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Electrolyte disturbances in Liberian children with kwashiorkor
T R O P I C A L P E D I A T R I C S DerriekB. Jelliffe, Editor
Plasma electrolytes and blood p H were measured in recently hospitalized Libedaa children with kwashiorkor. Severe hypokalemia, hypomagnesemia, hyponatremia, and alkalemia were common and important disturbances. Sodium depletion was common, but congestive cardiac [ailure, hypoglycemia, and hypothermia, be[ore and alter treatment, were not. The etiology o[ these disturbances was analyzed. It was concluded that the dietary content o[ electrolytes was an important [actor influencing the development o[ hypokalemia and hypomagnesemia, and that geographic and cultural [actors might be implicated in the cause o[ the other disturbances.
Michael Kingston, M.R.C.P. (London), M.R.C.P. (Edinburgh), D.T.M.H., D.A., Harbel, Liberia, W e s t A[rica
L A R O E differences in electrolyte fluid disturbances in children with kwashiorkor have been reported from several countries, especially in potassium depletion which unjustifiably has been considered to be characteristic of kwashiorkor?, ~ Low tissue potassium levels have been reported from Jamaica a but not from Mexico 4 or the Congo, 5 and the incidence of hypokalemia is highly variable. Magnesium depletion has been considered to be the most important electrolyte disturbance in children with kwashiorkor in Nigeria, s but not elsewhere. 7 There are marked differences in the incidence of hyponatremia, sodium depletion, edema, and cardiac failure; the latter is common in Ja-
From The Firestone Medical Center. Present address: The Foothills Hospital, Calgary, Alberta, Canada.
maica s and K a m p a l a 9 but uncommon in Cape Town, South Africa?0 Severe electrolyte disturbances, especially hypokalemia, were commonly found in malnourished children in Liberia. These disturbances and their clinical manifestations were documented, and their etiology was investigated. The literature was reviewed to determine if the regional variations in electroIyte fluid disturbances in children with kwashiorkor could be explained.
SUBJECTS AND METHODS One hundred children with severe kwashiorkor who were admitted to the Firestone Hospital, Liberia, during a 13 month period between 1968 and 1970 were the subjects for this study. The diagnosis was based on the following signs: apathy, edema, muscle wasting with relative sparing of fat, and Vol. 83, No. 5, pp. 859-866
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The Journal o[ Pediatrics November 1973
Fig. I, 12 and D. Child with severe marasmic kwashiorkor. C, Before treatment. D, Seven weeks after treatment. Age 18 months, weight 5.9 Kg. Plasma electrolytes on admission: Na* 128 mEq. per liter, K + 1.8 mEq. per liter, Mg +§ 0.95 mEq. per liter, urea 9.0 rag. per 100 ml.
F i g . I, A and B. Child with severe kwashiorkor.
Note swollen cheeks, severe edema, severe skin changes, misery, and apathy. Age 24 months, weight 5.5 Kg., plasma albumin 0.73 Gm. per 100 ml. Plasma electrolytes: Na § 115 mEq. per liter, K + 2.0 mEq. per liter, Mg +§ 0.9 mEq. per liter, Ca ++ 3.0 mEq. per liter, arterial pH 7.13.
skin a n d hair dyspigmentation (Fig. 1). T h e mean age was 28 months (range 5 to 72 m o n t h s ) , and only two children were less than one year of age. T h e m e a n weight of the subjects was 60 p e r cent of the fiftieth Boston percentiles 11 (range 47 to 75 per cent). T h e following additional diseases were diagnosed in them: helminthic infestation in 57 patients, 33 due to strongyloidiasis; infective d i a r r h e a in 24; m a l a r i a in 22; pneumonia, measles a n d pertussis, 7 cases each; a n d tuberculosis in 6. Blood glucose concentration was measured in all children with m e n t a l or neurologic abnormalities. T h e t e m p e r a t u r e was recorded twice daily. Plasm a sodium a n d potassium concentrations were measured on admission in 50 of the subjects, a n d o t h e r biochemical m e a s u r e m e n t s were carried out in some of these. A p a r t from a slight bias in favor of critically ill children, consecutively "available" infants were selected for these m e a s u r e m e n t s : shortage of time, initiation of t r e a t m e n t in the author's absence, and b r e a k d o w n of equip-
Volume 83 Number 5
Electrolyte disturbances with kwashiorkor
86 t
ment prevented naeasurement in all cases. The urine specific gravity and sodium and potassium concentrations at the time of passage of the first urine were measured in the majority of children who had electrolyte measurements; all urine passed by 20 hypokalemic subjects was collected during the period of intravenous replacement of potassium to determine approximate retention of potassium in them. Electrocardiograms were recorded in 20 children. Plasma samples from 15 children who were hypokalemic were sent to the Akron City Hospital for measurement of magnesium by the atomic absorption technique. Blood for biochemistry measurements was obtained by femoral vein or arterial puncture. The biochemical methods used were similar to those previously reported. 1~ The reproducibility and normal ranges (in parentheses) of biochemical measurements J were as follows: plasma potassium _+ 0.1 mEq. per liter (3.8 to 4.6), sodium _+ 2.0 mEq. per liter (132 to 145), chloride _+ 3.0 mEq. per liter (90 to 105), calcium _+ 0.5 rag. per 100 ml., urea + 10 rag. per 100 ml., and blood p H _+ 0.1 (7.36 to 7.42). TREATMENT
The children were fed a Casilan formula 13 containing 20 mEq. of sodium and 40 mEq. of potassium. All children received penicillin, chloroquine, and magnesium sulfate in doses of 1 to 2 ml. of a 50 per cent solution intramuscularly daily starting 48 hours after admission. Children with severe sodium depletion initially received a volume of isotonic electrolyte fluid equivalent to 10 per cent of their body weight at the time of admission in four to six hours, half as Ringer's lactate and half as Darrow's solution. Additional sodium bicarbonate or lactate was not given. RESULTS
Results are shown in Table I and Figs. 2 and 3. The most important biochemical disturbance was hypokalemia: Approximately half the plasma potassium levels were less than 2.1 mEq. per liter, and 22 per cent were less than 1.6 mEq. per liter. Severe
Fig. 1, E and F. Child with classical infantile marasmus. E, Before treatment. F, Ten weeks after treatment. Note anxiety, prominent eyes, severe wasting with loss of subcutaneous fat, finger sucking, and absence of apathy, edema, and skin and hair changes.
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The Journal of Pediatrics November 1973
Table I. Biochemical results in 50 children with severe kwashiorkor before treatment ~
Mean biochemical data (No. measured)
Plasma potassium (mEq./L.) (50) Plasma sodium (mEq./L.) (50) Blood pH before treatment (33) Blood pH after treatment (13) Plasma calcium (rag./100 ml.)
Moderate or severe sodium depletion ( N z 23)
Mild or no sodium depletion (N = 27)
1.8 (0.57) (1.0-3.1) 120 (9.4) (100-145) 7.34 (0.14) (7.03-7.49)
2.6 (0.84) (1.3-4.3) 129 (6.2) (116-141) 7.41 (0.12) (7.20-7.64)
7.6
8.4
Plasma urea (mg./100 ml.) (22)
22
17
Mean urine specific gravity~ (26)
1,004 (0.002) (1,001-1,010) 2.9 (1.6) (1.0-7.0) 9.0 (6.2) (1.0-24.0)
1,005 (0.003) (1,001-1,010) 2.8 (1.2) (1.0-4.0) 11.7 (8.0) (1.0-35)
Plasma magnesium (rag./100 ml.) (15)
Mean urine potassium (mEq./L.) (22) Mean urine sodium (mEq./L.) (20) Standard deviation and range (in parentheses)
Mean whole group
Significance O[ difference between means (t test)
2.2 (0.8)
p ~ 0.001
125 (9.4)
p > 0.01
7.36 (0.14)
p > 0.01
7.49 (0.04) (7.37-7.65) 8.0 (6.0-9.5) 1.34 (0.25) (0.9-1.8) 20 (9-45) 1,004 (0.002) 2.9 (1.4) 10.0 (7.0)
are shown adjacent to and under the mean level, respectively.
e~'Urine in some eases was passed and collected following the
hyponatremia was common whereas hypernatremia was absent. Alkalemia (pH > 7.43) was present in 14 of 33 children at the time of admission. Twenty-three children had signs of moderate or severe sodium depletion: severe enophthalmos and skin inelasticity, signs of hypovolemia, and moist mucous membranes. They had significantly lower plasma sodium and potassium values than those without these signs (Table I ) . The following manifestations were due to hypokalemia: The electrocardiograms in 20 hypokalemic children showed ST depression, absent or flat T waves, and prominent U waves, singly or in combination. Supraventricular tachyarrhythmias were present in five of them, 50 per cent of those with a plasma potassium concentration below 1.5 mEq. per liter, and frequent multiphasic ventricular ectopic beats were seen in one other patient. Severe abdominal distension, which rapidly subsided during infusion of potassium, occurred in five children. A complaint of respiratory difficulty in two children without pneumonia was made by their
start o[ rehydratlon.
mothers. One child was unable to walk or support his head. The only manifestations which occurred in all children with severe hypokalemia were apathy, weakness, and hypotonia. The signs described above rapidly disappeared, and the general condition of all subjects showed marked improvement after correction of fluid and electrolyte abnormalities. Cardiac failure did not develop in any child receiving intravenous fluids, although large amounts were often given. Large volumes of hypotonic urine containing low concentrations of sodium and potassium were passed by the majority of children (Table I ) . The urinary excretion of potassium indicated that conservation of this ion was efficient when hypokalemia was severe. The serum potassium levels measured by the author in recently hospitalized malnourished children (older than 1 year) in Tanzania (Table I I ) were significantly different from those of the Liberian subjects (t test: p < 0.001). The incidence and severity of alkalemia increased following rehydration. The
Volume 83 Number 5
Electrolyte disturbances w i t h kwashiorkor
18~ IBBDEHYDRATED 16 ITiTi'INOT
14
Table II. D a t a on serum potassium values in malnourished children before treatment reported from several countries
DEHYDRATED
12 z
5
Place
8
P,
+ :L =E
.=2 Below I(0
110-119 1~0-129 150-139 140-149
PLASMA
SODIUM
NOT DEHYDRATED" m
Mean serum potassium (mEq./L.) No. of , (range in parentheeases i ~es)
Congo ~ M e x i c o ' , !,+
43 :35
jamaica 3 Kampaia I+ Cape Town TM Jakarta ~ Cairo is
23 20 36 34 46
D a k a r 19
MEQ/L
Fig. 2. Plasma sodium in 50 cases of kwashiorkor on admission.
12
8 6 3
DEHYDRATED
Nigeria s Tanzania* Liberia (present series)
5. ! 4.?
I . I - 7 7~
4.0 4.0 :L2-5.d 3.4 4.1 (2.7-6.0) . 3.7 3.8
22 20 50
2.6 3.5 (2.4-5.8) 2.2 (1.0-4.3)
*Unpublished data, measured by the author in Tanzania.
child and hypothermia (temperature < 36 ~ C.) in three during the course of their hospitalization. DISCUSSION
10-1,5 PLASMA
1.6-2.0 2.1-2.5 2.6-3.1 3.2-4-1 POTASSIUM M E Q / L
Fig. 3. Plasma potassium in 50 cases of kwashiorkor on admission. p H was measured in 13 children both before and after rehydration (no sodium bicarbonate or lactate was added to the standard solutions used). In 11 cases it rose above 7.44 and in 7 (50 per cent) it rose above 7.50. T e t a n y developed in two of them following correc}ion of hypokalemia. Fifteen of the 100 subjects died; electrolyte and fluid disturbances were an important cause of death in three cases and severe infection in 12 (6 had septicemia). Severe enteric ulceration and esophageal moniliasis occurred in seven ctiildren (50 per cent incidence at autopsy). Hypokalemic nephrophathy was found in only one of n.ine children who died and who had severe hypokalemia on admission. Hypoglycemia occurred in one
T h e incidence of severity of hypokalemia in malnourished children vary a great deal in different regions (Table I I ) . Potassium depletion occurs when stool and renal losses exceed the dietary content of potassium. Renal losses of potassium are unlikely to have been of major importance, because renal conservation was efficient, with few exceptions (Table I ) . Diarrhea, which is the main cause of abnormal potassium losses in malnourished children, may have been more severe than usual in the subjects because of their high incidence of infective gastroenteritis and strongyloides infestation. However, it is the author's opinion that the most important factor responsible for the high incidence of severe hypokalemia in these subjects and for the regional variations in its incidence is the dietary content of potassium. There are considerable differences in the potassium content of several staple foods utilized in underdeveloped countries (Table I I I ) . I n the Liberian children described here, rice, cassava, and breast m i l k - each very low in potassium--were the main
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The Journal of Pediatrics November 1973
Table I I I . Content of electrolytes in various foods MiUiequivaIents per 100 Gin. Food Rice, white (20-22)
K 2.6 (1.7-3.2) Maize, dried (20-22) 7.9 (7.25-8.5) Sweet dried (20) 10.1 Meal 5.4 Banana (20-21) 9.3 (8.7-10.0) Beans (20) 15.3 Sweet potato (20) 10.0 Leaf vegetables and fruits (20-21) 8.7 (7.5-10.0) Manioc (cassava) (5) 0.6 Breast milk (11) 1.2 Cow's milk (11 ) 3.6 Goat's milk (20) 3.6 Mean levels, with ranges in parentheses, of referred sources.
foods. T h e former two are also staple foods in areas of Nigeria and D a k a r where hypokalemia is reported to be common. Maize contains two to three times the potassium content of rice, and bananas, plantains, beans, and cow's milk contain even more. It is therefore not surprising that hypokalemia is u n c o m m o n in Jamaica, Mexico, Kampala, the Congo, and Tanzania, where one or more of these are staple foods. A 2year-old child who receives all of his caloric intake (1,000 to 1,200 calories per day) as white rice will receive only 8 to 10 mEq. of potassium daily, whereas a child who ingests mainly maize or plantains will receive 30 to 40 mEq. of potassium daily, an a m o u n t sufficient to cover abnormal diarrheal losses of potassium which may be as high as 30 mEq. daily2 a Foods which are low in potassium are also low in magnesium; depletion of these ions will therefore probably coexist, although the low magnesium level will probably be less severe because of its high concentration in the skeleton. T h e cause of the alkalemia may have been the high alkaline ash content of the diet, the development of severe potassium depletion (although there was no correlation between the plasma potassium value and the arterial p H ) , or the chloride depletion. The latter appears unlikely because common salt, which
Mg 0.95 (.6-1.3) 5.0
Na 0.6 (.3-1.1) 1.5
5.0 3.5 1.5 (1.2-1.8)
4.0 1.5 1.8
1.2
3.5 1.8
.19 0.5 0.5
0.3 .55 2.2 3.4
I
Cl 1.t (.8-1.5) 1.2
2.2
1.0 1.25
has a ratio of chloride to sodium higher than that of extracellular fluid, was the main dietary source of sodium. Although hypokalemia has been uncommonly reported in malnourished children, potassium depletion is considered to be characteristic of kwashiorkor because of the low total body potassium values measured isotopically, X, 2~ low cellular concentrations of potassium derived from tissue analysis, 4' 1~, z.~ and retention of potassium in excess of a potassium:nitrogen ( K : N ) ratio of 2.8:1, as demonstrated in balance studies. 1~ Even apart from the large errors involved in the methodology, 7' 2~, 2.~ the preceding data by themselves should not be used to define potassium depletion. Low total body potassium values are more likely to be due to tissue depletion. T h e K : N ratio of children reforming brain ( K : N ratio 6 : 1 ) ~ and muscle ( K : N ratio 3.2: 1) 4 in preference to collagen, which is relatively well preserved, 7 is likely to exceed 2.8: 1. A low cellular potassium concentration (reference water) may have no more significance than the same finding in water intoxication. A low muscle potassium concentration, referred to noncollagen nitrogen ( K : n o n c o l l a g e n nitrogen ratio), may occur soon after admission in children with kwashiorkor, because they are likely to have decreased muscle glycogen, which may bind 10 per cent of muscle potas-
Volume 83 Number 5
slum, 27 or increased basic amino acids (following high-protein feeding) which may displace potassium. A low tissue potassium concentration may also be due to magnesium depletion, 28 hypocalcemia, 2:J abnormal cellular metabolism, 4 or decreased binding by muscle protein. 27 The pathogenesis, significance, manifestations, and treatment of potassium depletion present in the subjects described here are likely to be completely different from what is found in subjects who have low tissue potassium levels in the absence of hypokalemia. It is ambiguous and inappropriate to cover both circumstances by the same definition; potassium depletion may be much less common in malnourished children than the literature would indicate. T h e main causes of death in malnourished children are electrolyte fluid disturbances, infection, cardiac failure, hypothermia, and hypoglycemia. The trapid treatment of electrolyte imbalance--especially h y p o k a l e m i a - was probably the main factor responsible for the marked reduction in the mortality rate (100 per cent) a m o n g the malnourished Liberian children reported here in comparison to the rate in previous years when glucose fluids low in electrolyte content were used in treatment. Hypokalemia m a y cause cardiac necrosis a~ or arrhythmias, ~1 including ventricular fibrillation, 32 which may be precipitated by infusion of glucose fluids containing a potassium concentration of less than 20 mEq. per liter? 1 Severe hypokalemia is likely to remain undiagno~ed and uncorrected in children with kwashiorkor because its only common manifestations are severe apathy and weakness, which are also characteristic of kwashiorkor, per se. Furtherfnore, hypokalemia is likely to develop rapidly because of the low potassium capacity of the malnourished child, which may be two or three times lower than that of a well-nourished child of similar age. Two to three days of severe diarrhea may result in the loss of 60 mEq. of potassium, perhaps one third of a malnourished child's potassium capacity. However, the amount of potassium required
Electrolyte disturbances wzth kwashiorkor
865
for treatment of the same degree of hypokalemia in such a child would be considerably less than that in the normally nourished child; this has important implications for treatment. It is possible that regional cultural and geographic variations also accounted for the absence of cardiac failure and the low incidence of hypoglycemia and hypothermia in our subjects. Thus hypothermia is likely to be more c o m m o n in areas of high rather than low altitude; the prevalence of cardiac failure in malnourished children may be influenced by the sodium content of the diet, factors promoting sodium depletion or excess, and the incidence of associated anemia or vitamin deficiency; and hypoglycemia, reactive in type, m a y be more c o m m o n in areas where starch or sugar intake is excessive prior to hospitalization. Regional variations in culture and geography may influence several disturbances which develop in malnourished children. Potassium and magnesium depletion are not necessarily characteristic of malnourished children. The dietary content of these ions, which is highly variable in different regions, is an important factor in determining the incidence of these deficiencies. REFERENCES
1. Behar, I. M.0 Viteri, F., Bressani, R., et al.: Principles of treatment and prevention of severe protein malnutrition in children, Ann. N. Y. Acad. Sci. 69: 954, 1958. 2. Alleyne, G. A. O.: Studies in total body potassium in infantile malnutrition, CIin. Sci. 34: 199, 1968. 3. Alleyne, G. A. O.: Studies in total body potassium in malnourished infants, Br. J. Nutr. 24: 205, 1970. 4. Metcoff, J., Frenk S., Yoshida, T., et al.: Cell composition and metabolism in kwashiorkor, Medicine 45: 365, 1966. 5. Vis, H., Dubois,R., Vanderborght, H., and de Maeyer, E.: Etudes des troubles electrolytiques accompagnant le kwashiorkor marastique, Rev. Fr. Etudes Clin. Biol. 10: 729, 1965. 6. Caddell, J. L., and Goddard, D. R.: Studies in protein calorie malnutrition, N. Engl. J. Med. 276: 533, 535, t967. 7. Garrow, J. S., Smith, R., and Ward, E. E.: Electrolyte metabolism in severe infantile malnutrition, Oxford, 1968, Pergamon Press, Inc. 8. Garrow, J. S., Picou, D., and Waterlow, J. C.: The treatment and prognosis of infantile
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9. 10. 11. 12. 13. 14.
15.
16. 17.
18. 19. 20. 21.
Kingston
malnutrition in Jamaican children, West Indian Med. J. 2: 217, 1963. Wharton, B. A., Balmer, S. E., Somers, K., et al.: The myocardium in kwashiorkor, Q. J. Med. 38: 107, 1969. Smythe, P. M., Swanepool, A., and Campbell, J. A. H.: The heart in kwashiorkor, Br. Med. J. 1: 67, 1962. Nelson, W. E.: Textbook of pediatrics, ed. 7, Philadelphia, I~)59, W. B. Saunders Company. Kingston, M. E.: Biochemical disturbances in breast-fed infants with gastroenteritis and dehydration, J. PEDIATR. 82: 1073, 1973. Staff, T. H.: Treatment of severe kwashiorkor and marasmus in hospital, East Afr. Med. J. 45: 399, 1966. Frenk, S., Metcoff, J., Gomez, F., et al.: Intracellular composition and homeostatic mechanisms in severe chronic infantile malnutrition. II. Composition of tissues, Pediatrics 20: 105, 1957. McCance, R. A., Crowne, R. S., and Hall, T. S.: The effect of malnutrition and food habits on the concentrating power of the kidney, Clin. Sci. 37: 471, 1969. Hansen, J. D. L., and Jenkinson, V.: Electrolytes and nitrogen metabolism in kwashiorkor, S. Afr. J. Lab. Clin. Med. 2: 206, 1956. Tumbelaka, W., Ranti, I., Sunarwati, T., and Kho, L.: Sodium and potassium content of serum in dehydrated children, Pediatr. I n donesia 5: 689, 1965. Diwany, M., et al.: The story of kwashiorkor, Pediatr. Indonesia 5: 543, 1965. Senecal, J.: The treatment and prevention of kwashiorkor in French West Africa, Ann. N. Y. Acad. Sci. 69: 916, 1958. Shermann, H. C.: In McLester, J. S., editor: Nutrition and diet, ed. 2, Philadelphia, 1931, W. B. Saunders Company. McCanee, R., and Widdowson, E. M.: The
The Journal o[ Pediatrics November 1973
22.
23. 24.
25.
26. 27. 28. 29. 30.
31.
32.
composition of foods, ed. 3, Her Majesty's Stationary Office, 1969, Medical Research Council. Bills, E., McDonald, F. G., Nedermier, W., and Schwartz, M. G.: Sodium and potassium in foods and associated waters--determination by the flame photometer, J. Am. Diet Assoc. 25: 304, 1949. Waterlow, J. G., and Mendes. C.: Composition of muscle in malnourished infants, Nature 180: 1361, 1957. Threefoot, S. A.: Some factors influencing interpretation of studies of body water and electrolytes with isotopic tracers, Progr. Cardiovasc. Dis. 5: 32, 1962. Barnes, B. A., Gordon, E. B., and Cope, O.: Skeletal muscle analyses in health and in certain metabolic disorders. I. Method of analyses and values in normal muscle, J. Clin. Invest. 36: 1239, 1957. Garrow, T. S.: Loss of brain potassium in kwashiorkor, Lancet 2: 643, 1967. Alleyne, G. A. O.: Personal communication, 1971. Whang, R., and Welt, L. G.: Observations in experimental magnesium deficiency, J. Clin. Invest. 42: 305, 1963. Copp, D. H.: In Mineral metabolism, Comar and Bronner III, 1969, p. 434. Perkins, J. G., Petersen, A. B., and Riley, J. A.: Renal and cardiac lesions in potassium deficiency due to chronic diarrhea, Am. J. Med. 8: 115, 1950. Kunin, A. S., Surawicz, B., and Sims, E.: Decrease in serum potassium concentrations and appearance of cardiac arrhythmias during infusion of potassium with glucose in potassium depleted patients, N. Engl. J. Med. 266: 228, 1962. Tamura, K., Tamura, T., and Yoshida, S.: Transient recurrent ventricular fibrillation due to hypopotassemia, Jap. Heart J. 70: 1, 1965.
Plasma electrolytes and blood p H were measured in recently hospitalized Libedaa children with kwashiorkor. Severe hypokalemia, hypomagnesemia, hyponatremia, and alkalemia were common and important disturbances. Sodium depletion was common, but congestive cardiac [ailure, hypoglycemia, and hypothermia, be[ore and alter treatment, were not. The etiology o[ these disturbances was analyzed. It was concluded that the dietary content o[ electrolytes was an important [actor influencing the development o[ hypokalemia and hypomagnesemia, and that geographic and cultural [actors might be implicated in the cause o[ the other disturbances.
Michael Kingston, M.R.C.P. (London), M.R.C.P. (Edinburgh), D.T.M.H., D.A., Harbel, Liberia, W e s t A[rica
L A R O E differences in electrolyte fluid disturbances in children with kwashiorkor have been reported from several countries, especially in potassium depletion which unjustifiably has been considered to be characteristic of kwashiorkor?, ~ Low tissue potassium levels have been reported from Jamaica a but not from Mexico 4 or the Congo, 5 and the incidence of hypokalemia is highly variable. Magnesium depletion has been considered to be the most important electrolyte disturbance in children with kwashiorkor in Nigeria, s but not elsewhere. 7 There are marked differences in the incidence of hyponatremia, sodium depletion, edema, and cardiac failure; the latter is common in Ja-
From The Firestone Medical Center. Present address: The Foothills Hospital, Calgary, Alberta, Canada.
maica s and K a m p a l a 9 but uncommon in Cape Town, South Africa?0 Severe electrolyte disturbances, especially hypokalemia, were commonly found in malnourished children in Liberia. These disturbances and their clinical manifestations were documented, and their etiology was investigated. The literature was reviewed to determine if the regional variations in electroIyte fluid disturbances in children with kwashiorkor could be explained.
SUBJECTS AND METHODS One hundred children with severe kwashiorkor who were admitted to the Firestone Hospital, Liberia, during a 13 month period between 1968 and 1970 were the subjects for this study. The diagnosis was based on the following signs: apathy, edema, muscle wasting with relative sparing of fat, and Vol. 83, No. 5, pp. 859-866
860
Kingston
The Journal o[ Pediatrics November 1973
Fig. I, 12 and D. Child with severe marasmic kwashiorkor. C, Before treatment. D, Seven weeks after treatment. Age 18 months, weight 5.9 Kg. Plasma electrolytes on admission: Na* 128 mEq. per liter, K + 1.8 mEq. per liter, Mg +§ 0.95 mEq. per liter, urea 9.0 rag. per 100 ml.
F i g . I, A and B. Child with severe kwashiorkor.
Note swollen cheeks, severe edema, severe skin changes, misery, and apathy. Age 24 months, weight 5.5 Kg., plasma albumin 0.73 Gm. per 100 ml. Plasma electrolytes: Na § 115 mEq. per liter, K + 2.0 mEq. per liter, Mg +§ 0.9 mEq. per liter, Ca ++ 3.0 mEq. per liter, arterial pH 7.13.
skin a n d hair dyspigmentation (Fig. 1). T h e mean age was 28 months (range 5 to 72 m o n t h s ) , and only two children were less than one year of age. T h e m e a n weight of the subjects was 60 p e r cent of the fiftieth Boston percentiles 11 (range 47 to 75 per cent). T h e following additional diseases were diagnosed in them: helminthic infestation in 57 patients, 33 due to strongyloidiasis; infective d i a r r h e a in 24; m a l a r i a in 22; pneumonia, measles a n d pertussis, 7 cases each; a n d tuberculosis in 6. Blood glucose concentration was measured in all children with m e n t a l or neurologic abnormalities. T h e t e m p e r a t u r e was recorded twice daily. Plasm a sodium a n d potassium concentrations were measured on admission in 50 of the subjects, a n d o t h e r biochemical m e a s u r e m e n t s were carried out in some of these. A p a r t from a slight bias in favor of critically ill children, consecutively "available" infants were selected for these m e a s u r e m e n t s : shortage of time, initiation of t r e a t m e n t in the author's absence, and b r e a k d o w n of equip-
Volume 83 Number 5
Electrolyte disturbances with kwashiorkor
86 t
ment prevented naeasurement in all cases. The urine specific gravity and sodium and potassium concentrations at the time of passage of the first urine were measured in the majority of children who had electrolyte measurements; all urine passed by 20 hypokalemic subjects was collected during the period of intravenous replacement of potassium to determine approximate retention of potassium in them. Electrocardiograms were recorded in 20 children. Plasma samples from 15 children who were hypokalemic were sent to the Akron City Hospital for measurement of magnesium by the atomic absorption technique. Blood for biochemistry measurements was obtained by femoral vein or arterial puncture. The biochemical methods used were similar to those previously reported. 1~ The reproducibility and normal ranges (in parentheses) of biochemical measurements J were as follows: plasma potassium _+ 0.1 mEq. per liter (3.8 to 4.6), sodium _+ 2.0 mEq. per liter (132 to 145), chloride _+ 3.0 mEq. per liter (90 to 105), calcium _+ 0.5 rag. per 100 ml., urea + 10 rag. per 100 ml., and blood p H _+ 0.1 (7.36 to 7.42). TREATMENT
The children were fed a Casilan formula 13 containing 20 mEq. of sodium and 40 mEq. of potassium. All children received penicillin, chloroquine, and magnesium sulfate in doses of 1 to 2 ml. of a 50 per cent solution intramuscularly daily starting 48 hours after admission. Children with severe sodium depletion initially received a volume of isotonic electrolyte fluid equivalent to 10 per cent of their body weight at the time of admission in four to six hours, half as Ringer's lactate and half as Darrow's solution. Additional sodium bicarbonate or lactate was not given. RESULTS
Results are shown in Table I and Figs. 2 and 3. The most important biochemical disturbance was hypokalemia: Approximately half the plasma potassium levels were less than 2.1 mEq. per liter, and 22 per cent were less than 1.6 mEq. per liter. Severe
Fig. 1, E and F. Child with classical infantile marasmus. E, Before treatment. F, Ten weeks after treatment. Note anxiety, prominent eyes, severe wasting with loss of subcutaneous fat, finger sucking, and absence of apathy, edema, and skin and hair changes.
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The Journal of Pediatrics November 1973
Table I. Biochemical results in 50 children with severe kwashiorkor before treatment ~
Mean biochemical data (No. measured)
Plasma potassium (mEq./L.) (50) Plasma sodium (mEq./L.) (50) Blood pH before treatment (33) Blood pH after treatment (13) Plasma calcium (rag./100 ml.)
Moderate or severe sodium depletion ( N z 23)
Mild or no sodium depletion (N = 27)
1.8 (0.57) (1.0-3.1) 120 (9.4) (100-145) 7.34 (0.14) (7.03-7.49)
2.6 (0.84) (1.3-4.3) 129 (6.2) (116-141) 7.41 (0.12) (7.20-7.64)
7.6
8.4
Plasma urea (mg./100 ml.) (22)
22
17
Mean urine specific gravity~ (26)
1,004 (0.002) (1,001-1,010) 2.9 (1.6) (1.0-7.0) 9.0 (6.2) (1.0-24.0)
1,005 (0.003) (1,001-1,010) 2.8 (1.2) (1.0-4.0) 11.7 (8.0) (1.0-35)
Plasma magnesium (rag./100 ml.) (15)
Mean urine potassium (mEq./L.) (22) Mean urine sodium (mEq./L.) (20) Standard deviation and range (in parentheses)
Mean whole group
Significance O[ difference between means (t test)
2.2 (0.8)
p ~ 0.001
125 (9.4)
p > 0.01
7.36 (0.14)
p > 0.01
7.49 (0.04) (7.37-7.65) 8.0 (6.0-9.5) 1.34 (0.25) (0.9-1.8) 20 (9-45) 1,004 (0.002) 2.9 (1.4) 10.0 (7.0)
are shown adjacent to and under the mean level, respectively.
e~'Urine in some eases was passed and collected following the
hyponatremia was common whereas hypernatremia was absent. Alkalemia (pH > 7.43) was present in 14 of 33 children at the time of admission. Twenty-three children had signs of moderate or severe sodium depletion: severe enophthalmos and skin inelasticity, signs of hypovolemia, and moist mucous membranes. They had significantly lower plasma sodium and potassium values than those without these signs (Table I ) . The following manifestations were due to hypokalemia: The electrocardiograms in 20 hypokalemic children showed ST depression, absent or flat T waves, and prominent U waves, singly or in combination. Supraventricular tachyarrhythmias were present in five of them, 50 per cent of those with a plasma potassium concentration below 1.5 mEq. per liter, and frequent multiphasic ventricular ectopic beats were seen in one other patient. Severe abdominal distension, which rapidly subsided during infusion of potassium, occurred in five children. A complaint of respiratory difficulty in two children without pneumonia was made by their
start o[ rehydratlon.
mothers. One child was unable to walk or support his head. The only manifestations which occurred in all children with severe hypokalemia were apathy, weakness, and hypotonia. The signs described above rapidly disappeared, and the general condition of all subjects showed marked improvement after correction of fluid and electrolyte abnormalities. Cardiac failure did not develop in any child receiving intravenous fluids, although large amounts were often given. Large volumes of hypotonic urine containing low concentrations of sodium and potassium were passed by the majority of children (Table I ) . The urinary excretion of potassium indicated that conservation of this ion was efficient when hypokalemia was severe. The serum potassium levels measured by the author in recently hospitalized malnourished children (older than 1 year) in Tanzania (Table I I ) were significantly different from those of the Liberian subjects (t test: p < 0.001). The incidence and severity of alkalemia increased following rehydration. The
Volume 83 Number 5
Electrolyte disturbances w i t h kwashiorkor
18~ IBBDEHYDRATED 16 ITiTi'INOT
14
Table II. D a t a on serum potassium values in malnourished children before treatment reported from several countries
DEHYDRATED
12 z
5
Place
8
P,
+ :L =E
.=2 Below I(0
110-119 1~0-129 150-139 140-149
PLASMA
SODIUM
NOT DEHYDRATED" m
Mean serum potassium (mEq./L.) No. of , (range in parentheeases i ~es)
Congo ~ M e x i c o ' , !,+
43 :35
jamaica 3 Kampaia I+ Cape Town TM Jakarta ~ Cairo is
23 20 36 34 46
D a k a r 19
MEQ/L
Fig. 2. Plasma sodium in 50 cases of kwashiorkor on admission.
12
8 6 3
DEHYDRATED
Nigeria s Tanzania* Liberia (present series)
5. ! 4.?
I . I - 7 7~
4.0 4.0 :L2-5.d 3.4 4.1 (2.7-6.0) . 3.7 3.8
22 20 50
2.6 3.5 (2.4-5.8) 2.2 (1.0-4.3)
*Unpublished data, measured by the author in Tanzania.
child and hypothermia (temperature < 36 ~ C.) in three during the course of their hospitalization. DISCUSSION
10-1,5 PLASMA
1.6-2.0 2.1-2.5 2.6-3.1 3.2-4-1 POTASSIUM M E Q / L
Fig. 3. Plasma potassium in 50 cases of kwashiorkor on admission. p H was measured in 13 children both before and after rehydration (no sodium bicarbonate or lactate was added to the standard solutions used). In 11 cases it rose above 7.44 and in 7 (50 per cent) it rose above 7.50. T e t a n y developed in two of them following correc}ion of hypokalemia. Fifteen of the 100 subjects died; electrolyte and fluid disturbances were an important cause of death in three cases and severe infection in 12 (6 had septicemia). Severe enteric ulceration and esophageal moniliasis occurred in seven ctiildren (50 per cent incidence at autopsy). Hypokalemic nephrophathy was found in only one of n.ine children who died and who had severe hypokalemia on admission. Hypoglycemia occurred in one
T h e incidence of severity of hypokalemia in malnourished children vary a great deal in different regions (Table I I ) . Potassium depletion occurs when stool and renal losses exceed the dietary content of potassium. Renal losses of potassium are unlikely to have been of major importance, because renal conservation was efficient, with few exceptions (Table I ) . Diarrhea, which is the main cause of abnormal potassium losses in malnourished children, may have been more severe than usual in the subjects because of their high incidence of infective gastroenteritis and strongyloides infestation. However, it is the author's opinion that the most important factor responsible for the high incidence of severe hypokalemia in these subjects and for the regional variations in its incidence is the dietary content of potassium. There are considerable differences in the potassium content of several staple foods utilized in underdeveloped countries (Table I I I ) . I n the Liberian children described here, rice, cassava, and breast m i l k - each very low in potassium--were the main
864
Kingston
The Journal of Pediatrics November 1973
Table I I I . Content of electrolytes in various foods MiUiequivaIents per 100 Gin. Food Rice, white (20-22)
K 2.6 (1.7-3.2) Maize, dried (20-22) 7.9 (7.25-8.5) Sweet dried (20) 10.1 Meal 5.4 Banana (20-21) 9.3 (8.7-10.0) Beans (20) 15.3 Sweet potato (20) 10.0 Leaf vegetables and fruits (20-21) 8.7 (7.5-10.0) Manioc (cassava) (5) 0.6 Breast milk (11) 1.2 Cow's milk (11 ) 3.6 Goat's milk (20) 3.6 Mean levels, with ranges in parentheses, of referred sources.
foods. T h e former two are also staple foods in areas of Nigeria and D a k a r where hypokalemia is reported to be common. Maize contains two to three times the potassium content of rice, and bananas, plantains, beans, and cow's milk contain even more. It is therefore not surprising that hypokalemia is u n c o m m o n in Jamaica, Mexico, Kampala, the Congo, and Tanzania, where one or more of these are staple foods. A 2year-old child who receives all of his caloric intake (1,000 to 1,200 calories per day) as white rice will receive only 8 to 10 mEq. of potassium daily, whereas a child who ingests mainly maize or plantains will receive 30 to 40 mEq. of potassium daily, an a m o u n t sufficient to cover abnormal diarrheal losses of potassium which may be as high as 30 mEq. daily2 a Foods which are low in potassium are also low in magnesium; depletion of these ions will therefore probably coexist, although the low magnesium level will probably be less severe because of its high concentration in the skeleton. T h e cause of the alkalemia may have been the high alkaline ash content of the diet, the development of severe potassium depletion (although there was no correlation between the plasma potassium value and the arterial p H ) , or the chloride depletion. The latter appears unlikely because common salt, which
Mg 0.95 (.6-1.3) 5.0
Na 0.6 (.3-1.1) 1.5
5.0 3.5 1.5 (1.2-1.8)
4.0 1.5 1.8
1.2
3.5 1.8
.19 0.5 0.5
0.3 .55 2.2 3.4
I
Cl 1.t (.8-1.5) 1.2
2.2
1.0 1.25
has a ratio of chloride to sodium higher than that of extracellular fluid, was the main dietary source of sodium. Although hypokalemia has been uncommonly reported in malnourished children, potassium depletion is considered to be characteristic of kwashiorkor because of the low total body potassium values measured isotopically, X, 2~ low cellular concentrations of potassium derived from tissue analysis, 4' 1~, z.~ and retention of potassium in excess of a potassium:nitrogen ( K : N ) ratio of 2.8:1, as demonstrated in balance studies. 1~ Even apart from the large errors involved in the methodology, 7' 2~, 2.~ the preceding data by themselves should not be used to define potassium depletion. Low total body potassium values are more likely to be due to tissue depletion. T h e K : N ratio of children reforming brain ( K : N ratio 6 : 1 ) ~ and muscle ( K : N ratio 3.2: 1) 4 in preference to collagen, which is relatively well preserved, 7 is likely to exceed 2.8: 1. A low cellular potassium concentration (reference water) may have no more significance than the same finding in water intoxication. A low muscle potassium concentration, referred to noncollagen nitrogen ( K : n o n c o l l a g e n nitrogen ratio), may occur soon after admission in children with kwashiorkor, because they are likely to have decreased muscle glycogen, which may bind 10 per cent of muscle potas-
Volume 83 Number 5
slum, 27 or increased basic amino acids (following high-protein feeding) which may displace potassium. A low tissue potassium concentration may also be due to magnesium depletion, 28 hypocalcemia, 2:J abnormal cellular metabolism, 4 or decreased binding by muscle protein. 27 The pathogenesis, significance, manifestations, and treatment of potassium depletion present in the subjects described here are likely to be completely different from what is found in subjects who have low tissue potassium levels in the absence of hypokalemia. It is ambiguous and inappropriate to cover both circumstances by the same definition; potassium depletion may be much less common in malnourished children than the literature would indicate. T h e main causes of death in malnourished children are electrolyte fluid disturbances, infection, cardiac failure, hypothermia, and hypoglycemia. The trapid treatment of electrolyte imbalance--especially h y p o k a l e m i a - was probably the main factor responsible for the marked reduction in the mortality rate (100 per cent) a m o n g the malnourished Liberian children reported here in comparison to the rate in previous years when glucose fluids low in electrolyte content were used in treatment. Hypokalemia m a y cause cardiac necrosis a~ or arrhythmias, ~1 including ventricular fibrillation, 32 which may be precipitated by infusion of glucose fluids containing a potassium concentration of less than 20 mEq. per liter? 1 Severe hypokalemia is likely to remain undiagno~ed and uncorrected in children with kwashiorkor because its only common manifestations are severe apathy and weakness, which are also characteristic of kwashiorkor, per se. Furtherfnore, hypokalemia is likely to develop rapidly because of the low potassium capacity of the malnourished child, which may be two or three times lower than that of a well-nourished child of similar age. Two to three days of severe diarrhea may result in the loss of 60 mEq. of potassium, perhaps one third of a malnourished child's potassium capacity. However, the amount of potassium required
Electrolyte disturbances wzth kwashiorkor
865
for treatment of the same degree of hypokalemia in such a child would be considerably less than that in the normally nourished child; this has important implications for treatment. It is possible that regional cultural and geographic variations also accounted for the absence of cardiac failure and the low incidence of hypoglycemia and hypothermia in our subjects. Thus hypothermia is likely to be more c o m m o n in areas of high rather than low altitude; the prevalence of cardiac failure in malnourished children may be influenced by the sodium content of the diet, factors promoting sodium depletion or excess, and the incidence of associated anemia or vitamin deficiency; and hypoglycemia, reactive in type, m a y be more c o m m o n in areas where starch or sugar intake is excessive prior to hospitalization. Regional variations in culture and geography may influence several disturbances which develop in malnourished children. Potassium and magnesium depletion are not necessarily characteristic of malnourished children. The dietary content of these ions, which is highly variable in different regions, is an important factor in determining the incidence of these deficiencies. REFERENCES
1. Behar, I. M.0 Viteri, F., Bressani, R., et al.: Principles of treatment and prevention of severe protein malnutrition in children, Ann. N. Y. Acad. Sci. 69: 954, 1958. 2. Alleyne, G. A. O.: Studies in total body potassium in infantile malnutrition, CIin. Sci. 34: 199, 1968. 3. Alleyne, G. A. O.: Studies in total body potassium in malnourished infants, Br. J. Nutr. 24: 205, 1970. 4. Metcoff, J., Frenk S., Yoshida, T., et al.: Cell composition and metabolism in kwashiorkor, Medicine 45: 365, 1966. 5. Vis, H., Dubois,R., Vanderborght, H., and de Maeyer, E.: Etudes des troubles electrolytiques accompagnant le kwashiorkor marastique, Rev. Fr. Etudes Clin. Biol. 10: 729, 1965. 6. Caddell, J. L., and Goddard, D. R.: Studies in protein calorie malnutrition, N. Engl. J. Med. 276: 533, 535, t967. 7. Garrow, J. S., Smith, R., and Ward, E. E.: Electrolyte metabolism in severe infantile malnutrition, Oxford, 1968, Pergamon Press, Inc. 8. Garrow, J. S., Picou, D., and Waterlow, J. C.: The treatment and prognosis of infantile
866
9. 10. 11. 12. 13. 14.
15.
16. 17.
18. 19. 20. 21.
Kingston
malnutrition in Jamaican children, West Indian Med. J. 2: 217, 1963. Wharton, B. A., Balmer, S. E., Somers, K., et al.: The myocardium in kwashiorkor, Q. J. Med. 38: 107, 1969. Smythe, P. M., Swanepool, A., and Campbell, J. A. H.: The heart in kwashiorkor, Br. Med. J. 1: 67, 1962. Nelson, W. E.: Textbook of pediatrics, ed. 7, Philadelphia, I~)59, W. B. Saunders Company. Kingston, M. E.: Biochemical disturbances in breast-fed infants with gastroenteritis and dehydration, J. PEDIATR. 82: 1073, 1973. Staff, T. H.: Treatment of severe kwashiorkor and marasmus in hospital, East Afr. Med. J. 45: 399, 1966. Frenk, S., Metcoff, J., Gomez, F., et al.: Intracellular composition and homeostatic mechanisms in severe chronic infantile malnutrition. II. Composition of tissues, Pediatrics 20: 105, 1957. McCance, R. A., Crowne, R. S., and Hall, T. S.: The effect of malnutrition and food habits on the concentrating power of the kidney, Clin. Sci. 37: 471, 1969. Hansen, J. D. L., and Jenkinson, V.: Electrolytes and nitrogen metabolism in kwashiorkor, S. Afr. J. Lab. Clin. Med. 2: 206, 1956. Tumbelaka, W., Ranti, I., Sunarwati, T., and Kho, L.: Sodium and potassium content of serum in dehydrated children, Pediatr. I n donesia 5: 689, 1965. Diwany, M., et al.: The story of kwashiorkor, Pediatr. Indonesia 5: 543, 1965. Senecal, J.: The treatment and prevention of kwashiorkor in French West Africa, Ann. N. Y. Acad. Sci. 69: 916, 1958. Shermann, H. C.: In McLester, J. S., editor: Nutrition and diet, ed. 2, Philadelphia, 1931, W. B. Saunders Company. McCanee, R., and Widdowson, E. M.: The
The Journal o[ Pediatrics November 1973
22.
23. 24.
25.
26. 27. 28. 29. 30.
31.
32.
composition of foods, ed. 3, Her Majesty's Stationary Office, 1969, Medical Research Council. Bills, E., McDonald, F. G., Nedermier, W., and Schwartz, M. G.: Sodium and potassium in foods and associated waters--determination by the flame photometer, J. Am. Diet Assoc. 25: 304, 1949. Waterlow, J. G., and Mendes. C.: Composition of muscle in malnourished infants, Nature 180: 1361, 1957. Threefoot, S. A.: Some factors influencing interpretation of studies of body water and electrolytes with isotopic tracers, Progr. Cardiovasc. Dis. 5: 32, 1962. Barnes, B. A., Gordon, E. B., and Cope, O.: Skeletal muscle analyses in health and in certain metabolic disorders. I. Method of analyses and values in normal muscle, J. Clin. Invest. 36: 1239, 1957. Garrow, T. S.: Loss of brain potassium in kwashiorkor, Lancet 2: 643, 1967. Alleyne, G. A. O.: Personal communication, 1971. Whang, R., and Welt, L. G.: Observations in experimental magnesium deficiency, J. Clin. Invest. 42: 305, 1963. Copp, D. H.: In Mineral metabolism, Comar and Bronner III, 1969, p. 434. Perkins, J. G., Petersen, A. B., and Riley, J. A.: Renal and cardiac lesions in potassium deficiency due to chronic diarrhea, Am. J. Med. 8: 115, 1950. Kunin, A. S., Surawicz, B., and Sims, E.: Decrease in serum potassium concentrations and appearance of cardiac arrhythmias during infusion of potassium with glucose in potassium depleted patients, N. Engl. J. Med. 266: 228, 1962. Tamura, K., Tamura, T., and Yoshida, S.: Transient recurrent ventricular fibrillation due to hypopotassemia, Jap. Heart J. 70: 1, 1965.