Various types of anesthetic techniques were described for oocyte recovery. Different anesthetic agents have been used with different effects on oocyte quality and embryonic development and studies on the potential toxicity of general anesthesia ended up with conflicting results. Many experiments as well as human studies documented the existence of anesthetic agents in the follicular fluid (FF) with possible adverse effects on the oocyte quality and subsequent embryo development. Ketamine and remifentanil were used for the studied groups to compare oocytes and embryos characteristic of infertile women during oocytes retrieval under general anesthesia: one group receiving ketamine, midazolam, and propofol and the other group receiving remifentanil, midazolam and propofol. 60 infertile females were undergoing intracytoplasmic sperm injection categorized in two groups, group I received midazolam, remifentanil and propofol; whereas, group II received midazolam, ketamine and propofol. There was highly significant difference in mean abnormal oocyte between ketamine and remifentanil groups. Grade III embryos were significantly limited to ketamine group. FF ketamine and remifentanil were not significantly correlated to any of oocyte characteristics or embryo characteristics. Anesthetic agents, ketamine and remifentanil, were detected in the FF of infertile women and within recommended doses. Ketamine resulted in adverse effects on oocyte and embryo quality in comparison with remifentanil represented by greater percentage of abnormal oocytes and that bad quality embryos were limited to ketamine group.

Ketamine; Remifentanil; General anesthesia; Oocyte retrieval; Oocyte and embryo quality; ICSI

A significant proportion of couples worldwide are going to face the problem of infertility. For instance, about 10-15 % of couples worldwide had the experience of infertility (Moridi, et al. ‎^[1]). One of the highly advanced and recently introduced treatment approaches in infertility management is in vitro fertilization (IVF) (Sharma, et al. ^‎[2]). This technique involves the aspiration of mature oocytes from the infertile women's ovaries. In vitro fertilization of these oocytes is subsequently carried out and the developing embryo is eventually transferred to the infertile woman's uterus (Vlahos, et al. ‎^[3]). The harvesting of oocytes is one of the most important aspects of the IVF cycle, as oocyte quality affects fertilization, embryo quality, and implantation (Tola, EN. ^‎[4]). The process is very painful and stressful as the pain is caused by the passage of the needle through the vaginal wall and by the manipulation of the ovary mechanically (Kwan, et al. ^‎[5]; Oliveira Júnior, et al. ‎^[6]; Rolland, et al. ^‎[7]). Therefore, managing anxiety and pain when retrieving oocytes makes anesthesia an integral part of the IVF procedure (Urfalioglu and Yaylali ‎^[8]). Various types of anesthetic techniques described for oocyte recovery include neuraxial anesthesia (spinal or epidural), general anesthesia, regional block techniques (paracervical/preovarian block), conscious sedation, and electro-acupuncture or any combination of the above (Rolland, et al. ‎^[7]; Urfalioglu and Yaylali ^‎[8]; Bümen, et al. ‎^[9]; Goutziomitrou, et al. ‎^[10]; Vasudevan, et al. ‎^[11]). General anesthesia (GA), involving a depressing consciousness level, must be carried out and maintained by an anesthesia specialist in a hospital setting. Despite being used in the majority of fertility centers, agreement by clinicians about the type of aesthetic drugs used is still lacking (Bümen, et al. ^‎[9]; Tola, EN. ^‎[4]). Different anesthetic agents have been used with different effects on oocyte quality and embryonic development and studies on the potential toxicity of GA ended up with conflicting results (Vlahos, et al. ^‎[3]; Rolland, et al. ^‎[7]; Bümen, et al. ‎^[9]; Matsota, et al. ^‎[12]; Piroli, et al. ^‎[13]; Matsota, et al. ^‎[14]). Several experimental, as well as human studies, documented the existence of anesthetic agents in the follicular fluid (FF) with possible adverse effects on the oocyte quality and subsequent embryo development (Oliveira Júnior, et al. ^‎[6]; Urfalioglu and Yaylali ‎^[8]; Bümen, et al. ‎^[9]; Matsota, et al. ‎^[12]; Wilhelm, et al. ^‎[15]; Jarahzadeh, et al. ‎^[16]); however, data about ketamine are lacking (Matsota, et al. ^‎[14]). The ideal agent used for the oocyte recovery technique should preserve hemodynamic and respiratory stability during the procedure, be free of toxic effects on oocytes, produce rapid onset and fast recovery at the end of the procedure, and be easy to administer (Sarikaya, et al. ‎^[17]). Remifentanil is ultra-short acting and very potent synthetic opioid analgesic. It is 20 times more potent than alfentanil (Beleña, et al. ^‎[18]). It is characterized by fast onset (one minute) and a short-acting time (8 to 10 minutes) with rapid elimination from systemic circulation (Bümen, et al. ‎^[9]). Ketamine is a perfect anesthetic agent as it offered all the components of anesthesia needed for surgery: loss of consciousness, satisfactory pain relief, and antegrade amnesia (Gales and Maxwell ^‎[19]). It is recommended for surgical interventions of a short time because of its short duration of action (10 to 15 minutes) and fast onset (45 to 50 seconds) (Kolp, et al. ^‎[20]). Both ketamine and remifentanil are commonly used during aesthetic procedures required for oocyte retrieval (Tola, EN. ‎^[4]; Bümen, et al. ^‎[9]; Jarahzadeh, et al. ^‎[16]; Lier, et al. ‎^[21]). To the best of the knowledge, there is no available data comparing ketamine and remifentanil in a single study during oocyte retrieval with respect to fertility outcome. Therefore, the current study aimed to compare oocytes and embryos characteristic obtained from two groups of infertile women during oocytes retrieval under general anesthesia: one group receiving ketamine, midazolam, and propofol, and the other group receiving remifentanil, midazolam, and propofol.

This prospective comparative study was done on 60 infertile females who were undergoing intracytoplasmic sperm injection (ICSI) at the infertility center of the High Institute of Infertility Diagnosis and Assisted Reproductive Technologies, Reproductive Physiology, Al Nahrain University, Baghdad, Iraq, during the period from July 2019 until April 2020. Ethical approval of the current study was issued by the Local Medical Ethical Committee of the Institute. Patients with poor ovarian reserve, hyperprolactinemia, chronic disease like diabetes, hypertension, chronic renal disease and those underwent oocyte retrieval with anesthesia method other than GA were excluded. All patients were subjected to full history taking, physical examination, and investigation. Controlled Ovarian Hyperstimulation with flexible Gonadotropin-Releasing Hormone (GnRH) antagonist protocol was used for all patients. Final oocytes maturation was established by the administration of hCG or hCG and Triptorelin (dual triggering) when two to three leading follicles were observed at an average diameter of 18 mm.

An assessment of hemodynamic status was done for all participant females as well as the demographic data (age, height, weight, and American Society Anesthesiologist (ASA) status). Standard Monitoring (heart rate (HR), non-invasive blood pressure (NIBP), pulse oximetry (SpO₂), 3 lead ECG) applied to all patients on admission to the institute's operating room for oocyte recovery. Then patients were categorized into two groups randomly. Patients in Group I received 0.05 mg/kg IV midazolam and 0.5-1 mcg/kg IV remifentanil with 2 mg/kg IV propofol. Group II received 0.05 mg/kg IV midazolam and 0.5 mg/kg IV ketamine with 2 mg/kg IV propofol. In either group, maintenance of anesthesia was done with 2% Sevoflurane and a 100% O₂ introduced by the facial mask.

Transvaginal oocyte retrieval was performed 34-36 hours after the injection of the trigger with ultrasound guidance. Then the FF was immediately brought to an embryology specialist in order to gather the retrieved cumulus-oocytes complexes (COC). Following the isolation of the oocyte, the remaining FF was centrifuged for 10 minutes at 3000 rpm for the separation of debris and cellular contents. The FF supernatant was then transferred into a sterile collecting tube, followed by storage at -20°C waiting for assay time. Assessment of each oocyte (after denudation) was carefully done, observing the existence, or lacking the first polar body or germinal vesicle. Ova that were morphologically intact and extruded the first polar body (metaphase II) were selected for microinjection. Fertilization was assessed for evidence of normality, about 12 to 18 hours following the ICSI process, based on the existence of two pronuclei (2PN). The developed embryos were graded following the Istanbul consensus workshop (Alpha scientists in reproductive medicine and ESHRE special interest of embryology ^‎[22]) and classified into grades I, II, and III. Grade I embryo with less than 10% fragmentation, stage-specific cell size, no multinucleation. Grade II embryo with 10–25% fragmentation, stage-specific cell size for the majority of cells, no evidence of multinucleation. Grade III embryo with severe fragmentation (>25%), cell size did not stage-specific, evidence of multinucleation.

Follicular fluid obtained on the day of oocyte retrieval was used for the estimation of ketamine and remifentanil levels by Reversed-Phase High-performance Liquid Chromatography (HPLC) technique. FF samples were analyzed in the Ministry of Science and Technology/ Department of Environment and Water by HPLC model (SYKAM) Germany. Pump model: S 2100 Quaternary Gradient Pump, Autosampler model: S 5200, Detector: UV (S 2340) and Column Oven model: S 4115. The mobile phase was (acetonitrile: phosphate buffer) (80:20 v/v), the column is C18-ODS (25 cm * 4.6 mm), and detector UV – 270 nm for Ketamine at a flow rate (1.1 ml/min) and 220 nm for Remifentanil at flow rate 0.8 ml/min. at 37°C. Anesthetic drugs concentration was measured by using the following equation (Ewadh and Jawad ‎^[23])

Sample Concentration = (Sample Area / Standard Area) × Standard Concentration

Data were analyzed using a statistical package for social sciences (SPSS, IBM, Chicago, USA, version 23). Qualitative data were expressed as number and percentage; whereas quantitative data were expressed as mean, and standard deviation. Independent sample t-test was used to compare the mean between two groups, whereas, the chi-square test was used to compare proportions between two groups. The degree of association between continuous variables was calculated by Pearson’s correlation coefficient (r) and the level of significance was chosen at p≤0.05.

The demographic characteristics of infertile women enrolled in this study were shown in Table 1. There was no significant difference in mean age, mean body mass index (BMI), mean duration of infertility, type of infertility, causes of infertility, and several previous IVF cycles, between ketamine and remifentanil, treated groups, (p>0.05), Table 1. The oocyte characteristics of infertile women enrolled in the current study are shown in Table 2. There was no significant difference in mean total oocyte number, mean metaphase II(MII)%, mean metaphase I (MI)%, and mean germinal vesical (GV) oocyte % between ketamine and remifentanil treated groups (p > 0.05), as shown in Table 2. However, there was a highly significant difference in mean abnormal oocyte % between ketamine and remifentanil groups, 14.31±11.26 versus 6.00±7.66, respectively (p =0.001); being higher in the ketamine group, Table 2. The embryo characteristics of infertile women enrolled in the current study are shown in Table 3. There was no significant difference in grade I and grade II embryos between the ketamine group and remifentanil groups (p>0.05); however, grade III embryos were significantly limited to the ketamine group (p=0.014), Table 3. FF concentration of ketamine and remifentanil were not significantly correlated to any of oocyte characteristics or embryo characteristics (p> 0.05), Table 4.

In this study, to compare the outcome of intracytoplasmic sperm injection (ICSI) cycle, namely oocyte characteristics and embryo characteristics, 60 infertile women were chosen randomly and classified into two groups, 30 receiving ketamine and 30 receiving remifentanil during general anesthesia for oocyte retrieval. The results showed that there are no significant differences in demographic characteristics, namely age, BMI, duration of infertility, type of infertility, causes of infertility, and the number of previous IVF cycles between the remifentanil group and ketamine group (p>0.05). The lack of significant difference can lead to avoidance of any bias in fertility outcome related to a younger age, shorter duration of infertility, optimum BMI, or variation in causes of infertility which will limit the explanation of any possible difference in fertility outcome to variation in the type of anesthetic drug used namely remifentanil and ketamine. There was no significant difference in mean total oocyte number, mean MII oocyte %, mean MI oocyte %, and mean germinal vesical (GV) oocyte % between ketamine and remifentanil treated groups (p>0.05). However, there was a highly significant difference in mean abnormal oocyte% between ketamine and remifentanil groups (p=0.001); being higher in the ketamine group. It has been found that remifentanil has no adverse effect on the quality of retrieved oocytes when compare the anesthetic techniques using propofol and fentanil versus midazolam and remifentanil associated with the paracervical block with lidocaine or comparing GA (atropine, remifentanil, and propofol) versus paracervical block or analgesia with remifentanil versus anesthesia with propofol and alfentanil (Oliveira Júnior, et al. ^‎[6]; Bümen, et al. ‎^[9]; Matsota, et al. ‎^[12]). Also, remifentanil has the advantage of significantly higher total oocyte number when it was given in continuous intravenous infusion and compare with local anesthesia (Milanini, et al. ^‎[24]) or given in GA (remifentanil with either propofol or isoflurane) and compare with sedation (midazolam, diazepam, or propofol) (Hammadeh, et al. ^‎[25]). Nevertheless, no significant difference in the total number of oocytes has been found by other studies (Bümen, et al. ^‎[9]; Matsota, et al. ^‎[12]; Lier, et al. ^‎[21]). Regarding ketamine, some authors found no significant negative effect subjected by ketamine on oocyte quality when comparing the effect of ketamine, thiopental, and propofol for sedation during oocyte retrieval (Nossair and Maaty ^‎[26]); however, a negative drawback on oocyte quality linked to ketamine had been shown by (Tola, EN. ‎^[4]) when compared to propofol or propofol/ketamine. Other studies concluded no significant negative impact related to ketamine regarding oocyte quality and number when compared to propofol or fentanyl/propofol/isoflurane (Urfalioglu and Yaylali ‎^[8]; Ben-Shlomo, et al. ‎^[27]). So far, two points can be inferred from the above discussion, the first one is the lack of a previous study comparing ketamine to remifentanil. The second point is that the effect of either drug on oocyte quality and the number is still controversial and needs further research work; however, current results favor remifentanil in this regard. The acting time of remifentanil is shorter than ketamine. Thus, a longer-acting time of ketamine could probably cause damage in the oocyte (as abnormal oocytes were highly significant with the ketamine group) due to longer exposure of ketamine on oocytes. There was no significant difference in grade I and grade II embryos between the ketamine and remifentanil treated group (p>0.05); however, grade III embryos were significantly limited to the ketamine treated group (p=0.014), as none of the women within remifentanil treated group had grade III embryos. Hence, obtaining good quality embryos was comparable in both groups while bad quality embryos were limited to the ketamine treated group. Some studies showed no significant difference in embryo quality when remifentanil compared to alfentanil/propofol, local anesthesia, pethidine/midazolam (Matsota, et al. ^‎[12]; Lier, et al. ^‎[21]; Milanini, et al. ^‎[24]; Barut, et al. ^‎[28]). However, other studies showed that remifentanil is superior to fentanyl with respect to embryo score (Jarahzadeh, et al. ^‎[16]). In a previous study, ketamine was found not to adversely affect embryo quality when compared to propofol (Tola, EN. ^‎[4]). However, (Nossair and Maaty ‎^[26]) stated a negative impact subjected by ketamine on embryo quality, embryo development, cleavage rate, fertilization rate, pregnancy, and implantation rate, with more abortion rate when compared to propofol for sedation during oocyte retrieval. Therefore, there is no previous study comparing the effect of ketamine and remifentanil on embryo quality in women undergoing oocyte retrieval for IVF/ICSI program. Whereas, the current study to the best of our knowledge, is the first one to make a comparison between remifentanil and ketamine on embryo quality and it has shown that remifentanil is superior to ketamine as bad quality embryos were limited to ketamine treated group. This may be explained by that remifentanil has a short duration of action with rapid elimination from systemic circulation without drug accumulation (Bümen, et al. ‎^[9]; Lier, et al. ^‎[21]). This may lead to less exposure to anesthesia with less determinate effect on oocyte and after the embryo. The rapid elimination and clearance of remifentanil are due to its rapid and predictable metabolism by tissue and plasma non-specific esterase, mainly to a carboxylic acid (non-active byproduct) (Beleña, et al. ‎^[18]; Ziesenitz, et al. ^‎[29]). However, the metabolism of ketamine is mainly hepatic (80%) producing nor-ketamine which is a weak analgesic with 20 to 30 % ketamine potency. Nor-ketamine is then hydroxylated via glucuronoconjugation and excreted in urine and bile (Mion and Villevieille ‎^[30]). In the current study, the FF concentration of both ketamine and remifentanil were not significantly correlated to oocyte characteristics and embryo characteristics (p>0.05). Previously, a little number of researchers measured the FF concentration of anesthetic agents and some of them use a little number of participants thus, further investigation should be carried out to achieve a safe conclusion (Matsota, et al. ‎^[14]). Some studies (Endler, et al. ‎^[31]; Imoedemhe, et al. ^‎[32]; Wikland, et al. ‎^[33]; Soussis, et al. ^‎[34]; Ben-Shlomo, et al. ‎^[35]) measured the concentration of a variety of anesthetic agents (thiopental, thiamylal, lidocaine, midazolam, fentanyl, alfentanil, and propofol) in FF however, data about ketamine are lacking. (Imoedemhe, et al. ‎^[32]; Ben-Shlomo, et al. ^‎[35]) found that the FF concentration of propofol not significantly correlated to oocytes characteristic during IVF/ICSI cycles. It is worth to mention that the current study was the first one to include FF assessment for ketamine. In addition to there is no previous study comparing the impact of the FF concentration of both ketamine and remifentanil on oocyte and embryo characteristics in women undergoing oocyte retrieval for IVF/ICSI program.

In conclusion, both anesthetic agents, ketamine, and remifentanil were detected in the follicular fluid of infertile women and within recommended doses, ketamine resulted in significant adverse effects on oocyte and embryo quality in comparison with remifentanil represented by a significantly greater percentage of abnormal oocytes and that bad quality embryo were limited to ketamine group.

We would like to express deep thanks to all members of the High Institute of Infertility Diagnosis and Assisted Reproductive Technologies, Reproductive Physiology, Al Nahrain University, Baghdad, Iraq.

This work received no funding

Mohsin, HAH performed the study, examined and reviewed results, and manuscript writing with the help and supervision of Jwad MA, and Reshan, RG.

The author declares no conflict of interest.

The study was approved by the Ethical Approval Committee.

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Mohsin HAH. Jwad MA, Reshan, RG. Effect of drugs used in general anesthesia on oocyte and embryo quality in Iraqi infertile females undergoing intracytoplasmic sperm injection; Iraqi Journal of Embryos and Infertility Researches (IJEIR), (2020); 10(1): 83-100.

Doi: http://doi.org/10.28969/IJEIR.v10.i1.r6