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Hum. Reprod. Advance Access originally published online on June 21, 2006
Human Reproduction 2006 21(10):2606-2611; doi:10.1093/humrep/del234
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A double-blind, randomized controlled trial on the use of a 50:50 mixture of nitrous oxide/oxygen in pain relief during suction evacuation for the first trimester pregnancy termination

Anita Sik Yau Kan1,4, Natalie Caves2, Sylvia Yuen Wai Wong3, Ernest Hung Yu Ng1 and Pak Chung Ho1

1 Department of Obstetrics and Gynaecology 2 Department of Anaesthesiology and 3 Operation Theatre Service, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China

4 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China. E-mail: kansy{at}ha.org.hk


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: This prospective study assessed the role of a 50:50 mixture of nitrous oxide (N2O) and oxygen for pain relief during the termination of first trimester pregnancies by suction evacuation under conscious sedation. METHODS: Ninety women undergoing suction evacuation up to 12 weeks of gestation were randomized by a computer-generated randomization list and allocated using sealed envelopes to receive the N2O/O2 mixture or air during the operation. Pain scores during and after suction evacuation, post-operative side effects and satisfaction level were compared. RESULTS: No statistically significant differences in pain scores, post-operative side effects and satisfaction levels were found between the two groups. CONCLUSION: N2O/O2 did not reduce the pain level during suction evacuation for the first trimester pregnancy termination under conscious sedation.

Key words: N2O/oxygen/pain relief/suction evacuation


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Entonox [50% nitrous oxide (N2O) and 50% oxygen] is an inhalational analgesic agent commonly used to control labour pain. While it has been extensively studied for obstetric use, its use in gynaecological practice has seldom been reported. Midwives usually offer Entonox to parturient women, who can self-administer it after initial supervision. It has a quick onset of action and quick recovery time. It also possesses amnesic and anxiolytic effects, which are beneficial for patients undergoing short surgical procedures. Nitrous oxide sedation has widespread use in other specialties including dentistry (Davies et al., 1975Go), emergency medicine (Roberts et al., 2003Go) and fracture reduction in children (Wattenmaker et al., 1990Go), where it is considered effective and safe.

Suction evacuation is a common minor gynaecological procedure performed worldwide. The common indications include termination of pregnancy, management of miscarriages and molar pregnancy. While it can be done under general or local anaesthesia, the latter is associated with lower morbidity. Although it is a brief procedure lasting for ~5 to 10 min, 97% of women experience pain during abortion (Belanger et al., 1989Go). Pain mainly comes from two components: cervical dilatation and uterine contractions during the suction procedure. Paracervical block has been shown to reduce the level of pain of suction evacuation in several studies (Wiebe, 1992Go; Donati et al., 1996Go; Cetin and Cetin, 1997Go; Glantz and Shomento, 2001Go). However, its efficacy was not shown in our previous randomized study when suction evacuation was performed under intravenous sedation after cervical priming with misoprostol (Kan et al., 2004Go). The uterine cramps experienced during suction evacuation are similar to labour pain, which is due to uterine contraction and ischaemia. In a systematic review on nitrous oxide for relief of labour pain, no objective, quantitative evidence of its analgesic efficacy could be demonstrated (Rosen, 2002Go). However, nitrous oxide appears to provide benefit for many parturient women, who describe effective analgesia with nitrous oxide use and would choose to continue its use even after the study period had ended. In one study, a dose-dependent analgesic effect was observed (Westling et al., 1992Go), whereas Carstoniu et al. (1994)Go failed to show any beneficial effect of self-administered nitrous oxide in pain relief during labour. Whether or not Entonox can relieve the pain experienced during suction evacuation has yet to be studied.

The aim of this double-blind, randomized controlled trial was therefore to assess the role of Entonox in pain relief during the termination of first trimester pregnancies by suction evacuation under conscious sedation.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Protocol
The study was approved by the local institutional review board. Women attending the Department of Obstetrics and Gynaecology, the University of Hong Kong, at Queen Mary Hospital for suction termination of pregnancies under conscious sedation were recruited when the following criteria were met: (i) age of women >16 years; (ii) normal general and gynaecological examination; (iii) up to 12 weeks gestation on the day of recruitment and (iv) the size of the uterus on pelvic examination compatible with the estimated duration of pregnancy. Those with history of severe respiratory or cardiac disease, severe and recurrent liver disease, myasthenia gravis, psychiatric conditions requiring medication or disorders that constitute contraindications to the use of prostaglandins were excluded. Those with a history of Entonox use, upper respiratory infections or sinus blockage, recent history of middle or inner ear surgery or history of bone marrow suppression were also excluded.

Assignment to study group
Patients were approached by one designated research nurse who kept the randomization list which had been generated by a computer program. Every patient was fully counselled and gave written informed consent before participation in the study. An opaque, sequentially numbered envelope containing the allocated intervention was attached to the participating patient’s record. The study group was Entonox whereas the control group was air. On arrival in the operating theatre, this envelope was opened by the theatre nurse, who supervised administration of the allocated gas and who was not involved in the assessment of pain scores.

Assessment of pain, anxiety, sedation and satisfaction levels and the presence of side effects
A project nurse who was not involved in the operation evaluated each patient’s pain, anxiety and satisfaction levels and the presence of post-operative side effects. Basal anxiety levels were assessed using the Chinese version of the State Anxiety Questionnaire (Shek, 1993Go). Thereafter anxiety levels were measured using a 100-mm linear visual analogue scale (VAS; 0 = none, 100 = most severe). Pain levels were also evaluated throughout using a 100-mm linear VAS (0 = none, 100 = most painful). The level of sedation achieved was graded according to a sedation scale proposed by Ramsay et al. (1974)Go (level 1: patient anxious and agitated or restless or both; level 2: patient co-operative, orientated and tranquil; level 3: response to commands only; level 4: asleep and a brisk response to a loud auditory stimulus; level 5: asleep and a sluggish response to loud auditory stimulus and level 6: asleep and no response to loud auditory stimulus). Satisfaction levels (excellent, satisfactory, fair and unsatisfactory) and the presence of side effects including nausea, vomiting, dreams, paraesthesia, dizziness, dry mouth, memory of operation and euphoria were assessed using a simple questionnaire.

Procedure
Once a patient was admitted into the study their basal anxiety level was assessed in the ward. They were subsequently asked to rate their pain levels during venepuncture, insertion of intravenous cannula and during vaginal examination. Before suction evacuation, prophylactic antibiotics were given to patients according to our departmental protocol and 400 µg misoprostol was given vaginally 3–6 h before the operation for cervical priming (Ngai et al., 1999Go).

After admission into the operating theatre, the patient’s pre-operative anxiety level was evaluated by a theatre nurse not involved in assessment of pain score. Routine monitoring was commenced consisting of continuous electrocardiogram (ECG) and pulse oximetry recording, and intermittent non-invasive blood pressure monitoring at intervals of 5 min. In addition, the patient’s respiratory rate, fractional inspired oxygen and fractional inspired nitrous oxide levels were measured throughout the procedure via a sample line that connected the T-piece breathing circuit to the anaesthetic gas monitor (Hewlett Packard M1026A).

Conscious sedation was then administered using 2 mg midazolam and 25 µg fentanyl intravenously, as described by Wong et al. (2002)Go. After 2 min, the doctor assessed the patient and decided if their sedation level was adequate. A Ramsay sedation scale of level 2 along with the patient self-reporting that she was comfortable for surgery to proceed was considered adequate sedation. If the sedation level was felt to be inadequate, a further 1 mg intravenous (i.v.) dose of midazolam was given. Continuous verbal communication with the patient was maintained at all times. Entonox or air was supplied via a face mask and T-piece breathing circuit. The patient was instructed to begin inhalation by the theatre nurse. The face mask had a demand valve, which opened only when the user applied negative pressure by inspiring through the mask. The patient was instructed to continue inhaling the gas when she felt pain.

The cervix was then dilated with Hegar dilator if necessary, and suction evacuation was performed using a number 8 or 10 Karmen catheter with an electrical vacuum machine. The need for additional analgesia (50 mg i.v. pethidine) was recorded. Any adverse events during the operation were noted. Need for cervical dilatation, size of Hegar dilator used and duration of operation were recorded. Paracervical block was not given in our practice because pain relief was not demonstrated in our previous study (Kan et al., 2004Go).

The patient’s pain level during the procedure, 1 h post-procedure along with the anxiety and satisfaction levels and the presence or absence of side effects were assessed (see above) 1 h after the operation. All patients were discharged from the hospital 4 h after suction evacuation.

Masking
Both the patient and the surgeon were blinded to the gas being inhaled, which was given by a theatre nurse not involved in the assessment of pain score. The project nurse who assessed the base line and post-operative anxiety level and pain levels was blinded to the study group of the patient.

Statistical analysis
According to our previous study (Wong et al., 2002Go), the pain level of suction evacuation with conscious sedation was 62.8 ± 24.5 (mean ± SD) on a 100-point VAS. Assuming that a 25% reduction of pain level from 62.8 to 47.1 was acceptable after Entonox administration, a sample size of 40 in each arm of therapy was required to give a test of significance of P < 0.05 and a power of 0.8 (Sokel and Rolf, 1981Go). Estimating that up to 10% of patients might be excluded retrospectively from the analysis, we therefore recruited 45 patients in each arm of the study. The primary outcome measure was the pain level during suction evacuation. Secondary outcome measures included the need for additional analgesia, anxiety level, satisfaction level and side effects. Data were expressed as medians (2.5–97.5th percentiles), unless indicated. Statistical analysis was performed using the Statistical Program for Social Sciences (SPSS Inc., Version 11, Chicago, IL, USA). A P value of <0.05 (two-tailed test) was considered statistically significant. Comparison was done by Mann–Whitney U-test for continuous variables and chi-square test and Fisher’s exact test for categorical data. Univariate analysis was applied to evaluate the impact of the age of the women, parity, gestational age, cervical dilatation, duration of operation and sedation scale on the pain level during suction evacuation. Data analysis was performed by the assessor blinded to the assignment groups.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Participant flow
A total of 90 patients were recruited from May 2004 to January 2005. All patients followed the study protocol and were available for analysis as shown in Figure 1.


Figure 1
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  		Figure 1. Flow of participants through the stages of this randomised trial.

 
Analysis
There were no statistically significant differences in the demographic data between the two groups (Table I). The two groups of patients experienced similar pain levels during blood taking, insertion of intravenous catheter, vaginal examination, suction evacuation and 1 h post-suction evacuation (Table II). One patient in the Entonox group required pethidine injection during the operation.


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  		Table I. Comparison of demographic data

 

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  		Table II. Comparison of pain levels measured by 100-mm linear visual analogue scale (0 = none, 100 = most painful)

 
Table III summarizes the anxiety level, sedation level and satisfaction level of the two groups. The patients were most anxious before the operation when they were in the operating theatre, but there was no statistically significant difference between the two groups. Most patients were cooperative, oriented and tranquil during the operation. Two patients in both groups required 3 mg midazolam for intravenous sedation. About one-third of the patients in each group regarded the pain relief as unsatisfactory, though overall more than half of the women would agree to have the operation under the same condition again.


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  		Table III. Comparison of anxiety level, sedation level and satisfaction level

 
The minimum oxygen saturation and fractional inspired oxygen were lower for patients breathing air than Entonox as summarized in Table IV. Patients breathing Entonox achieved a median level of 42% nitrous oxide. Patients in the air group had a significantly faster respiratory rate than those in the Entonox group during the operation (P = 0.006). There was no correlation between fractional inhaled nitrous oxide level or respiratory rate with the pain level of suction evacuation.


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  		Table IV. Comparison of oxygen saturation, fractional inspired oxygen and nitrous oxide level and respiratory rate

 
The presence and severity of post-operative side effects are given in Figure 2, which shows that both the Entonox and the air group had similar side-effect patterns. There were no adverse events in either group during the operation. Karmen catheters of size number 8 or 10 were used in all the patients. The duration of operation was similar between the two groups (median 6 min in Entonox group and 5 min in air group). All patients were discharged on the same day. Three patients in Entonox group and five in air group used additional analgesia after the operation.


Figure 2
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  		Figure 2. Side effects of patients breathing Entonox or air.

 
Univariate analysis showed that pre-operative anxiety level was correlated with the pain level of suction evacuation (B = 0.205, P = 0.042). Age, parity, sedation level and gestational age did not affect the pain levels.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Entonox has been used for over a hundred years for controlling labour pain in obstetrics. However, studies have not provided clear, quantitative, objective evidence of the analgesic efficacy of nitrous oxide for relief of labour pain (Rosen, 2002Go). Limitations of previous studies included methodological flaws like lack of randomization, lack of placebo or treatment controls, failure to blind the investigators and non-standardized methods of measuring pain (Carstoniu et al., 1994Go). Therefore, we designed this study to assess its use in suction evacuation under a randomized, controlled and blinded setting to reduce bias.

Air was used as the control agent in this study. Women were blinded to the treatment; they were given the face mask and instructed to continue inhaling the gas when they felt pain. To reduce bias further, women who had had history of Entonox use, mainly those multiparous women who used Entonox in previous labour, were excluded from the study because they might remember the characteristic smell of Entonox and realize into which of the treatment group they were allocated. The pain level was measured objectively using the 100-mm VAS and by the project nurse, who was not aware of the study group of the patient. The doctor who performed the operation was also unaware of the study group into which the patient was allocated.

Suction evacuation is a painful procedure as rated by our patients in this study. The mean pain level was 79.8, which was comparable with our previous study in the subgroup of patients when no paracervical block was given (Kan et al., 2004Go). The very high level of pain may be related to the fact that most patients (80%) were nulliparous in our study, and most required cervical dilatation, which is known to be painful. Although cervical priming with misoprostol reduces the need for cervical dilatation, the cervices of nulliparous women are relatively tighter than those of multiparous women, when cervical dilatation is often not necessary. Only nine of our study patients did not require cervical dilatation before suction evacuation (four in Entonox, five in air group). It is therefore not surprising that women experienced significant pain during the procedure.

Over 90% of the patients were co-operative, orientated and tranquil during the operation although they reported significant pain. We limited the dose of intravenous sedation used to ensure patient safety. In addition to its analgesic action, Entonox also possesses some sedative effects and therefore oversedation of patients with associated respiratory depression was a concern. Patients were given a 2 mg intravenous bolus of midazolam and were then assessed before the suction evacuation to see if they required an additional top-up dose of 1 mg intravenous midazolam. Three patients in each group received this top-up.

One limitation of this study was the inability to quantify the amount of Entonox that patients had received. We measured the fractional inhaled nitrous oxide level and respiratory rate as an indirect way to reflect the amount of Entonox the patient had inhaled. The exact amount of gas inhaled varied according to the patients’ tidal volumes and the total number of inhalations each patient made, neither of which was measured in this study. There was no correlation between either the fractional inhaled nitrous oxide level or the respiratory rate and the pain level experienced by the patient. Because suction evacuation is a very short procedure (median of 5–6 min in our study), there is also little chance to pick up any differences in blood pressure as it was only measured at every 5-min interval in this study.

This randomized controlled trial failed to show any benefit of using Entonox in patients undergoing suction evacuation for termination of pregnancy. There was no difference in pain level in the Entonox group compared with the control group. It may be related to the lack of analgesic effect of Entonox for suction evacuation or due to inadequate concentration of nitrous oxide being achieved by this administration method. Yet we failed to distinguish between the two because the quantity of gas inhaled could not be measured, and no correlation was found between the fractional inspired nitrous oxide level and pain. Westling et al. (1992)Go showed that continuous inhalation of nitrous oxide provided more pronounced degree of pain relief compared to intermittent inhalation. Therefore, we concluded that self-administered Entonox was not useful for pain relief in suction evacuation during the first trimester pregnancy termination under intravenous sedation.

Pre-operative anxiety level was correlated with the level of pain perceived by patients. This relationship was observed in previous clinical studies (Scott et al., 1983Go; Kain et al., 2000Go; Ng et al., 2002Go; Pud and Amit, 2005Go). The clinical implication is that utilizing anxiety-reducing therapies might be beneficial for pain relief. Therefore, apart from analgesia, adequate sedation should be an important aspect of operative management of suction evacuation. Non-pharmacological measures including information giving and cognitive-behavioural intervention before surgery also have a positive influence on the pre-operative anxiety and experience of pain after surgery (Doering et al., 2000Go; LaMontagne et al., 2003Go; Sjoling et al., 2003Go). It is uncertain whether these measures are also useful to reduce pain of suction evacuation and is worthwhile to explore.

In conclusion, self-administered Entonox did not reduce pain level during suction evacuation for the first trimester pregnancy termination under conscious sedation.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Ngai SW, Chan YM, Tang OS, Ho PC. (1999) The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial. Hum Reprod 14:82139–2142.[Abstract/Free Full Text]

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Submitted on March 16, 2006; resubmitted on May 16, 2006; accepted on May 18, 2006.


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