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LOW VENTILATORY RESPONSE TO CARBON DIOXIDE NOT ASSOCIATED WITH INCREASED DEPRESSION BY MORPHINE
Br.J. Anaesth. (1978), 50, 767
LOW VENTILATORY RESPONSE TO CARBON DIOXIDE NOT ASSOCIATED WITH INCREASED DEPRESSION BY MORPHINE J. R. A. RIGG SUMMARY
Patients with chronic airways obstruction are more likely to develop hyper capnia if they have a low rather than a high ventilatory response to carbon dioxide (Lane and Howell, 1970). Similarly, patients with asthma and known to have a small response to carbon dioxide when their airways resistance is normal, are more likely to develop hypercapnia during an acute exacerbation than are those who have a large carbon dioxide response (Rebuck and Read, 1971). These observations confirmed the original suggestion of Lambertsen that a low sensitivity to carbon dioxide might predispose patients to the development of carbon dioxide retention in various clinical conditions (Lambertsen, 1960). He suggested also that individuals with low ventilatory response to carbon dioxide might be more susceptible to ventilatory depression by narcotic agents (Lambertsen, 1960). Although the rebreathing method for the measurement of ventilatory response to carbon dioxide (Read, 1967) has been used in clinical studies (Jennett, Barker and Forrest, 1968; Rebuck et al., 1973; Rigg, Rebuck and Campbell, 1974) this hypothesis has not been tested, except in a small group of volunteer subjects in whom recovery of ventilatory response to carbon dioxide was assessed following thiopentone, morphine and fentanyl, when the results were inconclusive (Rigg and Goldsmith, 1976). There remains the important JOHN R. A. RIGG, M.B., B.S., F.F.A.R.A.C.S., Department of
Anaesthesia, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada, L8S 4J9. 0007-O912/78/005O-O767 S01.00
possibility that measurement of the ventilatory response to carbon dioxide might be used to predict an increased risk of ventilatory depression after anaesthesia. The hypothesis has now been tested in a group of surgical patients with no history of lung disease, and who received morphine i.m. as premedication before elective surgery. METHODS
Ventilation (KE), end-tidal and mixed venous carbon dioxide partial pressure (.PE'COS an and ventilatory response to carbon dioxide APco2) were measured before and within 90 min after morphine 0.15 mg kg" 1 i.m., given to 17 adult patients (American Society of Anesthesiologists' physical status I and II) before elective surgery under general anaesthesia. Details of the experimental procedure are given by Rigg (1978). The slope of the ventilatory response to carbon dioxide was determined by least squares regression, using the procedure of Read (1967). The positions of the response curves before and after morphine were compared in each subject using the procedure described by Rigg (1978) to determine the response curve position variables i^EH and KE L . To test the hypothesis that response to carbon dioxide before injection determines the magnitude of morphine-induced changes in KE and AKfi/APcOg, control AFE/APCOJ, KE H and KEL, were plotted © Macmillan Journals Ltd 1978
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Ventilation ( ^E), end-tidal (.PE'CO,)> mixed venous />co2 CPvco.) and the ventilatory response to carbon dioxide (A ^E/APCO 2 ) were measured before and within 90 min after morphine 0.15 mg kg" 1 i.m. given to 17 adult patients undergoing elective surgery under general anaesthesia. The hypothesis that patients with a low ventilatory response to carbon dioxide are more susceptible to the ventilatory depressant effects of morphine was tested. Morphine induced increases in PE'co.andPvco, were not correlated with either the slope or the position of the preinjection response to carbon dioxide. Mean APE/APCO 2 was depressed after morphine (P<0.05), but individual responses varied widely. Seven patients whose control A^E/PCX^ was 9.9 litre min" 1 kPa" 1 or less decreased A^E/APCO 2 after morphine. In four patients, AI^E/APCO 2 increased after morphine; however, in each case, PE'CO, and Pvco 2 increased also. Morphine displaced the carbon dioxide response to the right (P< 0.001)' but no correlation was found between either the magnitude of the displacement or change in slope and control A^E/A/ 3 CO 2 . The results suggest that patients with a low value for A KE/APCO 2 are not more susceptible to the ventilatory depressant action of morphine.
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against per cent changes of P E ' C 0 2 A K E / A P C 0 2 , KE H and KE L after morphine. The relationships between these variables were explored vising least squares regression analysis. The significance of all changes following injection was determined using paired t tests.
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Increases in P E ' C O O and PvCO2 induced by morphine were not correlated with preinjection AKE/APCO 2 , KE L or KE H (fig. 1). Similarly, the magnitude of changes in F E L and KE H were not related to control
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FIG. 2. Control carbon dioxide response slope, (AJ^E/APCO 2 (litre m i n - 1 kPa"1) plotted against morphine-induced changes in carbon dioxide response position variables VEL and V E H (as per cent of control).
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FIG. 3. Relationship between control and morphine carbon 20
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FIG. 1. Control carbon dioxide response slope (KE/APCO 2 ) (litre min" 1 kPa" 1 ) and position variables KE^ and I^EH (litre min- 1 ) plotted against morphine-induced changes in end-tidal (PE'CQJ and mixed venous / 3 co 2 (Pvco,) (per cent of control).
The mean slope of the ventilatory response to carbon dioxide decreased from 12.3 to 10.05 litre min" 1 kPa" 1 after morphine (P<0.05) but individual responses varied widely. Seven patients with preinjection AKE/APCO 2 of 9.9 litre min- 1 kPa" 1 or less showed a decrease in AFE/APCO 2 after morphine; the
dioxide response slopes, AKE/APCO 2 (litre min" 1 kPa - 1 ).
largest per cent decrease occurred in three patients with control AKE/APCO 2 less than 7.5 litre min- 1 kPa"1. Of 10 patients in whom the value before injection ranged from 10.2 to 23.0 litre min- 1 kPa" 1 , four increased and six decreased AKE/APCO 2 after morphine. All four of the patients with increased AKE/APCO 2 after morphine had typical ventilatory depression on the basis of increases of P E ' C 0 2 and Pv C02 . Comparison AKE/APCO 2 before and after injection did not suggest a greater susceptibility to morphine in individuals with a low response (fig. 3).
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 25, 2015
7.5
AKE/APCO 2 (fig. 2).
CO, RESPONSE AND MORPHINE DISCUSSION
* 1 mm Hg = 0.13 kPa.
mm H g - 1 (Irsigler, 1976). Eighty per cent of these subjects had ventilatory response curve slopes between 1.5 and 5.0, 16% less than 1.5 and 4% greater than 5.0 litre min" 1 mm Hg" 1 . Rebuck and Read (1971) found champion sprint and endurance athletes at the high and low extremes of the range of carbon dioxide response curve slopes, with limits of 0.4 and 8.0 litre min" 1 mm Hg- 1 in their subjects; the range of AKE/APCO 2 in the present study of 4.323.0 litre min" 1 kPa" 1 (0.58-3.07 litre min- 1 mm Hg" 1 ) is within these limits. Thus, it seems reasonable to define "low" AKE/APCO 2 as less than 7.5 litre m i n ^ k P a - 1 (1.0 litre min' 1 mm Hg- 1 ) and "high" 1 1 AKE/APCO 2 as greater than 52.5 litre min- kPa" (7.0 litre min- 1 mm Hg- 1 ). The three subjects in the present study who had control A FE/APCO 2 of less than 7.5 litre min" 1 kPa" 1 all had response slopes of less than 60% of control following morphine. However, the decrease in absolute levels of ventilation during the latter part of rebreathing after morphine in these patients was less than that of the remaining patients in whom control AKE/APCO 2 was greater. Furthermore, in none of the three patients with A FE/APCO 2 less than 7.5 litre min" 1 kPa" 1 was the increase in PE'OO2 o r Pv C02 substantially greater than that of the other patients. However, these changes in Pco 2 during air breathing were small and close to the limits of precision of infra-red capnography. It is possible that a greater likelihood of hypercapnia might be found in patients with low carbon dioxide responses if a larger dose of a narcotic was studied. There was wide variation in the plasma concentrations of morphine in individual patients, both in the maximum plasma concentrations and in the time course of the concentrations (Rigg, 1978). These differences reflect, presumably, wide inter-individual differences in absorption of morphine from the i.m. site of injection (all 17 patients were injected in the right gluteal region) and in the distribution to the brain. It is possible that after a single dose of morphine i.m., different effects on ventilation and ventilatory response to carbon dioxide may reflect differences between individuals in the pharmacokinetics of the drug. That there was no correlation between the magnitude of the effect of morphine on ventilatory variables and plasma concentration of the drug argues against this possibility (Rigg, 1978). Nevertheless, it remains possible that, if plasma concentrations of morphine were maintained constant by i.v. infusion, patients with a low response to carbon dioxide might be more susceptible to ventilatory depression.
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Many studies have defined the effect of narcotics and other central nervous depressant drugs on ventilation in man (Dripps and Dumke, 1943; Eckenhoff and Helrich, 1958; Bellville and Seed, 1960; Severinghaus and Larson,1965; Munson et al., 1966; Larson et al., 1969). The present study differs in its method in that morphine was used in an attempt to characterize differences in ventilatory control that might have an important bearing on the recovery of adequate spontaneous ventilation following general anaesthesia. The findings support those of Bellville and Seed (1960) who concluded that opiates caused a large displacement of the carbon dioxide response and little alteration in slope. The results of the present study suggest that patients with normal lungs and a low ventilatory response to carbon dioxide are not more susceptible to the depressant action of morphine, as judged by the effect on P E ' C 0 2 , PVCO2 and AFE/APCO 2 . However, caution should be exercised in extending this conclusion to the general population or to the effects of other narcotics or depressant drugs. Few attempts have been made previously to define a "normal" "low" or "high" carbon dioxide response. This problem has been compounded by the identification of several characteristics that influence ventilatory response to carbon dioxide. These include body size, athleticism and personality (Avery et al., 1963; Rebuck and Read, 1971; Saunders, Heilpern and Rebuck, 1972; Rebuck et al., 1974; Rigg, Rebuck and Campbell, 1974; Hirshman, McCullough and Weil, 1975; Irsigler, 1976). Hirshman, McCullough and Weil reported data obtained from 44 normal non-athletic subjects aged between 21 and 51 yr (Hirshman, McCullough and Weil, 1975). They compared their findings (AKE/ APco 2 and SEM = 2.69 ± 0.19 litre min" 1 mm Hg- 1 , BTPS)* with those of previous reports (Read, 1967; Byrne-Quinn et al., 1971; Forster et al., 1971; Kallos et al., 1972; Saunders, Heilpern and Rebuck, 1972; Kronenberg and Drage, 1973; Rebuck et al., 1973), in which mean AKE/APCO 2 ranged from 1.84 to 3.4 litre min" 1 mm Hg- 1 .* They concluded that it is difficult to characterize an individual as abnormal because of the large tolerance limits of the ventilatory response to hypercapnia. More recently, Irsigler studied 126 healthy medical students and found mean AKE/APCO 2 and SEM = 2.60 + 0.11 litre min" 1
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Read, D. J. C. (1967). A clinical method for assessing the ventilatory response to carbon dioxide. Aust. Ann. Med., 1,20. Rebuck, A. S., Kangalee, M., Pengelly, L. D., and Campbell, E. J. M. (1973). Correlation of ventilatory responses to hypoxia and hypercapnia. J. Appl. Physiol., 35, 173. Read, J. (1971). Patterns of ventilatory response to CO 2 during recovery from severe asthma. Clin. Sci., 41, 13. Rigg, J- R- A., Kangalee, M., and Pengelly, L. D. (1974). Control of tidal volume during rebreathing. J. REFERENCES Appl. Physiol., 37, 475. Avery, M. E., Chernick, V., Dutton, R. E., and Permutt, S. Rigg, J. R. A. (1978). Ventilatory effects and plasma con(1963). Ventilatory response to inspired carbon dioxide in centration of morphine in man. Br. J. Anaesth., 50, 759. infants and adults. J. Appl. Physiol., 18, 895. Goldsmith, C. H. (1976). Recovery of ventilatory Bellville, J. W., and Seed, J. C. (1960). The effect of drugs response to carbon dioxide after thiopentone, morphine on the respiratory response to carbon dioxide. Anesand fentanyl in man. Can. Anaesth. Soc. J., 23, 370. thesiology, 21, 727. Rebuck, A. S., and Campbell, E. J. M. (1974). Effect Byrne-Quinn, E., Weil, J. V., Sodal, I. E., Filley, G. F., of posture on the ventilatory response to CO 2 . J. Appl. and Grover, R. F. (1971). Ventilatory control in the Physiol., 37, 487. athlete. J. Appl. Physiol, 30, 91. Saunders, N. A., Heilpern, S., and Rebuck, A. S. (1972). Dripps, R. D., and Dumke, P. R. (1943). The effect of Relation between personality and ventilatory response to narcotics on the balance between central and chemocarbon dioxide in normal subjects: a role in asthma. Br. receptor control of respiration. J. Pharmacol. Exp. Ther., Med.J., 1,719. 77, 290. Eckenhoff, J. R., and Helrich, M. (1958). Effect of narcotics, Severinghaus, J. W., and Larson, C. P. jr (1965). Respiration in anaesthesia; in Handbook of Physiology, Vol. II, p. 1219. thiopental and nitrous oxide upon respiration and Washington, D.C.: Am. Physiol. Soc. respiratory responses to hypercapnia. Anesthesiology, 19, 240. Forster, H. V., Dempsey, J. A., Birnbaum, M. L., Reddan, W. G., Thoden, J., Grover, R. F., and Rankin, J. (1971). FAIBLE REPONSE VENTILATOIRE AU GAZ Effect of chronic exposure to hypoxia on ventilatory CARBONIQUE NON ASSOCIEE A UNE response to CO 2 and hypoxia. J. Appl. Physiol., 31, 586. AUGMENTATION DE LA DEPRESSION PAR Hirshman, C. A., McCullough, R. E., and Weil, J. V. (1975). LA MORPHINE Normal values for hypoxic and hypercapnic ventilatory RESUME drives in man. J. Appl. Physiol., 38, 1095. Irsigler, S. B. (1976). Carbon dioxide response lines in young La ventilation (KE), le volume courant final (PE'O,), le adults: the limits of the normal response. Am. Rev. Pco 2 (Pvco,) veineux mixte et la reponse ventilatoire au Respir. Dis., 114, 529. gaz carbonique ( AFE/APco 2 ) ont 6t6 mesur£s avant et Jennett, S., Barker, J., and Forrest, J. B. (1968). A double- dans un delai de 90 min apres qu'une injection de morphine a raison de 0,15 mg kg" 1 ait 6t6 administr£e par voie blind controlled study of the effects on respiration of pentazocine, phenoperidine and morphine in normal man. intramusculaire a 17 malades adultes subissant une intervention chirurgicale a froid sous anesthfisie gen£rale. On a Br. J. Anaesth., 40, 864. Kallos, T., Hudson, H. E., Rouge, J. C , and Smith, T. C. procede a des testes pour verifier l'hypothese supposant que (1972). Interaction of the effects of naloxone and oxy- les malades ayant une faible response ventilatoire au gaz morphone on human respiration. Anesthesiology, 36, carbonique sont plus susceptibles aux effets ventilatoires d£primants de la morphine. Les augmentations du .PE'CO, 278. Kronenberg, R. G., and Drage, C. W. (1973). Attenuation et du PvWt provoquees par la morphine n'ont et£ relives of the ventilatory and heart rate responses to hypoxia and ni au coefficient angulaire ni a la position de la reponse de hypercapnia with aging in normal man. J. Clin. Invest., la pre-injection au gaz carbonique. La AKE/APCO 2 moyenne s'est trouvee d£primee apres la morphine 52, 1812. Lambertsen, C. J. (1960). Carbon dioxide and respiration in (P<0,05), mais les r£ponses individuelles ont accuse de vastes variations. Sept malades, dont la valeur t£moin de acid-base homeostasis. Anesthesiology, 21, 642. AKE/ APCO 2 £tait de 9,9 litre min" 1 kPa" 1 ou moins, ont Lane, D. J., and Howell, J. B. L. (1970). Relationship between sensitivity to carbon dioxide and clinical features vu leur Al^E/APcOa diminuer apres la morphine. Sur in patients with chronic airways obstruction. Thorax, 25, quatre malades, la AKE/APCO 2 a augmente apres o nlat morphine; mais dans chaque cas le PE'QO, et le Pvco, 150. Larson, C. P., Eger, E. I. II, Muallem, M., Buechel, D. R., aussi augmented La morphine a d6plac£ la reponse au gaz Munson, E. S., and Eisele, J. H. (1969). The effects of carbonique vers la droite (P< 0,001) mais on n'a trouv£ diethyl ether and methoxyflurance on ventilation: a aucune correlation entre l'importance du d£placement et les variations du coefficient angulaire et de la valeur temoin comparative study in man. Anesthesiology, 30, 174. AKE/APCO 2 . Les risultats obtenus laissent penser que les Munson, E. S., Larson, C. P. jr, Babad, A. A., Regan, M. J., Buechel, D. R., and Eger, E. I. II (1966). The effects of malades ayant une faible valeur de AKE/ APCO 2 ne sont pas halothane, fluoroxene and cyclopropane on ventilation: a plus susceptibles a l'action ventilatoire d£primante de la morphine. comparative study in man. Anesthesiology, 27, 716. ACKNOWLEDGEMENTS
I thank Drs A. S. Rebuck and E. J. M. Campbell for encouragement and advice, and Mrs E. M. Inman for expert technical assistance. This research was supported by the Canadian Thoracic Society and the Medical Research Council of Canada (Grant No. MA5472).
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CO, RESPONSE AND MORPHINE GERINGE BELUFTUNGSREAKTION AUF KOHLENDIOXYD NICHT VERBUNDEN MIT ERHOHTER UNTERDRUCKUNG DURCH MORPHIUM
771 REDUCIDA RESPUESTA VENTILATORIA AL DIOXIDO DE CARBONO NO ASOCIADA CON UNA MAYOR DEPRESION CAUSADA POR MORFINA SUMARIO
Se midieron la ventilation (KE), mareal final (PE'CO^J PCO2 venoso mezclado (Pvco,) y la respuestaventilatoria al dioxido de carbono (AK E/ APCO 2 ) antes y al cabo de 90 min de haberse suministrado morfina 0,15 mg kg" 1 a 17 pacientes adultos sometidos a cirugia electiva bajo anestesia general. Se examino la hipotesis segiin la cual los pacientes con una respuesta ventilatoria baja al dioxido de carbono son mas susceptibles a los efectos deprimentes ventilatorios de la morfina. Los aumentos inducidos por morfina en el PE'CO y PVQO, n 0 s e correlacionaron con la inclinacion ni la posicion de la respuesta de preinyeccion al dioxido de carbono. El AKE/APCO 2 medio se deprimio despues de suministar morfina (P<0,05), pero las respuestas individuales variaron en gran medida. En siete pacientes cuyo AKE/APCO, de control fue de 9,9 litros min" 1 kPa" 1 o menos disminuyeron su AKE/ APCO 2 despues de la administracion de morfina. En cuatro pacientes, el AVE/APCO 2 aumento despues de la morfina; sin embargo, en cada caso, el PE'CO, y el Pvcot tambien aumentaron. La morfina desplazo la respuesta de dioxido de carbono a la derecha (P< 0,001) pero no se descubrio una correlacion, ya sea entre la magnitud del desplazamiento o un cambio en la inclinaci6n y el AVE/APCO 2 de control. Los resultados sugieren que los pacientes con un valor bajo de AKE/ APCO 2 no son mas susceptibles a la accion depresiva ventilatoria de la morfina.
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ZUSAMMENFASSUNG
Beluftung (KE), Ausatmungsvolumen (PE'CO,)J venoses Gemisch Pco 2 (Pvco,) un^ die Beluftungsreaktion auf Kohlendioxyd (AKE/APCO 2 ) wurden vor und innerhalb von 90 min nach Verabreichung von 0,15 mg kg" 1 intxamuskular an 17 erwachsene Patienten gemessen, die verschiedenen chirurgischen EingrifFen unter allgemeiner Narkose unterzogen wurden. Die Hypothese, dass Patienten mit geringer Beluftungsreaktion auf Kohlendioxyd anfalliger auf die Beluftungsunterdruckungswirkung von Morphium sind, wurde gepruft. Morphium fuhrte Anstiege von PE'CO, und von Pvco, herbei, die weder auf Gefalle oder Position der Vorinjektionsreaktion auf Kohlendioxyd bezogen waren. Der Mittelwert von AKE/APCO 2 war nach Morphium unterdruckt (P<0,05), doch die individuellen Reaktionen variierten stark. Sieben Patienten der Kontrollwert von AFE/APCO 2 9,9 liter min" 1 kPa"1 oder weniger war, senkte AKE/APCO 2 nach dem Morphium. Bei vier Patienten stieg AKE/APCO 2 nach Morphium; in jedem Falle aber stiegen auch PE'CO, ua^ P^co,- Morphium verschob die Kohlendioxydreaktion nach rechts (P< 0,001), doch konnte man keine Korrelation mit der Grosse der Verschiebung oder mit einer Veranderung in Abfall oder Kontrollwert von AFE/APCO 2 feststellen. Daraus schliesst man, dass Patienten mit neidrigen Werten fur AFE/APCO 2 nicht anfalliger auf die Beluftungsunterdruckungswirkung von Morphium sind.
LOW VENTILATORY RESPONSE TO CARBON DIOXIDE NOT ASSOCIATED WITH INCREASED DEPRESSION BY MORPHINE J. R. A. RIGG SUMMARY
Patients with chronic airways obstruction are more likely to develop hyper capnia if they have a low rather than a high ventilatory response to carbon dioxide (Lane and Howell, 1970). Similarly, patients with asthma and known to have a small response to carbon dioxide when their airways resistance is normal, are more likely to develop hypercapnia during an acute exacerbation than are those who have a large carbon dioxide response (Rebuck and Read, 1971). These observations confirmed the original suggestion of Lambertsen that a low sensitivity to carbon dioxide might predispose patients to the development of carbon dioxide retention in various clinical conditions (Lambertsen, 1960). He suggested also that individuals with low ventilatory response to carbon dioxide might be more susceptible to ventilatory depression by narcotic agents (Lambertsen, 1960). Although the rebreathing method for the measurement of ventilatory response to carbon dioxide (Read, 1967) has been used in clinical studies (Jennett, Barker and Forrest, 1968; Rebuck et al., 1973; Rigg, Rebuck and Campbell, 1974) this hypothesis has not been tested, except in a small group of volunteer subjects in whom recovery of ventilatory response to carbon dioxide was assessed following thiopentone, morphine and fentanyl, when the results were inconclusive (Rigg and Goldsmith, 1976). There remains the important JOHN R. A. RIGG, M.B., B.S., F.F.A.R.A.C.S., Department of
Anaesthesia, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada, L8S 4J9. 0007-O912/78/005O-O767 S01.00
possibility that measurement of the ventilatory response to carbon dioxide might be used to predict an increased risk of ventilatory depression after anaesthesia. The hypothesis has now been tested in a group of surgical patients with no history of lung disease, and who received morphine i.m. as premedication before elective surgery. METHODS
Ventilation (KE), end-tidal and mixed venous carbon dioxide partial pressure (.PE'COS an and ventilatory response to carbon dioxide APco2) were measured before and within 90 min after morphine 0.15 mg kg" 1 i.m., given to 17 adult patients (American Society of Anesthesiologists' physical status I and II) before elective surgery under general anaesthesia. Details of the experimental procedure are given by Rigg (1978). The slope of the ventilatory response to carbon dioxide was determined by least squares regression, using the procedure of Read (1967). The positions of the response curves before and after morphine were compared in each subject using the procedure described by Rigg (1978) to determine the response curve position variables i^EH and KE L . To test the hypothesis that response to carbon dioxide before injection determines the magnitude of morphine-induced changes in KE and AKfi/APcOg, control AFE/APCOJ, KE H and KEL, were plotted © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 25, 2015
Ventilation ( ^E), end-tidal (.PE'CO,)> mixed venous />co2 CPvco.) and the ventilatory response to carbon dioxide (A ^E/APCO 2 ) were measured before and within 90 min after morphine 0.15 mg kg" 1 i.m. given to 17 adult patients undergoing elective surgery under general anaesthesia. The hypothesis that patients with a low ventilatory response to carbon dioxide are more susceptible to the ventilatory depressant effects of morphine was tested. Morphine induced increases in PE'co.andPvco, were not correlated with either the slope or the position of the preinjection response to carbon dioxide. Mean APE/APCO 2 was depressed after morphine (P<0.05), but individual responses varied widely. Seven patients whose control A^E/PCX^ was 9.9 litre min" 1 kPa" 1 or less decreased A^E/APCO 2 after morphine. In four patients, AI^E/APCO 2 increased after morphine; however, in each case, PE'CO, and Pvco 2 increased also. Morphine displaced the carbon dioxide response to the right (P< 0.001)' but no correlation was found between either the magnitude of the displacement or change in slope and control A^E/A/ 3 CO 2 . The results suggest that patients with a low value for A KE/APCO 2 are not more susceptible to the ventilatory depressant action of morphine.
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o a:
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against per cent changes of P E ' C 0 2 A K E / A P C 0 2 , KE H and KE L after morphine. The relationships between these variables were explored vising least squares regression analysis. The significance of all changes following injection was determined using paired t tests.
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Increases in P E ' C O O and PvCO2 induced by morphine were not correlated with preinjection AKE/APCO 2 , KE L or KE H (fig. 1). Similarly, the magnitude of changes in F E L and KE H were not related to control
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FIG. 2. Control carbon dioxide response slope, (AJ^E/APCO 2 (litre m i n - 1 kPa"1) plotted against morphine-induced changes in carbon dioxide response position variables VEL and V E H (as per cent of control).
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FIG. 3. Relationship between control and morphine carbon 20
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FIG. 1. Control carbon dioxide response slope (KE/APCO 2 ) (litre min" 1 kPa" 1 ) and position variables KE^ and I^EH (litre min- 1 ) plotted against morphine-induced changes in end-tidal (PE'CQJ and mixed venous / 3 co 2 (Pvco,) (per cent of control).
The mean slope of the ventilatory response to carbon dioxide decreased from 12.3 to 10.05 litre min" 1 kPa" 1 after morphine (P<0.05) but individual responses varied widely. Seven patients with preinjection AKE/APCO 2 of 9.9 litre min- 1 kPa" 1 or less showed a decrease in AFE/APCO 2 after morphine; the
dioxide response slopes, AKE/APCO 2 (litre min" 1 kPa - 1 ).
largest per cent decrease occurred in three patients with control AKE/APCO 2 less than 7.5 litre min- 1 kPa"1. Of 10 patients in whom the value before injection ranged from 10.2 to 23.0 litre min- 1 kPa" 1 , four increased and six decreased AKE/APCO 2 after morphine. All four of the patients with increased AKE/APCO 2 after morphine had typical ventilatory depression on the basis of increases of P E ' C 0 2 and Pv C02 . Comparison AKE/APCO 2 before and after injection did not suggest a greater susceptibility to morphine in individuals with a low response (fig. 3).
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7.5
AKE/APCO 2 (fig. 2).
CO, RESPONSE AND MORPHINE DISCUSSION
* 1 mm Hg = 0.13 kPa.
mm H g - 1 (Irsigler, 1976). Eighty per cent of these subjects had ventilatory response curve slopes between 1.5 and 5.0, 16% less than 1.5 and 4% greater than 5.0 litre min" 1 mm Hg" 1 . Rebuck and Read (1971) found champion sprint and endurance athletes at the high and low extremes of the range of carbon dioxide response curve slopes, with limits of 0.4 and 8.0 litre min" 1 mm Hg- 1 in their subjects; the range of AKE/APCO 2 in the present study of 4.323.0 litre min" 1 kPa" 1 (0.58-3.07 litre min- 1 mm Hg" 1 ) is within these limits. Thus, it seems reasonable to define "low" AKE/APCO 2 as less than 7.5 litre m i n ^ k P a - 1 (1.0 litre min' 1 mm Hg- 1 ) and "high" 1 1 AKE/APCO 2 as greater than 52.5 litre min- kPa" (7.0 litre min- 1 mm Hg- 1 ). The three subjects in the present study who had control A FE/APCO 2 of less than 7.5 litre min" 1 kPa" 1 all had response slopes of less than 60% of control following morphine. However, the decrease in absolute levels of ventilation during the latter part of rebreathing after morphine in these patients was less than that of the remaining patients in whom control AKE/APCO 2 was greater. Furthermore, in none of the three patients with A FE/APCO 2 less than 7.5 litre min" 1 kPa" 1 was the increase in PE'OO2 o r Pv C02 substantially greater than that of the other patients. However, these changes in Pco 2 during air breathing were small and close to the limits of precision of infra-red capnography. It is possible that a greater likelihood of hypercapnia might be found in patients with low carbon dioxide responses if a larger dose of a narcotic was studied. There was wide variation in the plasma concentrations of morphine in individual patients, both in the maximum plasma concentrations and in the time course of the concentrations (Rigg, 1978). These differences reflect, presumably, wide inter-individual differences in absorption of morphine from the i.m. site of injection (all 17 patients were injected in the right gluteal region) and in the distribution to the brain. It is possible that after a single dose of morphine i.m., different effects on ventilation and ventilatory response to carbon dioxide may reflect differences between individuals in the pharmacokinetics of the drug. That there was no correlation between the magnitude of the effect of morphine on ventilatory variables and plasma concentration of the drug argues against this possibility (Rigg, 1978). Nevertheless, it remains possible that, if plasma concentrations of morphine were maintained constant by i.v. infusion, patients with a low response to carbon dioxide might be more susceptible to ventilatory depression.
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Many studies have defined the effect of narcotics and other central nervous depressant drugs on ventilation in man (Dripps and Dumke, 1943; Eckenhoff and Helrich, 1958; Bellville and Seed, 1960; Severinghaus and Larson,1965; Munson et al., 1966; Larson et al., 1969). The present study differs in its method in that morphine was used in an attempt to characterize differences in ventilatory control that might have an important bearing on the recovery of adequate spontaneous ventilation following general anaesthesia. The findings support those of Bellville and Seed (1960) who concluded that opiates caused a large displacement of the carbon dioxide response and little alteration in slope. The results of the present study suggest that patients with normal lungs and a low ventilatory response to carbon dioxide are not more susceptible to the depressant action of morphine, as judged by the effect on P E ' C 0 2 , PVCO2 and AFE/APCO 2 . However, caution should be exercised in extending this conclusion to the general population or to the effects of other narcotics or depressant drugs. Few attempts have been made previously to define a "normal" "low" or "high" carbon dioxide response. This problem has been compounded by the identification of several characteristics that influence ventilatory response to carbon dioxide. These include body size, athleticism and personality (Avery et al., 1963; Rebuck and Read, 1971; Saunders, Heilpern and Rebuck, 1972; Rebuck et al., 1974; Rigg, Rebuck and Campbell, 1974; Hirshman, McCullough and Weil, 1975; Irsigler, 1976). Hirshman, McCullough and Weil reported data obtained from 44 normal non-athletic subjects aged between 21 and 51 yr (Hirshman, McCullough and Weil, 1975). They compared their findings (AKE/ APco 2 and SEM = 2.69 ± 0.19 litre min" 1 mm Hg- 1 , BTPS)* with those of previous reports (Read, 1967; Byrne-Quinn et al., 1971; Forster et al., 1971; Kallos et al., 1972; Saunders, Heilpern and Rebuck, 1972; Kronenberg and Drage, 1973; Rebuck et al., 1973), in which mean AKE/APCO 2 ranged from 1.84 to 3.4 litre min" 1 mm Hg- 1 .* They concluded that it is difficult to characterize an individual as abnormal because of the large tolerance limits of the ventilatory response to hypercapnia. More recently, Irsigler studied 126 healthy medical students and found mean AKE/APCO 2 and SEM = 2.60 + 0.11 litre min" 1
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Read, D. J. C. (1967). A clinical method for assessing the ventilatory response to carbon dioxide. Aust. Ann. Med., 1,20. Rebuck, A. S., Kangalee, M., Pengelly, L. D., and Campbell, E. J. M. (1973). Correlation of ventilatory responses to hypoxia and hypercapnia. J. Appl. Physiol., 35, 173. Read, J. (1971). Patterns of ventilatory response to CO 2 during recovery from severe asthma. Clin. Sci., 41, 13. Rigg, J- R- A., Kangalee, M., and Pengelly, L. D. (1974). Control of tidal volume during rebreathing. J. REFERENCES Appl. Physiol., 37, 475. Avery, M. E., Chernick, V., Dutton, R. E., and Permutt, S. Rigg, J. R. A. (1978). Ventilatory effects and plasma con(1963). Ventilatory response to inspired carbon dioxide in centration of morphine in man. Br. J. Anaesth., 50, 759. infants and adults. J. Appl. Physiol., 18, 895. Goldsmith, C. H. (1976). Recovery of ventilatory Bellville, J. W., and Seed, J. C. (1960). The effect of drugs response to carbon dioxide after thiopentone, morphine on the respiratory response to carbon dioxide. Anesand fentanyl in man. Can. Anaesth. Soc. J., 23, 370. thesiology, 21, 727. Rebuck, A. S., and Campbell, E. J. M. (1974). Effect Byrne-Quinn, E., Weil, J. V., Sodal, I. E., Filley, G. F., of posture on the ventilatory response to CO 2 . J. Appl. and Grover, R. F. (1971). Ventilatory control in the Physiol., 37, 487. athlete. J. Appl. Physiol, 30, 91. Saunders, N. A., Heilpern, S., and Rebuck, A. S. (1972). Dripps, R. D., and Dumke, P. R. (1943). The effect of Relation between personality and ventilatory response to narcotics on the balance between central and chemocarbon dioxide in normal subjects: a role in asthma. Br. receptor control of respiration. J. Pharmacol. Exp. Ther., Med.J., 1,719. 77, 290. Eckenhoff, J. R., and Helrich, M. (1958). Effect of narcotics, Severinghaus, J. W., and Larson, C. P. jr (1965). Respiration in anaesthesia; in Handbook of Physiology, Vol. II, p. 1219. thiopental and nitrous oxide upon respiration and Washington, D.C.: Am. Physiol. Soc. respiratory responses to hypercapnia. Anesthesiology, 19, 240. Forster, H. V., Dempsey, J. A., Birnbaum, M. L., Reddan, W. G., Thoden, J., Grover, R. F., and Rankin, J. (1971). FAIBLE REPONSE VENTILATOIRE AU GAZ Effect of chronic exposure to hypoxia on ventilatory CARBONIQUE NON ASSOCIEE A UNE response to CO 2 and hypoxia. J. Appl. Physiol., 31, 586. AUGMENTATION DE LA DEPRESSION PAR Hirshman, C. A., McCullough, R. E., and Weil, J. V. (1975). LA MORPHINE Normal values for hypoxic and hypercapnic ventilatory RESUME drives in man. J. Appl. Physiol., 38, 1095. Irsigler, S. B. (1976). Carbon dioxide response lines in young La ventilation (KE), le volume courant final (PE'O,), le adults: the limits of the normal response. Am. Rev. Pco 2 (Pvco,) veineux mixte et la reponse ventilatoire au Respir. Dis., 114, 529. gaz carbonique ( AFE/APco 2 ) ont 6t6 mesur£s avant et Jennett, S., Barker, J., and Forrest, J. B. (1968). A double- dans un delai de 90 min apres qu'une injection de morphine a raison de 0,15 mg kg" 1 ait 6t6 administr£e par voie blind controlled study of the effects on respiration of pentazocine, phenoperidine and morphine in normal man. intramusculaire a 17 malades adultes subissant une intervention chirurgicale a froid sous anesthfisie gen£rale. On a Br. J. Anaesth., 40, 864. Kallos, T., Hudson, H. E., Rouge, J. C , and Smith, T. C. procede a des testes pour verifier l'hypothese supposant que (1972). Interaction of the effects of naloxone and oxy- les malades ayant une faible response ventilatoire au gaz morphone on human respiration. Anesthesiology, 36, carbonique sont plus susceptibles aux effets ventilatoires d£primants de la morphine. Les augmentations du .PE'CO, 278. Kronenberg, R. G., and Drage, C. W. (1973). Attenuation et du PvWt provoquees par la morphine n'ont et£ relives of the ventilatory and heart rate responses to hypoxia and ni au coefficient angulaire ni a la position de la reponse de hypercapnia with aging in normal man. J. Clin. Invest., la pre-injection au gaz carbonique. La AKE/APCO 2 moyenne s'est trouvee d£primee apres la morphine 52, 1812. Lambertsen, C. J. (1960). Carbon dioxide and respiration in (P<0,05), mais les r£ponses individuelles ont accuse de vastes variations. Sept malades, dont la valeur t£moin de acid-base homeostasis. Anesthesiology, 21, 642. AKE/ APCO 2 £tait de 9,9 litre min" 1 kPa" 1 ou moins, ont Lane, D. J., and Howell, J. B. L. (1970). Relationship between sensitivity to carbon dioxide and clinical features vu leur Al^E/APcOa diminuer apres la morphine. Sur in patients with chronic airways obstruction. Thorax, 25, quatre malades, la AKE/APCO 2 a augmente apres o nlat morphine; mais dans chaque cas le PE'QO, et le Pvco, 150. Larson, C. P., Eger, E. I. II, Muallem, M., Buechel, D. R., aussi augmented La morphine a d6plac£ la reponse au gaz Munson, E. S., and Eisele, J. H. (1969). The effects of carbonique vers la droite (P< 0,001) mais on n'a trouv£ diethyl ether and methoxyflurance on ventilation: a aucune correlation entre l'importance du d£placement et les variations du coefficient angulaire et de la valeur temoin comparative study in man. Anesthesiology, 30, 174. AKE/APCO 2 . Les risultats obtenus laissent penser que les Munson, E. S., Larson, C. P. jr, Babad, A. A., Regan, M. J., Buechel, D. R., and Eger, E. I. II (1966). The effects of malades ayant une faible valeur de AKE/ APCO 2 ne sont pas halothane, fluoroxene and cyclopropane on ventilation: a plus susceptibles a l'action ventilatoire d£primante de la morphine. comparative study in man. Anesthesiology, 27, 716. ACKNOWLEDGEMENTS
I thank Drs A. S. Rebuck and E. J. M. Campbell for encouragement and advice, and Mrs E. M. Inman for expert technical assistance. This research was supported by the Canadian Thoracic Society and the Medical Research Council of Canada (Grant No. MA5472).
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CO, RESPONSE AND MORPHINE GERINGE BELUFTUNGSREAKTION AUF KOHLENDIOXYD NICHT VERBUNDEN MIT ERHOHTER UNTERDRUCKUNG DURCH MORPHIUM
771 REDUCIDA RESPUESTA VENTILATORIA AL DIOXIDO DE CARBONO NO ASOCIADA CON UNA MAYOR DEPRESION CAUSADA POR MORFINA SUMARIO
Se midieron la ventilation (KE), mareal final (PE'CO^J PCO2 venoso mezclado (Pvco,) y la respuestaventilatoria al dioxido de carbono (AK E/ APCO 2 ) antes y al cabo de 90 min de haberse suministrado morfina 0,15 mg kg" 1 a 17 pacientes adultos sometidos a cirugia electiva bajo anestesia general. Se examino la hipotesis segiin la cual los pacientes con una respuesta ventilatoria baja al dioxido de carbono son mas susceptibles a los efectos deprimentes ventilatorios de la morfina. Los aumentos inducidos por morfina en el PE'CO y PVQO, n 0 s e correlacionaron con la inclinacion ni la posicion de la respuesta de preinyeccion al dioxido de carbono. El AKE/APCO 2 medio se deprimio despues de suministar morfina (P<0,05), pero las respuestas individuales variaron en gran medida. En siete pacientes cuyo AKE/APCO, de control fue de 9,9 litros min" 1 kPa" 1 o menos disminuyeron su AKE/ APCO 2 despues de la administracion de morfina. En cuatro pacientes, el AVE/APCO 2 aumento despues de la morfina; sin embargo, en cada caso, el PE'CO, y el Pvcot tambien aumentaron. La morfina desplazo la respuesta de dioxido de carbono a la derecha (P< 0,001) pero no se descubrio una correlacion, ya sea entre la magnitud del desplazamiento o un cambio en la inclinaci6n y el AVE/APCO 2 de control. Los resultados sugieren que los pacientes con un valor bajo de AKE/ APCO 2 no son mas susceptibles a la accion depresiva ventilatoria de la morfina.
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ZUSAMMENFASSUNG
Beluftung (KE), Ausatmungsvolumen (PE'CO,)J venoses Gemisch Pco 2 (Pvco,) un^ die Beluftungsreaktion auf Kohlendioxyd (AKE/APCO 2 ) wurden vor und innerhalb von 90 min nach Verabreichung von 0,15 mg kg" 1 intxamuskular an 17 erwachsene Patienten gemessen, die verschiedenen chirurgischen EingrifFen unter allgemeiner Narkose unterzogen wurden. Die Hypothese, dass Patienten mit geringer Beluftungsreaktion auf Kohlendioxyd anfalliger auf die Beluftungsunterdruckungswirkung von Morphium sind, wurde gepruft. Morphium fuhrte Anstiege von PE'CO, und von Pvco, herbei, die weder auf Gefalle oder Position der Vorinjektionsreaktion auf Kohlendioxyd bezogen waren. Der Mittelwert von AKE/APCO 2 war nach Morphium unterdruckt (P<0,05), doch die individuellen Reaktionen variierten stark. Sieben Patienten der Kontrollwert von AFE/APCO 2 9,9 liter min" 1 kPa"1 oder weniger war, senkte AKE/APCO 2 nach dem Morphium. Bei vier Patienten stieg AKE/APCO 2 nach Morphium; in jedem Falle aber stiegen auch PE'CO, ua^ P^co,- Morphium verschob die Kohlendioxydreaktion nach rechts (P< 0,001), doch konnte man keine Korrelation mit der Grosse der Verschiebung oder mit einer Veranderung in Abfall oder Kontrollwert von AFE/APCO 2 feststellen. Daraus schliesst man, dass Patienten mit neidrigen Werten fur AFE/APCO 2 nicht anfalliger auf die Beluftungsunterdruckungswirkung von Morphium sind.