Of the many inhalation drugs available today, nitrous oxide is the only one which is both non-explosive and non-toxic. Although the compound is rarely listed as a primary agent, it is used on almost every patient. The usefulness of nitrous oxide tends to be dismissed because it is considered to be relatively weak. However, with the continuing trend toward lighter anesthesia seen during the past quarter century, this viewpoint is no longer reasonable. The fact that MAC for halothane can be reduced to one third by the addition of 70% nitrous oxide attests to the drug\u27s potency

Keenan, Richard L.

VCU Scholars Compass

Nitrous Oxide-Curare Anesthesia: Reappraisal* RICHARD L. KEENAN, M. D. Chairman, Department of Anesthesiology, The Roosevelt Hospital , New York , New York Of the many inhal ation drugs available today, nitrous ox ide is the only one which is both non-ex plosive and non-tox ic. Although the compound is rarely listed as a primary agent , it is used on almost every patient. The usefulness of nitrous oxide tends to be dismissed because it is considered to be rela-tively weak. However, with the continuing trend toward lighter anesthesia see n during the past qu ar-ter century, this viewpoint is no longer reasonable. The fac t th at MA C for haloth ane can be reduced to one third by the addition of 70 % nitrous oxide attests to the drug's potency. The ex perience of many prac ticing anesthetists throughout the United States indicates that anesthetic administration currently is more striking in its simi-lar ities than in its differences. It may even be said that a universal modern anesthetic sequence has evolved ( fig . I ) . First, almost eve ryone uses thio-MOD ERN ANESTH ETI C SEQUENCE I . T HIOPENTAL INDUCTION 2. N ITROUS OXIDE J. MUSCLE RELAXANT 4. (ADJUNCT I VE AGENT) Fig. I- Modern anes theti c seq uence. pental or some other barbiturate for induction , as a soc ial necess ity. Second , nit rous ox ide in a concen-tration of 50% to 70% is invariably empl oyed dur-ing the mai ntenance phase of anesthesia. Third, a muscle rel axant is use·d in most major cases, both to facilitate intubation and to produce surgical rel axa-tion. Deep anes thesia is almost never relied upon. Finally, some other drug, perhaps halothane, ether, * Prese nted at th e 25th Annu a l Stoneburner Lecture Series, February 26 , 1972 , a t the Med ica l Co llege o f Vir-ginia, Richmond. 142 or Innovar may be adopted-in conjunction with nitrous oxide-for the maintenance of anesthesia. According to tradition this is called the primary agent. But with the aforementioned trend toward very light anesthesia, more often than not, this agent is adjunctive in nature. In fact, in some instances, an adjunctive drug is not used at all . In the I 950's the British developed a technique in which very large doses of curare were used in combination with nothing more than nitrous oxide to produce the condition of anesthesia. No other adjunctive drug was used for maintenance. In this way, explosive agents were avoided. The process became known as the "Liverpool Technique" (Ged-des and Gray, 1959). Part and parcel of the Liver-pool Technique was the intentional production of respiratory alkalosis by hyperventilation. It was felt that alkalosis increased the depth of anesthesia. In recent years, however, the depressant effects of this condition have been questioned and, indeed, alka-losis itself has been shown to be not without its hazards. During the past four years, we at Roosevelt Hospital have been increasingly interested in avoid-ing not only explosives but also potentially toxic agents. We have adopted essentially the Liverpool Technique (that is , nitrous oxide without supple-mentation, and curare) and modified it in two major aspects: we have employed normal ventilation, and we have modified the curare dosage. To date this technique has been applied to approximately 3,200 patients. Technique. Figure 2 is a step-by-step descrip-tion of the technique as we have employed it. Pre-medication has been variable, but we prefer a narcotic in the usual clinical doses. Thiopental is used for the induction of anesthesia in a dosage sufficient to abolish the lid reflex. One hundred per-cent oxygen is administered by mask for about two minutes, e ither prior to or immediately after the thiopental, and then after intravenous succinyl-M CV QUARTERLY 8(2): 14 2,147 , 197 2 KEENAN: NITROUS OXIDE-CURARE ANESTHESIA: REAPPRAISAL 143 }. PREMEDICATION : NARCOTIC PREFERRED 2. THIOPENTAL, 4-8 mg / kg 3. o, 100' '0 2 MIN. 4. SUCCINYLCHOLINE I mg / kg 5. INTUBATION 6. N ,O 3.5 L. O, 1.5 L. 7. VENTILATOR, MV = 90 ml / kg 8. CURARE: BY DOSAGE SCHEDULE 9. REVERSAL: NEOST IGMINE 2.5 mg ATROP INE 1.0 mg I 0. DEC,SION TO EXTUBA TE Fig. 2-Rooseve lt Hospital's adapta tion of the Live rpoo l Tech nique. choline, endotracheal intubation is carried out. Im-mediately after intubation, nit rous ox ide 3.5 liters and oxygen 1.5 liters are allowed to fl ow into the par-tial rebreathing ci rcle system. This fl ow is then main-tained throughout the remainder of the operation . A mechanical ventil ator is employed in all instances promptly after intubation. The ventil ator is set to deliver a calculated minute volume of 90 ml per kg. A relatively slow respiratory rate , approx im ately 8 to 10 per minute, with a relatively large tidal volume is preferred. The minute volume is routinely checked with a Wright vent ilometer. With signs of returning muscle power following succinylcholine, curare is ad-ministered by a dosage schedule described in figure 5. Full curarization is maintained th roughout the pro-cedure. At the termination of the surgical procedure, reversal of curare is accomplished with the use of neost igmine 2.5 mg and a tropine l mg given simultaneously intrave nously and repeated once if necessary. Finally, a decision to extubate is made by clinical means. If the patient is capable of cough-ing vigorously on the endot racheal tube and of usi ng his upper intercostal muscles to take a deep breath, and can lift his head off the table, the endot racheal tube is removed. If not, the patient is taken to the recovery room where mechanical ventilat ion is con-tinued until full motor power returns spontaneously. It should be noted that the above desc ription of the nitrous ox ide-curare technique contai ns nothing really extraordinary. Mechanical ventil ation perh aps is not commonly employed , but it is generally ac-cepted in modern anesthesia. Everything else on the list is very much a part of standard practice every day everywhere th roughout the United States. In-deed, this sequence is really an example of the basic structure on which an anesthetic in this day and age is often built. What is surpri si ng about the list, therefore, is not what is on it but what is missing from it. Note that there is no ad junctive drug listed. Or to use the more traditional terminology, there is no prim ary age nt. Once the nit rous oxide is begun and the cura re is given, no other agent is admin-istered , ei ther int ravenously or by inhalation. Nitrous oxide is relied upon totally to produce unconsc ious-ness, and curare is relied upon totally to keep the patient on the table. Memory. The most significant question about this technique is whether 70% nitrous oxide by itself is enough to produce unconsc iousness reli ably in all patients. The only way to answe r thi s is with the evidence of extensive ex perience . As mentioned earlier, we have used this technique fairly widely in all age groups on approxim ately 3,200 adult patients and in all types of surgery with the excep-tion of intrathoracic procedures. Approximately two thirds of the cases were intra-abdominal. The tech-nique has been used in operations ranging from one hour in length to well in excess of 6 hours, with an average of th ree hours, and it has been adopted for patients representing all grades of ASA physical status from I to 5, although the majori ty were either 2 or 3. As of this date , we know of no pat ient of the 3,200 who were ac tually receiving 70% nitrous ox ide, who had any pain or any other conscious memory of the surgical procedure. We did have five pat ients who remembered certain things due to a break in technique. Four of the five remembered either intubation or extuba-tion. As a result , we have begun to use liberal amounts of induction thiopental and to continue nit rous oxide up to the moment of curare reversal. In one patient, a bri ef period of memory did occur during the operation. This patient remembered severe pai n and a conversation which we knew did occ ur. On further investigation, howeve r, we found that just before the period of memory the anes-thetist had disconnected the endotracheal tube for suctioning for approximate ly 20 seconds. During this time the ventil ator continued to operate . It emptied itself of nitrous oxide and drew air into the system through the open connector. For the next several minutes the patient received air instead of nitrous oxide. We conclude that nitrous oxide in a concentra-tion of 70%, does prevent memory totally and in all patients. However, the slightest break in technique 144 KEENAN: NITROUS OXIDE-CURARE ANESTHESIA: REAPPRAISAL can result in memory and must be gua rded against continuously. Ventilation. A mechanical ventil ator has been utili zed in all cases in our experience. In addition, a Wright ventilometer is routinely used to verify the presence of proper minute volume. We have selected a figure of 90 ml per kg body weight fo r est imation of the minute volume on the bas is of prior experience, both in the operating room and in our respirato ry intensive care unit where a rteri al blood gas analysis revealed a PaC0 2 of between 35 and 45 mm H g in most patients. This fact has also been documented in a study independent from ours (Ocbo and T erry, 1969) . Our real conce rn , however, was whether, with normocapnea, adequate a rterial P02 levels could be reliably p roduced. We fo und in our early stud ies on healthy patients undergoing abdominal surgery, that PO/s in excess of I 00 mm Hg were produced rou-tinely. However, in an attempt to look at the worst poss ible c ircum stance, we also studied 16 patients unde rgoing abdomin al ao rti c graft procedures with 70% N20-cura re anesthes ia. Serial blood gas deter-minations during surgery yielded the results li sted in figure 3. In no case was the P02 eve r below 60 Abdomina l Ao rt ic Grafts Mean Age 68 - 7 (S.D.) ASA Sta tus 2 - 4 Lowest PaO, N umber Under 60 0 60 - 69 4 70 - 79 6 80 - 89 90 - 99 3 100 + 2 Total 16 Fig. 3- Serial blood gas de term inat ions during surge ry with N :O·curare anesthesia. mm Hg, and in 12 of the 16, the lowest P02 recorded was above 70 mm Hg. While this does not indicate lush oxyge nation, these P02 va lues p roba bl y do represe nt th e no rm al levels fo r this age group. The average PC0 2 in this se ri es was 38 mm Hg. It is worth repea ting that a ve ry slow ventil ato ry rate, 8 to IO per minute with a rela ti ve ly high tida l volume, was employed. It has bee n our ex perience that this venti -30 20 20 NUMBER OF 15 PATIENTS 10 .26-.30 .31 - .35 .36 - .40 '.41- ... 5 .46-.50 .51-.55 .56 - .60 INI TIAL CU RARE , mc;i /k9 Fig. 4-Graph showing study o f cu rare dosage necessary to prod uce para lys is. latory pattern yields consistently higher P02 values than a rapid , shall ow pattern . We conclude that with normocapnea, adequate oxygenation can be produced, so long as the ventila-tory pattern is p roper, and so long as patients with severe int rapulmonary shunt ing, such as occurs in intra tho rac ic surgery, are avoided. Curare Dosage. Traditionally, a clinically effec-ti ve single dose of cura re is sa id to be in the range of 0.5 to 0.6 mgm per kg body weight. In a se ries of I 00 cases of patients undergoing elective surgery with thiopental-N20-0 , anesthes ia , we found that a dose of 0.3 mg per kg produced a clinically adequate degree of paralys is in about half the patients, as seen in figure 4 . F rom this expe rience we developed the curare dosage schedule outlined in figure 5 . A dose of curare is calculated on the bas is of 0.3 mg per kg and is ad-mini stered to each patient. If this is not suffic ient to CU RAR E DOSAGE SCH ED U LE J. IN IT IAL a) 0.3 mg / kg b) IF INSUF FIC IENT. I ml INCREMENTS 2. SUBSEQUENT DOSES a) G IVEN rj 20- 40 MIN b) EACH DOSE = /; PREVIOUS DOSE Fig. 5- 0 utl ine o f curare dosage sc hed ul e. KEENAN: NITROUS OXIDE -CURARE ANESTHESIA : REAPPRAISAL 145 24 CURARE, mQ 12 TIME, HOURS Fig. 6- Dosage schedule of cura re adm ini st ratio n. abolish all coughing and respiratory ac tivity , add i-tional curare is administered in I ml (3 mgm) incre-ments until all gross motor ac tivity ceases. The total amount of curare is noted at this point, and becomes the basis for a ll subsequent doses. Each subsequent dose needs be only one half its previous dose , and it is required eve ry 20 to 40 minutes when signs of returning muscle activity occ ur. When a dose of 3 mgm is reached, it is repeated , without halving, as necessary. An example of a dosage schedule in a typical case is shown in figure 6. Using this dosage schedule, we have been able to 1.7 1.5 1.3 I.I TOTAL CURARE m9/k9 .9 .7 .5 .3 . I Y• .37+ . 002 X R• ,667 "• 100 . . . .. . . . . .. . . . • • ~ • • • I . . .. . .. .. . ... . . .... ::,·: . :• 60 120 180 240 300 360 ANESTHESIA TIME, MINUTES Fig. 7-Graph showing total curare dose as measured against duration of anesthesia in I 00 cases. reliably produce adequate continuous curarization with reasonable total curare doses. Figure 7 is a plot of the total curare dose in one hundred consecutive cases aga inst the total duration of anesthesia . Total dose was clearly related to time. More important , the average dose was approximately 0.7 mg per kg which, for the average patient , represents a total of 50 mgm curare during a 3-hour anesthetic. This compares very favorably with the ex perience of the British . Blood Pressure Changes. Significant hypoten-sion incident to the ad mini stration of clinical doses of curare has been reported (Thomas, 1957). Tn our ex perience, however, this has not been a problem. Figure 8 is a compilation of the lowest and highest blood pressures noted in I 00 patients, as measured by the cuff method, during the twenty minutes fol-lowing the initi al curare dose. While some patients responded with very low-and some with very high - blood pressures, the majority showed only mild changes, and no definite trend of clinical significance could be discerned. Figure 9 is a plot of the degree of hypotension seen in those 55 patients in the series who suffered a fa ll in pressure, versus the dosage in each case. We could discern no dose-response relationship . We con-clude that while curare has been reported by others to cause hypotension it does not do so to a clinically significant degree in the dosage range employed in this se ries. Curare Reversal. Early in our experience we noted an occasional patient who was unable to main-tain adequate spontaneous ventil ation following the ad ministrat ion of neostigmine, even though these patients had not received excessive doses of curare . This was surpri sing in view of the well-documented fact that neostigmine is a highly predictable antago-nist for cu ra re (Bridenbaugh and Churchill-David-son, 1968; Katz, 1967) . However, review of these cases disclosed the fac t that many had received intraperitoneal antibio tics of the type known to pro-duce mu scle paralysis ( Pittinger, et al .. 1970) , and all the others had been eith er hypothermic or hypo-volemic a t the time of attempted curare reversal. These factors have been shown to delay significantly the redistribution of curare (Dal Santo, 1964 ) . Fol-lowing this discovery we instituted the practice of omitting neostigmine reversal in those patients who had received intraperitoneal antibiotics, who were hypoth ermic, or in whom a hypoperfu sion state was judged to be present. The endotracheal tube was left 146 KEENAN : NITROUS OXIDE-CURARE ANESTHESIA : REAPPRAISAL 30 NUMBER 20 OF PATIENTS 10 70 60 50 40 30 20 10 10 20 30 40 50 60 70+ FALL, mm Hg RISE, mm Hg SYSTOLIC BLOOD PRESSURE, CHANGE FROM PRE-INDUCTION VALUE Fig. 8-Blood pressure readi ngs of 100 patients fo ll owing induct ion of cura re. in place, and muscle powe r was allowed to return spontaneously while the pati ent was ventil ated me-chanically in the recovery room. After the institution of this prac tice, experience in 100 consecutive pa-ti ents was reviewed and is summarized in fi gure I 0. Eighteen patients were intentionally not reve rsed ; of these, six had unde rgone procedures, such as ab-domin al aortic grafts, in which pos to perative me-chanica l ventilation is utili zed in our institution as 70 - . . • . . ~~lJi~~i 50 L •• . Foll , mm H9 .... . .. 30 . ... . . . , . --• • . 10 ..... .,...,._ --• • 30 ,40 .50 .60 INITIAL CURARE, m9/kg Fig. 9-Graph showi ng degrees o f hypote nsion in pat ient s as measured aga in st ind ivid ua l c urare do sage. a matter of course. H ypoperfusion , hypothermi a, the use of intraperitoneal antibiotics, or a combination of these, were present in all other instances. Of the 82 cases in which neostigmine was em-ployed, only one fa iled to develop adequate spon-taneous ventil ation, and in this one case, severe hypovolemia from unrecognized surgical blood loss was noted sho rtly the reafter; spontaneous ventilation returned with the transfusion of two units of whole blood. We conclude that neostigmine is indeed a predictable antagonist for curare so long as the pa-thologic conditions noted above a re excluded . Conclusions . 1. Seventy percent N20 , as a sole depressant agent , is adequate to prevent pa in -and mem-ory in 100% of cases. There is no evidence CU RA R E NOT R EVERSED : 18 PATI ENTS I. PLANNED POSTOP. VENTI LATION 6 2 . H YPO PERFUS ION 7 3. H YPOTHERM I A 6 4. I. P. ANT IBIOTIC 7 Fig. I 0-Results of rev iew where cura re was no t reversed. KEENAN: NITROUS OXIDE-CURARE ANESTHESIA: REAPPRAISAL 147 that it is ever inadequate as an anesthetic, even in deep intra-abdominal operations. Therefore, with this technique, the use of other potent depressant agents either by in-halation or by vein is unnecessary. Major organ toxicity is thus avoided, and recovery from anesthesia is prompt. Furthermore, major cardiovascular abnormalities occur-ring during surgery can be assumed to be due to factors other than anesthesia, since neither N20 nor curare alter cardiovascular function significantly. 2. Curare dosage need not be excessive . When used according to the recommended sched-ule, it is well within the range known to be successfully antagonized with neostigmine and below the level known to produce sig-nificant hypotension. 3. Hypoxia need not occur, so long as me-chanical ventilation is properly applied and meticulously measured. Whenever there is doubt, arterial blood gas analysis should be available. 4. Curare reversal has proved to be successful in all cases except in those instances in which there is some pathologic process which delays curare redistribution such as hypovolemia, or hypothermia, or in those instances in which intraperitoneal antibi-otics are used. In those cases, one must be prepared to utilize postoperative mechanical ventilation . REFERENCES BRIDENBAUGH, P . 0 . AND CHURCHILL-DAVIDSON, H. C. Re-sponse to tubocu ra rine chloride and it s reversal by neostig-mine methyl sulfate in man . JAMA 203:541 - 544, 1968. DAL SANTO, G . Kinetics of distribution of radioactive labe lled muscle re laxa nts: I. In vesti ga tions with C -14-dimethyl-d-tubocurarine. Anesth esiolvgy 25:788- 800. 1964. GEDDES, I. C. AND GRAY, T. C. Hyperve ntil a tion for the maintenance of anesthesia. Lancet II : 4-6, 4 July, 1959 . KATZ, R. L. Neuromuscula r effects of d-tubocura rine , edrophonium, a nd neostigmine in m an. Anesth esiology 28: 327- 336, 1967. O c s o , E . M. AND T ERRY , R. N . Proposed formul a for venti-la tory requirements in apneic a nesthetised pa tients. Anesth. & Analg. 48 :455--460, 1969 . PITTING ER. C. G. , ERYOSA. Y ., AND A DAMSON , R. Anti-biotic-induced pa ralysis. A nesth. & A na/g. 49 :487- 50 I , 1970. THOMAS. E . T . Effect of d-tubocurarine chloride on the blood pressure of a nesthe tised pa tients. Lancet 722 , IO October, 1957 . 

Nitrous Oxie-Curare Anesthesia: Reappraisal

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Nitrous Oxie-Curare Anesthesia: Reappraisal

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