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Drugs responsible for anaphylactoid reactions in anaesthesia in the United Kingdom
ANAPHYLACTOID RISK IN ANAESTHESIA
(~ Masson, Paris. Ann Fr Anesth Reanim, 12: 105-108, 1993
Drugs responsible for anaphylactoid reactions in anaesthesia in the United Kingdom Medicaments responsables des reactions anaphylactdides en Grande-Bretagne R.S.J. CLARKE *, d. WATKINS ** * Department of Anaesthetics, The Queen's University of Belfast, Whitla Medical Building, 97, Lisburn Road, Belfast BT9 7BL ** Department of Immunology, The Medical School, University of Sheffield, Royal Hallamshire Hospital, Sheffield FIO 2JF
RI~SUMI~: L'incidence des rdactions anaphylactoides peranesthdsiques survenant au Royaume-Uni n'est pas clairement rdpertori6e. Elle a 6t6 appr~cide, dans diff6rentes dtudes, fi 1/10 000 ou 1/500. Le seul service auquel sont rdguli6rement rapport6s des accidents est le Ddpartement d'immunologie de Sheffield : 120 ~ 150 cas y sont ddclar6s chaque annde, ce qui laisse sugg6rer qu'au Royaume-Uni il doit y avoir dix lois plus d'accidents non ddclards. Les dosages de tryptase et mdthylhistamine urinaires sont pratiqu~s h Sheffield et permettent de distinguer les accidents anaphylacto~des des accidents dus h d'autres causes (surdosage ou autres erreurs). Ont ainsi 6t6 ddtaillds les cas recensds depuis 1988, en les classant par grades de gravit6 clinique croissante (grades II fi IV). Le hombre d'accidents est restd constant de 1988 5 1990 mais a diminu6 de 30 % en 1991, peut-~tre en rapport avec la distribution ~ tousles anesthdsistes de recommandations de l'Association des Anesth6sistes Anglais sur la pr6vention et le traitement de ces accidents. Les eurarisants sont en rate des accidents, avec le suxam6thonium dans 45 % des cas, suivi de l'atracurium (16 %), du vdcuronium (12 %), de l'alcuronium (10 %), et du paneuronium (2 %). Quant aux hypnotiques, le thiopental est en cause dans 57 % des cas, le propofol dans 23 % et l'6tomidate dans 4 %. L'hypnotique est toujours associ6 ~, un curare, de sorte que, en l'absence de dosage des anticorps spdcifiques aux mddicaments, il est impossible de savoir si les accidents sont spdcifiquement dus ~ un seul produit ou ~ une association de produits, mettant ainsi en cause le concept d'anesth6sie balanc6e.
INCIDENCE The i m p o r t a n c e of a n a p h y l a c t o i d reactions still remains highly controversial, in the U n i t e d Kingdom ( U K ) at least, a n d m a n y studies of a n a e s t h e tic mortality in the U K do n o t m e n t i o n it [2, 5]. There is always difficulty in o b t a i n i n g reliable d a t a on the progress of such p a t i e n t s b u t of those analysed by LUNN and MUSHIN [5] only 58 could be b l a m e d totally o n the a n a e s t h e t i c a n d of these, few were a t t r i b u t e d to any p h a r m a c o l o g i c a l cause. Part of the difficulty is p r o b a b l y that o v e r d o s e leading to h y p o t e n s i o n can be disguised by inaccurate reporting. A n o t h e r p r o b l e m is that assessors who do n o t believe in a n a p h y l a c t o i d b r o n c h o s p a s m could a t t r i b u t e such cases as due to o e s o p h a g e a l
Presented at the meeting ,, New Trends in Anaphylactoid Risk in Anaesthesia ,,. Nancy (France), ll-12 June 1992.
i n t u b a t i o n (table I). It m u s t be said that the authors in these a n d e v e n m o r e recent studies in the U K are n o t p r i m a r i l y trying to elucidate the cause of d e a t h b u t r a t h e r to look at the quality of anaesthesia. It does seem, however, that an i m p o r t a n t factor is o v e r l o o k e d in such analyses. There are a p p r o x i m a t e l y 3,500,000 g e n e r a l anaesthetics given a n n u a l l y in the U n i t e d Kingdom. T h e f r e q u e n c y of severe r e a c t i o n is u n c e r t a i n but it p r e s u m a b l y lies b e t w e e n a figure of approximately 1 in 10,000 [3] and 1 in 500 [8] which w o u l d m e a n a p p r o x i m a t e l y 350 to 5,000 cases per year in the U K . LAXENAIRE et al. [4] give a rate of 1 in 1,500 for F r a n c e . W h a t is certain is that the only service in the U K which brings t o g e t h e r reports of such clinical m i s h a p s is that in Sheffield
Tires a part : R.S.J. Clarke.
106
R.S.J. CLARKE, J. WATKINS
which has 120-150 reports yearly. Analysis of these would exclude some as being not drug-related or due to drug overdose but only tryptase testing and urinary methylhistamine estimation [9] can clearly and positively distinguish those mishaps not due to drug hypersensitivity. Since many of these are avoidable and are possibly the fault of the anaesthetist, it is important to establish the exact problem at the outset. For statistical purposes it is essential also to grade reactions [6] and the classification in table II is useful [5]. Immunologists will argue about details but this is a clinical classification based on the anaesthetist's description.
Table I. - - Assessment of possible pharmacological causes in 58 deaths totally due to anaesthesia in UK in the year 19791980 [51.
Cases Accidental hypotension Overdose of premedication Malignant hyperthermia Induced hypotension Recurarisation ? Oesophageal intubation
10 6 3 2 2 3
Table II. - - Classification of hypersensitivity (histaminoid) reactions by severity (not all features are present in every case).
Classification I. Cutaneous II. Systemic
Clinical features
Flushing Marked flush Hypotension 20-40 Slight bronchospasm III. Life threatening Marked flush Hypotension 40-70 Severe bronchospasm IV. Potentially fatal Marked flush Hypotension > 70 Severe bronchospasm
hypotension (involving a systolic pressure below 50 mmHg <
Table III. - - Analysis of reports of reactions to anaesthetic drugs (including plasma expanders) of grade II to IV, sent to the Immunology Laboratory in Sheffield during 1988-end of March 1992.
Typical plasma histaminelevels (ng- ml-I) 0-1 1-10 10-100 > 100
1988
1989
1990
1991
1992 (3 months)
Total reports Exclusionson basis of history Grade II Grade 11I Grade IV
143
165
175
109
23
30 25 33 55
25 32 35 73
30 35 40 70
1l 20 32 46
2 6 7 8
Grades II-IV
113
144
145
98
21
CAUSATION
On this basis the anaesthetic history in the reports of reactions sent to the Department of Immunology, Hallamshire Hospital, Sheffield in the years from 1988 to 1992 has been analysed (table III). Previous years had also involved 120150 reports per year and there is no reason to assume major fluctuations in incidence from year to year. Reactions which appeared not to be drugrelated or those occurring after the anaesthetic was over and of doubtful causation have been excluded. In 1988, for instance the grade 1V group included 5 deaths and 14 cases in which the operation was postponed. The remainder had flushing,
M u s c l e relaxants
The figures from the study by LUNN and MUSHIN [5] of usage in 1979 show that in the patients whose deaths were totally related to the anaesthetic, muscle relaxants were used in 90 % and suxamethonium most commonly (table IV). This of course is partly related to the fact that suxamethonium is used in the majority of ill patients having emergency surgery. The distribution of non-depolarising relaxants probably reflects usage at that time.
ANAPHYLACTOID REACTIONS IN THE UNITED KINGDOM
Table IV. - - Percentage usage of muscle relaxants in reported deaths in the UK [5] (many patients had more than one drug).
Suxamethonium Pancuronium Alcuronium Tubocurarine Gallamine Others None
58 43 16 8 4 1 10
Figures for the frequency of appearance of these drugs in reports of reactions during 1984-1986 [7] show that suxamethonium was involved in nearly 50 % which is certainly higher than its general overall usage. Similarly, in the individual nondepolarising relaxants, alcuronium has a much higher place and pancuronium a lower place than their national usage (table V).
Table V. - - Percentage usage of muscle relaxants in reported reactions in the UK involving these drugs [7].
Suxamethonium Alcuronium Atracurium Tubocurarine Vecuronium Pancuronium
50 22 12 6 6 3
Table VI. - - Usage of muscle relaxants in the grade II-IV reactions reported to Sheffield 1988-1992.
1992 Total Percen1988 1989 1990 1991 (3 months) tage 145 73
alcuronium in reports is at last declining, not because it is becoming safer but because it is being replaced by the newer atracurium and vecuronium. It is perhaps surprising that tubocurarine, the most m a r k e d histamine-liberator, is still used at all a n d pancuronium is lowest of this group in reaction-liability. Gallamine, for no very scientific reason, continues to be preferred by some anaesthetists before giving suxamethonium to reduce the likelihood of muscle pains. Induction a g e n t s
Figures for reaction reports to Sheffield, 19881992, classified recording to the induction agent are given in table V I I and the decline of reports following thiopentone and the rise of those following propofol is notable. This reflects the increased usage of propofol but it also shows that propofot is unlikely to be quite as benign as was originally thought. However, m a n y of these patients were also given a muscle relaxant and no attempt has been made in the table of to identify which agent was responsible. Table VII. - - Usage of induction agents in the .grade II-IV reactions reported to Sheffield 1988-1992.
In the figures reported to Sheffield for 19881992, out of 529 grade I I - I V reactions the distribution of relaxants was as shown in table VI. Again suxamethonium was used in nearly half the patients - - approximately equal to the total of non-depolarising relaxants. In spite of all the figures showing its dangers (and not only in these reactions) it is unfortunately still widely used for non-emergency cases. The appearance of
Total 113 144 Suxamethonium 52 61 Pancuronium 2 Vecuroniurn 15 12 Atracurium 10 23 Alcuronium 16 ' 21 Tubocurafine 7 3 Gallamine (+ suxamethonium) 3 2
107
14 25 l0 5
87 44 3 15 22 6 1
29 17 3 5 3 -1
529 237 8 61 83 53 17
45 2 12 16 10 3
2
3
2
12
2
Total Thiopentone (%) Propofol (%) Etomidate (%)
I988
1989
1990
1992 1991 (3months) Total
133 81 (61) 19 (17) 4 (4)
144 88 (61) 23 (16) 6 (4)
145 80 (55) 37 (26) 7 (5)
98 51 (52) 34 (35) 2 (2)
29 14 (48) 14 (48) 1 (3)
549 314 (57) 127 (23) 20 (4)
L a b o r a t o r y testing
When appropriate blood samples have been available the patients have been assessed by immunological tests. The test of choice is the plasma tryptase level which is an absolute measure of mast cell degranulation and drug action. Measurement of total IgE does not measure specific antibodies but rather gives a measure of the immune reactivity. It is not u n c o m m o n to have a normal IgE but specific antibodies to suxamethonium, for instance. The presence of specific antibodies to suxamethonium does not, of course, prove that a reaction was due to this drug since the patient could have such antibodies from a previous anaesthetic ( o r - o t h e r w i s e ) and yet not have received it on this occasion. In addition, it is not yet clear whether patients with such antibodies always react to injected suxamethonium and the value of testing for specific antibodies is reduced
108
by the f r e q u e n c y of cross-sensitivity between the muscle relaxant drugs. A l t h o u g h the majority of adverse reports ( A D R s ) a p p e a r to implicate the n e u r o m u s c u l a r blocker it was clear f r o m l a b o r a t o r y investigation that the newer induction agent p r o p o f o l was increasingly implicated in adverse reactions [8]. This has p o s e d p r o b l e m s in attempting to attribute relative incidence of serious A D R s to the n e u r o m u s c u l a r drugs. To attempt such reporting it also b e c o m e s necessary to assess relative usage of the drugs, as distinct f r o m C o m p a n y sales figures. O u r attempts to do so not surprisingly indicate a similar <
It must be emphasised that hypersensitivity reactions r e m a i n a p r o m i n e n t cause of anaesthetic morbidity t h o u g h with i m p r o v e d u n d e r s t a n d i n g the mortality remains low. T h e y occur with all drugs which the anaesthetist uses and to a large extent the f r e q u e n c y of reports reflects the frequency of usage of a particular drug. S u x a m e t h o n i u m is the only drug in wide use n o w with a high incidence of reactions. P e r h a p s the most i m p o r t a n t point to m a k e is that m a n y reactions are not drug specific but related to a c o m b i n a t i o n of drugs going into a particular patient at o n e time. Finally, there is the c o n c e p t o f aggregate anaphylaxis and plainly it would be better if drugs could be given singly and slowly. H o w e v e r , if anaesthetists gave anaesthetics. the way immunologists would suggest with each
R.S.J. CLARKE, J. WATKINS
drug taking effect before adding another, the concept of balanced anaesthesia would have to be a b a n d o n e d and our operating lists would never finish.
REFERENCES
1. ASSOCIATIONOF ANAESTHETISTS.Anaphylactic reactions associated with anaesthesia. London, Association of Anacsthefists, 1990. 2. BUCK N, DEVLINHB, LUNN JN. The report of a confidential enquiry into perioperative deaths_ Nuffield Provincial Hospitals Trust and King's Fund Publishing Office, London, 1990. 3. FISHER MM, BALOOBA. Anaphylactoid reactions in anaesthesia (pp 677-692). In : Adverse reactions. Clinics in anaesthesiology, 2, No 3. MM FISHER ed_ Saunders, London, 1984. 4. LAXENAIREMC, MONERET-VALrrR1NDA, BOILEAUS, MOELLER R. Adverse reactions to intravenous agents in anaesthesia in France. Klin Wochenschr, 60: 1006-1009, 1982. 5. LUNN JN, MUSH1NWW. Mortality associated with anaesthesia. Report issued by Association of Anaesthetists of G.B_ and Ireland. Nuffield Provincial Hospitals Trust, London, 1982. 6. RING J, MESSMERK. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet, 2: 466-469, 1977. 7. WATKINS J. Anaphylactoid response to neuromuscular blockers (pp 13-20). In: Recent developments in muscle relaxation : atracurium in perspective. RM JUNKS, JP PAYNE eds_ RSM Services International Congress and Symposium Series, London, 1988. 8. WATKINS J. Immediate hypersensitivity-type reactions in anaesthesia. Theor Surg, 6 : 119-233, 1991. 9. WATKINSJ_ Tryptase release and clinical severity of anaesthetic reactions. Agents Actions, Special conference issue: C203-C205, 1992.
(~ Masson, Paris. Ann Fr Anesth Reanim, 12: 105-108, 1993
Drugs responsible for anaphylactoid reactions in anaesthesia in the United Kingdom Medicaments responsables des reactions anaphylactdides en Grande-Bretagne R.S.J. CLARKE *, d. WATKINS ** * Department of Anaesthetics, The Queen's University of Belfast, Whitla Medical Building, 97, Lisburn Road, Belfast BT9 7BL ** Department of Immunology, The Medical School, University of Sheffield, Royal Hallamshire Hospital, Sheffield FIO 2JF
RI~SUMI~: L'incidence des rdactions anaphylactoides peranesthdsiques survenant au Royaume-Uni n'est pas clairement rdpertori6e. Elle a 6t6 appr~cide, dans diff6rentes dtudes, fi 1/10 000 ou 1/500. Le seul service auquel sont rdguli6rement rapport6s des accidents est le Ddpartement d'immunologie de Sheffield : 120 ~ 150 cas y sont ddclar6s chaque annde, ce qui laisse sugg6rer qu'au Royaume-Uni il doit y avoir dix lois plus d'accidents non ddclards. Les dosages de tryptase et mdthylhistamine urinaires sont pratiqu~s h Sheffield et permettent de distinguer les accidents anaphylacto~des des accidents dus h d'autres causes (surdosage ou autres erreurs). Ont ainsi 6t6 ddtaillds les cas recensds depuis 1988, en les classant par grades de gravit6 clinique croissante (grades II fi IV). Le hombre d'accidents est restd constant de 1988 5 1990 mais a diminu6 de 30 % en 1991, peut-~tre en rapport avec la distribution ~ tousles anesthdsistes de recommandations de l'Association des Anesth6sistes Anglais sur la pr6vention et le traitement de ces accidents. Les eurarisants sont en rate des accidents, avec le suxam6thonium dans 45 % des cas, suivi de l'atracurium (16 %), du vdcuronium (12 %), de l'alcuronium (10 %), et du paneuronium (2 %). Quant aux hypnotiques, le thiopental est en cause dans 57 % des cas, le propofol dans 23 % et l'6tomidate dans 4 %. L'hypnotique est toujours associ6 ~, un curare, de sorte que, en l'absence de dosage des anticorps spdcifiques aux mddicaments, il est impossible de savoir si les accidents sont spdcifiquement dus ~ un seul produit ou ~ une association de produits, mettant ainsi en cause le concept d'anesth6sie balanc6e.
INCIDENCE The i m p o r t a n c e of a n a p h y l a c t o i d reactions still remains highly controversial, in the U n i t e d Kingdom ( U K ) at least, a n d m a n y studies of a n a e s t h e tic mortality in the U K do n o t m e n t i o n it [2, 5]. There is always difficulty in o b t a i n i n g reliable d a t a on the progress of such p a t i e n t s b u t of those analysed by LUNN and MUSHIN [5] only 58 could be b l a m e d totally o n the a n a e s t h e t i c a n d of these, few were a t t r i b u t e d to any p h a r m a c o l o g i c a l cause. Part of the difficulty is p r o b a b l y that o v e r d o s e leading to h y p o t e n s i o n can be disguised by inaccurate reporting. A n o t h e r p r o b l e m is that assessors who do n o t believe in a n a p h y l a c t o i d b r o n c h o s p a s m could a t t r i b u t e such cases as due to o e s o p h a g e a l
Presented at the meeting ,, New Trends in Anaphylactoid Risk in Anaesthesia ,,. Nancy (France), ll-12 June 1992.
i n t u b a t i o n (table I). It m u s t be said that the authors in these a n d e v e n m o r e recent studies in the U K are n o t p r i m a r i l y trying to elucidate the cause of d e a t h b u t r a t h e r to look at the quality of anaesthesia. It does seem, however, that an i m p o r t a n t factor is o v e r l o o k e d in such analyses. There are a p p r o x i m a t e l y 3,500,000 g e n e r a l anaesthetics given a n n u a l l y in the U n i t e d Kingdom. T h e f r e q u e n c y of severe r e a c t i o n is u n c e r t a i n but it p r e s u m a b l y lies b e t w e e n a figure of approximately 1 in 10,000 [3] and 1 in 500 [8] which w o u l d m e a n a p p r o x i m a t e l y 350 to 5,000 cases per year in the U K . LAXENAIRE et al. [4] give a rate of 1 in 1,500 for F r a n c e . W h a t is certain is that the only service in the U K which brings t o g e t h e r reports of such clinical m i s h a p s is that in Sheffield
Tires a part : R.S.J. Clarke.
106
R.S.J. CLARKE, J. WATKINS
which has 120-150 reports yearly. Analysis of these would exclude some as being not drug-related or due to drug overdose but only tryptase testing and urinary methylhistamine estimation [9] can clearly and positively distinguish those mishaps not due to drug hypersensitivity. Since many of these are avoidable and are possibly the fault of the anaesthetist, it is important to establish the exact problem at the outset. For statistical purposes it is essential also to grade reactions [6] and the classification in table II is useful [5]. Immunologists will argue about details but this is a clinical classification based on the anaesthetist's description.
Table I. - - Assessment of possible pharmacological causes in 58 deaths totally due to anaesthesia in UK in the year 19791980 [51.
Cases Accidental hypotension Overdose of premedication Malignant hyperthermia Induced hypotension Recurarisation ? Oesophageal intubation
10 6 3 2 2 3
Table II. - - Classification of hypersensitivity (histaminoid) reactions by severity (not all features are present in every case).
Classification I. Cutaneous II. Systemic
Clinical features
Flushing Marked flush Hypotension 20-40 Slight bronchospasm III. Life threatening Marked flush Hypotension 40-70 Severe bronchospasm IV. Potentially fatal Marked flush Hypotension > 70 Severe bronchospasm
hypotension (involving a systolic pressure below 50 mmHg <
Table III. - - Analysis of reports of reactions to anaesthetic drugs (including plasma expanders) of grade II to IV, sent to the Immunology Laboratory in Sheffield during 1988-end of March 1992.
Typical plasma histaminelevels (ng- ml-I) 0-1 1-10 10-100 > 100
1988
1989
1990
1991
1992 (3 months)
Total reports Exclusionson basis of history Grade II Grade 11I Grade IV
143
165
175
109
23
30 25 33 55
25 32 35 73
30 35 40 70
1l 20 32 46
2 6 7 8
Grades II-IV
113
144
145
98
21
CAUSATION
On this basis the anaesthetic history in the reports of reactions sent to the Department of Immunology, Hallamshire Hospital, Sheffield in the years from 1988 to 1992 has been analysed (table III). Previous years had also involved 120150 reports per year and there is no reason to assume major fluctuations in incidence from year to year. Reactions which appeared not to be drugrelated or those occurring after the anaesthetic was over and of doubtful causation have been excluded. In 1988, for instance the grade 1V group included 5 deaths and 14 cases in which the operation was postponed. The remainder had flushing,
M u s c l e relaxants
The figures from the study by LUNN and MUSHIN [5] of usage in 1979 show that in the patients whose deaths were totally related to the anaesthetic, muscle relaxants were used in 90 % and suxamethonium most commonly (table IV). This of course is partly related to the fact that suxamethonium is used in the majority of ill patients having emergency surgery. The distribution of non-depolarising relaxants probably reflects usage at that time.
ANAPHYLACTOID REACTIONS IN THE UNITED KINGDOM
Table IV. - - Percentage usage of muscle relaxants in reported deaths in the UK [5] (many patients had more than one drug).
Suxamethonium Pancuronium Alcuronium Tubocurarine Gallamine Others None
58 43 16 8 4 1 10
Figures for the frequency of appearance of these drugs in reports of reactions during 1984-1986 [7] show that suxamethonium was involved in nearly 50 % which is certainly higher than its general overall usage. Similarly, in the individual nondepolarising relaxants, alcuronium has a much higher place and pancuronium a lower place than their national usage (table V).
Table V. - - Percentage usage of muscle relaxants in reported reactions in the UK involving these drugs [7].
Suxamethonium Alcuronium Atracurium Tubocurarine Vecuronium Pancuronium
50 22 12 6 6 3
Table VI. - - Usage of muscle relaxants in the grade II-IV reactions reported to Sheffield 1988-1992.
1992 Total Percen1988 1989 1990 1991 (3 months) tage 145 73
alcuronium in reports is at last declining, not because it is becoming safer but because it is being replaced by the newer atracurium and vecuronium. It is perhaps surprising that tubocurarine, the most m a r k e d histamine-liberator, is still used at all a n d pancuronium is lowest of this group in reaction-liability. Gallamine, for no very scientific reason, continues to be preferred by some anaesthetists before giving suxamethonium to reduce the likelihood of muscle pains. Induction a g e n t s
Figures for reaction reports to Sheffield, 19881992, classified recording to the induction agent are given in table V I I and the decline of reports following thiopentone and the rise of those following propofol is notable. This reflects the increased usage of propofol but it also shows that propofot is unlikely to be quite as benign as was originally thought. However, m a n y of these patients were also given a muscle relaxant and no attempt has been made in the table of to identify which agent was responsible. Table VII. - - Usage of induction agents in the .grade II-IV reactions reported to Sheffield 1988-1992.
In the figures reported to Sheffield for 19881992, out of 529 grade I I - I V reactions the distribution of relaxants was as shown in table VI. Again suxamethonium was used in nearly half the patients - - approximately equal to the total of non-depolarising relaxants. In spite of all the figures showing its dangers (and not only in these reactions) it is unfortunately still widely used for non-emergency cases. The appearance of
Total 113 144 Suxamethonium 52 61 Pancuronium 2 Vecuroniurn 15 12 Atracurium 10 23 Alcuronium 16 ' 21 Tubocurafine 7 3 Gallamine (+ suxamethonium) 3 2
107
14 25 l0 5
87 44 3 15 22 6 1
29 17 3 5 3 -1
529 237 8 61 83 53 17
45 2 12 16 10 3
2
3
2
12
2
Total Thiopentone (%) Propofol (%) Etomidate (%)
I988
1989
1990
1992 1991 (3months) Total
133 81 (61) 19 (17) 4 (4)
144 88 (61) 23 (16) 6 (4)
145 80 (55) 37 (26) 7 (5)
98 51 (52) 34 (35) 2 (2)
29 14 (48) 14 (48) 1 (3)
549 314 (57) 127 (23) 20 (4)
L a b o r a t o r y testing
When appropriate blood samples have been available the patients have been assessed by immunological tests. The test of choice is the plasma tryptase level which is an absolute measure of mast cell degranulation and drug action. Measurement of total IgE does not measure specific antibodies but rather gives a measure of the immune reactivity. It is not u n c o m m o n to have a normal IgE but specific antibodies to suxamethonium, for instance. The presence of specific antibodies to suxamethonium does not, of course, prove that a reaction was due to this drug since the patient could have such antibodies from a previous anaesthetic ( o r - o t h e r w i s e ) and yet not have received it on this occasion. In addition, it is not yet clear whether patients with such antibodies always react to injected suxamethonium and the value of testing for specific antibodies is reduced
108
by the f r e q u e n c y of cross-sensitivity between the muscle relaxant drugs. A l t h o u g h the majority of adverse reports ( A D R s ) a p p e a r to implicate the n e u r o m u s c u l a r blocker it was clear f r o m l a b o r a t o r y investigation that the newer induction agent p r o p o f o l was increasingly implicated in adverse reactions [8]. This has p o s e d p r o b l e m s in attempting to attribute relative incidence of serious A D R s to the n e u r o m u s c u l a r drugs. To attempt such reporting it also b e c o m e s necessary to assess relative usage of the drugs, as distinct f r o m C o m p a n y sales figures. O u r attempts to do so not surprisingly indicate a similar <
It must be emphasised that hypersensitivity reactions r e m a i n a p r o m i n e n t cause of anaesthetic morbidity t h o u g h with i m p r o v e d u n d e r s t a n d i n g the mortality remains low. T h e y occur with all drugs which the anaesthetist uses and to a large extent the f r e q u e n c y of reports reflects the frequency of usage of a particular drug. S u x a m e t h o n i u m is the only drug in wide use n o w with a high incidence of reactions. P e r h a p s the most i m p o r t a n t point to m a k e is that m a n y reactions are not drug specific but related to a c o m b i n a t i o n of drugs going into a particular patient at o n e time. Finally, there is the c o n c e p t o f aggregate anaphylaxis and plainly it would be better if drugs could be given singly and slowly. H o w e v e r , if anaesthetists gave anaesthetics. the way immunologists would suggest with each
R.S.J. CLARKE, J. WATKINS
drug taking effect before adding another, the concept of balanced anaesthesia would have to be a b a n d o n e d and our operating lists would never finish.
REFERENCES
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