- Email: [email protected]
SUPPORTIVE THERAPY AN IMPROVED TYPE OF DEXTRAN
59
being constantly found. Nucleated red cells were numerous haemorrhages. Necropsy showed bone-marrow hyperplastic with very the numerous megakaryocytes, some with ingested cells; spleen with myeloid metaplasia, megakaryocytes not conafter the
spicuous, some fibrosis, and malpighian bodies few and small; and the liver with very slight myeloid metaplasia. Case 8.-A man, aged 51, died in July, 1950, of weakness and wasting, after four
a
half
years’
observation.
myeloid metaplasia involving erythroblasts, leucoblasts, megakaryocytes than in patients with typical myeloid leukaemia or with typical primary polycythaemia. and
The
presenting symptom was intestinal haemorrhage in March, 1946, when a large spleen was found. The first intestinal haemorrhage teok place in 1942, and these were repeated until 1948. The patient was subject to abnormal bruising in 1949 and 1950. He had no polycythaemia while under observation, He had never had severe nor any history suggesting it. ansemia except after intestinal haemorrhages. His leucocytes normal in 1946-48 but later increased to 20,000 per and in 1949-50 he had leucopenia. Immature leucocytes were 8-12% before the first course of X-ray treatment in November and December, 1948, which improved his health considerably. A second course, in 1949, also had a good effect, but a third course, in 1950, had no effect. The patient had gout in his great toes in 1948-49. His serumuric-acid level was 6-6-8-3 mg. per 100 ml. in 1948-50. Necropsy showed fibrosis throughout all parts of the bonemarrow examined, very dense in places ; but in most areas the bone-marrow cells, especially the megakaryocytes, were recognisable ; the spleen with myeloid metaplasia and very small and scanty malpighian bodies ; and the liver with very were
c.mm.,
slight myeloid metaplasia only. Case 9.-A woman, aged 74, died in January, 1946, of heart-failure, after six and three-quarters years’ observation. The presenting symptoms were diarrhoea and the passage of blood per rectum in April, 1939, when a large spleen and a large liver were found. The patient was subject to abnormal bruising from 1937 onwards. She had " chlorotic polycythaemia" in 1939, with more than 7,000,000 red cells per c.mm., but her Hb was 70%. After having iron by mouth she developed typical polycythsemia, which later disappeared. She had high leucocytosis (40,000-60,000 per c.mm. with less than 1% immature leucocytes) ; later the number of leucocytes became normal, but a few immature leucocytes persisted. The patient had gout in her hands and feet in 1940-41. Her blood-uric-acid level was above 7 mg. per 100 ml. in 1939-41. She died of congestive heart-failure. No necropsy was done. DISCUSSION
Gout
SUMMARY
The relationships between gout, myeloid leuksemia., and primary polycythsemia are stated. Gout occurs much more commonly in patients with
fairly often in patients who have myeloid metaplasia involving all three main bone-marrow elements-erythroblasts, leucoblasts, and especially megakaryocytes-but it does not occur commonly in patients who have mainly leucoblastic myeloid metaplasia or mainly erythroblastic myeloid metaplasia. The blooduric-acid level is usually normal in typical cases of primary polycythaemia (Wintrobe 1951), and most cases of typical chronic myeloid leukaemia under my care occurs
The most have had a normal blood-uric-acid level. striking fact is that myeloid metaplasia occurs in some patients who have had gout for many years, and this must be of great importance in considering the causes of myeloid metaplasia, and may throw light on the cause of chronic myeloid leukaemia. In most of the published cases in which gout occurred years before the myeloid splenomegaly was discovered there is no means of knowing when the disorder of the blood-forming tissues began ; but 1 patient was seen with gout three years before splenomegaly was found (Coste et al. 1948). In the type of case under discussion gout may occur more commonly than is generally believed, for the descriptions of several patients suggest that they had gout, though not diagnosed as such (Rosenthal and Bassen 1938, Vaughan and Harrison 1939, Dustin 1947). Several other patients under my care, with " megakaryocytic myelosis " or " myelosclerosis," had constantly high blood-uric-acid levels, though they did not develop gout. Rarely gout may occur in acute myeloid leukaemia ; and a patient with chronic gout may have an acute fatal illness closely simulating acute myeloid leukaemia.
REFERENCES
Avery, H. (1930) Lancet, i, 342. Brunner, H. (1932) Z. klin. Med. 121, 700. Coste, F., Galmiche, P., Sors, C. (1948) Rev. Rhum. 15, 89. Duckworth, D. (1889) A Treatise on Gout. London ; p. 198. Dustin, P. jun. (1947) Acta clin. belg. 2, 212. Forkner, C. E. (1938) Leukemia and Allied Disorders. New York ; p. 42. Hagedorn, K. (1926) Z. klin. Med. 104, 124. Hoffmann, A. (1926) Klin. Wschr. 5, 124. Merskey, C. (1949) Arch. intern. Med. 84, 277. Reifenstein, G. H. (1939) Amer. J. med. Sci. 197, 215. (1945) Ibid, 210, 638. Roberts, W., Bradford, J. R. (1907) In Allbutt, T. C., Rolleston, H. D. System of Medicine. London ; vol. III, p. 127. Rosenthal, N., Bassen, F. A. (1938) Arch. intern. Med. 62, 903. Shorvon, L. M. (1946) Lancet, ii, 378. Stone, D. M., Woodman, D. (1938) J. Path. Bact. 47, 327. Tinney, W. S., Polley, H. F., Hall, B. E., Giffin, H. Z. (1945) Proc. Mayo Clin. 20, 49. Vaughan, J. M., Harrison, C. V. (1939) J. Path. Bact. 48, 339. Videbaek, A. (1950) Acta med. scand. 138, 179. Weber, F. P. (1921) Polycythæmia, Erythrocytosis, and Erythræmia (Vaquez-Osler Disease). London ; p. 83. (1934) Lancet, ii, 808. Wintrobe, M. M. (1951) Clinical Hematology. 3rd ed., London. Wyatt, J. P., Sommers, S. C. (1950) Blood, 5, 329. —
—
SUPPORTIVE THERAPY AN IMPROVED TYPE OF DEXTRAN
A. M. BOYD Lond., F.R.C.S.
M.B.
PROFESSOR OF SURGERY IN THE UNIVERSITY OF MANCHESTER
F. FLETCHER M.D. Mane. RESEARCH FELLOW IN THE UNIVERSITY
A. HALL RATCLIFFE M.A., B.Sc., D.Phil. Oxfd SPECIAL LECTURER IN EXPERIMENTAL METHODS IN THE UNIVERSITY
INTENSIVE investigation into the causes, prevention, and treatment of shock was made necessary by two wars. But in a world of increasing mechanisation, with its heavy toll of accidents, shock is far from being a purely war-time problem. Collaborative research has resulted in a clearer understanding of supportive therapy, and the importance of maintaining the circulating blood volume has been firmly established. The wide use of blood-transfusion and plasma infusion means that surgical shock, as formerly known, is no longer seen. The expense and potential shortage of stored blood and the danger of virus hepatitis after infusion of plasma have stimulated a revival of the search for alternative substances for supportive therapy. These substances have been termed " plasma substitutes," but with the development of materials which in many respects are preferable to plasma it is felt that a new designation is required. Since the primary use of these substances is to restore or to maintain the circulating blood volume, the term " blood-volume restorer " is suggested. CRITERIA FOR BLOOD-VOLUME RESTORERS
Ease of infusion.-The viscosity of the material should be such that it is easily infusable in all climates. Freedom from undesirable effects.-The substance must not be toxic or antigenic. It must not produce hoemolysis. It must be easily sterilisable and free from pyrogens. Jtfon-e/M-ce standards.-The of manufacturing material must be capable of rapid and economic manufacture on a large scale, with exactly reproducible composition. It must be storable, without alteration, for long periods under varying conditions of temperature.
60 Elimination from the body.-The material should eventually be excreted or metabolised. Any storage in the body should be brief, and there should be no adverse effect, either immediate or delayed, on any organs or at the site of injection. Retention in circulation.-A satisfactory blood-volume restorer should remain in the blood-stream with levels of not less than 50% of the amount infused at the end of twenty-four hours. This implies that the material should not be rapidly katabolised, excreted, or readily diffusible through the capillary wall. The retained material must also have an adequate water-holding
capacity. The mechanism bv which macromolecular colloids hold water in the circulation is complex. There are two main factors involved : (1) the osmotic pressure of the solution, which depends on the molecular concentration and hence decreases with increase in molecular weight ; and (2) the water-binding capacity of the colloid, which increases with increase in molecular weight. The combined effect of these two factors, which tend to balance one another, may be termed the water-holding capacity of the colloid. TYPES OF MATERIAL
the last few years interest has been focused three polymers : polygelatin, polyvinylpyrrolidone, Because these substances are polymers and dextran. be in various ranges of molecular can produced they size, and it is possible to obtain samples of the same polymer having widely differing properties. It is shown below that molecular size is of the utmost importance. In the form which has been used for infusion gelatin produces a highly viscous solution which does not flow easily at room-temperature in this country. In our experience it is necessary to warm this material before infusion. Injudicious heating may cause denaturation ; this may also happen with prolonged storage. Evidence has also been produced of tissue changes after the infusion of gelatin (Skinsnes 1947). A derivative, oxypolygelatin, has been produced which is less viscous in solution and stable to storage. The advantage, however, has only been achieved at the expense of a high excretionrate and a low blood level. Polyvinylpyrrolidone cannot be broken down in the body and tends to be accumulated in the liver and reticulo-endothelial system (Nelson and Lusky 1951). The German army used a form of polyvinylpyrrolidone during the war 1939-45, and Muller (1946) reported that the appearance of the spleen and lymph-nodes at necropsy after the infusion of this material was comparable to that seen in the storage diseases. The use of the material was given up after army pathologists had found widespread liver and kidney damage. More recently a type of polyvinylpyrrolidone has been prepared with a much smaller molecular size than that used by the Germans. It -is claimed that this does not give rise to organic changes, but the excretion-rate is so high that the effect on the circulation volume can only be transient. Dextran, which is a polymerised form of glucose, does not seem to be stored in the body in significant amounts, and is probably eliminated by being broken down to a molecular size small enough to be excreted by the kidneys, or glucose elements may be broken off and utilised as such. A few reactions of an anaphylactic type were reported with some of the earlier kinds of dextran ; these were considered to be due to the presence of large molecules, but the possibility of contamination cannot be completely excluded. More complete hydrolysis of the crude dextran produced a material virtually free from reactions but at the cost of a high excretionrate and a low twenty-four-hour blood level. Because of its basic advantages it was decided to investigate the possibility of preparing an effective blood-volume restorer from dextran. The problem was to determine the best molecular range, and to find out if the material could be produced on an economic scale.
During
on
correspondingly
DETERMINATION OF BEST MOLECULAR RANGE
Dextran is prepared biosynthetically from sucrose by the action of Leuconostoc mesenteroides, which polymerises the glucose half of the molecule. Before it can be used the crude dextran must be hydrolysed, the resulting product containing molecules of molecular weight ranging from a few thousand to several million in a proportion depending on the time and conditions of hydrolysis. From a physiological point of view the molecular spectrum may be divided arbitrarily into four ranges :
(1) are so
highest range consists of those molecules which large that they may produce undesirable reactions.
The
(2) The lowest range consists of those through the glomeruli and are excreted.
molecules which pass
(3) Above this is the range of molecules which
are
too
large to be excreted but small enough to capillary wall and thus be lost from the
diffuse through the circulation into the tissue fluid. These molecules are undesirable because, apart from any effect on the intracellular-extracellular fluid balance, they have a certain water-holding capacity, and this associated water is lost from the circulation. (4) The next highest range contains those molecules which are too large to diffuse through the capillary wall but not large enough to produce reactions.
It therefore seems logical that the ideal form of dextran should be that containing the largest amount possible in the last-mentioned range. To estimate the transition values between the various ranges it was necessary to obtain a distribution curve of the molecular spectrum for each of the types of dextran involved. This was done by obtaining samples of a very small part of each range by repeated fractionation from a suitable solvent, and by measuring the intrinsic viscosity of each sample. For the sake of clarity the charac. teristics of each type of dextran used are described here in terms of molecular weight. Since the values of the molecular weight have been derived from intrinsic viscosity measurements, the figures given must be regarded as approximations until they can be confirmed by ultracentrifuge studies on the type of dextran used. From studies of excretion-rate and blood levels in the rabbit and man with various types of dextran, described in more detail below, the glomerular threshold seems to correspond to a molecular weight of 60,000 ; and the capillary threshold appears to be about 130,000 in man and a little higher in the rabbit. It must be borne in mind, if tempted to compare these figures with that of albumin, that diffusion depends on other factors besides molecular weight-e.g., charge and shape. Itisimpracticable to produce anaphylaxis in man, and it was impossible to demonstrate it in the rabbit with any form of hydrolysed dextran free from pyrogens and other contaminants. It is therefore thought that an upper limit at a molecular weight of 250,000 leaves an adequate margin of safety. PERCENTAGE
Fig. distribution
of molecular
weight
of standard dextran.
61 EXPERIMENTAL DATA
large molecules. However, it still contained a small quantity of the molecular range we consider undesirably high. Because of the fewer small molecules the excretionrate was reduced to 20%, but the twenty-four-hour the
types has been infused into patients undergoing surgical operation. The observations reported have been made on five types of dextran whose molecularweight distribution makes them of special interest. The Dextran of various
blood level
onlv raised to 35%.
This meant that first twenty-four hours after infusion more of the dextran was lost from the circulation than remained in it. The observations made at this stage suggested that, to obtain a satisfactory twenty-four-hour blood level, a type of dextran must be made containing a much greater proportion of molecules in the middle range immediately above the diffusion threshold. It was also felt that the larger molecules should be completely removed. These requirements necessitated a re-design of the process of manufacture and the development of a large-scale method of intensive fractionation. We have called material prepared by this method " narrow-fraction dextran " to distinguish it from that prepared by methods not involving intensive fractionation. We are aware that the purist physical-chemist may object to the designation on the grounds that the material contains molecules outside Fig. 2—Distribution of mo!eeu)af weight of dextran as used by Bull et a]. ()949). the desired range, but we are unrepentant. The molecular-weight distribution of the third type of Urst two types described were each given to 5 patients, the third type to 58 patients, the fourth to 22 patients _ dextran (narrow-fraction A) to be investigated is shown in fig. 3. It will be seen that most of the material is in and the fifth to 36. patients. the molecular ranges close to the diffusion threshold. To estimate the excretion-rate -the patients’ urinewas The excretion-rate was 11%, and the twenty-four-hour collected in two batches : (1) for the first twenty-four hours after the start of the infusion ; and (2) for from blood level was 47%, which was felt to be encouragingly to hours after. Blood twenty-four forty-eight samples close to the 50% considered to be the desirable minimum. This was achieved with narrow-fraction B (fig. 4) with were taken before infusion and at five minutes, and six, twenty-four, forty-eight, seventy-two, ninety-six, and one an average twenty-four-hour blood level of 55%. This material had a slightly higher proportion of small hundred and twenty hours after the end of infusion. than the previous type, and the excretionmolecules Discussion of the techniques and problems of accurate rate was in consequence raised to 14%. The final type estimation of the amount of dextran remaining in the investigated in this series, narrow-fraction C (fig. 5), had circulation is beyond the scope of this paper. the highest blood level so far obtained, 68%, at twentyTo obtain a true value it is necessary to measure the four hours and also, at 8%, the lowest excretion-rate. blood volume at the time of taking each sample, and this As would be expected, the material with the highest is not always feasible in the postoperative patient. It twenty-four-hour blood level is also the best maintained has been found, however, that reliable results may be over longer periods. At the end of the five-day period obtained by taking the five-minute sample as a reference about 20% of narrow-fraction C dextran remained in the level and applying a correction factor-0.9 in the case of circulation as opposed to less than 15% of narrowthe low-excretion types of dextran-to the later readings. fraction A and B. Patients who experienced severe haemorrhage or with CLINICAL DATA postoperative oliguria or other factors which might have clinical assessment of the role -of narrowComplete influenced the results were excluded from the -series. dextran fraction must depend on observations on a large Patients who received blood or any other supportive therapy in addition to the dextran were likewise excluded. In the cases reported the amount infused was two bottles-about a litre-of a 6% solution of the dextran under test in physiological saline solution. The first type to be investigated was a standard material prepared by long hydrolysis and fractionation to remove any large molecules which might still be present. The molecular-weight distribution of this type is shown in fig. 1 as an equal-area diagram. Each block in the diagram has a molecular-weight range of 25,000, and the height of any block represents the amount of dextran in that particular range expressed as a percentage of the whole. As would be expected of material having a preponderance of small molecules, the excretion-rate was high-35% in twenty-four hours-and_ the blood level at the end of twenty-four hours was low, being 20% of the amount infused. The distribution of the next type of dextran is shown in fig. 2. This standard material was similar in character to that reported by Bull et al. (1949), being prepared by short hydrolysis followed by fractionation to remove Fig. 3-Distribution of molecular weight of narrow-fraction A dextran.
during
-
-
r
was
the
62 cases of various types. From study of about 120 cases in which narrow-fraction dextran has been used it is possible to make some general observations.
number of
Prophylaxis The
use
of narrow-fraction C dextran
as an
infusion for
patients undergoing major surgical operations enables supportive therapy to be given in the simplest possible manner. The infusion is started soon after the patient is anaesthetised and while he is still in the anaesthetic room. The dextran is run in slowly-ten to twenty drops a minute--at first. At the first sign of any fall in bloodpressure during the course of the operation the infusionrate is increased. By occasional adjustment of the drip it is possible to maintain the blood-pressure at a steady level through even the most severe operations. Since narrow-fraction dextran is retained in the circulation at an adequate level over the critical postoperative forty-eight hours, it is rarely necessary to continue the infusion after the operation has been completed. This presents a considerable advantage, since it enables the drip to be taken down while the patient is still in the theatre. Apart from the psychological effect-the patient recovering from anaesthesia to find an infusion in progress immediately fears the worsthe is not cluttered up with the paraphernalia of the infusion equipment, and the nurses are consequently spared complicated manoeuvres in attending to him. Unless there is excessive loss of blood during the operation, narrow-fraction dextran is all that is needed. The requirements for the prevention of shock are the maintenance of circulation volume and blood-pressure ; reduction of the oxygen-carrying capacity of the blood by dilution with dextran is now of minor importance, because with the narrow-fraction material the total volume of the infusion required is far less than with the earlier standard material, which was rapidly lost from the circulation. If there is severe haemorrhage, blood may be given at the same time as the dextran. It its an advantage to give blood and dextran simultaneously, rather than to replace the dextran by blood. In some cases dextran has been more effective than blood in
restoring
a
falling blood-pressure.
Shock If the
patient arrives at the hospital with the shock syndrome already established, a sample of blood is taken for typing (see below), and a bottle of dextran is next infused as rapidly as possible. A second bottle is given at a rate depending on the blood-pressure. Most of the patients in this series have responded adequately to the infusion of two bottles of narrowfraction dextran, but occasionally a third bottle has
Fig. 4-Distribution of molecular weight of narrow-fraction
B dextran.
Fig.
5-Distribution of molecular
weight of narrow-fraction C dextran.
been found desirable. After the infusion of three bottles of dextran a bottle of blood should be given to prevent undue hsemodilution. If further infusion is then dextran and blood may be given alternately. necessary, An inadequate number of cases of burns have been observed for any definite pronouncement to be made now. Since the primary cause of loss of fluid from the circulation is effusion from the damaged capillaries of the burnt areas, it seems logical that the less easily diffusible material would be the better. This, however, must be the subject of further investigation. Reactions No reactions have been observed with any of the cases infused with narrow-fraction dextran in the surgical professorial unit at Manchester Royal Infirmary. A mild rigor after the infusion of this material has been reported from one of the associated hospitals. Since the incidence of reactions with a standard type of dextran containing molecules of a higher molecular weight than any of the narrow-fraction dextran used has been shown to be very low (Maycock 1952), any attempt to estimate the reaction-rate must be left until several thousand patients have been infused. Other Observations Many macromolecular substances, when present in the serum, have been shown to produce a pseudoagglutination which may make cross-matching difficult for the inexperienced, and narrow-fraction dextran is no exception to this rule. A routine blood sample to enable grouping to be done should therefore be taken before the administration of dextran. In common with other types, this dextran also has a pronounced effect on the erythrocyte-sedimentation rate (E.s.R.), which is increased for from three to five days after infusion. Gronwall and Ingelman (1945) have shown that the E.S.R. increased with the concentration of dextran, and Thorsen and Hint (1950) have shown that with a given concentration the increase depends on the molecular size. Hardwicke et al. (1950) have demonstrated& relationship between these parameters. Experiments are at present being made as a result of which it is hoped that it will be possible to obviate both the effect on the E.S.R. and on the blood-grouping. At one period during the investigation alarm was caused by the incidence of haematomata in patients.in this series. It was at first thought that this might be due to some hitherto unobserved effect on the bleeding-time by dextran molecules of the range used when present in sufficient concentration. It was then found that a common factor in all these cases had been the use of gallamine as a muscle relaxant. Similar cases were then
63 treated with dextran, but tubarine was used as a muscle no haematomata were observed. A further check showed a correlation between the occurrence of haematomata and the use of gallamine in cases which had not been treated with dextran, but the incidence was not so high as when dextran and gallamine were used together. This is considered to be due to the mechanical effect of the maintained blood-pressure rather than to a formation of a gallamine-dextran compound.
relaxant, and
SUMMARY
of macromolecular substances in supportive is described. Since it is now possible to prepare a solution of macromolecular substances possessing advantages over plasma itself, the term " plasma substitute " should be discarded. Since the primary use of these substances is for the restoration or maintenance of the circulating blood volume the term " blood-volume restorer " is suggested. The criteria for an effective blood-volume restorer are : ease of infusion, freedom from undesirable effects, reproducible composition under manufacturing conditions, elimination from the body, and maintenance of a blood level of not less than 50% of the amount infused at the end of twenty-four hours. These criteria could only be met by the development of a new type of dextran solution. The steps in the development of the new material are described and its clinical advantages are discussed. The
use
therapy
The number of people involved in this investigation makes individual acknowledgment impossible. We wish to thank everybody concerned, particularly members of the department of surgery and the nurses of Manchester Royal Infirmary, and Mr. W. A. Magauran, F.R.e.s., of the Lancaster Royal Infirmary, for their assistance in the clinical investigation ; Mr. L. E. Martin for the physical chemistry ; Mr. F. Fowler for the large-scale production of the various types of material ; and Messrs. Bengers Ltd. for unlimited supplies of’Dextraven.’ The diagrams were drawn by the department of medical illustration of Manchester Royal Infirmary. REFERENCES
Bull, J. P., Ricketts, C., Squire, J. R., Maycock, W. d’A., Spooner, S. J. L., Mollison, P. L., Paterson, J. C. S. (1949) Lancet, i, 134. Grönwall, A., Ingelman, B. (1945) Acta physiol. scand. 9, 1. Hardwicke, J., Ricketts, C. R., Squire, J. R. (1950) Nature, Lond. 166, 988. Maycock, W. d’A. (1952) Lancet, i, 1081. Müller, W. (1946) Dtsch. med. Wschr. 71, 32. Nelson, A. A., Lusky, L. M. (1951) Proc. Soc. exp. Biol., N.Y. 76, 765. Skinsnes, O. K. (1947) Surg. Gynec. Obstet. 85, 563. Thorsén, G., Hint, H. C. (1950) Acta. chir. scand. suppl. 154.
REJECTION DYSPEPSIA G. GLADSTONE ROBERTSON M.D.
Glasg.
TilE considerable recent advances in the knowledge of body-mind relationships have sprung largely from the so-called psychosomatic approach, whereby the mental states of those suffering from various physical disorders and diseases are assessed and compared. Contributors in this field do not claim that disorders of the body are due to those found concurrently in the psyche or vice versa. They are generally psychiatrists or physicians with a psychological leaning, primarily motivated in outlook and training by a desire to improve mental health, and tend to lay emphasis on factors in the earliest years of life. This paper is based
experience in general practice whose among ordinary people higher levels are intact, the girls who are the mothers of the future and the boys who marry them, folks who suffer from crops of boils one year and a succession of colds the next, those who get cancer of the breast and others who develop fibroids, women with dysmenorrhœa and men with peptic ulcer - in fact the whole range of the common afflictions acquired by mankind.. The frequent occurrence of a on
sequence of different illnesses in the same person suggested that the affections were determined not in the earliest years but by variations in the later conditions of life. I do not claim originality for my method of approach or for many of my observations ; but I believe that certain of my correlations are new, and that my interpretation of a common and troublesome disorder may be useful to practitioners and physicians who have not been working or thinking on the same lines.
These particular observations may be said to date from 1935, when the work of Halliday and others led me to consider emotional factors in the causation of the chronic disorders now termed psychosomatic. I time to take at that histories from this viewpoint. began I found that many of my patients were women complaining of abdominal distension, eructations of wind and of small quantities of gastric secretion (usually termed " acidity "), nausea, and occasional vomiting. At first these symptoms would appear infrequently and pass off quickly, but later there would be acute exacerbations (often called bilious attacks), usually attributed to had a day free greasy food ; and some patients from belching or dyspepsia. What struck me first was that it was very rare for men to have such symptoms and yet have no pain : typically the digestive troubles of the male began with pain and not nausea, whereas the female might have nausea but remain free from pain for years. I began to wonder, therefore, why only women-and they were almost always married women-were bilious in this way. I questioned them and got them to talk ; but, though some of them mentioned their marital relations, these were not emphasised. Often the stomach disorder was mentioned only as a subsidiary complaint : the predominant symptoms might be those of an anxiety state, premenstrual tension, varicose veins, visceroptosis, uterine prolapse, gall-stones, hypertension, or rheumatism. I felt that there must be a definite answer ; and then, as so often happens, the case turned up that provided the key to the others.
rarely
AN ILLUMINATING CASE
Case 1.—Mrs. A., aged 52, had had her first menstrual period at 16 years 3 months ; she had been married 30 years but had never been pregnant. Complaint.-Abdominal distension with noisy eructations of wind, burning abdominal pain, sensation of " stone " in the epigastrium, nausea,frequent vomiting unrelated to eating,
constipation sore
with occasional attacks of
throats, palpitation and general
diarrhoea, frequent
nervousness, extreme
irritability, falling sensation centred in the uterus and bladder. Physical Examination.-Each organ system had been investigated in turn, to the limit of ordinary hospital technique, with negative result. History.-The youngest of five siblings, she was shy and self-conscious as a child. Her relationship with her parents lacked warmth, affection, intimacy, and understanding. From
her earliest recollection her mother, who was often confined to bed until she died at the age of 81, had required her help in the home. On this account her school work was poor and she became unpopular with teachers as well as classmates. The onset of headaches terminated her scholastic career at the age of 12. Sore throats commenced when she was 14, after the death of her only girl friend from diphtheria. In 1916, at the age of 22, she married her fiancé while he had 48 hours’ leave from military service. They did not live together until a year later when a varicose ulcer secured for him a month’s convalescence. He joined her in Prestwick where she was spending a holiday. Within a few days of his arrival she began to feel bilious. Nausea and vomiting continued until her husband rejoined his unit. Her unfortunate indisposition was assumed to be due to sewage contamination of seawater at the bathing site. Next summer her husband, now stationed in the south of England, was released from duty owing to a recurrence of the leg ulcer. She decided to spend a few months with him, but the reappearance of nausea and vomiting soon after her arrival convinced her that the ’’ air did not suit her and led to a speedy retreat northwards. Once "
being constantly found. Nucleated red cells were numerous haemorrhages. Necropsy showed bone-marrow hyperplastic with very the numerous megakaryocytes, some with ingested cells; spleen with myeloid metaplasia, megakaryocytes not conafter the
spicuous, some fibrosis, and malpighian bodies few and small; and the liver with very slight myeloid metaplasia. Case 8.-A man, aged 51, died in July, 1950, of weakness and wasting, after four
a
half
years’
observation.
myeloid metaplasia involving erythroblasts, leucoblasts, megakaryocytes than in patients with typical myeloid leukaemia or with typical primary polycythaemia. and
The
presenting symptom was intestinal haemorrhage in March, 1946, when a large spleen was found. The first intestinal haemorrhage teok place in 1942, and these were repeated until 1948. The patient was subject to abnormal bruising in 1949 and 1950. He had no polycythaemia while under observation, He had never had severe nor any history suggesting it. ansemia except after intestinal haemorrhages. His leucocytes normal in 1946-48 but later increased to 20,000 per and in 1949-50 he had leucopenia. Immature leucocytes were 8-12% before the first course of X-ray treatment in November and December, 1948, which improved his health considerably. A second course, in 1949, also had a good effect, but a third course, in 1950, had no effect. The patient had gout in his great toes in 1948-49. His serumuric-acid level was 6-6-8-3 mg. per 100 ml. in 1948-50. Necropsy showed fibrosis throughout all parts of the bonemarrow examined, very dense in places ; but in most areas the bone-marrow cells, especially the megakaryocytes, were recognisable ; the spleen with myeloid metaplasia and very small and scanty malpighian bodies ; and the liver with very were
c.mm.,
slight myeloid metaplasia only. Case 9.-A woman, aged 74, died in January, 1946, of heart-failure, after six and three-quarters years’ observation. The presenting symptoms were diarrhoea and the passage of blood per rectum in April, 1939, when a large spleen and a large liver were found. The patient was subject to abnormal bruising from 1937 onwards. She had " chlorotic polycythaemia" in 1939, with more than 7,000,000 red cells per c.mm., but her Hb was 70%. After having iron by mouth she developed typical polycythsemia, which later disappeared. She had high leucocytosis (40,000-60,000 per c.mm. with less than 1% immature leucocytes) ; later the number of leucocytes became normal, but a few immature leucocytes persisted. The patient had gout in her hands and feet in 1940-41. Her blood-uric-acid level was above 7 mg. per 100 ml. in 1939-41. She died of congestive heart-failure. No necropsy was done. DISCUSSION
Gout
SUMMARY
The relationships between gout, myeloid leuksemia., and primary polycythsemia are stated. Gout occurs much more commonly in patients with
fairly often in patients who have myeloid metaplasia involving all three main bone-marrow elements-erythroblasts, leucoblasts, and especially megakaryocytes-but it does not occur commonly in patients who have mainly leucoblastic myeloid metaplasia or mainly erythroblastic myeloid metaplasia. The blooduric-acid level is usually normal in typical cases of primary polycythaemia (Wintrobe 1951), and most cases of typical chronic myeloid leukaemia under my care occurs
The most have had a normal blood-uric-acid level. striking fact is that myeloid metaplasia occurs in some patients who have had gout for many years, and this must be of great importance in considering the causes of myeloid metaplasia, and may throw light on the cause of chronic myeloid leukaemia. In most of the published cases in which gout occurred years before the myeloid splenomegaly was discovered there is no means of knowing when the disorder of the blood-forming tissues began ; but 1 patient was seen with gout three years before splenomegaly was found (Coste et al. 1948). In the type of case under discussion gout may occur more commonly than is generally believed, for the descriptions of several patients suggest that they had gout, though not diagnosed as such (Rosenthal and Bassen 1938, Vaughan and Harrison 1939, Dustin 1947). Several other patients under my care, with " megakaryocytic myelosis " or " myelosclerosis," had constantly high blood-uric-acid levels, though they did not develop gout. Rarely gout may occur in acute myeloid leukaemia ; and a patient with chronic gout may have an acute fatal illness closely simulating acute myeloid leukaemia.
REFERENCES
Avery, H. (1930) Lancet, i, 342. Brunner, H. (1932) Z. klin. Med. 121, 700. Coste, F., Galmiche, P., Sors, C. (1948) Rev. Rhum. 15, 89. Duckworth, D. (1889) A Treatise on Gout. London ; p. 198. Dustin, P. jun. (1947) Acta clin. belg. 2, 212. Forkner, C. E. (1938) Leukemia and Allied Disorders. New York ; p. 42. Hagedorn, K. (1926) Z. klin. Med. 104, 124. Hoffmann, A. (1926) Klin. Wschr. 5, 124. Merskey, C. (1949) Arch. intern. Med. 84, 277. Reifenstein, G. H. (1939) Amer. J. med. Sci. 197, 215. (1945) Ibid, 210, 638. Roberts, W., Bradford, J. R. (1907) In Allbutt, T. C., Rolleston, H. D. System of Medicine. London ; vol. III, p. 127. Rosenthal, N., Bassen, F. A. (1938) Arch. intern. Med. 62, 903. Shorvon, L. M. (1946) Lancet, ii, 378. Stone, D. M., Woodman, D. (1938) J. Path. Bact. 47, 327. Tinney, W. S., Polley, H. F., Hall, B. E., Giffin, H. Z. (1945) Proc. Mayo Clin. 20, 49. Vaughan, J. M., Harrison, C. V. (1939) J. Path. Bact. 48, 339. Videbaek, A. (1950) Acta med. scand. 138, 179. Weber, F. P. (1921) Polycythæmia, Erythrocytosis, and Erythræmia (Vaquez-Osler Disease). London ; p. 83. (1934) Lancet, ii, 808. Wintrobe, M. M. (1951) Clinical Hematology. 3rd ed., London. Wyatt, J. P., Sommers, S. C. (1950) Blood, 5, 329. —
—
SUPPORTIVE THERAPY AN IMPROVED TYPE OF DEXTRAN
A. M. BOYD Lond., F.R.C.S.
M.B.
PROFESSOR OF SURGERY IN THE UNIVERSITY OF MANCHESTER
F. FLETCHER M.D. Mane. RESEARCH FELLOW IN THE UNIVERSITY
A. HALL RATCLIFFE M.A., B.Sc., D.Phil. Oxfd SPECIAL LECTURER IN EXPERIMENTAL METHODS IN THE UNIVERSITY
INTENSIVE investigation into the causes, prevention, and treatment of shock was made necessary by two wars. But in a world of increasing mechanisation, with its heavy toll of accidents, shock is far from being a purely war-time problem. Collaborative research has resulted in a clearer understanding of supportive therapy, and the importance of maintaining the circulating blood volume has been firmly established. The wide use of blood-transfusion and plasma infusion means that surgical shock, as formerly known, is no longer seen. The expense and potential shortage of stored blood and the danger of virus hepatitis after infusion of plasma have stimulated a revival of the search for alternative substances for supportive therapy. These substances have been termed " plasma substitutes," but with the development of materials which in many respects are preferable to plasma it is felt that a new designation is required. Since the primary use of these substances is to restore or to maintain the circulating blood volume, the term " blood-volume restorer " is suggested. CRITERIA FOR BLOOD-VOLUME RESTORERS
Ease of infusion.-The viscosity of the material should be such that it is easily infusable in all climates. Freedom from undesirable effects.-The substance must not be toxic or antigenic. It must not produce hoemolysis. It must be easily sterilisable and free from pyrogens. Jtfon-e/M-ce standards.-The of manufacturing material must be capable of rapid and economic manufacture on a large scale, with exactly reproducible composition. It must be storable, without alteration, for long periods under varying conditions of temperature.
60 Elimination from the body.-The material should eventually be excreted or metabolised. Any storage in the body should be brief, and there should be no adverse effect, either immediate or delayed, on any organs or at the site of injection. Retention in circulation.-A satisfactory blood-volume restorer should remain in the blood-stream with levels of not less than 50% of the amount infused at the end of twenty-four hours. This implies that the material should not be rapidly katabolised, excreted, or readily diffusible through the capillary wall. The retained material must also have an adequate water-holding
capacity. The mechanism bv which macromolecular colloids hold water in the circulation is complex. There are two main factors involved : (1) the osmotic pressure of the solution, which depends on the molecular concentration and hence decreases with increase in molecular weight ; and (2) the water-binding capacity of the colloid, which increases with increase in molecular weight. The combined effect of these two factors, which tend to balance one another, may be termed the water-holding capacity of the colloid. TYPES OF MATERIAL
the last few years interest has been focused three polymers : polygelatin, polyvinylpyrrolidone, Because these substances are polymers and dextran. be in various ranges of molecular can produced they size, and it is possible to obtain samples of the same polymer having widely differing properties. It is shown below that molecular size is of the utmost importance. In the form which has been used for infusion gelatin produces a highly viscous solution which does not flow easily at room-temperature in this country. In our experience it is necessary to warm this material before infusion. Injudicious heating may cause denaturation ; this may also happen with prolonged storage. Evidence has also been produced of tissue changes after the infusion of gelatin (Skinsnes 1947). A derivative, oxypolygelatin, has been produced which is less viscous in solution and stable to storage. The advantage, however, has only been achieved at the expense of a high excretionrate and a low blood level. Polyvinylpyrrolidone cannot be broken down in the body and tends to be accumulated in the liver and reticulo-endothelial system (Nelson and Lusky 1951). The German army used a form of polyvinylpyrrolidone during the war 1939-45, and Muller (1946) reported that the appearance of the spleen and lymph-nodes at necropsy after the infusion of this material was comparable to that seen in the storage diseases. The use of the material was given up after army pathologists had found widespread liver and kidney damage. More recently a type of polyvinylpyrrolidone has been prepared with a much smaller molecular size than that used by the Germans. It -is claimed that this does not give rise to organic changes, but the excretion-rate is so high that the effect on the circulation volume can only be transient. Dextran, which is a polymerised form of glucose, does not seem to be stored in the body in significant amounts, and is probably eliminated by being broken down to a molecular size small enough to be excreted by the kidneys, or glucose elements may be broken off and utilised as such. A few reactions of an anaphylactic type were reported with some of the earlier kinds of dextran ; these were considered to be due to the presence of large molecules, but the possibility of contamination cannot be completely excluded. More complete hydrolysis of the crude dextran produced a material virtually free from reactions but at the cost of a high excretionrate and a low twenty-four-hour blood level. Because of its basic advantages it was decided to investigate the possibility of preparing an effective blood-volume restorer from dextran. The problem was to determine the best molecular range, and to find out if the material could be produced on an economic scale.
During
on
correspondingly
DETERMINATION OF BEST MOLECULAR RANGE
Dextran is prepared biosynthetically from sucrose by the action of Leuconostoc mesenteroides, which polymerises the glucose half of the molecule. Before it can be used the crude dextran must be hydrolysed, the resulting product containing molecules of molecular weight ranging from a few thousand to several million in a proportion depending on the time and conditions of hydrolysis. From a physiological point of view the molecular spectrum may be divided arbitrarily into four ranges :
(1) are so
highest range consists of those molecules which large that they may produce undesirable reactions.
The
(2) The lowest range consists of those through the glomeruli and are excreted.
molecules which pass
(3) Above this is the range of molecules which
are
too
large to be excreted but small enough to capillary wall and thus be lost from the
diffuse through the circulation into the tissue fluid. These molecules are undesirable because, apart from any effect on the intracellular-extracellular fluid balance, they have a certain water-holding capacity, and this associated water is lost from the circulation. (4) The next highest range contains those molecules which are too large to diffuse through the capillary wall but not large enough to produce reactions.
It therefore seems logical that the ideal form of dextran should be that containing the largest amount possible in the last-mentioned range. To estimate the transition values between the various ranges it was necessary to obtain a distribution curve of the molecular spectrum for each of the types of dextran involved. This was done by obtaining samples of a very small part of each range by repeated fractionation from a suitable solvent, and by measuring the intrinsic viscosity of each sample. For the sake of clarity the charac. teristics of each type of dextran used are described here in terms of molecular weight. Since the values of the molecular weight have been derived from intrinsic viscosity measurements, the figures given must be regarded as approximations until they can be confirmed by ultracentrifuge studies on the type of dextran used. From studies of excretion-rate and blood levels in the rabbit and man with various types of dextran, described in more detail below, the glomerular threshold seems to correspond to a molecular weight of 60,000 ; and the capillary threshold appears to be about 130,000 in man and a little higher in the rabbit. It must be borne in mind, if tempted to compare these figures with that of albumin, that diffusion depends on other factors besides molecular weight-e.g., charge and shape. Itisimpracticable to produce anaphylaxis in man, and it was impossible to demonstrate it in the rabbit with any form of hydrolysed dextran free from pyrogens and other contaminants. It is therefore thought that an upper limit at a molecular weight of 250,000 leaves an adequate margin of safety. PERCENTAGE
Fig. distribution
of molecular
weight
of standard dextran.
61 EXPERIMENTAL DATA
large molecules. However, it still contained a small quantity of the molecular range we consider undesirably high. Because of the fewer small molecules the excretionrate was reduced to 20%, but the twenty-four-hour the
types has been infused into patients undergoing surgical operation. The observations reported have been made on five types of dextran whose molecularweight distribution makes them of special interest. The Dextran of various
blood level
onlv raised to 35%.
This meant that first twenty-four hours after infusion more of the dextran was lost from the circulation than remained in it. The observations made at this stage suggested that, to obtain a satisfactory twenty-four-hour blood level, a type of dextran must be made containing a much greater proportion of molecules in the middle range immediately above the diffusion threshold. It was also felt that the larger molecules should be completely removed. These requirements necessitated a re-design of the process of manufacture and the development of a large-scale method of intensive fractionation. We have called material prepared by this method " narrow-fraction dextran " to distinguish it from that prepared by methods not involving intensive fractionation. We are aware that the purist physical-chemist may object to the designation on the grounds that the material contains molecules outside Fig. 2—Distribution of mo!eeu)af weight of dextran as used by Bull et a]. ()949). the desired range, but we are unrepentant. The molecular-weight distribution of the third type of Urst two types described were each given to 5 patients, the third type to 58 patients, the fourth to 22 patients _ dextran (narrow-fraction A) to be investigated is shown in fig. 3. It will be seen that most of the material is in and the fifth to 36. patients. the molecular ranges close to the diffusion threshold. To estimate the excretion-rate -the patients’ urinewas The excretion-rate was 11%, and the twenty-four-hour collected in two batches : (1) for the first twenty-four hours after the start of the infusion ; and (2) for from blood level was 47%, which was felt to be encouragingly to hours after. Blood twenty-four forty-eight samples close to the 50% considered to be the desirable minimum. This was achieved with narrow-fraction B (fig. 4) with were taken before infusion and at five minutes, and six, twenty-four, forty-eight, seventy-two, ninety-six, and one an average twenty-four-hour blood level of 55%. This material had a slightly higher proportion of small hundred and twenty hours after the end of infusion. than the previous type, and the excretionmolecules Discussion of the techniques and problems of accurate rate was in consequence raised to 14%. The final type estimation of the amount of dextran remaining in the investigated in this series, narrow-fraction C (fig. 5), had circulation is beyond the scope of this paper. the highest blood level so far obtained, 68%, at twentyTo obtain a true value it is necessary to measure the four hours and also, at 8%, the lowest excretion-rate. blood volume at the time of taking each sample, and this As would be expected, the material with the highest is not always feasible in the postoperative patient. It twenty-four-hour blood level is also the best maintained has been found, however, that reliable results may be over longer periods. At the end of the five-day period obtained by taking the five-minute sample as a reference about 20% of narrow-fraction C dextran remained in the level and applying a correction factor-0.9 in the case of circulation as opposed to less than 15% of narrowthe low-excretion types of dextran-to the later readings. fraction A and B. Patients who experienced severe haemorrhage or with CLINICAL DATA postoperative oliguria or other factors which might have clinical assessment of the role -of narrowComplete influenced the results were excluded from the -series. dextran fraction must depend on observations on a large Patients who received blood or any other supportive therapy in addition to the dextran were likewise excluded. In the cases reported the amount infused was two bottles-about a litre-of a 6% solution of the dextran under test in physiological saline solution. The first type to be investigated was a standard material prepared by long hydrolysis and fractionation to remove any large molecules which might still be present. The molecular-weight distribution of this type is shown in fig. 1 as an equal-area diagram. Each block in the diagram has a molecular-weight range of 25,000, and the height of any block represents the amount of dextran in that particular range expressed as a percentage of the whole. As would be expected of material having a preponderance of small molecules, the excretion-rate was high-35% in twenty-four hours-and_ the blood level at the end of twenty-four hours was low, being 20% of the amount infused. The distribution of the next type of dextran is shown in fig. 2. This standard material was similar in character to that reported by Bull et al. (1949), being prepared by short hydrolysis followed by fractionation to remove Fig. 3-Distribution of molecular weight of narrow-fraction A dextran.
during
-
-
r
was
the
62 cases of various types. From study of about 120 cases in which narrow-fraction dextran has been used it is possible to make some general observations.
number of
Prophylaxis The
use
of narrow-fraction C dextran
as an
infusion for
patients undergoing major surgical operations enables supportive therapy to be given in the simplest possible manner. The infusion is started soon after the patient is anaesthetised and while he is still in the anaesthetic room. The dextran is run in slowly-ten to twenty drops a minute--at first. At the first sign of any fall in bloodpressure during the course of the operation the infusionrate is increased. By occasional adjustment of the drip it is possible to maintain the blood-pressure at a steady level through even the most severe operations. Since narrow-fraction dextran is retained in the circulation at an adequate level over the critical postoperative forty-eight hours, it is rarely necessary to continue the infusion after the operation has been completed. This presents a considerable advantage, since it enables the drip to be taken down while the patient is still in the theatre. Apart from the psychological effect-the patient recovering from anaesthesia to find an infusion in progress immediately fears the worsthe is not cluttered up with the paraphernalia of the infusion equipment, and the nurses are consequently spared complicated manoeuvres in attending to him. Unless there is excessive loss of blood during the operation, narrow-fraction dextran is all that is needed. The requirements for the prevention of shock are the maintenance of circulation volume and blood-pressure ; reduction of the oxygen-carrying capacity of the blood by dilution with dextran is now of minor importance, because with the narrow-fraction material the total volume of the infusion required is far less than with the earlier standard material, which was rapidly lost from the circulation. If there is severe haemorrhage, blood may be given at the same time as the dextran. It its an advantage to give blood and dextran simultaneously, rather than to replace the dextran by blood. In some cases dextran has been more effective than blood in
restoring
a
falling blood-pressure.
Shock If the
patient arrives at the hospital with the shock syndrome already established, a sample of blood is taken for typing (see below), and a bottle of dextran is next infused as rapidly as possible. A second bottle is given at a rate depending on the blood-pressure. Most of the patients in this series have responded adequately to the infusion of two bottles of narrowfraction dextran, but occasionally a third bottle has
Fig. 4-Distribution of molecular weight of narrow-fraction
B dextran.
Fig.
5-Distribution of molecular
weight of narrow-fraction C dextran.
been found desirable. After the infusion of three bottles of dextran a bottle of blood should be given to prevent undue hsemodilution. If further infusion is then dextran and blood may be given alternately. necessary, An inadequate number of cases of burns have been observed for any definite pronouncement to be made now. Since the primary cause of loss of fluid from the circulation is effusion from the damaged capillaries of the burnt areas, it seems logical that the less easily diffusible material would be the better. This, however, must be the subject of further investigation. Reactions No reactions have been observed with any of the cases infused with narrow-fraction dextran in the surgical professorial unit at Manchester Royal Infirmary. A mild rigor after the infusion of this material has been reported from one of the associated hospitals. Since the incidence of reactions with a standard type of dextran containing molecules of a higher molecular weight than any of the narrow-fraction dextran used has been shown to be very low (Maycock 1952), any attempt to estimate the reaction-rate must be left until several thousand patients have been infused. Other Observations Many macromolecular substances, when present in the serum, have been shown to produce a pseudoagglutination which may make cross-matching difficult for the inexperienced, and narrow-fraction dextran is no exception to this rule. A routine blood sample to enable grouping to be done should therefore be taken before the administration of dextran. In common with other types, this dextran also has a pronounced effect on the erythrocyte-sedimentation rate (E.s.R.), which is increased for from three to five days after infusion. Gronwall and Ingelman (1945) have shown that the E.S.R. increased with the concentration of dextran, and Thorsen and Hint (1950) have shown that with a given concentration the increase depends on the molecular size. Hardwicke et al. (1950) have demonstrated& relationship between these parameters. Experiments are at present being made as a result of which it is hoped that it will be possible to obviate both the effect on the E.S.R. and on the blood-grouping. At one period during the investigation alarm was caused by the incidence of haematomata in patients.in this series. It was at first thought that this might be due to some hitherto unobserved effect on the bleeding-time by dextran molecules of the range used when present in sufficient concentration. It was then found that a common factor in all these cases had been the use of gallamine as a muscle relaxant. Similar cases were then
63 treated with dextran, but tubarine was used as a muscle no haematomata were observed. A further check showed a correlation between the occurrence of haematomata and the use of gallamine in cases which had not been treated with dextran, but the incidence was not so high as when dextran and gallamine were used together. This is considered to be due to the mechanical effect of the maintained blood-pressure rather than to a formation of a gallamine-dextran compound.
relaxant, and
SUMMARY
of macromolecular substances in supportive is described. Since it is now possible to prepare a solution of macromolecular substances possessing advantages over plasma itself, the term " plasma substitute " should be discarded. Since the primary use of these substances is for the restoration or maintenance of the circulating blood volume the term " blood-volume restorer " is suggested. The criteria for an effective blood-volume restorer are : ease of infusion, freedom from undesirable effects, reproducible composition under manufacturing conditions, elimination from the body, and maintenance of a blood level of not less than 50% of the amount infused at the end of twenty-four hours. These criteria could only be met by the development of a new type of dextran solution. The steps in the development of the new material are described and its clinical advantages are discussed. The
use
therapy
The number of people involved in this investigation makes individual acknowledgment impossible. We wish to thank everybody concerned, particularly members of the department of surgery and the nurses of Manchester Royal Infirmary, and Mr. W. A. Magauran, F.R.e.s., of the Lancaster Royal Infirmary, for their assistance in the clinical investigation ; Mr. L. E. Martin for the physical chemistry ; Mr. F. Fowler for the large-scale production of the various types of material ; and Messrs. Bengers Ltd. for unlimited supplies of’Dextraven.’ The diagrams were drawn by the department of medical illustration of Manchester Royal Infirmary. REFERENCES
Bull, J. P., Ricketts, C., Squire, J. R., Maycock, W. d’A., Spooner, S. J. L., Mollison, P. L., Paterson, J. C. S. (1949) Lancet, i, 134. Grönwall, A., Ingelman, B. (1945) Acta physiol. scand. 9, 1. Hardwicke, J., Ricketts, C. R., Squire, J. R. (1950) Nature, Lond. 166, 988. Maycock, W. d’A. (1952) Lancet, i, 1081. Müller, W. (1946) Dtsch. med. Wschr. 71, 32. Nelson, A. A., Lusky, L. M. (1951) Proc. Soc. exp. Biol., N.Y. 76, 765. Skinsnes, O. K. (1947) Surg. Gynec. Obstet. 85, 563. Thorsén, G., Hint, H. C. (1950) Acta. chir. scand. suppl. 154.
REJECTION DYSPEPSIA G. GLADSTONE ROBERTSON M.D.
Glasg.
TilE considerable recent advances in the knowledge of body-mind relationships have sprung largely from the so-called psychosomatic approach, whereby the mental states of those suffering from various physical disorders and diseases are assessed and compared. Contributors in this field do not claim that disorders of the body are due to those found concurrently in the psyche or vice versa. They are generally psychiatrists or physicians with a psychological leaning, primarily motivated in outlook and training by a desire to improve mental health, and tend to lay emphasis on factors in the earliest years of life. This paper is based
experience in general practice whose among ordinary people higher levels are intact, the girls who are the mothers of the future and the boys who marry them, folks who suffer from crops of boils one year and a succession of colds the next, those who get cancer of the breast and others who develop fibroids, women with dysmenorrhœa and men with peptic ulcer - in fact the whole range of the common afflictions acquired by mankind.. The frequent occurrence of a on
sequence of different illnesses in the same person suggested that the affections were determined not in the earliest years but by variations in the later conditions of life. I do not claim originality for my method of approach or for many of my observations ; but I believe that certain of my correlations are new, and that my interpretation of a common and troublesome disorder may be useful to practitioners and physicians who have not been working or thinking on the same lines.
These particular observations may be said to date from 1935, when the work of Halliday and others led me to consider emotional factors in the causation of the chronic disorders now termed psychosomatic. I time to take at that histories from this viewpoint. began I found that many of my patients were women complaining of abdominal distension, eructations of wind and of small quantities of gastric secretion (usually termed " acidity "), nausea, and occasional vomiting. At first these symptoms would appear infrequently and pass off quickly, but later there would be acute exacerbations (often called bilious attacks), usually attributed to had a day free greasy food ; and some patients from belching or dyspepsia. What struck me first was that it was very rare for men to have such symptoms and yet have no pain : typically the digestive troubles of the male began with pain and not nausea, whereas the female might have nausea but remain free from pain for years. I began to wonder, therefore, why only women-and they were almost always married women-were bilious in this way. I questioned them and got them to talk ; but, though some of them mentioned their marital relations, these were not emphasised. Often the stomach disorder was mentioned only as a subsidiary complaint : the predominant symptoms might be those of an anxiety state, premenstrual tension, varicose veins, visceroptosis, uterine prolapse, gall-stones, hypertension, or rheumatism. I felt that there must be a definite answer ; and then, as so often happens, the case turned up that provided the key to the others.
rarely
AN ILLUMINATING CASE
Case 1.—Mrs. A., aged 52, had had her first menstrual period at 16 years 3 months ; she had been married 30 years but had never been pregnant. Complaint.-Abdominal distension with noisy eructations of wind, burning abdominal pain, sensation of " stone " in the epigastrium, nausea,frequent vomiting unrelated to eating,
constipation sore
with occasional attacks of
throats, palpitation and general
diarrhoea, frequent
nervousness, extreme
irritability, falling sensation centred in the uterus and bladder. Physical Examination.-Each organ system had been investigated in turn, to the limit of ordinary hospital technique, with negative result. History.-The youngest of five siblings, she was shy and self-conscious as a child. Her relationship with her parents lacked warmth, affection, intimacy, and understanding. From
her earliest recollection her mother, who was often confined to bed until she died at the age of 81, had required her help in the home. On this account her school work was poor and she became unpopular with teachers as well as classmates. The onset of headaches terminated her scholastic career at the age of 12. Sore throats commenced when she was 14, after the death of her only girl friend from diphtheria. In 1916, at the age of 22, she married her fiancé while he had 48 hours’ leave from military service. They did not live together until a year later when a varicose ulcer secured for him a month’s convalescence. He joined her in Prestwick where she was spending a holiday. Within a few days of his arrival she began to feel bilious. Nausea and vomiting continued until her husband rejoined his unit. Her unfortunate indisposition was assumed to be due to sewage contamination of seawater at the bathing site. Next summer her husband, now stationed in the south of England, was released from duty owing to a recurrence of the leg ulcer. She decided to spend a few months with him, but the reappearance of nausea and vomiting soon after her arrival convinced her that the ’’ air did not suit her and led to a speedy retreat northwards. Once "