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THE RENAL FACTOR IN THE ALKALOSIS OF POTASSIUM DEFICIENCY
848
THE RENAL FACTOR IN THE ALKALOSIS OF POTASSIUM DEFICIENCY * M. G. FITZGERALD M.B. Birm., M.R.C.P. RESEARCH FELLOW
PAUL FOURMAN M.D. Lond., M.R.C.P. UNIT, CARDIFF ROYAL
were
pooled
Potassium and sodium were estimated by flame photoet al. 1951), chloride in plasma and urine by potentiometric titration (Sanderson 1952) and in the faeces by van Slyke’s method (Hawk et al. 1954), phosphate by Gomori’ss (1942) method, nitrogen and urinary ammonia by microdiffusion (Conway 1950), organic acids in the urine by van Slyke and Palmer’s method (Hawk et al. 1954) after the urine had been stored for some time with hydrochloric acid 2% vlv, creatinine according to Roscoe (1953), plasma pH with a Stadie glass electrode at room-temperature (a correction of -0-014 pH unit per °C was applied for the difference from body-temperature), and urine pH colorimetricany with capillary tubes.
metry (Wallace
SENIOR LECTURER IN MEDICINE
THE MEDICAL
analysed from daily collections and from collections from each experimental period. The latter values were used to compute the cumulative changes. Blood was drawn from a wrist vein, without stasis, into heparinised tubes. The following chemical methods were used :
urine
INFIRMARY
WHEN the cells of the body lack potassium, the extracellular fluid may become abnormally alkaline, though the cells are themselves more acid than normal (Cooke et al. 1952, Black and Milne 1952, Gardner et al. 1952). Studies made during the correction of potassium deficiencies suggested that a movement of H+ ions from the extracellular fluid to the intracellular fluid accounted for the extracellular alkalosis, and that its production did not depend on the kidneys (Orloff et al. 1953). But it has always seemed that the kidneys must play some part in allowing the alkalosis to arise at all (Darrow et al. 1948). The production of the extracellular alkalosis in a clinical deficiency of potassium can best be investigated in a patient who has not already got an alkalosis, and for our study we selected a patient whose deficiency of potassium accompanied a renal acidosis.
The
experiment took the
days, during which the containing 59 m.eq. daily
lasted 32
diet
patient of potassium, 122 m.eq. of sodium, 111m.eq. of chloride, 1.26 g. of phosphorus, and 9.1 g. of nitrogen. The study was divided into three parts : same
18 days without treatment; 3 days with 357 m.eq. (30 g.) daily of sodium bicarbonate added to her diet ; (3) 11 days with 100 m.eq. (10 g.) daily of potassium bicarbonate, as well as the sodium bicarbonate, added to the diet.
(1) (2)
Results
Case-report _
A woman, aged 38, who weighed 64 kg., was admitted hospital because she had become paralysed after a period of increasing weakness, which had lasted 5 weeks. Before that she had been well except for an attack of renal colic 5 years before, when she had passed a stone ; she also admitted to having been unusually thirsty for some months. The level of potassium in her serum was only 1-8 m.eq. per litre. with sodium 139, chloride 111, and bicarbonate In spite of this extracellular acidosis 14 m.eq. per litre. her urine was nearly neutral (pH 6-5) and contained very little titratable acid or ammonia, indicating that her acidosis The urine contained a trace of albumin was of renal origin. but no pus cells, and cultures were invariably sterile. Neither stones nor calcification could be demonstrated in the kidneys, and an intravenous pyelogram revealed no structural change in them. The blood-urea level was 58 mg. per 100 ml. The clearance of inulin was 60 ml. per min., and that of p-aminohippurate 214 ml. per min. In spite of the low plasmapotassium level she was excreting about 40 m.eq. of potassium daily in her urine. The administration of 100 m.eq. of ammonium chloride daily for 2 days did not increase her excretion of acid or of ammonia and did not change the pH of her urine. An infusion of neutral phosphate also had no important effect (cf. Milne et al. 1952). Her serum-calcium level and her urinary excretion of calcium were normal. to
When this patient was treated with potassium chloride and sodium bicarbonate, her potassium deficiency and her acidosis were rapidly corrected. But when we treated her acidosis with sodium bicarbonate alone, 30 g. daily, without correcting her potassium deficiency, this rapidly produced a severe extracellular alkalosis, and her plasma-bicarbonate rose to 45 m.eq. per litre. The same dose of sodium bicarbonate did not produce an alkalosis after her potassium deficiency had been treated with potassium chloride. Several weeks later she readily consented to an experimental study. After letting her become deficient in potassium again we investigated the ability of her kidneys to dispose of a large dose of sodium bicarbonate, and bicarbonate-first then bicarbonate. potassium Methods The procedure for the metabolic balance followed that of earlier experiments (Fourman 1952). Aliquots of *
to the Association of Britain and Ireland in May, 1955.
Paper presented
Physicians
of Great
Period1 When at the beginning of this period, the patient’s treatment with potassium chloride and sodium bicarbonate was withdrawn, she excreted more sodium and potassium than her diet provided. Table i shows OF K, NA, AND CL DITRING FIRST PERIOD WITHOUT TREATMENT, AND COMPOSITION OF PLASMA AT BEGINNING AND END OF PERIOD
TABLE OF
I-LOSSES
18
DAYS
her losses of
potassium, sodium,
and chloride and the
resulting changes in the composition of her plasma. Her deficit of potassium at the end of the period was 340 m.eq., too small to produce any clinical changes but sufficient for the purpose of the experiment. She lost a much smaller amount of sodium and very little chloride. Her plasma-potassium level fell from 4.4 to 3.6 m.eq. per litre; her plasma-sodium level hardly changed. Her plasma-chloride level rose and her plasma-bicarbonate level fell and the pH of her blood at the end of the period was 7-26 ; hence the deficit of potassium was accompanied by an acidosis in the plasma. The packed-cell volume was 41% of her whole blood. Her clearance of endogenous creatinine, a measure of the glomerular filtration-rate, was 76 ml. per minute in this period.
correspondingly,
Period2 When we added sodium bicarbonate 357 m.eq. daily to her diet, she became thirsty and drank more water but excreted less urine ; in 3 days she gained 3 kg. in weight and her face and legs became oedematous (cf. Fourman and Hervey 1955). On the 2nd day Trousseau’s sign was elicited, and on the 3rd day she had spontaneous tetanic- spasms in her hands and feet. Table 11 shows the chemical changes in this period. She continued to lose potassium, but her kidneys excreted only a fraction of the sodium she had taken, and in the
849 TABLE II-CHANGES IN AMOUNTS OF K, NA, AND CL IN BODY AND COMPOSITION OF PLASMA AFTER ADDITION OF 357 M.EQ. OF NAHCOg TO DIET FOR 3 DAYS
3 days of this period the amount of sodium in her body increased by 780 m.eq. ; the amount of chloride in her body did not increase. Her plasma-potassium level, which had already fallen in the first period, fell further Her plasma-sodium level now to 2-5 m.eq. per litre. rose by 10 m.eq. to 145 m.eq. per litre ; but her plasmachloride level fell by - 19 m.eq. to 91 m.eq. ; and her plasma-bicarbonate level rose by 23 m.eq. to 39 m.eq. The pH of her blood was now 7-55 ; so she had a severe The packed-cell volume was extracellular alkalosis. 36% of her whole blood. Her glomerular filtration-rate was 74 ml. per minute, virtually the same as in the
first
remained small at the beginning of the third period. The pH of her urine was 7’2 initially and decreased to 6-8 before the sodium bicarbonate was given ; it then increased to 8-3 and remained about the same after that. The excretion of ammonia averaged 31 m.eq. daily in the period without treatment. At the height of the alkalosis it was 20 m.eq. daily, and it averaged 9-5 m.eq. daily while potassium bicarbonate was given. The changes in the excretion of organic acids, though small, were in the same sense as found by Cooke et al. (1954). The excretion was initially 93 m.eq. daily and decreased to 60 m.eq. daily during the first period. In the second period it was 64 m.eq. daily ; during the first 4 days that potassium bicarbonate was given it increased again to 82 m.eq. daily, and it averaged 72 m.eq. daily after that. Discussion
administration
sodium
bicarbonate 30 g. extracellular alkalosis on the two occasions the patient was deficient in potassium. This amount of sodium bicarbonate does not normally produce an alkalosis (van Goidsenhoven et al. 1954), and we have also established that it did not do so The
daily produced rapidly
of a
severe
period.
Period3 When we now added potassium bicarbonate 100 m.eq. daily to her intake of sodium bicarbonate, her tetany promptly diminished, and after 4 days there was no sign of it. Her weight then decreased, and in the following 7 days she lost her cedema. Table m shows the chemical changes in the first 4 days of this period. She gained 265 m.eq. of potassium. Her kidneys were now excreting all the sodium she was taking and more, with the result that her body lost 90 m.eq. of sodium ; and they excreted less chloride than she was taking, with the result that she gained 155 m.eq. of chloride. The analyses of each day’s collection of urine revealed that the excretion of chloride decreased on the first day that potassium Her plasma-sodium level fell bicarbonate was given. to its original value of 135 m.eq. per litre, her plasmachloride rose, and her plasma-bicarbonate fell. Her alkalosis was largely corrected, and the pH of her blood became normal again. Table 111 also shows the chemical changes in the last 7 days of the experiment, when she lost weight (see figure). She gained a further 258 m.eq. of potassium, _
more
than
enough
to correct her
original deficit ;
and
she lost 302 m.eq. of sodium and 132 m.eq. of chloride. At the end of the experiment the composition of her plasma was normal. Her glomerular filtration-rate was 71 ml. per minute. The results of the other chemical analyses need not be described in detail. During the whole experiment the excretion of nitrogen did not change significantly. The excretion of phosphorus did not change appreciably until the second period, when sodium bicarbonate was given. The amount of phosphate in the urine then decreased, by 240 mg. daily, and it TABLE III-CHANGES IN AMOUNTS OF K. NA, AND CL IN BODY AND COMPOSITION OF PLASMA AFTER ADDITION TO DIET OF 100 M.EQ. OF KHC03 AS WELL AS 357 M.EQ. OF NAHC03 FOR
11DAYS
Changes
in
weight during
3
periods of experiment.
in our patient when her stores of potassium were nearly normal. The experimental observations suggest the following mechanism for her alkalosis :
(1) In 3 days she retained 780 m.eq. of sodium out of 1070 m.eq. taken. Her glomerular filtration-rate had not fallen, and her failure to excrete the sodium could only be explained by assuming that her renal tubules absorbed too much of it. (2) At the same time she retained 3 litres of water, shown by her sudden gain in weight. She became eedematous, and from the change in her hasmatocrit it can be calculated that (if the total volume of her red cells did not change) the volume of her plasma increased by 23 %. Thus the volume of her extracellular fluids had increased. (3) She did not retain a significant amount of chloride ; hence the chloride in her extracellular fluid became diluted, and her plasma-chloride level fell-by 17% of its original value. The concentration of the bicarbonate ion increased to take the place of the chloride ion, and her extracellular alkalosis
was
established.
The part played by her kidneys in the production of her extracellular alkalosis was therefore to reabsorb too much sodium and too little chloride from the glomerular filtrate. Rats’ kidneys seem to do the same when they are deficient in potassium (Cooke et al. 1954, Schwartz et al. 1953, Orent-Keiles and McCollum 1941) but the changes in the function of the rats’ kidneys was not measured directly. Sodium is reabsorbed either in exchange for another In our study the sodium cation or with an anion. reabsorbed in excess of chloride could not have been reabsorbed by an exchange with H, K, or NH4 ions. (whose excretion hardly changed) and it must have been reabsorbed with an anion. Only some of this was phosphate ; so most of the excess of sodium reabsorbed
850 must have formed bicarbonate. The result would be an apparent increase in the reabsorption of the bicarbonate filtered through the glomerulus, as Roberts et al. (1955)
found when they infused sodium lactate into patients deficient in potassium. The renal response we found during an extracellular alkalosis with potassium deficiency is what might ordinarily be expected during an acidosis ; and the intracellular acidosis of potassium deficiency may determine the paradoxical response of the kidneys to the accompanying extracellular alkalosis, as Roberts et a]. (1955) have also suggested. When the patient was given potassium bicarbonate, her kidneys excreted sodium and retained chloridei.e., they were responding normally to an alkalosis and in this way were able to correct her extracellular alkalosis. It is quite remarkable that they began to do this on the day she first had potassium and therefore before there had been any great change in the total deficit of potassium in her body. When potassium is given to a healthy animal, a disproportionate amount is taken up by the kidneys, to be released to the rest of the body only later (Emery et al. 1955). This might enable the kidney cells to return to a normal composition before the other cells of the body during the correction of a deficiency. The therapeutic implications of this experiment may be mentioned. Firstly, the abnormal alkalosis produced by sodium bicarbonate in patients with pyloric stenosis (van Goidsenhoven et al. 1954) may possibly be related to a deficiency of potassium (Black and Jepson 1954) as well as cf chloride. Secondly, it may be dangerous to treat an acidosis with free doses of alkali if the patient also has a deficiency of potassium. An extracellular alkalosis may result which the kidneys cannot rectify, and it may be advisable to add potassium to the treatment.
Summary
.
Sodium bicarbonate 30 g. daily given to a patient with potassium deficiency produced a severe extracellular alkalosis. During the period of this extracellular alkalosis her kidneys reabsorbed too much sodium and water, and she gained 780 m.eq. of sodium and 3 litres of water. But her kidneys did not reabsorb chloride in corresponding amounts, and there was no gain of chloride. When potassium bicarbonate was subsequently added to her treatment, her extracellular alkalosis was rapidly corrected; her kidneys were then excreting sodium and retaining chloride. This is the normal response to an alkalosis. The abnormal response of the kidneys during a potassium deficiency may perhaps be ascribed to the intracellular acidosis which accompanies a potassium
PENNYROYAL POISONING A FATAL CASE
W. B. VALLANCE M.B. Edin. MEDICAL
REGISTRAR,
ROYAL
INFIRMARY, BRADFORD
PENNYROYAL has long had a reputation as an abortifacient, although its action is known to be unpredictable and even dangerous. In the following case it produced abortion, vaginal bleeding, haemolytic anaemia, and acute tubular necrosis of the kidney, with death from urtmia. Pennyroyal is a volatile oil and belongs to the same group as apiol, turpentine, and the oils of savin, tansy, saffron, and rue. It is prepared by distillation of 31
whooping-cough. Case-report
Mrs. A., aged 24, was admitted to a general medical ward at 8.15 P.M. on Oct. 15, 1954, with a tentative diagnosis of drug-sensitivity reaction. She had visited her doctor on the previous day, complaining of general malaise, for which he Three hours before her gave her some codeine tablets. admission he was called to see her because she had suddenly developed a widespread rash and pyrexia. The ward-sister discovered she had severe vaginal bleeding, and her story was elicited. Wishing to terminate a three months’ pregnancy, she had bought a bottle of pennyroyal mixture and had taken this on the evening of Oct. 14. Next morning she had bought a further bottle, consumed its contents, and had a hot bath. Several hours later she had had an abortion, followed by heavy bleeding, and shortly after this she developed a widespread rash. deficiency. On admission, she complained of nausea, vomiting, abdomiWe are indebted to the patient, first of all, for her willing nal pain, and diarrhoea. There was no history of ill health, to Dr. J. S. E. W. and Mr. Nethercott, cooperation ; Keyser and she was the mother of two healthy children. of the Biochemical Laboratory, for many analyses of plasma ; She was a well-nourished woman : temperature 100°F; to Miss G. H. Powell and Miss J. W. Hosegood for help with the 130 per min. ; respirations 30 per min. On her face, and to Mr. E. pulse-rate and their Miss M. Williams for diet; Morgan trunk, and upper limbs and the proximal third of the lower technical help. M. G. F. holds the Cardiff Royal Infirmary limbs, there was a diffuse, non-itching, slightly elevated, research fellowship in medicine. REFERENCES
Black, D. A. K., Jepson, R. P. (1954) Quart. J. Med. 23, 367. Milne, M. D. (1952) Clin. Sci. 11, 397. Conway, E. J. (1950) Microdiffusion Analysis and Volumetric Error. 3rd ed., Lond. Cooke, R. E., Segar, W. E., Cheek, D. B., Coville, F. E., Darrow, D. C. (1952) J. clin. Invest. 31, 798. Reed, C., Etzwiler, D. D., Vita, M., Brusilow, S., Darrow, D. C. (1954) Amer. J. Med. 17, 180. Darrow, D. C., Schwartz, R., Iannucci, J. F., Coville, F. E. (1948) J. clin. Invest. 27, 198. Emery, E. W., Holmes, R., Davies, H. E. F., Black, D. A. K. (1955) Clin. Sci. 14, 241. Fourman, P. (1952) Ibid, 11, 387. Hervey, G. R. (1955) Ibid, 14, 75. Gardner, L. I., MacLachlan, E. A., Berman, H. (1952) J. gen. Physiol. 36, 153. —
—
—
—
FITZGERALD, DR. FOURMAN: REFERENCES—continued Gomori, G. (1942) J. Lab. clin. Med. 27, 955. Hawk, P. B., Oser, B. L., Summerson, W. H. (1954) Practical Physiological Chemistry. 13th ed., London. Milne, M. D., Stanbury, S. W., Thompson, A. E. (1952) Quart. J. Med. 21, 61. Orent-Keiles, E., McCollum, E. V. (1941) J. biol. Chem. 140, 337. Orloff, J., Kennedy, T. J. jun., Berliner, R. W. (1953) J. clin. Invest. 32, 538. Roberts, K. E., Randall, H. T., Sanders, H. L., Hood, M. (1955) Ibid, 34, 666. Roscoe, M. H. (1953) J. clin. Path. 6, 201. Sanderson, P. H. (1952) Biochem. J. 52, 502. Schwartz, R., Cohen, J., Wallace, W. M. (1953) Amer. J. Physiol. 172, 1. van Goidsenhoven, G. M. T., Gray, O. V., Price, A. V., Sanderson, P. H. (1954) Clin. Sci. 13, 383. Wallace, W. M., Holliday, M., Cushman, M., Elkinton, J. R. (1951) J. Lab. clin. Med. 37, 621. DR.
THE RENAL FACTOR IN THE ALKALOSIS OF POTASSIUM DEFICIENCY * M. G. FITZGERALD M.B. Birm., M.R.C.P. RESEARCH FELLOW
PAUL FOURMAN M.D. Lond., M.R.C.P. UNIT, CARDIFF ROYAL
were
pooled
Potassium and sodium were estimated by flame photoet al. 1951), chloride in plasma and urine by potentiometric titration (Sanderson 1952) and in the faeces by van Slyke’s method (Hawk et al. 1954), phosphate by Gomori’ss (1942) method, nitrogen and urinary ammonia by microdiffusion (Conway 1950), organic acids in the urine by van Slyke and Palmer’s method (Hawk et al. 1954) after the urine had been stored for some time with hydrochloric acid 2% vlv, creatinine according to Roscoe (1953), plasma pH with a Stadie glass electrode at room-temperature (a correction of -0-014 pH unit per °C was applied for the difference from body-temperature), and urine pH colorimetricany with capillary tubes.
metry (Wallace
SENIOR LECTURER IN MEDICINE
THE MEDICAL
analysed from daily collections and from collections from each experimental period. The latter values were used to compute the cumulative changes. Blood was drawn from a wrist vein, without stasis, into heparinised tubes. The following chemical methods were used :
urine
INFIRMARY
WHEN the cells of the body lack potassium, the extracellular fluid may become abnormally alkaline, though the cells are themselves more acid than normal (Cooke et al. 1952, Black and Milne 1952, Gardner et al. 1952). Studies made during the correction of potassium deficiencies suggested that a movement of H+ ions from the extracellular fluid to the intracellular fluid accounted for the extracellular alkalosis, and that its production did not depend on the kidneys (Orloff et al. 1953). But it has always seemed that the kidneys must play some part in allowing the alkalosis to arise at all (Darrow et al. 1948). The production of the extracellular alkalosis in a clinical deficiency of potassium can best be investigated in a patient who has not already got an alkalosis, and for our study we selected a patient whose deficiency of potassium accompanied a renal acidosis.
The
experiment took the
days, during which the containing 59 m.eq. daily
lasted 32
diet
patient of potassium, 122 m.eq. of sodium, 111m.eq. of chloride, 1.26 g. of phosphorus, and 9.1 g. of nitrogen. The study was divided into three parts : same
18 days without treatment; 3 days with 357 m.eq. (30 g.) daily of sodium bicarbonate added to her diet ; (3) 11 days with 100 m.eq. (10 g.) daily of potassium bicarbonate, as well as the sodium bicarbonate, added to the diet.
(1) (2)
Results
Case-report _
A woman, aged 38, who weighed 64 kg., was admitted hospital because she had become paralysed after a period of increasing weakness, which had lasted 5 weeks. Before that she had been well except for an attack of renal colic 5 years before, when she had passed a stone ; she also admitted to having been unusually thirsty for some months. The level of potassium in her serum was only 1-8 m.eq. per litre. with sodium 139, chloride 111, and bicarbonate In spite of this extracellular acidosis 14 m.eq. per litre. her urine was nearly neutral (pH 6-5) and contained very little titratable acid or ammonia, indicating that her acidosis The urine contained a trace of albumin was of renal origin. but no pus cells, and cultures were invariably sterile. Neither stones nor calcification could be demonstrated in the kidneys, and an intravenous pyelogram revealed no structural change in them. The blood-urea level was 58 mg. per 100 ml. The clearance of inulin was 60 ml. per min., and that of p-aminohippurate 214 ml. per min. In spite of the low plasmapotassium level she was excreting about 40 m.eq. of potassium daily in her urine. The administration of 100 m.eq. of ammonium chloride daily for 2 days did not increase her excretion of acid or of ammonia and did not change the pH of her urine. An infusion of neutral phosphate also had no important effect (cf. Milne et al. 1952). Her serum-calcium level and her urinary excretion of calcium were normal. to
When this patient was treated with potassium chloride and sodium bicarbonate, her potassium deficiency and her acidosis were rapidly corrected. But when we treated her acidosis with sodium bicarbonate alone, 30 g. daily, without correcting her potassium deficiency, this rapidly produced a severe extracellular alkalosis, and her plasma-bicarbonate rose to 45 m.eq. per litre. The same dose of sodium bicarbonate did not produce an alkalosis after her potassium deficiency had been treated with potassium chloride. Several weeks later she readily consented to an experimental study. After letting her become deficient in potassium again we investigated the ability of her kidneys to dispose of a large dose of sodium bicarbonate, and bicarbonate-first then bicarbonate. potassium Methods The procedure for the metabolic balance followed that of earlier experiments (Fourman 1952). Aliquots of *
to the Association of Britain and Ireland in May, 1955.
Paper presented
Physicians
of Great
Period1 When at the beginning of this period, the patient’s treatment with potassium chloride and sodium bicarbonate was withdrawn, she excreted more sodium and potassium than her diet provided. Table i shows OF K, NA, AND CL DITRING FIRST PERIOD WITHOUT TREATMENT, AND COMPOSITION OF PLASMA AT BEGINNING AND END OF PERIOD
TABLE OF
I-LOSSES
18
DAYS
her losses of
potassium, sodium,
and chloride and the
resulting changes in the composition of her plasma. Her deficit of potassium at the end of the period was 340 m.eq., too small to produce any clinical changes but sufficient for the purpose of the experiment. She lost a much smaller amount of sodium and very little chloride. Her plasma-potassium level fell from 4.4 to 3.6 m.eq. per litre; her plasma-sodium level hardly changed. Her plasma-chloride level rose and her plasma-bicarbonate level fell and the pH of her blood at the end of the period was 7-26 ; hence the deficit of potassium was accompanied by an acidosis in the plasma. The packed-cell volume was 41% of her whole blood. Her clearance of endogenous creatinine, a measure of the glomerular filtration-rate, was 76 ml. per minute in this period.
correspondingly,
Period2 When we added sodium bicarbonate 357 m.eq. daily to her diet, she became thirsty and drank more water but excreted less urine ; in 3 days she gained 3 kg. in weight and her face and legs became oedematous (cf. Fourman and Hervey 1955). On the 2nd day Trousseau’s sign was elicited, and on the 3rd day she had spontaneous tetanic- spasms in her hands and feet. Table 11 shows the chemical changes in this period. She continued to lose potassium, but her kidneys excreted only a fraction of the sodium she had taken, and in the
849 TABLE II-CHANGES IN AMOUNTS OF K, NA, AND CL IN BODY AND COMPOSITION OF PLASMA AFTER ADDITION OF 357 M.EQ. OF NAHCOg TO DIET FOR 3 DAYS
3 days of this period the amount of sodium in her body increased by 780 m.eq. ; the amount of chloride in her body did not increase. Her plasma-potassium level, which had already fallen in the first period, fell further Her plasma-sodium level now to 2-5 m.eq. per litre. rose by 10 m.eq. to 145 m.eq. per litre ; but her plasmachloride level fell by - 19 m.eq. to 91 m.eq. ; and her plasma-bicarbonate level rose by 23 m.eq. to 39 m.eq. The pH of her blood was now 7-55 ; so she had a severe The packed-cell volume was extracellular alkalosis. 36% of her whole blood. Her glomerular filtration-rate was 74 ml. per minute, virtually the same as in the
first
remained small at the beginning of the third period. The pH of her urine was 7’2 initially and decreased to 6-8 before the sodium bicarbonate was given ; it then increased to 8-3 and remained about the same after that. The excretion of ammonia averaged 31 m.eq. daily in the period without treatment. At the height of the alkalosis it was 20 m.eq. daily, and it averaged 9-5 m.eq. daily while potassium bicarbonate was given. The changes in the excretion of organic acids, though small, were in the same sense as found by Cooke et al. (1954). The excretion was initially 93 m.eq. daily and decreased to 60 m.eq. daily during the first period. In the second period it was 64 m.eq. daily ; during the first 4 days that potassium bicarbonate was given it increased again to 82 m.eq. daily, and it averaged 72 m.eq. daily after that. Discussion
administration
sodium
bicarbonate 30 g. extracellular alkalosis on the two occasions the patient was deficient in potassium. This amount of sodium bicarbonate does not normally produce an alkalosis (van Goidsenhoven et al. 1954), and we have also established that it did not do so The
daily produced rapidly
of a
severe
period.
Period3 When we now added potassium bicarbonate 100 m.eq. daily to her intake of sodium bicarbonate, her tetany promptly diminished, and after 4 days there was no sign of it. Her weight then decreased, and in the following 7 days she lost her cedema. Table m shows the chemical changes in the first 4 days of this period. She gained 265 m.eq. of potassium. Her kidneys were now excreting all the sodium she was taking and more, with the result that her body lost 90 m.eq. of sodium ; and they excreted less chloride than she was taking, with the result that she gained 155 m.eq. of chloride. The analyses of each day’s collection of urine revealed that the excretion of chloride decreased on the first day that potassium Her plasma-sodium level fell bicarbonate was given. to its original value of 135 m.eq. per litre, her plasmachloride rose, and her plasma-bicarbonate fell. Her alkalosis was largely corrected, and the pH of her blood became normal again. Table 111 also shows the chemical changes in the last 7 days of the experiment, when she lost weight (see figure). She gained a further 258 m.eq. of potassium, _
more
than
enough
to correct her
original deficit ;
and
she lost 302 m.eq. of sodium and 132 m.eq. of chloride. At the end of the experiment the composition of her plasma was normal. Her glomerular filtration-rate was 71 ml. per minute. The results of the other chemical analyses need not be described in detail. During the whole experiment the excretion of nitrogen did not change significantly. The excretion of phosphorus did not change appreciably until the second period, when sodium bicarbonate was given. The amount of phosphate in the urine then decreased, by 240 mg. daily, and it TABLE III-CHANGES IN AMOUNTS OF K. NA, AND CL IN BODY AND COMPOSITION OF PLASMA AFTER ADDITION TO DIET OF 100 M.EQ. OF KHC03 AS WELL AS 357 M.EQ. OF NAHC03 FOR
11DAYS
Changes
in
weight during
3
periods of experiment.
in our patient when her stores of potassium were nearly normal. The experimental observations suggest the following mechanism for her alkalosis :
(1) In 3 days she retained 780 m.eq. of sodium out of 1070 m.eq. taken. Her glomerular filtration-rate had not fallen, and her failure to excrete the sodium could only be explained by assuming that her renal tubules absorbed too much of it. (2) At the same time she retained 3 litres of water, shown by her sudden gain in weight. She became eedematous, and from the change in her hasmatocrit it can be calculated that (if the total volume of her red cells did not change) the volume of her plasma increased by 23 %. Thus the volume of her extracellular fluids had increased. (3) She did not retain a significant amount of chloride ; hence the chloride in her extracellular fluid became diluted, and her plasma-chloride level fell-by 17% of its original value. The concentration of the bicarbonate ion increased to take the place of the chloride ion, and her extracellular alkalosis
was
established.
The part played by her kidneys in the production of her extracellular alkalosis was therefore to reabsorb too much sodium and too little chloride from the glomerular filtrate. Rats’ kidneys seem to do the same when they are deficient in potassium (Cooke et al. 1954, Schwartz et al. 1953, Orent-Keiles and McCollum 1941) but the changes in the function of the rats’ kidneys was not measured directly. Sodium is reabsorbed either in exchange for another In our study the sodium cation or with an anion. reabsorbed in excess of chloride could not have been reabsorbed by an exchange with H, K, or NH4 ions. (whose excretion hardly changed) and it must have been reabsorbed with an anion. Only some of this was phosphate ; so most of the excess of sodium reabsorbed
850 must have formed bicarbonate. The result would be an apparent increase in the reabsorption of the bicarbonate filtered through the glomerulus, as Roberts et al. (1955)
found when they infused sodium lactate into patients deficient in potassium. The renal response we found during an extracellular alkalosis with potassium deficiency is what might ordinarily be expected during an acidosis ; and the intracellular acidosis of potassium deficiency may determine the paradoxical response of the kidneys to the accompanying extracellular alkalosis, as Roberts et a]. (1955) have also suggested. When the patient was given potassium bicarbonate, her kidneys excreted sodium and retained chloridei.e., they were responding normally to an alkalosis and in this way were able to correct her extracellular alkalosis. It is quite remarkable that they began to do this on the day she first had potassium and therefore before there had been any great change in the total deficit of potassium in her body. When potassium is given to a healthy animal, a disproportionate amount is taken up by the kidneys, to be released to the rest of the body only later (Emery et al. 1955). This might enable the kidney cells to return to a normal composition before the other cells of the body during the correction of a deficiency. The therapeutic implications of this experiment may be mentioned. Firstly, the abnormal alkalosis produced by sodium bicarbonate in patients with pyloric stenosis (van Goidsenhoven et al. 1954) may possibly be related to a deficiency of potassium (Black and Jepson 1954) as well as cf chloride. Secondly, it may be dangerous to treat an acidosis with free doses of alkali if the patient also has a deficiency of potassium. An extracellular alkalosis may result which the kidneys cannot rectify, and it may be advisable to add potassium to the treatment.
Summary
.
Sodium bicarbonate 30 g. daily given to a patient with potassium deficiency produced a severe extracellular alkalosis. During the period of this extracellular alkalosis her kidneys reabsorbed too much sodium and water, and she gained 780 m.eq. of sodium and 3 litres of water. But her kidneys did not reabsorb chloride in corresponding amounts, and there was no gain of chloride. When potassium bicarbonate was subsequently added to her treatment, her extracellular alkalosis was rapidly corrected; her kidneys were then excreting sodium and retaining chloride. This is the normal response to an alkalosis. The abnormal response of the kidneys during a potassium deficiency may perhaps be ascribed to the intracellular acidosis which accompanies a potassium
PENNYROYAL POISONING A FATAL CASE
W. B. VALLANCE M.B. Edin. MEDICAL
REGISTRAR,
ROYAL
INFIRMARY, BRADFORD
PENNYROYAL has long had a reputation as an abortifacient, although its action is known to be unpredictable and even dangerous. In the following case it produced abortion, vaginal bleeding, haemolytic anaemia, and acute tubular necrosis of the kidney, with death from urtmia. Pennyroyal is a volatile oil and belongs to the same group as apiol, turpentine, and the oils of savin, tansy, saffron, and rue. It is prepared by distillation of 31
whooping-cough. Case-report
Mrs. A., aged 24, was admitted to a general medical ward at 8.15 P.M. on Oct. 15, 1954, with a tentative diagnosis of drug-sensitivity reaction. She had visited her doctor on the previous day, complaining of general malaise, for which he Three hours before her gave her some codeine tablets. admission he was called to see her because she had suddenly developed a widespread rash and pyrexia. The ward-sister discovered she had severe vaginal bleeding, and her story was elicited. Wishing to terminate a three months’ pregnancy, she had bought a bottle of pennyroyal mixture and had taken this on the evening of Oct. 14. Next morning she had bought a further bottle, consumed its contents, and had a hot bath. Several hours later she had had an abortion, followed by heavy bleeding, and shortly after this she developed a widespread rash. deficiency. On admission, she complained of nausea, vomiting, abdomiWe are indebted to the patient, first of all, for her willing nal pain, and diarrhoea. There was no history of ill health, to Dr. J. S. E. W. and Mr. Nethercott, cooperation ; Keyser and she was the mother of two healthy children. of the Biochemical Laboratory, for many analyses of plasma ; She was a well-nourished woman : temperature 100°F; to Miss G. H. Powell and Miss J. W. Hosegood for help with the 130 per min. ; respirations 30 per min. On her face, and to Mr. E. pulse-rate and their Miss M. Williams for diet; Morgan trunk, and upper limbs and the proximal third of the lower technical help. M. G. F. holds the Cardiff Royal Infirmary limbs, there was a diffuse, non-itching, slightly elevated, research fellowship in medicine. REFERENCES
Black, D. A. K., Jepson, R. P. (1954) Quart. J. Med. 23, 367. Milne, M. D. (1952) Clin. Sci. 11, 397. Conway, E. J. (1950) Microdiffusion Analysis and Volumetric Error. 3rd ed., Lond. Cooke, R. E., Segar, W. E., Cheek, D. B., Coville, F. E., Darrow, D. C. (1952) J. clin. Invest. 31, 798. Reed, C., Etzwiler, D. D., Vita, M., Brusilow, S., Darrow, D. C. (1954) Amer. J. Med. 17, 180. Darrow, D. C., Schwartz, R., Iannucci, J. F., Coville, F. E. (1948) J. clin. Invest. 27, 198. Emery, E. W., Holmes, R., Davies, H. E. F., Black, D. A. K. (1955) Clin. Sci. 14, 241. Fourman, P. (1952) Ibid, 11, 387. Hervey, G. R. (1955) Ibid, 14, 75. Gardner, L. I., MacLachlan, E. A., Berman, H. (1952) J. gen. Physiol. 36, 153. —
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FITZGERALD, DR. FOURMAN: REFERENCES—continued Gomori, G. (1942) J. Lab. clin. Med. 27, 955. Hawk, P. B., Oser, B. L., Summerson, W. H. (1954) Practical Physiological Chemistry. 13th ed., London. Milne, M. D., Stanbury, S. W., Thompson, A. E. (1952) Quart. J. Med. 21, 61. Orent-Keiles, E., McCollum, E. V. (1941) J. biol. Chem. 140, 337. Orloff, J., Kennedy, T. J. jun., Berliner, R. W. (1953) J. clin. Invest. 32, 538. Roberts, K. E., Randall, H. T., Sanders, H. L., Hood, M. (1955) Ibid, 34, 666. Roscoe, M. H. (1953) J. clin. Path. 6, 201. Sanderson, P. H. (1952) Biochem. J. 52, 502. Schwartz, R., Cohen, J., Wallace, W. M. (1953) Amer. J. Physiol. 172, 1. van Goidsenhoven, G. M. T., Gray, O. V., Price, A. V., Sanderson, P. H. (1954) Clin. Sci. 13, 383. Wallace, W. M., Holliday, M., Cushman, M., Elkinton, J. R. (1951) J. Lab. clin. Med. 37, 621. DR.