ 27 to +225) + 137 .0 (+ 95 to + 193) -16.5 (- 52 to +7) - 5.2 (-17 to +16) - 9.6 (- 31 to +1) - 1.50 (-6.0 to +1.5) + 0.34 (-3 .0 to + 1.7) +0 . 34 (-1. 4 to +1.4) -2.3 (- 9 to +8) -7 .6 ( -13 to - 3) - 8 .8 (-13 to - 4) - 17 .3 (- 55 to + 8) + 1. 4 (- 17 to +22) +2.2 (- 2 to +5)

I

T he mean value for eac h group is shown during eac h control and study period. T he range of observations f or the group is listed beneath each mean. Wa ter and individu al electrolyte balance data are s hown separately. Posit ive bala nce indi cates intragastric intake exceeding stool ou tpu t. a

335

Vol. 55, No.3

PIERCE ET AL.

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FIG. 1. Effect of oral (intragastric) infusion upon stool output of water and electrolyte. Mean stool output of water and each electrolyte is shown during study and control periods. M ean intragastric infusion rate is shown for the study period. During control periods net balance equals stool production, intragastric intake being zero. During the study period net balance equals intragastric intake minus stool output.

each group (13 of 14 patients). Net electrolyte loss during t he study period was consistently less than in either the preceding or succeeding control period. In groups II and III potassium and chloride balances were positive. Examination by analysis of variance showed no significant difference (P > 0.10) between groups in mean stool output of water and each electrolyte during the initial control period. In each group stool water and electrolyte passed during the study period consistently exceeded that in the followin g control period and usually exceeded that in the preceding one indicating that intragastric fluid infusion increased stool volume, the increase being greatest in group I. The amount by which study period stool water and electrolyte

output exceeded that of either the preceding or following control period was, with the exception of bicarbonate, significantly greater in group I than in groups II or III (P < 0.05 to < 0.001) . Groups II and III did not differ significantly in this regard. Likewise, total stool output of water and electrolyte (except bicarbonate) during the study period was significantly greater in group I than in groups II or III (P < 0.05 to <0.001), while groups II and III were not signifi cantly different. The intragastric intake of water and electrolyte required to maintain approximate balance with stool losses was also significantly greater in group I than in groups II or III (P < 0.01 to <0.001) . Groups II and III did not differ significantly in this regard. Although actual stool output was in-

September 1968

creased by intragastric infusion, net balance (oral intake minus stool output of water and electrolyte) was improved (less negative or even positive) during infusion of each glucose-electrolyte solution studied. The study design permits an estimation of the amount by which net (gastrointestinal tract) balance of water and electrolyte was altered. T his value would be the difference between the net balance observed during the study period and that expected if control conditions had existed during the study period. The expected net balance would equal expected stool output, oral intake being zero, and can be closely ap proximated by assuming that it equals the mean of the rates of stool out put in the control period immediately preceding and the one immediately fo llowing. This assumption is supported by our observations made in a separate series of 12 cholera patients treated without antibiotics and receiving only intravenous fluids. I n this TABLE

337

INTRAGASTRIC INFUSION I N ASI ATI C CHOLERA

group mean 6-hr stool output during the first 48 hr after admission decreased in a linear manner. It is further supported by the observation that the rate of stool output in cholera is not affected by the presence or absence of intravenous replacement until dehydration becomes very severe.6 The fo llowing formula is then applicable:

R=B -E In which R = the change in net balance during intra gastric infusion (a positive value indicating balance to be less negative or more positive), E = the expected net balance (stool output) during the study period determined as above, and B = the net balance observed during the study period (oral intake minus stool output), all in milliliters or milliequivalents per hour. The results obtained using this formula are shown in table 4. The improvement in net balance of water and electrolyte during the study period was comparable in each

4. Effect of intmgastric infusion of glucose-electrolyte solution u pon net wat er and electrolyte balance in cholem• Water

Sodium

Potassium

I Bicarbonate I

Chloride

mEq/ hr

ml/hr

Group I Expected net balance. . . . .. .. . . . . . . . . . . . ... . .. . . . . . Observed net balance .. . . . . . . . Change in net bala nce .. . .. . . . . . . ...... . . . . . Per cent of infusion fluid re tained . .. .. .. . . .

I

-414.4 +73.0 +487 . 4 37

-59.4 - 16. 5 +42.9 28

-4.95 - 1.50 +3.45 31

- 19.7 -2 . 2 +17 . 5 33

- 44 .9 -17.3 +27.6 24

-487.2 +128 .8 +616.0 71

- 68.4 -5 . 2 +63.2 68

-5. 17 + 0.34 +5.51 70

-26.0 - 7.6 +18.4 53

- 46.2 +1.4 +47.6 69

- 363.0 +137. 7 + 500. 7 72

-50.2 -9.6 +40.6 58

-4 .79 +0.34 + 5.13 87

-19.8 -8.8 +11 .0 45

- 34.5 +2.2 +36 . 7

Group II Expected net bala nce ... . . . . . ... .. . . . . . . . . . Observed net balance . . . .. . .. . . . . . . ... .. . . Change in net balance ..... . . . . . . . . . . . . . . . .. Per cent of infusion fluid retained ... . . . .. . Group III Expected net bala nce .. . . .. . . ...... . . . .... . Observed net balance ..... ... . . . .. . . . . .. . .. Change in net bala nce .. . . . ... . . . . . .. . ... Per cent of infusion fluid reta ined . .. . . ... . .

71

• Values are means for each group during the period of intragastric infusion. Expected net balance represents the mean of the rates of stool output du ring the control period preceding and the one succeeding the study period. Observed net balance is the difference between the rate of intragastric infusion and the rate of stool output,(+) values indicating intragastric intake exceeded stool output, the(-) in dicating the opposite . The change in net balance is the difference between the observed and expected net balance. In all instances this was a positive value representing an improvement in net balance. T he per cent retained indica tes that portion of the hourly int ragastric water and electrolyte intake which is equivalent to the hourly improvement in net balance.

Vol. 55, No. 3

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Fro. 2. Effect of infusion fluid glucose concentration and osmolarity upon improvement in net water and sodium balance per millimole of glucose absorbed. The method of determining the improvement in water and electrolyte balance is presented in the text. Mean figures for each group are plotted with the brackets indicating the mean ± one standard deviation.

group. If it is considered that a portion of the intragastric infusion was retained by the patient thus accomplishing the improvement in net balance, this portion was (table 4), with the exception of bicarbonate, about 2-fold greater in groups II and III than in group I, the results with groups II and III being similar. Calculating on the basis of complete absorption of administered glucose, the amount by which water or sodium balance was improved per millimole of glucose absorbed was not constant but decreased markedly as glucose concentration and osmolarity of the infusion solution increased (fig. 2). Glucose administered during the study period was completely absorbed (as indicated by absence of detectable stool glucose) in all but 2 patients, one each in groups II and III. In these, stool glucose increased in concentration during the study period reaching a maximum of 286 mg per 100 ml after 12 hr in one and of 153 mg per 100 ml after 8 hr in the other. In both, stool glucose was less than 2 mg per 100 ml, 6 hr after the study period. Even in these instances more than 95% of ad-

ministered glucose was absorbed. One patient had transient glycosuria associated with a plasma glucose of 239 mg per 100 ml. Other plasma glucose determinations in this and in all other patients were within normal postprandial limits. Stool composition. Stool composition at admission and at the end of each period for the first 36 hr is shown in table 5. In each group stool sodium and chloride concentrations decreased and bicarbonate increased during successive periods. There was no significant difference between groups at any given time, with the exception of chloride concentration which was higher at 24 hr in group I than in groups II or III (P < 0.05 in both cases) . The changes in concentration during the study period were consistent with the trend of changing composition for the entire 36-hr period. Plasma determinations. Plasma electrolyte, pH, and specific gravity detenninations taken at the beginning and end of the study period are shown in table 6. In each group plasma sodium, potassium, chloride, and pH varied within nearly normal limits. Bicarbonate concentrations

339

INTRAGASTRIC INFUSION IN ASIATIC CHOLERA

September 1968 TABLE

5. Stool composition at 12-hr intervals during the first 36 hr of study• Sodium

Group

Time

I

Potassium

I

Chloride

I

Bicarbonate

mEq/liter

I II III I II III I II III I II III

Admission

12 Hours (start of intragastric infusion) 24 Hours (end of intragastric infusion) 36 Hours

140.5 141.2 138.8 144.8 138.6 134.8 137.7 133.6 134.8 133.5 136.6 133 . 6

± ± ± ± ± ± ± ± ± ± ± ±

14.3 5. 1 10.6 20.9 8.5 6.1 10.8 5.5 6.1 5.3 5.9 5.7

11.9 11 .4 15.9 13.6 10.3 13 .9 9.9 7.9 8. 7 10.7 10.2 8.1

± ± ± ± ± ± ± ± ± ± ± ±

5.8 3.6 8.6 5.5 3.0 4.8 1.2 7.3 2.2 2.8 4.1 3 .7

106.5 95.8 109.6 115.8 97.6 101.2 98.7 81.4 83.8 70 .8 77.4 73.0

± ± ± ± ± ± ± ± ± ± ± ±

13.0 13.8 14.4 7.8 9.1 14.0 8.1 7.9 5. 3 4. 7 11.9 6.4

..

45.3 43.0 45.6 45.0 62.0 64 . 2 66.3 66.2 73.2

± ± ± ± ± ± ± ± ±

13.0 6.7 7. 4 10.2 15.4 13.6 14.2 15.7 17.4

• The mean concentration and standard deviation of each stool electrolyte is shown for each group at admission and at the end of each 12-hr period for 36 hr. When examined by analysis of variance there was no significant difference in the means of each group with regard to any electrolyte at any time with one exception . Chloride content at the end of 24 hr was significantly higher in group I than in either group II or III (P < 0.05 in each instance). TABLE

6. ATterial plasma determinations at staTt and end of peTiod of intragastTic "inf1tsion• Sodium

I

Potassium

I

Chloride

I

HCOa

pH

Plasma specific gravity

mEq/liter

Group I Start End Group II Start End Group III Start End

a

143.0 (140-145) 140.0 (137-'-144)

4. 63 (4 . 1-5.9) 4.13 (3. 6-4. 5)

107.7 (98-114) 103.0 (93-109)

23.5 (19-25) 24.0 (18-35)

7.403 (7. 35-7. 44) 7.420 (7 . 38-7. 45)

1. 0275 (1. 026-1. 030) 1.0290 (1. 027-1. 030)

144.6 (143-147) 141.2 (137-143)

4.28 (3. 5-5.1) 4 .04 (3.8-4 .8)

109.0 (107-112) 106.4 (104-108)

24.1 (19-29) 21.8 (18-26)

7. 380 (7. 30-7. 45) 7.384 (7. 36-7 .44)

1.0262 (1. 026-1. 027) 1.0254 (1. 024-1. 026)

145 .2 (144-146) 143.4 (140-149)

4.58 (3.6-5.3) 4. 18 (3.5-4.6)

110.4 (106-113) 104.3 (99-107)

25.7 (24-28) 26.5 (22-32)

7.450 (7 . 38-7. 53) 7.433 (7. 36-7. 52)

1.0253 (1. 024-1. 027) 1.0265 (1. 024-1.027)

Figures represent mean values for each group with range indicated in parentheses:

varied more widely depending upon the adequacy of bicarbonate replacement at the start of the period and the amount of improvement of net bicarbonate balance during intragastric infusion. Mean plasma specific gravity rose slightly in group I but remained normal in groups II and III. No patient developed significant dehydration during the study period; however, 1 patient in each group received intravenous

fluids (80 to 160 ml per hr) during this period, the reasons being (1) a high plasma specific gravity (1.030) at the start of the study period, (2) a rising plasma specific gravity (1.0255 to 1.0273) associated with vomiting and glucose in the stool, and (3) a slight rise in plasma specific gravity (1.0271 to 1.0276) associated with com·_ plaints of thirst. Side effects. Three patients vomited clur-

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ing intragastric infusion. Two of these (in groups II and III) also had incomplete glucose absorption, an increase in abdominal girth of 4.5 to 8.0 em, mild abdominal discomfort, and a rising plasma specific gravity. The third (group III) also had an increase in abdominal girth of 4.5 em. Abdominal girth was not measured in group I or in other members of group II. In group III girth increased an average of 4.5 em. One patient had a rise in rectal temperature to 103 F at the end of the study period. Other elevations during the study period did not exceed 101 F and were of equal incidence with similar elevations during the prior control period. Changes in other vital signs were not remarkable. Most patients rested comfortably during intragastric infusion. Discussion Present knowledge of the pathophysiology of :- cholera indicates that diarrheal fluid arises throughout the small intestine, predominantly in the jejunum, and is the result of an increased plasma to lumen flux of water and electrolytes, the lumen to plasma flux remaining normal.7· 8 Small bowel mucosa in cholera has been shown to be essentiaJly normal to light and electron microscopy. 9 • 10 Studies in man indicate that there is no increase in mucosal permeability to large molecules such as radioactive iodinated serum albumin or polyvinylpyrrolidone11· 12 and in vitro studies of human ileum have shown that active sodium transport remains intact following the introduction of crude cholera exotoxin into fluids bathing the ileal mucosa.12 The exact mechanism of diarrheal fluid production in cholera has not yet been defined. The present study demonstrates that patients with severe cholera are able to absorb glucose. In most instances (12 of 14 patients) glucose absorption appeared to be an active process, no glucose being detectable in the cholera stool despite prolonged and rapid intragastric infusion of solutions containing up to 220 mM glucose per liter in the presence of a very rapid stomach to anus transit time. Since active glucose absorption is a small bowel phe-

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nomenon and cholera stool originates primarily in the small bowel, this indicates the preservation of a significant absorptive process at the site of diarrheal fluid production. Preservation of active glucose absorption is of particular interest because of the important role glucose absorption plays in the absorption of water and sodium. Fordtran and Rector 5 have indicated that most small bowel sodium (and therefore water) absorption occurs by either active sodium absorption or as a passive consequence of active glucose absorption. In vitro studies of the human ileum have already shown that active sodium absorption is not altered by cholera toxin. 13 It appears, therefore, that the two major small bowel mechanisms of sodium (and water) absorption are intact in cholera. This being the case, it is unlikely that cholera stool forms because of a failure of the normal small bowel absorptive mechanism for sodium and water, as has been previously proposed. 14 Additional evidence of preservation of intestinal mucosal function in cholera is provided in this study by the observation that stool electrolyte content, which differed significantly from that of plasma, was unaltered by large intragastric infusions of varying volume, composition, and osmolarity (table 5). The failure of 2 patients in this study to absorb completely the infused glucose could have been caused by a specific alteration of glucose absorptive capacity in cholera, but could also have resulted from the rapid intestinal transit time observed or from pre-existing malabsorption, which Lindenbaum15 has shown to be common in the population in this region. Consistent with the discussion above is the demonstration in this study that net balances (oral intake less stool output) of water and electrolyte are significantly improved during glucose-electrolyte infusion. The effect of electrolyte solutions not containing glucose was not determined in this study but was previously examined by Phillips et al.l 6 in a similar study. They demonstrated improvement in net potassium and bicarbonate balance during oral administration of an isotonic electrolyte

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solution similar in composition to cholera stool. Similar results were obtained in the present study. Phillips' study showed, however, no improvement in net water or sodium (chloride) balance during administration of the same isotonic solution. Improved sodium (chloride) balance was observed only during administration of a hypertonic (480 milliosmoles, 230 mEq of sodium per liter) electrolyte solution and was associated with an increased negative water balance. Using an hypotonic electrolyte solution (110 milliosmoles, 45 mEq of sodium per liter) water balance improved but an increased negative sodium (chloride) balance was observed. In no instance did they observe simultaneous improvement in sodium (chloride) and water balance. Their results can be adequately explained on the basis of passive movement of water and sodium (chloride) along concentration gradients between the intestinal lumen and plasma which were created by the infused solution, an improvement in net sodium (chloride) balance being accompanied by a greater net water loss, and vice versa. In contrast the present study indicates that a concwTent improvement in net balance of water and sodium (chloride) occurred during intragastric administration of glucose-containing electrolyte solutions in which sodium concentration was less than that of plasma. It is apparent that the presence of glucose in the infusion solution and probably its absorption are responsible for the differing results in our study and that of Phillips. An improvement in the net balance of water and electrolyte during glucose-electrolyte infusion could result from either diminished cholera stool formation or increased intestinal lumen to plasma flux of water and electrolyte associated with glucose absorption, the process of cholera stool formation being una ltered. The present study does not indicate which of these is the case but evidence from studies of normal human subjects and animal models of cholera makes the latter explanation more likely. :Malawar et aP and Fordtran and Rector 5 in studies of normal human jejunal ' have shown that sodmm . function, and

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water absorption are markedly enhanced by absorption of intralumenal glucose. In vitro studies of cholera-infected rabbit ileal loops by Love 17 have shown that intralumenal glucose enhances the lumen to plasma sodium flux equally in normal and cholera-infected ileal loops. And he has also shown that the plasma to lumen sodium flux was increased by cholera infection but was not altered by the presence or absence of intralumenal glucose during infection. Finally, Carpenter et aJ.l 8 have shown that glucose absorption from canine jejunal and ileal Thiry-Vella loops is normal during water and electrolyte loss into the loop induced by the introduction of crude cholera exotoxin into the loop. They also demonstrated that the net rate of loss of water and electrolyte into such loops induced by challenge with cholera exotoxin was significantly reduced during perfusion with glucose-electrolyte solutions but not during perfusion with nonglucose-containing electrolyte solutions. The amount of this reduction was comparable to the increase in water and electrolyte absorption observed in normal loops following the addition of glucose to an electrolyte perfusion solution. These observations support the conclusion that glucose absorption remains intact in cholera. They also suggest that the normal enhancement of water and sodium (chloride) absorption associated with glucose absorption remains intact in cholera and is responsible for the improvement in net water and electrolyte balance observed during infusion of glucose-electrolyte solution in this study. Finally, they suggest that the mechanism of cholera stool formation is separate from that of glucose absorption and glucoserelated water and sodium absorption. The three glucose-electrolyte solutions evaluated in this study differed in glucose content and osmolarity, the first being isotonic, and the second and third, slightly and moderately hypertonic, respectively. Since each was administered at a rate sufficient to maintain approximate balance with stool output, the amount of improvement in net water and electrolyte balance achieved with each was approximately

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equal. However, a significantly higher rate of infusion was required to maintain balance when infusing ·an isotonic solution of low glucose concentration ( 40 mM per liter) than was required with an hypertonic solution. of higher glucose concentration (160 mM per liter). This suggests that either the increased glucose concentration or the increase in the total amount of glucose infused, or both, permitted maintenance of balance with a slower rate of intragastric infusion despite the concurrent increase in osmolarity. If the improvement in net balance observed during infusion of glucose-electrolyte solution was caused by absorption of water and electrolyte associated with glucose absorption it is possible to conclude that a significantly larger portion of the solution with 160 mM per liter glucose was absorbed than of the solution with 40 mM per liter glucose despite the hypertonicity of the former (table 4) . When glucose concentration and osmolarity were further increased (220 mM per liter glucose), no further reduction in the rate of fluid administration was required to maintain balance. This could be the result of a maximum glucose concentration effect having been achieved by the 160 mM per liter glucose solution or of an offsetting of any additional glucose effect by the further increase in osmolarity of the third solution. The amount of improvement in net hourly sodium and water balance per millimole of glucose absorbed decreased steadily as glucose concentration and osmolarity of the infusion solution increased (fig. 2). This again could be caused by either the increasing osmolarity or the increasing glucose concentration of the infusion solution, or by both. Hypertonic solutions entering the small bowel could be expected to be diluted toward isotonicity by the entrance of water, and perhaps some electrolyte into the bowel lumen. This would offset in part the effect of glucose on net water and electrolyte balance thus reducing the amount of improvement in net balance per millimole of glucose absorbed. Alternatively the mole for mole effect of glucose absorption on net water and electrolyte balance may diminish as glucose concentration within the lumen is increased. This

has been shown to be the case in studies of the normal human jejunum by Malawar et al. 3 They showed that the amount of sodium and water absorbed per millimole of glucose absorbed decreased steadily as glucose concentration increased. In this study, 11 of 14 patients with severe cholera were maintained in satisfactory water, electrolyte, and acid-base balance for 12 hr by intragastric infusion alone. The improvement in net water and electrolyte balance demonstrated during intragastric infusion was sufficient to equal or exceed stool losses occurring in most cholera patients. These observations suggest that an appropriately composed glucose-electrolyte solution given by mouth could be used in the replacement of water and electrolytes in cholera. Although such an approach might have no advantage over the customary and highly effective method of intravenous fluid replacement when the latter is possible, it could be of value in situations in which sufficient pyrogen-free intravenous fluids, administration sets, and persons skilled in their use were unavailable. Cholera frequently occurs in such conditions. An oral solution used to supplement intravenous fluids or to replace them would have the advantages of low cost, easy preparation, not requiring sterilization, and freedom from the complications of intravenous therapy. This report does not constitute a recommendation for such use but does indicate the need for further investigation of their role in prolonged therapy and in combination with antibiotics. It should be stressed that at present intravenous fluids remain the mainstay of the successful treatment of cholera. 19 Summary

A study of patients with severe cholera has demonstrated absorption of glucose and a definite improvement in net water and electrolyte balance during intragastric infusion of glucose-electrolyte solution. Glucose absorption in cholera patients appeared to be an active process, only 2 of 14 patients having any glucose detectable in their stool during intragastric infusion. The probability that glucose absorption in

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cholera patients enhances water and sodium (chloride) absorption as occurs in the normal small bowel, but does not alter the mechanism by which cholera stool is formed, is discussed. The demonstration that glucose absorption remains intact in cholera indicates the preservation of a significant absorptive function and an important mechanism of sodium and water absorption at the site of cholera stool formation, the small bowel. When glucose concentration and osmolarity of the infusion solution were increased from 40 to 160 mM per liter and from 274 to 380 milliosmoles per liter, respectively, t he rate of intragastric infusion required to maintain approximate balance with stool losses was halved. A further increase in glucose to 220 tnM per liter and osmolarity t o 421 milliosmoles per liter did not allow a further reduction in the infusion rate required to maintain balance. In most patients studied, water, electrolyte, and acid-base balance were maintained satisfactorily for 12 hr solely by the intragastric infusion of glucose-electrolyte solution. The possibility that such solutions could play a useful role in water and electrolyte replacement in persons ·with cholera is discussed. REFERENCES 1. Wisman, G. 1964. Absorption from the int estine. Academic Press, London. 2. Fordtran, J. S., and J. M . Dietschy. 1966. Water and electrolyte movement in the intestine. Gastroent erology 50: 263-285. 3. Malawar, S. J ., M . Ewton, J. S. Fordtran, and F . J. Ingelfinger. 1965. Interrelation between jejunal absorption of sodium, glucose and water in man . J. Clin. Invest. 44 : 1072. 4. Curran, P . F. 1960. Na, Cl and water transport by rat ileum in vitro . J. Gen. Physiol. 43: 1137-1148. 5. Fordtran, J . S., F. C. R ector, Jr., and N. W. Carter. 1968. The mechanisms of sodium absorption in the human small intestine. .J. Clin. Invest. 47 : 884-900. 6. Phillips, R. A., C. K. Wallace, and R. Q. Blackwell. 1963. Gastrointestinal physiology. I. Experimental design. Failure of an oral solution comparable to stool in volume and electrolyte composition to replace stool losses in cholera. Absorption of oral water

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in cholera. NAMRU-2 Research Report MR005.09-1040.1 .14. 7. Banwell, J. G., N. F. Pierce, R. Mitra, G. J . Caranasos, R. I. K eimowitz, A. Monda!, and P. M. M anji. 1968. Preliminary results of a study of small intestinal water and solute movement in acute and convalescent human cholera . Indian J. Med. Res. In press. 8. Sack, R. B., C. C . J . Carpenter, R. W. Steenberg, and N. F . Pierce. 1966. Experimental cholera: a canine model. Lancet 2 : 205-207. 9. Gangarosa, E. J., W. R. Biesel, C. Benyajati, H . Sprinz, and P. Piyaratn. 1960. The nature of the gastrointestinal lesion in Asiatic Cholera and its relation to pathogenesis: a biopsy study. Amer. J . Trop . Med . 9: 125135. 10. Elliott, H. L., C. C. J . Carp enter, R. B. Sack, and J . H . Yardley. 1968. Small bowel morphology in experimental canine cholera . Amer. J. Path . 52 : in press. 11. Weaver, R. H ., M. K. Johnson, and R. A. Phillips. 1948. Biochemical studies of cholera. J. Egypt Public Health Assn. 23 : 5-11. 12. Gordon, R. S., J r. 1960. The failure of Asiatic Cholera to give rise to exudative enteropathy. SEATO Conference on Cholera, D acca, Pakistan, December 5- 8, 1960. 13. Grady, G. F., M. A. Madoff, R. C. Duhamel, E. W. M oore, and T. C. Chalmers. 1967. Sodium transport by human ileum in vitro and its response to cholera entero toxin. Gastroenterology 53 : 737-744. 14. Huber, G. S., and R. A. Phillips. 1960. Cholera and the sodium pump, p. 37-40. SEATO Conference on Cholera. D acca, Pakistan, December 5-8, 1960. 15. Lindenbaum, J. 1965. Malabsorption during and after recovery from acute intestinal infection. Brit. Med. J . 2 : 326-329. 16. Phillips, R. A., C. K. Wallace, and R. Q. Blackwell. 1965. Water and electrolyte absorption by the intestine in cholera, p. 299311. Proceedings of the Cholera Research Symposium (NIH ). 17. Love, A. H. G. 1965. The effect of glucose on cation transport, p. 144--147. Proceedings of t he Cholera R esearch Symposium (NIH). 18. Carpenter, C. C. J ., R. B. Sack, J. C. Feeley, and R. W . Steenberg. 1968. Site and characteristics of electrolyte loss and effect of intraluminal glucose in experimental canine cholera. J. Clin. I nvest. 47 : 1210- 1220. 19. Carpenter, C. C. J., R. N . Chaudhuri and A. Monda!. 1964. A simple effective th~rapy of cholera. Indian J. Med. Res. 52 : 924-932.