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Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial
ORIGINAL ARTICLE: Clinical Endoscopy
Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial Nam Q. Nguyen, MBBS(hons), FRACP, PhD,1 Leanne Toscano, B.Nursing,1 Matthew Lawrence, MBBS, FRACS, MD,2 James Moore, MBBS, FRACS, MD,2 Richard H. Holloway, BSc(med), MBBS, FRACP, MD,1 Dylan Bartholomeusz, MBBS, MD, FRACP,1 Ilmars Lidums, MBBS, PhD, FRACP,3 William Tam, MBBS, PhD, FRACP,1,4 Ian C. Roberts-Thomson, MBBS, MD, FRACP,3 Venkataswamy N. Mahesh, MBBS,1 Tamara L. Debreceni, B.BioSc(hons),1 Mark N. Schoeman, MBBS, PhD, FRACP1 Adelaide, South Australia
Objective: Inhaled methoxyflurane (Penthrox, Medical Device International, Melbourne, Australia) has been used extensively in Australasia (Australia and New Zealand) to manage trauma-related pain. The aim is to evaluate the efficacy, safety, and outcome of Penthrox for colonoscopy. Design: Prospective randomized study. Setting: Three tertiary endoscopic centers. Patients: Two hundred fifty-one patients were randomized to receive either Penthrox (n Z 125, 70 men, 51.4 1.1 years old) or intravenous midazolam and fentanyl (M&F; n Z 126, 72 men, 54.9 1.1 years old) during colonoscopy. Main Outcome Measurement: Discomfort (visual analogue scale [VAS] pain score), anxiety (State-Trait Anxiety Inventory Form Y [STAI-Y] anxiety score), colonoscopy performance, adverse events, and recovery time. Results: Precolonoscopy VAS pain and STAI-Y scores were comparable between the 2 groups. There were no differences between groups in (1) pain VAS or STAI Y-1 anxiety scores during or immediately after colonoscopy, (2) procedural success rate (Penthrox: 121/125 vs M&F: 124/126), (3) hypotension during colonoscopy (7/125 vs 8/126), (4) tachycardia (5/125 vs 3/126), (5) cecal arrival time (8 1 vs 8 1 minutes), or (6) polyp detection rate (30/125 vs 43/126). Additional intravenous sedation was required in 10 patients (8%) who received Penthrox. Patients receiving Penthrox alone had no desaturation (oxygen saturation [SaO2] ! 90%) events (0/115 vs 5/126; P Z .03), awoke quicker (3 0 vs 19 1 minutes; P ! .001) and were ready for discharge earlier (37 1 vs 66 2 minutes; P ! .001) than those receiving intravenous M&F. Limitations: Inhaled Penthrox is not yet available in the United States and Europe. Conclusions: Patient-controlled analgesia with inhaled Penthrox is feasible and as effective as conventional sedation for colonoscopy with shorter recovery time, is not associated with respiratory depression, and does not influence the procedural success and polyp detection. (Gastrointest Endosc 2013;78:892-901.)
Colonoscopy has become an integral part of patient management, especially in the prevention of colorectal cancer.1,2 This is especially the case given our aging
population as well as governmental initiation of national bowel cancer screening programs.3-5 Hence, as gastroenterologists, it is important that we provide this service in
Abbreviations: IV, intravenous; M&E, midazolamand fentanyl; STAI-Y, State-Trait Anxiety Inventory Form Y; VAS, visual analogue scale.
Current affiliations: Department of Gastroenterology and Hepatology (1), Colo-Rectal Surgical Unit (2), Royal Adelaide Hospital, Adelaide, South Australia; Department of Gastroenterology, The Queen Elizabeth Hospital, Adelaide, South Australia (3), Department of Gastroenterology, Lyell McEwin Health Service, Adelaide, South Australia (4).
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. Copyright ª 2013 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.05.023
Reprint requests: Dr Nam Q. Nguyen, Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000.
Received February 18, 2013. Accepted May 13, 2013.
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Methoxyflurane inhaler versus sedation for colonoscopy
a safe and comfortable manner.6 Currently, sedation for colonoscopic procedures involves using a combination of an analgesic (such as fentanyl) and a sedative (such as midazolam).2,6-9 These drugs are given as an initial bolus, with additional boluses given according to patient discomfort. Establishing the correct dose of medication can sometimes be challenging. Excessive administration can lead to respiratory depression, whereas under-dosing may lead to unnecessary patient distress.6,7 Furthermore, over-sedation from the excessive administration of these agents can lead to a prolonged recovery time and, occasionally, the need to use medication to reverse the sedative effect.6,7 The use of patient-controlled analgesia for colonoscopy has been studied previously.10-14 Nitric oxide has been shown to be associated with less hypotension, a shorter recovery time, and less respiratory compromise than conventional sedation.13,14 In a relatively healthy selected group of patients who were willing to participate in the trial, meta-analyses11,12 found that the effectiveness of intraprocedural nitric oxide gas was equivalent to that of intravenous (IV) sedation and was associated with a shorter recovery time. In Australia, portable inhaled methoxyflurane (Penthrox, 3 mL per inhaler; Medical Device International, Melbourne, Australia) has become available as an analgesic agent outside of the hospital environment.15-18 Methoxyflurane is halogenated ether that was used extensively for general anesthesia in the early 1960s.19,20 Its anesthetic use, however, was withdrawn in the late 1970s because of nephrotoxicity and hepatotoxicity,19,20 and these adverse effects make the agent contraindicated in patients with renal impairment and chronic liver disease. Over the last 15 years, the uniquely powerful analgesic property of methoxyflurane, at well below full anesthetic doses, has revived its clinical use as an emergency analgesic. Because inhalation is the route of administration, the use of methoxyflurane avoids the need for an IV cannula, and thus portable Penthrox has been widely used in the Australasian community by ambulance services in the prehospital setting to provide pain relief from limb and musculoskeletal injuries, chest and abdominal pain, and back and spinal injuries.15-18 The maximum recommended dose is 6 mL (or 2 inhalers) per day or 15 mL (or 5 inhalers) per week because of the risk of cumulative dose-related nephrotoxicity.17 The amount of drug administration is controlled by the patient, via frequency and depth of inhalation. The onset of action is rapid and can be noticed after 3 to 6 breaths. Each inhaler (3 mL) provides analgesic effect for approximately 30 minutes.17 Concurrent uses of any potential nephrotoxic drugs (eg, aminoglycosides) or tetracyclines are not recommended because of the potential increase risk of nephrotoxicity.15-18 To date, the use of Penthrox at current dosage has a good safety profile in over 2.5 million patients.17
This randomized, controlled, multicenter trial involved adult participants who were referred for colonoscopy. Patients were recruited from endoscopic centers of 3 main tertiary-level care hospitals in South Australia: The Royal Adelaide Hospital, The Queen Elizabeth Hospital, and the Lyell McEwin Health Service. The inclusion criteria were age 18 to 75 years, ability to give informed consent, and ability to understand adequately the use of the Penthrox inhaler. Exclusion criteria were as follows: (1) a history of significant alcohol (O40 g/day for men, 20 g/day for women) or narcotic use; (2) previous history of significant liver, cardiac, or respiratory illnesses (ie, ischemic heart disease, chronic obstructive pulmonary disease, chronic liver disease); (3) weight ! 45 kg; (4) smoking history of more than 20 pack/years; (5) previous history of GI surgery (likely to increase difficulty of colonoscopy); (6) renal impairment; (7) diabetes mellitus with known diabetic nephropathy; (8) previous possible allergy to the medication by the patient or a relative; (9) hypersensitivity to fluorinated agents; (10) previous head injury; (11) difficulty in following instructions (including language barrier); (12) concurrent use of any potential nephrotoxic drugs (eg, aminoglycosides) or tetracyclines; and (13) personal or a family history of malignant hyperthermia. The subjects were withdrawn if there was an adverse event, the subject wished to discontinue, or the presence of significant pain necessitated the subject to request extra analgesia (fentanyl) and/or sedation (midazolam).
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Take-home Message Patient-controlled analgesia with inhaled Penthrox for colonoscopy is feasible and as effective as conventional sedation, is associated with shorter recovery time, is not associated with respiratory depression, and does not influence procedural success and polyp detection. With appropriate patient selection, the use of Penthrox analgesia for colonoscopy facilitates rapid recovery, allows earlier discharge, and improves the workflow of endoscopy units.
We previously conducted a pilot study (n Z 24) suggesting that patients who were given Penthrox for colonoscopy experienced as good an analgesic effect as those who were sedated with midazolam and fentanyl but without any adverse event.21 Given these promising results, the aim of this larger, multicenter study was to confirm the effectiveness and safety of the Penthrox inhaler as patient-controlled analgesia compared with conventional IV sedation during colonoscopy.
METHODS Subjects
Methoxyflurane inhaler versus sedation for colonoscopy
The study was approved by the Human Research Ethics Committees of all 3 hospitals, and informed written consent was obtained from each patient. The trial was registered with the ANZ trial registry (record number 100721). All participated investigators-authors made significant contributions in various areas of the study that enabled the trial to be successfully completed.
Study protocol Upon agreeing to participate in the study, the subjects were randomized to receive either Penthrox or conventional IV sedation (midazolam and fentanyl) in a 1:1 ratio fashion. The randomization was computer-generated. Each subject’s pain and anxiety scores were assessed in the waiting room before colonoscopy using, respectively, the visual analogue scale (VAS) pain score22 and the Spielberger State-Trait Anxiety Inventory Form Y (STAI-Y)-1 anxiety score.23,24 An IV cannula was then inserted in all patients. To minimize technical variability, the colonoscopy was performed only by consultant gastroenterologists. Supplemental oxygen was provided via nasal speculum at a rate between 2 and 4 L/min, and vital signs, oxygen saturation, and aerodynamics were monitored continuously and recorded every 3 minutes by a registered nurse. For patients who were randomized to receive sedation, the initial dosages of IV fentanyl and midazolam were based on their ages25: Age ! 60 years: 2.5 mg midazolam and 100 mg fentanyl Age O 60 years: 1.5 mg midazolam and 50 mg fentanyl Further boluses of these medications were given during the procedure at the discretion of the endoscopist to minimize the patient’s discomfort: 1 to 2 mg midazolam every 10 to 15 minutes and 25 to 50 mg fentanyl every 10 to 15 minutes. Subjects randomized to receive Penthrox were educated on the use of the Penthrox inhaler by a dedicated research nurse. The subject was asked to inhale slowly and gently through the Penthrox inhaler for approximately 2 minutes to become accustomed to its sweet-tasting smell. Once the colonoscopy had started, the subject was encouraged to take a deeper inhalation to optimize drug delivery and to provide sufficient analgesia. All colonoscopies were performed with a standard technique, using carbon dioxide insufflation. The procedure was deemed to be complete if the terminal ileum or cecum was reached. Patients were allowed to self-administer as much methoxyflurane as they believed they required within the safety limit as recommended by the manufacturer (up to 6 mL/day; ie, 2 Penthrox inhalers). At times, patients were recommended to self-administer further doses of methoxyflurane by the endoscopist if the endoscopist anticipated potential loops that might cause discomfort. In instances when methoxyflurane did not provide sufficient analgesia or at the patient’s request, rescue combination therapy of IV fentanyl and midazolam was given according to the age guidelines above. 894 GASTROINTESTINAL ENDOSCOPY Volume 78, No. 6 : 2013
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Signs of over-sedation such as drowsiness, pallor, and unresponsiveness were monitored closely. In addition, details related to the colonoscopy procedure such as duration, time to reach cecum, endoscopic therapy (ie, polypectomy, argon plasma coagulation), or occurrence of adverse events were also recorded. The endoscopist was also asked to complete a questionnaire to assess the patient’s level of pain, anxiety, and cooperation as well the level of technical difficulty related to the colonoscopy. In recovery, the patient’s vital signs, alertness, mental state, and abdominal symptoms were monitored. Once patients were alert and able to obey commands appropriately, they were allowed to sit out of bed and have oral intake. At this time, patients were asked to complete a questionnaire to assess their current pain and anxiety scores as well as their scores during the colonoscopy, retrospectively. The patients were then assessed for the ability to be discharged home. Patients were asked to report any adverse events occurring up to 30 days after study participation. The research nurse contacted all patients at 24 to 48 hours and 30 days after the colonoscopy to check for the occurrence of any adverse events related to either the drugs or the colonoscopy.
Measured outcomes Primary endpoints were as follows: (1) pain and anxiety scores during colonoscopy, (2) time of discharge (defined as the time the caring nurses and physician deemed it to be “medically safe” for the patients to leave the Endoscopy Unit; any delay because of transport need or other unrelated medical issue was excluded), and (3) the proportion of patients who were willing to undergo the procedure again with the given analgesic/sedative modality. Timing from the end of the procedure to the time the patient was awake, time to oral intake, and time to be ready for discharge were also documented prospectively. Secondary endpoints were (1) time to cecal intubation, (2) rate of completing colonoscopy, (3) polyp detection rate, (4) total colonoscopy procedural time, (5) rate of adverse events, (6) use of rescue medication before completion of procedure, and (7) patient’s recollection of the procedure. Hypotension was defined as a reduction of systolic blood pressure below 80% of baseline and/or below 100 mm Hg.26 A heart rate over 100 beats per minute was accepted as tachycardia. Respiratory depression was defined as the need for high-flow oxygen supply (8-10 L) because of an oxygen desaturation below 90% (SaO2 ! 90%) that continued for more than 20 seconds.27 In both groups, patients were encouraged to increase their respirations when oxygen desaturation occurred.
Assessment tools VAS pain score. A VAS score is widely used to assess pain.22 This is a 100-mm VAS scale for pain severity on www.giejournal.org
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Methoxyflurane inhaler versus sedation for colonoscopy
TABLE 1. Comparison of demographics, initial pain and anxiety scores, dosage of sedatives, and procedural indications between patients who received Penthrox inhaler and conventional sedation during colonoscopy Sedation (n [ 126)
Penthrox (all) (n [ 125)
Penthrox, success (92%) (n [ 115)
Penthrox, failure (8%) (n [ 10)
54.9 1.1
51.4 1.1
51.9 1.0
44.7 1.2y
72:54
70:55
66:49
4:6
0.62 0.13
0.60 0.12
0.53 0.11
1.40 0.15*
Total score
43.7 0.7
46.2 0.5*
46.2 0.5*
46.4 1.0*
Nervous score
15.8 0.5
14.9 0.5
14.7 0.5
14.2 1.4
60 3
53 3
54 3
68 12*
Midazolam
3.7 0.1
NA
NA
4.5 0.1
Fentanyl
83.2 1.9
Age, y Gender (male:female) VAS (0-10) pain score before colonoscopy STAI-Y anxiety score
Colonoscopist perception of patient’s anxiety state (VAS) (0 Z very calm, 100 Z most anxious) Dosage of sedation
92.5 1.1
Indications for colonoscopy Polyp surveillance
28
20
20
0
Bowel cancer screening
20
32
32
0
Rectal bleeding
37
21
17
4
Abdominal pain
10
24
22
2
IBD related
12
10
8
2
Constipation
3
4
4
0
Diarrhea
7
7
6
1
Anemia
1
3
3
0
Constipation/diarrhea
5
3
2
1
VAS, Visual analog scale; STAI-Y, State-Trait Anxiety Inventory Form Y; NA, not available; IBD, inflammatory bowel disease. *P ! .05, vs sedation. yP ! .01, vs all other groups.
symptoms of a state of anxiety,29,30 but in preoperative patients the cut-off point for the total score is set at 44 to 45.31,32
which 0 indicates absence of pain and 100 the worst pain possible. STAI-Y anxiety score. The Spielberger STAI is a 40-item instrument measuring transient and enduring levels of anxiety.23,24 Of the 3 forms of the STAI, the current study used the adult STAI Form Y (ie, STAI-Y), which assesses both temporary emotional state anxiety and the longstanding personality trait anxiety. The STAI-Y score system consists of 2 underlying dimensions that broadly assess “nervousness” and “well-being.” The nervousness factor consists of 7 items (“tense,” “upset,” “frightened,” “nervous,” “jittery,” “confused,” and “steady”) and well-being consists of 6 items (“secure,” “at ease,” “satisfied,” “comfortable,” “content,” and “pleasant”).28 In this study we used both the STAI sum score and the nervousness subscore to assess the effects of Penthrox and IV sedation. A cut-off point for the total score of 39 to 40 is normally used for clinically significant
Sample size calculations were made based on the results of our previous pilot study.21 When we used the endpoint of mean “patient’s discomfort score” and related standard deviation, the power calculation with a 2-sided significance level of .05, power of 90%, and assuming that a difference of 1.0 in mean discomfort score was clinically important indicated that the trial needed to recruit a minimum of 112 participants per treatment arm. Data are expressed as mean standard deviation. The Fisher exact test was used for comparison of categorical data and independent Student t test for continuous data. Analyses were performed using GraphPad Prism statistical software, version 6 (GraphPad Software Inc., La Jolla, CA). P ! .05 was accepted as indicating statistical significance.
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Data analysis
Methoxyflurane inhaler versus sedation for colonoscopy
Figure 1. Outline of study design and outcomes.
RESULTS Overall, 125 patients received Penthrox and 126 patients received conventional sedation. In the Penthrox group, no patient had to use more than 1 Penthrox inhale (3 mL). There were no differences in age, gender, precolonoscopy VAS pain scores, and colonoscopist’s perception of patient’s anxiety level and indication for colonoscopy between the groups (Table 1). Although the total STAI-Y anxiety scores were higher in the Penthrox group, the nervousness scores were similar between the groups. Patients with conventional sedation received a mean dosage of 3.4 0.1 mg midazolam and 83.6 2.9 mg fentanyl. Of those who received Penthrox, 10 patients (8%) required additional IV sedation for completion of colonoscopy (Fig. 1). The characteristics of this subgroup of patients were different from those who completed the procedure with Penthrox or IV sedation alone: They were younger and had higher precolonoscopy VAS pain score and colonoscopist’s perception of patient’s anxiety level (Table 1).
Pain and STAI-Y anxiety scores There were no differences in VAS pain scores before, during, and after colonoscopy between patients who received IV sedation and Penthrox (overall or Penthrox alone) (Fig. 2). However, patients who received both Penthrox and IV sedation for colonoscopy reported higher VAS pain score before and during colonoscopy and 24 hours after colonoscopy than those receiving either Penthrox or IV sedation alone. Although the total STAI-Y anxiety scores were higher in the Penthrox group, the “nervousness” scores were similar between the groups (Table 2). Both Penthrox and IV sedation were able to reduce the nervousness score in all patients after administration.
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time, and the success rate of completed colonoscopy (Table 3). There were no differences in the rate of polyp detection and polypectomy between the groups. Patients who required combination of Penthrox and IV sedation were perceived to have more discomfort, less cooperation, and a more technically difficult colonoscopy than the other groups and had the lowest success rate for completion of colonoscopy. Although the rates of adverse events were similar between the Penthrox (all) and IV sedation group, most adverse events occurred in patients who required IV sedation in addition to the Penthrox (Table 3). In particular, none of the patients who had a successful procedure with Penthrox alone had respiratory depression. These adverse events only occurred in patients who received IV sedation, either alone or combined with Penthrox. The risks of hypotension during colonoscopy and tachycardia were similar between the groups. At telephone follow-up 24 hours and 30 days after colonoscopy, no patient reported or was found to have been readmitted to the hospital for abnormal renal or liver function tests as an indicator of nephrotoxicity or hepatoxicity.
Recovery time Compared with those who received IV sedation, patients who received Penthrox had significantly shorter times to being awake, to have oral intake, and to be ready for discharge (Fig. 3). Overall, patients who had a successful procedure with Penthrox were discharged on average 15 minutes earlier than those with IV sedation.
Patient’s perception on the use of Penthrox for colonoscopy Patients who completed colonoscopy with Penthrox alone indicated that the inhaler was helpful and easy to use. The patients liked being able to use the drug at their discretion. They also had better recall of the procedure and findings (Table 4). The overall satisfaction score was 94 out of 100. Of patients who had successful colonoscopy with Penthrox alone, 97% were willing to use Penthrox again for future colonoscopy.
DISCUSSION
There were no differences between the groups in procedural preparation time, cecal arrival time, total colonoscopy
This is the first study to show that patient-controlled analgesia with inhaled methoxyflurane (Penthrox) as a method of discomfort relief for colonoscopy is feasible, safe, and as effective as IV sedation. The main advantages of using Penthrox over conventional IV sedation for colonoscopy are a lack of respiratory depression, a more reliable memory of the procedural findings by the patients, a substantial shorter recovery time, and avoiding IV cannulation. The high satisfaction score (94/100) and the finding that most patients (97%) were willing to use Penthrox again for future colonoscopy support the use of Penthrox
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Procedural performance, intraprocedural adverse events, and perception of colonoscopist on patient cooperation
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Figure 2. VAS pain scores before and during colonoscopy, at recovery, and 24 hours after colonoscopy between groups.
TABLE 2. Effects of Penthrox, conventional sedation, and combination therapy on STAI-Y anxiety scores during and after colonoscopy between groups Sedation (n [ 126)
Penthrox (all) (n [ 125)
Penthrox, success (92%) (n [ 115)
Penthrox, failure (8%) (n [ 10)
Precolonoscopy
43.7 0.7
46.2 0.5*
46.2 0.5*
46.4 1.0*
Postcolonoscopy
45.4 0.7
47.6 0.5*
47.7 0.5*
45.4 1.5
24 h after
49.1 0.3
48.2 0.8
48.1 0.9
49.1 1.1
Precolonoscopy
15.8 0.5
14.9 0.5
14.7 0.5
14.2 1.4
Postcolonoscopy
11.3 0.2
11.4 0.3
11.54 0.3
10.7 0.5
24 h after
10.8 0.3
10.6 0.3
10.6 0.3
10.4 0.3
4.5 0.2y
3.3 0.1y
3.3 0.1y
3.8 0.1y
STAI-Y Anxiety Score Total score
“Nervousness” subscore
Reduction in “nervousness” score after medication STAI-Y, State-Trait Anxiety Inventory Form Y. *P ! .05, vs sedation. yP ! .01, vs all other groups.
as an alternative and possibly safer analgesic modality for colonoscopy. More importantly, the use of Penthrox does not influence the performance and the polyp detection rate of the procedure. Together with the rapid recovery, the use of Penthrox for colonoscopy can facilitate earlier discharge, improve workflow, and optimize the health economics of endoscopic units, especially those with long waiting lists. In addition to the analgesic effect, Penthrox has a good anxiolytic effect that is comparable with that from IV
sedation. Although the literature on the analgesic effects of Penthrox is extensive,15-18 the current study is the first to show the anxiolytic effects of Penthrox as demonstrated by a significant reduction in nervousness score from the STAI-Y assessment. Furthermore, the rapid onset of anxiolytic effect of Penthrox was also observed in the current trial. This is a major benefit because it settles most of the initial anxiety related to colonoscopy and, along with the analgesic effect, allows most patients to tolerate the procedure well without being sedated. Consequently, patients
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TABLE 3. Effects of Penthrox, conventional sedation, and combination therapy on the procedural performance and patient’s cooperation during colonoscopy between groups Sedation (n [ 126)
Penthrox (all) (n [ 125)
Penthrox, success (n [ 115)
Penthrox, failure (n [ 10)
Preparation time, min
61
61
61
61
Cecal arrival time, min
81
81
71
14 1
Total colonoscopy time, min
17 1
15 1
15 1
21 1
124 (98%)
121 (97%)
114 (99%)
7 (70%)
Severe sigmoid diverticulosis
1
2
0
2
Significant looping
1
1
1
0
Obstructing lesion
0
1
0
1
10 (7%)
10 (7%)
4 (7%)
6 (60%)
Respiratory depression
5
5
0
5
Hypotension
8
7
5
2
Cardiac arrhythmia
3
5
3
2
43 (34%)
30 (24%)
30 (26%)
0 (0%)
Colonoscopist perception of patient’s discomfort during colonoscopy (0 Z no pain, 100 Z worst pain)
43 3
42 3
41 3
59 13
Colonoscopist perception of procedural difficulty (0 Z easy; 100 Z most difficult)
52 3
52 2
51 2
68 3
Colonoscopist perception of patient’s cooperation (0 Z none; 100 Z excellent)
80 2
77 2
79 2
48 13
NA
75 3
79 2
40 15
Rate of complete colonoscopy Reason for incomplete colonoscopy
Adverse event
Polypectomy rate
Colonoscopist perception of patient’s technique in using Penthrox inhaler (0 Z very bad; 100 Z excellent) NA, not available.
who undergo colonoscopy with Penthrox are fully alert almost immediately after the procedure and are able to be discharged earlier than those who receive IV sedation. Furthermore, because patients are not sedated during the procedure, they are able to watch, be informed of, and remember the procedural findings, increasing the likelihood that patients are aware of their colonoscopic results on discharge. Although the current study has shown that Penthrox has little sedative effect, it remains unclear whether these patients can drive home after the procedure, and this warrants further evaluation. As observed with IV sedation, the use of Penthrox for colonoscopy is not suitable for all patients, especially those who have significant anxiety disorders or visceral hypersensitivity. A reported 10% of patients who undergo colonoscopy with IV sedation fail to tolerate the procedure33-35 and require a deeper level of sedation technique, such as neuroleptic sedation with propofol or general anesthesia.36-38 In the current study, 8% of Penthrox patients failed to tolerate the procedure and required additional IV sedation. In contrast to the rest of the group, these
patients are different and have predictive clinical features of a “difficult” patient, such as young women with significantly higher precolonoscopy pain and anxiety scores and higher pain scores during colonoscopy. Although these patients had a lower colonoscopy completion rate (7/10; 70%), this was not related to the mode of analgesia or sedation and rather was because of encountered colonic pathology that prevented colonoscope advancement in a safe manner (Table 3). Furthermore, these patients also had higher pain scores 24 hours after the procedure, suggesting a possible contribution of underlying visceral hypersensitivity. Therefore, to optimize the success rate of Penthrox for colonoscopy, patients should be selected carefully. In addition to medical contraindications, patients who are young women with high preoperative anxiety or pain level are also less suitable for Penthrox use. These patients are most likely to benefit from the use of deep sedation techniques for the procedure. Our results are the first to show that it is feasible to perform unsedated colonoscopy in most patients using combined Penthrox analgesia and carbon dioxide insufflation,
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Figure 3. Differences in recovery time between patients who received Penthrox and patients who received IV sedation for colonoscopy.
which has been shown to reduce patient discomfort during and after colonoscopy.39 An alternative insertion technique of warm water immersion has also been shown to improve comfort and tolerance in patients who underwent sedated40,41 and unsedated42 colonoscopy. The combination use of such insertion techniques and Penthrox analgesia may therefore provide a new approach to perform unsedated colonoscopy with adequate pain relief. The safety profile of Penthrox for colonoscopy in the current study is consistent with the literature.17 In contrast to the dosage given for anesthesia, the much-smaller amount of methoxyflurane administered by 1 Penthrox inhaler for colonoscopy in the current study did not cause any clinically significantly adverse events, especially nephrotoxicity or hepatotoxicity and respiratory depression. The toxicity of methoxyflurane is dose dependent. Although serial measurements of renal or liver functions were not adopted in the current study, 30-day telephone follow-up for any adverse events was used, and no adverse events were reported. It is important to note that despite its safety profile, to prevent nephrotoxicity or hepatotoxicity related to Penthrox, all patients with or suspected renal and liver diseases must be excluded from using the agent. Almost all serious adverse events in the Penthrox group were related to patients who had additional IV sedation. Respiratory depression was only observed in patients who received both Penthrox and IV sedation, indicating that caution must be taken when additional IV sedation
is used in patients who failed Penthrox analgesia. Because nearly half of the patients who failed Penthrox alone also failed after additional IV sedation, “failure” of Penthrox for colonoscopy appears to be a good indication to identify “difficult” patients who would be best managed with deep sedation (eg, with propofol). Although a small proportion of patients had hypotension (7%) and tachyarrhythmia (4%) after Penthrox, these adverse effects are also seen in patients who had IV sedation43 and may more likely relate to dehydration from fasting and bowel preparation than to the Penthrox.44 A potential weakness of the current study is selection bias toward patients who are healthy and with no serious medical conditions such as liver, renal, or cardiorespiratory diseases. In addition, because we did not collect the STAI-Y and pain scores of patients who refused to participate in our trial, it is not possible to rule out the possibility that patients in the current study were less anxious than general patients referred for colonoscopy and thus account for the higher successful procedure rate with Penthrox and a lack of a difference as compared with IV sedation. Furthermore, although power calculation was performed to determine the sample size, the analysis was based on the primary outcomes of pain and anxiety scores. This calculated sample size, however, may not be large enough to prevent a potential Type II error for outcomes, such as polyp detection and adverse event rate; thus, the interpretation of these outcomes must be made with caution. Because our trial was not blinded, it is most
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TABLE 4. Patient perception of Penthrox use for colonoscopy, stratified by those who successfully completed the procedure with Penthrox alone vs those who required additional sedation Penthrox, success (92%) (n [ 115)
Penthrox, failure (8%) (n [ 10)
Ease of use
92 1
78 7
.005
Taste and smell
61 3
22 7
!.001
Helpful
84 2
30 10
!.001
Ability to use at discretion
86 2
53 12
!.001
Recollection of the procedural detail and findings
84 2
54 8
!.001
Overall satisfaction
94 1
64 8
!.001
Would use Penthrox again for future colonoscopy
92 2
22 9
!.001
Ease of use
95 1
85 6
.04
Taste and smell
56 3
26 10
.006
Helpful
87 2
38 11
!.001
Ability to use at discretion
88 2
45 13
!.001
Recollection of the procedural detail and findings
81 2
65 10
.09
Overall satisfaction
96 1
72 12
!.001
Would use Penthrox again for future colonoscopy
93 2
21 10
!.001
P
Immediately after colonoscopy
24 h after colonoscopy
Visual analogue scale: 0 Z don’t like it at all; 100 Z like it very much.
likely that the nursing staff in recovery were also not blinded to the type of analgesia or sedation used. However, we have a standardized protocol in assessing and recording time to awake, time to oral intake, time ready for discharge, and actual time of discharge. The assessments are based on alertness and vital signs and are very objective. Recognizing a number of factors can influence the actual time of discharge, such as delayed pick-up and inability to organize transport, we have deliberately assessed time ready for discharge, which was based on objective measures. This is a potential reason why the differences in actual time of discharge between the groups were least compared with the other measured outcomes. Finally, our results are probably most applicable to subjects who were referred for colonoscopy from screening programs related to colorectal cancer. In conclusion, patient-controlled analgesia with Penthrox for colonoscopy is feasible and as effective as conventional sedation for relieving pain and anxiety without affecting the procedural success and polyp detection rates. It appears to be safer than sedation with no adverse effects on respiratory function. The addition of IV sedation to patients who do not tolerate colonoscopy with Penthrox, however, should be used with caution. With appropriate patient selection, the use of Penthrox analgesia for colonoscopy facilitates rapid recovery, allows earlier discharge, and improves the workflow of endoscopy units. 900 GASTROINTESTINAL ENDOSCOPY Volume 78, No. 6 : 2013
REFERENCES 1. Bourke MJ. Making every colonoscopy count: ensuring quality in endoscopy. J Gastroenterol Hepatol 2009;24(Suppl 3):S43-50. 2. Jover R, Herraiz M, Alarcon O, et al. Clinical practice guidelines: quality of colonoscopy in colorectal cancer screening. Endoscopy 2012;44: 444-51. 3. Plumb AA, Halligan S, Taylor SA, et al. CT colonography in the English Bowel Cancer Screening Programme: national survey of current practice. Clin Radiol 2012;12:549-51. 4. Lieberman D. Colorectal cancer screening: practice guidelines. Dig Dis 2012;30(Suppl 2):34-8. 5. Lee TJ, Rutter MD, Blanks RG, et al. Colonoscopy quality measures: experience from the NHS Bowel Cancer Screening Programme. Gut 2012;61:1050-7. 6. Bannert C, Reinhart K, Dunkler D, et al. Sedation in screening colonoscopy: impact on quality indicators and complications. Am J Gastroenterol 2012;107:1837-48. 7. Cohen LB. Sedation issues in quality colonoscopy. Gastrointest Endosc Clin North Am 2010;20:615-27. 8. Hayee B, Dunn J, Loganayagam A, et al. Midazolam with meperidine or fentanyl for colonoscopy: results of a randomized trial. Gastrointest Endosc 2009;69:681-7. 9. Ladas SD, Satake Y, Mostafa I, et al. Sedation practices for gastrointestinal endoscopy in Europe, North America, Asia, Africa and Australia. Digestion 2010;82:74-6. 10. Loberg M, Furholm S, Hoff I, et al. Nitrous oxide for analgesia in colonoscopy without sedation. Gastrointest Endosc 2011;74: 1347-53. 11. Aboumarzouk OM, Agarwal T, Syed Nong Chek SA, et al. Nitrous oxide for colonoscopy. Cochrane Database Syst Rev 2011:CD008506.
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12. Welchman S, Cochrane S, Minto G, et al. Systematic review: the use of nitrous oxide gas for lower gastrointestinal endoscopy. Aliment Pharmacol Ther 2010;32:324-33. 13. Maslekar S, Gardiner A, Hughes M, et al. Randomized clinical trial of Entonox versus midazolam-fentanyl sedation for colonoscopy. Br J Surg 2009;96:361-8. 14. Lee DW, Chan AC, Wong SK, et al. The safety, feasibility, and acceptability of patient-controlled sedation for colonoscopy: prospective study. Hong Kong Med J 2004;10:84-8. 15. Bendall JC, Simpson PM, Middleton PM. Prehospital analgesia in New South Wales, Australia. Prehosp Disaster Med 2011;26:422-6. 16. Johnston S, Wilkes GJ, Thompson JA, et al. Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service. Emerg Med J 2011;28:57-63. 17. Grindlay J, Babl FE. Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting [Review]. Emerg Med Australas 2009;21:4-11. 18. Buntine P, Thom O, Babl F, et al. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas 2007;19:509-14. 19. Toomath RJ, Morrison RB. Renal failure following methoxyflurane analgesia. N Z Med J 1987;100:707-8. 20. Rubinger D, Davidson JT, Melmed RN. Hepatitis following the use of methoxyflurane in obstetric analgesia. Anesthesiology 1975;43:593-5. 21. George B, Bate J, Tse E, et al. Patient-controlled analgesia with inhaled methoxyflurane versus conventional sedation for colonoscopy. J Gastroenterol Hepatol 2008;23:A227. 22. Chen PJ, Li CH, Huang TY, et al. Carbon dioxide insufflation does not reduce pain scores during colonoscope insertion in unsedated patients: a randomized, controlled trial. Gastrointest Endosc 2013;77:79-89. 23. Iwata N, Mishima N, Shimizu T, et al. Positive and negative affect in the factor structure of the State-Trait Anxiety Inventory for Japanese workers. Psychol Rep 1998;82:651-6. 24. Spielberger CD, Vagg PR. Psychometric properties of the STAI: a reply to Ramanaiah, Franzen, and Schill. J Pers Assess 1984;48:95-7. 25. Royal College of General Practioner and Pharmaceutical Society of Australia. Australian Medicines Handbook 2012, Australian Medicines Handbook Pty Ltd; Adelaide. Australian medical handbook. 2012. 26. Dahlgren G, Irestedt L. The definition of hypotension affects its incidence. Acta Anaesthesiol Scand 2010;54:907-8. 27. Horiuchi A, Nakayama Y, Kajiyama M, et al. Safety and effectiveness of propofol sedation during and after outpatient colonoscopy. World J Gastroenterol 2012;18:3420-5. 28. Kvaal K, Laake K, Engedal K. Psychometric properties of the state part of the Spielberger State-Trait Anxiety Inventory (STAI) in geriatric patients. Int J Geriatr Psychiatry 2001;16:980-6.
29. Knight RG, Waal-Manning HJ, Spears GF. Some norms and reliability data for the State-Trait Anxiety Inventory and the Zung Self-Rating Depression scale. Br J Clin Psychol 1983;22(Pt 4):245-9. 30. Forsberg C, Bjorvell H. Swedish population norms for the GHRI, HI and STAI-state. Qual Life Res 1993;2:349-56. 31. Millar K, Jelicic M, Bonke B, et al. Assessment of preoperative anxiety: comparison of measures in patients awaiting surgery for breast cancer. Br J Anaesth 1995;74:180-3. 32. Kindler CH, Harms C, Amsler F, et al. The visual analog scale allows effective measurement of preoperative anxiety and detection of patients’ anesthetic concerns. Anesth Analg 2000;90:706-12. 33. Church JM. Complete colonoscopy: how often? And if not, why not? Am J Gastroenterol 1994;89:556-60. 34. Brahmania M, Park J, Svarta S, et al. Incomplete colonoscopy: maximizing completion rates of gastroenterologists. Can J Gastroenterol 2012;26:589-92. 35. Shah HA, Paszat LF, Saskin R, et al. Factors associated with incomplete colonoscopy: a population-based study. Gastroenterology 2007;132: 2297-303. 36. Cardin F, Minicuci N, Campigotto F, et al. Difficult colonoscopies in the propofol era. BMC Surg 2012;12(Suppl 1):S9. 37. Fanti L, Agostoni M, Gemma M, et al. Sedation and monitoring for gastrointestinal endoscopy: a nationwide web survey in Italy. Dig Liver Dis 2011;43:726-30. 38. Vargo JJ. Procedural sedation. Curr Opin Gastroenterol 2011;26:421-4. 39. Amato A, Radaelli F, Paggi S, et al. Carbon dioxide insufflation or warmwater infusion versus standard air insufflation for unsedated colonoscopy: a randomized controlled trial. Dis Colon Rectum 2013;56:511-8. 40. Leung FW, Aharonian HS, Leung JW, et al. Impact of a novel water method on scheduled unsedated colonoscopy in U.S. veterans. Gastrointest Endosc 2009;69:546-50. 41. Leung JW, Mann SK, Siao-Salera R, et al. A randomized, controlled comparison of warm water infusion in lieu of air insufflation versus air insufflation for aiding colonoscopy insertion in sedated patients undergoing colorectal cancer screening and surveillance. Gastrointest Endosc 2009;70:505-10. 42. Leung FW, Harker JO, Jackson G, et al. A proof-of-principle, prospective, randomized, controlled trial demonstrating improved outcomes in scheduled unsedated colonoscopy by the water method. Gastrointest Endosc 2010;72:693-700. 43. Gasparovic S, Rustemovic N, Opacic M, et al. Comparison of colonoscopies performed under sedation with propofol or with midazolam or without sedation. Acta Med Austriaca 2003;30:13-6. 44. Holte K, Nielsen KG, Madsen JL, et al. Physiologic effects of bowel preparation. Dis Colon Rectum 2004;47:1397-402.
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Volume 78, No. 6 : 2013 GASTROINTESTINAL ENDOSCOPY 901
Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial Nam Q. Nguyen, MBBS(hons), FRACP, PhD,1 Leanne Toscano, B.Nursing,1 Matthew Lawrence, MBBS, FRACS, MD,2 James Moore, MBBS, FRACS, MD,2 Richard H. Holloway, BSc(med), MBBS, FRACP, MD,1 Dylan Bartholomeusz, MBBS, MD, FRACP,1 Ilmars Lidums, MBBS, PhD, FRACP,3 William Tam, MBBS, PhD, FRACP,1,4 Ian C. Roberts-Thomson, MBBS, MD, FRACP,3 Venkataswamy N. Mahesh, MBBS,1 Tamara L. Debreceni, B.BioSc(hons),1 Mark N. Schoeman, MBBS, PhD, FRACP1 Adelaide, South Australia
Objective: Inhaled methoxyflurane (Penthrox, Medical Device International, Melbourne, Australia) has been used extensively in Australasia (Australia and New Zealand) to manage trauma-related pain. The aim is to evaluate the efficacy, safety, and outcome of Penthrox for colonoscopy. Design: Prospective randomized study. Setting: Three tertiary endoscopic centers. Patients: Two hundred fifty-one patients were randomized to receive either Penthrox (n Z 125, 70 men, 51.4 1.1 years old) or intravenous midazolam and fentanyl (M&F; n Z 126, 72 men, 54.9 1.1 years old) during colonoscopy. Main Outcome Measurement: Discomfort (visual analogue scale [VAS] pain score), anxiety (State-Trait Anxiety Inventory Form Y [STAI-Y] anxiety score), colonoscopy performance, adverse events, and recovery time. Results: Precolonoscopy VAS pain and STAI-Y scores were comparable between the 2 groups. There were no differences between groups in (1) pain VAS or STAI Y-1 anxiety scores during or immediately after colonoscopy, (2) procedural success rate (Penthrox: 121/125 vs M&F: 124/126), (3) hypotension during colonoscopy (7/125 vs 8/126), (4) tachycardia (5/125 vs 3/126), (5) cecal arrival time (8 1 vs 8 1 minutes), or (6) polyp detection rate (30/125 vs 43/126). Additional intravenous sedation was required in 10 patients (8%) who received Penthrox. Patients receiving Penthrox alone had no desaturation (oxygen saturation [SaO2] ! 90%) events (0/115 vs 5/126; P Z .03), awoke quicker (3 0 vs 19 1 minutes; P ! .001) and were ready for discharge earlier (37 1 vs 66 2 minutes; P ! .001) than those receiving intravenous M&F. Limitations: Inhaled Penthrox is not yet available in the United States and Europe. Conclusions: Patient-controlled analgesia with inhaled Penthrox is feasible and as effective as conventional sedation for colonoscopy with shorter recovery time, is not associated with respiratory depression, and does not influence the procedural success and polyp detection. (Gastrointest Endosc 2013;78:892-901.)
Colonoscopy has become an integral part of patient management, especially in the prevention of colorectal cancer.1,2 This is especially the case given our aging
population as well as governmental initiation of national bowel cancer screening programs.3-5 Hence, as gastroenterologists, it is important that we provide this service in
Abbreviations: IV, intravenous; M&E, midazolamand fentanyl; STAI-Y, State-Trait Anxiety Inventory Form Y; VAS, visual analogue scale.
Current affiliations: Department of Gastroenterology and Hepatology (1), Colo-Rectal Surgical Unit (2), Royal Adelaide Hospital, Adelaide, South Australia; Department of Gastroenterology, The Queen Elizabeth Hospital, Adelaide, South Australia (3), Department of Gastroenterology, Lyell McEwin Health Service, Adelaide, South Australia (4).
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. Copyright ª 2013 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.05.023
Reprint requests: Dr Nam Q. Nguyen, Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000.
Received February 18, 2013. Accepted May 13, 2013.
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Methoxyflurane inhaler versus sedation for colonoscopy
a safe and comfortable manner.6 Currently, sedation for colonoscopic procedures involves using a combination of an analgesic (such as fentanyl) and a sedative (such as midazolam).2,6-9 These drugs are given as an initial bolus, with additional boluses given according to patient discomfort. Establishing the correct dose of medication can sometimes be challenging. Excessive administration can lead to respiratory depression, whereas under-dosing may lead to unnecessary patient distress.6,7 Furthermore, over-sedation from the excessive administration of these agents can lead to a prolonged recovery time and, occasionally, the need to use medication to reverse the sedative effect.6,7 The use of patient-controlled analgesia for colonoscopy has been studied previously.10-14 Nitric oxide has been shown to be associated with less hypotension, a shorter recovery time, and less respiratory compromise than conventional sedation.13,14 In a relatively healthy selected group of patients who were willing to participate in the trial, meta-analyses11,12 found that the effectiveness of intraprocedural nitric oxide gas was equivalent to that of intravenous (IV) sedation and was associated with a shorter recovery time. In Australia, portable inhaled methoxyflurane (Penthrox, 3 mL per inhaler; Medical Device International, Melbourne, Australia) has become available as an analgesic agent outside of the hospital environment.15-18 Methoxyflurane is halogenated ether that was used extensively for general anesthesia in the early 1960s.19,20 Its anesthetic use, however, was withdrawn in the late 1970s because of nephrotoxicity and hepatotoxicity,19,20 and these adverse effects make the agent contraindicated in patients with renal impairment and chronic liver disease. Over the last 15 years, the uniquely powerful analgesic property of methoxyflurane, at well below full anesthetic doses, has revived its clinical use as an emergency analgesic. Because inhalation is the route of administration, the use of methoxyflurane avoids the need for an IV cannula, and thus portable Penthrox has been widely used in the Australasian community by ambulance services in the prehospital setting to provide pain relief from limb and musculoskeletal injuries, chest and abdominal pain, and back and spinal injuries.15-18 The maximum recommended dose is 6 mL (or 2 inhalers) per day or 15 mL (or 5 inhalers) per week because of the risk of cumulative dose-related nephrotoxicity.17 The amount of drug administration is controlled by the patient, via frequency and depth of inhalation. The onset of action is rapid and can be noticed after 3 to 6 breaths. Each inhaler (3 mL) provides analgesic effect for approximately 30 minutes.17 Concurrent uses of any potential nephrotoxic drugs (eg, aminoglycosides) or tetracyclines are not recommended because of the potential increase risk of nephrotoxicity.15-18 To date, the use of Penthrox at current dosage has a good safety profile in over 2.5 million patients.17
This randomized, controlled, multicenter trial involved adult participants who were referred for colonoscopy. Patients were recruited from endoscopic centers of 3 main tertiary-level care hospitals in South Australia: The Royal Adelaide Hospital, The Queen Elizabeth Hospital, and the Lyell McEwin Health Service. The inclusion criteria were age 18 to 75 years, ability to give informed consent, and ability to understand adequately the use of the Penthrox inhaler. Exclusion criteria were as follows: (1) a history of significant alcohol (O40 g/day for men, 20 g/day for women) or narcotic use; (2) previous history of significant liver, cardiac, or respiratory illnesses (ie, ischemic heart disease, chronic obstructive pulmonary disease, chronic liver disease); (3) weight ! 45 kg; (4) smoking history of more than 20 pack/years; (5) previous history of GI surgery (likely to increase difficulty of colonoscopy); (6) renal impairment; (7) diabetes mellitus with known diabetic nephropathy; (8) previous possible allergy to the medication by the patient or a relative; (9) hypersensitivity to fluorinated agents; (10) previous head injury; (11) difficulty in following instructions (including language barrier); (12) concurrent use of any potential nephrotoxic drugs (eg, aminoglycosides) or tetracyclines; and (13) personal or a family history of malignant hyperthermia. The subjects were withdrawn if there was an adverse event, the subject wished to discontinue, or the presence of significant pain necessitated the subject to request extra analgesia (fentanyl) and/or sedation (midazolam).
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Take-home Message Patient-controlled analgesia with inhaled Penthrox for colonoscopy is feasible and as effective as conventional sedation, is associated with shorter recovery time, is not associated with respiratory depression, and does not influence procedural success and polyp detection. With appropriate patient selection, the use of Penthrox analgesia for colonoscopy facilitates rapid recovery, allows earlier discharge, and improves the workflow of endoscopy units.
We previously conducted a pilot study (n Z 24) suggesting that patients who were given Penthrox for colonoscopy experienced as good an analgesic effect as those who were sedated with midazolam and fentanyl but without any adverse event.21 Given these promising results, the aim of this larger, multicenter study was to confirm the effectiveness and safety of the Penthrox inhaler as patient-controlled analgesia compared with conventional IV sedation during colonoscopy.
METHODS Subjects
Methoxyflurane inhaler versus sedation for colonoscopy
The study was approved by the Human Research Ethics Committees of all 3 hospitals, and informed written consent was obtained from each patient. The trial was registered with the ANZ trial registry (record number 100721). All participated investigators-authors made significant contributions in various areas of the study that enabled the trial to be successfully completed.
Study protocol Upon agreeing to participate in the study, the subjects were randomized to receive either Penthrox or conventional IV sedation (midazolam and fentanyl) in a 1:1 ratio fashion. The randomization was computer-generated. Each subject’s pain and anxiety scores were assessed in the waiting room before colonoscopy using, respectively, the visual analogue scale (VAS) pain score22 and the Spielberger State-Trait Anxiety Inventory Form Y (STAI-Y)-1 anxiety score.23,24 An IV cannula was then inserted in all patients. To minimize technical variability, the colonoscopy was performed only by consultant gastroenterologists. Supplemental oxygen was provided via nasal speculum at a rate between 2 and 4 L/min, and vital signs, oxygen saturation, and aerodynamics were monitored continuously and recorded every 3 minutes by a registered nurse. For patients who were randomized to receive sedation, the initial dosages of IV fentanyl and midazolam were based on their ages25: Age ! 60 years: 2.5 mg midazolam and 100 mg fentanyl Age O 60 years: 1.5 mg midazolam and 50 mg fentanyl Further boluses of these medications were given during the procedure at the discretion of the endoscopist to minimize the patient’s discomfort: 1 to 2 mg midazolam every 10 to 15 minutes and 25 to 50 mg fentanyl every 10 to 15 minutes. Subjects randomized to receive Penthrox were educated on the use of the Penthrox inhaler by a dedicated research nurse. The subject was asked to inhale slowly and gently through the Penthrox inhaler for approximately 2 minutes to become accustomed to its sweet-tasting smell. Once the colonoscopy had started, the subject was encouraged to take a deeper inhalation to optimize drug delivery and to provide sufficient analgesia. All colonoscopies were performed with a standard technique, using carbon dioxide insufflation. The procedure was deemed to be complete if the terminal ileum or cecum was reached. Patients were allowed to self-administer as much methoxyflurane as they believed they required within the safety limit as recommended by the manufacturer (up to 6 mL/day; ie, 2 Penthrox inhalers). At times, patients were recommended to self-administer further doses of methoxyflurane by the endoscopist if the endoscopist anticipated potential loops that might cause discomfort. In instances when methoxyflurane did not provide sufficient analgesia or at the patient’s request, rescue combination therapy of IV fentanyl and midazolam was given according to the age guidelines above. 894 GASTROINTESTINAL ENDOSCOPY Volume 78, No. 6 : 2013
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Signs of over-sedation such as drowsiness, pallor, and unresponsiveness were monitored closely. In addition, details related to the colonoscopy procedure such as duration, time to reach cecum, endoscopic therapy (ie, polypectomy, argon plasma coagulation), or occurrence of adverse events were also recorded. The endoscopist was also asked to complete a questionnaire to assess the patient’s level of pain, anxiety, and cooperation as well the level of technical difficulty related to the colonoscopy. In recovery, the patient’s vital signs, alertness, mental state, and abdominal symptoms were monitored. Once patients were alert and able to obey commands appropriately, they were allowed to sit out of bed and have oral intake. At this time, patients were asked to complete a questionnaire to assess their current pain and anxiety scores as well as their scores during the colonoscopy, retrospectively. The patients were then assessed for the ability to be discharged home. Patients were asked to report any adverse events occurring up to 30 days after study participation. The research nurse contacted all patients at 24 to 48 hours and 30 days after the colonoscopy to check for the occurrence of any adverse events related to either the drugs or the colonoscopy.
Measured outcomes Primary endpoints were as follows: (1) pain and anxiety scores during colonoscopy, (2) time of discharge (defined as the time the caring nurses and physician deemed it to be “medically safe” for the patients to leave the Endoscopy Unit; any delay because of transport need or other unrelated medical issue was excluded), and (3) the proportion of patients who were willing to undergo the procedure again with the given analgesic/sedative modality. Timing from the end of the procedure to the time the patient was awake, time to oral intake, and time to be ready for discharge were also documented prospectively. Secondary endpoints were (1) time to cecal intubation, (2) rate of completing colonoscopy, (3) polyp detection rate, (4) total colonoscopy procedural time, (5) rate of adverse events, (6) use of rescue medication before completion of procedure, and (7) patient’s recollection of the procedure. Hypotension was defined as a reduction of systolic blood pressure below 80% of baseline and/or below 100 mm Hg.26 A heart rate over 100 beats per minute was accepted as tachycardia. Respiratory depression was defined as the need for high-flow oxygen supply (8-10 L) because of an oxygen desaturation below 90% (SaO2 ! 90%) that continued for more than 20 seconds.27 In both groups, patients were encouraged to increase their respirations when oxygen desaturation occurred.
Assessment tools VAS pain score. A VAS score is widely used to assess pain.22 This is a 100-mm VAS scale for pain severity on www.giejournal.org
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Methoxyflurane inhaler versus sedation for colonoscopy
TABLE 1. Comparison of demographics, initial pain and anxiety scores, dosage of sedatives, and procedural indications between patients who received Penthrox inhaler and conventional sedation during colonoscopy Sedation (n [ 126)
Penthrox (all) (n [ 125)
Penthrox, success (92%) (n [ 115)
Penthrox, failure (8%) (n [ 10)
54.9 1.1
51.4 1.1
51.9 1.0
44.7 1.2y
72:54
70:55
66:49
4:6
0.62 0.13
0.60 0.12
0.53 0.11
1.40 0.15*
Total score
43.7 0.7
46.2 0.5*
46.2 0.5*
46.4 1.0*
Nervous score
15.8 0.5
14.9 0.5
14.7 0.5
14.2 1.4
60 3
53 3
54 3
68 12*
Midazolam
3.7 0.1
NA
NA
4.5 0.1
Fentanyl
83.2 1.9
Age, y Gender (male:female) VAS (0-10) pain score before colonoscopy STAI-Y anxiety score
Colonoscopist perception of patient’s anxiety state (VAS) (0 Z very calm, 100 Z most anxious) Dosage of sedation
92.5 1.1
Indications for colonoscopy Polyp surveillance
28
20
20
0
Bowel cancer screening
20
32
32
0
Rectal bleeding
37
21
17
4
Abdominal pain
10
24
22
2
IBD related
12
10
8
2
Constipation
3
4
4
0
Diarrhea
7
7
6
1
Anemia
1
3
3
0
Constipation/diarrhea
5
3
2
1
VAS, Visual analog scale; STAI-Y, State-Trait Anxiety Inventory Form Y; NA, not available; IBD, inflammatory bowel disease. *P ! .05, vs sedation. yP ! .01, vs all other groups.
symptoms of a state of anxiety,29,30 but in preoperative patients the cut-off point for the total score is set at 44 to 45.31,32
which 0 indicates absence of pain and 100 the worst pain possible. STAI-Y anxiety score. The Spielberger STAI is a 40-item instrument measuring transient and enduring levels of anxiety.23,24 Of the 3 forms of the STAI, the current study used the adult STAI Form Y (ie, STAI-Y), which assesses both temporary emotional state anxiety and the longstanding personality trait anxiety. The STAI-Y score system consists of 2 underlying dimensions that broadly assess “nervousness” and “well-being.” The nervousness factor consists of 7 items (“tense,” “upset,” “frightened,” “nervous,” “jittery,” “confused,” and “steady”) and well-being consists of 6 items (“secure,” “at ease,” “satisfied,” “comfortable,” “content,” and “pleasant”).28 In this study we used both the STAI sum score and the nervousness subscore to assess the effects of Penthrox and IV sedation. A cut-off point for the total score of 39 to 40 is normally used for clinically significant
Sample size calculations were made based on the results of our previous pilot study.21 When we used the endpoint of mean “patient’s discomfort score” and related standard deviation, the power calculation with a 2-sided significance level of .05, power of 90%, and assuming that a difference of 1.0 in mean discomfort score was clinically important indicated that the trial needed to recruit a minimum of 112 participants per treatment arm. Data are expressed as mean standard deviation. The Fisher exact test was used for comparison of categorical data and independent Student t test for continuous data. Analyses were performed using GraphPad Prism statistical software, version 6 (GraphPad Software Inc., La Jolla, CA). P ! .05 was accepted as indicating statistical significance.
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Data analysis
Methoxyflurane inhaler versus sedation for colonoscopy
Figure 1. Outline of study design and outcomes.
RESULTS Overall, 125 patients received Penthrox and 126 patients received conventional sedation. In the Penthrox group, no patient had to use more than 1 Penthrox inhale (3 mL). There were no differences in age, gender, precolonoscopy VAS pain scores, and colonoscopist’s perception of patient’s anxiety level and indication for colonoscopy between the groups (Table 1). Although the total STAI-Y anxiety scores were higher in the Penthrox group, the nervousness scores were similar between the groups. Patients with conventional sedation received a mean dosage of 3.4 0.1 mg midazolam and 83.6 2.9 mg fentanyl. Of those who received Penthrox, 10 patients (8%) required additional IV sedation for completion of colonoscopy (Fig. 1). The characteristics of this subgroup of patients were different from those who completed the procedure with Penthrox or IV sedation alone: They were younger and had higher precolonoscopy VAS pain score and colonoscopist’s perception of patient’s anxiety level (Table 1).
Pain and STAI-Y anxiety scores There were no differences in VAS pain scores before, during, and after colonoscopy between patients who received IV sedation and Penthrox (overall or Penthrox alone) (Fig. 2). However, patients who received both Penthrox and IV sedation for colonoscopy reported higher VAS pain score before and during colonoscopy and 24 hours after colonoscopy than those receiving either Penthrox or IV sedation alone. Although the total STAI-Y anxiety scores were higher in the Penthrox group, the “nervousness” scores were similar between the groups (Table 2). Both Penthrox and IV sedation were able to reduce the nervousness score in all patients after administration.
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time, and the success rate of completed colonoscopy (Table 3). There were no differences in the rate of polyp detection and polypectomy between the groups. Patients who required combination of Penthrox and IV sedation were perceived to have more discomfort, less cooperation, and a more technically difficult colonoscopy than the other groups and had the lowest success rate for completion of colonoscopy. Although the rates of adverse events were similar between the Penthrox (all) and IV sedation group, most adverse events occurred in patients who required IV sedation in addition to the Penthrox (Table 3). In particular, none of the patients who had a successful procedure with Penthrox alone had respiratory depression. These adverse events only occurred in patients who received IV sedation, either alone or combined with Penthrox. The risks of hypotension during colonoscopy and tachycardia were similar between the groups. At telephone follow-up 24 hours and 30 days after colonoscopy, no patient reported or was found to have been readmitted to the hospital for abnormal renal or liver function tests as an indicator of nephrotoxicity or hepatoxicity.
Recovery time Compared with those who received IV sedation, patients who received Penthrox had significantly shorter times to being awake, to have oral intake, and to be ready for discharge (Fig. 3). Overall, patients who had a successful procedure with Penthrox were discharged on average 15 minutes earlier than those with IV sedation.
Patient’s perception on the use of Penthrox for colonoscopy Patients who completed colonoscopy with Penthrox alone indicated that the inhaler was helpful and easy to use. The patients liked being able to use the drug at their discretion. They also had better recall of the procedure and findings (Table 4). The overall satisfaction score was 94 out of 100. Of patients who had successful colonoscopy with Penthrox alone, 97% were willing to use Penthrox again for future colonoscopy.
DISCUSSION
There were no differences between the groups in procedural preparation time, cecal arrival time, total colonoscopy
This is the first study to show that patient-controlled analgesia with inhaled methoxyflurane (Penthrox) as a method of discomfort relief for colonoscopy is feasible, safe, and as effective as IV sedation. The main advantages of using Penthrox over conventional IV sedation for colonoscopy are a lack of respiratory depression, a more reliable memory of the procedural findings by the patients, a substantial shorter recovery time, and avoiding IV cannulation. The high satisfaction score (94/100) and the finding that most patients (97%) were willing to use Penthrox again for future colonoscopy support the use of Penthrox
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Figure 2. VAS pain scores before and during colonoscopy, at recovery, and 24 hours after colonoscopy between groups.
TABLE 2. Effects of Penthrox, conventional sedation, and combination therapy on STAI-Y anxiety scores during and after colonoscopy between groups Sedation (n [ 126)
Penthrox (all) (n [ 125)
Penthrox, success (92%) (n [ 115)
Penthrox, failure (8%) (n [ 10)
Precolonoscopy
43.7 0.7
46.2 0.5*
46.2 0.5*
46.4 1.0*
Postcolonoscopy
45.4 0.7
47.6 0.5*
47.7 0.5*
45.4 1.5
24 h after
49.1 0.3
48.2 0.8
48.1 0.9
49.1 1.1
Precolonoscopy
15.8 0.5
14.9 0.5
14.7 0.5
14.2 1.4
Postcolonoscopy
11.3 0.2
11.4 0.3
11.54 0.3
10.7 0.5
24 h after
10.8 0.3
10.6 0.3
10.6 0.3
10.4 0.3
4.5 0.2y
3.3 0.1y
3.3 0.1y
3.8 0.1y
STAI-Y Anxiety Score Total score
“Nervousness” subscore
Reduction in “nervousness” score after medication STAI-Y, State-Trait Anxiety Inventory Form Y. *P ! .05, vs sedation. yP ! .01, vs all other groups.
as an alternative and possibly safer analgesic modality for colonoscopy. More importantly, the use of Penthrox does not influence the performance and the polyp detection rate of the procedure. Together with the rapid recovery, the use of Penthrox for colonoscopy can facilitate earlier discharge, improve workflow, and optimize the health economics of endoscopic units, especially those with long waiting lists. In addition to the analgesic effect, Penthrox has a good anxiolytic effect that is comparable with that from IV
sedation. Although the literature on the analgesic effects of Penthrox is extensive,15-18 the current study is the first to show the anxiolytic effects of Penthrox as demonstrated by a significant reduction in nervousness score from the STAI-Y assessment. Furthermore, the rapid onset of anxiolytic effect of Penthrox was also observed in the current trial. This is a major benefit because it settles most of the initial anxiety related to colonoscopy and, along with the analgesic effect, allows most patients to tolerate the procedure well without being sedated. Consequently, patients
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TABLE 3. Effects of Penthrox, conventional sedation, and combination therapy on the procedural performance and patient’s cooperation during colonoscopy between groups Sedation (n [ 126)
Penthrox (all) (n [ 125)
Penthrox, success (n [ 115)
Penthrox, failure (n [ 10)
Preparation time, min
61
61
61
61
Cecal arrival time, min
81
81
71
14 1
Total colonoscopy time, min
17 1
15 1
15 1
21 1
124 (98%)
121 (97%)
114 (99%)
7 (70%)
Severe sigmoid diverticulosis
1
2
0
2
Significant looping
1
1
1
0
Obstructing lesion
0
1
0
1
10 (7%)
10 (7%)
4 (7%)
6 (60%)
Respiratory depression
5
5
0
5
Hypotension
8
7
5
2
Cardiac arrhythmia
3
5
3
2
43 (34%)
30 (24%)
30 (26%)
0 (0%)
Colonoscopist perception of patient’s discomfort during colonoscopy (0 Z no pain, 100 Z worst pain)
43 3
42 3
41 3
59 13
Colonoscopist perception of procedural difficulty (0 Z easy; 100 Z most difficult)
52 3
52 2
51 2
68 3
Colonoscopist perception of patient’s cooperation (0 Z none; 100 Z excellent)
80 2
77 2
79 2
48 13
NA
75 3
79 2
40 15
Rate of complete colonoscopy Reason for incomplete colonoscopy
Adverse event
Polypectomy rate
Colonoscopist perception of patient’s technique in using Penthrox inhaler (0 Z very bad; 100 Z excellent) NA, not available.
who undergo colonoscopy with Penthrox are fully alert almost immediately after the procedure and are able to be discharged earlier than those who receive IV sedation. Furthermore, because patients are not sedated during the procedure, they are able to watch, be informed of, and remember the procedural findings, increasing the likelihood that patients are aware of their colonoscopic results on discharge. Although the current study has shown that Penthrox has little sedative effect, it remains unclear whether these patients can drive home after the procedure, and this warrants further evaluation. As observed with IV sedation, the use of Penthrox for colonoscopy is not suitable for all patients, especially those who have significant anxiety disorders or visceral hypersensitivity. A reported 10% of patients who undergo colonoscopy with IV sedation fail to tolerate the procedure33-35 and require a deeper level of sedation technique, such as neuroleptic sedation with propofol or general anesthesia.36-38 In the current study, 8% of Penthrox patients failed to tolerate the procedure and required additional IV sedation. In contrast to the rest of the group, these
patients are different and have predictive clinical features of a “difficult” patient, such as young women with significantly higher precolonoscopy pain and anxiety scores and higher pain scores during colonoscopy. Although these patients had a lower colonoscopy completion rate (7/10; 70%), this was not related to the mode of analgesia or sedation and rather was because of encountered colonic pathology that prevented colonoscope advancement in a safe manner (Table 3). Furthermore, these patients also had higher pain scores 24 hours after the procedure, suggesting a possible contribution of underlying visceral hypersensitivity. Therefore, to optimize the success rate of Penthrox for colonoscopy, patients should be selected carefully. In addition to medical contraindications, patients who are young women with high preoperative anxiety or pain level are also less suitable for Penthrox use. These patients are most likely to benefit from the use of deep sedation techniques for the procedure. Our results are the first to show that it is feasible to perform unsedated colonoscopy in most patients using combined Penthrox analgesia and carbon dioxide insufflation,
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Figure 3. Differences in recovery time between patients who received Penthrox and patients who received IV sedation for colonoscopy.
which has been shown to reduce patient discomfort during and after colonoscopy.39 An alternative insertion technique of warm water immersion has also been shown to improve comfort and tolerance in patients who underwent sedated40,41 and unsedated42 colonoscopy. The combination use of such insertion techniques and Penthrox analgesia may therefore provide a new approach to perform unsedated colonoscopy with adequate pain relief. The safety profile of Penthrox for colonoscopy in the current study is consistent with the literature.17 In contrast to the dosage given for anesthesia, the much-smaller amount of methoxyflurane administered by 1 Penthrox inhaler for colonoscopy in the current study did not cause any clinically significantly adverse events, especially nephrotoxicity or hepatotoxicity and respiratory depression. The toxicity of methoxyflurane is dose dependent. Although serial measurements of renal or liver functions were not adopted in the current study, 30-day telephone follow-up for any adverse events was used, and no adverse events were reported. It is important to note that despite its safety profile, to prevent nephrotoxicity or hepatotoxicity related to Penthrox, all patients with or suspected renal and liver diseases must be excluded from using the agent. Almost all serious adverse events in the Penthrox group were related to patients who had additional IV sedation. Respiratory depression was only observed in patients who received both Penthrox and IV sedation, indicating that caution must be taken when additional IV sedation
is used in patients who failed Penthrox analgesia. Because nearly half of the patients who failed Penthrox alone also failed after additional IV sedation, “failure” of Penthrox for colonoscopy appears to be a good indication to identify “difficult” patients who would be best managed with deep sedation (eg, with propofol). Although a small proportion of patients had hypotension (7%) and tachyarrhythmia (4%) after Penthrox, these adverse effects are also seen in patients who had IV sedation43 and may more likely relate to dehydration from fasting and bowel preparation than to the Penthrox.44 A potential weakness of the current study is selection bias toward patients who are healthy and with no serious medical conditions such as liver, renal, or cardiorespiratory diseases. In addition, because we did not collect the STAI-Y and pain scores of patients who refused to participate in our trial, it is not possible to rule out the possibility that patients in the current study were less anxious than general patients referred for colonoscopy and thus account for the higher successful procedure rate with Penthrox and a lack of a difference as compared with IV sedation. Furthermore, although power calculation was performed to determine the sample size, the analysis was based on the primary outcomes of pain and anxiety scores. This calculated sample size, however, may not be large enough to prevent a potential Type II error for outcomes, such as polyp detection and adverse event rate; thus, the interpretation of these outcomes must be made with caution. Because our trial was not blinded, it is most
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TABLE 4. Patient perception of Penthrox use for colonoscopy, stratified by those who successfully completed the procedure with Penthrox alone vs those who required additional sedation Penthrox, success (92%) (n [ 115)
Penthrox, failure (8%) (n [ 10)
Ease of use
92 1
78 7
.005
Taste and smell
61 3
22 7
!.001
Helpful
84 2
30 10
!.001
Ability to use at discretion
86 2
53 12
!.001
Recollection of the procedural detail and findings
84 2
54 8
!.001
Overall satisfaction
94 1
64 8
!.001
Would use Penthrox again for future colonoscopy
92 2
22 9
!.001
Ease of use
95 1
85 6
.04
Taste and smell
56 3
26 10
.006
Helpful
87 2
38 11
!.001
Ability to use at discretion
88 2
45 13
!.001
Recollection of the procedural detail and findings
81 2
65 10
.09
Overall satisfaction
96 1
72 12
!.001
Would use Penthrox again for future colonoscopy
93 2
21 10
!.001
P
Immediately after colonoscopy
24 h after colonoscopy
Visual analogue scale: 0 Z don’t like it at all; 100 Z like it very much.
likely that the nursing staff in recovery were also not blinded to the type of analgesia or sedation used. However, we have a standardized protocol in assessing and recording time to awake, time to oral intake, time ready for discharge, and actual time of discharge. The assessments are based on alertness and vital signs and are very objective. Recognizing a number of factors can influence the actual time of discharge, such as delayed pick-up and inability to organize transport, we have deliberately assessed time ready for discharge, which was based on objective measures. This is a potential reason why the differences in actual time of discharge between the groups were least compared with the other measured outcomes. Finally, our results are probably most applicable to subjects who were referred for colonoscopy from screening programs related to colorectal cancer. In conclusion, patient-controlled analgesia with Penthrox for colonoscopy is feasible and as effective as conventional sedation for relieving pain and anxiety without affecting the procedural success and polyp detection rates. It appears to be safer than sedation with no adverse effects on respiratory function. The addition of IV sedation to patients who do not tolerate colonoscopy with Penthrox, however, should be used with caution. With appropriate patient selection, the use of Penthrox analgesia for colonoscopy facilitates rapid recovery, allows earlier discharge, and improves the workflow of endoscopy units. 900 GASTROINTESTINAL ENDOSCOPY Volume 78, No. 6 : 2013
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