Br.J. Anaesth. (1978), 50, 73
PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY LONDON MEETING OCTOBER 22, 1977
J. WATKINS, S. UDNOON AND P. E. TAUSSIG Departments of Immunology and Anaesthetics, Hospital Medical School, Sheffield
Hallamshire
We have reported previously on the role of complement proteins in "anaphylactic reactions" to i.v. anaesthetic agents (Watkins et al., 1976). Our analyses of reactions reported during 1974, 1975 and 1976 are summarized in table I.
Cases analysed
Complement involved
IgE involved
1974 Althesin Methohexitone
5 1
5 1
2 1
1975 Althesin Thiopentone
7 1
7 0
2 0
1976 Althesin Propanidid Thiopentone
to to to
TABLE I. Complement and IgE involvement in adverse response
10 2 1
1 0 2
Three types of mechanism were recognized: Type I reactions involving IgE and the direct liberation of histamine, immune reactions releasing histamine via the classical (C4) complement pathway and the alternate pathway involving direct activation of C3. Differences in complement pathway activation may account for the variability in response time and clinical severity observed in reactions to Althesin. Although IgE was involved in some Althesin reactions, a higher incidence of involvement occurred in the barbiturate responses. The factors likely to predispose to an anaphylactoid response are: genetic, pre-existing immunopathological conditions, frequency of exposure to a particular drug and combinations of these. Genetic factors include both IgE (atopy) and complement anomalies. Immunopathological conditions involving circulatory immune complexes, such as chronic infection, SLE and RA, may
"prime" complement systems, making them susceptible to activation by i.v. drugs. This aspect was studied in vitro by incubation of plasma samples with synthetic primers (for example, heat aggregated IgG) and anaesthetic drugs. Complement activation was assessed by two-dimensional immunoelectrophoresis. Some of the results were unexpected: one particular plasma revealed a high level of C3 conversion with thiopentone, but not Althesin, propanidid or etomidate, indicating a necessary combination of genetic and immunopathological factors. We conclude that an anaphylactoid response can be attributed to a range of mechanisms and predisposing factors and no drug may be considered to be completely safe. REFERENCE
Watkins, J., Udnoon, S., Appleyard, T. N., and Thornton, J. A. (1976). Br. J. Anaesth., 48, 457.
IMMUNOSUPPRESSION AMONG ANAESTHETISTS K. W. PETTINGALE, N. AL-AFFAS, D. E. H. TEE AND L. STRUNIN Department of Medicine, Immunology and Anaesthetics, King's College Hospital and Medical School, London
Volatile anaesthetic agents have been shown to be toxic to lymphocytes at anaesthetic concentrations in vivo and in vitro (Duncan and Cullen, 1976). This has led to concern that exposure to low concentrations of volatile and gaseous anaesthetics in the operating theatre may induce a degree of immunosuppression in anaesthetists. Two studies (Bruce, 1972; Salo and Vapaavuori, 1976) failed to demonstrate any reduced immunocompetence in theatre personnel, but the number of subjects studied was small and the age range restricted. In the present study, tests of immunological competence were performed on venous blood samples from 14 anaesthetists and 14 age- and sex-matched control subjects not engaged in anaesthetic practice. There was a significant reduction in the total lymphocyte count, the T-lymphocyte count and the phytohaemagglutinin (PHA) transformation on washed whole blood in the anaesthetists compared with the control subjects. Among the anaesthetists there was no relationship between the reduction in total lymphocyte count and either age or time (in years) engaged in anaesthetic practice.
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COMPLEMENT ACTIVATION PATHWAYS AND ADVERSE (ANAPHYLACTOID) RESPONSES TO I.V. ANAESTHETIC AGENTS
BRITISH JOURNAL OF ANAESTHESIA
74 However, there was a highly significant inverse correlation between PHA transformation and age and time engaged in anaesthetic practice. It is suggested that immunocompetence of anaesthetists may not be normal, and that a large study over the whole working age range is indicated. REFERENCES
Examination of the cross-relationship between atopy and allergy showed that atopic patients were more likely to have an allergy than non-atopic patients (36.2% v. 11.4%). Of the 10 000 patients, 309 had both an atopy and an allergy. This group may be most at risk of developing an adverse reaction and it represents about three per onehundred patients.
THE INCIDENCE OF ATOPY AND ALLERGY IN 10 000 PREANAESTHETIC PATIENTS
THE EFFECTS OF ANAESTHETICS ON SOME ENZYMES S. M. KING and D. C. WHITE*
J. P. H. FEE, J. R. MCDONALD, R. S. J. CLARKE, J. W. DUNDEE AND P. K. PAL
Memorial University, Newfoundland
Department of Anaesthetics, The Queen's University of Belfast G. D. ADEY Department of Biochemistry, University of Aberdeen Adverse reactions to i.v. anaesthetic agents may be an increasing problem for anaesthetists. Studies of 100 patients Most enzymes which have been studied in vitro have been who had experienced adverse reactions to thiopentone or found to be unaffected by anaesthetics even at high concenAlthesin revealed a high incidence of a history of atopy or trations (Brammall, Beard and Hulands, 1974). One excepallergy (Clarke et al., 1975). This survey was designed to tion is bacterial luciferase, which has been shown to be assess the significance of these findings. depressed reversibly in vitro by anaesthetics at concentraAnaesthetists at various hospitals in Great Britain and tions within the clinical range (White, Wardley-Smith and Ireland were asked to complete a data sheet on consecutive Adey, 1975). The structure of this enzyme has not been patients presenting for anaesthesia during part of 1976 elucidated fully, but it is known to have a highly hydroand 1977. The incidences of atopy (eczema, hay fever, phobic active centre with a reactive sulphydryl group at or asthma) and allergy (to penicillin, other antibiotics, narcotics, close to the active centre (Nicoli, Meighen and Hastings, iodine, zinc oxide plaster and other causes) were calculated 1974). from 10 000 completed data sheets. The frequency of Review of the structure of those enzymes of which seconatopy or allergy, or both, in the study group was signifi- dary and tertiary structures are known, showed that papain cantly lower than in those who had experienced reactions and bromelain resembled luciferase in the chemical nature to thiopentone or Althesin (P< 0.0001) (table I). of their active sites and the presence of an active sulphydryl group. By contrast, lysozyme and a-chymotrypsin do not TABLE I. Percentage incidence of atopy {eczema, hay fever possess active sulphydryls, and their active centres are less or asthma) and allergy {to drugs or other materials) in patientshydrophobic than papain or bromelain. The actions of these four enzymes in the presence of who had an adverse reaction to thiopentone or Althesin anaesthetic agents were studied using standard assay tech{reported cases) and in the patients in this survey niques. It was found that papain and bromelain were Atopy depressed reversibly by anaesthetic concentrations within and/or the clinical range. Lysozyme and a-chymotrypsin were Atopy Allergy allergy unaffected. No. Patients These observations may be relevant to the mechanism Adverse reactions to 100 14 29 41 of anaesthesia, since it is known that the site of action of thiopentone or anaesthetics is of a hydrophobic nature. Althesin REFERENCES
This survey
10 000
8.5
13.5
19.0
Female patients had a higher incidence of atopy than males (9.2% v. 7.5%) and a higher incidence of allergy than males (16.2% v. 9.2%). Grouping into four age ranges (less than 13, 13-20, 21-59 and more than 59 yr) showed that the incidence of atopy was highest in the 13-20 age group in females and in the over-59 age group in males. The incidence of allergy was highest in the 21-59 age group in both sexes.
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Bruce, D. L. (1972). Anesthesiology, 37, 76. Duncan, P. G., and Cullen, B. F. (1976). Anesthesiology, REFERENCE 45, 522. Clarke, R. S. J., Dundee, J. W., Garrett, R. T., McArdle, Salo, M., and Vapaavuori, M. (1976). Br. J. Anaesth., 48, G. K., and Sutton, J. A. (1975). Br.J. Anaesth., 47, 575. 877.
Brammall, A., Beard, D. J., and Hulands, G. H. (1974). Br. J. Anaesth., 46, 643. Nicoli, M. A., Meighen, E. A., and Hastings, J. W. (1974). J. Biol. Chem., 249, 2385. White, D. C , Wardley-Smith, B., and Adey, G. D. (1975). In Progress in Anesthesiology, Vol. 1 (ed. B. R. Fink). New York: Raven Press. * Present address: Division of Anaesthesia, Clinical Research Centre, Watford Road, Harrow, Middlesex.
PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY HYPOXIC PULMONARY VASOCONSTRICTOR RESPONSE IN DOGS DURING AND AFTER THE INFUSION OF SODIUM NITROPRUSSIDE ANNE E. H. HILL, M. K. SYKES, B. CARRUTHERSJ M. K. CHAKRABARTI AND A. R. TAIT
Department of Anaesthetics, Royal Postgraduate Medical School, Hammersmith Hospital, London
REFERENCES
Sykes, M. K., Hill, A. E. G., Loh, L., and Tait, A. R. (1977). Br. J. Anaesth., 49, 285. Wildsmith, J. A. W., Drummond, G. B., and MacRae, W. R. (1975). Br. J. Anaesth., 47, 1205.
THE ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE PATHOGENESIS OF HALOTHANE-INDUCED MALIGNANT HYPERTHERMIA IN THE PIETRAIN PIG J. N. LUCKE AND H. R. DENNY
Department of Veterinary Surgery, University of Bristol, Langford, Bristol
G. M. HALL
Department of Anaesthetics, Royal Postgraduate Medical School, Hammersmith Hospital, London
R. LOVELL AND D . LISTER
A.R.C. Meat Research Institute, Langford, Bristol The effect of total adrenal suppression has been investigated in Pietrain pigs in order to determine if the sympathetic response either plays an important role in the course of malignant hyperthermia (MH) or occurs as a secondary response to the biochemical and physiological changes which initiate the syndrome. Bilateral adrenalectomy was carried out through a midline laparotomy in 10 Pietrain pigs (mean weight 40 kg + 4 SEM). The anaesthetic technique involved i.m. injection with ketamine 20 mg kg- 1 to induce basal narcosis, endotracheal intubation after the injection of thiopentone 3-5 mg kg- 1 pancuronium 0.2 mg kg"1 and ventilation with 66% nitrous oxide in oxygen using a volume-cycled ventilator with no rebreathing. After extraction in perchloric acid, noradrenaline and adrenaline contents of excised adrenal glands were measured by the semi-automated fluorimetric method (McCullough, 1968). Noradrenaline was found to be the predominant adrenal catecholamine. All the pigs recovered from the anaesthetic, but four died 7-13 h after surgery despite glucocorticoid and mineralocorticoid supplementation before surgery. Six pigs survived adrenalectomy and were studied 7 days later using the anaesthetic technique and surgical preparation described previously (Lucke, Hall and Lister, 1976). Bretylium tosylate 20 mg kg"1 was administered i.v. and, after 45 min was allowed for establishment of adrenergic blockade, the pigs were ventilated with 1 % halothane for three 10-min periods, separated by 5-min intervals. All six pigs survived the halothane challenge and did not show any metabolic or physiological changes characteristic of porcine MH. The separate effects of adrenalectomy and bretylium on the halothane-induced response were investigated using the same experimental protocol. Three of four adrenalectomized pigs survived with no signs of increased muscle metabolism, but the remaining adrenalectomized animal developed MH 5 min after halothane exposure. One of four pigs given bretylium 10 mg kg"1 failed to develop MH but in another, a dose of 10 mg kg- 1 and in two others a dose of 20 mg kg- 1 did not prevent a hyperthermic response to halothane. It is concluded that adrenergic blockade produced by bilateral adrenalectomy together with bretylium abolished completely the sensitivity to halothane-induced MH in Pietrain pigs. Adrenalectomy alone provided partial protection, which indicates that catecholamines derived from the adrenal medulla are probably more important than those produced elsewhere. It is suggested that during adrenergic blockade muscle metabolism is so low that, when challenged with halothane, the intracellular calcium concentration fails to reach the value that will precipitate MH. This situation is similar to that suggested for partial protection against halothane-induced MH produced by neuromuscular blockade with large doses of pancuronium (Hall, Lucke and Lister, 1976).
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Arterial hypoxaemia in patients has been reported during induced hypotension with sodium nitroprusside (Wildsmith, Drummond and MacRae, 1975). A possible explanation is that the drug might cause a redistribution of blood flow to underventilated areas of lung either by a direct or indirect action on the pulmonary vasculature, or by depression of the pulmonary vasoconstrictor response to alveolar hypoxia. Experiments wereperformed to determine if sodium nitroprusside could affect the hypoxic vasoconstrictor response by measuring the redistribution of blood flow between the lungs in response to unilateral hypoxia. Ten dogs were anaesthetized with thiopentone and pentobarbitone and a double-lumen endotracheal tube was inserted to permit separate ventilation of the right and left lungs. Tidal volumes were maintained constant and the distribution of blood flow to each lung was followed by recording the radioactivity of the mixed expired gas during the continuous i.v. infusion of xenon-133 (Sykes et al., 1977). The pulmonary vasoconstrictor response was tested by ventilating the left lung with 7% oxygen followed by 100% nitrogen before, during and after an i.v. infusion of sodium nitroprusside. When the drug was given at a rate sufficient to reduce mean arterial pressure to 80 mm Hg, there was a significant reduction in the pulmonary vasoconstrictor response to both levels of alveolar hypoxia when compared with control responses. The responses after administration of the drug were significantly greater than the initial responses. During unilateral hypoxia, arterial oxygen tensions were less, while mixed venous oxygen tensions were unchanged during the administration of sodium nitroprusside compared with the control hypoxic periods. These results suggest that sodium nitroprusside may increase arterial hypoxaemia by depressing the homeostatic diversion of blood flow away from hypoxic areas of lung.
75
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BRITISH JOURNAL OF ANAESTHESIA REFERENCES
paedic surgery may be influenced by the choice of anaesthetic agents. Since a low spinal anaesthetic has minimal effects on the reactivity of the circulation or on the respiratory centre, the changes in acid-base status were studied in a group of 14 healthy adults undergoing elective orthopaedic surgery on the lower limb under spinal analgesia. The mean tourniquet time was 75 min. There was a statistically significant decrease in arterial base excess which reached a peak 5 min after tourniquet release, and which was not fully restored 20 min after the limb had been perfused with blood (fig. 1). There was a statistically significant decrease in Paco,> but the maximum hypocapnia time was phase-shifted from the time of maximum metabolic acidosis by approximately 10 min (fig. 1). This phase shift is presumably attributable to the delay in crossing the blood-brain barrier of hydrogen ions and suggests that peripherally located hydrogen ion receptors have little influence on respiratory centre control of acidof the base homeostasis. orthoKnee joint replacement in the arthritic elderly atherosclerotic patient is performed frequently with techniques 12 designed to minimize blood loss. Since these patients tolerate acidosis very badly, we suggest that it would be useful to administer a small quantity of sodium bicarbonate just before release of the tourniquet.
Hall, G. M., Lucke, J. N., and Lister, D. (1976). Br. J. Anaesth., 48, 1135. Lucke, J. N., Hall, G. M., and Lister, D. (1976). Br. J. Anaesth., 48, 297. McCullough, H. (1968). J. Clin. Pathol., 21, 759. BLOOD-GAS CHANGES FOLLOWING TOURNIQUET RELEASE DURING SPINAL ANAESTHESIA Sundsvall Hospital, Sweden P. J. TOMLIN
University Department of Anaesthetics, Birmingham The extent of metabolic acidosis and the response respiratory centre following limb ischaemia during 11 1
CESS (i
l-2..
* « — / 1
BASE
X)
THE EFFECT OF THIOPENTONE AND SUXAMETHONIUM ON GASTROOESOPHAGEAL PRESSURE GRADIENTS G. SMITH, R. DALLING, L. R. DOUGAN AND T. I. R. WILLIAMS
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H. HASSAN AND J. GJESSING
University Departments of Anaesthesia and Surgery, Western Infirmary, Glasgow -0.4
O U _nu
t -0.1
5
10
15
20
TIME AFTER TOURNIQUET RELEASE (min) FIG. 1. Blood-gas changes following tourniquet release (mean + SEM).
Several investigations have revealed an increase in gastric pressure occurring during fasciculations induced by suxamethonium, and it has been suggested that this increase predisposes to regurgitation of gastric contents (La Cour, 1969; Miller and Way, 1971). To test this hypothesis, we have measured the pressure gradient between the stomach and the lower oesophageal sphincter (high pressure zone, or HPZ) during the administration of suxamethonium. Fifteen patients undergoing vagotomy and pyloroplasty received premedication comprising morphine 10 mg i.m. Thirty minutes before anaesthesia was induced, a triple-catheter orogastric tube was passed for measurement of pressures in the stomach, HPZ and oesophagus. Each catheter was perfused continuously with saline 1 ml min- 1 . After gastric motility had returned to normal, pre-oxygenation was carried out for 3 min before anaesthesia was induced with thiopentone 4 mg kg- 1 followed by suxamethonium 100 mg. Before anaesthesia, the mean gradient between oesophageal sphincter and stomach (HPZ —gastric pressure) was 5.4 mm Hg (+ 0.64 SEM) and, during fasciculations, this increased to 6.9 + 1.2 mm Hg. Thiopentone produced a small decrease in both gastric and HPZ pressures.
PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY As patients with gastro-duodenal pathology may have altered HPZ characteristics, we are currently obtaining data in patients undergoing anaesthesia for minor surgery. REFERENCES
La Cour, D. (1969). Acta Anaesthesiol. Scand., 13, 255. Miller, R. D., and Way, W. L. (1971). Anesthesiology, 34, 185.
REFERENCES
Aitkenhead, A. R., Wishart, H. Y., and Peebles-Brown, D. A. (1977). Br. J. Anaesth., 50 (in press). Everett, W. G. (1974). Ann. R. Coll. Surg. Engl., 55, 31. Goligher, J. C , Morris, C , McAdam, W. A. F., De Dombal, F. T., and Johnston, B. (1970). Br. J. Surg., 57, 817.
CLINICAL EVALUATION OF THE ISO-SHUNT DIAGRAM P. G. LAWLER
Division of Anaesthesia, Clinical Research Centre, Harrow A. R. AITKENHEAD, D. G. GILMOUR, A. P. HOTHERSALL AND I. McA. LEDINGHAM
A. M. HEWLETT
Departments of Anaesthesia and Surgery, Western Infirmary, Division of Clinical Anaesthesia, Northwick Park Hospital, Harrow Glasgow The incidence of dehiscence after colonic anastomoses may be as high as 69% (Goligher et al., 1970) and the mortality following clinically evident anastomotic dehiscence is about 35%. The blood supply to the colon is an important factor in maintaining an intact anastomosis (Everett, 1974). A recent survey (Aitkenhead, Wishart and Peebles-Brown, 1977) has suggested that spinal anaesthesia may reduce the incidence of anastomotic breakdown following large bowel surgery. The present study was designed to investigate the effects of subarachnoid spinal nerve block on colonic blood flow. Cardiac output, e.c.g., systemic and pulmonary arterial and right atrial pressures were recorded in 19 artificially ventilated dogs anaesthetized with pentobarbitone 30-40 mg kg-1. Following splenectomy, a catheter was positioned with its tip in the superior mesenteric artery just proximal to the branch supplying the colon, and a second catheter was positioned in the main marginal vein of the colon. Colonic blood flow was measured by injecting xenon-133 500 (iCi through the mesenteric arterial catheter and recording its clearance from the colon with a collimated scintillation counter. Under radiographic control, an 18-gauge needle was introduced at L6-7 into the subarachnoid space for the injection of 0.5% bupivacaine 0.2 ml kg-1. A comparison has been made between measurements obtained immediately before and 20 min after the injection of bupivacaine. Spinal nerve block produced decreases in mean arterial pressure (33.1%) and heart rate (9.6%) but an increase in colonic blood flow of 22.4% in association with a 44.5% decrease in colonic vascular resistance. There were no changes in cardiac output, colonic oxygen consumption, or arterial oxygen or carbon dioxide tensions. It is postulated that, by increasing blood flow to the colon, spinal nerve block may improve the oxygenation of colonic anastomoses both during operation and also in the early period after operation, and thereby may reduce the incidence of dehiscence occurring clinically.
Benatar, Hewlett and Nunn (1973) proposed that the gas exchange abnormality occurring in patients during anaesthesia or in the intensive therapy unit-could be considered as "shunt". They expressed this as "virtual shunt" and derived relationships correlating inspired oxygen fraction (Flo,), arterial oxygen tension (/"ao,) and "virtual shunt", expressed as a percentage (£)s/()t%). This information was expressed graphically. This concept has been evaluated in 16 patients admitted consecutively to the intensive therapy unit. One patient was investigated on two separate occasions. In these patients, cardiovascular and respiratory status was' considered stable. In all patients an arterial line had been inserted for other reasons. The patients were ventilated mechanically using a minute volume divider (Brompton Manley). ' During the investigation, which lasted approximately 2 h, the patient remained supine and received no physiotherapy. Flo, w a s increased in steps at 20-min intervals until F i 0 w a s !-0. After a further 20 min Flo w a s reduced stepwise.' Minute and tidal volume remained constant throughout. Arterial blood-gases were measured at the end of each 20-min period. A minimum of five blood-gas measurements was made. In general, virtual shunt during the periods of both increasing and decreasing inspired oxygen remained constant and followed the same path, suggesting that no absorption collapse occurred during the period of ventilation with 100% oxygen. Some scatter of results compatible with the random error of measurement occurred. In order to gain greater precision, the virtual shunt at each point was calculated, using a programmable calculator. Results were plotted as virtual shunt (%) against Flo,, and regression lines drawn. Three groups of patients were distinguished: (1) Those in whom virtual shunt remained largely unchanged (9/15).
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THE EFFECTS OF SUBARACHNOID SPINAL BLOCK ON COLONIC BLOOD FLOW IN THE DOG
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BRITISH JOURNAL OF ANAESTHESIA
(2) Those in whom virtual shunt decreased with increasing Flo, ( o n e patient on two occasions). (3) Those in whom virtual shunt increased as Flo, w a s increased (four patients).
FRESH GAS REQUIREMENTS DURING SPONTANEOUS VENTILATION WITH THE BAIN ANAESTHETIC SYSTEM
In the majority of patients the data allowed prediction of Flo, f° r a safe -f^o, from a given mean ()s/$t o r from that derived when breathing 100% oxygen (Pontoppidan, Geffin and Lowenstein, 1972). It is therefore proposed that the use of the virtual shunt concept enables reasonable prediction of the required FIQ, in the clinical situation. To this end, a further graph, to be used in conjunction with the iso-shunt graph, has been drawn.
Magill Department of Anaesthetics, Westminster Hospital, London Five conscious volunteers breathed a non-anaesthetic gas through a Bain anaesthetic system arranged as a modified Mapleson D system. Measurements of ventilation and of tidal gas composition were made whilst fresh gas flow was reduced from initial high values to one at which rebreathing occurred. Marked increases in ventilation occurred in these subjects when fresh gas flow was between two-and-a-half and three times minute volume. Fresh gas flows of at least three times minute volume appear to be necessary to prevent rebreathing during use of this system with spontaneous ventilation.
LOCAL SEQUELAE FOLLOWING THE I.V. INJECTION OF THREE BENZODIAZEPINES J. E. HEGARTY AND J. W. DUNDEE
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REFERENCES
Benatar, S. R., Hewlett, A. M., and Nunn, J. F. (1973). Br.J. Anaesth., 45, 711. Pontoppidan, H., Geffin, B., and Lowenstein, E. (1972). N. Engl. J. Med., 287, 743.
H. F. SEELEY, P. K. BARNES AND C. M. CONWAY
INDUCTANCE PLETHYSMOGRAPHY
Department of Anaesthetics, The Queen's University of Belfast
C. D. HANNING, H. C. SMITH, I. McA.
Opinion varies regarding the incidence of venous sequelae following the injection of benzodiazepines (Miller, 1968; Langdon, Harlan and Bailey, 1973). A study has been undertaken, therefore, to estimate this incidence during the 10 days following a single injection of drug. Patients were given diazepam 10 mg, flunitrazepam 1-2 mg or lorazepam 4 mg as a single i.v. injection for sedation or premedication. At 2-3 days and 7-10 days following injection, the vein was examined for the presence of thrombosis, phlebitis or thrombophlebitis, using criteria previously described from this department (Hewitt et al., 1966). One hundred and twenty-seven patients were studied and the results are summarized in table I. Venous damage was greater at 7-10 days than at 2-3 days (x2 = 4.48; P
PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY LONDON MEETING OCTOBER 22, 1977
J. WATKINS, S. UDNOON AND P. E. TAUSSIG Departments of Immunology and Anaesthetics, Hospital Medical School, Sheffield
Hallamshire
We have reported previously on the role of complement proteins in "anaphylactic reactions" to i.v. anaesthetic agents (Watkins et al., 1976). Our analyses of reactions reported during 1974, 1975 and 1976 are summarized in table I.
Cases analysed
Complement involved
IgE involved
1974 Althesin Methohexitone
5 1
5 1
2 1
1975 Althesin Thiopentone
7 1
7 0
2 0
1976 Althesin Propanidid Thiopentone
to to to
TABLE I. Complement and IgE involvement in adverse response
10 2 1
1 0 2
Three types of mechanism were recognized: Type I reactions involving IgE and the direct liberation of histamine, immune reactions releasing histamine via the classical (C4) complement pathway and the alternate pathway involving direct activation of C3. Differences in complement pathway activation may account for the variability in response time and clinical severity observed in reactions to Althesin. Although IgE was involved in some Althesin reactions, a higher incidence of involvement occurred in the barbiturate responses. The factors likely to predispose to an anaphylactoid response are: genetic, pre-existing immunopathological conditions, frequency of exposure to a particular drug and combinations of these. Genetic factors include both IgE (atopy) and complement anomalies. Immunopathological conditions involving circulatory immune complexes, such as chronic infection, SLE and RA, may
"prime" complement systems, making them susceptible to activation by i.v. drugs. This aspect was studied in vitro by incubation of plasma samples with synthetic primers (for example, heat aggregated IgG) and anaesthetic drugs. Complement activation was assessed by two-dimensional immunoelectrophoresis. Some of the results were unexpected: one particular plasma revealed a high level of C3 conversion with thiopentone, but not Althesin, propanidid or etomidate, indicating a necessary combination of genetic and immunopathological factors. We conclude that an anaphylactoid response can be attributed to a range of mechanisms and predisposing factors and no drug may be considered to be completely safe. REFERENCE
Watkins, J., Udnoon, S., Appleyard, T. N., and Thornton, J. A. (1976). Br. J. Anaesth., 48, 457.
IMMUNOSUPPRESSION AMONG ANAESTHETISTS K. W. PETTINGALE, N. AL-AFFAS, D. E. H. TEE AND L. STRUNIN Department of Medicine, Immunology and Anaesthetics, King's College Hospital and Medical School, London
Volatile anaesthetic agents have been shown to be toxic to lymphocytes at anaesthetic concentrations in vivo and in vitro (Duncan and Cullen, 1976). This has led to concern that exposure to low concentrations of volatile and gaseous anaesthetics in the operating theatre may induce a degree of immunosuppression in anaesthetists. Two studies (Bruce, 1972; Salo and Vapaavuori, 1976) failed to demonstrate any reduced immunocompetence in theatre personnel, but the number of subjects studied was small and the age range restricted. In the present study, tests of immunological competence were performed on venous blood samples from 14 anaesthetists and 14 age- and sex-matched control subjects not engaged in anaesthetic practice. There was a significant reduction in the total lymphocyte count, the T-lymphocyte count and the phytohaemagglutinin (PHA) transformation on washed whole blood in the anaesthetists compared with the control subjects. Among the anaesthetists there was no relationship between the reduction in total lymphocyte count and either age or time (in years) engaged in anaesthetic practice.
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COMPLEMENT ACTIVATION PATHWAYS AND ADVERSE (ANAPHYLACTOID) RESPONSES TO I.V. ANAESTHETIC AGENTS
BRITISH JOURNAL OF ANAESTHESIA
74 However, there was a highly significant inverse correlation between PHA transformation and age and time engaged in anaesthetic practice. It is suggested that immunocompetence of anaesthetists may not be normal, and that a large study over the whole working age range is indicated. REFERENCES
Examination of the cross-relationship between atopy and allergy showed that atopic patients were more likely to have an allergy than non-atopic patients (36.2% v. 11.4%). Of the 10 000 patients, 309 had both an atopy and an allergy. This group may be most at risk of developing an adverse reaction and it represents about three per onehundred patients.
THE INCIDENCE OF ATOPY AND ALLERGY IN 10 000 PREANAESTHETIC PATIENTS
THE EFFECTS OF ANAESTHETICS ON SOME ENZYMES S. M. KING and D. C. WHITE*
J. P. H. FEE, J. R. MCDONALD, R. S. J. CLARKE, J. W. DUNDEE AND P. K. PAL
Memorial University, Newfoundland
Department of Anaesthetics, The Queen's University of Belfast G. D. ADEY Department of Biochemistry, University of Aberdeen Adverse reactions to i.v. anaesthetic agents may be an increasing problem for anaesthetists. Studies of 100 patients Most enzymes which have been studied in vitro have been who had experienced adverse reactions to thiopentone or found to be unaffected by anaesthetics even at high concenAlthesin revealed a high incidence of a history of atopy or trations (Brammall, Beard and Hulands, 1974). One excepallergy (Clarke et al., 1975). This survey was designed to tion is bacterial luciferase, which has been shown to be assess the significance of these findings. depressed reversibly in vitro by anaesthetics at concentraAnaesthetists at various hospitals in Great Britain and tions within the clinical range (White, Wardley-Smith and Ireland were asked to complete a data sheet on consecutive Adey, 1975). The structure of this enzyme has not been patients presenting for anaesthesia during part of 1976 elucidated fully, but it is known to have a highly hydroand 1977. The incidences of atopy (eczema, hay fever, phobic active centre with a reactive sulphydryl group at or asthma) and allergy (to penicillin, other antibiotics, narcotics, close to the active centre (Nicoli, Meighen and Hastings, iodine, zinc oxide plaster and other causes) were calculated 1974). from 10 000 completed data sheets. The frequency of Review of the structure of those enzymes of which seconatopy or allergy, or both, in the study group was signifi- dary and tertiary structures are known, showed that papain cantly lower than in those who had experienced reactions and bromelain resembled luciferase in the chemical nature to thiopentone or Althesin (P< 0.0001) (table I). of their active sites and the presence of an active sulphydryl group. By contrast, lysozyme and a-chymotrypsin do not TABLE I. Percentage incidence of atopy {eczema, hay fever possess active sulphydryls, and their active centres are less or asthma) and allergy {to drugs or other materials) in patientshydrophobic than papain or bromelain. The actions of these four enzymes in the presence of who had an adverse reaction to thiopentone or Althesin anaesthetic agents were studied using standard assay tech{reported cases) and in the patients in this survey niques. It was found that papain and bromelain were Atopy depressed reversibly by anaesthetic concentrations within and/or the clinical range. Lysozyme and a-chymotrypsin were Atopy Allergy allergy unaffected. No. Patients These observations may be relevant to the mechanism Adverse reactions to 100 14 29 41 of anaesthesia, since it is known that the site of action of thiopentone or anaesthetics is of a hydrophobic nature. Althesin REFERENCES
This survey
10 000
8.5
13.5
19.0
Female patients had a higher incidence of atopy than males (9.2% v. 7.5%) and a higher incidence of allergy than males (16.2% v. 9.2%). Grouping into four age ranges (less than 13, 13-20, 21-59 and more than 59 yr) showed that the incidence of atopy was highest in the 13-20 age group in females and in the over-59 age group in males. The incidence of allergy was highest in the 21-59 age group in both sexes.
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Bruce, D. L. (1972). Anesthesiology, 37, 76. Duncan, P. G., and Cullen, B. F. (1976). Anesthesiology, REFERENCE 45, 522. Clarke, R. S. J., Dundee, J. W., Garrett, R. T., McArdle, Salo, M., and Vapaavuori, M. (1976). Br. J. Anaesth., 48, G. K., and Sutton, J. A. (1975). Br.J. Anaesth., 47, 575. 877.
Brammall, A., Beard, D. J., and Hulands, G. H. (1974). Br. J. Anaesth., 46, 643. Nicoli, M. A., Meighen, E. A., and Hastings, J. W. (1974). J. Biol. Chem., 249, 2385. White, D. C , Wardley-Smith, B., and Adey, G. D. (1975). In Progress in Anesthesiology, Vol. 1 (ed. B. R. Fink). New York: Raven Press. * Present address: Division of Anaesthesia, Clinical Research Centre, Watford Road, Harrow, Middlesex.
PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY HYPOXIC PULMONARY VASOCONSTRICTOR RESPONSE IN DOGS DURING AND AFTER THE INFUSION OF SODIUM NITROPRUSSIDE ANNE E. H. HILL, M. K. SYKES, B. CARRUTHERSJ M. K. CHAKRABARTI AND A. R. TAIT
Department of Anaesthetics, Royal Postgraduate Medical School, Hammersmith Hospital, London
REFERENCES
Sykes, M. K., Hill, A. E. G., Loh, L., and Tait, A. R. (1977). Br. J. Anaesth., 49, 285. Wildsmith, J. A. W., Drummond, G. B., and MacRae, W. R. (1975). Br. J. Anaesth., 47, 1205.
THE ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE PATHOGENESIS OF HALOTHANE-INDUCED MALIGNANT HYPERTHERMIA IN THE PIETRAIN PIG J. N. LUCKE AND H. R. DENNY
Department of Veterinary Surgery, University of Bristol, Langford, Bristol
G. M. HALL
Department of Anaesthetics, Royal Postgraduate Medical School, Hammersmith Hospital, London
R. LOVELL AND D . LISTER
A.R.C. Meat Research Institute, Langford, Bristol The effect of total adrenal suppression has been investigated in Pietrain pigs in order to determine if the sympathetic response either plays an important role in the course of malignant hyperthermia (MH) or occurs as a secondary response to the biochemical and physiological changes which initiate the syndrome. Bilateral adrenalectomy was carried out through a midline laparotomy in 10 Pietrain pigs (mean weight 40 kg + 4 SEM). The anaesthetic technique involved i.m. injection with ketamine 20 mg kg- 1 to induce basal narcosis, endotracheal intubation after the injection of thiopentone 3-5 mg kg- 1 pancuronium 0.2 mg kg"1 and ventilation with 66% nitrous oxide in oxygen using a volume-cycled ventilator with no rebreathing. After extraction in perchloric acid, noradrenaline and adrenaline contents of excised adrenal glands were measured by the semi-automated fluorimetric method (McCullough, 1968). Noradrenaline was found to be the predominant adrenal catecholamine. All the pigs recovered from the anaesthetic, but four died 7-13 h after surgery despite glucocorticoid and mineralocorticoid supplementation before surgery. Six pigs survived adrenalectomy and were studied 7 days later using the anaesthetic technique and surgical preparation described previously (Lucke, Hall and Lister, 1976). Bretylium tosylate 20 mg kg"1 was administered i.v. and, after 45 min was allowed for establishment of adrenergic blockade, the pigs were ventilated with 1 % halothane for three 10-min periods, separated by 5-min intervals. All six pigs survived the halothane challenge and did not show any metabolic or physiological changes characteristic of porcine MH. The separate effects of adrenalectomy and bretylium on the halothane-induced response were investigated using the same experimental protocol. Three of four adrenalectomized pigs survived with no signs of increased muscle metabolism, but the remaining adrenalectomized animal developed MH 5 min after halothane exposure. One of four pigs given bretylium 10 mg kg"1 failed to develop MH but in another, a dose of 10 mg kg- 1 and in two others a dose of 20 mg kg- 1 did not prevent a hyperthermic response to halothane. It is concluded that adrenergic blockade produced by bilateral adrenalectomy together with bretylium abolished completely the sensitivity to halothane-induced MH in Pietrain pigs. Adrenalectomy alone provided partial protection, which indicates that catecholamines derived from the adrenal medulla are probably more important than those produced elsewhere. It is suggested that during adrenergic blockade muscle metabolism is so low that, when challenged with halothane, the intracellular calcium concentration fails to reach the value that will precipitate MH. This situation is similar to that suggested for partial protection against halothane-induced MH produced by neuromuscular blockade with large doses of pancuronium (Hall, Lucke and Lister, 1976).
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Arterial hypoxaemia in patients has been reported during induced hypotension with sodium nitroprusside (Wildsmith, Drummond and MacRae, 1975). A possible explanation is that the drug might cause a redistribution of blood flow to underventilated areas of lung either by a direct or indirect action on the pulmonary vasculature, or by depression of the pulmonary vasoconstrictor response to alveolar hypoxia. Experiments wereperformed to determine if sodium nitroprusside could affect the hypoxic vasoconstrictor response by measuring the redistribution of blood flow between the lungs in response to unilateral hypoxia. Ten dogs were anaesthetized with thiopentone and pentobarbitone and a double-lumen endotracheal tube was inserted to permit separate ventilation of the right and left lungs. Tidal volumes were maintained constant and the distribution of blood flow to each lung was followed by recording the radioactivity of the mixed expired gas during the continuous i.v. infusion of xenon-133 (Sykes et al., 1977). The pulmonary vasoconstrictor response was tested by ventilating the left lung with 7% oxygen followed by 100% nitrogen before, during and after an i.v. infusion of sodium nitroprusside. When the drug was given at a rate sufficient to reduce mean arterial pressure to 80 mm Hg, there was a significant reduction in the pulmonary vasoconstrictor response to both levels of alveolar hypoxia when compared with control responses. The responses after administration of the drug were significantly greater than the initial responses. During unilateral hypoxia, arterial oxygen tensions were less, while mixed venous oxygen tensions were unchanged during the administration of sodium nitroprusside compared with the control hypoxic periods. These results suggest that sodium nitroprusside may increase arterial hypoxaemia by depressing the homeostatic diversion of blood flow away from hypoxic areas of lung.
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paedic surgery may be influenced by the choice of anaesthetic agents. Since a low spinal anaesthetic has minimal effects on the reactivity of the circulation or on the respiratory centre, the changes in acid-base status were studied in a group of 14 healthy adults undergoing elective orthopaedic surgery on the lower limb under spinal analgesia. The mean tourniquet time was 75 min. There was a statistically significant decrease in arterial base excess which reached a peak 5 min after tourniquet release, and which was not fully restored 20 min after the limb had been perfused with blood (fig. 1). There was a statistically significant decrease in Paco,> but the maximum hypocapnia time was phase-shifted from the time of maximum metabolic acidosis by approximately 10 min (fig. 1). This phase shift is presumably attributable to the delay in crossing the blood-brain barrier of hydrogen ions and suggests that peripherally located hydrogen ion receptors have little influence on respiratory centre control of acidof the base homeostasis. orthoKnee joint replacement in the arthritic elderly atherosclerotic patient is performed frequently with techniques 12 designed to minimize blood loss. Since these patients tolerate acidosis very badly, we suggest that it would be useful to administer a small quantity of sodium bicarbonate just before release of the tourniquet.
Hall, G. M., Lucke, J. N., and Lister, D. (1976). Br. J. Anaesth., 48, 1135. Lucke, J. N., Hall, G. M., and Lister, D. (1976). Br. J. Anaesth., 48, 297. McCullough, H. (1968). J. Clin. Pathol., 21, 759. BLOOD-GAS CHANGES FOLLOWING TOURNIQUET RELEASE DURING SPINAL ANAESTHESIA Sundsvall Hospital, Sweden P. J. TOMLIN
University Department of Anaesthetics, Birmingham The extent of metabolic acidosis and the response respiratory centre following limb ischaemia during 11 1
CESS (i
l-2..
* « — / 1
BASE
X)
THE EFFECT OF THIOPENTONE AND SUXAMETHONIUM ON GASTROOESOPHAGEAL PRESSURE GRADIENTS G. SMITH, R. DALLING, L. R. DOUGAN AND T. I. R. WILLIAMS
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H. HASSAN AND J. GJESSING
University Departments of Anaesthesia and Surgery, Western Infirmary, Glasgow -0.4
O U _nu
t -0.1
5
10
15
20
TIME AFTER TOURNIQUET RELEASE (min) FIG. 1. Blood-gas changes following tourniquet release (mean + SEM).
Several investigations have revealed an increase in gastric pressure occurring during fasciculations induced by suxamethonium, and it has been suggested that this increase predisposes to regurgitation of gastric contents (La Cour, 1969; Miller and Way, 1971). To test this hypothesis, we have measured the pressure gradient between the stomach and the lower oesophageal sphincter (high pressure zone, or HPZ) during the administration of suxamethonium. Fifteen patients undergoing vagotomy and pyloroplasty received premedication comprising morphine 10 mg i.m. Thirty minutes before anaesthesia was induced, a triple-catheter orogastric tube was passed for measurement of pressures in the stomach, HPZ and oesophagus. Each catheter was perfused continuously with saline 1 ml min- 1 . After gastric motility had returned to normal, pre-oxygenation was carried out for 3 min before anaesthesia was induced with thiopentone 4 mg kg- 1 followed by suxamethonium 100 mg. Before anaesthesia, the mean gradient between oesophageal sphincter and stomach (HPZ —gastric pressure) was 5.4 mm Hg (+ 0.64 SEM) and, during fasciculations, this increased to 6.9 + 1.2 mm Hg. Thiopentone produced a small decrease in both gastric and HPZ pressures.
PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY As patients with gastro-duodenal pathology may have altered HPZ characteristics, we are currently obtaining data in patients undergoing anaesthesia for minor surgery. REFERENCES
La Cour, D. (1969). Acta Anaesthesiol. Scand., 13, 255. Miller, R. D., and Way, W. L. (1971). Anesthesiology, 34, 185.
REFERENCES
Aitkenhead, A. R., Wishart, H. Y., and Peebles-Brown, D. A. (1977). Br. J. Anaesth., 50 (in press). Everett, W. G. (1974). Ann. R. Coll. Surg. Engl., 55, 31. Goligher, J. C , Morris, C , McAdam, W. A. F., De Dombal, F. T., and Johnston, B. (1970). Br. J. Surg., 57, 817.
CLINICAL EVALUATION OF THE ISO-SHUNT DIAGRAM P. G. LAWLER
Division of Anaesthesia, Clinical Research Centre, Harrow A. R. AITKENHEAD, D. G. GILMOUR, A. P. HOTHERSALL AND I. McA. LEDINGHAM
A. M. HEWLETT
Departments of Anaesthesia and Surgery, Western Infirmary, Division of Clinical Anaesthesia, Northwick Park Hospital, Harrow Glasgow The incidence of dehiscence after colonic anastomoses may be as high as 69% (Goligher et al., 1970) and the mortality following clinically evident anastomotic dehiscence is about 35%. The blood supply to the colon is an important factor in maintaining an intact anastomosis (Everett, 1974). A recent survey (Aitkenhead, Wishart and Peebles-Brown, 1977) has suggested that spinal anaesthesia may reduce the incidence of anastomotic breakdown following large bowel surgery. The present study was designed to investigate the effects of subarachnoid spinal nerve block on colonic blood flow. Cardiac output, e.c.g., systemic and pulmonary arterial and right atrial pressures were recorded in 19 artificially ventilated dogs anaesthetized with pentobarbitone 30-40 mg kg-1. Following splenectomy, a catheter was positioned with its tip in the superior mesenteric artery just proximal to the branch supplying the colon, and a second catheter was positioned in the main marginal vein of the colon. Colonic blood flow was measured by injecting xenon-133 500 (iCi through the mesenteric arterial catheter and recording its clearance from the colon with a collimated scintillation counter. Under radiographic control, an 18-gauge needle was introduced at L6-7 into the subarachnoid space for the injection of 0.5% bupivacaine 0.2 ml kg-1. A comparison has been made between measurements obtained immediately before and 20 min after the injection of bupivacaine. Spinal nerve block produced decreases in mean arterial pressure (33.1%) and heart rate (9.6%) but an increase in colonic blood flow of 22.4% in association with a 44.5% decrease in colonic vascular resistance. There were no changes in cardiac output, colonic oxygen consumption, or arterial oxygen or carbon dioxide tensions. It is postulated that, by increasing blood flow to the colon, spinal nerve block may improve the oxygenation of colonic anastomoses both during operation and also in the early period after operation, and thereby may reduce the incidence of dehiscence occurring clinically.
Benatar, Hewlett and Nunn (1973) proposed that the gas exchange abnormality occurring in patients during anaesthesia or in the intensive therapy unit-could be considered as "shunt". They expressed this as "virtual shunt" and derived relationships correlating inspired oxygen fraction (Flo,), arterial oxygen tension (/"ao,) and "virtual shunt", expressed as a percentage (£)s/()t%). This information was expressed graphically. This concept has been evaluated in 16 patients admitted consecutively to the intensive therapy unit. One patient was investigated on two separate occasions. In these patients, cardiovascular and respiratory status was' considered stable. In all patients an arterial line had been inserted for other reasons. The patients were ventilated mechanically using a minute volume divider (Brompton Manley). ' During the investigation, which lasted approximately 2 h, the patient remained supine and received no physiotherapy. Flo, w a s increased in steps at 20-min intervals until F i 0 w a s !-0. After a further 20 min Flo w a s reduced stepwise.' Minute and tidal volume remained constant throughout. Arterial blood-gases were measured at the end of each 20-min period. A minimum of five blood-gas measurements was made. In general, virtual shunt during the periods of both increasing and decreasing inspired oxygen remained constant and followed the same path, suggesting that no absorption collapse occurred during the period of ventilation with 100% oxygen. Some scatter of results compatible with the random error of measurement occurred. In order to gain greater precision, the virtual shunt at each point was calculated, using a programmable calculator. Results were plotted as virtual shunt (%) against Flo,, and regression lines drawn. Three groups of patients were distinguished: (1) Those in whom virtual shunt remained largely unchanged (9/15).
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THE EFFECTS OF SUBARACHNOID SPINAL BLOCK ON COLONIC BLOOD FLOW IN THE DOG
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(2) Those in whom virtual shunt decreased with increasing Flo, ( o n e patient on two occasions). (3) Those in whom virtual shunt increased as Flo, w a s increased (four patients).
FRESH GAS REQUIREMENTS DURING SPONTANEOUS VENTILATION WITH THE BAIN ANAESTHETIC SYSTEM
In the majority of patients the data allowed prediction of Flo, f° r a safe -f^o, from a given mean ()s/$t o r from that derived when breathing 100% oxygen (Pontoppidan, Geffin and Lowenstein, 1972). It is therefore proposed that the use of the virtual shunt concept enables reasonable prediction of the required FIQ, in the clinical situation. To this end, a further graph, to be used in conjunction with the iso-shunt graph, has been drawn.
Magill Department of Anaesthetics, Westminster Hospital, London Five conscious volunteers breathed a non-anaesthetic gas through a Bain anaesthetic system arranged as a modified Mapleson D system. Measurements of ventilation and of tidal gas composition were made whilst fresh gas flow was reduced from initial high values to one at which rebreathing occurred. Marked increases in ventilation occurred in these subjects when fresh gas flow was between two-and-a-half and three times minute volume. Fresh gas flows of at least three times minute volume appear to be necessary to prevent rebreathing during use of this system with spontaneous ventilation.
LOCAL SEQUELAE FOLLOWING THE I.V. INJECTION OF THREE BENZODIAZEPINES J. E. HEGARTY AND J. W. DUNDEE
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REFERENCES
Benatar, S. R., Hewlett, A. M., and Nunn, J. F. (1973). Br.J. Anaesth., 45, 711. Pontoppidan, H., Geffin, B., and Lowenstein, E. (1972). N. Engl. J. Med., 287, 743.
H. F. SEELEY, P. K. BARNES AND C. M. CONWAY
INDUCTANCE PLETHYSMOGRAPHY
Department of Anaesthetics, The Queen's University of Belfast
C. D. HANNING, H. C. SMITH, I. McA.
Opinion varies regarding the incidence of venous sequelae following the injection of benzodiazepines (Miller, 1968; Langdon, Harlan and Bailey, 1973). A study has been undertaken, therefore, to estimate this incidence during the 10 days following a single injection of drug. Patients were given diazepam 10 mg, flunitrazepam 1-2 mg or lorazepam 4 mg as a single i.v. injection for sedation or premedication. At 2-3 days and 7-10 days following injection, the vein was examined for the presence of thrombosis, phlebitis or thrombophlebitis, using criteria previously described from this department (Hewitt et al., 1966). One hundred and twenty-seven patients were studied and the results are summarized in table I. Venous damage was greater at 7-10 days than at 2-3 days (x2 = 4.48; P
