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1536 JUNE BRITISH 156JN 28,8 195815 SURGICALUGC , MEDICAL JOURNAL vicious cycle: venous return decreased, and this diminished ; pressure fell; occurred, and this caused and increased ANAESTHETISTS AT R.C.S. permeability; finally, the increase in permeability [FROM A SPECIAL CORRESPONDENT] further reduced the effective circulatory volume. It was therefore the tissue perfusion rather than the On June 14 the Faculty of Anaesthetists held a whole-day which was important. The ganglion-blocking agents were meeting at the Royal College of Surgeons to discuss " Shock either adrenergic ones such as phenoxybenzamine or direct and Allied Phenomena." ganglionic blockers such as hexamethonium. Noradrenaline Sir HENRY DALE, O.M., F.R.S., who opened the meeting, as a means of maintaining the blood pressure during these defined shock as any condition of depressed vitality with major interventions was clearly contraindicated, as it would circulatory deficiency as its central feature but without increase tissue hypoxia; it would also encourage haemor- evidence of haemorrhage or gross infection. Wound shock, rhage from the point of least resistance. Ganglion-blocking he continued, might be due to absorption of toxic sub- agents, on the other hand, protected the peripheral circula- stances from the injured tissues. The analogy between tion, as shown by fluorescein studies, and phenoxybenzamine wound shock and shock was very close: in both also prevented the release of " vasodilator material by the the effective circulatory volume was greatly reduced, owing liver. In animals the survival rate after haemorrhage was to stagnation of the blood and haemoconcentration from the increased by giving ganglion-blocking agents, all the sur- leakage of plasma. He recalled some interesting experiments vivors showing haemodilution and the fatal cases haemo- showing that histamine given intravenously to normal un- concentration. assays showed also that the anaesthetized cats did not produce shock, but when they blood levels of adrenaline in the " blocked dogs " were were anaesthetized by chloroform, ether, or urethane the much lower than in the controls. same dose of histamine produced shock. Moreover, he showed that it was not the state of anaesthesia itself but the Patients on Steroids sensitization effect of the anaesthetic agents which produced Dr. R. I. S. BAYLIS presented a very useful paper on the the shock-like state. Similarly, haemorrhage and adrenal- management of cases receiving cortisone and other steroids. ectomy increased the sensitivity of the animals to histamine. The long-continued administration of like hydro- cortisone and prednisone led to a reduction in weight of Causes of Irreversible Shock the adrenal glands, which was accompanied by decreased Professor W. D. M. PATON, F.R.S., suggested that a pituitary corticotrophic activity due to pituitary inhibition. number of causes could account for irreversible shock in Corticotrophin exerted a similar effect on the pituitary by dogs after haemorrhage. Thus " vasoexcitatory material " overstimulating the adrenal gland. After only seven days' produced in response to haemorrhage would ordinarily be prednisone therapy there was considerable adrenal depres- counteracted by " vasodilator material " from the liver, but sion in response to corticotrophin as measured by the out- if the latter's action were prolonged shock would ensue. put of urinary ketosteroids. The duration of this prednisone Sluggish circulation coupled with an increased coagulability effect was at present unknown, but it probably lasted for a of the blood might lead to the formation of microemboli. number of months. From the practical point of view, it Or, since clostridia were normally present in dogs' muscles, was clearly vital for the surgeon to elicit any history of any hypoxia of the muscles would lead to elaboration of prednisone administration ; equally patients should always clostridial toxins. Finally, he suggested that vasoconstric- be told if they were given prednisone. tion in itself could be the harmful factor in shock by Prophylactically, patients on steroids or who had had producing tissue anoxia. A sluggish flow of blood through steroids during the previous 12 months should receive hydro- constricted arterioles into a progressively distending cortisone, 100-200 mg. intramuscularly, 24 hours before capillary bed would cause ischaemia, which in turn led to operation, a similar dose two hours before operation, and the release of and histamine. This local release 75-100 mg. after the operation. In addition they should of histamine might not be accompanied by a detectable be given 100 mg. daily by mouth for the next few days. and level in the peripheral blood. Other substances such as the dosage could then be reduced gradually over the next hydroxytryptamine and even the proteolytic systems of the two weeks. If the patient was the could be body themselves acted on smooth muscle under these condi- given intramuscularly. tions. The toxic effects of adrenaline were well known. It If shock occurred despite these measures, hydrocortisone blocked ganglia, and this effect lasted longer than its vaso- hemisuccinate should be given intravenously (134 mg. is constrictor effect. Adrenaline could act, therefore, as a equivalent to 100 mg. of hydrocortisone); 400 mg. should vasodilator and lymphagogue. In adrenaline shock, pre- be given in the first 24 hours, and, if there was no response sumably the vasodilator effects completely overshadowed any to the intravenous administration of 100 mg. within 15 vasoconstriction. minutes, noradrenaline should be added in order to maintain Experimentally, if the systolic pressure was maintained at the blood pressure until the steroid took effect. about 40 mm. Hg by exsanguination, sympathetic amines Dr. A. J. W. BEARD presented a film on " ," were released, followed by histamine-like substances. If stressing the importance of teamwork, speed rather than the was then restored, these histamine-like haste, and effective cardiac massage. Cardiac massage could substances were washed into the general circulation in large be performed adequately only through a thoracotomy. quantities. They seemed to be released only so long as the and its efferent pathways remained intact. The Estimation of Blood Loss vasoconstrictor effect of defibrinated blood was due to Mr. RUSCOE CLARKE, from the Birmingham Accident hydroxytryptamine. Hospital, maintained that wound shock was entirely due to During shock the output of adrenaline continued, and haemorrhage. By ingenious limb measurements after therefore even in profound shock the vasomotor centre was trauma he showed that even in simple fractures of the still active. Vasoconstriction was essentially a damaging femur as much as 3.5 litres of blood might be lost into the process, said Professor Paton: the periphery of the body tissues. These results had been checked by blood-volume was sacrificed to save the centre, but as a result of the studies using 51Cr and 32P. He pointed out, moreover, that sacrifice the centre died. nobody had yet demonstrated a return of this " stagnant blood" into the circulation. It was important to remember The Role of Gangliontblockers that each bottle of blood contained only 400 ml. of blood, Dr. J. B. WYMAN then discussed the use of ganglion- the remainder being citrate solution, and this might be im- blocking agents in major surgical procedures usually associ- portant when large transfusions were given. Tissue-swell- ated with severe shock. After haemorrhage there was a ing after trauma occurred within an hour or so, and it must JUNE 28, 1958 SURGICAL SHOCK BRITisH MEDICAL JOURNAL 1537 be assumed to be due to extravasation of blood or plasma, were katabolized at a constant relative rate, whereas the rate with a corresponding diminution in the effective circulating of katabolism of gamma-globulins declined in the course volume. of an experiment in the way that would be expected if Estimates of visible blood loss were always too low; but they were heterogeneous. Correlation between the rates of for practical purposes a fist was equivalent to a pint formation of specific and non-specific globulin after anti- (570 ml.). In very extensive studies on blood volume, genic stimulation by the intravenous and subcutaneous correlated with physical signs, he had found that, if the routes cast some doubt on the supposition that any high blood pressure was high and the slow, then the proportion of gamma-globulin was manufactured in peri- effective blood volume was probably not below 80% of pheral lymphoid tissue. normal. In cases with a low blood pressure and a rapid Dr. P. BURTIN (Pasteur Institute, Paris) said that gamma- pulse the blood volume might be reduced to below 50% globulins, when used as , had a similar immuno- and would certainly be below 60% of normal. However, chemical structure, but contained a number of different the blood pressure and pulse were unreliable indices of determinant groups. The gamma-globulins cross-reacted blood volume. After transfusion, the blood pressure and with the Bence Jones found in the of patients pulse returned to normal before the blood volume was fully with multiple myeloma, each such containing a few, restored. Clinically, the toes became warm last of all and usually one, of the determinant groups. this was good evidence of a normal blood volume. An injured patient might lose 30 to 40% of his blood volume, and if was contemplated this must be replaced, Hyper- and Hypo-gammaglobulinaemia as a further loss of as little as one or two pints might The discussion now turned to problems of more prove critical: adequate pre-operative transfusion allowed immediate clinical importance. Dr. N. H. MARTIN (St. adequate primary surgical treatment. In Mr. Ruscoe George's Hospital), reviewing hypergammaglobulinaemia, Clarke's opinion, noradrenaline at this stage was not inldi- limited his remarks to diseases such as chronic , cated and the use of morphine and other drugs was entirely some collagen diseases, and some neoplasias, in which the ancillary to transfusion. circulating gamma-globulin levels were persistently greater The meeting ended with an account, by Dr. R. I. than 1.6 g. per kg. body weight, so excluding the " healthy " BODMAN, of the use of helicopters for the transport of transient increases that accompany other diseases. In patients. chronic hepatitis the plasma cell count was proportional to the quantity of circulating gamma-globulin. Electro- phoretic analysis of the serum in hepatitis suggested that the globulins present in excess extended over a wide range of mobility; over this range they were reactive to specific BRITISH SOCIETY FOR IMMUNOLOGY anti-gamma-globulin sera. As a corollary, modifying the normal [FROM A SPECIAL CORRESPONDENT] gamma-globulins by simple chemical methods altered the electrophoretic behaviour without corresponding The great success of the British Society for Immunology, changes in specificity. Studies of globulins isolated from surprising even to its sponsors, is evidence that immunology individual patients suffering from myelomatosis or having has fully emerged from the temporary recession caused by macroglobulinaemia showed clear-cut differences by the development of . The spring meeting at the physicochemical techniques, even though their globulins National Institute for Medical Research on June 13 and 14, appeared to retain areas of common immunological pattern. attended by more than 250 people, began with a symposium He suggested that the differences might be of secondary on gamma-globulins, the protein fraction of the blood in structure rather than of primary amino-acid sequence. which most humoral antibodies are found, and-as Dr. Professor J. R. SQuiRE (Birmingham University) defined J. H. HUMPHREY (N.I.M.R.) pointed out in his introductory hypogammaglobulinaemia in terms of a gamma-globulin paper-the first molecules to have been used as " tracers " in level less than 200 mg. per 100 ml. plasma, subject to there biological research. being an otherwise normal electrophoretic pattern and no protein in the urine. In such patients antibodies were Nature of Humoral Antibodies generally absent even after active immunization. Hypo- gammaglobulinaemia was a low-production syndrome and The theme of the first part of the symposium was the was not due to an abnormally high rate of elimination, physical heterogeneity of the globulins. The alpha- and since normal gamma-globulins injected as replacement beta-globulins and the three components of gamma- therapy showed a normal rate of decay in the circulation. globulin were defined by their electrophoretic mobility, said He suggested that lack of a plasma cell maturation factor Dr. Humphrey, though- this could be misleading: the might be the cause of hypogammaglobulinaemia, for large immuno-electrophoretic definition might be nearer the truth. numbers of plasma cell precursors were found in the liver. There was some evidence that not all gamma-globulins were Most patients also lacked two of the beta components of in the strict sense antibodies: under antigenic stimulation serum globulins and the ABO iso-agglutinins, but where the isolated perfused produced "non-combining" spontaneous recovery occurred, as it did in 20% of cases, globulin as well as specific antibody. The antibodies pro- the beta-2m factor was always present. In eight of the duced by a single might also be heterogeneous, forty known British cases, tuberculin sensitivity and drug different components being directed against different com- allergy were demonstrable, indicating that hypersensiti- bining sites on the antigenic molecule. vity reactions were unaffected by the gamma-globulin Dr. R. R. PORTER (N.I.M.R.) said that the physical hetero- deficiencies. geneity of antibodies was shown up by their particle sizes Dr. R. G. WHITE (London Hospital) described work on and solubilities quite independently of their electric charges; the cells concerned with the synthesis of gamma-globulins if to these three were added the serological variations of and antibodies. By the fluorescent-antibody technique he the antibodies directed against a single antigen, then anti- showed localization of antibody in the nucleus and cyto- bodies could be said to be heterogeneous in four independent plasm of plasma cells, and these cells were histologically physical dimensions. These variations were not, however, similar to other cells secreting proteins. By preparing reflected in their amino-acid composition. Some progress fluorescent antibodies to gamma-globulins in other species had been made with the partial proteolytic digestion of anti- he demonstrated the accumulation of gamma-globulin in bodies with papain: fragments with molecular weights of the cytoplasm of some plasma cells. Immature cells showed between 40,000 and 50,000 might retain their specific com- the greatest antibody content, and the appearance of bining power. Still further evidence of heterogeneity was Russell's bodies might mark the end of the antibody-form- brought forward by Dr. A. S. McFARLANE (N.I.M.R.). ing response. It appeared from this and other evidence Labelled proteins belonging to a single molecular species that individual plasma cells responded to a single antigenic