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An effective dose of ketamine for eliminating pain during injection of propofol: A dose response study
Annales Franc¸aises d’Anesthe´sie et de Re´animation 32 (2013) e103–e106
Original article
An effective dose of ketamine for eliminating pain during injection of propofol: A dose response study Une dose effective de ke´tamine pour e´liminer la douleur pendant l’injection du propofol M. Wang *, Q. Wang, Y.Y. Yu, W.S. Wang Department of anesthesiology, Wuxi maternity and child health hospital affiliated Nanjing medical university, 48, Huaishu-Xiang, 214002 Wuxi, Jiangsu, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 December 2012 Accepted 27 June 2013
Background and purpose. – Ketamine can completely eliminate pain associated with propofol injection. However, the effective dose of ketamine to eliminate propofol injection pain has not been determined. The purpose of this study was to determine the effective dose of ketamine needed to eliminate pain in 50% and 95% of patients (ED50 and ED95, respectively) during propofol injections. Methods. – This study was conducted in a double-blinded fashion and included 50 patients scheduled for elective gynecological laparoscopy under general anesthesia. The initial dose of ketamine used in the first patient was 0.25 mg/kg. The dosing modifications were in increments or decrements of 0.025 mg/ kg. Ketamine was administered 15 seconds before injecting propofol (2.5 mg/kg), which was injected at a rate of 1 mL/s. Patients were asked to rate their pain during propofol injection every 5 seconds using a 0– 3 pain scale. The highest pain score was recorded. The ED50, ED95 and 95% confidence intervals (CI) were determined by probit analyses. Results. – The dose of ketamine ranged from 0.175 to 0.275 mg/kg. The ED50 and ED95 of ketamine for eliminating pain during propofol injection were 0.227 mg/kg and 0.283 mg/kg, respectively (95%CI: 0.211–0.243 mg/kg and 0.26–0.364 mg/kg, respectively). Conclusion. – Ketamine at an approximate dose of 0.3 mg/kg was effective in eliminating pain during propofol injection. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved.
Keywords: Ketamine Propofol Pain on injection
R E´ S U M E´
Mots cle´s: Ke´tamine Propofol Douleur
Objectif. – La ke´tamine peut comple`tement e´liminer la douleur accompagnant une injection intraveineuse de propofol. Cependant, la dose requise pour ce faire n’a pas e´te´ de´termine´e. L’objectif de la pre´sente e´tude e´tait donc de de´terminer la dose de ke´tamine ne´cessaire pour e´liminer la douleur a` l’injection de propofol chez 50 % et 90 % des patients (ED50 et ED95 respectivement). Me´thodes. – Cette e´tude a` double insu inclut 50 patientes pour une chirurgie e´lective gyne´cologique laparoscopique sous anesthe´sie ge´ne´rale. La dose initiale de ke´tamine e´tait de 0,25 mg/kg chez la premie`re patiente. Chez les patientes subse´quentes, la dose e´tait augmente´e ou diminue´e de 0,025 mg/kg. La ke´tamine e´tait administre´e 15 secondes avant l’injection de propofol (2.5 mg/kg) qui e´tait injecte´ a` une vitesse de 1 mL/s. La douleur des patientes e´taient cote´ durant l’injection de propofol toutes les 5 secondes sur une e´chelle de 0 a` 3. La douleur la plus intense e´tait retenue. Les ED50, ED95 et l’intervalle de confiance a` 95 % (95 % IC) e´taient de´termine´s par analyse de probit. Re´sultats. – Les doses de ke´tamine administre´es allaient de 0,175 a` 0,275 mg/kg. Les ED50 et ED95 de ke´tamine calcule´es pour l’e´limination de douleur a` l’injection de propofol e´taient respectivement 0,227 et 0,283 mg/kg (95 % IC : 0,211–0,243 mg/kg et 0,26–0,364 mg/kg).
* Corresponding author. E-mail address: [email protected] (M. Wang). 0750-7658/$ – see front matter ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.annfar.2013.06.013
M. Wang et al. / Annales Franc¸aises d’Anesthe´sie et de Re´animation 32 (2013) e103–e106
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Conclusion. – La ke´tamine a` une dose approximative de 0,3 mg/kg a e´limine´ la douleur a` l’injection de propofol. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Publie´ par Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Propofol is the most popular clinical intravenous anesthetic induction drug due to its rapid onset, short duration of action, and easy titration. However, propofol can cause injection pain. The incidence of injection pain ranges between 28% and 90%, with an average of 60–70% [1–3]. Several methods have been used to reduce injection pain, including the use of a larger vein, cooling, warming or diluting the propofol solution, and pre-injecting lidocaine, benzodiazepines, ondansetrone, metoclopramide, opioids, thiopental, flurbiprofen, ephedrine or ketamine [2,3]. Ketamine pre-injection is the only method that has been shown to completely eliminate propofol injection pain [4]. Moreover, the administration of small doses of intravenous ketamine has been shown to improve postoperative pain, patient satisfaction and second day Visual Analogue Scale (VAS) scores, as well as decrease total postoperative meperidine consumption [5]. Some previous reports have also suggested that the co-administration of small doses of ketamine and propofol can reduce the opioid requirement during the recovery period [6–8]. This double-blind dose response study was performed to estimate the 50% and 95% effective dose (ED50 and ED95, respectively) of ketamine to eliminate propofol injection pain. 2. Materials and methods This study was approved by the Research Ethics Board of Wuxi Maternity and Child Health Hospital Affiliated Nanjing Medical University. Fifty ASA I-II patients (aged 23–51 years old and weighing 40–86 kg) scheduled for elective gynecological laparoscopy under general anesthesia were included in the study. Patients did not receive premedication before arrival to the operating room or any opioids within 24 hours before surgery. Patients taking sedatives or analgesics, patients having an allergy to the study drugs and patients with a neurological or cardiovascular disease were excluded. In all patients, after attaching routine monitors, an 18-gauge intravenous cannula was inserted in the radial vein at the wrist of the right hand approximately thirty minutes before the induction of anesthesia. An infusion of lactated Ringer’s solution was started at a minimal rate to keep the vein open. The initial dose of ketamine used in the first patient was 0.25 mg/kg. This dose was chosen based on our clinical experience and statistical simulations at various doses. Each subsequent dose was based on the response of the previous patient using a Dixon’s up-and-down design. We administered ketamine based on the actual body weight of the patients. Ketamine was injected 0. 3
3. Results The sequence of effective and ineffective responses in each patient is shown in Fig. 1. The ketamine dose ranged from 0.175 to 0.275 mg/kg. A ketamine dose of 0.275 mg/kg was effective in all five patients who received that dose, while a dose of 0.25 mg/kg was effective in nine of 14 patients, a dose of 0.225 mg/kg was effective in 10 of 18 patients, a dose of 0.2 mg/kg was effective in two of 11 patients, and a dose of 0.175 mg/kg was ineffective in two patients. The number of patients and the corresponding VRS score was as follows: 0, n = 26; 1, n = 20; and 2, n = 4 (Table 1). The ED50 and ED95 of ketamine for eliminating propofol injection pain was 0.227 mg/kg and 0.283 mg/kg, respectively (95% CI: 0.211– 0.243 mg/kg and 0.26–0.364 mg/kg, respectively) (Fig. 2). None of Table 1 Incidence and intensity of pain on injection of propofol. Dose (mg/kg)
0. 275
Ketamine(mg/kg)
15 seconds before propofol administration. Propofol (2.5 mg/kg) was then injected at room temperature at a rate of 1 mL/s. During the administration of propofol, each patient was asked by an anesthesiologist, who was blinded to the ketamine dose, to immediately rate the pain every 5 seconds using the verbal rating scale (VRS) as follows [9,10]: 0 = no pain; 1 = mild pain or soreness; 2 = moderate pain; and 3 = severe pain associated with grimacing, withdrawal movement of forearm, or both. The highest pain score was recorded. The dosing modifications were conducted in increments or decrements of 0.025 mg/kg. If the pain VRS score was greater or equal to 1, the ketamine dose was increased before the next subject. If the patient reported no pain, the ketamine dose was decreased in the next subject. Ketamine was diluted with 0.9% normal saline up to 5 mL, and the drugs were prepared by an investigator not involved in drug injection or in the assessment of patient responses. Following loss of consciousness, fentanyl (3 mg/kg) and midazolam (0.05 mg/kg) were administered. Vecuronium was used to facilitate intubation, and anesthesia was maintained with propofol (6–7 mg/kg/h) and remifentanil (5 mg/kg/h) infusions. Muscle relaxation was maintained with intermittent intravenous injections of vecuronium. Patients’ emergence reactions, such as delusions and agitation, were assessed in the recovery room by an anesthesiologist blinded to the patient groups. Data were analyzed by IBM SPSS 19.0 and were expressed as mean SD. The ED50, ED95 and 95% confidence intervals (CI) were determined with a logistic regression model without log-transformation of the doses by using the probit method. We selected 50 patients for this study based on previous studies that investigated the ED50 and ED95 [11–13].
0. 25 effective
0. 225
ineffective
0. 2 0. 1 75 0. 1 5 0
5
10
15
20 25 30 Patient number
35
40
45
Fig. 1. Ketamine dose and responses.
50
0.275 0.250 0.225 0.200 0.175 Total
Intensity of pain None (n)
Mild (n)
Moderate (n)
Severe (n)
5 9 10 2 0 26
0 5 7 7 1 20
0 0 1 2 1 4
0 0 0 0 0 0
Data are expressed in number of patients.
Successes (n)
Trials (n)
5 9 10 2 0 26
5 14 18 11 2 50
M. Wang et al. / Annales Franc¸aises d’Anesthe´sie et de Re´animation 32 (2013) e103–e106
Fig. 2. Observed probabilities (*) of effective responses to ketamine doses using logistic regression (Logarithmic Modelss of Curve Estimaton) and maximum likelihood estimation of the raw data (95% confidence interval). No cases of emergence agitation delirium were reported.
the patients experienced adverse effects, such as hallucinations, due to ketamine during recovery. 4. Discussion Although the mechanism of pain associated with propofol injection remains obscure, direct irritant effects on the vein wall, osmolality changes, non-pharmacologic pH changes and activation of the pain cascade have been suggested [14–17]. Jalota et al. [3] suggested using an antecubital vein instead of a hand vein as a simple and effective method to avoid propofol injection pain. In addition, lidocaine pretreatment has been commonly proposed to decrease propofol-induced pain, but its failure rate is between 13–32% [15]. Lidocaine in conjunction with venous occlusion has also been effective, but it does not completely eliminate propofol injection pain [3]. Iwata et al. [4] found that 1 mg/kg ketamine completely eliminated propofol injection pain. In addition, Saadawi et al. [17] observed that pretreatment with ketamine (0.4 mg/kg) was the most effective for attenuating pain associated with propofol injection when compared to thiopental, meperidine and lidocaine pretreatment. As a non-competitive NMDA receptor antagonist, ketamine can inactivate NMDA receptors either in the vascular endothelium or in the central nervous system. The effectiveness of small dose ketamine in eliminating the pain of propofol injection may suggest a peripheral local anesthetic action. Larger doses of ketamine (1.0 mg/kg) may eliminate pain completely through a central analgesic effect, which modulates pain induced by propofol [4,10,14,16]. Pretreatment with ketamine before propofol induction results in more stable hemodynamics, which is preferable for hemodynamically unstable patients, such as those with hypovolaemia, ischaemic heart disease or ischaemic cerebral vessel disease [17]. In addition, Mortero et al. [8] concluded that co-administration of propofol and ketamine improved propofol-induced hypoventilation and positive mood effects, and might have improved postoperative analgesia. In Saadawi’s study, 92% patients who were pretreated with 0.4 mg/kg ketamine had no pain during propofol injection [17]. In our study, the ED95 (0.283 mg/kg) was lower than the report by Saadawi. This may be related to the site of propofol injection. In our study, we chose the wrist vein, while Saadawi’s study used the hand vein.
105
One limitation of our study was that all the patients were female. The other limitation was that the ethnic composition of the population in our study was of Han nationality (China). The method that we used to determine the intensity of pain was based on previous reports [9,10]. All of the patients were injected with a similar dose of propofol (2.5 mg/kg) at the same rate of 1 mL/s, and pain intensity during propofol injection was evaluated by the same ‘‘blinded’’ anesthesiologist. Finally, we recorded the highest pain score using the same method with each patient. The initial dose of ketamine (0.25 mg/kg) was chosen based on our clinical experience and previous literature [10,17]. In Koo’s study, they found that administration of 0.1 mg/kg ketamine immediately before propofol injection provided the optimal dose and timing to reduce propofol-induced pain during injection [10]. In another study, patients were pretreated with 0.4 mg/kg ketamine [17]. Therefore, we selected an intermediate dose of 0.25 mg/kg. In our preliminary experiments, we found that administration of 0.25 mg/kg ketamine could reduce the pain during propofol injection. A sample size of 50 patients was determined based on the assumed model [13], which indicated bias-free estimates of the ED95 with a standard error of approximately 0.025 mg/kg, sufficient precision to guide clinical practice. Ketamine can induce some adverse effects, such as hallucinations, delayed recovery and dissociation from surroundings. In our study, none of the patients experienced adverse effects. This was most likely because low doses of ketamine were used and midazolam (0.05 mg/kg) was used to prevent ketamine-induced side effects. The addition of midazolam can significantly reduce the incidence of recovery reactions following ketamine treatment [18,19]. 5. Conclusion In conclusion, the estimated ED50 of ketamine for eliminating propofol injection pain in the wrists of female adult patients was 0.227 mg/kg (95% CI: 0.21–0.24 mg/kg), and the ED95 was 0.283 mg/kg (95% CI: 0.26–0.36 mg/kg). Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Tan CH, Onsiong MK. Pain on injection of propofol. Anaesthesia 1998;53: 468–76. [2] Picard P, Tramer MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000;90:963–9. [3] Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, et al. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ 2011;342: d1110. [4] Iwata M, Inoue S, Kawaguchi M, Kimura T, Tojo T, Taniguchi S, et al. Ketamine eliminates propofol pain but does not affect hemodynamics during induction with double-lumen tubes. J Anesth 2010;24:31–7. [5] Cagla Ozbakis Akkurt B, Inanoglu K, Kalaci A, Turhanoglu S, Asfuroglu Z, Tumkaya F. Effects of intravenous small dose ketamine and midazolam on postoperative pain following knee arthroscopy. Pain Practice 2009;9:289–95. [6] Frey K, Sukhani R, Pawlowski J, Pappas AL, Mikat-Stevens M, Slogoff S. Propofol versus propofolketamine edation for retrobulbar nerve block: comparison of sedation quality, intraocular pressure changes, and recovery profiles. Anesth Analg 1999;89:317–21. [7] 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. [8] Mortero RF, Clark LD, Tolan MM, Metz RJ, Tsueda K, Sheppard RA. The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain. Anesth Analg 2001;92:1465–9. [9] McCrirrick A, Hunter S. Pain on injection of propofol: the effect of injectate temperature. Anaesthesia 1990;45:443–4.
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[10] Koo SW, Cho SJ, Kim YK, Ham KD, Hwang JH. Small-dose ketamie reduces the pain of propofol injection. Anesth Analg 2006;103:1444–7. [11] Whitty R, Goldszmidt E, Parkes RK, Carvalho JC. Determination of the ED95 for intrathecal plain bupivacaine combined with fentanyl in active labor. Int J Obstet Anesth 2007;16:341–5. [12] Tanaka M, Balki M, Parkes RK, Carvalho JC. ED95 of phenylephrine to prevent spinal-induced hypotension and/or nausea at elective cesarean delivery. Int J Obstet Anesth 2009;18:125–30. [13] George RB, McKeen D, Columb MO, Habib AS. Up-down determination of the 90% effective dose of phenylephrine for the treatment of spinal anesthesiainduced hypotension in parturients undergoing cesarean delivery. Anesth Analg 2010;110:154–8. [14] Tan CH, Onsiong MK, Kua SW. The effect of ketamine pretreatment on propofol injection pain in 100 women. Anaesthesia 1998;53:302–7.
[15] Cheong MA, Kim KS, Choi WJ. Ephedrine reduces the pain from Propofol injection. Anesth Analg 2002;95:1293–6. [16] Ozkocak I, Altunkaya H, Ozer Y, Ayog˘lu H, Demirel CB, Cic¸ek E. Comparison of ephedrine and ketamine in prevention of injection pain and hypotension due to propofol induction. Eur J Anaesthesiol 2005;22:44–8. [17] Saadawi I, Ertok E, Boker A. Painless injection of propofol: pretreatment with ketamine vs thiopental, meperidine, and lidocaine. Middle East J Anesthesiol 2007;19:631–44. [18] Sener S, Eken C, Schultz CH, Serinken M, Ozsarac M. Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial. Ann Emerg Med 2011;57:109–14. [19] Dilli D, Dallar Y, Sorgui NH. Intravenous ketamine plus midazolam vs intravenous ketamine for sedation in lumbar puncture: a randomized controlled trial. Indian Pediatr 2008;45:899–904.
Original article
An effective dose of ketamine for eliminating pain during injection of propofol: A dose response study Une dose effective de ke´tamine pour e´liminer la douleur pendant l’injection du propofol M. Wang *, Q. Wang, Y.Y. Yu, W.S. Wang Department of anesthesiology, Wuxi maternity and child health hospital affiliated Nanjing medical university, 48, Huaishu-Xiang, 214002 Wuxi, Jiangsu, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 December 2012 Accepted 27 June 2013
Background and purpose. – Ketamine can completely eliminate pain associated with propofol injection. However, the effective dose of ketamine to eliminate propofol injection pain has not been determined. The purpose of this study was to determine the effective dose of ketamine needed to eliminate pain in 50% and 95% of patients (ED50 and ED95, respectively) during propofol injections. Methods. – This study was conducted in a double-blinded fashion and included 50 patients scheduled for elective gynecological laparoscopy under general anesthesia. The initial dose of ketamine used in the first patient was 0.25 mg/kg. The dosing modifications were in increments or decrements of 0.025 mg/ kg. Ketamine was administered 15 seconds before injecting propofol (2.5 mg/kg), which was injected at a rate of 1 mL/s. Patients were asked to rate their pain during propofol injection every 5 seconds using a 0– 3 pain scale. The highest pain score was recorded. The ED50, ED95 and 95% confidence intervals (CI) were determined by probit analyses. Results. – The dose of ketamine ranged from 0.175 to 0.275 mg/kg. The ED50 and ED95 of ketamine for eliminating pain during propofol injection were 0.227 mg/kg and 0.283 mg/kg, respectively (95%CI: 0.211–0.243 mg/kg and 0.26–0.364 mg/kg, respectively). Conclusion. – Ketamine at an approximate dose of 0.3 mg/kg was effective in eliminating pain during propofol injection. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved.
Keywords: Ketamine Propofol Pain on injection
R E´ S U M E´
Mots cle´s: Ke´tamine Propofol Douleur
Objectif. – La ke´tamine peut comple`tement e´liminer la douleur accompagnant une injection intraveineuse de propofol. Cependant, la dose requise pour ce faire n’a pas e´te´ de´termine´e. L’objectif de la pre´sente e´tude e´tait donc de de´terminer la dose de ke´tamine ne´cessaire pour e´liminer la douleur a` l’injection de propofol chez 50 % et 90 % des patients (ED50 et ED95 respectivement). Me´thodes. – Cette e´tude a` double insu inclut 50 patientes pour une chirurgie e´lective gyne´cologique laparoscopique sous anesthe´sie ge´ne´rale. La dose initiale de ke´tamine e´tait de 0,25 mg/kg chez la premie`re patiente. Chez les patientes subse´quentes, la dose e´tait augmente´e ou diminue´e de 0,025 mg/kg. La ke´tamine e´tait administre´e 15 secondes avant l’injection de propofol (2.5 mg/kg) qui e´tait injecte´ a` une vitesse de 1 mL/s. La douleur des patientes e´taient cote´ durant l’injection de propofol toutes les 5 secondes sur une e´chelle de 0 a` 3. La douleur la plus intense e´tait retenue. Les ED50, ED95 et l’intervalle de confiance a` 95 % (95 % IC) e´taient de´termine´s par analyse de probit. Re´sultats. – Les doses de ke´tamine administre´es allaient de 0,175 a` 0,275 mg/kg. Les ED50 et ED95 de ke´tamine calcule´es pour l’e´limination de douleur a` l’injection de propofol e´taient respectivement 0,227 et 0,283 mg/kg (95 % IC : 0,211–0,243 mg/kg et 0,26–0,364 mg/kg).
* Corresponding author. E-mail address: [email protected] (M. Wang). 0750-7658/$ – see front matter ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.annfar.2013.06.013
M. Wang et al. / Annales Franc¸aises d’Anesthe´sie et de Re´animation 32 (2013) e103–e106
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Conclusion. – La ke´tamine a` une dose approximative de 0,3 mg/kg a e´limine´ la douleur a` l’injection de propofol. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Publie´ par Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Propofol is the most popular clinical intravenous anesthetic induction drug due to its rapid onset, short duration of action, and easy titration. However, propofol can cause injection pain. The incidence of injection pain ranges between 28% and 90%, with an average of 60–70% [1–3]. Several methods have been used to reduce injection pain, including the use of a larger vein, cooling, warming or diluting the propofol solution, and pre-injecting lidocaine, benzodiazepines, ondansetrone, metoclopramide, opioids, thiopental, flurbiprofen, ephedrine or ketamine [2,3]. Ketamine pre-injection is the only method that has been shown to completely eliminate propofol injection pain [4]. Moreover, the administration of small doses of intravenous ketamine has been shown to improve postoperative pain, patient satisfaction and second day Visual Analogue Scale (VAS) scores, as well as decrease total postoperative meperidine consumption [5]. Some previous reports have also suggested that the co-administration of small doses of ketamine and propofol can reduce the opioid requirement during the recovery period [6–8]. This double-blind dose response study was performed to estimate the 50% and 95% effective dose (ED50 and ED95, respectively) of ketamine to eliminate propofol injection pain. 2. Materials and methods This study was approved by the Research Ethics Board of Wuxi Maternity and Child Health Hospital Affiliated Nanjing Medical University. Fifty ASA I-II patients (aged 23–51 years old and weighing 40–86 kg) scheduled for elective gynecological laparoscopy under general anesthesia were included in the study. Patients did not receive premedication before arrival to the operating room or any opioids within 24 hours before surgery. Patients taking sedatives or analgesics, patients having an allergy to the study drugs and patients with a neurological or cardiovascular disease were excluded. In all patients, after attaching routine monitors, an 18-gauge intravenous cannula was inserted in the radial vein at the wrist of the right hand approximately thirty minutes before the induction of anesthesia. An infusion of lactated Ringer’s solution was started at a minimal rate to keep the vein open. The initial dose of ketamine used in the first patient was 0.25 mg/kg. This dose was chosen based on our clinical experience and statistical simulations at various doses. Each subsequent dose was based on the response of the previous patient using a Dixon’s up-and-down design. We administered ketamine based on the actual body weight of the patients. Ketamine was injected 0. 3
3. Results The sequence of effective and ineffective responses in each patient is shown in Fig. 1. The ketamine dose ranged from 0.175 to 0.275 mg/kg. A ketamine dose of 0.275 mg/kg was effective in all five patients who received that dose, while a dose of 0.25 mg/kg was effective in nine of 14 patients, a dose of 0.225 mg/kg was effective in 10 of 18 patients, a dose of 0.2 mg/kg was effective in two of 11 patients, and a dose of 0.175 mg/kg was ineffective in two patients. The number of patients and the corresponding VRS score was as follows: 0, n = 26; 1, n = 20; and 2, n = 4 (Table 1). The ED50 and ED95 of ketamine for eliminating propofol injection pain was 0.227 mg/kg and 0.283 mg/kg, respectively (95% CI: 0.211– 0.243 mg/kg and 0.26–0.364 mg/kg, respectively) (Fig. 2). None of Table 1 Incidence and intensity of pain on injection of propofol. Dose (mg/kg)
0. 275
Ketamine(mg/kg)
15 seconds before propofol administration. Propofol (2.5 mg/kg) was then injected at room temperature at a rate of 1 mL/s. During the administration of propofol, each patient was asked by an anesthesiologist, who was blinded to the ketamine dose, to immediately rate the pain every 5 seconds using the verbal rating scale (VRS) as follows [9,10]: 0 = no pain; 1 = mild pain or soreness; 2 = moderate pain; and 3 = severe pain associated with grimacing, withdrawal movement of forearm, or both. The highest pain score was recorded. The dosing modifications were conducted in increments or decrements of 0.025 mg/kg. If the pain VRS score was greater or equal to 1, the ketamine dose was increased before the next subject. If the patient reported no pain, the ketamine dose was decreased in the next subject. Ketamine was diluted with 0.9% normal saline up to 5 mL, and the drugs were prepared by an investigator not involved in drug injection or in the assessment of patient responses. Following loss of consciousness, fentanyl (3 mg/kg) and midazolam (0.05 mg/kg) were administered. Vecuronium was used to facilitate intubation, and anesthesia was maintained with propofol (6–7 mg/kg/h) and remifentanil (5 mg/kg/h) infusions. Muscle relaxation was maintained with intermittent intravenous injections of vecuronium. Patients’ emergence reactions, such as delusions and agitation, were assessed in the recovery room by an anesthesiologist blinded to the patient groups. Data were analyzed by IBM SPSS 19.0 and were expressed as mean SD. The ED50, ED95 and 95% confidence intervals (CI) were determined with a logistic regression model without log-transformation of the doses by using the probit method. We selected 50 patients for this study based on previous studies that investigated the ED50 and ED95 [11–13].
0. 25 effective
0. 225
ineffective
0. 2 0. 1 75 0. 1 5 0
5
10
15
20 25 30 Patient number
35
40
45
Fig. 1. Ketamine dose and responses.
50
0.275 0.250 0.225 0.200 0.175 Total
Intensity of pain None (n)
Mild (n)
Moderate (n)
Severe (n)
5 9 10 2 0 26
0 5 7 7 1 20
0 0 1 2 1 4
0 0 0 0 0 0
Data are expressed in number of patients.
Successes (n)
Trials (n)
5 9 10 2 0 26
5 14 18 11 2 50
M. Wang et al. / Annales Franc¸aises d’Anesthe´sie et de Re´animation 32 (2013) e103–e106
Fig. 2. Observed probabilities (*) of effective responses to ketamine doses using logistic regression (Logarithmic Modelss of Curve Estimaton) and maximum likelihood estimation of the raw data (95% confidence interval). No cases of emergence agitation delirium were reported.
the patients experienced adverse effects, such as hallucinations, due to ketamine during recovery. 4. Discussion Although the mechanism of pain associated with propofol injection remains obscure, direct irritant effects on the vein wall, osmolality changes, non-pharmacologic pH changes and activation of the pain cascade have been suggested [14–17]. Jalota et al. [3] suggested using an antecubital vein instead of a hand vein as a simple and effective method to avoid propofol injection pain. In addition, lidocaine pretreatment has been commonly proposed to decrease propofol-induced pain, but its failure rate is between 13–32% [15]. Lidocaine in conjunction with venous occlusion has also been effective, but it does not completely eliminate propofol injection pain [3]. Iwata et al. [4] found that 1 mg/kg ketamine completely eliminated propofol injection pain. In addition, Saadawi et al. [17] observed that pretreatment with ketamine (0.4 mg/kg) was the most effective for attenuating pain associated with propofol injection when compared to thiopental, meperidine and lidocaine pretreatment. As a non-competitive NMDA receptor antagonist, ketamine can inactivate NMDA receptors either in the vascular endothelium or in the central nervous system. The effectiveness of small dose ketamine in eliminating the pain of propofol injection may suggest a peripheral local anesthetic action. Larger doses of ketamine (1.0 mg/kg) may eliminate pain completely through a central analgesic effect, which modulates pain induced by propofol [4,10,14,16]. Pretreatment with ketamine before propofol induction results in more stable hemodynamics, which is preferable for hemodynamically unstable patients, such as those with hypovolaemia, ischaemic heart disease or ischaemic cerebral vessel disease [17]. In addition, Mortero et al. [8] concluded that co-administration of propofol and ketamine improved propofol-induced hypoventilation and positive mood effects, and might have improved postoperative analgesia. In Saadawi’s study, 92% patients who were pretreated with 0.4 mg/kg ketamine had no pain during propofol injection [17]. In our study, the ED95 (0.283 mg/kg) was lower than the report by Saadawi. This may be related to the site of propofol injection. In our study, we chose the wrist vein, while Saadawi’s study used the hand vein.
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One limitation of our study was that all the patients were female. The other limitation was that the ethnic composition of the population in our study was of Han nationality (China). The method that we used to determine the intensity of pain was based on previous reports [9,10]. All of the patients were injected with a similar dose of propofol (2.5 mg/kg) at the same rate of 1 mL/s, and pain intensity during propofol injection was evaluated by the same ‘‘blinded’’ anesthesiologist. Finally, we recorded the highest pain score using the same method with each patient. The initial dose of ketamine (0.25 mg/kg) was chosen based on our clinical experience and previous literature [10,17]. In Koo’s study, they found that administration of 0.1 mg/kg ketamine immediately before propofol injection provided the optimal dose and timing to reduce propofol-induced pain during injection [10]. In another study, patients were pretreated with 0.4 mg/kg ketamine [17]. Therefore, we selected an intermediate dose of 0.25 mg/kg. In our preliminary experiments, we found that administration of 0.25 mg/kg ketamine could reduce the pain during propofol injection. A sample size of 50 patients was determined based on the assumed model [13], which indicated bias-free estimates of the ED95 with a standard error of approximately 0.025 mg/kg, sufficient precision to guide clinical practice. Ketamine can induce some adverse effects, such as hallucinations, delayed recovery and dissociation from surroundings. In our study, none of the patients experienced adverse effects. This was most likely because low doses of ketamine were used and midazolam (0.05 mg/kg) was used to prevent ketamine-induced side effects. The addition of midazolam can significantly reduce the incidence of recovery reactions following ketamine treatment [18,19]. 5. Conclusion In conclusion, the estimated ED50 of ketamine for eliminating propofol injection pain in the wrists of female adult patients was 0.227 mg/kg (95% CI: 0.21–0.24 mg/kg), and the ED95 was 0.283 mg/kg (95% CI: 0.26–0.36 mg/kg). Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Tan CH, Onsiong MK. Pain on injection of propofol. Anaesthesia 1998;53: 468–76. [2] Picard P, Tramer MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000;90:963–9. [3] Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, et al. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ 2011;342: d1110. [4] Iwata M, Inoue S, Kawaguchi M, Kimura T, Tojo T, Taniguchi S, et al. Ketamine eliminates propofol pain but does not affect hemodynamics during induction with double-lumen tubes. J Anesth 2010;24:31–7. [5] Cagla Ozbakis Akkurt B, Inanoglu K, Kalaci A, Turhanoglu S, Asfuroglu Z, Tumkaya F. Effects of intravenous small dose ketamine and midazolam on postoperative pain following knee arthroscopy. Pain Practice 2009;9:289–95. [6] Frey K, Sukhani R, Pawlowski J, Pappas AL, Mikat-Stevens M, Slogoff S. Propofol versus propofolketamine edation for retrobulbar nerve block: comparison of sedation quality, intraocular pressure changes, and recovery profiles. Anesth Analg 1999;89:317–21. [7] 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. [8] Mortero RF, Clark LD, Tolan MM, Metz RJ, Tsueda K, Sheppard RA. The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain. Anesth Analg 2001;92:1465–9. [9] McCrirrick A, Hunter S. Pain on injection of propofol: the effect of injectate temperature. Anaesthesia 1990;45:443–4.
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