Histamine Release and Atracurium

Br.J. Anaesth. (1986), 58, 19S-22S

HISTAMINE RELEASE AND ATRACURIUM J. WATKINS In their extensive review of histamine and its clinical significance, Lorenz and his colleagues Histamine is largely contained in the fixed mast (1981) suggest that immediate histamine release cells and the circulating basophils of the blood. By reactions fall into two broadly defined groups: its action on smooth muscle it facilitates vasodilata- anaphylactoid reactions and allergoid reactions. tion and permits the movement of phagocytic cells Anaphylactoid reactions (Watkins and Clarke, across the tissues to their point of action during 1978) are likely to involve varying degrees of the inflammatory response. While not the only im- systemic histamine action such as hypotension, portant "chemical" effector of the inflammatory tachycardia or cardiac arrhythmia, and bronchoresponse, it is a major candidate for the initiation spasm, as well as the usual cutaneous effects such of its clinical manifestations. This was demon- as flushing and urticaria; allergoid reactions strated very elegantly by Lorenz and his colleagues predominantly exhibit only cutaneous effects (1982), who administered low doses of histamine (Lorenz et al., 1980). Cutaneous manifestations (1-2 ng/ml plasma) to informed volunteers, being the most prevalent, it is obvious that minor reproducing the manifestations of minor anaphyl- anaphylactoid reactions will be clinically undisactoid shock. tinguishable from allergoid reactions; the latter at The release of histamine is facilitated by worst have nuisance value and are largely immune reaction (IgE or other antibodies), by self-limiting, but the former disguises several complement activation, by the presence of mechanisms and implications for the patient's immune complexes (or aggregates of molecules future care. resembling such complexes) and directly by the action of drugs and other chemicals upon cell Medical decision making surface receptors. In terms of untoward response, atracurium It is possible to make some generalizations resembles tubocurarine in producing a high (Lorenz et al., 1982) about the concentration of incidence of essentially cutaneous manifestations. plasma histamine and the observed clinical Tubocurarine continues to be quite extensively manifestations (table I). At concentrations greater than 30 ng/ml plasma, life-threatening situations TABLE I. Plasma histamine release (immediate, shock release of are almost certainly present. Generally, the release histamine with rapidly attained plasma concentrations) and its sequelae of even 1-2 ng ml"1 is sufficient to generate mild clinical manifestations, but at this concentration Concentration wide individual tolerances to histamine become (ngml1 ) Likely clinical manifestation apparent. Further, it seems apparent that, while Basal, no manifestation. about 30% of the population as a whole are 0.2-0.8 Mild histaminoid effects. capable of releasing such small quantities of 1-2 Flushing, headache, tachycardia. histamine (1—2 ng ml"1) in response to a wide Poor correlation between manifestation range of substances administered i.v., such release and concentration. may be self-limiting and not indicative of a 2-10 More serious systemic response, life tendency to release harmful amounts of histamine threatening. Better correlation between manifestation and concentration. in that individual upon further stimulus. AN INTRODUCTION TO fflSTAMINE

JOHN WATKINS, PH.D., University Department of Immunology, Royal Hallamshire Hospital, Sheffield S10.

>30

Extreme cardiovascular collapse, bronchospasm, life threatening. Correlation with concentration. Death likely.

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5= 10

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TABLE II. Adverse clinical manifestations after inductum of anaesthesia with thiopentone and atracurium (n = 41) (Westminster Hospital Study).*Basal (control) concentrations: range 0.2—0.5 ng mt~l. Value above control after thiopentone: range 0.4—1.5 ng mt~* mean 1.0ngmt~l. Value above control after atracurium: range 0S—5.0ngmt~1, mean 2.6 ngmt~l. (Adapted from Barnes, de Renzy-Marlin, Thomas and Wathns, in preparation) Increased* plasma histamine

No response (18) Minimal (13) More severe (10)

Cutaneous response

Hypotension ( > 10% control)

After thiopentone

After atracurium

0 13 10

0 0 9

0 0 3

5 5 6

HISTAMINE RELEASE BY ATRACURIUM

All i.v. substances are capable of releasing histamine by a variety of mechanisms, although with different drugs broad patterns of preferred mechanisms occur (Watkins, 1981). Following multiple exposure of any patient to any drug the possibility of immune sensitization and Type I hypersensitivity response increases. So far no genuine immune reaction to atracurium appears to have been reported. While our own studies (Westminster Hospital Study: Barnes, De Renzy-Martin, Thomas and Watkins, in preparation) indicated plasma histamine release (< 2 ng/ml plasma) to atracurium in a number of patients, in the absence of clinical response, this release was of an order similar to that encountered with thiopentone alone and did not generally correlate with a high incidence (> 50% of study group) of skin flushing or mild degrees of hypotension. In the few patients (table II) in whom more significant clinical manifestations were encountered it was considered that

the histamine waves released by both thiopentone and atracurium had become superimposed, prolonging the action of the released histamine and generating a composite anaphylactoid response implicating both drugs. The cutaneous response to atracurium appears predominantly the result of skin histamine release, but the mechanism remains unknown. Such response has a similarity to that produced on occasion by etomidate or dextrans, and even to the "needle response" (Watkins, 1981). The most hazardous systemic response to atracurium is a version of aggregate anaphylaxis. The latter may be initiated by the formation of aggregates of mixed, precipitated drugs, with or without inclusion of certain of the patient's plasma proteins. Sufficient precipitate is often produced when the anaesthetist fails to wash out an indwelling cannula between the administration of different drugs. It is most marked with thiopentone and atracurium. The usual manifestation is simply a reddening along the site of the injection vein, representing the precipitation of various types of complexes (compare thiopentone injections alone), but if the precipitate is of the appropriate size and concentration it will initiate acute, often life-threatening bronchospasm when swept into the capillaries of the lungs. Figure 1 records a typical case report to this laboratory. The absence of hypotension in such cases is most striking and the circulating aggregates can be measured. The combination fentanyl-etomidateatracurium seems free of this complication, but nevertheless saline washings should be used between all drugs. None of this explains the high level of cutaneous manifestations observed with atracurium. As remarked upon earlier, these apparently allergoid reactions are similar in appearance and frequency to those initiated by tubocurarine administration, yet the general level of plasma histamine release by

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used in anaesthesia since, in clinical practice, it has proved no more hazardous than many other drugs in current use. The inference is that most adverse reactions to both tubocurarine and atracurium are self-limiting, generally harmless, allergoid responses. However, it would be very unwise to attempt to use clinical manifestations alone to provide a diagnosis of anaphylactoid or allergoid reaction. Bronchospasm may occur for a variety of reasons unconnected with drug therapy. Tachycardia may be induced by surgery, or manipulation, or by various drug effects (e.g. of atropine) unconnected with the release of histamine. Laboratory analysis thus becomes essential in defining reactions, particularly the measurement of plasma histamine release (Lorenz et al., 1981).

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HISTAMINE RELEASE AND ATRACURIUM She i s a fit woman with no history of allergy. She smokes. There have been three previous minor operations, of which no d e t a i l s are available. Today's operation wao laparoscopy for oral temazepam premedication had been anaesthesia was by droperidol (5 mg), and atracurium C+0. mg). No flushing

secondary i n f e r t i l i t y . An given. Induction of fentanyl (0.2 mg), thiopentone was performed between the drugs.

An inflammatory rash spread up the arm used for the injection. Ventilation of the lungs was made d i f f i c u l t by moderate small airways obstruction. Treatment was by intravenous aminophylline and chlorpheniramine. An infusion of llartmann's solution was given through a new cannula in the other arm. There was no hypotension. The operation took place while treatment continued.

atracurium is on par with that of pancuronium, while that of tubocurarine is some four times higher (Moss et al.,1982). We must look elsewhere for explanations and indications of clinical significance. SKIN RESPONSES TO NEUROMUSCULAR BLOCKERS

Robertson and colleagues (1983) studied the responses in volunteers to intradermal injections of diluted atracurium, tubocurarine and vecuronium. As expected, a high incidence of weal and flare reactions was observed to the two former drugs, but not to vecuronium. On this basis these workers proposed that vecuronium was likely to be the safer drug when used clinically. This is not a valid conclusion for any drug tested in this way: even drugs like pethidine and atropine, with a low incidence of anaphylactoid reactions when administered i.v., produce weal and flare reactions when injected intradermally. In order to investigate the true prognostic value of intradermal testing with atracurium and tubocurarine, the Sheffield Unit skin-tested 22 female patients who gave informed consent 24 h before undergoing gynaecological surgery for non-malignant conditions (Wood et al., 1985). A high incidence of positive "intradermal" weals was obtained at dilutions of 1:1000 of the clinical dosage with each drug, and half the test group responded positively to both drugs (table III). The test conditions and criteria of a positive reaction (a weal of 1 cm in diameter or greater, persisting

for more than 30 min) were those described by Fisher (1984). Irrespective of the findings, 24 h later the patients had anaesthesia induced with thiopentone and were then given atracurium or tubocurarine on a randomized schedule. There were no clinically significant anaphylactoid reactions and such flushing and transient minor hypotension which was observed was surprisingly biased towards the non-reactors in table III. In retrospective surveys of clinically severe

anaphylactoid reactions throughout the U.K. and reported to the Sheffield-based National Adverse Anaesthetic Reaction Advisory Service (NAARAS), a ranking table of neuromuscular blocking agents co-administered with the hypnotic agents (table IV) did appear to support the observations of Robertson and colleagues (1983). It can be seen that tubocurarine and atracurium share an intermediate position in the ranking, behind suxamethonium and alcuronium, but considerably ahead of pancuronium and vecuronium. This ranking is not in the expected use TABLE III. Intradermal response in a prospective drug trial. {Five patients did not react to either drug at 1 :IOOG) Intradermal test concentration 1:1000 Atracurium Tubocurarine Both drugs

15 12 11

1:10000

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Bronchial narrowing improved. After reversal of residual paralysis she was extubated awake. In the recovery ward the lungs were now clear. FIG. 1. Extract from an original anaesthetic adverse reaction report to the Sheffield Unit. This is typical of more severe reactions involving atracurium. Note that it was still possible to complete the operation.

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TABLE IV. Frequency of adverse reaction reports. Sux. = suxamethonium; Ale. => alcuronium; Atr. = atracurium; Tub. = tubocurarine; Pan. = pancwonium; Vec. = vecuromum; Gall. = gallamxnt. (Reproduced, with permission, from Watkins (1985)) Hypnotic agent Thiopentone Methohezitoae Etomidate Altbesin

Year 1984 1983 1984 1983 1984 1983 1984 1983

Reported cues 39 28 7 2 7 5 5 13

Number of deaths

Hypnotic given alone 1 3 0 1 0 3 11

Co-adminiitered neuromuscular drug Sux.

Ale.

Atr.

Tub.

Pan.

Vec.

Gall.

17 11 5 1 3 3 0 0

CONCLUSIONS

In clinical terms, atracurium emerges as a safe drug with useful neuromuscular blocking properties. It does have a tendency to produce a high incidence of cutaneous manifestations, the majority of which are harmless allergoid reactions resulting in skin histamine, rather than plasma histamine release. A number of systemic anaphylactoid situations may also be generated which reflect both the chemical nature of the drug and insufficient care by the anaesthetist. While for the most part these additional reactions are also harmless clinically, the mixing and precipitation which occurs between thiopentone and atracurium injected through the same indwelling cannula without saline wash-through may initiate systemic aggregate anaphy laxis and potentially life threatening bronchospasm.

and Savarese, J. J. (1982). Histamine release by neuromuscular blocking agents in man. Klin. Wochenschr., 60, 891. Robertson, E. N., Booij, L. H. D., Fragen, R. J., and Crul, J. T. (1983). Intradermal histamine release by 3 muscle relaxants. Acta Anaeslhesiol. Scand., 27, 203. Watkins, J. (1981). Mechanisms and factors predisposing towards advene response to intravenous anaesthetic substances; in Adverse Reactions of Anaesthetic Drugs (ed. J. A. Thornton), p. 137. Amsterdam: Elsevier/North Holland. (1985). Adverse anaesthetic reactions. An update from a proposed national reporting and advisory service. Anaesthesia, 40, 797. Clarke, R. S. J. (1978). Report of a symposium: adverse responses to intravenous agents. Br. J. Anaesth., 50, 1159. Wild, G., and Clarke, R. S. J. (1985). Allergy, plasma IgE level and anaphylactoid response: a hypothesis. Anaesthesia, 40,362. Wood, M., Watkins, J., Wild, G., Levy, C. J., and Harrington, C. (1985). Skin testing in the investigations of reactions to intravenous anaesthetic drugs. A prospective trial of atracurium and tubocurarine. Ann. Franc. Anesth. Reamm., 4, 176.

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of these drugs, with the exception of the extenREFERENCES sive use of suxamethonium. However, although Fisher, M. (1984). Intradennal testing after anaphylactoid specific IgE antibodies were detected against reaction to anaesthetic drugs: practical aspects of performance and interpretation. Anaeslh. Intens. Care, 12, 115. suxamethonium in one patient, the hypnotic drugs appeared to be implicated in most reactions. The Lavery, G. G., Clarke, R. S. J., and Watkins, J. (1985). Histaminoid responses to atracurium, vecuronium and ranking is thus likely to represent the relative risks tubocurarine. Arm. Franc. Anesth. Reamm., 4, 180. of various drug combinations, rather than specific Lorenz, W., Doenicke, A., Scheming, B., Mamorski, J., Weber, individual neuromuscular agent responses. D., Schwartz, B., and Neugebauer, E. (1980). H1 + H2 receptor antagonists for premedication in anaesthesia and Current studies in this Department (Watkins, surgery: a critical view based on randomized clinical trials Wild and Clarke, 1985) and with our colleagues in with Haemaccel and various anti-allergic drugs. Agents Belfast (Lavery, Clarke and Watkins, 1985) Actions, 10, 114. indicate that the release of histamine by both Neugebauer, E. (1981). The role of histamine in adverse reactions to intravenous agents; in Adverse tubocurarine and atracurium occurs in intradermal Reactions of Anaesthetic Drvgs (ed. J. A. Thornton), p. 169. tests predominantly in patients with low circulating Amsterdam: Elsevier/North Holland. concentrations of plasma IgE (10 u. ml"1). About Ohmann, C , Grote, B., and Neugebauer, E. 20 % of the population possess such low concentra(1982). Definition and classification of the histamine-release tions, and these also appear to predispose to response to drugs in anaesthesia and surgery: studies in the conscious human subject. Klin. Wochtnsckr., 60, 896. clinical systemic anaphylactoid response by nonMoss, J., Philbin, D. M., Rosow, C. E., Basta, S. J., Gelb, C , immune histamine release.