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THE EFFECT OF REPEATED ALBUMIN INFUSIONS IN PATIENTS WITH CIRRHOSIS
Saturday I December 1962
THE EFFECT OF REPEATED ALBUMIN INFUSIONS IN PATIENTS WITH CIRRHOSIS* PATRICIA WILKINSON M.B., B.Sc. Lond., M.R.C.P. MEDICAL REGISTRAR
M.D.
SHEILA SHERLOCK Edin., F.R.C.P., F.R.C.P.E. PROFESSOR OF MEDICINE
From the
Department of Medicine, Royal Free Hospital, London, W.C 1
IN
cirrhosis, the diseased liver may be temporarily or permanently unable to produce enough albumin to maintain a normal concentration in the plasma. This results in a low colloid osmotic pressure and contributes to the production of oedema or ascites. Efforts to restore plasma-albumin levels in such patients include raising the dietary protein intake (Patek et al. 1948a), and infusions of plasma (Ricketts 1951) or ascitic fluid (Greene 1943). In 1944 salt-poor human albumin became available, and infusions were used to treat cirrhotic patients, with varying results. Some workers failed to induce a diuresis, although all noted an improved sense of well-being in their patients (Janeway et al. 1944, Thorn et al. 1946, Armstrong 1948, Mankin and Lowell 1948, Patek et al. 1948b, Faloon et al. 1949, Watson and Greenberg 1949). Other workers, however, reported that more than half of the cases treated were relieved of ascites and oedema (Kunkel et al. 1948, Havens and Bleumle 1950, Post et al. 1951). These early studies were directed mainly to the initial relief of ascites or oedema, but in a few patients maintenance infusions were continued, in 1 patient for over eight months, with apparent benefit (Faloon et al.
1949). More recently, Losowsky and Atkinson (1961) controlled ascites by maintenance infusion in 7 out of 9 patients who had not responded to sodium restriction and diuretics. Dykes (1961) produced a diuresis in 7 out of 13 similar patients, and later maintained them free of ascites and oedema. Albumin is expensive, and its administration is not without hazard. More and more cases of " resistant ascites " yield to the newer diuretics (Shaldon et al. 1960, Summerskill et al. 1961), but these drugs also are costly and have their own complications. This work was undertaken, therefore, to determine whether repeated albumin infusions are of value in the management of cirrhosis. When the investigation was begun, patients were selected who were resistant to all other forms of medical treatment then available. As more powerful diuretics became available, such cases became fewer. Also, in most patients who responded to diuretics, the serum-albumin concentrations returned to normal, which suggested that the previous low levels were due either to a temporary defect in synthesis, * Based on a report to the Blood-transfusion Subcommittee of the Medical Research Council. 7266
redistribution of body stores. But a few patients still had low serum-albumin levels after diuresis. These, together with any remaining patients with " resistant ascites ", were included in the study. To try to separate the effect of the albumin from the effects of other treatment and the natural course of the disease, the patients were put at random into two groups, one of which received repeated albumin infusions over long periods, while the other was observed as a control or to a
group. Material
Patients were selected from inpatients admitted for investigation and treatment of cirrhosis. At first they were included in the study if, after six weeks’ treatment with diet and the diuretics currently available, they still had fluid retention, or if, after successful treatment, the serum-colloid osmotic levels remained below 30 cm. of This level represents a moderate but definite depletion in serum-albumin level, corresponding to water.
3-0-3-2 g. per 100 ml. When aldosterone antagonists became readily available patients were included only when diuresis was complete.
patients selected were allocated at random into two control and a treated group (table I). 4 of these had ascites which had not cleared with diuretic therapy (nos. 1-3, 10). The others were included after diuresis; of these 7 (nos. 4, 5, 7, 11, 14, 15, and 16) originally came with ascites, 2 (nos. 8 and 13) had mainly peripheral oedema with little ascites, and 2 (nos. 6 and 12) had peripheral oedema after portacaval anastomosis. Thus, 7 patients with ascites and 2 with oedema fell into the control group, and 5 with ascites and 2 with oedema into the treated group. The duration of symptoms varied from two months to eight years. In 12 patients the cause of the cirrhosis was unknown, in nos. 5, 7, 10, and 11 there was a history of alcoholism. In all but 2 of the patients histological The 16
groups,
a
TABLE I-DETAILS OF PATIENTS
1126 confirmation of the diagnosis was obtained. In case no. 9 coincident tuberculous peritoneal infection was found post
TABLE II-DETAILS OF ALBUMIN INFUSIONS
mortem.
The period of follow-up and treatment varied from one to twenty-two months, and totalled 116 patient-months in the control group and 95 patient-months in the treated group. Treatment
Patients in both control and treated groups received dietary and diuretic treatment as required. Patients in the treated group received salt-poor human serum-albumin (Lister Institute), reconstituted with pyrogenfree water to a 25% solution. Infusions varied between 25 and 100 g. each, and were given over one to three hours. At first infusions were given daily or at intervals of two days until the serum-colloid osmotic pressure reached 38-40 cm. of water. Subsequently, the level was maintained between 35 and 40 cm. of water by weekly or fortnightly infusions given in the
outpatient department. No placebo infusions were given to patients in the control group and, as far as possible, patients in this group were seen separately but at similar intervals from those in the treated group. At each visit patients were weighed, and their well-being was assessed in terms of working ability and sexual function. Serum-albumin levels were measured by a biuret method (Gornall et al. 1949) for total protein, and fractionation by paper electrophoresis (Owen 1956). Serum-colloid osmotic pressure was estimated with the Rowe colloid osmometer (Rowe 1957), the range in 38 normal subjects being 29-043-0 cm. (mean 36-5 cm.). These agree with results obtained by Losowsky and Atkinson (1961). Serum-bilirubin, glutamic oxaloacetic transaminase (S.G.O.T.), and prothrombin concentration were estimated every two to three months. In 6 patients the albumin infusions were stopped after six to nine months, and three to four weeks later the serumalbumin and colloid osmotic pressure were again measured before resuming treatment. In the treated patients who survived until the end of the study, these measurements were again made one month after the albumin had been stopped
permanently. Results
Fell to 12-5 g. after albumin.
ten
months and after further
two
months received no
The amount of albumin necessary to maintain the serumcolloid osmotic pressure level between 35 and 40 cm. of water varied from 12-5 to 100 g. weekly, and depended on the patient’s own serum-albumin level after diuresis; the lower this level, the higher the maintenance dose required. In 5 patients maintenance requirements did not change. 1 patient (no. 11) required 25 g. weekly for ten months; then this diminished over four months, until, for the last two months, he received no albumin. Immediate Effects and Complications of Infusions
All patients experienced a sense of well-being, usually greatest on the day after the albumin infusion. Serial estimations of the packed-cell volume made during this time showed a fall (figs. 1 and 2). 3 patients who still had predominant ascites (nos. 2, 3, and 15) showed an acceleration in fluid retention. Judged by the gain in weight (fig. 1), the volume of fluid retained sometimes
exceeded the volume infused. Normal serum-colloid osmotic pressures were obtained in these patients, but the ascitic colloid-osmotic pressure also rose by a similar or a slightly smaller amount. The 2 patients with predominantly peripheral oedema (nos. 6 and 8), however, had a diuresis of water and sodium (fig. 2). The other 2 patients (nos. 11 and 16) had been treated successfully with diuretics before they were, given albumin. Only one infusion reaction, thought to be due to an imperfectly
patients with cirrhosis were seen during the investigation, 60 of whom had fluid retention. In 14 this was transient and cleared spontaneously or after dietarysodium restriction and thiazide diuretics. After diuresis, the serum-albumin and serum-colloid osmotic pressure levels returned to normal. In 24 patients fluid retention formed part of the picture of terminal liver failure. In 2 cases liver biopsy revealed a- primary carcinoma. 2 patients were only briefly in hospital and were not included. The remaining 16 (11%) were selected for the 145
study. Quantities of Albumin Used The 7 patients treated received a total of 15,125 g. albumin in 242 infusions (table 11). In 6 of the 7 patients, normal serumalbumin and serum-colloid osmotic pressure levels were achieved, and maintained for periods varying from eight to nineteen months. The 7th patient (no. 15) died after haemorrhage from oesophageal varices, precipitated perhaps by the first dose of albumin. The amounts of albumin needed to raise the serum-colloid osmotic pressure to normal varied between 275 and 675 g. and seemed to depend on the clinical state, the initial serum-colloid osmotic pressure, and the time taken to complete the first course. In patients with massive ascites some of the infused albumin was lost into the ascitic fluid, the colloid osmotic pressure of which rose. Normal levels were achieved more economically when large infusions could be given at short intervals, there being less time then for the infused albumin to be catabolised.
Fig. 1-Patient
no. 3. Unsuccessful result after initial intravenous infusion of human serum-albumin.
course
of
Infusion of 600 g. of human serum-albumin restored serum-colloid osmotic pressure to normal, but produced no diuresis; fluid retention with gain in weight. Colloid osmotic pressure of ascitic fluid rose by nearly as much as serum-colloid osmotic pressure; fall in packed-cell volume during infusions.
1127
cleaned rubber giving-set, was noted during the course of 242 infusions. 1 patient (no. 3) had an attack of virus hepatitis fourteen months after starting treatment with intravenous albumin. As infectious hepatitis was epidemic in her neighbourhood at the time this may have been naturally acquired, although no contact history was established. Homologous serum jaundice could not be excluded, although this is unlikely, since other patients were treated from the same batch of albumin without ill effect. 1 patient (no. 15) had a fatal haemorrhage from oesophageal varices after the infusion of 100 g. of albumin. No
TABLE III-GENERAL HEALTH AND WORKING ABILITY IN CONTROL AND TREATED GROUPS
phlebothrombosis resulted. No patient, except no. 15 who bled, de-
teriorated mentally after the infusions. Patient no. 6 was
and 3 in the treated group (nos. 3, 11, and 16), are leading normal lives at home or at work. 3 of these 6 had been alcoholics and had stopped drinking during the investigation. The period of observation was 116 patient-months in the control group, and 95 patient-months in the treated group. There is no difference in the attainment of restricted or full activity in the two groups (table iv). 3 patients in the control group (nos. 5, 7, and 10) and 2 in the treated group (nos. 3 and 11) have gained more than 16 lb. in weight-an increase repre-
given
several infusions while precomatose or
comatose
without further clinical or electroence-
phalographic
TABLE IV--COMPARISON OF WORKING ABILITY IN CONTROL AND TREATED
deterioration. No circulatory
overloading produced in any patient.
GROUPS
was
General Health 6 patients (table m) died
Fig. 2-Patient
no. 6. Successful result after initial course of intravenous human serumalbumin.
Infusion of 400 g. of human serum-albumin restored serum-colloid osmotic pressure to normal, produced diuresis with fall in weight, and coincident fall in packed-cell volume.
of terminal liver failure, 3 in the control group (nos. 1, 9, and 14), and 3 in the treated group (nos. 2, 6, and 15). In 1 (no. 15) death was due to bleeding from resophageal varices. 4 patients are living restricted lives at home; of these, 3 (nos. 4, 10, and 13) are in the control group, and 1 (no. 8) has received treatment with albumin. The remaining 6, 3 in the control group (nos. 5, 7, and 12),
senting flesh and not fluid. 1 control patient (no. 7) has begun regularly again, and 1 male patient in each group (no. 5 control, no. 11 treated) had had a return of libido. The patients who improved were all alcoholics, except no. 3. to menstruate
Diuretic Needs
8) who had very low serum-albumin with intravenous albumin, but who responded to thiazide diuretics alone, could dispense with these 2
patients (nos.
levels before
6 and
treatment
TABLE V-CHANGES IN LIVER-FUNCTION TESTS IN CONTROL AND TREATED GROUPS
Serum-albumin and serum-colloid osmotic pressure values: a, first value obtained after successful diuresis; b, in control group at end of investigation; in treated group
one
month after
stopping infusions during
or at
end of investigation.
1128
drugs when the serum-albumin was maintained at normal by repeated infusions. Continued dietary-sodium restriction, however, was necessary. Patients nos. 2, 3, 11, and 16, who had relatively higher serum-albumin levels and required aldosterone antagonists in addition to thiazides to promote a diuresis, still needed these levels
diuretics in the same doses even when the serum-colloid osmotic pressure was raised to normal. When the diuretics were reduced or withheld, fluid re-accumulated-most rapidly immediately after an infusion. 1 patient (no. 11), after twelve months’ treatment with diuretics and albumin, needed a smaller dose of diuretics as well as less albumin. This patient had a history of alcoholism, and resembled 2 patients (nos. 5 and 7) in the control group with a similar history. The diuretic requirements of these patients also diminished during the investigation, and they In the were able to increase their dietary-sodium intake. remaining 7 patients in the control group, diuretic treatment could not be reduced.
of Liver Function significant change was noted
Biochemical Tests
in serum-bilirubin levels No and serum-glutamicoxaloacetic-transaminase levels, or in the prothrombin concentration (table v), after treatment with albumin. Serum-colloid osmotic pressure and serum-albumin levels improved in patients nos. 5 and 7 in the control group. In the treated group when infusions were stopped for long enough to allow the infused albumin to be metabolised, the serum-colloid osmotic pressure and serum-albumin levels rose above pre-treatment values only in patient no. 11. Discussion
In selecting patients, a critical level of serum-colloid osmotic pressure, after diuresis of 30 cm. of water, was chosen to reflect a significant defect in albumin synthesis. Patients included in the series with initial serum-colloid osmotic pressure levels approaching 30 cm. of water needed very small maintenance infusions; it is, therefore, unlikely that the level chosen was too low and that patients who might have profited were wrongly excluded. If suboptimal levels of serum-colloid osmotic pressure were contributing to the patient’s symptoms, continued elevation might be expected to produce some immediate or late benefit. The level chosen, although near the lower limit of normal, is still well above the critical level for producing the ascites and oedema reported by other workers (Bjornboe et al. 1949, Cherrick et al. 1960). The amounts of albumin needed at first to raise the serum-colloid osmotic pressure to normal were surprisingly large, a fact noted by Faloon (1949), Post et al. (1951), and more recently by Dykes (1961). More than twice the normal total exchangeable albumin was needed in patients with ascites. Since high serum levels were reached some of the albumin was undoubtedly catabolised rapidly. Much also was lost into the enormously expanded extravascular compartment, since considerably smaller amounts sufficed when there was no ascites, yet the fate of some of the albumin remains obscure. The amounts of albumin needed to maintain normal serumcolloid osmotic pressure levels does not depend on the size of the patient. Instead, they vary approximately with the initial serum-colloid osmotic pressure; the lower this value, the larger the maintenance infusion needed. This variation in the rise of serum-colloid osmotic pressure agrees with Dykes’ finding (1961) that with infused labelled albumin, as the serum level rose, the rate of catabolism increased, and suggests that the rate of albumin breakdown is dependent on the serum concentration.
Although expensive and time-consuming to patient and doctor, the infusions have proved relatively safe. There
fewer pyrogenic reactions than in earlier work (Watson and Greenberg 1949), probably mainly because of improved transfusion techniques. Also, pulmonary oedema and haemorrhage from oesophageal varices were less common Faloon et al. 1949, (Watson and Greenberg 1949, Havens and Bluemle 1950). This is probably because the infusions were usually given when there was no fluid retention; hence sudden massive expansion of the plasma volume by withdrawal of extracellular fluid into
were
the circulation
was
avoided.
The immediate effect of the infusions in producing a of well-being commented on by Kunkel and coworkers (1948) and Dykes (1961) was seen in every case, and may be related to a coincident expansion of the plasma volume. Where the albumin produced a diuresis this might also have been achieved by increasing the plasma volume and therefore the renal blood-flow, rather than by altering an osmotic equilibrium. Patek and coworkers (1948b) found an increased renal blood-flow after albumin infusions in patients with cirrhosis and ascites. sense
By the time serum-albumin and serum-colloid osmotic fallen, albumin synthesis and, with it, other functions of the liver have been seriously deranged, and the prognosis must be poor. It may be difficult then to prolong life by any means, and any benefit should be correspondingly easy to detect, particularly if a simultaneous control series is under observation. Repeated albumin infusions neither in life our patients nor made it more enjoyable prolonged pressure levels have
or
useful.
Treatment with albumin did not reduce diuretic needs, and in this respect also our findings differ from previous results. Earlier successes, in which control observations were not made, may have been wrongly attributed to the albumin. Patients with cirrhosis of the alcoholic type are known to improve when they are carefully supervised and are persuaded to stop drinking (Summerskill et al. 1960, 1961), whereas in patients with no history of alcoholism the disease pursues a more relentless downhill course. This has been confirmed; the alcoholics had a more favourable prognosis. The relatively good results reported in some earlier studies (Kunkel et al. 1948, Faloon et al. 1949) may have partly been due to remissions after the withdrawal of alcohol. The careful supervision inherent in any clinical trial inevitably confers benefit on both the treated and the control groups. Dietary sodium restriction is more efficient, and more attention is paid to diuretic needs. In the absence of a control group improvement could be wrongly attributed to the albumin.
Serum-colloid osmotic pressure is a more important factor than portal blood-pressure in the pathogenesis of ascites (Cherrick et al. 1960). It is, therefore, surprising that restoring the serum-colloid osmotic pressure to normal for long periods did not help the continued control of ascites once remission had been induced with diuretics. This suggests that, in our patients at least, the primary disturbance was not only a colloid osmotic imbalance.
Summary 60 out of 145 patients with cirrhosis of the liver seen in the past two years have shown fluid retention. 16 of these, even when free of ascites or oedema, had a persistent defect of albumin synthesis, judged by lowered serumalbumin and serum-colloid osmotic pressure levels. They
1129 were
allocated
at
random into
a
control group
CARDIAC IRREGULARITIES
(9 patients)
and a treated group (7 patients). Both groups received dietary and diuretic therapy as required, and 6 in the treated group also received infusions of 25-100 g. salt-poor human serum-albumin every one to two weeks for up to nineteen months to keep serum-colloid osmotic pressures at normal levels. The amount of albumin required was proportional to the initial deficit in serum-albumin level, suggesting that artificially raising the serum-albumin level increased the rate of
breakdown. The albumin caused no reactions, and did not induce or exacerbate hepatic precoma. It precipitated haemor-
rhage in a patient with oesophageal varices, and it may have transmitted homologous serum jaundice to 1 patient. In the treated compared with the untreated group, repeated albumin infusions did not affect general fitness, working ability, or the course of the disease. Maintenance of normal serum-colloid osmotic pressures by albumin infusions kept 2 patients with predominantly peripheral cedema free of fluid without diuretics. Patients with predominant ascites, however, needed the same dietetic and diuretic therapy, whether or not they received albumin infusions. If other treatment was stopped, continued infusions accelerated the reaccumulation of fluid. Serum-bilirubin, glutamic-oxaloacetic transaminase, and prothrombin concentrations were not affected by treatment. When infusions were stopped temporarily, the serum-colloid osmotic pressure returned to pre-treatment levels, suggesting that albumin synthesis was not affected
by treatment. Consistent improvement in health, activity, body-weight, diuretic needs, and serum-albumin levels was seen only in patients with a previous history of alcoholism who became abstemious-whether they were treated with albumin infusions
or not.
We are indebted to Dr. W. d’A. Maycock and the Lister Institute for supplying the human serum-albumin; to Dr. P. C. Reynell of the Royal Infirmary, Bradford, and Dr. J. M. Cowan of the Stafford General Infirmary for their help in treating 2 of the patients; and to Mr. P. Murfin for technical assistance. One of us (P. W.) was in receipt of a grant from the Dowager Countess Peel Research Fund during part of this study. REFERENCES
Armstrong, S. H. (1948) Amer. J. Med. 4, 390. Bjorneboe, M., Brune, C., Raaschou, F. (1949) Arch. intern. Med. 83, 539. Cherrick, G. R., Kerr, D. N. S., Read, A. E., Sherlock, S. (1960) Clin. Sci. 19, 361. Dykes, P. (1961) Quart. J. Med. 30, 297. Faloon, W. W., Eckhardt, R. D., Murphy, T. L., Cooper, A. M., Davidson, C. S. (1949) J. clin. Invest. 28, 583. Gornall, A. G., Bardawill, C. J., David, M. M. (1949) J. biol. Chem. 177, 751. Greene, C. H. (1943) J. Amer. med. Ass. 121, 715. Havens, W. P., Jr., Bluemle, L. W. (1950) Gastroenterology, 16, 455. Janeway, C. A., Gibson, S. T., Woodruff, L. M., Heyl, J. T., Bailey, O. T., Newhouser, L. R. (1944) J. clin. Invest. 23, 465. Kunkel, H. G., Labby, D. H., Ahrens, E. H., Jr., Shank, R. E., Hoagland, C. L.
(1948) ibid. 27, 305.
Losowsky, M., Atkinson, M. (1961) Lancet, ii, 386. Mankin, H., Lowell, A. (1948) J. clin. Invest. 27, 145. Owen, J. A. (1956) Analyst, 81, 26. Patek, A. J., Post, J., Ratnoff, O. D., Mankin, H., Hillman,
R. W. (1948a) J. Amer. med. Ass. 138, 543. - Mankin, H., Colcher, H., Lowell, A., Earle, D. P., Jr. (1948b) J. clin. Invest. 27, 135. Post, J., Rose, J. V., Shore, S. M. (1951) Arch. intern. Med. 87, 775. Ricketts, W. E. (1951) Ann. intern. Med. 34, 37. Rowe, D. S., Abrams, M. E. (1957) Biochem. J. 67, 431. Shaldon, S., McLaren, J., Sherlock, S. (1960) Lancet, i, 609. Summerskill, W. H. J., Davidson, C. S., Dible, J. H., Mallory, G. K., Sherlock, S., Turner, M. D., Wolfe, S. J. (1960) New Engl. J. Med. 262, 1. - Clowdus, B. H., Rosevear, J. W. (1961) Gut, 2, 285. Thorn, G. W., Armstrong, S. H., Jr., Davenport, V. D. (1946) J. clin. Invest. 25, 304. Watson, C. J., Greenberg, A. (1949) Amer. J. med. Sci. 217, 651.
Some Clinical Features *
GEOFFREY BOURNE CONSULTING
M.D. Lond., F.R.C.P. CARDIOLOGIST TO ST. BARTHOLOMEW’S HOSPITAL, LONDON, E.C.1
IT used to be said a generation ago that patients with disease could be divided into two main groups: those with and those without a positive Wassermann reaction-the first only being curable. Within fairly recent years it might also have been suggested that cardiac irregularities could be divided into two main groups: those treatable, and those not responding to treatment, by nervous
digitalis. Time has invalidated both generalisations. I shall deal with some clinical and therapeutic aspects of the commoner varieties of irregularities of the heart’s action. These can be roughly summarised into premature beats, auricular and ventricular; paroxysmal auricular tachycardia ; auricular flutter ; auricular fibrillation; and heart-block Premature Beats
The ventricular type of premature beat causes sympbecause of the longer compensatory pause that follows this variety. The symptoms, when present, are usually a thump in the chest or a momentary sinking sensation. Sometimes, however, a sensitive patient will exaggerate the momentary thump into what is described as a stab, or even a sudden pain. The fundamental treatment for this variety of premature beat is a full cardiovascular check-up, so that the subsequent reassurance may be convincing. Attention must also be paid to the digestion, the state of the teeth, and adequacy of the bite. Appropriate advice and treatment of the dyspepsia will toms
greatly help. The drugs that are of most use in treating the symptoms caused by premature beats are the sedatives and tranquillisers, and, if the number of thumps or disturbances is sufficiently great, benefit may be obtained by quinidine sulphate gr. 3 three times daily, sometimes combined with atropine sulphate gr. 1/150’ But premature beats are sometimes present with organic heart-disease. When exercise increases their number, particularly in elderly people, this may be presumed to be the case, for the usual effect of exercise on harmless premature beats is to disperse them for a number of minutes after the exercise has ceased. Premature beats also occur in patients to whom digitalis is being administered, and when they occur as coupled beats, each following a normal ventricular complex, digitalis overdose or susceptibility must be deduced. Here the digitalis should be stopped for two or three days and resumed at a lower dose. Sometimes the state of failure is such that it is felt that digitalis must be resumed at the former dose, but there is then always a risk of ventricular fibrillation, and consequently of sudden death. Should it be desired to damp down the premature beats, potassium citrate, gr. 15, three or four times daily, or quinidine sulphate, gr. 3, three times daily may help. ’
Within the past year I have had to treat a patient, whom I had observed for five years, for premature beats occurring in such numbers that, in my opinion, they constituted a threat of sudden death in the form of ventricular fibrillation. The patient had a very long-standing aortic regurgitation,
previously
* A lecture given to the March 6, 1962.
Anglo-Continental
Medical
Society
on
THE EFFECT OF REPEATED ALBUMIN INFUSIONS IN PATIENTS WITH CIRRHOSIS* PATRICIA WILKINSON M.B., B.Sc. Lond., M.R.C.P. MEDICAL REGISTRAR
M.D.
SHEILA SHERLOCK Edin., F.R.C.P., F.R.C.P.E. PROFESSOR OF MEDICINE
From the
Department of Medicine, Royal Free Hospital, London, W.C 1
IN
cirrhosis, the diseased liver may be temporarily or permanently unable to produce enough albumin to maintain a normal concentration in the plasma. This results in a low colloid osmotic pressure and contributes to the production of oedema or ascites. Efforts to restore plasma-albumin levels in such patients include raising the dietary protein intake (Patek et al. 1948a), and infusions of plasma (Ricketts 1951) or ascitic fluid (Greene 1943). In 1944 salt-poor human albumin became available, and infusions were used to treat cirrhotic patients, with varying results. Some workers failed to induce a diuresis, although all noted an improved sense of well-being in their patients (Janeway et al. 1944, Thorn et al. 1946, Armstrong 1948, Mankin and Lowell 1948, Patek et al. 1948b, Faloon et al. 1949, Watson and Greenberg 1949). Other workers, however, reported that more than half of the cases treated were relieved of ascites and oedema (Kunkel et al. 1948, Havens and Bleumle 1950, Post et al. 1951). These early studies were directed mainly to the initial relief of ascites or oedema, but in a few patients maintenance infusions were continued, in 1 patient for over eight months, with apparent benefit (Faloon et al.
1949). More recently, Losowsky and Atkinson (1961) controlled ascites by maintenance infusion in 7 out of 9 patients who had not responded to sodium restriction and diuretics. Dykes (1961) produced a diuresis in 7 out of 13 similar patients, and later maintained them free of ascites and oedema. Albumin is expensive, and its administration is not without hazard. More and more cases of " resistant ascites " yield to the newer diuretics (Shaldon et al. 1960, Summerskill et al. 1961), but these drugs also are costly and have their own complications. This work was undertaken, therefore, to determine whether repeated albumin infusions are of value in the management of cirrhosis. When the investigation was begun, patients were selected who were resistant to all other forms of medical treatment then available. As more powerful diuretics became available, such cases became fewer. Also, in most patients who responded to diuretics, the serum-albumin concentrations returned to normal, which suggested that the previous low levels were due either to a temporary defect in synthesis, * Based on a report to the Blood-transfusion Subcommittee of the Medical Research Council. 7266
redistribution of body stores. But a few patients still had low serum-albumin levels after diuresis. These, together with any remaining patients with " resistant ascites ", were included in the study. To try to separate the effect of the albumin from the effects of other treatment and the natural course of the disease, the patients were put at random into two groups, one of which received repeated albumin infusions over long periods, while the other was observed as a control or to a
group. Material
Patients were selected from inpatients admitted for investigation and treatment of cirrhosis. At first they were included in the study if, after six weeks’ treatment with diet and the diuretics currently available, they still had fluid retention, or if, after successful treatment, the serum-colloid osmotic levels remained below 30 cm. of This level represents a moderate but definite depletion in serum-albumin level, corresponding to water.
3-0-3-2 g. per 100 ml. When aldosterone antagonists became readily available patients were included only when diuresis was complete.
patients selected were allocated at random into two control and a treated group (table I). 4 of these had ascites which had not cleared with diuretic therapy (nos. 1-3, 10). The others were included after diuresis; of these 7 (nos. 4, 5, 7, 11, 14, 15, and 16) originally came with ascites, 2 (nos. 8 and 13) had mainly peripheral oedema with little ascites, and 2 (nos. 6 and 12) had peripheral oedema after portacaval anastomosis. Thus, 7 patients with ascites and 2 with oedema fell into the control group, and 5 with ascites and 2 with oedema into the treated group. The duration of symptoms varied from two months to eight years. In 12 patients the cause of the cirrhosis was unknown, in nos. 5, 7, 10, and 11 there was a history of alcoholism. In all but 2 of the patients histological The 16
groups,
a
TABLE I-DETAILS OF PATIENTS
1126 confirmation of the diagnosis was obtained. In case no. 9 coincident tuberculous peritoneal infection was found post
TABLE II-DETAILS OF ALBUMIN INFUSIONS
mortem.
The period of follow-up and treatment varied from one to twenty-two months, and totalled 116 patient-months in the control group and 95 patient-months in the treated group. Treatment
Patients in both control and treated groups received dietary and diuretic treatment as required. Patients in the treated group received salt-poor human serum-albumin (Lister Institute), reconstituted with pyrogenfree water to a 25% solution. Infusions varied between 25 and 100 g. each, and were given over one to three hours. At first infusions were given daily or at intervals of two days until the serum-colloid osmotic pressure reached 38-40 cm. of water. Subsequently, the level was maintained between 35 and 40 cm. of water by weekly or fortnightly infusions given in the
outpatient department. No placebo infusions were given to patients in the control group and, as far as possible, patients in this group were seen separately but at similar intervals from those in the treated group. At each visit patients were weighed, and their well-being was assessed in terms of working ability and sexual function. Serum-albumin levels were measured by a biuret method (Gornall et al. 1949) for total protein, and fractionation by paper electrophoresis (Owen 1956). Serum-colloid osmotic pressure was estimated with the Rowe colloid osmometer (Rowe 1957), the range in 38 normal subjects being 29-043-0 cm. (mean 36-5 cm.). These agree with results obtained by Losowsky and Atkinson (1961). Serum-bilirubin, glutamic oxaloacetic transaminase (S.G.O.T.), and prothrombin concentration were estimated every two to three months. In 6 patients the albumin infusions were stopped after six to nine months, and three to four weeks later the serumalbumin and colloid osmotic pressure were again measured before resuming treatment. In the treated patients who survived until the end of the study, these measurements were again made one month after the albumin had been stopped
permanently. Results
Fell to 12-5 g. after albumin.
ten
months and after further
two
months received no
The amount of albumin necessary to maintain the serumcolloid osmotic pressure level between 35 and 40 cm. of water varied from 12-5 to 100 g. weekly, and depended on the patient’s own serum-albumin level after diuresis; the lower this level, the higher the maintenance dose required. In 5 patients maintenance requirements did not change. 1 patient (no. 11) required 25 g. weekly for ten months; then this diminished over four months, until, for the last two months, he received no albumin. Immediate Effects and Complications of Infusions
All patients experienced a sense of well-being, usually greatest on the day after the albumin infusion. Serial estimations of the packed-cell volume made during this time showed a fall (figs. 1 and 2). 3 patients who still had predominant ascites (nos. 2, 3, and 15) showed an acceleration in fluid retention. Judged by the gain in weight (fig. 1), the volume of fluid retained sometimes
exceeded the volume infused. Normal serum-colloid osmotic pressures were obtained in these patients, but the ascitic colloid-osmotic pressure also rose by a similar or a slightly smaller amount. The 2 patients with predominantly peripheral oedema (nos. 6 and 8), however, had a diuresis of water and sodium (fig. 2). The other 2 patients (nos. 11 and 16) had been treated successfully with diuretics before they were, given albumin. Only one infusion reaction, thought to be due to an imperfectly
patients with cirrhosis were seen during the investigation, 60 of whom had fluid retention. In 14 this was transient and cleared spontaneously or after dietarysodium restriction and thiazide diuretics. After diuresis, the serum-albumin and serum-colloid osmotic pressure levels returned to normal. In 24 patients fluid retention formed part of the picture of terminal liver failure. In 2 cases liver biopsy revealed a- primary carcinoma. 2 patients were only briefly in hospital and were not included. The remaining 16 (11%) were selected for the 145
study. Quantities of Albumin Used The 7 patients treated received a total of 15,125 g. albumin in 242 infusions (table 11). In 6 of the 7 patients, normal serumalbumin and serum-colloid osmotic pressure levels were achieved, and maintained for periods varying from eight to nineteen months. The 7th patient (no. 15) died after haemorrhage from oesophageal varices, precipitated perhaps by the first dose of albumin. The amounts of albumin needed to raise the serum-colloid osmotic pressure to normal varied between 275 and 675 g. and seemed to depend on the clinical state, the initial serum-colloid osmotic pressure, and the time taken to complete the first course. In patients with massive ascites some of the infused albumin was lost into the ascitic fluid, the colloid osmotic pressure of which rose. Normal levels were achieved more economically when large infusions could be given at short intervals, there being less time then for the infused albumin to be catabolised.
Fig. 1-Patient
no. 3. Unsuccessful result after initial intravenous infusion of human serum-albumin.
course
of
Infusion of 600 g. of human serum-albumin restored serum-colloid osmotic pressure to normal, but produced no diuresis; fluid retention with gain in weight. Colloid osmotic pressure of ascitic fluid rose by nearly as much as serum-colloid osmotic pressure; fall in packed-cell volume during infusions.
1127
cleaned rubber giving-set, was noted during the course of 242 infusions. 1 patient (no. 3) had an attack of virus hepatitis fourteen months after starting treatment with intravenous albumin. As infectious hepatitis was epidemic in her neighbourhood at the time this may have been naturally acquired, although no contact history was established. Homologous serum jaundice could not be excluded, although this is unlikely, since other patients were treated from the same batch of albumin without ill effect. 1 patient (no. 15) had a fatal haemorrhage from oesophageal varices after the infusion of 100 g. of albumin. No
TABLE III-GENERAL HEALTH AND WORKING ABILITY IN CONTROL AND TREATED GROUPS
phlebothrombosis resulted. No patient, except no. 15 who bled, de-
teriorated mentally after the infusions. Patient no. 6 was
and 3 in the treated group (nos. 3, 11, and 16), are leading normal lives at home or at work. 3 of these 6 had been alcoholics and had stopped drinking during the investigation. The period of observation was 116 patient-months in the control group, and 95 patient-months in the treated group. There is no difference in the attainment of restricted or full activity in the two groups (table iv). 3 patients in the control group (nos. 5, 7, and 10) and 2 in the treated group (nos. 3 and 11) have gained more than 16 lb. in weight-an increase repre-
given
several infusions while precomatose or
comatose
without further clinical or electroence-
phalographic
TABLE IV--COMPARISON OF WORKING ABILITY IN CONTROL AND TREATED
deterioration. No circulatory
overloading produced in any patient.
GROUPS
was
General Health 6 patients (table m) died
Fig. 2-Patient
no. 6. Successful result after initial course of intravenous human serumalbumin.
Infusion of 400 g. of human serum-albumin restored serum-colloid osmotic pressure to normal, produced diuresis with fall in weight, and coincident fall in packed-cell volume.
of terminal liver failure, 3 in the control group (nos. 1, 9, and 14), and 3 in the treated group (nos. 2, 6, and 15). In 1 (no. 15) death was due to bleeding from resophageal varices. 4 patients are living restricted lives at home; of these, 3 (nos. 4, 10, and 13) are in the control group, and 1 (no. 8) has received treatment with albumin. The remaining 6, 3 in the control group (nos. 5, 7, and 12),
senting flesh and not fluid. 1 control patient (no. 7) has begun regularly again, and 1 male patient in each group (no. 5 control, no. 11 treated) had had a return of libido. The patients who improved were all alcoholics, except no. 3. to menstruate
Diuretic Needs
8) who had very low serum-albumin with intravenous albumin, but who responded to thiazide diuretics alone, could dispense with these 2
patients (nos.
levels before
6 and
treatment
TABLE V-CHANGES IN LIVER-FUNCTION TESTS IN CONTROL AND TREATED GROUPS
Serum-albumin and serum-colloid osmotic pressure values: a, first value obtained after successful diuresis; b, in control group at end of investigation; in treated group
one
month after
stopping infusions during
or at
end of investigation.
1128
drugs when the serum-albumin was maintained at normal by repeated infusions. Continued dietary-sodium restriction, however, was necessary. Patients nos. 2, 3, 11, and 16, who had relatively higher serum-albumin levels and required aldosterone antagonists in addition to thiazides to promote a diuresis, still needed these levels
diuretics in the same doses even when the serum-colloid osmotic pressure was raised to normal. When the diuretics were reduced or withheld, fluid re-accumulated-most rapidly immediately after an infusion. 1 patient (no. 11), after twelve months’ treatment with diuretics and albumin, needed a smaller dose of diuretics as well as less albumin. This patient had a history of alcoholism, and resembled 2 patients (nos. 5 and 7) in the control group with a similar history. The diuretic requirements of these patients also diminished during the investigation, and they In the were able to increase their dietary-sodium intake. remaining 7 patients in the control group, diuretic treatment could not be reduced.
of Liver Function significant change was noted
Biochemical Tests
in serum-bilirubin levels No and serum-glutamicoxaloacetic-transaminase levels, or in the prothrombin concentration (table v), after treatment with albumin. Serum-colloid osmotic pressure and serum-albumin levels improved in patients nos. 5 and 7 in the control group. In the treated group when infusions were stopped for long enough to allow the infused albumin to be metabolised, the serum-colloid osmotic pressure and serum-albumin levels rose above pre-treatment values only in patient no. 11. Discussion
In selecting patients, a critical level of serum-colloid osmotic pressure, after diuresis of 30 cm. of water, was chosen to reflect a significant defect in albumin synthesis. Patients included in the series with initial serum-colloid osmotic pressure levels approaching 30 cm. of water needed very small maintenance infusions; it is, therefore, unlikely that the level chosen was too low and that patients who might have profited were wrongly excluded. If suboptimal levels of serum-colloid osmotic pressure were contributing to the patient’s symptoms, continued elevation might be expected to produce some immediate or late benefit. The level chosen, although near the lower limit of normal, is still well above the critical level for producing the ascites and oedema reported by other workers (Bjornboe et al. 1949, Cherrick et al. 1960). The amounts of albumin needed at first to raise the serum-colloid osmotic pressure to normal were surprisingly large, a fact noted by Faloon (1949), Post et al. (1951), and more recently by Dykes (1961). More than twice the normal total exchangeable albumin was needed in patients with ascites. Since high serum levels were reached some of the albumin was undoubtedly catabolised rapidly. Much also was lost into the enormously expanded extravascular compartment, since considerably smaller amounts sufficed when there was no ascites, yet the fate of some of the albumin remains obscure. The amounts of albumin needed to maintain normal serumcolloid osmotic pressure levels does not depend on the size of the patient. Instead, they vary approximately with the initial serum-colloid osmotic pressure; the lower this value, the larger the maintenance infusion needed. This variation in the rise of serum-colloid osmotic pressure agrees with Dykes’ finding (1961) that with infused labelled albumin, as the serum level rose, the rate of catabolism increased, and suggests that the rate of albumin breakdown is dependent on the serum concentration.
Although expensive and time-consuming to patient and doctor, the infusions have proved relatively safe. There
fewer pyrogenic reactions than in earlier work (Watson and Greenberg 1949), probably mainly because of improved transfusion techniques. Also, pulmonary oedema and haemorrhage from oesophageal varices were less common Faloon et al. 1949, (Watson and Greenberg 1949, Havens and Bluemle 1950). This is probably because the infusions were usually given when there was no fluid retention; hence sudden massive expansion of the plasma volume by withdrawal of extracellular fluid into
were
the circulation
was
avoided.
The immediate effect of the infusions in producing a of well-being commented on by Kunkel and coworkers (1948) and Dykes (1961) was seen in every case, and may be related to a coincident expansion of the plasma volume. Where the albumin produced a diuresis this might also have been achieved by increasing the plasma volume and therefore the renal blood-flow, rather than by altering an osmotic equilibrium. Patek and coworkers (1948b) found an increased renal blood-flow after albumin infusions in patients with cirrhosis and ascites. sense
By the time serum-albumin and serum-colloid osmotic fallen, albumin synthesis and, with it, other functions of the liver have been seriously deranged, and the prognosis must be poor. It may be difficult then to prolong life by any means, and any benefit should be correspondingly easy to detect, particularly if a simultaneous control series is under observation. Repeated albumin infusions neither in life our patients nor made it more enjoyable prolonged pressure levels have
or
useful.
Treatment with albumin did not reduce diuretic needs, and in this respect also our findings differ from previous results. Earlier successes, in which control observations were not made, may have been wrongly attributed to the albumin. Patients with cirrhosis of the alcoholic type are known to improve when they are carefully supervised and are persuaded to stop drinking (Summerskill et al. 1960, 1961), whereas in patients with no history of alcoholism the disease pursues a more relentless downhill course. This has been confirmed; the alcoholics had a more favourable prognosis. The relatively good results reported in some earlier studies (Kunkel et al. 1948, Faloon et al. 1949) may have partly been due to remissions after the withdrawal of alcohol. The careful supervision inherent in any clinical trial inevitably confers benefit on both the treated and the control groups. Dietary sodium restriction is more efficient, and more attention is paid to diuretic needs. In the absence of a control group improvement could be wrongly attributed to the albumin.
Serum-colloid osmotic pressure is a more important factor than portal blood-pressure in the pathogenesis of ascites (Cherrick et al. 1960). It is, therefore, surprising that restoring the serum-colloid osmotic pressure to normal for long periods did not help the continued control of ascites once remission had been induced with diuretics. This suggests that, in our patients at least, the primary disturbance was not only a colloid osmotic imbalance.
Summary 60 out of 145 patients with cirrhosis of the liver seen in the past two years have shown fluid retention. 16 of these, even when free of ascites or oedema, had a persistent defect of albumin synthesis, judged by lowered serumalbumin and serum-colloid osmotic pressure levels. They
1129 were
allocated
at
random into
a
control group
CARDIAC IRREGULARITIES
(9 patients)
and a treated group (7 patients). Both groups received dietary and diuretic therapy as required, and 6 in the treated group also received infusions of 25-100 g. salt-poor human serum-albumin every one to two weeks for up to nineteen months to keep serum-colloid osmotic pressures at normal levels. The amount of albumin required was proportional to the initial deficit in serum-albumin level, suggesting that artificially raising the serum-albumin level increased the rate of
breakdown. The albumin caused no reactions, and did not induce or exacerbate hepatic precoma. It precipitated haemor-
rhage in a patient with oesophageal varices, and it may have transmitted homologous serum jaundice to 1 patient. In the treated compared with the untreated group, repeated albumin infusions did not affect general fitness, working ability, or the course of the disease. Maintenance of normal serum-colloid osmotic pressures by albumin infusions kept 2 patients with predominantly peripheral cedema free of fluid without diuretics. Patients with predominant ascites, however, needed the same dietetic and diuretic therapy, whether or not they received albumin infusions. If other treatment was stopped, continued infusions accelerated the reaccumulation of fluid. Serum-bilirubin, glutamic-oxaloacetic transaminase, and prothrombin concentrations were not affected by treatment. When infusions were stopped temporarily, the serum-colloid osmotic pressure returned to pre-treatment levels, suggesting that albumin synthesis was not affected
by treatment. Consistent improvement in health, activity, body-weight, diuretic needs, and serum-albumin levels was seen only in patients with a previous history of alcoholism who became abstemious-whether they were treated with albumin infusions
or not.
We are indebted to Dr. W. d’A. Maycock and the Lister Institute for supplying the human serum-albumin; to Dr. P. C. Reynell of the Royal Infirmary, Bradford, and Dr. J. M. Cowan of the Stafford General Infirmary for their help in treating 2 of the patients; and to Mr. P. Murfin for technical assistance. One of us (P. W.) was in receipt of a grant from the Dowager Countess Peel Research Fund during part of this study. REFERENCES
Armstrong, S. H. (1948) Amer. J. Med. 4, 390. Bjorneboe, M., Brune, C., Raaschou, F. (1949) Arch. intern. Med. 83, 539. Cherrick, G. R., Kerr, D. N. S., Read, A. E., Sherlock, S. (1960) Clin. Sci. 19, 361. Dykes, P. (1961) Quart. J. Med. 30, 297. Faloon, W. W., Eckhardt, R. D., Murphy, T. L., Cooper, A. M., Davidson, C. S. (1949) J. clin. Invest. 28, 583. Gornall, A. G., Bardawill, C. J., David, M. M. (1949) J. biol. Chem. 177, 751. Greene, C. H. (1943) J. Amer. med. Ass. 121, 715. Havens, W. P., Jr., Bluemle, L. W. (1950) Gastroenterology, 16, 455. Janeway, C. A., Gibson, S. T., Woodruff, L. M., Heyl, J. T., Bailey, O. T., Newhouser, L. R. (1944) J. clin. Invest. 23, 465. Kunkel, H. G., Labby, D. H., Ahrens, E. H., Jr., Shank, R. E., Hoagland, C. L.
(1948) ibid. 27, 305.
Losowsky, M., Atkinson, M. (1961) Lancet, ii, 386. Mankin, H., Lowell, A. (1948) J. clin. Invest. 27, 145. Owen, J. A. (1956) Analyst, 81, 26. Patek, A. J., Post, J., Ratnoff, O. D., Mankin, H., Hillman,
R. W. (1948a) J. Amer. med. Ass. 138, 543. - Mankin, H., Colcher, H., Lowell, A., Earle, D. P., Jr. (1948b) J. clin. Invest. 27, 135. Post, J., Rose, J. V., Shore, S. M. (1951) Arch. intern. Med. 87, 775. Ricketts, W. E. (1951) Ann. intern. Med. 34, 37. Rowe, D. S., Abrams, M. E. (1957) Biochem. J. 67, 431. Shaldon, S., McLaren, J., Sherlock, S. (1960) Lancet, i, 609. Summerskill, W. H. J., Davidson, C. S., Dible, J. H., Mallory, G. K., Sherlock, S., Turner, M. D., Wolfe, S. J. (1960) New Engl. J. Med. 262, 1. - Clowdus, B. H., Rosevear, J. W. (1961) Gut, 2, 285. Thorn, G. W., Armstrong, S. H., Jr., Davenport, V. D. (1946) J. clin. Invest. 25, 304. Watson, C. J., Greenberg, A. (1949) Amer. J. med. Sci. 217, 651.
Some Clinical Features *
GEOFFREY BOURNE CONSULTING
M.D. Lond., F.R.C.P. CARDIOLOGIST TO ST. BARTHOLOMEW’S HOSPITAL, LONDON, E.C.1
IT used to be said a generation ago that patients with disease could be divided into two main groups: those with and those without a positive Wassermann reaction-the first only being curable. Within fairly recent years it might also have been suggested that cardiac irregularities could be divided into two main groups: those treatable, and those not responding to treatment, by nervous
digitalis. Time has invalidated both generalisations. I shall deal with some clinical and therapeutic aspects of the commoner varieties of irregularities of the heart’s action. These can be roughly summarised into premature beats, auricular and ventricular; paroxysmal auricular tachycardia ; auricular flutter ; auricular fibrillation; and heart-block Premature Beats
The ventricular type of premature beat causes sympbecause of the longer compensatory pause that follows this variety. The symptoms, when present, are usually a thump in the chest or a momentary sinking sensation. Sometimes, however, a sensitive patient will exaggerate the momentary thump into what is described as a stab, or even a sudden pain. The fundamental treatment for this variety of premature beat is a full cardiovascular check-up, so that the subsequent reassurance may be convincing. Attention must also be paid to the digestion, the state of the teeth, and adequacy of the bite. Appropriate advice and treatment of the dyspepsia will toms
greatly help. The drugs that are of most use in treating the symptoms caused by premature beats are the sedatives and tranquillisers, and, if the number of thumps or disturbances is sufficiently great, benefit may be obtained by quinidine sulphate gr. 3 three times daily, sometimes combined with atropine sulphate gr. 1/150’ But premature beats are sometimes present with organic heart-disease. When exercise increases their number, particularly in elderly people, this may be presumed to be the case, for the usual effect of exercise on harmless premature beats is to disperse them for a number of minutes after the exercise has ceased. Premature beats also occur in patients to whom digitalis is being administered, and when they occur as coupled beats, each following a normal ventricular complex, digitalis overdose or susceptibility must be deduced. Here the digitalis should be stopped for two or three days and resumed at a lower dose. Sometimes the state of failure is such that it is felt that digitalis must be resumed at the former dose, but there is then always a risk of ventricular fibrillation, and consequently of sudden death. Should it be desired to damp down the premature beats, potassium citrate, gr. 15, three or four times daily, or quinidine sulphate, gr. 3, three times daily may help. ’
Within the past year I have had to treat a patient, whom I had observed for five years, for premature beats occurring in such numbers that, in my opinion, they constituted a threat of sudden death in the form of ventricular fibrillation. The patient had a very long-standing aortic regurgitation,
previously
* A lecture given to the March 6, 1962.
Anglo-Continental
Medical
Society
on