The role of intrathecal morphine in the anesthetic management of patients undergoing coronary artery bypass surgery

ORIGINAL

ARTICLES

The Role of Intrathecal Morphine in the Anesthetic Management of Patients Undergoing Coronary Artery Bypass Surgery William F. Casey, MB, FFARCSI, J. Earl Wynands, MD, FRCP(C1, Fiona E. Ralley, MB, FFARCS, James G. Ramsay, MD, FRCP(C), J. Patrick O’Connor, MD, FRCP(C), Joel M. Katz, MD, FRCP(C), and Saul Wiesel, MD The study was undertaken to assess the effects of intrathecal morphine (ITM) on perioperative hemodynamics, and anesthetic and postoperative analgesic requirements in patients anesthetized with fentanylfenflurane undergoing coronary artery bypass surgery. Forty patients were randomized in a doubleblind fashion to receive either intrathecal morphine or saline. Nineteen patients received ITM, 0.02 mg/ kg, and 21 intrathecal saline K’S) after induction of anesthesia. Anesthesia included fentanyl, 40 pug/kg, and pancuronium, 0.15 mg/kg, and was supplemented with enflurane when systolic blood pressure was 20% higher than ward pressure. lntrathecal morphine did not improve hemodynamic stability or reduce enflurane requirements perioperatively. No

P

OSTOPERATIVE pain control for surgical patients continues to be a major problem. Parenteral narcotics and regional anesthesia are the mainstays of postoperative pain relief; however, their effects are often intermittent and of short duration. New methods of analgesic administration have been developed, including continuous intravenous and patient-controlled infusion of narcotics. In addition, the identification of opiate receptors in the spinal cord has

This article is accompanied by an editorial. Please see: Stanley TH: Opiates, receptors, and the Cardiothoracic Anesth 1503-509, 1987.

From the Departments of Anaesthesia, Royal Victoria Hospital and McGill University. Montreal. Address reprint requests to Dr J.E. Wynands, Department of Anaesthesia. Royal Victoria Hospital, 687 Pine Ave W, Montreal. Quebec, Canada, H3A IAI. 0 1987 by Grune & Stratton, Inc. 0888~6296/87/0106-0002$3.00/O

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significant difference was found between ITM and ITS groups for postoperative requirements of morphine (3.5 + 0.5 Y 4.5 f 0.6 mg). diazepam (5.6 f 1.25 v 3.9 + 1.26 mg), and vasodilators (6 v 13 patients), respectively. Comparable and significant reductions of peak expiratory flow rates (PEFRL forced vital capacity (FVC). and forced expiratory volume (FEV,) occurred in both groups postextubation when compared with preoperative values. Intrathecal morphine at the dose of 0.02 mglkg does not offer any clear benefit to patients anesthetized with fentanyl, 40 pglkg, for coronary artery bypass surgery. e 1987 by Grune & Stratton,

inc.

permitted introduction of intrathecal and epidural narcotics.’ Intrathecal opiates have been shown to produce intense analgesia for up to 24 hours.‘” Fentanyl is a potent analgesic commonly used for induction and maintenance of anesthesia in patients undergoing coronary artery bypass grafting (CABG) because it provides good cardiovascular stability.6 At this institution, a dose of 40 pg/kg of fentanyl supplemented by an inhalation agent is used during surgery, since very high doses of fentanyl (150 pg/kg) do not guarantee hemodynamic stability and are associated with increased postoperative hypotension and prolonged respiratory depression.7 Patients receiving this lower dose of fentanyl often require supplementary anesthesia intraoperatively and analgesia in the postoperative period. Use of intrathecal morphine (ITM) for open heart surgery has been reported to provide satisfactory analgesia during the postoperative period for up to 24 hours.8-10These studies did not use fentanyl as the mainstay of their anesthesia technique, nor were the hemodynamic effects of intrathecal

Journal of Cardiothoracic Anesthesia, Vol 1, No 6 (Decembw), 1987: pp 5 1O-5 16

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ROLE OF INTRATHECAL MORPHINE FOR CABG SURGERY

morphine recorded during the perioperative and postoperative periods. The present study was designed to assess, in a double blind and randomized fashion, the effects of ITM on perioperative hemodynamic stability, enflurane requirement, postoperative pain relief, and respiratory function and mechanics. METHODS With informed consent and ethics committee approval, 40 patients scheduled for elective CABG surgery who had left ventricular ejection fractions greater than 0.4 and no contraindications to lumbar puncture were studied. Preoperatively, prothrombin time (PT), partial thromboplastin time (PTT), and platelet counts were normal. Respiratory function was assessed preoperatively by forced vital capacity (FVC), forced expiratory volume in one second (FEV,) using a Vitalograph (Model R Vitalograph Corp, Kansas City), and peak expiratory flow rates (PEFR) using a peak expiratory flowmeter. Premeditation consisted of diazepam, 0.15 mg/kg, orally, morphine, 0.1 mg/kg, and scopolamine, 0.4 mg, intramuscularly (IM), administered one hour preoperatively. Monitoring consisted of a continuous electrocardiogram (modified leads V, and II), arterial pressure via a radial artery catheter, and pulmonary artery pressure and central venous pressure (CVP) via a pulmonary artery catheter; both inserted prior to induction of anesthesia. Thermodilution cardiac outputs were measured and hemodynamic profiles computed using a Gould Hemodynamic Profile Cardiac Output Computer (Gould Inc, Oxnard, CA). A mass spectrometer (Allegheny International Medical Technology SARA system) was used to measure end-tidal PCOr (Par. CO*) and end-tidal enflurane concentrations during anesthesia. Following induction of anesthesia, temperature was measured with nasopharyngeal and bladder temperature probes (Mon-a-Therm Model 6500 System, St Louis). Anesthesia was induced with fentanyl, 40 pg/kg, and pancuronium, 0.15 mg/kg, given over three minutes. Patients received 0.2 times the total dose of pancuronium prior to fentanyl administration to prevent muscle rigidity, and were ventilated with 100% oxygen to a P&Or of 30 + 6 mmHg. Intubation was performed three minutes after administration of the total dose of muscle relaxant. The intrathecal injectate was prepared by the pharmacist. Following induction of anesthesia, patients were turned to the lateral position and, with standard aseptic technique, a 25-gauge spinal needle was placed intrathecally at the L,-L, interspace. Patients were given either preservative-free ITM, 0.02 mg/kg, or intrathecal saline (ITS) in the equivalent volume in a randomized double-blind manner. Hemodynamic measurements were recorded pre- and post-induction of anesthesia, following the intrathecal injection, skin incision, sternotomy, aortic dissection and at frequent intervals after cardiopulmonary bypass (CPB) and surgery until 24 hours after the intrathecal injection. Systolic blood pressure increases of more than 20% above ward values were treated intraoperatively with enflurane, and with nitroglycerin or nitroprusside in the postoperative period.

Nitroglycerin was used intraoperatively when there were electrocardiographic signs of myocardial ischemia and when elevation in systolic blood pressure was not controlled by enflurane. Systolic blood pressure decreases of greater than 20% below ward values were treated with intravenous fluids and/or inotropes or vasoconstrictors. The intervention used was dictated by the cardiac output, filling pressures, and systemic vascular resistance. Heart rates greater than 80 beats/min were treated with I-mg increments of propranolol before cardiopulmonary bypass; heart rates greater than 110 beats/min were treated postoperatively. The dosage of enflurane used intraoperatively was computed into “MAC minutes” as follows: the number of minutes spent at one enflurane concentration (end-tidal) was multiplied by the concentration, and then divided by the minimal alveolar concentration (MAC). The total number of MAC minutes was then the sum of values obtained at all enflurane concentrations. Diazepam was administered intraoperatively for additional sedation at insertion of monitoring lines and as an amnesic agent given at the onset of cardiopulmonary bypass, at the discretion of the anesthesiologist. A visual linear analogue pain score was explained to the patient preoperatively,” and used initially along with direct questioning to assess pain. It became clear that patients experienced difficulty in using a visual scale during the postoperative period. For this reason, pain was then assessed by direct questioning only beginning with “Do you have pain?” and, if the answer was yes, “Do you want treatment for the pain?” If the answers to both questions were positive the patients were given 2.5mg increments of morphine intravenously as required. Evaluation of pain commenced when the patients responded appropriately to verbal commands. Pain assessment was carried out hourly by an anesthesiologist in the intensive care unit when the patients were pain free, and every 15 minutes when the patients were being treated for pain. Pain was differentiated from endotracheal tube discomfort by direct questioning. Sedation was used to help patients tolerate the endotracheal tube, relieve anxiety, and treat restlessness, provided they were not in pain.

Table 1. Demographic Requirements,

Data, lntraoperative

and Cardiopulmonary

Enflurane

Bypass Time

(mean + SEMI ITM

19

Number of patients 56.6

Age Sax

ITS

21

t 2.6

59.1

M: 16

f 1.8

M: 19

F: 3

F: 2

Weight (kg)

81 f 2.7

75.3

Height (cm)

171 * 1.7

168 + 2.0

f 2.8

No. of vessels grafted

3.3 f 0.2

3.6 f 0.2

13.8 + 2.3

13.5 f 3.0

Prebypass enflurane (MAC min) Postbypass enflurane (MAC min)

2.0 + 1.0

1.6 f 0.5

117.7

f 6.3

115.1

& 5.9

Bypass time (min)

93.6

+ 5.4

95.3

f 6.8

Postbypass time fmin)’

75.9

f 3.8

74.9

f 6.0

Prebypass time (min)

NOTE. P -c .05 is considered significant. *Time from end of CPS to end of surgery.

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CASEY ET AL

Table 2. lntraoperative

Drug Requirements

extubation, if normocarbia was maintained. The same pulmonary function tests that were carried out preoperatively were repeated one hour and 24 hours after extubation. Data were analyzed using one-way analysis of variance and unpaired Student’s t test and, where appropriate, chi-square test. P < .05 was considered significant.

No. of Patients Drug Diazepam Propranolol Enflurane Nitroglycerin

ITS

ITM ,D/-SCPB 11

,3_/-11 PAC

CPB

12PAC

5

8

16

18

7

9

RESULTS

Abbreviations: CPB, cardiopulmonary bypass; PAC. during pulmonary artery catheterization;

ITS, intrathecal

saline

group.

Criteria for return to full level of consciousness was when the patient responded appropriately to a verbal command, moved all four limbs, and was making spontaneous efforts to breathe. Postoperatively, patients were ventilated with intermittent mandatory ventilation (IMV) at a rate of 12 breaths/ min. tidal volume of 10 mL/kg and FIOl of 0.5. When patients maintained a normal P&O, (less than 40 mmHg) with an IMV rate of four to six breaths/min, they were given a trial of spontaneous ventilation on a T-piece, followed by

Baseline

Induction

lntubation

Injection

Nineteen patients received ITM and 21 patients received ITS. There was no difference in the demographic data between the two groups (Table 1). There were no significant differences between the two groups in enflurane requirements during the prebypass (13.8 v 13.5 MAC minutes) and postbypass (2.0 v 1.6 MAC minutes) periods (Table 1). There was no difference between the two groups in the number of patients requiring enflurane, diazepam, or vasodilators intraoperatively (Table 2). There were no significant differences (NS) between the hemodynamic

Incision

Sternotomy

Aortic Dissection

6ff

End

Fig 1. Serial measurement of systolic blood pressure (SBP), heart rate (HR), pulmonary capillary wedge pressure IPCWP), and cardiac index (Cl) of ITM and ITS groups when measured at specific events perioperatively. The events are baseline, induction, intubation. intrathecal injection, incision, sternotomy, aortic dissection, off cardiopulmonary bypass (OFF), and at the end of surgery (END). All values were recorded one minute after each event. Data represented as mean f SEM.

ROLE OF INTRATHECAL MORPHINE FOR CABG SURGERY

513

Table 3. Postoperative Analgesia, Sedative and Cardiovascular Drug Requirements (mean + SEM) ITM

ITS

Morphine (mg)

3.5 f 0.5

4.5 & 0.6

Diazepam (mg)

5.6 * 1.2

3.9 + 1.2

No. of patients requiring Vasodilators

6

13

B-blockers

1

2

Vasoconstrictors

4

4

lnotropes

9

8

Morphine

13

15

14

8

3.0 ir 0.42

4.3 + 0.25

Diazepam Time of awakening (h) Extubation time (h after IT injection)

21.8

f 1.2

22.9

+ 1.5

NOTE. P < .05 considered significant.

measurements in the 2 groups during the operative period (Fig 1). Postoperatively, there was a trend for the ITM patients to receive less intravenous morphine (3.5 + 0.5 mg, mean + SEM) than the ITS (4.5 + 0.6 mg) and more diazepam (5.6 + 1.2 v 3.9 * 1.2 mg), but these differences did not reach statistical significance. Thirteen patients in the

ITS group required vasodilators for hypertension v six patients in the ITM group (NS). No difference was found in the number of patients in each group requiring beta-blockers or vasoconstrictors (Table 3). No difference was found in the hemodynamic parameters between the two groups in the postoperative period (Fig 2). Mean time to awakening was 3 hours in the ITM group and 4.3 hours in the ITS group (NS). The mean time to extubation after the intrathecal injection was 21.8 hours in the ITM and 22.9 hours in the ITS group (NS, Table 3). PEFR, FVC, and FEV, showed comparable significant reductions in both groups from preoperative values at both one and 24 hours postextubation (P < .05) as illustrated in Fig 3, but no difference was found between the two groups. Arterial blood samples obtained when patients were breathing spontaneously on a Tpiece and one hour postextubation showed a trend to higher PaCO, levels in the ITM group, but the differences were not statistically significant (Fig 4).

1401308

PI 2 E E.

120110 loo-

60 -

Two-hourly postoperative Fig 2. measurements of SSP, HR. PCWP, and Cl of the ITM and ITS groups. Data represented as mean + SEM.

\

2

4

6

6

10

12

HOURS POST-OP

14

16

18

CASEY ET AL

514

ITM

ITS

Peak Expiratory Flow Rate

.-.

o111111mo

FVC

.-.

0111.1110

FEV

*II.

o.w...o

I

I

I

Preop

1 hour

24 hours

POST EXTUBATION There was a trend to a higher incidence of nausea in the ITM group v the ITS group (six v three, respectively), but this did not reach statistical significance. No patients complained of pruritus and one patient in the ITM group developed a headache during performance of an FVC postoperatively, which disappeared on lying down and did not recur. DISCUSSION

The major finding in this study is the failure of intrathecal morphine to provide measurable benefits to patients receiving 40 pg/kg of fentanyl for CABG surgery. There was no additional cardiovascular stability, no additional postoperative pain relief, and no improvement in postoperative respiratory function. These findings are contrary to previous reports using ITM for cardiac patients, where postoperative analgesic requirements were significantly decreased.g*‘OThis may be explained by the fact that these studies used volatile agents as mainstays of their anesthetic technique, and

Fig 3. FVC, FEV,, and PEFR measured preoperatively (PREOP), one, and 24 hours postextubation. ?? P -c .05 when compared with baseline values.

low doses of fentanyl (1 to 15 pg/kg). One study also used higher doses of ITM (2 or 4 mg v approximately 1.5 mg in the present study patients).g The failure of ITM to affect intraoperative cardiovascular stability may be the result of two factors. First, the onset of ITM is slow, requiring approximately 40 minutes to achieve thoracic analgesia when injected in the lumbar region.‘* In addition, cerebrospinal fluid (CSF) fentanyl levels have been shown to rapidly approach 46% of plasma levels.” The very high CSF levels reached with 40 pg/kg of fentanyl most likely saturated opiate receptors so that 1.5 mg of ITM had no significant effect. Before undertaking this study, the charts of 15 patients who had received 40 pg/kg of fentanyl for CABG surgery were retrospectively reviewed to assess postoperative analgesic requirements. The mean morphine dose was 12 mg, suggesting that despite a large dose of fentanyl, further analgesia was required. The surprising observation in the present investigation was the small amount of morphine required in

ROLE OF INTRATHECAL MORPHINE FOR CABG SURGERY

515

150 5 o”l *f PE

Fig 4. Mean + SEM values of arterial oxygen (PaO,), carbon dioxide (PaCO,), pH, and bicarbonate (HC0,7 in ITM and ITS groups measured preoperatively (PREOP). when patients were breathing spontaneously on a T-piece, and one hour after extubation.

140 I) 130 120 110

-

100 i 90 80 j

7.5 7.4 =a

7.3 7.2 7.1

both groups, with 12 patients (30%) requiring no analgesics at all. Morphine was given only for pain as requested by the patient. It may be that morphine was given for sedation or hypertension in those patients whose charts were retrospectively analyzed. The minimal analgesic requirements of the study patients are consistent with recent pharmacologic data on fentanyl. A study in five elderly patients receiving a dose of 60 Kg/kg demonstrated plasma levels greater than 1 ng/ mL at 14 hours, and in two patients levels were greater than 1 ng/mL at 24 hours.14 Unpublished data of the authors in a similar group of patients showed a mean plasma fentanyl level of 1.l ng/mL (range 0 to 3.2 ng/mL) 21 hours after a dose of 40 pg/kg. Bovill and Sebel have shown an increased elimination half-life after CPB (423 minutes v 360 minutes in general surgical patients).14 This, in addition to reduced drug metabolism and excretion in elderly patients with limited cardiac reserve, may explain the persistence of fentanyl levels.‘5-‘7 While there have been few studies correlating plasma levels of

PRiOP

T-PiECE

P&T EXTUBATION

fentanyl with analgesia, one study in general surgical patients has shown that concentrations in the range of l-2 ng/mL are associated with requests for analgesia.” Thus, it would appear that patients receiving 40 erg/kg of fentanyl for CABG surgery may have adequate fentanyl levels for analgesia for prolonged periods postoperatively. The time required for return to a full level of consciousness and the time to extubation were comparable with those previously reported.” Similarly, the postoperative reductions of PEFR, FVC, and FEV, were comparable to a previous study.20 However, ITM in a dose of 4 mg has been reported to significantly improve PEFR for up to 36 hours,” unlike the present study using ITM at a lower dose (0.02 mg/kg) after a fentanyl-based anesthetic technique. It may be that sufficient analgesia is provided by either the ITM, the residual effects of fentanyl, or both, to facilitate quiet breathing, but that this analgesia is not intense or prolonged enough to facilitate pulmonary function testing. Epidural and intrathecal injections in

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516

patients who are subsequently anticoagulated is a controversial issue. A recent review reported a patient who had a traumatic dural puncture, was subsequently heparinized and developed a hematoma resulting in paraplegia.‘l While this report is worrisome, two large studies on patients having epidural or subarachnoid anesthesia followed by subsequent heparinization resulted in no neuThere were no neurologic rologic sequelae. 22*23 complications of lumbar puncture in the present 40 study patients, and there are no case reports of neurologic sequelae as a result of subarachnoid injection immediately prior to cardiac surgery. Provided the coagulation of the patient has been verified as normal preoperatively, subarachnoid injections are not contraindicated prior to heparinization. Evidence of frank bleeding during the lumbar puncture would have resulted in the patient being rescheduled for surgery 24 hours later, as recommended by Rao and E1-Etr.23 Recently, El-Baz and Goldin reported on

the successful use of a continuous epidural infusion of morphine after CABG.24 An infusion rate of 0.1 mg/h was used in 30 patients and compared to intravenous morphine administered at 2 mg/h. This was used after an anesthetic technique consisting of thiopental, N20, 02, halothane, and pancuronium without any narcotics. Pain relief was better in the epidural morphine group, but all patients also required intravenous (IV) morphine supplementation. This study also found no complications after epidural catheter placement prior to induction of anesthesia and heparinization. In conclusion, contrary to results in patients who receive primarily an inhalation anesthetic for cardiac surgery, intrathecal morphine in the dose studied (0.02 mg/kg) does not offer any clear benefit to patients anesthetized with 40 pg/kg of fentanyl for coronary artery bypass surgery.

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cerebrospinal fluid and plasma and its relationship to ventilatory depression in the dog. Anesthesiology 50:342-349, 1979 14. Bovill JG, Sebel PS: Pharmacokinetics of highdose fentanyl: A study in patients undergoing cardiac surgery. Br J Anaesth 52:795-801, 1980 15. McClain DA, Hug CC: Intravenous fentanyl kinetics. Clin Pharmacol Ther 28:106-l 14, 1980 16. Murphy MR. Olson WA, Hug CC: Pharmacokinetics of 3H fentanyl in the dog anesthetized with enflurane. Anesthesiology 50:13-19, 1979 17. Crooks J, O’Malley K, Stevenson IM: Pharmacokinetics of the elderly. Clin Pharmacokinet 1:280-296, 1976 18. Cartwright P, Prys-Roberts C, Gill K, et al: Ventilatory depression related to plasma fentanyl concentration during and after anesthesia in humans. Anesth Analg 621966-974, 1983 19. Sanford TJ Jr, Smith NT, Dee Silver H, et al: A comparison of morphine, fentanyl and sufentanil anesthesia for cardiac surgery. Anesth Analg 65:259-266, 1986 20. Anderson NB, Glia J: Pulmonary function, cardiac status, and postoperative course in relation to cardiopulmonary bypass. J Thorac Cardiovasc Surg 59:474-483, 1970 21. Owens EL, Kasten GW, Hessel EA: Spinal subarachnoid hematoma after lumbar puncture and heparinization: A case report, review of the literature and discussion of anesthetic implications. Anesth Analg 65:1201-1207, 1986 22. Odoom JA, Sih IL: Epidural analgesia and anticoagulant therapy. Anaesthesia 38:254-259, 1983 23. Rao TLK, El-Etr A: Anticoagulation following placement of epidural and subarachnoid catheters. Anesthesiology 55:618-620, 1981 24. El-Baz N, Goldin M: Continuous epidural infusion of morphine for pain relief after cardiac operations. J Thorac Cardiovasc Surg 93:878-883, 1987