74

Histamine and Antihistamines in

Anaesthesia and SurgerySEVENTY years after the characterisation of

histamine by DALE and LAIDLAW, with our H, and H2receptor antagonists2 and our sensitive assays,3,4 stillno-one seems willing to assign a distinct function to thisamine in health or disease.5 When some worker bringshistamine back into the reckoning, the substance tendsto be coupled, dispiritingly, with "serotonin, kinins,prostaglandins, leukotrienes, and so on". Surely, withthe powerful tools now at our disposal, we can dobetter.

’

In type I hypersensitivity the involvement ofhistamine is almost certain, but quantitativeinformation is hard to get. Much more obvious is therole of histamine in reactions to certain intravenousanaesthetic drugs, muscle relaxants, and plasmasubstitutes.6 The accompanying figure shows how, bymeans of a decision tree, a reaction mainly. due tohistamine release can be identified. A tree of this sort,with H, and H2 receptor antagonists at node 3,indicates that anaphylactoid reactions to propanididand polygeline (the outdated formulation’) were dueprincipally to histamine release whereas anaphylactoidreactions to dextran were not.6 There is no denying thatother mediators were released or generated by mastcells, but these did not seem to cause the symptoms;and three observations speak for the predominant roleof histamine.6 Firstly, the severity and time course ofsigns and symptoms-in order of frequency tachy-cardia, metallic taste, flush, cough, head congestion,runny eyes, nausea, hypotension, bronchospasm,circulatory arrest, cardiac arrest-correlated well withthe plasma histamine concentration in peripheralblood. Secondly, a small intravenous dose of exogenoushistamine (0’ 6 g/kg), in subjects who had had anaphy-lactoid reactions, mimicked the symptoms of the reac-tions and raised plasma histamine levels to the extentseen in the original reactions. Thirdly, in controlledtrials these clinical reactions, were prevented by pro-phylactic administration of HI and H2 receptor anta-gonists in combination (0’ 1 mg/kg dimethpyrindeneand 5 mg/kg cimetidine intravenously).

1. Dale HH, Laidlaw PP The physiological action of &bgr;-imidazolyl ethylamine. J Physiol(Lond) 1910, 41: 318

2 Black JW, Duncan WAM, Durant CJ, Ganellin CR, Parsons EM. Definition andantagonism of histamine H2-receptors. Nature 1972; 236: 385-90.

3 Lorenz W, Benesch L, Barth H, Matejka E, Meyer R, Kusche J, Hutzel M, Werle E.Fluorometric assay of histamine in tissues and body fluids: Choice of the

purification procedure and identification in the nanogram range. Z Analyt Chem1970; 252: 94-98

4. Beaven MA, Jacobsen S, Horáková Z. Modification of the enzymatic isotopic assay ofhistamine and its application to measurement of histamine in tissues, serum andurine. Clin Chim Acta 1972; 37: 91-103

5 Black JW, Uvnäs B. Paper read at meeting on Histamine and Antihistamines inAnaesthesia and Surgery, Munich, June 3-5, 1981

6 Lorenz W, Doenicke A, Schöning B, Neugebauer E The role of histamine in adversereactions to intravenous agents. In: Adverse reactions of anaesthetic drugs.Amsterdam Elsevier/North-Holland Biomedical Press, 1980: 169-238.

7. Lorenz W, Doenicke A, Schoning B, Karges H, Schmal A. Incidence and mechanismsof adverse reactions to polypeptides in man and dog WHO Symposium onStandardization of Albumin, Plasma Substitutes and Plasmapheresis. Geneva-W H.O. (in press).

Decison tree.

From Lorenz et al. 6

These observations were the stimulus for a

symposium in Munich last month on histamine andantihistamines in anaesthesia and surgery.8 Raised

plasma histamine concentrations were reported afteradministration of the general anaesthetic agentspropanidid, althesin, thiopentone, and metho-

hexitone, and of the benzodiazepines flunitrazepamand lormetrazepam-whereas etomidate and diazepam(when not dissolved in cremophor El) seemed free ofthis effect. When etomidate was used as the induction

agent, to avoid the uncertainty of drug combinations, araised- plasma histamine was encountered with suc-cinylcholine, alcuronium, and pancuronium, and also,in a controlled clinical trial in the U.S.A., with tubo-curarine. In clinical use, atropine was no more likely tocause histamine release than was saline. Histaminerelease was reported even with the histamine receptorantagonists chlorpheniramine, cimetidine, and raniti-dine when they were injected as intravenous boluses;but, in a controlled trial in 300 patients, this effect wasnot seen with cimetidine given slowly (over 2 minutes).Single instances of massive life-threatening histaminerelease, with plasma levels of 20-110 ng/ml, werereported after administration of human albumin, thelocal anaesthetic agent mepivacaine, and bone cement.The 4th node of the decision tree asks whether the

histamine is endogenous or exogenous. When blood istransfused through a filter and under pressure,histamine is squeezed from cells and results in a raisedplasma level; and, in operations such as

cholecystectomy, detachment of adhesions results in aflush of histamine into the circulation. In neither ofthese circumstances is the raised histamine due to truerelease. Where drugs do cause histamine release themechanisms are various-pharmacological, activation

8. Symposium on Histamine and Antihistamines in Anaesthesia and Surgery, Munich,June 3-5, 1981. Proceedings to be published in Klinische Wochenschrift.

75

of the complement system by the classical or alternativepathway, and type I IgE or IgG4 mediated

anaphylaxis.9 At the symposium it became clear thatthe reporting of adverse reactions of this sort variesenormously. In several controlled trials the incidenceof systemic anaphylactoid reactions has been over 1%,whereas in reviews10 and committees reports I 1,12 it hasbeen 300 times lower. Only in the circumstances ofcohort research (definitions fixed in advance; at leastsingle-blind assessment) will the milder effects such astachycardia emerge as adverse reactions.Already there are ways of preventing these side-

effects of anaesthesia and surgery. In animals,’ and inthe human heart in vitro,14 a combination ofH and H2antagonists counters the effects of exogenoushistamine; and in patients, volunteers, and dogs withincreasingly severe reactions to polygeline1s,16 andmorphine17 (cutaneous and systemic life-threateninghistamine release) the first results of controlled trialsare encouraging. But there are other ways which havebeen successfully pursued in the past decade-thediscarding of some histamine-releasing drugs, 18development of better drugs’9 and solvents,20limitation of prescribing indications, and avoidance ofunduly rapid administration.

CARBON MONOXIDE, AN OLD ENEMY FORGOT

TWENTY years ago town gas in Britain might contain up to30% carbon monoxide, and the average was 12%. Every yearthis lethal mixture claimed between 1500 and 2000 lives byaccident or suicide. The past decade has seen the final changeto carbon-monoxide-free natural gas and the latest figureslshow the effect:

9 Watkins J, Udnoon S, Taussig PE. Mechanisms of adverse response to intravenousagents in man. In Adverse response to intravenous drugs. London: Academic Press.New York. Grune and Stratton, 1978: 71-82

10 Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volumesubstitutes. Lancet 1977; i: 466-69.

11. Ahnefeld FW, Fischer F, Frey R, Kilian J, Schöning B. Der Infusions-zwischenfallnach kunsthchen Plasmasubstituten im Meldekollektiv derArzneimittelkommission. Anaesthesist 1979; 28: 207-20.

12 Furhof AK Anaphylactoid reaction to dextran-A report of 133 cases. Acta AnaesthScand 1977; 21: 161-67.

13. Owen D Effects of exogenous and endogenous histamine on the circulatory systems.Paper read at Symposium on Histamine and Antihistamines in Anaesthesia andSurgery, Munich, June 3-5, 1981.

14 Levi R Effects of histamine on the heart: Involvement of H1-and H2-receptors Paperread at Symposium on Histamine and Antihistamines in Anaesthesia and Surgery,Munich, June 3-5, 1981.

15. Schoning B, Lorenz W Prevention of allergoid (cutaneous anaphylactoid) reactions topolygeline (Haemaccel® ) in orthopaedic patients by premedication with H1 andH-receptor antagonists. WHO-Symposium on Standardization of Albumin,Plasma Substitutes and Plasmapheresis. Geneva: W.H O. (in press).

16. Lorenz W, Doenicke A Histamine release in clinical conditions Mount Sinai J Med1978; 45: 357-86

17 Philbin DM, Moss J, Rosow CE, Savarese JJ. Evaluation of and protection fromnarcotic induced histamine release in man. Paper read at Symposium on Histamineand Antihistamines in Anaesthesia and Surgery, Munich, June 3-5, 1981

18 Clarke RSJ, Dundee JW Adverse reactions to intravenous induction agents. In:

Adverse reactions to anaesthetic drugs. Amsterdam- Elsevier/North-HollandBiomedical Press, 1981 29-46.

19. Doenicke A Lorenz W, Beigl R, Bezecny H, Uhlig G, Kalmar L, Praetorius B, MannG Histamine release after intravenous application of short-acting hypnotics Acomparison of etomidate, althesin (CT 1341) and propanidid. Br J Anaesth 1973;45: 1097-1104.

20 Watkins J Mechanisms and factors predisposing towards adverse response to

intravenous anaesthetic substances. In: Adverse reactions to anaesthetic drugs.Amsterdam Elsevier/North-Holland Biomedical Press, 1981: 137-68.

1 Hansard (Commons), March 4, 1981, col. 124.

Deaths from Gas-induced Carbon-monoxide Poisoning inEngland and Wales

Nevertheless people still die and the figure for 1979 showsan increase large enough to be disturbing. The above figuresinclude the gaseous fuels, propane and butane, as well as gasdistributed from the mains. It is also estimated that there are30-60 deaths a year due to carbon-monoxide poisoning fromother domestic fuels, such as coal, coke, and wood.Many people are unaware that carbon monoxide can be

generated by incomplete combustion of these fuels. Thecause may be a leaking appliance, inadequate flues, or

restriction of air supply. Fuel is expensive, labour is

expensive. Over-enthusiastic amateur draught proofmg, do-it-yourself installations, and the use of auxiliary heaters,burning paraffin or bottled gas, in small rooms are waysof keeping warm more cheaply. The poor, the old, the sick,and the student are likely to be particularly vulnerable, Theimmigrant from warmer climates is also at special risk.For every death there may be many people with chronic ill-

health of unidentified cause which is in fact the result of

exposure to carbon monoxide. In some fatal cases the victimshad consulted a doctor or a hospital in the weeks precedingthe disaster for symptoms which could have been caused bycarbon monoxide.

Symptoms of chronic exposure are vague. Headache is themost constant, often accompanied by nausea and vomiting insevere cases. Muscular weakness and tiredness on moderateexertion and other symptoms suggestive of myocardialinadequacy, such as reluctance to climb stairs or hurry, maynot be what the patient complains of, but they may be elicitedin the history. Physical examination is unhelpful. The pulseis usually more rapid than might be expected, but within thehigh normal range. The diagnosis is best made by beingaware of the possibility. In the winter months a questionabout how the rooms are heated is relevant. The doctor on ahome visit may see staining around stoves and fire surrounds,suggesting the escape of fumes ; or excessive draught proofmgmay be restricting air supply. That neglected organ, the nose,may also provide evidence. In the summer, particularly theEnglish summer, the sudden collapse of a family in a caravanmay be due to carbon monoxide and not a surfeit of cockles orother unaccustomed foods.The diagnosis can be confirmed by estimating

carboxyhaemoglobin in the blood, which does not require alaboratory but can be done quickly and easily by measuringcarbon monoxide in expired air with an apparatus similar tothe breathalyser. Carbon monoxide in the expired air is inequilibrium with carbon monoxide in the blood2 and thepercentage of carboxyhaemoglobin is read directly from thetube. The method is accurate enough for clinical purposes.The significance of low blood levels of carboxyhaemo-

globin is still debated. Endogenous production of carbon

2. Peterson JE. Post-exposure relationship of carbon monoxide in blood and expired air.Arch Envir Hlth 1970; 21: 171-73.