Infertility
Conditions
Keywords
fentanyl, midazolam, pethidine, diazepam
Brief summary
The objective of the trial is to compare fentanyl and midazolam vs diazepam and pethidine in terms of the pain levels and post-operative side effects of TUGOR
Detailed description
In-vitro fertilization / embryo transfer (IVF / ET) is a well-established method to treat various causes of infertility. It involves multiple follicular development, retrieval of oocytes and embryo transfer after fertilization. Egg retrieval at the majority of IVF units is performed through the transvaginal route under ultrasound guidance (TUGOR) \[1\]. During TUGOR, the needle has to pass through the mucosa in the vaginal vault in order to puncture the follicles in the ovary. The procedures are generally short, lasting about 20-30 minutes but are still painful without anaesthesia or analgesia. Intravenous sedation with or without local anaesthesia is the most widely used method. Conscious sedation is a safe and cost-effective method of providing analgesia and anesthesia for TUGOR. \[2\] It is easy to administer in cooperative and motivated patients. It has a relatively low risk for adverse effects on oocyte and embryo quality and pregnancy rates. \[3\] Paracervical block (PCB) in conjunction with conscious sedation during TUGOR was shown to significantly reduce the pain during TUGOR when compared to PCB alone \[4\]. A Cochrane review on various methods of sedation and analgesia for pain relief during TUGOR has shown no single method or delivery system appeared superior for pregnancy rates and pain relief. \[5\] Most of the methods seemed to work well and the effect was usually enhanced by addition of another method such as pain relief with paracervical block. \[6\] The investigators' reproductive centre has recently aligned with the Assisted Reproduction Centre of the University of Hong Kong (HKU). The investigators are using 0.1mg fentanyl and 5mg midazolam intravenously for pain relief in TUGOR at Kwong Wah Hospital (KWH) whereas 5mg diazepam and 25mg pethidine intravenously are being used in HKU. The investigators would like to compare fentanyl and midazolam vs diazepam and pethidine in terms of pain levels and post-operative side effects of TUGOR in this prospective non-inferiority randomized double-blinded trial. The investigators postulate there are no differences in the pain levels between two groups but the postoperative side effects may be different.
Interventions
DRUGfentanyl
arm A receiving iv fentanyl
DRUGpethidine
arm B receiving iv pethidine
DRUGDiazepam
arm B receiving iv diazepam
DRUGMidazolam
arm A receiving iv midazolam
Sponsors
The University of Hong Kong
Queen Mary Hospital, Hong Kong
Kwong Wah Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* presence of both ovaries; * body mass index less than 30 * written informed consent and * Chinese
Exclusion criteria
* IVF cycle converted from ovulation induction or intrauterine insemination cycles; * patient requests general anaesthesia for TUGOR; * history of drug sensitivity to lignocaine/fentanyl/midazolam/diazepam/pethidine; * less than 3 dominant follicles present; * dominant follicles present in one ovary only and * TUGOR performed on one side only.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Level During Oocyte Retrieval | will be assessed within 4 hours of oocyte retrieval | The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful |
| Pain Level After Oocyte Retrieval | will be assessed within 4 hours of oocyte retrieval | The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Pregnancy Rate | will be assessed within ten weeks of oocyte retrieval | presence of intrauterine sac in ultrasound after a positive pregnancy test |
| Ongoing Pregnancy Rate | will be assessed within ten weeks of oocyte retrieval | positive fetal heart pulsation seen in ultrasound at eight weeks of gestation |
| Percentage of Participants With Side Effects by Type | will be assessed within 4 hours of oocyte retrieval | side effects will be scored by yes or no |
| Sedation Level | immediately after retrieval | S = sleeping, easily aroused; 1 = awake and alert; 2 = occasionally drowsy, easy to arouse; 3 = frequently drowsy, arousable, drifts off to sleep during conversation; 4 = somnolent, minimal or no response to stimuli |
| Patient's Satisfaction on Pain Relief | within 4 hours after retrieval | satisfaction on pain relief will be scored at 0-10 (10 being most satisfied) |
| Patient's Satisfaction on Oocyte Retrieval | will be assessed within 4 hours of oocyte retrieval | satisfaction will be scored from 0-3 (0=excellent, 1=satisfactory, 2=fair, 3=unsatisfactory) |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A: Intravenous Fentanyl, Midazolam group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval
fentanyl: arm A receiving iv fentanyl
Midazolam: arm A receiving iv midazolam | 85 |
| B: Intravenous Pethidine, Diazepam group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval
pethidine: arm B receiving iv pethidine
Diazepam: arm B receiving iv diazepam | 85 |
| Total | 170 |
Baseline characteristics
| Characteristic | A: Intravenous Fentanyl, Midazolam | B: Intravenous Pethidine, Diazepam | Total |
|---|---|---|---|
| Age, Continuous | 36 years | 37 years | 37 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 85 Participants | 85 Participants | 170 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Hong Kong | 85 participants | 85 participants | 170 participants |
| Sex: Female, Male Female | 85 Participants | 85 Participants | 170 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 85 | 0 / 85 |
| other Total, other adverse events | 0 / 85 | 0 / 85 |
| serious Total, serious adverse events | 0 / 85 | 0 / 85 |
Outcome results
Primary
Pain Level After Oocyte Retrieval
The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful
Time frame: will be assessed within 4 hours of oocyte retrieval
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Pain Level After Oocyte Retrieval | vaginal pain | 0 score on a scale |
| A: Intravenous Fentanyl, Midazolam | Pain Level After Oocyte Retrieval | abdominal pain | 2.3 score on a scale |
| B: Intravenous Pethidine, Diazepam | Pain Level After Oocyte Retrieval | vaginal pain | 0 score on a scale |
| B: Intravenous Pethidine, Diazepam | Pain Level After Oocyte Retrieval | abdominal pain | 2 score on a scale |
Primary
Pain Level During Oocyte Retrieval
The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful
Time frame: will be assessed within 4 hours of oocyte retrieval
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Pain Level During Oocyte Retrieval | vaginal pain | 0 score on a scale |
| A: Intravenous Fentanyl, Midazolam | Pain Level During Oocyte Retrieval | abdominal pain | 2.5 score on a scale |
| B: Intravenous Pethidine, Diazepam | Pain Level During Oocyte Retrieval | vaginal pain | 4 score on a scale |
| B: Intravenous Pethidine, Diazepam | Pain Level During Oocyte Retrieval | abdominal pain | 5 score on a scale |
Secondary
Clinical Pregnancy Rate
presence of intrauterine sac in ultrasound after a positive pregnancy test
Time frame: will be assessed within ten weeks of oocyte retrieval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Clinical Pregnancy Rate | 14.1 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Clinical Pregnancy Rate | 23.5 percentage of participants |
Secondary
Ongoing Pregnancy Rate
positive fetal heart pulsation seen in ultrasound at eight weeks of gestation
Time frame: will be assessed within ten weeks of oocyte retrieval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Ongoing Pregnancy Rate | 12.9 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Ongoing Pregnancy Rate | 21.2 percentage of participants |
Secondary
Patient's Satisfaction on Oocyte Retrieval
satisfaction will be scored from 0-3 (0=excellent, 1=satisfactory, 2=fair, 3=unsatisfactory)
Time frame: will be assessed within 4 hours of oocyte retrieval
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Patient's Satisfaction on Oocyte Retrieval | excellent | 47.7 percentage of participants |
| A: Intravenous Fentanyl, Midazolam | Patient's Satisfaction on Oocyte Retrieval | satisfactory | 38.8 percentage of participants |
| A: Intravenous Fentanyl, Midazolam | Patient's Satisfaction on Oocyte Retrieval | fair | 11.8 percentage of participants |
| A: Intravenous Fentanyl, Midazolam | Patient's Satisfaction on Oocyte Retrieval | unsatisfactory | 4.7 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Patient's Satisfaction on Oocyte Retrieval | unsatisfactory | 7.1 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Patient's Satisfaction on Oocyte Retrieval | excellent | 15.3 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Patient's Satisfaction on Oocyte Retrieval | fair | 22.4 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Patient's Satisfaction on Oocyte Retrieval | satisfactory | 55.3 percentage of participants |
Secondary
Patient's Satisfaction on Pain Relief
satisfaction on pain relief will be scored at 0-10 (10 being most satisfied)
Time frame: within 4 hours after retrieval
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Patient's Satisfaction on Pain Relief | 8 score on a scale |
| B: Intravenous Pethidine, Diazepam | Patient's Satisfaction on Pain Relief | 7 score on a scale |
Secondary
Percentage of Participants With Side Effects by Type
side effects will be scored by yes or no
Time frame: will be assessed within 4 hours of oocyte retrieval
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Percentage of Participants With Side Effects by Type | vomiting | 0 percentage of participants |
| A: Intravenous Fentanyl, Midazolam | Percentage of Participants With Side Effects by Type | drowsiness | 8.2 percentage of participants |
| A: Intravenous Fentanyl, Midazolam | Percentage of Participants With Side Effects by Type | dizziness | 16.5 percentage of participants |
| A: Intravenous Fentanyl, Midazolam | Percentage of Participants With Side Effects by Type | shortness of breath | 0 percentage of participants |
| A: Intravenous Fentanyl, Midazolam | Percentage of Participants With Side Effects by Type | nausea | 2.4 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Percentage of Participants With Side Effects by Type | shortness of breath | 1.2 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Percentage of Participants With Side Effects by Type | nausea | 7.1 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Percentage of Participants With Side Effects by Type | vomiting | 1.2 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Percentage of Participants With Side Effects by Type | dizziness | 4.7 percentage of participants |
| B: Intravenous Pethidine, Diazepam | Percentage of Participants With Side Effects by Type | drowsiness | 3.5 percentage of participants |
Secondary
Sedation Level
S = sleeping, easily aroused; 1 = awake and alert; 2 = occasionally drowsy, easy to arouse; 3 = frequently drowsy, arousable, drifts off to sleep during conversation; 4 = somnolent, minimal or no response to stimuli
Time frame: immediately after retrieval
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| A: Intravenous Fentanyl, Midazolam | Sedation Level | missing data | 1 Participants |
| A: Intravenous Fentanyl, Midazolam | Sedation Level | S | 18 Participants |
| A: Intravenous Fentanyl, Midazolam | Sedation Level | 1 | 15 Participants |
| A: Intravenous Fentanyl, Midazolam | Sedation Level | 2 | 14 Participants |
| A: Intravenous Fentanyl, Midazolam | Sedation Level | 3 | 16 Participants |
| A: Intravenous Fentanyl, Midazolam | Sedation Level | 4 | 21 Participants |
| B: Intravenous Pethidine, Diazepam | Sedation Level | 3 | 4 Participants |
| B: Intravenous Pethidine, Diazepam | Sedation Level | 4 | 5 Participants |
| B: Intravenous Pethidine, Diazepam | Sedation Level | 2 | 17 Participants |
| B: Intravenous Pethidine, Diazepam | Sedation Level | missing data | 0 Participants |
| B: Intravenous Pethidine, Diazepam | Sedation Level | S | 7 Participants |
| B: Intravenous Pethidine, Diazepam | Sedation Level | 1 | 52 Participants |