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Regional Anesthesia and Pain Management

A Comparison of Propofol with a Propofol-Ketamine Combination for Sedation During Spinal Anesthesia

Frizelle, Henry P. MB, FFARCSI; Duranteau, Jacques MD; Samii, Kamran MD

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Abstract

Propofol has been shown to be a good sedative when administered by infusion during regional anesthesia [1]. Although it compares favorably with other sedative drugs, it can cause dose-related cardiovascular and respiratory depression. This may prove to be an important clinical consideration for its use as an adjunct to spinal anesthesia, as hypotension is a frequent complication of sympathetic blockade. Ketamine increases heart rate and arterial blood pressure by its activation of the sympathetic nervous system and reduces the incidence of spinal anesthesia-induced hypotension [2]. However, the occurrence of hallucinations, confusion, and other emergence phenomena have tended to limit its widespread use. Hui et al. [3] reported a few of these emergence phenomena when ketamine was combined with propofol for general anesthesia.

Therefore, we believed that the addition of a small-dose ketamine infusion to propofol might provide the ideal sedative combination for use with spinal anesthesia, producing titratable sedation, increased hemodynamic stability, and less respiratory depression without any psychomimetic effects. Accordingly, we compared a propofol-ketamine combination with propofol alone as a sedative adjunct to spinal anesthesia.

Methods

After institutional ethical committee approval, 40 patients, ASA physical status I and II, aged 18-80 yr, undergoing spinal anesthesia for urologic or orthopedic procedures were studied according to a double-blind protocol. Patients with a history of allergic reaction to propofol or ketamine and/or obesity, significant central nervous system, cardiac, pulmonary, hepatic, or renal disease were excluded from participation in the study. Patients with hypertension, glaucoma, or a history of chronic sedative dependence were also excluded. Once informed consent had been obtained, patients were allocated to one of two groups using a computer-generated sequence of random numbers. All patients received hydroxyzine 100 mg as premedication 1 h prior to surgery.

On arrival in the anesthetic induction room, usual monitoring was put in place. Baseline measurements were taken prior to the administration of spinal anesthesia and were recorded at 5-min intervals for the first 30 min of the operation and every 15 min thereafter. Patients were then positioned in the left lateral position for spinal anesthesia, and a sedative bolus followed by infusion was administered according to the randomization. Lidocaine 2% or bupivacaine 0.5% was administered in doses sufficient to provide a satisfactory sensory block for the procedure in question. The choice of local anesthetic agent was determined by the expected duration of the procedure. The sensory block level was evaluated every 3 min using a cold swab until the level was sufficient for surgery to begin and every 10 min thereafter until maximum block height was achieved.

Those patients assigned to Group 1 (n = 20) received a combination of propofol and ketamine beginning with a loading dose of 0.4 mg/kg propofol and 0.1 mg/kg ketamine prior to spinal anesthesia followed by a continuous infusion with an initial rate of 1.2 mg [centered dot] kg-1 [centered dot] h-1 and 0.3 mg [centered dot] kg-1 [centered dot] h-1, respectively. Group 2 patients (n = 20) received a bolus of 0.5 mg/kg of propofol alone followed by a continuous infusion of 1.5 mg [centered dot] kg-1 [centered dot] h-1. The level of sedation was recorded every 5 min, and subsequent infusion rates were titrated to a predetermined level (Level 3) on a 5-point sedation score (Table 1) [4]. The anesthesiologist assessing the level of sedation was blinded to the sedative infusion being administered. Hemodynamic and respiratory indices were recorded at the previously described intervals. Oxygen was administered in a stepwise fashion to those patients who exhibited SpO2 values of 95% or less, commencing at a flow of 1.0 L/min and increasing in 1-L increments until a value of more than 95% was sustained. Fluid and vasopressor requirements were noted. Ephedrine was administered in 3-mg increments after a sustained (3-min) reduction in mean arterial pressure of 25% from baseline or less than 60 mm Hg absolute value had been obtained. Sedation was stopped if the respiratory rate was less than 8 bpm. The infusion was finally discontinued at the end of the surgical procedure, and total sedative requirements were noted.

T1-26
Table 1:
Sedation Score

Observation was continued in the recovery room; heart rate, blood pressure, and SpO2 were noted at 15-min intervals until the patient's return to the ward. Patient color, level of consciousness, oxygen requirements, and return of motor function were recorded. All patients were closely observed for evidence of hallucinations or other emergence phenomena. Patients remained in the recovery room until motor function had returned to the lower limbs, the autonomic effects of spinal anesthesia had resolved, and standard discharge criteria had been met (stable vital signs, awake and oriented). Any requirements for fluids, vasopressors, antiemetics, or other medications in the recovery room were noted. All patients were visited 24 h after their anesthetic and were questioned about postoperative pain experienced (using a visual analog scale [VAS]), their impressions of and satisfaction with the anesthetic technique used, and any other side effects experienced. Patients were specifically asked about hallucinations, nightmares, visual problems, nausea, vomiting, and headache.

Descriptive variables were analyzed using Student's t-test and chi squared test as appropriate. Mean arterial pressure, heart rate changes, and drug requirements were compared using analysis of variance with repeated measures. Sedation levels were analyzed using the chi squared test. A P value < 0.05 was considered to be statistically significant. Values are expressed as mean +/- SD.

Results

The two groups did not differ with respect to age, sex, weight, or height (Table 2). There were no significant differences between the groups regarding local anesthetic used or final block height achieved. The dermatomal level of anesthesia achieved was satisfactory in all patients. Although the duration of surgery was shorter in Group 2, this did not reach statistical significance. There were no differences between the groups in the interval from first injection of sedative to the start of the surgical procedure.

T2-26
Table 2:
Demographic and Pharmacologic Variables for the Two Treatment Groups

Sedation scores were practically identical for both groups (Figure 1), with a constant degree of sedation being maintained over time. The total dose of propofol administered was similar in each group (Group 1 146 +/- 94 mg and Group 2 137 +/- 52 mg), while Group 1 alone received ketamine (37 +/- 24 mg). Mean propofol infusion rates at equilibrium were also comparable. Arterial pressure dropped after the administration of spinal anesthesia and bolus doses of sedative. Mean arterial pressures were significantly lower in the propofol only group for the first 25 min (Figure 2). Diminishing patient numbers prevented further data from reaching significance. The requirement for supplemental ephedrine was similar for both groups. There were no differences between the groups regarding respiratory rate, end-tidal carbon dioxide levels, SpO2, or need for supplemental oxygen.

F1-26
Figure 1:
Intraoperative cumulative sedation scores (mean +/- SD) for the two patient groups at 5- and 15-min intervals. Cumulative represents the sum of the mean sedation scores for each group over time. Group 1 is represented by the black bars, and Group 2 is represented by the white bars.
F2-26
Figure 2:
Mean arterial pressure values (mean +/- SD) recorded during the intraoperative course at 5- and 15-min intervals for each of the two groups. Symbols represent Group 1 (fill circle) and Group 2 (open circle). The groups were significantly different (P < 0.05) from 0 to 25 min only, as patient numbers decreased after this time point.

The incidence of postoperative complications was similar in both groups. Four patients in each group experienced a hypotensive episode in the recovery room (Table 3), but this was short lived in all cases and was not clinically important. More Group 2 patients required supplemental oxygen while in the recovery room. Nausea was a greater problem in those patients who received the propofol-ketamine combination. No patient suffered from hallucinations in the initial postoperative period. The postoperative pain experienced was similar in both groups, with VAS scores of 38 +/- 10 mm and 35 +/- 15 mm in Groups 1 and 2, respectively. Postoperative analgesic requirements were comparable. Only one patient had an unfavorable opinion regarding the anesthetic technique chosen, preferring a spinal anesthetic without any form of sedation. Three patients reported headache the following day, one of which was migraine. No headache was typically postdural puncture in character. Three patients, only two of whom had received ketamine, described either short-lived auditory hallucinations or vivid dreams. No other emergence phenomena were reported.

T3-26
Table 3:
Incidence of Postoperative Complications and Side Effects in the Two Treatment Groups

Discussion

Propofol has become an accepted standard for sedation during procedures performed under regional anesthesia, both central and peripheral [5]. However, it has some properties that limit its usefulness when used in conjunction with subarachnoid blockade. It causes a reduction in myocardial contractility and in peripheral vascular resistance, which results in a reduction of mean arterial pressure. Recent work [4] has illustrated a continued hypotensive effect when a propofol infusion was used to sedate patients who were undergoing spinal anesthesia. Hemmingsen and Klint Neilsen [2] showed that a patient group receiving a bolus dose of ketamine (0.7 mg/kg) prior to spinal anesthesia had a higher mean arterial pressure when compared with a group given fentanyl (1.5 micro g/kg). Ketamine produces dose-related increases in the rate-pressure product and a transient increase in cardiac index. Both peripheral vascular resistance and heart rate are augmented. However, there is no increase in stroke index, and ketamine is a mild direct cardiac depressant. The stimulant effects are dependent on an intact sympathetic nervous system. When used with propofol for induction of general anesthesia, the cardiostimulant effects of ketamine, even in subanesthetic doses, balance the cardiodepressant effects of propofol [3,6]. In the present study, we demonstrated consistently higher mean arterial pressures throughout the study period in the group that received the propofol-ketamine combination. There was no appreciable effect on heart rate. Although both groups received the same total dose of propofol, the addition of ketamine to the regimen produced improved hemodynamic stability. The stimulant effect of ketamine on the remaining intact sympathetic nervous system may have balanced the depressant effects both of propofol and of the local anesthetic agent used in spinal blockade.

Although the additive effect for the 50% effective dose (ED50) for sedation of propofol and ketamine has been well demonstrated [3], we did not confirm this in the present study. Drug administration was titrated to effect Level 3 of the sedation score, i.e., eyes closed but rousable to verbal stimuli. Both groups received the same total dose of propofol, despite Group 2 receiving a larger initial bolus and despite the concomitant administration of ketamine in Group 1. Hui and coworkers [3] describe an additive effect for a hypnotic end point at ED50 values of 0.63 mg/kg propofol and 0.21 mg/kg ketamine given as bolus doses. However, the hypnotic end point used in Hui et al.'s paper was failure to open the eyes to verbal command, equivalent to Level 4 of the sedation scale we used. It is possible that our failure to show an additive effect was due to the small dose of ketamine given, which had little sedative effect. When designing our study, we chose a ketamine bolus based on the described additive effect with propofol and the target sedation level anticipated. The infusion rates were similarly based on a modification of previously described figures [7]. Increasing the dose of ketamine, both bolus and infusion, may well demonstrate the previously described additive effect and produce the expected propofol sparing. The dose of ketamine administered may be limited by an increasing side effect profile, reducing patient acceptance of the technique. Alternatively, the described additive effect for sedation may be a function of the drug ratios used, a criterion that differed between the studies. Finally, our use of titrated infusions may have influenced the observed effect. Descriptions of an additive effect between propofol and ketamine primarily concern bolus doses, which may not be immediately applicable to their administration by infusion.

Ketamine's effects on the respiratory system are unique among the anesthetic sedative drugs. While it may cause transient apnea at anesthetic induction doses, it does largely preserve the integrity of laryngeal and pharyngeal reflexes and is a recognized bronchodilator. Its effects on central respiratory drive are minimal, preserving the response to carbon dioxide. The addition of ketamine had little effect on the respiratory variables monitored. Respiratory rate, SpO2, ETCO2, and oxygen requirements were similar for both groups. These similarities were probably due to the decision to titrate the sedation to a similar level for both groups. The incidence of upper airway obstruction and snoring was not recorded. The small dose of ketamine used may have had little effect, but it is also possible that the dose of propofol used and the target level of sedation had little respiratory effect in the first place. Previous work suggests that significant respiratory depression is unlikely at propofol bolus doses less than 0.7 mg/kg, although data concerning infusion regimens are limited [5].

Patient recovery after sedation was similar for both groups, which again is a possible reflection of the similar levels of sedation achieved. A postoperative visit 24 h postanesthesia revealed an auditory hallucinatory experience in three patients, including one in the propofol only group. Although these experiences were numerically greater in the propofol-ketamine group, the overall patient satisfaction with the technique chosen illustrates that the hallucinations were not perceived to be problematic. The one patient who would not opt for the same anesthetic again would have preferred sedative-free management. The postoperative pain experienced was similar for the two groups, although failure to standardize the surgical procedures means that direct comparison is impossible. Detailed comment on postoperative pain is limited by the study design, but some relevant points can be made. Although previously described [8], an analgesic effect with ketamine administration was not evident in this study. Roytblat et al. [8] showed that subanesthetic doses of ketamine at induction reduced total morphine consumption and lengthened the time to first analgesic request. In their study, VAS scores up to five hours were less for the ketamine group but not from 5 to 24 hours. The types of operation are not comparable between the two studies; our patients underwent urologic and orthopedic procedures compared with Roytblat et al.'s patients, who underwent open cholecystectomy. In addition, the continued effect of spinal analgesia would minimize the patients' initial pain experience. Finally, while measuring VAS scores in the recovery room and 24 hours postoperatively, we did not use patient-controlled analgesia to monitor a morphine-sparing effect. Postoperative analgesic requests in each group were minimal.

We chose a clinical end point for sedation in this study, choosing not to measure propofol and ketamine serum levels. Mean plasma propofol levels do increase with increasing infusion rates. However, previous work [5] has shown a poor correlation between the serum level of propofol and the sedation level achieved, with considerable variability in individual patients. The use of a clinical end point for sedation allowed compensation for added variables, including interpatient differences in relaxation and background noise. A clinical end point proves more applicable to daily patient care and gives the result more clinical relevance.

In conclusion, we have found that the use of a small-dose ketamine infusion in combination with propofol is of significant hemodynamic benefit when compared with propofol alone during spinal anesthesia. We failed to confirm the additive sedative effect of ketamine with propofol. This may have been due to the small dose of ketamine used. Further studies exploring a larger dose of ketamine may describe this additive effect, possibly at the cost of an increased incidence of side effects.

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© 1997 International Anesthesia Research Society