diazepam anesthesia

Variations in Hemodynamic and Stress Hormonal Responses in Open Heart Surgery With Buprenorphine/Diazepam Anesthesia Ryu Okutani, MD, Katsuakira Kono, MD, Osamu Kinoshita, MD, Harumasa Nakamura, MD, Hiroatsu Ishida, MD, and Daniel M. Philbin, MD The use of buprenorphine-diazepam-N20 (60%)-02 anesthesia in open heart surgery was investigated. The authors examined the hemodynamic changes produced and the response of stress hormones. Twenty adult patients with atrial septal defects undergoing surgical correction were studied in two groups of 10, receiving either 6 / ~ g / k g of buprenorphine (B6) or 12 /~g/kg of buprenorphine (B12) for the induction of anesthesia. Both groups received a subsequent dose of 6 / ~ g / k g of buprenorphine with the commencement of extracorporeal circulation (ECC). With surgery, mean arterial pressure showed a transient increase in both groups and thereafter was stable. Heart rate in the B6 group was increased from the onset of surgery to the day after, while the B12 group showed no significant change. Filling pressures showed no change in either group. Plasma

catecholamine concentrations in the B6 group, in contrast to the B12 group, increased significantly from midoperation to after completion of the operation (ECC 10 minutes, B6 group v B12 group: plasma norepinephrine 616 _+ 231 v 195 _+ 38 pg/mL, plasma epinephrine 1 3 8 5 _+ 3 9 2 v 572 _+ 132 p g / m L , P < 0.05). Plasma ADH levels in both groups rose with the commencement of surgery, reaching a peak at ECC 10 minutes (B6 group 88.1 _+ 8.4 vB12 group 124.4 _+ 27.2 pg ! mL). However, in contrast to plasma catecholamines, the antidiuretic hormone (ADH) levels in the B12 group remained higher until the first postoperative day. Therefore, patients who received the larger dose of buprenorphine had better control of hemodynamics and catecholamines, but a greater elevation of plasma ADH levels.

N R E C E N T YEARS, high-dose fentanyl, sufentanil, and morphine have become the most common anesthetics administered to patients undergoing open heart surgery. 15 However, these drugs are used in high doses, and because they are narcotics (controlled substances) require careful handling and control as well as a significant amount of recordkeeping. Buprenorphine-HCL, on the other hand, has the advantage of being a nonaddicting agonistantagonist drug with a powerful analgesic effect. 6 It has been used successfully in pain management 7q2 and for anesthesia in abdominal surgery. 13 In this study, during cardiac surgery, the preselected induction dose of 6 lzg/kg of buprenorphine was used, based on a previous report of its use in abdominal surgery, and then the dose was doubled to 12 #g/kg. The drug was administered in conjunction with diazepam, N20 , and halothane to two separate groups of 10 patients each who were scheduled for elective open heart surgery. Hemodynamic and endocrine responses, especially the fluctuations in c a t e c h o l a m i n e s and a n t i d i u r e t i c h o r m o n e (ADH), were recorded.

class I-II disease, undergoing elective primary closure operations. Cases complicated by any other heart defect or by pulmonary hypertension were excluded. The patients were randomly divided into two groups: the 6/~g/kg of buprenorphine (B6) group, composed of 10 subjects, and the 12 #g/kg of buprenorphine (B 12) group, also composed of 10 subjects. As premedication, 0.15 mg/kg of morphine sulphate and 0.4 mg of scopolamine were injected intramuscularly (IM) one hour before the anesthesia. Upon arrival in the induction room, an electrocardiogram (lead II) was monitored and a 20g arterial catheter and a pulmonary artery catheter (93A-831H, 7.5Fr, AHS, Edwards Laboratories, Santa Ana, CA) were introduced under local anesthesia with hemodynamic data subsequently recorded (78342A and 78205D, Hewlett Packard, Palo Alto, CA). After intravenous (IV) injection of 6 #g/kg of buprenorphine in the B6 group and 12 ug/kg of buprenorphine in the B12 group (both groups receiving 100% oxygen via oxygen mask), a sedative dose of diazepam was infused. Tracheal intubation was performed after administration of pancuronium bromide, 0.1 mg/kg. Anesthesia was maintained with inhalation of N20 (60%) and 02 (40%), and controlled ventilation to maintain the PaCO2 at 35 to 40 mmHg. If systolic blood pressure (BP) rose by more than 30% over basal (preanesthetic) values, 0.5% to 0.8% halothane was added to the inspired gases.

I

PATIENTS AND METHODS This research protocol was approved by the Institutional Ethics Board, and informed oral consent was obtained from all patients. The subjects were 20 adult patients with atrial septal defects (ASD) and New York Heart Association

© 1989 b y W.B. Saunder s

Company.

From the Department of Anesthesia, Hyogo College of Medicine, Nishinomiya, 663, Japan, the Department of Anesthesia, Himeji Brain and Heart Center, Himeji, 670, Japan, and the Department of Anesthesia, Harvard Medical School and Massachusetts General Hospital, Boston, MA. Address reprint requests to Daniel M. Philbin, MD, Department of Anesthesia, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114. © 1989 by W.B. Saunders Company. 0888-6296/89/0304-0004503.00/0

Journal of Cardiothoracic Anesthesia, Vol 3, No 4 (August), 1989: pp 401-406

401

OKUTANI ET AL

402

With the commencement of extracorporeal circulation (ECC), each group received an additional dose of 6 ug/kg of buprenorphine and 0.1 mg/kg of diazepam. During ECC, perfusion pressure was maintained between 60 and 80 mmHg and flow at 2.2 to 2.4 L / m i n / m z, rectal temperature at 33°C, and the operation was performed with the heart fibrillating. No patient received a blood transfusion or vasoactire drugs. Blood samplings for determination of hormone levels, blood gases, and hemodynamic parameters were performed: (1) before anesthesia induction, (2) immediately after endotracheal intubation, (3) at 15 minutes of anesthesia, (4) at 10 minutes of surgery (after sternotomy), (5) at 30 minutes of surgery (after pericardiotomy), (6) subsequent to aortic cannulation, (7) at ECC 10 minutes, (8) 30 minutes, (9) 60 minutes, (10) post-ECC one hour, (11) two hours (postsurgery), (12) six hours, and (13) nine AM the day after surgery. Mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and right atrial pressure (RAP) were recorded and samples withdrawn for determination of plasma free catecholamine and plasma ADH levels. The plasma buprenorphine level was also determined in four patients (two in each group). Plasma free catecholamine concentrations were measured by using high-performance liquid chromatography with fluorescent detection after purification and concentration with albumin. The variation coetfieients (CV) for the values in one specimen were 3% to 14% for norepinephrine and 4% to 12% for epinephrine. The average recovery rates were 65% each. Plasma ADH was determined using the radioimmunoassay method of Philbin et al after acetone extraction. 4 Intraassay-CV was 6% to 8%, interassay-CV was 4% to 13%, respectively. Plasma buprenorphine was determined with the radioimmunoassay method of Barlett et al. 14 Results were indicated as mean -+ SEM. Statistical analysis was conducted using Student's t test. RESULTS

No differences were observed between the two groups of patients in age, body surface area, preoperative cardiac catheterization data, dura-

Table 1. Demographic Data for the Two Groups Group B6

Group B 12

Number (m/f) Age (yr) BSA (m 2)

10(8/2) 38 -+ 4 1.52 4- 0.04

10(4/6) 42 -+ 4 1.50 4- 0.05

EF (%) Operation time (rain) ECCtime (min) VF time (min)

70.4 224 52 24

67.2 237 64 36

Buprenorphine (#g/kg) Diazepam (rng/kg)

12.0 4- 0.7 0.47 -+ 0 . 0 3 "

-+ 4-+ 4-

1.5 9 2 2

-+ 4+ 4-

2.8 16 10 5

17.6 4- 0.8 0.34 -+ 0.01

Values are expressed as mean 4- SEM. Abbreviations: BSA, body surface area; EF, ejection fraction; ECC, extracorporeal circulation; VF, ventricular fibrillation. * P < 0.05.

tion of ECC, or ventricular fibrillation time. However, the dose of diazepam was significantly greater in the B6 group, (B12 group 0.34 + 0.01 mg/kg, B6 group 0.47 + 0.03 mg/kg, P < 0.05) (Table 1). Mean arterial pressure decreased significantly in both groups after 15 minutes of anesthesia, then showed a significant increase at 10 minutes of surgery (Table 2). It remained elevated in the B 12 group until ECC. Once ECC was completed, both groups had a lower BP than control. During the course of the operation, inhalation of 0.5% to 0.8% halothane was administered in 60% of the B6 group and 40% of the B12 group, usually during the sternotomy for a period of less than 10 minutes. A significant difference in BP (P < 0.05) was observed between the two groups at 30 minutes (midsurgery after pericardiotomy). Heart rate in the B6 patients increased significantly at 30 minutes of

Table 2. Changes in Hemodynamic Parameters for the Two Groups PostPreanesthesia intubation MAP (mmHg)

B6

B12 HR (beats/min) B6 B12 PCWP (mmHg) B6 B12 MPAP (mmHg) B6 B12 RAP (mmHg) B6 B12

92 4- 3 92 81 95 12 10 20 19 6 7

-+ 5 4- 4 4- 10 4- 2 4- 1 4- 2 4- 2 4- 1 4- 1

85 + 3 95 -+ 8 93-+ 8 t 100 4- 8 10_+1 104-2 17+2 174-2 64-0 84-1

Anesthesia Operation 15 min 10 min 82-+3" 73 + 3 * 80 + 5 80-+ 5 84-2 8_+2 144-3 144-3 54-1 7-+1

101 4- 3 t 110 4- 3 t 85 4- 4 85 4- 3 94-1 94-2 164-2 17-+2 74-1 94-1

30 min 82 + 4 t 100 4- 5~t 93-+ 4 t 86 4- 3::1: 104-1 104-2 164-2 164-2 84-1 104-1

Pre-ECC 81 + 5 t 88 + 4 t 90 4- 5 88-+ 4 94-3 104-1 154-2 164-2 74-1 94-1

Post-ECC 1 hr

2 hr

77 + 5 t 83-+ 6 76 + 4 79 _+ 6 105 4- 7 * 101 4- 8 * 89 4- 4:~ 84_+ 4:[: 134-2 13_+2 12_+1 11_+1 194-2 20_+3 16+1 16_+1 84-1 8-+2 10_+1 10_+2

6 hr

Day After Operation

76 + 3 * 71 + 3 * 97 4- 6 t 87 4- 4 114-2 104-2 19-+3 164-1 54-1 94-2

73 + 3 " 79 + 21' 84 4-5 83 4- 3 124-1 114-2 184-2 164-1 84-1 84-2

Values are expressed as mean + SEM. Abbreviations: MAP, mean arterial pressure; HR, heart rate; PCWP, pulmonary capillary wedge pressure; MPAP, mean pulmonary artery pressure; RAP, right atrial pressure. *Significant difference from preanesthetic value, P < 0.01. tSignificant difference from preanesthetic value, P < 0.05. :[:Significant difference between each group, P < 0.05.

BUPRENORPHINE/DIAZEPAM

ANESTHESIA

403

~ lO00~B12

z O~ F< n." IZ

w 500 (3 ooz w z < to < o J13_ A

I ECC OP

t

PRE' PO;TA~IES. I ANES. INT. 15M. I

1 ]

I I

I I

' ' 1OM.30M. 60M.

STERNOTOMY I PERICARDIOTOMY Ao CANNULATION

1500] ½

{B6 {B12

+/1\1

5001

0.05, [] P < 0.01.

' 6H.

' DAY AFTER OP,

' 6H.

i DAYAFTER OP

~ i

t+++ Fig 1. (A,B) Changes in plasma catecholamines for both groups. Values are expressed as mean ± S E M . Significant difference from preanesthetic v a l u e ; + P < 0.05, + + P < 0.01. Significant difference between each group; [ ] P

P0~ST ECC ' 1H 2H,

+

_

i ,+ OP

PRE.' POSTANES.OP. I PRE. ECC' ' + I ANES. INT 15M IOM.30M ECC IOM. 30M. 60M.

surgery and after ECC, but not in the B12 patients (Table 2). Plasma norepinephrine was 298 _+ 31 pg/ mL in the B6 group before anesthesia (Fig 1A), significantly decreased during anesthesia before incision, then rose and was 1.6-fold higher at the outset of surgery, 2.1-fold higher during ECC, and remained elevated after the completion of ECC until the day after operation. The B12 group showed no significant change, except for a transient increase at ECC 60 minutes. Plasma epinephrine decreased in both groups during anesthesia before incision (Fig 1B). In the B6 group, however, the preanesthesia level of 276 ___ 93 pg/mL increased 3.3-fold with the commence-

POST ECC 1H. 2H.

ment of surgery, was further elevated 5.0-fold during ECC, and remained elevated after ECC, but returned to preanesthesia levels on the day after operation. On the other hand, plasma epinephrine concentrations in the B12 group, (297 _+ 136 pg/mL), showed no significant change until ECC 30 minutes and 60 minutes when it rose significantly. After ECC it returned to the preanesthesia level. There were significant differences between the two groups at 10 minutes and 30 minutes of surgery, pre-ECC and postECC. High concentrations of plasma ADH were observed before anesthesia, 7.2 _+ 0.7 pg/mL in the B6 group and 9.8 _+ 3.2 pg/mL in the B12

404

~

OKUTANI ET AL

-'H-

150B6

Z

_o

BlZ

-.-

< I1" 100" I-Z hi 0 Z 0 0 "1" 50" D < if) < n"J

0

I

OP

PRE: PO;T ANE?, I I ECC ' ' ANES INT, 15M. l IOM 30M.60M STERNOTOMY PERICARD]OTOM'd A0 CAHNULAT]ON

] POST E{~C 1H. 2H,

6'1"1,

DAY AFTER OP.

group (normal <4 pg/mL) (Fig 2). With the commencement of surgery they rose and reached maximums of 88.1 ___8.4 pg/mL for the B6 group and 124.4 _+27.2 pg/mL for the B12 group at 10 minutes of ECC, thereafter decreasing gradually and returning to their preanesthesia levels two hours after ECC and the day after operation, respectively. From the initiation of ECC to the day after operation, there seemed to be a trend for higher plasma ADH levels in the B12 compared with the B6 group, but no statistical difference was detected.

Fig 2. Changes in plasma A D H for both groups. Values are expressed as mean _+ SEM. Normal range of A D H in human plasma is 0.5 to 3.0 p g / m L in the laboratory. Significant difference from preanesthetic value; + P < 0.05, + + P < 0.01. Note that the plasma A D H was higher in the B12 group than in the B6 group from the beginning of ECC until the day after operation.

Plasma buprenorphine concentrations were determined in four cases. In all cases a peak was reached 5 minutes after IV injection, then subsequently decreased. The concentrations rose again, reflecting the additional dosage at the initiation of ECC, then dropped to undetectable levels the day after operation (Fig 3). DISCUSSION

The subjects of this study were all patients with significant intracardiac shunts, and thus

"8 r..) z 0 uJ z

o_ n- 4 O Z LIJ OZ) QQ

< ~E (/)

I

\

--

B6

/

"\,

---

B12

I \\

\~A

/A',

. . . .

!/^ \

,2-. ~-.>\

7\\

"-. ~,,-o

< ._J Q.

x

I ECCl t

Fig3. Plasma buprenorphineconcentrations for four patients (two Group B6 and t w o Group B12).

_~---~

OP

I

PRE, P(~STA'NES. ECC ' f PO'ST E'CC ANES. rNT. 15M | I I IOM. 30M. 60M 1H, 2H. STERNOTOMYI PE~CARDOTOMY A0 CANllULATION

6H,

DAY AFTER OP.

BUPRENORPHINE/DIAZEPAM ANESTHESIA

405

accurate determination of cardiac output was not possible. Nonetheless, it would appear from the hemodynamic measurements obtained that there was no evidence of myocardial depression with the administration of buprenorphine and relatively large doses of diazepam, plus N20 and some halothane. Rosenfeldt et a115 previously reported minimal cardiovascular effects with a 5 ~g/kg dose of buprenorphine in postoperative cardiac patients. They did note a decrease in heart rate, not observed in the present study. This would perhaps suggest that the level of analgesia obtained was inadequate in this study. This might also mask any depressant effects of the diazepam. The suppression of the stress response to surgery, using catecholamine concentrations as an index, was also inadequate in the B6 group with significant increases occurring. The higher dose of buprenorphine was considerably more effective in obtunding these catecholamine responses, at least until the initiation of ECC. The changes that occurred were comparable to those reported with halothane, 13 high-dose fentanyl, 3'16 and sufentanil.17 The most interesting finding in this study was the greater increases in A D H after ECC in the B12 group as compared with the B6 group. It has been suggested that buprenorphine blood concentrations are not necessarily related to the degree of analgesia produced. 6'18'19 However, in the higher dose group there was greater suppression of the catecholamine responses and less (though not significantly less) need for the addition of halothane, implying greater analgesic effect. Yet, A D H concentrations increased more, suggesting the intriguing possibility that buprenorphine may have a stimulatory effect on A D H secretion. Increases in plasma A D H concentrations have been reported with several anesthetic agents, 2°24 but this was usually associated

with an indirect effect mediated by baroreceptor mechanisms, 25'26with a direct effect less likely. It is possible to postulate such a direct effect on the hypothalamo-hypophyseal pituitary axis for buprenorphine. This compound is classified as a narcotic agonist-antagonist, and thus behaves quite differently from the narcotic drugs commonly used in the management of cardiac patients. It is thought to be a partial mu agonist that disassociates very slowly from opioid receptors. It is highly lipophylic and has a potency of 25 to 50 times that of morphine, but with less potential for abuse. Indeed, Pechnick et al have reported that buprenorphine appeared to act directly on the anterior pituitary and accelerated the release of growth hormone in a dosedependent manner. 27 It is conceivable, though purely speculative at this stage, that a similar effect could be produced on the posterior pituitary with the release of ADH. It is wellrecognized that in very high concentration (above 30 pg/mL), ADH is a potent vasoconstrictor with a direct effect on arteriolar beds, particularly in the splanchnic, renal, and coronary circulations. 28 Such effects are now also thought to occur in the physiological concentration range. 29'3° This would suggest that increases in ADH would be less than desirable in patients with coronary and/or renal disease. No adverse effects were detected in this study, but patients with coronary artery disease were excluded. In summary, a dose of buprenorphine reported as adequate for use in abdominal surgery was inadequate to suppress the hemodynamic and catecholamine responses during cardiac surgery. Doubling the dose provided better suppression of these responses, but resulted in a significant increase in plasma A D H levels, which may be undesirable. These results suggest the possibility of a direct stimulatory effect on the posterior pituitary by buprenorphine.

REFERENCES

1. Stanley TH, Webster LR: Anesthetic requirements and cardiovascular effects of fentanyl-oxygenand fentanyl-diazepam-oxygenanesthesia in man. Anesth Analg 57:411-416, 1978 2. Quintin L, Whalley DG, Wynands JE, et al: High-dose fentanyl anesthesia with oxygen for aortocoronary bypass surgery. Can Anaesth Soc J 28:314-320, 1981 3. Kono K, Philbin DM, Coggins CH, et al: Renal function and stress response during halothane or fentanyl anesthesia. Anesth Analg 60:552-556, 1981

4. Philbin DM, Wilson NE, SokoloskiJ, et al: Radioimmunoassayof antidiuretic hormoneduring morphineanesthesia. Can Anaesth Soc J 23:290-295, 1976 5. Lowenstein E, Hallowell P, Levine FH, et al: Cardiovascular response to large doses of intravenous morphine in man. N Engl J Med 281:1389-1393,1969 6. CowanA, LewisJW, Macfarlane IR: Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmaco160:537-545,1977 7. DobkinAB: Buprenorphinehydrochloride;Deter-

406

mination of analgesia potency. Can Anaesth Soc J 24: 186-194, 1977 8. Dowing JW, Leary WP, White ES: Buprenorphine: A new potent long-acting synthetic analgesic. Comparison with morphine. Br J Anaesth 49:251-255, 1977 9. Kamel MM, Geddes IC: A comparison of buprenorphine and pethidine for immediate postoperative pain relief by the IV route. Br J Anaesth 50:599-603, 1978 10. Hovell BC: Comparison of buprenorphine, pethidine, and pentazocine for the relief of pain after operation. Br J Anaesth 49:913-916, 1977 11. Watson PJQ, McQuay H J, Bullingham RES, et al: Single-dose comparison of buprenorphine, 0.3 and 0.6 mg, IV, given after operation: Clinical effects and plasma concentrations. Br J Anaesth 54:37-43, 1982 12. McQuay H J, Bullingham RES, Paterson GMC, et al: Clinical effects of buprenorphine during and after operation. Br J Anaesth 52:1013-1019, 1980 13. Kay B: A double-blind comparison between fentanyl and buprenorphine in analgesic-supplemented anesthesia. Br J Anaesth 52:453-457, 1980 14. Barlett AJ, Lloyd-Jones JG, Rance MJ, et al: The radioimmunoassay of buprenorphine. Eur J Clin Pharmacol 18:339-345,3980 15. Rosenfeldt FL, Houton B, Thompson D, et al: Haemodynamtc effects of buprenorphine after heart surgery. Br Med J 2:1;602-1603, 1978 16. Stanley TH, Berman L, Green O, et al: Plasma catecholamine responses to fentanyl-oxygen anesthesia for coronary artery operations. Anesthesiology 53:250-253, 1980 17. Bovill JG, Sebel PS, Fiolet JWT, et al: The influence of sufentanil on endocrine and metabolic responses to cardiac surgery. Anesth Analg 62:391-397, 1983 18. Jacob JJC, Ramabadran K: Enhancement of nocioceptive reaction by opioid antagonists in mice. Br J Pharmaco164.'91-98, 1978 19. Bovill JG: Which potent opioid? Important criteria for selection. Drugs 33:520-530, 1987

OKUTANI ET AL

20. Oyama T, Kimura K: Plasma levels of antidiuretic hormone in man during diethyl ether anesthesia and surgery. Can Anaesth Soe J 18:614-620, 1971 21. Oyama T, Sato K, Kimura K: Plasma levels of antidiuretic hormone in man during halothane anesthesia and surgery. Can Anaesth Soe J 18:614-620. 22. Oyama T, Taniguchi K, Ishihara H, et al: Effects of enflurane anesthesia and surgery on endocrine function in man. Br J Anaesth 51:141-148, 1979 23. Debado RC: The antidiuretic action of morphine and its mechanism. J Pharmacol Exp Ther 82:74-80, 1944 24. Inturrisi CE, Fujimoto JM: Studies on the antidiuretic action of morphine in the rat. Eur J Pharmacol 2:301-307, 1968 25. Philbin DM, Coggins CH: Plasma antidiuretie hormone levels in cardiac surgical patients during morphine and halothane anesthesia. Anesthesiology 49:95-98, 1978 26. Stanley TH, Philbin DM, Coggins CH: Fentanyloxygen anaesthesia for coronary artery surgery. Cardiovascular and antidiuretic hormone responses. Can Anaesth Soc J 26:168-172, 1979 27. Pechnick RN, George R, Poland RE: The effects of the acute administration of buprenorphine hydrochloride on the release of anterior pituitary hormone in the rat: Evidence for the involvement of multiple opiate receptors. Life Sciences 37:1861-1868, 1985 28. Nakano J: Cardiovascular responses to neurohypophyseal hormones. Handbook of Physiology, Section 7, Endocrinology vol 4, part I. Bethesda, MD, Am Physiol Soc 1974, pp 395-442 29. Altura BM, Altura BT: Actions of vasopressin, oxytocin, and synthetic analogs on vascular smooth muscle. Fed Proe 43:80-86, 1984 30. Cowley AM Jr, Quillen EW Jr, Skelton MM: Role of vasopressin in cardiovascular regulation. Fed Proc 42:3170-3176, 1983