Total intravenous anesthesia with a propofol-ketamine combination during coronary artery surgery

Total Intravenous Anesthesia With a Propofol-Ketamine Combination During Coronary Artery Surgery Carlos A. Botero, MD, Charles E. Smith, MD, FRCPC, Curtis Holbrook, MD, Altagracia M. Chavez, MD, Norman J. Snow, MD, Joan F. Hagen, BA, and Alfred C. Pinchak, PhD, PE, MD Objective: To evaluate the cardiovascular effects of a propofol-ketamine combination in patients undergoing coronary artery surgery. Design: Prospective, randomized study. Setting: Tertiary care teaching hospital, single center. Participants: Seventy-eight adult patients. Interventions: Patients were randomly allocated to receive propofol-ketamine for induction and maintenance of anesthesia (n ⴝ 36) or fentanyl-enflurane (controls, n ⴝ 42). Measurements and Main Results: Hemodynamics and other variables were recorded during and after surgery and for 24 hours in the intensive care unit. Before cardiopulmonary bypass (CPB), there was similar incidence of treatment for hypotension (42% of patients in both groups), tachycardia (propofol-ketamine, 6%; controls, 5%), and myocardial ischemia (propofol-ketamine, 3%; controls, 12%). In the propofol-ketamine group, there was a decreased requirement for inotropic agents after CPB (22% of patients)

compared with controls (49% of patients; p ⴝ 0.02). There was a reduced incidence of myocardial infarctions (creatine kinase myocardial band G133 U/L) in the propofol-ketamine group compared with the control group (0% v 14%; p ⴝ 0.02; Fisher’s exact test). Patients in the propofol-ketamine group were more likely to have their tracheas extubated within 8 hours of arrival in the intensive care unit compared with controls (33% v 7%; p ⴝ 0.01; Cochran-Mantel-Haenzel test). Conclusions: The propofol-ketamine combination was associated with a similar incidence of pre-CPB hypotension and ischemia, a decreased need for inotropes after CPB, an earlier time to tracheal extubation, and a reduced incidence of myocardial infarctions compared with controls. Copyright r 2000 by W.B. Saunders Company

P

fentanyl, 25 to 50 µg, were given intravenously for sedation and analgesia during insertion of intravascular catheters. In group 1, an infusion of propofol, 100 µg/kg/min, and ketamine, 25 µg/kg/min, was started (propofol, 400 mg, and ketamine, 100 mg, mixed together in a 60-mL syringe) (Baxter Infusion Pump, Model AS40A, Baxter Healthcare Corp, Round Lake, IL). After 3 minutes of this infusion, a bolus of propofol, 1 mg/kg, and ketamine, 2 mg/kg, was given over 30 seconds. After loss of consciousness, rocuronium or vecuronium was given to facilitate tracheal intubation. After 1 hour, the propofol-ketamine infusion was decreased to a rate of propofol, 75 µg/kg/min, and ketamine, 18.75 µg/kg/min. After an additional hour, the infusion was decreased to propofol, 50 µg/kg/min, and ketamine, 12.5 µg/kg/min, and maintained at this rate until the end of surgery. After skin incision and during CPB, pancuronium, 0.5 to 1.0 µg/kg/min, was given. During the first 4 hours in the intensive care unit (ICU), patients received propofol-ketamine at a rate of propofol, 20 µg/kg/min, and ketamine, 5 µg/kg/min. Before CPB, hypotension (systolic BP ⬍90 mmHg) was treated with fluid boluses and titrated phenylephrine, ephedrine, or both. Hypertension (systolic BP ⬎140 mmHg) was treated with nitroglycerin infusion. Bradycardia (HR ⬍45 beats/min) was treated with atropine, and tachycardia (HR ⬎90 beats/min) was treated with esmolol, labetalol, or both. Myocardial ischemia (ST-segment depression ⬎1 mm) was treated with a nitroglycerin infusion or esmolol or labetalol, or a combination.

ROPOFOL ANESTHESIA offers several advantages over long-acting opioids, such as rapid emergence and return to spontaneous ventilation and reduction in time to tracheal extubation.1-3 Propofol can, however, result in intraoperative hypotension and an increased use of inotropic/vasopressor medications during coronary artery bypass graft (CABG) surgery.4 Ketamine is a phencyclidine anesthetic that produces intense analgesia, sympathetic nervous system stimulation, and increased blood pressure (BP) and heart rate (HR). Previous studies have shown that the cardiovascular depressant effects of propofol can be offset by the sympathomimetic effects of ketamine, resulting in cardiovascular stability and minimal emergence phenomena.5,6 Ketamine combined with diazepam has been shown to result in a lower incidence of myocardial ischemia and hypotension requiring treatment with vasopressors compared with opioid-based techniques.7 Ketamine may be associated with neuroprotection and preemptive analgesia.8,9 The purpose of this prospective, randomized study was to determine the cardiovascular effects of a propofol-ketamine combination for CABG surgery. The propofol-ketamine combination was compared with a control group receiving fentanyl and enflurane. The hypotheses were that compared with controls, propofol-ketamine would be associated with a decreased incidence of intraoperative hemodynamic disturbances, myocardial ischemia, and inotrope requirement after cardiopulmonary bypass (CPB) and faster time to tracheal extubation.

METHODS After institutional review board approval and written informed consent, 78 American Society of Anesthesiologists (ASA) physical status III and IV adults undergoing elective CABG surgery were studied. Exclusion criteria were emergency procedures and preoperative requirement for inotropes or intraaortic balloon counterpulsation. Randomization was with a table of random numbers. Premedication was with lorazepam, 1 to 2 mg orally 1 hour preoperatively. Patients received their usual dose of oral cardiac medications before surgery. Titrated midazolam, 1 to 2 mg, and

KEY WORDS: cardiac anesthesia, propofol, ketamine, fentanyl, enflurane, coronary artery bypass graft surgery, myocardial infarction

From the Department of Anesthesiology and Division of Cardiothoracic Surgery, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH. Presented in part at the Society of Cardiovascular Anesthesiologists Annual Meeting, Salt Lake City, UT, May 4-8, 1996; Canadian Anaesthetists’ Society Annual Meeting, Montreal, Canada, June 14-18, 1996; American Society of Anesthesiologists’ Annual Meeting, New Orleans, LA, October 19-23, 1996; and the American Heart Association Scientific Sessions, New Orleans, LA, November 10-13, 1996. Address reprint requests to Charles E. Smith, MD, Department of Anesthesiology, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH, 44109. Copyright r 2000 by W.B. Saunders Company 1053-0770/00/1404-0010$10.00 doi:10.1053/jcan.2000.7933

Journal of Cardiothoracic and Vascular Anesthesia, Vol 14, No 4 (August), 2000: pp 409-415

409

410

In group 2, an infusion of fentanyl, 0.1 µg/kg/min, was started. After 3 minutes of this infusion, a bolus of fentanyl, 15 µg/kg, was given over 30 seconds. Anesthesia was maintained with fentanyl, 0.05 to 0.1 µg/kg/min, and enflurane, 0.3% to 0.5%, inspired. During CPB and in the ICU, benzodiazepines were given as needed. Intravenous morphine was given in the ICU as clinically indicated. The dose of benzodiazepine and use of midazolam, diazepam, or both were at the discretion of the attending anesthesiologist and not dictated by protocol. The remainder of the anesthesia management was identical to that outlined for group 1. Monitors consisted of electrocardiogram (ECG) with computerized ST-segment analysis of leads II and V5, oxygen saturation (SaO2 ), invasive BP, end-tidal carbon dioxide, and continuous cardiac index (CI), mixed venous oxygen saturation (SvO2 ), and pulmonary artery catheter. Management of CPB included moderate hypothermia (28°C) with a centrifugal pump. Bypass flow was approximately 2.4 L/min/m2. Mean BP was maintained between 60 and 80 mmHg using nitroprusside or phenylephrine. Myocardial protection was with antegrade and retrograde cold and hyperkalemic blood cardioplegic arrest. A standardized protocol was used during separation from CPB10 that consisted of atrial or atrioventricular pacing if the HR was less than 90 beats/min; calcium chloride, 1 g; gradually occluding the venous outflow of the pump and infusing CPB reservoir blood by the aortic cannula to maintain cardiac filling pressures near pre-CPB values; titrated phenylephrine for systolic BP less than 100 mmHg and CI greater than 2.0 L/min/m2; epinephrine or dobutamine infusion for CI less than or equal to 2.0 L/min/m2; norepinephrine infusion for persistent systolic BP less than 100 mmHg; increasing the rate of nitroglycerin infusion for systolic BP greater than 140 mmHg; and nitroprusside infusion for persistent systolic BP greater than 140 mmHg. Hemodynamic measurements were recorded at baseline, 5 and 10 minutes after tracheal intubation, 1 minute after incision, 1 minute after sternotomy, 15 minutes after separation from CPB, in the ICU on admission, and 12 and 24 hours after ICU admission. Arterial blood was sampled before induction, 10 minutes after intubation, and after CPB. Vasoactive drug requirements were recorded. Twelve-lead ECGs were done on admission to the ICU and the morning after surgery. ECGs were read by the cardiology attending physician, who was not aware of patient group. Serum levels of creatine kinase–myocardial fraction (CK-MB) were measured on admission to the ICU and every 8 hours for 24 hours. Myocardial infarction was defined as new Q waves and CK-MB greater than 100 U/L or CK-MB greater than 133 U/L. Patients were questioned by a single individual (C.A.B.) 48 hours after discharge from the ICU regarding the occurrence of dreams or recall. The following 2 questions were asked: (1) ‘‘How much do you remember after going into the operating room?’’ (2) ‘‘Did you have any dreams while you were in the operating room?’’ If there was no memory and no dreams, no further questions were asked. If there was explicit memory or dreams, the patient was questioned as to the nature of the memory or dreams. Calculations were as follows: arterial oxygen content (CaO2 ) ⫽ Hbg ⫻ 1.34 ⫻ SaO2; mixed venous oxygen content (CvO2 ) ⫽ Hbg ⫻ 1.34 ⫻ SvO2; oxygen delivery (DO2 ) ⫽ cardiac output (CO) ⫻ CaO2 ⫻ ˙ O2 ) ⫽ CO ⫻ (CaO2 ⫺ CvO2 ) ⫻ 10; oxygen 10; oxygen consumption (V ˙ O2/DO2 ⫻ 100. Percent change from baseline extraction ratio (ER) ⫽ V was calculated for each measurement interval. Data are reported as mean values ⫾ standard deviation. Betweengroup hemodynamic and metabolic data were analyzed with repeated measures analysis of variance (ANOVA) followed by Tukey’s test (GLM procedure, SAS software). Unpaired Student’s t-tests were used to compare other parametric data between groups. Chi-square analysis, Fisher’s exact test, and the Cochran-Mantel-Haenzel test were used to compare categorical data between groups. Within-group data were compared using repeated measures ANOVA followed by the Manova test criteria and exact F statistics (GLM procedure, SAS software).

BOTERO ET AL

Survival analysis was performed to determine the probability of the trachea remaining intubated at different postoperative times using product-limit survival estimates (Lifetest procedure, SAS software). A p value ⬍ 0.05 was considered significant. RESULTS

Demographic data were similar between groups (Table 1). There was a high incidence of unstable angina (47/78 patients, 60%), and many patients were receiving continuous infusions of intravenous heparin (56%) and nitroglycerin (44%) (Table 1). More patients received angiotensin-converting enzyme inhibitors in the propofol-ketamine group compared with controls (Table 1). There were 2 perioperative deaths. One patient in the control group developed hypotension, facial flushing, ischemia, and ventricular fibrillation shortly after receiving vancomycin. Despite resuscitation, including open cardiac massage and venous bypass grafts, the patient was unable to be weaned from CPB. Data for this patient are reported up to sternotomy. The other patient (control group) died on the ninth postoperative day from complications related to myocardial infarction. Duration of aortic occlusion and CPB was similar between groups, as was fluid balance (Table 2). There were no intergroup differences in pH (7.38 to 7.43), PaO2 (216 to 315 mmHg), PaCO2 (35.7 to 38.7 mmHg), HCO3 (22.5 to 24.4), and ionized calcium (1.13 to 1.16 mmol/L) before and after CPB. Hemoglo-

Table 1. Patient Data

Age (y) Sex (M/F) Height (cm) Weight (kg) BSA (m2) Previous MI (No. patients) Recent MI (⬍3 mo) Unstable angina COPD Hypertension CHF Diabetes Left ventricular ejection fraction (%) Hematocrit (%) Creatinine (mg/dL) Preoperative medications ␤-blocker Calcium channel blocker ACE inhibitor IV nitroglycerin IV heparin Digoxin Diuretic Clonidine

PropofolKetamine (n ⫽ 36)

FentanylEnflurane (n ⫽ 42)

63 ⫾ 2 26/10 172 ⫾ 10 84 ⫾ 16 1.99 ⫾ 0.22 21 (58) 13 (36) 23 (64) 10 (28) 28 (78) 7 (19) 14 (39) 48 ⫾ 13 40 ⫾ 5 1.0 ⫾ 0.3

62 ⫾ 9 28/14 172 ⫾ 11 89 ⫾ 9 2.05 ⫾ 0.26 18 (43) 10 (24) 24 (57) 6 (14) 28 (67) 4 (10) 15 (36) 51 ⫾ 12 40 ⫾ 4 0.9 ⫾ 0.2

19 (53) 12 (33) 15 (42) 17 (47) 21 (58) 4 (11) 7 (19) 1 (3)

21 (50) 17 (40) 5 (12)* 17 (40) 23 (55) 4 (10) 13 (31) 1 (2)

NOTE. Data are means ⫾ standard deviation or number of patients (%). Abbreviations: BSA, body surface area; MI, myocardial infarction; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; ACE, angiotensin-converting enzyme; IV, intravenous. *p ⬍ 0.05 versus propofol-ketamine.

TVIA WITH PROPOFOL-KETAMINE

411

Table 2. Intraoperative Data PropofolKetamine (n ⫽ 36)

Duration of (min) Anesthesia Surgery Aortic cross-clamp Cardiopulmonary bypass Median No. grafts Anesthetic drugs Propofol (mg) Ketamine (mg) Fentanyl (mg) Midazolam (mg) Diazepam (mg) Fluid balance Crystalloid (L) Colloids (L) PRBC (U) FFP (U) Platelets (U) Estimated blood loss (mL) New Q waves CK-MB ⱖ100 U/L CK-MB ⱖ133 U/L Q waves ⫹ CK-MB ⱖ100 U/L

FentanylEnflurane (n ⫽ 42)

451 ⫾ 87 341 ⫾ 79 77 ⫾ 32

473 ⫾ 85 364 ⫾ 78 81 ⫾ 24

152 ⫾ 48 4

169 ⫾ 51 4

1817 ⫾ 575 571 ⫾ 187 0.32 ⫾ 0.35 (n ⫽ 23) 4.9 ⫾ 2.8 (n ⫽ 30) 22.0 ⫾ 4.4 (n ⫽ 5)

— — 5.03 ⫾ 1.77 (n ⫽ 42) 9.3 ⫾ 10 (n ⫽ 35) 24.5 ⫾ 8 (n ⫽ 21)

2.4 ⫾ 0.8 0.5 ⫾ 0 (n ⫽ 2) 2.1 ⫾ 2.4 (n ⫽ 9) 10 ⫾ 0 (n ⫽ 1) 9 ⫾ 4 (n ⫽ 2)

2.4 ⫾ 0.8 0.4 ⫾ 0.1 (n ⫽ 4) 2.6 ⫾ 0.8 (n ⫽ 13) 6 ⫾ 0 (n ⫽ 1) 6 ⫾ 0 (n ⫽ 3)

490 ⫾ 620 6 (17) 1 (3) 0

510 ⫾ 350 2 (5) 9 (21)* 6 (14)†

1 (3)

5 (12)

NOTE. Data are means ⫾ standard deviation or number of patients (%). Abbreviations: PRBC, packed red blood cells; FFP, fresh frozen plasma; CK-MB, creatine kinase–myocardial fraction. *p ⫽ 0.013 versus propofol-ketamine. †p ⫽ 0.017 versus propofol-ketamine.

bin was similar between groups before (12.1 to 12.6 g/dL) and after (8.9 to 9.3 g/dL) CPB. Hemodynamic and oxygen metabolism data are summarized in Tables 3 and 4. There were no differences between groups before induction. Five minutes after intubation, HR was increased by 14% ⫾ 3% in the propofol-ketamine group and by 2% ⫾ 2% in the control group ( p ⫽ 0.002). Mean BP decreased more in the control group compared with the propofol-ketamine group (15% ⫾ 2% decrease v 5% ⫾ 4% decrease; p ⫽ 0.02). In ˙ O2 and oxygen extraction decreased (by 35% and both groups, V 30%) and SvO2 increased (by 13%) after induction and intubation. Compared with baseline, HR was increased by 6% ⫾ 5% in the propofol-ketamine group and decreased by 9% ⫾ 3% in the ˙ O2 was decreased control group ( p ⫽ 0.01). After sternotomy, V more in the control group compared with the propofol-ketamine group (38% ⫾ 2% decrease from baseline v 22% ⫾ 6% decrease; p ⫽ 0.01). CI and DO2 were decreased in the control group (by 15% ⫾ 3% and 14% ⫾ 3%) but not in the propofolketamine group compared with baseline. A similar number of patients required ephedrine, phenylephrine, or both for hypotension before CPB (42% in both groups). Two patients in each group had tachycardia, which was treated with esmolol or labetalol. One patient in the propofol-ketamine group and 5 patients in the control group had ischemia, which

was treated with nitroglycerin. One patient in each group required epinephrine, and 1 patient (propofol-ketamine group) received renal-dose dopamine. Fifteen minutes after separation from CPB, HR and mean pulmonary artery pressures were increased in both groups compared with baseline (by 36% and 22%). Patients in the control group were more likely to require continuous infusions of epinephrine, dobutamine, or norepinephrine for hypotension and low CI compared with the propofol-ketamine group (20/41 patients or 49%, v 8/36 or 22%; p ⫽ 0.02 between groups). This higher inotrope requirement was also evident in the ICU (control, 51%; propofol-ketamine, 28%; p ⫽ 0.056). The requirement for nitroprusside for hypertension was similar between groups after CPB (propofol-ketamine, 28%; control, 12%) and in the ICU (propofol-ketamine, 50%; control, 46%). ˙ O2, oxygen extraction ratio, and Compared with baseline, V HR were increased (by 70%, 45%, and 35%) and SvO2 was decreased (by 13%) in both groups. Mean BP was decreased to a greater extent in the control compared with the propofolketamine group at 12 and 24 hours (18% ⫾ 3% and 16% ⫾ 2% decrease v 7% ⫾ 3% and 8% ⫾ 3% decrease; p ⫽ 0.007). Five patients in the propofol-ketamine group had ischemia after CPB, one of whom had an acute myocardial infarction. Four patients had post-CPB ischemia in the control group, all of whom had acute myocardial infarctions. More patients in the control group had increased CK-MB compared with the propofol-ketamine group ( p ⫽ 0.02) (Table 3). Patients in the propofol-ketamine group were more likely to have their tracheas extubated during the first 8 hours after admission to the ICU, whereas patients in the control group were more likely to have prolonged (⬎16 hours) tracheal extubation (Figs 1 and 2), ( p ⫽ 0.01). Three patients in the control group had explicit recall of intraoperative events, and 1 reported dreaming. No patient in the propofol-ketamine group had explicit recall, and 4 patients experienced dreams, 1 of whom stated the dream was extremely unpleasant.

DISCUSSION

The present study showed that a propofol-ketamine combination resulted in stable hemodynamics and oxygen metabolism during induction and maintenance of anesthesia and was associated with a decreased requirement for inotropic agents after CPB and a decreased incidence of CK-MB greater than 133 U/L. There was a low incidence of pre-CPB ischemia in the propofol-ketamine group (2.8%), and patients receiving the propofol-ketamine combination had their tracheas extubated earlier in the ICU. Propofol has become an accepted standard for fast tracking cardiac surgical patients.2 Propofol is associated with intraoperative hypotension,11 however, resulting from decreased cardiac contractility and systemic vascular resistance.12,13 This hypotension may result in an increased requirement for inotropic support and vasoconstrictor therapy before4,14 and after4 CPB. Ketamine is a sympathomimetic anesthetic agent that increases BP and CO. Although ketamine has been shown to have a positive inotropic effect resulting from inhibition of neuronal catecholamine uptake, ␤-receptor activation, and an increase in calcium influx,15,16 ketamine may also exert a direct negative

412

BOTERO ET AL

Table 3. Pre–Cardiopulmonary Bypass Hemodynamic and Metabolic Data

Heart rate (beats/min) Propofol-ketamine Fentanyl-enflurane Mean BP (mmHg) Propofol-ketamine Fentanyl-enflurane CVP (mmHg) Propofol-ketamine Fentanyl-enflurane Mean PAP (mmHg) Propofol-ketamine Fentanyl-enflurane CI (L/min/m2) Propofol-ketamine Fentanyl-enflurane SvO2 (%) Propofol-ketamine Fentanyl-enflurane DO2 (mL/min/m2) Propofol-ketamine Fentanyl-enflurane V˙O2 (mL/min/m2) Propofol-ketamine Fentanyl-enflurane Extraction ratio (%) Propofol-ketamine Fentanyl-enflurane

Baseline*

5 Min After Intubation

10 Min After Intubation

1 Min After Incision

1 Min After Sternotomy

72 ⫾ 11 74 ⫾ 14

81 ⫾ 14 75 ⫾ 16

74 ⫾ 13 71 ⫾ 14

74 ⫾ 20 67 ⫾ 13

72 ⫾ 22 71 ⫾ 15

96 ⫾ 18 100 ⫾ 17

83 ⫾ 17 89 ⫾ 21

80 ⫾ 15 83 ⫾ 14

89 ⫾ 15 87 ⫾ 16

96 ⫾ 13 96 ⫾ 13

7⫾5 8⫾4

9⫾4 10 ⫾ 4

9⫾4 11 ⫾ 4

11 ⫾ 4 11 ⫾ 3

10 ⫾ 4 11 ⫾ 4

20 ⫾ 6 21 ⫾ 6

21 ⫾ 5 21 ⫾ 6

19 ⫾ 5 21 ⫾ 7

20 ⫾ 6 21 ⫾ 5

19 ⫾ 7 22 ⫾ 6

2.7 ⫾ 0.6 2.8 ⫾ 0.6

2.5 ⫾ 0.6 2.6 ⫾ 0.5

2.5 ⫾ 0.5 2.5 ⫾ 0.5

2.5 ⫾ 0.5 2.3 ⫾ 0.5

2.5 ⫾ 0.6 2.3 ⫾ 0.5

72 ⫾ 7 72 ⫾ 6

80 ⫾ 7 81 ⫾ 4

81 ⫾ 6 81 ⫾ 4

80 ⫾ 6 80 ⫾ 5

78 ⫾ 7 81 ⫾ 5

494 ⫾ 110 515 ⫾ 126

465 ⫾ 122 473 ⫾ 114

448 ⫾ 108 456 ⫾ 114

448 ⫾ 118 433 ⫾ 120

456 ⫾ 131 430 ⫾ 114

128 ⫾ 30 133 ⫾ 35

87 ⫾ 35 84 ⫾ 21

81 ⫾ 29 83 ⫾ 23

82 ⫾ 26 82 ⫾ 19

93 ⫾ 29 79 ⫾ 20

26 ⫾ 7 26 ⫾ 6

19 ⫾ 8 18 ⫾ 5

18 ⫾ 7 18 ⫾ 5

19 ⫾ 6 20 ⫾ 5

21 ⫾ 7 19 ⫾ 5

NOTE. Data are means ⫾ standard deviation. There were no significant intergroup differences. Abbreviations: BP, blood pressure; CVP, central venous pressure; PAP, pulmonary artery pressure; CI, cardiac index; SvO2, mixed venous oxygen saturation; DO2, oxygen delivery index; V˙O2, oxygen consumption index. *Before induction of anesthesia.

inotropic effect mediated by a decrease in availability of calcium in ventricular muscle.17 In patients undergoing surgery, the use of subanesthetic doses of ketamine in combination with propofol has been shown to result in hemodynamic stability without the need for additional analgesics.18 The decreases in BP and CO by propofol are offset by the sympathomimetic effects of ketamine.6 Because propofol and ketamine have opposite cardiovascular effects, this combination may provide hemodynamic stability and rapid recovery in patients undergoing cardiac surgery. The dosages of propofol and ketamine used in the current study were based on the authors’ clinical experience and a review of the literature. Hui et al6 determined dose-response curves for propofol, ketamine, and propofol-ketamine combinations in 180 patients. At the anesthetic endpoint, the ED50s for the propofol-ketamine combination were propofol, 1.05 mg/kg, and ketamine, 0.35 mg/kg.6 Frizelle et al5 administered propofol, 0.4 mg/kg, and ketamine, 0.1 mg/kg, followed by a continuous infusion of propofol, 20 µg/kg/min, and ketamine, 5 µg/kg/min, to achieve sedation in patients undergoing spinal anesthesia. Although serum concentrations of propofol-ketamine were not measured in the present study, after a dose of ketamine, 2 mg/kg, followed by an infusion of 50 µg/kg/min, ketamine concentrations of 2.34 to 3.27 mg/L have been reported during aortic cannulation and CPB in adults.19 After cessation of the infusion, ketamine concentrations declined rapidly in a log-

linear fashion with a half-life of 2.12 hours. It is likely that ketamine concentrations were lower in the present study because the infusion rate was 12.5 to 25 µg/kg/min in the operating room. The propofol bolus, 1 mg/kg, and infusion, 50 to 100 µg/kg/min, that were used in this study would be expected to achieve target plasma concentrations of 2 to 3 µg/mL, similar to those used for maintenance of general anesthesia during cardiac surgery.11 Although there were no instances of intraoperative awareness in the propofol-ketamine group, 4 patients (11%) did report dreams or hallucinations, and in 1 patient, the dream and visual hallucination was an extremely frightening and disturbing experience. Highly unpleasant psychotomimetic reactions, such as hallucinations and vivid dreams, are likely related to ketamine’s interaction with multiple binding sites in the central nervous system, including the phencyclidine receptor in the N-methyl-D-aspartate channel,9 and may limit ketamine’s usefulness in routine clinical practice. For example, Blakeley et al20 reported that 2 of 20 patients receiving total intravenous anesthesia with propofol-ketamine experienced vivid dreams, were not satisfied with the anesthesia, and would choose a different anesthetic for a future operation. Similarly, Frizelle et al5 reported that 10% of patients receiving propofol-ketamine for sedation during spinal anesthesia reported auditory hallucinations or vivid dreams. Pleasant dreams after total intravenous anesthesia with propofol-ketamine were not perceived to be problematic in the present study and in others.18,21-23 The

TVIA WITH PROPOFOL-KETAMINE

413

Table 4. Post–Cardiopulmonary Bypass Hemodynamic and Metabolic Data

Heart rate (beats/min) Propofol-ketamine Fentanyl-enflurane Mean BP (mmHg) Propofol-ketamine Fentanyl-enflurane CVP (mmHg) Propofol-ketamine Fentanyl-enflurane Mean PAP (mmHg) Propofol-ketamine Fentanyl-enflurane CI (L/min/m2) Propofol-ketamine Fentanyl-enflurane SvO2 (%) Propofol-ketamine Fentanyl-enflurane DO2 (mL/min/m2) Propofol-ketamine Fentanyl-enflurane V˙O2 (mL/min/m2) Propofol-ketamine Fentanyl-enflurane Extraction ratio (%) Propofol-ketamine Fentanyl-enflurane

Baseline*

15 Min After Bypass

72 ⫾ 11 74 ⫾ 14

96 ⫾ 12 99 ⫾ 14

96 ⫾ 18 100 ⫾ 17

Admission to ICU

12 H After Admission to ICU

24 H After Admission to ICU

97 ⫾ 9 105 ⫾ 14

99 ⫾ 10 95 ⫾ 12

97 ⫾ 11 94 ⫾ 12

83 ⫾ 11 82 ⫾ 12

86 ⫾ 13 94 ⫾ 20

86 ⫾ 8 80 ⫾ 11

86 ⫾ 9 82 ⫾ 13

7⫾5 8⫾4

11 ⫾ 4 13 ⫾ 4

8⫾3 11 ⫾ 4

9⫾4 12 ⫾ 3

10 ⫾ 3 12 ⫾ 4

20 ⫾ 6 21 ⫾ 6

22 ⫾ 6 24 ⫾ 5

19 ⫾ 6 23 ⫾ 7

20 ⫾ 5 21 ⫾ 5

20 ⫾ 5 21 ⫾ 5

2.7 ⫾ 0.6 2.8 ⫾ 0.6

3.0 ⫾ 0.6 3.0 ⫾ 0.7

2.9 ⫾ 0.8 2.8 ⫾ 0.5

3.2 ⫾ 0.8 3.1 ⫾ 0.6

3.2 ⫾ 0.7 3.0 ⫾ 0.7

72 ⫾ 7 72 ⫾ 6

76 ⫾ 7 73 ⫾ 7

65 ⫾ 8 68 ⫾ 8

62 ⫾ 7 63 ⫾ 7

62 ⫾ 8 61 ⫾ 8

494 ⫾ 110 515 ⫾ 126

544 ⫾ 124 548 ⫾ 159

529 ⫾ 178 507 ⫾ 111

584 ⫾ 164 566 ⫾ 150

568 ⫾ 147 538 ⫾ 154

128 ⫾ 30 133 ⫾ 35

145 ⫾ 38 129 ⫾ 46

173 ⫾ 67 150 ⫾ 39

211 ⫾ 59 199 ⫾ 57

201 ⫾ 55 200 ⫾ 62

26 ⫾ 7 26 ⫾ 6

27 ⫾ 7 24 ⫾ 8

34 ⫾ 8 30 ⫾ 8

37 ⫾ 7 36 ⫾ 7

36 ⫾ 8 38 ⫾ 8

NOTE. Data are means ⫾ SD. There were no significant intergroup differences. Abbreviations: ICU, intensive care unit; BP, blood pressure; CVP, central venous pressure; PAP, pulmonary artery pressure; CI, cardiac index; SvO2, mixed venous oxygen saturation; DO2, oxygen delivery index; V˙O2, oxygen consumption index. *Before induction of anesthesia.

separation of the enantiomers S(⫹) and R(⫺) may allow administration of smaller doses of the more potent S(⫹) enantiomer in the future to reduce or eliminate these undesirable psychotomimetic effects.9

Fig 1. Histogram shows the number of patients having their tracheas extubated at each time interval after admission to the surgical intensive care unit. Patients in the propofol-ketamine group were more likely to have their tracheas extubated earlier compared with the control group (p ⴝ 0.01; Cochran-Mantel-Haenzel test.) 䊐, propofol-ketamine; 䊏, fentanyl-enflurane.

The sample size of the present study was too low to validate the outcome of intraoperative awareness (0% in the propofolketamine group and 7% in the fentanyl-enflurane group). The incidence of awareness during cardiac surgery previously has been reported to be 1.1% to 1.5%,24,25 which is considerably higher than in patients undergoing general anesthesia for a variety of noncardiac elective surgeries (incidence 0.4%).26 In a

Fig 2. Product-limit survival estimates show the percent of tracheal intubation after admission to the surgical intensive care unit. Solid line ⴝ propofol-ketamine; broken line ⴝ fentanyl-enflurane. (p ⴝ 0.01 between groups; Wilcoxon statistics.)

414

BOTERO ET AL

study of fast-track cardiac anesthesia using a combination of agents for preoperative sedation and analgesia (lorazepam, diazepam, morphine) and intraoperative anesthesia (fentanyl, thiopental, midazolam, pancuronium, isoflurane, propofol), however, the incidence of explicit memory of intraoperative events was 0.3%.27 ˙ O2 decreased to Despite the fact that mean BP, CI, DO2 and V a greater extent from baseline in the control group, there were no differences in pre-CPB vasoactive drug requirements for the treatment of hypotension. The authors were unable to confirm their hypothesis that the use of propofol-ketamine would be associated with a lower incidence of pre-CPB hypotension. It is possible that the higher preoperative use of angiotensinconverting enzyme inhibitors in the propofol-ketamine group could have contributed to the failure to confirm this hypothesis. Multivariate analysis to examine the relationship among MAP, time of MAP measurement, angiotensin-converting enzyme inhibitor use, and anesthetic treatment group failed to reveal a significant angiotensin-converting enzyme inhibitor/treatment group effect. Although HR tended to be faster in the propofol-ketamine group during the pre-CPB period, this was not associated with an increased incidence of ischemia, and a similar number of patients (2 in each group) required treatment for tachycardia. After CPB, there was a decreased need for inotropic agents in the propofol-ketamine group. This reduced inotropic drug requirement may be related to enhanced cardiovascular performance with propofol-ketamine. At clinically relevant concentrations, ketamine has been shown to exert a positive inotropic effect. Cook et al15 showed that ketamine increased contractility in isolated mammalian ventricular muscle. In the model, ketamine activated the ␤-adrenoceptor indirectly through the inhibition of catecholamine uptake at the sympathetic neuroeffector junction.15 Confounding effects of sympathetic tone, vascular resistance, preload, and afterload, however, can all have an impact on the cardiostimulatory actions of ketamine on the heart and circulation. Only 1 patient in the propofol-ketamine group had CK-MB greater than 100 U/L, and none had CK-MB greater than 133 U/L (v 9 and 6 patients in the control group). The percentage of patients in the control group (21%) who had CK-MB greater than 100 U/L is similar to that reported in a multicenter study of CABG surgery patients anesthetized with fentanyl, midazolam, and thiopental.28 In the study, 20% of patients met CK-MB criteria for myocardial infarction, 10% of patients met Q-wave criteria for myocardial infarction, and there was a striking disparity in the incidence of myocardial infarctions between the different clinical sites (0% to 50% incidence of myocardial infarctions).28 Myocardial infarction is not the only cause of elevated

CK-MB after CABG surgery,29 although CK-MB greater than 133 U/L is associated with autopsy criteria for myocardial infarction.30 The lower-than-expected incidence of myocardial infarction in the propofol-ketamine group is unclear. There were no intergroup differences in extent of coronary stenosis, ventricular dysfunction, and aortic occlusion time, although patients in the propofol-ketamine group did have a lower inotropic drug requirement after CPB. It is possible that improved cardiovascular stability in the propofol-ketamine group after CPB and in the ICU accounted for the differences in the lower incidence of myocardial infarction observed in the propofol-ketamine group, although the possibility of direct myocardial protection by the propofol-ketamine combination cannot be excluded. Although a large and unexpected statistically significant difference in the incidence of myocardial infarction between groups was observed, the study was not designed specifically to test this hypothesis, and the power of detecting such differences given the sample size was low (0.3 at an ␣ of 0.05). There are several limitations to the present study. First, the anesthesiologists were not blinded to the treatment groups. This situation may have introduced bias in the study, although the use of a prospective, randomized design and standardized, predetermined interventions for the treatment of hemodynamics and ischemia would tend to minimize this bias. The nurses and other personnel caring for the patients in the ICU were not blinded to the groups. The higher benzodiazepine use during the intraoperative period may have resulted in prolonged sedation in the ICU and longer time to tracheal extubation. Patients in the propofol-ketamine group were more likely to have their tracheas extubated within 8 hours of arrival in the ICU. Extubation within this time frame is more likely to facilitate earlier transfer from the ICU and allow for more efficient and coordinated scheduling of recovery and hospital discharge, although it is recognized that there is a complex association among duration of intubation, length of stay, and costs.31 Although the chosen doses were based on available pharmacokinetic and pharmacodynamic information, the use of a fixed dose ratio of propofolketamine may limit wider applicability. In conclusion, compared with controls, propofol-ketamine was associated with cardiovascular stability, a reduced incidence of myocardial ischemia and infarction, a decreased need for inotropic agents after CPB, and an earlier time to tracheal extubation. If these findings are confirmed by other studies, it would support the use of propofol-ketamine anesthesia for CABG surgery. ACKNOWLEDGMENT

The authors are grateful to Fran Hall, for assistance in preparing the manuscript.

REFERENCES 1. Cheng DCH, Karski J, Peniston C, et al: Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use. Anesthesiology 85:1300-1310, 1996 2. Cheng DCH, Karski J, Peniston C, et al: Morbidity outcome in early versus conventional tracheal extubation following coronary artery bypass graft (CABG) surgery: A prospective randomized controlled trial. J Thorac Cardiovasc Surg 112:755-764, 1996

3. Myles PS, Buckland MR, Weeks AM, et al: Hemodynamic effects, myocardial ischemia, and timing of tracheal extubation with propofolbased anesthesia for cardiac surgery. Anesth Analg 84:12-19, 1997 4. Jain U, Body SC, Bellows W, et al: Multicenter study of target-controlled infusion of propofol-sufentanil or sufentanil-midazolam for coronary artery bypass graft surgery. Anesthesiology 85:522535, 1996

TVIA WITH PROPOFOL-KETAMINE

5. Frizelle HP, Duranteau J, Samii K: A comparison of propofol with a propofol-ketamine combination for sedation during spinal anesthesia. Anesth Analg 84:1318-1322, 1997 6. Hui TW, Short TG, Hong W, et al: Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 82:641-648, 1995 7. Tuman KJ, McCarthy RJ, Spiess BD, et al: Does choice of anesthetic agent significantly affect outcome after coronary artery surgery? Anesthesiology 70:189-198, 1989 8. Hoffman WE, Pelligrino D, Werner C, et al: Ketamine decreases plasma catecholamines and improves outcome from incomplete cerebral ischemia in rats. Anesthesiology 76:755-762, 1992 9. Kohrs R, Durieux ME: Ketamine: Teaching an old drug new tricks. Anesth Analg 87:1186-1193, 1998 10. Smith CE, Botero CA, Podufal E, et al: Blinded, randomized, placebo-controlled study of epinephrine versus norepineprine during separation from cardiopulmonary bypass. Am J Anesthesiol 24:75-83, 1997 11. Jain U: Perioperative use of propofol for cardiac surgery. J Clin Anesth 8:61S-66S, 1996 12. Hall RI, Murphy JT, Moffitt EA, et al: A comparison of the myocardial metabolic and hemodynamic changes produced by propofolsufentanil and enflurane-sufentanil anaesthesia for patients having coronary artery bypass graft surgery. Can J Anaesth 38:996-1004, 1991 13. Kaplan JA, Guffin AV, Mikula S, et al: Comparative hemodynamic effects of propofol and thiamylal sodium during anesthetic induction for myocardial revascularization. J Cardiothor Anesth 2:297302, 1988 14. Mora CT, Dudek C, Torjman MC, White PF: The effects of anesthetic technique on the hemodynamic response and recovery profile in coronary revascularization patients. Anesth Analg 81:900-910, 1995 15. Cook DJ, Carton EG, Housmans PR: Mechanism of the positive inotropic effect of ketamine in isolated ferret ventricular papillary muscle. Anesthesiology 74:880-888, 1991 16. Riou B, Lecarpentier Y, Viars P: Inotropic effect of ketamine on rat cardiac papillary muscle. Anesthesiology 71:116-125, 1989 17. Kanaya N, Murray PA, Damron DS: Propofol and ketamine only inhibit intracellular Ca2⫹ transients and contraction in rat ventricular myocytes at supraclinical concentrations. Anesthesiology 88:781-791, 1998 18. Guit JBM, Koning HM, Coster ML, et al: Ketamine as analgesic

415

for total intravenous anaesthesia with propofol. Anaesthesia 46:24-27, 1991 19. McLean RF, Baker AJ, Walker SE: Ketamine concentrations during cardiopulmonary bypass. Can J Anaesth 43:580-584, 1996 20. Blakely KR, Klein KW, White PF, et al: A total intravenous anesthetic technique for outpatient facial laser resurfacing. Anesth Analg 87:827-829, 1998 21. Friedberg BL: Propofol-ketamine technique. Aesth Plast Surg 17:297-300, 1993 22. Schuttler J, Schuttler M, Kloos S, et al: Total intravenous anesthesia with ketamine and propofol with optimized dosing strategies. Anaesthetist 40:199-204, 1991 23. Botero C, Raghupathy AK, Smith CE, et al: Sedative infusions during surgery: Propofol vs. propofol-ketamine. Can J Anaesth 43:A11, 1996 24. Phillips AA, McLean RF, Devitt JH, Harrington EM: Recall of intraoperative events after general anaesthesia and cardiopulmonary bypass. Can J Anaesth 40:922-926, 1993 25. Ranta S, Jussila J, Hynynen M: Recall of awareness during cardiac anaesthesia: Influence of feedback information to the anaesthesiologist. Acta Anaesthesiol Scand 40:554-560, 1996 26. Ranta S, Laurila R, Saario J, et al: Awareness with recall during general anesthesia: Incidence and risk factors. Anesth Analg 86:10841089, 1998 27. Dowd NP, Cheng DCH, Karski JM, et al: Intraoperative awareness in fast-track cardiac anesthesia. Anesthesiology 89:1068-1073, 1998 28. Jain U, Laflamme CJA, Aggarwal A, et al: Electrocardiographic and hemodynamic changes and their association with myocardial infarction during coronary artery bypass surgery. Anesthesiology 86:576591, 1997 29. Jain U: Myocardial infarction during coronary artery bypass surgery. J Cardiothorac Vasc Anesth 6:612-623, 1992 30. Van Lente F, Martin A, Ratliff NB, et al: The predictive value of serum enzymes for perioperative myocardial infarction after cardiac operations: An autopsy study. J Thorac Cardiovasc Surg 98:704-710, 1989 31. Butterworth J, James R, Prielipp RC, et al: Do shorter-acting neuromuscular blocking drugs or opioids associate with reduced intensive care unit or hospital lengths of stay after coronary artery bypass grafting? CABG Clinical Benchmarking Data Base Participants. Anesthesiology 88:1437-1446, 1998