ANESTH ANALG 1990;71:591-6
591
No Finding of Increased Myocardial Ischemia During or After Carotid Endarterectomy Under Anesthesia With Nitrous Oxide Steven V. Kozmary, MD, George H. Lampe, MD,David Benefiel, MD, Michael K. Cahalan, MD,Linda Z. Wauk, RN, Patricia Whitendale, RN, Nelson B. Schiller, MD,and Edmond I. Eger 11, MD KOZMARY SV, LAMPE H, BENEFIEL D, CAHALAN MK, WAUK LZ, WHITENDALE P, SCHILLER NB, EGER EI 11. No finding of increased myocardial ischemia during or after carotid endarterectomy under anesthesia with nitrous oxide. Anesth Analg 1990;71:591-6.
Nitrous oxide (N,O) has been implicated as a cause of myocardial ischemia. We investigated whether substitution of N20for a portion of the anesthesia supplied by isoflurane increased myocardial ischemia in patients at risk for such ischemia. Seventy patients having carotid endarterectomies (63 patients) or other carotid surgery (seven patients) were prospectively, randomly assigned to an anesthetic regimen that included or excluded N,O. All other aspects of anesthetic management were similar, except for greater concentrations of oxygen and isoflurane in patients not given
Because of its perceived safety, nitrous oxide (N20)is widely used in patients who have myocardial ischemia. However, several reports implicate N2 0 as a cause of such ischemia. In dogs with an imposed critical stenosis of the coronary artery, N 2 0 increases postsystolic shortening of the myocardium (1,2), a change that can be interpreted as an early indicator of myocardial ischemia. Nitrous oxide also increases postsystolic shortening in the isolated perfused dog heart (3), depresses the rate of recovery of the “stunned, canine myocardium, and increases the risk of death from coronary artery occlusion in dogs (4).It causes epicardial coronary artery vasoconstriction in both dogs (5,6) and pigs (7). Only one clinical study of N 2 0 indicates that
Supported in part by PO1 AG03104A, the Anesthesia Research Foundation, and a grant from Anaquest, Inc. Received from the Departments of Anesthesia and Cardiology, University of California, San Francisco, California. Accepted for publication August 6, 1990. Address correspondence to Dr. Eger, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. 01990 by the International Anesthesia Research Society
N,O. Perioperative monitoring for myocardial ischemia and infarction included 12- or 5-lead electrocardiography, transesophageal echocardiography, and creatine kiriase isoenzyme levels. By transesophageal echocardiographic or electrocardiographiccriteria, 44% of patients given oxygen but only 21 % of those given N 2 0 had myocardial ischemia intraoperatively (P = 0.065). Similarly, myocardial infarction, identified by changes in creatine kinase isoenzymes, occurred in only one patient given N,O but in three given oxygen (not significantly diferent). Thus we found no trend indicating a greater incidence of myocardial ischemia or infarction associated with the use of N,O.
Key Words: ANESTHETICS, GAsEs-nitrous oxide. HEART, MYOCARDIAL ISCHEMIA, MYOCARDIAL INFARCTION-tlitrOUS oxide.
patients may manifest metabolic and electrocardiographic (ECG) evidence of myocardial ischemia (8). However, these findings were not statistically significant, and the changes observed may have resulted from changes in hemodynamics (e.g., hypotension), rather than being a direct effect of N20. Accordingly, we investigated whether the use of 60% N 2 0 with isoflurane and fentanyl increases the incidence of myocardial ischemia above ,that associated with isoflurane and fentanyl alone. We chose to study the ischemic effects of N 2 0 in patients undergoing carotid endarterectomy (or operations on the carotid artery) because such patients have a high incidence of coronary artery disease, which makes them susceptible to perioperative ischemia and infarction. The incidence of ischemic heart disease may be 40% in asymptomatic patients and 92% in patients with symptoms or abnormal ECGs indicative of myocardial ischemia (9-11). Additionally, carotid endarterectomy may be associated with labile hemodynamics that may predispose surgical patients to ischemia by altering myocardial work, myocardial perfusion pres-
592
ANESTH ANALG 1990;71:5914
sure, and heart rate (time available for myocardial perfusion).
Methods Seventy patients scheduled for carotid endarterectomy or other surgery on the carotid artery consented to participate in our institutionally approved study. Sixty-three had a carotid endarterectomy. Seven had other procedures: carotid-carotid bypass (one patient); carotid aneurysm repair (two patients); and carotid dilatation (four patients). All patients received isoflurane, fentanyl (2-5 pg/kg), thiopental (2-5 mg/ kg), and vecuronium, but were randomly assigned to receive 60% N20/40%oxygen (0,) ( n = 34) or 100% O2 ( n = 36). Four patients who had contralateral carotid endarterectomies separated by at least 6 wk were studied twice. The anesthetic for the first procedure was assigned randomly, and the alternate regimen was used for the second procedure. Premedication (triazolam, morphine, or none) and inhaled concentrations of isoflurane were determined by the attending anesthesiologist, and not by study protocol. Neuromuscular blockade was antagonized with edrophonium and atropine before extubation. All patients were mechanically ventilated with tidal volumes of 10 mL/kg at a rate sufficient to produce an end-tidal carbon dioxide (CO,) of 30-35 mm Hg. Previously prescribed cardiac and antihypertensive medications were given the morning of surgery. Routine perioperative monitoring for all patients included a 5-lead ECG and pulse oximeter, precordial or esophageal stethoscope, temperature sensor (esophageal), nerve stimulator, and mass spectrometer measurements. Insertion of a radial arterial catheter permitted transduction of blood pressure and acquisition of blood for bloodlgas analyses. We monitored for myocardial ischemia using 12lead ECG (Marquette MAC 1, Marquette Electronics, Milwaukee, Wis.) and transesophageal echocardiography (TEE). A baseline 12-lead ECG was obtained before anesthetic induction. After induction and intubation, a 9-mm gastroscope having a 3.5- or 5.0-mHz ultrasound transducer (Diasonics, Milpitas, Calif., or Hewlett-Packard, Palo Alto, Calif.) connected to an ultrasonograph (Diasonics or HewlettPackard) was inserted through the mouth into the esophagus or stomach to produce a cross-sectional, short-axis view of the left ventricle at the midpapillary level. Images obtained were recorded on halfinch VHS videotape. Measurements were made preinduction (except
KOZMARY ET AL.
for TEE or anesthetic variables), 3 min after intubation (postinduction), 3 min before carotid crossclamping (preclamp), 3 min after carotid crossclamping (postclamp), 3 min after removal of the carotid cross-clamp (postunclamp), and during skin closure. We also obtained ECG and TEE recordings when systolic blood pressure or heart rate changed 30% from the baseline (ward) value for 3 or more minutes. We considered such changes indicative of a “hemodynamic event.” Twelve-lead ECGs were obtained on postoperative days 1,2, and 3 and compared with the preoperative recording. Data from patients who had intraventricular conduction block or paced rhythm were excluded from this analysis. We also measured creatine kinase enzyme (CKs) and isoenzyme (MB fraction) levels preoperatively and on postoperative days 1 and 2 in approximately the last half of our patients ( n = 34; 18 given N,O, 16 not given N,O). Finally, we interviewed patients preoperatively and on postoperative days 1, 2, and 5 and asked if they had “chest pain or angina.” Patients were unaware of the anesthetic group to which they were assigned. The attending anesthesiologist was not blinded to the patient’s study group, had access to the 5- and 12-lead ECG and TEE data, but did not discuss the interpretation of these data with the research staff. Experts unaware of the choice of anesthetic analyzed the data. Transesophageal echocardiographic data were analyzed for new segmental wall motion abnormalities, as described previously (12). Two observers read the short-axis views of the left ventricle. The ventricle was divided into four quadrants, and the wall for each quadrant was graded as normal, mildly hypokinetic, severely hypokinetic, akinetic, or dyskinetic. Myocardial ischemia was diagnosed if wall motion worsened by more than one grade without concurrent worsening of all walls. A third, senior echocardiographer (M.K.C.) arbitrated any grading discrepancy between the two observers. The 12-lead ECG data were read by two observers for changes in baseline of the ST segment 80 ms after the J point. Ischemia was defined as elevation or depression of the ST segment by 1 mm or more. Perioperative myocardial infarction was diagnosed by the development of Q waves on the ECG or by the finding of a total CK > 100 IU with >4% MB isoenzyme present. Data for the groups were compared using unpaired Student’s t-test for parametric data and Fisher‘s exact test (two-tailed) for counted data. We accepted P 5 0.05 as significant.
NITROUS OXIDE AND MYOCARDIAL ISCHEMIA
593
ANESTH ANALG 1990;71:591-6
Table 1. Patient Demographic and Clinical
Table 2. Variables Associated With Anesthesia
(Preoperative)Characteristics
No N,O
N2O ~
n Age (yr) ASA 1 or I1 (%) Women (%) Weight (kg) Baseline ward systolic blood pressure (mm Hg) Low ward pulse rate (beats/min) Hypertensive (%) History of myocardial infarct I yr (%) No current angina (%) Medications Antihypertensives (7%) &Blockers (%) Calcium channel blockers (%) Nitrates (%) Diuretics (%) History of respiratory disease
No N,O ~~
34 65 t10 26 41 74 t 13 140 t 20 68 t 10 56 0
36 67 t 8 33 56 72 2 14 140 t 21 67
2
12
56 6
18
19
85
94
9 15 12 9 26 21
17 19 14 11 39 19
24
31
(%)
Smokers (%) ~~
N,O, nitrous oxide. Values for age, weight, baseline ward systolic blood pressure, and low ward pulse rate are expressed as an average ? SD.
Results The two study groups were not significantly different demographically or clinically (Table l), but some trends were suggested. Patients not given N,O on average were more likely to receive calcium channel blocking, diuretic, nitrate, and antihypertensive drugs preoperatively, suggesting that they may have had more severe cardiovascular disease. However, these differences were not statistically significant. Most aspects of anesthetic management were similar for the two groups, including the use of adjuvant agents for premedication and of thiopental, fentanyl, and vecuronium (Table 2). A higher concentration of isoflurane was given to the patients who did not receive N,O. Esophageal temperature and the duration of anesthesia did not differ between the two groups. The intraoperative use of cardiovascular drugs also did not differ between groups: 75% of patients given N,O and 73.5% given 0, received phenylephrine; 25% versus 12.5% received P-blockers; 3.1% versus 5.9% received nitroglycerin; and 3.1% versus 5.9% required atropine beyond the dose given with edrophonium. The incidence of hemodynamic events (30% change from ward median systolic blood pressure or
I1
Premedication Triazolam (70) Morphine (%) Thiopental (mg) Fentanyl (fig) Vecuronium (mg) Maintenance end-tidal isoflurane (%) 10-60 min 160 min Lowest intraoperative temperature (OC) Duration of anesthesia (min)
34
36
24 6 290 5 170 180 t_ 180 13 2 6
17 0 350 t 200 150 t loo 12 t 5
0.53 t 0.20 0.60 t 0.23 35.6 t 0.6
0.74 0.27' 0.83 t 0.28" 35.7 ? 0.6
196 2 54
*
189 5 51
N,O, nitrous oxide. Values are expressed as a percentage of the patients with the indicated characteristic or as an average ? SD. " P < 0.001. compared with the N,O group.
heart rate for at least 3 min) did not differ between groups either in sum or for individual hernodynamic events (Table 3). Twenty-one patients given N,O (61.8%)had at least one hemodynamic event, as did 21 patients (58.3%) given 0,. Similarly, hemodynamic events per patient equaled 1.44 k 1.60 in the N,O group and 1.78 k 1.35 in the 0, group. The large standard deviations indicate the wide variation in the number of hemodynamic events per patient and the skewed nature of these results. The median value for each anesthetic group was one hemodynamic event per patient. Of 110 (total) hemodynamic events 44 were hypertension, 29 tachycardia, 10 both hypertension and tachycardia, 19 hypotension, and 8 bradycardia. Nine of 61 patients (2 of 28 given N,O; 7 of 33 given 0,) had ECG evidence of intraoperative ischemia (no significant difference). Evidence for ischemia was found primarily in leads V,, V,, and V5.Intraoperative 12-lead ECG data from nine patients were not evaluated for ischemia because of intraventricular conduction defect (five patients), paced rhythm (two patients), immediate reoperation (one patient), or lost data (one patient). The TEES showed evidence of intraoperative ischemia in 16 of 62 patients (eight patients with unreadable echocardiograms). Two of the patients having echocardiographic evidence of ischemia also had ECG evidence of ischemia. Of the 1804 TEE short-axis quadrant views, 195 were unreadable (10.8%). In the N,O group, 5 of 29 patients (17.2%) had at least one intraoperative ischemic episode, compared with 11of 33 patients (33.3%)in the 0, group (not a statistically
594
KOZMARY ET AL.
ANESTH ANALG 1990;71:591-6
Table 3. Numbers of Patients Having Specific Hemodynamic Events‘ N2O
Event
n
Hypertension Hypotension Tachycardia Bradycardia Hypertension and tachycardia No event
12 5 7 0 2 13
0 2
Median number of events per patient
Number ischemic
n
Median number of events per patient
Number ischemic
1 1 1
3 2 2 1
9 6 11 3 3
2 2 1 2 1
3 4 6 1 1
-
-
3 -
1
15
-
6”
For each anesthetic group, ti is the total number of patients having a specific hemodynamic event. This is followed by the median number of events; the average is not given because of the skewed nature of the data. The third column for each anesthetic group is the number of patients who had ischemia by either electrocardiographic or transesophageal echocardiographic criteria and had the indicated hemodynamic event. Because a patient might have more than one event, the total numbers for all events exceed the total number of patients in the study. Similarly, ischemic events listed with a given event may not be associated with that event and may be counted more than once. “Defined as a change >302 from the ward value and lasting >3 min. ’P = 0.12 compared with N,O group, by Fisher’s two-tailed exact test.
significant difference). No pattern was apparent during the time at which ischemia occurred. Hemodynamic events usually were not associated with ischemia as defined by TEE or ECG (Table 3). Transesophageal echocardiographic changes indicative of intraoperative ischemia usually occurred in patients (10 of 16, or 62.5%)who experienced a hemodynamic event, but this did not differ from the incidence of hemodynamic events in patients who had no TEE evidence of ischemia (32 of 54, or 59.3%). Postoperative CK isoenzyme levels in 4 of 34 patients indicated postoperative myocardial infarction. Three of the four were in the oxygen group. Two of the four patients also had postoperative ECG evidence of ischemia (ST elevation or depression); the remaining two patients had bundle branch blocks (one preexisting and one new) that precluded evaluation of ischemia. Two additional patients who had positive CK isoenzymes preoperatively had negative isoenzymes postoperatively. No patient ever displayed Q waves on the ECG. Five patients (three given N20) had postoperative ECG evidence of ischemia. Two additional patients (0, only) had new left bundle branch blocks. No patient responded affirmatively when asked (as all were) if they had “chest pain or angina” on postoperative days 1, 2, and 5.
Discussion We did not find that N,O causes myocardial ischemia or infarction in patients with coronary artery disease. However, our power to find a significant change was limited by the small size of our population. Of pa-
tients in whom intraoperative ischemia could be assessed from the ECG, 15% (9/61) had evidence of ischemia. Given the average size of each group, N,O would have had to increase this to 45% (a 30% increase) to give a power of 0.8 in a one-tailed test for detection of a significant difference (P < 0.05) (13). Indeed, we did see a 15% difference between groups (2/28 for the group given N 2 0 compared with 7/33 for the group not given N,O), but the change favored finding ischemia with the group not given N20. Similarly, of patients in whom intraoperative ischemia could be assessed from TEE, 26% (16/62) had evidence of ischemia. Nitrous oxide would have had to have increased this to 58% (a 32% increase) to give a power of 0.8. We found a 16% difference (5/29 compared with 11/33), but again the change favored finding ischemia with the group not given N,O. Finally, evidence of myocardial infarction (defined by CK changes) were found in 12% of patients (4/34). This would have to be increased to 52% (a 40% increase) to have a power of 0.8. We found a 13% difference (1118 compared with 3/16), but again the change favored finding ischemia with the group not given N20. In summary, we found a trend suggesting that the use of N,O was associated with less intraoperative ischemia and a lower incidence of myocardial infarction but emphasize that these trends were not statistically significant and that we did not have the power to detect small differences between the effects of the two anesthetic regimens. In designing this study, we debated whether to use 0, or 0, plus N, as the background gas for the patients not receiving N,O. We selected 0, because that is the usual choice of the clinician who decides not to apply N20. That is, we considered that the use
NITROUS OXIDE AND MYOCARDIAL ISCHEMIA
of 0, increased the clinical relevance of our results. The substitution of N,O for some of the 0, and isoflurane might have affected our results by altering hemodynamics. This would be the implication of results from studies in volunteers where substitution of N 2 0 produced a greater arterial blood pressure, peripheral resistance, and cardiac output/oxygen consumption at a given MAC level (14,15). However, under the conditions of our study, the measurements we made of pulse rate and blood pressure did not show any meaningful difference between the patients who did and did not receive N 2 0 (16). In part, this may have resulted from the imposition of surgical stimulation. In part, it may have resulted from the application of a slightly higher MAC level (but lower concentration of isoflurane) in the patients given N,O. In any event, we have no evidence indicating that alterations in hemodynamics affected our results. Our results are consistent with those of two other studies in which patients undergoing coronary artery bypass graft surgery were anesthetized with fentanyl and given N 2 0 or nitrogen in a crossover design (17,18). The presence of myocardial ischemia was evaluated by both 12-lead ECG and TEE and did not occur more frequently in association with NzO. Our study strengthens the conclusions from these previous studies in that our patients did not have the confounding effect of an operation upon the heart, and we studied patients throughout the operative experience. The conclusion that N 2 0 does not adversely affect the patient with coronary artery disease is supported by results from studies in animals. In animal models in which critical stenosis of a coronary artery has been imposed but hemodynamics held constant, N 2 0 does not affect myocardial fiber shortening more than nitrogen (19), nor does it alter the duration of postsystolic shortening (20). These results probably differ from those from earlier studies suggesting an adverse effect of N,O (3) because the design of the earlier studies did not maintain sufficient stability of hemodynamics. Our results indicate that including N 2 0 in anesthesia for carotid artery surgery results in no more myocardial ischemia than replacing the N,O with 0, and isoflurane. This suggests that N 2 0 does not cause myocardial ischemia, but another possibility may exist. The use of N 2 0 decreased the requirement for isoflurane, which also has been implicated as causing ischemia (21). Possibly, both agents cause ischemia and do so to the same extent. If so, substitution of one for the other might not change the incidence of ischemia. However, because recent epidemiologic evidence does not implicate isoflurane as
ANESTH ANALG 1990;71:5914
595
more likely than other inhaled anesthetics or narcotics to cause myocardial ischemia (22,23), this explanation is unlikely. The evidence presently available does not indicate that N,O puts patients with coronary artery disease at greater risk of myocardial ischemia or infarction than other general anesthetics. The editorial assistance of Winifred von Ehrenberg is gratefully acknowledged, as is the assistance with study design and statistical analysis provided by Dr. David Heilbron and Mark Spitalny.
References 1. Philbin DM, Foex P, Drummond G, Lowenstein E, Ryder WA, Jones LA. Postsystolic shortening of canine left ventricle supplied by a stenotic coronary artery when nitrous oxide is added in the presence of narcotics. Anesthesiology 1985;62:16674. 2. Leone BJ, Philbin DM, Lehot JJ, Foex P, Ryder WA. Gradual or abrupt nitrous oxide administration in a canine model of critical coronary stenosis induces regional myocardial dysfunction that is worsened by halothane. Anesth Analg 1988;6781422. 3. Nathan HJ. Nitrous oxide worsens myocardial ischemia in isoflurane-anesthetized dogs. Anesthesiology 1988;68:407-15. 4. Siker D, Pelc LR, Kampine JP, Schmeling WT, Warltier DC. Nitrous oxide depresses functional recovery of stunned rnyocardium in dogs. Anesthesiology 1989;71:A476. 5. Sill JC, Bove AA, Nugent M, Blaise GA, Dewey JD, Grabau C. Effects of isoflurane on coronary arteries and coronary arterioles in the intact dog. Anesthesiology 1987;66:273-9. 6. Wilkowski DA, Sill CJ, Bonta W, Owen R, Bove AA. Nitrous oxide constricts epicardial coronary arteries without effect on coronary arterioles. Anesthesiology 1987;66:659-65. 7. Pettis MS, Witzeling TM, Sill JC, Hughes JM, Rorie DK, Blaise GA. Nitrous oxide constricts coronary arteries in pigs via an endothelium dependent mechanism. Anesthesiology 1989;71: A533. 8. Reiz S. Nitrous oxide augments the systemic and coronary haemodynamic effects of isoflurane in patients with ischaemic heart disease. Acta Anaesthesiol Scand 1983;27:464-9. 9. Rokey R, Rolak LA, Harati Y, Kutka N, Verani MS. Coronary artery disease in patients with cerebrovascular disease: a prospective study. Ann Neurol 1984;16:50-3. 10. Tomatis LA, Fierens EE, Vergrugge GP. Evaluation of surgical risk in peripheral vascular disease by coronary arteriography: a series of 100 cases. Surgery 1972;71:429-35. 11. Hertzer NR, Beven EG, Young YR, et al. Coronary artery disease in peripheral vascular patients. Ann Surg 1984;199: 223-33. 12. Smith JS, Cahalan MK, Benefiel DJ, et al. lntraoperative detection of myocardial ischemia in high-risk patients: electrocardiography versus two-dimensional echocardiography. Circulation 1985;72:1015-21. 13. Hulley SB, Cummings SR. Designing clinical research. Baltimore: Williams & Wilkins, 19882167. 14. Stevens WC, Cromwell TH, Halsey MJ, Eger EI 11, Shakespeare TF, Bahlman SH. The cardiovascular effects of a new inhalation anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 1971;35:&16. 15. Dolan WM, Stevens WC, Eger EI 11, et al. The cardiovascular and respiratory effects of isoflurane-nitrous oxide anaesthesia. Can Anaesth SOCJ 1974;21:557-68.
596
ANESTH ANALG 1990;71:591-6
16. Eger El 11, Lampe GH, Wauk LZ, Whitendale P, Cahalan MK, Donegan JH. Clinical pharmacology of nitrous oxide: an argument for its continued use. Anesth Analg 1990;71:575-85. 17. Mitchell MM, Prakash 0, Rulf ENR, et al. Nitrous oxide does not induce myocardial ischemia in patients with ischemic heart disease and poor ventricular function. Anesthesiology 1989;71: 526-34. 18. Slavik JR, LaMantia KR, Kopriva CJ, Prokop E, Ezekowitz MD, Barash PG. Does nitrous oxide cause regional wall motion abnormalities in patients with coronary artery disease? Anesth Analg 1988;67695-700. 19. Cason BA, Mazer CD, Demas KA, Hickey RF. Nitrous oxide does not worsen ischemic left ventricular dysfunction in the pig. Anesthesiology 1988;67A46.
KOZMARY ET AL.
20. Nathan HJ. Should nitrous oxide be used for patients with ischemic heart disease? Evidence of safety from a laboratory investigation. Anesthesiology 1988;69:A82. 21. Reiz S , Balfors E, Sorensen MB, Ariola S Jr, Friedman A, Truedsson H. Isoflurane-a powerful coronary vasodilator in patients with coronary artery disease. Anesthesiology 1983;59: 91-7. 22. Slogoff S , Keats AS. Randomized trial of primary anesthetic agents on outcome of coronary artery bypass operations. Anesthesiology 1989;70:179-88. 23. Tuman KJ, McCarthy RJ, Spiess BD, DaValle M, Dabir R, Ivankovich AD. Does choice of anesthetic agent significantly affect outcome after coronary artery surgery? Anesthesiology 1989;70:189-98.
591
No Finding of Increased Myocardial Ischemia During or After Carotid Endarterectomy Under Anesthesia With Nitrous Oxide Steven V. Kozmary, MD, George H. Lampe, MD,David Benefiel, MD, Michael K. Cahalan, MD,Linda Z. Wauk, RN, Patricia Whitendale, RN, Nelson B. Schiller, MD,and Edmond I. Eger 11, MD KOZMARY SV, LAMPE H, BENEFIEL D, CAHALAN MK, WAUK LZ, WHITENDALE P, SCHILLER NB, EGER EI 11. No finding of increased myocardial ischemia during or after carotid endarterectomy under anesthesia with nitrous oxide. Anesth Analg 1990;71:591-6.
Nitrous oxide (N,O) has been implicated as a cause of myocardial ischemia. We investigated whether substitution of N20for a portion of the anesthesia supplied by isoflurane increased myocardial ischemia in patients at risk for such ischemia. Seventy patients having carotid endarterectomies (63 patients) or other carotid surgery (seven patients) were prospectively, randomly assigned to an anesthetic regimen that included or excluded N,O. All other aspects of anesthetic management were similar, except for greater concentrations of oxygen and isoflurane in patients not given
Because of its perceived safety, nitrous oxide (N20)is widely used in patients who have myocardial ischemia. However, several reports implicate N2 0 as a cause of such ischemia. In dogs with an imposed critical stenosis of the coronary artery, N 2 0 increases postsystolic shortening of the myocardium (1,2), a change that can be interpreted as an early indicator of myocardial ischemia. Nitrous oxide also increases postsystolic shortening in the isolated perfused dog heart (3), depresses the rate of recovery of the “stunned, canine myocardium, and increases the risk of death from coronary artery occlusion in dogs (4).It causes epicardial coronary artery vasoconstriction in both dogs (5,6) and pigs (7). Only one clinical study of N 2 0 indicates that
Supported in part by PO1 AG03104A, the Anesthesia Research Foundation, and a grant from Anaquest, Inc. Received from the Departments of Anesthesia and Cardiology, University of California, San Francisco, California. Accepted for publication August 6, 1990. Address correspondence to Dr. Eger, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. 01990 by the International Anesthesia Research Society
N,O. Perioperative monitoring for myocardial ischemia and infarction included 12- or 5-lead electrocardiography, transesophageal echocardiography, and creatine kiriase isoenzyme levels. By transesophageal echocardiographic or electrocardiographiccriteria, 44% of patients given oxygen but only 21 % of those given N 2 0 had myocardial ischemia intraoperatively (P = 0.065). Similarly, myocardial infarction, identified by changes in creatine kinase isoenzymes, occurred in only one patient given N,O but in three given oxygen (not significantly diferent). Thus we found no trend indicating a greater incidence of myocardial ischemia or infarction associated with the use of N,O.
Key Words: ANESTHETICS, GAsEs-nitrous oxide. HEART, MYOCARDIAL ISCHEMIA, MYOCARDIAL INFARCTION-tlitrOUS oxide.
patients may manifest metabolic and electrocardiographic (ECG) evidence of myocardial ischemia (8). However, these findings were not statistically significant, and the changes observed may have resulted from changes in hemodynamics (e.g., hypotension), rather than being a direct effect of N20. Accordingly, we investigated whether the use of 60% N 2 0 with isoflurane and fentanyl increases the incidence of myocardial ischemia above ,that associated with isoflurane and fentanyl alone. We chose to study the ischemic effects of N 2 0 in patients undergoing carotid endarterectomy (or operations on the carotid artery) because such patients have a high incidence of coronary artery disease, which makes them susceptible to perioperative ischemia and infarction. The incidence of ischemic heart disease may be 40% in asymptomatic patients and 92% in patients with symptoms or abnormal ECGs indicative of myocardial ischemia (9-11). Additionally, carotid endarterectomy may be associated with labile hemodynamics that may predispose surgical patients to ischemia by altering myocardial work, myocardial perfusion pres-
592
ANESTH ANALG 1990;71:5914
sure, and heart rate (time available for myocardial perfusion).
Methods Seventy patients scheduled for carotid endarterectomy or other surgery on the carotid artery consented to participate in our institutionally approved study. Sixty-three had a carotid endarterectomy. Seven had other procedures: carotid-carotid bypass (one patient); carotid aneurysm repair (two patients); and carotid dilatation (four patients). All patients received isoflurane, fentanyl (2-5 pg/kg), thiopental (2-5 mg/ kg), and vecuronium, but were randomly assigned to receive 60% N20/40%oxygen (0,) ( n = 34) or 100% O2 ( n = 36). Four patients who had contralateral carotid endarterectomies separated by at least 6 wk were studied twice. The anesthetic for the first procedure was assigned randomly, and the alternate regimen was used for the second procedure. Premedication (triazolam, morphine, or none) and inhaled concentrations of isoflurane were determined by the attending anesthesiologist, and not by study protocol. Neuromuscular blockade was antagonized with edrophonium and atropine before extubation. All patients were mechanically ventilated with tidal volumes of 10 mL/kg at a rate sufficient to produce an end-tidal carbon dioxide (CO,) of 30-35 mm Hg. Previously prescribed cardiac and antihypertensive medications were given the morning of surgery. Routine perioperative monitoring for all patients included a 5-lead ECG and pulse oximeter, precordial or esophageal stethoscope, temperature sensor (esophageal), nerve stimulator, and mass spectrometer measurements. Insertion of a radial arterial catheter permitted transduction of blood pressure and acquisition of blood for bloodlgas analyses. We monitored for myocardial ischemia using 12lead ECG (Marquette MAC 1, Marquette Electronics, Milwaukee, Wis.) and transesophageal echocardiography (TEE). A baseline 12-lead ECG was obtained before anesthetic induction. After induction and intubation, a 9-mm gastroscope having a 3.5- or 5.0-mHz ultrasound transducer (Diasonics, Milpitas, Calif., or Hewlett-Packard, Palo Alto, Calif.) connected to an ultrasonograph (Diasonics or HewlettPackard) was inserted through the mouth into the esophagus or stomach to produce a cross-sectional, short-axis view of the left ventricle at the midpapillary level. Images obtained were recorded on halfinch VHS videotape. Measurements were made preinduction (except
KOZMARY ET AL.
for TEE or anesthetic variables), 3 min after intubation (postinduction), 3 min before carotid crossclamping (preclamp), 3 min after carotid crossclamping (postclamp), 3 min after removal of the carotid cross-clamp (postunclamp), and during skin closure. We also obtained ECG and TEE recordings when systolic blood pressure or heart rate changed 30% from the baseline (ward) value for 3 or more minutes. We considered such changes indicative of a “hemodynamic event.” Twelve-lead ECGs were obtained on postoperative days 1,2, and 3 and compared with the preoperative recording. Data from patients who had intraventricular conduction block or paced rhythm were excluded from this analysis. We also measured creatine kinase enzyme (CKs) and isoenzyme (MB fraction) levels preoperatively and on postoperative days 1 and 2 in approximately the last half of our patients ( n = 34; 18 given N,O, 16 not given N,O). Finally, we interviewed patients preoperatively and on postoperative days 1, 2, and 5 and asked if they had “chest pain or angina.” Patients were unaware of the anesthetic group to which they were assigned. The attending anesthesiologist was not blinded to the patient’s study group, had access to the 5- and 12-lead ECG and TEE data, but did not discuss the interpretation of these data with the research staff. Experts unaware of the choice of anesthetic analyzed the data. Transesophageal echocardiographic data were analyzed for new segmental wall motion abnormalities, as described previously (12). Two observers read the short-axis views of the left ventricle. The ventricle was divided into four quadrants, and the wall for each quadrant was graded as normal, mildly hypokinetic, severely hypokinetic, akinetic, or dyskinetic. Myocardial ischemia was diagnosed if wall motion worsened by more than one grade without concurrent worsening of all walls. A third, senior echocardiographer (M.K.C.) arbitrated any grading discrepancy between the two observers. The 12-lead ECG data were read by two observers for changes in baseline of the ST segment 80 ms after the J point. Ischemia was defined as elevation or depression of the ST segment by 1 mm or more. Perioperative myocardial infarction was diagnosed by the development of Q waves on the ECG or by the finding of a total CK > 100 IU with >4% MB isoenzyme present. Data for the groups were compared using unpaired Student’s t-test for parametric data and Fisher‘s exact test (two-tailed) for counted data. We accepted P 5 0.05 as significant.
NITROUS OXIDE AND MYOCARDIAL ISCHEMIA
593
ANESTH ANALG 1990;71:591-6
Table 1. Patient Demographic and Clinical
Table 2. Variables Associated With Anesthesia
(Preoperative)Characteristics
No N,O
N2O ~
n Age (yr) ASA 1 or I1 (%) Women (%) Weight (kg) Baseline ward systolic blood pressure (mm Hg) Low ward pulse rate (beats/min) Hypertensive (%) History of myocardial infarct I yr (%) No current angina (%) Medications Antihypertensives (7%) &Blockers (%) Calcium channel blockers (%) Nitrates (%) Diuretics (%) History of respiratory disease
No N,O ~~
34 65 t10 26 41 74 t 13 140 t 20 68 t 10 56 0
36 67 t 8 33 56 72 2 14 140 t 21 67
2
12
56 6
18
19
85
94
9 15 12 9 26 21
17 19 14 11 39 19
24
31
(%)
Smokers (%) ~~
N,O, nitrous oxide. Values for age, weight, baseline ward systolic blood pressure, and low ward pulse rate are expressed as an average ? SD.
Results The two study groups were not significantly different demographically or clinically (Table l), but some trends were suggested. Patients not given N,O on average were more likely to receive calcium channel blocking, diuretic, nitrate, and antihypertensive drugs preoperatively, suggesting that they may have had more severe cardiovascular disease. However, these differences were not statistically significant. Most aspects of anesthetic management were similar for the two groups, including the use of adjuvant agents for premedication and of thiopental, fentanyl, and vecuronium (Table 2). A higher concentration of isoflurane was given to the patients who did not receive N,O. Esophageal temperature and the duration of anesthesia did not differ between the two groups. The intraoperative use of cardiovascular drugs also did not differ between groups: 75% of patients given N,O and 73.5% given 0, received phenylephrine; 25% versus 12.5% received P-blockers; 3.1% versus 5.9% received nitroglycerin; and 3.1% versus 5.9% required atropine beyond the dose given with edrophonium. The incidence of hemodynamic events (30% change from ward median systolic blood pressure or
I1
Premedication Triazolam (70) Morphine (%) Thiopental (mg) Fentanyl (fig) Vecuronium (mg) Maintenance end-tidal isoflurane (%) 10-60 min 160 min Lowest intraoperative temperature (OC) Duration of anesthesia (min)
34
36
24 6 290 5 170 180 t_ 180 13 2 6
17 0 350 t 200 150 t loo 12 t 5
0.53 t 0.20 0.60 t 0.23 35.6 t 0.6
0.74 0.27' 0.83 t 0.28" 35.7 ? 0.6
196 2 54
*
189 5 51
N,O, nitrous oxide. Values are expressed as a percentage of the patients with the indicated characteristic or as an average ? SD. " P < 0.001. compared with the N,O group.
heart rate for at least 3 min) did not differ between groups either in sum or for individual hernodynamic events (Table 3). Twenty-one patients given N,O (61.8%)had at least one hemodynamic event, as did 21 patients (58.3%) given 0,. Similarly, hemodynamic events per patient equaled 1.44 k 1.60 in the N,O group and 1.78 k 1.35 in the 0, group. The large standard deviations indicate the wide variation in the number of hemodynamic events per patient and the skewed nature of these results. The median value for each anesthetic group was one hemodynamic event per patient. Of 110 (total) hemodynamic events 44 were hypertension, 29 tachycardia, 10 both hypertension and tachycardia, 19 hypotension, and 8 bradycardia. Nine of 61 patients (2 of 28 given N,O; 7 of 33 given 0,) had ECG evidence of intraoperative ischemia (no significant difference). Evidence for ischemia was found primarily in leads V,, V,, and V5.Intraoperative 12-lead ECG data from nine patients were not evaluated for ischemia because of intraventricular conduction defect (five patients), paced rhythm (two patients), immediate reoperation (one patient), or lost data (one patient). The TEES showed evidence of intraoperative ischemia in 16 of 62 patients (eight patients with unreadable echocardiograms). Two of the patients having echocardiographic evidence of ischemia also had ECG evidence of ischemia. Of the 1804 TEE short-axis quadrant views, 195 were unreadable (10.8%). In the N,O group, 5 of 29 patients (17.2%) had at least one intraoperative ischemic episode, compared with 11of 33 patients (33.3%)in the 0, group (not a statistically
594
KOZMARY ET AL.
ANESTH ANALG 1990;71:591-6
Table 3. Numbers of Patients Having Specific Hemodynamic Events‘ N2O
Event
n
Hypertension Hypotension Tachycardia Bradycardia Hypertension and tachycardia No event
12 5 7 0 2 13
0 2
Median number of events per patient
Number ischemic
n
Median number of events per patient
Number ischemic
1 1 1
3 2 2 1
9 6 11 3 3
2 2 1 2 1
3 4 6 1 1
-
-
3 -
1
15
-
6”
For each anesthetic group, ti is the total number of patients having a specific hemodynamic event. This is followed by the median number of events; the average is not given because of the skewed nature of the data. The third column for each anesthetic group is the number of patients who had ischemia by either electrocardiographic or transesophageal echocardiographic criteria and had the indicated hemodynamic event. Because a patient might have more than one event, the total numbers for all events exceed the total number of patients in the study. Similarly, ischemic events listed with a given event may not be associated with that event and may be counted more than once. “Defined as a change >302 from the ward value and lasting >3 min. ’P = 0.12 compared with N,O group, by Fisher’s two-tailed exact test.
significant difference). No pattern was apparent during the time at which ischemia occurred. Hemodynamic events usually were not associated with ischemia as defined by TEE or ECG (Table 3). Transesophageal echocardiographic changes indicative of intraoperative ischemia usually occurred in patients (10 of 16, or 62.5%)who experienced a hemodynamic event, but this did not differ from the incidence of hemodynamic events in patients who had no TEE evidence of ischemia (32 of 54, or 59.3%). Postoperative CK isoenzyme levels in 4 of 34 patients indicated postoperative myocardial infarction. Three of the four were in the oxygen group. Two of the four patients also had postoperative ECG evidence of ischemia (ST elevation or depression); the remaining two patients had bundle branch blocks (one preexisting and one new) that precluded evaluation of ischemia. Two additional patients who had positive CK isoenzymes preoperatively had negative isoenzymes postoperatively. No patient ever displayed Q waves on the ECG. Five patients (three given N20) had postoperative ECG evidence of ischemia. Two additional patients (0, only) had new left bundle branch blocks. No patient responded affirmatively when asked (as all were) if they had “chest pain or angina” on postoperative days 1, 2, and 5.
Discussion We did not find that N,O causes myocardial ischemia or infarction in patients with coronary artery disease. However, our power to find a significant change was limited by the small size of our population. Of pa-
tients in whom intraoperative ischemia could be assessed from the ECG, 15% (9/61) had evidence of ischemia. Given the average size of each group, N,O would have had to increase this to 45% (a 30% increase) to give a power of 0.8 in a one-tailed test for detection of a significant difference (P < 0.05) (13). Indeed, we did see a 15% difference between groups (2/28 for the group given N 2 0 compared with 7/33 for the group not given N,O), but the change favored finding ischemia with the group not given N20. Similarly, of patients in whom intraoperative ischemia could be assessed from TEE, 26% (16/62) had evidence of ischemia. Nitrous oxide would have had to have increased this to 58% (a 32% increase) to give a power of 0.8. We found a 16% difference (5/29 compared with 11/33), but again the change favored finding ischemia with the group not given N,O. Finally, evidence of myocardial infarction (defined by CK changes) were found in 12% of patients (4/34). This would have to be increased to 52% (a 40% increase) to have a power of 0.8. We found a 13% difference (1118 compared with 3/16), but again the change favored finding ischemia with the group not given N20. In summary, we found a trend suggesting that the use of N,O was associated with less intraoperative ischemia and a lower incidence of myocardial infarction but emphasize that these trends were not statistically significant and that we did not have the power to detect small differences between the effects of the two anesthetic regimens. In designing this study, we debated whether to use 0, or 0, plus N, as the background gas for the patients not receiving N,O. We selected 0, because that is the usual choice of the clinician who decides not to apply N20. That is, we considered that the use
NITROUS OXIDE AND MYOCARDIAL ISCHEMIA
of 0, increased the clinical relevance of our results. The substitution of N,O for some of the 0, and isoflurane might have affected our results by altering hemodynamics. This would be the implication of results from studies in volunteers where substitution of N 2 0 produced a greater arterial blood pressure, peripheral resistance, and cardiac output/oxygen consumption at a given MAC level (14,15). However, under the conditions of our study, the measurements we made of pulse rate and blood pressure did not show any meaningful difference between the patients who did and did not receive N 2 0 (16). In part, this may have resulted from the imposition of surgical stimulation. In part, it may have resulted from the application of a slightly higher MAC level (but lower concentration of isoflurane) in the patients given N,O. In any event, we have no evidence indicating that alterations in hemodynamics affected our results. Our results are consistent with those of two other studies in which patients undergoing coronary artery bypass graft surgery were anesthetized with fentanyl and given N 2 0 or nitrogen in a crossover design (17,18). The presence of myocardial ischemia was evaluated by both 12-lead ECG and TEE and did not occur more frequently in association with NzO. Our study strengthens the conclusions from these previous studies in that our patients did not have the confounding effect of an operation upon the heart, and we studied patients throughout the operative experience. The conclusion that N 2 0 does not adversely affect the patient with coronary artery disease is supported by results from studies in animals. In animal models in which critical stenosis of a coronary artery has been imposed but hemodynamics held constant, N 2 0 does not affect myocardial fiber shortening more than nitrogen (19), nor does it alter the duration of postsystolic shortening (20). These results probably differ from those from earlier studies suggesting an adverse effect of N,O (3) because the design of the earlier studies did not maintain sufficient stability of hemodynamics. Our results indicate that including N 2 0 in anesthesia for carotid artery surgery results in no more myocardial ischemia than replacing the N,O with 0, and isoflurane. This suggests that N 2 0 does not cause myocardial ischemia, but another possibility may exist. The use of N 2 0 decreased the requirement for isoflurane, which also has been implicated as causing ischemia (21). Possibly, both agents cause ischemia and do so to the same extent. If so, substitution of one for the other might not change the incidence of ischemia. However, because recent epidemiologic evidence does not implicate isoflurane as
ANESTH ANALG 1990;71:5914
595
more likely than other inhaled anesthetics or narcotics to cause myocardial ischemia (22,23), this explanation is unlikely. The evidence presently available does not indicate that N,O puts patients with coronary artery disease at greater risk of myocardial ischemia or infarction than other general anesthetics. The editorial assistance of Winifred von Ehrenberg is gratefully acknowledged, as is the assistance with study design and statistical analysis provided by Dr. David Heilbron and Mark Spitalny.
References 1. Philbin DM, Foex P, Drummond G, Lowenstein E, Ryder WA, Jones LA. Postsystolic shortening of canine left ventricle supplied by a stenotic coronary artery when nitrous oxide is added in the presence of narcotics. Anesthesiology 1985;62:16674. 2. Leone BJ, Philbin DM, Lehot JJ, Foex P, Ryder WA. Gradual or abrupt nitrous oxide administration in a canine model of critical coronary stenosis induces regional myocardial dysfunction that is worsened by halothane. Anesth Analg 1988;6781422. 3. Nathan HJ. Nitrous oxide worsens myocardial ischemia in isoflurane-anesthetized dogs. Anesthesiology 1988;68:407-15. 4. Siker D, Pelc LR, Kampine JP, Schmeling WT, Warltier DC. Nitrous oxide depresses functional recovery of stunned rnyocardium in dogs. Anesthesiology 1989;71:A476. 5. Sill JC, Bove AA, Nugent M, Blaise GA, Dewey JD, Grabau C. Effects of isoflurane on coronary arteries and coronary arterioles in the intact dog. Anesthesiology 1987;66:273-9. 6. Wilkowski DA, Sill CJ, Bonta W, Owen R, Bove AA. Nitrous oxide constricts epicardial coronary arteries without effect on coronary arterioles. Anesthesiology 1987;66:659-65. 7. Pettis MS, Witzeling TM, Sill JC, Hughes JM, Rorie DK, Blaise GA. Nitrous oxide constricts coronary arteries in pigs via an endothelium dependent mechanism. Anesthesiology 1989;71: A533. 8. Reiz S. Nitrous oxide augments the systemic and coronary haemodynamic effects of isoflurane in patients with ischaemic heart disease. Acta Anaesthesiol Scand 1983;27:464-9. 9. Rokey R, Rolak LA, Harati Y, Kutka N, Verani MS. Coronary artery disease in patients with cerebrovascular disease: a prospective study. Ann Neurol 1984;16:50-3. 10. Tomatis LA, Fierens EE, Vergrugge GP. Evaluation of surgical risk in peripheral vascular disease by coronary arteriography: a series of 100 cases. Surgery 1972;71:429-35. 11. Hertzer NR, Beven EG, Young YR, et al. Coronary artery disease in peripheral vascular patients. Ann Surg 1984;199: 223-33. 12. Smith JS, Cahalan MK, Benefiel DJ, et al. lntraoperative detection of myocardial ischemia in high-risk patients: electrocardiography versus two-dimensional echocardiography. Circulation 1985;72:1015-21. 13. Hulley SB, Cummings SR. Designing clinical research. Baltimore: Williams & Wilkins, 19882167. 14. Stevens WC, Cromwell TH, Halsey MJ, Eger EI 11, Shakespeare TF, Bahlman SH. The cardiovascular effects of a new inhalation anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 1971;35:&16. 15. Dolan WM, Stevens WC, Eger EI 11, et al. The cardiovascular and respiratory effects of isoflurane-nitrous oxide anaesthesia. Can Anaesth SOCJ 1974;21:557-68.
596
ANESTH ANALG 1990;71:591-6
16. Eger El 11, Lampe GH, Wauk LZ, Whitendale P, Cahalan MK, Donegan JH. Clinical pharmacology of nitrous oxide: an argument for its continued use. Anesth Analg 1990;71:575-85. 17. Mitchell MM, Prakash 0, Rulf ENR, et al. Nitrous oxide does not induce myocardial ischemia in patients with ischemic heart disease and poor ventricular function. Anesthesiology 1989;71: 526-34. 18. Slavik JR, LaMantia KR, Kopriva CJ, Prokop E, Ezekowitz MD, Barash PG. Does nitrous oxide cause regional wall motion abnormalities in patients with coronary artery disease? Anesth Analg 1988;67695-700. 19. Cason BA, Mazer CD, Demas KA, Hickey RF. Nitrous oxide does not worsen ischemic left ventricular dysfunction in the pig. Anesthesiology 1988;67A46.
KOZMARY ET AL.
20. Nathan HJ. Should nitrous oxide be used for patients with ischemic heart disease? Evidence of safety from a laboratory investigation. Anesthesiology 1988;69:A82. 21. Reiz S , Balfors E, Sorensen MB, Ariola S Jr, Friedman A, Truedsson H. Isoflurane-a powerful coronary vasodilator in patients with coronary artery disease. Anesthesiology 1983;59: 91-7. 22. Slogoff S , Keats AS. Randomized trial of primary anesthetic agents on outcome of coronary artery bypass operations. Anesthesiology 1989;70:179-88. 23. Tuman KJ, McCarthy RJ, Spiess BD, DaValle M, Dabir R, Ivankovich AD. Does choice of anesthetic agent significantly affect outcome after coronary artery surgery? Anesthesiology 1989;70:189-98.
