Invited Comment 79
Nitrous Oxide - No Laughing Matter? L Brandt Depa rtmen t of Anaes thes iology. Joha nnes Gutenberg-Univers ity Medical School, Mainz. FB(;
N, O ha s a limited poten cy and requires suppleme nta tion with other anaesthe tics or narcotics in order to achieve a sta te of surgical anaesthes ia (because th e need for 0 ,supplementation limits the concentration that can be administe red). On th e othe r hand N,O may limit th e inspirat ory 0 2-con cen tration needed for complete saturation of haemoglobin . Also N,O shift s the oxygen dissociati on curve to the left, thus reducing O,- supply to tissu e. N2 0 may increas e intracrani al pressure by increasin g cere bra l blood flow. It also may decrea se methionine synthase activity by inactivating vita min BI " thus impairing DNA synt hes is in bon e marrow cells. Thi s may pr odu ce megaloblastic changes similar to those seen in untreat ed pernicious anaemia. Following chronical administration it may also lead to neurological disord er s simil ar to th e well known subac ute combined degen eratio n of the cord. The se seem e nough rea sons to agree with an Ame rican anaesthes iologist who ass umed that "if lIitrous oxide had to tak e th e hurdles ofth e FDA nouiadaus, it wouldn't ha ve the least cha nce ofreqist ration ". Dr. Eger, Anaesthes iologist at th e Univers ity of Californ ia states: "I believe that the risks of nitrous oxide outweigh the benefits and 1 pe rsona lly don't use nitrous oxide any more. " But th ere ar e othe r opinions as well. Joh n Nunn for exam ple holds an oppo sin g view: "Nitrous oxide is a supe rb anaesthetic ill th e run -of-the-mill surgical patient. It has some of th e most extra ordinary properti es of any anaesthetic known to us. In routine use you cannot detect any harm tha t results from nitro us oxide ana est hesia. A nd to withdraw lIitrous ox ide f rom use as all anaes thetic would be all ove rreaction. ..
But the list of side effects of N, O is not yet complete . In the pr esen ce of air-filled cav ities like pn eumothor ax, N, O may actually be contra indicated du e to its tende ncy to diffuse into such cavities , expa nding those th at are disten sible and incr easing th e pressure in those tha t are rigid . Thi s is of particular concern in patients undergoing cardiac
surg ery, which is as sociated with an increased incidence of air emboli and pneum othora x. N,O produces muscle rigidity, whi ch may imp air both s pontaneo us br eathin g and mech an ical ventilation of the lungs. Last not least, N, O ha s seve ra l und esirab le effects on the cardiovascular system that indeed may outwe igh its ben efits in cardiac patients.
1. It has been shown to depress myocardial con tractility and O,-supply to the myocardium es pecia lly in patients with cardiac dise ase and impaired ve ntricular function (3, 9). 2 . In patients with preexistin g pulmon ary hyperten sion , pulmonary vas cular resistanc e is further increa sed in the presence ofN, O (3) .
Due to a stimulating effect of N, O on th e sympat he tic nervous system a modest increa se in circulating catec holamines ca n be obs erved . This may be the rea son why th e cardiovas cular effects of N, O are sma ll and som ewhat inconsistent in normal subjects. In patients with cardiac diseas e, however, esp ecially in tho se with impaired ventricular function , haemodynamic changes may be more mark ed , thou gh not consis te nt. The depression of ca rdiac output is relati vely greater and is furth er enhance d by the rise in systemic and pulmon ary vasc ular resistance . Significa nt degr ees of hypotension may result, possibly requi rin g a reduction of the Fe"2o or eve n its discontinu ation . Combination of N2 0 with othe r drugs which by the mse lves have no effect on myoca rdial contr actility, such as ben zodi azepin es , narcotic an algesics (3) , or both, su pports th e evide nce of cardiovasc ula r effects of N2 0 . The deg ree of hypoten sion may be somewhat gre ate r than with N, Oalone indi cating a n int erferenc e of the i. v. drugs with th e sympath om imeti c properties of N, O. A combination of N, O with volatile anaes the tics may impair myocardi al oxygen balan ce as well, as demonstrated by Moffi tt and cowo rkers for hal oth an e in 19 83 (7) and for enfluran e in 1984 (8). But there are also several investigations showi ng almos t no untoward effect of NzO on haemodynamic s , eve n in cardiovascular risk patients : - Dottori and coworkers stat ed in 197 6 that N, O did not exert any neg ative effects on the myocardium (2) . - Lilleaasen and coworkers found neith er any decrea se in left ventricular performance nor deterioration of Oj-supply to the myocardium with 50% N, O in O2 (4). - Mer et oj a and coworkers report ed a decreas e of C. l. and LVSWI in patients with left vent ricular wall hypokinesia and EF < 55%, but also a marked reduction in myocardial O, -consumption, wh en 70 % N, O was administered (5) .
Thorac. cardiovasc. Surgn 38 (19901 79 - 80 © Georg Thieme Verlag Stuttga rt · New York
Heceived for Publicati on : Februa ry 5, 1()YO
Downloaded by: University of British Columbia. Copyrighted material.
Nitro us Oxide (N,O) is the oldest and most widely used an aesth etic age nt and the only "class ical" substa nce to maintain its position in modern balanced anaes thes ia. For many anaesthes iologists it is as unrenouncable in ge ne ral anaesthes ia as is 0 , . But ca n it really still be cons ide re d the "inert" subst ance th at it see me d to be for decad es? A revie w of th e literature shows that within the last yea rs a number of features became apparent that may put the universal administra tion of N, O in question . Once again , A dams and his cowo rkers raise this questio n in th eir pap er (1) .
Thom e. eardiolluse. Surgn.18 (1990)
- Michaels. Kay and Barash denounced a cardioselective depressant effect of N,O (6). What conclusions may be dr awn from these controversial findings? To withd raw N,O from clinical use? Certa inly not. In spite of its side elTects - which drug has none? - it is still one ofthe sa fest anaes thet ics and it indeed has stood the test of time. Furthe rmore there is no altern ative an aesthetic in near sight to replace N,O, with all its advantages . However, in cardiac surgery it must be und erstood th at N, Omay alTect the ca rdiovascular system especially in the high-ri sk patient and that such elTects may dictate its disconti nuation. Usually the ha emod ynami c variables return to the pr e-Njt) state within a few minut es because N,O is elimina ted through the lungs rap idly. In conclusion, although N, O is no longer a laughin g matt er , it really would be an overreaction to dispar age it, because none of the quoted patho logical findings has any proven bearing on clinical outcome.
I,. Brandt J
4
5
b
7
Il
'J
Referen ces 1
2
Adams. II. A . D. Klino. J. Boldt. F. Dapper. and G. Hempelmann: Effects of nitrou s oxide on end ocrine stress res ponse and haem odynamic parameters duri ng coro na ry artery surge ry. Thoracic cardiovasc. Surgn 38 (1990) 73 - 78 Douori. 0 .. M. Korsqren , B. A. Lijj. and L. Wilhelmsen: The hae modyna mic effects of unsupplemen ted nitrous oxide-oxygenrelaxant anaesthes ia in cardiac pati ents. Acta Anaesth. Scand. 20 (1976) 195- 200
Lappas. D. G.. M. 1. Buckley. M. B. Laver. W. M. Daggett. and E. Lowenstein: Left ventric ular performa nce and pulm onary circulation following addit ion of nitrou s oxide to mor phin e during corona ry-artery surgery. Anest hes iology 43 (1975 ) 61-69 Lilleaasen. P.. B. Semb. H. Lindbe rg. K. Hatt eland, S. Ottesen. and S. S imonsen: Haemodynamic cha nges with the administrat ion ofn itr ous oxide during coro na ry artery su rge ry. Acta Anaesth . Sca nd. 25 (198 1) 533-537 Meretoj a. 0. A.. O. Takkunen. I/. lI eikk ilii. and U. Wegelius : Haemodynamic response to nitrous oxide duri ng high-dos e fentan yl pancuro niu m anaesthesia . Acta Anae sthesio!. Scand . 29 (1985) 137-1 41 Michaels. I.. H. Kay. and P. Barash: Docs nitrous oxide or a redu ced FJ02 alter hemodynamic fun tion duri ng high dose fenta nyl anae sthesia? Anest hesiology 57 (1982) A44 Moffitt . E. A.. D. 1l. Sethna. R. 1. Gary. M. J. Raymond. J. M.MatlofJ, and 1. A. Bussell: Nitrous oxide added to ha lotha ne reduces coro nary blood now and myocardial oxygen cons umption in patient s with corona ry disease. Can. Anaesth . Soc. J. 30 (1983 )5-9 Moffi tt . E. A., J. E. S covil. R. A Barker. D. D. Imri e. 1. 1. Glenn. C.L. Cousins. J. A Sullivan. and E. Kinl ey: The effects of nitrous oxide on myocardial metaboli sm and hemody na mics duri ng fentanyl or enflurane ane sthesi a in patien ts with coro na ry disease. Anesth . Analg. 63 (1984 ) ) -5 Philbin , D. M.. P. Foex, E. Lowenstein. W. A Ry der. and L. A. Jone s: Nitrou s oxide cau ses myocardial dysfunction . Anest hesio logy 59 (198 31A80
Prof Dr. 1.. Brandt
Abteilung filr Anasthes iologie Johannes Gutenbe rg Univers itat 0 -6500 Mainz/ FRG
Downloaded by: University of British Columbia. Copyrighted material.
SO
Nitrous Oxide - No Laughing Matter? L Brandt Depa rtmen t of Anaes thes iology. Joha nnes Gutenberg-Univers ity Medical School, Mainz. FB(;
N, O ha s a limited poten cy and requires suppleme nta tion with other anaesthe tics or narcotics in order to achieve a sta te of surgical anaesthes ia (because th e need for 0 ,supplementation limits the concentration that can be administe red). On th e othe r hand N,O may limit th e inspirat ory 0 2-con cen tration needed for complete saturation of haemoglobin . Also N,O shift s the oxygen dissociati on curve to the left, thus reducing O,- supply to tissu e. N2 0 may increas e intracrani al pressure by increasin g cere bra l blood flow. It also may decrea se methionine synthase activity by inactivating vita min BI " thus impairing DNA synt hes is in bon e marrow cells. Thi s may pr odu ce megaloblastic changes similar to those seen in untreat ed pernicious anaemia. Following chronical administration it may also lead to neurological disord er s simil ar to th e well known subac ute combined degen eratio n of the cord. The se seem e nough rea sons to agree with an Ame rican anaesthes iologist who ass umed that "if lIitrous oxide had to tak e th e hurdles ofth e FDA nouiadaus, it wouldn't ha ve the least cha nce ofreqist ration ". Dr. Eger, Anaesthes iologist at th e Univers ity of Californ ia states: "I believe that the risks of nitrous oxide outweigh the benefits and 1 pe rsona lly don't use nitrous oxide any more. " But th ere ar e othe r opinions as well. Joh n Nunn for exam ple holds an oppo sin g view: "Nitrous oxide is a supe rb anaesthetic ill th e run -of-the-mill surgical patient. It has some of th e most extra ordinary properti es of any anaesthetic known to us. In routine use you cannot detect any harm tha t results from nitro us oxide ana est hesia. A nd to withdraw lIitrous ox ide f rom use as all anaes thetic would be all ove rreaction. ..
But the list of side effects of N, O is not yet complete . In the pr esen ce of air-filled cav ities like pn eumothor ax, N, O may actually be contra indicated du e to its tende ncy to diffuse into such cavities , expa nding those th at are disten sible and incr easing th e pressure in those tha t are rigid . Thi s is of particular concern in patients undergoing cardiac
surg ery, which is as sociated with an increased incidence of air emboli and pneum othora x. N,O produces muscle rigidity, whi ch may imp air both s pontaneo us br eathin g and mech an ical ventilation of the lungs. Last not least, N, O ha s seve ra l und esirab le effects on the cardiovascular system that indeed may outwe igh its ben efits in cardiac patients.
1. It has been shown to depress myocardial con tractility and O,-supply to the myocardium es pecia lly in patients with cardiac dise ase and impaired ve ntricular function (3, 9). 2 . In patients with preexistin g pulmon ary hyperten sion , pulmonary vas cular resistanc e is further increa sed in the presence ofN, O (3) .
Due to a stimulating effect of N, O on th e sympat he tic nervous system a modest increa se in circulating catec holamines ca n be obs erved . This may be the rea son why th e cardiovas cular effects of N, O are sma ll and som ewhat inconsistent in normal subjects. In patients with cardiac diseas e, however, esp ecially in tho se with impaired ventricular function , haemodynamic changes may be more mark ed , thou gh not consis te nt. The depression of ca rdiac output is relati vely greater and is furth er enhance d by the rise in systemic and pulmon ary vasc ular resistance . Significa nt degr ees of hypotension may result, possibly requi rin g a reduction of the Fe"2o or eve n its discontinu ation . Combination of N2 0 with othe r drugs which by the mse lves have no effect on myoca rdial contr actility, such as ben zodi azepin es , narcotic an algesics (3) , or both, su pports th e evide nce of cardiovasc ula r effects of N2 0 . The deg ree of hypoten sion may be somewhat gre ate r than with N, Oalone indi cating a n int erferenc e of the i. v. drugs with th e sympath om imeti c properties of N, O. A combination of N, O with volatile anaes the tics may impair myocardi al oxygen balan ce as well, as demonstrated by Moffi tt and cowo rkers for hal oth an e in 19 83 (7) and for enfluran e in 1984 (8). But there are also several investigations showi ng almos t no untoward effect of NzO on haemodynamic s , eve n in cardiovascular risk patients : - Dottori and coworkers stat ed in 197 6 that N, O did not exert any neg ative effects on the myocardium (2) . - Lilleaasen and coworkers found neith er any decrea se in left ventricular performance nor deterioration of Oj-supply to the myocardium with 50% N, O in O2 (4). - Mer et oj a and coworkers report ed a decreas e of C. l. and LVSWI in patients with left vent ricular wall hypokinesia and EF < 55%, but also a marked reduction in myocardial O, -consumption, wh en 70 % N, O was administered (5) .
Thorac. cardiovasc. Surgn 38 (19901 79 - 80 © Georg Thieme Verlag Stuttga rt · New York
Heceived for Publicati on : Februa ry 5, 1()YO
Downloaded by: University of British Columbia. Copyrighted material.
Nitro us Oxide (N,O) is the oldest and most widely used an aesth etic age nt and the only "class ical" substa nce to maintain its position in modern balanced anaes thes ia. For many anaesthes iologists it is as unrenouncable in ge ne ral anaesthes ia as is 0 , . But ca n it really still be cons ide re d the "inert" subst ance th at it see me d to be for decad es? A revie w of th e literature shows that within the last yea rs a number of features became apparent that may put the universal administra tion of N, O in question . Once again , A dams and his cowo rkers raise this questio n in th eir pap er (1) .
Thom e. eardiolluse. Surgn.18 (1990)
- Michaels. Kay and Barash denounced a cardioselective depressant effect of N,O (6). What conclusions may be dr awn from these controversial findings? To withd raw N,O from clinical use? Certa inly not. In spite of its side elTects - which drug has none? - it is still one ofthe sa fest anaes thet ics and it indeed has stood the test of time. Furthe rmore there is no altern ative an aesthetic in near sight to replace N,O, with all its advantages . However, in cardiac surgery it must be und erstood th at N, Omay alTect the ca rdiovascular system especially in the high-ri sk patient and that such elTects may dictate its disconti nuation. Usually the ha emod ynami c variables return to the pr e-Njt) state within a few minut es because N,O is elimina ted through the lungs rap idly. In conclusion, although N, O is no longer a laughin g matt er , it really would be an overreaction to dispar age it, because none of the quoted patho logical findings has any proven bearing on clinical outcome.
I,. Brandt J
4
5
b
7
Il
'J
Referen ces 1
2
Adams. II. A . D. Klino. J. Boldt. F. Dapper. and G. Hempelmann: Effects of nitrou s oxide on end ocrine stress res ponse and haem odynamic parameters duri ng coro na ry artery surge ry. Thoracic cardiovasc. Surgn 38 (1990) 73 - 78 Douori. 0 .. M. Korsqren , B. A. Lijj. and L. Wilhelmsen: The hae modyna mic effects of unsupplemen ted nitrous oxide-oxygenrelaxant anaesthes ia in cardiac pati ents. Acta Anaesth. Scand. 20 (1976) 195- 200
Lappas. D. G.. M. 1. Buckley. M. B. Laver. W. M. Daggett. and E. Lowenstein: Left ventric ular performa nce and pulm onary circulation following addit ion of nitrou s oxide to mor phin e during corona ry-artery surgery. Anest hes iology 43 (1975 ) 61-69 Lilleaasen. P.. B. Semb. H. Lindbe rg. K. Hatt eland, S. Ottesen. and S. S imonsen: Haemodynamic cha nges with the administrat ion ofn itr ous oxide during coro na ry artery su rge ry. Acta Anaesth . Sca nd. 25 (198 1) 533-537 Meretoj a. 0. A.. O. Takkunen. I/. lI eikk ilii. and U. Wegelius : Haemodynamic response to nitrous oxide duri ng high-dos e fentan yl pancuro niu m anaesthesia . Acta Anae sthesio!. Scand . 29 (1985) 137-1 41 Michaels. I.. H. Kay. and P. Barash: Docs nitrous oxide or a redu ced FJ02 alter hemodynamic fun tion duri ng high dose fenta nyl anae sthesia? Anest hesiology 57 (1982) A44 Moffitt . E. A.. D. 1l. Sethna. R. 1. Gary. M. J. Raymond. J. M.MatlofJ, and 1. A. Bussell: Nitrous oxide added to ha lotha ne reduces coro nary blood now and myocardial oxygen cons umption in patient s with corona ry disease. Can. Anaesth . Soc. J. 30 (1983 )5-9 Moffi tt . E. A., J. E. S covil. R. A Barker. D. D. Imri e. 1. 1. Glenn. C.L. Cousins. J. A Sullivan. and E. Kinl ey: The effects of nitrous oxide on myocardial metaboli sm and hemody na mics duri ng fentanyl or enflurane ane sthesi a in patien ts with coro na ry disease. Anesth . Analg. 63 (1984 ) ) -5 Philbin , D. M.. P. Foex, E. Lowenstein. W. A Ry der. and L. A. Jone s: Nitrou s oxide cau ses myocardial dysfunction . Anest hesio logy 59 (198 31A80
Prof Dr. 1.. Brandt
Abteilung filr Anasthes iologie Johannes Gutenbe rg Univers itat 0 -6500 Mainz/ FRG
Downloaded by: University of British Columbia. Copyrighted material.
SO
