Anesth Analg 2005;101:365-370
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000159379.54705.84
AMBULATORY ANESTHESIA
Section Editor:
Paul F. White
Remifentanil as a Single Drug for Extracorporeal Shock Wave Lithotripsy: A Comparison of Infusion Doses in Terms of Analgesic Potency and Side Effects
Hector J. Medina, MD,
Eilish M. Galvin, MB, FCARCSI,
Maaike Dirckx, MD,
Preveen Banwarie, MSc,
Johannes F. H. Ubben, MSc,
Freek J. Zijlstra, PhD,
Jan Klein, MD, PhD, and
Serge J. C. Verbrugge, MD, PhD
Department of Anesthesiology, Erasmus University Medical Center, Rotterdam, The Netherlands
Address correspondence and reprint requests to Eilish Galvin, MB, FCARCSI, Department of Anesthesiology, Erasmus University Medical Center, P.O. Box 2040, 3015 GD Rotterdam, The Netherlands. Address e-mail to eilishgalvin{at}hotmail.com.
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Abstract
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This randomized, double-blind study was designed to evaluate analgesic effectiveness and side effects of two remifentanil infusion rates in patients undergoing extracorporeal shock wave lithotripsy (ESWL) for renal stones. We included 200 patients who were administered remifentanil either 0.05 µg · kg–1 · min–1 (n = 100) or 0.1 µg · kg–1 · min–1 (n = 100) plus demand bolus of 10 µg of remifentanil via a patient-controlled analgesia (PCA) device. No other sedating drugs were given. The frequencies of PCA demands and deliveries were recorded. Arterial blood pressure, oxygen saturation, and respiratory rate were recorded throughout the procedure; postoperative nausea and vomiting (PONV), dizziness, itching, agitation, and respiratory depression were measured posttreatment. Visual analog scale (VAS) scores were taken preoperatively, directly postoperatively, and 30 min after finishing the procedure. There were no statistically significant differences in the frequency of PCA demands and delivered boluses or among perioperative VAS scores. The extent of PONV and frequency of dizziness and itching immediately after and dizziness 30 min after the end of treatment were significantly reduced in the smaller dose group. We conclude that a remifentanil regimen of 0.05 µg · kg–1 · min–1 plus 10 µg demands is superior to 0.1 µg · kg–1 · min–1 plus demands, as there was no difference in the VAS scores recorded between groups and it has a less frequent incidence of side effects in patients receiving ESWL.
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Introduction
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Extracorporeal shock wave lithotripsy (ESWL) is a noninvasive procedure used for the treatment of kidney stones. Acoustic shock waves break stones down into sand-like fragments that may then be excreted. The treatment may be associated with significant pain, depending on the strength of the shock waves delivered. In general, the treatment is an outpatient procedure and the choice of sedatives and analgesics is limited to those that provide rapid recovery. The ideal drug provides effective analgesia for the duration of the procedure in combination with a low level of sedation and minimal side effects. Numerous studies have been performed to determine the most suitable drug for this procedure and several drugs, including midazolam, sufentanil, fentanyl, ketamine, desflurane, and propofol, have been studied (1–4).
Remifentanil, an opioid agonist, appears to be a suitable option; administered IV, it has a fast onset time, may be delivered by a continuous infusion, and is rapidly metabolized by esterases (5). This means that both its analgesic effect and potential side effects are quickly reversed, which is important in ESWL treatment, as pain is experienced mainly during the procedure itself, with minimal postoperative pain. Intermittent boluses of remifentanil with propofol sedation have been shown to be a useful alternative to fentanyl, alfentanil, and sufentanil to provide analgesia during ESWL (2). One study suggested that an infusion rate of remifentanil of 0.05 µg · kg–1 · min–1 plus a remifentanil bolus of 12.5 µg in combination with a propofol infusion provided adequate analgesia and sedation for ESWL (6). Remifentanil use as a sole drug for ESWL treatment has not been investigated. The purpose of the current single-blind study was to determine whether the administration of remifentanil as a single drug provided adequate analgesia for ESWL treatment and to determine which dose is associated with the fewest side effects. Remifentanil infusion doses of 0.1 µg · kg–1 · min–1 and 0.05 µg · kg–1 · min–1 plus demands of 10 µg of remifentanil via a patient-controlled analgesia (PCA) pump were compared.
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Methods
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We studied 200 ASA physical status I–II adult patients aged 18–80 yr old who were scheduled for elective ESWL treatment of kidney stones using a Dornier Lithotripter S (MedTech, Wessling, Germany). Written informed consent was obtained from each patient before the ESWL treatment commenced. The study protocol was approved by the institutional ethics committee. Patients with any conditions precluding the ability to use a PCA device or known allergy to remifentanil and those receiving preoperative opioids were excluded from the study. After the insertion of a peripheral 18-gauge or 20-gauge IV cannula on the forearm or hand, normal saline 0.9% was infused slowly. Patients received diclofenac 75 mg IV before commencement of the ESWL treatment unless contraindicated, in which case paracetamol 1 g was administered in suppository form to provide posttreatment analgesia. No preoperative sedatives were administered. Prophylactic antiemetics were not administered. Patients with a history of postoperative nausea and vomiting (PONV) after previous ESWL treatment were excluded, as it is the policy of our department to administer prophylactic antiemetics routinely to such patients. The number of previous ESWL treatments was noted for each patient, as was data on age (years), sex (male/female), ASA classification, and kidney being treated (left or right).
Before commencement of the ESWL treatment, patients were asked to score their level of pain from the presence of kidney stones using an 11-point visual analog scale (VAS) from 0–10, with 0 being no pain and 10 being the worst pain imaginable. Routine monitors were applied before the commencement of treatment to measure noninvasive arterial blood pressure, electrocardiogram, and oxygen saturation (Spo2). All patients received 6 L/min oxygen administered via a facemask. Patients were randomly allocated remifentanil (Ultiva®, GlaxoSmithKline, Zeist, The Netherlands) either 0.05 µg · kg–1 · min–1 (n = 100) or 0.1 µg · kg–1 · min–1 (n = 100). Remifentanil solutions were prepared by an anesthetic nurse and were randomly allocated to patients by drawing numbers from a bag. The investigator who recorded all study data was unaware of the remifentanil concentration administered to the patient. The patients were also blinded as to which remifentanil concentration was being administered. All patients were given a PCA device (IVAC Medical systems, Hampshire, England) capable of delivering a bolus dose of 10 µg of remifentanil on demand with a lockout period of 1 min. We included a PCA demand feature as we believe that it would be unethical to test a smaller infusion dose of analgesic without offering patients an additional source of analgesia. Patients were instructed to press the PCA button when they experienced pain during the ESWL treatment. Each patient received 3000 shocks over exactly 30 min. During the procedure routine monitoring was maintained and the occurrence of hypertension or hypotension (20% change from the baseline value), oxygen desaturation (Spo2 <94%), and respiratory depression (respiratory frequency of <8 breaths per minute) was recorded. Three minutes before the treatment procedure was completed the remifentanil infusion was discontinued. Both the frequency of demands by the patient during the 30-min period and the actual number of deliveries via the PCA were recorded for each patient.
Immediately after ESWL treatment a VAS from 0–10 was used to record the pain experienced during the entire treatment session. The occurrence of PONV was recorded on a scale of 0–3 (0 = no nausea or vomiting; 1 = mild, no pharmacological treatment required; 2 = moderate, pharmacological treatment administered with good effect; 3 = severe, pharmacological treatment administered with no relief of PONV). Pharmacological treatment of PONV consisted of granisetron 1 mg IV. The presence of dizziness, itching, and agitation were also noted directly postoperatively.
Thereafter, patients were transferred to the recovery room. Half an hour after the end of treatment, a third VAS was recorded, as was the presence of dizziness, nausea, and respiratory depression. At the same time, patient satisfaction was noted (satisfied, not satisfied, or neutral). Patients were discharged to the ward when all discharge criteria were met; i.e., with stable vital signs and absence of pain and nausea.
The VAS score was our primary outcome variable. To evaluate the standard deviation of the VAS score in our practice, we conducted a pilot study on 100 patients receiving ESWL treatment with 0.1 µg · kg–1 · min–1 during a 2-mo period. The patients reported a mean ± sd VAS score of 1.7 ± 2.0 on a 0–10 scale. Therefore, we assumed an expected standard deviation of 2.0 in both study groups. With 100 patients in both groups, our study was able to demonstrate a difference of 0.8 in VAS score between groups (
= 0.05, 2-sided unpaired Student’s t-test, ß = 0.80). We felt this was an acceptable level.
Between-group comparisons for numerical data were performed with Student‘s t-test. Within-group comparison for VAS scores over time were performed with repeated-measures analysis of variance with Bonferroni post-testing. Data distribution and frequency differences were analyzed with either a Fisher’s exact test or a 
2 test for independence. Statistical significance was accepted at P < 0.05.
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Results
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Patient demographics are shown in Table 1, with statistically significant differences indicated.
Perioperative measurements are shown in Table 2. In both study groups the VAS score recorded immediately after treatment was significantly higher than the preoperative VAS score and the VAS score 30 min after the procedure. The average extra dose received from the PCA was 0.017 ± 0.024 µg · kg–1 · min–1 in group 0.05 and 0.024 ± 0.031 µg · kg–1 · min–1 in group 0.1 µg · kg–1 · min–1, which was not statistically significant.
In Figure 1, the frequencies of dizziness and itching directly postoperatively and of dizziness 30 min after the procedure are shown. In the group that received 0.1 µg · kg–1 · min–1 of remifentanil, there was significantly more itching and dizziness.
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Figure 1. Postoperative side effects. Data on postoperative dizziness and itching and dizziness after 30 min. Gray bars represent the group receiving 0.05 µg · kg–1 · min–1 of remifentanil; black bars represent the group receiving 0.1 µg · kg–1 · min–1 of remifentanil. Statistical significance: a, between both study groups.
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Data on PONV are shown in Figure 2. In the group receiving 0.1 µg · kg–1 · min–1 of remifentanil, there was significantly more PONV.
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Figure 2. Data on postoperative nausea and vomiting (PONV). Gray bars represent the group receiving 0.05 µg · kg–1 · min–1 of remifentanil; black bars represent group receiving 0.1 µg · kg–1 · min–1 of remifentanil. Statistical significance: a, between both study groups.
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Discussion
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ESWL is performed in several hundred centers throughout the world on a daily basis, but although there are relatively fixed guidelines for the urological management of renal stones, there is a great deal of variation in methods used to manage the pain associated with ESWL. Many different options have been used, including regional, general, local, and sedation techniques, with varying degrees of success (7–9). In general, ESWL is done as an ambulatory procedure, with the patient discharged home within hours of treatment completion. This has implications in terms of cost effectiveness and efficiency and improving patient acceptance of the treatment. Remifentanil, because of its unique profile, appears to be emerging as the drug of choice for the management of such patients. However, the ideal dose regimen has yet to be identified accurately when remifentanil is used as the sole drug.
The remifentanil continuous infusion rates used in our study were based on our observations during a 6-month period before commencing the study. We initially adopted the recommendations of a previously published study (10) and infused remifentanil at a rate of 0.025 µg · kg–1 · min–1, reducing shock wave intensity when patients experienced pain. However, we noted that this had the effect of prolonging the total treatment time and, therefore, the period of time during which patients had to maintain a relatively fixed position—a factor which potentially increases patient anxiety and may not be appropriate for patients with co-morbidities such as arthritis and muscular complaints. We therefore opted to use larger doses of analgesia to maintain the intensity of the shock waves, allowing more accurate prediction of total treatment time. This also allows for better scheduling of patient treatments and more efficient use of the ESWL equipment and trained personnel.
The method of remifentanil administration used in this study (i.e., continuous infusion in combination with PCA boluses) allowed us to assess remifentanil requirements. The amount of remifentanil required as a single drug may be larger than when used in combination with other sedatives or analgesics. Remifentanil administration as a bolus dose is a controversial topic in the literature (11). Clinically significant hypoventilation after bolus administration of remifentanil in spontaneously breathing patients has been shown to occur (12). However, Egan et al. (13) recently demonstrated that boluses of 25 µg of remifentanil or less had algometry responses similar to placebo (P < 0.05). In the current study, in addition to a continuous infusion, a demand dose of 10 µg of remifentanil was used with a lockout period of 1 minute. As an additional precaution, all patients received supplemental oxygen during the treatment.
We also noted the experience of a previous study by Sa Rego et al. (6), who suggested that using intermittent bolus injections of remifentanil 25 µg or a continuous infusion of 0.05 µg · kg–1 · min–1 supplemented with intermittent bolus 12.5-µg injections may be more effective than a variable-rate infusion of remifentanil during propofol sedation. They did not demonstrate any increased risk of hypoventilation associated with the use of remifentanil boluses, even though all patients studied received a propofol infusion of 50 µg · kg–1 · min–1 and midazolam 2 mg orally before commencement of treatment. In the current study, we choose to administer remifentanil as a single drug rather than in combination with another sedating drug. Additionally, we did not administer sedating premedication. Such use of remifentanil as a sole drug may lessen the potential for respiratory depression; however, this study was not designed to compare remifentanil use as a sole drug to the use of remifentanil in combination with sedating drugs.
A study by Babenco et al. (14) showed that peak respiratory depression occurred 2.5 minutes after administering a remifentanil bolus. In the current study, rather than administer an initial bolus, we opted to start the remifentanil infusion 1 to 3 minutes before the commencement of shock therapy, thus ensuring that the time of potential remifentanil-induced respiratory depression coincided with the time of initial pain stimulation thus limiting the potential for reduced respiratory function.
Our results show that remifentanil infusions of both 0.05 µg · kg–1 · min–1 and 0.1 µg · kg–1 · min–1, plus an additional PCA bolus of 10 µg, provide adequate analgesia for ESWL treatment of renal stones. Interestingly, we noted that although one group received twice the basal remifentanil infusion rate of the other, there was no significant difference between the total doses of additional remifentanil administered via the PCA. This suggests that, despite instruction on PCA use, patients may tend to press such self-controlled devices in excess of requirements for pain. Such an occurrence may be related to anxiety levels, which were not specifically assessed during the treatment but would appear to be similar in the two groups based on the results for the number of PCA bolus demands and deliveries administered. Indeed, it has been shown that psychological factors can significantly influence postoperative pain and PCA use (15). We noted that there was no difference in the degree of agitation observed in the immediate posttreatment phase in the recovery room.
This is the first study in which remifentanil as a single drug was studied during ESWL therapy. We found no significant difference in the VAS scores obtained directly after treatment between the two groups, suggesting that the lower infusion rate of 0.05 µg · kg–1 · min–1, plus demands of 10 µg, provides adequate analgesia for ESWL treatment. The posttreatment VAS score referred to the overall pain experienced throughout the entire treatment session. Such posttreatment pain scores have been shown to be an accurate measure of analgesic effect during the actual procedure (16). The degree of respiratory depression, hypertension or hypotension, and oxygen desaturation did not differ significantly between the groups, which were similar in terms of gender and number of previous ESWL treatments. Although the groups did differ in age (53.1 ± 11.5 years versus 46.9 ± 13.0 years in the 0.05 µg · kg–1 · min–1 and 0.1 µg · kg–1 · min–1 groups, respectively), we believe that it is unlikely that this contributed to any differences observed between groups. The absence of significant respiratory depression provides useful information in terms of the potential for respiratory problems associated with remifentanil usage in the group of patients studied (i.e., ASA I–II patients). Of course, higher-risk patients may be more prone to hemodynamic and respiratory abnormalities.
The potential emetic effect of remifentanil has been documented (17,18). Our study supports the belief that nausea and vomiting associated with remifentanil use is dose-related. Although only reported once in the literature (19), in our study a common side effect of remifentanil use was dizziness. The occurrence of dizziness appears to be dose-related, with an almost twofold increased incidence in the larger infusion rate group in the immediate postoperative period, increasing to an almost threefold difference at 30 minutes after cessation of the remifentanil infusion. There is no pharmacological treatment available for postoperative dizziness. Because the incidence is likely to be dose-related, it is therefore important that patients receive the minimal effective analgesic dose of remifentanil.
Itching or pruritus is a side effect associated with the use of opioids (20,21). Our study confirmed this finding, with 15 of 200 patients studied reporting itching. As with dizziness, the occurrence of pruritus appears to be dose-related, with a sixfold more frequent incidence reported in the 0.1 µg · kg–1 · min–1 versus the 0.05 µg · kg–1 · min–1 remifentanil group immediately posttreatment. Our results suggest that using a smaller dose of remifentanil would significantly reduce the occurrence of pruritus.
In this study, VAS scores for pain were taken after the actual ESWL session had been completed; i.e., in the recovery room, where patients were asked to score overall pain experienced during the treatment. Although this method has been validated elsewhere (16), it could be seen as a potential deficiency in the study design.
In conclusion, this study suggests that the single use of an IV remifentanil infusion of 0.05 µg · kg–1 · min–1, plus intermittent demands of 10 µg, is as effective as an infusion of 0.1 µg · kg–1 · min–1 plus intermittent demands of 10 µg in providing analgesia for ESWL treatment. The smaller dose is associated with statistically significantly fewer side effects, such as PONV, dizziness, and pruritus.
We would like to thank the staff and patients of the ambulatory unit of Erasmus University Medical Center, Rotterdam, for their contribution to this study.
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Footnotes
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Supported, in part, by the Department of Anesthesiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Accepted for publication February 1, 2005.
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References
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Abstract
Introduction
