Introduction
Endoscopic ultrasound (EUS) has become an indispensable modality for diagnosis of
pancreatobiliary diseases. Studies actively investigating interventional therapy with
EUS are expected to widen the clinical application of EUS [1 ]
[2 ]. Echoendoscope is thicker than the conventional upper gastrointestinal endoscope,
and the end of the scope with the transducer is rigid, which causes discomfort during
insertion. In addition, visibility is poor during insertion due to the nature of the
side-view endoscope [3 ]. Therefore, echoendoscope is more difficult to insert than the conventional endoscope
and may be associated with additional complications. In general, upper endoscopy is
associated with minor throat discomfort. In a single prospective study, approximately
2.5 % of patients reported seeking medical services due to such discomfort [4 ]. In the case of endoscopic retrograde cholangiopancreatography (ERCP), one-third
to one-half of patients felt pain and discomfort and 6 % reported moderate-to-severe
pain in the neck [5 ]. In the case of echoendoscope with a thicker diameter and side view, more severe
and frequent discomfort can be expected.
A balloon is attached around the tip of the probe, which can be inflated with water
through an endoscope. Usually, the balloon is inflated after positioning the echoendoscope
appropriately. If the balloon is inflated at the time of insertion, it may reduce
pharyngeal mucosal injury and subsequent complications caused by the hard tip of the
scope. In this study, we evaluated the degree of neck pain after the procedure with
balloon inflation, compared with standard insertion.
Patients and methods
Patients
A single-blinded, prospective, randomized study was performed from October 2016 to
September 2018 at a single tertiary center in Seoul, Korea. This study was approved
by the institutional review board of Seoul National University Hospital and registered
in ClinicalTrials.gov (NCT02924948). Patients aged at least 20 years who underwent
radial EUS for diagnosis of pancreatobiliary disease were enrolled. Patients who underwent
linear EUS were excluded from the study. Informed consent was obtained from all patients.
Absent any previous study of complications with EUS, 6 % of patients with moderate-to-severe
pharyngeal pain were estimated based on ERCP study [5 ]. Balloon inflation was assumed to reduce the rate of moderate-to-severe pain by
nearly 67 %. A total of 482 subjects including 241 in each group were calculated to
provide a power of 80 % and α = 0.05. Randomization was done by assigning patients
according to a computer-generated random number list with 1:1 allocation using a random
block size of 4 or 6 by personnel not involved in the trial.
Intervention
All interventions were performed by six clinical fellows (A-F) using a radial-array
echoendoscope (GF-UE260; Olympus) with a balloon (MH-303; Olympus) applied at the
tip. The first 6 months were studied by A and B, the next year by C and D, and the
last 6 months by E and F. Since A and B had 6 to 7 months of EUS experience at the
time of study participation, the EUS procedure performed by A and B were classified
as more than 6 months. C and D had several days of EUS experience when they participated
in the study, and about 1 year of experience at the end of the study participation.
The procedures, which were performed by C and D for 1 year, were classified into three
categories; less than 3 months, 3 to 6 months, and more than 6 months. E and F had
several days of experience with EUS at the time of participation. They accumulated
about 6 months of experience at the end of the study. The procedures performed by
these patients were divided into two categories; less than 3 months and 3 to 6 months.
After conscious sedation with only midazolam (0.05 mg/kg), the randomized assignments
were opened by an attending nurse before inserting EUS. In the case of patients who
were assigned to the balloon inflation group, the EUS was inserted with a half-inflated
balloon. Except for the insertion, the subsequent procedure was no different between
the two groups.
After patients recovered from sedation with full consciousness with the ability to
engage in adequate conversation. Nurses who did not participate in the endoscopy procedure
evaluated the degree of pharyngeal pain with the Numeric Rating Scale (NRS) which
is validated in most settings [6 ]
[7 ].
Outcomes
The primary outcome was the rate of moderate-to-severe pharyngeal pain with an NRS
score of 4 or more [8 ]
[9 ] according to the insertion method. Secondary outcomes included the degree of pharyngeal
pain, rates of insertion failure at first attempt and balloon loss according to the
insertion method, adverse events (AEs), the difference in pain level according to
the physicians’ experience. Balloon loss was defined as the balloon not inflating
due to damage during insertion. Risk factors for post-procedural pain were also evaluated.
Statistical analysis
The analyses were performed according to intention-to-treat (ITT) analysis and per-protocol
(PP) analysis. ITT analysis was performed with all the subjects and PP analysis was
performed after exclusion of subjects who underwent additional endoscopy in the same
session. Data are expressed as a number and percentage for categorical variables,
and as the mean ± standard deviation (SD) or the median for continuous variables.
Significance of differences in clinical parameters between groups was assessed using
the chi-squared test or Fisher’s exact test, as appropriate. Continuous variables
distributed normally were analyzed using the t -test, otherwise, the Mann-Whitney U test was used. Risk factors for pharyngeal pain
were evaluated by logistic regression analysis. Demographic, disease-related, and
procedure-related factors were assessed in the analysis. Factors with a significance
level of 0.1 based on the univariable analysis were considered in the multivariable
analysis. Results were expressed as hazard ratios (HRs) and 95 % confidence interval
(CI). Statistical significance was assumed at a confidence level of 0.05. Statistical
analyses were performed using SPSS 23 (SPSS, Chicago, Illinois, United States).
Results
Patients’ clinical characteristics
From October 2016 to September 2018, a total of 1,092 patients underwent radial EUS
for evaluation of pancreatobiliary disease. We obtained informed consent from 481
of these patients and registered 238 for standard insertion and 243 for balloon inflation.
These patients constituted the ITT population. Fifty-five patients were excluded from
the per-protocol analysis because of additional endoscopy in the same session with
radial EUS. The per-protocol analysis included 213 cases in standard insertion and
217 cases in balloon inflation ([Fig. 1 ]). Demographic, disease-related and procedure-related characteristics of the two
groups were not significantly different ([Table 1 ]).
Fig. 1 Flowchart of the study.
Table 1
Baseline characteristics of patients.
Total
Standard (N = 238)
Balloon (N = 243)
P value
Age (mean, range)
57.3 (24–80)
57.1 (26–80)
57.6 (24–80)
0.675
Gender
0.927
Male
228
112 (47.1 %)
116 (47.7 %)
Female
253
126 (52.9 %)
127 (52.3 %)
Etiology
0.121
Pancreas
232
124 (52.1 %)
108 (44.4 %)
Biliary tract
258
119 (50.0 %)
139 (47.2 %)
Patients' experience
0.581
No
450
221 (92.9 %)
229 (94.2 %)
Yes
31
17 (7.1 %)
14 (5.8 %)
Endoscopistsʼ experience
0.865
> 6 months
156
78 (32.8 %)
78 (32.1 %)
3–6 months
170
84 (35.3 %)
86 (35.4 %)
≤ 3 months
155
76 (31.9 %)
79 (32.5 %)
Observation time (min, mean±SD)
6.2 ± 4.2
6.0 ± 3.9
6.5 ± 4.4
0.232
SD, standard deviation
Primary outcome
One hundred and twelve patients (23.3 %) reported moderate-to-severe pharyngeal pain
after the procedure. The ratio of patients reporting moderate-to-severe pain with
an NRS score of 4 or more was slightly lower in the balloon insertion group, without
any statistical significance (26.5 % vs. 20.2 %; P = 0.107). In PP analysis, the difference in the ratio of moderate-to-severe pain
was also lower in the balloon group but was not statistically significant (23.9 %
vs. 16.1 %; P = 0.053, [Table 2 ]).
Table 2
Primary outcome: moderate-to-severe pharyngeal pain according to the insertion method.
ITT analysis
Standard (N = 238)
Balloon (N = 243)
P value
NRS < 4
175 (73.5 %)
194 (79.8 %)
0.107
NRS ≥ 4
63 (26.5 %)
49 (20.2 %)
PP analysis
Standard (N = 213)
Balloon (N = 217)
P value
NRS < 4
162 (76.1 %)
179 (83.9 %)
0.053
NRS ≥ 4
51 (23.9 %)
38 (16.1 %)
ITT, intention-to-treat; PP, per-protocol; NRS, numeric rating scale
Secondary outcomes
Post-procedural pain score was slightly lower in the balloon group, but did not reach
statistical significance (2.04 ± 2.39 vs. 1.83 ± 2.11, P = 0.297). Rate of insertion failure at first attempt (standard vs. balloon 8.4 %
vs. 5.8 %; P = 0.289) and the rate of balloon loss (standard vs. balloon 8.0 % vs. 6.6 %; P = 0.601) were not significantly different between the two groups. PP analysis did
not show any significant differences in those outcomes, either ([Table 3 ]). During the trial period, no procedure-related AEs such as bleeding, perforation,
or subsequent infection occurred.
Table 3
Secondary outcomes according to the insertion method.
ITT analysis
Standard (N = 238)
Balloon (N = 243)
P value
NRS (mean±SD)
2.04 ± 2.39
1.83 ± 2.11
0.297
Insertion at 1st attempt
0.289
Success
218 (91.6 %)
229 (94.2 %)
Fail
20 (8.4 %)
14 (5.8 %)
Loss of balloon
0.601
No
219 (92.0 %)
227 (93.4 %)
Yes
19 (8.0 %)
16 (6.6 %)
Procedure-related complications
0
0
ns
PP analysis
Standard (N = 213)
Balloon (N = 217)
P value
NRS (mean±SD)
1.70 ± 2.17
1.65 ± 2.01
0.651
Insertion at 1st attempt
0.274
Success
194 (91.1 %)
204 (94.0 %)
Failure
19 (8.9 %)
13 (6.0 %)
Loss of balloon
0.854
No
197 (92.5 %)
202 (93.1 %)
Yes
16 (7.5 %)
15 (6.9 %)
Procedure-related complications
0
0
ns
ITT, intention-to-treat; PP, per-protocol; NRS, numeric rating scale; SD: standard
deviation
Risk factors for pharyngeal pain
Risk factors for moderate-to-severe pharyngeal pain were evaluated according to the
various characteristics. Gender, age, observation time, patient’s prior EUS experience,
the endoscopist’s experience at time of procedure, and the insertion method were considered
as variables in logistic regression analysis. Age and observation time were classified
based on interquartile ranges. Female gender and endoscopist's experience with less
than 3 months were associated with severe pain, whereas older age ( > 66 years) and
balloon inflation were associated with less pain in multivariable analysis ([Table 4 ]).
Table 4
Risk factors for pharyngeal pain.
Factors
N
Univariable
Multivariable
HR (95 % CI)
P value
HR (95 % CI)
P value
Gender
228
1
1
253
2.263 (1.434–3.572)
< .001
2.168 (1.349–3.483)
0.001
Age
121
1
1
121
0.960 (0.550–1.678)
0.887
0.945 (0.528–1.691)
0.945
121
0.810 (0.458–1.432)
0.469
0.779 (0.429–1.416)
0.413
118
0.414 (0.217–0.790)
0.007
0.341 (0.174–0.671)
0.002
Insertion method
238
1
1
243
0.666 (0.427–1.040)
0.074
0.645 (0.423–0.983)
0.041
Patients‘ experience
450
1
31
0.912 (0.383–2.176)
0.836
Observation time (min)
87
1
119
0.935 (0.523–1.675)
0.822
116
0.824 (0.452–1.503)
0.528
159
1.057 (0.594–1.882)
0.851
Endoscopistsʼ experience
156
1
1
170
1.015 (0.582–1.773)
0.957
1.095 (0.618–1.942)
0.755
155
2.409 (1.431–4.054)
0.001
2.861 (1.658–4.938)
< 0.001
HR, hazard ratio; CI, confidence interval
We compared the proportion of patients experiencing moderate-to-severe pharyngeal
pain according to the insertion method in patients with identified risk factors. No
differences based on the insertion method were found in female (30.7 % vs. 22.8 %,
P = 0.177) or younger patients (29.1 % vs. 23.6 %, P = 0.367). In patients who were undergoing EUS by endoscopists with less than 3 months’
experience, pain score was significantly higher than in other groups (< 3 months:
2.4, 3 – 6 months: 1.7, > 6 months: 1.7, P = 0.016). However, balloon inflation decreased the proportion of patients experiencing
moderate-to-severe pharyngeal pain when performed by endoscopists with less than 3
months’ experience (44.7 % vs. 25.3 %, P = 0.012) ([Fig. 2 ]).
Fig. 2 Rates of moderate-to-severe pharyngeal pain according to the physician’s experience
with EUS and the insertion method. Fewer patients reported moderate-to-severe pharyngeal
pain with inflated balloon when EUS was performed by endoscopists with less than 3
months’ experience of EUS.
Discussion
Results of this study indicate that EUS insertion with an inflated balloon was effective
in terms of post-procedural pain without disturbing procedure, especially performed
by physicians with less than 3 months of experience.
Although there was no statistically significant difference in average pain intensity
and rate of moderate-to-severe pain according to insertion method. Balloon inflation
tended to be lower than the standard method in both outcomes. In addition, no increase
was found in rates of insertion failure or balloon loss with increased diameter due
to the inflated balloon. Balloon inflation did not hinder the procedure.
Compared with results of the referenced study, the rate of moderate-to-severe pharyngeal
pain after EUS was much higher than expected, while the average pain level was mild
(NRS ≤2). Therefore, it is possible that more participants may have been needed to
reach statistical significance. There are several reasons for this result. First,
the structural difference between endoscope should be considered. Second, the absence
of analgesics such as meperidine or fentanyl during conscious sedation may have affected
pain level. Third, this study involved a higher proportion of female patients who
are known to be more sensitive to pain. In addition, the difference in the proficiency
level of the endoscopists may have been influential.
Several factors were identified as associated with pharyngeal pain. Balloon inflation
may be a protective factor. During insertion, the portion of the endoscope contacting
the mucous membrane is soft and plastic with compliance. Because it has a curved surface,
it is expected to reduce mucosal damage due to physical contact. The total force exerted
upon insertion and pharyngeal pain caused by force may not be reduced [10 ]
[11 ] but the possibility of additional pain can be decreased by reduced physical injury.
Younger age was identified as a risk factor for pain. A study showed that younger
patients complained of pain after the ERCP procedure [5 ]. The tone of the upper esophageal sphincter is increased in younger patients, and
reflex response to the stimulus is also higher than in the elderly [12 ]. Therefore, younger patients are more likely to feel greater pain, because greater
pressure is needed to offset the elevated muscle tone and reflexes.
Gender was also one of the risk factors for pain. In the study of conventional upper
gastrointestinal endoscopy, the rate of pain complaints was higher in women [4 ]. Higher prevalence of moderate-to-moderate pain in women suggests the effect of
gender difference. It is known that women are likely to suffer from more severe pain
than men in diseases like irritable bowel syndrome (IBS) [13 ]. The reason for the lower pain threshold in women is not yet clear. In previous
studies, psychosocial factors and behavioral stress related to social learning were
the main factors [14 ]
[15 ]. Recently, the hormonal factor is also postulated as important from a recent gender-specific
perspective [13 ]
[16 ].
Experience level in endoscopy was identified as a major risk factor for pain. The
shorter the experience, the harder can be the insertion procedure and greater the
risk of complications. In this study, pain associated with insertion was reduced and
plateaued after 70 procedures and approximately 3 months of experience. Studies of
endoscopy learning curves showed that in the case of EUS, a certain level of technical
competence was achieved after 50 to 75 procedures [17 ]
[18 ]
[19 ]. In this study, a comparable level of technical competence was reached in accordance
with previous studies.
Based on these results, we examined conditions under which balloon inflation can alleviate
pharyngeal pain. It was effective in reducing the rate of moderate-to-severe pain
for physicians with less than 3 months of EUS experience. Because balloon inflation
did not significantly increase the rate of insertion failure or balloon loss, it may
prevent the risk of pain and complications for unexperienced endoscopists.
Our study has several limitations. First, it was a single-blind trial. Although pain
evaluation was made by a third-party nurse not related to the study, possible biases
from the operators still remained. Second, we did not evaluate factors from a socioeconomic
aspect or quality-of-life perspective. Mental health and quality of life may play
an important role in pain thresholds [5 ]
[15 ]. Third, there were no complications, such as clinically important gastrointestinal
bleeding or perforation associated with EUS insertion. Therefore, the role of pain
as a surrogate marker was limited.
Our study also has some strengths. First, it is the first prospective study of complications
associated with EUS. Second, it identified risk factors for pain during EUS insertion.
Third, it showed that balloon inflation can be used to prevent complications by novices.
Fourth, although the study did not identify learning curves, it indirectly demonstrated
that 3 months is needed to become technically competent in echoendoscope insertion,
as the pain associated with insertion was significantly reduced after performing 70
procedures.
Conclusion
In conclusion, when performed by physicians with EUS experience of fewer than 3 months,
the balloon inflation method can reduce the proportion of patients with moderate-to-severe
pharyngeal pain.
