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THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG
Brit. J. Anaesth. (1965), 37, 560
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG BY
N. W. B. CRAYTHORNE AND T. D. DARBY*
Division of Anesthesiology and Department of Pharmacology, West Virginia University, Morgantovm, U.S.A. SUMMARY
Nitrous oxide was introduced as an anaesthetic agent over one hundred years ago. Despite its wide use, there is a marked paucity of data regarding its effects on the cardiovascular system (Hamilton, 1963). This is especially true with regard to the effects of this agent on the intact, innervated cardiovascular system. This project was carried out to study the effects of nitrous oxide on myocardial function and haemodynamic parameters. Haemodynamic measurements included arterial blood pressure, central venous pressure and cardiac output. Measurements of myocardial function included maximum isometric systolic tension, rate of tension development with systole, rate of relaxation and heart rate. A Brodie-Walton strain gauge was used to measure isometric tension so that our data could be compared with those of others who have studied the effects of various anaesthetic agents using this instrument (Mehaffey et al., 1960; Brown, 1960; Boniface, Brown and Kronen, 1957; Bagwell and Woods, 1962; Bagwell, Woods and Durst, 1964; Bagwell, Woods and Linker, 1964). METHOD
Thirteen mongrel dogs weighing between 8 and 17 kg were premedicated with atropine 0.1 mg/ kg. Anaesthesia was induced with halothane and
endotracheal intubation with a cuffed tube was carried out with the aid of suxamethonium. Pulmonary ventilation was controlled with a Medtronic respirator and a Fluotec vaporizer was included on the inspiratory side of this non-rebreathing system for the maintenance of anaesthesia. A fine polyethylene catheter was inserted through the wall of the endotracheal tube and passed down into the trachea. End-expiratory gas was drawn at a constant rate through the detector chamber of a Beckman LB-1 carbon dioxide analyzer which was calibrated with room air and 5 per cent carbon dioxide. Ventilation was determined by the nomogram of Kleinman and Radford* and adjusted slightly from time to time to maintain a normal end-expired carbon dioxide concentration (5 per cent). Alveolar Pcoa, as calculated from the end-expiratory carbon dioxide concentration, did not differ from arterial Pcoa by more than 3 mm Hg provided that a good expiratory plateau was obtained and the blood pressure did not fall. Arterial Pco3 and pH were measured intermittently throughout the experiment using a Severinghaus carbon dioxide electrode and a Radiometer pH electrode. The electrodes were immersed in a water bath kept at 37 °C. PcOj readings were reproducible to ± 1 mm Hg. The Radiometer pH electrode was calibrated with two primary phosphate buffers according to the speci-
This investigation was supported in part by Public Health Service Grant No. HE-06151-04 from the National Heart Institute. • Made by L. Kleinman, MJJ., and E. P. Radford, MJ3., * This investigator is supported by Public Health ' Department of Physiology, School of Public Health, Service Career Development Award 5K3HE6254-02 Harvard University, for the Harvard Apparatus Co., Inc., Dover, Massachusetts. from the National Heart Institute.
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on June 8, 2015
The cardiovascular effects of nitrous oxide were studied in thirteen dogs. Nitrous oxide depressed the myocardial contractile force in the deg as measured with the BrodieWalton gauge. Cardiac output, central venous pressure, arterial blood pressure, and heart rate were not significantly changed. Sympathetic nervous responses were neither inhibited nor continuously stimulated by this agent. The effect of nitrous oxide on the efficiency of the heart is discussed.
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG
inotropic action (Brown, 1960; West et al., 1956; Brewster et al., 1960). The animals were studied in four groups as follows: Group 1: 75 per cent nitrous oxide in oxygen was administered once to all animals. Group 2: 50 per cent nitrous oxide in oxygen was administered 9 times to 6 of these animals, Group 3 : 75 per cent nitrous oxide was administered to 5 dogs pathetic block. Group 4 : 50 per cent nitrous oxide was administered to the 5 sympathetic block.
in oxygen after symin oxygen dogs with
Air, 75 per cent nitrous oxide in oxygen, or 50 per cent nitrous oxide in oxygen in 10 l./min flow rate was delivered from a pre-calibrated Heidbrink anaesthetic machine into a "bag in a bottle ventilator" (Bird Mark IV Assistor) which was driven by a Medtronic animal respirator (instead of the conventional Bird Mark VIII respirator). This was a volume-constant type of respirator. The bag of the respirator was substituted for the reservoir bag in the semidosed circle system of the Heidbrink machine. As significant changes in myocardial contractility can be produced by small changes in arterial Pco3 (Boniface and Brown, 1953), the end-expiratory carbon dioxide concentration was monitored and was kept constant before each administration of nitrous oxide, and afterwards when control values were reached. During the study when nitrous oxide was being administered, the broadening effect (Bergman, Rackow and Frumin, 1958) of this agent led to inaccuracy, so ventilation was maintained at that volume which had kept endexpiratory carbon dioxide constant during the control period. Inspired oxygen concentration was monitored intermittently with a Pauling oxygen meter (Beckman Model D). During the control period when the dog was being ventilated with room air, arterial pressure, heart rate, central venous pressure, and contractile force were recorded continuously. Cardiac output was again measured just before nitrous oxide was breathed. A mixture of 75 per cent nitrous oxide in oxygen, or 50 per cent nitrous oxide in oxygen was administered at a flow rate of 10
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on June 8, 2015
fications of the National Bureau of Standards and was accurate to ± 0.003 pH units. The pH of the arterial blood was always in the range of 7.3 to 7.4. Polyethylene catheters were placed in mid-aorta and mid-vena cava via the left femoral artery and vein respectively. Arterial and venous pressures were measured using Statham transducers. Cardiac output was measured by injecting indocyanine green through a catheter placed in the right atrium via the right femoral vein, and sampling was through a catheter placed in the aorta via the right femoral artery. Arterial blood was drawn at a constant rate through a Gilford densitometer and the resulting dye curve was recorded on a Varian recorder. Cardiac output was calculated in the usual manner from the area under the curve (Kinsman, Moore and Hamilton, 1929). Cardiac output calculated from duplicate dye curves did not differ by more than 10 per cent. All parameters except dye dilution curves were recorded on a Grass Polygraph. A fine polyethylene catheter was inserted into the epidural space. A right thoracotomy was performed and a Brodie-Walton strain gauge was sutured to the right ventricle (Boniface, Brodie and Walton, 1953; Cotten, 1953; Cotten and Bay, 1956). When all surgery was completed and the chest closed, the administration of halothane was discontinued and the dog was allowed to awaken. When the animals had fully recovered and there was no further change in contractile force, the administration of nitrous oxide was started. Nitrous oxide was administered 22 times to 13 dogs with sympathetic innervation intact and 10 times to 5 of the 13 dogs after sympathetic block. All animals acted as their own controls. Sympathetic block was produced by the injection of 20 ml of 0.5 per cent lignocaine through the catheter placed in the epidural space. The block was considered to be satisfactory when there was constriction of the pupils, when the blood pressure tracing showed a characteristic momentary rise followed by depression, and when there was absence of "sympathetic bursts". Following inhibition of sympathetic influences, changes in contractility secondary to hypotension (Walton et al., 1950) were prevented by maintaining blood pressure about normal levels with a slow infusion of methoxaminc (0.02 mg/ml), which has no
561
BRITISH JOURNAL OF ANAESTHESIA
562
percentage of control values. The mean percentage change, the standard error of that mean, and the confidence interval of the mean were calculated. An analysis of variance was made on the four groups of data. All statistical values were determined as described by Snedecor (1959). RESULTS
When nitrous oxide was administered to the dog, there was a significant initial decrease in contractile force in every case. In 6 out of 13 dogs in Group I (75 per cent nitrous oxide) and 3 out of 6 dogs in Group 2 (50 per cent nitrous oxide) this was followed by a "sympathetic burst", characterized by an increase in the blood pressure and contractile force to levels in some 2OO-I .soIOO-
ARTERIAL RIAL BLOOD FPRESSURE
60-
•ICON'S!
»
••C»»6'
'
" " " "
CONTRACTILE fORCE
FIG. 1 This figure shows a "sympathetic burst". Arterial blood pressure is represented by the upper tracing and ventricular uometric tension by the lower. It is seen that both blood pressure and contractility rises abruptly. At the right-hand side of the tracing both parameters are beginning to return to a lower level. Heart rate is increased during the burst.
TABLE I
Dogs with sympathetic innervation intact.* 50 per cent nitrous oxide in oxygen (group II) •Contractile force Control values (g) Per cent maximum increase Per cent maximum decrease Per cent change after 10 minutes
No. of dogs
Mean
Sx
_
13
28.7
2
16.2
NS
7
15.3
7.3
NS
23.2
4.5
P<0.001
13
22.2
4.2
P<0.001
-18.7
7.2
P<0.05
13
-18.9
4.5
P<0.005
No. of dogs
Mean
Sx
9
23.5
2.5
4
35.5
9 9
Significance
75 per cent nitrous oxide in oxygen (group I)
* All values except control expressed as per cent change over control. NS = not significant.
Significance
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1,/min for 10 minutes and cardiac output was again measured. It had been found in a pilot study that there was no further decrease in contractility after 10 minutes ventilation with nitrous oxide and oxygen. After each administration of nitrous oxide, the dog was ventilated for at least 20 minutes with room air by which time control conditions were again established. Tension curves recorded before and after nitrous oxide on the Grass curvilinear paper were plotted on rectilinear paper and the maximum rate of development of tension (dT/dt max.) and the maximum rate of relaxation (dR/dt max.) were measured graphically from these curves. The data were compiled as follows. Controls were expressed as actual values. The lowest (maximum decrease) and the highest (maximum increase) contractile force and the force at 10 minutes were expressed as percentage change from the control. The actual control tension depends upon the amount by which the myocardial segment is stretched when the gauge is applied. However, no matter what gauge length is used (provided that length does not exceed 35 per cent of the end-diastolic length) the percentage change of that tension produced by a given stimulus will be the same (Gotten, 1953). The control value was that taken while the animal was ventilated with oxygen or air immediately before the inhaled mixtures were changed. Heart late and blood pressure were measured at the time of the maximum increase and the rnaximnm •decrease of contractile force, and also after 10 minutes. These changes were also presented as
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG instances greater than control (fig. 1). Tachycardia was invariably present during these "bursts" which were of sudden onset and rarely lasted more than 20 sec. Table I shows the extent of the initial depression of contractile force, the maximum increase during a "sympathetic burst" and the depression after 10 minutes. Figure 2 shows a typical tracing following nitrous oxide administration. There was no significant difference between 50 per cent nitrous oxide in oxygen and 75 per cent nitrous oxide in oxygen in any group. In no case was a sympathetic burst present at the 10-minute reading.
257. OXTGEN
there was no significant change in blood pressure or heart rate. Cardiac output did not change significantly. When animals were deprived of sympathetic innervation (Groups 3 and 4), contractile force was decreased after the administration of nitrous oxide (table II) and "sympathetic bursts" no longer occurred. There was no significant change in blood pressure, heart rate, or cardiac output in Groups 3 and 4. Changes in contractile force in Groups 3 and 4 were not significantly different from those in Groups 1 and 2. No change in venous pressure was seen in any groups following the inhalation of nitrous oxide. Both dT/dt max. and dR/dt max. decreased, dR/dt more than: dT/dt max.
AITIBIAL BIOOO PRESSURE
DISCUSSION
FIG. 2 This is a typical response to nitrous oxide. The upper tracing is arterial blood pressure and the lower tracing isometric tension; 75 per cent nitrous oxide and 25 per cent oxygen was administered at the arrow. There is an initial marked decrease in contractility which recovers slightly and then becomes gradually depressed again. Blood pressure does not vary significantly in this part of the tracing.
In all animals with intact sympathetic innervation, contractile force after administration of nitrous oxide was less than control. However,
The changes in contractility demonstrated in the heart with intact innervation are essentially in agreement with the results reported by Price and Helrich (1955), working with the heart-lung preparation. The absence of sustained haemodynamic changes supports clinical experience (Parry Brown, 1959; Adriani, 1955; Hamilton, 1963). Bloch (1963) has reported changes in heart rate and blood pressure with nitrous oxide anaesthesia, but these data are most difficult to interpret because of a large number of other variables such as premedication, surgical trauma, other anaesthetic agents, hypothermia, etc. The presence of numerous short periods of "sympathetic burst" indicate that nitrous oxide does not depress autonomic regulation, and the general depression observed is interspersed with
TABLE II
Dogs with sympathetic block.* 50 per cent nitrous oxide in oxygen (group IV) Contractile force Control values (g) Per cent maximum decrease Per cent change after 10 minutes
No. of dogs
Mean
Sx
5
15.3
2.0
5
23.4
6.4
5
-23.4
6.4
Significance
75 per cent nitrous oxide in oxygen (group III) No. of dogs
Mean
Sx
5
18.9
1.8
P<0.025
5
19.2
7.6
P<0.01
P<0.025
5
-19.2
7.6
P<0.01
•All values except control expressed as per cent change over control. NS = not significant.
Significance
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75% NITROUS OXIDE
56?
564
must be regarded as a decrease in cardiac efficiency though not necessarily an indication of decrease in cardiac function. REFERENCES
Adriani, J. (1955), in Selection of Anesthesia, p. 32. Springfield: Thomas. Bagwell, E. E., and Woods, E. F. (1962). Cardiovascular effects of methoiyflurane, Anesthesiology, 23, 51. Durst, G. G. (1964). Influence of reserpine on cardiovascular and sympatho-adrenal responses to cyclopropane anesthesia in the dog. Anesthesiology, 25, 148. Linker, R. P. (1964). Influence of reserpine in cardiovascular and sympatho-adrenal responses to ether anesthesia in the dog. Anesthesiology, 25, 15. Bergman, N. A., Rackow, H., and Frumin, M. T. (1958). Collision broadening effects of nitrous oxide upon improved analysis of carbon dioxide during anesthesia. Anesthesiology, 19, 19. Bloch, M. (1963). Some systemic effects of nitrous oxide. Brit. J. Anaesih., 35, 631. Boniface, K. J., and Brown, J. M. (1953). Effects of carbon dioxide excess on contractile force of the heart in situ. Amer. J. Physiol., 172, 752. Brodie, O. J., and Walton, R. P. (1953). Resistance strain gauge arches for direct measurement of heart contractile force in animals. Proc. Soc. exp. Biol., 84, 263. Brown, J. M., and Kronen, P. S. (1957). The influence of some inhalation anesthetic agents on the contractile force of the heart. J. Pharmacol, exp. Ther., 119, 378. Brewster, W. R., Isaacs, J. P., and Andersen, W. T. (1953). Depressant effect of ether on the myocardium of the dog and its modification by reflex release of epinephrine and norepinephrine. Amer. J. Physiol, 175, 399. Osgood, P. F., Isaacs, J. P., and Goldberg, L. I. (1960). Hemodynamic effects of a pressor amine (methoxamine) with predominant vasoconstrictive activity. Circulat. Res., 8, 980. Brown, A. I. Parry (1959), in General Anaesthesia, Vol. I (eds. Evans, F. T., and Gray, T. C). Ch. 7, p. 122. London: Butterworth. Brown, J. M. (1960). Anesthesia and the contractile force of the heart Aneslh. Analg. Curr. Res., 39, 487. Cotten, M. de V. (1953). Circulatory changes affecting measurement of heart force in situ with strain gauge arches. Amer. J. Physiol., 174, 365. Bay, E. (1956). Direct measurement of changes in cardiac contractile force. Amer. J. Physiol., 187, 122. Deutsch, S., Linde, H. W., and Price, H. L. (1962). Circulatory and sympatho-adrenal responses to cyclopropane in the dog. J. Pharmacol, exp. Ther., 135, 354.
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short periods of stimulation of myocardial function and of the measured haemodynamic parameters. As contractility was decreased to the same degree in dogs with or without inhibition of sympathetic influences, it is probable that, unlike cyclopropane (Deutsch, Linde and Price, 1962) and ether (Brewster, Isaacs and Andersen, 1953), nitrous oxide does not stimulate the sympathetic nervous system. The absence of changes in heart rate after 10 minutes would tend to support this conclusion. Reeves and his associates (1960) have pointed out that the rate of tension development seems to be most closely related to ventricular function. It would be expected, therefore, that the d T / d t would be decreased during nitrous oxide anaesthesia. However, at present there is no explanation for the change in rate of relaxation. It is possible that the lack of agreement between developed tension and haemodynamic parameters is due to failure of most haemodynamic calculations to include the factor of velocity of flow. Rushmer (1964) has demonstrated that during systole left ventricular pressure rises sharply, whereas in the right ventricle (which usually has the same output) the pressure rises more slowly and is more prolonged. In other words, the left ventricle behaves like a pressure or impulse pump and the right ventricle like a volume pump. However, both ventricles have an equal stroke volume under normal circumstances. Rushmer considers the initial ventricular impulse (the pressure gradient between the left ventricle and the aorta) as a good index of myocardial power and has recently discussed the importance of variation in initial ventricular impulse with anaesthesia. It is true that the ventricular impulse would be reduced by a reduction in rate of tension development. If the rate of relaxation of the ventricle were also reduced, however, the left ventricle would function more as a volume rather than an impulse or pressure pump and would tend to behave in the same manner as a normal right ventricle. In other words, the power of the heart (i.e. the work done per unit time) would be less yet the stroke volume might remain unchanged. Myocardial contractility is only one of the many factors responsible for cardiovascular homoeostasis. In the healthy heart, however, decrease in contractility produced by anaesthesia
BRITISH JOURNAL OF ANAESTHESIA
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG
West, J. W., Guzman, S. V., Aviado, D. M., and Bellet, S. (1956). Cardiac effects of methoxamine. Circulation, 4, 10, 7.
LES EFFETS CARDIO-VASCULATRES DE L'OXYDE NITREUX CHEZ LE CHIEN SOMMAIKE
On a etudii les effets cardio-vasculaircs de l'oxyde nitreux chcz 13 chiens. L'oxyde nitreux a deprimi la force contractile myocardique mesuree avec l'appareil de Brodie-Walton. Le volume systolique, la pression veineusc centrale, la tension artirielle et la frequence cardiaque n'^taient pas notablement changes. Les responses du systeme sympathique n'itaicnt ni inhibees ni continument stirnulees par cet agent. On discute l'effet de l'oxyde nitreux sur l'acrivitd cardiaque. DIE KARDIOVASKULAREN WIRKUNGEN VON LACHGAS BEIM HUND ZUSAMMENFASSUNG
Die Wirkungen von Lachgas auf Herz und Kreislauf wurden an 13 Hunden untersucht. Lachgas senkte beim Hund die Kontraktionskraft des Myokards, gemessen mit dem Gerat nach Brodie-Walton. Herzminutenvolumen, zentraler Venendruck, Blutdruck und Herzfrequenz zeigten keine signifikanten Anderungen. Reaktionen des sympathischen Nerven systems wurden durch diese Substanz weder gehemmt noch anhaltend stimuliert. Der EinfluO von Lachgas auf den Wirkungsgrad des Herzmuskels wird diskutiert.
BOOK REVIEW The Motor Endplate. By Sumner I. Zacks. Published by W. B. Saunders Company, Philadelphia. Pp. 227 +index; illustrated. Price £5 19*. The reviewer is no expert in the field of histology— indeed he has not even a dilettante interest. However, this is a book which, although written by a recognized authority on the morbid histology of its subject, covers more than just the normal structure and its variation in disease of that intriguing junctional tissue —the endplate. Indeed, its physiology and physiopathology are well covered and it makes for fascinating reading. The electron microscope and the delicate intracellular explorations made possible by microelectrode techniques have transformed our knowledge of nerve impulse transmission and the structures concerned with it. Dr. Zacks has efficiently collated material garnered from the outstanding workers in this field and has added his own not inconsiderable contribution which has been particularly in the histopathology of the area in disease. The list of diseases in which abnormalities in this area affecting transmission can be found is impressive. The field covered is thus not so narrow as might be feared from the title of the monograph and, although much of the text is highly technical and detailed, it is made extremely readable for the non-
specialist by the inclusion of many interesting "titbits" of information. It was, for example, surprising to learn that the organic phosphate parathion had been reported as accounting for 286 fatalities in Finland in the years 1952-57, of which 7 were the result of homicide and 237 of suicide. There will be few who will not be intensely interested by the review of the so-called "guidance" problem during nerve re-innervation after injury and if ever it is required to exemplify the scholastic's argument from design one hardly need search further. For anaesthetists the data on acetylcholine release and its sites of formation and storage and the study of the structure of the post-synaptic membrane in general will be of special interest. It must be admitted, however, that the information garnered must be extracted from a deal of detail and the vocabulary will not be familiar to many clinicians. The book is beautifully produced with many quite outstanding illustrations, among which will be specially noted the many fine reproductions of electron micrographs. In summary, this is a very specialized work, but one from which all anaesthetists who have more than a purely technical interest in their subject will profit and many will find it absorbing. Cecil Gray
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Hamilton, W. K. (1963). Limited pharmacology of nitrous oxide, Clm. Pharmacol. Ther., 4, 663. Kinsman, J. At, Moore, J. W., and Hamilton, W. F. (1929). Studies on the circulation; injection method: physical and mathematical considerations. Amer. J. Physiol., 89, 322. Mehaffey, J. E., Aldinger, E. E., Sprouse, J. H., Darby, T. D., and Thrower, W. B. (1960). The cardiovascular effects of halothane. Anesthesiology, 22, 982. Price, H. C , and Helrich, M. (1955). The effect of cyclopropane, diethyl ether, nitrous oxide, thiopental and hydrogen ion concentration on the myocardial function of the dog. J. Pharmacol, exp. Ther., 115, 206. Reeves, T. J., Hefner, L. L., Jones, W. B., Coglan, Q, Prieto, G., and Carroll, J. (1960). The hemodynamic determinants of the rate of change of pressure in the left ventricle during isometric contraction. Amer. Heart J., 60, 745. Rushmer, R. F. (1966). Initial ventricular impulse—a potential key to cardiac evaluation. Circulation, 29, 268. Snedecor, G. W. (1959). Statistical Methods 5th ed. Iowa: Iowa State College Press. Spencer, M. P., and Greiss, F. C. (1962). Dynamics of ventricular ejection. Circulat. Res., 10, 274. Walton, R. P., Cotten, Marion de V., Brill, H. H., and Gazes, P. C. (1950). Factors influencing measurement of contractile force of heart muscle in situ. Amer. J. Physiol, 161, 489.
565
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG BY
N. W. B. CRAYTHORNE AND T. D. DARBY*
Division of Anesthesiology and Department of Pharmacology, West Virginia University, Morgantovm, U.S.A. SUMMARY
Nitrous oxide was introduced as an anaesthetic agent over one hundred years ago. Despite its wide use, there is a marked paucity of data regarding its effects on the cardiovascular system (Hamilton, 1963). This is especially true with regard to the effects of this agent on the intact, innervated cardiovascular system. This project was carried out to study the effects of nitrous oxide on myocardial function and haemodynamic parameters. Haemodynamic measurements included arterial blood pressure, central venous pressure and cardiac output. Measurements of myocardial function included maximum isometric systolic tension, rate of tension development with systole, rate of relaxation and heart rate. A Brodie-Walton strain gauge was used to measure isometric tension so that our data could be compared with those of others who have studied the effects of various anaesthetic agents using this instrument (Mehaffey et al., 1960; Brown, 1960; Boniface, Brown and Kronen, 1957; Bagwell and Woods, 1962; Bagwell, Woods and Durst, 1964; Bagwell, Woods and Linker, 1964). METHOD
Thirteen mongrel dogs weighing between 8 and 17 kg were premedicated with atropine 0.1 mg/ kg. Anaesthesia was induced with halothane and
endotracheal intubation with a cuffed tube was carried out with the aid of suxamethonium. Pulmonary ventilation was controlled with a Medtronic respirator and a Fluotec vaporizer was included on the inspiratory side of this non-rebreathing system for the maintenance of anaesthesia. A fine polyethylene catheter was inserted through the wall of the endotracheal tube and passed down into the trachea. End-expiratory gas was drawn at a constant rate through the detector chamber of a Beckman LB-1 carbon dioxide analyzer which was calibrated with room air and 5 per cent carbon dioxide. Ventilation was determined by the nomogram of Kleinman and Radford* and adjusted slightly from time to time to maintain a normal end-expired carbon dioxide concentration (5 per cent). Alveolar Pcoa, as calculated from the end-expiratory carbon dioxide concentration, did not differ from arterial Pcoa by more than 3 mm Hg provided that a good expiratory plateau was obtained and the blood pressure did not fall. Arterial Pco3 and pH were measured intermittently throughout the experiment using a Severinghaus carbon dioxide electrode and a Radiometer pH electrode. The electrodes were immersed in a water bath kept at 37 °C. PcOj readings were reproducible to ± 1 mm Hg. The Radiometer pH electrode was calibrated with two primary phosphate buffers according to the speci-
This investigation was supported in part by Public Health Service Grant No. HE-06151-04 from the National Heart Institute. • Made by L. Kleinman, MJJ., and E. P. Radford, MJ3., * This investigator is supported by Public Health ' Department of Physiology, School of Public Health, Service Career Development Award 5K3HE6254-02 Harvard University, for the Harvard Apparatus Co., Inc., Dover, Massachusetts. from the National Heart Institute.
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on June 8, 2015
The cardiovascular effects of nitrous oxide were studied in thirteen dogs. Nitrous oxide depressed the myocardial contractile force in the deg as measured with the BrodieWalton gauge. Cardiac output, central venous pressure, arterial blood pressure, and heart rate were not significantly changed. Sympathetic nervous responses were neither inhibited nor continuously stimulated by this agent. The effect of nitrous oxide on the efficiency of the heart is discussed.
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG
inotropic action (Brown, 1960; West et al., 1956; Brewster et al., 1960). The animals were studied in four groups as follows: Group 1: 75 per cent nitrous oxide in oxygen was administered once to all animals. Group 2: 50 per cent nitrous oxide in oxygen was administered 9 times to 6 of these animals, Group 3 : 75 per cent nitrous oxide was administered to 5 dogs pathetic block. Group 4 : 50 per cent nitrous oxide was administered to the 5 sympathetic block.
in oxygen after symin oxygen dogs with
Air, 75 per cent nitrous oxide in oxygen, or 50 per cent nitrous oxide in oxygen in 10 l./min flow rate was delivered from a pre-calibrated Heidbrink anaesthetic machine into a "bag in a bottle ventilator" (Bird Mark IV Assistor) which was driven by a Medtronic animal respirator (instead of the conventional Bird Mark VIII respirator). This was a volume-constant type of respirator. The bag of the respirator was substituted for the reservoir bag in the semidosed circle system of the Heidbrink machine. As significant changes in myocardial contractility can be produced by small changes in arterial Pco3 (Boniface and Brown, 1953), the end-expiratory carbon dioxide concentration was monitored and was kept constant before each administration of nitrous oxide, and afterwards when control values were reached. During the study when nitrous oxide was being administered, the broadening effect (Bergman, Rackow and Frumin, 1958) of this agent led to inaccuracy, so ventilation was maintained at that volume which had kept endexpiratory carbon dioxide constant during the control period. Inspired oxygen concentration was monitored intermittently with a Pauling oxygen meter (Beckman Model D). During the control period when the dog was being ventilated with room air, arterial pressure, heart rate, central venous pressure, and contractile force were recorded continuously. Cardiac output was again measured just before nitrous oxide was breathed. A mixture of 75 per cent nitrous oxide in oxygen, or 50 per cent nitrous oxide in oxygen was administered at a flow rate of 10
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on June 8, 2015
fications of the National Bureau of Standards and was accurate to ± 0.003 pH units. The pH of the arterial blood was always in the range of 7.3 to 7.4. Polyethylene catheters were placed in mid-aorta and mid-vena cava via the left femoral artery and vein respectively. Arterial and venous pressures were measured using Statham transducers. Cardiac output was measured by injecting indocyanine green through a catheter placed in the right atrium via the right femoral vein, and sampling was through a catheter placed in the aorta via the right femoral artery. Arterial blood was drawn at a constant rate through a Gilford densitometer and the resulting dye curve was recorded on a Varian recorder. Cardiac output was calculated in the usual manner from the area under the curve (Kinsman, Moore and Hamilton, 1929). Cardiac output calculated from duplicate dye curves did not differ by more than 10 per cent. All parameters except dye dilution curves were recorded on a Grass Polygraph. A fine polyethylene catheter was inserted into the epidural space. A right thoracotomy was performed and a Brodie-Walton strain gauge was sutured to the right ventricle (Boniface, Brodie and Walton, 1953; Cotten, 1953; Cotten and Bay, 1956). When all surgery was completed and the chest closed, the administration of halothane was discontinued and the dog was allowed to awaken. When the animals had fully recovered and there was no further change in contractile force, the administration of nitrous oxide was started. Nitrous oxide was administered 22 times to 13 dogs with sympathetic innervation intact and 10 times to 5 of the 13 dogs after sympathetic block. All animals acted as their own controls. Sympathetic block was produced by the injection of 20 ml of 0.5 per cent lignocaine through the catheter placed in the epidural space. The block was considered to be satisfactory when there was constriction of the pupils, when the blood pressure tracing showed a characteristic momentary rise followed by depression, and when there was absence of "sympathetic bursts". Following inhibition of sympathetic influences, changes in contractility secondary to hypotension (Walton et al., 1950) were prevented by maintaining blood pressure about normal levels with a slow infusion of methoxaminc (0.02 mg/ml), which has no
561
BRITISH JOURNAL OF ANAESTHESIA
562
percentage of control values. The mean percentage change, the standard error of that mean, and the confidence interval of the mean were calculated. An analysis of variance was made on the four groups of data. All statistical values were determined as described by Snedecor (1959). RESULTS
When nitrous oxide was administered to the dog, there was a significant initial decrease in contractile force in every case. In 6 out of 13 dogs in Group I (75 per cent nitrous oxide) and 3 out of 6 dogs in Group 2 (50 per cent nitrous oxide) this was followed by a "sympathetic burst", characterized by an increase in the blood pressure and contractile force to levels in some 2OO-I .soIOO-
ARTERIAL RIAL BLOOD FPRESSURE
60-
•ICON'S!
»
••C»»6'
'
" " " "
CONTRACTILE fORCE
FIG. 1 This figure shows a "sympathetic burst". Arterial blood pressure is represented by the upper tracing and ventricular uometric tension by the lower. It is seen that both blood pressure and contractility rises abruptly. At the right-hand side of the tracing both parameters are beginning to return to a lower level. Heart rate is increased during the burst.
TABLE I
Dogs with sympathetic innervation intact.* 50 per cent nitrous oxide in oxygen (group II) •Contractile force Control values (g) Per cent maximum increase Per cent maximum decrease Per cent change after 10 minutes
No. of dogs
Mean
Sx
_
13
28.7
2
16.2
NS
7
15.3
7.3
NS
23.2
4.5
P<0.001
13
22.2
4.2
P<0.001
-18.7
7.2
P<0.05
13
-18.9
4.5
P<0.005
No. of dogs
Mean
Sx
9
23.5
2.5
4
35.5
9 9
Significance
75 per cent nitrous oxide in oxygen (group I)
* All values except control expressed as per cent change over control. NS = not significant.
Significance
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1,/min for 10 minutes and cardiac output was again measured. It had been found in a pilot study that there was no further decrease in contractility after 10 minutes ventilation with nitrous oxide and oxygen. After each administration of nitrous oxide, the dog was ventilated for at least 20 minutes with room air by which time control conditions were again established. Tension curves recorded before and after nitrous oxide on the Grass curvilinear paper were plotted on rectilinear paper and the maximum rate of development of tension (dT/dt max.) and the maximum rate of relaxation (dR/dt max.) were measured graphically from these curves. The data were compiled as follows. Controls were expressed as actual values. The lowest (maximum decrease) and the highest (maximum increase) contractile force and the force at 10 minutes were expressed as percentage change from the control. The actual control tension depends upon the amount by which the myocardial segment is stretched when the gauge is applied. However, no matter what gauge length is used (provided that length does not exceed 35 per cent of the end-diastolic length) the percentage change of that tension produced by a given stimulus will be the same (Gotten, 1953). The control value was that taken while the animal was ventilated with oxygen or air immediately before the inhaled mixtures were changed. Heart late and blood pressure were measured at the time of the maximum increase and the rnaximnm •decrease of contractile force, and also after 10 minutes. These changes were also presented as
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG instances greater than control (fig. 1). Tachycardia was invariably present during these "bursts" which were of sudden onset and rarely lasted more than 20 sec. Table I shows the extent of the initial depression of contractile force, the maximum increase during a "sympathetic burst" and the depression after 10 minutes. Figure 2 shows a typical tracing following nitrous oxide administration. There was no significant difference between 50 per cent nitrous oxide in oxygen and 75 per cent nitrous oxide in oxygen in any group. In no case was a sympathetic burst present at the 10-minute reading.
257. OXTGEN
there was no significant change in blood pressure or heart rate. Cardiac output did not change significantly. When animals were deprived of sympathetic innervation (Groups 3 and 4), contractile force was decreased after the administration of nitrous oxide (table II) and "sympathetic bursts" no longer occurred. There was no significant change in blood pressure, heart rate, or cardiac output in Groups 3 and 4. Changes in contractile force in Groups 3 and 4 were not significantly different from those in Groups 1 and 2. No change in venous pressure was seen in any groups following the inhalation of nitrous oxide. Both dT/dt max. and dR/dt max. decreased, dR/dt more than: dT/dt max.
AITIBIAL BIOOO PRESSURE
DISCUSSION
FIG. 2 This is a typical response to nitrous oxide. The upper tracing is arterial blood pressure and the lower tracing isometric tension; 75 per cent nitrous oxide and 25 per cent oxygen was administered at the arrow. There is an initial marked decrease in contractility which recovers slightly and then becomes gradually depressed again. Blood pressure does not vary significantly in this part of the tracing.
In all animals with intact sympathetic innervation, contractile force after administration of nitrous oxide was less than control. However,
The changes in contractility demonstrated in the heart with intact innervation are essentially in agreement with the results reported by Price and Helrich (1955), working with the heart-lung preparation. The absence of sustained haemodynamic changes supports clinical experience (Parry Brown, 1959; Adriani, 1955; Hamilton, 1963). Bloch (1963) has reported changes in heart rate and blood pressure with nitrous oxide anaesthesia, but these data are most difficult to interpret because of a large number of other variables such as premedication, surgical trauma, other anaesthetic agents, hypothermia, etc. The presence of numerous short periods of "sympathetic burst" indicate that nitrous oxide does not depress autonomic regulation, and the general depression observed is interspersed with
TABLE II
Dogs with sympathetic block.* 50 per cent nitrous oxide in oxygen (group IV) Contractile force Control values (g) Per cent maximum decrease Per cent change after 10 minutes
No. of dogs
Mean
Sx
5
15.3
2.0
5
23.4
6.4
5
-23.4
6.4
Significance
75 per cent nitrous oxide in oxygen (group III) No. of dogs
Mean
Sx
5
18.9
1.8
P<0.025
5
19.2
7.6
P<0.01
P<0.025
5
-19.2
7.6
P<0.01
•All values except control expressed as per cent change over control. NS = not significant.
Significance
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75% NITROUS OXIDE
56?
564
must be regarded as a decrease in cardiac efficiency though not necessarily an indication of decrease in cardiac function. REFERENCES
Adriani, J. (1955), in Selection of Anesthesia, p. 32. Springfield: Thomas. Bagwell, E. E., and Woods, E. F. (1962). Cardiovascular effects of methoiyflurane, Anesthesiology, 23, 51. Durst, G. G. (1964). Influence of reserpine on cardiovascular and sympatho-adrenal responses to cyclopropane anesthesia in the dog. Anesthesiology, 25, 148. Linker, R. P. (1964). Influence of reserpine in cardiovascular and sympatho-adrenal responses to ether anesthesia in the dog. Anesthesiology, 25, 15. Bergman, N. A., Rackow, H., and Frumin, M. T. (1958). Collision broadening effects of nitrous oxide upon improved analysis of carbon dioxide during anesthesia. Anesthesiology, 19, 19. Bloch, M. (1963). Some systemic effects of nitrous oxide. Brit. J. Anaesih., 35, 631. Boniface, K. J., and Brown, J. M. (1953). Effects of carbon dioxide excess on contractile force of the heart in situ. Amer. J. Physiol., 172, 752. Brodie, O. J., and Walton, R. P. (1953). Resistance strain gauge arches for direct measurement of heart contractile force in animals. Proc. Soc. exp. Biol., 84, 263. Brown, J. M., and Kronen, P. S. (1957). The influence of some inhalation anesthetic agents on the contractile force of the heart. J. Pharmacol, exp. Ther., 119, 378. Brewster, W. R., Isaacs, J. P., and Andersen, W. T. (1953). Depressant effect of ether on the myocardium of the dog and its modification by reflex release of epinephrine and norepinephrine. Amer. J. Physiol, 175, 399. Osgood, P. F., Isaacs, J. P., and Goldberg, L. I. (1960). Hemodynamic effects of a pressor amine (methoxamine) with predominant vasoconstrictive activity. Circulat. Res., 8, 980. Brown, A. I. Parry (1959), in General Anaesthesia, Vol. I (eds. Evans, F. T., and Gray, T. C). Ch. 7, p. 122. London: Butterworth. Brown, J. M. (1960). Anesthesia and the contractile force of the heart Aneslh. Analg. Curr. Res., 39, 487. Cotten, M. de V. (1953). Circulatory changes affecting measurement of heart force in situ with strain gauge arches. Amer. J. Physiol., 174, 365. Bay, E. (1956). Direct measurement of changes in cardiac contractile force. Amer. J. Physiol., 187, 122. Deutsch, S., Linde, H. W., and Price, H. L. (1962). Circulatory and sympatho-adrenal responses to cyclopropane in the dog. J. Pharmacol, exp. Ther., 135, 354.
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short periods of stimulation of myocardial function and of the measured haemodynamic parameters. As contractility was decreased to the same degree in dogs with or without inhibition of sympathetic influences, it is probable that, unlike cyclopropane (Deutsch, Linde and Price, 1962) and ether (Brewster, Isaacs and Andersen, 1953), nitrous oxide does not stimulate the sympathetic nervous system. The absence of changes in heart rate after 10 minutes would tend to support this conclusion. Reeves and his associates (1960) have pointed out that the rate of tension development seems to be most closely related to ventricular function. It would be expected, therefore, that the d T / d t would be decreased during nitrous oxide anaesthesia. However, at present there is no explanation for the change in rate of relaxation. It is possible that the lack of agreement between developed tension and haemodynamic parameters is due to failure of most haemodynamic calculations to include the factor of velocity of flow. Rushmer (1964) has demonstrated that during systole left ventricular pressure rises sharply, whereas in the right ventricle (which usually has the same output) the pressure rises more slowly and is more prolonged. In other words, the left ventricle behaves like a pressure or impulse pump and the right ventricle like a volume pump. However, both ventricles have an equal stroke volume under normal circumstances. Rushmer considers the initial ventricular impulse (the pressure gradient between the left ventricle and the aorta) as a good index of myocardial power and has recently discussed the importance of variation in initial ventricular impulse with anaesthesia. It is true that the ventricular impulse would be reduced by a reduction in rate of tension development. If the rate of relaxation of the ventricle were also reduced, however, the left ventricle would function more as a volume rather than an impulse or pressure pump and would tend to behave in the same manner as a normal right ventricle. In other words, the power of the heart (i.e. the work done per unit time) would be less yet the stroke volume might remain unchanged. Myocardial contractility is only one of the many factors responsible for cardiovascular homoeostasis. In the healthy heart, however, decrease in contractility produced by anaesthesia
BRITISH JOURNAL OF ANAESTHESIA
THE CARDIOVASCULAR EFFECTS OF NITROUS OXIDE IN THE DOG
West, J. W., Guzman, S. V., Aviado, D. M., and Bellet, S. (1956). Cardiac effects of methoxamine. Circulation, 4, 10, 7.
LES EFFETS CARDIO-VASCULATRES DE L'OXYDE NITREUX CHEZ LE CHIEN SOMMAIKE
On a etudii les effets cardio-vasculaircs de l'oxyde nitreux chcz 13 chiens. L'oxyde nitreux a deprimi la force contractile myocardique mesuree avec l'appareil de Brodie-Walton. Le volume systolique, la pression veineusc centrale, la tension artirielle et la frequence cardiaque n'^taient pas notablement changes. Les responses du systeme sympathique n'itaicnt ni inhibees ni continument stirnulees par cet agent. On discute l'effet de l'oxyde nitreux sur l'acrivitd cardiaque. DIE KARDIOVASKULAREN WIRKUNGEN VON LACHGAS BEIM HUND ZUSAMMENFASSUNG
Die Wirkungen von Lachgas auf Herz und Kreislauf wurden an 13 Hunden untersucht. Lachgas senkte beim Hund die Kontraktionskraft des Myokards, gemessen mit dem Gerat nach Brodie-Walton. Herzminutenvolumen, zentraler Venendruck, Blutdruck und Herzfrequenz zeigten keine signifikanten Anderungen. Reaktionen des sympathischen Nerven systems wurden durch diese Substanz weder gehemmt noch anhaltend stimuliert. Der EinfluO von Lachgas auf den Wirkungsgrad des Herzmuskels wird diskutiert.
BOOK REVIEW The Motor Endplate. By Sumner I. Zacks. Published by W. B. Saunders Company, Philadelphia. Pp. 227 +index; illustrated. Price £5 19*. The reviewer is no expert in the field of histology— indeed he has not even a dilettante interest. However, this is a book which, although written by a recognized authority on the morbid histology of its subject, covers more than just the normal structure and its variation in disease of that intriguing junctional tissue —the endplate. Indeed, its physiology and physiopathology are well covered and it makes for fascinating reading. The electron microscope and the delicate intracellular explorations made possible by microelectrode techniques have transformed our knowledge of nerve impulse transmission and the structures concerned with it. Dr. Zacks has efficiently collated material garnered from the outstanding workers in this field and has added his own not inconsiderable contribution which has been particularly in the histopathology of the area in disease. The list of diseases in which abnormalities in this area affecting transmission can be found is impressive. The field covered is thus not so narrow as might be feared from the title of the monograph and, although much of the text is highly technical and detailed, it is made extremely readable for the non-
specialist by the inclusion of many interesting "titbits" of information. It was, for example, surprising to learn that the organic phosphate parathion had been reported as accounting for 286 fatalities in Finland in the years 1952-57, of which 7 were the result of homicide and 237 of suicide. There will be few who will not be intensely interested by the review of the so-called "guidance" problem during nerve re-innervation after injury and if ever it is required to exemplify the scholastic's argument from design one hardly need search further. For anaesthetists the data on acetylcholine release and its sites of formation and storage and the study of the structure of the post-synaptic membrane in general will be of special interest. It must be admitted, however, that the information garnered must be extracted from a deal of detail and the vocabulary will not be familiar to many clinicians. The book is beautifully produced with many quite outstanding illustrations, among which will be specially noted the many fine reproductions of electron micrographs. In summary, this is a very specialized work, but one from which all anaesthetists who have more than a purely technical interest in their subject will profit and many will find it absorbing. Cecil Gray
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Hamilton, W. K. (1963). Limited pharmacology of nitrous oxide, Clm. Pharmacol. Ther., 4, 663. Kinsman, J. At, Moore, J. W., and Hamilton, W. F. (1929). Studies on the circulation; injection method: physical and mathematical considerations. Amer. J. Physiol., 89, 322. Mehaffey, J. E., Aldinger, E. E., Sprouse, J. H., Darby, T. D., and Thrower, W. B. (1960). The cardiovascular effects of halothane. Anesthesiology, 22, 982. Price, H. C , and Helrich, M. (1955). The effect of cyclopropane, diethyl ether, nitrous oxide, thiopental and hydrogen ion concentration on the myocardial function of the dog. J. Pharmacol, exp. Ther., 115, 206. Reeves, T. J., Hefner, L. L., Jones, W. B., Coglan, Q, Prieto, G., and Carroll, J. (1960). The hemodynamic determinants of the rate of change of pressure in the left ventricle during isometric contraction. Amer. Heart J., 60, 745. Rushmer, R. F. (1966). Initial ventricular impulse—a potential key to cardiac evaluation. Circulation, 29, 268. Snedecor, G. W. (1959). Statistical Methods 5th ed. Iowa: Iowa State College Press. Spencer, M. P., and Greiss, F. C. (1962). Dynamics of ventricular ejection. Circulat. Res., 10, 274. Walton, R. P., Cotten, Marion de V., Brill, H. H., and Gazes, P. C. (1950). Factors influencing measurement of contractile force of heart muscle in situ. Amer. J. Physiol, 161, 489.
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