An appropriate level of sedation and pharmacological assist are essential during percutaneous transluminal balloon angioplasty (PTA). Ketamine provides good analgesia while preserving airway patency, ventilation, and cardiovascular stability with an opioid sparing effect suggesting that it would be ideal in combination with remifentanil and midazolam in spontaneously breathing patients. We evaluated the effect of a small dose of ketamine added to midazolam and remifentanil on analgesia/sedation for PTA procedures.
Sixty-four patients receiving PTA were enrolled. The Control group received midazolam 1.0 mg i.v. and continuous infusion of remifentanil 0.05 µg/kg/min. The Ketamine group received, in addition, an intravenous bolus of 0.5 mg/kg ketamine. Patients' haemodynamic data were monitored before remifentanil infusion, 5 min after remifentanil infusion, at 1, 3, 5, 30 min after incision, and at admission to the recovery room. Verbal numerical rating scales (VNRS) and sedation [OAA/S (Observer's Assessment of Alertness/Sedation)] scores were also recorded.
The VNRS values at 1, 3, and 5 min after incision and OAA/S scores at 5 min after remifentanil infusion, and 1, 3, and 5 min after incision were lower in the Ketamine group than in the Control group. In the Control group, the VNRS value at 1 min after incision significantly increased and OAA/S values at 3, 5, and 30 min after incision significantly decreased compared to baseline values, while there were no significant changes in the ketamine group.
A small dose of ketamine as an adjunct sedative to the combination of midazolam and remifentanil produced a better quality of sedation and analgesia than without ketamine and provided stable respiration without cardiopulmonary deterioration.
For successful percutaneous transluminal balloon angioplasty (PTA), sedation is essential so that patients remain immobile during the procedure in an uncomfortable environment. Since it takes a long time and is sensitive to motion artifacts [
Midazolam and various opioids are frequently used in combination to provide sedation, anxiolysis and analgesia during short-term surgical procedures or interventional radiologic procedures [
Ketamine in subhypnotic doses provides good analgesia while preserving airway patency, ventilation, and cardiovascular stability [
This study tested the hypothesis that adding a small dose of ketamine to midazolam and remifentanil combination can provide more effective analgesia/sedation for PTA procedures without adverse effects compared with a combination of midazolam and remifentanil only.
From 2008 to 2010, we prospectively studied 64 patients aged 27 to 84 years who underwent PTA. The study was approved by the hospital ethics committee, and written informed consent was obtained from all participants. All patients had American Society of Anesthesiologists (ASA) physical status I to III. Patients were excluded if they had ASA status IV, hepatic or renal insufficiency, history of allergy to the drugs used, need for inotropic agents, or need for mechanical ventilation. Patients were randomly assigned to one of the two treatment groups. During the entire study, an anesthesiologist who was blinded to patient group assignment recorded the variables.
No premedication was given to the patients. The Control group received normal saline, the same amount of 0.5 mg/kg of ketamine and then were managed with the standard protocol including intravenous injection of 1.0 mg of midazolam and continuous infusion of remifentanil 0.05 µg/kg/min. The Ketamine group received the sedation protocol consisting of an intravenous bolus of 0.5 mg/kg ketamine followed by a bolus of 1.0 mg midazolam and continuous infusion of remifentanil 0.05 µg/kg/min. If signs of insufficient analgesia (facial grimace, movement, sudden increase in heart rate, spontaneous complaint of pain) were observed, an additional intravenous bolus of remifentanil 0.2 µg/kg was injected without changing the infusion rate of remifentanil in both groups. A local anesthetic agent was injected into the incision site before the incision by a cardiologist. Oxygen was delivered by a face mask to all patients throughout the procedure. Any episodes of hypoventilation (spontaneous RR < 8 /min), desaturation (SpO2 < 90%) or apnea during the infusion phase was recorded and the jaw thrust maneuver was applied to patients, if necessary. When those episodes persisted even with stimulation, the remifentanil infusion rate was reduced to 0.03 µg/kg/min.
The patients were monitored for mean arterial blood pressure (MAP), heart rate (HR), peripheral oxygen saturation (SpO2), and respiratory rate (RR) before the remifentanil infusion, 5 min after remifentanil infusion (baseline value), at 1, 3, 5, 30 min after incision, and at admission to the recovery room. The verbal numerical rating scales (VNRS), sedation score [OAA/S (Observer's Assessment of Alertness/Sedation)] and the presence of nausea, vomiting, itching sense or apnea were recorded at the same time points. The quality of analgesia was assessed by VNRS using and 11 point scale (0-10) [
Statistical analysis was performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA). The normality of distribution was assessed with a q-q plot and the Shapiro-Wilk test. Patient characteristics (age, height, weight, duration of remifentanil infusion) were analysed using an independent t-test. Categorical variables (remifentanil bolus number, apnea after bolus, amnesia at recovery room and side effects) were evaluated by a χ2 test or a Fisher's exact test when appropriate. Repeated measures analysis of variance (ANOVA) was used for the comparison of and VNRS scores for pain. If significant differences were detected, differences between two means were compared by an independent t-test with Bonferroni correction. Comparisons between the two groups with regard to pain and sedation scores were done with the Mann-Whitney U test, and intragroup comparisons were done with the Wilcoxon signed rank test. All values were expressed as mean ± standard deviation, median (interquartile range) or the number of patients. A P value < 0.05 was considered statistically significant. Sample size calculations were based on previous studies. To detect a two-point difference in VNRS score for pain (two-sided α of 5% and β of 20%), 32 subjects were required in each group.
Demographic and clinical parameters were comparable between the groups. The duration of remifentanil infusion (80 ± 39 min vs. 71 ± 28 min) and the total amount infused (278 ± 164 µg vs. 246 ± 176 µg), apnea after bolus (4 cases vs. 3 cases) were higher in the Control group but none of these differences were statistically significant (
The satisfaction scale (1 to 4) of the surgeons and the patients were high in both groups (4 vs. 4). Between group differences in haemodynamic and respiratory parameters during and after the procedures were not significant except for respiratory rates. After skin incision, respiratory rates were significantly lower in the Ketamine group compared to the Control group (
VNRS values at 1, 3, and 5 min after incision were significantly lower in the Ketamine group than in the Control group. In the Ketamine group, lower OAA/S scores were found at 5 min after remifentanil infusion, and 1, 3, and 5 min after incision than in the Control group. In the Control group, VNRS value at 1 min after incision significantly increased and OAA/S values at 3, 5, and 30 min after incision significantly decreased compared to baseline values, while there were no significant changes in VNRS and OAA/S values in the Ketamine group (
Apnea without a bolus developed in one patient in the Control group and two patients in the Ketamine group and all patients recovered self respiration after tactile stimulation without significant desaturation. Remaining side effects during the study were comparable between the groups and were not significant in both groups (
In this prospective study evaluating the effects of a small dose of ketamine as an adjunct sedative to the combination of midazolam and remifentanil in patients undergoing PTA, we found that the addition of a low dose of ketamine produced a better quality of sedation and analgesia than without ketamine, although the patients' satisfaction scores were high enough even in the Control group. The addition of ketamine provided more stable respiration without cardiopulmonary deterioration.
Sedation with various degrees of depth and duration is essential for both the patients' and interventionists' conveniences for interventional procedures. Medications should be administered to achieve: 1. adequate analgesia, sedation, anxiolysis, and amnesia during the procedures, 2. control of unwanted motor behavior that inhibits the performance of procedures, 3. rapid return of the patient to consciousness, and 4. less risk of adverse events. For stable conditions of sedation and haemodynamics, continuous intravenous infusion rather than repetitive bolus doses [
Midazolam, a short acting benzodiazepine, has been the most commonly used sedative agent for PTA. Midazolam produces dose-related sedation, amnesia, and anxiolysis, but has a poor analgesic effect, and recovery may be prolonged due to its cumulative hypnotic effect. Therefore, midazolam usually requires the use of an adjunctive analgesic agent. The synergistic effect of opioids and midazolam in combination is well known [
Ketamine is a nonspecific N-methyl-d-aspartate (NMDA) receptor antagonist that provides intrinsic analgesia and apparent anesthesia with relative hemodynamic stability and protects airway reflexes [
In this study, we added a small dose of ketamine to a combination of midazolam and remifentanil for more satisfactory sedation with limited effects on cardio-respiratory function in patients undergoing PTA. We observed that the VNRS and OAA/S scores were significantly lower in the Ketamine group, demonstrating a better quality of sedation. Among various interventional procedures, PTA requires a long duration and motionless field. Therefore, deep sedation with spontaneous ventilation is needed during PTA. Frequently, a large amount of repetitive midazolam or a higher dose of remifentanil infusion are required, which may result in delayed awakening or significant respiratory depression, especially in compromised patients. Therefore, this study demonstrated that a small dose of ketamine given as a pre-procedural bolus intensified the analgesic and sedative effects of the drug combination without cardiorespiratory depression could have a significant clinical impact on PTA procedures. Most patients in the Ketamine group were in a painless and motionless state during the procedures, and their haemodynamics and respiration remained stable without adverse events. Interestingly, although ketamine was known to counteract opioid induced respiratory depression [
Large doses of ketamine (>2 mg/kg) are frequently associated with unpleasant side effects including hallucinations, dreams, cognitive decline, and emergence confusion. Also, ketamine can cause involuntary muscle movement, potentially limiting its suitability in interventional radiology procedures. However, a small bolus of ketamine (0.5-1.0 mg/kg) without continuous infusion rarely causes such side effects [
In some studies, remifentanil elicited hyperalgesia (increased sensitivity to noxious stimuli) and rapid intolerance, which was associated with the intraoperative opioid dosage. Despite the fact that ketamine was reported to mitigate remifentanil induced hyperalgesia during the postoperative period, we could not assess the presence of hyperalgesia after the procedure. This might be a limitation of this study, although we believe that the degree of pain after PTA is usually mild and the dose of ketamine in this study was not enough to exert a preventive effect on remifentanil induced hyperalgesia.
In conclusion, a small dose of ketamine as an adjunct sedative to the combination of midazolam and remifentanil in patients undergoing PTA produced a better quality of sedation and analgesia than without ketamine, and provided stable respiration without cardiopulmonary deterioration.
We would like to thank Dr Jae Kwang Shim for his assistance with the study.
This work was supported by the Department of Anaesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Korea
OAA/S: Observer's Assessment of Alertness/Sedation.
Patient Demographics and Preoperative Clinical Data
Data are expressed as mean ± SD or number of patients (%). ASA: American Society of Anesthesiologists. *Measured after recovery room admission.
Haemodynamic Data
Data are expressed as mean ± SD. T0: before remifentanil infusion, T1: 5 min after remifentanil infusion, T2: 1 min after incision, T3: 3 min after incision, T4: 5 min after incision, T5: 30 min after incision, T6: admission to recovery room, RR: respiratory rate, MAP: mean arterial pressure, HR: heart rate, SpO2: peripheral oxygen saturation. *P < 0.05 compared with group 1 at each time point of measurement. †P < 0.01 compared with T1.
Pain and Sedation Score
Data are expressed as median (interquartile range). T1: 5 min after remifentanil infusion, T2: 1 min after incision, T3: 3 min after incision, T4: 5 min after incision, T5: 30 min after incision, T6: admission to recovery room, VNRS: verbal numerical rating scales, OAA/S: Observer's Assessment of Alertness/Sedation Scale. *P < 0.05 compared with group 1 at each time point. †P < 0.01 compared with T1.
Adverse Effects in the Two Groups
Data are expressed as number of patients.