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Propofol-ketamine versus propofol-fentanyl for outpatient laparoscopy
Original Contributions Propofol-Ketamine Versus Propofol-Fentanyl for Outpatient Laparoscopy: Comparison of Postoperative Nausea, Emesis, Analgesia, and Recovery Manuel C. Vallejo, MD,* Ryan C. Romeo, MD,* Derek J. Davis, MD* Sivam Ramanathan, MD† Department of Anesthesia, Magee-Women’s Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA
*Assistant Professor of Anesthesiology †Professor of Anesthesiology Address correspondence to Dr. Vallejo at the Department of Anesthesia, Magee-Women’s Hospital, 300 Halket St., Pittsburgh, PA 15213 USA. E-mail: vallejomc@anes. upmc.edu Received for publication January 24, 2002; revised manuscript accepted for publication April 23, 2002.
Study Objective: To compare postoperative nausea, emesis, analgesia, and recovery between propofol-ketamine and propofol-fentanyl in outpatient laparoscopic tubal ligations with general anesthesia. Study Design: Prospective, randomized, blinded study. Setting: Tertiary-care women’s hospital. Patients: 120 ASA physical status I and II ambulatory patients scheduled for elective laparoscopic tubal ligation. Interventions: Patients were randomized to two groups to receive either ketamine (1-1.5 mg/kg) or fentanyl (3-5 g/kg). Measurements: Measured variables included total dose of ketamine, fentanyl, propofol, and operating time. Vital signs, pain visual analog scale scores (VAS), nausea VAS, presence of emesis, treatment for nausea and vomiting, pruritus, sedation, and presence of dreaming were recorded on postanesthesia care unit (PACU) admission, PACU discharge, stepdown unit admission, and hospital discharge. Results are expressed as means ⫾ SD or medians and analyzed using t-test, Chi-square, or Mann-Whitney (p ⬍ 0.05). Main Results: No differences were noted with respect to propofol dose, operating times, pain or nausea VAS scores, emesis, treatment for nausea and vomiting, pruritus, and sedation on PACU admission, PACU discharge, stepdown unit admission, and hospital discharge. The ketamine group had a higher heart rate, required more pain medication, and had a higher frequency of dreaming on PACU admission than the fentanyl group. These differences became insignificant on PACU discharge. Conclusions: For outpatient laparoscopic tubal ligations with general anesthesia, propofol-ketamine does not improve postoperative nausea, emesis, analgesia or recovery compared with the propofol-fentanyl combination. © 2002 by Elsevier Science Inc. Keywords: Anesthesia; ambulatory; fentanyl; ketamine; nausea and vomiting; postoperative; recovery; postoperative.
Journal of Clinical Anesthesia 14:426 – 431, 2002 © 2002 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/02/$–see front matter PII S0952-8180(02)00391-4
Propofol-ketamine: Vallejo et al.
Introduction The overall incidence of postoperative nausea and vomiting (PONV) following anesthesia is reported to be 20% to 30%.1 Seventy percent of all anesthetics given in the United States are done on an ambulatory basis.2 In this era of health care cost containment, it is important that anesthetic drugs have rapid emergence, less PONV, adequate analgesia, and quick recovery. Opioids are used to provide analgesia but are associated with a 15% to 40% incidence of PONV.3 Ketamine also produces analgesia and, when combined with propofol instead of fentanyl, can lower the incidence of PONV to 0.6% when used for intravenous (IV) conscious sedation.3 Jakobsson et al. 4 compared propofol in combination with ketamine or fentanyl. They found that the propofolfentanyl combination produced a lower frequency of postoperative pain and dreaming, with no difference in recovery or PONV in patients undergoing termination of pregnancy with IV general anesthesia. However, gynecologic surgery involving laparoscopy (using peritoneal insufflation) for diagnostic and therapeutic purposes is associated with a very high incidence of PONV (36% to 60%).5 The purpose of this study was to determine if propofol in combination with ketamine or fentanyl provides less PONV, improved postoperative analgesia, quicker recovery, and a shorter hospital stay for outpatient laparoscopic tubal ligations with general endotracheal anesthesia in patients known to be at high risk for PONV.
Materials and Methods This study was approved by the Magee Women’s Hospital Investigational Review Board. Written informed consent was obtained from 120 women on admission to the same-day surgery suite from October 1999 to August 2001. Patients who were ASA physical status I or II, and scheduled for elective outpatient laparoscopic tubal ligation with general anesthesia were enrolled into the study. Patients were randomized into two groups using a computer-generated program (Corel Quattro Pro 9, Corel Corp., Ottawa, Canada). Group 1 received ketamine 1 to 1.5 mg/kg and Group 2 received fentanyl 3 to 5 g/kg. General endotracheal anesthesia was standardized except for the use of ketamine (Group 1) or fentanyl (Group 2). The choice of total dose for both ketamine and fentanyl to provide general anesthesia came from a previous study.5 In addition, fentanyl in the dose range of 3 to 5 g/kg is a common dose range used for tubal ligations during general anesthesia at our institution. Induction drugs included propofol (2 mg/kg), midazolam (1-2 mg), dtubocurarine (3 mg), succinylcholine (1.5 mg/kg), and ketorolac (30 mg IV). Patients in the ketamine group also received glycopyrrolate (0.2 mg) during induction. Maintenance of general anesthesia consisted of isoflurane (0.5%–1.5% end-tidal) with oxygen (50%), nitrous oxide (50%), and rocuronium (0.6 mg/kg). Nitrous oxide was used to supplement maintenance of general anesthesia because it decreases the anesthetic requirement without
increasing PONV, while also allowing for quicker emergence.6 Neuromuscular function was monitored with a peripheral nerve stimulator and neuromuscular blockade was reversed with neostigmine (35-70 g/kg) and glycopyrrolate (5-10 g/kg) at the end of the procedure. A dedicated clinical research coordinator who collected the data was blinded to the anesthetic technique used for each patient. Multiple doses of the study drug (ketamine or fentanyl) were administered to provide general anesthesia within the specified dose limitations described above. Criteria used for additional administration of the study drug were to provide adequate intraoperative analgesia, maintaining blood pressure and heart rate (HR) within ⫾ 20% of preoperative baseline values. The modified Pomeroy procedure was used for tubal ligation. No local anesthetics were injected into the operative site during the procedure. Measured variables included total doses of ketamine, fentanyl, and propofol, operating time, PACU stay time, and stepdown unit stay time. Vital signs (mean arterial blood pressure, HR, and respiratory rate), postoperative pain as measured by visual analog scale scores (VAS; 100-mm sliding scale), nausea VAS, presence of emesis, treatment for nausea and vomiting, pruritus, sedation, and presence of dreaming were recorded on PACU admission, PACU discharge, stepdown unit admission, and at hospital discharge. Additionally, dreaming was characterized as pleasant or unpleasant. Discharge times were recorded when the patient met specific criteria for discharge in both the PACU and stepdown unit. PACU discharge criteria includes being awake, alert and oriented, stable vital signs, pulse oximeter saturation at baseline or ⱖ95%, intact incision site with minimal drainage, and able to ambulate to stepdown unit with minimal pain, and/or nausea. Stepdown unit discharge criteria include being alert and oriented, with stable vital signs, ambulation with minimal assistance, minimal nausea, emesis, and pain, intact and dry operative site, and able to verbalize understanding of discharge instructions. Postoperative medications used for the treatment of PONV and pain were recorded when given in the PACU, stepdown unit, and/or at hospital discharge. Study criteria used for administration of postoperative analgesics included the presence of moderate to severe pain (VAS pain ⱖ30). Study criteria used for the administration of postoperative antiemetics included the presence of mild to severe nausea and/or emesis. Based on the patient’s past medical history, allergies and/or side effects, available postoperative medications used for rescue analgesia included fentanyl, meperidine, morphine, propoxyphene/acetaminophen (Darvocet®), hydrocodone/acetaminophen (Vicodan®), oxycodone/ acetaminophen (Percocet®), ibuprofen, and acetaminophen. Available study rescue PONV medications included metoclopramide, ondansetron, droperidol, and dexamethasone. Patients were asked whether they remembered dreaming, and they were encouraged to describe their experience as pleasant or unpleasant. In this study, dreaming is J. Clin. Anesth., vol. 14, September 2002
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Table 1. Demographic Data, and Total Dosages of Propofol, Ketamine, and Fentanyl
Ketamine Group
Fentanyl Group
p-value
34.1 ⫾ 5.9 164.3 ⫾ 6.1 70.0 ⫾ 13.2 167.5 ⫾ 43.5 77.8 ⫾ 42.0 0
34.3 ⫾ 6.1 163.6 ⫾ 7.7 73.2 ⫾ 17.6 164.4 ⫾ 39.2 0 220.0 ⫾ 80.7
0.870 0.580 0.263 0.689 – –
Age (yrs) Height (cm) Weight (kg) Propofol (mg) Ketamine (mg) Fentanyl (g)
defined as patient recall of ideas or images unrelated to perioperative events.
Figure 1. Mean surgical time, postanesthesia care unit (PACU) time, and stepdown unit stay time.
Statistical Analysis
Differences between groups occurred only during PACU admission, where HR was higher (not clinically significant), more patients required pain medication, and there was a higher rate of dreaming (Table 2). Of the 10 patients in the ketamine group who had dreaming on PACU admission, only two patients described the dream as unpleasant. Only one patient in the fentanyl group had dreaming on PACU admission, which was described as pleasant. These differences became insignificant on PACU discharge and remained so until hospital discharge (Table 3, Table 4, and Table 5). No differences were noted in the other measured variables on PACU discharge (Table 3), stepdown unit admission (Table 4), and on hospital discharge (Table 5). Of the two patients who experienced an unpleasant dream
For statistical purposes, we used a PONV frequency of 15% using the propofol-fentanyl combination and a PONV frequency of 0.6% using the propofol-ketamine combination and no opioid.3 With an alpha of 0.05 and a power of 80%, 54 patients per group would be required to detect statistical significance.7 To allow for patients who would possibly be unable to complete the study, a total of 120 patients were recruited. Results are expressed as means ⫾ SD, or medians. Parametric data were analyzed using unpaired t-test. Nominal data were analyzed using Chisquare analysis of contingency. Pain VAS and nausea VAS were analyzed using Mann-Whitney rank sum test. A p-value ⬍ 0.05 was considered significant.
Results One patient assigned to the ketamine group refused surgery and thus did not complete the study. Hence, a total of 59 patients in the propofol-ketamine group and 60 patients in the propofol-fentanyl group completed the study. The overall frequency of PONV in the ketamine group was 15.3% and it was 15.0% in the fentanyl group (p ⫽ 0.83). Demographic data and mean total doses of propofol, ketamine, and fentanyl are presented in Table 1. No differences between groups were noted with respect to age, height, weight, or total propofol dose. No differences were noted in surgical operating time in the ketamine group (33.1 ⫾ 13.5 min) compared with the fentanyl group (30.7 ⫾ 17.9 min, p ⫽ 0.41). Likewise, no differences were noted in PACU time (106.7 ⫾ 39.1 vs. 94.8 ⫾ 33.1 min) or in stepdown unit stay time (73.4 ⫾ 47.0 vs. 62.8 ⫾ 35.8) (Figure 1). Table 2 shows PACU admission measured variables. No differences were noted with respect to mean arterial blood pressure, respiratory rate, pain VAS scores, maximum pain scores (VAS ⬎75), nausea VAS scores, maximum nausea scores (VAS ⬎75), presence of emesis, treatment medication for nausea and or vomiting, presence of pruritus, or sedation (Table 2). 428
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Table 2. Postanesthesia Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Care
Unit
(PACU)
Admission
Ketamine Group
Fentanyl Group
p-value
92.2 ⫾ 13.4 91.0 ⫾ 13.0* 17.5 ⫾ 4.1
91.4 ⫾ 15.0 85.2 ⫾ 15.0 16.3 ⫾ 3.3
0.739 0.027 0.059
0 (0–100)
0 (0–100)
0.109
8 19*
6 8
0.776 0.025
0 (0–85)
0 (0–100)
0.631
2 0 7 1 19 10*
1 1 4 2 21 1
1.000 0.993 0.508 0.988 0.897 0.010
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert *p ⬍ 0.05 compared with fentanyl group.
Propofol-ketamine: Vallejo et al.
Table 3. Postanesthesia Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Care
Unit
(PACU)
Discharge
Ketamine Group
Fentanyl Group
p-value
86.5 ⫾ 11.5 69.3 ⫾ 14.1 17.5 ⫾ 3.3
82.9 ⫾ 11.7 70.7 ⫾ 13.9 17.2 ⫾ 2.7
0.099 0.584 0.557
30.0 (0–90)
27.5 (0–100)
0.726
3 37
6 35
0.488 0.763
0 (0–90)
0 (0–100)
0.631
3 3 9 0 1 5
4 2 9 4 0 0
1.000 0.985 0.828 0.131 0.993 0.065
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert.
Table 5. Hospital Discharge Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Ketamine Group
Fentanyl Group
p-value
87.4 ⫾ 9.8 73.1 ⫾ 8.6 16.4 ⫾ 1.9
86.1 ⫾ 8.9 72.1 ⫾ 9.2 16.6 ⫾ 1.4
0.471 0.525 0.671
10.0 (0–70)
10.0 (0–50)
0.198
0 6
0 3
– 0.472
0 (0–75)
0 (0–25)
0.941
1 0 0 0 0 0
0 0 0 1 0 0
1.000 – – 0.993 – –
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert.
reported late PONV, compared with no patients (0%) in the ketamine group. on PACU admission, neither patient could recall the dream on hospital discharge. There were no unanticipated hospital admissions as a result of the surgery or anesthetic technique, and no patients had any hallucinations or bad dreams following discharge home. After hospital discharge, patients were contacted the next day by telephone. Only one patient (1.7%) in the fentanyl group
Table 4. Stepdown Unit Admission Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain Medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Ketamine Group
Fentanyl Group
p-value
87.9 ⫾ 10.8 72.9 ⫾ 9.8 16.8 ⫾ 2.0
86.0 ⫾ 9.6 71.7 ⫾ 10.3 16.7 ⫾ 1.7
0.314 0.511 0.882
27.5 (0–80)
20.0 (0–80)
0.252
3 21
2 22
1.000 0.945
0 (0–100)
0 (0–100)
0.600
2 4 6 0 0 1
2 2 7 2 0 0
0.611 0.660 0.974 0.483 – 0.993
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert.
Discussion Outpatient ambulatory surgery is the fastest growing segment of surgery and anesthesia.2 Seventy percent of all anesthetics given in the United States are done on an ambulatory basis.2 In this era of health care cost containment, it is important to decrease costs without compromising patient care. Nausea and vomiting is the most common reason for unanticipated outpatient hospital admissions, and the potential savings of outpatient surgery may be negated by an unanticipated hospital admission. The goals of outpatient ambulatory anesthesia include a rapid and smooth induction, effective intraoperative anesthesia, and a smooth and prompt recovery with minimal, if any, postoperative side effects, leading to a quicker return to “home readiness” and an overall shorter outpatient stay. Ketamine has been used in combination with propofol for both general and IV sedation and to supplement general anesthesia.3,4,8 –12 Hui et al.11 found that there is synergism between propofol and ketamine when they are used for induction of general anesthesia in female patients. They calculated the effective dose for 95% of patients (ED95) for the combination to be 2.02 mg/kg propofol and 0.67 mg/kg ketamine. However, Hui et al. recommend caution in extrapolating these induction dosage recommendations for IV maintenance of general anesthesia.11 In our study, the mean total dose for the propofol-ketamine combination used for both induction and maintenance was 2.39 mg/kg propofol and 1.11 mg/kg ketamine. Side effects limiting the total dose of ketamine are emergence psychotomimetic reactions (dreaming, delirJ. Clin. Anesth., vol. 14, September 2002
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ium, and hallucinations), visual disturbances (blurred vision, nystagmus), dose-dependent PONV, and delay in hospital discharge.3,4,8 –10,12 Several investigators reported a decrease in psychotomimetic emergence reactions when ketamine is used in combination with a sedative-hypnotic (e.g., benzodiazepines, propofol) or a general anesthetic (e.g., halothane, nitrous oxide).8,12 Subhypnotic doses of propofol fail to block ketamine-induced hallucinations;12,13 however, hypnotic doses of propofol are reported to block these hallucinations.9,12 Hui et al.11 calculated the ED95 for hypnosis to be 1.93 mg/kg for propofol, 0.84 mg/kg for ketamine, and for the propofol-ketamine combination to be 0.97 mg/kg propofol and 0.33 mg/kg ketamine. We did not find propofol (mean total dose of 2.39 mg/kg) to block ketamine-induced hallucinations in our study in combination with midazolam and isoflurane-nitrous oxide inhalation anesthetic. In contrast to our study, Guit et al.8 found longer recovery time with propofol-ketamine compared with propofol-fentanyl, the reason being that they used a bolus dose of ketamine (1 mg/kg) followed by continuous infusion of ketamine (2 mg/kg/hr), which most likely added to the longer recovery time. However, their study was limited because of the number of patients studied and the longer duration of surgery (60 ⫾ 27 min).8 Frizelle et al.10 compared propofol with a propofolketamine (2.0 mg/kg propofol plus 0.5 mg/kg ketamine) combination for sedation during spinal anesthesia and found a higher frequency of nausea, similar postoperative pain between the two groups, and two patients (10%) who reported auditory hallucinations or vivid dreams. Similarly, Badrinath et al.9 compared multiple concentrations of ketamine in a ketamine-propofol combination during monitored anesthesia care and found an increase in PONV, an increase in psychotomimetic effects, prolonged recovery, and delay in discharge with an increasing dose of ketamine. We did not find a higher frequency of postoperative nausea (p ⫽ NS) in our study, but more patients required pain medication in the immediate postoperative period even though pain VAS scores and maximum pain VAS scores were similar. Patients in the ketamine group received more pain medication on PACU admission than patients in the fentanyl group despite similar pain scores, most likely because of elevated HR and the presence of psychotomimetic reactions. There was a higher frequency of psychotomimetic reactions in the propofol-ketamine group (17.0%) compared with the propofol-fentanyl group (1.7%). Differences in pain medication requirements and psychotomimetic reactions in our study became insignificant during the remainder of the postoperative stay (PACU discharge, stepdown unit admission and discharge, and hospital discharge). Similar to our study, Jakobsson et al.4 compared propofol in combination with ketamine (20 mg) or fentanyl (0.1 mg) in patients undergoing termination of pregnancy with IV general anesthesia, and they found that the propofol-fentanyl combination produced a lower frequency of postoperative pain and dreaming with no 430
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difference in recovery or PONV. However, our study is different from Jakobsson et al.’s in that patients were intubated, they received an inhalational drug for maintenance of general anesthesia, and they also received midazolam to reduce psychotomimetic side effects. Additionally, the operative procedure (laparoscopic tubal ligation) was longer, and it is also associated with a higher incidence of PONV.5 Friedberg3 found that propofol-ketamine in plastic surgery procedures was associated with a 0.6% frequency of PONV. However, our study involved patients undergoing high-risk, emetogenic laparoscopic procedures.5 Additionally, Friedberg neither intubated nor gave inhalational drugs to his patients. The difference in the frequency of dreaming in Friedberg’s study (1%) versus our study (17%) can be explained by the duration of surgery. Friedberg3 administered ketamine at the beginning of surgery to suppress the pain of local infiltration, and the surgery continued for another 2 hours only with propofol sedation. Ketamine-induced dreams were short-lived, and the high-risk period for ketamine-induced dreams and hallucinations were well covered by propofol (151-160 min). In our study, the duration of surgery was only 30 to 40 minutes and ketamine’s psychomimetic effects became evident postoperatively. In conclusion, for outpatient laparoscopic tubal ligations, hypnotic-anesthetic doses of propofol-ketamine combination do not improve postoperative nausea, emesis, analgesia, and recovery compared with the propofolfentanyl combination. Although differences were not significant on hospital discharge, ketamine (1 mg/kg) is not recommended because of the high incidence of psychotomimetic reactions in the immediate postoperative period.
Acknowledgments The authors would like to thank Jewel DeSisto, CRNA, and Kathy Marks, CRNA, for their assistance with the study.
References 1. Watcha MF, White PF: Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992;77:162– 84. 2. Hall MJ, Lawrence L: Ambulatory surgery in the United States, 1996. Adv Data 1998;12:1–16. 3. Friedberg BL: Propofol-ketamine technique: dissociative anesthesia for office surgery (a 5-year review of 1264 cases). Aesthetic Plast Surg 1999;23:70 –5. 4. Jakobsson J, Oddby E, Rane K: Patient evaluation of four different combinations of intravenous anaesthetics for short outpatient procedures. Anaesthesia 1993;48:1005–7. 5. Lerman J: Surgical and patient factors involved in postoperative nausea and vomiting. Br J Anaesth 1992;69(7 Suppl 1):24S–32S. 6. Tang J, Chen L, White PF, et al: Use of propofol for office-based anesthesia: effect of nitrous oxide on recovery profile. J Clin Anesth 1999;11:226 –30. 7. Glantz SA: Primer of Biostatistics, 4th ed. New York: Mc-Graw-Hill, 1997.
Propofol-ketamine: Vallejo et al. 8. Guit JB, Koning HM, Coster ML, Niemeijer RPE, Mackie DP: Ketamine as analgesic for total intravenous anesthesia with propofol. Anaesthesia 1991;46:24 –7. 9. Badrinath S, Avramov MN, Shadrick M, Witt TR, Ivankovich AD: The use of a ketamine-propofol combination during monitored anesthesia care. Anesth Analg 2000;90:858 –62. 10. Frizelle HP, Duranteau J, Samii K: A comparison of propofol with a propofol-ketamine combination for sedation during spinal anesthesia. Anesth Analg 1997;84:1318 –22.
11. Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J: Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 1995;82: 641–8. 12. Friedberg BL: Propofol-ketamine technique. Aesthetic Plast Surg 1993;17:297–300. 13. Smith I, White PF: Use of intravenous adjuvants during local and regional anesthesia (monitored anesthesia care). Curr Rev Nurse Anesth 1992;14:186 –92.
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*Assistant Professor of Anesthesiology †Professor of Anesthesiology Address correspondence to Dr. Vallejo at the Department of Anesthesia, Magee-Women’s Hospital, 300 Halket St., Pittsburgh, PA 15213 USA. E-mail: vallejomc@anes. upmc.edu Received for publication January 24, 2002; revised manuscript accepted for publication April 23, 2002.
Study Objective: To compare postoperative nausea, emesis, analgesia, and recovery between propofol-ketamine and propofol-fentanyl in outpatient laparoscopic tubal ligations with general anesthesia. Study Design: Prospective, randomized, blinded study. Setting: Tertiary-care women’s hospital. Patients: 120 ASA physical status I and II ambulatory patients scheduled for elective laparoscopic tubal ligation. Interventions: Patients were randomized to two groups to receive either ketamine (1-1.5 mg/kg) or fentanyl (3-5 g/kg). Measurements: Measured variables included total dose of ketamine, fentanyl, propofol, and operating time. Vital signs, pain visual analog scale scores (VAS), nausea VAS, presence of emesis, treatment for nausea and vomiting, pruritus, sedation, and presence of dreaming were recorded on postanesthesia care unit (PACU) admission, PACU discharge, stepdown unit admission, and hospital discharge. Results are expressed as means ⫾ SD or medians and analyzed using t-test, Chi-square, or Mann-Whitney (p ⬍ 0.05). Main Results: No differences were noted with respect to propofol dose, operating times, pain or nausea VAS scores, emesis, treatment for nausea and vomiting, pruritus, and sedation on PACU admission, PACU discharge, stepdown unit admission, and hospital discharge. The ketamine group had a higher heart rate, required more pain medication, and had a higher frequency of dreaming on PACU admission than the fentanyl group. These differences became insignificant on PACU discharge. Conclusions: For outpatient laparoscopic tubal ligations with general anesthesia, propofol-ketamine does not improve postoperative nausea, emesis, analgesia or recovery compared with the propofol-fentanyl combination. © 2002 by Elsevier Science Inc. Keywords: Anesthesia; ambulatory; fentanyl; ketamine; nausea and vomiting; postoperative; recovery; postoperative.
Journal of Clinical Anesthesia 14:426 – 431, 2002 © 2002 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/02/$–see front matter PII S0952-8180(02)00391-4
Propofol-ketamine: Vallejo et al.
Introduction The overall incidence of postoperative nausea and vomiting (PONV) following anesthesia is reported to be 20% to 30%.1 Seventy percent of all anesthetics given in the United States are done on an ambulatory basis.2 In this era of health care cost containment, it is important that anesthetic drugs have rapid emergence, less PONV, adequate analgesia, and quick recovery. Opioids are used to provide analgesia but are associated with a 15% to 40% incidence of PONV.3 Ketamine also produces analgesia and, when combined with propofol instead of fentanyl, can lower the incidence of PONV to 0.6% when used for intravenous (IV) conscious sedation.3 Jakobsson et al. 4 compared propofol in combination with ketamine or fentanyl. They found that the propofolfentanyl combination produced a lower frequency of postoperative pain and dreaming, with no difference in recovery or PONV in patients undergoing termination of pregnancy with IV general anesthesia. However, gynecologic surgery involving laparoscopy (using peritoneal insufflation) for diagnostic and therapeutic purposes is associated with a very high incidence of PONV (36% to 60%).5 The purpose of this study was to determine if propofol in combination with ketamine or fentanyl provides less PONV, improved postoperative analgesia, quicker recovery, and a shorter hospital stay for outpatient laparoscopic tubal ligations with general endotracheal anesthesia in patients known to be at high risk for PONV.
Materials and Methods This study was approved by the Magee Women’s Hospital Investigational Review Board. Written informed consent was obtained from 120 women on admission to the same-day surgery suite from October 1999 to August 2001. Patients who were ASA physical status I or II, and scheduled for elective outpatient laparoscopic tubal ligation with general anesthesia were enrolled into the study. Patients were randomized into two groups using a computer-generated program (Corel Quattro Pro 9, Corel Corp., Ottawa, Canada). Group 1 received ketamine 1 to 1.5 mg/kg and Group 2 received fentanyl 3 to 5 g/kg. General endotracheal anesthesia was standardized except for the use of ketamine (Group 1) or fentanyl (Group 2). The choice of total dose for both ketamine and fentanyl to provide general anesthesia came from a previous study.5 In addition, fentanyl in the dose range of 3 to 5 g/kg is a common dose range used for tubal ligations during general anesthesia at our institution. Induction drugs included propofol (2 mg/kg), midazolam (1-2 mg), dtubocurarine (3 mg), succinylcholine (1.5 mg/kg), and ketorolac (30 mg IV). Patients in the ketamine group also received glycopyrrolate (0.2 mg) during induction. Maintenance of general anesthesia consisted of isoflurane (0.5%–1.5% end-tidal) with oxygen (50%), nitrous oxide (50%), and rocuronium (0.6 mg/kg). Nitrous oxide was used to supplement maintenance of general anesthesia because it decreases the anesthetic requirement without
increasing PONV, while also allowing for quicker emergence.6 Neuromuscular function was monitored with a peripheral nerve stimulator and neuromuscular blockade was reversed with neostigmine (35-70 g/kg) and glycopyrrolate (5-10 g/kg) at the end of the procedure. A dedicated clinical research coordinator who collected the data was blinded to the anesthetic technique used for each patient. Multiple doses of the study drug (ketamine or fentanyl) were administered to provide general anesthesia within the specified dose limitations described above. Criteria used for additional administration of the study drug were to provide adequate intraoperative analgesia, maintaining blood pressure and heart rate (HR) within ⫾ 20% of preoperative baseline values. The modified Pomeroy procedure was used for tubal ligation. No local anesthetics were injected into the operative site during the procedure. Measured variables included total doses of ketamine, fentanyl, and propofol, operating time, PACU stay time, and stepdown unit stay time. Vital signs (mean arterial blood pressure, HR, and respiratory rate), postoperative pain as measured by visual analog scale scores (VAS; 100-mm sliding scale), nausea VAS, presence of emesis, treatment for nausea and vomiting, pruritus, sedation, and presence of dreaming were recorded on PACU admission, PACU discharge, stepdown unit admission, and at hospital discharge. Additionally, dreaming was characterized as pleasant or unpleasant. Discharge times were recorded when the patient met specific criteria for discharge in both the PACU and stepdown unit. PACU discharge criteria includes being awake, alert and oriented, stable vital signs, pulse oximeter saturation at baseline or ⱖ95%, intact incision site with minimal drainage, and able to ambulate to stepdown unit with minimal pain, and/or nausea. Stepdown unit discharge criteria include being alert and oriented, with stable vital signs, ambulation with minimal assistance, minimal nausea, emesis, and pain, intact and dry operative site, and able to verbalize understanding of discharge instructions. Postoperative medications used for the treatment of PONV and pain were recorded when given in the PACU, stepdown unit, and/or at hospital discharge. Study criteria used for administration of postoperative analgesics included the presence of moderate to severe pain (VAS pain ⱖ30). Study criteria used for the administration of postoperative antiemetics included the presence of mild to severe nausea and/or emesis. Based on the patient’s past medical history, allergies and/or side effects, available postoperative medications used for rescue analgesia included fentanyl, meperidine, morphine, propoxyphene/acetaminophen (Darvocet®), hydrocodone/acetaminophen (Vicodan®), oxycodone/ acetaminophen (Percocet®), ibuprofen, and acetaminophen. Available study rescue PONV medications included metoclopramide, ondansetron, droperidol, and dexamethasone. Patients were asked whether they remembered dreaming, and they were encouraged to describe their experience as pleasant or unpleasant. In this study, dreaming is J. Clin. Anesth., vol. 14, September 2002
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Table 1. Demographic Data, and Total Dosages of Propofol, Ketamine, and Fentanyl
Ketamine Group
Fentanyl Group
p-value
34.1 ⫾ 5.9 164.3 ⫾ 6.1 70.0 ⫾ 13.2 167.5 ⫾ 43.5 77.8 ⫾ 42.0 0
34.3 ⫾ 6.1 163.6 ⫾ 7.7 73.2 ⫾ 17.6 164.4 ⫾ 39.2 0 220.0 ⫾ 80.7
0.870 0.580 0.263 0.689 – –
Age (yrs) Height (cm) Weight (kg) Propofol (mg) Ketamine (mg) Fentanyl (g)
defined as patient recall of ideas or images unrelated to perioperative events.
Figure 1. Mean surgical time, postanesthesia care unit (PACU) time, and stepdown unit stay time.
Statistical Analysis
Differences between groups occurred only during PACU admission, where HR was higher (not clinically significant), more patients required pain medication, and there was a higher rate of dreaming (Table 2). Of the 10 patients in the ketamine group who had dreaming on PACU admission, only two patients described the dream as unpleasant. Only one patient in the fentanyl group had dreaming on PACU admission, which was described as pleasant. These differences became insignificant on PACU discharge and remained so until hospital discharge (Table 3, Table 4, and Table 5). No differences were noted in the other measured variables on PACU discharge (Table 3), stepdown unit admission (Table 4), and on hospital discharge (Table 5). Of the two patients who experienced an unpleasant dream
For statistical purposes, we used a PONV frequency of 15% using the propofol-fentanyl combination and a PONV frequency of 0.6% using the propofol-ketamine combination and no opioid.3 With an alpha of 0.05 and a power of 80%, 54 patients per group would be required to detect statistical significance.7 To allow for patients who would possibly be unable to complete the study, a total of 120 patients were recruited. Results are expressed as means ⫾ SD, or medians. Parametric data were analyzed using unpaired t-test. Nominal data were analyzed using Chisquare analysis of contingency. Pain VAS and nausea VAS were analyzed using Mann-Whitney rank sum test. A p-value ⬍ 0.05 was considered significant.
Results One patient assigned to the ketamine group refused surgery and thus did not complete the study. Hence, a total of 59 patients in the propofol-ketamine group and 60 patients in the propofol-fentanyl group completed the study. The overall frequency of PONV in the ketamine group was 15.3% and it was 15.0% in the fentanyl group (p ⫽ 0.83). Demographic data and mean total doses of propofol, ketamine, and fentanyl are presented in Table 1. No differences between groups were noted with respect to age, height, weight, or total propofol dose. No differences were noted in surgical operating time in the ketamine group (33.1 ⫾ 13.5 min) compared with the fentanyl group (30.7 ⫾ 17.9 min, p ⫽ 0.41). Likewise, no differences were noted in PACU time (106.7 ⫾ 39.1 vs. 94.8 ⫾ 33.1 min) or in stepdown unit stay time (73.4 ⫾ 47.0 vs. 62.8 ⫾ 35.8) (Figure 1). Table 2 shows PACU admission measured variables. No differences were noted with respect to mean arterial blood pressure, respiratory rate, pain VAS scores, maximum pain scores (VAS ⬎75), nausea VAS scores, maximum nausea scores (VAS ⬎75), presence of emesis, treatment medication for nausea and or vomiting, presence of pruritus, or sedation (Table 2). 428
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Table 2. Postanesthesia Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Care
Unit
(PACU)
Admission
Ketamine Group
Fentanyl Group
p-value
92.2 ⫾ 13.4 91.0 ⫾ 13.0* 17.5 ⫾ 4.1
91.4 ⫾ 15.0 85.2 ⫾ 15.0 16.3 ⫾ 3.3
0.739 0.027 0.059
0 (0–100)
0 (0–100)
0.109
8 19*
6 8
0.776 0.025
0 (0–85)
0 (0–100)
0.631
2 0 7 1 19 10*
1 1 4 2 21 1
1.000 0.993 0.508 0.988 0.897 0.010
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert *p ⬍ 0.05 compared with fentanyl group.
Propofol-ketamine: Vallejo et al.
Table 3. Postanesthesia Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Care
Unit
(PACU)
Discharge
Ketamine Group
Fentanyl Group
p-value
86.5 ⫾ 11.5 69.3 ⫾ 14.1 17.5 ⫾ 3.3
82.9 ⫾ 11.7 70.7 ⫾ 13.9 17.2 ⫾ 2.7
0.099 0.584 0.557
30.0 (0–90)
27.5 (0–100)
0.726
3 37
6 35
0.488 0.763
0 (0–90)
0 (0–100)
0.631
3 3 9 0 1 5
4 2 9 4 0 0
1.000 0.985 0.828 0.131 0.993 0.065
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert.
Table 5. Hospital Discharge Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Ketamine Group
Fentanyl Group
p-value
87.4 ⫾ 9.8 73.1 ⫾ 8.6 16.4 ⫾ 1.9
86.1 ⫾ 8.9 72.1 ⫾ 9.2 16.6 ⫾ 1.4
0.471 0.525 0.671
10.0 (0–70)
10.0 (0–50)
0.198
0 6
0 3
– 0.472
0 (0–75)
0 (0–25)
0.941
1 0 0 0 0 0
0 0 0 1 0 0
1.000 – – 0.993 – –
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert.
reported late PONV, compared with no patients (0%) in the ketamine group. on PACU admission, neither patient could recall the dream on hospital discharge. There were no unanticipated hospital admissions as a result of the surgery or anesthetic technique, and no patients had any hallucinations or bad dreams following discharge home. After hospital discharge, patients were contacted the next day by telephone. Only one patient (1.7%) in the fentanyl group
Table 4. Stepdown Unit Admission Measured Variables
MAP Heart rate (bpm) Respiratory rate (breaths/min) Pain VAS (median, range) Pain VAS ⱖ 75 (n) Pain Medication given (n) Nausea VAS (median, range) Nausea VAS ⱖ 75 (n) Emesis (n) N/V Treatment (n) Pruritus (n) Sedation (n) Dreaming (n)
Ketamine Group
Fentanyl Group
p-value
87.9 ⫾ 10.8 72.9 ⫾ 9.8 16.8 ⫾ 2.0
86.0 ⫾ 9.6 71.7 ⫾ 10.3 16.7 ⫾ 1.7
0.314 0.511 0.882
27.5 (0–80)
20.0 (0–80)
0.252
3 21
2 22
1.000 0.945
0 (0–100)
0 (0–100)
0.600
2 4 6 0 0 1
2 2 7 2 0 0
0.611 0.660 0.974 0.483 – 0.993
MAP ⫽ mean arterial blood pressure, N/V Treatment ⫽ treatment for nausea and or vomiting, Sedation ⫽ rousable, not fully awake and alert.
Discussion Outpatient ambulatory surgery is the fastest growing segment of surgery and anesthesia.2 Seventy percent of all anesthetics given in the United States are done on an ambulatory basis.2 In this era of health care cost containment, it is important to decrease costs without compromising patient care. Nausea and vomiting is the most common reason for unanticipated outpatient hospital admissions, and the potential savings of outpatient surgery may be negated by an unanticipated hospital admission. The goals of outpatient ambulatory anesthesia include a rapid and smooth induction, effective intraoperative anesthesia, and a smooth and prompt recovery with minimal, if any, postoperative side effects, leading to a quicker return to “home readiness” and an overall shorter outpatient stay. Ketamine has been used in combination with propofol for both general and IV sedation and to supplement general anesthesia.3,4,8 –12 Hui et al.11 found that there is synergism between propofol and ketamine when they are used for induction of general anesthesia in female patients. They calculated the effective dose for 95% of patients (ED95) for the combination to be 2.02 mg/kg propofol and 0.67 mg/kg ketamine. However, Hui et al. recommend caution in extrapolating these induction dosage recommendations for IV maintenance of general anesthesia.11 In our study, the mean total dose for the propofol-ketamine combination used for both induction and maintenance was 2.39 mg/kg propofol and 1.11 mg/kg ketamine. Side effects limiting the total dose of ketamine are emergence psychotomimetic reactions (dreaming, delirJ. Clin. Anesth., vol. 14, September 2002
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ium, and hallucinations), visual disturbances (blurred vision, nystagmus), dose-dependent PONV, and delay in hospital discharge.3,4,8 –10,12 Several investigators reported a decrease in psychotomimetic emergence reactions when ketamine is used in combination with a sedative-hypnotic (e.g., benzodiazepines, propofol) or a general anesthetic (e.g., halothane, nitrous oxide).8,12 Subhypnotic doses of propofol fail to block ketamine-induced hallucinations;12,13 however, hypnotic doses of propofol are reported to block these hallucinations.9,12 Hui et al.11 calculated the ED95 for hypnosis to be 1.93 mg/kg for propofol, 0.84 mg/kg for ketamine, and for the propofol-ketamine combination to be 0.97 mg/kg propofol and 0.33 mg/kg ketamine. We did not find propofol (mean total dose of 2.39 mg/kg) to block ketamine-induced hallucinations in our study in combination with midazolam and isoflurane-nitrous oxide inhalation anesthetic. In contrast to our study, Guit et al.8 found longer recovery time with propofol-ketamine compared with propofol-fentanyl, the reason being that they used a bolus dose of ketamine (1 mg/kg) followed by continuous infusion of ketamine (2 mg/kg/hr), which most likely added to the longer recovery time. However, their study was limited because of the number of patients studied and the longer duration of surgery (60 ⫾ 27 min).8 Frizelle et al.10 compared propofol with a propofolketamine (2.0 mg/kg propofol plus 0.5 mg/kg ketamine) combination for sedation during spinal anesthesia and found a higher frequency of nausea, similar postoperative pain between the two groups, and two patients (10%) who reported auditory hallucinations or vivid dreams. Similarly, Badrinath et al.9 compared multiple concentrations of ketamine in a ketamine-propofol combination during monitored anesthesia care and found an increase in PONV, an increase in psychotomimetic effects, prolonged recovery, and delay in discharge with an increasing dose of ketamine. We did not find a higher frequency of postoperative nausea (p ⫽ NS) in our study, but more patients required pain medication in the immediate postoperative period even though pain VAS scores and maximum pain VAS scores were similar. Patients in the ketamine group received more pain medication on PACU admission than patients in the fentanyl group despite similar pain scores, most likely because of elevated HR and the presence of psychotomimetic reactions. There was a higher frequency of psychotomimetic reactions in the propofol-ketamine group (17.0%) compared with the propofol-fentanyl group (1.7%). Differences in pain medication requirements and psychotomimetic reactions in our study became insignificant during the remainder of the postoperative stay (PACU discharge, stepdown unit admission and discharge, and hospital discharge). Similar to our study, Jakobsson et al.4 compared propofol in combination with ketamine (20 mg) or fentanyl (0.1 mg) in patients undergoing termination of pregnancy with IV general anesthesia, and they found that the propofol-fentanyl combination produced a lower frequency of postoperative pain and dreaming with no 430
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difference in recovery or PONV. However, our study is different from Jakobsson et al.’s in that patients were intubated, they received an inhalational drug for maintenance of general anesthesia, and they also received midazolam to reduce psychotomimetic side effects. Additionally, the operative procedure (laparoscopic tubal ligation) was longer, and it is also associated with a higher incidence of PONV.5 Friedberg3 found that propofol-ketamine in plastic surgery procedures was associated with a 0.6% frequency of PONV. However, our study involved patients undergoing high-risk, emetogenic laparoscopic procedures.5 Additionally, Friedberg neither intubated nor gave inhalational drugs to his patients. The difference in the frequency of dreaming in Friedberg’s study (1%) versus our study (17%) can be explained by the duration of surgery. Friedberg3 administered ketamine at the beginning of surgery to suppress the pain of local infiltration, and the surgery continued for another 2 hours only with propofol sedation. Ketamine-induced dreams were short-lived, and the high-risk period for ketamine-induced dreams and hallucinations were well covered by propofol (151-160 min). In our study, the duration of surgery was only 30 to 40 minutes and ketamine’s psychomimetic effects became evident postoperatively. In conclusion, for outpatient laparoscopic tubal ligations, hypnotic-anesthetic doses of propofol-ketamine combination do not improve postoperative nausea, emesis, analgesia, and recovery compared with the propofolfentanyl combination. Although differences were not significant on hospital discharge, ketamine (1 mg/kg) is not recommended because of the high incidence of psychotomimetic reactions in the immediate postoperative period.
Acknowledgments The authors would like to thank Jewel DeSisto, CRNA, and Kathy Marks, CRNA, for their assistance with the study.
References 1. Watcha MF, White PF: Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992;77:162– 84. 2. Hall MJ, Lawrence L: Ambulatory surgery in the United States, 1996. Adv Data 1998;12:1–16. 3. Friedberg BL: Propofol-ketamine technique: dissociative anesthesia for office surgery (a 5-year review of 1264 cases). Aesthetic Plast Surg 1999;23:70 –5. 4. Jakobsson J, Oddby E, Rane K: Patient evaluation of four different combinations of intravenous anaesthetics for short outpatient procedures. Anaesthesia 1993;48:1005–7. 5. Lerman J: Surgical and patient factors involved in postoperative nausea and vomiting. Br J Anaesth 1992;69(7 Suppl 1):24S–32S. 6. Tang J, Chen L, White PF, et al: Use of propofol for office-based anesthesia: effect of nitrous oxide on recovery profile. J Clin Anesth 1999;11:226 –30. 7. Glantz SA: Primer of Biostatistics, 4th ed. New York: Mc-Graw-Hill, 1997.
Propofol-ketamine: Vallejo et al. 8. Guit JB, Koning HM, Coster ML, Niemeijer RPE, Mackie DP: Ketamine as analgesic for total intravenous anesthesia with propofol. Anaesthesia 1991;46:24 –7. 9. Badrinath S, Avramov MN, Shadrick M, Witt TR, Ivankovich AD: The use of a ketamine-propofol combination during monitored anesthesia care. Anesth Analg 2000;90:858 –62. 10. Frizelle HP, Duranteau J, Samii K: A comparison of propofol with a propofol-ketamine combination for sedation during spinal anesthesia. Anesth Analg 1997;84:1318 –22.
11. Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J: Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 1995;82: 641–8. 12. Friedberg BL: Propofol-ketamine technique. Aesthetic Plast Surg 1993;17:297–300. 13. Smith I, White PF: Use of intravenous adjuvants during local and regional anesthesia (monitored anesthesia care). Curr Rev Nurse Anesth 1992;14:186 –92.
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