...
. WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANT~
REGIONAL OFFICE FOR THE WESTERN PACIFIC BUREAU R~GIONAL DU PACIFIQUE OCCIDENTAL
REGIONAL COMMrTTEE Thirteenth Session Manila 20- 25 September 1962 Agenda Item 13 THE PATHO-PHYSIOLOGY OF CHOLERAI by
WP/RC13/7 18 July 1962 ORIGINAL: ENGLISH
Robert A. Phillips Captain, ~d.ical Corps, United States Navy United States Naval Medical Research Unit No. 2 (NAMRU-2), Taipei, Taiwan
)
1
INTRODUCTION first exposed to this disease in the 1947 epidemic in of the literature disclosed the paucity of preCise aspects of this disease, in particular the absence of of the extent of the physiological derangement.
The writer was Cairo, and a review information on many conclusive evidence
• oJ.. ).
In fact, there was no quantitative information on (1) the extent of the water and electrolyte 10ss;(2) the extent of the acidosisj(3) the tonicity of the body fluids in the disease and (4) the cause of death in the early and in the late stages of this disease - or in other words did a "toxin(S)" cause, or contribute to, the deaths in the stage of collapse and in the stage of uremia, or could these deaths be entirely attributed to the severe, prolonged shock which was present in varying degree in all but the mildest cases.
Further, (5) the wealth of epidemiological information could only be viewed as incomplete; while man and contaminated drinking water were probably the most important vectors, were foods, flies and animals also vectors of any importance, and (6) is any vaccine of any value? The above delineates but a few of the areas in which our Imowledge of this disease was deficient. 2 THE PATHOLOGY OF INTESTINAL MUCOSA IN CHOLERA
It is appropriate now to discuss in more detail what has been a controversial area in cholera. In this instance the problem is pathological and is one which, I believe, has been resolved. /Since the ••• Paper presented at the WHO Meeting of the Scientific Group on Cholera Research, Geneva, Switzerland, 2-7 A~ril 1962 1
HP/RC13/7 page 2 Since the discovery of the Vibrio cholerae by Koch in 1883,1 controversy has raged as to whether there is a loss of the intestinal mucosa as a result of action of the vibrio or its metabolic products. 2 VirchovT was the leading exponent of the denudation hypothesis. This hypothesis 1~S first ably denied by Cohnheim? and his views that there was no loss of mucosal inte~ity were ably supported by the excellent studies of Goodpasture in 1923. Studies by the NAMRU-3 staff in Cairo in the 1947 epidemic demonstrated in several cases that the .Seitz-filtered cholera stool contained about 0.1 gram per cent protein. Since a transudate contains about 2 grams per cent of protein, this was strong evidence that there was no or little denudation of the intestinal mucosa.5 It seemed obvious to us at that time that the proponents of the denudation theory failed to take into account the fact that in severe shock from any cause there may be ischemic damage of the intestine with death of mucosal cells and their subsequent sloughing. It is now evident that the vibrio and its products do not cause sloughing of the mucosal cells (unless the patient has been in severe, prolonged shock). Support for this was provided in 1959 by Dr. Eugene Gangarosa working in collaboration with T~ai physicians and the NAMRU-2 staff in the Chulalongkorn Hospital in Bangl~ok. He passed a Crosby capsule orally into the duodenum, jejunum or ileum and obtained snippets of intestinal tissue which when studied histologically failed to show loss of mucosal continuity. Samples of colon mucosa were also obtained in these cholera patients by attaching the Crosby capsule to a rectal tube: again, there was no loss of mucosal integrity. The coup de grace to the denudation theory was delivered by Dr. R.S. Gordon of the National· Institutes of Health who worked in the NAMRU-2 laboratory in Bangltok in 1959. Dr. Gordon had developed an elegant .method for quantitating protein loss from plasma through the intestine into the bowel lumen. He tagged polyvinylpyrrolidone with iodine 131. PVP was chosen because the material was not attacked by intestinal bacteria. He found that when his 1-131 tagged PVP was infused intravenously into cholera patients there was no greater PVP content in the stool of cholera patients per unit time than there was in the stool of normal individuals.? The above evidence indicated that one must search for an alteration in cell physiology to account for the copious stool. We will discuss the altered physiology in a later section.
• ..y 1.
3
THE ELECTROLYTE LOSSES IN CHOLERA
Studies on cholera patients by English clinicians and chemists in the early part of the nineteenth century and by Schmidt on patients in the Hamburg epidemic in 185 demonstrated for the first time the magnitude of the electrolyte losses. Unfortunately, none of these studies were guantitative.
g
Aron,9 in 1910, reviewed previous chemical studies of the blood in cholera patients and presented results in a small series which he had /studied •••
" page 3
Wf/RC13/7
studied. Aron comments on Schmidt's studies as follows: "However, Schmidt's conclusion that there is a constant withdrawal of water from the blood in stages of collapse has been doubted by several authors because he used too few control subjects". Rogers, 10 in 1909, pointed out the large loss of salts as a result of which he thought that the blood became hypotonic. Aron comments on Rogers' studies as follows: 'The accuracy of his chemical method of estimating the content of chlorides in the blood serum is open to criticism; furthermore, his differences depend upon results showing that the blood of the average healthy Bengalese contains relatively more chloride than that of Europeans". Aron is the first to point out (so far as I am aware) that 'The quantity of salts should be compared in relation to the quantity of water* and then it should be determined whether the loss in salts is proportional to the loss in water, or greater or Ie ss ". Aron aclmowledge s that his observations confirm Schmidt's. Rogers did not determine solids, and Axon presumes, and I think correctly, that Rogers was hence misled into believing that there was a greater. 106S of salt than of water. Unfortunately, there were no analyses of electrolytes in stool water and plasma water in serial samples from the same patient let alone on several patients in any of the literature on this disease prior to 1953. In 1958, at the invitation of the Royal Thai Government, NAMRU-2 conducted studies of the electrolyte losses in cholera in collaboration with Thai colleagues at the Chulalongkorn Hospital. The experimental design l-TaS simple. On admission to the experimental ward, patients were treated entirely by the administration of intravenous fluids for the first twenty-four hours of their hospital stay; neither fluids nor food was allowed by mouth. It was thus possible to relate concentrations of electrolytes in plasma water to the concentration of electrolytes in stool water. If fluids had been given by mouth, this, of course, would not have been possible. It ~aG found that the dehydration was in essence an isotonic dehydration,ll Table la, lb and 2. In other words, the cation concentration in stOol water equalled the cation concentration in plasma water; likewise, the anion concentrations were nearly equal. It was again demonstrated that there was a large loss of bicarbonate ions and that there were large losses of potaSSium ions. The bicarbonate ion loss, first observed by Sellards12 in 1909, ifaS responsible
Ifor the acidosis •••
*Protein in plasma averages about 7 grams per cent. The apparent partial specific volume of human plasma protein is about 0.73. 25 Thus, in a litre of plasma some (70 X 0.73 = 51) 51 ml of the volume would be occupied by protein leaving not 1000 m1 but 949 m1 of water. It is not infrequent to find a plasma protein concentration of 14 grams per cent for the admission value of a cholera patient. In this instance the protein in a litre of plasma would occupy a volume of 102 m1 and there would be only 898 ml of water. Thus in these two examples if there were in both instances 150 mEq of Na per litre of plasma water, then if the recording were made per litre of plasma, the values would be 142.3 and 136 respectively. From the abOve it is obvious that in recording ion analyses in biological fluids the recording should be in units of volume of (plasma) blood, etc.) water.
page 4- .
WP/RC13/7
for the acidosis. It was also found that the potassium loss could result in a 15-30 per cent deficit of the body potassium stores in patients who experienced a severe diarrhoea for four or five days.13 There have been proponents of hypo-, iso- and hypertonic solutions in the treatment of cholera. These studies demonstrated for the first time that the electrolyte loss was an isotonic one and in the average case the ideal treatment would be the administration of a solution with the following composition, Table 3. Our stUdies also explained why hypertonic solutions have senerally given better results than hypotonic solutions. If the patient is allowed water by mouth, then a hypertonic solution would have to be given intravenously in order to provide an isotonic stool; this assumes that the electrolyte losses are under a feed-back type of control. In a cholera epidemic it is impossible to give each patient ideal treatment. The number of admissions is usually so great that the hospital staff and the laboratory facilities are usually overwhelmed. A simple adequate method of therapy for the avefage patient was developed on the basis of our experience in Cairo in 1947. 14 This treatment regimen which relies on isotonic NaCl and 2 per cent sodium bicarbonate solutions was tested in Bangkok in 1958, 1959 and 1960 and a refined therapy version has been published. 15 On the basis of our experience in Manila in the fall of 1961, the procedure has been further simplified. Present suggestions will be presented later at these meetings. Briefly, we have found, in confirmation of the work of Sellards12 and Rogers,lO that one cannot ignore the acidosis without increasing mortality. On the contrary, in the mild cases one can ignore the potassium loss without increasing mortality. The bicarbonate loss is of a magnitude that if one gives 1 litre of 2 per cent bicarbonate for every 3 litres of normal saline solution, the acidosis will be treated suffiCiently so that the patient's life is not jeopardized. In our experience, if the diarrhoea doe s not exceed 3 litre s per 24 hours and it does not last more than 3 days, then one does not have to provide potassium intravenously in the uncomplicated case. On the other hand, it should be pointed out that since the potassium concentration in stool water averages from 10 mEq per litre in patients with large stool volumes (10-15 litres per 24 hOurs) to 15 mEq in patients with lower stool volumes (3 litres per 24 hOurs) one probably can add 10 mEq of potassium to each litre of intravenous fluid with impunity regardless of urine output. Further there is evidence that the potassium loss in this disease is responsible for some of the renal damage in cholera. lb There is available an abundance of data supporting the value of intravenous NaCl and NaHCO~ in the treatment of cholera.8,11,1~,14 While there is some informati6n on the potassium 10ss,5,11,13,10 we believe there is not sufficient information to mal~e sweeping therapeutic recommendations. For this reason, it is our present recommendation that potassium not be incorporated into the stock solutions butshotild be-added on the physician I s recommendation in each individual case.
•
/4
THE •••
WP/RCl3/7 page 5 4 THE OVERPRODUCTION THEORY
Occasionally one hears of attempts to argue that the voluminous diarrhoea is the result of an outpouring of fluid into the gut lumen in a volume in excess of the absorptive ability of the intestine. A brief consideration of diabetes insipidus will serve to eliminate this theory. There are numerous instances in the literature documenting the fact that patients with diabetes insipidus have produced a volume of urine in 24 hours equal to more than two-thirds their body weight. Figure 1 illustrates this situation. The information was obtained from a patient on our Taipei wards and it will be seen that his urine output per 24 hours averaged about 75 per cent of his body weight for this seven-day period. This rate of absorption of fluids is about twice the rate of.stool output we have seen in cholera patients. It is thus evident that in cholera we must be dealing with a defect or failure in the reabsorptive ability of the intestine. 5 THE PHYSIOLOGICAL THEORY OF CHOLERA
As the result of our studies of cholera in Bangkok in 1958, we postulated that the diarrhoea could be explained as a result of "sodium pump" inhibition due to matabolic products of the vibrio. ll The evidence for this concept is now presented. Visscher and his colleagues in 194417 ,18 and Berger and Steel19 have documented, by the use of isotopes, the movement of large volumes of electrolyte solutions, (1) from plasma to gut lumen, and (2) from gut lumen to plasma in normal dogs. If their studies can be directly transposed to man, the following would be true: in a 50-leilo man, a total of 40 to 80 litres of fluid would pa.ss from his plasma into the gut lumen and back again in 24 hours; thus the net fluid flux is zero. Visscher's studies have also shown that this flux of fluid from gut lumen to plasma is accomplished primarily by an active transport of sod.ium. There is still debate as to whether there is also active transport of water, chloride and other ions. Visscher's stUdies demonstrated that the flux from lumen to pla.sma could be inhibited by a variety of metabolic poisons. It was our theory that the source of the enormous stool volumes which occur in cholera and which produce the rapid profound, dehydration is due to inhibition of the "sodium pump" of the intestinal mucosal cells by metabolic products of the vibrio. In consequence of the above we decided to attack ~he~robl~m directly using the procedures developed in Ussing's laboratory. 0, ,22, 3 A schematic diagram is shown in Figure 2 and results of a typical experiment in Figure 3. Studies in Bangkok in 1960 revealed the presefce of a sodium pump inhibitor in the stool water of cholera patients. 2 A sodium pump inhibitor could not be found in the stool water of normal heal thy individuals. This observation was verified in Dacca in 1961 at the SEATO Cholera Research Laboratory, in Hong Kong in the late summer of 1961, and again in Manila in the fall of 1961. /This finding •••
WP/RC13/7 page 6 This finding is consistent and we have also found a sodium pump inhibitor in the plasma of three patients in our Manila series who were experiencing a severe attack of the disease. We have found this sodium pump inhibitor to be thermolabile which makes unlilcely the possibility of it being an endotoxin. Further, we have tested purified endotoxins from several sources and they do not inhibit the frog sInn sodium pump. We have found the material to be dialyzable and we are making every effort to characterize and identify it. To date we have found no difference between the sodium pump inhibitor obtained from stools of patients with classical cholera or from stools of patients whose disease is caused by the El Tor vibriO. studies in the Philippines have revealed a rather high incidence of "carriers", that is, individuals who ha.ve vibrios in their gastrointestinal tract but who do not have diarrhoea. There are two obvious alternative explanations which would explain the situation. Either the individual who is a carrier does not provide the vibrio with the necessary metabolic ingredients to produce the sodium pump inhibitor, or there is an X factor in the individual who acquires the disease which permits the sodium pump inhibitor to penetrate the mucosal cell; this X factor not being available to the "carrier ". We hope to obtain an answer to this problem in our next field studies. If cholera vaccine does provide some protection against this disease or ameliorates the course, and if our present concept of the machanism for the elaboration of the stool in cholera is correct, then our classical notions on the mechanism of action of vaccines will have to undergo considerable modification.
<
6
SUMrIARY
Since 1958, great advances have been made in our understanding of cholera. Included in these achievements are the following: 1. The theory that the cholera stool is a sort of transudate which results from the sloughing of the intestinal mucosa has been disproved and it has been demonstrated that there is no loss of mucosal integrity and that large synthetic molecules, which approximate the physico-chemical properties of the albumin molecule, do not readily pass from plasma to gut lumen. 2. The electrolyte and water losses have been studied quantitatively and it has been found that the electrolyte loss is essentially an isotonic loss but with stool potassium and stool bicarbonate much higher than is the concentration of these ions in plasma water; there is a proportionate decrease in the concentration of sodium and chloride ions in the cholera stool.
3. A theory has been propounded to explain the very copious water and electrolyte loss in this disease. This theory invokes the elaboration by the chOlera vibrio of an inhibitor of the active sodium transport by / the mucosal •••
page
WP/RCl3/7 7/8
the mucosal cell. Such a sodium pump inhibitor has been found. repeatedly in the stools of patients suffering from classical Asiatic cholera and from disease due to the El Tor vibrio. Despite the above, much remains to be ascertained. would include:
In this area one
4. 5·
The effectiveness of vaccines. The explanation of the carrier state. The role of nutrition in cholera. The elaboration of the epidemiology of the disease.
6. 7.
8. Is the inability to reproduce the disease with regularity in animals a fact or an artefact? 9. Does the low attacl{ rate in this disease of high mortality (in the untreated clinical case) indicate the presence of an auto-immune component?
WP/RC13/7 page 9
REFERENCES 1.
Koch, R. (1884) Vierter bericht des leiters der deutschen wissenschaft1ichen cOmmission zur erforschung der cholera, geheimen regierungsRaths Dr. Koch. Dtsch. med. Wschr. 10, 63. Virchow, R. (1879) Gesamme1te ubhand1ungcn auf dem debiete der affent lichen Medizin, Berlin, vol. 1, p.151. Cohnheim, J.F. (1889-1890) Lectures on eneral atho10 ---a handbook for ractitioners and students, London translated from the 2nd German edition by McKee, A.B.
2.
4. 5. 6.
Goodpasture, E.W. (1923) Histopathology of intestine in cholera. Philipp.J.Sci. (Sect.B), 22, 413. We E;l.ver, R.H., Johnson, M.K., and Phillips, R.A. (1948) Biochemical studies of cholera. J.Egypt.pub1.Hlth Ass., 23, 5. Gangarosa, E.J., Beisel, W.R., Benyajati, C., Sprinz, H., and Piyaratn, P. (1960) The nature of the gastrointestinal lesion in Asiatic cholera and its relation to pathogenesis: A biopsy study. Amer.J.trop.Med., 2, 125. Summary of SEATO Conference on Cholera. 1.§., 323. (1961) Pub1.Hlth.Rep.(Wash.)
7. 8. jL
Po11itzer, R. (1959) Cholera (World Health Organization: Monograph Series No. 43)
9. 10.
Axon, H. (1910) The chemical composition of the blood in Asiatic cholera. Philipp.J.Sci. (Sect.B),
2,
395
Rogers, L. (1909) The treatment of cholera by injections of hypertonic saline solutions with a simple and rapid method of intraabdominal administration. Phi1ipp.J.Sci. (Sect.B), !, 99 Watten, R.H., Morgan, F.M., Songlilila, Y. na, Vanikiati, B., and Phillips, R.A. (1959) Water and electrolyte studies in cholera. J.c1in.Invest., 38, 1879. Sellards, A.W. (1910) Tolerance for alkalies in Asiatic cholera. Phi1ipp.J.Sci. (Sect.B), 2, 363 Watten, R.H., and Phillips, R.A. (1960) Potassium in the treatment of cholera. Lancet, 999. Johnson, M.K., Weaver, R.H., and Phillips, R.A. (1948) of cholera. J.Egypt.publ.Hlth Ass., 23, 15. The treatment
11.
12. 13. 14. 15.
Morgan, F.M., Watten, R.H., Bidyabhed, L.B., Vejasalmhi, L.P., Bangxang, E., na, and Phillips, R.A. (1959) Treatment of cholera. J.med.Ass.Thai1and, 42, 413. /16. Benyajati •••
WP/RC13/7 page 10· 16. Benyajati, C., Keop1ug, M., Beisel, W.R., Gangarosa, E.J., Sprinz, H., and Sitprija, V. (1960) Acute renal failure in Asiatic cholera: Clinicopathologic correlations with acute tubular necrosis and hypolcalemic nephropathy. Ann.intern.~d., 2,g, 960. Visscher, M.B., Varco, R.H., Carr, C.W., Dean, R.B., and Erickson, D. (1944) Sodium ion movement between the intestinal lumen and the blood. Amer.J.Physiol., 141, 488. Visscher, M.B., Fetcher, E.S., Jr., Carr, C.W., Gregor, H.P., Bushey, M.S., and Barker, D.E. (1944) Isotopic tracer studies on the movement of water and ions between intestinal lumen and blood. Amer.J.Physiol., 142, 550. Berger, E.Y., Kanzaki, G., Homer, M.A., and Steele, J.M. (1959) Simultaneous flux of sodium into and out of the dog intestine. AlDer.J .Physiol., 196, 74 Us sing, H.H., and Zerahn, K. (1951) Active transport of sodium as the source of electric current in the short circuited isolated frog skin. Acta Physiol.scand., 23, 110.
17.
18.
19.
20.
21. 22. 23.
Ke ofoed-Johnsen , V., and Ussing, H.H. (1958) The nature of the frog sldn .potential. Acta physiol. scand., 42, 298 Us sing, H.H. (1960) The frog skin potential. J.gen.Physiol., 43, 135. Ussing, H.H. (1960) Handbuch der expcrimentellen phurmakologie, vol. 13, O.Eichler and A.Farah: Eds. Springer-Verlag, Berlin, Gottigen, Heidelberg. Huber, G.S., and Phillips, R.A. (1960) Cholera and the sodium pumpNAMRU-2 Research Report MR005.09-1040.1.7. Van Slyke, D.D., Hiller, A., Phillips, R.A., IDw11ton, P.B., Dole, V.P., Archibald, R.M., and Eder, H.A. (1950) The estimation of plasma protein concentration from plasma specific gravity. J.biol.Chem., 183, 331.
24. 25.
,~'-,
,
,
e Period Time
.' Hcrt
TABLE 10
e
,t
:'{
·t
WHOLE BLOOD and PLASMA VALUES in PATIENTS with LESS THAN 3 LITERS of STOOL per 24 HR. Blood Sp.Gr. Plasma mEq I L Plasma Weter (Gb) (Gp) CO2 K No CI Osmolarity Total* (mOsm/L) Protien
Potient
(Ve)
7
Admission Rehydration 2 Hours 24 Hours Convalescence (Died) Admission Rehydration 2. 5 Hours 24 Hours Convalescence 4 Days Admission Rehydration 3 Hours 24 Hours Convalescence 2 Days Admission Rehydration I Hour 24 Hours Convalescence 2 Days
40 1.057 30 48 49 31
-
9
20
54 1.064 4I 55 39 49 37 50 57 1.064 47 58 47 36 38 49
--
1.029 28 25
-
19.7 18.3 17.4
-
151 150 151
.
-
113 121 126
4.6 4.0 3.6
-
-
314 324 337
-
8.1 7.8 6.7
-
53 I. 065 47 58 37 49 38 51 24' Admission 53 1.062 Rehydration I Hour 54 46 24 Hours 42 52 Convalescence 4 Days 41 49 Admission 41 1.059 25 Rehydration 2 Hours 30 48 24 Hours 46 28 Convalescence 2 Days 29 48 Admission Mean 49.7 62 Values Rehydration 40.2 54 35.5 49 24 Hours Convalescence 36.6 49 4056Normal 44 Ranges 58 * Derived from Gp
23'
-
1.034 25 23 22 1.034 27 23 23 1.035 30 25 26 1.032 26 26 24 1.034 27 25 28 33 27 25 25 2527
2 I .5 17.6 23.8 17.0 15.6 22.6 35.5 19.8 21.1 3 I. 7 28.2
-
152 153 156 150 151 154 153 145
122 137 139 116 121 128 126 119 117 108 "5 116 112 104 118 116 124 127 122 121 118 121 124 118 107114
5.2 5.1 3.2 3.3 7.5 5.8 5.7 4.2 5.4 4.0 3.8 3.5 2.8 3.2 3.9 3.5 4.2 3.4 3.2 3.5 5.0 4.3 3.9 3.6 3.85.4
313
-
318 286 307 306 306 304
167 137 154 151 23.4 148 22.9 139 24.1 143 136 13.2 15/ 2 1.5 154 19.3 147 20.0 148 19.1 153 19.5 148 23.0 151 26.9 146 25.7- 14630.0 156
320 301 30 !
302 272 298 297
-
293 308 312 313 291 280300
10.0 6.7 5.9 5.5 10.0 7.4 5.9 5.9 10.4 8.5 6.7 7.0 9.3 7.0 7.0 6.3 10.0 7.4 6.7 7.8 9.6 7.5 6.5 6.5 7.2 7.8
I I I I
i
, Initially rehydrated with 5% dextrose in distilled water.
i~ ~ .......... -J
..... ~
TABLE Ib WHOLE BLOOD and PLASMA VALUES in PATIENTS with MORE THAN 3 LITERS of STOOL per 24 HRS. Patient Period
'd~
1j!6~ I-' I-..J
£XI
'!!.. o
-----
Ho't Time (Ve)
Blood Sp. Gr. Plasma mEq/L Plasma Water (Gb) (Gp) C02 No Cl ,-.-----,----.
Osmolarity Totol It K (mOsm/L) Protein ,
"-) \>I -..J
.......,
l
2
Admission Rehydration 2 Hours 24 Hours Convalescence 7Days .~
__
""_"",.~",
_ _ _ _ ,,,_.•
52 1.067 50 65 3I 45 35 50 _~
....
_~
________
1.042 :3 2 2:.3 23 .~_,~~_~
_ _ _ _ _ .......... __ .·_· _ _ _ ..-._¥IT'..
22.2 ! 8 .3 27 , 6 29.3
162 I 49 160 !57
Ii 9 I I6 I 22 120 ! II
4.5 4 .3 2. 8 3.8 _·,_~.~'"
! 3.0 9 .3
__ ....,,_ _ •_ __._ ....... ___....... __ ..__..........." _ _ .........i
343 305
5 .9 5.9
,
6
. I
~
8-"
Admission Rehydration 2 Hours 24 Hours Convalescence 4 Days Admission
44 1.060 29 44 25 43 25 40 .-.-.----- 6 j-"'L 0 7 3
----1·:04 3--~2-2-:-i--l·-5 8 30
1.038 15.0 149 26 16 3 152 2514.9162 22 28.0 149
1.2.6 146 ! 12 I24 124 108
3.5 3. I 2.8 2.2
305 302 328 280
11,2 7.0 6.7 5.5
i~-l 3--5~2-------T3A
-JI i !I'
~1-14-·-·~;~~~- ~=--~rl.-o~~-i~OrrIf i:1r:1f-:-f-I~1T:fl '. Rehydration I ,5 Hours 24 Hours Convalescence 4 Days
~~ '; 4. 4. !
5~
52
53
~ I.. i c.3,1 28;2? . 4 27
I 5 () 159 I 42
~ .~
3.9 :3 . 3
~~0 3,54 279
~ 5 7.4 7 .8
I
.
I I I !
2:3 . 9 I 5 2 ! 2 0 3.I 300 7 .0 . 28 . ! I 48 Ii2 3 .3 ~, I 2 7.0 ; 1--1-5--Ad~i~~;~n------·----·---·6-2- ..·-!-.(J 72 -"-'-l"~ (}39 ·-··--20·~5·- . ·15-5 ~-··i"-i-7----4~9·-~···--·=·-- ..--..--·i!·~-5--·1
2 4 Hours Convalescence 6 Days
4 i 5 :3 36 52
2 () 26
!
Rehydration 0.5 Hour 52 59 2.4 Hours 38 54 Convalescence -r Days 43 52 c ..._._~ _ _ .'" _ _ _, _ ._ _ _ ..__.'__ ............ _., •.•••"..... ,., ,., ............. __., .",. ..... 0' I
2.9 23.0 ::26 40.3 2:3:3 ~1. 3 '.. . I f"l1£1(-1 • '-
147 ! 77 I 52 .~<;
124 i28 I I0 .' ... , ............ _ l!h
6.4 362 a. I , 2.8 348 7,0 ! 3 . 4 " 5 . 9 ! .....- _.....,._•.•••• , ••- ...... ,,-- ...- ........~... - ... , ..- .......1
I '-
~ehyd~~~i~~ 24 Hours
"dm'l",ri""
2 Hours
~8 37
;::0
I
.. 58 51
07C1
29 I 9:4 ;4'5 ~:9
., Q
f)
Meon-- ~;~::i~~ce_,,~:_ .~~~s Values
·-~.·~~8"--~~·-··· . ~~--~ ~~: ~ ...:"~~- ..-.+~~.,, ",,,~,: ~ ~~.~-- 'i'~'~-~---ll ·:14.2 :35 . 5 56 50
2525.9156
; i9 125
5 9
10
6 : :3 3.6
3i3 31i
6.7,
8.'(
-11
! I
;~~:~~~~~-.-=-·:~·Igil· :. g;t.l?t ~litj?~··--tl-iit-ti:1 'It Derived
Rehydration 24 Hours
2: 5
20.''') 26. 0
149 !6 I
122 126
4.9 3. 2
325 32 6
8.2 6.6
from Plosma Specific Gravity
-.J
I
1..-_ _ _ _ ._____________...______....____....... __ • ___..............._ ......- ... ---......... -..... - .... - .....- ...~....... - .... " ....- .... -.....- -..~-----------
~
e
•
e
t
'\
t
> ~'
- .' TABLE 2 Urine Volume .
e
i
-..v
I.f\
TWENTY-FOUR HOUR INTAKE AND OUTPUT AND FECAL ELECTROLYTE CONCENTRATIONS IN CHOLERA PATIENTS WITH OVER 3 LITERS OF STOOL. Weight I. V. Fluids Pot~ Sex Age _~~.__ Vo~_ Fecal Volume Fecal Electrolyte Contents Osmolarity (mEq/L) (mOsm/L) CI CO2 K No
----3,465 11,430 6,750 3,125 7,700 8,320 5,650 7,260 10,000 17,435 8,240
-- -130 165 68
I
2 3 5 6 8 10
12 14
15 21
M 28 65 M 83 45 M 30 43 F 15 36 F 30 35 M 38 55 F 23 34 F 23 40 M 58 58 M 34 55 M 23 52
10,200 18,100 12100 6,700 19,400 13,250 10,700 10,500 13,000 21,000 12,880
1,425 305 1,795 1,005 210 360 1,650 1,480 855 1,175 1,665
142 152 135
107 109 123 130 107
33.3 9.5 15.6 13.6
..
-
-
337 328 291 307 311
14.8 16.5
46.3
139 119 132 129
142 122
104 113 93 118 100
16.7 14.3 16.0 9.7 17.3
51.4 42.7 40.2
324 259 297 . 279 279 282 ,~ ............ -J
~~ \);~
TABLE 3.
it Electrolyte Concentrations in Cholera Patients Sample Admission Plasma Stool After Rehydration Plasma Stool 158 138 I 19 I 12 ~t: ......... -3
~
Na+
CI
mEq ILiter H20 HC03K+
Total
154
121 120
18
5
298
128
43 30 41
26
317 311 310
4 19
~
e
.
e .,
f!
y
A../
If'
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e
• FIGURE I
e ', "
,'-i
\~
RELATIONSHIP of BODY WEIGHT to FLUID I NTAKE and OUTPUT in a Case of Diabetes Insipidus
10
II Weight Intake ~ Output
Kg
5
o I 9 20 21 22 23 24 25 December 1961
i! f-tS VI~ ~
FIGURE 2 ELECTRICAL CIRCU ITRY FOR MEASURING ACTIVE TRANSPORT OF SODIUM ION rrW - Millivoltmeter (high impedance input).
It ~! -.J
p. p~ Saturated colomel
electrodes for senSing skin potentials.
E,E!. Silver-silver chloride electrodes connecting chamber to external circuit.
A,t/..-Aerator
connections
----+ . . . . . .11---- ------- --feltl'"-------' DC THE SHORT CIRCUITED FROG SKIN In this method, under conditions of electrical and chemical neutrality, the sodium ion is the only ion exhibiting a net unidirectional flux. This flux is equal to the short circuit current when compared in the some units.
p, A-Microommeter S - Frog skin
oI-
Chamber bathing outside surface of skin. Chamber bathing inside surface of skin.
PD- Potential divider. DC - Source of neutraHzing potential.
All electrical connections to chamber mode through Agor- Ringer bridges.
r
-
•
e
~
,-\
"
l'
e
ilr
e
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~~'
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FIGURE 3 _ .... ~
. . . . . . . . . . . . . . . . IIIWII'
22
t
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20 I18 J 16 ~
IU1
,
I \~, • , I \\
•
TYPICAL BIOELECTRIC RESPONSE OF FROG SKIN EXPOSED TO ACUTE CHOLERA STOOL.
\ \
...-'... ... ,
-
14 ~
\
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"" \
\
12 l 10 ~
\. \.,
\
\ , man
"''''... , ....
SKIN POTENTIAL (mV) _-------=I
8' I
~ StslN _CURRENT (J/A) I I
..L
aMUiillllU
41'
\(
0
2 HOURS
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..........