The Use of Inhaled Nitrous Oxide for Flexible Sigmoidoscopy: A Placebo-Controlled Trial

• Introduction
• Patients and Methods
• Setting
• Flexible Sigmoidoscopy
• Patient Assessment
• Results
• Discussion
• Acknowledgments
• References

Background and Study Aims: Flexible sigmoidoscopy is a widely used diagnostic technique which is increasingly being adopted as part of bowel cancer screening programmes. It is conventionally performed without sedation or analgesia, but significant numbers of patients experience mild to moderate discomfort during the procedure. The aim of this study was to assess the usefulness of self-administered nitrous oxide to reduce discomfort during flexible sigmoidoscopy, which may have an effect of improving compliance.

Patients and Methods: In a double-blind, randomized, placebo-controlled study, 87 patients were enrolled. Of these, 45 received nitrous oxide/oxygen (50 % mix) to inhale during the procedure and 42 received oxygen alone. The patients recorded their opinions on the efficacy of the agent in a questionnaire after the examination. The endoscopist recorded the success of the procedure.

Results: The groups were well matched for age and sex. Significant reductions in levels of discomfort and increased levels of agreement to undergo the procedure again were noted for the actively treated group (P < 0.05). No significant differences in side effects or success of the procedure were observed.

Conclusions: The addition of self-administered nitrous oxide offered significant benefits in the area of patient discomfort during flexible sigmoidoscopy. The availability of this agent is useful in clinical practice and may enhance compliance with a screening programme.

Introduction

Flexible sigmoidoscopy is a widely used technique for diagnostic examination of patients with symptoms attributable to the lower gastrointestinal tract. It is now also included as an integral part of the screening programme for bowel cancer in the USA [1]. Current practice is generally for flexible sigmoidoscopy to be performed in the clinic or outpatient setting without sedation or analgesia. This allows the procedure to be quickly and efficiently performed without the need for a significant recovery period or accompanying companion for the patient. However, more than a third of patients experience significant discomfort during the procedure [2] [3] . This may carry a significant deterrent effect, especially for patients needing recurrent examinations, or who were asymptomatic entrants into a screening programme.

Self-administered nitrous oxide/oxygen (N₂O/O₂) has been shown to provide effective analgesia for colonoscopy [4] [5] . In this situation it has been compared to conventional sedation with a benzodiazepine and opiate. Evidence shows that recovery from N₂O/O₂ in this situation is very rapid, without the delays associated with injectable analgesics [6]. Evidence for the use of N₂O/O₂ in flexible sigmoidoscopy is limited and conflicting [7] [8] .

The present study was designed to compare patient response to N₂O/O₂ versus a placebo (oxygen) in patients undergoing flexible sigmoidoscopy. We also assessed whether the active agent produced greater success in completing the examination.

Patients and Methods

Setting

The study was undertaken in the endoscopy unit of Stafford General Hospital. After approval from the local ethics committee, all patients attending for flexible sigmoidoscopy over a 6-month period were invited to participate (87 patients enrolled). Patients who were driving themselves were excluded from this study. Informed consent was obtained.

Randomization was performed using a sealed-envelope technique of block randomization. The gas cylinders were covered beneath the endoscopy trolley, meaning that both patient and endoscopist were unaware of the allocated grouping. The patients received either N₂O/O₂ (Entonox; British Oxygen Company Ltd., Manchester, UK) or oxygen, administered via a mouthpiece. The attending nurse gave brief instructions on appropriate usage. The patients were instructed to breathe the agent as and when they felt discomfort.

Flexible Sigmoidoscopy

The patient preparation for the examination was standard for this unit: two sachets of Klean-Prep (Polyethylene glycol; Norgine Pharmaceuticals, Harefield, UK) and a low-residue diet. The examination was performed by one of five endoscopists, all experienced in performing diagnostic and therapeutic flexible sigmoidoscopy. Pulse rate and oxygen saturation were monitored during the procedure. Immediately after completing the examination, the endoscopist recorded the anatomical level reached (as assessed by the endoscopist), the findings and therapies undertaken (if any) plus a subjective recording of the patient's degree of discomfort.

Patient Assessment

After completing the examination, patients filled in a short questionnaire. Demographic details were recorded (age, sex, whether they had previously undergone the examination, and whether they actually used the gas offered). They then indicated their agreement (or otherwise) with six statements which explored their attitude to the administered agent (Table [1]). The answers were given using a summative (Likert) scoring system (from 1 to 10).

Statistics. The data were considered to be not normally distributed and were therefore analysed using the Mann-Whitney U test. Fisher's exact test was used to compare the levels reached, endoscopy type, and the demographic data. Statistical significance was tested at P < 0.05.

Results

Over the 6-month period, 87 patients were enrolled into the study. Of these, 45 were randomly allocated to the Entonox group whilst 42 received oxygen. Five patients in each group did not actually use the offered gas, and so did not answer further questions. Thus the numbers used for data analysis were 40 for the Entonox group and 37 for the oxygen group. No complications were noted in either group.

There was no significant difference in age or sex of the subjects between the two arms of the study (Table [2]).

The questionnaire responses showed significant differences between the two arms for all the factors assessed except for side effects, with Entonox showing improvements in patient comfort and likelihood of reattending (Table [3]).

The endoscopist recorded the type of examination with regard to purely diagnostic features (including routine biopsies) or to whether any therapeutic procedure had been undertaken. The impression of the endoscopist as to the anatomical level reached was recorded. For analytical purposes, examinations were divided into those which reached the descending colon (and so could be regarded as a “complete” examination) and those which did not. The endoscopists scored their subjective impression of the pain experienced by the patient (nil, mild, or significant).The numbers of patients felt to be experiencing significant levels of pain were compared. Table [4] shows the results of the endoscopists' responses.

Discussion

Flexible sigmoidoscopy has been performed without analgesia for many years. Many patients, however, experience significant pain or discomfort during the procedure. Clearly it is desirable to reduce this. However, options based on benzodiazepines or opiates carry a small but definite associated morbidity, as well as increased resource implications due to the need for a formal recovery period. In addition, intravenous agents can impair responses for up to 24 hours after the examination. This has limited their usefulness.

Flexible sigmoidoscopy is taking an increasing role in bowel cancer screening programmes [1]. Screening tests need to meet important criteria to be successful. These include being relatively easy to perform and safe, having a high level of sensitivity and detecting a lesion whose natural history is significantly altered (and ideally cured) by its treatment. The resource implications are also important, with a minimization of financial and manpower implications being essential for widespread implementation. The minimization of discomfort is all-important in achieving both widespread uptake and appropriate reattendance. Regimes which have real or perceived levels of significant discomfort for the patient will inevitably suffer from a reduction in compliance levels.

Estimates exist that up to 70 % of colorectal cancers may be preventable by detection (and subsequent removal) of adenomas at flexible sigmoidoscopy [9].

Nitrous oxide has an established safety record in both accident and emergency and obstetric practice. In these situations supervision and administration by paramedical staff is widespread. This may have particular relevance to screening flexible sigmoidoscopy, which by virtue of the numbers involved would require significant input from nonmedical staff. Studies involving older patients (which may be more relevant to flexible sigmoidoscopy) have demonstrated maintained or enhanced oxygen saturation during administration [10]. The rapid recovery of psychomotor function after cessation of inhalation may allow patients to drive following their examination [6]. This may require further clarification before being widely accepted.

We advised patients to inhale the offered agent as soon as they began to experience discomfort. The benefits of nitrous oxide might have been even more impressive if instructions had been given to prebreathe for 30 - 60 seconds before the painful stimuli (this technique allows maximal analgesic efficacy to be achieved). However, in clinical practice it is not always easy to predict which manoeuvres an individual will find painful.

In this study we have demonstrated a significant reduction in patient-recorded discomfort levels and significantly enhanced levels of relaxation during the procedure compared to the placebo. Patients also recorded an increased willingness to undergo the examination again if it was felt necessary, suggesting a potential for increasing compliance with a screening programme. The anatomical level reached during the procedure was documented. The accuracy of this was not independently verified (it can be difficult to assess clinically), but no differences between the groups were seen. No major side effects or complications were noted.

It is noteworthy that despite significant benefits being reported by the patients, the endoscopists did not notice significant differences in perceived discomfort during the examination. This suggests that endoscopists may be poorly equipped to assess the discomfort levels experienced by their patients. Alternatively, the amnesic effect of nitrous oxide may have contributed to these differences.

These results are at variance with those of Fich et al. [7] who failed to demonstrate a difference between nitrous oxide and a control group. The most likely explanation for this lack of consistency is the difference in size of the studies. In our study 87 patients were enrolled in contrast to 38 in the study by Fich et al. The smaller numbers in the previous study make the possibility of a type 2 statistical error more likely.

In summary, flexible sigmoidoscopy is a useful diagnostic test and has potential benefits as a screening modality. We have found that the addition of nitrous oxide/oxygen (in a 1 : 1 ratio) has useful effects in reducing patient discomfort, and increasing the acceptability of the procedure. There appeared to be no major side effects from this therapy, and because of the established safety profile, no additional personnel or monitoring resources were required. We would suggest consideration of making inhaled nitrous oxide available for the practice of flexible sigmoidoscopy. This may have especial relevance if flexible sigmoidoscopy is used as part of a screening regime where compliance is of particular importance.

Acknowledgments

We are very grateful to all the staff in the endoscopy unit of Stafford General Hospital who assisted in the running of this study.

References

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T. A. Harding, M.D.

Dept. of Gastroenterology (c/o Dr ET Swarbrick sec) New Cross Hospital

Wednesfield Road Wolverhampton WV10 0PQ United Kingdom

Fax: Fax:+ 44-1902-643027

Email: E-mail:timh@shrewsbury97.freeserve.co.uk

References

• 1 Levin B T, Rothenberger D, Dodd G D, Smith R A. The American Cancer Society guidelines for colorectal cancer screening: have we gone too far (or not far enough)?.  Gastroenterology. 1998;  114 1341-1343
  PubMedSearch in Google Scholar
• 2 Cockburn J, Thomas R JS, McLaughlin S J, Reading D. Acceptance of screening for colorectal cancer by flexible sigmoidoscopy.  J Med Screen. 1995;  2 79-83
  PubMedSearch in Google Scholar
• 3 McCarthy B D, Moskowitz M A. Screening flexible sigmoidoscopy: patient attitudes and compliance.  J Gen Int Med. 1993;  8 120-125
  PubMedSearch in Google Scholar
• 4 Lindblom A, Jansson O, Jeppsson B, et al. Nitrous oxide for colonoscopy discomfort: a randomised double-blind study.  Endoscopy. 1994;  26 283-286
  Thieme ConnectPubMedSearch in Google Scholar
• 5 Saunders B P, Fukumoto M, Halligan S, et al. Patient administered nitrous oxide/oxigen inhalation provides effective sedation and analgesia for colonoscopy.  Gastrointest Endosc. 1994;  40 418-421
  PubMedSearch in Google Scholar
• 6 Trojan J, Saunders B P, Woloshynowych M, et al. Immediate recovery of psychomotor function after patient administered nitrous oxide/oxygen inhalation for colonoscopy.  Endoscopy. 1997;  29 17-22
  Thieme ConnectPubMedSearch in Google Scholar
• 7 Fich A, Efrat R, Sperber A, et al. Nitrous oxide inhalation as sedation for flexible sigmoidoscopy.  Gastrointest Endosc. 1997;  45 10-12
  PubMedSearch in Google Scholar
• 8 Saunders B P, Elsby B, Boswell A M, et al. Intravenous antisplasmodic and patient-controlled analgesia are of benefit for screening flexible sigmoidoscopy.  Gastrointest Endosc. 1995;  42 123-127
  PubMedSearch in Google Scholar
• 9 Atkin W S, Cuzick J, Northover J MA, Whynes D K. Prevention of colorectal cancer by once only sigmoidoscopy.  Lancet. 1993;  341 736-740
  CrossrefPubMedSearch in Google Scholar
• 10 Baskett P JF, Eltringham R J, Bennett J A. An assessment of the oxygen tensions obtained with pre-mixed 50% nitrous oxide and oxygen mixture used for pain relief.  Anaesthesia. 1973;  28 449-450
  PubMedSearch in Google Scholar

T. A. Harding, M.D.

Dept. of Gastroenterology (c/o Dr ET Swarbrick sec) New Cross Hospital

Wednesfield Road Wolverhampton WV10 0PQ United Kingdom

Fax: Fax:+ 44-1902-643027

Email: E-mail:timh@shrewsbury97.freeserve.co.uk