Hemodynamic effect of calcium channel blockade during anesthesia for coronary artery surgery

Hemodynamic

Effect of Calcium Channel Blockade Dwing Coronary Artery Surgery

Anesthesia

for

P. Colson, MD, P. Médioni, MD, M. Saussine, MD, J.R. Séguin, MD, D. Cuchet, MD, D. Grolleau, MD, P.A. Chaptal, MD, B. Roquefeuil, MD Because the choice of anesthetic technique does not influence the incidence of perioperative myocardial ischemia, reduction of ischemic risk may require specific antianginal therapy. Calcium entry blockers are effective drugs in antianginal therapy. Diltiazem reduces myocardial oxygen demand through decreases in heart rate, inotropy, and systolic function, while increasing myocardial oxygen delivery through coronary vasodilation. These potentially beneficial effects of diltiazem were evaluated in 15 of 29 patients (diltiarem Y placebo, double-blind study) scheduled for coronary artery bypass graft surgery. Continuous infusion of diltiazem (0.15 mgl kg bolus followed by 2 pg/kg/min], during anesthesia and surgery before cardiopulmonary bypass, significantly reduced the major MV02 determinants during anesthesia with moderate doses of fentanyl and a benzodiazepine

P

ATIENTS scheduled for coronary artery bypass grafting (CABG) are invariably exposed to ischemic episodes during anesthesia and surgery.rJ Because the threat of postoperative myocardial infarction (MI) appears to be related to perioperative ischemia,‘J any reduction in the ischemic burden should be beneficial. The frequency of perioperative ischemic episodes varies widely from one study to another,1-5 and the majority may be unrelated to hemodynamic changes.2y3%6 However, the frequency of ischemic episodes is markedly increased when heart rate (HR) exceeds 110 BPM.‘j Because the choice of anesthetic technique may not significantly affect the incidence of perioperative ischemia,4,5 reduction in the incidence of ischemia may require specific therapy, as wel1 as improvements in monitoring to detect myocardial ischemia.7 Although preoperative antianginal therapy is maintained until the day of surgery, this alone does not offer adequate protection from perioperative myocardial ischemia, especially with calcium Channel antagonists. 6,8On the contrary, intravenous (IV) administration of diltiazem, a calcium Channel antagonist, has been found to reduce the frequency of intraoperative ischemic episodes during noncardiac surgery.9 Diltiazem has potentially beneficial effects on systemic hemodynamics and the coronary circulation (ie, both a reduction in myocardial oxygen consumption (MV02) and an increase in oxygen supply) .ia This study was designed to document the influence of diltiazem on cardiovascular function and the incidence of myocardial ischemia during anesthesia for CABG prior to cardiopulmonary bypass (CPB).

Front the Departments of Anesthesiology and Cardiovascular Surgery, Laboratory of Cardiovascular Physiology, Sr-Eloi Hospital, Montpellier, France. Address reprint requests to P. Colson, DAR B, Hospita1 St-Eloi, Avenue Bertin-Sans, 34 059 Montpellier cedex, France. Copyright o 1992 by WB. Saunders Company 1053.077019210604-0006$3.00/0 424

(midazolam in 8 of 14 control patients and g of 15 treated patients, or flunitrazepam in the others). Heart rata, maan arterial pressure, and inotropy were decreased during the most stressful events of surgery when plasma diltiarem concentrations were in the therapeutic range (~-96 ng/mL). The number of patients with perioperative ischemia was 2 of 15 in the treated group and 4 of 14 in the control group. Provided that diltiazem plasma concentrations are sufficient, it can contribute to lowering the ischemic burden during anesthesia for coronary artery surgery. Copyright o 1992 by W.B. Saunders Company KEY WORDS: pharmacology, calcium entry blocker, diltiazem, anesthesie. coronary artery disease, surgery, coronary artery bypass graft surgery METHODS

Each patient gave informed consent to the protocol, which was approved by the institutional Committee for Ethics in Clinical Research. Twenty-nine patients scheduled for CABG participated in this study. Patients suffering from cardiac failure (ejection fraction <40% as estimated by ventriculography), with prior renal dysfunction (serum creatinine > 1.8 mg/dL), or atrioventricular conduction black were not included. Preoperative antianginal therapy was maintained until the day before surgery, all patients were treated with calcium Channel antagonists, 22 subjects were chronically treated with nitrates, and 4 with beta-adrenergic blocking drugs. AI1 patients received diltiazem (60 mg, orally) 1 hour before going to the operating room so that interaction of anesthesia and other antianginal therapies could be avoided. Premedication consisted of either midazolam (0.15 mg/kg, IM) or Aunitrazepam (1 mg, orally), administered preoperatively at 30 and 60 minutes, respectively. In the operating room, patients were allocated to the treatment group (n = 15) and received 0.15 mgikg over 2 minutes, followed by 2 uglkgimin of diltiazem, or to the control group (placebo: 0.9% saline, n = 14) according to a randomized double-blind design. Before induction of anesthesia and after diltiazem or placebo administration, a 7-Fr thermodilution pulmonary artery catheter and a radial artery catheter were introduced using local anesthesia. Anesthesia was induced 30 minutes after the beginning of the diltiazem or placebo infusion with fentanyl (8 ugikg), midazolam (0.2 mgikg) or flunitrazepam (0.03 mg/kg), according to the routine of the anesthesiologist, and pancuronium (0.1 mg/kg). Anesthesia was maintained with fentanyl(6 uglkgih) and nitrous oxide (50%), as wel1 as intermittent boluses of midazolam or flunitrazepam and pancuronium. Additional doses of fentanyl(O.l to 0.2 mg) and, occasionally, droperidol, were used as required to maintain mean arterial pressure (MAP) at less than 105 mmHg and HR at less than 100 BPM. Hypotension (MAP < 60 mmHg) was treated with volume loading ( < 500 mL of crystalloid solution), and occasionally doses of phenylephrine (0.5 mg) were used. Hemodynamic measurements were recorded at specific events: Tl (Baseline)-before induction of anesthesia, T2 (Intubation)immediately after trachea1 intubation, T3 (Zncision)-immediately after skin incision, T4 (Stemotomy)-after sternotomy. ECG leads 11 and Vs were continuously monitored. Hard-copy tracings of ECG were obtained for analysis during each specific event and when ECG monitoring showed ST-T wave alterations. Myocardial

Journalof Cardiothoracic and Vascular Anesthesia, Vol 6, NO 4 (August), 1992: pp 424-428

INTRAVENOUS

425

DILTIAZEM DURING ANESTHESIA

Table 1. Demographic and Preoperative

Data

HEART RATE

Control

Treated

Patients

Patients

14

15

Age (years)

59.3 5 2.6

62.0 + 2.1

Weight (kg)

71.7 -t 1.7

74.5 2 2.0

Number of patients

2.6 2 0.2

2.3 ? 0.2

Ejection fraction (%)

56.4 c 2.3

57.5 I 2.3

Calcium antagonists

14114

15115

Nifedipine

4114

5115

Diltiazem

9114

10/15

Bepridil

1114

C.V. bypassed (N)

Beta-blockers Nitrates

70

.r E ô

2115

10114

12115

I

??

I I

55

0

2114

l

60

50 -.-Base. Intub. Control

NOTE. Means + SEM.

+ ~ ~_-- .St&. Incis.

.

Treatod

Abbreviation: C.V. bypassed, number of coronary vessels bypassed.

ischemia was diagnosed on calibrated paper recordings (1 mm = 0.1 mV; paper speed of 25 mm/s) as horizontal or down-sloping ST segment depression of at least 0.1 mV, extending at least 60 ms beyond the J point when compared with the preoperative ECG. Myocardial ischemia was treated by deepening anesthesia or giving IV nitroglycerin (NTG) when ischemic-type ST segment depression persisted for more than 5 minutes and was not associated with hypotension (MAP < 60 mmHg). Plasma diltiazem concentration (high-pressure liquid chromatography technique) was measured in 17 patients (8 controls and 9 treated patients) before the diltiazemiplacebo bolus, and after trachea1 intubation. Each 10 mL bloed sample was withdrawn into nonheparinized test tubes. The plasma was immediately separated and stored at -20°C until analyzed at a later date. Data are expressed as mean -C SEM. Two-way ANOVA, xz analysis for percent comparison, Bonferroni’s test for repeated within-group measurements, and Student’s t test between groups were used when appropriate to determine statistical significante. P values of less than 0.05 were considered significant. RESULTS

Demographic and preoperative data were similar in both groups (Table 1). Anesthetic requirements from induction to aortic cannulation (mean duration: 56.2 i 2.8 and 54.6 2 2.9 minutes for control and treated patients, respectively) were not statistically different between the groups. Eight of 14 control patients and 9 of 15 treated patients received midazolam while the others received flunitrazepam (6 patients in both groups). Ten of 14 control patients and 12 of 15 treated patients received supplemental doses of fentanyl in addition to the continuous infusion. Seven control patients and 8 treated patients required smal1 doses of droperidol (Table 2). NO B-blocker

Table 2. Supplemental

Doses of Fentanyl or Droperidol Required

Control Fentanyl

(Fg)

Droperidol (mg)

NOTE. Means + SEM.

was used and HR never exceeded 100 BPM in any patient at any time. Plasma diltiazem concentrations were not significantly different between groups before the diltiazemiplacebo bolus: at this time, the mean plasma diltiazem leve1 from 17 patients of both groups (8 controls and 9 treated patients) was 125.1 2 16.4 ng/mL (134.6 * 26.3 ng/mL in controls and 116.5 r 21.2 ng/mL in treated patients, NS). After induction of anesthesia and trachea1 intubation, plasma diltiazem concentration was significantly lower in controls (85.8 +I 28.4 ng/mL) than in treated patients (184.6 -r 24.3 ng/mL) (P < 0.02). Hemodynamic data in the control and treatment groups are presented in Figs 1 through 5. HR and MAP were lower in the treatment group than in the control group at each event: the groups differed significantly with regards to MAP after trachea1 intubation and HR after sternotomy (P < 0.02) (Figs 1 and 2). In the treatment group, PCWP increased significantly from baseline after skin incision and sternotomy (both P < 0.02), but was not statistically different from the control group at any time in the study (Fig 3). MEAN ARTERIAL BLOOD PRESSURE

f % E

Treated

Group

Group

215 + 29.9

200 * 29.5

(10/14)

(12/15)

5.7 I 0.7

6.3 + 1.3

(7/14)

Fig 1. Means f SEM. Base, baseline; Intub, intubation; Incis, incision; Stern, sternotomy. ?? p < 0.05 between groups; “p < 0.05 within groups compared with baseline values.

@/15)

I 65c----t

l Base Intub. Control

+_~_.__~___i_.

*

Incis. Treated

_

.-

Stern.

Fig 2. Means t SEM. Base, baseline; Intub, intubation; Incis, incision; Stern, sternotomy. *P < 0.05 between groups; “P c 0.05 within groups compered with baseline values.

COLSON ET AL

426

SYSTEMIC

PULMONARY CAPILLARY WEDGE PRESSURE

/

g

11

$ :

109

Ë :. i

I

R

7-

iñ

1000

6

-_.Base. -

Incis. Treated

Intub. Control

.

k,__.,(

1500

1250

8

5-

?

1750.

13 12

REStSTANCES

2000

15. 14

ol

VASCULAR

.~~~~,

1

1

i Stern.

-

Cardiac index decreased significantly from baseline in both groups: after intubation (P < 0.05) incision and sternotomy (P < 0.01) in the treatment group, and after sternotomy (P < 0.05) in the control group (Fig 4). CI was significantly lower in the treatment group when compared to the control group at the time of skin incision (P < 0.01) (Fig 4). Systemic vascular resistance increased significantly from baseline after skin incision in the treatment group (P < 0.01) and after sternotomy in both groups (P < 0.01). SVR was not statistically different between the two groups at any time (Fig 5). Patients from both groups did not differ in mean SVO,, which remained above 75% at al1 times after anesthetic induction. NO patient had ischemia at the time of coming to the operating room. During the study, ST segment changes occurred in 4 of the 14 control patients (28.6%) and 2 of the 15 treated patients (13.3%) when compared with the preoperative ECG (Fig 6) (NS). Ischemic episodes were not associated with hypotension in any group, but they were associated with hypertension in 2 control patients when NTG was required. Neither prolonged hypotension (defined as MAP < 60

1

750+iiz3rIncir------ <

Stern.

Fig 3. Means f SEM. Base, baseline; Intub, intubation; Incis, incision; Stern, sternotomy. *P < 0.05 between groups; “f < 0.05 within groups compared with baseline values.

*,’

Control

.

Treated

Fig 5. Means f SEM. Base, baseline; Intub, intubation; Incis, incision; Stern, sternotomy. ?? P e 0.65 between groups; “P c 0.05 within groups compared with baseline values.

mmHg lasting more than 10 minutes) nor prolonged bradycardia (defined as HR < 40 BPM lasting more than 10 minutes) occurred in the treatment group. One control patient required 0.5 mg of phenylephrine to treat a prolonged hypotensive episode before skin incision. However, hypotensive episodes (MAP < 60 mmHg lasting less than 10 minutes) were more frequent in treated patients than in controls (8 of 15, and 5 of 14 patients, respectively). Perioperative MI occurred in 2 control patients. One of them was associated with an intractable low cardiac output (CO), which caused the death of the patient during the first postoperative hours. The other was also associated with a low CO, but was successfully treated with dobutamine. In the treatment group, no perioperative MI occurred, but one patient suffered from a low CO syndrome during the first postoperative day. DISCUSSION

This study demonstrates that therapeutic plasma diltiazem concentrationsr’ were maintained with a continuous diltiazem infusion during anesthesia for CABG. Combined with moderate doses of fentanyl, plus midazolam or fluni-

CARDIAC INDEX

PERCENT OF ISCHEMIC

4r

PATIENTS

100% 90% 80% * f ..$

~~ -

Control

’

Incis. Treeted

_+-- _~~

70% 60%

a

50%

Tj e Q

40% 30% 20%

Stern.

Fig 4. Means -t SEM. Base, baseline; Intub, intubation; Incis. incision; Stern, sternotomy. *P c 0.05 between groups; “P -Z 0.05 within groups compared with baseline values.

Control Ischemic

LI1

Fig 6. Percent of ischemic patients pass in both groups.

Treated Non-ischemic

before csrdiopulmonary

by

INTRAVENOUS

DILTIAZEM

DURING ANESTHESIA

427

trazepam, diltiazem reduced HR, BP, and CI during the stressful events occurring before CPB. An important finding of this study was the rapid decline in plasma diltiazem concentrations after oral administration given with the premedication. Patients of both groups received oral diltiazem (60 mg) with their premedication, which provided higher plasma diltiazem concentrations than the therapeutic threshold (96 ng/mL), as defined by Joyal et al,” upon arrival in the operating room. Thirty minutes later, at the time of trachea1 intubation (about 90 minutes after the last dose of oral diltiazem), plasma diltiazem concentrations were lower than the therapeutic leve1 in the major@ (90%) of control patients. These results are in agreement with data of Godet et a1.9Unfortunately, neither of the two previous studies dealing with preoperative use of calcium entry blockers before CABG6*8 reported plasma concentrations of these drugs. One oral dose of a calcium entry blocker given prior to anesthesia is not enough to maintain therapeutic plasma levels through prolonged surgery such as CABG. Differences in plasma drug concentrations underlie the discrepancy between the effective protection from ischemia with IV diltiazem” and the absente of protection with chronic oral preoperative treatment with calcium Channel blockers.h.8 Beneficial effects of calcium antagonists cannot be ruled out in studies in which therapeutic plasma concentrations were not controlled.@ The combination of benzodiazepines with narcotics is routinely used and is normally wel1 tolerated in moderate doses.1z-14The purpose of this study was not to clarify the continuing debate on the narcotic-benzodiazepine combinations.15,*h However, hemodynamic response to fentanylmidazolam may be different from that to fentanylflunitrazepam in the presence of diltiazem. Even though the smal1 sample size of the study does not allow any definite conclusion, no differente in hemodynamics was noticeable between midazolam and flunitrazepam in these patients. In the control patients, requirements for additional doses of fentanyl or droperidol were minimal, and

only one patient required administration of a vasoconstrictor for prolonged hypotension. These data suggest that the anesthetic protocol was appropriate with respect to the hemodynamic objectives, lowering of MV02 and preservation of myocardial oxygen supply. Within the therapeutic range, diltiazem further reduced HR, BP, and CI. The MVO2 was reduced during the most stressful events of CABG, ie, incision and sternotomy. The decrease in CI in association with a rise in PCWP suggests that inotropy was reduced. Nevertheless, systemic oxygen supply was maintained over the study as assessed by SVO, values greater than 75%, which implies that oxygen consumption may have been further decreased by the calcium antagonist. The depression of myocardial function may have been partly responsible for the high incidence of hypotensive episodes (even of short duration) in the treatment group, but no ischemia was detected during these episodes. This seems to be at odds with reports in the literature, which state that hypotension plays a major role in perioperative ischemic risk.*7x18However, as demonstrated by Buffington,18 a lower HR increases the ischemic threshold. Moreover, myocardial oxygen demand/supply matching can be explained by an improvement in the coronary circulation (or oxygen suppl~),~~ as wel1 as a decrease in myocardial work. The smal1 number of patients precludes any statistical conclusion from the reduction in the incidence of ischemia in the treated group. Continuous infusion of diltiazem reduces the risk of myocardial ischemia mediated by an increase in MV02 (increased HR and cardiac work).y The effect of diltiazem on ischemia related to a decrease in oxygen supply is suggested by tolerante to hypotension in the treated patients. Perioperative myocardial ischemia determinants are multifactorial, but al1 lead to a myocardial oxygen demand/ supply imbalance. Diltiazem mainly reduces MV02 by blocking increases in cardiac work or even by decreasing it. This effect can be regarded as potentially beneficial during anesthesia for CABG.

REFERENCES

1. Slogoff S, Keats A: Does preoperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology 62:107114,198s 2. Slogoff S, Keats A: Further observations on perioperative myocardial ischemia. Anesthesiology 6.5539-542, 1986 3. Knight AA, Hollenberg M, Londen MJ, et al: Perioperative myocardial ischemia: Importante of the preoperative ischemic pattern. Anesthesiology 68:681-688, 1988 4. Slogoff S, Keats A: Randomized trial of primary anesthetic agents on outcome of coronary artery bypass operations. Anesthesiology 70:179-188, 1989 5. Tuman KJ, McCarthy RJ, Spiess BD, et al: Does the choice of anesthetic agent significantly affect outcome after coronary artery surgery? Anesthesiology 70~189-198, 1989 6. Slogoff S, Keats AS: Does chronic treatment with calcium entry blocking drugs reduce perioperative myocardial ischemia? Anesthesiology 68:676-680,1988 7. Dodds TM, Delphin E, Stone JG, et al: Detection of

perioperative myocardial ischemia using Holter monitoring with real-time ST segment analysis. Anesth Analg 67890893, 1988 8. Chung F, Houston PL, Cheng DCH, et al: Calcium Channel blockade does not offer adequate protection from perioperative myocardial ischemia. Anesthesiology 69:343-347,1988 9. Godet G, Coriat P, Baron JF, et al: Prevention of intraoperative myocardial ischemia during noncardiac surgety with intravenous diltiazem: A randomized trial versus placebo. Anesthesiology 66:241-245, 1987 10. Taira N: Differences in cardiovascular profile among calcium antagonists. Am J Cardiol59:24B-29B, 1987 ll. Joyal M, Pieper J, Cremer K, et al: Pharmacodynamic aspects of intravenous diltiazem administration. Am Heart J 111:54-61, 1986 12. Colson P, Ribstein J, Mimran A, et al: Effect of angiotensinconverting enzyme inhibition on blood pressure and renal function during open heart surgery. Anesthesiology 72:23-27,199O 13. Tuman KJ, McCarthy RJ, El-Ganzouri AR, et al: Sufentanil-

428

COLSON ET AL

midazolam anesthesia for coronary artery surgery. J Cardiothorac Anesth 4:308-313,199O 14. Ruff R, Reves JG: Hemodynamic effects of a lorazepamfentanyl anesthetic induction for coronary artery bypass surgery. J Cardiothorac Anesth 4:314-317,199O 15. Howie MB: Pro: Benzodiazepines are contraindicated as induction agents for coronary artery surgery. J Cardiothorac Anesth 2:841-843,1988 16. Reves JG: Con: Benzodiazepines

are not contraindicated

as

induction agents for coronary artery surgery. J Cardiothorac Anesth 2:844-848,1988 17. Rao TLK, Jacobs KH, El-Etr AA: Reinfarction following anesthesia in patients with myocardial infarction. Anesthesiology 59:499-505, 1983 18. Buffington CHW: Hemodynamic determinants of ischemic myocardial dysfunction in the presence of coronary stenosis in dogs. Anesthesiology 63:651-662,1985 19. Braunwald E: Mechanism of action of calcium-channelblocking agents. N Eng1 J Med 307:1618-1627,1982