337

The cardiovascular effects of high-dose butorphanol- nitrous oxide anaesthesia before and during Theodore H. Stanley MD, Parsad Reddy MD, Stephen Gilmore as, George Bennett MD operation

The cardiovascular effects of high doses of butorphanol Butorphanol (Stadol) is a new synthetic agonist- (0.3-.0.45 mg.kg 1) plus 60 per cent NzO anaesthesia antagonist opioid which has become popular as a were measured at unconsciousness, following tracheal postoperative analgesic because of its reduced intubation, and immediately before and at one and ten liability for producing respiratory depression, t-3 minutes after surgical stimulation in 17A. S.A. class I and Butorphanol is also being used as the intravenous II patients undergoing elective gastric or gall bladder analgesic component of nitrous oxide-narcotic- surgery. Butorphanol atut NzO produced unconscious. oxygen anaesthesia in a number of centres. 4-6 We ness with only small decreases in heart rate and cardiac previously measured the cardiovascular effects of output but did not result in sufficient analgesia to block or morphine-N20, meperidine-NzO and fentanyl-N20 treat stimulation of the cardiovascular system secondary in man and found that nitrous oxide plus any of the to tracheal intubation or surgical incision, even when above pure agonist opioids results in cardiovascular supplemented with additional butorphanol to high cumu- depression both before and during operation. 7-1~ lative dose levels (1.0 mg.kg-l ). The data suggest that The objective of this investigation was to measure even high dose butorphanol - N20 anaesthesia requires the cardiovascular effects of high doses of butor- supplementation with other anaesthetics or anaesthetic phanol (up to 1.0 mg'kg <) plus N20 in man before adjuvants to prevent cardiovascular stimulation during and during surgical stimulation to determine if they general abdominal surgery. were different from those of the other commonly used opioids plus N20. Key words ANALGESICS, NARCOTIC: butorphanol, mepeddine, Methods moiphine, fentanyl, SURGERY:general, abdominal, The investigation was approved by the University CARDIOVASCULARDYNAMICS: stimulation, of Utah Human Research Committee. Informed depression. consent for performance of the study was obtained the night before operation from 17 A. S.A. class I or II patients taking no cardiac, pulmonary or renal medication and scheduled to undergo elective gas- From the Department of Anesthesiology, The University tric or gall bladder surgical operations. None of the of Utah School of Medicine, Salt Lake City, Utah patients were receiving any medication except 84132, antacid preparations or sedatives. Premedieation Address correspondence to: Theodore H. Stanley, included pentobarbital (l mg'kg -1) and atropine M.D., Professor of Anesthesiology, The Department of (0.1 mg-kg-1) intramuscularly 90 minutes before Anesthesiology, The University of Utah School of the scheduled operation. Medicine, Salt Lake City, Utah 84132. Prior to anaesthetic induction, an intravenous Supported in part by Stanley Research Foundation, infusion of lactated Ringers solution was started in Salt Lake City, Utah. an upper extremity and given at 200 ml/hr. A

CAN ANAESTH SOC I 1983 / 30: 4/pp337-34| 338 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL central venous pressure catheter was placed percu- pancuronium (0.1 mg'kg -l) was given intraven- taneously into the right atrium from the antecubital ously over a five-minute period. fossa or neck, and a catheter was inserted into the All patients were questioned 24 to 48 hours radial or brachial artery percutaneously and thread- postoperatively with regard to their memory of the ed 30 to 40 cm into the central aorta. The aortic anaesthetic induction and operative procedure. pressure catheter was attached via an arterial pres- Data were analyzed for statistical significance using sure transducer to a central digital computer substa- analysis of variance. P < 0.05 was considered tion in the operating room. Warner's method ~l of statistically significant. analyzing the central aortic pulse-pressure curve, which was recently validated by English et al., 12 Results was used to determine cardiac output (QT), stroke Buto~hanol (mean 0.13 -+ 0.02mg.kg -l) and volume (SV), heart rate (HR), mean arterial blood nitrous oxide produced unconsciousness in all pressure (BP), systolic arterial blood pressure patients in an average of 7 -+ 0.5 minutes. Five (SBP), and systemic vascular resistance (SVR). minutes after induction HR and QT were slightly but Initial cardiovascular data were recorded 15 significantly reduced but all other variables re- minutes after all catheters were implanted with the mained unchanged (Table). Tracheal intubation patients awake and breathing room air. Following resulted in marked increases in SBP, BP, SV and this, the patients were given N20 (60 per cent) in QT above control values. These variables were only oxygen to breathe, and butorphanol (0.1-0.15 mg- slightly decreased with additional butorphanol, kg -l) was given slowly intravenously over a ten- SBP, BP and SV increased again with surgical minute period until the patients were non-respon- stimulation while HR returned to control values and sive to verbal command. When unconscious the SVR became elevated. Eight of the 17 patients palients were given an additional 0.2 mg.kg -I of moved with initial surgical stimulation. Frequent butorphanol intravenously. Respirations were first additional boluses of butorphanot stopped move- assisted and then controlled to maintain end-tidal ment and reduced Q'r and sv to control values but I'CO2, and then later PaCO2, between 4.3-4.9 kPa were ineffective in decreasing SBP, BP and SVR to (32-37 tore) as measured in aortic blood every preanaesthetic values. This was true even when 15-30 minutes. Fifteen minutes "after beginning butorphanol was given to a total dose above anaesthesia, when all patients had respirations 1.0 mg-kg-I. Thus, all 17 patients required diaz- controlled and were unconscious, succinylcholine epam or enflurane before the study was completed. (1.5 mg.kg -1, IV) was given and the trachea intu- The latter two comp.__ounds were effective in de- bated. Additional butorphanol (0.1 mg.kg -1) was creasing SBP and BP to desirable levels but also given five minutes later (before surgical stimulus) produced significant decreases in Q'r. and, following this, the surgical procedure began. When intensively questioned postoperatively, all Supplemental butorphanol (0.05-0.1 mg.kg-1 , IV) patients related that their last memory prior to was given after the operation began whenever operation was either coming into the operating systolic arterial blood pressure (SBP) became >20 room or having a face mask placed on their faces per cent of preoperative (control) values. If three and their first memory postoperatively was upon supplemental doses of butorphanol did not reduce recovering consciousness in the recovery room or SBP to within 20 per cent of control values in five to their hospital room. No patients recalled tracheal ten minutes, enflurane (0,3-1.5 per cent) or diaz- intubation or any aspect of the surgical procedure. epam (0.1-0.2mg-kg -~, IV) was added to the anaesthetic regime. Cardiovascular dynamics were Discussion measured before induction of anaesthesia, five The results of this study demonstrate that high dose minutes following anaesthetic induction with butor- butorphanoI-NxO produces unconsciousness with phanol and nitrous oxide, one minute after endo- only a minimum of cardiovascular depression. tracheal intubation, one minute after additional Unfortunately, the technique, even when supple- butorphanol (before surgical stimulation) and one mented with additional doses of butorphanol (up to and ten minutes after surgical stimulation (abdom- a total butorphanol dosage of 1.0 mg'kg-I), does inal incision). Following the last measurement not produce sufficient analgesia to block or effe~- Stanh;y etal.: ntG~ DOSE Bu'roRPHANOL 339

TABLE Cardiovasculareffects of butorphanolplus niUeus oxide bef~te and during operation(mean • SD)

Following surgical 5 minutes after After additional stimulation induction with Following Butorphanol Control ButorphunolplusN20 intubation (0,1 rag) 1 rain lO rain

Stroke volume (mI) 5 I 49 69t 63* 72? 54 -'- 8 + 7 + 10 -- 8 -+ 10 + 7 Heart rate (beats/mix) 79 70" 83 7g* 84 76 -+ 8 -+ 6 .4- 8 --- 7 • 9 • 7 Cardiac output (l/mirt) 4.4 3.5* 5.8* 5.0* 5.4 4,0 - 0.7 -+ 0.4 0.9 -+ 0.6 • 0.7 - 0,8 Systetaic vascular 2800 3384 3344 3192 3922* 4652* rcsislance (PRU) • -+610 -+520 ---480 -+590 -+560 Systolic blood 17.0 17.2 21.It 19.4" 21.87 19.7" pressure (kPa) • 1.3 -+ 1.2 -+ 19 -+ 1.6 -4- 1.9 + 1.5 Mean blood 12.5 12.6 15~21" 13,8" 16.17 14.0" pressure (kPa) • l_l + 1.2 -+ 1.5 • 1.9 --. 1.7 +- 1.3 *p <0.05, "~p < 0.01, analysis of variance. tively treat cardiovascular "stress responses" to but results in a ceiling effect on respiratory depres- tracheal intubafion and surgical stimulation. Our sion as well. 3'2~ These, plus other data which show data suggest, therefore, that high dose butorphanol- that intravenous butorphanol produces minimal N20 anaesthesia must be supplemented with other cardiovascular changes, suggest that the drug might agents (inhalation or intravenous) to prevent car- be effective as a component of nitrous oxide- diovascular stimulation during general abdominal narcotic-oxygen anaesthesia. surgery. Preliminary studies by Del Pizzo s and Zauder 6 in The advantages of nitrous oxide-narcotic- which butorphanol plus nitrous oxide were used in oxygen anaesthesia are said to be a minimum Of surgical patients yielded encouraging initial results. cardiovascular depression, a reasonably rapid re- Unfortunately, our data in this study are not so cover,/ time and an absence of pain in the early encouraging. While we are not completely sure why postoperative period, m't3-1s A significant dis- even extremely high doses of butorphanol were advantage of these techniques is early postoperative ineffective in producing sufficient levels of analge- respiratory depression, especially when high doses sia to block or treat hypertension with surgical of the narcotic are used intraoperativety. I~ A stimulus, our and others' previous experience with number of recent reports suggest that high doses of this compound in dogs22'23 suggests that in contrast agonist type narcotic compounds may sometimes be to morphine, fentanyl and other pure agonist nar- necessary to prevent or treat intraoperative hyper- cotic compounds, j5-2~ butorphanol has a ceiling tension.9' ~5-20 Unfortunately, high doses of agonist effect with regard to analgesia. By ceiling effect it is type narcotics result in a higher incidence of meant that increasing doses of the compound do not prolonged postoperative respiratory depres- result in increasing analgesia. The mechanism of sion. 15'|7'2~ Considering the above it would be increased analgesia with increased dosage of pure desirable to have available a narcotic compound agonists is not precisely known but may be related that could be used with or without N20 that to increased central nervous system opiate receptor produced anaesthesia with little influence on car- binding. Clinical exper/ence and investigation have diovascular dynamics but had a ceiling effect on shown that the dose of a pure agonist narcotic that respiratory depression (produced only a limited results in unconsciousness may not be sufficient to degree of respiratory depression irrespective of prevent cardiovascular stimulation during endo- dosage). There are data which demonstrate that tracheal intubation. ~~ However, if the dosage is in- buto:rphanol not only produced less respiratory creased suffieiently (usually 50-75 per cent of the depression than equi-analgesic doses of morphine sleep dose) cardiovascular stimulation will not 340 CANADIAN ANAESTHETISTS ~ SOCIETY JOURNAL occur during tracheal intubation but may during employed, The results indicate that butorphan- surgical incision. ~7-19 Likewise, a further increase ol-N20 anaesthesia must be supplemented with (10-20 per cent of the sleep dose) in narcotic other anaesthetics or anaesthetic adjuvants to be dosage will enable incision without cardiovascular used successfully for general abdominal surgery. stimulation but may not allow a more stressful surgical stimulus e.g,, osteotomy, visceral thoracic References or abdominal manipulations.t7 In our experience 1 Gilbert MS, Hanover RM, Moyfan DS, Caruso with pure agonist narcetic compounds, if the dosage FS. Intramuscular butorphanol and meperidine in of the agonist narcotic is increased sufficiently postoperative pain. Clin Pharmacol Ther 1976; 20: eventually a dosage is reached in which all forms of 359-64. surgical trauma are tolerated without cardiovascular 2 Galloway FM, Hrdlicka J, Losada M, Noveck stimulation or other evidences of inadequate anaes- RJ, Caruso FS. Double-blind evaluation of intra- thesia. This appears not to be the case with venous butorphanol and meperidine in patients with butorphanol as twice or three times the dose that postoperative pain. Can Anaesth Soc J 1977; 24: produced unconsciousness (sleep dose) was unable 90-102. to block or treat hypertension and tachycardia 3 PopioKA, JacksonDH. RosoAM. SchreinerBF. Yu during or after tracheal intubation. Furthermore, PM. Hemodynamic and respiratory effects of doses up to ten times the sleep dose were ineffective morphine and butorphanol. Clin Pharmacol Ther in blocking or treating cardiovascular stimulation 1978; 23:281-7. with surgical stimulation. We and others (Isern- 4 Dobkin AB, Arandia HY, Byle~ PH, Africa BF, Ameral, J, personal communication) have had Caruso FS, Noveck RJ. Butorphanol titrate: safety similar experiences with other agonist-antagonist and efficacy in balanced anesthesia. Can Anaesth opioids (pentazocine and nalbuphlne, Port D and $oe J 1976; 23: 601-8. Stanley TH, unpublished data). Why this occurs is 5 Del Pozzo A. A double-blind study of the effects unknown but it may be related to the different of butorphanol compared with morphine in balanced opiate receptors these compounds stimulate. Un- anesthesia. Can Anaesth Soc J 1978; 25: 392-7. fortunately there is so little information currently 6 Zauder I'lL. Butorphanol, a new non-narcotic anal- available relating central nervous system opiate gesic. In: Trends in Intravenous Anesthesia, Aldrete receptor binding to clinical actions of any of the JA, Stanley TH, Eds. Chicago, Year Book, 1980, narcotic compounds that further speculation is un- pp 367-83. warranted. 7 McDermott R, Stanley TH. The effects of low con- The clinical implications of our findings in this centrations of nitrous oxide on cardiovascular study are that when used without other anaesthetics dynamics during morphine anesthesia. Anesthesiol- or anaesthetic adjuvants, nitrous oxide-butor- ogy 1974; 41: 89-91. phanol results in sufficient amnesia but insufficient 8 Stanley TH, Liu WS. Cardiovascular effects of analgesia to prevent cardiovascular stimulation meperidine-NzO anesthesia before and after pan- during tracheal intubation and abdominal surgical curonium. Anesth Analg 1977; 56: 669-73. stimulation. While this problem may be overcome 9 Lunn J, Webster LR, Stanley TH, Woodward A. by adding other supplements such as enflurane or High dose fantanyl anesthesia for open heart sur- diazepam the advantages of this practice (deeper gery: Plasma fentanyl concentration and influence levels of anaesthesia) must be weighed against the of NzO on cardiovascular dynamies~ Anesth Analg disadvantages (increased after-load, myocardial 1979; 58:390 5. depression, increased potential for detrimental drug 10 Bennett GM, Stanley TH. Human cat~diovascalar interactions, etc.). responses to endotracheal intubation during mor- In conclusion, our data demonstrate that high phine-N20 and fen~nyl-N20 anesthesia. Anes- dose butorphanol-N20 produces unconsciousness thesiology 1980; 52: 520-2. with only a minimum of cardiovascular depression 11 Warner HR, Gardner RM, Toronto AR. Computer- but does not produce sufficient analgesia to block based monitoring of cardiovascular functions in cardiovascular "stress responses" to abdominal postoperative patients. Circulation 27(Suppl) 1968; surgery, irrespective of the dosage of butorphanol H 68-74. Stanley et al.: HIGH DOSE BUTORPHANOL 341

12 English J, Hodges MR, Semker C, Johamen R, R~sam6 Stanley TH. Comparison of aortic pulse contour On a mesur~ les effets cardio-vasculaires de l'anesth~sie analysis and thermodilution methods of measur- au bulorphanol d haute dose (0.3-0.45 rag"kg -1) associd ing cardiac output during anesthesia in the dog. d 60 pour cent de protoxyde d'azote 1'120 chez 17 patients Anesthesiology 1980; 52: 56-61. de classe I et H de I'A.S.A., subissant une chirurgie 13 Neff W, Mayer EC, de la L~ Percales M. dlective de t'estomac ou de la v~.sicule bitiaire. Les Nitrous oxide and oxygen anesthesia with curare mesures dtaient prises au moment de la perle de cons- relaxation. Calif Mud 1947; 66: 67. cience, aprds l'intubation endotracMale, immediate- I4 Stoelting RK, Gibbs PS. Hemodynamic effects ment avam la stimulation chirurgicale el dune et dix of morphine and morphine-nitrous oxide in valvular minutes aprds cette stimulation. heart disease and coronary artery disease. Anes- Le butorphanol-NtO ont amen~. I'inconacience en ne thesiology 1973; 38: 45-52. produisan t qu' une l~gkre diminution de ta fr~quence et du 15 Stanley TH. The pharmacology of intravenous ddbit cardiaque, mais l'analgdsie ne rut paa suffisante narcotic anesthetics, ln: Anesthesia, Miller RD, Ed., pour bloquer ou traiter la stimulation du systdme cardio- New York, Churchill Livingstone, 198 I, pp 425-49. vasculaire due ~ f'intubation endotrachdale ou ~t t'inci- 16 de Lange S, Boscoe M, Stanley TH, Pace N. sion chirurgicale et cela, m~me en ajoutant du butor- Comparison of sufentanil-O7 and fentanyl-O2 for phanol ~ des doses aneignant 1 mg'kg -j. Cene dtude coronary artery surgery. Anesthesiology 1982; 56: sugg~re que l'anesthdsie au butorphanol d haute dose 112-8. associde au N20 demande l' addition d' un autre agent ou 17 de Lange S. Stanley Ttt, Boscee M. Femanyl- adjuvant anesthdsique de fa~on d prdvenir ta stimulation oxygen anesthesia: Comparison of anesthetic re- cardio-vasculaire durant la ehirurgie abdominale. quirements and cardiovascular responses in Salt Lake City, Utah and Leiden, Holland. Abstracts 7th World Congress of Anesthesiologists, Hamburg, 1980, p. 313. 18 Stanley TH. High-dose narcotic anesthesia. Semi- nars in Anesthesia 1982; 1: 21-32. 19 SebeI PS, Bovill JG, Boekhorst RAA, Rog P. Cardiovascular effects of high dose fentanyl anaes- thesia. Acta Anesthesiol Scand 1982; 26: 308-15. 20 Stanley TH, Gray NH, Stanford W, Armstrong R. The effects of high dose morphine on fluid and Erratum blood requirements in open heart procedures. Anes- thesiology 1973; 38: 536-41. Re: Nauta J, Stanley TH, de Lange S, Koopman 21 Nagashima H, Karamanian A, Molovany R, D, Spierdijk J, van Kleef J. Anaesthetic induc- Rodnay P, Ang M, Koerner S, Foldes FF. Respira- tion with alfentanil: Comparison with thiopental, tory and circulatory effects of intravenous butor- midazolam, and etomidate. Can Anaesth Soc J phanol and morphine. Clin Pharmacol Ther 1976; 1983; 30:53-60 (January). 19: 738-45. 22 Sederberg J, Stanley TH, Ruddy P, Liu WS, Port D, The correct infusion rates for the four agents are: Gillmor S. Hemodynamic effects of butorphanol- oxygen anesthesia in dogs. Anesth Analg 1981; 60: Alfentanil: 120 p,g'kg'-' rain -1 rather than 715-9. 20 ~g-kg'-lmin -1 23 Murphy MR, Hug CC. "Ceiling effect" of butor- Thiopental: 4 rng'kg.-lmia -t rather than phanol (Stadol) as an anesthetic supplement. Anes- 84 I~g-kg'-lmin-1 thesiology 1981; 55: A260. Etomidate: 300 p,g'kg'-~min-1 rather than 5 I~g'kg'-~min -1 Midazolam: 100 I~g'kg--lmin -1 rather than 20 ~g-kg'-lmin -1