SOME CIRCULATORY AND RESPIRATORY EFFECTS OF MORPHINE IN PATIENTS WITHOUT PRE-EXISTING CARDIAC DISEASE

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1 Br.J. Anaesth. (1977), 49, 927 SOME CIRCULATORY AND RESPIRATORY EFFECTS OF MORPHINE IN PATIENTS WITHOUT PRE-EXISTING CARDIAC DISEASE I. O. SAMUEL, R. S. J. CLARKE AND J. W. DUNDEE SUMMARY Haemodynamic and respiratory effects of i.v. morphine (10 mg/70 kg body weight) were studied in 10 adults with unimpaired circulatory function. There were significant changes in mean arterial pressure, mean heart rate, respiratory rate and tidal volume, at 10-, 30- and 60-min intervals. Transient changes in mean total systemic resistance and mean stroke volume were also seen at 10 min. The results strongly suggest a peripheral vasodilator response to morphine. Respiratory depression was not demonstrated. Although opium has been used from antiquity and despite the lack of knowledge of the precise haemodynamic effects of morphine, there are large amounts of data concerning the actions of narcotics on circulation and respiration (Kreuger, Eddy and Sumwalt, 1941; Eddy, Halbach and Braenden, 1957; Reynolds and Randall, 1957). Many published studies show lack of appreciation of the importance of standardization of patient population regarding such factors as their mental and emotional state, physical condition, intensity of pain and type of anaesthesia. In many instances, concomitant respiratory depression secondary to administration of morphine had not been taken into account while assessing the haemodynamic effects. Sufficient attention had not been given to standardization of the dose (in relation to body size), the rate or even the site of injection. Moreover, many studies were undertaken when methods of measuring circulatory and respiratory changes were less accurate than those available today. Results from animal experiments have even been taken to represent a human response, disregarding the species difference. Since a review of published data on the cardiorespiratory effects of morphine failed to reveal a consistent pattern of response, it was felt that a re-evaluation of its cardiovascular effects, under rigidly controlled clinical conditions, would be both relevant and justifiable. The present study, therefore, is to assess the haemodynamic effeas of a clinically used dose (10 mg/70 kg body weight) of morphine, in patients with unimpaired circulatory function. This investigation not only provides a "baseline" for studies on patients with impaired cardiovascular I. O. SAMUEL, M.S., D.A.; R. S. J. CLARKE, M.D., PH.D., F.F.A.R.C.S. ; J. W. DUNDEE, M.D., PH.D., F.F.A.R.C.S., M.R.C.P.; Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland. function, but also points the way in which future studies, aimed to elucidate the precise mode of action of this drug, could be pursued. These studies could be carried out either in healthy volunteers or in patients to whom the opiate had been given as part of the medical care. In the latter it is appreciated that any observed changes may be influenced both qualitatively and quantitatively by other therapy. However, it was felt that, from the ethical standpoint, a study of this nature was unsuitable to be carried out on volunteer subjects. Since morphine is a drug of addiction there is an element of risk in giving it to healthy volunteers and, furthermore, simple procedures like cannulation of major arteries and central veins are not without their complications (Coppel and Samuel, 1974). Therefore, subjects from the Intensive Care Unit, who would normally have received morphine and in whom arterial and venous cannulation had been performed for purposes of clinical monitoring, were studied. METHOD Ten adults, male or female, suffering from multiple trauma, who had been treated in the Intensive Care Unit, were studied when the acute phase of the injury had passed (5-7 days) and they were in steady haemodynamic and metabolic states. All had a tracheostomy. Their ages ranged from 21 to 49 yr and weights from 63 to 71 kg. The criteria for inclusion in the study were: Normal pulmonary function as shown by repeated blood-gas analysis and chest x-ray. Absence of any known cardiovascular pathology. No morphine or other opiate given in the 8 h immediately preceding the study. Indwelling radial artery and right atrial catheters.

2 928 BRITISH JOURNAL OF ANAESTHESIA Absence of acute pain or distress. No recent nausea or vomiting. The following were recorded: (a) Arterial pressure. The radial artery catheter was connected to a strain-gauge (SE labs 4-88) and chart recorder (Elema-Schonander-Mingograf 34) allowing continuous recording. (b) Right atrial pressure. The right atrial catheter was connected to a saline manometer. (c) E.c.g. A simultaneous continuous record was made together with that of arterial pressure. (d) Cardiac output. The Hamilton-Stewart dye dilution method (Kinsman, Moore and Hamilton, 1929) was used, employing indocyanine green as marker. Injection was made into the right atrium and sampling was from the radial artery. The curves were analysed by a computer but checked by direct measurement in each case. At each determination of cardiac output the mean result from two curves was used. (e) Blood-gases. Arterial blood was sampled from the radial artery catheter into heparinized plastic syringes and analysed immediately for oxygen tension using a polarograph and carbon dioxide tension using the method of Siggaard-Andersen and others (1960). (f) Respiratory frequency and minute ventilation. These were measured using a previously calibrated Wright electronic anemometer connected to the tracheostomy tube with a catheter mount. Derived from the above measurements were: Mean arterial pressure (mm Hg) = diastolic pressure + one-third of pulse pressure Total systemic vascular resistance mean arterial pressure (mm Hg) right arterial pressure (mm Hg) cardiac output (litre. min" 1 ) This was expressed as mm Hg. litre" 1, min" 1. Cardiac index (litre. min" 1. m~ 2 ) _ cardiac output (litre. min" 1 ) surface area of patient (m 2 ) cardiac output (ml. min" 1 ) Stroke volume = heart rate (beat. min" 1 ) Tidal volume = minute ventilation (ml. min" 1 ) respiratory frequency (b.p.m.) The protocol followed in each patient was: (1) Control recordings of arterial pressure, right atrial pressure, e.c.g., respiratory frequency and minute ventilation. TABLE I. Changes in mean values of various measured or derived haemodynamic indices following morphine 10 mg/70 kg i.v. Before morphine (control) After morphine (min) Arterial pressure (mmhg) Heart rate (beat/min) Stroke volume (ml) ±2.5 Total systemic 25.0 resistance ±1.26 (mm Hg.litre"" 1.min" 1 ) Right atrial 4.1 pressure ±0.30 (mmhg) Cardiac index 3.3 (litre.min~ l m~ 2 ) ± ± P< P< ± ± ± ± ± ± ±3.24

3 CIRCULATORY AND RESPIRATORY EFFECTS OF MORPHINE 929 (2) Two dye curves. (3) Arterial sample for gas analysis. (4) Morphine 10 mg/70 kg body weight injected, via the right atrial catheter, at the rate of 2 mg. min" 1. (5) The sequence of measurements (1, 2 and 3) was repeated 10, 30 and 60 min following the morphine injection. Each patient acted as his own control. The paired data were analysed by the Student t test. o 1-5 RESULTS Cardiovascular data {table I) Mean arterial pressure. Consistent statistically significant decreases from control occurred in all the patients at all times of measurements. Heart rate. Decreased significantly in all the patients. Figure 1 shows that there was a good correlation between the decrease in arterial pressure and heart rate. Total systemic vascular resistance. The mean value decreased transiently. The change was statistically significant at 10 min. Right atrial pressure. In no patient was the change following morphine greater than 2 cm H 2 O and the difference in the mean values for the group was not significant. Cardiac index. Individual variations were minimal and the average values following morphine remained virtually unchanged from the control recording.»mean ARTERIAL PRESSURE O OMEAN HEART RATE 30 TIME <MIN) FIG. 1. Percentage change in mean arterial pressure and heart rate following morphine 10 mg/70 kg. Stroke volume. A small but transient increase occurred 10 min after morphine, but this had returned to the control value by 30 min. Respiratory data {table II) Respiratory frequency decreased considerably and significantly throughout the period of observation. Minute ventilation remained substantially unchanged throughout the study, but the calculated TABLE II. Changes in mean values of various measured or derived respiratory indices following morphine 10 mgllo kg i.v. Respiratory rate (b.p.m.) Minute ventilation (litre, min" 1 ) Tidal volume (ml) Standard bicarbonate (mmol. litre" 1 ) ^ao, (kpa) (kpa) Before morphine (control) 20 ± ± ± ± ± ' ± ± ± ±0.10 After morphine (min) ± ± ± ± ± ± ±0.10

4 930 BRITISH JOURNAL OF ANAESTHESIA average tidal volume was increased significantly at all observation times following morphine. There were no significant changes in the average Pa Oi or Pa C02 at any time; the derived value for standard bicarbonate remained unchanged. DISCUSSION Cardiovascular changes Studies published previously suggest that the normal cardiovascular system in a recumbent man is little affected by morphine in the usual dose range (Papper and Bradley, 1942; Drew, Dripps and Comroe, 1946). More recently, Lowenstein and colleagues (1969) observed that, even in doses sufficiently large to suppress respiration, morphine usually did not have discernible effects on the cardiovascular system. The results of the present study appear to support these claims. Nevertheless, two notable changes the slight but significant hypotensive response (average decrease of 6% of control value) and slowing of heart rate and respiratory changes need further consideration. Although it has been stated frequently that the "central vagotonic" effects of morphine may cause slowing of the pulse (Reynolds and Randall, 1957) this effect has not been reported consistently in the published data. Papper and Bradley (1942) considered the change in heart rate to be insignificant in six normal subjects lying supine and receiving morphine 10 mg i.v. Denton and Beecher (1949) observed a significant slowing of the heart (an average of 7 beat. min" 1 ) in 29 subjects receiving morphine or another narcotic. In contrast, Drew, Dripps and Comroe (1946) recorded an average increase of 19 beat.min" 1 in 19 supine subjects and patients receiving morphine mg i.v. The sedative effects of morphine alone might be responsible for the small but significant change observed in this study. Hypotensive changes following morphine or other narcotics could be produced by a direct action on three "target sites": central nervous system, myocardium and peripheral blood vessels. In intact man, there is difficulty in separating these effects. Secondary effects of morphine such as release of catecholamines and histamine and respiratory depression may affect the primary target sites indirectly. Central nervous system The role of c. in the maintenance of arterial pressure is undisputed (Folkow, 1960), but the mechanism is not understood fully (Domino, 1962). Vasomotor centre. It has been claimed that hypotension following morphine was a result of its action on the vasomotor centre (Reynolds and Randall, 1957), but Evans, Nasmyth and Stewart (1952) postulated a "central effect" (in addition to histamine release). Wikler (1950) could not find support for the idea that morphine exerted a significant effect upon the vasomotor centre. In many clinical studies (Papper and Bradley, 1942; Drew, Dripps and Comroe, 1946; Denton and Beecher, 1949) demonstrable changes in arterial pressure were not seen. It is now accepted generally that the vasomotor centre is affected little when the dose of morphine administered is within the normal therapeutic range; even with toxic doses the arterial pressure is usually well maintained until hypoxia supervenes (Jaffe, 1965). Vomiting centre. Nausea and vomiting produced by morphine are unpleasant side-effects caused by direct stimulation of the chemoreceptor trigger zone for emesis, in the area postrema of the medulla (Jaffe, 1965). It is known that hypotension is normally associated with the act of nausea and vomiting. Patients in the present study did not vomit, nor did they complain of nausea. Therefore stimulation of the vomiting centre could be excluded as a possible cause of the changes in arterial pressure in this study. Sedation. It could be argued that a small decrease in arterial pressure was the result of sedation alone. However, our subjects did not appear to be distressed or apprehensive at any time during the study and they were not in acute pain. Although the majority fell asleep for 2-5 min soon after the injection of morphine, they were fully awake when the first set of observations was made. Therefore, it seems unlikely that the circulatory changes at 10-, 30- and 60-min intervals were related to such a brief period of sleep. Objective evidence for the lack of "stress" (apprehension) and associated high sympathetic activity during the control period was provided by the normal plasma catecholamine concentrations ( fj.g.litre" 1 ) observed in a comparable group of patients (Samuel, 1976). These resting concentrations did not decrease after morphine. Direct myocardial depression The changes in cardiac index, stroke volume and right atrial pressure in the present investigation do not suggest myocardial depression as the cause of decreases in mean arterial pressure. Schmidt and Livingston (1933) concluded that, whereas morphine depressed the isolated heart, indicating a direct myocardial effect, the intact heart was not affected by

5 CIRCULATORY AND RESPIRATORY EFFECTS OF MORPHINE 931 doses sufficient to cause a marked reduction in arterial pressure. There are no observations to contradict this conclusion (Eckenhoff and Oech, 1960). On the contrary, when large doses of morphine ( mg/kg) were given to patients with cardiac disease, remarkable circulatory stability was reported (Lowenstein et al., 1969; Hasbrouck, 1970) and detailed analysis of myocardial function showed no evidence of depression. These doses of morphine have now been recommended for use in patients with poor myocardial reserve and who are undergoing surgery. Direct action on the peripheral blood vessels A decrease in peripheral vascular resistance following morphine has been well documented in animal experiments and in man. Schmidt and Livingston (1933) concluded, from their observations of the effect of morphine in the dog, that hypotension was a result primarily of a dilatation of cutaneous and muscular blood vessels by a direct action of morphine upon their walls. Drew, Dripps and Comroe (1946) snowed that healthy subjects receiving morphine developed orthostatic hypotension in the upright position and this could be reduced by bandaging the legs to prevent venous pooling. The small decrease in the mean arterial pressure, with a transient reduction in the total systemic resistance accompanied by an unchanged cardiac index, in the present study, suggest a peripheral vasodilator response to morphine. There is, however, still a need for a well-designed clinical study to establish a direct vasodilator action in man. Some of the benefit of morphine in the treatment of pulmonary oedema may be attributable to its ability to decrease the peripheral vascular resistance with a redistribution of blood to the periphery. The hypotensive response to morphine seen in various animals has been attributed to histamine release (Feldberg and Paton, 1951; Thompson and Walton, 1964). Several clinicians have noted histamine-like responses in patients who have had sudden severe hypotension and collapse following narcotics, particularly pethidine (Butler, 1951; Zuck, 1951). Such reactions are suggestive, but not proof, of a relationship between narcotics and histamine release (Eckenhoff and Oech, 1960). Feldberg and Paton (1951) noted that the absence of, or slow recovery from, hypotension after narcotics was different from that noted after other histamine liberators. More recently, Zelis and co-workers (1974) and Samuel (1976) were able to assess the effect of morphine after histamine receptor blockade in the human forearm. Pyribenzamine was injected to an artery of one forearm followed by i.v. morphine, and blood flow in both forearms was measured simultaneously. Morphine-induced arteriolar dilatation was similar in both forearms. This suggests that, in man, histamine plays little role in the vasodilatation produced by i.v. morphine and is unlikely to be the cause of the changes in arterial pressure in the present study. Effects on respiration Respiratory depression has been acknowledged as a natural sequel to administration of narcotic analgesic drugs, even with doses too small to produce sleep or disturb consciousness (Jaffe, 1965). Therefore, respiratory measurements should accompany cardiovascular measurements to assess the effect of concomitant respiratory depression on the haemodynamic function. It was not the primary aim of this study to make a quantitative assessment of the degree of depression, nor to define the precise mode of action of morphine on the respiratory control mechanisms. It was necessary, however, to know whether hypotension and other circulatory changes could have been secondary to hypoxia or hypercarbia. The present study has shown a consistent and significant decrease in the average respiratory rate of 3 b.p.m. which is in keeping with the observations of other workers (Dripps and Comroe, 1945). "The diminution in tidal volume from a therapeutic dose of narcotics is not of great magnitude in the normal individual breathing oxygen or room air and... may be sufficiently small to be overlooked" (Eckenhoff and Oech, 1960). In the present investigation expired minute volume changed little from the control value. Our results are at variance with those of Jennet, Barker and Forrest (1968), who found a significant reduction of 30% in the expired minute volume in healthy volunteers following morphine 10 mg/70 kg given i.v. A difference in the rate of injection of morphine may partially explain this difference; Jennett and her colleagues injected the morphine over 2.5 min and the same quantity of the drug was injected over 5 min in the present study. Several criteria have been used to define the term "respiratory depression"; on most occasions, changes in frequency and minute ventilation alone are considered. However, the effects of morphine on breathing have been related to metabolism (Orkin, Egge and Rovenstine, 1955; Smith et al., 1967). Jennet, Barker and Forrest (1968) showed that a

6 932 BRITISH JOURNAL OF ANAESTHESIA reduction in ventilation alone does not necessarily indicate respiratory depression, since ventilation could be expected to decrease if metabolic rate were to decrease. They found an average reduction of 20-30% in oxygen consumption within 10 min of the injection of morphine 10 mg/70 kg. Thus the reduction of ventilation has both a respiratory and a metabolic component. As with the haemodynamic changes, it might be argued that respiratory effects could be a result of sedation or sleep. Bellville and his colleagues (1959) have observed that natural sleep per se can mimic the depressive effects of narcotics on respiration. Observations in the present study, however, do not seem to support this, for the measured changes in respiratory parameters appear to outlast the brief period (2-5 min) of sleep observed in these patients. Whatever the mechanism of the alteration in respiratory pattern, there were no changes likely to have been responsible for the haemodynamic effects. ACKNOWLEDGEMENTS We thank our colleagues in the Intensive Care Unit of the Royal Victoria Hospital, Belfast, for their co-operation. I.O.S. is grateful to the Eastern Health and Social Services Board for a research grant from the endowment funds of the Royal Victoria Hospital which enabled him to carry out this work. The authors also wish to thank V. Hodgkinson and P. Fitzsimmons for technical assistance during the study. REFERENCES Bellville, J. W., Howland, W. S., Seed, J. C, and Houde, R. W. (1959). The effect of sleep on the respiratory response to carbon dioxide. Anesthesiology, 20, 628. Butler, E. B. (1951). A case of hypersensitivity to pethidine in a woman in labour. Br. Med.J., 2, 715. Coppel, D. L., and Samuel, I. O. (1974). A complication of long venous catheters. Anaesthesia, 29, 175. Denton, J. E., and Beecher, H. K. (1949). New analgesics. II: A clinical appraisal of the narcotic power of methadone and its isomers. J.A.M.A., 141, Domino, E. F. (1962). Sites of action of some central nervous system depressants. Ann. Rev. Pharmacol., 2,215. Drew, J. H., Dripps, R. D., and Comroe, J. H., jr (1946). Clinical studies on morphine. II: The effect of morphine upon the circulation of man and upon the circulatory and respiratory responses to tilting. Anesthesiology, 7, 44. Dripps, R. D., and Comroe, J. H. (1945). Clinical studies on morphine. I: The immediate effect of morphine administered intravenously and intramuscularly upon the respiration of normal man. Anesthesiology, 6, 462. Eckenhoff, J. E., and Oech, S. R. (1960). The effects of narcotics and antagonists upon respiration and circulation in man. Clin. Pharmacol. Ther., 1, 483. Eddy, N. B., Halbach, H., and Braenden, O. J. (1957). Synthetic substances with morphine-like effect: clinical experience: potency, side effects, addiction liability. Bull. W.H.O., 17, 569. Evans, A. G. J., Nasmyth, P. A., and Stewart, H. C. (1952). The fall of blood pressure caused by intravenous morphine in the rat and the cat. Br. J. Pharmacol.. 7, 542. Feldberg, W., and Paton, W. D. M. (1951). Release of histamine from skin and muscle in the cat by opium alkaloids and other histamine liberators. J. Physiol. (Lond.), 114, 490. Folkow, B. (1960). Role of the nervous system in the control of vascular tone. Circulation, 21, 760. Hasbrouck, J. D. (1970). Morphine anesthesia for open heart surgery. Ann. Thorac. Surg., 10, 364. Jaffe, J. H. (1965). Narcotic analgesics; in The Pharmacological Basis of Therapeutics (eds. L. S. Goodman and A. Gilman), 3rd edn, p New York: Macmillan. Jennett, S., Barker, J. G., and Forrest, J. B. (1968). A double-blind, controlled study of the effects on respiration of pentazocine, phenoperidine and morphine in normal man. Br. J. Anaesth., 40, 864. Kinsman, J. M., Moore, J. W., and Hamilton W. F. (1929). 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7 CIRCULATORY AND RESPIRATORY EFFECTS OF MORPHINE 933 QUELQUES EFFETS CIRCULATOIRES ET RESPIRATOIRES DE LA MORPHINE SUR DES MALADES N'AYANT PAS DE MALADIE CARDIAQUE PRE-EXISTANTE RESUME On a etudie sur 10 adultes n'ayant aucune alteration de la fonction circulatoire les effets hemodynamiques et respiratoires de la morphine administree par voie intraveineuse a raison de 10 mg/70 kg de poids du corps. II s'est produit des changements significatifs dans la tension arterielle moyenne, la frequence cardiaque moyenne, le taux respiratoire et le volume courant a des intervalles de 10,30 et 60 min. Des variations transitoires dans la resistance systemique totale moyenne et dans le volume systolique moyen ont egalement ete observees apres 10 min. Les resultats obtenus laissent penser a une reaction vasodilatatrice peripherique due a la morphine. La depression respiratoire n'a pas ete demontree. EINIGE ZIRKULATORISCHE UND RESPIRATORISCHE WIRKUNGEN VON MORPHIUM BEI PATIENTEN OHNE VORHERIGE HERZFEHLER ZUSAMMENFASSUNG Die hamodynamischen und respiratorischen Wirkungen von intravenos verabreichtem Morphium (10 mg/70 kg Korpergewicht) wurden bei 10 erwachsenen Patienten mit normalen Zirkulationsfunktionen untersucht. Es kam zu wesentlichen Veranderungen bei mittlerem arteriellem Druck, mirtlerer Herztatigkeit, Respirationsrate und Atemvolumen, in Intervallen von 10, 30 und 60 Minuten. Voriibergehende Veranderungen im mittleren gesamtsystemischen Widerstand und beim mittleren Schlagvolumen ergaben sich ebenfalls nach 10 Minuten. Die Resultate lassen klar eine periphere Vasodilatorreaktion auf Morphium erkennen. Eine respiratorische Dampfung wurde nicht gezeigt. ALGUNOS EFECTOS CIRCULATORIOS Y RESPIRATORIOS DE LA MORFINA EN PACIENTES CARENTES DE CARDIOPATIA PREEXISTENTE SUMARIO Se estudiaron en 10 adultos exentos de disfuncion circulatoria los efectos hemodinamicos y respiratorios de morfina i.v. (10 mg/70 kg peso corporal). Se produjeron cambios significativos en la presion arterial media, ritmo cardiaco medio, indice respiratorio y volumen de ventilation pulmonar, a intervalos de 10, 30 y 60 min. Tambien se apreciaron a 10 min cambios pasajeros en la resistencia sistemica total media y en la descarga sistolica media. Los resultados sugieren firmemente una respuesta vasodilatadora periferica a la morfina. No se demostro depresion respiratoria.