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From the Departments of *Anesthesiology and Urology, Cumhuriyet University School of Medicine, Sivas, Turkey.
Address correspondence and reprint requests to Dr. Kenan Kaygusuz, Department of Anesthesiology, Cumhuriyet University School of Medicine, 58140 Sivas, Turkey. Address e-mail to kaygusuz{at}cumhuriyet.edu.tr.
Abstract
BACKGROUND: Dexmedetomidine, because it has both sedative and analgesic properties, may be suitable for conscious sedation during painful procedures. Extracorporeal shockwave lithotripsy (ESWL) is a minimal to mildly painful procedure that requires conscious sedation. We thus evaluated the utility of dexmedetomidine compared with propofol during an ESWL procedure.
METHODS: Forty-six patients were randomly allocated into two groups to receive either dexmedetomidine or propofol for elective ESWL. Dexmedetomidine was infused at 6 µg · kg–1 · h–1 for 10 min followed by an infusion rate of 0.2 µg · kg–1 · h–1. Propofol was infused at 6 mg · kg–1 · h–1 for 10 min followed by an infusion of 2.4 mg · kg–1 · h–1. Fentanyl 1 µg/kg IV was given to all patients 10 min before ESWL. Pain intensity was evaluated with a visual analog scale at 5-min intervals during ESWL (10–35 min). Sedation was determined using the Observer's Assessment of Alertness/Sedation. The Observer's Assessment of Alertness/ Sedation scores and hemodynamic and respiratory variables were recorded regularly during ESWL (35 min) and up to 85 min after.
RESULTS: Forty patients were evaluated. Visual analog scale values with dexmedetomidine were significantly lower than those with propofol only at the 25–35 min assessments (P < 0.05). During sedation, the respiratory rate with dexmedetomidine was significantly slower but Spo2 was significantly higher than with propofol (P < 0.05). Other clinical variables were similar (P > 0.05).
CONCLUSION: A combination of dexmedetomidine with fentanyl can be used safely and effectively for sedation and analgesia during ESWL.
During the extracorporeal shockwave lithotripsy (ESWL) procedure, newer generation lithotriptors are less painful than their prototypes. Thus, the trend in anesthesia for ESWL has progressively shifted from general to sedative analgesic techniques.1,2 Combinations of a sedative hypnotic and opioid analgesic are frequently used to provide patient comfort, analgesia, and sedation.3,4 Although propofol is a widely used sedative hypnotic with minimal analgesic properties, it may cause some respiratory depression, an effect that can be amplified in the presence of opioids.5,6
Dexmedetomidine is a highly selective 
2-adrenergic receptor agonist that has analgesic and sedative properties with little effect on ventilation. This pharmacologic profile, combined with a very impressive safety margin, has made it an attractive choice for anesthesiologists and intensivists.7 The agonistic action on the 2-adrenergic receptors in the sympathetic ganglia modulates the release of catecholamines, resulting in a sympatholytic effect and there have been reports of bradycardia and hypotension.8 As the dose of dexmedetomidine is increased, there is a direct action on the blood vessels causing vasoconstriction and a possible increase in mean arterial blood pressure (MAP).9 Presently, dexmedetomidine is only approved for short-term sedation in ventilated patients in an intensive care unit. However, based on its pharmacological profile, it may be a valuable sedative for procedures with minimal to mild pain.
This randomized, double-blind, clinical study was designed to compare the hemodynamic, analgesic, sedative, and respiratory effects of dexmedetomidine and propofol in combination with fentanyl during ESWL. We hypothesized that dexmedetomidine would provide better analgesia during adequate sedation (modified Observer's Assessment Alertness/Sedation (OAA/S) scale 3) than propofol.
METHODS
The study protocol was approved by our Human Ethics Committee (No: B.30.2.CUM.0.1H.00.00; Date: May 07, 2003) and written informed consent was obtained from each subject. Patient enrollment took place between May 2003 and December 2003. Our sample size was based on our primary outcome measure of improved analgesia. We defined an average difference of 15 mm on a 100-mm visual analog scale (VAS) as clinically relevant. Based on experience from our previous studies, it was expected that 95% of the reported VAS scores would range between 0 and 80 mm, resulting in a mean ± sd of 47 ± 19.7 mm. A sample size of 40 patients (20 in each arm of the study) was calculated to be necessary to detect a 15-mm reduction of VAS score with a power of 80% and an error of 5%. It was assumed that the study drop-out rate would be approximately 15% and, therefore, a sample of 46 patients was recruited and randomly allocated to one of two of the study groups. Randomization was achieved by using sequentially numbered, opaque-sealed envelopes containing computer-generated random allocations in a ratio of 1:1 in balanced blocks of 8. To reduce selection and pretest biases, our anesthesia technician prepared the study drugs and wrapped the IV bag and tubing with an opaque covering.
Forty-six patients of ASA physical status I and II, aged 18–60 yr, who were scheduled for elective ESWL, were enrolled in this randomized, double-blind, clinical study. Exclusion criteria were age <18 yr, a history of drug or alcohol abuse, chronic use of drugs known to alter the anesthetic or analgesic requirements, allergy to any of the study medications, second- or third-degree heart block, chronic use of any 2-agonists, and a current psychiatric or respiratory disorder. Patients with a body weight more than 50% more than the ideal body weight were also excluded. All patients had only one renal stone without pain, and none of them had undergone an ESWL procedure before.
On arrival in the ESWL unit and after the placement of an IV catheter, a baseline measurement of respiratory rate (RR), heart rate (HR), noninvasive MAP, and oxygen saturation (Spo2) were obtained (Criticare System, Waukesha, WI). Sedation level was assessed by using the modified OAA/S scale: 5 = responds readily to name spoken in normal tone (awake/alert), 4 = lethargic response to name spoken in normal tone, 3 = responds only after name spoken loudly or repeatedly, 2 = responds after mild prodding or shaking 1 = does not respond to mild prodding or shaking (asleep/unarousable).10 Pain intensity was evaluated on a 0 to 100-mm VAS. The OAA/S and VAS scores were evaluated by an observer blinded to the patients group (S.G.).
In patients randomized to the dexmedetomidine group, an initial dose of dexmedetomidine was infused IV over 10 min at 6 µg · kg–1 · h–1, followed by a maintenance infusion of 0.2 µg · kg–1 · h–1.11 In patients randomized to the propofol group, an initial dose of propofol was infused IV over 10 min at 6 mg · kg–1 · h–1, followed by a maintenance infusion of 2.4 mg · kg–1 · h–1.12 All patients received fentanyl 1 µg/kg IV 10 min before initiation of ESWL. The ESWL procedure was started after the initial dose infusion of dexmedetomidine or propofol. All patients received 2000 shocks (80 per min; total 25 min) at 18 kV using the PCK Stonelith system (PCK Electronic Industry and Trade CO, Ankara, Turkey). Drug infusions were discontinued 2 min before the end of ESWL in both groups.
The OAA/S scores and hemodynamic (MAP and HR) and respiratory (RR and Spo2) variables were recorded at 5-min intervals after the baseline measurements until the termination of the ESWL procedure. The baseline measurements were obtained just before the start of the study drugs. The OAA/S scores and hemodynamic and respiratory variables were recorded post-ESWL at 45, 60, 90, and 120 min from the original baseline measurement. The VAS scores were recorded at 5-min intervals during the ESWL procedure at 10, 15, 20, 25, 30, and 35 min.
To achieve adequate sedation in both groups, infusion doses of test drugs were increased by 50% if sedation was inadequate (OAA/S 
4) and decreased by 50% if patients were over-sedated (OAA/S <3). If the OAA/S score was 2 or less, we reduced the infusion of the study drugs for 2 min; after the OAA/S score returned to 3 or higher, we obtained a VAS score. During the procedure, if bradypnea (RR <10) or Spo2 was 92% or less, bradycardia (HR <45), and hypotension (MAP <50) were recorded, 4 L/min of supplemental oxygen was administered via a nasal canula, 0.5-mg atropine was administered, and 0.9% saline was infused, respectively.
The incidence of nausea and vomiting, and dry mouth were recorded. All patients were asked, using a questionnaire, to rate their overall pain experience (0, no pain; 1, mild; 2, moderate; or 3, severe) and their degree of overall satisfaction with the management of their pain (0, poor; 1, adequate; 2, good; or 3, excellent) after the completion of the ESWL procedure.
Data are presented as mean ± sd and percentage as appropriate. Statistical analyses were performed using Statistica 7.0. Software (Statsoft, Tulsa, AR). Demographics were compared with t-test. The proportions of men/women, dose increase due to inadequate sedation, nausea, oxygen supplementation, overall pain experience scores 2 and 3, and overall satisfaction scores 0 and 1 of the study groups were compared with 
2 test. RR, Spo2, MAP, HR, and VAS were compared with repeated measures analysis of variance (ANOVA) with post hoc Tukey test. OAA/S was analyzed with Friedman's nonparametric repeated measures ANOVA with post hoc Tukey test. To simplify the presentation of RR, Spo2, MAP, and HR, we chose, for each individual, the lowest values achieved during sedation, and the highest value during recovery. A P value of <0.05 was considered significant.
RESULTS
During the study period, 54 consecutive patients with the required ESWL indication were identified. Two were excluded because of obesity, three refused to participate, and three were not asked because of high workload. Of these 46 patients, three in the dexmedetomidine group and three in the propofol group were excluded from data analysis because of protocol violations resulting from delayed evaluation. In only one patient, who was in the dexmedetomidine group, did the OAA/S score decrease to 2. In this patient, we reduced the infusion of study drug and, after 2 min, the patient's OAA/S score was 3 and we obtained a VAS score.
The two groups were similar in age, men/women ratio, and weight (P > 0.05) (Table 1). VAS values in the dexmedetomidine group at 25–35 min were significantly lower than those of the propofol group at 25–35 min (P < 0.05). The rest of the VAS values at 10–20 min were similar (P > 0.05) (Fig. 1). The OAA/S value in the dexmedetomidine group at 35 min was significantly lower than that of the propofol group (P < 0.05). The OAA/S values at 5–35 min were significantly lower than those at baseline in both the dexmedetomidine and propofol groups (P < 0.05) (Fig. 2).
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In the dexmedetomidine group, RRs were 15 ± 1.7, 12 ± 1.1, and 15 ± 1.1 at baseline and during sedation and recovery, respectively. In the propofol group, RRs were 17 ± 3.0, 15 ± 3.0, and 17 ± 2.4 at baseline and during sedation and recovery, respectively. RR values of the dexmedetomidine group were significantly lower than those in the propofol group during sedation (P < 0.05). The RR values during sedation were significantly lower than those at baseline and during recovery in both the dexmedetomidine and propofol groups (P < 0.05).
In the dexmedetomidine group, Spo2 values were 98.0 ± 0.7, 97.0 ± 0.9, and 98.1 ± 0.4 at baseline and during sedation and recovery, respectively. In the propofol group, Spo2 values were 97.0 ± 1.4, 95.0 ± 2.7, and 98.0 ± 0.6 at baseline and during sedation and recovery, respectively. Spo2 values of the dexmedetomidine group during sedation were significantly higher than those of the propofol group (P < 0.05). The Spo2 values during sedation were significantly lower than those at baseline and during recovery in the propofol group (P < 0.05).
There were no differences in the MAP values between the dexmedetomidine and propofol groups (P > 0.05). The MAP values during sedation were significantly lower than those at baseline and during recovery in both the dexmedetomidine and propofol groups (P < 0.05) (Fig. 3).
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There were no differences in the HR values between the dexmedetomidine and propofol groups (P > 0.05). In the dexmedetomidine and propofol groups, HR significantly decreased during sedation and recovery, compared with baseline (P < 0.05). The HR values during sedation were significantly lower than those during recovery in dexmedetomidine group (P < 0.05) (Fig. 3).
The number of dose increases due to inadequate sedation was similar between two groups (one in the dexmedetomidine group and three in the propofol group). The incidence of dry mouth, nausea, vomiting, oxygen supplementation, and the overall pain experience scores 2 and 3 and overall satisfaction scores 0 and 1 were similar between the study groups (Table 1). Deep sedation causing hypotension, bradycardia, or respiratory depression (Spo2 <92%) was not encountered in any patient.
DISCUSSION
The primary aim of this study was to compare dexmedetomidine and propofol in combination with fentanyl for sedation and analgesia during ESWL. In combination with fentanyl, IV dexmedetomidine provided safe and effective analgesia. The RR was more rapid with propofol than dexmedetomidine, and Spo2 was less with propofol than dexmedetomidine. Study drugs were comparable with regard to sedation, MAP, HR, overall pain experience and satisfaction scores, and side effects.
For maximal patient comfort, the most suitable drug for ESWL should provide sufficient sedation, adequate analgesia, minimal side effects, and rapid recovery. There are numerous factors influencing the amount of pain during ESWL. Apart from patient-related factors, the type of lithotripter, the size, and site of the stone burden, the location of the shockwave front, cavitation effect of the shockwave, shockwave peak pressure, the size of the focal zone, and the area of shockwave entry at the skin can change the severity and duration of the pain.2,3
Alhashemi and Kaki13 found that dexmedetomidine is an effective and safe drug for sedation during ESWL. Unlike their study evaluating the effect of dexmedetomidine alone, our study sought to compare the effects of dexmedetomidine to propofol, which is one of the most common IV sedative drugs used during ESWL. The present study demonstrated that comparable sedation could be achieved with either dexmedetomidine or propofol during ESWL. In our study, we observed that in the dexmedetomidine group patients achieved higher Spo2, slower RR, and lower VAS pain scores. These findings suggest that dexmedetomidine (in combination with fentanyl) may provide advantages over propofol as a sedative drug during ESWL.
The observed analgesic effects of dexmedetomidine in this study agree with the findings of both animal and human studies.14–16 We found that dexmedetomidine has better analgesic properties than propofol. Jalowiecki et al.17 evaluated the ability of dexmedetomidine to provide analgesia and sedation for outpatient colonoscopy. In contrast to our study, they suggested that the use of dexmedetomidine to provide analgesia/sedation for colonoscopy is limited by its distressing side effects, pronounced hemodynamic instability, prolonged recovery, and a complicated administration regimen. Our study differed in that, for both the dexmedetomidine and propofol groups, we added fentanyl 1 µg/kg IV to enhance the analgesic effects of the study drugs. Although this dose of fentanyl is lower than its standard use, our data suggest that this combination of dexmedetomidine and fentanyl provides good pain relief during an ESWL procedure.
At equipotent sedative doses, propofol and dexmedetomidine resulted in an equivalent mild reduction in MAPs. However, this decrease in MAP did not require treatment in either group. The numerous adverse cardiovascular events seen previously with the initial loading infusion of dexmedetomidine and propofol18,19 were not seen in this study. The effect of a dexmedetomidine-induced change on RR is controversial. Hsu et al.20 have reported a significant increase in RR with dexmedetomidine, whereas Belleville et al.21 reported a significant decrease in RR. This discrepancy may result from the physiologic reactions due to arousal phenomenon. This discrepancy could also have resulted from the fact that boluses were used in the study of Belleville et al., whereas Hsu et al.20 used infusions that resulted in sustained and higher dexmedetomidine concentrations.
Although RRs decreased in the dexmedetomidine group similar to that seen by Belleville at al., in our study, Spo2 values did not decrease. This may have been related to the initial dose given as an infusion and over a much longer time (10 min) in our study. Interestingly, Ebert et al.16 used dexmedetomidine infusions similar to Hsu et al.20 and that study showed a significant increase in RR as well. Sedative doses of propofol have minimal depressant effects on tidal volume and minute ventilation, with end-tidal CO2 tension and arterial blood gas values remaining unchanged.22 However, larger doses of propofol can depress the hypoxic ventilatory response23 and cause more frequent and longer apnea than barbiturates.24 In our study, decreases in RR were smaller with propofol when compared with dexmedetomidine but, in the propofol group, the decrease of Spo2 was more than that with dexmedetomidine. This may be related to the effect on tidal volume, i.e., in the dexmedetomidine group, although RR decreased, tidal volume probably remained unchanged or increased, whereas in the propofol group tidal volume probably decreased, while RR did not change. Because we added fentanyl to the management of all patients, its effect should also be considered to impact respiratory function. In addition, the effects of sedatives on respiratory depression may be widely influenced by the balance between pain and the effects of the administered sedatives/opioid.
Several previous studies comparing propofol to dexmedetomidine did not evaluate the effect of these drugs on RR25,26 because they were performed in mechanically ventilated patients. We found that, in spontaneously breathing patients, the respiratory-depressant effect of dexmedetomidine was less remarkable compared with that observed with propofol.
In conclusion, although infusion of dexmedetomidine and propofol provided safe and adequate analgesia, sedation and patient comfort in the ESWL procedure, analgesic and respiratory variables were better with dexmedetomidine than propofol. Therefore, dexmedetomidine in combination with small-dose fentanyl can be useful during ESWL and it may be a valuable alternative to propofol.
ACKNOWLEDGMENTS
This research was not supported by any funding source.
Footnotes
Accepted for publication September 10, 2007.
REFERENCES
2-agonist-induced peripheral vasoconstriction in humans. Anesthesiology 2003;99:65–70[Web of Science][Medline]
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