Assessing dosing errors in legacy and low dose tip ENFit® syringes.

WHAT IS KNOWN AND OBJECTIVE: To avoid misconnections between different medical devices, a unique standardized design of connectors (ENFit® ) for enteral medical devices has been developed. It was expected that the syringes with these connectors will replace the pre-existing syringes, henceforth referred to as legacy syringes. However, the changes in the connector's design led to concerns regarding dosing errors for low volume syringes (≤2 ml). Therefore, novel low dose tip (LDT) syringes were designed to address these concerns. These LDT syringes can connect with the standardized ENFit® male connectors. Only a few studies have investigated dosing errors, and findings have largely been mixed. The objective of this report was to calculate the contributions of unavoidable dosing errors for LDT syringes, compare with legacy syringes and to suggest strategies to optimize dose accuracy for enteral applications. METHODS: Studies performed with a limited number of syringes to date may not reflect the actual diversity of dosing error that can occur across syringe orientations, batches, manufacturers, medications, etc. A computer-aided design software SolidWorks® was used to calculate the dosing errors in 0.5 and 1.0 ml legacy syringe connectors and were compared with dosing errors in LDT syringe connectors with the same nominal volume. Influence of orientation during delivery, spillage and flushing on dosing error was also investigated. RESULTS AND DISCUSSION: For 0.5 and 1.0 ml LDT syringes, in absence of medication in the moat area, the maximum dosing error will be ±5% when delivering 100% of nominal volume, which is also equal to the dosing error in 0.5 and 1.0 ml slip tip legacy syringes. However, with medication present in moat area, and with syringe reused during flushing, the LDT dosing error can range from 1% to 18% and 28% to 35% for 1.0 and 0.5 ml syringes, respectively. The corresponding dosing error for legacy syringes would be when the same syringe is used for flushing or when syringe disengages pointing vertically up. The corresponding dosing errors for legacy syringes could range from -7 to 12% and -9% to 19% for 1.0 and 0.5 ml syringes, respectively. Dosing errors for legacy and LDT syringes increase as the nominal capacity of syringe reduces, or when the dose delivered is lower than the nominal capacity of the syringe. WHAT IS NEW AND CONCLUSION: For LDT syringes, dosing errors can be reduced by clearing the moat area of the syringe and by using a new syringe for flushing post-delivery of medication. For legacy syringes, dosing errors can be minimized by ensuring the female connector points up during disengagement from the syringe post-medication administration, and by using a new syringe for flushing.

Proceedings from the First Global Artificial Intelligence in Gastroenterology and Endoscopy Summit.

BACKGROUND AND AIMS: Artificial intelligence (AI), specifically deep learning, offers the potential to enhance the field of GI endoscopy in areas ranging from lesion detection and classification to quality metrics and documentation. Progress in this field will be measured by whether AI implementation can lead to improved patient outcomes and more efficient clinical workflow for GI endoscopists. The aims of this article are to report the findings of a multidisciplinary group of experts focusing on issues in AI research and applications related to gastroenterology and endoscopy, to review the current status of the field, and to produce recommendations for investigators developing and studying new AI technologies for gastroenterology. METHODS: A multidisciplinary meeting was held on September 28, 2019, bringing together academic, industry, and regulatory experts in diverse fields including gastroenterology, computer and imaging sciences, machine learning, computer vision, U.S. Food and Drug Administration, and the National Institutes of Health. Recent and ongoing studies in gastroenterology and current technology in AI were presented and discussed, key gaps in knowledge were identified, and recommendations were made for research that would have the highest impact in making advances and implementation in the field of AI to gastroenterology. RESULTS: There was a consensus that AI will transform the field of gastroenterology, particularly endoscopy and image interpretation. Powered by advanced machine learning algorithms, the use of computer vision in endoscopy has the potential to result in better prediction and treatment outcomes for patients with gastroenterology disorders and cancer. Large libraries of endoscopic images, "EndoNet," will be important to facilitate development and application of AI systems. The regulatory environment for implementation of AI systems is evolving, but common outcomes such as colon polyp detection have been highlighted as potential clinical trial endpoints. Other threshold outcomes will be important, as well as clarity on iterative improvement of clinical systems. CONCLUSIONS: Gastroenterology is a prime candidate for early adoption of AI. AI is rapidly moving from an experimental phase to a clinical implementation phase in gastroenterology. It is anticipated that the implementation of AI in gastroenterology over the next decade will have a significant and positive impact on patient care and clinical workflows. Ongoing collaboration among gastroenterologists, industry experts, and regulatory agencies will be important to ensure that progress is rapid and clinically meaningful. However, several constraints and areas will benefit from further exploration, including potential clinical applications, implementation, structure and governance, role of gastroenterologists, and potential impact of AI in gastroenterology.

Impact of Design Changes in Gastrostomy Tube (G-tube) Devices for Patients Who Rely on Home-Based Blenderized Diets for Enteral Nutrition.

OBJECTIVE: Blenderized diets are gaining increasing popularity among enteral tube users. Connectors in gastrostomy tubes (G-tubes) are undergoing standardization to reduce misconnections. These standardized G-tubes are referred to as ENFit G-tubes. This study was performed to quantify the in vitro performance of existing (legacy) G-tubes and compare them with ENFit G-tubes for blenderized diets. METHOD: Patient blenderized diet recipes and practices were obtained through patient advocacy groups. Different blenders and blending times were studied. Five legacy G-tube brands and three corresponding ENFit brands, sized between 14 Fr and 24 Fr, were studied under gravity and push modes of feeding. RESULTS: Considering both thin and thick blenderized gravity mode diets, an average increase in feeding time from 20 minutes to 32 ± 18 minutes in transitioning from legacy to ENFit was observed with standard G-tubes, compared to 22 ± 3.5 minutes for low profiles. For push-mode diets, a 60-second push with standard ENFit G-tubes was easier compared to standard legacy G-tubes (61% ± 21% as much force), but faster 5-second pushes required considerably more effort for ENFit standard G-tubes (167% ± 96%). Low-profile ENFit G-tubes required slightly less effort compared to low-profile legacies for both 60-second and 5-second pushes (72% ± 22% and 90% ± 19%, respectively). Clogging was common in both legacy and ENFit devices, particularly under gravity mode. CONCLUSIONS: For a push mode of feeding, patients will largely be unimpacted after the transition to ENFit. For a gravity mode of feeding, some ENFit users may need higher-powered blenders and should expect increased feeding times.

Spaced administration of PA32540 and clopidogrel results in greater platelet inhibition than synchronous administration of enteric-coated aspirin and enteric-coated omeprazole and clopidogrel.

BACKGROUND: A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinal complications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel, although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administration of a clopidogrel and a single-tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered as an alternative that might reduce this potential pharmacodynamic interaction. METHODS AND RESULTS: A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two 7-day treatments were separated by 14-day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mg maintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). The primary end point was the inhibition of platelet aggregation (20 µM adenosine diphosphate, maximal extent) after 7 days. CYP2C19 and ABCB1 genotypes were determined. Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + EC aspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid-induced aggregation. The effect of spacing on pharmacodynamics was independent of genotype. CONCLUSIONS: PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronously administered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directly relevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection.

Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies.

OBJECTIVES: We analyzed the antiplatelet effects of different P2Y(12) receptor blockers with VerifyNow P2Y12 assay (VN-P2Y12) and light transmittance aggregometry (LTA). BACKGROUND: The point-of-care VN-P2Y12 has been used to assess the antiplatelet effects in clopidogrel-treated patients but has not been evaluated in detail in patients treated with ticagrelor. METHODS: Patients were randomly assigned to either ticagrelor [180 mg loading/90 mg twice daily (n = 37)] or clopidogrel [600 mg loading/75 mg daily (n = 39)] on top of aspirin treatment, and platelet reactivity was measured serially during onset, maintenance, and offset phases. High on-treatment platelet reactivity (HPR) was defined as 5 and 20 µM adenosine diphosphate-induced maximal platelet aggregation ≥46% and ≥59%, respectively, and P2Y12 reaction units ≥235. RESULTS: Platelet function measured by VN-P2Y12 correlated well with LTA (.812 ≤ ρ ≤ .823, P < .001). VN-P2Y12 "BASE" values were consistent during administration of both agents. Calculated and reported percent inhibitions by VN-P2Y12 were similar (difference, -0.6%; 95% agreement limits, -22.9% to 21.6%). Platelet inhibition by VN-P2Y12 during clopidogrel and ticagrelor administrations was comparable to platelet inhibition by LTA. HPR determined by LTA and VN-P2Y12 were well matched, and the risk stratification between the two methods showed strong agreement after both therapies (κ > .7). CONCLUSIONS: The VerifyNow P2Y12 assay is effective in assessing the antiplatelet effects and in identifying HPR during clopidogrel or ticagrelor therapy.

Synthesis of research on ENFit gastrostomy tubes with potential implications for US patients using these devices.

Misconnections between enteral devices and other medical devices have been associated with patient death and serious injuries. To minimize such misconnections, the design of connectors on enteral devices has been standardized. The most common adaptation of the standardized enteral connector is called ENFit. Gastrostomy tubes (G-tubes), which may or may not possess the ENFit connector, are increasingly used to deliver commercial and blenderized diets in home settings to enteral device users. To investigate and compare the performance of G-tubes with and without ENFit connectors, research investigations have recently been performed. However, synthesis of such investigations and quantitative discussion of the consequences of transitioning to ENFit-based G-tube devices has not yet occurred. Here we review the research findings from these studies, with data on patient practices from a Mayo Clinic survey, to estimate the impact on tube feeders in home settings of transitioning to ENFit-based G-tube devices. Extrapolating the findings from these studies to US enteral G-tube patients, 1.5%-8.6% of adult patients and 0.2%-1.9% of pediatric patients may experience perceptible slowing in their gravity feeds if using ENFit-based G-tube devices. About 2.5%-8.6% of adult patients and 0.5%-5.5% of pediatric patients (or their caregivers) may need to push with perceptibly more force for syringe push-based feeding using ENFit-based G-tube devices. Lastly, the article offers suggestions for patients and device manufacturers. [Correction added on 2 May 2022, after first online publication: In the preceding sentence, the percentage of adult patients was revised from 2.5%-8.6% to 1.5%-8.6%.].

Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study.

BACKGROUND: The antiplatelet effects of the Platelet Inhibition and Patient Outcomes (PLATO) trial dose of ticagrelor in patients nonresponsive to clopidogrel and after they switch agents are unknown. METHODS AND RESULTS: Patients with stable coronary artery disease on aspirin therapy received a 300-mg clopidogrel load; nonresponders were identified by light transmittance aggregometry. In a 2-way crossover design, nonresponders (n=41) and responders (n=57) randomly received clopidogrel (600 mg/75 mg once daily) or ticagrelor (180 mg/90 mg twice daily) for 14 days during period 1. In period 2, all nonresponders switched treatment; half of the responders continued the same treatment, whereas the others switched treatment. Inhibition of platelet aggregation was higher in nonresponders treated with ticagrelor compared with clopidogrel (P<0.05). Treatment with ticagrelor among nonresponders resulted in a >10%, >30%, and >50% decrease in platelet aggregation from baseline in 100%, 75%, and 13% of patients, respectively. Platelet aggregation fell from 59+/-9% to 35+/-11% in patients switched from clopidogrel to ticagrelor and increased from 36+/-14% to 56+/-9% in patients switched from ticagrelor to clopidogrel (P<0.0001 for both). Platelet reactivity was below the cut points previously associated with ischemic risk measured by light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation in 98% to 100% of patients after ticagrelor therapy versus 44% to 76% of patients after clopidogrel therapy. CONCLUSIONS: Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. Nearly all clopidogrel nonresponders and responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00642811.

Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.

BACKGROUND: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. METHODS AND RESULTS: In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 micromol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P<0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved >50% IPA (98% versus 31%, P<0.0001) and >70% IPA (90% versus 16%, P<0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72-hour slope [% IPA/h] -1.04 versus -0.48, P<0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS). CONCLUSIONS: Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation.

Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events.

BACKGROUND: Poststenting ischemic events occur despite dual-antiplatelet therapy, suggesting that a "one size fits all" antithrombotic strategy has significant limitations. Ex vivo platelet function measurements may facilitate risk stratification and personalized antiplatelet therapy. METHODS: We investigated the prognostic utility of the strength of adenosine diphosphate (ADP)-induced (MA(ADP)) and thrombin-induced (MA(THROMBIN)) platelet-fibrin clots measured by thrombelastography and ADP-induced light transmittance aggregation (LTA(ADP)) in 225 serial patients after elective stenting treated with aspirin and clopidogrel. Ischemic and bleeding events were assessed over 3 years. RESULTS: Overall, 59 (26%) first ischemic events occurred. Patients with ischemic events had higher MA(ADP), MA(THROMBIN), and LTA(ADP) (P < .0001 for all comparisons). By receiver operating characteristic curve analysis, MA(ADP) >47 mm had the best predictive value of long-term ischemic events compared with other measurements (P < .0001), with an area under the curve = 0.84 (95% CI 0.78-0.89, P < .0001). The univariate Cox proportional hazards model identified MA(ADP) >47 mm, MA(THROMBIN) >69 mm, and LTA(ADP) >34% as significant independent predictors of first ischemic events at the 3-year time point, with hazard ratios of 10.3 (P < .0001), 3.8 (P < .0001), and 4.8 (P < .0001), respectively. Fifteen bleeding events occurred. Receiver operating characteristic curve and quartile analysis suggests MA(ADP)

Technical considerations for medical device manufacturers when designing gastrostomy tubes (G-tubes) using the new ISO 80369-3 connector.

BACKGROUND: Gastrostomy tubes (G-tubes) are typically used when people cannot eat food by mouth. The connector section that allows G-tubes to connect to other devices, such as feeding sets or syringes, has been modified on some of the devices to reduce misconnections in hospital settings. The narrow internal diameter of the new connector, standardized under ISO 80369-3, has caused some users to express concern about a reduced flow rate. Previous studies performed on commercial devices determined that it was not conclusive how much the ISO 80369-3 connector contributed towards the reduced flow rate, because when manufacturers designed these new connector-based devices, they often changed other geometric variables (such as distal tube diameter, or length) at the same time. Thus, it became difficult isolating the effect of the connector from other geometric variables. METHOD: The key objective of this study was to investigate how different design variables impacted the flow rate through the G-tubes. 3D-printed devices were used to assess the geometric parameters in a systematic manner. Commercial diets and Newtonian analog fluids with matched viscosities were used for testing. RESULTS: The flow path length of the "transition section" encompassing the standardized ISO 80369-3 connector in the new devices was found to cause reduced flow. Additionally, results showed that a shortened (≤ 10 mm) transition section, along with a 10% increase in the distal inner diameter of large bore devices (e.g., 24 Fr), can restore flow rates to levels consistent with the previous devices prior to the connector standardization. CONCLUSIONS: The strategy for restoring flow rates to previous levels may help alleviate concerns raised by multiple stakeholders such as health care professionals, patients, caregivers and device manufacturers. In addition, the approach proposed here can be used as a tool for designing future G-tube devices.