pattern of reduction of ventilatory and occlusion pressure response to

Br. J. Anaesth. (1982), 54, 87

PATTERN OF REDUCTION OF VENTILATORY AND OCCLUSION PRESSURE RESPONSE TO CARBON DIOXIDE BY PENTAZOCINE IN MAN G. B. DRUMMOND, J. FISHER, A. ZIDULKA AND J. MILIC-EMILI SUMMARY

Mean inspiratory flow, occlusion pressure and end-tidal Pco 2 were measured in six healthy, sitting subjects, during breathing air and rebrcathing carbon dioxide, before and after pentazocine 0.5 mgkg"' l.v. and again after naloxone 20 ug kg"'. Pentazocine reduced the occlusion pressure and inspiratory flow responses at a given Pco 2 during carbon dioxide rebreathing and these effects were antagonized by naloxone. The relationship of inspiratory flow and end-tidal carbon dioxide during rebreathing was used to measure the Poo2 value at which mean inspiratory flow was 1 litre s ~'. Occlusion pressure at this Pco 2 was reduced in all the subjects by pentazocine, suggesting that the generation of inspiratory flow required less muscle activity This effect was antagonized by naloxone.

Drugs such as sedatives, narcotics and general anaesthetics are thought to cause respiratory depression by a central action. Externally imposed loads to breathing, such as an added resistance, may also cause respiratory depression (Lourenco et al., 1966), but in these circumstances, neuromuscular activity is augmented although the resultant ventilation is diminished. By occlusion of the airway and measurement of the decrease in airway pressure during an inspiratory effort, a more direct assessment of the activity of the respiratory muscles can be made (Whitelaw, Derenne and Milic-Emili, 1975). This is because no gas flow and no lung volume changes occur during the measurement and the composite action of the inspiratory muscles is transformed into decrease of airway pressure. If the inspiratory attempt starts at the same lung volume on each occasion, then the muscles will be at the same initial length, and the pressure decrease correlates well with the neural activation of the muscles (Eldridge, 1975). The ratio of the rate of change of pressure during an occluded breath to the rate of change of lung volume during a normal breath is an index of the "effective impedance" of the respiratory system during active inspiration. G. B. DRUMMOND,* M.A., M.B., CH.B., F.F.A.R.CS.; J. FISHER, B.SC., M.sc.; A. ZIDULKA, M.D.; J. MILIC-EMILI, M.D.; Depart-

ments of Anaesthesia, Physiology and Medicine, McGill University, Montreal, Quebec, Canada. •Present address: Department of Anaesthetics, Royal Infirmary, Edinburgh EH3 9YW. 0007-0912/82/010087-10 801.00

Derenne and others (1976) measured occlusion pressure and rate of change of lung volume (as mean inspiratory flow rate, FT/ 7I) during carbon dioxide rebreathing in patients anaesthetized with methoxyflurane. The average response of occlusion pressure to carbon dioxide was reduced less than the response of mean inspiratory flow rate. This was interpreted as an increase in effective impedance and attributed to the decreased passive compliance of the respiratory system during anaesthesia. They suggested that part of the ventilatory depression observed during anaesthesia was the result of the reduced compliance of the respiratory system. In animals, however, ventilatory depression or stimulation are not associated with changes in effective impedance (Goldberg and Milic-Emili, 1977; Bopp et al., 1979). We have studied the effects of pentazocine in conscious subjects to determine if the ventilatory depression was associated with a change in effective impedance. METHODS

Six healthy male volunteers were studied after written consent. The study was approved by the Montreal General Hospital Ethics Committee. No subject was taking medication or had taken drinks containing caffeine for 12 h before. One subject (PB) smoked 20 cigarettes daily. Each subject was studied 2-3 h after a light non-fatty breakfast. Vital capacity and forced expiratory volume in 1 s were measured with the subject © Macmillan Publishers Ltd 1982

88

standing. Functional residual capacity (FRC) was measured in the sitting position in a constant volume body plethysmograph (Warren Collins). The subject then left the plethysmograph and sat comfortably with the arms supported in a carefully standardized position in an adjustable chair. He wore a noseclip, and breathed through the apparatus mouthpiece. The apparatus consisted of two one-way valves connected to taps to allow either air breathing or rebreathing from a bag in box system (fig. 1). A pneumotachograph (Fleisch no. 2) was connected

BRITISH JOURNAL OF ANAESTHESIA

inspiratory valve. The piston movement could not be seen or heard by the subject. The solenoid was activated during expiration * without the knowledge of the subject, to prevent inspiratory flow during the early part of the next inspiratory effort. The expiratory valve was adjusted and checked to make sure that no return flow could occur during this inspiratory attempt. The resultant subatmospheric pressure was measured at the mouthpiece (Hewlett-Packard ** 267B transducer) and recorded on FM magnetic tape. The piston was withdrawn from the inspiratory port after about 300 ms of the effort and the delayed inspiration started, and in this way the rhythm of breathing was not greatly disturbed. The frequency response of the pressure * measurement system was linear to 20 Hz. The flow, pressure, volume and carbon dioxide concentration signals were processed and displayed on a chart recorder. An electrocardiogram taken from chest leads was displayed continuously on an oscilloscope and arterial pressure measured intermittently by sphygmomano- -" meter. After the subject had breathed from the mouthpiece until PE' C O ] was constant, 10 airway occlusions were performed at random intervals, each separated by at least 10 normal breaths. The taps of the apparatus were then turned to allow rebreathing, and random occlusions made at _ ^PRESSURE intervals of about 10 breaths during rebreathing. .• > COj CONCENTRATION The bag volume was adjusted to about half the MOUTHPIECE subject's vital capacity. The bag was filled with FIG. 1 Diagram of apparatus used (not to scale). The plunger 50% oxygen, 7% carbon dioxide and nitrogen. of the occlusion device (shaded) can be moved electncally to After a practice run, a control series of measureocclude the inspiratory valve port. ments were made. A slow i.v. infusion of sodium i 1 so that inspiratory flow could be measured in both chloride 154mmol litre" was then started and circumstances using a Hewlett-Packard 270 trans- pentazocine 0.5mgkg"' given i.v. over a 5-min ducer. This position allowed only room air to pass period, while arterial pressure was checked. Ten through the pneumotachograph, which was not minutes later, the subject was moved into the heated. Inspired volume was derived by electrical body plethysmograph and FRC was measured integration of the inspiratory flow signal again. He returned from the box and a further 4 (Hewlett-Packard 8815A). The inspiratory and series of measurements of occlusion pressure and expiratory flow resistances of the apparatus were ventilation was made during air breathing and , 0.14 and 0.15 kPa litre"' s respectively at a flow rebreathing. About 30min after the pentazocine rate of 3 litre s "'. Gas was sampled at the mouth- had been given, naloxone 20ugkg~' was given piece with a mass spectrometer (Medspect MS8) i.v. over a 5-min period and all measurements to allow measurement of end-tidal Pco2 (PE'CO:) were repeated for a third time lOmin later. and Po2 to check that hyperoxia was present Measurements were taken from the rebreathing throughout the rebreathing manoeuvre. records after the increase in .PE'COJ had become ' A pneumatically-damped solenoid was used to linear. Measurements were made from the breath move a piston to close the channel of the preceding the airway occlusion (fig. 2). The

VENTILATORY DEPRESSION BY PENTAZOCINE

89

made at a suitable speed for measurement of occlusion pressure (50 mm s"1). This avoided making changes in recorder speed during the experiment which could have warned the subject that an airway occlusion was imminent. Occlusion pressure was measured 100 ms after the airway pressure had become less than Flow — O.lkPa (Po i) rather than after the pressure became less than atmospheric (fig. 3). This method is similar to that advocated by Kryger, McCullough and Weil (1976) who measured the pressure change from 50 to 100 ms after the pressure became less than atmospheric. Occlusion pressure was also measured by the original method of Whitelaw, Derenne and Milic-Emili (1975). Mouth Pressure' The mean values of the measured and derived + variables during air breathing were compared FIG. 2 A typical record showing the measurements made. using Student's t test for paired values. Linear Tl = inspiratory time, 7",,,, = total cycle duration; FT = tidal regression relationships for the values obtained volume, F o , = volume inspired in 0.5 s An occlusion has during rebreathing were calculated by the least been performed at the onset of the third inspiration. squares technique. Occlusion pressure values at an inspiratory flow rate of 1 litre s ~' were estimated from the linear regression relationship of mean inspiratory flow PE'COI, and the logarithm of occlusion pressure with .PE'CO2- These values were compared using the Wilcoxon signed rank test. C0

2 Concentration

Mouth pressure

RESULTS

Details of subjects are given in table I. Subject JF had a moderately reduced FRC and RV. 0— No significant changes in breathing pattern were found after pentazocine or naloxone when FIG. 3 A typical pressure record showing the measurements the subjects breathed air. Mean PE' CO] in the made control state was 5.95 kPa +0.62, and this duration of inspiration (Ti) was measured from the flow record. The end of the respiratory cycle was measured from the pressure trace to allow measurement of the total cycle duration (r tot ). TABLE I. Details of subjects studied. FEV, 0 = forced exThe pressure trace was used to indicate the end of piratory volume in 1 s, VC = vital capacity; R V = residual residual capacity; FVC = forced expiration, since inspiratory flow was occluded in volume; FRC = functional vital capacity the following breath. Inspired tidal volume (FT) and the volume inspired in the first 0.5 s of FEV 10 / Age Height Weight FVC VC RV FRC inspiration (Vo 5) were measured from the volume (kg) (%) (% predicted) trace. Inspiratory minute volume (Vi) was Subject (yr) (m) calculated as PTx60xl/r t o t and was not 96 36 178 79 71 119 100 AZ corrected to BTPS. Mean inspiratory flow was 27 115 97 96 RR 85 80 1 79 calculated as VT/TI. 76 90 74 95 65 25 1.85 JF 99 77 99 93 30 63 PB 1.75 The pressure signal was replayed from the tape 89 BH 28 74 78 110 88 1 72 recording to the chart recorder at the end of the 99 83 94 RD 22 180 68 93 experiment to allow part of the chart record to be


90

60

60

40

40

20

20

65

70

75 80 PE'Co2 (kPa)

40

J

85

1

2 VT (litre)

2O

3

05

1.0 15 20 VT/T\ (litres' 1 )

14' 12 10' r

Barcroft, J., and Margana, R. (1931). Some effects of carbonic acid in high concentration on respiration. J. Phystol (Lond.), 74, 156 Belville, J. W., and Green, J. (1965). The respiratory and subjective effects of pentazocine Clin. Pharmacol. Ther., 6, 152. Bopp, P , Drummond, G. B., Fisher, J , and Mihc-Emih, J (1979) Effect of doxapram on control of breathing in cats. Can. Anaesth. Soc. J , 26, 191. Burki, N. K. (1977). The effects of changes in functional and residual capacity with posture on mouth occlusion pressure and ventilatory pattern. Am. Rev Resptr. Du , 116, 895. Cotes, J. E. (1975) Lung Function, 3rd edn, p.82 Oxford: Blackwell. Derenne, J.-P , Couture, J., Iscoc, S , Whitclaw, W. A., and Milic-Emili., J (1976). Occlusion pressures in man rebreathing CO2 under methoxyflurane anaesthesia. J. Appl Phystol., 40, 805. Drummond, G. B., and Scon, D. H. T. (1980). Tracheal intubation alters the shape of the occlusion pressure wave. Br. J. Anaesth., 52, 232P. Eldndge, F L. (1975) Relationship between respiratory nerve and muscle activity and muscle force output. J. Appl Physwl, 39, 567. Vaughn, K. Z (1977). Relationship of thoracic volume and airway occlusion pressure, muscular effects. J Appl. Physwl, 43, 312. Evans, J. A , Hogg, M. I. S., Lunn, J. N., and Rosen, M (1974). A comparative study of the narcotic agonist activity of naloxone and levallorphan. Anaesthesia, 29, 721. Fleetham, J A., Clarke, H., Dhingra, S., Chemick, V., and Anthonisen, N. R. (1980). Endogenous opiates and chemical control of breathing in humans. Am. Rev. Resp Du., 121, 1045. Freund, F. G., Martin, W E , Wong, K. C , and Hombein, T. F (1973). Abdominal muscle rigidity induced by morphine and nitrous oxide. Anestheswlogy, 38, 358. Goldberg, M. S., and Milic-Emili, J. (1977) Effect of pentobarbital sodium on respiratory control in newborn rabbits J. Appl. Phystol., 42, 845. Goldman, M. (1974). Mechanical coupling of the diaphragm and nb cage- in Loaded Breathing (eds L. D. Pengelly, A. S. Rebuck and E. J. M. Campbell) p. 50 Toronto, CanadaLongman Hanato, S , Keane, D M., Wade, M. A , and Sadove, M. S (1975). Naloxone reversal for anaesthetic dosages of pentazocine. Anesthesiol. Rev., 1, 11. Kallos, T., and Smith, T. C. (1968). Naloxone reversal of pentazocine induced respiratory depression J.A.M.A., 204, 932. Krull, R., Cosgrove., J. D , Olley, P. M., and Levinson, H. (1976). Components of respiratory depression after narcotic premedication in adolescents. Can. Anaesth. Soc J., 23,449. Kryger, M., McCullough, E., and Weil, S (1976). Aspects of technique which affect precision in mouth occlusion pressure measurement. Am Rev. Resptr. Dis , 113, 246. Yacoub, O., Dosman, J., Macklem, P. T., and Anthonisen, N R. (1976). Effect of mependine on occlusion pressure responses to hypercapnia and hypoxia with and without external inspiratory resistance. Am. Rev. Respir. Du., 114,333. Lynne-Davies, P , Couture, J., Pengelly, L. D., and MilicEmili, J. (1971). Immediate ventilatory response to added inspiratory elastic loads in cats. J. Appl. Physwl., 30, 512.

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Lourenco, R. V., Cherruack, N S , Malm, J. R , and Fishman, A. P (1966) Nervous output from the respiratory center during obstructed breathing. J Appl Physwl, 21, 527 Margana, C. E , Iscoe, S., Pengelly, L D , Couture, J., Don, H , and Mihc-Emih, J. (1973). Immediate ventilatory response to elastic loads and positive pressure in man. Resptr. Physwl., 18, 347. Mognoni, P., Saibene, F., Sant'Ambrogio, G ,.and Agostom, E (1968) Dynamics of the maximal contraction of the respiratory muscles. Resptr Physwl, 4, 193. Sharp, J. T., Goldberg, N. B., Druz, W S , and Danon, J (1975). Relative contributions of nbcage and abdomen to breathing in normal subjects. J. Appl. Physwl, 39, 608. Sokoll, M. D , Hoyt, J L , and Gergis, S. D (1972). Studies in muscle rigidity, nitrous oxide and narcotic analgesic agents Anesth. Analg. (Cleve.), 51, 16. Whitelaw, W. A , Derenne, J.-P , and Mihc-Emih, J. (1975) Occlusion pressure as a measure of respiratory center output in conscious man Respir Physwl., 23, 181. Zackon, H., Despas, P J , and Anthonisen, N R. (1976) Occlusion pressure responses in asthma and chronic obstructive pulmonary disease. Am. Rev. Resptr. Du., 114, 917 TYPE DE REDUCTION DE LA REPONSE DE LA PRESSION DE VENTILATION ET D'OCCLUSION A L'ANHYDRIDE CARBONIQUE DUE A LA PENTAZOCINE CHEZ L'HOMME RESUME

On a mesure chez six sujets sains en position assise le flux inspiratoire moyen, la pression d'occlusion et le Pco 2 rcspiratoire terminal, au cours de la respiration d'air et d'une nouvelle respiration d'anhydnde carboruque, avant et apres avoir adrrunistre 0,5 mgkg"' de pentazocine l.v et de nouveau apres 20ugkg"' dc naxolone. La pentazocine a fait diminuer la response de pression d'occlusion et du flux inspiratoire a un Ptx>2 donne au cours d'une nouvelle respiration d'anhydnde carbonique et ces effets ont cte antagonises par la naxolone. Le rapport entre le flux inspiratoire et 1'anhydnde carbonique respiratoire terminal au cours de la nouvelle respiration a ete utilise pour mesurer la valeur du Pco2 a laquelle le flux inspiratoire moyen etait de 1 litres"'. La pression d'occlusion a ce Pco2 a baisse chez tous les sujets sous l'effet de la pentazocine, ce qui suggere ^ue la generation du flux inspiratoire exige moms d'acuvite musculaire. Cet effet fut antagonise par la naxolone.

REDUKTIONSBILD DER ATMUNGSDRUCK- UND ABSCHLIESSUNGSDRUCK-REAKTION AUF KOHLENDIOXYD DURCH PENTAZOCIN BEIM MENSCHEN ZUSAMMENFASSUNG

Mittlerer inspiratorischer Druck, Abschliessungsdruck und Endatmungs-PcOj wurden bei sechs gesunden sitzenden Menschen wahrend der Atmung von Luft und der Wiedereinatmung von Kohlendioxyd vor und nach der Verabreichung intravendsen von 0,5mgkg~l und auch nach Naloxon 20ugkg~' gemessen. Pentazocin reduzierte die


96 Abschhessungsdruck- und Einatmungsfluss-Reaktionen bei einem vorgegebencn Pco2 Wert wahrend der Wiedereinatmung von Kohlendioxyd, und die Auswirkungen wurden durch Naloxon bekampft Die Verbindung zwischen mspiratonschem Fluss und Endatmungs-.Pco2 wahrend der Wiedereinatmung wurde verwendet, um den Pco2-Wert zu messen, bei dem der mittlere inspiratonsche Fluss 1 litres" 1 entsprach. Der Abschhessungsdruck bei diesem Pco2-Wert wurde bei alien Versuchspersonen mittels Pentazocin reduziert, was vermuten lasst, dass die Erzeugung des mspiratonschen Flusses wemger Muskelaktivitat braucht Diese Auswirkung wurde durch Naloxon bekampft. CONFIGURACION DE LA REDUCCION DE LA RESPUESTA DE LA PRESION VENTILATORIA Y DE OCLUSION AL ANHIDRIDO CARBONICO POR LA PENTAZOCINA EN EL HOMBRE SUMARIO

Se midieron el flujo inspiratono medio, la presion de oclusion y el Pco2 respiratono terminal en seis personas sentadas en el

curso de la respiracion de aire y de la nueva respiracion de anhidndo carbonico, antes y despues de administrarles 0,5 mg kg "' de pentazocina I.v y, de nuevb, despues de una de 20 ug kg "' de naxolona. La pentazocina redujo las respuestas de la presion de oclusion y del flujo mspiratorio en un Pco2 dado en el curso de una nueva respiracion de anhidndo carbonico y dichos efectos se hallaron antagoruzados por la naxolona. La relacion entre el flujo inspiratono y el anhidndo carbonico respiratono terminal en el curso de la nueva respiracion se uso para medir el valor del fco 2 en que el flujo inspiratono medio era dc lhtros" 1 La presion de oclusion en este Pco2 se reducia por accion de la pentazocina en todas las personas, lo que hace pensar que la generaci6n del flujo inspiratorio necesitaba una actividad muscular menor. La naxolona antagonizo dicho efecto.