During surgical procedures performed under local anesthesia and sedation, supplemental analgesics are commonly administered to enhance analgesia and improve patient comfort. Opioids, however, especially when used in combination with sedative-hypnotics, may produce clinically significant respiratory depression and increase the incidence of postoperative nausea and vomiting (PONV) (1,2). The IV anesthetic ketamine possesses analgesic properties (3) and has been used in combination with propofol for general anesthesia (4). The analgesic effects of ketamine are present at plasma concentrations significantly lower than those producing hypnosis (0.2 μg/mL versus 1.5 to 2.5 μg/mL, respectively) (5,6). Preliminary studies indicate that ketamine may be a useful alternative to opioid adjuncts during propofol sedation (7), and that the sympathomimetic actions of ketamine may be effective in counteracting the hemodynamic depression of propofol (8). The combined use of propofol and ketamine may minimize the need for supplemental opioid analgesics. However, the psychomimetic effects of ketamine would be a limiting factor for its use in the outpatient setting. The effect of differing doses of ketamine during propofol sedation has not been studied.
We investigated the dose-dependent effects of ketamine during propofol sedation for monitored anesthesia care (MAC). To determine the optimal ketamine/propofol combination, this double-blinded, placebo-controlled study was designed to evaluate the effect of different ketamine-propofol dosing regimens on analgesia, sedation, and patient recovery, as well as the patients’ and surgeons’ acceptance of this anesthetic technique during procedures performed under local anesthesia.
One hundred consenting ASA physical status I and II female outpatients undergoing breast biopsy procedures under local anesthesia were studied according to a randomized, double-blinded, placebo-controlled, institutional review board approved protocol. Patients with clinically significant cardiovascular, respiratory, or hepatic diseases were excluded from participating. In addition, patients with a history of drug or alcohol abuse, as well as those currently taking sedative or analgesic drugs, were also excluded. All study patients gave a written informed consent before enrollment.
In the preoperative waiting area, an IV catheter was placed under local anesthesia in the nondominant arm for the administration of fluids and IV medications. Baseline measurements included blood pressure, heart rate, respiratory rate, and psychological evaluation by using 100-mm visual analog scales (VAS) for discomfort (“no discomfort”–“worst discomfort ever experienced”), pain (“no pain”–“worst pain ever experienced”), anxiety (“not nervous”–“extremely nervous”), sleepiness (“not sleepy”–“almost asleep”), and nausea (“no nausea”–“worst nausea”). The level of sedation was determined by using the Observer Assessment of Alertness/Sedation (OAA/S) scale (9) modified from the original such that 1 = awake, alert and 5 = unresponsive, as described previously (10). Patients were asked to evaluate their level of discomfort (on an 11-point verbal rating scale, 0 = none to 10 = extreme) and pain (on a 4-point scale, 0 = none; 1 = mild, 2 = moderate, 3 = severe).
A propofol/ketamine admixture was prepared extempore by an assistant who was not involved in the clinical management of the study patients. According to a prestudy randomization schedule of study group assignment, a standard volume of 1.2 mL containing either 0 mg, 20 mg, 40 mg, or 60 mg ketamine in saline was added to 20 mL of propofol. Thus, the study drug solutions consisted of propofol, 9.4 mg/mL, and ketamine, 0, 0.94, 1.88, or 2.83 mg/mL, respectively.
All patients received midazolam, 2 mg IV, for premedication before transfer to the operating room where standard monitoring devices were placed. Supplemental oxygen, 3 L/min, was administered via nasal prongs with a CO2 sampling port. One of the four study drug admixtures was administered by using Bard InfusOR® pump (C.R. Bard, Inc., North Reading, MA), set up for delivery of propofol, as an initial bolus of 300 μg/kg IV, followed by an initial maintenance infusion at 100 μg · kg−1 · min−1. The level of sedation was assessed at 1- to 3-min intervals, and the initial infusion rate was adjusted (in 25 μg · kg−1 · min−1 increments) to achieve OAA/S score of 4 before infiltrating the operative field with local anesthetic (field block with 0.5% lidocaine).
The patient’s response to local anesthetic infiltration was evaluated for pain (on a 4-point verbal scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe), discomfort (on an 11-point verbal scale, 0 = none to 10 = worst discomfort), and body movement. Patients responding with pain ≥1, discomfort >3, or movement to the infiltration of local anesthetic by the surgeon were treated with a “rescue” bolus of sufentanil, 2.5 μg IV. The patients’ vital signs, discomfort, pain, and level of sedation were evaluated at 5- to 10-min intervals until the end of the procedure. During the procedure, the study drug infusion rate was varied to maintain a deep level of sedation (OAA/S score of 4, tested at 5- to 10-min intervals) and normal cardiovascular and respiratory variables (i.e., respiratory rate > 8 breaths/min, SpO2 > 90%). Complaints of pain/discomfort were treated by an incremental increase in the study drug infusion rate if OAA/S score was <4 or, at adequately deep levels of sedation, by a bolus of sufentanil, 2.5 μg IV. Moderate to severe pain not responding to an adjustment in the study drug infusion and/or a bolus dose of sufentanil was treated by injecting additional local anesthetic.
The study drug infusion was discontinued at the end of the surgical procedure (last skin suture), and the total drug requirements were noted. After the completion of the procedure, the surgeon was asked to evaluate the quality of intraoperative condition by using a 4-point rating scale (1 = highly satisfactory, 2 = satisfactory, 3 = somewhat satisfactory, 4 = unsatisfactory). If an Aldrette score ≥9 was confirmed in the operating room, patients were transferred directly to a Phase II “step-down” unit, where they remained until ready for discharge. The recovery room nurses were blinded to the study medication received by the patients. The incidence of any episode of PONV or any other side effects (e.g., nystagmus, double vision, hallucinations) was noted. The patients’ vital signs, level of sedation, and readiness for discharge were assessed at 15-min intervals. Patients were considered “ready for discharge” when they had stable vital signs, were oriented, were able to ambulate unassisted, had no intractable nausea or vomiting, and had minimal wound drainage and pain. Discharge times were determined from the time the study drug infusion was discontinued. Before discharge patients were asked to complete a second set of VAS and asked about their recall of intraoperative events, dreams, and any unusual psychological experiences.
In a telephone interview on the first postoperative day, patients were asked if they had experienced nausea, vomiting, pain, or any unusual psychological reactions after their discharge from the ambulatory surgery center. Patients were asked to rate their satisfaction with the anesthetic management and their overall experience by using a 5-point verbal rating scale (1 = very satisfied, 2 = satisfied, 3 = somewhat satisfied, 4 = dissatisfied), as well as whether they would choose to receive the same sedative-analgesic medications should they require a similar surgical procedure in the future.
Data were presented as mean ± SD or median (range). Parametric data were analyzed by using analysis of variance, followed by post hoc pair-wise multiple comparisons with Bonferroni tests. Nominal data were analyzed by using the χ2 test statistic. P values < 0.05 were considered statistically significant.
There were no significant demographic differences among patients in the four study groups (Table 1). The interval from the start of the infusion to the injection of local anesthetic was not significantly different among the four study groups. Also, the duration of the study drug infusion, the total propofol dose, as well as the average infusion rates of propofol and the amounts of local anesthetic used, were similar in the four study groups (Table 1). Ketamine produced a dose-dependent reduction in the incidence of patient responsiveness to the local anesthetic infiltration: 44% of the patients in Group 1 (placebo) had a response that required “rescue” sufentanil versus 8% of the patients in Group 2 and none in Groups 3 and 4 (P < 0.05) (Table 1). The analgesic requirements for “rescue” opioid throughout the procedure remained minimal in the two higher ketamine dosage groups (P < 0.05) (Table 1).
Similar levels of sedation were achieved in the four study groups before the infiltration of local anesthetic (OAA/S score 4), as well as throughout the procedure (OAA/S scores 4 to 5). The study drug infusion produced a 10- to 15-mm Hg decrease in mean arterial pressure and no significant changes in heart rate values. The reduction in mean arterial pressure values, however, was not statistically significant compared with baseline values as well as among the four study groups. There were no incidents of bradypnea (respiratory rate < 8 breaths/min) or hemoglobin oxygen desaturation (SpO2 < 90%) in the four study groups. However, support of the airway (chin lift) during the procedure was required in 52% of the patients in Group 1 versus only 20% of the patients in Group 4 (P < 0.05) (Table 2). The anesthetic technique was highly satisfactory to the surgeon in more than 90% of the cases, and the most common reason for reduced satisfaction with the intraoperative conditions was patient movement during the infiltration of local anesthetic.
All patients reached an Aldrette score ≥9 in the operating room and were transferred directly to a Phase II (step-down) unit. On admission to Phase II recovery, there was a trend for patients in the two larger ketamine dosage groups (Group 3 and 4) to be more sedated than patients who received placebo (Group 1) (not significant). Psychotomimetic effects (e.g., dreams, hallucinations) and visual disturbances (e.g., double vision, nystagmus) were experienced predominantly by patients in Group 4 (Table 2). Ketamine was associated with a dose-dependent increase in the incidence of PONV. Interestingly, most of the emetic episodes occurred after the discharge from the ambulatory surgery facility and only one patient (in Group 4) experienced emesis during the Phase II recovery period.
Before discharge, patients in all study groups reported increased VAS scores for pain and lower anxiety VAS scores compared with preoperative baseline scores (P < 0.05) (data not presented). Patients receiving ketamine reported an increase in sleepiness and discomfort at discharge (P < 0.05). There was a trend for a ketamine dose-dependent delay in the times to ambulation and to being judged “ready for discharge,” and the times to actual discharge were prolonged for patients in Group 4 (P < 0.05) (Table 1).
At the interview 24 h after discharge, patients did not report any delayed psychotomimetic-type reactions. More than 90% of the patients were satisfied with their anesthesia and were willing to receive the same anesthetic technique again in the future.
Our study was designed to determine an analgesic ketamine dosage, which is not associated with psychotomimetic side effects when coadministered with propofol. The psychotomimetic responses to ketamine, often referred to as “emergence reactions,” are well known sequelae of ketamine anesthesia. However, psychotomimetic effects have also been reported with subhypnotic ketamine dosages (11,12). Subhypnotic dosages of ketamine, 9 ± 2 to 18 ± 7 μg · kg−1 · min−1, administered in combination with propofol infusion for sedation contributed significant analgesia without hemodynamic and respiratory depression or psychotomimetic side effects. Larger dosages of ketamine, 24 ± 8 μg · kg−1 · min−1, were associated with a clinically significant increase in PONV and psychotomimetic side effects.
To prevent ketamine-induced emergence reactions, pretreatment with benzodiazepines is commonly used (3). Likewise, the incidence of psychotomimetic responses was small when ketamine was combined with propofol for general anesthesia (4,13) or sedation (6). The overall incidence of clinically significant psychotomimetic effects was small, 8% to 16%, and occurred predominantly in the large-dose ketamine group. A neurophysiological basis for these observations can be found in a dose-dependent interaction of the excitatory anesthetic ketamine (14) with a pure central nervous system depressant, such as propofol (15).
There were no statistically significant differences in the hemodynamic responses among the four study groups. Furthermore, ketamine-induced tachycardia and hypertension (12) was not evident in the hemodynamic response of patients treated with the propofol/ketamine combination. It appears that the sympathomimetic effect of ketamine may be attenuated when administered in combination with propofol. The hemodynamic stability of the propofol/ketamine combination makes it suitable for use during outpatient anesthesia.
The respiratory depression associated with small doses of ketamine (<1 mg/kg IV) is minimal (16,17). Although deep levels of sedation were maintained in our study, there were no incidents of oxygen desaturation; however, support of the airway was required in 20% to 56% of all patients. It is noteworthy that support of the airway was required significantly less often for patients receiving the largest ketamine dosage (Group 4). Also, because patients in Group 4 had only minimal requirements for “rescue” opioids, this underscores the clinically significant effect of supplemental sufentanil on the respiratory function in the setting of MAC. However, ketamine was dose-dependently associated with an increase in PONV. Therefore, it appears that the type of analgesic supplement used during propofol sedation has a differential impact on outcome (i.e., opioids producing predominantly respiratory depression and larger dose ketamine producing an increase in PONV).
In conclusion, subhypnotic dosages of ketamine coadministered with propofol for sedation during MAC exert an opioid-sparing effect with no clinically significant respiratory depression and a low incidence of psychotomimetic effects.
The authors thank the CRNAs and recovery room nurses of Rush SurgiCenter for their help with the study.
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