Br.J. Anaesth. (1979), 51-, 989P

PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY GLASGOW MEETING JULY 7, 1979

EFFECT OF ON TRANSMISSION a 50% depression in the response to carbachol 5.46 x 10~6 1 5 IN SYMPATHETIC GANGLIA mol litre" was determined (IC50 ketamine = 8.5 x 10" 1 mol litre" , r = 0.83). Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 V. MAHMOODI, A. J. BYRNE, T. E. J. HEALY AND In the concentrations used ketamine has been shown to S. Z. HUSSAIN interfere with the sympathetic final common pathway but Department of Surgery {Anaesthesia), Queen's Medical the results do not preclude a central effect at lower con- Centre, University Hospital, Clifton Boulevard, centrations. Nottingham ACKNOWLEDGEMENT An increase in arterial pressure following the injection of We gratefully acknowledge financial support from Parke ketamine is well documented and has been explained by Davis and Co. both central (Ivankovich et al., 1974) and peripheral actions (Nedergaard, 1973). The sympathetic division of REFERENCES the autonomic nervous system is the link between central Hukovic, S. (1961). Br. J. Pharmacol, 16, 188. and peripheral mechanisms for increasing arterial pressure. Ivankovich, A. D., Miletich, D. J., Reimann, C, Albrecht, It was therefore decided to investigate the effects of keta- R. F., and Zahed, B. (1974). Anesth. Analg. {Cleve.), 53, mine on this final common pathway. 924. The hypogastric nerve, hypogastric plexus and vas Nedergaard, O. A. (1973). Eur. J. Pharmacol, 23, 153. deferens of adult guineapigs were dissected (Hukovic, 1961) and mounted in Krebs' solution bubbled with oxygen 95% and carbon dioxide 5% at 32 °C. Supramaximal trans- mural (postganglionic) and nerve stimuli (preganglionic) EFFECTS OF KETAMINE ON AUTONOMIC were applied alternately and contractions of the vas deferens TRANSMISSION IN RAT ISOLATED ATRIA were measured using an isotonic transducer. The concentration of ketamine in the bath was increased A. J. BYRNE, D. R. TOMLINSON AND T. E. J. HEALY at 16-min intervals. The effect of each concentration was Department of Surgery (Anaesthesia) and Department of expressed as a percentage of the control response. For Physiology and Pharmacology, Queen's Medical Centre, comparison, the effect of hexamethonium was also studied. University Hospital, Clifton Boulevard, Nottingham Ketamine produced a dose-dependent reduction in the response to preganglionic stimulation (IC 60 2.05 x It is well recognized that ketamine stimulates the heart. 10"4 mol litre"1, r = 0.9), but did not reduce the response Adams, Parker and Mathew (1977) showed that ketamine to post-ganglionic stimulation. The response to post gan- changed the response of isolated atria to catecholamines, glionic stimulation was blocked by guanethidine 1 x but interactions between autonomic neurotransmission and 10~* mol litre"1. ketamine have not been studied in vitro. The present study The preganglionic electrodes in this study were placed was designed to investigate the effects of ketamine on the considerably proximal to the ganglionic synapse, and it response of rat atria to stimulation of the autonomic nerve was necessary therefore to confirm that ketamine was supply and to exogenous catecholamines. acting as a nicotinic blocking agent rather than as a non- Atria were removed from freshly killed Wistar rats (300- specific of nerve action potentials. Experiments 450 g). Each atrium was suspended between parallel plati- were performed using the frog (Rana temporarid) rectus num wire electrodes in an organ bath containing Krebs' abdominis muscle. The muscle was mounted in frog's solution gassed with 95% O2 and 5% CO2 at 37 °C. The Ringer solution bubbled with air at 18 CC. left atrium was paced at 3 Hz by field stimulation (10-V, The contraction of the muscle in response to carbachol 2-ms pulses) to study inotropic changes. Ths right 5.46 xl0"7-1.6xl0"5 mol litre"1 was measured. The atrium was allowed to beat spontaneously and used to contractions of the preparation in the presence of carbachol study chronotropy. Noradrenergic nerves in both atria in the same concentrations with ketamine 1 x 10"4 mol were stimulated in the presence of 1 x 10"6 mol litre"1 were recorded also. Ketamine caused a reversible and left atrial cholinergc nerves n the presence of pro- depression of the response to carbachol. The response of pranolol 1 x 10~e mol according to the method of Blinks the preparation to potassium chloride 3.3 x 10~2 mol litre"1 (1966). This gave graded chronotropic responses to different was unchanged by ketamine. frequencies of stimulation (2-20 Hz) from the right atrium The muscle contraction produced by carbachol 5.46 x and a single inotropic response to the pacing frequency 10~6 mol litre"1 in the presence of increasing concentra- from the left atrium. tions of ketamine was also studied. Ketamine produced a Ketamine 5 x 10~6 mol increased the maximum amplitude dose-dependent reduction in the contraction produced by of the inotropic response of the left atrium to noradrenergic carbachol. The concentration of ketamine which produced nerve stimulation (/><0.01). The duration of the response 990P BRITISH JOURNAL OF ANAESTHESIA was also markedly enhanced. In a concentration of 4x has been developed into which this ratio can be set for the 10~4 mol, ketamine caused a slight increase in resting force MGA 200 quadrupole apparatus (Centronic Limited, of contraction but a significant (P< 0.001) decrease in the Croydon); circuits to add the undesired fragmentation positive inotropy seen in response to noradrenergic nerve peaks and subtract them from the apparent, but erroneous, stimulation. reading allow the true value of the gas to be analysed. The Ketamine produced a dose-dependent slowing of the outputs of these circuits can be fed to the MGA 200 auto- right atrium. The control rate of 284 ±4 beat min"1 de- matic stability control mode (ASC) circuit providing stab- creased to 155 + 5 beat min"1 in the presence of ketamine ility of calibration of +1 % (full scale-deflection) for each 4 x 10~4 mol. This masked the effects of ketamine on the gas or vapour for more than 24 h. positive chronotropic response to noradrenergic nerve Mass spectrometers are unlikely to be of value in clinical stimulation. anaesthesia unless one instrument can be shared between Ketamine, in concentrations up to 4 x 10~4 mol, decreased several anaesthetizing locations. We have demonstrated Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 the negative inotropic response to cholinergic nerve stimu- that gas can be sampled over distances of 40 m (sample lation in left atria but this effect was unrelated to the keta- flow 25 ml min"1) without serious loss of the respiratory mine concentrations used. waveform; the 90% rise time using a conventional 1-m The effects of ketamine on the responses of left atria probe was 80 ms"1 but increased to 500 ms"1 with a 40-m to exogenous noradrenaline and isoprenaline were studied. probe. The patient to mass spectrometer transit time was Potentiation of the response of the left atrium to nor- approximately 30 s. A shared facility between four opera- adrenaline by ketamine 5 x 10~6 mol was seen as a parallel ting theatres allows analysis of at least two b.p.m. for each leftward shift of the noradrenaline dose-response curve patient. (threefold increase in potency) with no increase in the maximum response. In a concentration of 2 x 10~4 mol, ketamine depressed the maximum response to noradren- 6 aline. Ketamine 5 x 10~ mol also potentiated the response MEASUREMENT OF BLOOD-GAS TENSIONS of the left atrium to isoprenaline (twofold increase in BY MASS SPECTROMETRY—THE "SUPER potency). RILEY BUBBLE" Ketamine has therefore been shown to increase the ino- tropic response both to noradrenergic nerve stimulation and to exogenous noradrenaline. This is consistent with W. W. MAPLESON, B. A. WILLIS AND R. T. CHILCOAT the hypothesis that ketamine causes a postjunctional Department of Anaesthetics, Welsh National School of sympathomimetic super-sensitivity combined with an Medicine, Cardiff increase in the available noradrenaline as a result of blockade of neuronal re-uptake which has been reported by Miletich If a small bubble of gas is equilibrated with a sample of and others (1973). blood at body temperature, the final partial pressures of gas in the bubble approximate to the initial tensions in ACKNOWLEDGEMENT the blood. This principle, with chemical analysis of the Financial assistance from Parke Davis and Co. is gratefully bubble, was used by Riley, Proemmel and Franke (1945) acknowledged. for the determination of O2 and CO2 tensions. In the present technique analysis by a respiratory mass spectro- REFERENCES meter (Centronic MGA 200) was used to determine the Adams, H. R., Parker, J. R., and Mathew, B. P. (1977). tensions of and CO2 in arterial blood from dogs J. Pharmacol. Exp. Ther., 201, 171. breathing a mixture of halothane and in Blinks, J. R. (1966). J. Pharmacol. Exp. Ther., 151, 221. oxygen. Miletich, D. J., Ivankovic, A. D., Albrecht, R. F., Zahed, A 5-ml all-glass syringe, modified to provide a conical B., and Ilahi, A. A. (1973). Anesthesiology., 39, 271. deadspace of about 0.2 ml and fitted with a nylon three- way tap, was flushed with the mixture which was delivered to the dog via a halothane vaporizer. The syringe was rilled with 2 ml of arterial blood and rotated in a water bath at body temperature in such a way that the bubble THE DEVELOPMENT OF THE MGA 200 MASS travelled to and fro inside the syringe for 2 min. The SPECTROMETER FOR CLINICAL USE IN plunger moved freely to ensure the maintenance of atmo- ANAESTHESIA spheric pressure in the bubble. The needle of a 100-(4 syringe was inserted through the tap into the gas bubble W. O. M. DAVIS and A. A. SPENCE and a 100-|J sample drawn up. This was injected deep University Department of Anaesthesia, Western into a wide-bore needle through which the mass spectro- Infirmary, Glasgow meter was continuously sampling room air. The resulting transient changes in gas composition were sensed by the Mass spectrometry is well established in respiratory investi- mass spectrometer and processed by an on-line digital gation but its application in anaesthesia is more complex computer to yield an analysis of the bubble. because of interference by fragmentation products of sub- Theory indicates that, at equilibrium, the partial pres- stances including nitrous oxide and halothane with the sures of halothane and CO2 in the bubble should be only signals from , oxygen and carbon dioxide. 2-3% smaller than the initial tensions in the blood; for As the ratio of fragmentation peaks is constant for any N2O there may be variation over a range of 10% of the gas or vapour for a period of at least 24 h, simple circuitry initial tension; and the oxygen partial pressure makes up PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY 991P

the total atmospheric pressure virtually irrespective of the scavenging system in operation. This was followed by initial blood oxygen tension. sampling for 5 days with routine scavenging by a system Experiments showed that the components of a 100-|J we have employed for over 2 years. sample of dry gas could each be measured to an accuracy Overall results from 19 hospitals are shown in table I. of the order of 2%; but for bubbles equilibrated with The detailed data with and without scavenging at North- tonometered blood the halothane and CO2 partial pres- wick Park Hospital will be presented. Comparisons between sures were smaller than predicted to a variable degree. these results indicate that the installation of relatively This shortfall could not be attributed to incomplete equili- simple active scavenging devices will probably be effective bration; it may have been a result of re-equilibration of in most hospitals. the bubble with traces of blood in the 100-|d syringe and wide-bore needle. Experiments showed that, with correc- TABLE I. Mean anaesthetic contamination {and range) for Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 tion for the systematic error, halothane and CO2 tensions 19 hospitals in dog blood could be measured with SD about 5%.

N2O Halothane ACKNOWLEDGEMENT (p.p.m.) (p.p.m.) This work was supported by a Medical Research Council grant. Induction room 187 1.9 (30-540) (< 0.1-6.3) REFERENCE Theatre periphery 171 1.3 Riley, R. L., Proemmel, D. D., and Franke, R. E. (1945). (50-670) (< 0.1-3.1) J. Biol. Chem.y 161, 621. Anaesthetist's area 189 2.0 (60-650) (< 0.1-7.1) Anaesthetist's session 381 3.1 (75-1100) (< 0.1-16.9) ANAESTHETIC CONTAMINATION IN Recovery room 30 0.43 DIFFERENT TYPES OF HOSPITAL (< 10-110) (< 0.1-1.8)

M. J. HALSEY, H. T. DAVENPORT AND BRIDGET REFERENCE WARDLEY-SMITH Davenport, H. T., Halsey, M. J., Wardley-Smith, B., and Clinical Research Centre and Northvrick Park Hospital, Wright, B. M. (1976). Br. Med. J., 2, 1219. Harrow, Middlesex A large number of studies on anaesthetic contamination have been published which support the common-sense conclusion that at least some precautions should be under- DIFFERENTIATION OF THE MOLECULAR taken to reduce the ambient concentrations of anaesthetic. SITES FOR ANAESTHESIA AND PRESSURE Unfortunately, many of the studies (including one from our institution; Davenport et al., 1976) have been carried BRIDGET WARDLEY-SMITH, M. J. HALSEY AND out in modern hospitals under controlled, contrived or C. J. GREEN "ideal" conditions. This makes it difficult to extrapolate Divisions of Anaesthesia and Comparative Medicine, such data to the routine conditions existing in many hos- Clinical Research Centre, Harrow, Middlesex pitals. In this paper we report anaesthetic measurements in operating room areas of 20 hospitals during normal unmodified operating sessions. We chose our minimum de- The multi-site expansion hypothesis (Halsey, Wardley- tectable limits as 10 p.p.m. of nitrous oxide and 0.1 p.p.m. Smith and Green, 1978) has been proposed as an explana- halothane and standardized our collection procedure in tion for the pressure reversal of anaesthesia. One aspect each hospital, using an integrated personal sampler (Daven- of this hypothesis is that high pressure may act at a different port et al., 1976). The following areas were studied: molecular site from the anaesthetic; also for a particular anaesthetic, one site may predominate in determining the 1. Induction room: In the periphery of an induction room characteristics of their interaction. during induction of anaesthesia for 10 min. Evidence for this idea is provided by differences between 2. Theatre periphery: On the periphery of the operating anaesthetics in their ability to protect against the high theatre during an anaesthetic, for 30 min. pressure nervous syndrome (HPNS). It was originally 3. Anaesthetists' area: Within 40 cm of the head of the thought that all anaesthetics would be equally effective in patient in the operating room at the level of the anaes- preventing adverse physiological changes induced by pres- thetist's nose, for 10 min. sure, but we have shown that this is not so. In rats, the 4. Anaesthetist's session: Continuous sampling from the convulsion threshold is accepted as a reproducible end- front of the mask of the anaesthetist during his varied point for studying HPNS, and results for six different activities over a duration of 2 h. anaesthetics are shown in table I. 5. Recovery room: In the periphery of the recovery room The use of structural isomers of anaesthetics is an with one or more patients in the room. approach which may make it possible to distinguish Finally, in Northwick Park Hospital, we sampled in an between separate molecular receptors for anaesthesia and exactly similar manner on 5 consecutive days without a pressure. Alphaxalone, the main constituent of Althesin, 992P BRITISH JOURNAL OF ANAESTHESIA has isomers including A16-alphaxalone and 3/J-hydroxy- was added sequentially until all the tadpoles were motion- alphaxalone which, although differing only slightly in less and unresponsive to touch. The experiments were structure3 are completely "non-anaesthetic". If a non- repeated in Darrow's solution. anaesthetic isomer of alphaxalone protected against HPNS, Group 2 experiments compared tadpoles reared on liver this would be further positive evidence of separate receptors powder, nettle powder, or aminosol and intralipid. Equal for anaesthetics and pressure, and preliminary results numbers of tadpoles from each group were exposed to support this. selected doses of thiopentone and dose-response curves It is probable however that these receptors are linked, were constructed. These experiments were carried out in since preliminary screening of a range of non-anaesthetic 200 ml of standing water and thiopentone was said to be anticonvulsants in mice have not indicated that this type 100% active when all the tadpoles were immobile. of drug will be of any value in treating pressure-induced Group 3 experiments compared tadpoles reared on liver convulsions. In view of all these data, it seems likely that powder and aminosol and intralipid. A fluorescent mem- Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 there is some interaction between the separate sites for brane probe was tested to see if it possessed anaesthetic anaesthesia and pressure. activity and was influenced by the diet of the tadpoles. These experiments followed exactly the same pattern as TABLE I. Convulsion and tremor thresholds expressed in atmo-Group 2, except that they were carried out in 100 ml of spheres absolute {atm) for six different anaesthetics standing water. In Group 1 experiments there was a significant differ- Convulsion Tremor ence in the response of the two groups of tadpoles to thio- threshold threshold pentone (statistical analysis by Wilcoxon's sum of ranks Anaesthetic (atm±SEM) (atm±SEM) test and the binomial expansion of BernouiUi). In Group 2 experiments there was a difference in re- Control 76.8 + 2.0 37.1 + 2.5 sponse which did not result from kinetic factors. The shift Althesin >100 73.4 ±3.1 in the dose-response curve between the nettle- and liver- Methohexitone 46.4 + 2.6 27.8 + 3.7 fed groups appeared to result from a competitive reaction Thiopentone 79.0 ±3.9 42.7 ±5.8 but non-competitive factors seemed to be present for the 58.2 ±2.4 42.7 + 3.3 intralipid group. Ketamine >100 >100 In Group 3 experiments the differences in response to Nitrous oxide >100 >100 the membrane probe were more pronounced.

REFERENCES REFERENCE Burns, C. P., Luttenegger, D. G., Wei, Shiao Ping, L., and Halsey, M. J., Wardley-Smith, Bridget, and Green, C. J. Spector, A. A. (1977). Lipids, 12, 747. (1978). Br.J. Anaesth., 50, 1091. Miller, K. W., and Pang, Kam-Yee Y. (1976). Nature (Lond.), 263, 253. Van Deenan, L. K. M., De Grier, J., and Demel, R. A. (1972). Biochem. Soc. Symp., 33, 377. THE INFLUENCE OF DIET ON THE SUSCEPTIBILITY OF XENOPUS LAEVIS TADPOLES TO THIOPENTONE AND A MEMBRANE PROBE THE EFFECT OF HALOTHANE AND ON SPECIFIC AIRWAYS M. E. HAW CONDUCTANCE IN MAN Department of Anaesthesia, Leeds General Infirmary, Leeds J. R. LEHANE, C. JORDAN AND J. G. JONES Anaesthetics can selectively perturb lipid bilayer mem- Division of Anaesthesia, Clinical Research Centre, Watford branes (Miller and Pang, 1976). The physical nature of a Road, Harrow, Middlesex membrane may be modified by altering the nature of its phospholipid molecules (Van Deenan, De Grier and Riigheimer, Himmler and Greiner (1974) reported that Demel, 1972). In addition, there is evidence that the enflurane increased airways resistance (Raw) whereas Roily nature of the fatty acids in the phospholipids of the mem- and Malcolm-Thomas (1975) found that both enflurane brane bilayer may be altered by the media or food which and halothane caused a reduction in Ravi. Changes in lung is available to the cells or animals concerned (Burns et al., volume during anaesthesia profoundly affect .Raw (Lehane, 1977). Jordan and Jones, 1979). However, neither Riigheimer and Xenopus laevis tadpoles were produced from wild-caught, colleagues nor Roily and Malcolm-Thomas allowed for the laboratory-reared toads, following induced mating and effects of changes in lung volume and this omission may spawning. Separate groups were fed on diets of: (1) liver account for the differences in their results. powder; (2) nettle powder; or (3) aminosol and intralipid. We have used the forced airflow oscillation method The tadpoles were reared for 3 weeks at 22 °C and then (Lehane, Jordan and Jones, 1979) to determine airflow numerous experiments were performed. resistance over a range of lung volumes during anaesthesia. Group 1 experiments compared tadpoles reared on The resulting hyperbolic plot of resistance against lung nettle powder and liver powder. Equal numbers of both volume can be redrawn after correcting for the asymptote groups of tadpoles were placed in 200 ml of free-standing to yield a linear plot of conductance against volume. The water and 1 nag of thiopentone dissolved in 0.5 ml of water slope of this line, the specific airways conductance (sGaw), PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY 993P

is independent of changes in lung volume. Changes in only at a very late stage from radiological evidence of pul- sGaw therefore reflect changes in bronchomotor tone. We monary oedema when the pulmonary artery wedge and have measured the change in sGaw when halothane 1.3% plasma colloid osmotic pressures are normal. We have or enflurane 2.5% was added during light nitrous oxide developed a simple technique to obtain an index of AEM anaesthesia. permeability in animals (Jones et al., 1978) and we now Patients were allocated randomly into two groups of 10, report a development of this technique for use in man. one group receiving halothane, the other enflurane. All An aerosol of the hydrophilic molecule 88mTc DTPA patients were non-smokers. Premedication was with oral (mol. wt 452 dalton) in saline was generated using a dis- 15 mg/70 kg. Following thiopentone and pancu- posable "Acorn" nebulizer and a settling bag to remove ronium, anaesthesia was maintained with 70% nitrous particles greater than 2.0 \aa in size (Taplin and Chopra, oxide and ventilation adjusted to give a PE'CO, of 5 kPa. 1978). Male staff volunteered to be subjects for the study. During this period of light nitrous oxide anaesthesia at After breathing the aerosol for 3 min, the disappearance Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 least three measurements of sGaw were made. Halothane rate of the isotope from the lung was derived using two or enflurane was added to the inspired gas mixture and scintillation detectors, one over the rib cage and the other further measurements of sGaw were obtained 3, 8, 15 over the thigh. The latter was used to correct for the and 25 min later. End-tidal concentrations of these agents increasing activity of 98mTc DTPA extracted from the were measured continuously using a mass spectrometer. lung into the circulation. The two curves were analysed to At 15 min the range of end-tidal concentrations of both produce a mono-exponential lung clearance curve. Seven agents was 0.76-0.93 MAC. Measurements of sGaw subjects who were non-smokers had a mean lung clearance during light nitrous oxide anaesthesia showed a skewed !Tj of 72.4 + 7.4 min (SEM), whereas 11 cigarette smokers distribution which was normalized by taking logarithms. had a mean clearance Th of 27.0 ± 6.2 min (SEM) (P < 0.001). This permitted the application of the paired t test. We have also studied three patients (non-smokers). Two with pulmonary oedema following myocardial infarction Following addition of halothane, sGaw increased signi- had 7"j of 88 min and 49 min, and one with permeability ficantly in each of five patients (P<0.05, two-sample t pulmonary oedema from systemic lupus had a Tj of 32 min. tests), mean values increasing from 7.5 to 19.4 kPa"1 s-1, 1 1 These results indicate that AEM permeability is in- and decreased in one patient from 6.3 to 4.8 kPa" s" creased in symptomless cigarette smokers but it is not CP<0.02). In four patients there was no significant change. known how this effect is mediated. Because of relatively Following addition of enflurane sGaw increased from 88m 1 1 low molecular weights of Tc DTPA the test provides 9.8 to 18.4kPa~ s- in three patients (P<0.05). There a sensitive index of early alveolar epithelial damage. In were no significant changes in seven patients. non-smokers a rapid clearance may suggest the presence The average change after 15 min of halothane was an of a pathological process predisposing to pulmonary increase in sGaw of 60% (n.s.: P = 0.09, paired t test) > oedema, but the addition to the test of a measurement of and after enflurane there was an increase of 43% (/ <0.02). the clearance of a second marker of larger molecular In conclusion, the majority of these patients responded weight would improve its value in predicting the develop- to both of these agents with bronchodilatation, and there ment of permeability pulmonary oedema in smokers and was no evidence that enflurane was more likely to induce non-smokers. bronchoconstriction than halothane.

REFERENCES REFERENCES Lehane, J. R., Jordan, C, and Jones, J. G. (1979). Br. J. Jones, J. G., Berry, M., Hulands, G. H., and Crawley, Anaesth., 51, 65P. J. C. W. (1978). Am. Rev. Respir. Dis., 118, 1007. Roily, G., and Malcolm-Thomas, B. (1975). Acta Anaes- Taplin, G. V., and Chopra, S. K. (1978). Progr. Nuclear thesiol. Belg., 26, (Suppl.) 43. Med., 5, 119. Riigheimer, E., Himmler, J., and Greiner, K. (1974). Prakt. Anasth., 9, 87. FRESH GAS AND VENTILATORY REQUIREMENTS DURING CONTROLLED A NEW METHOD FOR MEASURING VENTILATION WITH T-PIECE SYSTEMS ALVEOLAR EPITHELIAL MEMBRANE PERMEABILITY IN MAN C. M. CONWAY Westminster Hospital School, London J. G. JONES, B. D. MTNTY, G. H. HULANDS, J. C. W. CRAWLEY AND N. VEALL Measurements during controlled ventilation of gas compo- Divisions of Anaesthesia and Radioisotopes, Clinical sition within the corrugated tubing of both conventional Research Centre, Northwick Park Hospital, Harrow, and coaxial D systems have shown considerable longi- Middlesex tudinal mixing of fresh and expired gas along the system. If a uniform mix of these gases is assumed and if carbon An increase in permeability of the alveolar epithelial mem- dioxide output (KcOj) and VD/VT are assumed to be con- brane (AEM) is believed to be initiated by a large variety stant, the prevailing CO2 will be a function of fresh gas of processes associated with the development of the adult flow, [VF], minute ventilation, Vn, and the character of respiratory distress syndrome. There is no suitable method the inspiratory waveform. available for the early diagnosis of an increase in perme- Based on these assumptions, theoretical analyses have ability of the AEM in man. The diagnosis can be made been performed using square, sinusoidal, exponential and 994P BRITISH JOURNAL OF ANAESTHESIA a variety of triangular inspiratory waveforms. The result- With the vaporizer on mark 8, end-tidal enflurane con- ing predicted values of FAco, at various values of Vv, VV. centration varied from 1.5 to 3% and inspired concentra- and Fco2 nave been assessed in relation to a previous tion from 2.5 to 5%. One patient exhibited intermittent study in which dogs were ventilated to an acute steady sighing respiration throughout. End-tidal enflurane con- state using a Bain system and a variety of values of Vv centrations in excess of 2% were associated with a reduced and VE (Seeley, Barnes and Conway, 1977). The predicted tidal volume and increased end-tidal concentration of data for square wave inspiration agree closely with the carbon dioxide. observed data (r = 0.98). It is suggested that in practical Heart rates were within normal range and no arrhyth- use the optimal values of Vv and Vv. to provide normo- mias were detected. Arterial systolic pressure measure- capnia are in the order of 1.25 and 1.5 times the basal ments were in the low to normal range (90-110 mm Hg). (anaesthetized) minute volume respectively. In adult man The CFM traces varied greatly. Some exhibited a depth- this would entail a Vv of 100 ml"1 kg"1 min"1 and a Vv. of related decrease in trace position and two exhibited marked, Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 120 ml-1 kg min"1. persistent burst-suppression, which disappeared only with reduction in concentration of enflurane. Time taken for REFERENCE spontaneous recovery after operation varied from 25 to Seeley, H. F., Barnes, P. K., and Conway, C. M. (1977). 80 min. The volume of liquid enflurane used was between Br. J. Anaesth., 49, 107. 10 and 15 ml h"1. It is concluded that enflurane can be administered with oxygen in a closed-circuit system using a VIC. However, cerebral and respiratory depression may be marked and ENFLURANE IN A CLOSED CIRCLE- not easily detected clinically. Therefore, monitoring of cere- ABSORBER SYSTEM; VAPORIZER INSIDE bral function and end-tidal enflurane and carbon dioxide THE CIRCLE concentrations would appear to be proper safeguards.

P. I. E. JONES, G. ROBERTSON, R. J. WARE AND L. STRUNIN Department of Anaesthesia, Queen Victoria Hospital, INABILITY TO MAINTAIN VENTILATION East Grinstead, and King's College Hospital, London AGAINST LARGE INSPIRATORY THRESHOLD LOADS: MUSCLE FATIGUE OR PROGRESSIVE As an approach to the problems of pollution, economy FAILURE OF CO-ORDINATION? and in seeking an alternative to halothane, we have investi- gated the use of enflurane in a closed anaesthetic system. P. LAWLER, J. G. JONES, L. LOH* AND M. LONN* The Marrett apparatus, which incorporates an in-circle Division of Anaesthesia, Clinical Research Centre, vaporizer (VIC), was used. Watford Road, Harrow, Middlesex, and 'National Ten healthy adult patients undergoing orthopaedic or Hospital for Nervous Diseases, Queens Square, plastic surgical procedures on one or more limbs gave London WC1 informed consent for the study. Premedication consisted of 1.5-2.0 mg, 25 mg and hyos- Respiratory muscle fatigue may be an important cause of cine 0.3-0.4 mg i.m., 1 h before surgery. In the anaes- failure to wean patients from mechanical ventilation. thetic room a central venous catheter was inserted and the Roussos and Macklem (1977) have reported that diaphrag- leads of a cerebral function monitor (CFM) were attached. matic fatigue occurs in normal subjects during inspiratory Anaesthesia was induced with gallamine 20 mg, thio- loading when the transdiaphragmatic pressure (Pdi) per- pentone 250-500 mg and suxamethonium 100 mg i.v., sistently exceeds 40% of maximum. They used a difficult followed by topical analgesia with 4% lignocaine to the manoeuvre to control Pdi and we have simplified the larynx and trachea. The lungs were inflated with 100% manoeuvre by using inspiratory threshold loads. We have oxygen before passage of an Enderby-type endotracheal examined changes in respiratory muscle function in five tube containing a sampling catheter. The fresh gas flow subjects breathing against these loads by measuring pleural was set at 250-300 ml of 100% oxygen and initially the pressure (Ppl), gastric pressure (Pgast), mouth pressure, vaporizer was set to mark 8 (maximum—patient's breath end-tidal CO2 and tidal volume. In two subjects the ampli- only). The system was closed and ventilation allowed to tude of AP movements of abdomen/diaphragm (A/D) and return spontaneously. rib cage (RC) were monitored with magnetometers. Using the endotracheal sampling catheter, end-tidal We observed that: (1) Breathing could not be maintained carbon dioxide concentration was measured with a Hart- indefinitely when the load exceeded 60% of maximum mann and Braun infra-red carbon dioxide analyser. In negative Ppl. Above this load there was an inverse relation- addition, peak inspired and end-tidal enflurane concentra- ship between duration of ventilation and load. (2) There tions were measured using an infra-red Miran la analyser. was disco-ordination of movement of the chest wall upon The sampled gases (approximately 0.5 litre min"1) were initiating high load breathing identified by (a) asynchrony returned, after analysis, to the expiratory limb of the circle. of a Pgast v. Ppl plot leading to eventual cessation of The outputs of both infra-red analysers were fed continu- change of Pgast; (b) the magnetometer measurements ously into a two-channel recorder (Devices). Tidal and which showed that during inspiratory effort, but before minute volumes were measured using a Wright's respiro- gas flow, A/D and RC were opposite in phase while, during meter connected to a digital display. Systemic arterial gas flow, they tended to come into phase. As ventilation pressure and heart rate were measured during and after became more difficult to sustain there was progressive operation with an ostillotonometer. diminution in amplitude to the A/D component. (3) There PROCEEDINGS OF THE ANAESTHETIC RESEARCH SOCIETY 995P was an abrupt decrease of lung volume on loading inspira- man (Aveling et al., 1979; Davis et al., 1979). We have tion, shown by an increase in end-expiratory Pp\, a compared haemodynamic responses in the dog to induc- reduction in ERV, and from the magnetometer signals. As tion of anaesthesia with minaxolone, thiopentone, metho- subjects experienced increasing difficulty in maintaining hexitone and . loaded breathing, there was a further decrease in ERV Six beagle dogs (weight range 10.2-13.0 kg) were sub- almost to RV. jected to left lateral thoracotomy. An electromagnetic flow When the load became intolerable, the subject was transducer was placed around the ascending aorta and a allowed a single unloaded breath (SUB) before resuming Konigsberg P6.5 pressure transducer was inserted into the loaded breathing. Immediately following this breath, the left ventricular cavity. Pacing electrodes were sutured to Ppl/Pgast plot, the A/D-RC movement and the ERV were the left atrium and a catheter for recording aortic pressure all restored to the non-fatigue state seen soon after initial was introduced via a femoral artery. The dogs were allowed loading, and this transient unloading permitted a further at least 1 week for recovery before administration of the Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 prolonged period of loaded breathing, the duration of anaesthetics at 2-3-day intervals. Minaxolone and thio- which was a function of the magnitude of the load. pentone were administered to all six dogs, but metho- The ability of the respiratory muscles to sustain venti- hexitone and etomidate to only three. lation at high levels of load was compared with the ability Minaxolone 2.5 mg kg-1 i.v. (which produces about of the biceps muscle to support loads. When the biceps 60 min loss of righting reflex) elicited an immediate and muscle was intermittently loaded at 80% of its maximum persistent tachycardia (group mean preinjection control load-carrying capacity by 3-s contractions (12/min), it value ± SEM 89 ± 7.5 beat min-1; % change 5 min after showed a repeatable time to fatigue. In contrast with induction, A5' = +64 ±10.8%, P<0.05, paired t test). loaded breathing, a 5-s rest period at the fatigue point was This was accompanied by immediate and persistent signi- followed by only a brief recovery of ability to maintain ficant reductions in mean aortic pressure (120 ±7.1 mm Hg; load (table I). A5'= —31 ±2.9%), systemic vascular resistance (4750± 590 dyn s"1 cm"6; A5'= -38±4.4%) and LV dP/dr,,^ 1 TABLE I. Mean time to "fatigue" ±1 SD (s) (4180±287 mm Hg s" ; A5'= -27±8.8%). Although stroke volume was reduced significantly throughout anaes- 1 Inspira- thesia (2.1 ±0.18 ml kg- ; A5'= -30±5.1%), cardiac output increased immediately on induction, returned to tory Biceps 1 1 load load control over 15 min (188 ±25 ml kg- min- ; A0.5'= 80%Ppl After 80% After + 41 ±6.7%, A5' = +13 ±8.5%) and remained near control max SUB max value throughout the remaining period of recording. 5 s rest Minaxolone 1.25 mg kg-1 produced smaller but qualitatively Subject (1) 265 ±17 110+12 227 ±42 19.0 ±3.6 similar effects. Thiopentone 24 mg kg-1 produced anaesthesia of similar (J-G. J.) 1 Subject (2) 249 + 26 61 ±17 195 ±13 18.3 ±3.5 depth and duration to that of minaxolone 2.5 mg kg" and (P.L.) caused similar haemodynamic effects, although at 5 min after induction arterial pressure and systemic vascular resistance were reduced significantly less than after minaxo- We concluded that inspiratory musculature fails to main- lone. Thiopentone produced more respiratory depression tain ventilation when inspiratory loading exceeds 60% of than minaxolone (apnoea times, thiopentone 32 ± 4.5 s, maximum negative Ppl and that this results predominantly minaxolone 15 + 6.7 s), and there was a rebound recovery from a failure of co-ordination which may be restored im- in aortic pressure, systemic vascular resistance and LV mediately when loaded breathing is resumed after a single d^Vdfjjiax 1-2 min after injection. Ventricular arrhythmias unloaded breath. This may be the mechanism by which occurred in one dog. Thiopentone ^mgkg"1 produced intermittent mandatory ventilation could exert a beneficial more tachycardia but less depression of other haemo- effect during weaning from mechanical ventilation. dynamic variables than minaxolone 1.25 mg kg-1 but its duration of action was shorter. REFERENCE Methohexitone 12 mg kg"1 elicited a marked tachycardia Roussos, C. S., and Macklem, P. T. (1977). J. Appl. Phys. accompanied by reductions in aortic pressure, systemic Respirat. Environ. Exercise Physiol., 43, 189. vascular resistance and LV dP/dt^^, which were suc- ceeded by large rebound recoveries 1-2 min after injection. Cardiac output was increased during the period of maximum tachycardia. THE SYSTEMIC HAEMODYNAMIC EFFECTS Haemodynamic responses to etomidate 4 mg kg-1 dif- OF MINAXOLONE: A COMPARISON WITH fered from those occurring after minaxolone or the barbi- OTHER ANAESTHETICS IN THE DOG turates. Heart rate did not vary significantly on induction, but aortic pressure and LV dP/drmax were reduced signi- D. J. TWISSELL AND M. G. DODDS ficantly (A5'= -28±0.6% and -34±4.4%) and cardiac output decreased during sleep. Pharmacology Department, Glaxo Group Research Ltd, When minaxolone 2.5 mg kg-1 or thiopentone 24 mg kg-1 Greenford, Middlesex was given during atrial pacing at about 190 beat min-1, cardiac output remained near normal, indicating that rate Minaxolone is a water-soluble steroid anaesthetic with changes alone were not responsible for the maintenance of properties similar to those of alphaxalone in animals and cardiac output. 996P BRITISH JOURNAL OF ANAESTHESIA

REFERENCES The value of the analysis of volume-pressure relationships Aveling, W., Chang, H., Clements, E., Waters, A., Savege, in monitoring pulmonary function has been reported by T. M., Campbell, D., Fitch, W., Prys-Roberts, C, Sear, several workers (Peters, Hilberman and Hogan, 1972; J. W., and Simpson, P. (1979). Br.J. Anaesth., 51, 564P. Proctor and Woolson, 1973; Hilberman et al., 1975). The Davis, B., Dodds, M. G., Dolamore, P. G., Gardner, C. J., advantages of such analyses include the detection of mal- Sawyer, P. R., Twissell, D. J., and Vallance, D. K. function of the ventilator, the detection of pneumothorax (1979). Br. J. Anaesth., 51, 564P. and, from the calculation of respiratory work, the provision of a reliable index of the need for continued ventilator support. A program and interface have been developed for use THE EFFECTS OF HIGH-DOSE with the Commodore PET 2001/8 microcomputer to allow ON RENAL FUNCTION IN THE data obtained from a Siemens Servo 900B ventilator to be Downloaded from https://academic.oup.com/bja/article/51/10/989/304330 by guest on 29 September 2021 ANAESTHETIZED DOG processed. The interface is based on an integrated circuit which consists of an analog to digital converter combined J. M. HUNTER, R. S. JONES and J. E. UTTING with a 16-channel multiplexer. The ventilator has analog University Department of Anaesthesia, Royal Liverpool outputs for pressure, inspiratory flow and expiratory flow. Hospital, Liverpool Two channels of the multiplexer are used to obtain the inspiratory flow and pressure. The changeover to expira- The effect of fentanyl on renal function, even in high tion is detected and the expiratory values obtained. dosage, is usually considered to be small both in the human The accuracy and linearity of the system in measuring subject (Gorman and Craythorne, 1966) and in the dog pressure were determined by comparing the pressure dis- (Bidwai et al., 1976; Hunter et al., 1979). played by the computer with a water manometer at eight The effect of low-dosage and high-dosage fentanyl on values of pressure from 5 cm H2O to 40 cm H2O in incre- renal function has been investigated in 10 dogs anaesthe- ments of approximately 5 cm H2O pressure. Five separate tized with nitrous oxide and oxygen, neuromuscular block measurements were made at each pressure. being provided by alcuronium and ventilation being con- The accuracy of measurement of the inspiratory flow trolled. In each experiment the animal was initially given was determined by passing the gas flow from the inspira- fentanyl 0.005 mg kg"1 over a 90-min period and estimated tory port of the ventilator through a Parkinson Cowan gas renal plasma flow (ERPF: measured by clearance of para- meter over a period of 5 min. The average minute volume aminohippuric acid), glomerular filtration rate (GFR: obtained was compared with the value calculated by the measured by clearance of inulin), urine volume (F), mean computer over the same period. Five measurements were arterial pressure (MAP), and renal vascular resistance made at each of eight minute volumes from a ventilator (RVR) were measured at intervals of 30 min for 90 min. setting of 2.5 litre min"1 to 20 litre min-1 in increments Fentanyl 0.025 mg kg-1 was given i.v. over a 10-min period of 2.5 litre min-1. The expiratory flow was compared in a and the variables were measured at intervals of 30 min. A similar manner by passing the gas flow from the expiratory significant reduction in ERPF (/><0.01), GFR (P< 0.001), port of the ventilator through the gas meter. Five measure- V (P<0.01) and MAP (P< 0.001) occurred together with ments were made on the expiratory flow using the same an increase in RVR (0.02>P>0.01); these changes were ventilator settings as for the inspiratory measurements. accompanied by a bradycardia if no atropine was given. The system proved to be accurate and linear for pressure The administration of atropine before the high-dose fen- and flows over the ranges measured. The results of the tanyl prevented bradycardia but did not prevent the altera- comparison of the computed values with the measured tion in renal function. values were: The effect of high-dose fentanyl on renal function ap- Pressure: y =x + 0.19; r = 0.9999; SEM of estimate = peared to be of relatively short duration. Within 90 min the 0.193. measurements had returned to the values found with low- Inspiratory flow: y = x; r = 0.9993; SEM of estimate dose fentanyl. = 0.188. Expiratory flow: y = 0.94 x + 0.31; r = 0.9997; SEM of REFERENCES estimate = 0.124. Bidwai, A. V., Liu, W. S., Stanley, T. H., and colleagues To obtain such information using manual planimetry (1976). Can. Anaesth. Soc. J., 23, 296. would be time-consuming on anything other than a small Gorman, H. M. and Craythorne, N. W. B. (1966). Ada sample number of traces. An analog system which could Anaesthesiol. Scand. (Suppl.), 24, 111. produce an equivalent amount of information would be both Hunter, J. M., Jones, R. S., Lamplugh, G., and Utting, complex and expensive. The introduction of cheap micro- J. E. (1979). Br. J. Anaesth. (in press). processor-based computers allows such monitoring to be undertaken even in small intensive care units where re- sources are at a premium.

REFERENCES MONITORING RESPIRATORY FUNCTION Hilberman, M., Kamm, B., Tarter, M., and Osborn, J. J. WITH A MICROCOMPUTER (1975). Comput. Biomed. Res., 8, 447. Peters, R. M., Hilberman, M., and Hogan, J. S. (1972). G. N. C. KENNY, P. D. DAVIS and D. CAMPBELL Am. J. Surg., 124, 262. University Department of Anaesthesia, Glasgow Royal Proctor, H. J., and Woolson, R. (1973). Surg. Gynecol. Infirmary Obstet., 136, 367. Printed in Great Britain by John Wright and Sons Ltd. at The Stonebridge Press, Bristol BS4 5NU ©Macmillan Journals Ltd 1979