Hypoxemia is a common complication associated with anesthesia in painless gastroscopy. With the aging of the social population, the number of cases of hypoxemia among middle-aged and elderly patients is increasing. However, tools for predicting hypoxemia in middle-aged and elderly patients are lacking. In this study, we investigated the risk factors for hypoxemia in middle-aged and elderly outpatients undergoing painless gastroscopy based on machine learning and constructed a risk prediction model. In this retrospective study, we included the data on 1,348 outpatients undergoing painless gastroscopy. In total, 26 characteristic variables, including demographic information, past medical history, and clinical data of the patients were included, and BorutaShap was used for feature selection. Five machine learning algorithm models, including logistic regression (LR), support vector machine (SVM), random forest (RF), extreme gradient boosting (XGB), and light gradient boosting machine (LightGBM), were selected. The best models were selected based on the area under the receiver operating characteristic curve (AUROC). Model feature importance was explained and analyzed using Shapley Additive Explanations (SHAP). The endpoint event of this study was considered to be hypoxemia during the procedure, defined as at least one occurrence of pulse oxygen saturation below 90% without probe misalignment or interference from the beginning of anesthesia induction to the end of painless gastroscopy. In the final cohort of 984 patients, 11% of patients (108/984) experienced hypoxemia during the painless gastroscopy procedure. The AUROCs of the five models were as follows: Logistic Regression (AUROC = 0.893, 95CI: 0.881-0.899), SVM (AUROC = 0.855, 95CI: 0.812-0.884), Random Forest (AUROC = 0.914, 95CI: 0.889-0.924), XGB (AUROC = 0.902, 95CI: 0.865-0.919), and LightGBM (AUROC = 0.891, 95CI: 0.847-0.917). Regarding the explanation of the importance of SHAP features, preoperative variables (baseline SpO2, body mass index, and micrognathia) and intraoperative variables (operating time of gastroscopy, induction dose of etomidate and propofol mixture, append anesthetic, cough, and repeated pharyngeal irritation) significantly contributed to the model. We identified eight potential risk factors related to the occurrence of hypoxemia in middle-aged and elderly patients undergoing painless gastroscopy, based on machine learning feature engineering. Among the five machine learning algorithms, RF exhibited the best predictive performance in the internal test set and had a certain degree of generalization ability in the external validation set, which indicated that the RF model was more suitable for the data framework of this study. This model was more likely to enhance the accuracy of hypoxemia prediction in middle-aged and elderly patients undergoing painless gastroscopy, and thus, it is suitable for assisting anesthesiologists in clinical decision-making.

Background/Objectives: The administration of propofol without an anesthesiologist (NAAP) during endoscopic procedures is generally considered safe. However, the available data remain limited and fragmented due to legal constraints. This systematic review and meta-analysis aimed to evaluate the incidence of adverse events in adults undergoing procedural sedation with NAAP. Methods: A comprehensive search was conducted in three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) for studies published between 2010 and 2023. Eligible studies included randomized controlled trials and observational studies that reported predefined adverse events in adult patients receiving NAAP for procedural sedation. The analysis encompassed various types of endoscopic procedures and sedation protocols, including both balanced sedation and propofol monotherapy. Clinical heterogeneity was assessed by comparing patient characteristics, sedation methods, and outcome measures across studies. A random effects model was used for the meta-analysis, with results presented as estimated incidence rates. Subgroup analyses were conducted based on the hypoxia severity, sedation approach, and procedure type. Results: The search yielded 2963 records, of which 73 studies met the inclusion criteria, covering a total of 967,238 procedural sedations. Hypoxia was the most frequently reported adverse event, occurring in 40‱ of cases, followed by hypotension (38‱) and bradycardia (9‱). Severe adverse events requiring emergency intervention were rare, with an incidence of 0.12‱. The subgroup analysis indicated a low occurrence (6‱) of severe desaturation (SpO2 < 80%) and no significant differences in adverse event rates between balanced propofol sedation and propofol-only sedation. However, advanced endoscopic procedures (EUS, ERCP, PEG, enteroscopy, EMR/ESD) were associated with a higher risk of hypoxia (10% vs. 26‱; p < 0.00001) and major complications (3.1‱ vs. 0.1‱; p = 0.015) compared to diagnostic procedures. Conclusions: NAAP-based procedural sedation appears to be generally safe. While the minor adverse event rates vary depending on the sedation regimen and procedure type, major complications remain exceptionally rare.

Routine pre-transplant evaluations for heart or lung recipients often include upper and lower gastrointestinal endoscopies. However, given that these patients frequently have significant and multiple comorbidities, the risk-benefit ratio of endoscopy with sedation remains uncertain.

We conducted a retrospective chart review of all patients who underwent esophagogastroduodenoscopy (EGD) and/or colonoscopy as part of the pre-transplant evaluation for heart (HTX) or lung transplantation (LuTX) at our center over a 10-year period. All procedures were performed with either anesthesiologist-assisted sedation or general anesthesia (72%) or physician-assisted sedation (28%). The primary outcomes included the prevalence of pre/neoplastic lesions and the rate of adverse events, classified according to the American Society of Gastrointestinal Endoscopy.

A total of 315 patients (70% male, median age 55 years) were included, with ASA grades 3 (31%) and 4 (69%). Of these, 90% underwent both EGD and colonoscopy. While no neoplasia or findings relevant to transplantation were detected on EGD, a single rectal malignant pedunculated polyp was identified and curatively removed via colonoscopy (G2 pT1 L0 V0 R0). The adenoma detection rate during colonoscopy was 25%, including a 7% rate of advanced adenomas, with six additional lesions (< 10 mm) exhibiting high-grade dysplasia. Conversely, severe adverse events occurred in 2.5% of cases, involving both cardiovascular and colonoscopy-related complications. These included two cases of severe hypotension and bradyarrhythmia requiring cardiovascular resuscitation, with one resulting in death (0.3% mortality). Additionally, one splenic rupture, two colonic perforations, and two cases of severe post-polypectomy bleeding were observed.

The routine requirement for upper and lower gastrointestinal endoscopy as a screening measure before heart or lung transplantation should be reconsidered due to its unfavorable risk-benefit profile. An individualized approach should be taken.

Appropriate sedative and analgesic selection is essential to reduce patient discomfort and body movement to safely conduct endoscopic ultrasonography (EUS). However, few cases have examined sedation with propofol in EUS, and few studies the need for combined analgesia. In this study, we retrospectively evaluated the usefulness and safety of propofol without analgesics for sedation in biliopancreatic observational EUS.

This single-center retrospective study included 516 observational biliopancreatic EUS procedures using propofol alone performed between April 2021 and March 2023. The primary and secondary endpoints were the observational biliopancreatic EUS results obtained with propofol alone and adverse event occurrence, respectively.

The median examination time and total propofol dose were 22 (range: 10-67) min and 186.5 (range: 50-501) mg, respectively. The median starting Richmond Agitation-Sedation Scale and Visual Analog Scale scores were -5 (range: -5-1) and 0 (range: 0-10), respectively. The median recovery time was 22 (range: 5-80) min. Adverse events occurred in 60 (11.6%) patients. Trainee-performed examination (odds ratio [OR] 3.52, 95% confidence interval [CI]: 1.63-7.60, p = 0.0014) and examination length (>22 min; OR 1.67, 95% CI: 0.95-2.92, p = 0.07) were risk factors for adverse events.High body mass index (OR 1.87, 95% CI: 1.10-3.16, p = 0.02) and extended examination time (OR 4.23, 95% CI: 2.08-8. 57, p < 0.001) were risk factors for delayed recovery.

During observational biliopancreatic EUS, propofol is useful as a single sedative and offers high patient satisfaction and relative safety.

Propofol is commonly used for endoscopic sedation. However, it can induce adverse hemodynamic effects. Remimazolam is known to have a fast onset and short duration comparable to that of propofol, but with fewer effects on hemodynamics. We assessed the Oxygen Reserve Index to verify whether a sedative dose of remimazolam would better preserve oxygenation in the mild hyperoxic range than propofol in sedated patients undergoing diagnostic upper gastrointestinal endoscopy.

Patients scheduled for diagnostic upper gastrointestinal endoscopy were enrolled. Patients were randomly assigned to either the remimazolam or propofol groups and received 0.1 mg/kg remimazolam or 0.5 mg/kg propofol, respectively. Bolus injections of either 0.05 mg/kg remimazolam or 0.25 mg/kg propofol were added if required. The primary outcome was the prevalence of oxygen reserve depletion, defined as the Oxygen Reserve Index decreasing to 0.00, and hypoxia defined as peripheral oxygen saturation falling to <94%.

Among 69 patients, the incidence of oxygen reserve depletion was significantly higher in the propofol group (65.7% vs. 38.2%, P = 0.022). Hypoxia was frequently observed in the propofol group, whereas none was observed in the remimazolam group (11.4% vs. 0%, P = 0.042). Additional sedative injections were frequently required to complete endoscopy in the propofol group. None of the patients in the remimazolam group required airway interventions. Nausea was frequent in the propofol group in the recovery room.

Our results indicate that remimazolam is a safe and useful sedative for upper gastrointestinal endoscopy.

Anxiety is a common and significant problem in patients who need to undergo colonoscopy. However, the question of which non-pharmacological intervention is the best strategy to reduce anxiety in patients undergoing colonoscopy remains unanswered.

To evaluate and rank the effectiveness of various non-pharmacological interventions for reducing anxiety in patients undergoing colonoscopy in order to identify the most effective strategies.

We searched PubMed, Cochrane Library, Embase, Web of Science, and Medline for randomized controlled trials published from the database construction to March 2024. The primary outcome was the difference between pre- and post-intervention anxiety means. A network meta-analysis was conducted utilizing the "gemtc" package based on R4.3.0.

The analysis encompassed 24 randomized controlled trials, incorporating 2525 participants and evaluating 9 non-pharmacological interventions. All non-pharmacological interventions reduced anxiety in patients undergoing colonoscopy compared to standard care, with music intervention (SMD = -0.52, 95 %CI (-0.84,-0.20)), audiovisual distraction (SMD = -0.54, 95 %CI(-0.96,-0.12)), video information (SMD = -1.47, 95 %CI(-2.03,-0.90)), individual education (SMD = -1.72, 95 %CI(-2.76,-0.70)), and electroacupuncture (SMD = -1.12, 95 %CI(-2.10,-0.13)) having statistically significant effects. SUCRA ranking identified the priority of individual education (SUCRA: 92.5 %) and video information (SUCRA: 87.7 %). Meta-regression and sensitivity analysis further demonstrated the stability of the evidence. The certainty of the evidence was mostly rated as medium to low.

This review highlights the superior effects of individual education and video information in reducing anxiety in patients undergoing colonoscopy. The findings of our review could provide clinical decision-makers and healthcare practitioners, such as doctors and nurses, with evidence-based practices for selecting interventions to reduce anxiety in patients undergoing colonoscopy.

During sedation for gastroscopy, hypoxaemia represents the most common adverse event. The objective of this trial is to assess the efficacy and safety of bilevel positive airway pressure (BPAP) for the prevention of hypoxaemia, in comparison with nasal cannula oxygen therapy, among patients predisposed to hypoxaemia during sedation for gastroscopy.

This randomised controlled trial (RCT) will include 616 patients at risk of hypoxaemia when undergoing gastroscopy, including those with advanced age, frailty, American Society of Anesthesiologists grades III-IV, obesity, obstructive sleep apnoea-hypopnoea syndrome, cardiac disease, respiratory disease and diabetes. The patients will be randomly assigned to either the BPAP or nasal cannula group in a 1:1 ratio. The primary analysis for this study will use the modified intention-to-treat analysis set. The primary outcome is defined as the incidence of hypoxaemia (SpO275%-90%, duration 5-60 s). Outcomes data will be compared using the χ2 or Fisher's exact tests. Effect sizes will be used to assess the clinical effects of the intervention using absolute risk differences and 95% CIs. To assess the efficacy of BPAP in different patient subgroups, analyses will be performed based on clinical characteristics and risk factors associated with hypoxaemia.

The Ethics Committee of the First Affiliated Hospital of Zhengzhou University reviewed and approved this RCT (Scientific Research Ethics Review: 2023-KY-0815-003). Subsequently, the outcome will be published in peer-reviewed journals.

ChiCTR2400084596.

Procedural sedation is practised by a heterogeneous group of practitioners working in a wide array of settings. However, there are currently no accepted standards for the competencies a sedation practitioner should have, the content of sedation training programmes, and guidelines for credentialing. The multidisciplinary International Committee for the Advancement of Procedural Sedation sought to develop a consensus statement on the following: which competencies should medical or dental practitioners have for procedural sedation and how are they obtained, assessed, maintained, and privileged. Using the framework of Competency-Based Medical Education, the practice of procedural sedation was defined as a complex professional task requiring demonstrable integration of different competencies. For each question, the results of a literature review were synthetised into preliminary statements. Following an iterative Delphi review method, final consensus was reached. Using multispeciality consensus, we defined procedural sedation competence by identifying a set of core competencies in the domains of knowledge, skills, and attitudes across physical safety, effectiveness, psychological safety, and deliberate practice. In addition, we present a standardised framework for competency-based training and credentialing of procedural sedation practitioners.

Insufficient studies exist on capnography efficacy during endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, and no definitive conclusions have been drawn. To evaluate the feasibility and efficacy of a novel mainstream capnography using an over-the-biteblock end-tidal CO2 (EtCO2) detector in decreasing the risk of hypoxemia during endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP).

Patients undergoing EUS or ERCP with conscious sedation at a single Japanese center were randomized to a control or a novel capnography monitored (intervention) group in a 1:1 ratio. Hypoxemia correction maneuvers were pursued if the oxygen saturation decreased to <92% in the control or intervention group and if a 15-s suspension of EtCO2 wave occurred in the intervention group. The primary outcome was the incidence of hypoxemic events, defined as oxygen saturation <90%, during the procedures. Secondary outcomes included technical feasibility of EUS and ERCP with the use of this novel over-the-biteblock monitor.

In total, 250 patients were enrolled without dropouts or missing data (control group: 125; capnography group: 125). There was no significant difference in the incidence of hypoxemia between the control and capnography groups (29.6% [37/125] vs. 26.4% [33/125]; p = .573). The estimated odds ratio was 0.925 (95% confidence interval: 0.708-1.208). The EtCO2 concentration was successfully captured without impeding endoscopic maneuvers from the beginning to the end of the procedure in all patients.

Although the novel mainstream capnography with an over-the-biteblock EtCO2 detector captures the EtCO2 concentration in EUS or ERCP under conscious sedation, it does not lead to the prevention of hypoxemia.

Preoperative or preanesthesia evaluation is an established practice in patients undergoing surgery. The efficacy of a similar practice before endoscopic procedures has not yet been determined. At our medical center, patients with severe comorbidities, deemed at high risk for sedation, were assigned to an anesthesiologist-supervised endoscopic procedure (ASEP). Since late 2016 they are assessed at anesthesiology clinic pre-endoscopy. Our objective was to compare adverse events (AEs) between these 2 strategies.

A retrospective review of all ambulatory upper and lower endoscopies between 2016 and 2017 was performed. Data on postprocedural (14 d) emergency department (ED) admissions, hospitalizations, operations, and mortality before and after policy change (BPC and APC) were compared.

During the study period 18,240 ambulatory upper and lower endoscopic procedures were performed in 14,906 patients, 7447 (49.96%) BPC, and 7459 (50.04%) APC; 580 were ASEP. The proportions of ASEP were comparable between the 2 time periods (BPC 295 versus APC 285; P=0.721); however, APC there was a 25-fold increase in pre-endoscopy anesthesiology clinic assessments [BPC-6 patients (2.03%) versus APC-146 patients (51.22%), P<0.001]. Postprocedural sedation-related AEs were comparable between the groups [0.07%-BPC (head injury, stroke, myocardial infarction, and aspiration) versus 0.03%-APC (aspiration and dyspnea), P=0.256]. None of these patients were sedated by an anesthesiologist.

Policy change of pre-endoscopy evaluation for high-risk for sedation patients was not associated with a change in AE rates. Policy adherence was limited. The lack of AE rate reduction may indicate a marginal impact on an already low event rate with ASEP for high-risk patients.

Balanced propofol sedation (BPS) administered by adequately trained non-anaesthesiologist personnel has gained popularity in GI endoscopy because of its shorter procedure and recovery time, high patient satisfaction, and low rate of adverse events (AEs), despite being considered controversial. We report data from an audit of endoscopist-directed (ED) nurse-administered sedation in an Italian referral hospital.

Consecutive endoscopic procedures performed between 2020 and 2022 were considered. Under the guidance of the endoscopist, the nurse administered midazolam/fentanyl, followed by a progressive top-up dosage of a 10-20 mg bolus of propofol to achieve moderate to deep sedation. The endoscopists and nurses were all certified in our hospital with a continuous and scheduled training from 2006.

During the study period, a total of 19,407 examinations (7,803 EGDS, 10,439 colonoscopies, 77 PEG, 697 EUS, and 365 ERCP) and 14,415 patients were included. Of these, 29.4 % of patients were classified as ASA I, 66.5 % as ASA II, and 5.1 % as ASA III. Hypotension was recorded in 1,293 (6 %) examinations and bradycardia in 176 (0.9 %) patients. Eleven patients (0.06 %) had minor respiratory adverse events. Two patients (0.01 %) had major AEs requiring orotracheal intubation.

ED-BPS is safe in low-risk patients. Major AEs occurred in 0.01 % of procedures.

Sedation, ranging from minimal, moderate and deep sedation to general anesthesia, improves patient comfort and procedure quality in gastrointestinal endoscopy (GIE). There are currently no comprehensive recommendations on sedation practice in diagnostic and therapeutic GIE. We aimed to investigate real-life sedation practice in elective GIE.

We performed a multicentric observational study across 14 Endoscopy Units in Italy. We recorded consecutive data on all diagnostic procedures performed with Anesthesiologist-directed care (ADC) and all therapeutic procedures performed with ADC or non-Anesthesiologist sedation (NAS) over a three-month period.

Dedicated ADC is available five days/week in 28.6% (4/14), four days/week in 21.5% (3/14), three days/week in 35.7% (5/14), two days/week in 7.1% (1/14) and one day/week in 7.1% (1/14) of participating Centers. ADC use for elective diagnostic GIE varied from 15.4% to 75.1% of the total number of procedures performed with ADC among different Centers. ADC use for elective therapeutic GIE varied from 10.8% to 98.9% of the total number of elective therapeutic procedures performed among different Centers.

Our study highlights the lack of standardization and consequent great variability in sedation practice for elective GIE, with ADC being potentially overused for diagnostic procedures and underused for complex therapeutic procedures. A collaborative effort involving Endoscopists, Anesthesiologist and Institutions is needed to optimize sedation practice in GIE.

Background: By using optimal insertion techniques with water infusion and dynamic position changes, pain during colonoscopy is greatly reduced and the procedures can usually be performed without sedation. We investigated whether the excellent results with water-aided colonoscopy reported by experts are reproducible in daily practice in a regional hospital. Methods: During the year 2023, 500 consecutive outpatients 50-75 years old presenting for colorectal cancer screening and surveillance could choose between unsedated or on-demand minimally sedated colonoscopy, moderate sedation with midazolam, or deep sedation with propofol. A total of 57% opted for unsedated colonoscopy, and of those patients, 250 consecutive patients were included. The primary outcome was the feasibility of the procedure. Cecal intubation rate (CIR), pain scores, use of midazolam, and willingness to repeat future procedures in the same way were registered periprocedural. Additional outcomes were cecal intubation time (CIT), detection rate of lesions, polyp resection rate, rate of adequate bowel preparation, and volume of water aspirated during insertion. Results: 250 consecutive sedation-free or on-demand minimally sedated water-based colonoscopies were analyzed. The CIR was 98%. A total of 96.5% completed without sedation and 5% of the procedures were perceived as moderately painful, but none had severe pain. The willingness to repeat was 97%. The mean CIT was 8.2 min. Conclusions: Using water-aided insertion techniques, comfortable sedation-free, or on-demand minimally sedated colonoscopy in daily practice in a regional hospital is feasible in the vast majority of patients presenting for colorectal cancer screening and surveillance, and the willingness to repeat is very high.

Hypoxemia is the most frequent adverse event observed during gastrointestinal endoscopy under procedural sedation. An optimum oxygen therapy has still not been conclusively determined.

A systematic review and network meta-analysis of randomized clinical trials.

Digestive Endoscopy Center.

Adults (≥18 years old and of both sexes) during gastrointestinal endoscopy under procedural sedation.

Pubmed, MEDLINE, Web of Science, Embase, and Clinicaltrials.gov. were searched until June 30, 2023. Randomized clinical trials (RCTs) comparing any oxygen therapy with another oxygen therapy or with placebo (nasal cannula, NC) were included.

The primary outcome was the incidence of hypoxemia, defined as the pulse oxygen saturation (SpO2). Random-effects network meta-analyses were performed. Data are reported as odds ratios (OR), prediction intervals (PrI) and 95% CI. Bias risk was evaluated following the guidelines outlined by the Cochrane Collaboration. The quality of evidence was evaluated through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.

We included 27 RCTs with a total of 7552 patients. Compared to the use of NC, non-invasive positive pressure ventilation (NIPPV) demonstrated superior efficacy in mitigating hypoxemia (NIPPV vs. NC, OR = 0.16, 95% CI: 0.08-0.31, 95% PrI: 0.06-0.41), followed by Wei nasal jet tube (WNJT) (WNJT vs. NC, OR = 0.17, 95% CI: 0.10-0.30, 95% PrI: 0.07-0.42). The efficacy for preventing hypoxemia was ranked as follows: NIPPV > WNJT > oropharynx/nasopharyngeal catheter > high-flow nasal oxygenation > nasal mask > NC.

During gastrointestinal endoscopy under procedural sedation, all other advanced oxygen therapies were found to be more efficacious than nasal cannula. NIPPV and WNJT appear to be the most efficacious oxygen therapy for preventing hypoxemia. Additionally, clinicians should make a choice regarding the most suitable oxygen therapy based on the risk population, type of endoscopy and adverse events.

To evaluate the safety of propofol sedation administered by interventional radiologists during radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).

Propofol sedation was administered by interventional radiologists in 72 patients (85 procedures, 93 tumors) during RFA for HCC between August 2018 and December 2020. Interventional radiologists equipped with adequate knowledge and skills in sedation and respiratory management were responsible for sedation. Sedation was carefully assessed based on vital signs, including end-tidal carbon dioxide, consciousness status, and bispectral index. The primary endpoint was the incidence of sedation-related complications, which were evaluated separately as respiratory and cardiovascular complications. Secondary endpoints were technical success rate, ablation-related complications, and local tumor control rate. Technical success was defined as completion of ablation in the planned area. Complications were evaluated using the Clavien-Dindo classification. Sedation-related complications, technical success rate, and ablation-related complications were evaluated on a procedure basis, and local tumor control was evaluated on a tumor basis.

Respiratory and cardiovascular complications were observed in eight (8/85, 9.4%) and two (2/85, 2.4%) patients, respectively. Four patients required the jaw thrust maneuver due to glossoptosis, whereas a decrease in oxygen saturation to < 90% was recorded in the other four patients. However, these were temporary, and none required manual ventilation or endotracheal intubation. Bradycardia (< 50 bpm) was detected in two patients; one recovered immediately without treatment, whereas the other rapidly improved after atropine sulfate administration. No severe hypotension (< 80 mmHg) was observed. The technical success rate was 100% (85/85). Grade 3 ablation-related complications were identified in three patients (3/85, 3.5%). The local tumor control rate was 95.7% (89/93).

Propofol sedation can be safely administered by interventional radiologists during RFA for HCC. Although it requires special safety considerations, it may be a sedation option during hepatic RFA.

Colonoscopy is a key procedure for the early detection of colorectal cancer. Despite its importance, the discomfort associated with colonoscopy often requires sedation, and the ideal sedation regimen remains to be determined. In this prospective randomized controlled trial, patients scheduled for colonoscopy were randomly assigned to two different sedation protocols. Group A received a combination of midazolam and propofol, while group B was given midazolam and pethidine. The study analyzed data from 51 patients, with 23 in group A and 28 in group B. The incidence of adverse events was similar across both groups. Additionally, no significant differences were observed in cecal intubation times or total procedure durations. Notably, group A had a lower frequency of required postural changes (1.0±.7 vs. 1.5±0.7, p=0.02) and a reduced rate of manual compression (52.2% vs. 82.1%, p=0.02). There were no significant differences between the groups regarding subjective pain or overall satisfaction. Both sedation regimens were found to be safe and effective. The midazolam and propofol combination was associated with a smoother procedure, evidenced by fewer postural adjustments and less manual compression needed during colonoscopy.

This study aimed to elucidate the effects of propofol plus adjuvants on postoperative cognitive dysfunction (POCD) and patient satisfaction.

Studies published up to September 2023 on the Chinese National Knowledge Infrastructure (CNKI), Wanfang Data, Sinomed, PubMed, Embase, Cochrane Library, Web of Science, and Clinictrials.gov websites were searched. Binary summary of results was used for meta-analyses.

We included 18 studies (2691 patients). The combined sedation did not affect the processing speed (ES = 0.02, 95%CI: -0.01, 0.04; I2 = 79.3%, p < 0.001), attention (ES = 0.02, 95%CI: -0.02, 0.05; I2 = 95.0%, p < 0.001), nor working memory (ES = 0.02, 95%CI: -0.03, 0.06; I2 = 94.4%, p < 0.001) in CogState brief battery tool. A significant effect of combined sedation was observed in the domain of visual learning in CogState tool (ES = -0.03, 95%CI: -0.04, -0.02; I2 = 15.8%, p = 0.306). The TDT (ES = 4.96, 95%CI: 2.92, 7.00) indicates that combined sedation would increase error rates in the tests of cognitive function. The DSST (ES = 0.16, 95% CI: -0.44, 0.75) shown that combined sedation does not affect cognitive function. In addition, an insignificant difference in patient satisfaction between combined sedation and propofol alone was observed (ES = -0.03, 95%CI: -0.09, 0.02).

The available evidence suggests that propofol combined with adjuvants may affect POCD but not patient satisfaction.

INPLASY2023110092.

Sedation has become a standard practice for patients undergoing gastrointestinal (GI) endoscopy. However, considering the serious cardiopulmonary adverse events associated with sedatives, it is important to identify patients at high risk. Machine learning can generate reasonable prediction for a wide range of medical conditions. This study aimed to evaluate the risk factors associated with sedation during GI endoscopy and develop a predictive model for hypoxia during endoscopy under sedation.

This prospective observational study enrolled 446 patients who underwent sedative endoscopy at the Korea University Ansan Hospital. Clinical data were used as predictor variables to construct predictive models using the random forest method that is a machine learning algorithm.

Seventy-two of the 446 patients (16.1%) experienced life-threatening hypoxia requiring immediate medical intervention. Patients who developed hypoxia had higher body weight, body mass index (BMI), neck circumference, and Mallampati scores. Propofol alone and higher initial and total dose of propofol were significantly associated with hypoxia during sedative endoscopy. Among these variables, high BMI, neck circumference, and Mallampati score were independent risk factors for hypoxia. The area under the receiver operating characteristic curve for the random forest-based predictive model for hypoxia during sedative endoscopy was 0.82 (95% confidence interval, 0.79-0.86) and displayed a moderate discriminatory power.

High BMI, neck circumference, and Mallampati score were independently associated with hypoxia during sedative endoscopy. We constructed a model with acceptable performance for predicting hypoxia during sedative endoscopy.

Different sedo-analgesia and monitoring methods are used during endoscopic procedures. And yet, there is no consensus on optimal sedating agents. In this study, the main aim is to compare ketamine-propofol and remifentanil propofol sedo-analgesia protocols by monitoring integrated pulmonary index (IPI).

The study population is divided into two groups: Group ketamine received 0.25 mg/kg ketamine and 0.75 mg/kg propofol at the beginning of anesthesia. 1 mcg/kg of remifentanil and 0.75 mg/kg propofol were administered to group remifentanil patients at the induction of anesthesia. Anesthesia maintenance was provided by titration of drug doses according to the Ramsey sedation scale. Measurements were taken at four different points in time: just before anesthesia was induced, five minutes after sedation was induced, ten minutes later, and five minutes after the treatment was finished.

There was no significant difference in respiratory parameters such as respiratory rate, SPO2, and EtCO2 measured in the T1 time period between the groups. In the T2 time period, a significant difference was found between the groups in the integrated pulmonary index (IPI), sPO2, respiratory rate, and systolic pressure parameters were found to be significantly higher in group ketamine. T3 time period results were higher in these three parameters: IPI, sPO2, and respiration rate. In the T2, T3, T4 time periods, there was a difference between the groups in the respiration count parameter and it was found to be higher in group ketamine.

Although it causes slight prolongation in recovery, ketamine is a safe and effective drug that can be used during endoscopic procedures.

To assess the efficacy of an ECG-based method called thoracic impedance pneumography to reduce hypoxic events in endoscopy.

This was a single center, 1:1 randomized controlled trial.

The trial was conducted during the placement of percutaneous endoscopic gastrostomy (PEG).

173 patients who underwent PEG placement were enrolled in the present trial. Indication was oncological in most patients (89%). 58% of patients were ASA class II and 42% of patients ASA class III.

Patients were randomized in the standard monitoring group (SM) with pulse oximetry and automatic blood pressure measurement or in the intervention group with additional thoracic impedance pneumography (TIM). Sedation was performed with propofol by gastroenterologists or trained nurses.

Hypoxic episodes defined as SpO2 < 90% for >15 s were the primary endpoint. Secondary endpoints were minimal SpO2, apnea >10s/>30s and incurred costs.

Additional use of thoracic impedance pneumography reduced hypoxic episodes (TIM: 31% vs SM: 49%; p = 0.016; OR 0.47; NNT 5.6) and elevated minimal SpO2 per procedure (TIM: 90.0% ± 8.9; SM: 84.0% ± 17.6; p = 0.007) significantly. Apnea events >10s and > 30s were significantly more often detected in TIM (43%; 7%) compared to SM (1%; 0%; p < 0.001; p = 0.014) resulting in a time advantage of 17 s before the occurrence of hypoxic events. As a result, adjustments of oxygen flow were significantly more often necessary in SM than in TIM (p = 0.034) and assisted ventilation was less often needed in TIM (2%) compared with SM (9%; p = 0.053). Calculated costs for the additional use of thoracic impedance pneumography were 0.13$ (0.12 €/0.11 £) per procedure.

Additional thoracic impedance pneumography reduced the quantity and extent of hypoxic events with less need of assisted ventilation. Supplemental costs per procedure were negligible.

thoracic impedance pneumography, capnography, sedation, monitoring, gastrointestinal endoscopy, percutaneous endoscopic gastrostomy.

Nonanesthesiologist-administered propofol (NAAP) is increasingly accepted, but data are limited on drug administration using target-controlled infusion (TCI) in clinical practice. TCI adjusts the drug infusion based on patient-specific parameters, maintaining a constant drug dose to reduce the risk of adverse events (AEs) because of drug overdosing and to enhance patient comfort. The aims of this study were to assess the rate of AEs and to evaluate patient satisfaction with NAAP using TCI in a retrospective cohort of 18,302 procedures.

Low-risk patients (American Society of Anesthesiologists score I and II) undergoing outpatient GI endoscopic procedures, including EGDs and colonoscopies, were sequentially enrolled at IRCCS San Raffaele Hospital (Milan, Italy) between May 2019 and November 2021.

Data from 7162 EGDs and 11,140 colonoscopies were analyzed. Mean patient age was 59.1 ± 14.8 years, and mean body mass index was 24.9 ± 3.7 kg/m2. The male-to-female ratio was equal at 8798 (48.1%):9486 (51.9%). AEs occurred in 240 procedures (1.3%) out of the total cohort, with no differences between EGDs and colonoscopies (100 [1.4%] and 140 [1.2%], respectively; P = .418). Most patients (15,875 [98.9%]) indicated they would likely repeat the procedure with the same sedation protocol. Age (odds ratio, 1.02; 95% confidence interval, 1.01-1.03; P < .008) was the only independent factor associated with overall AEs.

NAAP using TCI is an effective and safe sedation method for routine endoscopy. The proper propofol dosage based on individual patients and the presence of trained operators are crucial for NAAP sedation management.

Hypoxemia is a common side effect of propofol sedation during endoscopy. Applying mild positive airway pressure (PAP) using a nasal mask may offer a simple way to reduce such events and optimize the conditions for diagnostic and therapeutic upper gastrointestinal endoscopies.

We compared overweight patients (body mass index >25 kg/m2) with a nasal PAP mask or standard nasal cannula undergoing upper gastrointestinal endoscopies by non-anesthesiologists who provided propofol sedation. Outcome parameters included the frequency and severity of hypoxemic episodes.

We analyzed 102 procedures in 51 patients with nasal PAP masks and 51 controls. Episodes of hypoxemia (oxygen saturation [SpO2] <90% at any time during sedation) occurred in 25 (49.0%) controls compared to 8 (15.7%) patients with nasal PAP masks (p<0.001). Severe hypoxemia (SpO2 <80%) occurred in three individuals (5.9%) in both groups. The mean delta between baseline SpO2 and the lowest SpO2 recorded was significantly decreased among patients with nasal PAP mask compared to controls (3.7 and 8.2 percentage points difference, respectively). There were significantly fewer airway interventions performed in the nasal PAP mask group (15.7% vs. 41.2%, p=0.008).

Using a nasal PAP mask may be a simple means of increasing patient safety and ease of examination.

Many studies have addressed safety and effectiveness of non-anaesthesiologist propofol sedation (NAPS) for gastrointestinal (GI) endoscopy Target controlled infusion (TCI) is claimed to provide an optimal sedation regimen by avoiding under- or oversedation.

To assess safety and performance of propofol TCI sedation in comparison with nurse-administered bolus-sedation.

Fouty-five patients undergoing endoscopy under TCI propofol sedation were prospectively included from November 2016 to May 2017 and compared to 87 patients retrospectively included that underwent endoscopy with NAPS. Patients were matched for age and endoscopic procedure. We recorded time of sedation and endoscopy, dosage of medication and adverse events.

There was a significant reduction in dose per time of propofol administered in the TCI group, compared to the NAPS group (8.2 ± 2.7 mg/min vs 9.3 ± 3.4 mg/min; P = 0.046). The time needed to provide adequate sedation levels was slightly but significantly lower in the control group (5.3 ± 2.7 min vs 7.7 ± 3.3 min; P < 0.001), nonetheless the total endoscopy time was similar in both groups. No differences between TCI and bolus-sedation was observed for mean total-dosage of propofol rate as well as adverse events.

This study indicates that sedation using TCI for GI endoscopy reduces the dose of propofol necessary per minute of endoscopy. This may translate into less adverse events. However, further and randomized trials need to confirm this trend.

Background and study aims Because of concerns about peri-procedural adverse events (AEs), guidelines recommend anesthetist-managed sedation (AMS) for long and complex endoscopic procedures. The safety and efficacy of physician-administered balanced sedation (PA-BS) for endoscopic mucosal resection (EMR) of large non-pedunculated colorectal polyps (LNPCPs) ≥20 mm is unknown. Patients and methods We compared PA-BS with AMS in a retrospective study of prospectively collected data from consecutive patients referred for management of LNPCPs (NCT01368289; NCT02000141). A per-patient propensity analysis was performed following a 1:2 nearest-neighbor (Greedy-type) match, based on age, gender, Charlson comorbidity index, and lesion size. The primary outcome was any peri-procedural AE, which included hypotension, hypertension, tachycardia, bradycardia, hypoxia, and new arrhythmia. Secondary outcomes were unplanned admissions, 28-day re-presentation, technical success, and recurrence. Results Between January 2016 and June 2020, 700 patients underwent EMR for LNPCPs, of whom 638 received PA-BS. Among them, the median age was 70 years (interquartile range [IQR] 62-76 years), size 35 mm (IQR 25-45 mm), and duration 35 minutes (IQR 25-60 minutes). Peri-procedural AEs occurred in 149 (23.4%), most commonly bradycardia (116; 18.2%). Only five (0.8%) required an unplanned sedation-related admission due to AEs (2 hypotension, 1 arrhythmia, 1 bradycardia, 1 hypoxia), with a median inpatient stay of 1 day (IQR 1-3 days). After propensity-score matching, there were no differences between PA-BS and AMS in peri-procedural AEs, unplanned admissions, 28-day re-presentation rates, technical success or recurrence. Conclusions Physician-administered balanced sedation for the EMR of LNPCPs is safe. Peri-procedural AEs are infrequent, transient, rarely require admission (<1%), and are experienced in similar frequencies to those receiving anesthetist-managed sedation.

 Worldwide, gastrointestinal endoscopies are predominantly performed under sedation. National and international guidelines and recommendations contain very different specifications for the use of sedation in gastrointestinal endoscopy. These differences come from specific requirements for staffing during endoscopy.

 The aim of the study is to evaluate whether endoscopist-guided sedation without additional sedation assistance is not inferior to endoscopist-guided sedation with additional sedation assistance with respect to the rate of sedation-associated complications in a defined low-risk population (low-risk procedure and low-risk patient).

 Prospective, multicenter, randomized study.

 27 German study centers participated in the study. A total of 30 569 endoscopies were recorded during the study period from 1.8.2015 to 10.3.2020. The final data analysis included 28 673 examinations (64.1 % esophagosgastroduodenoscopies and 35.9 % colonoscopies). In 307 (1.1 %) examinations, 322 sedation-associated complications occurred. Of these, 321 (1.1 %) were minor complications and one (0.003 %) was a major complication. There was no statistically significant difference in the frequency of sedation-associated complications between endoscopist-guided sedation with versus without additional sedation assistance. Within the legal framework, a "shadow" sedation assistant was present in the study group without sedation assistance. This assistant intervened because of sedation-associated complications in 101 (0.7 %) of the endoscopies.

 The study documents the safety of propofol-based endoscopist-guided sedation in a low-risk population. In 98.9 % of all endoscopies, no sedation-associated complication occurred or it was so minimal that no intervention (e. g., increase of oxygen supply) was necessary. The study cannot answer to what extent a serious complication was avoided by the active intervention of the "shadow" sedation assistance in the group without sedation assistance.The study proves in a randomized, prospective design that sedation in low-risk endoscopy (low-risk patient, low-risk procedure) can be performed as endoscopist-guided sedation without additional sedation assistance, without demonstrably accepting a reduction in safety.

All endoscopic procedures are invasive and carry risk. Accordingly, all endoscopists should involve the patient in the decision-making process about the most appropriate endoscopic procedure for that individual, in keeping with a patient's right to self-determination and autonomy. Recognition of this has led to detailed guidelines on informed consent for endoscopy in some countries, but in many no such guidance exists; this may lead to variations in care and exposure to risk of litigation. In this document, the European Society of Gastrointestinal Endoscopy (ESGE) sets out a series of statements that cover best practice in informed consent for endoscopy. These statements should be seen as a minimum standard of practice, but practitioners must be aware of and adhere to the law in their own country. 1:  Patients should give informed consent for all gastrointestinal endoscopic procedures for which they have capacity to do so. 2:  The healthcare professional seeking consent for an endoscopic procedure should ensure that the patient has the capacity to consent to that procedure. 3:  For patients who lack capacity, healthcare personnel should at all times try to engage with people close to the patient, such as family, friends, or caregivers, to achieve consensus on the appropriateness of performing the procedure. 4:  Where a patient lacks capacity to provide informed consent, the best interest decision should be clearly documented in the medical record. This should include information about the capacity assessment, reason(s) that the decision cannot be delayed for capacity recovery (or if recovery is not expected), who has been consulted, and where relevant the form of authority for the decision. 5:  There should be a systematic and transparent disclosure of the expected benefits and harms that may reasonably affect patient choice on whether or not to undergo any diagnostic or interventional endoscopic procedure. Information about possible alternatives, as well as the consequences of doing nothing, should also be provided when relevant. 6:  The information provided on the benefit and harms of an endoscopic procedure should be adapted to the procedure and patient-specific risk factors, and the preferences of the patient should be central to the consent process. 7:  The consent discussion should be undertaken by an individual who is familiar with the procedure and its risks, and is able to discuss these in the context of the individual patient. 8:  Patients should confirm consent to an endoscopic procedure in a private, unrushed, and non-coercive environment. 9:  If a patient requests that an endoscopic procedure be discontinued, the procedure should be paused and the patient's capacity for decision making assessed. If a competent patient continues to object to the procedure, or if a conclusive determination of capacity is not feasible, the examination should be terminated as soon as it is safe to do so. 10: Informed consent should be sufficiently detailed to cover all findings that can be reasonably anticipated during an endoscopic examination. The scope of this consent should not be expanded, nor a patient's implicit consent for additional interventions assumed, unless failure to proceed with such interventions would result in immediate and predictable harm to the patient.

Patients with Parkinson's disease (PD), often elderly with various comorbidities, may require a continuous intestinal infusion of carbidopa/levodopa gel by the placement of a percutaneous endoscopic gastrostomy (PEG) with a jejunal tube (PEG-J) to improve their motor outcome and quality of life. However, it is unclear what is the best procedural sedation protocol for PEG-J procedures. Fifty patients with PD and indication for PEG-J procedure (implantation, replacement, removal) underwent, from 2017 to 2022, a sedation protocol characterized by premedication with atropine (0.01 mg/Kg i.v.), midazolam (0.015-0.03 mg/Kg i.v.) and induction with bolus propofol (0.5-1 mg/Kg i.v.) as well as, finally, sedation with continuous infusion propofol (2-5 mg/Kg/h i.v.) by Target Controlled Infusion (TCI) technique. Ninety-eight per cent of patients experienced no intraprocedural or peri-procedural adverse events. All the procedures were technically successful. A good discharge time was recorded. The vital parameters recorded during the procedure did not vary significantly. A PEG-J procedure conducted within 30 min showed a significant advantage over end-tidal carbon dioxide (EtCO2). Indeed, the latter showed some predictive behavior (OR: 1.318, 95% CI 1.075-1.615, p = 0.008). In the real world, this sedation protocol showed a good safety and effectiveness profile, even with reduced doses of midazolam and a TCI propofol technique in moderate sedation.

The sedation method used during double-balloon endoscopic retrograde cholangiopancreatography (DB-ERCP) differs among countries and/or facilities, and there is no established method. This study aimed to evaluate the efficacy of non-anesthesiologist-administered propofol (NAAP) sedation using a target-controlled infusion (TCI) system during DB-ERCP.

This retrospective study was conducted between May 2017 and December 2020 at an academic center. One hundred and fifty-six consecutive patients who underwent DB-ERCP were sedated by gastroenterologists using diazepam (n = 77) or propofol with a TCI system (n = 79), depending on the period. The primary endpoint was a comparison of poor sedation rates between the two groups. Poor sedation was defined as a condition requiring the use of other sedative agents or discontinuation of the procedure. Secondary endpoints were sedation-related adverse events and risk factors for poor sedation.

Poor sedation occurred significantly more often in the diazepam sedation group (diazepam sedation, n = 12 [16%] vs. propofol sedation, n = 1 [1%]; P = 0.001). Vigorous body movements (3 or 4) (diazepam sedation, n = 40 [52%] vs. propofol sedation, n = 28 [35%]; P = 0.038) and hypoxemia (< 85%) (diazepam sedation, n = 7 [9%] vs. propofol sedation, n = 1 [1%]; P = 0.027) occurred significantly more often in the diazepam sedation group. In the multivariate analysis, age < 70 years old (OR, 10.26; 95% CI, 1.57-66.98; P = 0.015), BMI ≥ 25 kg/m2 (OR, 11.96; 95% CI, 1.67-85.69; P = 0.014), and propofol sedation (OR, 0.06; 95% CI, 0.01-0.58; P = 0.015) were associated factors for poor sedation.

NAAP sedation with the TCI system during DB-ERCP was safer and more effective than diazepam sedation.

The high-flow nasal cannula (HFNC) is a relatively recent method that provides high-flow, heated, humidified gas delivery.

We compared HFNC (group HF) and conventional nasal cannula (NC) (group CO) during deep sedation with propofol and remifentanil for endoscopic submucosal dissection (ESD).

Single-center, retrospective observational cohort study.

In this study, a total of 159 cases were analyzed (group CO, 71 and group HF, 88). We collected the data from electronic medical records from September 2020 to June 2021. The lowest oxygen saturation (SpO2), incidence of hypoxia (SpO2 < 90%), rescue interventions, and adverse events between the two groups were investigated.

There were significant differences between the two groups in lowest SpO2 and incidence of hypoxia [group CO versus group HF; 90.3 ± 9.7% versus 95.7 ± 9.0%, 25 (35.2%) versus 10 (11.4%); p < 0.001, p < 0.001; respectively]. Among the rescue interventions, the number of jaw thrust, patient stimulation, O2 flow increase, and nasal airway insertion were significantly higher in the CO group than in the HF group. However, postprocedural chest X-ray showed higher rates of abnormal findings (atelectasis, aspiration, and pneumoperitoneum) in group HF than in group CO [group CO: 8 (11.3%) versus group HF: 26 (29.5%), p = 0.005]. In multivariable analysis, besides group CO, difficult type of lesion was the risk factor for hypoxia.

Compared to the conventional NC, HFNC provided adequate oxygenation and a stable procedure without significant adverse events during sedation for ESD. However, caution is needed to avoid complications associated with deep sedation and difficult type of lesions.

Objective: Colonoscopy plays an important role in the diagnosis, prognosis prediction, assessment of disease activity and severity, and treatment of inflammatory bowel disease (IBD)-related complications. However, some patients refuse to undergo colonoscopy due to perceived pain and other discomfort, their diagnosis and treatment are affected. Therefore, we conducted a prospective study to explore the efficacy and safety of midazolam combined with dezocine for sedation in IBD patients undergoing colonoscopy. Methods: 224 patients were divided into sedative-colonoscopy-group (SCG, n = 93), anesthesia-colonoscopy-group (ACG, n = 90) and ordinary-colonoscopy-group (OCG, n = 41). The vital signs (blood pressure, pulse, respiration and blood oxygen saturation), pain degree during colonoscopy, satisfaction and complication rates of the three groups were compared. Results: Before colonoscopy, there was no significant difference among the vital signs of the three groups. The vital signs of the ACG were significantly lower than those of the SEG and the OCG (p < 0.05), and the difference was not significant between the SCG and OCG during colonoscopy. The colonoscopy pain score in the SCG was lower than that in the OCG (0.79 ± 1.09 vs. 2.98 ± 1.27, p < 0.001). The satisfaction score of the SCG (9.26 ± 1.16) was not significantly different from that of the ACG (9.42 ± 1.41) but was higher than that of the OCG (6.63 ± 1.13) (p < 0.001). The total complication rate of the ACG was 45.56% (41/90), which was significantly higher than that of the SCG [20.43% (19/93)] and the OCG [19.51% (8/41)]. Colon perforation, abnormal blood pressure fluctuation and hypoxemia were significantly more common in the ACG than in the SCG and the OCG (p < 0.05). However, there was no significant difference in the incidence of complications between the SCG and OCG. Conclusion: Compared with ordinary-colonoscopy, colonoscopy performed under midazolam and dezocine sedation is more comfortable for patients, thereby increasing satisfaction and compliance. Colonoscopy that is performed under midazolam and dezocine is similar to colonoscopy that is anesthesia with propofol in terms of comfort, satisfaction and compliance and similar to ordinary-colonoscopy in terms of safety. Considering the shortage of anesthesiologists, the application of midazolam combined with dezocine for digestive endoscopy is worthy of clinical promotion.

Guidelines for the management of upper gastrointestinal bleeding (UGIB) are regularly published, yet little is known concerning adherence to recommendations in practice.

We aimed to assess adherence to European Society of Gastrointestinal Endoscopy (ESGE) recommendations in patients with non-variceal UGIB.

All hospitalized patients with an esophagogastroduodenoscopy (EGD) performed due to suspected non-variceal UGIB at our department were included in a prospective registry. Data between 2018-2020 from this registry were retrospectively analyzed. Adherence to the 2015 ESGE bleeding and propofol sedation guidelines was assessed. Adherence to recommendations concerning preendoscopic (risk) evaluation, preendoscopic PPI, transfusion management, and endoscopic management of peptic ulcers was analyzed.

Among 1005 patients (mean age 70.4 years, 42.1% women) the most common bleeding etiologies were gastric or duodenal ulcers (16.8%), esophagitis/GERD (11.1%), and angiodysplasia (9.9%); mortality was 7.6%. Adherence to preendosopic risk evaluation was low, in 0% a Mallampati classification and in 37.5% an ASA scoring was documented. Preendoscopic PPI was started at 58.6%, and adherence to recommended transfusion management was >98%. Peptic ulcers were Forrest-graded in 72.8%. High-risk ulcers were treated appropriately in 77.9% and low-risk ulcers were not treated in 73.6%. Especially Forrest Ib ulcers were undertreated, with an adherence of 59.6%. Only 22/179 (12.3%) patients with peptic ulcers and early endoscopy were consistently managed according to ESGE recommendations.

Adherence to ESGE guidelines in patients with non-variceal UGIB is moderate to low, even at a tertiary university hospital. Strategies must be devised for guidelines to reach patients in everyday practice.