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PREVENTION OF URINARY SUPPRESSION AFTER INTRAVASCULAR HÆMOLYSIS
355 anterior nares, prepuce, anus, vulva, and scrotum) are anatomically differentiated from the rest of the integument. The skin in these areas (it is skin in each case and not mucous membrane, as some authors wrongly seem to believe) is of very fine texture and presents histological differences which cannot be overlooked. The sites are subject to repeated trauma and These I believe to be the are often warm and moist. factors which determine their liability to be affected. Aykroyd et al. (1939) have cited me as maintaining that angular stomatitis is an early sign of pellagra. When I expressed that opinion I did so on epidemiological grounds. I still believe that the abovementioned signs are signs of the pellagrous state, the state supervening on a fault in one or more links in the catalytic chain. A riboflavin deficiency would cause It is a break in the third link, coenzyme factor. possible that a fault in one link may cause a clinical picture rather different from that associated with a fault in another. The rate of failure at any one link or the relative rates of failure in two or more links might also have an effect in determining the symptoms - set and age almost certainly do so. The evidence that some factor in the causation of pellagra is synthesised in the stomach has been given elsewhere (Stannus 1937). The demonstration that gastric juice and ventriculin are curative has been already mentioned. The identity of that factor is not yet known, but it is possibly concerned with the coenzyme-factor link. Many other sides of the problem might be discussed, but they are better left until further knowledge has accumulated. REFERENCES
Aykroyd, W. R., and Krishnan, B. G. (1936) Indian J. med. Res. 24, 41. —
—
(1937) Ibid, p. 707.
(1938) Ibid, 25, 643. and Passmore, R. (1939) Lancet, 2, 825. Bandier, E. (1939) Acta med. scand. 101, 496. Boggs, T. R. and Padget, P. (1932) Bull. Johns Hopk. Hosp. 50, 21. Chain, E. (1939) Biochem. J. 33, 407. Clark, A. (1937) J. trop. Med. (Hyg.) pp. 269, 285. Corkill, N. L., (1934) Lancet, 1, 1387. Corran, H. S., Green, D. E., and Straub, F. B. (1939) Biochem. J. 33, 793. Dewan, J. G. (1937) Nature, 140, 1097. and Green, D. E. (1938) Biochem. J. 32, 626 ,855, 1200. Elvehjem, C. A., Madden, R. J., Strong, F. M., and Wooley, D. W. (1937) J. Amer. chem. Soc. 59, 1767. Euler, H. V. and Hellstrom, H. (1938a) Nature, 141, 870. (1938b) Hoppe-Seyl. Z. 252, 31. Katzenellenbogen, I. (1928) Arch. Derm. Syph., Wien, 154, 269. — (1939) Lancet, 1, 1260. Keilin, D. (1929) Proc. roy. Soc. B, 104, 206. (1930) Ibid, 106, 418. Hartree, E. F. (1938) Nature, 141, 870. Kohn, H. I., (1938) Biochem. J. 32, 2075. Landor, J. V. (1939) Lancet, 1, 1368. and Pallister, R. A. (1935) Trans. R. Soc. trop. Med. Hyg. —
—
-
-
-
-
-
-
—
-
29, 121. Lockhart, E. E. (1939) Biochem. J. 33, 613. Lutwak-Mann. C. (1938) Ibid, 32, 1365. Lwoff, A., and Lwoff, M. (1937) Proc. roy. Soc. B, 122, 352, 360. Oden, J. W., Oden, L. H., and Sebrell, W. H. (1939) Publ. Hlth Rep., Wash. 54, 790. Petri, S., and Wanscher, O. (1937) Acta. med. scand, 91, 370. Stubbe Teglbjaerg, E. and Stubbe Teglbjaerg, H. P. (1937) Ibid, 93, 450. Ramsdell, R. L., and Magness, W. H. (1933) Amer. J. med. Sci. 185, 568. Sebrell, W. H., and Butler, R. E. (1938) Publ. Hlth Rep. Wash. 53, 2282. Smith, D. J., Ruffin, J. M., and Smith, S. G. (1937) J. Amer. med. —
—
Ass. 109, 2054. T. D. (1933a) Proc. Soc. exp. Biol., N.Y. 30, 850. (1933b) Ibid, 31, 363. (1935) J. Amer, med. Ass. 104, 1377. Bean, W. B., and Ashe, F. (1939) Ann. Intern. med. 12, 1830. Cooper, C., and Blankenhorn, M. A. (1938) J. Amer. med. Ass. 110, 622. — Wolf, H. F. de (1933) Amer. J. med. Sci. 186, 521. Stannus, H. S. (1912) Trans. Soc. trop. Med. Hyg. 5, 112. (1913) Ibid, 7, 32. (1936) Trop. Dis. Bull. 33, 729, 815, 885.
Spies, -
-
-
-
-
—
(1937) Ibid, 34, 183.
—
Straub, F. B. (1939) Biochem. J. 33, 787. Vilter, R. W., Vilter, S. P., and Spies, T. D. (1939a) Sth. med. 32, 619.
—
—
—
(1939b)
J. Amer. med. Ass. 112, 420.
J.
PREVENTION OF
URINARY SUPPRESSION AFTER INTRAVASCULAR HÆMOLYSIS BY S. R. M. BUSHBY E. W. HART, M.B. Camb., M.R.C.P. A. KEKWICK, M.B. Camb., M.R.C.P. AND
WHITBY, M.D. Camb., F.R.C.P. (From the Army Blood-Transfusion Service) L. E. H.
DEATH is a common termination of those conditions which cause intravascular haemolysis, as in mismatched blood-transfusion, blackwater fever, and paroxysmal haemoglobinuria. The enrolment, for war emergencies, of vast numbers of group-0 donors, who will be used in circumstances precluding facilities for direct matching, has increased the possibility of mismatched transfusion. Death from incompatible transfusion is usually due to renal obstruction with its attendant " uraemia," because blood pigment is deposited in the tubules. Hesse and Filatov (1933), however, have advanced the view that acute capillary constriction plays a part in some cases. Baker and Dodds (1925) describe sudden death in rabbits after the injection of haemoglobin solutions which contain cell shadows. It is generally conceded that renal obstruction is more important than other theoretical considerations. No close relation has been established between the quantity of blood haemolysed and the development of renal obstruction. Some patients with massive intravascular haemolysis have survived, haemoglobin having been successfully eliminated by the kidneys, whereas others, with less severe haemolysis, have died. Death in many cases is undoubtedly avoidable under certain conditions. CONDITIONS NECESSARY FOR ELIMINATION OF HEMOGLOBIN IN URINE
The essential requirement for the elimination of haemoglobin in the urine is to maintain the htmoglobin in a soluble form to ensure excretion. Baker and Dodds (1925) described the post-mortem findings in two cases of incompatible blood-transfusion and experimental work which clearly explains the mechanism whereby blood pigment is deposited in and obstructs the renal tubules. Haemoglobin liberated in the blood is in solution in the plasma at pH 7-3-7-5. It passes through the glomeruli and remains unchanged until it reaches the tubules. In man the reaction of the urine here changes to pH 4.6-5-4. Under these conditions the haemoglobin is converted to methaemoglobin. which later crystallises out as acid hsematin. This substance causes the obstruction, which on histological section appears as tubular casts. Baker and Dodds demonstrated an additional factor in the concentration of the urinary mineral constituents. This factor operated when the urine was acid. They concluded that if the urinary reaction was maintained on the alkaline side of pH 6-4, no change took place in the haemoglobin, and it remained in solution. During the excretion of haemoglobin by the kidney the quantity of urine passed is important. A small urinary output means slower elimination and a more concentrated solution of haemoglobin and its products in the kidney. Both of these factors are unfavourable for maintaining the haemoglobin in soluble form. Alkalinisation of the urine must therefore go hand in hand with the maintenance of a high urinary output.
356 for the work quoted below lies in a Baker (1937) : " Since our paper was published in 1925 many cases of post-transfusion suppression have been reported, but in only very few of these can I find that alkalinisation has been attempted and even in these it has obviously been tried much too late."
(Haldane 1924). Since potassium citrate appeared to be as efficient and as rapid in action on the urine as any other alkali, all further experiments were conducted with this substance. It is probable that other alkalis would be equally efficient. To establish the rapidity with which the urine could be rendered alkaline, a single dose of potassium citrate (8 g.) was given to four
TABLE I-AVERAGE
were then asked to pass urine every 15 min. Table II shows that the urine reaches a pH of 7-0 or over in about 30 min. A determination of the optimal dose of potassium citrate necessary to guarantee the maintenance of urinary pH above 7.0 was then undertaken. Four volunteers were each given 20 g. of potassium citrate in twenty-four hours in doses divided in different ways over two periods of twenty-four hours. This amount of alkali was too low, for on seven occasions the urinary pH fell significantly below 7.0. These low pH’s were irrespective of the distribution of dose of alkali employed. Four other volunteers were
The
justification
statement
by
URINARY PH OF TWO SETS OF PATIENTS, BOTH HAVING 8 G. OF POTASSIUM CITRATE
PRACTICAL METHODS OF ENSURING ELIMINATION HAEMOGLOBIN IN URINE
OF
In view of the foregoing facts, we have assumed that the optimal conditions for harmless elimination of haemoglobin are a urinary output of at least 1500 c.cm. in twenty-four hours and a reaction not lower than pH 7-0. This last figure has been arbitrarily chosen to give a margin of safety. The maintenance of this urinary output can be accomplished by the daily administration of at least 3000 c.cm. of fluid (Coller and Maddock 1933). This amount is necessary because 1000 c.cm. is constantly eliminated by the skin and 500 c.cm. by the lungs and faeces. The intake has to be increased when there is any extra loss TABLE II-URINARY PH
IN
SUBJECTS ON HIGH FLUID 8 G. OF POTASSIUM CITRATE
INTAKE AFTER SINGLE DOSES OF
of fluid from normal or abnormal channels. As to the type of alkali and the dose most suitable, the only literature, based on experimental work, which we have had opportunity to consult has been the papers of Davis et al. (1920) and Haldane (1924). These have formed the basis for our preliminary work. Table I shows the average effect of a single dose of alkali (8 g. of potassium citrate) on two sets of patients, one with a high urinary output and one with a low output. The lower output of urine prolongs the effect of the alkali. The administration of sufficient alkali to maintain 1500 c.cm. of urine at pH 7.0 is larger, therefore, than the amount required to alkalinise a smaller volume of urine. The experimental data which follow are only from those cases where the urinary output has been above 1500 c.cm. in twenty-four hours. In practice it is desirable to combine the administration of fluid and alkali into This can be undertaken by one therapeutic measure. one of three routes : oral, rectal, or intravenous. Oral (KM-MMsMo.—Davis et al. (1920) and Haldane (1924) recommend the use of sodium acetate and sodium citrate for oral administration. They state that sodium bicarbonate, though a smaller dose is required to obtain the same effect, is irritating to the gastro-intestinal tract. This statement we confirmed by giving volunteers equivalent doses of different alkalis, 45 g. of sodium bicarbonate being equivalent
to 70 g. of sodium citrate
volunteers, who
TABLE III-URINARY PH
BEFORE
AND AFTER
20
G. OF
POTASSIUM CITRATE
given a single dose of 20 g. of potassium citrate and the urinary pH recorded before the alkali was given and twelve hours later. Table III shows that, at the end of twelve hours, the effect of the alkali on the urine was well maintained. During this period the subjects were at complete rest. The next experiment was undertaken with four volunteers who were given higher doses of potassium citrate. Two were given 46 g. of potassium citrate, and two 72 g. over a period of twenty-four hours. Table IV records the urinary pH of these subjects on all specimens. Towards the end of this time three out of the four subjects had developed symptoms of alkalosis. In one case these symptoms were fairly It will be noted also that the pH readings severe. TABLE IV-URINARY PH
IN SUBJECTS
INTAKE
DOSES
were were
AND
ON MASSIVE
than those made from these
higher
ON LARGE FLUID
OF POTASSIUM CITRATE
required. Three experiments :—
conclusions
(1) Change of urinary reaction to at least pH 7-0 be accomplished in about half an hour, when alkalis are administered by mouth. (2) The optimal dose of potassium citrate is below 46 g. in twenty-four hours. (3) The doses of potassium citrate need not be regularly spaced throughout the twenty-four hours. Before these conclusions were confirmed, various can
substances
were tried to take away the taste of the It was found that ordinary lemon citrate. potassium was most the efficient, and this was used in the squash final experiment. It was also decided that the optimal safe dose of potassium citrate would be about
357 TABLE V—AMBULANT
SUBJECTS TAKING
35
G. OF POTASSIUM CITRATE PER
A
therapeutic procedure, combining the above tried on twelve volunteers. They were points, given 35 g. of potassium citrate in 2000 c.cm. of water flavoured with lemon squash. They were instructed to drink all the fluid within twenty-four hours when and how they pleased and to continue their normal liberal diet. This was repeated for a further twentyfour hours. At the end of the forty-eight hours the 35 g.
was
alkali reserves of all volunteers were measured. Table V shows the urinary pH of every specimen of urine passed and the alkali reserves of each subject. One test had to be discarded. One volunteer (subject 6) developed mild symptoms of alkalosis after thirty-six hours. Her alkali reserve was 84. She was a slender girl weighing 114 lb. The results confirm that 35 g. of potassium citrate will maintain the alkalinisation of the urine. Since these patients were ambulant, it was thought that patients at rest in bed might not be able to tolerate the full dosage of 35 g. A final experiment was then undertaken : four volunteers from the convalescent ward of a hospital were given 35 g. of potassium citrate in 2000 c.cm. of lemon squash every twenty-four hours for three days. The urinary pH results are shown in table VI. Some of the patients taking the lemon-flavoured mixture complained that it progressively became more -monotonous. By the end of the third day several complained that it called for an effort to finish the two litres. Various other flavourings have been tried. Beef-tea, coffee, or milk completely disguises the flavour of the
24
HOURS FOR
2
DAYS
make the total fluid intake per day 3000 c.cm. Potassium citrate 35 g. (gr. 525) given in the same way should be taken every twenty-four hours until haemoglobinuria has ceased. In unconscious patients 35 g. of potassium citrate in 3 litres of water can be given by drip feed through a stomach-tube. Should the symptoms of alkalosis appear, the administration of potassium citrate should be stopped for six hours or until the symptoms have disappeared, and then restarted. These symptoms in the early stages are lassitude, giddiness, and headache ; later, vomiting and muscular cramps. Since urinary methaemoglobin has a brownish tinge and unchanged haemoglobin is bright red, the change of colour will afford a valuable clinical index of urinary pH. The appearance of a brownish tinge in the urine should be a sign to restart treatment. TABLE VI-SUBJECTS
AT REST IN BED TAKING
POTASSIUM CITRATE PER
24
HOURS FOR
3
35
G.
OF
DAYS
drug. intravascular hoemoof 8 g. (gr. 120) of dose lysis suspected,. single potassium citrate should be given. This will render the urine alkaline within half an hour. During the next twenty-four hours the remainder of the 35 g. of potassium citrate (27 g. gr. 415) should be given dissolved in 2000 c.cm. of lemon squash. Instructions must be given that the mixture must all be taken. Besides this the patient should take at least 1000 c.cm. of other fluid. After this time alternative flavourings may be used in the 2000 c.cm. of potassium-citrate mixture. A solid diet contains 1000c.cm. of fluid (Coller and Maddock 1933). This will
Recommendations.-As is
soon as
a
=
Rectal administration.-The large fluid intake which is required (3 litres a day) cannot be given rectally by the commonly employed methods of administration. Marriott and Kekwiek (1937) have shown that this is possible by employing Murphy’s
‘
358 This requires, however, the constant a trained nursing staff. Even then it is not possible for all patients and uncertain for others. The importance of ensuring the absorption of both fluid and alkali is so great that it negatives the employment of this technique. Intravenous administration.-In those cases where oral administration is impracticable the fluid and alkali may be given intravenously. The choice of alkali for these experiments has been sodium citrate, for it was already known from experience with massive blood-transfusion that a considerable amount of sodium citrate was well tolerated intravenously. A preliminary experiment was undertaken to determine the effect of a large single dose of sodium citrate on the urinary pH. A subject on a high fluid intake was given 6 g. of sodium citrate intravenously. Table VII shows the urinary pH every 15 min. for 1
principles.
attention of
TABLE VII-URINARY rH AFTER A SINGLE INTRAVENOUS DOSE OF 6 G. OF SODIUM CITRATE
of the citrate solution should be added to 2400 c.cm. of the glucose and a continuous drip should be established, the total volume of fluid, 2850 c.cm., being given during the first twenty-four hours. Sodium citrate solution 600 c.cm. (18 g. gr. 270) and 2400 c.cm. of glucose are mixed and administered by intravenous drip every twenty-four hours until the disappearance of the haemoglobinuria. The same precautions should be taken if the symptoms of alkalosis appear as were recommended above under oral administration. =
COMMENT
In this paper we have made recommendations for the prevention of suppression of urine after intra. vascular haemolysis. Final proof of the efficacy of these suggestions can only be obtained in the treatment of actual cases. These we have not had at our disposal. We submit, however, that a strong case has been made out for the trial of these procedures. SUMMARY
hours. It was concluded that alkalinisation of the urine was at least as rapid as with approximately the same dose of alkali as was given by mouth (see table II). Further, the effect of 6 g. of sodium citrate given intravenously, compared with that of 8 g. of potassium citrate given by mouth, was that the urinary pH rose higher and returned to normal more quickly. The former is probably due to the increased certainty of the total dose of alkali reaching the bloodstream. A 3 per cent. solution of sodium citrate has been shown to be isotonic with blood (Norgaard and Gram 1921 ; Hirschlaff 1936). This solution was prepared and autoclaved. A 5 per cent. solution of glucose was prepared separately and sterilised. These solutions cannot be sterilised together, owing to the changes produced in the glucose. Sodium citrate 35 g. in glucose was given to one patient over a period of twenty-four hours by the drip method. The administration was continued for thirty hours. A total of 3000 c.cm. of fluid was given for the first twenty-four hours. As was expected, this patient complained of definite symptoms of alkalosis. Three other patients were then given half this amount of sodium citrate (18 g.) for two periods of twenty-four hours. The urinary pH’s and alkali reserves are recorded in table VIII. TABLE VIII-URINARY PH
AFTER
CITRATE INTRAVENOUSLY EACH
24
18
G.
OF
(1) Suppression of urine after intravascular haemolysis is due to obstruction of the tubules with products derived from haemoglobin. (2) The conditions necessary for its prevention are a high urinary output of at least 1500 c.cm. a day and a constant urinary reaction of pH 6-4 or over. (3) These conditions can be fulfilled by the administration of fluid and alkalis orally or intravenously. (4) Recommendations regarding the dose of alkali by both routes are made. Our thanks are due to Dr. P. Phillips, medical superintendent of the Southmead Hospital, for placing cases at our disposal ; and to numerous members of the personnel of the Army Blood Transfusion Service. REFERENCES
Baker, S. L. (1937) Lancet, 1, 1390. and Dodds, E. C. (1925) J. exp. Path. 6, 247. Coller, F. A., and Maddock, W. G. (1933) Ann. Surg. 98, 952. Davis, H. W., Haldane, J. B. S., Kennaway, F. L. (1920) J. Phys. 54, 32. Haldane, J. B. S. (1924) Lancet, 1, 537. Hesse, E., and Filatov, A. (1933) Z. ges. exp. Med. 86, 211. Hirschlaff, B. (1936) Acta med. scand. 87, 530. Marriott, H. L., and Kekwick, A. (1937) Practitioner, 139, 250. Norgaard, A., and Gram, H. C. (1921) J. biol. Chem. 49, 263. -
DRUGS USED IN SURGERY TO RAISE BLOOD-PRESSURE WITH
SPECIAL REFERENCE TO VERITOL
BY HAROLD
DODD, Ch.M. Lpool, F.R.C.S.
SURGEON TO THE KING GEORGE HOSPITAL, ILFORD, AND TO THE ROYAL HOSPITAL, RICHMOND; ASSISTANT SURGEON TO THE LONDON HOMŒOPATHIC HOSPITAL
POTASSIUM 2 DAYS
HOURS FOR
IJRUGS that raise the
blood-pressure
are 01
particular
interest to the surgeon to counteract the serious falls that take place during major operations, especially with spinal anaesthesia, and in other conditions of shock. I have studied this subject since 1933 and tested many drugs to maintain the blood-pressure and to restore it from unduly low levels. Of these Veritol has proved to be the most satisfactory. CORAMINE
Recommendations.-A 3 per cent. solution of sodium citrate and a 5 per cent. solution of glucose are prepared and sterilised separately. As soon as intravascular haemolysis is suspected, 150 c.cm. of the 3 per cent. solution of sodium citrate (4-5 g. gr. 69) should be administered immediately with a syringe. This will render the urine alkaline. Next, 450 c.cm. =
Coramine has been given intravenously and intrain doses up to 2 c.cm. So far as can be measured with the ordinary sphygmomanometer or an oscillometer, no effect whatever is produced on the blood-pressure, nor has any other benefit been observed; consequently this preparation is not used for the purpose of raising the blood-pressure.
muscularly
Aykroyd, W. R., and Krishnan, B. G. (1936) Indian J. med. Res. 24, 41. —
—
(1937) Ibid, p. 707.
(1938) Ibid, 25, 643. and Passmore, R. (1939) Lancet, 2, 825. Bandier, E. (1939) Acta med. scand. 101, 496. Boggs, T. R. and Padget, P. (1932) Bull. Johns Hopk. Hosp. 50, 21. Chain, E. (1939) Biochem. J. 33, 407. Clark, A. (1937) J. trop. Med. (Hyg.) pp. 269, 285. Corkill, N. L., (1934) Lancet, 1, 1387. Corran, H. S., Green, D. E., and Straub, F. B. (1939) Biochem. J. 33, 793. Dewan, J. G. (1937) Nature, 140, 1097. and Green, D. E. (1938) Biochem. J. 32, 626 ,855, 1200. Elvehjem, C. A., Madden, R. J., Strong, F. M., and Wooley, D. W. (1937) J. Amer. chem. Soc. 59, 1767. Euler, H. V. and Hellstrom, H. (1938a) Nature, 141, 870. (1938b) Hoppe-Seyl. Z. 252, 31. Katzenellenbogen, I. (1928) Arch. Derm. Syph., Wien, 154, 269. — (1939) Lancet, 1, 1260. Keilin, D. (1929) Proc. roy. Soc. B, 104, 206. (1930) Ibid, 106, 418. Hartree, E. F. (1938) Nature, 141, 870. Kohn, H. I., (1938) Biochem. J. 32, 2075. Landor, J. V. (1939) Lancet, 1, 1368. and Pallister, R. A. (1935) Trans. R. Soc. trop. Med. Hyg. —
—
-
-
-
-
-
-
—
-
29, 121. Lockhart, E. E. (1939) Biochem. J. 33, 613. Lutwak-Mann. C. (1938) Ibid, 32, 1365. Lwoff, A., and Lwoff, M. (1937) Proc. roy. Soc. B, 122, 352, 360. Oden, J. W., Oden, L. H., and Sebrell, W. H. (1939) Publ. Hlth Rep., Wash. 54, 790. Petri, S., and Wanscher, O. (1937) Acta. med. scand, 91, 370. Stubbe Teglbjaerg, E. and Stubbe Teglbjaerg, H. P. (1937) Ibid, 93, 450. Ramsdell, R. L., and Magness, W. H. (1933) Amer. J. med. Sci. 185, 568. Sebrell, W. H., and Butler, R. E. (1938) Publ. Hlth Rep. Wash. 53, 2282. Smith, D. J., Ruffin, J. M., and Smith, S. G. (1937) J. Amer. med. —
—
Ass. 109, 2054. T. D. (1933a) Proc. Soc. exp. Biol., N.Y. 30, 850. (1933b) Ibid, 31, 363. (1935) J. Amer, med. Ass. 104, 1377. Bean, W. B., and Ashe, F. (1939) Ann. Intern. med. 12, 1830. Cooper, C., and Blankenhorn, M. A. (1938) J. Amer. med. Ass. 110, 622. — Wolf, H. F. de (1933) Amer. J. med. Sci. 186, 521. Stannus, H. S. (1912) Trans. Soc. trop. Med. Hyg. 5, 112. (1913) Ibid, 7, 32. (1936) Trop. Dis. Bull. 33, 729, 815, 885.
Spies, -
-
-
-
-
—
(1937) Ibid, 34, 183.
—
Straub, F. B. (1939) Biochem. J. 33, 787. Vilter, R. W., Vilter, S. P., and Spies, T. D. (1939a) Sth. med. 32, 619.
—
—
—
(1939b)
J. Amer. med. Ass. 112, 420.
J.
PREVENTION OF
URINARY SUPPRESSION AFTER INTRAVASCULAR HÆMOLYSIS BY S. R. M. BUSHBY E. W. HART, M.B. Camb., M.R.C.P. A. KEKWICK, M.B. Camb., M.R.C.P. AND
WHITBY, M.D. Camb., F.R.C.P. (From the Army Blood-Transfusion Service) L. E. H.
DEATH is a common termination of those conditions which cause intravascular haemolysis, as in mismatched blood-transfusion, blackwater fever, and paroxysmal haemoglobinuria. The enrolment, for war emergencies, of vast numbers of group-0 donors, who will be used in circumstances precluding facilities for direct matching, has increased the possibility of mismatched transfusion. Death from incompatible transfusion is usually due to renal obstruction with its attendant " uraemia," because blood pigment is deposited in the tubules. Hesse and Filatov (1933), however, have advanced the view that acute capillary constriction plays a part in some cases. Baker and Dodds (1925) describe sudden death in rabbits after the injection of haemoglobin solutions which contain cell shadows. It is generally conceded that renal obstruction is more important than other theoretical considerations. No close relation has been established between the quantity of blood haemolysed and the development of renal obstruction. Some patients with massive intravascular haemolysis have survived, haemoglobin having been successfully eliminated by the kidneys, whereas others, with less severe haemolysis, have died. Death in many cases is undoubtedly avoidable under certain conditions. CONDITIONS NECESSARY FOR ELIMINATION OF HEMOGLOBIN IN URINE
The essential requirement for the elimination of haemoglobin in the urine is to maintain the htmoglobin in a soluble form to ensure excretion. Baker and Dodds (1925) described the post-mortem findings in two cases of incompatible blood-transfusion and experimental work which clearly explains the mechanism whereby blood pigment is deposited in and obstructs the renal tubules. Haemoglobin liberated in the blood is in solution in the plasma at pH 7-3-7-5. It passes through the glomeruli and remains unchanged until it reaches the tubules. In man the reaction of the urine here changes to pH 4.6-5-4. Under these conditions the haemoglobin is converted to methaemoglobin. which later crystallises out as acid hsematin. This substance causes the obstruction, which on histological section appears as tubular casts. Baker and Dodds demonstrated an additional factor in the concentration of the urinary mineral constituents. This factor operated when the urine was acid. They concluded that if the urinary reaction was maintained on the alkaline side of pH 6-4, no change took place in the haemoglobin, and it remained in solution. During the excretion of haemoglobin by the kidney the quantity of urine passed is important. A small urinary output means slower elimination and a more concentrated solution of haemoglobin and its products in the kidney. Both of these factors are unfavourable for maintaining the haemoglobin in soluble form. Alkalinisation of the urine must therefore go hand in hand with the maintenance of a high urinary output.
356 for the work quoted below lies in a Baker (1937) : " Since our paper was published in 1925 many cases of post-transfusion suppression have been reported, but in only very few of these can I find that alkalinisation has been attempted and even in these it has obviously been tried much too late."
(Haldane 1924). Since potassium citrate appeared to be as efficient and as rapid in action on the urine as any other alkali, all further experiments were conducted with this substance. It is probable that other alkalis would be equally efficient. To establish the rapidity with which the urine could be rendered alkaline, a single dose of potassium citrate (8 g.) was given to four
TABLE I-AVERAGE
were then asked to pass urine every 15 min. Table II shows that the urine reaches a pH of 7-0 or over in about 30 min. A determination of the optimal dose of potassium citrate necessary to guarantee the maintenance of urinary pH above 7.0 was then undertaken. Four volunteers were each given 20 g. of potassium citrate in twenty-four hours in doses divided in different ways over two periods of twenty-four hours. This amount of alkali was too low, for on seven occasions the urinary pH fell significantly below 7.0. These low pH’s were irrespective of the distribution of dose of alkali employed. Four other volunteers were
The
justification
statement
by
URINARY PH OF TWO SETS OF PATIENTS, BOTH HAVING 8 G. OF POTASSIUM CITRATE
PRACTICAL METHODS OF ENSURING ELIMINATION HAEMOGLOBIN IN URINE
OF
In view of the foregoing facts, we have assumed that the optimal conditions for harmless elimination of haemoglobin are a urinary output of at least 1500 c.cm. in twenty-four hours and a reaction not lower than pH 7-0. This last figure has been arbitrarily chosen to give a margin of safety. The maintenance of this urinary output can be accomplished by the daily administration of at least 3000 c.cm. of fluid (Coller and Maddock 1933). This amount is necessary because 1000 c.cm. is constantly eliminated by the skin and 500 c.cm. by the lungs and faeces. The intake has to be increased when there is any extra loss TABLE II-URINARY PH
IN
SUBJECTS ON HIGH FLUID 8 G. OF POTASSIUM CITRATE
INTAKE AFTER SINGLE DOSES OF
of fluid from normal or abnormal channels. As to the type of alkali and the dose most suitable, the only literature, based on experimental work, which we have had opportunity to consult has been the papers of Davis et al. (1920) and Haldane (1924). These have formed the basis for our preliminary work. Table I shows the average effect of a single dose of alkali (8 g. of potassium citrate) on two sets of patients, one with a high urinary output and one with a low output. The lower output of urine prolongs the effect of the alkali. The administration of sufficient alkali to maintain 1500 c.cm. of urine at pH 7.0 is larger, therefore, than the amount required to alkalinise a smaller volume of urine. The experimental data which follow are only from those cases where the urinary output has been above 1500 c.cm. in twenty-four hours. In practice it is desirable to combine the administration of fluid and alkali into This can be undertaken by one therapeutic measure. one of three routes : oral, rectal, or intravenous. Oral (KM-MMsMo.—Davis et al. (1920) and Haldane (1924) recommend the use of sodium acetate and sodium citrate for oral administration. They state that sodium bicarbonate, though a smaller dose is required to obtain the same effect, is irritating to the gastro-intestinal tract. This statement we confirmed by giving volunteers equivalent doses of different alkalis, 45 g. of sodium bicarbonate being equivalent
to 70 g. of sodium citrate
volunteers, who
TABLE III-URINARY PH
BEFORE
AND AFTER
20
G. OF
POTASSIUM CITRATE
given a single dose of 20 g. of potassium citrate and the urinary pH recorded before the alkali was given and twelve hours later. Table III shows that, at the end of twelve hours, the effect of the alkali on the urine was well maintained. During this period the subjects were at complete rest. The next experiment was undertaken with four volunteers who were given higher doses of potassium citrate. Two were given 46 g. of potassium citrate, and two 72 g. over a period of twenty-four hours. Table IV records the urinary pH of these subjects on all specimens. Towards the end of this time three out of the four subjects had developed symptoms of alkalosis. In one case these symptoms were fairly It will be noted also that the pH readings severe. TABLE IV-URINARY PH
IN SUBJECTS
INTAKE
DOSES
were were
AND
ON MASSIVE
than those made from these
higher
ON LARGE FLUID
OF POTASSIUM CITRATE
required. Three experiments :—
conclusions
(1) Change of urinary reaction to at least pH 7-0 be accomplished in about half an hour, when alkalis are administered by mouth. (2) The optimal dose of potassium citrate is below 46 g. in twenty-four hours. (3) The doses of potassium citrate need not be regularly spaced throughout the twenty-four hours. Before these conclusions were confirmed, various can
substances
were tried to take away the taste of the It was found that ordinary lemon citrate. potassium was most the efficient, and this was used in the squash final experiment. It was also decided that the optimal safe dose of potassium citrate would be about
357 TABLE V—AMBULANT
SUBJECTS TAKING
35
G. OF POTASSIUM CITRATE PER
A
therapeutic procedure, combining the above tried on twelve volunteers. They were points, given 35 g. of potassium citrate in 2000 c.cm. of water flavoured with lemon squash. They were instructed to drink all the fluid within twenty-four hours when and how they pleased and to continue their normal liberal diet. This was repeated for a further twentyfour hours. At the end of the forty-eight hours the 35 g.
was
alkali reserves of all volunteers were measured. Table V shows the urinary pH of every specimen of urine passed and the alkali reserves of each subject. One test had to be discarded. One volunteer (subject 6) developed mild symptoms of alkalosis after thirty-six hours. Her alkali reserve was 84. She was a slender girl weighing 114 lb. The results confirm that 35 g. of potassium citrate will maintain the alkalinisation of the urine. Since these patients were ambulant, it was thought that patients at rest in bed might not be able to tolerate the full dosage of 35 g. A final experiment was then undertaken : four volunteers from the convalescent ward of a hospital were given 35 g. of potassium citrate in 2000 c.cm. of lemon squash every twenty-four hours for three days. The urinary pH results are shown in table VI. Some of the patients taking the lemon-flavoured mixture complained that it progressively became more -monotonous. By the end of the third day several complained that it called for an effort to finish the two litres. Various other flavourings have been tried. Beef-tea, coffee, or milk completely disguises the flavour of the
24
HOURS FOR
2
DAYS
make the total fluid intake per day 3000 c.cm. Potassium citrate 35 g. (gr. 525) given in the same way should be taken every twenty-four hours until haemoglobinuria has ceased. In unconscious patients 35 g. of potassium citrate in 3 litres of water can be given by drip feed through a stomach-tube. Should the symptoms of alkalosis appear, the administration of potassium citrate should be stopped for six hours or until the symptoms have disappeared, and then restarted. These symptoms in the early stages are lassitude, giddiness, and headache ; later, vomiting and muscular cramps. Since urinary methaemoglobin has a brownish tinge and unchanged haemoglobin is bright red, the change of colour will afford a valuable clinical index of urinary pH. The appearance of a brownish tinge in the urine should be a sign to restart treatment. TABLE VI-SUBJECTS
AT REST IN BED TAKING
POTASSIUM CITRATE PER
24
HOURS FOR
3
35
G.
OF
DAYS
drug. intravascular hoemoof 8 g. (gr. 120) of dose lysis suspected,. single potassium citrate should be given. This will render the urine alkaline within half an hour. During the next twenty-four hours the remainder of the 35 g. of potassium citrate (27 g. gr. 415) should be given dissolved in 2000 c.cm. of lemon squash. Instructions must be given that the mixture must all be taken. Besides this the patient should take at least 1000 c.cm. of other fluid. After this time alternative flavourings may be used in the 2000 c.cm. of potassium-citrate mixture. A solid diet contains 1000c.cm. of fluid (Coller and Maddock 1933). This will
Recommendations.-As is
soon as
a
=
Rectal administration.-The large fluid intake which is required (3 litres a day) cannot be given rectally by the commonly employed methods of administration. Marriott and Kekwiek (1937) have shown that this is possible by employing Murphy’s
‘
358 This requires, however, the constant a trained nursing staff. Even then it is not possible for all patients and uncertain for others. The importance of ensuring the absorption of both fluid and alkali is so great that it negatives the employment of this technique. Intravenous administration.-In those cases where oral administration is impracticable the fluid and alkali may be given intravenously. The choice of alkali for these experiments has been sodium citrate, for it was already known from experience with massive blood-transfusion that a considerable amount of sodium citrate was well tolerated intravenously. A preliminary experiment was undertaken to determine the effect of a large single dose of sodium citrate on the urinary pH. A subject on a high fluid intake was given 6 g. of sodium citrate intravenously. Table VII shows the urinary pH every 15 min. for 1
principles.
attention of
TABLE VII-URINARY rH AFTER A SINGLE INTRAVENOUS DOSE OF 6 G. OF SODIUM CITRATE
of the citrate solution should be added to 2400 c.cm. of the glucose and a continuous drip should be established, the total volume of fluid, 2850 c.cm., being given during the first twenty-four hours. Sodium citrate solution 600 c.cm. (18 g. gr. 270) and 2400 c.cm. of glucose are mixed and administered by intravenous drip every twenty-four hours until the disappearance of the haemoglobinuria. The same precautions should be taken if the symptoms of alkalosis appear as were recommended above under oral administration. =
COMMENT
In this paper we have made recommendations for the prevention of suppression of urine after intra. vascular haemolysis. Final proof of the efficacy of these suggestions can only be obtained in the treatment of actual cases. These we have not had at our disposal. We submit, however, that a strong case has been made out for the trial of these procedures. SUMMARY
hours. It was concluded that alkalinisation of the urine was at least as rapid as with approximately the same dose of alkali as was given by mouth (see table II). Further, the effect of 6 g. of sodium citrate given intravenously, compared with that of 8 g. of potassium citrate given by mouth, was that the urinary pH rose higher and returned to normal more quickly. The former is probably due to the increased certainty of the total dose of alkali reaching the bloodstream. A 3 per cent. solution of sodium citrate has been shown to be isotonic with blood (Norgaard and Gram 1921 ; Hirschlaff 1936). This solution was prepared and autoclaved. A 5 per cent. solution of glucose was prepared separately and sterilised. These solutions cannot be sterilised together, owing to the changes produced in the glucose. Sodium citrate 35 g. in glucose was given to one patient over a period of twenty-four hours by the drip method. The administration was continued for thirty hours. A total of 3000 c.cm. of fluid was given for the first twenty-four hours. As was expected, this patient complained of definite symptoms of alkalosis. Three other patients were then given half this amount of sodium citrate (18 g.) for two periods of twenty-four hours. The urinary pH’s and alkali reserves are recorded in table VIII. TABLE VIII-URINARY PH
AFTER
CITRATE INTRAVENOUSLY EACH
24
18
G.
OF
(1) Suppression of urine after intravascular haemolysis is due to obstruction of the tubules with products derived from haemoglobin. (2) The conditions necessary for its prevention are a high urinary output of at least 1500 c.cm. a day and a constant urinary reaction of pH 6-4 or over. (3) These conditions can be fulfilled by the administration of fluid and alkalis orally or intravenously. (4) Recommendations regarding the dose of alkali by both routes are made. Our thanks are due to Dr. P. Phillips, medical superintendent of the Southmead Hospital, for placing cases at our disposal ; and to numerous members of the personnel of the Army Blood Transfusion Service. REFERENCES
Baker, S. L. (1937) Lancet, 1, 1390. and Dodds, E. C. (1925) J. exp. Path. 6, 247. Coller, F. A., and Maddock, W. G. (1933) Ann. Surg. 98, 952. Davis, H. W., Haldane, J. B. S., Kennaway, F. L. (1920) J. Phys. 54, 32. Haldane, J. B. S. (1924) Lancet, 1, 537. Hesse, E., and Filatov, A. (1933) Z. ges. exp. Med. 86, 211. Hirschlaff, B. (1936) Acta med. scand. 87, 530. Marriott, H. L., and Kekwick, A. (1937) Practitioner, 139, 250. Norgaard, A., and Gram, H. C. (1921) J. biol. Chem. 49, 263. -
DRUGS USED IN SURGERY TO RAISE BLOOD-PRESSURE WITH
SPECIAL REFERENCE TO VERITOL
BY HAROLD
DODD, Ch.M. Lpool, F.R.C.S.
SURGEON TO THE KING GEORGE HOSPITAL, ILFORD, AND TO THE ROYAL HOSPITAL, RICHMOND; ASSISTANT SURGEON TO THE LONDON HOMŒOPATHIC HOSPITAL
POTASSIUM 2 DAYS
HOURS FOR
IJRUGS that raise the
blood-pressure
are 01
particular
interest to the surgeon to counteract the serious falls that take place during major operations, especially with spinal anaesthesia, and in other conditions of shock. I have studied this subject since 1933 and tested many drugs to maintain the blood-pressure and to restore it from unduly low levels. Of these Veritol has proved to be the most satisfactory. CORAMINE
Recommendations.-A 3 per cent. solution of sodium citrate and a 5 per cent. solution of glucose are prepared and sterilised separately. As soon as intravascular haemolysis is suspected, 150 c.cm. of the 3 per cent. solution of sodium citrate (4-5 g. gr. 69) should be administered immediately with a syringe. This will render the urine alkaline. Next, 450 c.cm. =
Coramine has been given intravenously and intrain doses up to 2 c.cm. So far as can be measured with the ordinary sphygmomanometer or an oscillometer, no effect whatever is produced on the blood-pressure, nor has any other benefit been observed; consequently this preparation is not used for the purpose of raising the blood-pressure.
muscularly