Midazolam/ketamine sedative combination compared with fentanyl/propofol/isoflurane anaesthesia for oocyte retrieval

Izhar Ben-Shlomo1,3, Roland Moskovich2, Yeshayahu Katz2,3,4 and Eliezer Shalev1,3

1 Department of Obstetrics and Gynecology, 2 Department of Anesthesiology, HaEmek Medical Centre, Afula, and 3 Rappaport School of Medicine, Technion–Israel Institute of Technology, Haifa, Israel


    Abstract
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 Abstract
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 Materials and methods
 Results
 Discussion
 References
 
Assisted reproduction may be associated with repeated occasions of surgical intervention. Propofol, which is frequently used for induction of anaesthesia in such procedures, has been suspected of damaging oocytes. We compared in a randomized prospective design the use of general anaesthesia with fentanyl 0.017 mg/kg, propofol 2.5 mg/kg and isoflurane to that of sedation with midazolam 0.06 mg/kg and ketamine 0.75 mg/kg for transvaginal oocyte retrieval in 50 patients with no premedication. Overall, patient satisfaction was not different between the groups. Sedated patients were more arousable than anaesthetized patients during the procedure and experienced less postoperative abdominal pain at 30 min. Despite some movement in response to pain, oocyte retrieval was conveniently feasible in all sedated patients, of which none required a switch to general anaesthesia. A comparable number of oocytes was retrieved per cycle, 10.8 (±7.8) versus 9.6 (±10.9) with sedation and anaesthesia respectively. No patient recalled any pain sensation during the procedure. The rate of embryo transfers and pregnancies were not different between the two groups. We conclude that the sedative combination of midazolam and ketamine for oocyte retrieval may serve as an alternative for general anaesthesia.

Key words: assisted reproduction/general anaesthesia/oocyte retrieval/sedation


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Women who undergo assisted reproduction treatment, with its attendant oocyte retrieval, may be subjected on several occasions to anaesthesia. Hence it is imperative to define forms of anaesthesia/analgesia that minimize drug administration and unwanted effects. Not less important for the patient is to have a positive experience with the anaesthetic/analgesic regimen, in order to reduce procedure-associated stress in future occasions.

Several forms of pain control have been reported as useful for transvaginal oocyte retrieval. Among these were: (i) general anaesthesia, induced with intravenous agents and maintained with inhalation agents (van der Ven et al., 1988Go); (ii) epidural anaesthesia (Botta et al., 1995Go); (iii) local anaesthesia (Wikland et al., 1990Go; Batzer et al., 1994Go; Christiaens et al., 1998Go); and (iv) sedation, either by intramuscular or intravenous administration (Ben-Shlomo et al., 1992Go; Trout et al., 1998Go).

Throughout the years, attention has been devoted to possible detrimental effects of anaesthetic and analgesic agents on the results of assisted reproductive treatment. In this regard, concentrations of the specific agents have been measured in the aspirated follicular fluid (Wikland et al., 1990Go; Coetsier et al., 1992Go; Soussis et al., 1995Go) and more direct observations tested possible toxicity in animal models (Janssenswillen et al., 1997Go). Propofol is chemically unrelated to earlier anaesthetic drugs. This highly lipophilic agent has a fast onset and short, predictable duration of action due to its rapid penetration of the blood–brain barrier and distribution to the central nervous system (Kanto and Gepts, 1989Go). It is very popular for a host of ambulatory procedures including oocyte retrieval (Coetsier et al., 1992Go). Although some reports have not found any detrimental effect of propofol on assisted reproductive treatment outcome, a recent report challenged its safety (Tatone et al., 1998Go). Our standard regimen for anaesthesia in women undergoing oocyte retrieval has been a combination of fentanyl with propofol and maintenance by isoflurane inhalation.

Sedation with a combination of midazolam and ketamine was found useful for pain control in several operative procedures (Rosenberg et al., 1995Go; Moscona et al., 1995Go). Therefore, we decided to compare prospectively the applicability of sedation with midazolam/ketamine combination in oocyte retrieval procedures with that of our standard protocol. We evaluated objective outcome measures as well as patients' satisfaction.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study group included 50 healthy American Society of Anesthesiologists Risk Classification (ASA I-II) women with no premedication scheduled for oocyte retrieval. Since both regimens are standard forms of drug administration, Institutional Review Board approval was not sought. However, the patients' consent was requested and five refused to participate. Patients were randomized to one of two regimens by random numbers, sealed in consecutive envelopes. The general anaesthesia protocol consisted of i.v. fentanyl 0.017 mg/kg followed after 2 min by i.v. propofol 2.5 mg/kg. Assisted ventilation with isoflurane was begun as soon as eyelash response was lost. The sedative protocol consisted of i.v. midazolam 0.06 mg/kg followed after 2 min by ketamine 0.75 mg/kg. The following variables were recorded for each case: patient's age and weight; initial and maximal heart rate; oxygen saturation as measured by pulse oximetry; arousability on a scale of 0–3 as estimated by the anaesthesiologist (0: no response to calling the patient's name; 3: fully coherent response); response to the painful stimulus of the oocyte retrieval procedure on a scale of 0–3 as jointly estimated by the anaesthesiologist and the gynaecologist (0: no response; 3: active withdrawal with a verbal element); patient's arousability after 10 min on a scale of 0–3; patient's subjective pain sensation after 30 min on a scale of 0–3 (0: none; 3: severe); and patient's overall satisfaction and willingness to undergo the same method of anaesthesia/sedation on future procedures, if needed.

Outcome parameters, recorded for assisted reproductive treatment, were: number of oocytes retrieved, fertilization rate, cleavage rate and clinical pregnancy.

Statistical analysis involved Student's t-test as applicable.


    Results
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 Abstract
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 Materials and methods
 Results
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Patients' age and weight did not differ significantly between the two groups. Mean age was 34.2 ± 5.6 in the anaesthesia group and 34.2 ± 6.5 (SD) years in the sedation group. Mean weight was 69.1 ± 13.3 kg versus 61.6 ± 10.7 in the anaesthesia and sedation groups respectively. Anaesthesia-related parameters evaluated during the procedures are summarized in Table IGo. It is notable that anaesthesia caused a significant (P < 0.001) decrease in oxygen saturation, whereas sedation did not prevent stress-related slight baseline tachycardia. The higher score of response to the pain incited by oocyte retrieval, while significant (P < 0.001), was not significantly high to render it unacceptable and therefore to dictate the need for general anaesthesia. With regard to the subjective parameters, abdominal pain 30 min after the operation was scored 2.1 ± 0.7 in the anaesthesia group as compared to 0.2 ± 0.5 in the sedation group (P < 0.001). In the anaesthesia group five patients requested postoperative pain relief by dipyron, compared to none in the sedation group. There were four cases of postoperative vomiting in the sedation group compared to two in the anaesthesia group. One patient rated her overall experience with the sedation as very bad and would not agree to the same method in the future; all other patients in both groups were satisfied with the modality of pain relief they received and would have agreed to receive the same in future procedures. Seven patients in the sedation group who experienced anaesthesia in the past replied that in the future they would prefer sedation.


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Table I. Anaesthesia-related parameters in two groups of patients undergoing oocyte retrieval for assisted reproductive treatment
 
Assisted reproductive treatment outcome parameters are detailed in Table IIGo. It is notable that the only difference between the two groups was in the mean number of embryos transferred.


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Table II. Treatment outcome parameters in two groups of patients undergoing oocyte retrieval for assisted reproductive treatment
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this randomized prospective study of two alternatives for pain control during oocyte retrieval for assisted reproduction we found that sedation with a combination of midazolam and ketamine is comparable to full anaesthesia by fentanyl, propofol and isoflurane. Sedation is but one option for pain control during oocyte retrieval. Nevertheless, if well accepted by patients, it is the least drastic means for this purpose. It has been used either with local, paracervical block or alone (Ben-Shlomo et al., 1992Go; Soussis et al., 1995Go). In this regard, in our patient population the recommendation for use of local anaesthesia alone is rarely accepted (Christiaens et al., 1998Go). Hence, we did not attempt to compare it with the other two options. In a recent review (Trout et al., 1998Go), it was suggested that sedation could even be used without the attendance of an anaesthetist. The specific sedative combination of midazolam and ketamine has been used in several clinical settings. In rhinoplasty, a combination of midazolam 0.1 mg/kg with ketamine 0.5 mg/kg was shown to be effective and superior to midazolam alone (Moscona et al., 1995Go). It was also used successfully in ophthalmic peribulbar surgery (Rosenberg et al., 1995Go) and in routine gynaecologic care for mentally handicapped individuals (Rosen et al., 1991Go). However, this specific combination was not evaluated previously for pain control in oocyte retrieval.

Although significant, the differences that we observed in oxygen saturation and heart rate alterations between the sedation and anaesthesia protocol are not of much clinical importance, due to their short duration. In itself, pain-induced slight tachycardia could be considered a disadvantage in older patients, but assisted reproduction patients are uniformly young. At the same time, tachycardia has been attributed to ketamine's effect, and does not necessarily reflect a response to pain (Morgan and Mikhail, 1996Go). What is clinically significant is the avoidance of anaesthesia with its inherent risk of occasional aspiration, which is significantly increased when oestrogen concentrations are high such as during ovarian stimulation. Since some degree of nausea and vomiting is inevitable, the regimen for sedation imposes less risk for aspiration owing to partial consciousness. In this regard, a combination with propofol has an inherent advantage due to its anti-emetic property. Such an advantage is admittedly of considerable value in simplifying postoperative care.

An additional aspect of sedation is the patients' perception that they are not undergoing general anaesthesia. It is also significant that patients reported much less abdominal pain after the use of sedation as compared to general anaesthesia. It is possible that the short-acting analgesic fentanyl used in the anaesthetic combination lacks enough residual analgesic effect to provide postoperative pain relief, whereas the combination of midazolam and ketamine does.

The number of patients allocated to each group in this study was designed to compare two methods for pain control and not to evaluate possible detrimental effect on in-vitro outcome parameters. Nevertheless, our results in both groups compare to a previously reported outcome with anaesthesia using propofol (Tontisirin et al., 1996Go). The degree of toxicity of propofol to human oocytes is still debated (Palot et al., 1988Go; Tontisirin et al., 1996Go; Alsalili et al, 1997Go; Janssenswillen et al., 1997Go). It may be of some advantage to use alternative anaesthetic/analgesic forms, even if not yet proven safe, until future studies clarify this issue. In conclusion, the sedative combination of midazolam with ketamine for oocyte retrieval in assisted reproduction is at least comparable to general anaesthesia with fentanyl, propofol and isoflurane.


    Notes
 
4 To whom correspondence should be addressed at: Department of Anaesthesiology, HaEmek Medical Center, Afula 18101, Israel Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on October 19, 1999; accepted on March 30, 1999.