Remifentanil compared with sufentanil during extra-corporeal shock wave lithotripsy with spontaneous ventilation: a double-blind, randomized study

H. Beloeil1, G. Corsia1, P. Coriat1 and B. Riou*,1,2

1 Department of Anaesthesiology and Critical Care and 2 Department of Emergency Medicine and Surgery, Groupe hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie, Paris, France*Corresponding author: Départment d’Anesthésie-Réanimation, Groupe hospitalier Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, F-75651 Paris cedex 13, France

Accepted for publication: May 8, 2002


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. The pharmacokinetic properties of remifentanil may allow a rapid analgesic action during painful procedures and short lasting postoperative respiratory depression.

Methods. We carried out a randomized, blind, study in 60 patients to compare remifentanil (continuous i.v. infusion starting at 0.025 µg kg–1 min–1) and sufentanil (i.v. doses of 0.15 µg kg–1) during extra-corporeal shock wave lithotripsy (ESWL). Pain was assessed using a numerical pain scale (0–100), and pain relief was defined as a score <=30. Respiratory depression was defined as a ventilatory frequency less than10 breaths min–1 on two occasions or a peripheral oxygen saturation <=92%, or administration of naloxone.

Results. The quality of analgesia was similar in both groups, during and after ESWL. During ESWL, there was no significant difference in respiratory depression in the remifentanil and sufentanil groups (53 vs 73%, NS). The percentage of satisfied patients (73 vs 83%, NS) and satisfied surgeons (97 vs 100%, NS) did not significantly differ between groups. After the procedure patients given remifentanil had less respiratory depression (20 vs 53%, P<0.05) and less nausea and vomiting (3 vs 20%, P<0.05).

Conclusion. A continuous i.v. infusion of remifentanil provided comparable analgesia and caused less respiratory depression and nausea and vomiting than i.v. boluses of sufentanil in patients undergoing extra-corporeal shock wave lithotripsy.

Br J Anaesth 2002; 89: 567–70

Keywords: analgesics opioid, remifentanil; analgesics opioid, sufentanil; complications, respiratory depression; recovery, postoperative; ventilation, spontaneous


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Extra-corporeal shock wave lithotripsy (ESWL) is a non-invasive procedure that allows urinary stones to be broken using acoustic shock waves. The impact of the shock waves causes transient stinging pain at the entry site and deep visceral discomfort, requiring analgesia during the procedure, usually by giving doses of sufentanil to spontaneously breathing patients. Respiratory depression during the procedure is treated with oxygen supplementation and verbal stimulation. After ESWL, patients no longer have pain but respiratory depression from the opioid can persist, requiring a stay in the postanaesthesia care unit (PACU), which can be long, depending on the amount of opioid given.

Remifentanil is a new opioid with short elimination half-life,1 2 whose duration of action does not increase with increasing duration of administration because of rapid clearance and lack of drug accumulation.1 3 These properties suggest that it may be particularly useful for ESWL with a rapid analgesic action during the painful procedure, and a very short duration of postoperative respiratory depression that could reduce the duration of stay in the PACU. We performed a double-blind randomized study to compare sufentanil and remifentanil during ESWL. The primary end-point was the occurrence of respiratory depression in PACU. The quality of analgesia during the ESWL was the secondary end-point.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient selection
After institutional review board approval, written informed consent was requested during the anaesthesia consultation, which was performed at least 48 h before ESWL. During this consultation, the assessment of pain was explained to the patient. Patients were asked to rate their pain on a scale from 0 (no pain) to 100 (worst possible). The criteria of inclusion were: patients undergoing only ESWL, American Society of Anesthesiologists’ (ASA) physical status I or II, and understanding of the pain score. We excluded patients if they were aged under 18 or had a major disability, a contraindication for using or allergy to opioids, severe chronic respiratory disease, a body mass index more than 35 kg m–2, tetraplegia or paraplegia, or if the surgery was emergency or involved other procedures such as installing a ureteric tube at the same time.

Study design
Oral premedication with hydroxizine (100 mg) was given 1 h before ESWL. Just before entering the operating room, the patients were randomly assigned to one of the two treatment groups: remifentanil or sufentanil by opening a sealed envelope. During ESWL, patients blindly received one of the two analgesic treatments. In the sufentanil group, i.v. doses of sufentanil (0.15 µg kg–1) were given as long as the reported pain score was greater than 30. A period of more than 5 min between two boluses was required. In the remifentanil group, remifentanil infusion (0.025 µg kg–1 min–1) was given approximately 1 or 2 min before ESWL. The infusion rate was increased in steps of 0.025 µg kg–1 min–1 each time the reported pain score was greater than 30. A period of more than 5 min between two steps was required. To ensure appropriate blinding, in the remifentanil group, patients received i.v. boluses of saline and a remifentanil infusion, whereas, in the sufentanil group, patients received a continuous infusion of saline and i.v. boluses of sufentanil. Moreover, when required, an i.v. bolus was given at the same time as the continuous i.v. infusion was increased. An anaesthetic nurse who did not take part in the care or the assessment of the patient prepared the solutions of the continuous infusion and boluses.

During ESWL, heart rate, arterial pressure, ventilatory frequency, peripheral oxygen saturation, and assessment of pain were recorded every 5 min. The level of energy of the ESWL shocks was decreased if pain was too severe. The same series of measurements were recorded every 10 min during the PACU period. Patients stayed at least 1 h in the PACU. After 1 h, patients left the PACU when the anaesthesiologist had assessed complete recovery with the modified Aldrete score.4

Study measurements
The primary end-point was the occurrence of a respiratory depression in the PACU. The respiratory depression was defined as a ventilatory frequency less than 10 breaths min–1 recorded at least two times (either in successive observations or not), or oxygen saturation <=92%, or administration of naloxone given to treat severe respiratory depression (subjective clinical assessment by the anaesthesiologist). Oxygen supplementation (5 litre min–1) was given during ESWL but not in the PACU, unless oxygen saturation was <=92%. Respiratory depression during ESWL was also assessed using the same definition.

Secondary end-points were the quality of intraoperative analgesia, and any adverse effects of opioids. Patients were asked to verbally rate their level of pain (by using a pain rating score on a 1–100 scale) every 10 min throughout the procedure. Global patient satisfaction was scored on a three-point scale (completely satisfied, incompletely satisfied, and not satisfied) at the end of the procedure. Patients were recorded as satisfied only if they stated ‘completely satisfied’. The surgeon completed a similar assessment at the end of the procedure. The maximum energy level of the ESWL, the duration of the procedure, and the need to decrease the energy level because of patient pain were also noted. We also noted: duration of stay in PACU, adverse effects of opioids during the intraoperative and PACU periods (pruritus, nausea and vomiting, sedation, vertigo, chest rigidity defined as difficulty to breathe normally using subjective assessment by the patient, and urinary retention), heart rate, arterial pressure, oxygen saturation, and ventilatory frequency.

Statistical analysis
Data are expressed as mean (SD) or median (extremes) for non-Gaussian variables, and numbers (percentages). Comparison of two means was performed using Student’s t-test. Comparison of two medians was performed using the Mann–Whitney test. Comparison of two percentages was performed using Fisher’s exact method. As most patients had low values for pain, neither the mean nor the median could appropriately describe the variable. Thus, only the number of patients with pain relief (score <=30) were used for comparison between groups.

In a preliminary study of 20 consecutive patients given sufentanil, we observed that respiratory depression in the PACU occurred in 50% of cases. Thus, assuming {alpha}=0.05, ß=0.10, and a reduction of the incidence of respiratory depression in the PACU from 50 to 10% with remifentanil, we calculated that at least 50 patients should be included.5 Randomization was done with a random number table. All P values are two-tailed and a P value of <0.05 was considered significant. Statistical analysis was performed on a computer using NCSS 6.0 software (Statistical Solutions Inc., Cork, Ireland).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient characteristics were not obviously different in the two groups (Table 1). The total dose of remifentanil was 221 (139) µg (range 47–625 µg) and the total dose of sufentanil 18 (7) µg (range 10–40 µg). During ESWL, there was no significant difference in the incidence of respiratory depression (53 vs 73%, NS) between the groups. Similarly, there was no significant difference in the quality of analgesia provided in the two groups (Fig. 1A). Only four patients reported some difficulty in breathing, but these difficulties were of moderate intensity and all patients find it acceptable. There were no significant differences between the two groups.


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Table 1 Characteristic of the patients. Data are mean (SD), [range], median {extremes} or number
 


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Fig 1 Percentage of patients with pain relief (defined as a reported pain score <=30) in the remifentanil (n=30) and sufentanil groups (n=30) during ESWL (A) and in the PACU (B). Analysis during ESWL was limited to the first 30 min because the median duration was only 30 min.

 
In the PACU, patients given remifentanil had less respiratory depression, nausea and vomiting, than those given sufentanil (Table 2). No patient required naloxone. There was no significant difference in the quality of postoperative analgesia (Fig. 1B). There were no significant differences in the percentages of satisfied patients (73 vs 83%, NS) and satisfied surgeons (97 vs 100%, NS).


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Table 2 Opioid-related adverse effects. Data are number. *P<0.05 vs sufentanil group. {dagger}No patient required naloxone. SpO2, peripheral oxygen saturation
 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Remifentanil and sufentanil were equally effective in providing analgesia and patient and surgeon satisfaction during ESWL, but remifentanil caused less respiratory depression and was associated with a lower incidence of nausea and vomiting, compared with sufentanil.

Remifentanil given along with propofol has been studied in patients spontaneously breathing via a laryngeal mask.6 7 These studies showed that the remifentanil doses required for general anaesthesia under propofol are not compatible with spontaneous ventilation. A technique with ventilation is more appropriate with this potent combination of respiratory depressant drugs. Only a few studies have used remifentanil alone in spontaneously breathing patients. Getsztesi and colleagues8 compared remifentanil with other opioids during ESWL in spontaneously breathing patients without any airway protection and showed that more patients had low respiratory frequencies with remifentanil, but they obtained analgesia without any major respiratory depression. However, propofol was also given in this study.8 In the same way, remifentanil provided adequate analgesia for ambulatory surgery without any respiratory depression at a dose of 1 µg kg–1 followed by a continuous infusion of 0.1 µg kg–1 min–1.9 However, in this study an injection of local anaesthetic was required to perform the surgery.9 To our knowledge, remifentanil has never been studied previously as a single agent for spontaneously breathing patients. Moreover, the manufacturer does not recommend using remifentanil during spontaneous ventilation. In healthy volunteers, remifentanil reduced the slope of the ventilatory response to carbon dioxide and the maximum ventilatory depression occurs 2.5 min after a single loading dose of 0.5 µg kg–1.10 The onset of respiratory depression appears to be more rapid than the onset of remifentanil-induced electroencephalographic slowing,11 so patients could be apnoeic but awake. In our study, we started the infusion of remifentanil 1 or 2 min before ESWL, so the peak effect of drug on ventilation and pain coincided with the stimulation of surgery, and this probably limited the occurrence of respiratory depression. Premedication with hydroxizine may have also contributed to the moderate respiratory depression observed in our study.

Compared with previous studies, we used lower doses of remifentanil (0.025 µg kg–1), which provided adequate analgesia for ESWL, which is not a very painful procedure. The doses allowed the prevention of intraoperative respiratory depression. Moreover, ESWL is not painful postoperatively. Remifentanil is the ideal opioid for this because its short half-life avoids adverse effects, including respiratory depression after the procedure time. The quality of analgesia provided was satisfactory for the patients and the surgeons. Less nausea and vomiting seen with remifentanil (Table 2) have not been described before to our knowledge, this is a clear advantage.

A potential shortcoming of our study is that we did not determine the ventilatory response to oxygen and carbon dioxide unlike Babenco and colleagues10 in their study in healthy volunteers. We chose ESWL, because even if it is only mildly painful, it is an interesting ‘model’ of surgery, which is only painful during the intraoperative period. In fact, a modern system of ESWL installed in our hospital is not painful and no analgesia is now required. Nevertheless, the doses needed to obtain pain relief in our study were not negligible: 10–40 µg for sufentanil and 47–625 µg for remifentanil. Remifentanil has been recently advocated for short procedures such as minor gynaecological surgery,11 prostatic and vesical biopsies,12 breast biopsies,13 and coronary percutaneous revascularization.14 Although, we did not observe any severe adverse events, the power of our study to detect these is severely limited by the small sample and larger studies are needed to establish safety.

In summary, we found that, remifentanil used in equi-analgesic doses caused less respiratory depression after the procedure than sufentanil when used for ESWL. We suggest that remifentanil is useful for this type of surgery (not painful after the procedure) and will reduce or even avoid stay in the PACU.


    References
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 Introduction
 Methods
 Results
 Discussion
 References
 
1 Glass PS, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil. Anesth Analg 1993; 77: 1031–40[Abstract]

2 Kapila A, Glass PSA, Jacobs JR, et al. Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995; 83: 968–75[ISI][Medline]

3 Westmoreland CL, Hoke JF, Sebel PS, Hug CC, Muir KT. Pharmacokinetics of remifentanil and its major metabolite in patients undergoing elective inpatient surgery. Anesthesiology 1993; 79: 893–903[ISI][Medline]

4 Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg 1970; 49: 924–34.[Medline]

5 Casagrande JT, Pike MC. An improved approximate formula for calculating sample sizes for comparing two binomial distributions. Biometrics 1978; 34: 483–6[ISI][Medline]

6 Peacock JE, Luntley JB, O’Connor B, et al. Remifentanil in combination with propofol for spontaneous ventilation anaesthesia. Br J Anaesth 1998; 80: 509–11[ISI][Medline]

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8 Gesztesi Z, Sa Rego M, White PF. The comparative effetiveness of fentanyl and its newer analogs during extracorporeal shock wave lithotripsy under monitored anesthesia care. Anesth Analg 2000; 90: 567–70[Free Full Text]

9 Gold MI, Watkins D, Sung YF, et al. Remifentanil versus remifentanil/midazolam for ambulatory surgery during monitored anesthesia care. Anesthesiology 1997; 87: 51–7[ISI][Medline]

10 Babenco HD, Conard PF, Gross JB. The pharmacodynamic effect of a remifentanil bolus on ventilatory control. Anesthesiology 2000; 92: 393–8[ISI][Medline]

11 Egan TD, Minto CF, Hermann DJ, Barr J, Muir KT, Shafer SL. Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology 1996; 84: 821–33[ISI][Medline]

12 Tablov V, Tablov B, Partenov P. Analgesia with remifentanil or remifentanil/midazolam for minor gynaecological surgery: efficacy and patient comfort. Eur J Anaesthesiol 2001; 18 (Suppl 21): 14(Abstract)

13 Drogheti L, Zopellari R, Morghen I, Forini E. Remifentanil in pump vs. alfentanil in bolus in outpatient anaesthesia. Eur J Anaesthesiol 2001; 18 (Suppl 21): 14(Abstract)

14 Unlügenç H, Ozalevli M, Güler T, Isik G. Comparison of different dosages of remifentanil administration during brief painful procedures. Eur J Anaesthesiol 2001; 18 (Suppl 21): 15(Abstract)

15 Robert A, Forestier F, Soubiron L, Domblides N, Janvier G. Conscious sedation with remifentanil during coronary atherectomy. Eur J Anaesthesiol 2001; 18 (Suppl 21): 90(Abstract)[ISI]