Dean, Geoffrey

English

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1 Maart 1969 S.A. TYDSKRIF VIR GENEESKUNDE 227A REPORT ON PROPANIDID, AN INTRAVENOUS ANAESTHETIC, INPORPHYRIA VARIEGATA*GEOFFREY DEAN, t M.D., ER.C.P., Eastern Cape Provincial Hospital. WITH THE COOPERATION OF THE ANAESTHETISTOF PORT ELIZABETHThe first account of acute porphyria after taking barbitu-rates was described in 1906 by Dobrschansky.' Since thenbarbiturates, particularly the pentobarbitones, have beenthe commonest drug to cause attacks of acute porphyriain all 3 Mendelian-dominant hepatic porphyrias, inter-mittent acute porphyria, porphyria variegata and copro-porphyria. Acute porphyria may result in the paralysisand death of the patient.Among the South African White population porphyriavariegata is common.' In the adult who has inheritedporphyria variegata there is usually, but not always, ahigh excretion of proto- and coproporphyrin in the stooL'At the Eastern Cape Provincial Hospital before 1959 wewould diagnose, on average, 12 cases of acute porphyriaeach year. Acute attacks of porphyria were so regular anoccurrence and so frequently followed a thiopentoneanaesthetic that it was decided in 1959 to examine thestools of all patients admitted to hospital in Port Elizabethfor excess porphyrin before an intravenous thiopentoneanaesthetic was administered. Following the introductionof routine stool testing, it became possible to estimate theprevalence of porphyria in the White population of theEastern Cape and later in South Africa as a whole. Theprevalence of porphyria variegata in the Eastern Cape is1 in 250 and for the whole of South Africa it is estimatedto be 1 in 400 of the White population. Over 9,000 of theWhite population of South Africa have inherited porphyriavariegata.' It is also fairly common among the Coloured• people of South Africa. I have attended 54 patients whohave developed acute porphyria after" a thiopentone anaes-thetic. although thiopentone was not the only barbiturateused in every case. Thiopentone does not always precipitatean acute attack of porphyria variegata when the disorderhas been inherited. In children and old people acuteattacks are rare, but in adults between the ages of 16 and60 years thiopentone will usually precipitate at least a mildattack of acute porphyria.The routine screening test of the stool for porphyriavariegata is very simple.' A small fragment of stool, suchas can be obtained, if necessary, on the gloved finger onrectal examination, is dissolved in a solvent consisting ofequal parts of amyl alcohol, glacial acetic acid and ether;after the solution has been decanted it is examined inultraviolet light.' In adults with porphyria variegata thereis usually a high excretion of porphyrin in the stool andthe decanted solution will show a brilliant pink fluores-cence in ultraviolet light. CWorophyll will also show apink fluorescence, but when N /1 hydrochloric acid is add-ed to the solution and the mixture is shaken the porphyrinwill settle in the acid solution at the bottom and thechlorophyll will stay in the ether solution at the top. Ifthe diagnosis is in doubt, it can then be confirmed by'Date received: IQ June 1968.tPresent address: Director of Medica-Social Research, 65 Merrion Square,Dublin 2, Ireland.3examination of the urine for porphyrin and by a quanti-tative analysis of the stool porphyrin using the method ofHolti and Rimington.' There are other conditions besidesporphyria variegata which can cause an increase in stoolporphyrin, such as. for instance, carcinoma of thestomach, and therefore not every patient with increasedstool porphyrin has necessarily inherited porphyriavariegata. However, it is usually fairly simple-by repeat-ing the screening examination, carrying out quantitativeanalysis of the stool porphyrin and by obtaining a per-sonal and family history of a sensitive skin on the back ofthe hands or attacks of acute porphyria-to confirm thediagnosis. Porphobilinogen, which can be detected by theWatson-Schwartz test using Ehrlich's aldehyde reagent.will only be positive in porphyria variegata during anacute attack. The Watson-Schwartz test, therefore, cannotbe used for screening for porphyria variegata in thequiescent phase. The urine should also be examined forexcess porphyrin.After the introduction of routine testing for porphyriavariegata before operation in the Eastern Cape, patientswho had positive stools on screening and who mighttherefore have been porphyric were given an alternativeanaesthetic to thiopentone, such as gas, oxygen and ether,although only a proportion of these patients had inheritedporphyria variegata. In the others there was usually onlya slight transient increase in porphyrin or there was pathO-logy in the gastro-intestinal tract.Porphyria occurs relatively frequently in South Africabecause a small nucleus of early settlers have become apeople so that over one-third of South Africa's 31- millionWhite population hold 40 family names which they havederived from 40 original Free BUllghers.' One of the earlyFree Burghers happened by chance to carry the gene forporphyria variegata. Porphyria variegata in South Africahas been traced back to either Gerrit the son of Jan, or hiwife Ariaantje the daughter of Jacob who married at theCape in 1688."Routine testing for porphyria variegata in Port Eliza-beth and in other Eastern Cape towns greatly reduced thenumber of patients who developed acute porphyria eachyear, but nevertheless every year 2 or 3 patients are stillseen with a severe attack of acute porphyria, often aftera thiopentone anaesthetic, because for some reason theroutine test had been neglected or occasionally becausethe increased porphyrin excretion was so slight that it wanot considered likely that the patient had porphyriavariegata. Many thousands of thiopentone anaesthetics aregiven in South Africa each year and the possibility thatthe patient has porphyria variegata has created a mostserious problem for anaesthetists. It is not always easy toobtain a specimen to carry out a routine test beforeoperation, and with a large number of patients theroutine testing does create considerable additional effortfor the hospital staff.228 S.A. MEDICAL JOURNAL 1 March 1969IABLE I. PATlE TS WITH PORPHYRIA VARlEGATA ANAESTHETIZED WITH PROPANIDIDUrine StoolCase PropanididNo. Sex Age (mg.) OperationP.orphobilinogen PorphyrinWatson-Schwartz U VLtest screenCopro- Proto-porphyrin porphyrinUVL !"g./G !"g./G Familyscreen dry wt. dry wt. history Personal histo,¥,500 Abscess jaw350 Dilatation cervix500 Operation on jaw350 Operation on jaw350 Dental extractions400 Draining pilonidal abscess350 Bronchoscopy Ca. lung350 Tonsillectomy350 Hysterectomy350 Vaginal repair350 Dental attention400 Hernia repair250 Antrum wash-out500 Bartholin cyst removed350 Curette cervixStool porphyrin raised. Confirmed byRimington. X-porphyrin 91 /Lg./G.Acute porphyria 1956, thiopentone.Sister had acute porphyria afterthiopentone.Father acute porphyria after thiopen-tone.Father died acute porphyria afterthiopentone.Acute porphyria after thiopentone.Delay in doing Watson-Schwartz test.No ill-effects from anaesthetic.High stool porphyrin 1960.Previous acute porphyria barbiturates"Groote Schuur, 1955. Sister acuteporphyria after thiopentone.Known porphyric.Skin lesions of porphyria when a youngman.No ill-effects from repeated propanididanaesthetic.Acute porphyria after barbiturates.Previous acute porphyria thiopentone(0) 1961, (b) 1964. Mother had acuteporphyria Groote Schuur. Aunt diedacute porphyria Watford Hospital,England, 1962.Acute porphyria 1956 after thiopentone.Skin lesions previously. Now porphyriaquiescent.Acute porphyria(0) 1958(b) One month before propanididboth after barbiturates.Mother died acute porphyria afterthiopentone.Father died acute porphyria afterbarbiturates.Father has had acute porphyria.Previous acute porphyria after barbitu·rates.Sister died acute porphyria afterthiopentone.Previous acute porphyria after thio-pentone. Skin lesions as a youngman. Porphyria now quiescenr.Daughter acute porphyria.Previous acute porphyria after thio·pentone. Paralysed 6 months.Became partly paralysed after pento-barbitone. D & C 1965.++++++++++++++++++++++++++++++++7001863142037022875216817074451378383731140261186557351,134496814243225022348431432953663491929534758222816481+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++Copro.2,959 !"g./litreUro.419 !"g./Iitre+++++like Coca-Cola+++++++++++++++++++++++++++++Uro.53 !"g./litre++++Neg.Neg.Neg.Neg.Neg.Neg.Pos.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.10'1 !"g./litreNeg.Neg.Neg.Neg.Neg.Neg.Neg.Neg.Neg. 10/6/6720·8 !"g./Iitre(Pos. 1/5/67)Liver biopsyAppendicectomyCuretteA bscess in earCuretteDental clearanceCuretteHysterectomyCystoscopyInsenion radium" 2 weeks laterIJ 2 weeks laterCuretteHaemorrhoidectomy6/6/67TonsillectomyRemoval of scarAngiogramLaparotomyDental attentionHaemorrhoidectomyCuretteColporrhaphyRemoval cartilage kn""Resection of polypTympanoplastyCurettageThyroidectomy400400400350300500400500300400400400400300350350300300300 ECT 7/l2/67300 14/12/67300 19/12/67300 21/12/67300 3/1/68300 4/1/68350 Cholecystectomy400 D&C350350350300350400400350350383813273252183931193117444249493436191869155528154144493027MFFFFFFFMFFFFFFFFFFFMFMMMMFFFMMF314IS1610111221201819S6728417251322232426272829303132The range of normal for quantitative porphyrin in stool is taken as coproporphyrin 0-36, protoporphyrin 0-113 !"g./G dry weight. A total porphyrin about 80 /Lg./Gis suspicious of porphyna.1 Maart 1969 S.A. TYDSKRIF VIR GENEESKU TOE 229PROPANIDIDIn the early 1960s a short-acting non-barbiturate intra-venous anaesthetic, Fabantol, was introduced (Epontol inthe United Kingdom-:-generic name propanidid). It is apale yellowish oil, insoluble in water.The usual anaesthetic dose of propanidid for adults is be-tween 5 and 10 mg./kg. of body-weight, given in a 5% solu-tion. It is given at an injection speed of 1 ml./2 seconds andproduces a rapid, smooth anaesthetic induction, conscious-ness being lost after 1 arm-brain circulation time. As withthiopentone, excitatory phenomena are sometimes seen dur-ing induction when atropine only is used as a premedicant,but this is very rare when an opiate premedicant is used.Recovery of consciousness is related to dosage and be-gins 3 - 6 minutes after a single injection and is usuallycomplete within 5 or 10 minutes. After induction withpropanidid it is practical to continue the anaesthetic withgas and oxygen and other anaesthetics. There is a veryrapid recovery time when propanidid is given alone, andthe majority of patients are able to leave hospital within20 minutes of the anaesthetic. Propanidid is therefore ex-cellent for minor operations. It is generally well tolerated,and nausea and vomiting are rare when it is used as thesole anaesthetic agent"·Dowdle studied the effects of the drug on the porphyrinp:oduction of embryo chicks and concluded that the drugdid cause some slight increase in porphyrin production."The Present StudyBecause of the unknown effects of propanidid inpatients with porphyria variegata, it was not possible torecommend that the drug be tried out in an experimentalform. The anaesthetists in Port Elizabeth and Dr A. C.Anderson of Bloemfontein took part in this study by in-forming me when any patient who was suspected to haveporphyria variegata had, at their discretion, been givenpropanidid. These patients were usually studied in hospi-tal after the operation. Their personal and family historywas taken, and they were examined for a sensitive skin onthe back of the hands. Their stools were examined forexcess porphyrin, and when there was any doubt about thediagnosis a quantitative porphyrin analysis was carriedout by the South African Institute for Medical Research.Johannesburg. The urine was examined for porphyrin andporphobilinogen on a number of occasions after theanaesthetic. After full study, about half of the suspectedpatients who had a positive stool test on routine screeningwere found to have inherited porphyria variegata.RESULTSThirty-two patients, 9 men and 23 women, with provedporphyria variegata who had been given 50 propanididanaesthetics, have been studied over a period of a year.Twenty-eight of these patients with porphyria variegatawere given the propanidid anaesthetic in Port Elizabeth(fable I). The other 4 patients were treated in Bloemfon-tein. Only one patient, who was almost certainly in anacute attack at the time of the anaesthetic, had any symp-toms suggestive of acute porphyria after the propanididanaesthetic. They all made uneventful recoveries. In nopatient did the Watson-Schwartz test become positivewhen it was previously negative, and in the case of the4patient with acute porphyria, where the Watson-Schwartztest was positive on the day following the anaesthetic, itbecame negative after a week. Six of the e patients hadsuffe.red from attacks of acute porphyria in the pa t aftera thiopentone anaesthetic, and a further 4 had had acuteporphyria after other barbiturate drugs. Most of thesepatient.s had. relatives who had developed acute porphyriafollowmg thIOpentone or barbiturate drugs.One patient (No. 7) was treated by me for an attack ofacute porphyria only 4 weeks before the propanididanaesthetic. During the acute attack, which followedbarbiturate sleeping tablets, the Watson-Schwartz test wastrongly positive. The patient suffered severe abdominalpain and had attacks of vomiting. Four weeks later, at thetime of the propanidid anaesthetic, the Watson-Schwartztest had become negative. In spite of the recent acute at-tack of porphyria the propanidid caused no flare-up ofporphyric symptoms and the Watson-Schwartz test forporphobilinogen remained negative. Patient No. 8, whoknew she had inherited porphyria, developed abdominalpain after taking barbiturate sleeping tablets. Her doctormade a presumptive diagnosis of acute appendicitis andremoved her appendix, using propanidid to induceanaesthesia. On the following day the Watson-Schwartztest was strongly positive and for a few days the abdomi-nal pain persisted. The appendix appeared to be normal.Over the period of a week the patient made a good re-covery and the Watson-Schwartz test for porphobilinogenbecame negative. In my opinion the patient was in anacute attack of porphyria at the time of operation.SUMMARYA retrospec!ive study of 3~ 'patients with porphyria variegatawho were given 50 propamdld anaesthetics showed no adversereactions to the anaesthetic and in no patient was an attack ofacute porphyria precipitated. Furthermore, acute porphyriaa~er a propanidid anaesthetic has not been reported in PortElizabeth or elsewhere in South Africa.'Yhen propanidid is used as an anaesthetic in porphyriavanegata great care must be taken that no barbiturate sedaliveis given e.it~er pre-operatively or postoperatively.Propamdld appears to be a safe intravenous anaesthetic forpatients who have inherited porphyria variegata.. This study was made possible by the wholehearted coopera-tIOn of the anaesthetists of Port Elizabeth, Drs E. C. Bloch,J. D. Coxon, B. G. Francis, P. B. Hafner, M. J. Louw, W. E.Owens, J. T. Russell, W. G. Staples, M. Towers and A. P. vanWyk, and of Dr A. C. Anderson of Bloemfontein. Quantitativeanalyses of stools were carried out by the SAIMR, Johannes-burg, and my thanks are due to the Director of the InstituteDr J. H. S. Gear of Johannesburg, and also to Dr W. C:Harington, Director, Port Elizabeth, and their staff. In one casethe high stool porphyrin was confirmed by Prof. C. Rimingtonof University College Hospital, London.I sh~uld like to ~hank FBA Pharmaceuticals SA (Pty) Ltdfor the~r expert adVIce about the properties of propanidid andfor theIr support of this project; in particular my thanks aredue to their Medical Director, Dr H. Kraus.REFERENCESI. Dobrschansky. M. (1906): Wien. med. Presse. 47, 2145.2. Dean, J. G. (1953): Brit. Med. J., 2, 1291.3. Idem (1956): S. Afr. Med. J., 30, 37.4. Idem (1960): Ibid., 34, 745.5. Holti, G., RiminglOn, C., Tate, B. C. and Thomas, G. (1958): Quart.J. Med.. 27, I.6. Dean, G. (1963): The Porphyrias: A Story of Inlteritance and En-vironment. London: Pilman.7. Van Wyk, A. P. and Kok. O. V. S. (1966): Med. P,OC., 12, 230.8. Goldman, V. (968): S. Afr. Med. J.• 42. 74.9. Dawdle, E.: Personal communication.

A report on propanidid, an intravenous anaesthetic, in Porphyria variegata

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A report on propanidid, an intravenous anaesthetic, in Porphyria variegata

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