Closure Integral Research Articles

Negative pressure wound therapy in modern orthopaedic practice

Negative pressure wound therapy (NPWT) is commonly used in orthopaedic practice. Biochemical and mechanical factors of NPWT optimize the local wound environment by increasing local angiogenesis, interleukin (IL)-8, and cell division to synergistically promote soft-tissue healing. Applications vary widely in orthopaedics. In trauma patients, it can temporize soft-tissue wounds in open fractures, aid in closure of fasciotomy wounds, and improve incorporation of skin grafts. Incisional vacuum therapy can maintain integrity of wound closure in high-risk patients and anatomic locations. When combined with instillation fluid, NPWT has the potential to treat infected tissue and deep hardware. Complications are avoidable but can include skin breakdown, wound contamination, and hemorrhage. Further research continues to clarify the role of NPWT in orthopaedic surgery.

Simulation of the Mode I fracture of concrete beam with cohesive models

Crack propagation modeling in quasi-brittle materials such as concrete is essential for improving the reliability and load-bearing capacity assessment. Crack propagation explains many failure characteristics of concrete structures using the fracture mechanics approach. This approach could better explain the softening behavior of concrete structures. A great effort has been made in developing numerical models; however, some models involve complex expressions with too many parameters, and the results are in some cases inaccurate. In this investigation, a numerical approach is developed to model the fracture process zone (FPZ). Based on the modified crack closure integral (MCCI) method, a new nonlinear spring is proposed to be placed between the interfacial node pairs to model crack propagation. A new strain energy release rates for Mode I is calculated as a function of opening in the softening part. Two benchmark beams are simulated by the ABAQUS software for the accuracy of cohesive zone model. The model decreases complexity of predicting crack propagation. It is observed that the cohesive zone model is robust, accurate and able to model the crack growth in the concrete beam. The prediction of the crack path is close to the experimental results (up to 90%). The peak loads had approximately 7.7% difference compared with the previous experimental loads. The accuracy of displacement in the present study is 15.9% compared with previously model at the same load intensity.

Time-Dependent Testing Evaluation and Modeling for Rubber Stopper Seal Performance.

Sufficient rubber stopper sealing performance throughout the entire sealed product life cycle is essential for maintaining container closure integrity in the parenteral packaging industry. However, prior publications have lacked systematic considerations for the time-dependent influence on sealing performance that results from the viscoelastic characteristics of the rubber stoppers. In this paper, we report results of an effort to study these effects by applying both compression stress relaxation testing and residual seal force testing for time-dependent experimental data collection. These experiments were followed by modeling fit calculations based on the Maxwell-Wiechert theory modified with the Kohlrausch-Williams-Watts stretched exponential function, resulting in a nonlinear, time-dependent sealing force model. By employing both testing evaluations and modeling calculations, an in-depth understanding of the time-dependent effects on rubber stopper sealing force was developed. Both testing and modeling data show good consistency, demonstrating that the sealing force decays exponentially over time and eventually levels off because of the viscoelastic nature of the rubber stoppers. The nonlinearity of stress relaxation derives from the viscoelastic characteristics of the rubber stoppers coupled with the large stopper compression deformation into restrained geometry conditions. The modeling fit with capability to handle actual testing data can be employed as a tool to calculate the compression stress relaxation and residual seal force throughout the entire sealed product life cycle. In addition to being time-dependent, stress relaxation is also experimentally shown to be temperature-dependent. The present work provides a new, integrated methodology framework and some fresh insights to the parenteral packaging industry for practically and proactively considering, designing, setting up, controlling, and managing stopper sealing performance throughout the entire sealed product life cycle.LAY ABSTRACT: Historical publications in the parenteral packaging industry have lacked systematic considerations for the time-dependent influence on the sealing performance that results from effects of viscoelastic characteristic of the rubber stoppers. This study applied compression stress relaxation testing and residual seal force testing for time-dependent experimental data collection. These experiments were followed by modeling fit calculations based on the Maxwell-Wiechert theory modified with the Kohlrausch-Williams-Watts stretched exponential function, resulting in a nonlinear, time-dependent sealing force model. Experimental and modeling data show good consistency, demonstrating that sealing force decays exponentially over time and eventually levels off. The nonlinearity of stress relaxation derives from the viscoelastic characteristics of the rubber stoppers coupled with the large stopper compression deformation into restrained geometry conditions. In addition to being time-dependent stress relaxation, it is also experimentally shown to be temperature-dependent. The present work provides a new, integrated methodology framework and some fresh insights to the industry for practically and proactively considering, designing, setting up, controlling, and managing of the stopper sealing performance throughout the entire sealed product life cycle.

Holistic Considerations in Optimizing a Sterile Product Package to Ensure Container Closure Integrity.

A new major chapter dealing with container closure integrity was released by the United States Pharmacopeial Convention. Chapter <1207> provides a significant amount of education and guidance concerning test methodologies to prove that a system is integral and safe for use. The test method used is only one of the major considerations in approaching the challenge of proving an integral system. This paper takes a holistic review of all the major considerations needed in qualifying a new vial system for container closure integrity. There is substantial interplay among many aspects in the process of sealing a vial. This review helps to define major risks that need to be considered and mitigated and reinforces the need to understand the maximum allowable leakage limit that is acceptable for a specific drug application. A typical risk-based approach considers materials, test methods, process, people, environment, and equipment. Each of these aspects is considered in some detail along with a recommended process flow for building a best practice, science-based approach. This approach will inform decision making for evaluating the correct combination of components and assuring they are assembled and tested in an appropriate manner. This work, once completed, can be the basis for a vial system platform or specific drug application qualification.LAY ABSTRACT: Container closure integrity is a fundamental requirement of every sterile drug package. With recent upgrading of compendia standards and guidance around this issue, there is an opportunity to better define a best practice approach to a complicated subject. It is important to recognize that there is substantial interplay among the components of the system, the process of assembly, and the test methods that are used. This paper takes a holistic approach to discussing these issues and identifying the risks that must be considered in assuring an integral container over the shelf life of a drug product.

XFEM with high-order material-dependent enrichment functions for stress intensity factors calculation of interface cracks using Irwin’s crack closure integral

This paper presents a high-order extended finite element method (XFEM) with a novel set of material-dependent enrichment functions for the linear elastic analysis of bimaterial interface cracks. With the proposed material-dependent high-order enrichment functions, highly accurate near-tip displacement and stress fields can be obtained for arbitrary material combinations. The aim of this contribution is the direct evaluation of the complex stress intensity factors (SIFs) of interface cracks based on Irwin’s crack closure integral. To this end, a closed-form SIF formulation in terms of the enriched degrees of freedom is derived by matching the leading term in the XFEM with an analytical expression of Irwin’s integral. Hence, the SIFs of interface cracks can be directly obtained upon the solution of the XFEM discrete system without cumbersome post-processing requirements.The performance of the proposed method is validated on several benchmark examples involving straight and curved interface cracks. In particular, we examine the effect of enrichment order, mesh refinement, bimaterial mismatch, crack tip position, and integration limit of Irwin’s integral. The method is shown to work well on all examples, giving accurate SIF results. Furthermore, while the popular interaction integral method requires special auxiliary fields for curved interface cracks and also needs cracks to be sufficiently apart from each other in settings with multiple cracks, none of these limitations are required by the proposed approach.

Direct evaluation of stress intensity factors for curved cracks using Irwin's integral and XFEM with high‐order enrichment functions

SummaryThis paper presents a comprehensive study on the use of Irwin's crack closure integral for direct evaluation of mixed‐mode stress intensity factors (SIFs) in curved crack problems, within the extended finite element method. The approach employs high‐order enrichment functions derived from the standard Williams asymptotic solution, and SIFs are computed in closed form without any special post‐processing requirements. Linear triangular elements are used to discretize the domain, and the crack curvature within an element is represented explicitly. An improved quadrature scheme using high‐order isoparametric mapping together with a generalized Duffy transformation is proposed to integrate singular fields in tip elements with curved cracks. Furthermore, because the Williams asymptotic solution is derived for straight cracks, an appropriate definition of the angle in the enrichment functions is presented and discussed. This contribution is an important extension of our previous work on straight cracks and illustrates the applicability of the SIF extraction method to curved cracks.The performance of the method is studied on several circular and parabolic arc crack benchmark examples. With two layers of elements enriched in the vicinity of the crack tip, striking accuracy, even on relatively coarse meshes, is obtained, and the method converges to the reference SIFs for the circular arc crack problem with mesh refinement. Furthermore, while the popular interaction integral (a variant of the J‐integral method) requires special auxiliary fields for curved cracks and also needs cracks to be sufficiently apart from each other in multicracks systems, the proposed approach shows none of those limitations. Copyright © 2017 John Wiley &amp; Sons, Ltd.

Virtual crack closure technique for an interface crack between two transversely isotropic materials

The virtual crack closure technique makes use of the forces ahead of the crack tip and the displacement jumps on the crack faces directly behind the crack tip to obtain the energy release rates $${{\mathcal {G}}}_I$$ and $${\mathcal {G}}_{II}$$ . The method was initially developed for cracks in linear elastic, homogeneous and isotropic material and for four noded elements. The method was extended to eight noded and quarter-point elements, as well as bimaterial cracks. For bimaterial cracks, it was shown that $${\mathcal {G}}_I$$ and $${\mathcal {G}}_{II}$$ depend upon the virtual crack extension $$\varDelta a$$ . Recently, equations were redeveloped for a crack along an interface between two dissimilar linear elastic, homogeneous and isotropic materials. The stress intensity factors were shown to be independent of $$\varDelta a$$ . For a better approximation of the Irwin crack closure integral, use of many small elements as part of the virtual crack extension was suggested. In this investigation, the equations for an interface crack between two dissimilar linear elastic, homogeneous and transversely isotropic materials are derived. Auxiliary parameters are used to prescribe an optimal number of elements to be included in the virtual crack extension. In addition, in previous papers, use of elements smaller than the interpenetration zone were rejected. In this study, it is shown that these elements may, indeed, be used.

Method Development for Container Closure Integrity Evaluation via Headspace Gas Ingress by Using Frequency Modulation Spectroscopy.

USP <1207.1> Section 3.5 states that "A deterministic leak test method having the ability to detect leaks at the product's maximum allowable leakage limit is preferred when establishing the inherent integrity of a container-closure system." Ideally, container closure integrity of parenteral packaging would be evaluated by measuring a physical property that is sensitive to the presence of any package defect that breaches package integrity by increasing its leakage above its maximum allowable leakage limit. The primary goals of the work presented herein were to demonstrate the viability of the nondestructive, deterministic method known as laser-based gas headspace analysis for evaluating container closure integrity and to provide a physical model for predicting leak rates for a variety of container volumes, headspace conditions, and defect sizes. The results demonstrate that laser-based headspace analysis provides sensitive, accurate, and reproducible measurements of the gas ingress into glass vial-stopper package assemblies that are under either diffusive or effusive leak conditions. Two different types of positive controls were examined. First, laser-drilled micro-holes in thin metal disks that were crimped on top of 15R glass vials served as positive controls with a well-characterized defect geometry. For these, a strong correlation was observed between the measured ingress parameter and the size of the defect for both diffusive and effusive conditions. Second, laser-drilled holes in the wall of glass vials served as controls that more closely simulate real-world defects. Due to their complex defect geometries, their diffusive and effusive ingress parameters did not necessarily correlate; this is an important observation that has significant implications for standardizing the characterization of container defects. Regardless, laser-based headspace analysis could readily differentiate positive and negative controls for all leak conditions, and the results provide a guide for method development of container closure integrity tests.LAY ABSTRACT: The new USP 39 <1207>, "Package Integrity Evaluation-Sterile Products", states in section 3.4.1: "tracer gas tests performed using … laser-based gas headspace analysis [have] been shown to be sensitive enough to quantitatively analyze leakage through the smallest leak paths found to pose the smallest chance of liquid leakage or microbial ingress in rigid packaging." In addition, USP <1207> also states that "for such methods, the limit of detection can be mathematically predicted on the basis of gas flow kinetics." Using the above statements as a foundation, this paper presents a theoretical basis for predicting the gas ingress through well-defined defects in product vials sealed under a variety of headspace conditions. These calculated predictions were experimentally validated by comparing them to measurements of changes in the headspace oxygen content or total pressure for several different positive controls using laser-based headspace analysis. The results demonstrated that laser-based headspace analysis can, by readily differentiating between negative controls and positive controls with a range of defect sizes on the micron scale, be used to assess container closure integrity. The work also demontrated that caution must be used when attempting to correlate a leak rate to an idealized defect-size parameter.

Basic Considerations for Container Closure Selection of Parenteral Drug Products

By definition, container closure system encompasses all components of the packaging system that hold and protect the drug product. It includes primary packaging system (components with which the drug product comes in direct contact) and secondary packaging system (components that offer additional protection to the system but do not come in direct contact with the drug product). This article focuses on primary packaging components as they have a significant effect on the critical quality attributes of the drug product throughout the product shelf-life. Selection of an appropriate container closure system for a parenteral drug product is of utmost importance as Food and Drug Administration (FDA) classified that the probability of interaction of the drug product with the packaging component is high and the risks associated from such interactions are highest for injections administered via parenteral route [1]. Impeachment of container closure integrity leads to compromised sterility of the drug product system, which in turn is one of the major reasons for FDA drug product recalls in 2016 [2].

Mixed-mode crack tip loading and crack deflection in 1D quasicrystals

Quasicrystals (QC) are a new class of materials besides crystals and amorphous solids and have aroused much attention of researchers since they were discovered. This paper presents a generalized fracture theory including the J-integral and crack closure integrals, relations between $$J_{1}$$ , $$J_{2}$$ and the stress intensity factors as well as the implementation of the near-tip stress and displacement solutions of 1D QC. Different crack deflection criteria, i.e. the J-integral and maximum circumferential stress criteria, are investigated for mixed-mode loading conditions accounting for phonon–phason coupling. One focus is on the influence of phason stress intensity factors on crack deflection angles.

Container Closure Integrity Testing-Practical Aspects and Approaches in the Pharmaceutical Industry.

The assurance of sterility of a parenteral drug product, prior to any human use, is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of product shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP <1207> aims to provide extensive and detailed guidance for CCI assessments for sterile products. However, practical questions and considerations are yet to be addressed by the pharmaceutical industry. These may include: (1) choice of method, for example whether a deterministic CCI method (e.g., helium leak) is preferable over the probabilistic CCI method (e.g., microbial ingress), (2) the type of primary packaging (e.g., vial, syringe, device), (3) dosage form (e.g., liquid versus lyophilisate), (4) suitable acceptance criteria, (5) appropriate sample size, (6) the most appropriate way to introduce artificial leaks into the CCS, (7) ensuring suitable assurance of CCI during drug product manufacturing, and (8) evaluating CCI under intended shipment and storage conditions (e.g., in the frozen state).A group of European industry peers have met to discuss these and other related questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).LAY ABSTRACT: The assurance of sterility of a parenteral drug product prior to any human use is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP <1207> aims to provide extensive and detailed guidance for CCI assessments for sterile products. However, practical questions and considerations are yet to be addressed by the pharmaceutical industry.A group of European industry peers have met to discuss these and other related questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).

Isogeometric boundary element methods for three dimensional static fracture and fatigue crack growth

We present a novel numerical method to simulate crack growth in 3D, directly from the Computer-Aided Design (CAD) geometry of the component, without any mesh generation. The method is an isogeometric boundary element method (IGABEM) based on non-uniform rational B-splines (NURBS). NURBS basis functions are used for the domain and crack representation as well as to approximate the physical quantities involved in the simulations. A stable quadrature scheme for singular integration is proposed to enhance the robustness of the method in dealing with highly distorted elements. Convergence studies in the crack opening displacement is performed for a penny-shaped crack and an elliptical crack. Two approaches to extract stress intensity factors (SIFs): the contour M integral and the virtual crack closure integral are compared using dual integral equations. The results show remarkable accuracy in the computed SIFs, leading to smooth crack paths and reliable fatigue lives, without requiring the generation of any mesh from the CAD model of the component under consideration.

Gene editing – From modeling diseases to treating patients

Parenteral drug products are protected by appropriate primary packaging to protect against environmental factors, including potential microbial contamination during shelf life duration. The most commonly used CCS configuration for parenteral drug products is the glass vial, sealed with a rubber stopper and an aluminum crimp cap. In combination with an adequately designed and controlled aseptic fill/finish processes, a well-designed and characterized capping process is indispensable to ensure product quality and integrity and to minimize rejections during the manufacturing process.In this review, the health authority requirements and expectations related to container closure system quality and container closure integrity are summarized. The pharmaceutical vial, the rubber stopper, and the crimp cap are described. Different capping techniques are critically compared: The most common capping equipment with a rotating capping plate produces the lowest amount of particle. The strength and challenges of methods to control the capping process are discussed. The residual seal force method can characterize the capping process independent of the used capping equipment or CCS. We analyze the root causes of several cosmetic defects associated with the vial capping process.

Artificial Leaks in Container Closure Integrity Testing: Nonlinear Finite Element Simulation of Aperture Size Originated by a Copper Wire Sandwiched between the Stopper and the Glass Vial.

Container closure integrity (CCI) testing is required by different regulatory authorities in order to provide assurance of tightness of the container closure system against contamination, for example, by microorganisms. Microbial ingress CCI testing is performed by incubation of the container closure system with microorganisms under specified testing conditions. Physical CCI uses surrogate endpoints, such as coloration by dye solution ingress or gas flow. In order to correlate microbial ingress CCI and physical CCI test methods and to evaluate the methods' capability to detect a given leak, artificially created defects (artificial leaks) are being introduced into the container closure system in a variety of different ways. In our study, artificial leaks were generated using inserted copper wires between the glass vial opening and rubber stopper. Up to date, the insertion of copper wires introduced leaks of unknown size and shape. With nonlinear finite element simulations, the effective aperture size between the rubber stopper and the glass vial was calculated, depending on wire diameter and capping force, and the leak shape was modelled. Our results suggest that the size as well as the shape of the artificial leaks should be taken into account when evaluating critical leak sizes, as flow rate does not, independently, correlate to the hole size.

Influence of Different Container Closure Systems and Capping Process Parameters on Product Quality and Container Closure Integrity (CCI) in GMP Drug Product Manufacturing.

Capping equipment used in good manufacturing practice manufacturing features different designs and a variety of adjustable process parameters. The overall capping result is a complex interplay of the different capping process parameters and is insufficiently described in the literature. It remains poorly studied how the different capping equipment designs and capping equipment process parameters contribute to the final capping result.In this study, we used different container closure system configurations from different good manufacturing process drug product fill & finish facilities to investigate the influence of the vial size and the rubber stopper design on the capping process. In addition, we compared two examples of large-scale good manufacturing process capping equipment and different capping equipment settings and their impact on product quality and integrity, as determined by residual seal force.

The Pharmaceutical Capping Process-Correlation between Residual Seal Force, Torque Moment, and Flip-off Removal Force.

The majority of parenteral drug products are manufactured in a glass vials with an elastomeric rubber stopper and a crimp cap. The vial sealing process is a critical process step during fill-and-finish operations, as it defines the seal quality of the final product. An adequate force to remove the flip-off button prior to usage is required to ensure product quality during storage and transportation until use. In addition, the complete crimp cap needs to be fixed in a tight position on the vial. In this study, we investigated the torque moment required to turn the crimp cap and the force required to remove the flip-off button of container closure system sealed with different capping equipment process parameters (having different residual seal force values).

Impact of Vial Capping on Residual Seal Force and Container Closure Integrity.

The vial capping process is a critical unit operation during drug product manufacturing, as it could possibly generate cosmetic defects or even affect container closure integrity. Yet there is significant variability in capping equipment and processes, and their relation to potential defects or container closure integrity has not been thoroughly studied. In this study we applied several methods-residual seal force tester, a self-developed system of a piezo force sensor measurement, and computed tomography-to characterize different container closure system combinations that had been sealed using different capping process parameter settings. Additionally, container closure integrity of these samples was measured using helium leakage (physical container closure integrity) and compared to characterization data. The different capping equipment settings lead to residual seal force values from 7 to 115 N. High residual seal force values were achieved with high capping pre-compression force and a short distance between the capping plate and plunge. The choice of container closure system influenced the obtained residual seal force values. The residual seal force tester and piezoelectric measurements showed similar trends. All vials passed physical container closure integrity testing, and no stopper rupture was seen with any of the settings applied, suggesting that container closure integrity was warranted for the studied container closure system with the chosen capping setting ranges. The vial capping process is a critical unit operation during drug product manufacturing, as it could possibly generate cosmetic defects or even affect container closure integrity. Yet there is significant variability in capping equipment and processes, and their relation to potential defects or container closure integrity has not been thoroughly studied. In this study we applied several methods-residual seal force tester, a self-developed system of a piezo force sensor measurement, and computed tomography-to characterize different container closure system combinations that had been sealed using different capping process parameter settings. The residual seal force tester can analyze a variety of different container closure systems independent of the capping equipment. An adequate and safe residual seal force range for each container closure system configuration can be established with the residual seal force tester and additional methods like computed tomography scans and leak testing. In the residual seal force range studied, the physical container closure integrity of the container closure system was warranted.

Feasibility of Using Fluorescence Spectrophotometry to Develop a Sensitive Dye Immersion Method for Container Closure Integrity Testing of Prefilled Syringes.

A feasibility study was conducted for a sensitive and robust dye immersion method for the measurement of container closure integrity of unopened prefilled syringes using fluorescence spectrophotometry as the detection method. A Varian Cary Eclipse spectrofluorometer was used with a custom-made sample holder to position the intact syringe in the sample compartment for fluorescence measurements. Methylene blue solution was initially evaluated as the fluorophore in a syringe with excitation at 607 nm and emission at 682 nm, which generated a limit of detection of 0.05 μg/mL. Further studies were conducted using rhodamine 123, a dye with stronger fluorescence. Using 480 nm excitation and 525 nm emission, the dye in the syringe could be easily detected at levels as low as 0.001 μg/mL. The relative standard deviation for 10 measurements of a sample of 0.005 μg/mL (with repositioning of the syringe after each measurement) was less than 1.1%. A number of operational parameters were optimized, including the photomultiplier tube voltage, excitation, and emission slit widths. The specificity of the testing was challenged by using marketed drug products and a protein sample, which showed no interference to the rhodamine detection. Results obtained from this study demonstrated that using rhodamine 123 for container closure integrity testing with in-situ (in-syringe) fluorescence measurements significantly enhanced the sensitivity and robustness of the testing and effectively overcame limitations of the traditional methylene blue method with visual or UV-visible absorption detection. Ensuring container closure integrity of injectable pharmaceutical products is necessary to maintain quality throughout the shelf life of a sterile drug product. Container closure integrity testing has routinely been used to evaluate closure integrity during product development and production line qualification of prefilled syringes, vials, and devices. However, container closure integrity testing has recently gained industry attention due to increased regulatory agency scrutiny regarding the analytical rigor of container closure integrity testing methods and expectations to use container closure integrity testing in lieu of sterility tests in stability programs. Methylene blue dye is often used for dye ingress testing of container closure integrity, but we found it unsuitable for reliable detection of small breaches in prefilled syringes of drug product. This work describes the suitability and advantages of using a fluorescent dye and spectroscopic detection for a robust, sensitive, and quality control-friendly container closure integrity testing method for prefilled syringes.

Percutaneous transgastric endoscopic tube ileostomy in a porcine survival model.

AIMTo introduce natural orifice transgastric endoscopic surgery (NOTES) tube ileostomy using pelvis-directed submucosal tunneling endoscopic gastrostomy and endoscopic tube ileostomy.METHODSSix live pigs (three each in the non-survival and survival groups) were used. A double-channeled therapeutic endoscope was introduced perorally into the stomach. A gastrostomy was made using a 2-cm transversal mucosal incision following the creation of a 5-cm longitudinal pelvis-directed submucosal tunnel. The pneumoperitoneum was established via the endoscope. In the initial three operations of the series, a laparoscope was transumbilically inserted for guiding the tunnel direction, intraperitoneal spatial orientation and distal ileum identification. Endoscopic tube ileostomy was conducted by adopting an introducer method and using a Percutaneous Endoscopic Gastrostomy Catheter Kit equipped with the Loop Fixture. The distal tip of the 15 Fr catheter was placed toward the proximal limb of the ileum to optimize intestinal content drainage. Finally, the tunnel entrance of the gastrostomy was closed using nylon endoloops with the aid of a twin grasper. The gross and histopathological integrity of gastrostomy closure and the abdominal wall-ileum stoma tract formation were assessed 1 wk after the operation.RESULTSTransgastric endoscopic tube ileostomy was successful in all six pigs, without major bleeding. The mean operating time was 71 min (range: 60-110 min). There were no intraoperative complications or hemodynamic instability. The post-mortem, which was conducted 1-wk postoperatively, showed complete healing of the gastrostomy and adequate stoma tract formation of ileostomy.CONCLUSIONTransgastric endoscopic tube ileostomy is technically feasible and reproducible in an animal model, and this technique is worthy of further improvement.

Hemodynamically significant ductus arteriosus:a new targeted approach

Debate on hemodynamically significant ductusarteriosus (hsDA) in premature infants remains unresolved. The association between patent ductus arteriosus (PDA) and the most adverse outcomes and comorbidities in preterms (peri-intraventricular haemorrhage, necrotizing enterocolitis, chronic lung disease, pulmonary haemorrhage and mortality) has led to the integration of ductal closure into neonatal intensive care. The recent theory that describes PDA as “an innocent bystander” is supported by the lack of evidence of significant benefits on long-term outcomes with therapeutic interventions. So, the causal relationship between PDA and comorbidities is questioned. Moreover, PDA can close spontaneously in a significant proportion of preterms[1]. Both the traditional assumption that all PDA are pathological and the most recent theory in favor of a conservative attitudeare oversimplifications[2]. The current management of PDA does not take into account the wide range of effects attributable to a ductal shunt. A more logical approach should considerthe ductus as a clinical continuum, from thephysiological PDA to the pathological hsDA. Placingthe patient in the spectrum of “ductal disease” seems to be possible through a continuous evaluation of the hemodynamic and clinical consequences of ductal patency[3]. The current definition of an hsDA is almost entirely based on size[4]. However, the magnitude of transductal shunt relates not only to the transductal diameter, but also to the pulmonary and systemic vascular resistance and to the compensatory ability of the immature myocardium[3]. New echocardiography markers have been evaluated to estimate the impact of transductal flow on both pulmonary over circulation (left atrial/aortic ratio, anterograde pulmonary artery diastolic flow) and systemic blood flow (retrograde diastolic flow in descending aorta, left ventricular output/superior vena cava flow ratio)[5]. The possibility to evaluate flows in the middle cerebral artery, renaland superior mesenteric artery with Doppler ultrasound, allows anearly and plausible detection of regional hypoperfusion due to the “ductal steal”[3]. Other technologies that enable direct measurement of tissue oxygenation, such as Near Infrared Spectroscopy (NIRS), may also be useful to unveil the hemodynamic effects of PDA[6,7]. We are becoming increasingly aware of the role of patient's characteristics (such as genetic profile[8], BNP levels[9], antioxidant status[10]) in PDA evolution. According to the current understanding, it seems appropriate to proposea more tailored approach to the management of PDA in preterms, based on the integration between clinical and hemodynamic status.