ORAL MAINTENANCE THERAPY FOR CHOLERA IN ADULTS

370

reaction of irritation may be found at any stage and no of red eyes is obtained. The patient with crystal deposition in the conjunctiva in renal failure may have acute renal failure or advanced chronic renal failure (glomerular filtration-rate less than 4 ml. per minute); the common factor is a high plasmainorganic-phosphate with a low or normal plasma-calcium, giving a plasma Ca x P product of more than 70. We have not yet observed a patient in whom the crystals disappeared on administration of aluminium-hydroxide tablets, 6 g. per day, although this apparently relieves the conjunctival injection (i.e., the red eyes, if present, become white). Crystals are often found in patients on regular dialysis (Abrams 1966); this probably reflects either the high Ca x P product before dialysis treatment was started or the intermittently high Ca x P product when dialysis is

no

history

inadequate (underdialysis syndrome). The cause of the limbal-arc calcification of renal failure is being investigated. Preliminary results suggest that this is due to the homoeostasis of hydrogen-ion concentration in the aqueous humor, which causes a relative alkalinity of the aqueous when compared to the plasma in severe renal failure with a high plasma Ca x P product. At the limbus there are two boundary zones in close contact with each other, the high Ca x P product of the plasma with its low pH coming into contact with (1) the higher pH of the aqueous and (2) the surface loss of carbon dioxide from the conjunctival epithelium at this site, causing a higher pH locally. Calcium-phosphate salts deposit more strikingly at the limbus than elsewhere in the eye. I thank Prof. Colbert Phillips for his interest and help and the cooperation of members of his unit, and the Smith Kline and French Foundation for funds to purchase a slit lamp and to allow me to study its use in Dr. E. Davis’ clinic, Hadassah Hospital, Jerusalem. REFERENCES

Abrams, J. D. (1966) Proc. R. Soc. Med. 59, 533. Berlyne, G. M., Shaw, A. B. (1967) Lancet, i, 4. Nilwarangkur, S. (1965) Nephron, 2, 129. Cogan, D. G., Albright, F., Barrter, F. C. (1948) Archs Ophthal. 40, 624. Duke-Elder, S. (1965) System of Ophthalmology; vol. VIII, part 2. London. McCarty, D. J., Kohn, N. N., Faires, J. S. (1962) Ann. intern. Med. 56, 711. —

—

ORAL MAINTENANCE THERAPY FOR CHOLERA IN ADULTS DAVID R. NALIN M.D. Albany

RICHARD A. CASH M.D. New York

RESEARCH FELLOWS

RAFIQUL ISLAM

MAJID

M.B. Dacca

MOLLA

M.B. Dacca CLINICAL PHYSICIANS

Hon.

ROBERT A. PHILLIPS M.B.E., M.D. Washington, St. Louis DIRECTOR

PAKISTAN-SEATO CHOLERA RESEARCH LABORATORY, INSTITUTE OF PUBLIC

HEALTH, G.P.O. BOX

128, DACCA-2,

EAST PAKISTAN

An oral solution containing glucose, sodium chloride, sodium bicarbonate, and or citrate was used as maintenance chloride potassium cholera. In comparison with control for acute therapy intravenous replacement of who received only patients their stool losses, the patients who received the oral solution required 80% less intravenous fluids for cure. This reduction in requirements for intravenous fluids could make therapy for acute cholera in adults more

Summary

widely available.

Introduction INTRAVENOUS fluid replacement of stool water and electrolyte losses is the recognised treatment of shock due to acute cholera (Phillips 1964, 1967, Wallace 1967), but in most areas affected by cholera intravenous fluid is either scarce or not available. An oral therapeutic solution, by reducing intravenous fluid requirements, would make replacement therapy available to larger numbers of cholera patients. We have tested the efficacy of an oral therapeutic solution containing sodium, potassium, bicarbonate, chloride, and glucose. Patients and Methods selected from those admitted to our patients acute diarrhoea whose stool on admission had positive for Vibrio cholera on dark-field examination. All field examinations were confirmed by stool cultures.

ward been darkThe patients were initially hydrated intravenously to treat shock and then assigned to one of the study groups when bloodpressure became normal. The first 20 patients were assigned alternately to the oral-therapy or control (intravenous) groups. The first 10 oral-therapy patients were given a solution containing electrolytes and glucose delivered into the stomach via a thin plastic orogastric tube. The 10 alternate control patients received only intravenous replacement of stool losses after initial rehydration. The next 9 patients were all assigned to oral therapy: these patients drank the solution. All oral solutions were preheated to 40-45’C (Love 1966). Patients in both groups received 250 ,mg. of tetracycline in syrup orally every six hours. The intravenous therapy used was almost entirely " 5/4/1 ", a solution which contains 5 g. sodium chloride, 4 g. sodium bicarbonate, and 1 g. potassium chloride per litre. The concentration of sodium, potassium, bicarbonate, and chloride in 5/4/1is similar to the concentration of these ions found in cholera stool (Phillips 1964, 1967). The first 10 oral-therapy patients (with orogastric tube) received a solution containing 0-5 g. potassium chloride, 4-22 g. sodium chloride, 4 g. sodium bicarbonate, and 20 g. glucose per litre. The 9 patients who drank the solution received 9-25 meq. of potassium per litre (as potassium citrate) instead of 6-5 meq. per litre (as potassium chloride). The potassium citrate improved the taste of the solution. The rate of oral infusion (or drinking) during the first four hours of oral therapy was 750 ml. per hour for patients weighing over 25 kg. and 500 ml. per hour for patients weighing under 25 kg. If the stooling-rate was over 750 ml. per hour during the first four hours an increased infusion-rate was permitted at the discretion of the physician. After the first four hours the amount of oral solution for each four-hour period equalled the amount of stool output plus vomitus of the previous four-hour period. An additional 25-50 ml. per hour was given if it was deemed necessary to replace insensible losses. Initial intravenous therapy was given until plasma sp. gr. was less than 1-030. To prevent a degree of dehydration deleterious to renal function, oral-therapy patients were given additional intravenous therapy if plasma sp. gr. rose above 1-030. When patients were shown to be in positive net gut fluid balance, intravenous therapy was discontinued. Studies were terminated when stooling-rate decreased to levels which did not 29 with

were

require special replacement therapy. All patients were given nothing by mouth, except for the oral solution and tetracycline. Serum-electrolytes were determined as follows: sodium and potassium on a Baird atomic flame photometer and bicarbonate by the Van Slyke manometric apparatus. I Results The patients are compared in tables i and n in terms of

severity of illness on admission as judged by admission examination, vital signs, and duration of diarrhoea,

371

stooling-rates, degree of acidosis, and dehydration. On initial examination all patients were in shock, were hyperventilating, and had notably decreased skin turgor, sunken eyeballs, and dry tongues. Gross stool outputs of all control and oral-therapy patients decreased progressively to normal during treatment. The rate of decrease in gross stool output with time was the same in all groups. Oral therapy did not prolong stooling duration or increase stooling-rate significantly compared with controls (table 11). Oral (Orogastric)

v.

Intravenous

TABLE II-RESPONSE TO

THERAPY*

Therapy

receiving oral therapy by orogastric tube required 78-8% less intravenous fluids than the amount required by control patients for replacement of stool fluid and electrolyte losses (see figure). The average volume of intravenous therapy given before the beginning of the study period was 3494 ml. for the oral-therapy patients and 3400 ml. for the control patients. After oral therapy was begun 3 of 10 patients receiving it were given additional intravenous therapy due to persistent elevation of plasma sp. gr. (1-030-1-031) and oliguria. These 3 patients each received an average of 2 litres of intravenous therapy after the start of oral therapy. The average total volume of intravenous therapy given to patients receiving oral therapy was 4304 ml. In the control group, the average total volume of intravenous therapy was 19,350 ml. After initial rehydration the average total volume of oral solution required for replacement therapy was 19-8 litres. Net positive gut-fluid balance was achieved in less than eight hours in 80% of patients. In 60% of the patients less than four hours were required. In 2 patients with particularly high stooling-rates net positive gut balance was achieved only after sixteen and twenty-four hours of Patients

therapy. Vomiting

was not

of major

significance in the

group

Analysis of the differences recorded in this table revealed only one item of statistical significance: the mean stooling-rate was higher in the control group than in those on oral (intubated) therapy (P<0’05).

which received the solution by orogastric tube and occurred with equal frequency in both the oral therapy and control groups (tables I and II). Average serum-sodium and potassium levels of all oral therapy and control patients remained normal (table 11). Serum-bicarbonate levels of oral therapy patients remained between 26 and 30 meq. per litre. Transient hypokalaemia (2’3-3’C meq. per litre) associated with excessive stool

TABLE I—COMPARISON OF PATIENTS RECEIVING ORAL THERAPY BY OROGASTRIC THE ORAL

SOLUTION, AND CONTROLS

TUBE,

PATIENTS WHO DRANK

372

Fluid

requirements in relation

to

stool volume.

potassium losses was observed in 5 of 19 oral-therapy patients. 3 were being treated with the oral solution with 6-5 meq. per litre of potassium and 2 with the solution containing 9-25 meq. per litre. Later work has confirmed the suitability of an oral therapy solution containing 15 meq. of potassium per litre: transiently low serum-potassium levels were not observed in any of the patients studied. The detailed results of metabolic studies during administration of the oral solution will be published. Urine outputs of 5 control patients and 1 oral-therapy patient were low at the beginning of the study period (4-16 ml. per hour during the first twenty hours of therapy). The oral-therapy patient with oliguria responded well

to treatment.

Patients who Drank the Solution

Patients who drank the oral solution tolerated it remarkably well (figure, table 11). During the first twenty hours patients drank from 400 to 1050 ml. per hour depending on their requirements as calculated from intake and output records. Of the 9 patients who drank the oral solution, 3 vomited insignificant amounts during the first few hours, but had no vomiting afterwards. Lemon juice was sometimes added for taste, causing a drop in bicarbonate concentration to 38 meq. per litre. No other significant change in electrolyte or glucose concentration resulted. Patients found the solution

pleasant

to taste.

Before the start of therapy, the average volume of intravenous fluid given to patients in this group was 2-3 litres. 2 of the 9 patients required intravenous therapy (4-6 and 6-8 litres) in addition to oral therapy during the study period because of persistent dehydration. These were the most severe cases among the oral-therapy patients. The average total intravenous requirement for patients who drank the solution was 3-6 litres-i.e., 19% of the amount required by the average control patient in the first part of this study (see figure). Discussion Phillips (1965) demonstrated that the cholera patient can absorb water, potassium, and bicarbonate from

the gut lumen; and Phillips (1964) investigated the effect of a solution containing sodium chloride, potassium chloride, sodium bicarbonate, and D-glucose on the fsecal loss of water and electrolytes in acute cholera. The D-glucose was absorbed and the solution produced a decrease in the loss of sodium and chloride ions in the cholera stool. Enhancement of net sodium and water absorption was found by Taylor et al. (1967) during intestinal glucose lavage in acute cholera patients. Hirschhorn et al. (1967) and Banwell et al. (1967) described a reduction of net stool output in cholera during glucose and electrolyte lavage. Our findings indicate that an oral solution containing glucose and electrolytes can eliminate the need for over three-quarters of the intravenous-fluid requirement in the therapy of acute cholera in adults. The ingredients of the oral solution are cheap and widely available in virtually all areas affected by cholera. The solution need not be sterile and it can be made up with any suitable drinking-water. Ingredients could be preweighed and stockpiled for use in cholera epidemics. The oral solution does not eliminate the need for initial intravenous therapy to treat shock in severe acute cholera. However, the average minimum intravenous fluid volume needed for the survival of adult cholera patients may be in the range of only 1-5-2-5 litres if oral therapy is begun immediately after admission. 81 % of the total intravenous fluid given to patients who received oral therapy was administered before the beginning of the test period. Other experiments (to be published elsewhere) show that glycine, an actively transported aminoacid, can also serve as a substrate for sodium absorption in a practical oral therapeutic solution in acute cholera; and an investigation of combined glucose and glycine therapy is in progress. We would emphasise that the continued need for intravenous therapy and for careful records of intake and output dictate that specially trained staff must supervise the management of cholera patients who are on oral maintenance therapy. The drastic reduction in the need for intravenous fluids which results from the use of an oral therapeutic solution should make it possible for choleratreatment centres with limited supplies of intravenous fluids to reduce the mortality from cholera to a level previously not possible in the absence of abundant intravenous fluids. Mild cases of cholera (without shock) may be treated with oral solution alone. The Pakistan-SEATO Cholera Research Laboratory is a part of the SEATO Cholera Research Program and is supported by the U.S. Agency for International Development, Department of State, the National Institutes of Health and the National Communicable Disease Center of the Department of Health, Education and Welfare, and by the Governments of Pakistan, United Kingdom, and other SEATO nations. The N.I.H. Cholera Advisory Committee coordinates the research programme. The studies were supported in part by research agreement no. 196802 between the National Institutes of Health, Bethesda, Maryland, U.S.A., and the PakistanSEATO Cholera Research Laboratory. We thank Miss D. G. Torrance and the metabolic-study nursing staff for their invaluable assistance and Mr. Radheshyam Bairagi for the statistical analyses. Requests for reprints should be addressed to D.R.N. REFERENCES

Banwell, J., Pierce, N. F., Mitra, R., Caranasos, G. J., Keimowitz, R. I. (1967) in Symposium on Cholera (edited by R. S. Gordon); p. 187. Palo Alto, California. Hirschhorn, N., Kinzie, J. L., Sachar, D. B., Taylor, J. O., Northrup, R. S., Phillips, R. A. (1967) ibid. p. 195. Love, A. H. G. (1966) J. Physiol. Lond. 185, 80p.