Propofol-alfentanil versus fentanyl-midazolam in coronary artery surgery

Propofol-Alfentanil Versus Fentanyl-Midazolam in Coronary Artery Surgery E. Collard, MD, V. Delire, MD, A. Mayn6, MD, J. Jamart, MD, Y. Louagie, MD, M. Gonzalez, MD, A. Ducart, MD, S. Broka, MD, P. Randour, MD, and K. Joucken, MD Objectives: To compare intraoperative hemodynamic profiles and recovery characteristics of propofol-alfentanil with fentanyl-midazolam anesthesia in elective coronary artery surgery. Design: Prospective, randomized study. Setting: University hospital. Participants: Fifty patients with impaired or good left ventricular function. Interventions: In group 1, (n = 25) anesthesia was reduced with an infusion of propofol, 3 to 4 m g / k g / h , alfentanil, 500 ~g, and pancuronium, 0.1 mg/kg, and maintained with propofol, 3 to 6 m g / k g / h (variable rate), and alfentanil infusions, 30 i~g/kg/h (fixed rate). Additional boluses of alfentanil, 1 mg, were administered before noxious stimuli; group 2 (n = 25) received a loading dose of fentanyl, 25 itg/kg, midazolam, 1.5 to 3 mg, and pancuronium, 0.1 mg/kg for induction, followed by an infusion of fentanyl, 7 i~g/kg / h, for maintenance. Additional boluses of midazolam (1 5 to 3 mg) and fentanyl (250 i~g) were administered before noxious

extubation, morphine consumption, and pain scores were recorded. Induction of anesthesia was associated in both groups with a small but significant decrease in mean arterial pressure ( 1 : 1 5 mmHg (15%); 2 : 8 mmHg (8%) with significant decreases in cardiac index (1.8%; 2: 8%) and left ventricular stroke work index (1: 24%; 2: 21%). Throughout surgery, hemodynamic profiles were comparable between groups except after intubation when the MAP was significantly lower in group 1 (75 --- 12 mmHg) than in group 2 (89 -- 17 mmHg). Group 1 required less inotropic support. Extubation was performed faster in group 1 (7.6 I1) than in group 2 (18.0 h). Morphine requirements and pain scores were comparable between groups. Conclusions: Propofol-alfentanil anesthesia provides good intraoperative hemodynamics and allows early extubation after coronary artery surgery.

stimuli. Measurements and Main Results: Cardiovascular parameters at eight intraoperative time points as well as time to

KEY WORDS: propofol, alfentanil, coronary artery surgery, early extubation, hemodynamics

HE OPTIMAL anesthetic techmque for coronary ar-

either propofol/alfentani1 (group 1) (n = 25) or fentanyl/ midazolam (group 2) (n = 25) by Taves minimization 18with dedicated software implementation for balancing risk factors among subjects. The criteria were as follows: sex, age, left ventricular ejection fraction (LVEF), type and severity of coronary artery disease, and use of beta-blockers. Patients over 75 years of age, obese (body mass index > 27 in men, >30 in women), with impaired renal or hepatic function, or requiring emergency surgery for failed percutaneous transluminal coronary angioplasty were excluded from the study. One hour before surgery, patients were premedicated with lormetazepam, 1 to 2 mg orally, morphine sulphate, 0.1 mg/kg IM, and glycopyrrolate, 0.2 mg IM, and received supplementary oxygen by nasal cannulae. Concomitant cardiac medications (beta-blockers, calcium channel blockers, nitrates, IV heparin) were continued until the mormng of surgery. On arrival in the operating room, supplemental oxygen was administered by face mask. A digital pulse oxlmeter and a 5-lead electrocardiogram (ECG) were placed, leads II and V5 being continuously displayed and recorded every 5 minutes during the procedure. The following catheters were placed under local anesthesia: a 16-gauge in two peripheral veins; a 20-gauge in the radial artery; and a 7.5F balloon-Upped thermodilution catheter in the pulmonary artery (model SP5507H;

T tery surgery (CAS) should preserve the myocardium by maintaining a positive balance between myocardial oxygen supply and demand Anesthetic management should maximize mtraoperatwe hemodynamlc stability and prevent lschemia. 1 High-dose fentanyl provides good hemodynam~c stability 2 but fads to completely suppress the sympathetic response to noxious stimulation 3-6 so that additional anesthetics may be required for maintenance, especially in patients with good left ventrlcular function 6 Furthermore, this technique may not consistently produce unconsciousness 7 and is associated with prolonged postoperative respiratory depression and delayed tracheal extubation. 4,8 However, "early" extubation, performed within 8 hours after surgery, has been reported to be safe m selected cardiac patients. 9-14 It does not appear to be associated with comphcations or increased morbidity. 9-11,13,14Moreover, it would improve cardiac function, Is allow rapid mobilization,910 shorten the intensive care unit (ICU) stay, 9,1°,14and decrease overall costs 1116To achieve this goal, rapid offset of anesthetic action must be provided. So far, an inhalationbased anesthetic technique has been preferred. II.12,~4,17 Propofol and alfentand, being short-acting agents, could also be agents of choice for induction and maintenance of anesthesia in CAS when early extubation as to be considered. The present study compares the hemodynamlc effects and the recovery characteristics of two combinations of drugs, propofol and alfentanil versus fentanyl and midazolam, when used for CAS

METHODS The study was approved by the Institutional Ethical Committee, and written informed consent was obtained from each patient Fifty patients scheduled for electwe coronary artery bypass grafting were allocated to receive

Copyright © I996by W.B. Saunders Company

From the Departments ofAnesthestology, Btostattsttcs, Cardlovascular and Thoracic Surgery, and Intenstve Care Mechcme, Untverslty Hospttal of Mont-Godmne (Cathohc Umverstty of Louvam), Yvotr, Belgmm Address repnnt requests to E Collard, MD, Department of Anesthestolog); Umverstty Hospttal U C L of Mont-Godinne, B-5530 Yvotr, Belgmm Copyrtght© 1996 by W.B Saunders Company 1053-0770/96/1007-000853.00/0

Journal of Cardlothoractc and Vascular Anesthesia, Vol 10, No 7 (December), 1996' pp 869-876

869

870

Viggo-Spectramed, Sarl, Montigny le Bretonneux, France). The arterial and pulmonary arterial catheters were connected to cahbrated transducers (Baxter pressure set urnflow 43-600F; Bentley Laboratories Europe, Uden, Holland) and monitoring system (Cat 111 425 07" Ser: 3157; Hellige GMBH, Freiburg Im Breisgau, Germany). A nasogastric tube, a bladder catheter, and rectal and nasopharyngeal temperature probes were placed after reduction of anesthesia. The following hemodynamic data were obtained before induction of anesthesia (Tt): mean arterial pressure (MAP); mean pulmonary arteNal pressure (MPAP); pulmonary capillary wedge pressure (PCWP); central venous pressure (CVP); and heart rate (HR) Thermodllutlon cardiac output (CO) was measured in triplicate using 10 mE of 5% dextrose in water at room temperature using a Hellige CO computer. From these data, cardiac index (CI), systemic (SVR) and pulmonary vascular resistance, and right and left ventricular stroke work index (LVSWI) were calculated using standard formulae. Anesthesia was reduced in group 1 with an infusion of propofol at an initial rate of 3 to 4 mg/kg/h, and alfentanil administered as a bolus of 500 Ixg followed immediately by an infusion of 30 ~xg/kg/h, and m group 2, with slowly injected IV fentanyl, 25 ixg/kg (typical duration: 2 mm), and IV midazolam, 1.5 to 3 mg. In both groups, pancuronium, 0 1 mg/kg IV, was administered in divided doses during the induction, and the lungs were ventilated manually with 100% oxygen to an end-tidal carbon dioxide of 35 to 40 mmHg. Induction hme was recorded as the time from start of propofol infusion or fentanyl injection untd loss of eyelash reflex. After endotracheal intubatlon, the lungs were mechanically ventilated to normocapma with a 50% oxygen in air mixture. Respiratory parameters were adjusted if necessary during surgery to keep arterial blood gas values within the normal range. In group 1, anesthesia was maintained by propofol and alfentanil infusions The infusion rate of propofol was adjusted m response to changes in systemic arterial pressure and to anticipate changes in the level of surgical stimulation. Two cases of awareness had occurred in a pilot study w~th infusion rates below 2 mg/kg/h; therefore, patients were never allowed to receive less than 2 mg/kg/h during this study Alfentaml infusion was kept at its initial rate until the end of operation. Additional bolus doses of alfentand, (1 mg). were injected immediately before endotracheal mtubatIon, surgical incision, and sternotomy In group 2, maintenance of anesthesia was achieved to the end of operation by an infusion of fentanyl, 7 ~zg/kg/h. initiated immediately after induction Addihonal doses of mldazolam, 1.5 to 3 rag, and fentanyl, 250 ixg, were administered before surgical incision and sternotomy. All infusions were administered with calibrated infusion pumps (Terumo STC521; Terumo Corp. Tokyo, Japan). The extracorporeal circulation was performed using roller pumps (model 10-00-00; Stockert Instrumente Gmbh, Munich, Germany) and a membrane oxygenator, an in-line arterial filter, and a colloid prime containing a stable 4% solution of plasma proteins (SSPP, Belgian Red Cross). The perfusionist aimed for a flow rate of 2.4

COLLARD ET AL

L / m m / m 2 and a mean arterial pressure of approximately 60 to 80 mmHg. Myocardial protection was achieved with antegrade crystalloid and multldose retrograde cold blood cardioplegia associated with topical cooling and is detailed in a previous article. 19 Patients were cooled to a rectal temperature of 25 to 28°C and warmed up to 36.5°C The hemodynamic measurements were repeated just before (T2) and 1 minute after (T3) intubation, before incision (T4), just before (Ts) and 1 minute after (T6) sternotomy, before heparin administration (T7), and finally after injection of protamlne and normalization of the activated coagulation time (T8). Hypertensive episodes, defined as an increase in systohc arterial pressure of more than 20% above baseline value, were treated if they lasted more than 1 minute with boluses of alfentanll, 1 to 3 mg (group 1), or fentanyl, 0.25 to 0 5 mg, (group 2). Addmonal vasodllators could be used to control blood pressure. In the event of hypotenslon, defined as a decrease of systohc arterial pressure of more than 20% below basehne value for 1 minute, colloids (SSPP) and/or vasopressors (ephedrine) were administered according to the CVP. In the ICU, patients were kept deeply sedated in group 1 with a propofol infusion, 2.5 to 4 mg/kg/h, and in group 2 with a midazolam infusion, 0 03 to 0 06 mg/kg/h, for at least 4 hours. In both groups, postoperative analgesia was provJded with IV morphine via patient-controlled analgesia devices (PCA) (Lifecare 4200 Abbott; Abbott Laboratories, North Chicago, IL) All patients were preoperatively instructed in the use of the pumps and a verbal pain score to assess pain. PCA was managed using a morphine dose of 1.5 mg with a lockout interval of 7 minutes to a maximum of 25 mg per 4 hours. No loading dose or continuous infusion was used Pain scores were verbally evaluated every 4 hours at rest and during cough. Before awakening of the patients, nurses were entitled to administer bolus doses of morphine for analgesia if necessary. Sedation time was defined as the interval from the end of surgery untd the end of the infusion of propofol or midazolam Emergence time was defined as the interval from the end of infusion of propofol or midazolam until tracheal extubatlon. Criteria for extubatlon were stable hemodynamics, normal arterial blood gas values at FIO2 less than 0 4, absence of active bleeding in the chest drams, rectal temperature from 37 to 38°C without shivering, and the patient being awake and responsive to verbal stimuli. A perloperatlve myocardial infarction was defined either as the appearance of a new Q wave on the ECG or/and a concentration of creatme kinase (CK) greater than 250 U / L with CK-MB lsoenzymes greater than 0 1 x total CK All patients were interviewed about their recall of events m the operating room Numerical values are expressed as the mean _+ SD. Time sequences of hemodynamlc measurements, expressed in crude values or in differences from baseline values, were compared using 2-way analysis of varmnce (ANOVA) for repeated measurements. In case of a statistically significant treatment effect, two by two comparisons were performed by Student's t test using residual variance from A N O V A Moreover, T2 was compared with T1 in each group by the same procedure. Other comparisons used Student's t or

PROPOFOL-ALFENTANIL FOR CARDIAC ANESTHESIA

871

Wilcoxon's rank sum tests for continuous variables and chi-square or Fisher's exact tests when appropriate for categorical ones. Statistical analysis was performed using DATASIM (Desktop Press, Lewiston, ME) and SC (Lambda-Plus, Gembloux, Belgium) softwares. RESULTS

Fifty patients agreed to participate in the study. One patient in group 2 had been withdrawn for protocol violation. The groups were comparable in weight, height, previous myocardial infarction rate, and preoperative cardiac drug therapy (Table 1). Both groups were also similar with respect to surgical course, specifically duration of surgery, cardiopulmonary bypass (CPB), aortic cross-clamp time, and revascularlzation procedures (Table 1). The average infusion rates of propofol varied from 2.5 to 4.6 mg/kg/h throughout surgery. They are displayed at different time points on F~g 1. The mean total doses of alfentanil and fentanyl lntraoperatively admimstered were 15.3 _-2-3.1 mg and 5 1 + 1.1 mg, respectively. Induction was smooth for all patients but significantly longer in group 1 versus group 2. Mean reduction time was 8 -+ 2 minutes m group 1 versus 3 --- 1 minute in group 2 (p < 10 -5) The mean induction doses of propofol and alfentanll were 33.7 _+ 11 mg and 779 - 89 Ixg, respectively. Hemodynamlc data are summarized in Table 2 and Fig 2. Two patients were excluded from the analysis m group l Table 1 Patients' Characteristics and Characteristics of Surgery

Age (yr) Sex (m/f) Weight (kg) Height (cm) Body surface area (m 2) Prewous myocardml infarction LV EF (%) <35 35 < & >50 >50 Unstable angina Number of dmeased vessels 2 3 Left mare Left main + other lesions Cardmc therapms Calcmm channel blocking drugs Nitrates Angpotensm antagomsts IV heparm IV isosorbide dmltrate Beta-blockers Characterlstjcs of surgery Duration of surgery (mm) Extracorporeal c~rculatton ttme (mm) Aortm cross-clamp time (mtn) Number of venous grafts Number of mammary artery grafts

Group 1 (n = 25)

Group2 (n = 24)

63 _+ 8 21/4 74 _+ 10 168 _+ 7 1 83 -+ 0 14 13

64 _+ 6 18/6 78-+ 15 168 -+ 8 1 87 + 0 20 10

1 6 18 6

1 5 18 4

8 14 1 2

6 15 1 2

13 21 2 6 3 17

14 20 1 4 2 18

274 -+ 31 (276)

298 -+ 85 (281)

117_+22(116) 72 +- 15 (67) (2) (1)

127+44(122) 77 -+ 25 (74) (1) (1)

NOTE Data are expressed as mean ± SD (medfan) or frequencres

6 ~_ o

S

.o

4

o~

3

._~-

2

W

I A

I B

I C

1 D

I E

I F

1 G

1 H

1 I

J

TIME Fig 1

Infusion rate of propofol throughout surgery. (A) induction,

(B) intubation; (C) between intubation and incision; (D) incmion; (E) sternotomy, {F) dissection of the internal mammary artery, (G) administration of heparin; (H) onset of cardiopulmonary bypass; (I)

rewarming; and (J) end of operation.

because of incomplete hemodynamic data. Baseline hemodynamic measurements were similar in both groups. Compared with values obtained in awake patients, both groups experienced a small but significant decrease in MAP (1:15 mmHg [15%] [p < 10-41; 2 : 8 mmHg [8%] [p = 0.012]) during induction of anesthesia combined with a significant decrease in CI (1: 8% [p = 0.058]; 2: 8% [p = 0.029]), LVSWI (1 24%; 2. 21%) (p < 10-4), and SV (1: 10% [p = 0.006]; II: 11% [p < 10-3]), but with no significant changes in HR, MPAP, PCWP, CVP, and SVR. It should be noted that after induction, no significant betweengroups differences were observed. From induction until start of CPB, time sequences of measurements, eventually corrected from baseline values, were not statistically different between both groups for any hemodynamic variable, except after intubation (T3), when the MAP was significantly lower In group 1 (75 - 12 mmHg) than in group 2 (89-+ 17 mmHg) (p = 10-4). However, the mean data shown in Table 2 obscure any particular change in cardiovascular dynamics occurring in individual patients. For this reason, all episodes of marked changes in systolic arterial pressure (SAP) were recorded. Eleven patients m group 1 versus two in group 2 (p = 0.01) had hypotensive episodes requiring treatment. In group 1, they occurred between mtubatlon and incision (lowest SAP ranging from 72 to 86 mmHg), whereas in group 2 they occurred during induction of anesthesia (lowest SAP = 70 and 80 mmHg). Four patients m group 1 had hypertensive episodes requiring treatment: 2 during intubation and 2 during aortic root dissection (with peak SAP from 171 to 210 mmHg). Seven patients in group 2 had hypertensive episodes requiring treatment: 1 at Induction, 4 during sternotomy, and 2 during aortic root dissection (with peak SAP from 154 to 198 mmHg). The difference in hypertensive episodes is not statistically significant. No ST-T segment changes suggestive of myocardial ischem]a were observed m either group during these changes in arterial pressure In the prebypass period, 16 patients in group 1 and 13 in group 2 lecelved a mean supplementary dose of alfentanil (2.4 _+ 2 mg) or

872

C O L L A R D ET A L

120

¢,4

+l+l+l+l+l+l+l+l

100

MAP

8O

P

~d

+I+l+l+l+l+l+l+l

E E

6O 4O

O

20'

~N

+1+1+1+1+1+1+1+1

0'

o

O

o

* p < 1 ~ , ** p = 0 012 : difference from baseline values ° p < 104

P +l+l+l÷l+l+l+l+[ O

~5. 4.

cN

3,5. 3. ÷l+l+i+l+l+l+l+i

d ~ r e n c e from the fent:nyl group

CI

~5,

2

~

2, 1,5, 1,

o

+l÷l+l+l+l+l+l+l

0,5, o

0,

o

* p = 0 058, ** p = 0.029 difference from basehne values

e,i

÷l+l+l+]+{+l+l+l 2 O

80 70 60

o

+1÷1÷1÷1÷1+[+1+1

50

E

E

40

E

30

LVSWI

20 o

+l+l+l+l+l÷l÷l+[

QI

Group I

TJ

o

+1+1+1+1+1÷1÷1÷1

ffP

e,l

•

÷l+l+l+l+l÷l÷l÷l

~

9 p-

g~

P o

d~

+l÷l÷l+l+l÷l÷l÷l

~X £

÷1÷1+1+1+1+1+[+1 c4

P o

+l+l+l+l+l+l+l+l

= E

e,i

+1

+l÷l+l+l+l+[+l÷l 9

vo

Group 2 i

I

0

o

._e

- -

10

"o

I T2

I T3

I T4

I T5

I T6

ic~Bj "1"7

I

T8

*, ~ p < 10.4 dlfference from baseline values

Fig 2. Changes in M A P , CI, L V S W I during surgery T1, awake; T 2 , before intubation, T3, a ~ e r intubatlon; T4, before incision, T5, before sternotomy; T6, after sternotomy; T7, before heparm; and T8, a ~ e r protamine

fentanyl (0.28 + 0.14 rag) to control the hemodynamlc response to noxxous st~mula. Additional vasodilators were required in 3 patients in group 2 during sternotomy. To be weaned offbypass, three patients (12%) in group 1 requared motropic support compared with 9 (38%) in group 2 (p = 0.038), one of whom also required the use of an intra-aortlc balloon pump (IABP). After protamine administration, there was no between-groups difference concerning the hemodynamlc parameters. The mean infusion rates of propofol and midazolam m the ICU were 3.2 + 0.8 mg/kg/h and 0.06 ± 0.02 mg/kg/h, respectively. Extubation was performed significantly earlier after operation m group 1 (7.6 hours) than in group 2 (18.0 hours) (p < ]0 -4) (Table 3). Twenty-one of 25 patients in

H÷I÷I+I+I÷[+[÷I

Table 3 N

m~

V-~ 6


Recovery Times Group 1

Group 2

(n = 25)

(n = 23)

p

Sedation time (mln)

382 -+ 254 (300)

481 -+ 332 (285)

NS

Emergence t~me (ram)

175 -+ 185 (135)

501 ± 218 (458)

< 10 -5

TJme to extubatlon (mm)

557 -+ 294 (458)

9 8 4 --_ 336 (1080)

< 10 -4

N O T E Data are expressed as m e a n +- SD ( m e d i a n )

PROPOFOL-ALFENTANIL FOR CARDIAC ANESTHESIA

873

Table 4 Postoperatwe Morphine Consumption (mg/h) Groupl(n= 16) Group2(n= 16) 14_+17(07) 10_+0.9(06) Before extubatmn Extubatlon --, 2 PM of the first postop16_+ 1 0 ( 1 6 ) * 11 _+09(0.8) eratwe day 2 PM --> 8 AM of the second postopera11_+07(10)

tJve day

09-+06(09)

NOTE Data are expressed as mean _+ SD (medmn) *p=009

group i were extubated the day of surgery versus 10 of 24 in group 2 (p = 0 002). No early extubated patients had to be remtubated Morphine consumptmn and pain scores were obtained from the Acute Pain Service from 16 patients in each group and were evaluated during three periods of time: from arrival in the ICU until extubation, from extubatlon until 2 PM of the first postoperative day, and from that moment until 8 AM of the second day. No significant differences were observed between groups, but there was a trend towards higher morphine requirements In group 1 during the second period (p = 0.09) (Tables 4 and 5). The patient who reqmred the use of an IABP to be weaned off bypass developed a penoperative myocardial infarction and daed in the ICU from cardiogenic shock. No other patient had new signs of myocardial infarction. Discharge from ICU occurred after a median of 2 days in both groups. No patient had any recall of operative events DISCUSSION

This randomized study compared the hemodynamic effects of propofol-alfentanll with those of fentanyl-midazolam during CAS in selected patients Induction of anesthesia in CAS with bolus of fentanyl > 20 to 25 p.g/kg is known to cause only mlmmal changes in cardiovascular dynamics, 2,2° even in patients with poor left ventricular function. 6 Conversely, administration of a bolus of propofol at induction can produce hypotension. This has been reported for noncardiac 2~-24and cardiac surgery. 25-2s Hypotension may be particularly deleterious in coronary patients because it may jeopardize the coronary perfusion and lead to lschemia. Several authors have recommended the use of propofol with the utmost care m the presence of cardiovascular disease 29-31or impaired myocardial function. 32 This study aimed to achieve cardiovascular stability during induction by combining a slow infusion of propofol at 3 to 4 mg/kg/h with an alfentanil bolus of 500 jxg followed by an infusion of 30 Ixg/kg/h With th]s induction Table 5. Verbal Pain Score Pertods of Twne

Group 1 (n = 16) Group2 (n = 16)

Extubatlon --> 2 PM of the first postoperatwe day 20_+12(20) At rest 42_+19(39) Cough 2 PM ~> 8 AM of the second postoperatwe day At rest Cough

11_+11(08) 38_+17(40)

NOTE Data are expressed as mean _+ SD (medmn)

17_+12(18) 39-+18(31)

15_+09(15) 35_+11(33)

scheme, the propofol-alfentanll induction as well as fentanylmidazolam produced a small decrease m MAP associated with significant decreases in CI, LVSWI and SV, whereas SVR, PCWP, and HR showed only minor changes. Moreover, it should be noted that no acute hypotensive episodes occurred in group 1 during induction of anesthesia. Although strict comparisons between studies are impossible, the decrease in MAP ( - 1 5 % ) in the propofol-treated patients was smaller than that reported in studies using boluses of propofol for induction (A1-Khudhair125: - 2 3 % ; PatrIck26: - 2 5 % ; Manara 33 - 2 2 % ) The advantage of using a slow infusion of propofol to preserve hemodynamic stability during induction of anesthesia has already been reported in elderly but not cardiac patients. 34 What are the mechanisms responsible for the cardiovascular effects of drugs used for induction? Regarding propofol, there is still no consensus in the current hterature and several mechanisms have been described. In vitro, propofol has a negative inotropic effect on the isolated ferret, guinea pig, and rabbit papillary muscle 35-37but not on the isolated rat papillary muscle 3s,39 or on the isolated blood-perfused rabbit heart. 4° Propofol also possesses a direct vasodilator effect. 36.41 In whole animals, Br/assel et a142 and Coetzee et a143 reported a negative inotropic effect as the primary cause of the cardiovascular depression associated with propofol. However, Goodschild, 44 in a study involving dogs in which all neurogenic cardiovascular reflexes were abolished, suggested the predominance of a direct venodilator effect. Extrapolating these effects In human beings is quite difficult because of differences between species and doses used. Moreover, in humans (as well as in intact animals), it must be considered that among the cardiovascular effects of an anesthetic drug, some are directly caused by the decrease in oxygen consumption induced by the anesthetic state, which in turn induces a decrease in CO, a reduction In parasympathetic tone, and modifications of the organasm's integrative response to any perturbation. 45 So it is impossible to isolate the direct effects of the drug on cardiovascular system because all components are interrelated. Furthermore, in vivo, the effects of a drug on intrinsic myocardial contractility are difficult to assess because of the absence of reliable indicators of contractility.46 In the authors' propofol-treated group, the hemodynamic effects on induction compared favorably with those of Manara, 33 Lippmann, 24 and Van Aken, 23 who have suggested that propofol reduces myocardial contractility. The same effect has been demonstrated by Mullier 47 usmg peak systolic pressure and the left ventricular end-systolic area as indices of contractility. In other studies, the decrease in arterial pressure aftel propofol has been attributed to simultaneous afterload reduction and negative inotropy, 21,2848 or a decrease in preload 49 suggesting a vasodilator effect. Several authors found propofol to produce direct vasodilation of the venous and/or arterial beds. 5°-52 In consequence, hypotension after propofol may be caused by impairment of myocardial contractility, which could be related to direct and/or indirect mechanisms such as changes in loading conditions of the heart or depressmn

874

COLLARD ET AL

of the sympathetic nervous system tone. 53-55 Concerning fentanyl, its cardiovascular effects are better understood No change an either myocardial contractlhty56 or coronary vasoreactivitys7was observed at clinicallyequivalent concentrations with in vitro models. Nevertheless, at higher concentrations, a dose-dependent negatwe inotropic effect has been described. 56.58 Animal studies clearly demonstrated that high dosages of fentanyl (up to 0.16 mg/kg) have no depressive effect on contractllaty59,6° and no effect on coronary arteries (up to 0.25 mg/kg). 57 In this study, the slight cardiovascular depression observed after induction of anesthesia in group 2 may be atmbuted to the addition of mldazolam, administered to prevent awareness. 61 Diazepam after large doses of fentanyl has also been reported to provide cardiovascular depression. 62 During the maintenance of anesthesia until the onset of CPB, no sigmficant difference in hemodynamics was observed between the two groups except for a decrease in MAP in the propofol-treated group after mtubation. This may reflect a too-deep level of anesthesia in the presence of low sympathetic stimulation. These hypotensive episodes were easily treated and could be prevented by decreasing the infusion rate of propofol just after intubat~on or reducing the interval between mtubation and incision. The authors' propofol-alfentanil techmque provided very good protection from hemodynamic responses during sternotomy but failed to do so in two patients during mtubatlon. The incidence of breakthrough hypertension (16% of the patients) is less than that observed in Roekaerts's study (44%). 63 In this study, additional boluses of alfentaml were systematically administered immediately before noxious stimuh, which improved the hemodynamic stability. To anticipate sympathetic responses to noxious stimulations, boluses of more than 1 nag of alfentanil can be required, especially m the youngest patients. It should be noted that alfentanil rapidly and effectively suppresses the hemodynamlc responses to noxious stimulations In accordance with the hterature, 3-6 in the fentanyl group most of the hypertensive episodes occurred during sternotomy, an effect that does not appear to be dose related. 64 Propofol-treated patients required significantly less inotropic support for separation from CPB. Although factors other than anesthetic technique must be considered, this

finding is in accordance with previous studies that reported that the administration of propofol in CAS was not associated with increased requirements for motropic support after CPB or an increased incidence of the postoperative low cardiac output syndrome.32,65 ICU sedation was deliberately maintained during at least 4 hours to allow adequate rewarmmg and to protect patients at the most likely time for ischemla and ventricular depression, which occur about 2 and 4 hours after CPB, respectively.66,67The protocol was to attempt extubation as soon as the criteria were met. Sixty-four percent of the propofol-treated patients were extubated within 8 hours after surgery versus none m the fentanyl group. Shapiro 68 has reported that the use of an inhalation-based anesthetic technique was the key to early extubation m cardiac surgery. This study shows that the combination of propofol and alfentanil for induction and maintenance of anesthesia in CAS is a suitable alternative when early extubatlon is planned. In both groups, postoperative pain was wellcontrolled by PCA systems. There was no cardiopulmonary morbidity that could be attributed to pain or early extubatlon. However, the low incidence of postoperative adverse outcomes, the small size of the groups, and the fact that the study was not designed for this purpose prevent any definite conclusions concerning direct or redirect influence of tested drug regimens on perioperative ischemia. The variations in extubation times did not affect length of ICU stay. This is consistent with Quasha's II study and can be explained by the fact that patients are retained in the ICU for many reasons (anvaslve momtoring, skilled personnel). In conclusaon, this study showed that propofol-alfentanil anesthesia as described provides adequate control of hemodynamics in patients undergoing coronary artery surgery provided a slow infusion rate of propofol is used to induce anesthesm and the infusion is carefully adjusted m anticipation of noxious stimulations, a practice analogous to that of inhalation anesthesm. This technique of anesthesia allows extubation at the earliest opportunity when the criteria are met In view of its good intraoperative hemodynamic profile, propofol-alfentanil anesthesia may be considered as an alternative to inhalation anesthesm when an early extubation policy is pursued after coronary artery surgery.

REFERENCES

1 Estafanous FG, Hlggins TL Oplolds and the cardiac patient, in Estafanous FG (ed)' Oploids in Anesthesia II Boston, MA, Butterworth, 1990, pp 93-109 2 Lunn JK, Stanley TH, Elsele J, et al High-dose fentanyl anesthesia for coronary artery surgery Plasma fentanyl concentrations and influence of nitrous oxide on cardiovascular responses Anesth Analg 58 390-395, 1979 3 Waller JL Hug CC, Nagle DM, et al Hemodynamlc changes during fentanyl-oxygenanesthesia for aortocoronary bypass operatlon. Anesthesiology 55:212-217, 1981 4. Sebel PS, Bovill JG, Boekhorst RA, et al Cardiovascular effects of high-dose fentanyl anaesthesia Acta Anaestheslol Scand 26'308-315, 1982 5 Wynands JE, Townsend GE, Wong P, et al Blood pressure

response and plasma fentanyl concentrations during high- and very h~gh-dose fentanyl anesthesia for coronary artery surgery. Anesth Analg 62'661-665, 1983 6 Wynands JE, Wong P, Whalley DG, et al Oxygen-fentanyl anesthesia in patients with poor left ventrlcular function Anesth Analg 62'476-482, 1983 7 Mummanem N, Rao TL, Montoya A Awareness and recall with high-dose fentanyl-oxygenanesthesia Anesth Analg 59 948949, 1980 8. Richman KA, Klm YL. Geer RT, et al' Respiratory depression from high-dose fentanyl in man Anesthesiology 53 $164, 1980 9. Prakash O, Jonson B, Meij S, et al' Criteria for early extubation after intracardiac surgery in adults. Anesth Analg 56 703-708, 1977

PROPOFOL-ALFENTANIL FOR CARDIAC ANESTHESIA

10. Khneberg PL, Geer RT, Hirsh RA, et al. Early extubatlon after coronary artery bypass graft surgery. Crit Care Med 5 272274. 1977 11 Quasha AL, Loeber N, Feeley TW, et al' Postoperative respiratory care A controlled trial of early and late extubatxon following coronary artery bypass grafting Anesthesiology 52.135141, 1980 12. Lachtenthal PR, Wade LD, Nxemyski PR, et al' Respiratory management after car&ac surgery with inhalatmn anesthesia Crit Care Med 11 603-605, 1983 13. Higglns TL. Pro: Early endotracheal extubation is preferable to late extubatlon in patients following coronary artery surgery. J Cardlothorac Vasc Anesth 6.488-493, 1992 14. Chong JL, Grebenlk C, Sinclair M, et al. The effect of a cardiac surgical recovery area on the timing of extubatlon J Car&othorac Vasc Anesth 7:137-141, 1993 15 Gall SA, Olsen CO, Reves JG, et al' Beneficial effects of endotracheal extubatlon on ventrlcular performance. J Thorac Cardaovasc Surg 95 819-827, 1988 16 Foster GH, Conway WA, Pamulkov N, et al' Early extubation after coronary artery bypass: Brief report Crlt Care Med 12 994-996, 1984 17 Shapiro BA, Lxchtenthal PR. Inhalation-based anesthetic techniques are the key to early extubation of the cardiac surgical patient. J Cardiothorac Vasc Anesth 7.135-136, 1993 18. Taves DR. Minimization: A new method of assigning patients to treatment and control groups Clln Pharmacol Ther 15 443-453, 1974 19 Louagle Y, Collard E, Gonzalez M, et al. Initial experience with low-potassium cold blood cardloplegia: A chnlcal comparative study Ann Thorac Surg 53.628-634, 1992 20 Stanley TH, Phllbln DM, Coggms CH Fentanyl-Oxygen Anaesthesia for Coronary Artery Surgery: Cardiovascular and Antldluretic Hormone Responses. Can Anaesth Soc J 26 168-172, 1979 21 Grounds RM, Twigley AJ, Carli F, et al: The haemodynamic effects of intravenous induction Comparison of the effects of thlopentone and propofol Anaesthesia 40:735-740, 1985 22. Coates DP, Monk CR, Prys-Roberts C, et al' Hemodynamlc effects of infusions of the emulsion formulation of propofol during nitrous oxide anesthesia in humans. Anesth Analg 66:64-70, 1987 23. Van Aken H, Memshausen E, Prien T, et al The influence of fentanyl and tracheal intubation on the hemodynamlc effects of anesthesm induction with propofol/N20 in humans Anesthesiology 68:157-163, 1988 24 Llppmann M, PalclUS R, Glngerich S, et al A controlled study of the hemodynamic effects of propofol versus thiopental during anesthesia induction. Semin Anesth 7'116-122, 1988 (suppl) 25 A1-Khudhairl D, Gordon G, Morgan M, et al Acute car&ovascular changes following dlsoprofol Anaesthesia 37:10071010, 1982 26 Patrick MR, Blair I J, Feneck RO, et al A comparison of the haemodynamic effects of propofol ('Dlprivan') and thiopentone in patients with coronary artery disease Postgrad Med J 61"23-27, 1985 (suppl 3) 27. Williams JP, McArthur JD, Walker WE, et al A comparison of the hemodynamics of dlprlvan (propofol), thlopental, and etomidate for induction of anesthesia in patients with coronary artery disease Semln Anesth 7 112-115, 1988 (suppl 1) 28 Kaplan JA, Guffin AV, Mlkula S, et al' Comparative hemodynamic effects of propofol and thiamylal sodium during anesthetic induction for myocardial revascularizatlon J Cardiothorac Vasc Anesth 2:297-302, 1988

875

29. Merln RG: Propofol causes cardiovascular depression I. Anesthesiology 72:393-394, 1990 30. Van Aken H, Brussel T: Propofol causes cardiovascular depression II Anesthesiology 72'394-395, 1990 31 Llppmann N, Mok MS: Propofol causes cardiovascular depression III Anesthesiology 72.395-396, 1990 32 Hall RI, Murphy JT, Moffitt EA, et al: A comparison of the myocardial metabolic and haemodynamic changes produced by propofol-sufentanfl and enflurane-sufentanI1 anaesthesia for patients having coronary artery bypass graft surgery. Can J Anaesth 38 996-1004, 1991 33 Manara AR, Monk CR, Bolsm SN, et al: Total IV anaesthesia with propofol and alfentanil for coronary artery bypass grafting. Br J Anaesth 66.716-718, 1991 34. Peacock JE, Lewis RP, Rellly CS, et al: Effect of different rates of infusion of propofol for induction of anaesthesia in elderly patients. Br J Anaesth 65'346-352, 1990 35. Cook D J, Housmans PR: Mechanism of the negative lnotropic effect of propofol in isolated ferret ventrlcular myocardlum Anesthesiology 80'859-871, 1994 36 Park WK, Lynch C' Propofol and thiopental depression of myocardial contractility" A comparative study of mechamcal and electrophyslologlc effects m isolated guinea pig ventricular muscle. Anesth Analg 74.395-405, 1992 37 Rusy BF, Thomas-King PY, King GP, et al. Effects of propofol on the contractile state of isolated rabbit papillary muscles under various stimulation conditions. Anesthesiology 73. A560, 1990 38 Rlou B, Besse S, Lecarpentler Y, et al. In vitro effects of propofol on rat myocardium Anesthesiology 76 609-616, 1992 39. Azuma M, Matsumura C, Kemmotsu O' Inotropic and electrophyslologic effects of propofol and thiamylal in isolated papillary muscles of the guinea pig and the rat Anesth Analg 77 557-563, 1993 40. Mouren S, Baron J, Albo C, et al. Effects of propofol and thlopental on coronary blood flow and myocardial performance in an Isolated rabbit heart Anesthesiology 80:634-641, 1994 41 Yamanoue T, Bruin JM, Estafanous FG. Vasodllatlon and mechanism of action of propofol in porcine coronary artery Anesthesiology 81 443-451, 1994 42 Brussel T, Thelssen JL, VIgfusson G, et al Hemodynamxc and cardxodynamic effects of propofol and etomldate: Negative motroplc properties of propofol Anesth Analg 69 35-40, 1989 43 Coetzee A, Fourle P, Coetzee J, et al' Effect of vgtrious propofol plasma concentrations on regional myocardial contractility and left ventricular afterload Anesth Analg 69'473-483, 1989 44. Goodchild CS, Serrao JM. Cardiovascular effects of propofol In the anaesthetized dog Br J Anaesth 63 87-92, 1989 45 Vatner SF Effects of anesthesia on cardiovascular control mechanisms Environ Health Perspect 26.193-206, 1978 46. Lowenstem E, Park KW, Relz S: Effects of Inhalation anesthetics on systemic hemodynamlcs and the coronary circulation, in Kaplan J (ed) Cardiac Anesthesia. Philadelphia, Saunders, 1993, pp 441-466 47 Mulher JP, Wouters PF, Van Aken H, et al: Car&odynamlc effects of propofol in comparison with thlopental. Assessment with a transesophageal echocardlographlc approach Anesth Analg 72'28-35, 1991 48 Gauss A, Helnnch H, Wilder-Smith OH. Echocardiographic assessment of the haemodynamic effects of propofol' a comparison with etomidate and thiopentone. Anaesthesia 46 9~-105, 1991 49. Lepage JM, Pinaud ML, Hehas JH, et al: Left ventrlcular function during propofol and fentanyl anesthesia in patients with

876

coronary artery &sease" Assessment wlth a radionuclide approach Anesth Analg 67.949-955, 1988 50. Muzl M, Berens RA, Kampine JP, et al' Venoddatlon contributes to propofol-medlated hypotenslon m humans Anesth Analg 74:877-883, 1992 51. Boer F, Ros P, Bovill JG, et al: Effect of propofol on peripheral vascular resistance durmg cardiopulmonary bypass. Br J Anaesth 65:184-189, 1990 52. Rouby GG, Andreev A, L6ger P, et al: Peripheral vascular effects of thiopental and propofol in humans with artificial hearts Anesthesiology 75:32-42, 1991 53 Sellgren J, Ponten J, Wallin BG: Percutaneous recording of muscle nerve sympathetic activity during propofol, nitrous oxide, and isoflurane anesthesia in humans. Anesthesiology 73:20-27, 1990 54. Ebert TJ, Muzl M, Berens R, et al: Sympathetic responses to induction of anaesthesia m humans with propofol or etomidate. Anesthesiology 76:725-733, 1992 55. Deegan R, Bing He H, Wood A, et al' Effects of anesthesia on norepmephrine kinetics. Anesthesiology 75:481-488, 1991 56. Strauer BE: Contractde responses to morphme, pintramide, mependme, and fentanyl: A comparative study of effects on the isolated ventnc~lar myocardium. Anesthesiology 37:304-310, 1972 57 Blaise JA, Witzeling TM, Sill JC, et al: Fentanyl is devoid of major effects on coronary vasoreactivity and myocardial metabolism in experimental animals. Anesthesiology 72.535-541, 1990 58. Goldberg AH, Padget CH. Comparative effects of morphine and fentanyl on isolated heart muscle. Anesth Analg 48:978-982, 1969

COLLARD ET AL

59. Freye E: Cardiovascular effects of high dosages of fentanyl, meperdine, and naloxone m dogs. Anesth Analg 53:40-47, 1974 60. Osthelmer GW, Shanahan EA, Guyton RA, et al. Effects of fentanyl and droperldol on canine left ventncular performance. Anesthesiology 42:288-291, 1975 61. Helkkila H, Jalonen J, Arola M, et al: Mldazolam as adjunct to high-dose fentanyl anaesthesia for coronary artery bypass grafting operation. Acta Anaesthesiol Scand 28 683-689, 1984 62. Stanley TH, Webster LR' Anesthetic requirements and cardiovascular effects of fentanyl-oxygen and fentanyl-&azepamoxygen anesthesia in man Anesth Analg 57:411-416, 1978 63. Roekaerts PM, Gerrits HJ, Timmerman BE, et al: Continuous infusions of alfentanil and propofol for coronary artery surgery J Cardiothorac Vasc Anesth 9:362-367, 1995 64. Philbin DM, Rosow CE, Schneider RC, et al: Fentanyl and sufentanll anesthesia revisited: How much in enough? Anesthesiology 73:5-11, 1990 65 Mora CT, Dudek C, Epstein RH, et al: Car&ac anesthesia techniques: Fentanyl alone or in combination with enflurane or propofol. Anesth Analg 68'$202, 1989 66 Smith RC, Leung JM, Mangano DT, S.P.I. Research Group' Postoperative myocardial ischemia m patients undergoing coronary artery bypass graft surgery. Anesthesiology 74:464-473, 1991 67. Brelsblatt WM, Stein KL, Wolfe CG, et al: Acute myocardial dysfunction and recovery. A common occurrence after coronary bypass surgery. J Am Coll Car&ol 15:1261-1269, 1990 68. Shapiro BA' Inhalation-based anesthetic techniques are the key to early extubation of the cardiac surgical patient J Cardlothorac Vasc Anesth 7' 135-136, 1993