Comparison of the Effect of Ketofol and Ketodex as Procedural Sedation and Analgesia for Oocyte Retrieval during In vitro Fertilisation Procedures: A Randomised Controlled Pilot Study.

The increasing demand for in vitro fertilisation (IVF) underscores the need for safe and effective procedural sedation techniques that optimise patient comfort while preserving reproductive outcomes.[ 1 ] Although various sedative agents are routinely employed during oocyte retrieval, there remains no consensus on the optimal anaesthetic regimen that balances adequate analgesia, haemodynamic stability, and minimal interference with oocyte quality.[ 2 ] Propofol, favoured for its rapid onset and short duration of action, has raised concerns regarding its potential effects on fertilisation and embryo development, as well as its frequent need for supplemental analgesics.[ 3 4 ] Several anaesthetic combinations such as midazolam with ketamine or fentanyl with propofol and isoflurane have been reported to provide satisfactory sedation during oocyte retrieval, although recovery profiles and complication rates differ.[ 5 ] Pain experienced during oocyte retrieval is comparable to menstrual pain, attributed to the puncture of the vaginal wall and mechanical stimulation of the ovaries and their capsules.[ 6 ] The severity of pain correlates with the number and duration of follicular aspirations, with nearly one-fifth of women reporting moderate-to-severe pain within 2 h post-procedure.[ 7 8 ] Inadequate analgesia may result in patient discomfort, movement and increased perioperative opioid requirements, thereby affecting procedural conditions and recovery. Adequate analgesia is essential to ensure immobility, prevent vascular injury and minimise anxiety, for which various modalities, including monitored anaesthesia care (MAC), regional blocks and total intravenous anaesthesia (TIVA), are employed.[ 9 ] Commonly used agents such as midazolam, propofol and fentanyl provide effective sedation but are limited by adverse effects such as nausea, respiratory depression and cardiovascular instability.[ 10 11 12 ] Moreover, detectable concentrations of these agents in follicular fluid raise concerns regarding potential adverse effects on oocyte fertilisation and embryo development.[ 13 ] Pharmacologically, propofol, an agonist at the γ-aminobutyric acid type A receptor, produces hypnosis within 30–45 s, with a distribution half-life of 2–4 min and an elimination half-life of 30–60 min.[ 11 ] Ketamine, an N-methyl-D-aspartate receptor antagonist, provides dissociative anaesthesia while maintaining airway reflexes and cardiovascular stability, with an onset of 30 s, distribution half-life of 10-15 min and elimination half-life of 2-3 h.[ 14 ] The combination of ketamine and propofol, termed Ketofol, merges their complementary effects. Propofol mitigates ketamine-related emergence reactions, while ketamine counters propofol-induced hypotension, resulting in haemodynamic stability, improved analgesia and faster recovery.[ 14 ] However, opioid supplementation is often required to achieve adequate analgesia, and respiratory adverse events may occur at deeper levels of sedation. Dexmedetomidine, a highly selective α₂-adrenergic agonist, produces cooperative sedation and analgesia with minimal respiratory depression, characterised by an onset of approximately 10 min, distribution half-life of 6 min and elimination half-life of about 2 h.[ 15 ] When combined with ketamine (Ketodex), dexmedetomidine attenuates ketamine-induced tachycardia and hypertension while reducing its psychomimetic effects; conversely, ketamine prevents dexmedetomidine-related bradycardia and hypotension, producing stable haemodynamics and balanced sedation.[ 15 16 ] This pharmacodynamic complementarity offers effective analgesia with minimal respiratory depression and reduced opioid requirement, making Ketodex a potentially advantageous regimen for oocyte retrieval. Recent clinical evidence supports these balanced combinations in reproductive anaesthesia. Retrospective and prospective analyses have shown that ketamine alone may lower fertilisation rates compared to propofol or the ketamine–propofol combination, whereas implantation and pregnancy rates remain comparable.[ 17 ] Other large-scale evaluations have demonstrated no significant difference in fertilisation outcomes between women receiving intravenous anaesthesia and those without, indicating that controlled use of intravenous agents does not adversely affect oocyte quality or fertilisation potential.[ 18 ] Furthermore, dexmedetomidine-based sedation has been associated with lower intraoperative pain scores, decreased propofol requirements, and comparable pregnancy outcomes.[ 1 ] Studies in endoscopy, paediatric lithotripsy and cardiac catheterisation also confirm that the ketamine–dexmedetomidine combination yields satisfactory sedation, stable haemodynamics and faster recovery.[ 19 20 ] Despite the frequent clinical use of both Ketofol and Ketodex for procedural sedation, direct prospective comparisons between these two regimens during IVF oocyte retrieval remain limited. Collectively, the available evidence suggests that Ketodex may offer a pharmacologically balanced alternative to Ketofol, combining effective sedation and analgesia with superior cardiovascular stability and minimal respiratory adverse effects. We hypothesised that Ketodex would provide superior analgesia and sedation quality with fewer respiratory complications and a reduced need for rescue analgesics compared with Ketofol during oocyte retrieval in IVF procedures.

A total of 60 patients were recruited for the study, and 30 patients were allocated to each group. The participant flow diagram is shown in Figure 1 . The baseline demographics of patients were similar in both groups [ Table 1 ]. CONSORT diagram depicting the flow of participants through each stage of the randomised controlled trial, including enrolment, allocation, follow-up and analysis Comparison of baseline demographic characteristics between Ketofol and Ketodex groups ( n =30) *Statistically significant ( P <0.05), † Chi-square test, ‡ Independent t -test, § Mann–Whitney U -test. BMI=Body mass index, ASA=American Society of Anaesthesiologists, RA=Rheumatoid Arthritis, TB=Tuberculosis, Apla=Anti-phospholipid syndrome Post-operative pain intensity assessed using the VAS demonstrated a progressive reduction over time in both groups. Between-group analysis showed that VAS scores were significantly lower in the Ketodex group at all assessed post-operative time points, including 10 min, 30 min, 1 h, and 2 h after oocyte retrieval [all P < 0.01; Table 2 ]. Within-group analysis using the Friedman test confirmed a significant reduction in VAS scores over the first two post-operative hours in both groups ( χ 2 = 145.0, df = 3, P < 0.001), indicating effective post-operative analgesia, with consistently lower pain scores observed in the Ketodex group. Primary outcomes - total cumulative pain scores intra-operatively and in the first 2 hours post-oocyte retrieval ( n =30) a Mann–Whitney U -test (between-group), ᵇ Friedman test with Bonferroni (within-group). Data shown as median (IQR), Fisher’s exact test used for categorical variables. Effect sizes as rank-Biserial correlation ( r ₛ). Significance: P <0.05. CPS=Cumulative pain score, IQR=Interquartile range, VAS=Visual Analogue Scale Intraoperative fentanyl requirement was markedly higher in the Ketofol group (median 30 μg) compared to none in the Ketodex group (median 0 μg; U = 180, P < 0.001, r = 0.600, large effect size). Post-operative fentanyl requirements remained low in both groups (median 0 μg), and the difference was not statistically significant [ U = 420, P = 0.161, r = 0.067, negligible effect size, Table 2 ]. The CPS was analysed as a post hoc exploratory outcome. The CPS was analysed as a continuous variable after normalisation and expressed as mean ± SD; inter-group comparison was performed using the Mann–Whitney U -test. The CPS, calculated as the sum of intraoperative fentanyl dose and post-operative VAS scores up to 2 h, was significantly lower in the Ketodex group compared to the Ketofol group (median [IQR]: 2.00 [2.00–2.00] vs. 33.00 [4.00–38.00]; Mann–Whitney U = 0, P < 0.001, rank-biserial correlation = 0.946), indicating a very large effect size [ Figure 2 ]. This finding demonstrates that Ketodex provided superior and sustained analgesia during and after oocyte retrieval, with minimal need for opioid supplementation. Cumulative pain score comparison between groups; Boxes represent the interquartile range (IQR), horizontal lines indicate the median and whiskers denote the minimum and maximum values within 1.5 × IQR Oocyte quality, assessed based on morphological grading, did not significantly differ between the Ketofol (KP) and Ketodex (KD) groups for Grade 1 ( P = 0.219) and Grade 3 oocytes ( P = 0.627). However, the KP group demonstrated a significantly higher median number of Grade 2 oocytes (4 [IQR 3–5]) compared to the KD group (2 [IQR 2–3.75]) ( P = 0.0007). Importantly, the median fertilisation rates were comparable between the two groups – 100% (range 80%–100%) in the KP group and 100% (range 84%–100%) in the KD group ( P = 0.411) [ Figure 3 ]. Comparison of fertility rate between group KP and KD (non-parametric variable, Box-whisker plot) Cleavage rates on day 2 were comparable between the KP (100% ± 0%) and KD (99.31% ± 3.71%) groups. Although not statistically significant, the cleavage rate on Day 3 was higher in the KD group (87% ± 17.8%) compared to the KP group (78.15% ± 31.56%). Although the cleavage rate on Day 3 was numerically higher in the Ketodex group, the difference was not statistically significant. The incidence of post-operative nausea varied significantly between the two groups. At 30 min post-operation, the KP group exhibited a significantly higher incidence of nausea alone (50% vs. 3.33%) and a lower incidence of nausea/vomiting (50% vs. 96.67%) compared to the KD group ( P < 0.0001). At 1 h, the KP group had significantly fewer cases of nausea alone (0% vs. 33.33%) and a higher absence of nausea/vomiting (100% vs. 66.67%) compared to the KD group ( P = 0.0008). Apnea – defined as cessation of spontaneous respiration for more than 20 s requiring assisted ventilation – was observed in a significantly higher proportion of patients in the Ketofol group compared with the Ketodex group (53.3% vs. 0%, P < 0.001). Conversely, all patients in the Ketodex group remained free of intra-operative complications, whereas only 46.7% of those receiving Ketofol experienced an uneventful course. No post-operative complications were noted in either group.

Ketamine–dexmedetomidine (Ketodex) and ketamine–propofol (Ketofol) were both effective for procedural sedation during IVF oocyte retrieval. Ketodex was associated with lower post-operative VAS pain scores during the first 2 h, eliminated the need for intraoperative fentanyl supplementation, and demonstrated a more favourable respiratory profile. Immediate embryological outcomes, including fertilisation and cleavage rates, were comparable between groups. An exploratory CPS, integrating early pain burden and opioid requirement, also favoured Ketodex and is presented as supportive evidence. Compared with general anaesthesia, sedation with Ketodex or Ketofol is cost-effective, avoids airway manipulation, enables faster recovery, and supports early discharge, making it a practical and patient-friendly option for oocyte retrieval. Within the limitations of this pilot study, Ketodex appears to be a safe and effective sedation option for IVF oocyte retrieval, with potential advantages in analgesic stability and respiratory safety. Larger, blinded, multicenter trials are warranted to validate these findings and assess their relevance to broader reproductive outcomes. S.V. conceptualised the study, developed the research protocol, recruited participants, conducted intraoperative and post-operative data collection, performed statistical analysis, interpreted results and drafted the manuscript. D.J. Contributed to study coordination in the IVF unit, supported data acquisition, provided a critical review of the manuscript and approved the final version. S.K. contributed to study design and methodology, supervision and approval of the final manuscript. S.H. assisted in patient recruitment, data collection, validated the statistical analysis, critically reviewed and revised the manuscript. P.K. provided expert input on anaesthetic management, contributed to methodological refinement, reviewed the manuscript and approved the final draft. L.K. provided expert input on anaesthetic management, reviewed the manuscript and approved the final draft. N.M. provided clinical guidance related to IVF protocols, supervised embryological outcome assessment, contributed to the interpretation of oocyte and embryo data and reviewed the final manuscript. R.M. provided clinical guidance related to IVF protocols, supervised embryological outcome assessment, contributed to the interpretation of oocyte and embryo data and reviewed the final manuscript. All authors meet ICMJE criteria for authorship and agree to be accountable for all aspects of the work. There are no conflicts of interest. The data supporting the findings of this study are available with the corresponding author and will be provided on reasonable request. During the writing of the manuscript, the authors used ChatGPT for grammatical errors and to improve the language and readability. After using this tool, the authors reviewed and edited the content as needed.

The present pilot randomised controlled trial compared ketamine–dexmedetomidine (Ketodex) with ketamine–propofol (Ketofol) for procedural sedation during oocyte retrieval. Post-operative pain assessed using VAS over the first 2 h was lower in the Ketodex group at all measured time points, suggesting improved early recovery comfort with Ketodex and a complete avoidance of intraoperative fentanyl supplementation, indicating a more consistent intraoperative analgesic profile [ Figure 2 ]. Although post-operative VAS scores were similar between groups, the Ketofol group required substantially more intraoperative fentanyl despite adequate sedation levels. This likely reflects differences in intraoperative analgesic depth rather than post-operative subjective pain perception. Dexmedetomidine’s opioid-sparing properties and its synergistic action with ketamine may explain this improved analgesic stability. These results align with previous studies demonstrating reduced opioid use and improved patient comfort when dexmedetomidine–ketamine combinations are used for procedural sedation.[ 1 7 14 ] A notable secondary finding was the significantly higher incidence of apnea in the Ketofol group. Propofol, particularly when combined with opioids, is known to cause dose-dependent respiratory depression, whereas dexmedetomidine has minimal effect on respiratory drive. The absence of apnea in the Ketodex group reinforces the respiratory safety advantages previously described for dexmedetomidine-based sedation protocols.[ 12 ] Dexmedetomidine is comparatively slightly costlier than propofol; however, it translates to a very mild increase in the total cost of the procedure. Oocyte morphology and embryological outcomes, including fertilisation and cleavage rates, were comparable between both groups [ Figure 3 ]. Although the Ketofol group demonstrated a slightly higher number of Grade 2 oocytes, this isolated observation did not translate into differences in fertilisation or cleavage rates. It is important to acknowledge that oocyte morphology is influenced by complex biological and laboratory factors. Mitochondrial distribution, cytoplasmic maturation, meiotic spindle integrity and oxidative stress, well-established determinants of oocyte quality, are governed primarily by intrinsic follicular physiology rather than anaesthetic exposure.[ 24 25 26 ] Therefore, no causal relationship between anaesthetic regimen and oocyte grading can be inferred. Our observations align with existing evidence that commonly used sedative techniques do not adversely affect immediate embryological outcomes.[ 4 10 17 ] This study has several strengths, including its randomised design, standardised sedation protocol and clearly defined rescue analgesia algorithm, which minimised inter-observer variability. The CPS, although not a traditionally used measure, provided a time-integrated assessment that captured both intraoperative opioid use and post-operative pain scores. However, this composite approach also represents a limitation, as it combines two variables with different measurement scales. The findings should therefore be interpreted as exploratovry, guiding future methodological refinement. Additional limitations include the modest sample size inherent to a pilot study. High-risk populations (ASA III/IV, BMI >30 kg/m 2 ) were excluded, limiting generalisability. Long-term outcomes such as implantation rates, clinical pregnancy or live birth rates could not be evaluated due to incomplete follow-up, which restricts conclusions about reproductive endpoints. The CPS was a post hoc exploratory outcome and was not prespecified in the trial registry, limiting definitive interpretation. As an additional ( post hoc ) exploratory analysis, we computed a CPS to integrate early pain burden (AUC of VAS over time) with opioid requirement. While the CPS differed significantly between groups, this outcome was not prespecified and combines measures on different scales; therefore, CPS results should be interpreted as hypothesis-generating rather than confirmatory.[ 21 22 23 ] Accordingly, conclusions of the study are primarily based on the VAS findings (primary outcome), with CPS presented as supportive exploratory evidence. Overall, the findings of this pilot trial support further evaluation of Ketodex as a potentially safer and more analgesically stable option for procedural sedation during oocyte retrieval.

This double blinded, single-centre, prospective, randomised controlled pilot study was conducted in the Department of Anaesthesiology, Pain Medicine and Critical Care at the All India Institute of Medical Sciences (AIIMS), New Delhi, India, between 3 December 2022 and 28 February 2023. The study was approved by the Institute Ethics Committee for Post-graduate Research (Ref. No. IECPG-192/24.02.2021, RT-28/24.03.2021) and conducted in accordance with the Declaration of Helsinki. The trial was prospectively registered in the Clinical Trials Registry of India (CTRI/2022/12/047865). Written informed consent was obtained from all participants before enrollment. Women aged 20–40 years, classified as American Society of Anesthesiologists (ASA) physical status I–II, scheduled for elective transvaginal oocyte retrieval for IVF, were recruited. Exclusion criteria included refusal to participate, BMI >30 kg/m 2 , ASA ≥III, known hypersensitivity to study drugs, autonomic dysfunction, uncontrolled systemic diseases and chronic hepatic, renal or neurological disorders. Patients with endometriosis or adenomyosis were not specifically excluded; however, subgroup analysis for these patients was not performed due to limited sample size. Participants were randomly allocated into two groups ( n = 30 each) using a computer-generated random number sequence. Randomisation was performed before oocyte retrieval. Allocation concealment was ensured using sequentially numbered, sealed opaque envelopes, which were opened immediately before induction. Although the anaesthesiologist administering the drug was aware of group allocation, the patients, principal investigator, embryologist and outcome assessors were blinded to minimise bias. All patients underwent a standardised pre-anaesthetic evaluation and provided informed written consent before participation. Pre-operative fasting was in accordance with ASA guidelines, with patients fasting for at least 8 h for solids and 2 h for clear fluids. Upon arrival in the operating room, baseline physiological parameters were recorded, including heart rate (HR), non-invasive blood pressure, respiratory rate (RR) and oxygen saturation (SpO 2 ). All patients received intravenous midazolam (1 mg) and glycopyrrolate (0.2 mg) as premedication. Ringer’s lactate infusion was started, and oxygen was administered through a face mask at 5 L/min. Patients were randomly allocated to one of two groups: The Ketofol group (KP) or the Ketodex group (KD). Study medications were prepared by an anaesthesia resident not involved in data collection. Propofol and ketamine were loaded in separate syringes and infused through independent syringe pumps to enable titration based on response. Dexmedetomidine was diluted to a concentration of 4 μg/mL using normal saline, ketamine was diluted to a concentration of 10 mg/ml and propofol was diluted to a concentration of 10 mg/ml. In the Ketofol group, patients received an intravenous bolus of propofol 1 mg/kg and ketamine 0.5 mg/kg. This was followed by a continuous infusion of propofol at 3 mg/kg/h and ketamine at 0.5 mg/kg/h. The propofol infusion was discontinued 10 min before the expected end of the procedure. In the Ketodex group, patients received a loading dose of dexmedetomidine 1 μg/kg administered over 10 min along with ketamine 0.5 mg/kg as an intravenous bolus. Maintenance sedation was achieved using a continuous infusion of dexmedetomidine at 0.3–0.7 μg/kg/h and ketamine at 0.5 mg/kg/h. The expected duration of oocyte retrieval was estimated in advance based on follicle count and prior cycle characteristics. In addition, real-time procedural progress was continuously assessed through interaction with the operating gynaecologist, particularly during bilateral follicular aspiration. Dexmedetomidine infusion was therefore planned to be discontinued approximately 10 min before the anticipated completion of the procedure, typically when aspiration of one ovary was completed, and only a few follicles remained on the contralateral side to facilitate timely recovery while maintaining adequate intraoperative sedation. All patients received IV paracetamol 1 g for baseline analgesia and ondansetron 4 mg for prophylaxis against nausea and vomiting. As patients were under procedural sedation, direct intraoperative Visual Analogue Scale (VAS) assessment was not feasible. Intraoperative pain was therefore assessed indirectly using predefined behavioural and physiological indicators, including patient movement, facial grimacing, limb withdrawal, and increases in HR or RR exceeding 20% of baseline. These indicators guided the administration of rescue analgesia as per protocol. Post-operative pain intensity was assessed using the VAS (0–10 cm) at 30 min, 1 h, and 2 h after the procedure, once patients were fully awake and able to comprehend the scale. The target sedation level was a Ramsay sedation score (RSS) >4 [ Annexure 1 ], which was monitored every 5 min by a dedicated anaesthesiologist. A standardised stepwise protocol was implemented to manage inadequate sedation or procedural pain. If the RSS was <4 or patient movement occurred (Step 1), patients in the Ketofol group received a bolus of propofol 0.5 mg/kg, whereas patients in the Ketodex group had their dexmedetomidine infusion titrated up to 0.7 μg/kg/h or received an IV bolus of propofol 0.5 mg/kg. If sedation was adequate (RSS >4) but the patient exhibited signs of pain, such as facial grimacing, increases in HR or RR >20% from baseline, or limb withdrawal (Step 2), fentanyl 0.5 μg/kg IV was administered. To avoid confounding effects on intraoperative haemodynamics and post-operative pain scores, rescue boluses of ketamine were strictly avoided (Step 3). All rescue interventions were performed by trained anaesthesia residents under direct consultant supervision. Airway interventions were initiated if oxygen saturation dropped below 94% or if apnea occurred. The initial response involved jaw thrust manoeuvres and increased oxygen supplementation. If ineffective, intermittent positive pressure ventilation via a face mask was provided. If ventilation remained inadequate, a supraglottic airway or endotracheal tube was inserted at the discretion of the attending anaesthesiologist. The primary outcome was to determine the mean pain scores within the first 2 h post-procedure, using the VAS (0–10 cm). On this scale, 0 was defined as no pain and 10 as the maximum imaginable pain. The patient was asked to point his pain on this scale. Pain intensity was recorded at predefined intervals intraoperatively, at 30 min, 1 h, and 2 h after oocyte retrieval. Secondary outcomes include intra- and post-operative haemodynamic parameters, total dose of intraoperative rescue bolus and post-operative rescue analgesia, procedure duration and time to discharge, Incidence of adverse events, including desaturation, airway interventions, or post-operative nausea and vomiting (PONV), surgeon and patient satisfaction (5-point Likert scale), fertilisation rate (total number of fertilised oocytes numbered by the total number of embryos transferred), and cleavage rate (total number of day 3 embryos by the total number of fertilised oocytes). Time to discharge was assessed by Modified Aldrete score ≥ 9 ( Annexure 2 ). The Cumulative Pain Score (CPS) was calculated as a post hoc exploratory outcome and was not prespecified in the trial registration. To provide an integrated measure of the overall analgesic burden, a CPS was calculated by combining both pain intensity and analgesic consumption. Pain intensity (VAS, 0–10 cm) was recorded at predefined intervals - 30 min, 1 h, and 2 h post-procedure. The area under the VAS–time curve (AUC_VAS) was computed using the trapezoidal rule, representing total pain exposure over time (expressed in VAS-hours). To ensure comparability between groups, AUC_VAS values were standardised to a 0–10 scale, and each participant’s intra-operative fentanyl requirement was normalised to the mean fentanyl dose of their respective group. The final CPS was calculated as: CPS = (Standardised AUC_VAS) + (Individual fentanyl dose/Mean group fentanyl dose) This weighted approach avoids the direct addition of dissimilar scales (pain intensity vs. opioid dose) and yields a dimensionless composite index reflecting both pain intensity × duration and analgesic requirement. This methodology was adapted from validated cumulative pain quantification models integrating subjective and objective pain parameters.[ 21 22 23 ] A lower CPS reflects reduced nociceptive load and opioid requirement. Hence, the CPS in this study served as a comprehensive indicator of cumulative pain experience during and immediately after oocyte retrieval. As this study is a pilot randomised controlled study to generate preliminary data, no formal sample size calculation was performed. The data were analysed using IBM SPSS Statistics, Version 26 (IBM Corp., Armonk, NY, USA) and Jamovi. Data distribution was assessed using the Shapiro–Wilk test. Continuous variables were expressed as mean ± standard deviation (SD) for normally distributed data and as median (interquartile range [IQR]) for skewed or ordinal data. Categorical variables were presented as percentages. Between-group comparisons were performed using the independent t -test for parametric data or the Mann–Whitney U -test for non-parametric data. Repeated measures (e.g., VAS scores and haemodynamic parameters) were analysed using repeated-measures ANOVA for parametric data or the Friedman test for non-parametric data, with Bonferroni correction applied for multiple comparisons. Effect sizes for non-parametric data were reported as rank biserial correlation ( r ). Categorical variables were compared using the Chi-square test or Fisher’s exact test, as appropriate. P < 0.05 was considered statistically significant for all analyses.