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Nitrous oxide: use in cardiovascular risk patients
Best Practice & Research Clinical Anaesthesiology Vol. 15, No. 3, pp. 429±435, 2001
doi:10.1053/bean.2001.0178, available online at http://www.idealibrary.com on
10 Nitrous oxide: use in cardiovascular risk patients Jean Neidecker Consultant Anaesthetist Service d'AnestheÂsie-ReÂanimation, HoÃpital Cardiovasculaire & Pneumologique L. Pradel, Boulevard Pinel, F-69394 Lyon, France
Nitrous oxide (N2O) has been used in clinical anaesthesia for more than 150 years. Its use is encouraged in combination with new anaesthetics to reduce the cost. Nevertheless there is some evidence to show that N2O impairs myocardial function: e.g. producing a decrease in myocardial contractility and abnormal coronary blood ¯ow. Regional myocardial ischaemia occurs and the recovery after N2O withdrawal is delayed. These dose-dependent eects are enhanced by an increase in sympathetic tone and by a direct eect on the myocardium (inhibition of trans-sarcolemmal calcium ion entry). Haemodynamic parameters are aected; namely a decreased blood pressure and cardiac index and an increase in systemic vascular resistance. Pulmonary circulation is dramatically aected if the pulmonary artery pressure is increased prior to N2O administration. Regional circulation is also modi®ed (decrease in splanchnic and renal blood ¯ow). Therefore the use of N2O cannot be recommended in patients with cardiovascular risk factors who are undergoing cardiac and/or non-cardiac procedures. Key words: nitrous oxide; anaesthesia; myocardial function; ischaemia; haemodynamics; cardiac patients; cardiac surgery; non-cardiac surgery.
Nitrous oxide (N2O) was introduced into anaesthesia more than 150 years ago. Since then it is, and remains, an essential agent in clinical anaesthesia because it has been shown that N2O decreases the amount needed for all other anaesthetics and, consequently, reduces the overall cost of anaesthesia.1,2 Whether N2O is safe or not when heart function is compromised is still questionable. N2O is rarely used as a single anaesthetic agent and in the inspired gas, its concentration can vary from 30±70%. Therefore it is often dicult to separate its eect on haemodynamics from those induced by other agents. CARDIOVASCULAR EFFECTS OF N2O Since 1975, N2O has been known to cause signi®cant depression of the heart and circulation especially in cardiac patients. Therefore several studies have been conducted to experimentally and/or clinically analyse the eects of N2O on the heart and haemodynamics. Sometimes their results are divergent and even controversial, probably because N2O does not, by itself, produce anaesthesia. Thus, these studies have to be 1521±6896/01/03042907 $35.00/00
c 2001 Harcourt Publishers Ltd. *
430 J. Neidecker
conducted using other agents (opioids, benzodiazepines, inhalational anaesthetics, etc) in combination with N2O. Therefore the mechanism (direct eect on the heart and/or the circulation) or side eects of the association with other agents, is still a matter for discussion. Eect on barore¯ex and sympathetic tone Ebert3 analysed the eect of N2O on barore¯ex control of heart rate in healthy volunteers. A mixture of 40% N2O with oxygen induced a stimulation of the sympathetic nerves directed to skeletal muscle and an increase in peripheral resistance was observed. At the same time there was no eect on the barore¯ex control of the heart rate. Since N2O had no direct eect on heart rate, an increase has to be related to either improper pain management to surgical stimuli or to a release in catecholamines.1,4,5 Myocardial function and coronary circulation N2O induces a decrease in myocardial contractility in a range that varies between 5 and 28% depending on the experimental model.6 Consequently all haemodynamic parameters are aected; however, some of these eects are counteracted by an increase in the sympathetic tone that is a consequence of the catecholamine release that is produced by N2O.4 Philbin et al7 showed, in dogs, that a contractile dysfunction appeared when N2O was added to an opioid-based anaesthesia. Similar ®ndings have been reported with halothane.8 Using working isolated heart preparations receiving 50% N2O in nitrogen, Carton and Housmans9 analysed the mechanism of negative inotropic eect as an inhibition of trans-sarcolemmal calcium ion entry. Using the peak rate of increase of left ventricular pressure (dP/dt) as an index of contractility, Pagel et al10 showed that a decrease in dP/dt occurred when N2O was added to sufentanil anaesthesia. This eect was more important when 70% N2O was used compared to 30%.10 This was con®rmed by a reduction in the percentage of segment shortening. Similar results have been reported when the baseline anaesthetic was halothane, iso¯urane or pentobarbital. An increase in sympathetic tone cannot be involved because this alteration in contractility is present when an autonomic nervous system blockade is given prior to N2O inhalation.10 N2O has a weak and dose-dependent direct myocardial depressant eect that may be balanced by sympathetic activation.11 By analysing the preload recruitable stroke work relationship, Pagel et al10 showed that N2O has direct negative inotropic eects that are independent of the autonomic nervous system tone. In normal dogs, 30% N2O produced an 8±17% decrease in contractile function, while it reached 28±41% if the concentration was 70%.10 However, other mechanisms are also involved in the myocardial eects of N2O, namely a small, consistent increase in chamber stiness, myocardial stiness and unstressed length, and a decrease in the peak lengthening rate.12 If the action of several anaesthetics on chamber stiness is controversial between studies, N2O is the ®rst anaesthetic that has been found to increase both myocardial stiness and unstressed length.12 Post-ischaemic myocardial recovery is impaired in the presence of 70% N2O when compared to 70% nitrogen or to other volatile halogenated agents.12,13 When 40% N2O was given, myocardial dysfunction occurred if blood was supplied via narrow coronary arteries.14 This may be due to a dierential eect of N2O on coronary vasculature: N2O produces an epicardial coronary vasoconstriction that dramatically decreases the distal blood supply to the myocardium in cases of coronary stenosis.15 N2O impairs the
N2O use in cardiovascular risk patients 431
functional recovery of ischaemic myocardium. Before and during coronary occlusion, N2O (70%) led to an increase in mortality by ventricular ®brillation when compared to 70% nitrogen.13 Myocardial ischaemia and re-perfusion are associated with an increased stiness in remote non-ischaemic myocardium, regardless of the anaesthetic used in combination with N2O.12 The mechanism of this depressed recovery of stunned myocardium is unknown. Increased sympathetic tone due to noradrenaline release during N2O may contribute to this process. These data have been con®rmed in patients with coronary disease without a new episode of ischaemia. A possible cause of the ischaemic events is a maldistribution of the transmural blood ¯ow, which is accompanied by some degree of systolic wall dysfunction.11 In an echocardiographic study, Houltz et al16 con®rmed that some segmental wall motion could occur while the global area ejection fraction was not modi®ed. In patients undergoing coronary bypass grafting, N2O did not modify segmental wall motion prior to cardiopulmonary bypass while abnormalities occurred after the bypass and possibly induced diastolic dysfunction.12,16 However, Mitchell et al14 showed that N2O did not create ST segment depression and regional wall motion abnormalities in a patient with impaired coronary circulation and impaired left ventricular function. Adding 50% N2O to an anaesthetic protocol induced a decrease in coronary blood ¯ow and coronary sinus oxygen content while coronary sinus lactate level was increased, indicating a switch towards an anaerobic energy metabolism.17 Globally, the myocardium was extracting more oxygen in spite of a decreased stroke work rate. This phenomenon has also been observed, with slightly dierent ranges, with both volatile anaesthetics (en¯urane and halothane) and opioids (fentanyl). A summary of the myocardial eects is given in Table 1. Finally, since N2O diuses more rapidly than nitrogen, an air bubble would tend to expand in the presence of N2O, particularly in coronary arteries and/or grafts.16 This could increase an unexpected ischaemia. Haemodynamics As a consequence of the eect of N2O on the myocardium, a decrease in cardiac output is recorded while systemic vascular resistance remains high when oxygen alone is compared with a mixture of 50% N2O in oxygen. Therefore regional circulation is also aected and a reduction in splanchnic and renal blood ¯ow is observed.18 Cutaneous and muscular blood ¯ow are decreased in proportion to the reduced cardiac output. During normocapnia, a cerebral vasodilation is induced by N2O and is accompanied by an increase in cerebral oxygen consumption, which is not
Table 1. Myocardial eect of nitrous oxide. Parameter
Eect
Contractility Ischaemia Global Regional Recovery after withdrawal dP/dt Coronary circulation
Decreased Unchanged Increased Delayed Decreased Epicardial vasoconstriction
432 J. Neidecker
proportional.19 Thus oxygen supply to peripheral organs may be impaired because of the reduction in cardiac output and the increase in systemic vascular resistance. In response to N2O administration, systemic vascular resistance and left ventricular end-diastolic volume increase. Both eects can be reversed by the administration of phentolamine, which con®rms the involvement of a sympathetic mechanism.20 Because of this increased sympathetic tone, splanchnic venous blood ¯ow might be increased and that would impair the haemodynamics, particularly if the patient was hypovolaemic.18 The transmitral ¯ow pro®le is altered as a result of ischaemic insults when N2O is given in the post-bypass period.16 N2O does not aect isovolumic relaxation. With regard to the pulmonary circulation, N2O has no signi®cant haemodynamic eect in patients with normal pulmonary artery pressure. However, a striking additional increase in pulmonary vascular resistance has been recorded in patients with elevated pulmonary artery pressure due to mitral valve stenosis. This eect might be particularly dangerous in cases with associated right coronary artery disease,21 and is related to the sympathetic stimulation that is induced by N2O.20 The increase in pulmonary artery pressure that is observed during N2O inhalation is not a direct eect, but is a consequence of the noradrenaline release and pulmonary vascular resistance increase.20 There is also some evidence that this increase in pulmonary vascular resistance is not only due to an elevation in sympathetic tone but also to a reduction in pulmonary blood ¯ow, which is induced by abnormalities in the myocardial contraction rate.20 These side eects can be partially reduced by increasing the dose of opioids. After mitral valve surgery, 50% N2O was accompanied by a decrease in blood pressure and cardiac index, while pulmonary vascular resistance was increased. When N2O was discontinued, the blood pressure returned to normal within 3 min while more than 10 min were necessary for cardiac output and pulmonary artery pressure to return to normal. This suggests that the myocardial depression eect was the more important.22 In children with congenital heart diseases where increased pulmonary artery pressure (or vascular resistance) corresponds to anatomical insults of the vessels, Hickey et al23 showed that N2O produces no or few modi®cations to the pulmonary haemodynamics. There is no data on the eect of N2O in patients who have bene®ted from a surgical repair of congenital heart disease and who might undergo a modern anaesthetic regimen for a non-cardiac procedure. A summary of the eects of N2O on haemodynamics is reported in Table 2. Table 2. Haemodynamic eects of nitrous oxide. Parameter
Eect
Blood pressure Cardiac index Heart rate Systemic vascular resistance Pulmonary artery pressure Pulmonary vascular resistance Splanchnic blood ¯ow Renal blood ¯ow Cerebral blood ¯ow Cutaneous and muscular circulation
Decreased Decreased Unchanged Increased Unchanged or increased Unchanged or increased Decreased Decreased Increased Decreased
N2O use in cardiovascular risk patients 433
CLINICAL UTILIZATION OF N2O IN CARDIAC PATIENTS Use in non-cardiac surgery Although in 1972 the use of a 50% N2O±oxygen mixture was advocated for pain relief after myocardial infarction, since 1975 we know that this should no longer be recommended because of its deleterious eects on the coronary circulation.24 From various experimental studies, it has been found that N2O induces a depression in cardiac contractility that increases with increasing concentration. It is particularly true when coronary artery disease is expected. Clearly N2O delays the functional recovery of the myocardium after an ischaemic event.13 While not always necessary in anaesthesia practice, N2O induces an insidious risk of myocardial dysfunction that may not always be identi®ed by ECG.25 Thus, N2O is contra-indicated in patients with con®rmed or suspected coronary artery disease. In patients with chronic heart failure, myocardial contractility is impaired and N2O will exacerbate this dysfunction. In addition, in these patients, pulmonary artery pressure is generally high and the use of N2O is potentially dangerous. In valvular patients, alterations in myocardial contractility and modi®cations of the peripheral vascular resistance make the inhalation of N2O particularly deleterious. In conclusion, the use of N2O in cardiac patients undergoing non-cardiac procedures (surgical or not) cannot be recommended. Use in cardiac surgery Cardiac surgery patients generally have some heart disease and it has been described, above, that in these patients the use of N2O can be dangerous. In addition, most cardiac surgery procedures may be accompanied by an expected or unexpected ischaemic event, which is, of course, systematic if a cardiopulmonary bypass with cross clamping is used. Therefore, all of these data are against the use of N2O during cardiac surgery. Some more speci®c studies have shown that: . The risk of air emboli in the coronary arteries and also in the aorta22 may be increased. . After coronary bypass graft surgery, 50% N2O added to a fentanyl anaesthesia protocol signi®cantly alters the mean arterial pressure and cardiac index.26 . During and after mitral valve surgery, the addition of N2O to oxygen can be deleterious because of its side eects on the haemodynamics.22 In conclusion, the use of N2O in cardiac patients undergoing cardiac surgery cannot be recommended and should, perhaps, be contra-indicated. SUMMARY For several years, a trend towards reducing the cost of anaesthesia has been developing. Therefore the use of cheap agents such as nitrous oxide (N2O) has been advocated. N2O is not potent enough to be used as the sole anaesthetic; consequently, in addition to its wide range of use (30±70%), this agent is always given with other anaesthetics (opioids, volatile agents, benzodiazepines etc) in clinical practice. Adverse or side eects of N2O should be analysed in the context of this use. However, in cardiac patients (i.e. cardiac patients undergoing non-cardiac surgery as well as cardiac surgery patients), there is
434 J. Neidecker
Practice points . nitrous oxide (N2O) has a negative inotropic eect that is dose-dependent and is due to a direct eect on the myocardium . N2O increases the peripheral sympathetic tone (noradrenaline release) and an epicardial coronary vasoconstriction could create regional ischaemia . N2O delays the functional recovery of the ischaemic or stunned myocardium . N2O increases mortality by lethal arrhythymia in the presence of coronary stenosis . N2O, therefore, cannot be recommended in cardiac risk patients (for both cardiac and non-cardiac procedures)
Research agenda . an assessment of the cardiovascular eects of nitrous oxide (N2O) when given in combination with the more recently available anaesthetics, such as remifentanyl, sevo¯urane or des¯urane, needs to be performed . data are lacking on the myocardial and haemodynamic eects of N2O when given in patients with congenital heart defects both before and after surgical repair. This point might be of importance because of the increasing number of patients with congenital heart disease who bene®ted from a surgical repair in infancy. Some of these patients are now reaching adulthood and may need to undergo various surgical procedures (either cardiac or non-cardiac). No data are available in this ®eld and would be of great interest . another ®eld of research is the possibly additive eects of N2O when used in combination with drugs that modify myocardial function, such as beta-blockers, calcium channel inhibitors or ACE inhibitors clear evidence that N2O has deleterious eects on myocardial function and haemodynamics: in particular, it causes alterations in myocardial performance that aect both systolic and diastolic function, together with causing regional ischaemia. Recovery after an ischaemia that has been induced by N2O is delayed after withdrawal of the N2O. These impairments are enhanced by increased peripheral sympathetic tone (noradrenaline release) and they are dose-dependent. N2O inhalation can be extremely dangerous if there is pre-existing pulmonary artery hypertension. Consequently, its use cannot be recommended in cardiovascular risk patients. In addition, the possible occurrence of air emboli in patients is clearly a contra-indication to its inhalation during open-heart surgery procedures, particularly those requiring the use of a cardiopulmonary bypass. Data are lacking on the eects of N2O in patients with congenital heart disease. REFERENCES 1. Inada T, Shingu K, Nakao S & Nagata A. Eects of nitrous oxide on haemodynamics and electroencephalographic responses induced by titanic electrical stimulation during propofol anaesthesia. Anaesthesia 1999; 54: 423±426. 2. Jakobsson J, Heidvall M & Davidson S. The sevo¯urane-sparing eect of nitrous oxide a clinical study. Acta Anaesthesiologica Scandinavica 1999; 43: 411±414.
N2O use in cardiovascular risk patients 435 3. Elbert TJ. Dierential eects of nitrous oxide on barore¯ex control of heart rate and peripheral sympathetic nerve activity in humans. Anesthesiology 1990; 72: 16±22. 4. Maze M & Fujinaga M. Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia 2000; 55: 311±314. 5. Schobel HP, Ringkamp M & Behrmann A. Hemodynamic and sympathetic nerve response to painful stimuli in normotensive and boderline hypertensive sujects. Pain 1996; 66: 117±124. 6. Stowe DF, Monroe SM, Marijic J et al. Eects of nitrous oxide on contractile function and metabolism of the isolated heart. Anesthesiology 1990; 73: 1220±1226. 7. Philbin DM, Foex P, Drummond G et al. Postsystolic shortening of canine ventricle supplied by a stenotic coronary artery when nitrous oxide is added in the presence of narcotics. Anesthesiology 1985; 62: 166±174. 8. Ramsey JG, Arvieux CC, Foex P et al. Regional and global myocardial function in the dog when nitrous oxide is added to halothane in presence of critical coronary artery constriction. Anesthesia and Analgesia 1986; 65: 431±436. 9. Carton EG & Housmans PR. Role of transsarcolemmal Ca2 entry in the negative inotropic eect of nitrous oxide in isolated ferret myocardium. Anesthesia and Analgesia 1992; 74: 575±579. *10. Pagel PS, Kampine JP, Schmeling WT & Warltier DC. Eects of nitrous oxide on myocardial contractility as evaluated by the preload recruitable stroke work relationship in chronically instrumented dogs. Anesthesiology 1990; 73: 1148±1157. *11. Hohner P & Reiz S. Nitrous oxide and the cardiovascular system. Acta Anaesthesiologica Scandinavica 1994; 38: 763±766. *12. Marsch SCU, Dalmas S, Philbin DM et al. Eects and interactions of nitrous oxide, myocardial ischemia, and reperfusion on left ventricular diastolic function. Anesthesia and Analgesia 1997; 84: 39±45. *13. Siker D, Pagel PS, Pelc LR et al. Nitrous oxide impairs functional recovery of stunned myocardium in barbiturate-anesthetized, acutely instrumented dogs. Anesthesia and Analgesia 1992; 75: 539±548. *14. Mitchell MM, Prakash O, Rulf ENR et al. Nitrous oxide does not induce myocardial ischemia in patients with ischemic heart disease and poor ventricular function. Anesthesiology 1989; 71: 526±534. 15. Wilkowski DA, Sill JC, Bonta W et al. Nitrous oxide constricts epicardial coronary arteries without eects on coronary arterioles. Anesthesiology 1987; 66: 659±665. *16. Houltz E, Caidahl K, HellstroÈm AÊ et al. The eect of nitrous oxide on left ventricular systolic and diastolic performance before and after cardiopulmonary bypass: evaluation by computer-assisted twodimensional and Doppler echocardiography in patients undergoing coronary artery surgery. Anesthesia and Analgesia 1995; 81: 243±248. 17. Mot EA, Scovill JE, Barker RA et al. The eects of nitrous oxide on myocardial metabolism and hemodynamics during fentanyl or en¯urane anesthesia in patients with coronary disease. Anesthesiology 1984; 63: 1071±1075. 18. Hahn RG, Riddez L & Brismar B. Haemodynamics during inhalation of a 50% nitrous-oxide-in-oxygen mixture with and without hypovolaemia. Acta Anaesthesiologica Scandinavica 1997; 41: 485±491. 19. Sakabe T, Kuramoto T, Kumagae S et al. Cerebral responses to the addition of nitrous oxide to halothane in man. British Journal of Anaesthesia 1976; 48: 957±962. *20. Heerdt PM & Caldwell RW. The mechanism of nitrous oxide induced changes in pulmonary vascular resistance in a dog model of left atrial out¯ow obstruction. Journal of Cardiothoracic Anesthesia 1989; 5: 568±573. 21. Schulte-Sasse U, Hess W & Tarnow J. Pulmonary vascular responses to nitrous oxide in patients with normal and high pulmonary vascular resistance. Anesthesiology 1982; 57: 9±13. *22. Tempe D, Mohan JC, Cooper A et al. Myocardial depressant eect of nitrous oxide after valve surgery. European Journal of Anaesthesiology 1994; 11: 353±358. 23. Hickey PR, Hansen DD, Straord M et al. Pulmonary and systemic eects of nitrous oxide in infants with normal and elevated pulmonary vascular resistance. Anesthesiology 1986; 65: 374±378. 24. Kerr F, Ewing DJ & Irving BJ. Nitrous-oxide analgesia in myocardial infarction. Lancet 1972; 7741: 63±66. 25. Mott EA & Sethna DH. The coronary circulation and myocardial oxygenation in coronary disease: eect of anesthesia. Anesthesia and Analgesia 1986; 65: 395±410. 26. Colson P, Galy A, Grolleau D et al. Myocardial depressant eect of nitrous oxide after coronary artery bypass graft surgery. British Journal of Anaesthesia 1992; 68: 420±421.
doi:10.1053/bean.2001.0178, available online at http://www.idealibrary.com on
10 Nitrous oxide: use in cardiovascular risk patients Jean Neidecker Consultant Anaesthetist Service d'AnestheÂsie-ReÂanimation, HoÃpital Cardiovasculaire & Pneumologique L. Pradel, Boulevard Pinel, F-69394 Lyon, France
Nitrous oxide (N2O) has been used in clinical anaesthesia for more than 150 years. Its use is encouraged in combination with new anaesthetics to reduce the cost. Nevertheless there is some evidence to show that N2O impairs myocardial function: e.g. producing a decrease in myocardial contractility and abnormal coronary blood ¯ow. Regional myocardial ischaemia occurs and the recovery after N2O withdrawal is delayed. These dose-dependent eects are enhanced by an increase in sympathetic tone and by a direct eect on the myocardium (inhibition of trans-sarcolemmal calcium ion entry). Haemodynamic parameters are aected; namely a decreased blood pressure and cardiac index and an increase in systemic vascular resistance. Pulmonary circulation is dramatically aected if the pulmonary artery pressure is increased prior to N2O administration. Regional circulation is also modi®ed (decrease in splanchnic and renal blood ¯ow). Therefore the use of N2O cannot be recommended in patients with cardiovascular risk factors who are undergoing cardiac and/or non-cardiac procedures. Key words: nitrous oxide; anaesthesia; myocardial function; ischaemia; haemodynamics; cardiac patients; cardiac surgery; non-cardiac surgery.
Nitrous oxide (N2O) was introduced into anaesthesia more than 150 years ago. Since then it is, and remains, an essential agent in clinical anaesthesia because it has been shown that N2O decreases the amount needed for all other anaesthetics and, consequently, reduces the overall cost of anaesthesia.1,2 Whether N2O is safe or not when heart function is compromised is still questionable. N2O is rarely used as a single anaesthetic agent and in the inspired gas, its concentration can vary from 30±70%. Therefore it is often dicult to separate its eect on haemodynamics from those induced by other agents. CARDIOVASCULAR EFFECTS OF N2O Since 1975, N2O has been known to cause signi®cant depression of the heart and circulation especially in cardiac patients. Therefore several studies have been conducted to experimentally and/or clinically analyse the eects of N2O on the heart and haemodynamics. Sometimes their results are divergent and even controversial, probably because N2O does not, by itself, produce anaesthesia. Thus, these studies have to be 1521±6896/01/03042907 $35.00/00
c 2001 Harcourt Publishers Ltd. *
430 J. Neidecker
conducted using other agents (opioids, benzodiazepines, inhalational anaesthetics, etc) in combination with N2O. Therefore the mechanism (direct eect on the heart and/or the circulation) or side eects of the association with other agents, is still a matter for discussion. Eect on barore¯ex and sympathetic tone Ebert3 analysed the eect of N2O on barore¯ex control of heart rate in healthy volunteers. A mixture of 40% N2O with oxygen induced a stimulation of the sympathetic nerves directed to skeletal muscle and an increase in peripheral resistance was observed. At the same time there was no eect on the barore¯ex control of the heart rate. Since N2O had no direct eect on heart rate, an increase has to be related to either improper pain management to surgical stimuli or to a release in catecholamines.1,4,5 Myocardial function and coronary circulation N2O induces a decrease in myocardial contractility in a range that varies between 5 and 28% depending on the experimental model.6 Consequently all haemodynamic parameters are aected; however, some of these eects are counteracted by an increase in the sympathetic tone that is a consequence of the catecholamine release that is produced by N2O.4 Philbin et al7 showed, in dogs, that a contractile dysfunction appeared when N2O was added to an opioid-based anaesthesia. Similar ®ndings have been reported with halothane.8 Using working isolated heart preparations receiving 50% N2O in nitrogen, Carton and Housmans9 analysed the mechanism of negative inotropic eect as an inhibition of trans-sarcolemmal calcium ion entry. Using the peak rate of increase of left ventricular pressure (dP/dt) as an index of contractility, Pagel et al10 showed that a decrease in dP/dt occurred when N2O was added to sufentanil anaesthesia. This eect was more important when 70% N2O was used compared to 30%.10 This was con®rmed by a reduction in the percentage of segment shortening. Similar results have been reported when the baseline anaesthetic was halothane, iso¯urane or pentobarbital. An increase in sympathetic tone cannot be involved because this alteration in contractility is present when an autonomic nervous system blockade is given prior to N2O inhalation.10 N2O has a weak and dose-dependent direct myocardial depressant eect that may be balanced by sympathetic activation.11 By analysing the preload recruitable stroke work relationship, Pagel et al10 showed that N2O has direct negative inotropic eects that are independent of the autonomic nervous system tone. In normal dogs, 30% N2O produced an 8±17% decrease in contractile function, while it reached 28±41% if the concentration was 70%.10 However, other mechanisms are also involved in the myocardial eects of N2O, namely a small, consistent increase in chamber stiness, myocardial stiness and unstressed length, and a decrease in the peak lengthening rate.12 If the action of several anaesthetics on chamber stiness is controversial between studies, N2O is the ®rst anaesthetic that has been found to increase both myocardial stiness and unstressed length.12 Post-ischaemic myocardial recovery is impaired in the presence of 70% N2O when compared to 70% nitrogen or to other volatile halogenated agents.12,13 When 40% N2O was given, myocardial dysfunction occurred if blood was supplied via narrow coronary arteries.14 This may be due to a dierential eect of N2O on coronary vasculature: N2O produces an epicardial coronary vasoconstriction that dramatically decreases the distal blood supply to the myocardium in cases of coronary stenosis.15 N2O impairs the
N2O use in cardiovascular risk patients 431
functional recovery of ischaemic myocardium. Before and during coronary occlusion, N2O (70%) led to an increase in mortality by ventricular ®brillation when compared to 70% nitrogen.13 Myocardial ischaemia and re-perfusion are associated with an increased stiness in remote non-ischaemic myocardium, regardless of the anaesthetic used in combination with N2O.12 The mechanism of this depressed recovery of stunned myocardium is unknown. Increased sympathetic tone due to noradrenaline release during N2O may contribute to this process. These data have been con®rmed in patients with coronary disease without a new episode of ischaemia. A possible cause of the ischaemic events is a maldistribution of the transmural blood ¯ow, which is accompanied by some degree of systolic wall dysfunction.11 In an echocardiographic study, Houltz et al16 con®rmed that some segmental wall motion could occur while the global area ejection fraction was not modi®ed. In patients undergoing coronary bypass grafting, N2O did not modify segmental wall motion prior to cardiopulmonary bypass while abnormalities occurred after the bypass and possibly induced diastolic dysfunction.12,16 However, Mitchell et al14 showed that N2O did not create ST segment depression and regional wall motion abnormalities in a patient with impaired coronary circulation and impaired left ventricular function. Adding 50% N2O to an anaesthetic protocol induced a decrease in coronary blood ¯ow and coronary sinus oxygen content while coronary sinus lactate level was increased, indicating a switch towards an anaerobic energy metabolism.17 Globally, the myocardium was extracting more oxygen in spite of a decreased stroke work rate. This phenomenon has also been observed, with slightly dierent ranges, with both volatile anaesthetics (en¯urane and halothane) and opioids (fentanyl). A summary of the myocardial eects is given in Table 1. Finally, since N2O diuses more rapidly than nitrogen, an air bubble would tend to expand in the presence of N2O, particularly in coronary arteries and/or grafts.16 This could increase an unexpected ischaemia. Haemodynamics As a consequence of the eect of N2O on the myocardium, a decrease in cardiac output is recorded while systemic vascular resistance remains high when oxygen alone is compared with a mixture of 50% N2O in oxygen. Therefore regional circulation is also aected and a reduction in splanchnic and renal blood ¯ow is observed.18 Cutaneous and muscular blood ¯ow are decreased in proportion to the reduced cardiac output. During normocapnia, a cerebral vasodilation is induced by N2O and is accompanied by an increase in cerebral oxygen consumption, which is not
Table 1. Myocardial eect of nitrous oxide. Parameter
Eect
Contractility Ischaemia Global Regional Recovery after withdrawal dP/dt Coronary circulation
Decreased Unchanged Increased Delayed Decreased Epicardial vasoconstriction
432 J. Neidecker
proportional.19 Thus oxygen supply to peripheral organs may be impaired because of the reduction in cardiac output and the increase in systemic vascular resistance. In response to N2O administration, systemic vascular resistance and left ventricular end-diastolic volume increase. Both eects can be reversed by the administration of phentolamine, which con®rms the involvement of a sympathetic mechanism.20 Because of this increased sympathetic tone, splanchnic venous blood ¯ow might be increased and that would impair the haemodynamics, particularly if the patient was hypovolaemic.18 The transmitral ¯ow pro®le is altered as a result of ischaemic insults when N2O is given in the post-bypass period.16 N2O does not aect isovolumic relaxation. With regard to the pulmonary circulation, N2O has no signi®cant haemodynamic eect in patients with normal pulmonary artery pressure. However, a striking additional increase in pulmonary vascular resistance has been recorded in patients with elevated pulmonary artery pressure due to mitral valve stenosis. This eect might be particularly dangerous in cases with associated right coronary artery disease,21 and is related to the sympathetic stimulation that is induced by N2O.20 The increase in pulmonary artery pressure that is observed during N2O inhalation is not a direct eect, but is a consequence of the noradrenaline release and pulmonary vascular resistance increase.20 There is also some evidence that this increase in pulmonary vascular resistance is not only due to an elevation in sympathetic tone but also to a reduction in pulmonary blood ¯ow, which is induced by abnormalities in the myocardial contraction rate.20 These side eects can be partially reduced by increasing the dose of opioids. After mitral valve surgery, 50% N2O was accompanied by a decrease in blood pressure and cardiac index, while pulmonary vascular resistance was increased. When N2O was discontinued, the blood pressure returned to normal within 3 min while more than 10 min were necessary for cardiac output and pulmonary artery pressure to return to normal. This suggests that the myocardial depression eect was the more important.22 In children with congenital heart diseases where increased pulmonary artery pressure (or vascular resistance) corresponds to anatomical insults of the vessels, Hickey et al23 showed that N2O produces no or few modi®cations to the pulmonary haemodynamics. There is no data on the eect of N2O in patients who have bene®ted from a surgical repair of congenital heart disease and who might undergo a modern anaesthetic regimen for a non-cardiac procedure. A summary of the eects of N2O on haemodynamics is reported in Table 2. Table 2. Haemodynamic eects of nitrous oxide. Parameter
Eect
Blood pressure Cardiac index Heart rate Systemic vascular resistance Pulmonary artery pressure Pulmonary vascular resistance Splanchnic blood ¯ow Renal blood ¯ow Cerebral blood ¯ow Cutaneous and muscular circulation
Decreased Decreased Unchanged Increased Unchanged or increased Unchanged or increased Decreased Decreased Increased Decreased
N2O use in cardiovascular risk patients 433
CLINICAL UTILIZATION OF N2O IN CARDIAC PATIENTS Use in non-cardiac surgery Although in 1972 the use of a 50% N2O±oxygen mixture was advocated for pain relief after myocardial infarction, since 1975 we know that this should no longer be recommended because of its deleterious eects on the coronary circulation.24 From various experimental studies, it has been found that N2O induces a depression in cardiac contractility that increases with increasing concentration. It is particularly true when coronary artery disease is expected. Clearly N2O delays the functional recovery of the myocardium after an ischaemic event.13 While not always necessary in anaesthesia practice, N2O induces an insidious risk of myocardial dysfunction that may not always be identi®ed by ECG.25 Thus, N2O is contra-indicated in patients with con®rmed or suspected coronary artery disease. In patients with chronic heart failure, myocardial contractility is impaired and N2O will exacerbate this dysfunction. In addition, in these patients, pulmonary artery pressure is generally high and the use of N2O is potentially dangerous. In valvular patients, alterations in myocardial contractility and modi®cations of the peripheral vascular resistance make the inhalation of N2O particularly deleterious. In conclusion, the use of N2O in cardiac patients undergoing non-cardiac procedures (surgical or not) cannot be recommended. Use in cardiac surgery Cardiac surgery patients generally have some heart disease and it has been described, above, that in these patients the use of N2O can be dangerous. In addition, most cardiac surgery procedures may be accompanied by an expected or unexpected ischaemic event, which is, of course, systematic if a cardiopulmonary bypass with cross clamping is used. Therefore, all of these data are against the use of N2O during cardiac surgery. Some more speci®c studies have shown that: . The risk of air emboli in the coronary arteries and also in the aorta22 may be increased. . After coronary bypass graft surgery, 50% N2O added to a fentanyl anaesthesia protocol signi®cantly alters the mean arterial pressure and cardiac index.26 . During and after mitral valve surgery, the addition of N2O to oxygen can be deleterious because of its side eects on the haemodynamics.22 In conclusion, the use of N2O in cardiac patients undergoing cardiac surgery cannot be recommended and should, perhaps, be contra-indicated. SUMMARY For several years, a trend towards reducing the cost of anaesthesia has been developing. Therefore the use of cheap agents such as nitrous oxide (N2O) has been advocated. N2O is not potent enough to be used as the sole anaesthetic; consequently, in addition to its wide range of use (30±70%), this agent is always given with other anaesthetics (opioids, volatile agents, benzodiazepines etc) in clinical practice. Adverse or side eects of N2O should be analysed in the context of this use. However, in cardiac patients (i.e. cardiac patients undergoing non-cardiac surgery as well as cardiac surgery patients), there is
434 J. Neidecker
Practice points . nitrous oxide (N2O) has a negative inotropic eect that is dose-dependent and is due to a direct eect on the myocardium . N2O increases the peripheral sympathetic tone (noradrenaline release) and an epicardial coronary vasoconstriction could create regional ischaemia . N2O delays the functional recovery of the ischaemic or stunned myocardium . N2O increases mortality by lethal arrhythymia in the presence of coronary stenosis . N2O, therefore, cannot be recommended in cardiac risk patients (for both cardiac and non-cardiac procedures)
Research agenda . an assessment of the cardiovascular eects of nitrous oxide (N2O) when given in combination with the more recently available anaesthetics, such as remifentanyl, sevo¯urane or des¯urane, needs to be performed . data are lacking on the myocardial and haemodynamic eects of N2O when given in patients with congenital heart defects both before and after surgical repair. This point might be of importance because of the increasing number of patients with congenital heart disease who bene®ted from a surgical repair in infancy. Some of these patients are now reaching adulthood and may need to undergo various surgical procedures (either cardiac or non-cardiac). No data are available in this ®eld and would be of great interest . another ®eld of research is the possibly additive eects of N2O when used in combination with drugs that modify myocardial function, such as beta-blockers, calcium channel inhibitors or ACE inhibitors clear evidence that N2O has deleterious eects on myocardial function and haemodynamics: in particular, it causes alterations in myocardial performance that aect both systolic and diastolic function, together with causing regional ischaemia. Recovery after an ischaemia that has been induced by N2O is delayed after withdrawal of the N2O. These impairments are enhanced by increased peripheral sympathetic tone (noradrenaline release) and they are dose-dependent. N2O inhalation can be extremely dangerous if there is pre-existing pulmonary artery hypertension. Consequently, its use cannot be recommended in cardiovascular risk patients. In addition, the possible occurrence of air emboli in patients is clearly a contra-indication to its inhalation during open-heart surgery procedures, particularly those requiring the use of a cardiopulmonary bypass. Data are lacking on the eects of N2O in patients with congenital heart disease. REFERENCES 1. Inada T, Shingu K, Nakao S & Nagata A. Eects of nitrous oxide on haemodynamics and electroencephalographic responses induced by titanic electrical stimulation during propofol anaesthesia. Anaesthesia 1999; 54: 423±426. 2. Jakobsson J, Heidvall M & Davidson S. The sevo¯urane-sparing eect of nitrous oxide a clinical study. Acta Anaesthesiologica Scandinavica 1999; 43: 411±414.
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