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Placebo versus low-dose ketamine infusion in addition to remifentanil target-controlled infusion for conscious sedation during oocyte retrieval

A double-blinded, randomised controlled trial

Morue, Hélène I.; Raj-Lawrence, Shalini; Saxena, Sarah; Delbaere, Anne; Engelman, Edgard; Barvais, Luc A.

European Journal of Anaesthesiology (EJA): September 2018 - Volume 35 - Issue 9 - p 667–674
doi: 10.1097/EJA.0000000000000826
Sedation
Free

BACKGROUND Currently, there is no gold standard for monitored anaesthesia care during oocyte retrieval.

OBJECTIVE In our institution, the standard is a conscious sedation technique using a target-controlled infusion (TCI) of remifentanil, titrated to maintain a visual analogue pain score less than 30 mm. This protocol is well accepted by patients but is associated with frequent episodes of respiratory depression. The main objective of this study was to evaluate whether the addition of a continuous intravenous infusion of ketamine could reduce these episodes.

DESIGN Controlled, randomised, prospective, double-blinded study.

SETTING The current study was conducted in a tertiary-level hospital in Brussels (Belgium) from December 2013 to June 2014.

PATIENTS Of the 132 women undergoing oocyte retrieval included, 121 completed the study.

INTERVENTION After randomisation, patients received either a ketamine infusion (40 μg kg−1 min−1 over 5 min followed by 2.5 μg kg−1 min−1) or a 0.9% saline infusion in addition to the variable remifentanil TCI.

MAIN OUTCOME MEASURES The primary outcome was the number of respiratory depression episodes. Effect site target remifentanil concentrations, side effects, pain score, patient satisfaction and incidence of pregnancy were also recorded.

RESULTS No significant difference in the incidence of respiratory events was noted (pulse oximetry oxygen saturation < 95% was 49% in the ketamine group and 63% in the control group; P = 0.121). No patient required ventilatory support. In the ketamine group, visual analogue pain score and remifentanil concentrations were significantly reduced, but the latter remained above 2 ng ml−1. Postoperative nausea was less frequent in the ketamine group, 4 versus 15% (P = 0.038). The addition of ketamine did not influence length of stay nor patient satisfaction.

CONCLUSION The addition of low plasma levels of ketamine to a TCI remifentanil conscious sedation technique did not decrease the incidence nor the severity of respiratory depression. Continuous monitoring of capnography and oxygen saturation is always required.

TRIAL REGISTRATION EUDRACT number 2013-003040-23.

From the Department of Anaesthesia, Ambroise Paré Hospital, Mons (HIM) and CUB Erasme Hospital, Free University of Brussels, Brussels, Belgium (SR-L, SS, EE, LAB) From the Department of the Fertility Clinic, CUB Erasme Hospital, Brussels, Belgium (AD)

Correspondence to Luc A. Barvais, MD, PhD, Head of Cardiovascular and Thoracic Anaesthesia Clinics, Department of Anaesthesia, Erasme Hospital, Route de Lennik 800, 1070 Brussels, Belgium E-mail: Luc.barvais@erasme.ulb.ac.be

Published online 30 April 2018

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Introduction

Since the first successful IVF in 1978, the surgical technique for oocyte retrieval has evolved. With the development of ultrasound, transvaginal ultrasound-guided puncture of the ovaries has reduced the risk of complications and improved the success rate of oocyte retrieval.1 Anaesthesia and analgesia for oocyte retrieval has also evolved, towards less invasive techniques such as conscious sedation, electro-acupuncture or a combination of different techniques.2

The large majority of oocyte retrieval procedures is now undertaken with conscious sedation. The goal is to obtain adequate pain relief for puncture of the vaginal mucosa, puncture of the capsule of the ovary and the required manipulation of the ovary during the procedure.3

Thus, the sedation technique should be flexible to cover the painful peaks and have a short duration of action and minimal side effects to allow rapid patient discharge. The technique must also be free of deleterious effects on the oocytes and embryos. To date, no anaesthetic technique has demonstrated superiority in terms of efficacy, safety or analgesia, but conscious sedation was preferred to other anaesthetic techniques in 84% of the oocyte retrieval procedures performed in the United Kingdom and in 95% of cases performed in the United States.4–6

Since 2009, our technique, at the Erasme Hospital, Brussels, has been a combination of anxiolysis (with low doses of alprazolam and midazolam) and titration of remifentanil using a target-controlled infusion (TCI). The effect site target concentration of remifentanil is adjusted to maintain the visual analogue pain score (VAS) less than or equal to 30 mm. During the sedation, the occurrence of bradypnoea with or without oxygen desaturation is quite frequent (33.5% according to a pilot study conducted in 2008), but this has always been resolved by verbal stimulation to the patient.

The main objective of this prospective, double-blind, randomised controlled study was to assess whether the addition of a low-dose ketamine infusion to the TCI remifentanil would reduce the number of episodes of respiratory depression or oxygen desaturation.

The secondary objectives were the assessment of postoperative analgesia, patient satisfaction, the number of side effects due to opiates and the rate of biological pregnancy.

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Methods

The study was conducted in the Erasme Hospital, a tertiary-level hospital in Brussels, Belgium, from December 2013 to June 2014. The study was approved by the local Ethics Committee (number P2013/245, 10 September 2013) and was registered [EUDRACT number (No. 2013-003040-23)].

Patients were subsequently recruited by two methods. For new patients, recruitment took place during the pre-operative anaesthetic consultation. For those patients previously seen by an anaesthetist, recruitment was undertaken via telephone contact a few days before surgery. After obtaining informed consent, patients were randomised into two groups based on a computer-generated randomisation list (QuickCalcs program; GraphPad Software Inc, La Jolla, San Diego, California, USA). As the study was designed to be double blinded, group allocation was concealed from both the patient and the anaesthetist involved with the oocyte retrieval procedure.

The inclusion criterion was any female patient undergoing oocyte retrieval by transvaginal ultrasound-guided ovarian puncture. Exclusion criteria were allergy or contra-indication to the use of ketamine (psychiatric disease, coronary insufficiency, intracranial hypertension, thyrotoxicosis or the presence of raised intraocular pressure).

On the day of the procedure, patients were fasted for 6 h prior to anaesthesia. All patients received oral premedication with 1 g of paracetamol (Prodafalgan, Bristol Myers, Squibb), 10 mg of butyl-hyoscine (Buscopan, Boehringer Ingelheim) and 0.5 mg of alprazolam (Xanax, Pfizer, New York City, New York, USA). In the operating room, after intravenous access was established, all patients received 0.033 mg kg−1 of midazolam i.v. and antiemetic prophylaxis with 5 mg of i.v. dexamethasone (Aacidexam, Aspen). The ketamine group received conscious sedation with a ketamine infusion and a TCI of remifentanil titrated to maintain a pain VAS equal to or less than 30 mm, whereas the control group received a placebo (0.9% saline) infusion along with the same doses of midazolam and TCI remifentanil.

The anaesthetist explained the visual analogue scale for pain assessment to each patient during the pre-operative visit or during the phone call recruitment and repeated the explanation in the operation room before the bolus dose of midazolam: VAS (0 mm = no pain, 100 mm = worst pain imaginable). Patients were then assigned to one of the two groups using the randomisation list. Syringes labelled ‘Group A’, containing ketamine (Ketalar, Pfizer) at a concentration of 1 mg ml−1, and ‘Group B’, containing 0.9% saline, were prepared by an independent anaesthetist. These labelled syringes were then given to the anaesthetist in charge of the conscious sedation who remained blind to the contents of the syringes.

In addition to standard monitoring [noninvasive blood pressure (NIBP), continuous pulse oximetry oxygen saturation (SpO2) and a 3-lead ECG], the depth of sedation was monitoring using the bispectral index (BIS, XP version; Medtronic, Minneapolis, Minnesota, USA). All patients received oxygen (2 l min−1) via nasal cannulae, which also enabled expired CO2 to be monitored (CapnoLine; Medline, Mundelein, Illinois, USA), thus allowing continuous monitoring of the breathing rate.

A rapid infusion of ketamine (40 μg kg−1 min−1) was administered over 5 min (i.e. a total dose of 0.2 mg kg−1) followed by a continuous infusion at a fixed rate of 2.5 μg kg−1 min−1 until the end of the surgery. The administration of the ketamine was controlled using TIVAtrainer pharmacokinetic simulation Software (Gutta BV, Aerdenhout, the Netherlands) using the model of Clements and Nimmo.7 At the infusion rates described above, this model predicts a theoretical plasma concentration of ketamine of 100 ng ml−1. In the control group, the delivery of 0.9% saline followed the same infusion scheme.

The TCI remifentanil was guided by a standardised protocol. A TCI Fresenius Agilia (injectomat agilia TIVA; Fresenius-Vial, Brezins, France) pump, using the Minto pharmacokinetic model, was used for the remifentanil infusion and the concentration was targeted according to the age, weight, height and sex of the patient.8 A concentration of 2 ng ml−1 of remifentanil was established before the start of the procedure, and the surgeon waited a further 2 min before the first painful stimulation. This concentration was increased in increments of 1 ng ml−1 until the pain experienced by the patient was less than 30 mm on the VAS. The remifentanil concentration was decreased at the onset of respiratory depression or excessive sedation. Hypopnoea (defined as breathing rate less than 8 bpm as observed on the capnographic trace, without oxygen desaturation) was treated by verbal stimulation (breathe deeply madam). Moderate respiratory depression (oxygen desaturation with SpO2 between 90 and 94%) was treated by changing the target concentration of remifentanil in decremental steps of 1 ng ml−1. Major respiratory depression (with desaturation SpO2 < 90%) was managed by the reduction of the target concentration of remifentanil by 2 ng ml−1 and verbal stimulation.

The Observer's Assessment of Alertness and Sedation Scale (OAAS) was used to measure the level of alertness in all the patients every 5 min.9 Excessive sedation (OAAS < 3) was managed by a decrease in remifentanil concentration by 1 ng ml−1. The administration of remifentanil and ketamine (or 0.9% saline) was stopped after the aspiration of the last follicle as this heralded the end of the procedure.

The patient was transferred to the postanaesthesia care unit (PACU) when the residual remifentanil concentration was less than 1 ng ml−1.

The values of NIBP, SpO2 and respiration rate were recorded every 5 min for the duration of the procedure. Total doses of midazolam, remifentanil and ketamine were recorded as well as the maximum and the most often used remifentanil concentration, and the minimum SpO2. We also recorded the occurrence of side effects: hypopnoea (respiratory rate below 8 bpm without oxygen desaturation), moderate respiratory depression (hypopnoea with SpO2 between 94 and 90%), major respiratory depression (hypopnoea with SpO2 < 90%), global respiratory impairment (hypopnoea with or without oxygen desaturation), tachycardia, hypertension, pruritus, nausea and vomiting, hallucinations, visual disturbances or unrest.

We specifically assessed the patients’ level of pain at three time points (20 s after the transvaginal puncture of the first ovary, 20 s after the transvaginal puncture of the other ovary and at the end of surgery) and their associated BIS values, OAAS score and remifentanil concentration at these time points. At the end of the intervention, the operating time (time from the introduction of the speculum to the withdrawal of the needle), the duration of occupation of the operating room (from the arrival of the gynaecologist until the patient left the operating room for the PACU), the minimum BIS values, the number of follicles punctured and the number of oocytes harvested were recorded.

We defined four protocol failure criteria: nonrapidly reversible excessive sedation (i.e. induction of unwanted general anaesthesia), a necessity to provide ventilatory assistance (airway manipulation, facemask or laryngeal mask ventilation), inadequate analgesia (high pain scores, uncontrolled by increasing the remifentanil concentration) and the occurrence of debilitating hallucinations.

In the PACU, four parameters were evaluated: the pain score and sedation of patients on arrival, the duration of their stay (assessed by the anaesthetist responsible for the PACU who was blind to patient allocation), the pain score at discharge from PACU and the analgesic treatment administered. Erasme Hospital's usual postoperative analgesia protocol was used, namely IV piritramide titration (Dipidolor; Janssen-Cilag, Beerse, Belgium) 2 mg every 5 min to maintain the VAS less than 30 mm. The occurrence of side effects such as pruritus, postoperative nausea and vomiting (PONV) and hallucinations were recorded. At two time points (discharge from the PACU and at nursing evaluation in the afternoon), the patient satisfaction was assessed using two scales. The first scale had four points: 4) very satisfied, 3) satisfied, 2) moderately satisfied, 1) not satisfied. The second evaluation was to ask patients whether they would choose the same sedation protocol for a future oocytes retrieval procedure.

The pain score, as well as the side effects and maximum pain score, experienced during the day were noted just before the final discharge of the patient.

Finally, the success rates of the procedure through the establishment of a pregnancy were analysed. To confirm this biological pregnancy, we measured the concentration of human chorionic gonadotropin (HCG) in a blood sample taken 15 days after implantation of the embryos resulting from the oocyte retrieval procedure: we used a threshold value of 4 mIU ml−1 as indicative of a biological pregnancy.

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Statistical analysis

A pilot study conducted in 2008 evaluated the efficacy and safety of our institution's standard conscious sedation protocol with midazolam and remifentanil TCI. That protocol used the same anxiolytic technique (alprazolam and midazolam) and an identical management of remifentanil concentration as the current study. Using the data from this pilot study, we calculated that the minimum size of each group had to be at least 60 patients to demonstrate a reduction in the frequency of overall respiratory impairment (i.e. including the three types of respiratory depression, hypopnoea without oxygen desaturation, moderate or major respiratory depression with either SpO2 below 95 or 90%, respectively) from 33.5 to 10% with 90% power and a bilateral α-error of 5%.

Continuous data (patient characteristics, drug doses, SpO2, BIS, satisfaction scores, pain VAS) were analysed using the Mann–Whitney U test, whereas dichotomous data (side effects, biological pregnancy, acceptance of the protocol) were analysed with the Chi-squared test. We used version 9.0 of the Statistix software (Analytical software, Tallahassee, Florida, USA) to process the data, and the results are presented as mean ± SD or number (%). P values less than 0.05 were considered statistically significant.

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Results

During the 7 months of recruitment, 575 patients underwent oocyte retrieval procedures. From the 202 patients who consented for the study, we experienced a 32% loss due to organisational problems, mainly due to the variable individual responses to hormonal stimulation resulting in a rescheduled procedure. Five patients were lost due to staff refusal. A total of 132 patients were included in this study (Fig. 1). No patients were excluded because of contra-indications to ketamine. We experienced a further 10% loss of data from these 132 patients due to the procedure being undertaken during a weekend.

Fig. 1

Fig. 1

There was no significant difference between the two groups in terms of patient characteristics, ASA classification, risk factors for PONV or respiratory problems. Only the incidence of endometriosis was found statistically different between the groups (P = 0.025) (Table 1).

Table 1

Table 1

Regarding our primary objective, the incidence of respiratory depression, no statistically significant difference was found between the groups (Table 2). The occurrence of global respiratory impairment (hypopnoea with or without desaturation) was 59% in the ketamine group and 63% for the control group, whereas the desaturation rate (SpO2 < 95%) was 49 and 63%, respectively (Table 2). Twenty-one patients in the ketamine group experienced major respiratory depression (hypopnoea with SpO2 < 90%) versus 25 in the control group. Reassuringly, no patient, regardless of group allocation, required respiratory support (airway manipulation, insertion of Guedel airway, facemask ventilation or laryngeal mask insertion).

Table 2

Table 2

Intra-operatively, no patient experienced general anaesthesia induced by accidental excessive sedation (OAAS > 3). No difference was found in the quality of conscious sedation [mean intra-operative OAAS scores were 4.4 ± 0.7 (ketamine group) and 4.5 ± 0.7 (control group)] (Table 3). The bispectral index remained above 85 throughout the procedure in both groups (Table 3).

Table 3

Table 3

The administration of ketamine not only reduced the consumption of remifentanil but also reduced the VAS scores (Table 3). In the ketamine group, 20% of patients had a pain VAS more than 30 mm at the beginning of the procedure, compared with 33% in the control group. A pain VAS more than 30 mm was observed midintervention in 17 and 53% of patients in ketamine and control groups, respectively.

The incidence of intra-operative side effects attributable to remifentanil (pruritus, nausea, vomiting) or ketamine (hallucination, visual impairment, hypertension or tachycardia) was not statistically different between the groups (Table 2). Neither the duration of the procedure nor the time in the operating room was different between the groups: operating time 13 ± 6 min (ketamine group) versus 14 ± 7 min (control group), P = 0.121; time in operating room 25 ± 9 min (ketamine group) and 27 ± 8 min (control group), P = 0.182.

Postoperatively, there was no statistically significant difference in terms of pruritus, vomiting or hallucination, but nausea was more common in the ketamine group during the late postoperative period in the hospital ward (Table 2). Postoperative pain scores were low overall with no statistically significant differences between the groups (Table 4). The additional analgesic needs were moderate in both groups but statistically higher in the control group during the stay in the hospital ward (Table 4). The average time of stay in the PACU was short in both groups, 43 ± 17 min (ketamine group) versus 44 ± 22 min (control group).

Table 4

Table 4

There were no differences between the groups in the number of punctured follicles (ketamine group 10 ± 7 versus control group 12 ± 8, P = 0.448), the number of oocytes harvested (ketamine group 7 ± 5 versus control group 8 ± 15, P = 0.779) or the number of pregnancies obtained (ketamine group 49% versus control group 37%, P = 0.221).

There was no difference between the groups in terms of patient satisfaction or future acceptance of the same protocol should additional procedures be required (Table 4). In both groups, satisfaction scores were high: ketamine group 3.6 ± 0.6 versus control group 3.5 ± 0.8.

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Discussion

During oocytes retrieval procedures, an effective analgo-sedation technique is essential for maintaining intra-operative VAS within acceptable limits. A Cochrane review of the literature on intra-operative IVF analgesia did not demonstrate the superiority of one anaesthetic technique over another in terms of effectiveness.4

Different anaesthetic methods have been investigated. In 1990, Ramsewak et al. studied pain at needle insertion during oocyte retrieval under conscious sedation, comparing a fentanyl bolus with 0.9% saline. VAS scores were 39 ± 8 mm in the fentanyl group versus 56 ± 9 mm in the saline group.10 Humaidan et al. compared the combination of a paracervical block with either electro-acupuncture or a conscious sedation technique (benzodiazepine and alfentanil bolus) in 200 patients scheduled for oocyte retrieval.11 They found that patients receiving conscious sedation with a paracervical block had significantly lower mean and maximum VAS: mean intra-operative VAS 26 ± 18 versus 18 ± 17 mm and mean maximum VAS 46 ± 25 versus 32 ± 23 mm for the conscious sedation with paracervical block versus electro-acupuncture with paracervical block, respectively.

The main objective of the current study was to evaluate whether the addition of a low plasma concentration of ketamine to remifentanil TCI titrated to obtain a pain VAS score or less 30 mm could reduce the incidence of global respiratory impairment. The infusion rate sequence of ketamine generated and maintained a theoretical low-plasma ketamine concentration of 100 ng ml−1 and allowed patients to maintain alertness and response to verbal stimulation.

The high prevalence of respiratory depression, when using remifentanil in spontaneous breathing patients is well known. In 2011, an oocyte retrieval study by Coskun et al.12, using a combination of propofol TCI with three different remifentanil concentrations, showed an increased risk of desaturation with increased remifentanil concentration. A remifentanil concentration of 1.5 ng ml−1 was not associated with respiratory depression, but it resulted in insufficient analgesia in 26% of patients. Remifentanil concentration values ≥ 2 ng ml−1 increased the risk of airway obstruction requiring anaesthetist intervention: 9% of cases with a remifentanil concentration of 2 ng ml−1 and 22% of cases with remifentanil concentration to 2.5 ng ml−1.12

In our study, compared with the control group, we noted a reduction in both the average and maximum required remifentanil. Despite this, the addition of ketamine did not result in a statistically significant difference in respiratory depression. This could be explained by the fact that to attain a VAS less than 30 mm, the ketamine infusion did not enable a sufficient reduction in the remifentanil concentration: in both groups, the concentration to maintain a VAS of 30 mm or less was always above 2 ng ml−1.

Pain scores, recorded at the start and in the middle of oocyte retrieval, were significantly higher in the control group, necessitating further increases in the remifentanil concentration during the procedure. The reduced VAS in the study group could be due to the fact that ketamine is a dissociative anaesthetic with analgesic properties at subanaesthetic doses. It is the most potent N-methyl-D-aspartate-receptor-blocker available for clinical use.13

Recent literature has shown that ketamine has antidepressant and mood modulation effects.14 Women undergoing oocyte retrieval treatment are usually anxious and a large component of the pain experience during the procedure could be due to this. It is possible that ketamine was not only able to reduce pain due to its analgesic properties, but also was able to reduce the patients’ anxiety.

One limitation of our study protocol was the administration of alprazolam and midazolam to prevent ketamine side effects, as these gamma-amino butyric acid-ergic drugs interact synergistically with opioids leading to respiratory depression: the respiratory depressive effect of benzodiazepines affects primarily the tidal volume rather than the respiratory rate.15 Regardless of group allocation, patients responded to verbal stimulation and maintained spontaneous ventilation and no patient required respiratory assistance.

Postoperative pain was anticipated by premedication based on paracetamol and butylhyoscine. The intra-operative administration of ketamine significantly reduced the demand for analgesics back on the ward.

Patient satisfaction was high in both groups and over 90% of patients would accept the same technique for a future oocyte retrieval procedure. Good acceptance of a sedation technique for these types of procedures is important: the pregnancy rate leading to a live foetus is only 25 to 30%,16 and patients generally undergo several cycles of stimulation and oocyte retrieval before carrying a pregnancy to term.

Failures of the sedation technique occurred in both groups with one patient per group having a high VAS due to uncontrollable pain, despite a very high remifentanil concentration.

The Apfel score in our study population was elevated (2.4 ± 0.6), corresponding to an estimated risk of more than 39% of PONV. Routine prophylaxis with dexamethasone and the addition of ketamine considerably reduced the incidence of nausea in the postoperative period.17

The speed of onset and offset of remifentanil has allowed us to reduce the time interval between the induction of sedation and the beginning of the procedure, as well as the time interval between the end of the procedure and the transfer of the patient to the PACU. This has optimised operating room turnover, with an average occupancy time of 25 ± 9 min. The addition of low-dose ketamine did not alter the rapidity of the turnover.

The impact of anaesthetic agents on the biological fate of oocytes and embryos from oocyte retrieval procedures is largely unknown, with the result that healthcare professionals tend to limit the drugs administered to patients. In our study, the number of punctured follicles, oocytes harvested and pregnancy rates based on blood HCG were the same in both groups, suggesting that the ketamine had no additional deleterious effects on the success rate of the procedure.

Future studies on conscious sedation for oocyte retrieval with ketamine in addition to remifentanil need to investigate the predicted plasma concentration of ketamine which would enable the remifentanil concentration to be less than 2 ng ml−1.

Finally, our experience indicates that during conscious sedation techniques using remifentanil, trained anaesthesia personnel should always be present to monitor patients for respiratory depression, using both continuous capnography and oxygen saturation.

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Conclusion

In this prospective, double-blind, randomised controlled trial, the addition of a low-dose ketamine infusion to a remifentanil TCI conscious sedation technique did not reduce the incidence or the severity of respiratory depression. Adding low-dose ketamine is not associated with clinical benefits, as the required remifentanil concentration is still more than 2 ng ml−1. Because of the incidence of respiratory depression, continuous monitoring of the patient with capnography and oxygen saturation is required during a remifentanil TCI conscious sedation technique.

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Acknowledgements relating to this article

Assistance with the study: we would like to thank the gynaecologists and the nurses of the fertility clinic. Without their support, this study would not have been possible.

Financial support and sponsorship: the Department of Anaesthesiology and the fertility clinic of the Erasme Hospital, Brussels, Belgium, supported this work.

Conflicts of interest: none.

Presentation: none.

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