Br. J. Anaesth. (1975), 47, 575
ADVERSE REACTIONS TO INTRAVENOUS ANAESTHETICS A Survey of 100 Reports R. S. J. CLARKE, J. W. DUNDEE, R. T . GARRETT, G. K. MCARDLE AND J. A. SUTTON
SUMMARY
Adverse reactions to a new drug may occur so infrequently that they are seen only after the drug has been generally released for clinical practice. However, when such reactions occur they may attract more attention than those associated with a drug that is familiar to its users. A survey of adverse reactions to intravenous anaesthetic drugs has been undertaken, so that those occurring with the newly introduced Althesin (Glaxo Laboratories Limited) may be seen in perspective and appraised. Interest in adverse reactions, particularly those appearing to be related to hypersensitivity, has been increasing in recent years. Reports of reactions to propanidid (Epontol, FBA Pharmaceuticals), attributable to hypersensitivity, occurred frequently in the literature from 1965 to 1972, and 23 reports have been analysed by Clarke (1974). The intensive studies of Lorenz and his colleagues (1972), with estimations of plasma histamine, suggest that liberation of histamine is a common factor in most of these reactions. Published reports of thiopentone reactions have been reviewed by Dundee and Wyant (1974) and, while less in number than those associated with Epontol, are similar in character. The wider aspects of hypersensitivity such as
delayed fever and liver dysfunction have been reviewed by Currie (1970). Large doses of all anaesthetic agents can induce involuntary muscle movements which may follow also the rapid injection of these drugs or the use of an "antanalgesic" premedicant. On occasions, however, epileptiform convulsions may be observed, and such reports have been included in this survey. The first 100 reports received up to May 3, 1974, have been analysed. Most concern immediately occurring reactions involving the skin, cardiovascular and respiratory systems. Forty-two of the Althesin reports have been presented in summary previously (Sutton, Garrett and McArdle, 1974). METHOD
Anaesthetists in the United Kingdom were invited (through correspondence with Anaesthetics Departments and a letter published in medical journals (Dundee and Clarke, 1973)) to submit reports about reactions associated with any intravenous anaesthetic. The reports received have been added to those concerning Althesin sent to the manufacturers or the Committee on Safety of Medicines. Details of the reactions were obtained, usually from the administering anaesthetist, using a standard questionnaire. In a few instances the reports are not complete, particularly with regard to the anaesthetic R. S. J. CLARKE, MJ>., F.F.AJtc.s., J. W. DUNDEE, M.D., F.F.A.R.C.S., Department of Anaesthetics, Queen's Univer- history. sity of Belfast, Belfast BT12 6BJ; R. T. GARRETT, M.P.S., Anaesthetists were encouraged to carry out intraG. K. MCARDLE. B.SC.. J. A. SUTTON,* M.B., B.S., D.OBST.R.C.O.G., Medical Department, Glaxo Laboratories dennal sensitivity tests with the anaesthetic inLtd, Greenford, Middlesex UB6 0HE. volved, but the patient's sensitivity to other agents •Present address: Anaesthetic Department, The Longiven at the induction of anaesthesia often was not don Hospital, Whitechapel, London El IBB.
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One hundred consecutive reports of reactions to intravenous anaesthetics Althesin, thiopentone and Epontol are reviewed and analysed. Ten reactions are attributed to causes other than the anaesthetic drug, and four are believed to have been caused by the muscle relaxant employed. The remaining 86 reactions were grouped according to their clinical presentation: histaminoid reactions (19), histaminoid with bronchospasm (33), bronchospasm (12), cardiovascular collapse (11), delayed histaminoid reactions (6), and clonic contractions (5). None of the first four reaction types was associated with only one anaesthetic. A knowledge of the sales of Althesin has allowed the incidence of reactions to be estimated as between one in 11,000 and one in 19,000.
576
BRITISH JOURNAL OF ANAESTHESIA
tested. In certain cases, leucocyte degranulation tests (Assem and McAllen, 1970) were performed, but the need for fresh blood and the time-consuming nature of the test severely limited the number of tests undertaken. As the total quantity of Althesin that had been made available to anaesthetists in the U.K. was known to us, an estimate could be made of the incidence of adverse reactions to this anaesthetic. RESULTS
TABLE
I.
Classification of 100 reported intravenous anaesthetics. ]Intravenous
Type of reaction
Althesin 17
reactions
to
anaesthetic used
Thiopentone
Epontol* Total
2 — 19 Histaminoid (H) Histaminoid with 8 — 33 bronchospasm (HB) 25 2 — 12 Bronchospasm only (B) 10 Cardiovascular 7 _ 4 11 collapse (CVS) Delayed histaminoid (dH) 6 — — 6 Clonic contractions (CQ 5 — — 5 Total of anaestheticrelated reactions 70 12 4 86 Attributed to muscle relaxant 3 1 — 4 Attributed to poor health of patient 9 1 — 10 Total number of reports 82 14 4 100 •The trade name "Epontol" has been used for propanidid injection throughout because of the complex nature of the marketed product and because either the eugenol or solvent may have been the cause of the reaction.
Histaminoid reactions (table II). "Histaminoid" has been used to describe 19 reactions which could possibly be accounted for by a release of histamine. Typically, there was peripheral vasodilatation (usually widespread) accompanied by a profound reduction in arterial pressure. The skin flush was more marked than that commonly seen at induction of anaesthesia, and oedema and weals were common. Histaminoid reactions with bronchospasm (table m ) . In 33 incidents, respiratory symptoms were seen in addition to the features common to the histaminoid group. Bronchospasm was reported in all but three of the incidents. One of the three exceptions was an 8-year-old boy (HB2) who coughed up copious mucus when not more than 0.25 ml of Althesin had been administered. A woman aged 23 years (HB9) exhibited pronounced flushing of the face and, before sufficient Althesin had been given to cause loss of consciousness, complained of difficulty in breathing. Laryngospasm, but not bronchospasm, was reported in the other patient (HB1). Coughing preceded the bronchospasm in seven patients but in only two (HB5 and HB17) could it be attributed to endotxacheal intubation. Whereas in some of the patients the bronchospasm could have been caused by aspiration of a small amount of saliva or gastric juice, the fact that other "histaminoid" signs were also present suggests that the bronchospasm was an integral part of the reaction. The only deaths judged to have been caused by the anaesthetic are in this group and all four occurred after the use of thiopentone. Bronchospasm reactions (table IV). In 12 incidents, bronchospasm occurred without accompanying vasodilatation or arterial hypotension. Sometimes it was preceded by coughing, but in all cases it occurred before endotracheal intubation. Cardiovascular collapse (table V). A profound reduction in arterial pressure was the predominant feature of 11 reactions. The flush of the "histaminoid" reactions was not seen, indeed facial pallor is recorded in six cases, and respiratory distress was not observed. All the reactions follow(continued on p. S82)
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A broad classification of the 100 reports in accordance with their clinical presentation is displayed in table I. Eighty-six reactions were considered to have been caused by the induction agent. To some extent, the allocations are arbitrary as, for example, the arterial hypotension reported for those in the histaminoid with bronchospasm group in some cases may have been secondary to hypoxia as a result of the bronchospasm. For this reason, the signs and symptoms in tables II-VI are numbered to indicate the order in which they appeared, so far as can be ascertained. A further seven reports were received but the events described were considered to be unconnected with the anaesthetic agent used: opisthotonus in an outpatient several hours after a brief procedure performed under Althesin anaesthesia; cata-
lepsy 2 hr after anaesthesia in a patient with a psychiatric history.
18
19
61
17
H9
H»
H11
T 1
nil
nil
nil
detergent
hayfoTer
not r«portod Altli thlopenton* eumo«ti»nlaa panouronluii
T
26
T A T mxaoeth poncur
H
60
H19
T
H17
H18
T
H16
T
18
H13
nil
T
32
nil
nil
K T I
T
hajfoTor
nil
M
M
nil
ftnilial
H
H14
H1J
H12
17
B8
nil
A
IV dropvrldol K Epontol
•orpMno atroplno
B«probaaat«
A
hjoscine papareretiB
A
none A
A
dia-p-
atropiiM
A
A
T
T
p«p«ToratiJB hyoseine
•tropln*
•aproti—*to none
panour
droporidiil fentanjl
atropine gallanino
•tropine
T
Sttxateth
none
nono
t
t
yt
a.
7 x3
A
DT > A 3»
nU
nil
A
1 t
nil
A W
strop in* •orphln*
Iodlno
H
7
nil
strop in* p«thldln«
aetals
T
S*
11
A W
t
A 2.
nil
Drags used a t Induction Anaeo- Other ProTions thetlo adrnlniatration
atroplo*
none
T
t
nil
T
hyoacin*
66
deraoQraphia familial aothso
Pronodicotion
droperidol
H
Hiptory of Atopy/ SonoitiTity
55
52
Ago yro
B7
H3
Report Hef.
1
X
2
2
3
1
fl.P. Pall
>
3
dg id nd pt oc
t
nd
nd
idl A*+
ldl At
nd
nd
nd
idl A+ 0*
nd
nd
dg: A+ C* ad+ azt
idi Att OM-
ptl A-
A+ ad+ A+
SanaltiTlty T«»t Ri oulto
louooayts dogrKmlatlan t«at ictr»(l*rsa*l thallonga » t don* patch teat trabcutnnoouo
3 'gooaa-plaples'
itchy, ocarlatinafors rooh
1 ooughing 3 veals on STBS and l*ga ^ oedema of lips and periorbltal
2 patch** of erythema vith bluish tinge
3 ankle oedosa
on extubation arytunoida palo and oedesatoos
3 epoooa k cirtninorol pallor 5 Baacle atony
2 'goose-piaplin^'
> sweating 4 facial oodema
I* tachycardia 2* woal at Injection s i t e
vld*«pr*ad u r t i o a r i a l w*als
1 ooogh, antmii
1 •hallow rapid respiration
2 facial i i i t i i
3 -tild tisme oedona
Features of Hqactlon Cyanosla
Nuabora abort Indicate order in vl*ii ch wore obverred
1
1
•k.
1
2
1
Fluoh
TABLE II. Reported reactions to intravenous anaesthetics—histaminoid type.
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alph&dolono aootato olphaxolono Croaophor EL poaitivo roaponac pooitiTO rooponoo with i
pyrcods (39°0) 12 hro. af Unmrdn
•pileptio
chronlo bronohltioj son«reliood rash day nftar akin toot
pro-op, tachycardia T*ry anxiounl blood loos 500-750*1
l e s s than 0.7 • !
(Dandeo and oth*ra, 197^)
OtahU, 1973)
oongeoital heart dlaoooo
(Horton, 1973)
Additional information
n
C/5
nil
nil
T
r
H
K
H
T
afi
u
Co
69
69
1
KT&
HB9
m to
HB11
mi;
HB13
penicillin
oil
r
T
7
nil
66
f
t
nil
'
•aplcllll
T
63
nil
F
HB7
nil
71
22
atropio*
nil
29
trijirprudn* atropinf
papaTeretm ocopoloaino
A
A
T
hjoncino popavrrotui
A
?
none
pothldln*
droperidol diaxepea
nil
8
History of Atopy/
nil
5«
3
A^ jra
HB6
HJ5
Bcport Bof.
IUI
A to tr 10a « I 12a
ldl
•d
Dd
Dd
t
»»•
Teit Rooulta
3
nd 1 blotchj, palt, bluish rttln; t«porar7 cardlao arr««t •IMD«Ct»d
nd
2 tachycardia 3 «pnoc* 5 (•light)
cfcln otdm*
3 ficlal oodemo k 'difficult to broatlu'
V poriorbltal and facial oedema
5 alld facial oedema) urticariol raah on legi
5 'potachial hae»orrhacca' OB oock aed ahouldors
i* oodc«a
3 copious Kooua, rales
Bronchoopaw
nd
Cough
1
Cyan0*1 B
none
B.P. fall
idi At d
Tluth
3
nonr
droporldol
norn-
momsth
tubocur
tubocur feotanjl
A Jw
A 'M
«t Induction Previous odninio trot ion
TABLE III. Reported reactions to intravenous anaesthetics—histaminoid tvith bronchospasm type.
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p l u t l o eors«i7 to hand
hxpert™.!.. n » . i , l ^
d«nt«l atraotioD
hjpj?rtpnoir« reocirlng •cthjldop* (TKocdlo 1 Ordlali, 197»)
prr-op health fair (TVccdie I Ordiao, t97