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Intravenous alkaline infusion in blackwater fever
488
I N T R A V E N O U S A L K A L I N E I N F U S I O N I N B L A C K W A T E R FEVER. BY H. M. HANSCHELL, D.S.C., L.R.C.P., M.R.C.S., D.T.M. & H.
Hon. Med. Supt. ~ Pathologist, Seamen's Hospital, Royal Albert Doch, London.
The alkaline treatment of blackwater fever was first brought to the writer's notice, four years ago, by Dr. JAMES WHITE THOMSON, West African Medical staff. This competent observer, in a very much greater first-hand experience of this disease, had obtained uniformly good results by the intensive use of alkalies, and, in verbal communications to the writer, had recommended it. This paper reports one case, rather severe, of blackwater fever, occurring in London, in September, 1925, in which recovery followed the intravenous administration of sodium bicarbonate. Modesty, and caution bred of some knowledge of this disease, would usually prevent one such case being thought worthy of record ; and, most of all, any claim for the specific efficacy of a drug used in one case only. Indeed, but for some recent work of BAKER and DODDS (Oct., 1925), the writer was resigned to the thought that he had put in an ineffectual attendance on yet another sick human being, doomed from the start to recovery. YORKE and Nauss (1911) injected rabbits with h~emoglobin solutions. In some they produced an intrarenal obstruction by precipitation of the pigment in the kidney tubules ; but this renal obstruction was produced only if the rabbits had been fed on a dry diet before the h~emoglobin injection. Rabbits on green diet rapidly excreted the h~emoglobin into the urine and appeared little affected by the injection. They suggested that the dry diet caused greater concentration of the urine and so precipitation of the h~emoglobin in the tubules. BAKER and DObbS' research was primarily concerned with intrarenal obstruction, as observed in two patients who died from renal insufficiency following transfusion of incompatible blood. In both, the transfusion produced lumbar pain ; fever ; jaundice ; h~emoglobinuria ; pigment casts in urine ; very high blood urea and other nitrogen retention ; and partial or total suppression of urine. They found that h~emoglobin solution injected into the rabbit's vein produced a high blood urea ; and that, as in the two human cases of blood-transfusion h~emoglobinuria, the rabbit sometimes passed dark-brown, cloudy urine and sometimes clear, red urine. The former contained a brown, granular precipitate with casts of renal tubules. This brown, granular urine was always very acid, while the clear, red urine was neutral or alkaline. The conversion of oxyh~emoglobin into a granular precipitate was then, in some way, connected with tile acidity rather than with the concentration of the urine.
ALKALI I N BLACKV~'ATER FEVER
489
Rabbits on green diet were found normally to pass strongly alkaline urine ; while those fed on oats and bread, though with unlimited water to drink, passed, normally, acid urine. Rabbit A was fed on oats and bread, with water to drink ; its urine became acid. Rabbit B was fed on greens ; its urine was strongly alkaline. Each was injected with 10 c.c. of a strong haemoglobin solution. A passed the haemoglobin out as a brown precipitate suspended in acid urine, with many brown, granular .casts, and its blood urea rose to 78 mgm. per 100 c.e. ; B passed red, alkaline urine, containing abundant oxybaemoglobin and no brown precipitate or casts, :and its blood urea remained n o r m a l - - 3 5 mgm. per 100 c.c. In their rabbit .experiments all the brown urines were acid and contained methaemoglobin ; all the red ones were alkaline or neutral and contained mostly oxyhaemoglobin. In vitro experiments showed that increased salt concentration was also a factor in the precipitation of haemoglobin. But this precipitation was not produced by high salt concentration in the absence of the required degree of acidity. They concluded from their experiments that h~emoglobin introduced into the circulation is excreted by the kidneys. Thus : - 1. If the urine reaction be above p H 6, the haemoglobin will all be excreted as oxyhaemoglobin ; the urine red and no ill-effects result. 2. If the urine reaction be below p H 6, and there be a sufficient concentration (1 per cent.) of NaC1, brown pigment will be precipitated in (and may block) the tubules. Their view is that the haemoglobin passes through Bowman's capsule in the dilute transudate, the reaction of which is nearly that of the blood. In the tubules, reabsorption, concentration, and increase of acidity, occur ; haemoglobin is then precipitated, probably as haematin ; as a result, the tubules may be blocked and renal function impaired. Pigment casts, like those seen in the rabbit's urine, do occur in blackwater fever, and they had found them also in the urine of a case of paroxysmal haemoglobinuria. Their photographs of kidney sections from the two fatal cases of blood-transfusion haemoglobinuria, and from the experimental rabbits, show the plugging of tubules with pigment casts, so often demonstrated in kidney sections from fatal cases of blackwater fever. The rabbits were able to get rid of the plugs in the tubules. The kidney, can therefore, clear itself of a certain amount of d6bris. The gravity of the renal lesion must depend, in part, upon the degree of haemoglobinuria and consequent plugging. BAKER and DODDS indicate the line of treatment in all cases of haemoglobinuria. It should be such as will reduce the factors leading to precipitation of the pigment in the kidney tubules. These factors are seen to be acidity and salt concentration of the urine. Alkaline diuretics, or transfusions of sodium bicarbonate, as soon as possible, should tend to minimize the haemoglobin precipitaxion in the tubules.
490
ALKALI IN BI,ACKWATER FEVER
In fact, their investigation gives direct experimental warrant for the intravenous administration, at once, of sodium bicarbonate in blackwater fever; and it is in the retrospective light cast by their work that the writer reports now the following case : European ~nale--cet. 47 years.--Had recently been employed in a West African mine. Had suffered many bouts of fever and was, from his own accounts, an assiduous quinin e taker--five grains daily, usually with whisky. Of the big, bulky kind, twenty-five years, off and on, in various parts of the tropics, had made him " hardened to fevers and mosquito bites, so as not to notice them." The writer treated him for syphilis over a period of five months, half way during which tile patient developed fever; subtertian malaria rings being found in his blood. Three months (September, 1925) after cessation of anti-syphilitic treatment, the writer was called one forenoon to see him in lodgings. T h e patient had then been ill two and a half days and without medical attention. He had diagnosed his own case as blackwater fever, which he claimed to know well, for he had often doctored and nursed it in others. He had kept in bed and treated himself by frequent liberal draughts of b e e r - - t h e labels on the many bottles about the room read " Light Luncheon Ale." T h e patient had deep jaundice ; anxious face ; pulsating neck ; large liver and spleen ; small, rapid pulse, easily stopped ; indistinct heart sounds and h~ernic murmurs. Axillary temperature, 103"4 ° F. Vomiting had begun eight hours before, and was now frequent. No urine had been voided for over five hours ; the whole of the last passed specimen, in the chamber-pot, measured just over one fluid ounce. It was almost black with heavy, brown, granular deposit. He compained of severe headache and lumbar pain and had " fainted " on sitting up in bed about two hours before the writer's arrival. Instructed thereto, the landlady removed all the bottles, even the full ones, and the patient was told to begin, and keep on, drinking water, in spite of vomiting. Rather over two hours later, and now armed with supplies, the writer again reached the patient, who was then unable to talk or move ; vomiting had ceased. Axillary temperature, 104"4 ° F. No urine had been passed. A catheter drew off about half an ounce of quite black urine with heavy, brown, granular deposit (found on later microscopic examination to contain many granular, yellowish brown, and a few celhdar, casts; epithelial cells, few leucocytes and erythrocytes and much yellowish, granular d6bris). The patient was given, intravenously, 20 fluid ounces of distilled water, in which had been dissolved 150 grains of sodium bicarbonate (the whole previously sterilised by boiling for five minutes). Noticeable improvement in pulse followed ; and one hour later this intravenous infusion of 150 grains of sodium bicarbonate in 20 ounces of distilled water was repeated. About fifteen minutes after this second injection, a catheter drew off about four ounces of urine, less black and with less deposit ; and the patient's general
ALKALI IN BLACKVCATER FEVER
491
condition had unmistakably improved. Yet an hour later, the catheter drew off some twelve ounces of translucent, deep red urine with little deposit ; and the patient, after a few minutes of shallow sighing, yawned, and fell asleep. Diuresis with progressively clearer urine continued. Convalescence followed rapidly enough to enable this heroic patient, with his admirable bent on recovery, to place himself two days later on the " light ale " solace, and in three weeks from the onset of illness to pronotmce himself fit to leave London, and, somewhat tottering and panting, to leave. During illness and convalescence he had received no drugs, at any time, but the two intravenous injections of sodium bicarbonate; water and tea to drink, and of course, the ale. It is plausibie to say that the ale had not prevented the close approach of total suppression of urine. I t is reasonable to claim that the sodium bicarbonate injections not only restored diuresis more fully, but also made that diuresis alkaline, and thus prevented the blocking of any naore renal tubules. In blackwater fever how much alkaline to give, and how often, and by what route, much more experience of this therapy can alone discover. It is clear already that the earlier it be given the better the prognosis.
REFERENCES. BA~;Ea, S. L. a n d Dot)Ds, E. C. (1925). '" O b s t r u c t i o n of the Renal T u b u l e s d u r i n g the excretion of H a e m o g l o b i n . " Brit..)tourn. of Exper. Path., vl, 245, Oct. Yore;E, W. a n d NAUss, R . W . (1911-12). Trot). Med. and Parasit., v.
~' Suppression of Urine in Blackwater F e v e r . "
~4nn.
I N T R A V E N O U S A L K A L I N E I N F U S I O N I N B L A C K W A T E R FEVER. BY H. M. HANSCHELL, D.S.C., L.R.C.P., M.R.C.S., D.T.M. & H.
Hon. Med. Supt. ~ Pathologist, Seamen's Hospital, Royal Albert Doch, London.
The alkaline treatment of blackwater fever was first brought to the writer's notice, four years ago, by Dr. JAMES WHITE THOMSON, West African Medical staff. This competent observer, in a very much greater first-hand experience of this disease, had obtained uniformly good results by the intensive use of alkalies, and, in verbal communications to the writer, had recommended it. This paper reports one case, rather severe, of blackwater fever, occurring in London, in September, 1925, in which recovery followed the intravenous administration of sodium bicarbonate. Modesty, and caution bred of some knowledge of this disease, would usually prevent one such case being thought worthy of record ; and, most of all, any claim for the specific efficacy of a drug used in one case only. Indeed, but for some recent work of BAKER and DODDS (Oct., 1925), the writer was resigned to the thought that he had put in an ineffectual attendance on yet another sick human being, doomed from the start to recovery. YORKE and Nauss (1911) injected rabbits with h~emoglobin solutions. In some they produced an intrarenal obstruction by precipitation of the pigment in the kidney tubules ; but this renal obstruction was produced only if the rabbits had been fed on a dry diet before the h~emoglobin injection. Rabbits on green diet rapidly excreted the h~emoglobin into the urine and appeared little affected by the injection. They suggested that the dry diet caused greater concentration of the urine and so precipitation of the h~emoglobin in the tubules. BAKER and DObbS' research was primarily concerned with intrarenal obstruction, as observed in two patients who died from renal insufficiency following transfusion of incompatible blood. In both, the transfusion produced lumbar pain ; fever ; jaundice ; h~emoglobinuria ; pigment casts in urine ; very high blood urea and other nitrogen retention ; and partial or total suppression of urine. They found that h~emoglobin solution injected into the rabbit's vein produced a high blood urea ; and that, as in the two human cases of blood-transfusion h~emoglobinuria, the rabbit sometimes passed dark-brown, cloudy urine and sometimes clear, red urine. The former contained a brown, granular precipitate with casts of renal tubules. This brown, granular urine was always very acid, while the clear, red urine was neutral or alkaline. The conversion of oxyh~emoglobin into a granular precipitate was then, in some way, connected with tile acidity rather than with the concentration of the urine.
ALKALI I N BLACKV~'ATER FEVER
489
Rabbits on green diet were found normally to pass strongly alkaline urine ; while those fed on oats and bread, though with unlimited water to drink, passed, normally, acid urine. Rabbit A was fed on oats and bread, with water to drink ; its urine became acid. Rabbit B was fed on greens ; its urine was strongly alkaline. Each was injected with 10 c.c. of a strong haemoglobin solution. A passed the haemoglobin out as a brown precipitate suspended in acid urine, with many brown, granular .casts, and its blood urea rose to 78 mgm. per 100 c.e. ; B passed red, alkaline urine, containing abundant oxybaemoglobin and no brown precipitate or casts, :and its blood urea remained n o r m a l - - 3 5 mgm. per 100 c.c. In their rabbit .experiments all the brown urines were acid and contained methaemoglobin ; all the red ones were alkaline or neutral and contained mostly oxyhaemoglobin. In vitro experiments showed that increased salt concentration was also a factor in the precipitation of haemoglobin. But this precipitation was not produced by high salt concentration in the absence of the required degree of acidity. They concluded from their experiments that h~emoglobin introduced into the circulation is excreted by the kidneys. Thus : - 1. If the urine reaction be above p H 6, the haemoglobin will all be excreted as oxyhaemoglobin ; the urine red and no ill-effects result. 2. If the urine reaction be below p H 6, and there be a sufficient concentration (1 per cent.) of NaC1, brown pigment will be precipitated in (and may block) the tubules. Their view is that the haemoglobin passes through Bowman's capsule in the dilute transudate, the reaction of which is nearly that of the blood. In the tubules, reabsorption, concentration, and increase of acidity, occur ; haemoglobin is then precipitated, probably as haematin ; as a result, the tubules may be blocked and renal function impaired. Pigment casts, like those seen in the rabbit's urine, do occur in blackwater fever, and they had found them also in the urine of a case of paroxysmal haemoglobinuria. Their photographs of kidney sections from the two fatal cases of blood-transfusion haemoglobinuria, and from the experimental rabbits, show the plugging of tubules with pigment casts, so often demonstrated in kidney sections from fatal cases of blackwater fever. The rabbits were able to get rid of the plugs in the tubules. The kidney, can therefore, clear itself of a certain amount of d6bris. The gravity of the renal lesion must depend, in part, upon the degree of haemoglobinuria and consequent plugging. BAKER and DODDS indicate the line of treatment in all cases of haemoglobinuria. It should be such as will reduce the factors leading to precipitation of the pigment in the kidney tubules. These factors are seen to be acidity and salt concentration of the urine. Alkaline diuretics, or transfusions of sodium bicarbonate, as soon as possible, should tend to minimize the haemoglobin precipitaxion in the tubules.
490
ALKALI IN BI,ACKWATER FEVER
In fact, their investigation gives direct experimental warrant for the intravenous administration, at once, of sodium bicarbonate in blackwater fever; and it is in the retrospective light cast by their work that the writer reports now the following case : European ~nale--cet. 47 years.--Had recently been employed in a West African mine. Had suffered many bouts of fever and was, from his own accounts, an assiduous quinin e taker--five grains daily, usually with whisky. Of the big, bulky kind, twenty-five years, off and on, in various parts of the tropics, had made him " hardened to fevers and mosquito bites, so as not to notice them." The writer treated him for syphilis over a period of five months, half way during which tile patient developed fever; subtertian malaria rings being found in his blood. Three months (September, 1925) after cessation of anti-syphilitic treatment, the writer was called one forenoon to see him in lodgings. T h e patient had then been ill two and a half days and without medical attention. He had diagnosed his own case as blackwater fever, which he claimed to know well, for he had often doctored and nursed it in others. He had kept in bed and treated himself by frequent liberal draughts of b e e r - - t h e labels on the many bottles about the room read " Light Luncheon Ale." T h e patient had deep jaundice ; anxious face ; pulsating neck ; large liver and spleen ; small, rapid pulse, easily stopped ; indistinct heart sounds and h~ernic murmurs. Axillary temperature, 103"4 ° F. Vomiting had begun eight hours before, and was now frequent. No urine had been voided for over five hours ; the whole of the last passed specimen, in the chamber-pot, measured just over one fluid ounce. It was almost black with heavy, brown, granular deposit. He compained of severe headache and lumbar pain and had " fainted " on sitting up in bed about two hours before the writer's arrival. Instructed thereto, the landlady removed all the bottles, even the full ones, and the patient was told to begin, and keep on, drinking water, in spite of vomiting. Rather over two hours later, and now armed with supplies, the writer again reached the patient, who was then unable to talk or move ; vomiting had ceased. Axillary temperature, 104"4 ° F. No urine had been passed. A catheter drew off about half an ounce of quite black urine with heavy, brown, granular deposit (found on later microscopic examination to contain many granular, yellowish brown, and a few celhdar, casts; epithelial cells, few leucocytes and erythrocytes and much yellowish, granular d6bris). The patient was given, intravenously, 20 fluid ounces of distilled water, in which had been dissolved 150 grains of sodium bicarbonate (the whole previously sterilised by boiling for five minutes). Noticeable improvement in pulse followed ; and one hour later this intravenous infusion of 150 grains of sodium bicarbonate in 20 ounces of distilled water was repeated. About fifteen minutes after this second injection, a catheter drew off about four ounces of urine, less black and with less deposit ; and the patient's general
ALKALI IN BLACKVCATER FEVER
491
condition had unmistakably improved. Yet an hour later, the catheter drew off some twelve ounces of translucent, deep red urine with little deposit ; and the patient, after a few minutes of shallow sighing, yawned, and fell asleep. Diuresis with progressively clearer urine continued. Convalescence followed rapidly enough to enable this heroic patient, with his admirable bent on recovery, to place himself two days later on the " light ale " solace, and in three weeks from the onset of illness to pronotmce himself fit to leave London, and, somewhat tottering and panting, to leave. During illness and convalescence he had received no drugs, at any time, but the two intravenous injections of sodium bicarbonate; water and tea to drink, and of course, the ale. It is plausibie to say that the ale had not prevented the close approach of total suppression of urine. I t is reasonable to claim that the sodium bicarbonate injections not only restored diuresis more fully, but also made that diuresis alkaline, and thus prevented the blocking of any naore renal tubules. In blackwater fever how much alkaline to give, and how often, and by what route, much more experience of this therapy can alone discover. It is clear already that the earlier it be given the better the prognosis.
REFERENCES. BA~;Ea, S. L. a n d Dot)Ds, E. C. (1925). '" O b s t r u c t i o n of the Renal T u b u l e s d u r i n g the excretion of H a e m o g l o b i n . " Brit..)tourn. of Exper. Path., vl, 245, Oct. Yore;E, W. a n d NAUss, R . W . (1911-12). Trot). Med. and Parasit., v.
~' Suppression of Urine in Blackwater F e v e r . "
~4nn.