|Year : 2016 | Volume
| Issue : 1 | Page : 116-121
Pregabalin versus bromazepam as a sedative in embryo transfer during in-vitro fertilization
Eman M Kamal Aboseif, Dalia M Elfawy MD , Niven Gerges
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||01-Jun-2015|
|Date of Acceptance||02-Oct-2015|
|Date of Web Publication||17-Mar-2016|
Dalia M Elfawy
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
The majority of infertile women are young and healthy but exhibit stress, anxiety, and other psychological disorders associated with infertility. This anxiety should be attenuated with appropriate drugs during premedication. Moreover, after the procedure, patients report visceral pain resulting from cervical manipulation, which should be relieved with appropriate analgesia.
The aim of this study was to evaluate and compare the clinical efficacy of oral premedication with pregabalin and bromazepam for sedation in terms of effectiveness and postoperative analgesia in patients undergoing embryo transfer during in-vitro fertilization (IVF).
Patients and methods
A total of 60 healthy infertile consented female patients younger than 39 years with ASA physical status I or II who were scheduled for embryo transfer during IVF were randomized to receive either pregabalin (300 mg) (group A), bromazepam (3 mg) (group B), or placebo (folic acid 0.5 mg) (group C) 90 min before surgery as oral premedication. The Ramsay sedation scale was used to evaluate preoperative sedation. Hemodynamic data were recorded before premedication, just after induction, after recovery, and 2 and 4 h postoperatively. Severity of postoperative pain was assessed using a visual analogue scale (VAS).
Perioperative sedation levels were lighter in the pregabalin group than in the bromazepam group, as there were statistically significant differences in terms of attenuation in mean arterial blood pressure and heart rate. Moreover, VAS score was significantly lower in the pregabalin group at induction, recovery, and 2 and 4 h after surgery.
This study showed that the use of pregabalin 300 mg or bromazepam 3 mg causes good preoperative sedation with hemodynamic stability intraoperatively together with decreasing postoperative pain in embryo transfer during IVF procedure.
Keywords: bromazepam, embryo transfer, pregabalin, premedication
|How to cite this article:|
Kamal Aboseif EM, Elfawy DM, Gerges N. Pregabalin versus bromazepam as a sedative in embryo transfer during in-vitro fertilization
. Ain-Shams J Anaesthesiol 2016;9:116-21
|How to cite this URL:|
Kamal Aboseif EM, Elfawy DM, Gerges N. Pregabalin versus bromazepam as a sedative in embryo transfer during in-vitro fertilization
. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 Apr 14];9:116-21. Available from: http://www.asja.eg.net/text.asp?2016/9/1/116/178890
| Introduction|| |
The majority of infertile women are young and healthy but exhibit stress, anxiety, and other psychological disorders associated with infertility. It is particularly important for the anesthesiologist to understand the patient's anxieties and take suitable measures to allay it. The serum hyperprolactinemic response to stress is well established  . Transient increase in serum prolactin levels during oocyte retrieval for in-vitro fertilization (IVF) has been reported under general anesthesia and may influence the outcome of IVF  . The need for repeated attempts of IVF before success is achieved also mandates taking care of psychological stress and alleviating it. The IVF procedures are also associated with pain and hence the need for minimization of pain is a major consideration  . The cooperation of patient is required during IVF procedure such as oocyte retrieval, which sometimes mandates the need for even anesthesia.
Embryo transfer is the final step in the IVF treatment process. It is also the last step in which clinical manipulation may directly affect the outcome of the assisted reproduction treatment cycle. The majority of patients undergoing IVF will reach the transfer stage with good quality embryos available for transfer, but only a small proportion of them will ever achieve a clinical pregnancy. It is estimated that up to 85% of the embryos replaced into the uterine cavity will fail to implant  . The pregnancy rate following embryo transfer is generally dependent upon multiple factors, including embryo quality, endometrial receptivity, and the technique of the embryo transfer itself  .
One important aspect of the embryo transfer technique that has received limited attention is the use of sedation or anesthesia during difficult embryo transfers. Whether sedation during embryo transfer could have a potential impact on conception is not clear from the medical literature. This issue was not even mentioned as an important variable that might affect the outcome of embryo transfer in two recent reviews of the literature , . Even so, it is clear from a recent systematic review and meta-analysis that difficult embryo transfer is associated with a significant drop in implantation rate when compared with 'easy' transfers (odds ratio = 0.64, 95% confidence interval = 0.52-0.77)  .
In the medical literature, there is conflicting evidence on the impact of different anesthetic agents used during oocyte retrieval on pregnancy rates following embryo transfer  . Moreover, only a few studies have discussed the impact of general anesthesia during the embryo transfer procedure on implantation and clinical pregnancy rates  .
The present study aimed to evaluate and compare the clinical effect of oral premedication with pregabalin and bromazepam on stress response, level of sedation, and postoperative analgesic consumption during embryo transfer procedures.
| Patients and methods|| |
This is a prospective double-blind randomized study conducted in Ain-Shams University Hospitals during the period from January 2014 to January 2015 on 60 patients of ASA physical status I or II scheduled for elective ultrasound-guided embryo transfer during IVF. The study was conducted after approval from the Medical Ethics Committee of Ain-Shams University Hospital and obtaining informed consent from subfertile couples undergoing embryo transfer under sedation. In this randomized parallel prospective double-blinded study, the inclusion criteria were as follows: age younger than 39 years, normal hormonal profile, and difficulty in cannulating the cervix during embryo transfer. Patients were randomized (using a computer-generated randomization list and opening sequentially numbered opaque envelopes immediately before entering the operating room) into one of the three groups according to the premedication drug given to the patients 90 min before entering the operating room and start of the procedure:
Exclusion criteria were as follows: anticipated difficult intubation, morbid obesity, arrhythmia, severe uncontrolled hypertension, known drug allergy to the used drug, history of receiving any sedative hypnotics, chronic strong analgesic use, or undergoing antidepressant treatment.
- Group A (20 patients) received pregabalin (lyrica 300 mg) oral capsule.
- Group B (20 patients) received bromazepam (calmepam 3 mg) oral tablet.
- Group C (20 patients) received placebo (folic acid 0.5 mg) oral tablet.
Routine monitors were attached to all patients just after arriving to the operating theater in the form of five-lead ECG, noninvasive blood pressure, and oxygen saturation after insertion of a 20-G intravenous cannula.
Embryo transfer was performed according to the standard procedure used in our center. In general, embryo transfer was performed 48-72 h after oocyte pick-up using the Wallace catheter (H. G. Wallace Ltd, West Sussex, UK). In both groups, the embryo transfer was performed at the lithotomy position. The previously taken ultrasound picture of the uterus and dummy embryo transfer were revised to get an idea of the length and direction of the uterine cavity. After performing the dummy embryo transfer, the embryos were loaded into a new catheter, either Wallace or Cook according to the dummy embryo transfer, as follows. The embryo transfer catheter was rinsed and then filled with tissue culture medium. About 10-20 ml of tissue culture medium was aspirated, and then the embryos (up to three) were aspirated in 10-20 ml tissue culture medium so that the embryos would be away from the tip of the catheter.
Each patient's vital parameters, including heart rate, mean systemic arterial blood pressure, and arterial oxygen saturation, were measured and recorded.
The Ramsay sedation scale is defined as follows  .
The Ramsay sedation scale was used to assess sedation score in all groups before the drug was taken, at the start of the procedure, and at recovery. Complications in the form of failure of analgesia were treated with intravenous fentanyl (0.5 μg/kg) when signs of inadequate sedation and analgesia (>20% increase in the heart rate and mean arterial blood pressure from the baseline) were observed. Hypotension (decreased systolic blood pressure below 90 mmHg or decreased mean blood pressure more than 20% from baseline measurement) and bradycardia (defined as heart rate slower than 50 beats/min) were treated with 0.5 mg intravenous atropine.
- Awake patient anxious or agitated.
- Patient cooperative, oriented tranquil, or both.
- Patient responds to commands only.
- A brisk response to a light glabellar tap.
- A sluggish response to a light glabellar tap.
- No response.
Patients were transferred to the postanesthesia care unit (PACU) and monitored. The severity of postoperative pain was assessed using a visual analogue scale (VAS), ranging from 0, no pain, to 10, worst imaginable pain. VAS assessment was carried out on arrival to the PACU (1 = 0 min time), at 30 min in the PACU, and 2 and 4 h postoperatively.
Postoperative analgesics required were also recorded, when VAS was greater than 4, in the form of Profeind (ketoprofene 100 mg) rectal suppository.
In a one-way analysis of variance study, sample sizes of 18, 18, and 18 were obtained from the three groups. A sample size of 54 individuals achieves 80% power to detect difference in the Ramsey Sedation Scale of 2 using an F-test with a 0.05000 significance level. The size of the variation in the means is represented by their SD, which is 1.63. The common SD within a group is assumed to be 3.75. PASS 13 (NCSS, LLC,USA) was used for sample size calculation. Twenty patients per group were included to replace dropouts.
Statistical analysis was carried out on a personal computer using the Statistical Package for Social Sciences, version 16.0 (SPSS© v. 16.0; SPSS Inc., Chicago, Illinois, USA).
Data were analyzed using SPSS 18.0 for Windows (SPSS Inc.). Analysis of variance was used to compare the three groups for quantitative parametric data with the post-hoc Scheffe test. The Kruskal-Wallis test was used for quantitative nonparametric data. The χ2 -test was used for comparison of qualitative data. Continuous parametric data were presented as mean ± SD, nonparametric data as median (interquartile range), and categorical data were presented as number of patients. P values less than 0.05 were considered statistically significant.
| Results|| |
The three groups were comparable with respect to age, weight, recovery time, infertility period, and pregnancy rate after the procedure [Table 1], and there were no statistically significant differences among the three groups with regard to preoperative clinical data.
A significant increase in sedation scale without respiratory depression was observed in both premedicated groups when compared with baseline sedation level and the control group. Preoperative anxiolysis and sedation were higher in the oral pregabalin group (group A) compared with the oral bromazepam group (group B), but the difference was statistically nonsignificant. However, there was a significant increase in sedation score in group A at recovery in comparison with the other two groups [Table 2] and [Figure 1].
|Figure 1: The Ramsey Sedation Scale (RSS): The middle line in each box represents the median, the outer margins of the box represent the interquartile range, and the whiskers represent minimum and maximum.|
*Represents the number of the patient with outlier data in each group.
Click here to view
A statistically significant decrease in the mean arterial pressure was noticed and maintained stable within 20% of baseline value during the procedure in the premedicated groups. In contrast, it was higher in the control group, and the maximum rise in mean arterial pressure was noted on introducing the US probe (*P < 0.01) [Table 3].
A statistically significant decrease in the heart rate was noticed and maintained acceptable and stable during the procedure in group A (*P < 0.01) [Table 4].
The incidence of postoperative dizziness in group A was higher (six patients; 30%) than that in group B (two patients; 10%), and there was no dizziness observed in any patient in group C (0%). This result was statistically significant.
Postoperative mean VAS for pain assessment showed a significant decrease in group A in comparison with other two groups at 2 and 4 h time intervals, and there was a significant difference between groups A and B and group C at 0 and 30 min [Table 5] and [Figure 2].
|Figure 2: Visual analogue scale (VAS): The middle line in each box represents the median, the outer margins of the box represent the interquartile range, and whiskers represent minimum and maximum. PACU, postanesthesia care unit. *Represents the number of the patient with outlier data in each group|
Click here to view
Postoperative analgesic consumption during the first 4 h showed more significant decrease in group A than in the other two groups [Table 6].
| Discussion|| |
Embryo transfer is the final and most crucial step in IVF. Patients experiencing difficult embryo transfer are not uncommon in daily practice, especially in large infertility centers. In general, difficultly in threading the cervix occurs in about 5% of all embryo transfers  . Several techniques have been discussed as ways of bypassing the unrelenting cervix. These include the use of cervical dilatation using dilators  or hygroscopic rods  , cervical shaving to widen the cervical canal in cases of cervical stenosis  , and the use of instrumental assistance during the embryo transfer, such as tenaculums, sounding, or dilatation. As a last resort, some authors prefer to use transmyometrial embryo transfer to deposit the embryos in the uterine cavity  . Even though these techniques may assist the clinician in reaching the endometrial cavity, they also carry associated risks, including stimulating uterine contractions, cervical and endometrial injuries and lacerations, increase in the presence of blood on the catheter tip and cervix, and, most importantly, cumulative decrease in clinical pregnancy and implantation rates  .
The present study evaluated the clinical effect of oral premedication with pregabalin or bromazepam on preoperative sedation, hemodynamic stability, and postoperative analgesic requirement during embryo transfer procedure.
In the present study, we used pregabalin 300 mg and did not use the smaller doses to achieve effective sedation and decreased postoperative analgesic consumption.
Although midazolam is the most commonly used sedative agent in IVF, minimal amount of this benzodiazipine is found in follicular fluid, no detrimental effects have been proven so far. A combination of midazolam and fentanyl was found to be safe for oocyte retrieval  .
A dose-ranging study conducted by Baidya et al.  found that, in the pregabalin 300 mg group, sedation scores were higher compared with the control group during the preinduction period and at 90 and 120 min postoperatively. Pregabalin exhibits a significant opioid-sparing effect during the first 24 h and a significant reduction in opioid-related adverse effects (vomiting).
The Ramsay sedation scale was higher without any sign of respiratory depression and without prolonged recovery times in group A compared with group B. However, the difference between the two groups was statistically nonsignificant.
Gupta et al.  evaluated the clinical efficacy of oral premedication with pregabalin (150 mg) and clonidine (200 μg) using 10-cm VAS for sedation (fully awake to extremely drowsy) and for anxiety scale (fully calm to worst possible anxiety). A clear increase in sedation (>6 cm) and a moderate decrease in anxiety (2.4-3.6 cm) were observed in both premedicated groups as compared with the control group. Preoperative anxiolysis and sedation were higher in the oral pregabalin group (group II) compared with the clonidine group (group III). Moreover, there was no statistically significant difference among groups with regard to recovery time. These results are in agreement with that reported in the current study despite the smaller dose of pregabalin (150 mg) used by Gupta and colleagues. Baidya et al.  found that, in the pregabalin 300 mg group, sedation scores were higher compared with the control group during the preinduction period and at 90 and 120 min postoperatively.
This may be explained by a novel mechanism of action of pregabalin as it binds potently and selectively to the α-2-d subunit of 'hyperexcited' voltage-gated calcium channels, which changes their conformation, reducing calcium influx at nerve terminals. Pregabalin only modulates the release of excitatory neurotransmitters in 'hyperexcited' neurons, restoring them to normal physiological state. This newly defined mechanism of action is believed to confer on pregabalin its anxiolytic, analgesic, and anticonvulsant properties  .
Neither pregabalin nor bromazepam prolonged recovery times, although they are well known for their sedative properties. This may be explained by the concomitant intraoperative anesthetic-sparing effects  .
The present study showed a significant decrease in postoperative pain scores in most times of measurement in both the pregabalin and bromazepam groups, as well a significant decrease in analgesic consumption postoperatively. Many patients required only single dose (30 ± 4.5 mg). These results of postoperative pain control coincide with the results obtained by Blaudszun et al.  and Przesmycki et al.  .
The present study showed no significant difference between the three groups as regards rate of pregnancy. This concludes that there is no evidence from our data that the administration of pregabalin or bromazepam during the procedure of embryo transfer had a negative impact on the embryos as measured by probability of a clinical pregnancy. Therefore, sedation may offer clinicians a complementary measure when dealing with a difficult embryo transfer. Even so, adequately powered randomized controlled trials are needed to confirm our findings. This is in agreement with the findings of Abou-Setta et al.  , who stated that there was no statistically significant difference in implantation or clinical pregnancy rates when they used propofol anesthesia during embryo transfer.
| Conclusion and recommendations|| |
This study showed that the use of oral premedication either with pregabalin 300 mg or bromazepam 3 mg versus placebo causes good preoperative sedation with hemodynamic stability intraoperatively together with decreasing postoperative pain and analgesic consumption in patients undergoing embryo transfer during IVF procedure.
Role : All three authors: Eman M. Kamal Aboseif, Dalia M. Elfawy, and Niven Gerges helped design the study, conduct the study, and write the manuscript.
Attestation: Eman M. Kamal Aboseif, Dalia M. Elfawy, and Niven Gerges have seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Niven Gerges is the author responsible for archiving the study files.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Forman RG, Fischel SB, Edwards RG, Walters E. The influence of transient hyperprolactinaemia on in vitro
fertilization in humans. J Clin Endocrinol Metab 1985; 60:517-522.
Robinson JN, Forman RG, Lockwood GM, Hickey JB, Chapman MG, Barlow DH. A comparison of the transient hyperprolactinaemic stress response obtained using two different methods of analgesia for ultrasound-guided transvaginal oocyte retrieval. Hum Reprod 1991; 6:1291-1293.
Stener-Victorin E. The pain-relieving effect of electro-acupuncture and conventional medical analgesic methods during oocyte retrieval: a systemic review of randomized controlled trials. Hum Reprod 2005; 20:339-349.
Edwards RG. Clinical approaches to increasing uterine receptivity during human implantation. Hum Reprod 1995; 10:60-66.
Mansour RT, Aboulghar MA. Optimizing the embryo transfer technique. Hum Reprod 2002; 17:1149-1153.
Schoolcraft WB, Surrey ES, Gardner DK. Embryo transfer: techniques and variables affecting success. Fertil Steril 2001; 76:863-870.
Sallam H, Sameh S, Sadek S, Agameya A. Does a difficult embryo transfer affect the results of IVF and ICSI? A meta-analysis of controlled studies. Fertil Steril 2003; 80:127.
Ben-Shlomo I, Moskovich R, Golan J, Eyali V, Tabak A, Shalev E. The effect of propofol anesthesia on oocyte fertilization and early embryo quality. Hum Reprod 2000; 15:2197-2199.
Diedrich K, van der Ven H, al-Hasani S, Krebs D. Establishment of pregnancy related to embryo transfer techniques after in-vitro
fertilization. Hum Reprod 1989; 4:111-114.
Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2:656-659.
Abusheikha N, Lass A, Akagbosu F, Brinsden P. How useful is cervical dilatation in patients with cervical stenosis who are participating in an in vitro
fertilizationembryo ransfer program? The Bourn Hall experience. Fertil Steril 1999; 72:610-612.
Serhal P, Ranieri DM, Khadum I, Wakim RA. Cervical dilatation with hygroscopic rods prior to ovarian stimulation facilitates embryo transfer. Hum Reprod 2003; 18:2618-2620.
Noyes N. Hysteroscopic cervical canal shaving: a new therapy for cervical stenosis before embryo transfer in patients undergoing in vitro
fertilization. Fertil Steril 1999; 71:965-966.
Sharif K, Afnan M, Lenton W, Bilalis D, Hunjan M, Khalaf Y. Transmyometrial embryo transfer after difficult immediate mock transcervical transfer. Fertil Steril 1996; 65:1071-1074.
Lesny P, Killick SR, Tetlow RL, Robinson J, Maguiness SD. Embryo transfer-can we learn anything new from the observation of junctional zone contractions?. Hum Reprod 1998; 13:1540-1546.
Trout SW, Vallenand AH, Kemmann E. Conscious sedation for in vitro
fertilization. Fertil Steril 1998; 69:799-808.
Baidya DK, Agarwal A, Khanna P, et al.
Pregabalin in acute and chronic pain. J Anaesthesiol Clin Pharmacol 2011; 27:307-314.
Gupta K, Sharma D, Gupta P. Oral premedication with pregabalin or clonidine for hemodynamic stability during laryngoscopy and laparoscopic cholecystectomy: a comparative evaluation. Saudi J Anaesth 2011; 5: 179-184.
Kavoussi R. Pregabalin: from molecule to medicine. Eur Neuropsychopharmacol 2006; 16:128-133.
Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology 2012; 116:1312-1322.
Przesmycki K, Wiater-Koziol E, Kotarski J, Czuczwar M, Jaskowiak R, et al.
Effect of pre-emptive pregabalin on pain intensity and morphine requirement after hysterectomy. Anestezjol Intens Ter 2011; 43:14-17.
Abou-Setta M, Mansour T, Al-Inany G. Difficult embryo transfer: the impact of propofol anesthesia. Middle East Fertil Soc J 2007; 12:96-101.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]