Cold water infusion enhances image quality in sedated miniprobe endoscopic ultrasonography: A prospective, multicenter, double-blind, randomized trial

Abstract

BACKGROUND

Miniprobe endoscopic ultrasonography (mEUS) plays an increasingly significant role in gastrointestinal (GI) lesions. Previous studies showed the water temperature could affect patients’ GI peristalsis and safety; however, the optimal water temperature for mEUS remains uncertain.

AIM

To evaluate the effects of different infusion water temperatures on image quality, diagnostic accuracy, safety, and comfort during sedated mEUS.

METHODS

This prospective, multicenter, double-blind, randomized controlled trial was conducted at five tertiary hospitals. A total of 240 patients were randomly assigned to cold water group (CG, 6-10 °C), warm water group (WG, 20-24 °C), or hot water group (HG, 35-39 °C) groups. Primary outcome was image quality. Secondary outcomes included diagnostic accuracy, peristaltic grade, haemodynamics, comfort and satisfaction scores, and adverse events. χ² test, ANOVA, and Kruskal-Wallis test were used for comparisons.

RESULTS

Between June 2022 and March 2024, 240 patients were randomly assigned to the three groups. The percentage of high-quality images (score 5) was significantly higher in the CG than in the WG and HG (88.8% vs 75.0% vs 65.0%, P = 0.002). Diagnostic accuracy was numerically higher in the CG than in the WG and HG (97.0% vs 81.5% vs 81.1%). Peristalsis scores were significantly lower in the CG compared to both the WG and HG (P < 0.001). No severe adverse events occurred. Comfort and satisfaction scores did not differ significantly among the groups.

CONCLUSION

Cold water infusion reduces GI peristalsis and improves image quality with excellent safety. Cold water (6-10 °C) may be the optimal temperature for sedated mEUS.

Key Words: Miniprobe endoscopic ultrasonography; Infusion water temperature; Sedation; Image quality; Diagnostic accuracy

Core Tip: Cold water (6-10 °C) significantly improves image quality and suppresses gastrointestinal peristalsis during sedated miniprobe endoscopic ultrasonography. Our multicenter trial showed higher rates of high-quality images (88.8% vs 75.0% vs 65.0%) and numerically higher diagnostic accuracy with cold water compared with warm (20-24 °C) and hot (35-39 °C) water. With excellent safety and comparable comfort, cold water may be the optimal temperature choice for miniprobe endoscopic ultrasonography under sedation.

INTRODUCTION

The global incidence of gastrointestinal (GI) tumors is increasing, posing a significant challenge to healthcare systems worldwide[1,2]. Missed or misdiagnosed GI tumors can lead to delayed treatment, increased therapeutic complexity, and worse patient outcomes, including elevated mortality risk[3]. Therefore, improving the diagnostic accuracy of GI tumors is of critical importance[4].

Miniprobe endoscopic ultrasonography (mEUS) integrates a GI endoscope with a miniature high-frequency ultrasound probe. This technique enables direct mucosal visualization and provides real-time sonographic assessment of lesions, determining their layer of origin, depth of infiltration, echogenicity, and relationship to adjacent structures[5]. Consequently, mEUS holds high value in diagnosing and differentiating GI protuberant lesions, and provides a crucial basis for selecting appropriate treatment strategies[6-10].

During mEUS, airless water is infused between the probe and the GI mucosa to create an acoustic interface, thereby improving image clarity. Previous studies have indicated that the temperature of infused water can influence GI peristalsis and patient hemodynamics during endoscopic procedures[11-16], which may consequently impact procedural image quality, diagnostic accuracy, and safety. However, the specific impact of infusion water temperature on image quality, diagnostic accuracy, and patient safety during sedated mEUS remains uninvestigated. Therefore, this study aimed to identify the optimal infusion water temperature for sedated mEUS by evaluating its effects on GI peristalsis, image quality, diagnostic accuracy, as well as patient safety and comfort.

MATERIALS AND METHODS

Study design

This multicenter, double-blind, randomized controlled trial was conducted at five institutions, namely The Third Xiangya Hospital of Central South University, The First Affiliated Hospital of South China University, Hunan Provincial People’s Hospital, The First People’s Hospital of Changde, and Affiliated Nanhua Hospital, University of South China, between June 2022 and March 2024. This study has been registered at ClinicalTrials.gov, No. NCT05454475, which is a primary registry recognized by the World Health Organization International Clinical Trials Registry Platform. This study was also approved by the Ethical Committee of the Third Xiangya Hospital of Central South University, No. 22177. All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki).

Patients

The inclusion criteria included patients aged ≥ 18 years who had GI mucosal or submucosal lesions detected by general endoscopy and required mEUS under sedation for definitive diagnosis. The exclusion criteria were as follows: (1) Failure to meet the requirements for mEUS examination and anaesthesia, or need to use multiple sedative and analgesic drugs; (2) Pregnancy or breastfeeding; (3) Chronic use of opioids and benzodiazepines; (4) Structural changes in the GI tract caused by abdominal surgery; (5) Presence of mental illness; and (6) Presence of lesions in the esophagus. All patients provided written informed consent prior to enrollment.

Randomisation and masking

A total of 240 patients were randomly assigned to the cold water group (CG), warm water group (WG), and hot water group (HG) according to the 1:1:1 random number table generated using SPSS 23.0 (Chicago, IL, United States). The infusion water temperature was concealed from patients and endoscopists performing mEUS via opaque, airtight containers labeled only with randomization codes, prepared by an independent researcher not involved in the procedure or data analysis. Opaque infusion tubing with insulation covering prevented condensation and temperature perception at the injection site. The statistician remained blinded to group allocation until completion of all analyses.

To ensure consistency across the five participating centers, all endoscopists were senior physicians (associate chief physician or above) with > 5 years of experience and > 250 mEUS procedures each, and had completed standardized training. All procedures used the same equipment platform (Fujifilm SU-9000 with 12 MHz miniprobe, Japan) with regular calibration. Image quality was assessed by the same endoscopists who performed the procedures, with videos de-identified and randomly ordered to ensure blinding.

Procedure for mEUS under sedation

Airless water, prepared in advance, was stored in the endoscopy room at 20-24 °C for ≥ 3 hours to stabilize its temperature. For the procedures, water was maintained at three target temperatures: Cold (6-10 °C, stored in a refrigerator), warm (20-24 °C, room temperature), and hot (35-39 °C, maintained in a thermostatically controlled water bath). Immediately before infusion, a researcher (not the endoscopist) filled the irrigation tank using opaque containers to ensure blinding. The infusion water temperature was verified with a calibrated thermometer (HYNAUT, Qingdao, China), and the endoscopist was blinded to the assignment.

Upper GI preparation: All patients fasted for at least 8 hours prior to the examination. The mucosal surface was cleansed with dimethicone emulsion to eliminate foam and subsequently rinsed with water to ensure a clear acoustic interface. Patients with gastric food retention or excessive intragastric fluid were excluded. Lower GI preparation: Patients with colorectal lesions underwent standard bowel preparation using polyethylene glycol electrolyte solution (2-3 L) administered orally the day before the procedure. Bowel preparation quality was assessed using the Boston Bowel Preparation Scale, and only patients with a Boston Bowel Preparation Scale score of 3 (excellent) were included to ensure optimal mucosal visualization.

Patients were placed in the left lateral decubitus position. To ensure consistency, patients requiring multiple sedative or analgesic drugs were excluded; all 240 patients received propofol monotherapy exclusively (1 mg/kg intravenous bolus for induction). Supplemental propofol (0.2-0.5 mg/kg) was administered as needed by dedicated anesthesiologists based on Modified Observer’s Assessment of Alertness/Sedation scores (target ≤ 2) and patient movement, with assessors blinded to water temperature allocation. No opioids, benzodiazepines, or anticholinergics were used during the procedure. All procedures were performed under monitored anesthesia care.

Following initial localization of the lesion with conventional endoscopy, the mucosal surface was cleansed with dimethicone to eliminate foam and then rinsed with water. Then the water was continuously infused until the lumen was filled. For anatomically challenging locations (gastric antrum lesser curvature, gastric fundus dome, and hepatic flexure) where standard left lateral decubitus positioning resulted in incomplete immersion, positional adjustments were permitted: Slight right lateral or supine position for lesser curvature lesions, Trendelenburg or right lateral position for fundic lesions, and supine or right anterior oblique position for hepatic flexure lesions. Strictly, total water volume was maintained within the standard range (50-600 mL) without increase due to positional changes; two patients requiring > 400 mL despite adjustment were excluded from the final analysis. Subsequently, a miniprobe (SU-9000, 12 MHz, Fuji, Tokyo, Japan) was inserted into the endoscope and delivered to the lesion under direct vision for scanning and recording video. After the examination, the water was completely aspirated, and the patients rested in the recovery room until they were fully awake. No anticholinergic agents were administered to any patient during the procedure to eliminate their potential confounding effect on GI peristalsis. All investigators attended a study group meeting before the study and received instructions on the methods for infusing water and for the video recording of GI peristalsis.

Outcomes

The primary outcomes were the mEUS image quality. Image quality was assessed using Soon et al’s scoring[17] method by two experts (excluding the endoscopist who performed the mEUS) on a predefined scale of 1 to 5 as follows: (1) The image contains air artefact, and the lesion of interest cannot be seen; (2) Image contains air artefact, severely compromising the assessment of lesion size and characteristics; (3) Image contains air artefact, mildly compromising the assessment of lesion size and characteristics; (4) Image contains air artefact, but the assessment of lesion size and characteristics uncompromised; and (5) Image contains no air artefact, and the assessment of lesion size and characteristics uncompromised (Figure 1A-C). Inter-rater reliability between the two independent experts (both senior endoscopists with > 250 mEUS procedures) was assessed using the two-way random-effects model intraclass correlation coefficient [ICC(2,1)] and linear weighted Cohen’s kappa coefficient. The ICC was 0.930 [95% confidence interval (CI): 0.886-0.969], indicating excellent reliability, and the linear weighted kappa was 0.913 (95%CI: 0.856-0.965), indicating almost perfect agreement. Raw agreement was 96.25% (231/240 cases), with all cases (100%) having score differences of ≤ 1 point.

Figure 1 Image quality assessment. A: Score 5, image contains no air artefact, and the assessment of lesion size and characteristics is uncompromised; B: Score 3, image contains air artefact, mildly compromising the assessment of lesion size and characteristics; C: Score 1, image contains severe air artefact, and the lesion of interest cannot be seen; D-F: Gastric antrum peristalsis after water infusion. Grade 1, no peristalsis (D); grade 2, mild peristalsis (E); grade 4, vigorous peristalsis (F); G-I: Colorectal peristalsis after water infusion. Grade 1, no peristalsis (G); grade 2, mild peristalsis (H); grade 4, vigorous peristalsis (I).

For disagreement resolution (defined as a score difference ≥ 2 points), a standardized protocol was established: (1) Both experts would review the video together to reach consensus; and (2) If consensus could not be reached, a third senior expert with 20 years of EUS experience would arbitrate. No cases in this study required this resolution protocol. For statistical analysis, image quality scores were categorized as follows: Poor (scores 1-2), good (scores 3-4), and excellent (score 5).

Secondary endpoints included the following: Diagnostic accuracy; GI peristaltic grade; haemodynamic indices at anaesthesia assessment (T0), endoscopy (T1), before water infusion (T2), at water infusion (T3), at the aspiration of all water (T4), and at wakefulness (T5); adverse events; and somatic and psychological feeling scores. For diagnostic accuracy assessment: For patients who underwent surgery, endoscopic submucosal dissection or had tissue specimens obtained by puncture, the pathologic results were used as the gold standard; for other patients, we conducted at least a 6-month follow-up and determined the benign or malignant nature of the lesions based on the patients’ clinical manifestations, test results, lesion sizes, and echogenic changes. The number of pathology-confirmed cases and follow-up-diagnosed cases was recorded for each group. Peristaltic scoring was graded by two experts (both senior endoscopists with > 250 mEUS procedures each) based on recorded video, using Hiki’s upper GI peristaltic score for the stomach and duodenum (1 = no peristalsis to 5 = markedly vigorous peristalsis)[18] (Figure 1D-F) and Likman Mui’s lower GI peristaltic score for the colorectum (1 = no peristalsis to 5 = markedly vigorous peristalsis)[19] (Figure 1G-I). Both assessors completed a standardized calibration session prior to formal scoring, including independent pilot scoring of training videos (pilot ICC = 0.85) and consensus discussion. A detailed scoring manual with representative images was provided for reference throughout the assessment. Inter-observer reliability for peristaltic grading was excellent: ICC(2,1) = 0.981 (95%CI: 0.959-0.996) and weighted κ = 0.975 (95%CI: 0.947-0.994), with 98.3% exact agreement (236/240) and all discrepancies ≤ 1 point. Scores from both experts were averaged for analysis.

Haemodynamic parameters included mean arterial pressure (MAP), heart rate (HR), and oxygen saturation (SpO₂). Adverse events included coughing, choking, aspiration, hypotension (defined as MAP < 65 mmHg[18-20] or MAP decrease > 20% from T2 baseline), bradycardia (HR < 50 beats/minute), tachycardia (HR > 100 beats/minute), hypoxaemia (SpO₂ < 90%), bleeding, perforation, and infection. Events were graded using a modified Common Terminology Criteria for Adverse Events (CTCAE)[21] version 5.0: Grade 1 (mild, self-limiting, no intervention required), grade 2 (moderate), and grade 3+ (severe).

After patients recovered from anaesthesia, a questionnaire assessed somatic discomfort (including nausea and vomiting, bloating, coldness, and anxiety), pain, comfort, and satisfaction. Pain scores were assessed using the visual analog scale (0 = no pain at all; 10 = very painful), and comfort and satisfaction scores were assessed using a 5-point Likert scale (1 = very uncomfortable or very dissatisfied; 5 = very comfortable or very satisfied).

Sample size calculation

PASS 21.0 (NCSS LLC, Kaysville, UT, United States) was used to calculate the sample size. According to the pre-experiment with 20 patients in each group, the excellent rates of image quality in the three groups were 0.83, 0.75, and 0.58, respectively. The sample size calculation was based on the primary outcome (image quality) only, with α = 0.05 (two-sided) and power = 0.8. A minimum of 60 cases per group was required. Considering a 20% dropout rate, 75 patients were needed in each group, yielding a total of 225 patients.

Statistical analysis

All statistical analyses were conducted using IBM SPSS Statistics software (version 23.0; IBM Corp., Armonk, NY, United States). Descriptive statistics were used to summarize the general observation index data. Continuous variables are expressed as mean ± SD if normally distributed, or as median with interquartile range otherwise. The normality of distribution was assessed using the Shapiro-Wilk test or visual inspection of histograms. For comparisons of continuous variables across the three groups, one-way analysis of variance (ANOVA) was used for normally distributed data, and the Kruskal-Wallis H test was used for non-normally distributed data. Categorical variables are summarized as n (%). Inter-group comparisons for categorical variables were performed using the χ² test or Fisher‘s exact test, with the latter applied when more than 20% of the expected cell counts were less than 5. Repeated measurement data were analysed using repeated-measures ANOVA. For intra-group comparisons of hemodynamic parameters before (T2) and during (T3) water infusion, the paired Student‘s t-test (for normal data) or the Wilcoxon signed-rank test (for non-normal data) was applied, as appropriate. A two-sided P value < 0.05 was considered statistically significant for all tests unless otherwise specified. For post-hoc pairwise comparisons following a significant ANOVA or Kruskal-Wallis test, the Bonferroni correction was applied, with an adjusted P value < 0.0125 indicating statistical significance.

RESULTS

Participants enrolled and assigned

Between June 2022 and March 2024, 270 patients satisfied the inclusion criteria, 14 patients required combining multiple sedative and analgesic drugs, and 16 patients with conditions such as cardiopulmonary and renal failure, asthma, and uncontrolled hypertension were excluded (Figure 2). Consequently, 240 patients were randomized into the three study groups: CG (n = 80), WG (n = 80), and HG (n = 80). The demographic and clinical baseline characteristics were well-balanced across all groups, with no statistically significant differences (Table 1).

Figure 2  Allocation of participants showing the flow of patients through the study from screening to final analysis according to the CONSORT 2010 statement.

Table 1 Demographic and other baseline characteristics, n (%)/mean ± SD/mean (interquartile range).

Variables	Cold water (n = 80)	Warm water (n = 80)	Hot water (n = 80)	F/χ2/H	P value
Sex
Male	37 (46.3)	35 (43.8)	38 (47.5)	0.235	0.889
Female	43 (53.8)	45 (56.3)	42 (52.5)
Age, years	52.7 ± 12.9	49.3 ± 13.1	51.7 ± 13.0	1.566	0.211
< 55	42 (52.5)	51 (63.7)	43 (53.8)	2.477	0.290
≥ 55	38 (47.5)	29 (36.3)	37 (46.3)
Height, cm	162.2 ± 7.0	162.3 ± 7.3	163.1 ± 7.6	0.381	0.684
Body weight, kg	58.9 ± 10.3	60.3 ± 11.1	59.2 ± 11.1	0.407	0.666
Body mass index, kg/m2	22.2 (19.9, 24.9)	22.4 (20.5, 24.8)	21.3 (19.9, 24.8)	2.068	0.356
Smoking	12 (15.0)	8 (10.0)	17 (21.3)	3.898	0.141
Alcohol	8 (10.0)	8 (10.0)	10 (12.5)	0.345	0.842
Location
Stomach	44 (55.0)	41 (51.2)	43 (53.8)	1.764	0.779
Duodenum	14 (17.5)	18 (22.5)	12 (15.0)
Colorectum	22 (27.5)	21 (26.3)	25 (31.3)
Lesion size, cm	0.8 (0.6, 1.5)	0.8 (0.5, 1.5)	0.8 (0.5, 1.5)	0.223	0.895
Total dose of propofol, mg	200 (185, 265)	200 (153, 200)	200 (193, 280)	2.653	0.265
Water volume, mL	200 (150, 300)	200 (150, 250)	200 (106, 300)	0.650	0.723
Procedure time1, minutes	8 (5, 12)	8 (5, 10)	8 (6, 11)	1.076	0.584
Ultrasonic diagnosis
Gastrointestinal stromal tumor	16 (20.0)	9 (11.3)	15 (18.8)
Leiomyoma	1 (1.3)	2 (2.5)	8 (10.0)
Neuroendocrine tumors	4 (5.0)	4 (5.0)	8 (10.0)
Lipoma	4 (5.0)	2 (2.5)	2 (2.5)
Ectopic pancreas	16 (20.0)	17 (21.3)	11 (13.8)
Lymphangioma	1 (1.3)	1 (1.3)	0 (0)
LST	11 (13.8)	11 (13.8)	11 (13.8)
Cyst	8 (10.0)	10 (12.5)	5 (6.3)
Abscess	1 (1.3)	0 (0)	1 (1.3)
Polyp	4 (5.0)	5 (6.3)	4 (5.0)
Vasculature	4 (5.0)	7 (8.8)	3 (3.8)
Inflammatory hyperplasia	7 (8.8)	8 (10.0)	8 (10.0)
Accessory nipple	0 (0)	2 (2.5)	2 (2.5)
External compression	3 (3.8)	2 (2.5)	2 (2.5)

¹Time from T2 (before water infusion) to T4 (after water suction).

LST: Laterally spreading tumor.

Image quality

Cold water infusion yielded significantly superior overall image quality compared to warm or hot water. The proportion of images rated as excellent (score 5) was 88.8% in the CG, compared to 75.0% in the WG and 65.0% in the HG (P = 0.002). No significant difference in the overall excellent rate of image quality was observed between the WG and HG (Figure 3). Stratified analysis revealed significant differences in image quality across anatomical locations (Kruskal-Wallis H = 15.206, P < 0.001). The stomach showed the highest excellent rate (82.0%, 95%CI: 74.8%-88.0%), followed by the colorectum (73.5%, 95%CI: 61.8%-82.9%) and duodenum (54.5%, 95%CI: 39.4%-69.2%). When analyzed by temperature and location, cold water demonstrated the most significant advantage in gastric lesions (95.5% vs 80.5% vs 69.8%, P = 0.013), while showing nonsignificant trends in the duodenum and colorectum, likely due to smaller sample sizes.

Figure 3 Comparison of the overall image quality scores of the three groups. ^aP < 0.0125 (Bonferroni-corrected significance threshold). NS: Not significant.

To assess whether lesion morphology confounded outcomes, we analyzed mucosal surface lesions with valid Paris classification (0-I, 0-II, and 0-II/III types, n = 71). No significant differences in image quality were observed across Paris types (Kruskal-Wallis H = 4.067, P = 0.397), indicating that lesion morphology did not influence the observed temperature effects.

Lesion size showed no significant correlation with image quality scores (Spearman rs = 0.040 and 0.045 for Experts 1 and 2, respectively; both P > 0.05), indicating consistent image quality across the range of lesion sizes (0.2-7.0 cm). Subgroup analyses based on anatomical location (upper vs lower GI tract) revealed no significant differences in image quality among the three groups. However, in the gastric antrum, the image quality was significantly higher in the CG than in the HG (100% vs 57.1%, P = 0.003).

Diagnosis accuracy

Diagnostic accuracy was evaluated based on histopathological confirmation (n = 63) or at least 6 months of clinical follow-up (n = 34) (Supplementary Table 1). The overall diagnostic accuracy was highest in the CG (97.0%, 32/33), followed by the WG (81.5%, 22/27) and the HG (81.1%, 30/37), although the difference did not reach statistical significance. The sensitivity and specificity with 95%CI for each group were as follows: CG: Sensitivity 100% (95%CI: 83.9%-100%), specificity 80.0% (95%CI: 54.8%-93.0%); WG: Sensitivity 90.9% (95%CI: 72.2%-97.5%), specificity 66.7% (95%CI: 35.4%-87.9%); HG: Sensitivity 68.7% (95%CI: 51.4%-82.1%), specificity 57.1% (95%CI: 38.5%-74.0%) (Supplementary Table 2). Pairwise comparisons using Fisher’s exact test showed that the CG had significantly higher sensitivity than the HG (P = 0.002), while no significant differences were observed in specificity among the three groups.

Peristaltic grade

There was no statistically significant difference in the peristaltic grade before water infusion. The peristaltic grade was significantly lower in the CG after water infusion, whereas no statistical difference was observed before and after water infusion between the WG and HG. After water infusion, the proportion of patients with a peristaltic grade of 1 was significantly higher in the CG than in the WG and HG (81.3% vs 37.5% vs 38.8%, P < 0.0125), and there was no significant difference between the WG and HG (Supplementary Table 3). The effects of cold water on different GI segments were further explored. In the gastric fundus, gastric antrum, descending duodenum, right colon, and rectum, the proportion of peristaltic grade 1 after water infusion was significantly higher than that before water infusion (P < 0.05; Figure 4).

Figure 4 Comparison of peristaltic grade in the cold water group (grade 1 no peristalsis). A: The proportion of peristalsis grade 1 before and after water infusion in the stomach; B: The proportion of peristalsis grade 1 before and after water infusion in the duodenum; C: The proportion of peristalsis grade 1 before and after water infusion in the colorectum. ^aP < 0.05.

Haemodynamics

The three groups had no differences in MAP at T0, T1, T2, or T5. However, at T3, the HG showed a significantly lower MAP (69.9 ± 10.8 mmHg) than the CG (73.5 ± 7.7 mmHg, P = 0.044) and WG (73.7 ± 9.5 mmHg, P = 0.030). Similarly, at T4, the HG exhibited a significantly lower MAP than the CG (69.3 ± 6.6 mmHg vs 73.0 ± 8.5 mmHg, P = 0.036) and WG (69.3 ± 6.6 mmHg vs 73.1 ± 9.6 mmHg, P = 0.025). No significant differences in MAP were found between the CG and WG at any time point. Moreover, no significant differences in HR and SpO₂ were observed among the three groups (Supplementary Tables 4-6; Figure 5).

Figure 5 Haemodynamic changes in the three groups. A: Mean arterial pressure at different time points; B: Heart rate at different time points; C: Oxygen saturation at different time points. ^bP < 0.05 the cold vs hot groups, ^cP < 0.05 the warm vs hot groups. SpO₂: Oxygen saturation.

Adverse outcomes

The overall adverse event rate was 12.5% (30/240, 95%CI: 8.8%-17.4%). All events were CTCAE grade 1 (mild) and self-limiting; no grade 2 or 3 events occurred. Hypotension occurred in 1.3% (1/80, 95%CI: 0.2%-6.7%) of the CG, 3.8% (3/80, 95%CI: 1.3%-10.4%) of the WG, and 11.3% (9/80, 95%CI: 6.0%-20.2%) of the HG (P = 0.025). Among 13 hypotensive events, 5 had MAP < 65 mmHg (all in HG; lowest 52 mmHg) and 8 had relative decrease > 20% only; all resolved spontaneously within 3.5 ± 1.8 minutes without intervention or procedure interruption. Other events (coughing, tachycardia/bradycardia) were transient and did not affect procedure completion (Supplementary Table 7).

Comfort

No significant differences in somatic discomfort (nausea, vomiting, bloating, coldness, and anxiety) were observed during or after the examination. All patients reported a pain score of 0. The comfort and satisfaction scores were similar (Supplementary Table 8).

DISCUSSION

mEUS is a crucial tool for diagnosing GI protuberant lesions, as its image quality directly influences the judgment of lesion nature and assessment of invasion depth. In this study, our key findings are as follows: The proportion of grade 1 GI peristalsis in the CG was significantly higher than those in the WG and HG (81.3% vs 37.5% vs 38.8%, P < 0.0125). In terms of image quality, the percentage of excellent image quality in the CG was significantly superior to that in the WG and HG (88.8% vs 75.0% vs 65.0%, P = 0.002). Additionally, although the inter-group difference did not reach statistical significance, diagnostic accuracy was numerically highest in the CG (97.0% vs 81.5% vs 81.1%), which also demonstrated the highest sensitivity (100%) and specificity (80%). Collectively, these findings indicate that cold water infusion enhances mEUS image quality and diagnostic performance, primarily through its effective inhibition of GI peristalsis.

In sedated mEUS, high-quality imaging is fundamental, allowing for precise assessment of lesion size, layer of origin, depth of infiltration, echogenicity, and relationship to adjacent structures. This comprehensive evaluation is crucial for improving diagnostic accuracy[22,23]. However, image quality is influenced by many factors, besides the experience of the endoscopist and frequency of the miniprobe. Among these, GI peristalsis is a major, yet modifiable, source of image degradation. Inhibiting GI peristalsis minimizes motion artifacts and bubble formation, thereby stabilizing the acoustic interface and improving image clarity, which ultimately enhances diagnostic accuracy. Previous studies have demonstrated that drinking beverages at 4 °C significantly inhibits gastric antrum peristalsis and delays gastric emptying[24,25]. However, no similar phenomenon was observed when drinking beverages at 37 °C and 50 °C[26]. Studies investigating water-infused colonoscopy under sedation found no significant difference in the effect of water at temperatures ranging from 35-38 °C and 20-23 °C on GI peristalsis[27,28]. Our results were similar, we observed that cold water (6-10 °C) effectively reduced GI peristalsis, whereas this phenomenon was not observed with warm (20-24 °C) and hot water (35-39 °C). In addition, we found that the image quality was significantly better in the CG than in the WG and HG, especially for the gastric antrum.

The core driving factors of GI peristalsis include the mechanical contraction of GI pressure waves and the electrophysiological regulation of gastric electrical rhythm[29]. Previous studies have shown that cold water activates cold-sensitive receptors in the GI wall and then transmits signals, which in turn inhibits GI peristalsis. Additionally, other studies found that drinking water at 4 °C or cold exposure at 7 °C significantly inhibit GI peristalsis[30]. This provides theoretical support for the validity of our research. Interestingly, we also observed a significant decrease in the gastric fundus and rectum, which was not evident previously. This may be related to the small sample sizes after subdividing the CG into different parts. Additionally, we found that the diagnostic accuracy of CG was higher than that of WG and HG, this difference likely reflects the improved image quality and reduced peristalsis observed with cold water, though the study was not powered to detect statistically significant differences in this secondary endpoint. We will subsequently expand the sample size for further study.

Regarding safety, Girona et al[12] found that drinking cold water (3 °C) and warm water (22 °C) increased cardiac vagal tone by activating heat-sensitive vagal afferent nerve fibres in the oesophagus and gastroduodenum, thereby reducing cardiac load. Subsequent studies observed higher MAP after ingestion of cold water (0-3 °C), while no significant difference was found between ingestion of hot (45 °C) and warm (22 ± 2 °C) water. Our results showed no significant difference in MAP before the operation (T0-T2). However, at T3 and T4, MAP was significantly higher in the CG and WG than in the HG. These results are similar to previous studies in healthy individuals. Notably, the MAP of the three groups showed a downward trend, which may be because sedative drugs can inhibit the efferent impulse of the sympathetic nerve and suppress pressure emission[31-35]. The HR and SpO₂ of all the patients showed a steady state. While the HG exhibited slightly higher rates of mild hypotension, all three groups maintained hemodynamic stability within clinically acceptable ranges. The observed 3-4 mmHg differences in MAP, though statistically significant, represent minor fluctuations below the threshold of clinical concern (typically ± 15 mmHg or ± 20% from baseline) and are smaller than reductions typically observed during propofol induction. Thus, all three water temperatures are hemodynamically safe for sedated mEUS, with cold water showing a statistical advantage in reducing mild hypotensive episodes.

A study reported that water at neither 35-38 °C nor 20-23 °C affected the amount of sedative drugs used in water-infused colonoscopy[28]. Similar results were observed in our study, as no statistical difference was observed among the three groups of sedative drug dosage, procedure time, and water volume. Additionally, we focused on patients with choking, hypotension, arrhythmia, hypoxaemia, bleeding, perforation, or infection. The incidence of hypotension was slightly higher in the HG than in the other two groups; however, there was no statistical difference in the incidence of total adverse events among the three groups. Notably, all adverse events were CTCAE grade 1 (mild) and self-limiting, with no severe events or interventions required. Furthermore, the overall adverse event rate was lower than that observed in mEUS with conventional propofol anaesthesia (12.5% vs 51.56%)[33]. To summarize, changing the infusion water temperature for patients undergoing mEUS under sedation is simple and safe.

To date, no studies have specifically focused on patient comfort, including the physical and psychological aspects. In our study, a questionnaire was provided to the patients after the examination. The results showed no significant difference in the overall feelings; all the patients felt comfortable. This may be because changing the infusion water temperature under sedation did not have a significant effect on the physical sensations of the patients.

This study has several limitations. First, it only included patients under propofol sedation, without covering non-sedated populations or special groups like children and elderly patients, so the generalizability of cold water intervention needs further verification. Second, patients with esophageal lesions were excluded. The straight nature of the oesophagus and its slight peristalsis makes it difficult to compare the peristalsis grades. Additionally, the proximity of the oesophagus to the heart may result in a greater haemodynamic effect following water infusion than the GI tract. Third, while the sample size was adequate for the primary endpoint of image quality (based on our power calculation of 60 patients per group providing 80% power), it was underpowered for the secondary endpoint of diagnostic accuracy (post-hoc power analysis indicated only 55% power to detect the observed difference of 97.0% vs 81.5% vs 81.1%). We assessed the diagnostic accuracy of the entire GI tract and did not discuss it by part because of the small sample size in individual anatomical subgroups. Future studies with larger sample sizes (approximately 400-500 patients) are needed to confirm the effect of water temperature on diagnostic accuracy and to enable more precise subgroup analyses by anatomical location. We are currently planning such a study.

CONCLUSION

Controlling infusion water temperature is a simple method that is easy to apply in the clinic and may even reduce the use of anticholinergic medications. The CG is more advantageous in reducing GI peristalsis and improving image quality than the WG and HG, and all groups have good safety and comfort. Cold water (6-10 °C) may be the optimal choice for performing mEUS under sedation; it is expected to improve the diagnostic accuracy of GI tumors and provide a reliable basis for the selection of therapeutic regimens.