33

vening emphysema. The appearance may become morefinely reticular after several months. Evidence of

pulmonary fibrosis and emphysema has persisted for aslong as five years after the original illness. 5 Commonlate symptoms include recurrent bronchospasm andrespiratory infection.

Respirator therapy and inspired oxygen concentra-tions of 80-100% were common to all cases of

pulmonary fibroplasia so far described. Those in whicha negative-pressure respirator was used 5 are of particularinterest in that physical trauma from positive pressure,prolonged intubation, or unsatisfactory humidificationseems to be excluded. Pulmonary fibroplasia after

respirator therapy has been described only in conditionsin which high concentrations of inspired oxygen weregiven continuously for at least two or three days. Muchcircumstantial evidence incriminates oxygen toxicity,apart from the obvious analogy to its action in retrolentalfibroplasia. Pure oxygen has been shown to damage thelungs of many animals,8 typically resulting in congestion,alveolar exudation, hxmorrhage, and even hyalinemembranes.9 9 The effects of breathing pure oxygenmay be due to pulmonary irritation, absorption collapse,or reduction of surfactant. The presence of surfactantwas inferred from the finding of low surface tensions oflung extracts from five infants in whom increasingpressures were required to inflate the lungs, which latershowed the typical fibrous changes.4 Apparently theeffect of oxygen toxicity on the respiratory tract is notmediated through surfactant but by some other directeffect. Pulmonary fibroplasia has been demonstrated inadult patients who died after prolonged mechanicalventilation with high inspired-oxygen concentrations.10Under normal working conditions, the " air-mix " con-trol of pressure-cycled ventilators is unsatisfactory,delivering over 90% oxygen, instead of the 5b-60%stated by the makers.1O Accurate control of the oxygenconcentration is usually no problem with volume-cycledrespirators, since the incoming gases can be passedthrough flow-meters; and the " respirator lung syn-drome " has not been seen in 90 newborn infants treated

by prolonged intermittent positive pressure from a

volume-cycled respirator.llThe findings in both adults and infants strongly indi-

cate that long exposure to over 80% oxygen is associatedwith pulmonary fibroplasia. Clearly, the most urgentneed is to modify pressure-cycled respirators such asthe Bird VIII, so that the inspired-oxygen concentrationmay be varied accurately and reliably from 21% to 80%.An accessory flow cartridge is already available, but itrequires a source of air under pressure and is not entirelysatisfactory. A simple solution is to use cylinders ofknown oxygen concentrations, but the storage of anadequate range and quantity of cylinders is unpractical.Cylinders of air and 100% oxygen joined by a manifold8. Binger, C. A. L., Faulkner, J. M., Moore, R. L. J. exp. Med. 1927,

45, 849.9. Bruns, P. D., Shields, L. V. Am. J. Obstet. Gynec. 1954, 67, 1224.

10. Nash, G., Blennerhassett, J. B., Pontoppidan, H. New Engl. J. Med.1967, 276, 368.

11. Tunstall, M. E., Cater, J. I., Thomson, J. S., Mitchell, R. G. ArchsDis. Childh. 1968, 43, 486.

will eventually equilibrate at a concentration of 60%,but the method does not allow variable concentrations

throughout the full range. It may well be that the most

acceptable and least costly solution will be that describedon p. 28 by Dr. NEWMAN and Dr. EVANS, who use anair-compression pump to the intake of which known andvarying amounts of oxygen can readily be added.

Renal TransplantationKIDNEY transplantation has advanced well beyond the

experimental stage when the operation was performedonly by a few units. Many surgical departments whichhave not hitherto undertaken renal transplantation areeither starting now or plan to do so soon. The experienceof pioneer units is therefore particularly valuable at thismoment, not only to future transplantation surgeons butalso to anyone responsible for the care of patients withprogressive renal disease; and results in two such unitsare recorded on earlier pages of this issue by ProfessorWOODRUFF and his colleagues in Edinburgh and by thegroup at St. Mary’s Hospital, London.

Several important facts are evident from these papersand from data collected by the Human Kidney Trans-plant Registry. Firstly, the survival-rates of grafts fromdonors unrelated to the patient are improving. MURRAYand BARNES 1 cite-transplant survival rates of 38% atone year and 29% at two years for kidneys taken fromcadaver donors, if the graft site was irradiated as part ofthe immunosuppressive regimen. These figures are fortransplants reported before January, 1967. The mostrecent figures of the St. Mary’s group, although notstrictly comparable for time, show that, of 21 patientsgiven a transplant in the past twelve months, 2 have died.Of the factors contributing to this improvement,adequate preoperative dialysis is one of the most impor-tant. In WooDRUFF’s experience, all patients whosurvived more than a year were in reasonable conditionbefore operation: the blood-urea levels of these patientsvaried between 30 mg. and 130 mg. per 100 ml. Active

urinary-tract infection, with or without severe uraemia,seriously increased the risk of postoperative death. TheSt. Mary’s team also found that time spent on pre-operative dialysis increased survival-rates. The averagetime spent on preoperative peritoneal dialysis of theirsurviving patients was 110 days, compared with 76 daysfor patients who died after transplantation. These figuresemphasise dramatically how important it is to ensurethat patients are carefully prepared for operation.The two articles confirm the experience of other

centres 2 that infections and sepsis are the commonestcause of death or transplant failure. If complicatinginfections are to be reduced, immunosuppression mustbe cut. And if immunological rejection of the transplantis to be averted when immunosuppressive treatment isreduced, the grafting of severely incompatible kidneys1. Murray, J. E., Barnes, B. A. in Human Transplantation (edited by F. T.

Rapaport and J. Dausset); p. 45. New York, 1968.2. Hume, D. M. ibid. p. 110.

34

must be avoided. At present two antigen systems areknown to influence graft compatibility in man-theABO and HL-A systems. Matching graft donor andrecipient for ABO-system antigens presents no seriousdifficulty and is generally practised. Prospective match-ing for HL-A compatibility does present difficulties andis certainly not yet in general use. Many of the diffi-culties of matching for HL-A antigens are obvious;shortage of people able to carry out the tests and theyinclude lack of necessary serological reagents. Because ofthe extreme complexity of the antigenic structure of theHL-A system, characterisation of HL-A antisera is alaborious task. In many countries, including the UnitedKingdom, sources of well-characterised sera are beingdeveloped, and this is an urgent task.

Before committing themselves to prospective HL-Amatching, however, transplantation surgeons mayreasonably ask whether the evidence justifies this step.The short answer now is " yes ". Considering thesituation where the donor is a living blood relative,RAPAPORT et al.3 found that 56% of patients receivingHL-A-incompatible kidney grafts had either rejectedsuch grafts or were ranked as being in a poor clinicalgrade at twelve months. The comparable figure forHL-A-compatible grafts was 16%. These figures werecalculated from a total of 50 patients. At twenty-eightmonths, the difference in a group of 37 patients was evenmore striking: 69% of the serologically incompatiblegrafts had either been rejected or were at a late stage inthe rejection process; but only 8% of the serologicallycompatible grafts were in this category, the remaining92% continuing to survive. The same general conclusionhas emerged from other studies.4-6 Since serologicallyincompatible kidneys have a so much poorer prognosis,this evidence must be kept clearly in mind when judgingthe ethical issues associated with the use of a live donor.When cadaver (unrelated) donors are to be used, the

value of ensuring HL-A compatibility has been doubteduntil recently. Evidence is now accumulating that, inthese circumstances also, serologically compatible graftsgive better results. PATEL et al. 7, analysing a series of 104patients who received kidneys from unrelated, and inmost cases cadaver, donors, found that patients withHL-A-compatible grafts were clinically superior andless prone to multiple or severe rejection crises thanpatients who had received incompatible grafts, and, onaverage, they had significantly better creatinine clear-ances. MORRIS et ail. 8, from an analysis of 27 transplants,concluded that the effect of HL-A compatibility wasevident at an early stage after transplantation. Otherworkers have had similar results.

Another particularly important aspect of HL-A3. Rapaport, F. T., Dausset, J., Hamburger, J., Hume, D. M., Kano, K.,

Williams, G. M., Milgrom, F. Ann. Surg. 1967, 166, 596.4. Terasaki, P. I., Vredevoe, D. L., Mickey, M. R. Transplantation, 1967,

5, 1057.5. van Rood, J. J., van Leeuwen, A., Bruning, J. W. J. clin. Path. 1967,

20, 504.6. Payne, R., Perkins, H. A., Najarian, J. S. in Histocompatibility Testing

(edited by E. S. Curtoni, P. L. Mattiuz, and R. M. Tosi); p. 237.Copenhagen, 1967.

7. Patel, R., Mickey, M. R., Terasaki, P. I. New Engl. J. Med. 1968,279, 501.

8. Morris, P. J., Kincaid-Smith, P., Ting, A., Stocker, J. W., Marshall,V. C. Lancet, 1968, ii, 803.

compatibility must be considered. Many prospectiverecipients have been previously sensitised against HL-Aantigens by pregnancies, blood-transfusions, or previousorgan transplantation. Some of these patients havedetectable titres of circulating antibodies. If such

patients are given kidneys bearing the particular antigenswith which their antibodies can combine, graft rejectioncan be immediate 8 lo-a result that is hardly surprisingin view of what is known about second-set responses of

experimental animals to incompatible grafts. One way ofreducing the incidence of immediate graft rejection is totest the sera of prospective recipients against the cells ofany prospective donor-a special kind of cross-match.Patients whose sera do react with the donor’s cells canthen be excluded as recipients in that particular instance.One practical point here is that " typing " laboratoriesshould keep several samples of all prospective recipients’sera taken at different times; and these should include arecent sample, because antibody levels do fluctuate andnew antibodies may develop after a recent transfusion.The problem of dealing with patients who have beenpreviously sensitised against HL-A antigens is likely toincrease as resources for long-term dialysis and trans-plantation increase. Obviously, we should now beginthinking of the best way to avoid sensitising patients.

Because of the evidence which shows that HL-A

compatibility is of clinical importance, because of theantigenic complexity of the HL-A system, and becauseof the shortage of organs for transplantation, the bestclinical results will be obtained either in large surgicalunits or in groups of closely cooperating smaller units.Such units or collaborating groups will be able to

assemble sufficient potential recipients so that the

kidneys which become available for transplantation areefficiently used, and grafting of severely incompatibleorgans is kept to a minimum. The organisation of thesecooperating units will mean much hard work over thenext few years.

Annotations

INFORMATION ABOUT ADVERSE EFFECTSOF DRUGS

PRECISE and practical information about the side-effects of drugs is needed at two points in the doctor-patient transaction: when the decision is made to prescribea drug; and when some unwanted manifestation, possiblyattributable to a drug, appears. At the point of prescribingin this country, information about the most importantadverse effects can usually be obtained from the BritishNational Formulary, Martindale’s Extra Pharmacopaeia,the manufacturer’s literature, and often from Prescribers’journal or Drug and Therapeutics Bulletin. All these textsdeal primarily with therapeutically desired effects, andrarely give much detail on unwanted reactions. Theycan draw attention only to special risks, so that difficulties-can be avoided or minimised.When trouble has arisen, the need for detailed informa-

9. Kissmeyer-Nielsen, F., Peterson, V. P., Olsen, S., Fieldborg, O.Lancet, 1966, i, 662.

10. Terasaki, P. I., Thrasher, D. L., Hauber, T. H. in Advances in Trans-plantation (edited by J. Dausset, J. Hamburger, G. Mathé); p. 225.Copenhagen, 1967.