British Journal of Anaesthesia 1991; 66: 60-65
PROPOFOL AS AN I.V. ANAESTHETIC INDUCTION AGENT IN VARIEGATE PORPHYRIA P. N. MEISSNER, G. G. HARRISON AND R. J. HIFT
The choice of an i. v. anaesthetic induction poses problems for the anaesthetist confronted with a patient with one of the acute porphyrias. We undertook a prospective clinical trial in 13 variegate porphyric subjects using propofol as an anaesthetic induction agent. Urinary porphyrin precursors and porphyrins were measured before operation and 1-5 days after operation. Stool and plasma porphyrin concentrations were measured over the same period. Comparison of these data in the porphyric patients and in 21 control subjects over the trial period revealed no significant change in porphyrin or porphyrin precursor output after operation. Urinary porphyrin precursor concentrations did not exceed the limits established for variegate porphyric patients in remission, and there were no changes in the stool and plasma porphyrin profiles or any symptoms of an acute porphyric attack. We conclude that propofol did not appear to be porphyrinogenic when used for the induction of anaesthesia in 13 patients with variegate porphyria. KEY WORDS Anaesthetics, intravenous: propofol.
Complications:
por-
phyria.
The porphyrias are a group of disorders in which there is disturbance of haem biosynthesis, resulting in excessive production of haem pathway intermediates, the porphyrins and their precursors 8-aminolaevulinic acid (ALA) and porphobilinogen (PBG). The underlying abnormality may be hereditary or acquired and reflects a defect of any one of the steps of haem formation (fig. 1) [1]. The clinical features of the porphyrias are two-fold: photocutaneous sensitivity, caused probably by tissue accumulation of the por-
phyrins, and the acute attack [2, 3]. The latter presents with mild to severe abdominal and neuropsychiatric symptoms and may be fatal. Such an attack is often precipitated by drugs. However, patients may develop spontaneous attacks in response to stress, infections, fasting and endogenous hormonal fluctuations [4,5]. Three types of porphyria may exhibit these acute symptoms: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). The acute attack is always associated with increased production and excretion of ALA and PBG [6]. These compounds are strongly implicated, therefore, in the genesis of acute symptoms, although a causal relationship has not been established unequivocally; increased urinary concentrations of ALA and PBG do serve, however, as markers of such an attack. Although not encountered commonly, the porphyrias are of particular importance to the anaesthetist, as anaesthetic agents are among those incriminated most strongly in the precipitation of the acute attack. The i.v. induction agents in particular pose problems. The barbiturates, thiopentone and methohexitone, are extremely dangerous in porphyria [7]. Propanidid was used safely as the standard i.v. induction agent for porphyric patients for more than 25 years. One author has reported an adverse effect on porphyria [8], but propanadid has been withdrawn from use because of a high incidence of anaphylactoid reactions. Althesin, withdrawn from use for the same reason, had been shown in both animal experiments and human subjects to be porphyrinogenic [8, 9]. Testing of etomidate in PETER N . MEISSNER, B.SC.(MED.XHONS), PH.D., RICHARD J. HlFT, M.B., CH.B., M.MED.(MED.), F.C.P.(S.A.) ( M R C / U C T
Liver Research Centre); GAISFORD G. HARRISON, M.D., F.C.ANAES. (Department of Anaesthetics); University of Cape Town Medical School, Observatory 7925, South Africa. Accepted for Publication: July 22, 1990.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
SUMMARY
PROPOFOL AND PORPHYRIA
61 Qlycine
Succinyl CoA
ALA Synthetase 5-Aminolaevulinic acid (ALA)
I
ALA Dehydretese
Porphobilinogen (PBQ) ACUTE INTERMITTENT PORPHYRIA
I
PBG Deamlnase
Hydroxymethylbilane CONGENITAL PORPHYRIA
Uro'gen Cosynthetase
Uro'gen Decarboxytase Coproporphyrirtogen
HEREDITARY COPROPORPHYRIA VARIEGATE PORPHYRIA
I-
_ Copro'gen Oxidase
Protoporphyrinogen
Pro to'gen Oxidase Protoporphyrin
ERYTHROPOIETIC PROTOPORPHYRIA
1
Ferrochelatase (+ Iron)
HAEM
FIG. 1. The haem biosynthetic pathway, showing the enzymatic abnormalities resulting in the various types of porphyria. The three porphyrias which may exhibit acute symptoms are shown within boxes.
study were those with severe underlying disease, an allergy to propofol, previous adverse experience with general anaesthesia, those undergoing operations on bladder or bowel, and those who were pregnant. These exclusion criteria were designed to ensure that there were no circumstances that could have an influence on the measurement of excreted porphyrins or precursors, or on porphyrin metabolism generally. The diagnosis was confirmed in each patient by the demonstration of diagnostic changes in stool, urine and plasma concentrations of porphyrin. A control group was recruited consisting of people without a history of porphyria and in whom porphyrin analysis was normal. All subjects gave written, informed consent. No restrictions were placed on the anaesthetic PATIENTS AND METHODS procedure except that induction should be with We studied porphyric subjects (ASA grades I and propofol and that porphyrinogenic drugs should II j aged 16—65 yr; normal renal function) re- be avoided thereafter. The mean induction dose quiring general anaesthesia for elective surgery of propofol administered to the 13 patients was Therewho presented to the participating anaesthetists 2.45 mg kg"1 (range 1.6-3.33 mg kg->). during a period of 1 year. As far as could be after, 10 received halothane and three enflurane. ascertained, no patient had been exposed to any Atracurium or suxamethonium was used for porphyrinogenic drugs in their recent clinical muscle relaxation and fentanyl, alfentanil and history (past 6 months). Patients excluded from the morphine for analgesia. Patients were observed animal experiments also suggests porphyrinogenicity [10, 11]. Ketamine has shown no evidence of porphyrinogenicity in animal models, even after 6 h of infusion in the diethoxycarbonyldihydrocollidine (DDC)-primed rat model [11], but, even though it possesses excellent analgesic properties, it has other drawbacks which preclude its use as a routine induction agent. Propofol, the most recently introduced i.v. agent, possesses many of the properties which characterize the ideal anaesthetic agent [12] and in addition, porphyrinogenicity could not be demonstrated in a rat model [13]. We report here a prospective controlled trial of propofol as an i.v. anaesthetic induction agent in porphyric subjects.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
Uroporphyrinogen PORPHYRIA CUTANEA TARDA
62
THE BRITISH JOURNAL OF ANAESTHESIA
Subjects
Only patients with VP, the most prevalent form of porphyria in South Africa, presented for surgery during the study period. Thirty-one subjeas believed by their physicians to have VP were enrolled. Twelve were excluded because biochemical evidence of porphyria was lacking or because data were incomplete. A further six were excluded from analysis because, despite an abnormal porphyrin profile, the diagnosis was not established beyond doubt. In most instances this was where the diagnosis rested on a mild increase in faecal excretion of protoporphyrin alone. Thus data were obtained for 13 subjeas with unequivocal VP. These were compared with 21 control subjects.
TABLE I. Urinary ALA, PBG and total porphynn (TP) concentrations (mean (5D))
Group
ALA concn PBG concn TP concn (nmol/10 mmol (uxnol/10 mmol (nmol/10 mmol creatinine) creatinine) creatinine)
Propofol controls (n = 21) Day 0 9.8 (5.8) 5.0 (3.9) Day 1 8.9 (5.2) 5.0 (3.8) Day 3 10.7 (4.6) 3.9 (2.4) Day 5 11.7(2.0) 3.5 (2.3) Propofol VP (n = 13) Day 0 24.1 (12.9) 9.6 (7.4) Day 1 26.8 (15.6) 11.4(10.1) Day 3 21.3(12.4) 6.6 (3.9) Day 5 24.4 (9.6) 9.1 (7.8) Normal ijopulation (n = 97) 14.0(12.7) 5.2 (4.4) Non-acute VP population (n = 228) 29.3 (27.6) 8.1 (23.6)
55. 3(50)
63.8 (40) 56.8 (39) 70. 5(58) 285 371 128 277
(243) (424) (70) (257)
112
(110)
473
(924)
RESULTS
It has been held traditionally that subjects with VP have normal urinary concentrations of ALA and PBG during remission. We have become aware that this is not so. We therefore redefined our normal ranges (mean, 2 SD) separately for a group of 221 subjects with VP known to be free of acute symptoms, and 93 non-porphyric subjects. These data were drawn from results from our laboratory over the past 5 years. The redefined normal ALA and PBG upper limits for VP subjeas free of acute symptoms were 78 and 55 nmol/10 mmol creatinine, respectively. The upper limits for non-porphyric subjects were 40 and 14 umol/10 mmol creatinine, respectively. c 50!
Day 3
Day 5
FIG. 2. Fluctuation of the mean (SD) urinary concentration of ALA for the control ( S ) find porphyric ( • ) groups. Individual values fell within the upper limits of "normal" for each respective group at all times.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
for any clinical symptoms suggestive of the acute attack for up to 5 days after anaesthesia and were asked to report any untoward developments thereafter. Random specimens of urine were obtained before operation (day 0) and on days 1, 3 and 5 after operation. Stool and plasma specimens were obtained also, wherever possible, on the same days. All specimens were protected from light to avoid spontaneous interconversion or photodegradation of the precursors or porphyrins. ALA and PBG were measured by an established ion-exchange technique [14] using test kits (Biorad, Munich, West Germany). Urinary, stool and plasma porphyrins were extracted, esterified, separated by thin-layer chromatography and measured by fluoroscanning, according to established methods [15-17]. Urinary concentrations of precursor and porphyrin were expressed as umol/10 mmol creatinine and nmol/10 mmol creatinine, respectively, to take account of variability in urinary concentration. Changes in concentration of precursor or porphyrin excretion between days 0 and 1, 0 and 3, and 0 and 5 were calculated. Data from each individual patient were examined to assess whether values remained within the range of values for non-acute VP. The significance of any variation in porphyrin, ALA or PBG concentration from day 0 to day 1, 3 or 5 was assessed with Student's t test (two-tailed). Similarly, variations in the VP group were compared with those in the control group, as were changes in the porphyric subjects' urinary concentrations of precursor and porphyrin from day 0 to days 1, 3 and 5 compared with those in the control group.
PROPOFOL AND PORPHYRIA
63
demonstrated by thin-layer chromatography (data not shown). Such a shift would be expected if the pathway were stressed. There were no changes in stool and plasma porphyrin profiles (data not shown). No symptoms suggestive of an acute attack of porphyria were noted in any subject at any stage. DISCUSSION
Day 3
Day 5
FIG. 3. Fluctuation of the mean (SD) urinary concentration of PBG for the control (S) and porphyric ( • ) groups. Individual values fell within the upper limits of "normal" for each respective group at all times.
The mean concentrations of ALA, PBG and porphyrin in the porphyric patients were greater than those in the control group at all times (table I), including day 0 (P < 0.001), but ALA and PBG concentrations did not exceed the limits established for VP patients in remission (figs 2, 3). No significant increase in output of porphyrin or porphyrin precursor over the baseline was found after operation (P>0.1); the porphyric group behaved similarly to the control group in this respect. The mean urinary concentrations of total porphyrin of the porphyric group varied greatly and were greater than those of the control group (fig. 4). Again, the change from day 0 to the postoperative days was not significant. No change in pattern of excretion of urinary porphyrin to the earlier haem pathway intermediates was
Day 0
Day 1
Day 3
Day 5
FIG. 4. Fluctuation of the mean (SD) urinary concentration of total porphyrin (TP) for the control (gj) and porphyric ( • ) groups. The concentrations in the porphyric group are high, indicative of the underlying porphyric status of the VP patients.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
Day 1
To be considered safe for use in the acute porphyrias, ideally a drug should meet the following criteria: first, it should not cause increase in production of porphyrin or porphyrin precursor, and should not induce ALA synthetase or diminish free haem concentrations in laboratory test systems, including various types of cell culture [6, 18-20] and laboratory animals rendered porphyric by the administration of agents such as DDC [6,9,21,22]; second, the drug should be devoid of porphyrinogenic potential in human subjects—its administration should not be followed by symptoms of the acute attack or by a significant increase in excretion of porphyrin and precursor. Such data are usually derived from personal experience, anecdotal evidence or from individual case reports. Few, if any, drugs have had porphyrinogenicity tested prospectively in controlled trials in porphyric patients. Thus doctors must often base their decision to use a particular drug in a porphyric subject on incomplete or possibly inaccurate data. Also, experience in human subjects and laboratory testing sometimes give conflicting results [6, 8, 23]. Propofol has been reported not to induce hepatic ALA synthetase in the rat [13] and therefore, by implication, to be non-porphyrinogenic, but it induces hepatic ALA synthetase in DDC-primed chick embryos [20 and personal communication, Deybach JC]. However, this system is considered by some to be extremely sensitive and may produce seemingly false positive results [6]. There have also been conflicting reports on its safety in humans. In one study, propofol was used to induce anaesthesia in a patient with AIP with apparent safety [24], whereas another case report indicated that urinary concentrations of porphyrin and PBG increased in a VP patient anaesthetized with propofol [25]. However, this patient had been exposed to several anaesthetics over a few days, including an infusion of propofol, and the changes in concentrations of
64
THE BRITISH JOURNAL OF ANAESTHESIA
3. Meissner PN, Meissner DM, Sturrock ED, Davidson B, Kirsch RE. Porphyria—the UCT experience. South African Medical Journal 1987; 72: 755-761. 4. Kappas A, Sassa S, Anderson KE. The Porphyrias. In: Stanbury JB, Wyngaarden JB, Fredirickson DS, eds. The Metabolic Basis of Inherited Disease, 5th Edn. New York: McGraw-Hill, 1983; 1301-1384. 5. Bloomer JR, Straka JG. Porphyrin Metabolism. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobtology, 2nd Edn. New York: Raven Press, 1988; 451-166. 6. Moore MR, McColl KEL, Rimington C, Goldberg A. Disorders of Haem Metabolism. New York and London: Plenum Medical, 1987. 7. Disler PB, Blekkenhorst GH, Eales L, Moore MR, Straughan J. Guidelines for drug prescription in patients with the acute porphyrias. South African Medical Journal 1982; 61: 656-660. 8. Moore MR. Internationa] review of drugs in acute porphyria—1980. International Journal of Biochemistry 1980; 12: 1088-1097. 9. Blekkenhorst GH, Harrison GG, Cooke ES, Eales L. Screening of certain anaesthetic agents for their ability to elicit acute porphyric phases in susceptible patients. British Journal of Anaesthesia 1980; 52: 759-762. 10. Parikh RK, Moore MR. The effect of certain anaesthetic agents on the activity of rat aminolaevulinate synthase. British Journal of Anaesthesia 1978; 50: 1099-1103. 11. Harrison GG, Moore MR, Meissner PN. Porphyrinogenicity of etomidate and ketamine as continuous infusions. British Journal of Anaesthesia 1985; 57: 420-423. 12. Symposium, Multiple Authors. Propofol—A new intravenous anaesthetic. Postgraduate Medical Journal 1985; 61 (Suppl. 3): 1-169. 13. Parikh RK, Moore MR. A comparison of the porphyrinogenicity of di-isopropyl phenol (propofol) and phenobarbitone. Biochemical Society Transactions 1986; 14: 726-727. 14. Davis JR, Andelman SI. Urinary delta-aminolcvulinic acid (ALA) levels in lead poisoning. I. A modified method for the rapid determination of urinary deltaaminolevulinic acid using disposable ion-exchange chromatography columns. Archives of Environmental Health 1967; 15: 53-59. 15. Day RS, Pimstone NR, Eales L. The diagnostic value of blood plasma porphyrin methyl ester profiles produced by quantitative TLC. International Journal of Biochemistry 1978;9: 897-904. 16. Day RS, Salamanca RE De, Eales L. Quantitation of red cell porphyrins by fluorescence scanning after thin layer ACKNOWLEDGEMENTS chromatography. Clinica Chimica Acta 1978; 89: 25-33. We are grateful to Dr S. Becker, Mrs L. van Jaarsveldt, Mrs 17. Moore MR. Laboratory investigation of disturbances of porphyrin metabolism. Association of Clinical Pathologists P. van Wyk, Mrs G. Francis and to Stuart Pharmaceuticals Broadsheet. London: British Medical Association, 1983; for their advice and assistance. 109. 18. Zimmer S, Taub H, Marks GS. A comparison of the porphyrin-induced activity of barbiturates and REFERENCES benzodiazepines in chick embryo liver cells. Canadian 1. Elder GH. Enzymatic defects in porphyria: An overview. Journal of Physiology and Pharmacology 1980; 58: Seminars in Liver Disease 1982; 2: 87-99. 991-995. 2. Eales L, Day RS, Blekkenhorst GH. The clinical and 19. Shedlofsky SI, Bonkowsky HL. Seizure management in biochemical features of variegate porphyria: An analysis the hepatic porphyrias: Results from a cell culture model of 300 cases studied at Groote Schuur Hospital, Cape of porphyria. Neurology 1984; 34: 399-406. Town. International Journal of Biochemistry 1980; 12: 20. Deybach JC, Da Silva V, Phung NL, Levy JC, Nordmann 837-853. Y. Drug risk in hepatic porphyrias: Rapid screening test
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
porphyrin and PBG were unconvincing [26, 27]. The patient did not experience acute symptoms. This study represents a clinical trial undertaken to assess the safety of propofol for the induction of anaesthesia in patients with an acute porphyria. The lack of significant increase in concentrations of ALA and PBG following administration of propofol suggests that the drug has low porphyrinogenic potential in porphyric subjects, at least when used in the dose and manner reported here. This is supported further by failure to alter the urinary, stool and plasma profiles of porphyrin either quantitatively or qualitatively. No symptoms suggestive of the acute attack were noted. We conclude, therefore, that propofol, as used for the induction of anaesthesia in 13 patients with VP, did not appear to be porphyrinogenic. However, the number of patients studied was small and the disease is unpredictable, so care should always be taken when using any drug in porphyria. We cannot extrapolate our findings to the use of propofol for maintenance of general anaesthesia by continuous infusion until further clinical experience has been obtained. In the light of the case report referred to above [25], we suggest that caution be exercised with propofol for this purpose. Comment is necessary on the choice of halothane for maintenance of anaesthesia in. this study. Two reports and some experimental data warn of its risk in porphyric patients [7, 20, 28], but this conflicts with other experimental data [10] and much clinical experience accumulated by our and other units, where it has been used safely in porphyric patients on numerous occasions. As 10 of our patients received halothane, this study presents substantial evidence that halothane, in addition to propofol, may be used safely in the acute porphyrias.
PROPOFOL AND PORPHYRIA of drug porphyrinogenicity. Bollcltino dell'Istituto Dermatologtco S. Gallicano 1986-87; 13: 131-140. 21. Yoda B, Schactcr BA, Israels LG. Induction of deltaaminolaevulinic acid synthetase in the kidney of chicks treated with porphyrinogenic drugs. Biochirmca et Biophysica Acta 1974; 372: 478-^81. 22. Blekkenhorst GH, Cook ES, Eales L. Effect of simultaneous treatment of rats with DDC and various drugs on hepatic 5-aminolaevulinate synthasc. Lancet 1980; 1: 1376. 23. Moore MR, Disler PB. Drug induction of the acute porphyrias. Adverse Drug Reaction—Acute Poison Review
1983;2: 149-189. 24. Mitterschiffthaler G, Theiner A, Hetzcl H, Fuith LC.
65
25. 26. 27. 28.
Safe use of propofol in a patient with acute intermittent porphyria. British Journal of Anaesthesia 1988; 60: 109-111. Weir PM, Hodkinson B. Propofol in patients with porphyria. Anaesthesia 1988; 43: 1023-1024. McNeill MJ, Parikh RK, Moore MR. Propofol in acute porphyria. Anaesthesia 1989; 44: 532. Meissner PN, Harrison GG, Hift RJ. Propofol and porphyria. Anaesthesia 1989; 44: 612-613. Wettcrberg L. Report on an international survey of safe and unsafe drugs in acute intermittent porphyria. In: Doss M, Nawrocki P, eds. Porphyrins in Human Diseases—Report on the Discussions. Freiburg: Falk, 1976:
191-202. Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
PROPOFOL AS AN I.V. ANAESTHETIC INDUCTION AGENT IN VARIEGATE PORPHYRIA P. N. MEISSNER, G. G. HARRISON AND R. J. HIFT
The choice of an i. v. anaesthetic induction poses problems for the anaesthetist confronted with a patient with one of the acute porphyrias. We undertook a prospective clinical trial in 13 variegate porphyric subjects using propofol as an anaesthetic induction agent. Urinary porphyrin precursors and porphyrins were measured before operation and 1-5 days after operation. Stool and plasma porphyrin concentrations were measured over the same period. Comparison of these data in the porphyric patients and in 21 control subjects over the trial period revealed no significant change in porphyrin or porphyrin precursor output after operation. Urinary porphyrin precursor concentrations did not exceed the limits established for variegate porphyric patients in remission, and there were no changes in the stool and plasma porphyrin profiles or any symptoms of an acute porphyric attack. We conclude that propofol did not appear to be porphyrinogenic when used for the induction of anaesthesia in 13 patients with variegate porphyria. KEY WORDS Anaesthetics, intravenous: propofol.
Complications:
por-
phyria.
The porphyrias are a group of disorders in which there is disturbance of haem biosynthesis, resulting in excessive production of haem pathway intermediates, the porphyrins and their precursors 8-aminolaevulinic acid (ALA) and porphobilinogen (PBG). The underlying abnormality may be hereditary or acquired and reflects a defect of any one of the steps of haem formation (fig. 1) [1]. The clinical features of the porphyrias are two-fold: photocutaneous sensitivity, caused probably by tissue accumulation of the por-
phyrins, and the acute attack [2, 3]. The latter presents with mild to severe abdominal and neuropsychiatric symptoms and may be fatal. Such an attack is often precipitated by drugs. However, patients may develop spontaneous attacks in response to stress, infections, fasting and endogenous hormonal fluctuations [4,5]. Three types of porphyria may exhibit these acute symptoms: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). The acute attack is always associated with increased production and excretion of ALA and PBG [6]. These compounds are strongly implicated, therefore, in the genesis of acute symptoms, although a causal relationship has not been established unequivocally; increased urinary concentrations of ALA and PBG do serve, however, as markers of such an attack. Although not encountered commonly, the porphyrias are of particular importance to the anaesthetist, as anaesthetic agents are among those incriminated most strongly in the precipitation of the acute attack. The i.v. induction agents in particular pose problems. The barbiturates, thiopentone and methohexitone, are extremely dangerous in porphyria [7]. Propanidid was used safely as the standard i.v. induction agent for porphyric patients for more than 25 years. One author has reported an adverse effect on porphyria [8], but propanadid has been withdrawn from use because of a high incidence of anaphylactoid reactions. Althesin, withdrawn from use for the same reason, had been shown in both animal experiments and human subjects to be porphyrinogenic [8, 9]. Testing of etomidate in PETER N . MEISSNER, B.SC.(MED.XHONS), PH.D., RICHARD J. HlFT, M.B., CH.B., M.MED.(MED.), F.C.P.(S.A.) ( M R C / U C T
Liver Research Centre); GAISFORD G. HARRISON, M.D., F.C.ANAES. (Department of Anaesthetics); University of Cape Town Medical School, Observatory 7925, South Africa. Accepted for Publication: July 22, 1990.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
SUMMARY
PROPOFOL AND PORPHYRIA
61 Qlycine
Succinyl CoA
ALA Synthetase 5-Aminolaevulinic acid (ALA)
I
ALA Dehydretese
Porphobilinogen (PBQ) ACUTE INTERMITTENT PORPHYRIA
I
PBG Deamlnase
Hydroxymethylbilane CONGENITAL PORPHYRIA
Uro'gen Cosynthetase
Uro'gen Decarboxytase Coproporphyrirtogen
HEREDITARY COPROPORPHYRIA VARIEGATE PORPHYRIA
I-
_ Copro'gen Oxidase
Protoporphyrinogen
Pro to'gen Oxidase Protoporphyrin
ERYTHROPOIETIC PROTOPORPHYRIA
1
Ferrochelatase (+ Iron)
HAEM
FIG. 1. The haem biosynthetic pathway, showing the enzymatic abnormalities resulting in the various types of porphyria. The three porphyrias which may exhibit acute symptoms are shown within boxes.
study were those with severe underlying disease, an allergy to propofol, previous adverse experience with general anaesthesia, those undergoing operations on bladder or bowel, and those who were pregnant. These exclusion criteria were designed to ensure that there were no circumstances that could have an influence on the measurement of excreted porphyrins or precursors, or on porphyrin metabolism generally. The diagnosis was confirmed in each patient by the demonstration of diagnostic changes in stool, urine and plasma concentrations of porphyrin. A control group was recruited consisting of people without a history of porphyria and in whom porphyrin analysis was normal. All subjects gave written, informed consent. No restrictions were placed on the anaesthetic PATIENTS AND METHODS procedure except that induction should be with We studied porphyric subjects (ASA grades I and propofol and that porphyrinogenic drugs should II j aged 16—65 yr; normal renal function) re- be avoided thereafter. The mean induction dose quiring general anaesthesia for elective surgery of propofol administered to the 13 patients was Therewho presented to the participating anaesthetists 2.45 mg kg"1 (range 1.6-3.33 mg kg->). during a period of 1 year. As far as could be after, 10 received halothane and three enflurane. ascertained, no patient had been exposed to any Atracurium or suxamethonium was used for porphyrinogenic drugs in their recent clinical muscle relaxation and fentanyl, alfentanil and history (past 6 months). Patients excluded from the morphine for analgesia. Patients were observed animal experiments also suggests porphyrinogenicity [10, 11]. Ketamine has shown no evidence of porphyrinogenicity in animal models, even after 6 h of infusion in the diethoxycarbonyldihydrocollidine (DDC)-primed rat model [11], but, even though it possesses excellent analgesic properties, it has other drawbacks which preclude its use as a routine induction agent. Propofol, the most recently introduced i.v. agent, possesses many of the properties which characterize the ideal anaesthetic agent [12] and in addition, porphyrinogenicity could not be demonstrated in a rat model [13]. We report here a prospective controlled trial of propofol as an i.v. anaesthetic induction agent in porphyric subjects.
Downloaded from http://bja.oxfordjournals.org/ at University of Saskatchewan on March 16, 2015
Uroporphyrinogen PORPHYRIA CUTANEA TARDA
62
THE BRITISH JOURNAL OF ANAESTHESIA
Subjects
Only patients with VP, the most prevalent form of porphyria in South Africa, presented for surgery during the study period. Thirty-one subjeas believed by their physicians to have VP were enrolled. Twelve were excluded because biochemical evidence of porphyria was lacking or because data were incomplete. A further six were excluded from analysis because, despite an abnormal porphyrin profile, the diagnosis was not established beyond doubt. In most instances this was where the diagnosis rested on a mild increase in faecal excretion of protoporphyrin alone. Thus data were obtained for 13 subjeas with unequivocal VP. These were compared with 21 control subjects.
TABLE I. Urinary ALA, PBG and total porphynn (TP) concentrations (mean (5D))
Group
ALA concn PBG concn TP concn (nmol/10 mmol (uxnol/10 mmol (nmol/10 mmol creatinine) creatinine) creatinine)
Propofol controls (n = 21) Day 0 9.8 (5.8) 5.0 (3.9) Day 1 8.9 (5.2) 5.0 (3.8) Day 3 10.7 (4.6) 3.9 (2.4) Day 5 11.7(2.0) 3.5 (2.3) Propofol VP (n = 13) Day 0 24.1 (12.9) 9.6 (7.4) Day 1 26.8 (15.6) 11.4(10.1) Day 3 21.3(12.4) 6.6 (3.9) Day 5 24.4 (9.6) 9.1 (7.8) Normal ijopulation (n = 97) 14.0(12.7) 5.2 (4.4) Non-acute VP population (n = 228) 29.3 (27.6) 8.1 (23.6)
55. 3(50)
63.8 (40) 56.8 (39) 70. 5(58) 285 371 128 277
(243) (424) (70) (257)
112
(110)
473
(924)
RESULTS
It has been held traditionally that subjects with VP have normal urinary concentrations of ALA and PBG during remission. We have become aware that this is not so. We therefore redefined our normal ranges (mean, 2 SD) separately for a group of 221 subjects with VP known to be free of acute symptoms, and 93 non-porphyric subjects. These data were drawn from results from our laboratory over the past 5 years. The redefined normal ALA and PBG upper limits for VP subjeas free of acute symptoms were 78 and 55 nmol/10 mmol creatinine, respectively. The upper limits for non-porphyric subjects were 40 and 14 umol/10 mmol creatinine, respectively. c 50!
Day 3
Day 5
FIG. 2. Fluctuation of the mean (SD) urinary concentration of ALA for the control ( S ) find porphyric ( • ) groups. Individual values fell within the upper limits of "normal" for each respective group at all times.
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for any clinical symptoms suggestive of the acute attack for up to 5 days after anaesthesia and were asked to report any untoward developments thereafter. Random specimens of urine were obtained before operation (day 0) and on days 1, 3 and 5 after operation. Stool and plasma specimens were obtained also, wherever possible, on the same days. All specimens were protected from light to avoid spontaneous interconversion or photodegradation of the precursors or porphyrins. ALA and PBG were measured by an established ion-exchange technique [14] using test kits (Biorad, Munich, West Germany). Urinary, stool and plasma porphyrins were extracted, esterified, separated by thin-layer chromatography and measured by fluoroscanning, according to established methods [15-17]. Urinary concentrations of precursor and porphyrin were expressed as umol/10 mmol creatinine and nmol/10 mmol creatinine, respectively, to take account of variability in urinary concentration. Changes in concentration of precursor or porphyrin excretion between days 0 and 1, 0 and 3, and 0 and 5 were calculated. Data from each individual patient were examined to assess whether values remained within the range of values for non-acute VP. The significance of any variation in porphyrin, ALA or PBG concentration from day 0 to day 1, 3 or 5 was assessed with Student's t test (two-tailed). Similarly, variations in the VP group were compared with those in the control group, as were changes in the porphyric subjects' urinary concentrations of precursor and porphyrin from day 0 to days 1, 3 and 5 compared with those in the control group.
PROPOFOL AND PORPHYRIA
63
demonstrated by thin-layer chromatography (data not shown). Such a shift would be expected if the pathway were stressed. There were no changes in stool and plasma porphyrin profiles (data not shown). No symptoms suggestive of an acute attack of porphyria were noted in any subject at any stage. DISCUSSION
Day 3
Day 5
FIG. 3. Fluctuation of the mean (SD) urinary concentration of PBG for the control (S) and porphyric ( • ) groups. Individual values fell within the upper limits of "normal" for each respective group at all times.
The mean concentrations of ALA, PBG and porphyrin in the porphyric patients were greater than those in the control group at all times (table I), including day 0 (P < 0.001), but ALA and PBG concentrations did not exceed the limits established for VP patients in remission (figs 2, 3). No significant increase in output of porphyrin or porphyrin precursor over the baseline was found after operation (P>0.1); the porphyric group behaved similarly to the control group in this respect. The mean urinary concentrations of total porphyrin of the porphyric group varied greatly and were greater than those of the control group (fig. 4). Again, the change from day 0 to the postoperative days was not significant. No change in pattern of excretion of urinary porphyrin to the earlier haem pathway intermediates was
Day 0
Day 1
Day 3
Day 5
FIG. 4. Fluctuation of the mean (SD) urinary concentration of total porphyrin (TP) for the control (gj) and porphyric ( • ) groups. The concentrations in the porphyric group are high, indicative of the underlying porphyric status of the VP patients.
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Day 1
To be considered safe for use in the acute porphyrias, ideally a drug should meet the following criteria: first, it should not cause increase in production of porphyrin or porphyrin precursor, and should not induce ALA synthetase or diminish free haem concentrations in laboratory test systems, including various types of cell culture [6, 18-20] and laboratory animals rendered porphyric by the administration of agents such as DDC [6,9,21,22]; second, the drug should be devoid of porphyrinogenic potential in human subjects—its administration should not be followed by symptoms of the acute attack or by a significant increase in excretion of porphyrin and precursor. Such data are usually derived from personal experience, anecdotal evidence or from individual case reports. Few, if any, drugs have had porphyrinogenicity tested prospectively in controlled trials in porphyric patients. Thus doctors must often base their decision to use a particular drug in a porphyric subject on incomplete or possibly inaccurate data. Also, experience in human subjects and laboratory testing sometimes give conflicting results [6, 8, 23]. Propofol has been reported not to induce hepatic ALA synthetase in the rat [13] and therefore, by implication, to be non-porphyrinogenic, but it induces hepatic ALA synthetase in DDC-primed chick embryos [20 and personal communication, Deybach JC]. However, this system is considered by some to be extremely sensitive and may produce seemingly false positive results [6]. There have also been conflicting reports on its safety in humans. In one study, propofol was used to induce anaesthesia in a patient with AIP with apparent safety [24], whereas another case report indicated that urinary concentrations of porphyrin and PBG increased in a VP patient anaesthetized with propofol [25]. However, this patient had been exposed to several anaesthetics over a few days, including an infusion of propofol, and the changes in concentrations of
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THE BRITISH JOURNAL OF ANAESTHESIA
3. Meissner PN, Meissner DM, Sturrock ED, Davidson B, Kirsch RE. Porphyria—the UCT experience. South African Medical Journal 1987; 72: 755-761. 4. Kappas A, Sassa S, Anderson KE. The Porphyrias. In: Stanbury JB, Wyngaarden JB, Fredirickson DS, eds. The Metabolic Basis of Inherited Disease, 5th Edn. New York: McGraw-Hill, 1983; 1301-1384. 5. Bloomer JR, Straka JG. Porphyrin Metabolism. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobtology, 2nd Edn. New York: Raven Press, 1988; 451-166. 6. Moore MR, McColl KEL, Rimington C, Goldberg A. Disorders of Haem Metabolism. New York and London: Plenum Medical, 1987. 7. Disler PB, Blekkenhorst GH, Eales L, Moore MR, Straughan J. Guidelines for drug prescription in patients with the acute porphyrias. South African Medical Journal 1982; 61: 656-660. 8. Moore MR. Internationa] review of drugs in acute porphyria—1980. International Journal of Biochemistry 1980; 12: 1088-1097. 9. Blekkenhorst GH, Harrison GG, Cooke ES, Eales L. Screening of certain anaesthetic agents for their ability to elicit acute porphyric phases in susceptible patients. British Journal of Anaesthesia 1980; 52: 759-762. 10. Parikh RK, Moore MR. The effect of certain anaesthetic agents on the activity of rat aminolaevulinate synthase. British Journal of Anaesthesia 1978; 50: 1099-1103. 11. Harrison GG, Moore MR, Meissner PN. Porphyrinogenicity of etomidate and ketamine as continuous infusions. British Journal of Anaesthesia 1985; 57: 420-423. 12. Symposium, Multiple Authors. Propofol—A new intravenous anaesthetic. Postgraduate Medical Journal 1985; 61 (Suppl. 3): 1-169. 13. Parikh RK, Moore MR. A comparison of the porphyrinogenicity of di-isopropyl phenol (propofol) and phenobarbitone. Biochemical Society Transactions 1986; 14: 726-727. 14. Davis JR, Andelman SI. Urinary delta-aminolcvulinic acid (ALA) levels in lead poisoning. I. A modified method for the rapid determination of urinary deltaaminolevulinic acid using disposable ion-exchange chromatography columns. Archives of Environmental Health 1967; 15: 53-59. 15. Day RS, Pimstone NR, Eales L. The diagnostic value of blood plasma porphyrin methyl ester profiles produced by quantitative TLC. International Journal of Biochemistry 1978;9: 897-904. 16. Day RS, Salamanca RE De, Eales L. Quantitation of red cell porphyrins by fluorescence scanning after thin layer ACKNOWLEDGEMENTS chromatography. Clinica Chimica Acta 1978; 89: 25-33. We are grateful to Dr S. Becker, Mrs L. van Jaarsveldt, Mrs 17. Moore MR. Laboratory investigation of disturbances of porphyrin metabolism. Association of Clinical Pathologists P. van Wyk, Mrs G. Francis and to Stuart Pharmaceuticals Broadsheet. London: British Medical Association, 1983; for their advice and assistance. 109. 18. Zimmer S, Taub H, Marks GS. A comparison of the porphyrin-induced activity of barbiturates and REFERENCES benzodiazepines in chick embryo liver cells. Canadian 1. Elder GH. Enzymatic defects in porphyria: An overview. Journal of Physiology and Pharmacology 1980; 58: Seminars in Liver Disease 1982; 2: 87-99. 991-995. 2. Eales L, Day RS, Blekkenhorst GH. The clinical and 19. Shedlofsky SI, Bonkowsky HL. Seizure management in biochemical features of variegate porphyria: An analysis the hepatic porphyrias: Results from a cell culture model of 300 cases studied at Groote Schuur Hospital, Cape of porphyria. Neurology 1984; 34: 399-406. Town. International Journal of Biochemistry 1980; 12: 20. Deybach JC, Da Silva V, Phung NL, Levy JC, Nordmann 837-853. Y. Drug risk in hepatic porphyrias: Rapid screening test
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porphyrin and PBG were unconvincing [26, 27]. The patient did not experience acute symptoms. This study represents a clinical trial undertaken to assess the safety of propofol for the induction of anaesthesia in patients with an acute porphyria. The lack of significant increase in concentrations of ALA and PBG following administration of propofol suggests that the drug has low porphyrinogenic potential in porphyric subjects, at least when used in the dose and manner reported here. This is supported further by failure to alter the urinary, stool and plasma profiles of porphyrin either quantitatively or qualitatively. No symptoms suggestive of the acute attack were noted. We conclude, therefore, that propofol, as used for the induction of anaesthesia in 13 patients with VP, did not appear to be porphyrinogenic. However, the number of patients studied was small and the disease is unpredictable, so care should always be taken when using any drug in porphyria. We cannot extrapolate our findings to the use of propofol for maintenance of general anaesthesia by continuous infusion until further clinical experience has been obtained. In the light of the case report referred to above [25], we suggest that caution be exercised with propofol for this purpose. Comment is necessary on the choice of halothane for maintenance of anaesthesia in. this study. Two reports and some experimental data warn of its risk in porphyric patients [7, 20, 28], but this conflicts with other experimental data [10] and much clinical experience accumulated by our and other units, where it has been used safely in porphyric patients on numerous occasions. As 10 of our patients received halothane, this study presents substantial evidence that halothane, in addition to propofol, may be used safely in the acute porphyrias.
PROPOFOL AND PORPHYRIA of drug porphyrinogenicity. Bollcltino dell'Istituto Dermatologtco S. Gallicano 1986-87; 13: 131-140. 21. Yoda B, Schactcr BA, Israels LG. Induction of deltaaminolaevulinic acid synthetase in the kidney of chicks treated with porphyrinogenic drugs. Biochirmca et Biophysica Acta 1974; 372: 478-^81. 22. Blekkenhorst GH, Cook ES, Eales L. Effect of simultaneous treatment of rats with DDC and various drugs on hepatic 5-aminolaevulinate synthasc. Lancet 1980; 1: 1376. 23. Moore MR, Disler PB. Drug induction of the acute porphyrias. Adverse Drug Reaction—Acute Poison Review
1983;2: 149-189. 24. Mitterschiffthaler G, Theiner A, Hetzcl H, Fuith LC.
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25. 26. 27. 28.
Safe use of propofol in a patient with acute intermittent porphyria. British Journal of Anaesthesia 1988; 60: 109-111. Weir PM, Hodkinson B. Propofol in patients with porphyria. Anaesthesia 1988; 43: 1023-1024. McNeill MJ, Parikh RK, Moore MR. Propofol in acute porphyria. Anaesthesia 1989; 44: 532. Meissner PN, Harrison GG, Hift RJ. Propofol and porphyria. Anaesthesia 1989; 44: 612-613. Wettcrberg L. Report on an international survey of safe and unsafe drugs in acute intermittent porphyria. In: Doss M, Nawrocki P, eds. Porphyrins in Human Diseases—Report on the Discussions. Freiburg: Falk, 1976:
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