\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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The virtual consortium of the authors has been created by using electronic exchanges; it comprises 50 authors from 18 different countries who have submitted 23 contributions to this collective product. In this sense, the volume can be added to a bookshelf with similar collective publications in scheduling, started by Coffman (1976) and successfully continued by Chretienne et al. (1995), Gutin and Punnen (2002), and Leung (2004).\r\nThis volume contains four major parts that cover the following directions: the state of the art in theory and algorithms for classical and non-standard scheduling problems; new exact optimization algorithms, approximation algorithms with performance guarantees, heuristics and metaheuristics; novel models and approaches to scheduling; and, last but least, several real-life applications and case studies.",isbn:null,printIsbn:"978-3-902613-02-8",pdfIsbn:"978-953-51-5819-6",doi:"10.5772/52",price:139,priceEur:155,priceUsd:179,slug:"multiprocessor_scheduling_theory_and_applications",numberOfPages:438,isOpenForSubmission:!1,isInWos:1,hash:null,bookSignature:"Eugene Levner",publishedDate:"December 1st 2007",coverURL:"https://cdn.intechopen.com/books/images_new/3596.jpg",numberOfDownloads:84304,numberOfWosCitations:59,numberOfCrossrefCitations:40,numberOfDimensionsCitations:91,hasAltmetrics:0,numberOfTotalCitations:190,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:null,dateEndSecondStepPublish:null,dateEndThirdStepPublish:null,dateEndFourthStepPublish:null,dateEndFifthStepPublish:null,currentStepOfPublishingProcess:1,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"25544",title:"Prof.",name:"Eugene",middleName:null,surname:"Levner",slug:"eugene-levner",fullName:"Eugene Levner",profilePictureURL:"https://mts.intechopen.com/storage/users/25544/images/system/25544.jpg",biography:"Eugene Levner received the B.S.+M.S. degree in computational mathematics from Lomonosov State University, Moscow, USSR, and the Ph.D. degree in computer & systems sciences from the Central Economic-Mathematical Institute of the Soviet Academy of Sciences, Moscow, in 1968 and 1973, respectively. From 1972 to 1990, he worked for the Soviet Academy of Sciences, Moscow, He joined the Department of Computer Science, Holon Institute of Technology, Holon, Israel, in 1994, and is currently a Full Professor of Computer Science.\n\nIn 1991-2009, he was a Visiting Scholar at the Eindhoven Technological University, the Netherlands (1991), Hebrew University of Jerusalem, Israel (1991-1992), Japan Advanced Institute of Science and Technology, Ishikawa, Japan (1997), INRIA, Metz, France (1998), Groningen University, the Netherlands (1999), Osaka University, Japan (2001), National Polytechnic Institute, Mexico (2004), University of La Laguna, Tenerife, Spain (2006-2007), Indian Institute of Technology, Kanpur (2007), and the Rutgers University, USA (2009).\n\nHe has authored/coauthored several books and more than 100 papers in refereed journals and chapters in books. 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CVD technology has recently grown at a rapid rate, and the number and scope of its applications and their impact on the market have increased considerably. Among several challenges associated with the CVD technique, the main challenge is a limited mechanistic understanding of the CVD growth process, which makes the predictions of desirable growth conditions difficult. Numerous important aspects of the process include nucleation, the nature of reaction intermediates, and the role of long-range transport that is still under exploration. The second challenge arises from the convoluted relationship between the system-specific process variables that can be conveniently controlled and the intrinsic thermodynamic and kinetic properties that ultimately govern crystal growth. There are a number of process parameters that need to be tuned to adjust the growth environment, including the heating zone temperature, vapor pressure, the number of precursors, and the distances between the substrate and the sources.
\r\n\r\n\tThe book is an update with a considerably expanded and revised scope.
\r\n\t
A biosensor can be defined as a device incorporating a biological sensing element connected to a transducer to convert an observed response into a measurable signal, whose magnitude is proportional to the concentration of a specific chemical or set of chemcials (Eggins 1996). According to the receptor type, biosensors can be classified as enzymatic biosensors, genosensors, immunosensors, etc. Biosensors can be also divided into several categories based on the transduction process, such as electrochemical, optical, piezoelectric, and thermal/calorimetric biosensors. Among these various kinds of biosensors, electrochemical biosensors are a class of the most widespread, numerous and successfully commercialized devices of biomolecular electronics (Dzyadevych et al., 2008). In this chapter, we will focus on the enzyme-based electrochemical biosensors since enzyme electrodes have attracted ever-increasing attentions due to the potential applications in many areas.
\n\t\t\tEnzyme-based electrochemical biosensors have been used widely in our life, such as health care, food safety and environmental monitoring. Health care is the main area in the biosensor applications, such as monitoring blood glucose levels and diabetics by glucose biosensors. Besides, the reliable detection of urea has potential applications for patients with renal disease either at home or in the hospital. Industrial applications for biosensors include monitoring fermentation broths or food processing procedures through detecting concentrations of glucose and other fermentative end products. The sensitive detection of phenolic compound is an important topic for environmental research because phenolic compouds often exist in the wastwaters of many industries, giving rise to problems for our living environment as many of them are very toxic.
\n\t\t\tThis chapter is on the enzyme-based electrochemical biosensors, which will begin with a section for enzyme immobilization methods due to their important roles in biosensors. The next section will focus on the recent advances in enzyme-based electrochemical biosensors. Nanomaterials play an important role in recent development of enzyme-based biosensors, thus some popular fabrication methods of nanomaterials will be briefly described towards their applications in nanomaterials synthesis. The emphsis of this chapter is on the recent advances particularly nanomaterials-based biosensors. Some important and intelligent nanomaterials including gold, ZnO, carbon nanotube and polypyrrole will be presented in a way to the current achievements in enzyme-based electrochemical biosensors. The last section of this chapter will discuss challenges currently faced to practical applications.
\n\t\tIn order to make a viable biosensor, the biological component has to be properly attached to the transducer with maintained enzyme activity. This process is known as enzyme immobilization. Biosensors are usually designed with high enzyme loading to insure sufficient biocatalyst activities, and the enzymes are provided with an appropriate environment to sustain their activities. The local chemical and thermal environment can have profound effects on the enzyme stability. The choice of immobilization method depends on many factors, such as the nature of the biological element, the type of transducer used, the physicochemical properties of the analyte and the operating conditions in which the biosensor is to function, and overriding all these considerations is necessary for the biological element to exhibit maximum activity in its immobilized microenvironment (Singh et al., 2008). A detailed information on advantages and drawbacks of different methods for enzyme immobilization could be found in the literature (Buerk 1993; Eggins 1996; Nunes & Marty, 2006). Generally, there are 4 regular methods for enzyme immobilization and they are briefly described as shown below:
\n\t\t\t\n\t\t\t\t
\n\t\t\t\t
\n\t\t\t\t
\n\t\t\t\t
Recent years witness the vigorous applications of various nanomaterials in the development of biosensors. Nanomaterials are generally referred to the materials with dimensions ranging from 1 to 100 nm, which have some special physicochemical characteristics resulting from their “small” size structures. Nanomaterials make contribution to the improvement of the performance and stability of enzyme electrodes in the electrochemical biosensors, which can be fabricated by many various techniques. The generally used techniques for nanomaterials in biosensor applications are described briefly as follows.
\n\t\t\t\tWet chemical route, also called chemical solution deposition, is one of the most widely used to fabricate nanomaterials, especially nanoparticles. For wet chemical route, solution of chemical species will be involved during the process, which thus differs from dry chemical route. Briefly, it uses a liquid precursor, usually a solution of organometallic powders, dissolved in an organic solvent. Chemical reactions then occur in order to get purposeful product(s). It is a quite common method to be used for nanomaterials fabrication, especially in the application of electrochemical biosensors.
\n\t\t\t\tThe vapor-liquid-solid method is based on a mechanism for the growth of nanostructural materials with one-dimension from chemical vapor deposition, such as nanowires. It is generally very slow for a crystal to grow through direct adsorption of a gas phase onto a solid surface. During vapor-liquid-solid process, this problem is overcome by inducing catalytic liquid alloy phase to rapidly adsorb a vapor to supersaturation levels, and thus crystal growth can subsequently occur from nucleated seeds at the liquid-solid interface. The physical characteristics of nanowires grown in this manner is closely associated with the size and physical properties of the liquid alloy.
\n\t\t\t\tHydrothermal synthesis is a method to synthesize crystalline materials from high-temperature aqueous solutions at high vapor pressures. The chemical reaction occurs in a vessel, which is separately from ambient environment. Hydrothermal synthesize will drive those hardly-dissolved compounds under normal conditions to dissolve in the solution under special conditions followed by recrystallization. The method can be used for the large crystal growth with high quality, where good control over composition is required. This method has been used for the fabrication of nanomaterials with low-dimentions.
\n\t\t\t\tThe sol-gel process, strictly, belongs to a wet-chemical technique (chemical solution deposition) for material fabrication. This process uses a chemical solution as the precursor for an integrated network (or gel) of either discrete particles or network polymers. The sol evolves towards the formation of a gel-like system with two phases (a liquid phase and a solid phase), whose morphologies range from discrete particles to continuous polymer networks. A drying process is generally required to remove the remaining liquid phase, during which a significant amount of shrinkage and densification occur. The precursor sol can be either deposited on a substrate to form a film or used to synthesize powders. The sol-gel approach is a cheap and low-temperature technique that allows for the fine control of the product’s chemical composition.
\n\t\t\t\tThin films are thin material layers ranging from fractions of a nanometre to several micrometres in thickness. There are many popular deposition techniques for thin film deposition, such as evaporation, sputtering, chemical vapor depositions, etc. For example, evaporation in vacuum involves two basic processes: evaporation of a hot source material and then condensation of the material vapor on the cold substrate surface in the form of thin film. The average energy of vapor atoms reaching the substrate surface is generally low ( i.e. tenths of eV) and thus normally results in a porous and little adherent material. Sputtering entails the bombardment of a target with energetic particles (usually positive gas ions), which causes some surface atoms to be ejected from the target. These ejected atoms deposit onto the substrates in the vicinity of the target. The target can be kept at a relatively low temperature, and sputtering is especially useful for compounds or mixtures. Chemical vapor deposition is done through exposure of the substrate to one of several vaporized compounds or reactive gases. A chemical reaction occurs initially near the substrate surface, producing desired material as it condenses on the substrate forming a layer of thin film. Commercial techniques often use very low pressures of precursor gas.
\n\t\t\tAmong nanomaterials, ZnO has attracted much attention due to wide range of applications. ZnO as a wide band gap (3.37 eV) semiconductor plays an important role in optics, optoelectronics, sensors, and actuators due to its semiconducting, piezoelectric, and pyroelectric properties. Nanostructured ZnO not only possesses high surface area, nontoxicity, good biocompatibility and chemical stability, but also shows biomimetic and high electron communication features, making it great potential applications in biosensors. More importantly, as a biocompatible material, it has a high isoelectric point (IEP) of about 9.5. This makes it suitable for absorption of proteins with low IEPs, as the protein immobilization is primarily driven by electrostatic interaction. ZnO with various nanostructures by same or different fabrication techniques has been widely used for enzyme immobilization in recent years. Figure 1 gives some examples to show various ZnO nanostructures in different shapes by several various synthesis techniques.
\n\t\t\t\t\tWet chemical route is quite a popular method to fabricate various ZnO nanostructures, such as nanoparticles, nanorods and nanosheets. It had been proposed to use these ZnO naonostructures as platform for cholesterol oxidase (ChOx) immobilization via physical adsorption. For example, using ZnO nanoparticles for enzyme immobilization, the prepared biosensor had a high and reproducible sensitivity of 23.7 µA/cm2.mM, detection limit of 0.37 nA and linear dynamic range from 1 to 500 nA (Umar et al., 2009). Recently, an ultra-sensitive cholesterol biosensor was developed using flowerlike ZnO nanostructure, in which ChOx was immobilized to the surface of modified electrode via physical adsorption followed by the covering of Nafion solution. Such biosensor exhibited a very high and reproducible sensitivity of 61.7 µA/cm2.mM with a Michaelis-Menten constant (KM) of 2.57 mM and fast response time of 5 s (Umar et al., 2009). A H2O2 biosensor was prepared using waxberry-like ZnO microstructures consisting of nanorods (8-10 nm) by wet chemical method (Cao et al., 2008). Such kind of ZnO microstructures with high surface area could provide the platform for the reduction of H2O2 by contributing excess electroactive sites and enhanced electrocatalytic activity. The transport characteristics of the electrode were controlled by diffusion process, and the prepared biosensor had a much wider linear range from 0.l5 to 15 mM.
\n\t\t\t\t\tGluose biosensors were also reported using ZnO nanocombs as platform by vapor-phase transport (Wang et al., 2006). For enzyme immobilization, glucose oxidase (GOD) were physically adsorpted to the nanocomb modified Au electrode, followed by Nafion solution covered on the surface of the modified electrode. The prepared biosensor had a diffusion-controlled electrochemical behavior. The covered linear range was from 0.02 to 4.5 mM and the reported sensitivity was 15.33 µA/cm2.mM. The value of KM was as low as 2.19 mM. Using a similar technique, Weber et al. obtained ZnO nanowires with a typical length of 0.5-2 µm and a diameter of 40-120 nm, which were grown on the substrate with an array of ZnO nanowires (Weber et al., 2008). Physical adsorption was also adopted to immobilize GOD onto the electrode. This kind of biosensor had a linear trend (0.1-10 mM). A reagentless
\n\t\t\t\t\tZnO nanostructure materials with various shapes. (a) nanocombs by vapor-phase-transport (
phenol biosensor was prepared by immobilizing tyrosinase on ZnO nanorods through electrostatic attraction and then covered by Nafion, in which ZnO nanorods were also fabricated by vapor-phase transport technique (Chen et al., 2008). Tyrosinase was adsorbed on the ZnO nanorods and its bioactivity can be well remained. Such prepared biosensor had a fast response within 5 s. The linear range of concentration spanned from 0.02 to 0.18 mM, and KM was calculated to be as low as 0.24 mM, reflecting a high affinity of tyrosinase to phenol on ZnO nanorods and a good bioactivity (Chen et al., 2008).
\n\t\t\t\t\tGluose biosensors were also reported using ZnO nanocombs as platform by vapor-phase transport (Wang et al., 2006). For enzyme immobilization, glucose oxidase (GOD) were physically adsorpted to the nanocomb modified Au electrode, followed by Nafion solution covered on the surface of the modified electrode. The prepared biosensor had a diffusion-controlled electrochemical behavior. The covered linear range was from 0.02 to 4.5 mM and the reported sensitivity was 15.33 µA/cm2.mM. The value of KM was as low as 2.19 mM. Using a similar technique, Weber et al. obtained ZnO nanowires with a typical length of 0.5-2 µm and a diameter of 40-120 nm, which were grown on the substrate with an array of ZnO nanowires (Weber et al., 2008). Physical adsorption was also adopted to immobilize GOD onto the electrode. This kind of biosensor had a linear trend (0.1-10 mM). A reagentless phenol biosensor was prepared by immobilizing tyrosinase on ZnO nanorods through electrostatic attraction and then covered by Nafion, in which ZnO nanorods were also fabricated by vapor-phase transport technique (Chen et al., 2008). Tyrosinase was adsorbed on the ZnO nanorods and its bioactivity can be well remained. Such prepared biosensor had a fast response within 5 s. The linear range of concentration spanned from 0.02 to 0.18 mM, and KM was calculated to be as low as 0.24 mM, reflecting a high affinity of tyrosinase to phenol on ZnO nanorods and a good bioactivity (Chen et al., 2008).
\n\t\t\t\t\tZnO nanowires can also be obtained using thermal evaporation, in which ZnS powders were thermal evaporated under controlled conditions with Au thin film as a catalyst layer (Zang et al., 2007). GOD was immobilized onto ZnO nanowires by physical adsorption. KM and sensitivity could be modulated in a wide range by the variation of the loading amount of ZnO/GOD onto the electrode. Umar et al. also using thermal evaporation to synthesize ZnO nanonails (Umar et al., 2008), where Zn powder was used as reaction source of Zn, and oxygen was introduced into the system. The constructed biosensor exhibited a diffusion-controlled electrochemical behavior with a linear calibration range from 0.1 to 7.1 mM. It showed a high sensitivity of 24.6 µA/cm2.mM, while KM was relatively higher around 15 mM. Uric acid biosensor was prepared based on ZnO nanorods also by thermal evaporation (Zhang et al., 2004). Uricase with a low IEP of 4.3, was immobilized on ZnO nanorods by electrostatic attraction. The prepared biosensor had a linear range from 5 µM to 1 mM and detection limit of 2 µM. Besides, it had a lower KM of 0.24 mM and a good thermal stability (10 - 85oC).
\n\t\t\t\t\tAmong the various strategies followed, a useful and simple way for ZnO is to grown directly on electrode. This was realized in the work of Wei et al. (Wei et al., 2006), where ZnO nanorods with a hexagonal cross section were grown directly on the standard Au electrode by hydrothermal decomposition. Enzyme immobilization was done via the cover of GOD solution on the surface of the electrode. The prepared biosensor presented a quite fast response within 5 s and a high sensitivity of 23 µA/cm2.mM. It also had a low KM value of 2.9 mM and a low detection limit of 10 µM.
\n\t\t\t\t\tZnO matrix by sol-gel procedure was developed for tyrosinase immobilization (Liu et al., 2005). The porous and positively charged ZnO sol-gel matrix provided a moderate microenvironment for the tyrosianse to remain its bioactivity. The so prepared biosensor had a sensitivity of 168 µA/mM, and the linear range covered from 0.15 to 40 µM (Liu et al., 2005). Another kind of matrix of ZnO/chitosan was developed for tyrosinase immobilization by dispersion of ZnO nanoparticles into the chitosan solution (Li et al., 2006). The matrix could provide a favorable microenvironment in terms of its isoelectric point for tyrosinase loading, and the immobilized tyrosinase could retain its bioactivity to a large extent. The biosensor using ZnO/chitosan matrix had a better performance than that using ZnO sol-gel matrix. KM was calculated to be 23 µM and the detection limit was lower to be 0.05 µM (Li et al., 2006).
\n\t\t\t\t\tDifferent from above mentioned ZnO nanostructures, a new kind of nanostructure, nanoclusters, was proposed for a novel biosensor construction (Zhao et al., 2007). These ZnO nanoclusters doped by Co (2%) were obtained by nanocluster-beam deposition (Zhao et al., 2005; Zhao et al., 2007). Home-made electrode based on PET plate was used for enzyme immobilization instead of traditional standard electrode. Briefly, Ti ions from the plasma were implanted into PET plate, followed by a thin Au layer deposited on Ti-implanted PET substrate by magnetron sputtering. After that ZnO-based nanoclusters were directly grown on the modified PET plate. Cross-linking was used via glutaraldehyde for enzyme immobilization. The prepared biosensor had a response time within 10 s and the sensitivity was over 13 µA/ cm2.mM. ZnO porous thin films by RF magnetron sputtering was also proposed for ChOx immobilization by physical adsorption. The film was grown under high pressure (50 mTorr) so as to creat native defects and therefore porous film formed. The prepared biosesnor had a KM of 2.1 mM. The wide linear range spanned from 0.65 to 10.34 mM.
\n\t\t\t\t\tIn recent years, nanostructured inorganic-organic hybrid materials have emerged to fabricate biosensors by entrapping enzymes, which combine the physicochemical attributes of components to improves their features. Organic components (e.g. Nafion, chitosan) benefit the formation of defect-free inorganic membranes and make these membranes less brittle, and organic membranes can have their chemical and thermal stability improved by an inorganic phase. A H2O2 biosensor with good stability was developed with horseradish peroxidase (HRP) entrapped in the nanoporous ZnO/chitosan composite (Yang et al., 2005). The sensor exhibited a sensitivity of 43.8 µA/cm2.mM, and it retained 80% of its initial current response after 40 days. It is expected that the numerous nanoscaled cavities on the surface of the microspheres are highly advantageous for the entrapment of enzymes by sequestering in the cavities or binding on the surface of the microspheres. Using this approach, Lu et al. synthesized the porous ZnO microspheres consisting of nanosheets using wet chemical route (Lu et al., 2008). Hemoglobin (Hb) was entrapped in the composite film of Hb, ZnO and Nafion. Besides the good reproducibility and long-term stability, the prepared biosensor had a sensitivity of 137 µA/cm2.mM and a low KM of 0.143 mM. Other nanocomposite consisting of ZnO nanoparticles and chitosan was also reported to immobilize ChOx by physical adsorption (Khan et al., 2008).
\n\t\t\t\t\tMore complex inorganic-organic composites are also commonly prepared in biosensor development by introducing other inorganic materials (e.g gold and multi-walled carbon nanotubes (MWCNTs)). It’s well known that gold and MWCNTs have been already used for enzyme immobilization to realize direct electron transfer between active sites and electrode. Besides, the presence of biocompatible Nafion in the biocomposite film not only makes the film uniform, but also could lead to the increased activity of enzyme. Recently, a biosensor under these approches was prepared using the platform consisting of ZnO, MWCNTs and Nafion, which showed a very high sensitivity of 1310 µA/cm2.mM and a very low of KM of 82.8 µM (Ma et al., 2009). The composites consisting of ZnO, Nafion and gold nanoparticles were also developed to entrap HRP for H2O2 biosensors (Xiang et al., 2009). The biosensor had a Km of 1.76 mM and a low detection limit of 9 µM. It showed reproducibility and good stability after one month. Other composites are also proposed consisting of ZnO crystals, gold nanoparticles and chitoson (Zhang et al., 2009). The principle of enzyme immobilization differed from the methods mentioned above. It is known that ZnO crystals with high IEP are suitable for the electrostatic adsorption of proteins with lower IEP. The positively-charged ZnO crystals and amine-derivatized chitosan could facilitate higher capability of assembling negatively charged nanogold through strong electrostatic adsorption and the covalent bonds between amine groups and gold (Zhang et al., 2009). Biocompatible nanogold could further allow HRP to be immobilized with well-remained bioactivity in addition to increased loading amount. The prepared biosensor can achieve sensitive electrochemical response to H2O2 at a potential of - 0.2 V. Similar composites for enzyme immobilization was reported by Duan et al. (Duan et al., 2008), but the composites were mixed by the solutions of ZnO/chitosan, Hb and gold. The as-prepared biosensor has a fast response to H2O2 within 4 s and a detection limit of 0.097 µM.
\n\t\t\t\t\tRecent advances in phenol biosensors witness the use of modern process in semiconductor industry, such as photolithograph for designed patterns. A new tyrosinase biosensor was constructed based on the covalent immobilization of tyrosinase by glutaraldehyde on the biofunctional ZnO nanorod microarrays via photolithograph (Zhao et al., 2009). The as-prepared biosensor had a ultrahigh sensitivity of 287 µA/cm2.mM and a detection limit of 0.25 µM. The linearity covered a wide range from 1-150 µM.
\n\t\t\t\t\tIn the development of uric acid biosensor, multilayer structure was introduced toward a highly sensitive and stable uric acid biosensor. Using ZnO nanoparticles and MWCNTs, multilayer structure was realized firstly by negatively charged MWNTs cast on pyrolytic wafers, followed by decoration of ZnO nanoparticles (Wang et al., 2009). Uricase was immobilized onto ZnO nanoparticles also by electrostatic attraction, and finally PDDA layer was coated on the surface of uricase. The as-prepared biosensor had a wide linear response range of 1mM to 5 M, a high sensitivity of 393 µA/cm2.mM. It also exhibited a long-term stability after 160 days.
\n\t\t\t\tGold nanoparticles could provide a stable immobilization for biomolecules retaining their bioactivity. Moreover, electron transfer between redox proteins and electron surfaces is facilitated, which is induced by many factors, such as the high surface-to-volume ratio, high surface energy, decreased proteins-metal particles distance and the functioning as electron-conducting pathways between prosthetic groups and the electrode surface from the gold nanoparticles. Pingarron et al. recently reported a review on gold nanoparticle-based electrochemical biosensors, in which gold-based enzyme biosensor are summarized (Pingarron et al., 2008). Gold nanoparticles are normally synthesized by chemical route and electrodeposition.
\n\t\t\t\t\tThe electrodes are usually modified by gold in different ways to improve the performance of the biosensor. The electrode surface could be roughened by gold nanoparticles to enhance the interaction of enzyme with the electrode. An example is the construction of acetylcholinesterase biosensor in which electrode was modified by electrodeposited gold nanoparticles at the electrode surface after hydrolysis of acethlthiocholine by the immobilization enzyme (Shulga & Kirchhoff, 2007). This method is valuable for the development of new devices for the sensitive detection of potentially dangerous and deadly neurotoxins. Carbon paste electrode could be modified by the colloidal gold consisting of pretreated graphite power with colloid gold solution and paraffin oil (Liu & Ju, 2003). GOD was immobilized onto the modified electrode via physical adsorption. Such kind of GOD biosensor can efficiently exclude the interference of commonly coexisted uric and ascorbic acid (Liu & Ju, 2003). The similar methodology is also favored for other substrate detection, such as phenol and hydrogen peroxide (Liu & Ju, 2002; Liu et al., 2003). Gold electrode can be modified by attachement of gold nanoparticles via covalent bond. These gold nanoparticles by chemical route were self-assembled on gold electrode by dithiol via Au-S bond, where dithiol was physically absorbed on the electrode surface by putting gold electrode immersed into a dithiol ethanol solution (Zhang et al., 2005). A cystamine monolayer was then chemisorbed onto those gold nanoparticles and exposed to an array of amino groups, after that GOD was immobilized by covalently attached to the cystamine modified electrode (Zhang et al., 2005). The scheme diagram in Figure 2 shows the steps for above procedure. The so prepared biosensor provided a linear response to glucose from 20 μM - 5.7 mM with a sensitivity of 88 µA/cm2.mM. The sensor had a good reproducibility and remained stable over 30 days.
\n\t\t\t\t\tA wide variety of matrices, including inorganic materials, organic polymers, and other commercially available solid supports, have been used for enzyme immobilization. Chitosan, as mentioned in pervious part, is one of the most promising immobilization matrices due to its excellent properties. Colloidal gold nanoparticles have been also used as the matrix for the enzyme immobilization to retain the macromolecules’ bioactivity. The adsorption of colloidal gold nanoparticles on the chitosan membrane could provide an assembly of gold nanoparticle mulilayers and a suitable microenvironment similar to the native environment of biomolecules. Based on this approach, a disposal biosensor was fabricated for the rapid detection of H2O2 by entrapping HRP in colloidal gold nanoparticle-modified chitosan membrane (Liu & Ju, 2003). The biosensor was characterized with good detection precision and storage stability. Based on a similar methodology, glucose (Luo et al., 2004) and HRP (Luo et al., 2005) biosensors were prepared by self-assembling gold bnanoparticles on chitosan hydrogel modified Au electrodes.
\n\t\t\t\t\tNanocomposites by combination of gold nanoparticles with inorganic or organic nanomaterials have shown to possess interesting properties, which can be profited for the development of electrochemical biosensors. An example of such nanocomposites is a colloidal gold-CNT composite electrode using Teflon as the non-conducting binding material (Manso et al., 2007). The constructed biosensor showeded significantly improved responses to H2O2, and the incorporation of GOD into the new composite matrix allowed the preparation of a mediatorless glucose biosensor with a remarkably higher sensitivity than that from other GOD-CNT bioelectrodes (Manso et al., 2007). Hybrid nanocomposites of gold nanoparticles and organic materials are proposed, in which gold and PPy are fabricated by wet chemical route using HAuCl4 and pyrrole as the reaction reagents (Njagi & Andreescu, 2007). The reaction occurs in mild aqueous conditions and doesn’t involve application of an electrical potential, surfactants or solvents that could affect the biological activity. A stable nanocomposite strongly adhered to the surface of GCE electrode and enzyme was entrapped into the matrix. The fabricated biosensor showed high sensitivity for phenol detection, fast response time, good operational stability and reproducibility (Njagi & Andreescu, 2007).
\n\t\t\t\t\tStepwise assembly of dithiol, gold, cystamine, IO4\n\t\t\t\t\t\t\t\t- oxidized GOD on a gold electrode, from paper (
Enzymes deposited in ordered monolayer or multilayer systems have an important significance for fabrication of biosensors and bioelectronic devices. Layer-by-layer self-assembly technique based on electrostatic interaction attracts extensive interest due to its simplicity of the procedure, wide choice of the composition and thickness of the layer on the molecular level (Yang et al., 2006). This technique was originally developed by Decher and coworkers (Decher et al., 1992; Lvov et al., 1993) for linear polyelectrolytes and later extended to proteins, enzymes, nanoparticles, and so on (Feldheim et al., 1996; Caruso et al., 1997; He et al., 1998). Using this technique, a glucose biosensor was constructed, in which PMMA dendrimers with modified gold nanoparticles were alternated with poly(vinylsulfonic acid) layers on ITO electrodes (Crespilho et al., 2006). The method of cross-linking was chosen for enzyme immobilization (Crespilho et al., 2006). Other glucose biosensor by layer-by-layer self-assembled technique could also be realized consisting of different multilayer films with chitosan, gold nanoparticles and GOD (Wu et al., 2007). A method of layer-by-layer covalent attachment of enzyme molecules was proposed to overcome the unstability occurring in the layer-by-layer self-assembly technique casued by the driving force of electrostatic interaction. Such kind of biosensor was prepared by construction of multilayer films consisting of glucose oxidase and gold nanoparticles using cysteamine as a cross-linker based on two covalent reactions: Schiff bases reaction between aldehyde-group of IO4-oxidized GOD and amino-group of cysteamine, and covalent bond between gold nanoparticles (GNPs) and sulphydryl of cysteamine (Yang et al., 2006). Layer-by-layer construction of GOD/GNPs multilayer film on an Au electrode were shown in Figure 3. The constructed biosensor exhibited a good stability and long lifetime up to 4 weeks.
\n\t\t\t\t\tLayer-by-layer construction of the GOD/gold nanoparticles multilayer films on an Au electrode (
Sol-gel technology provides unique means to prepare there-dimensional networks suited for the encapsulation of biomolecules. Sol-gel hybrid materials prepared by physically encapsulating gold nanoparticles into porous sol-gel networks have been used for the fabrication of biosensors. For instance, an acetylcholinesterase biosensor was constructed, where the sol-gel derived silicate network assembling gold nanoparticles provided a biocompatible microenvironment around the enzyme molecule to stabilize its biological activity and prevent them from leaking out of the interface (Du et al., 2008).
\n\t\t\t\tCNTs are unique one-dimensional materials with unique properties such as good electrical conductivity, strong adsorptive ability and excellent bioconsistency. CNTs have led to development of many new techniques, and the applications in the biosensors have shown that CNTs have an electrocatalytic effect and fast electron-transfer rate between the electroactive species and the electrode.
\n\t\t\t\t\tA biosensor could be simply fabricated using multi-walled CNTs (MWCNTs) as immobilization platform with direct electron transfer and enhanced catalytic effect. For example, bilirubin oxidase could be immobilized directly onto MWCNTs modified glassy carbon electrods (Weigel et al., 2007). Direct electron transfer reactions of bilirubin oxidase occur and the incorporation of MWCNTs enhances the catalytic bilirubin oxidase reaction up to a factor of 26 (Weigel et al., 2007).
\n\t\t\t\t\tAn extremely robust, sensitive and selective galactose biosensor was proposed by the dispersion of single-wallled CNTs (SWCNTs) into a chitosan matrix to form a stable dispersion, followed by the chemical cross-linking with glutaraldehyde and free aldehyde groups produced a substrate for covalent immobilization of galactose oxidase (Tkac et al., 2007). The detection of oxygen uptaken by galactose oxidase on chitosan/SWCNTs layer at - 0.4 V was robust with a low detection limit of 25 µM.
\n\t\t\t\t\tActivating CNT surfaces is an essential prerequisite in order to effectively improve the performance of the prepared biosensors. In practical, CNT solubilization in aqueous media is essential for CNTs as supporting matrix for the immobilization of proteins. This can be achieved by the surface functionalization of CNTs with ionic or hydrophilic groups or the functionalization of CNTs with water-soluable polymers. Based on this approach, MWCNTs are modified by redox polymer, poly(vinylimidazole) complexed with Os(4,4’dimethylbpy)2Cl(PVI-demeOs), resulting in the turning of MWCNT surface from hydrophobic to hydrophilic without changes of surface morporlogy (Cui et al., 2009). The prepared biosensor showed the enhanced sensing sensitivities induced by the redox polymer film, where the enzyme molecules was wired through the redox centers tethered on the mobile redox polymer backbones to the MWCNTs electrodes. MWCNTs could be modified by the coating of polyethylene imine (PEI) or poly(acrylic acid) (PAA) to obtain water-soluble MWCNTs (Yan et al., 2008). Recent development on the modified MWCNTs was to use O2 plasma to treat MWCNTs, and thus oxygen contained functional groups were introduced onto their surface without influencing their bulk properties (Lee et al., 2009). Attaching metal nanoparticles to CNT and to CNT sidewalls is of interest to obtain nanotube/nanoparticle hybrid materials with useful properties. By electrostatic interaction, CNTs could be coated with gold nanoparticles and further filled with gold nanocluster after heat treatment in NH3 (Jiang & Gao, 2003). Such heat treatment with NH3 could make CNTs open-ended and generate functional basic groups on the inner wall of the nanotubes.
\n\t\t\t\t\tThe composite of CNTs with other organic/inorganic materials has an important role in CNT-based enzyme biosensors. For instance, MWCNTs/PVP/Prussian blue (PB) composite film were synthesized by casting films of MWCNTs wrapped with PB on Au electrodes followed by electrochemical deposition of PB on the matrix (Li et al., 2007). The modified electrode thus shows prominent electrocatalytic activity towards the reduction of hydrogen peroxidase, due to the remarkablely synergistic effect of the MWCNTs and PB. Hydrogen peroxide biosensor could be also prepared by entrapping HRP in a new ormosil composite doped with ferrocene monocarboxylic acid-bovine serum albumin conjugate and MWCNTs (Tripathi et al., 2006), which exhibited a very low mass transport barrier to the substrate. Nafion and chitosan as organic materials are quite popular in the CNTs-based nanocomposites. In addition, sol-gel matrix, like titania and silica, were applied for effective enzyme immobilization (Lee et al., 2007;\n\t\t\t\t\t\tTiwari & Gong 2008,). Meanwhile, metal nanoparticles of platinum were also incorporated into the composites of chitosan and MWCNTs to improve the performance of the prepared biosensor (Tsai et al., 2008).\n\t\t\t\t\t
\n\t\t\t\t\tLactate detection is of great importance for the clinical analysis, fermentation as well as for food analysis. Enzyme-based electrochemical techniques for lactate detection is inexpensive, rapid and reliable compared to other methods, such as chromatographic and spectrometric analysis (Posner et al., 1996; Wulkan et al., 2001; Bariskaner et al., 2003; Fernandes et al., 2003). One kind of lactate biosensor was proposed by co-immobilization of lactate dehydrogenase (LDH) and Meldola’s Blue on MWCNTs through cross-linking with glutaraldehyde and agglutination with mineral oil (Pereira et al., 2007). The biosensor shows a good stability after 300 times of determinations within a wide linear response range (0.1-10 mM). A MWCNT-CHIT-LDH nanobiocomposite film as a lactate biosensor was developed (Tsai et al., 2007), where MWCNT, chitosan, and LDH were mixed by a simple solvent-evaporation process. The enzyme in this kind of biosensor was entrapped in the biocomposite and the prepared biosensor showed a much fast response around 3s. In addition to MWCNT and chitosan as immobilization materials, polyvinylimidazole-Os (PVI-Os), can be also introduced into the biocomposite to form network structure (Cui et al., 2007). In the nanocomposite of chitosan/PVI-Os/MWCNT/LOD(lactate oxidase), negatively charged LOD was entrapped by a positively charged chitosan. PVI-Os was used as a leachables electron mediator due to its polymeric redox form and its positive charge could also enhance the entrapment for LOD. Negatively charged CNT was designed as a cross-linker to network chitosan and PVI-Os for the nanocomposite. The prepared biosensor showed significantly improved conductivity, stability and electroactivity for lactate detection. The sensitivity could reach 19.7 µA/cm2.mM, and the low limit of detection of 5 µM. Recently, a new kind of hybrid composite for lactat biosensor was developed by introducing double-walled CNTs (DWCNTs) into alginate gel (Ma et al., 2008). DWCNTs with two concentric grapheme cylinders have attracted great interests in recent years because of their unique coaxial structure and promising mechanical, electrical, optical and thermal properties over SWCNTs and MWCNTs. LDH was prepared by pre-adsorbed on DWCNTs and then they were incorporated into alginate gel followed by Ca+ cross-linking. The prepared lactate biosensor could greatly reduce the water loss and LDH leakage.
\n\t\t\t\t\tRecent advances in CNT-based enzyme biosensors have shown to design a biocomposite biosensor so as to detect more than one substrate. An good example was given by a bienzyme biosensor with a bienzyme-channelling configuration, where toluidine blue functionalized MWCNTs were used for enzyme immobilization (Jeykumari & Narayanan, 2009). The constructed biosensor shows a short response time (< 2s), good stability and anti-interferant ability. Many efforts have been made to detect the biomolecules at very low
\n\t\t\t\t\tTilted cross-sectional schematics with corresponding SEM images portraying sequential fabrication process steps: (a) SWCNTs grown from the pores of the PAA via MPCVD, (b) electrodeposition of Pd to form Pd nanowires in pores and Pd nanocubes on SWCNTs and (c) electrodeposition to coat the existing Pd nanocubes with a thin layer of Au (
concentrations. Networks of SWCNTs decorated with Au-coated Pd nanocubes are employed as electrochemical biosensors showing a limit of detection as low as 2.3 nM for H2O2, in which Au-coated Pd nanocubes were grown at the defect sites of template SWCNT networks through a simple electrodeposition process (Claussen et al., 2009). Figure 4 shows the schematic fabrication process steps with corresponding SEM images.
\n\t\t\t\tAmong various conducting polymers, polypyrrole (PPy) as an intelligent material plays an important role in the electrochemical biosensors for the purpose of increased electrochemical activity and sensitivity, owing to its good biocompatibility, conductivity, stability, and efficient polymerization at neutral pH as well as easy synthesis. PPy films can be easily formed from aqueous solutions by chemical or electrochemical routes, and have a high degree of selectivity due to the inherent size-exclusion property. A recently good review on the applications of polymers in electrochemical biosensors could be found in the literature (Teles & Fonseca, 2008), in which polypyrrole was highlighted.
\n\t\t\t\t\tIn biosensor construction, PPy is often used as a conducting matrix and thus other organic/inorganic materials could be introduced into the matrix to further improve the performance of the biosensor. For example, stable and homogenous hybrid films consisting of PPy and copper hexacyanoferrate by electrochemical method were synthesized, aiming to obtain an electrocatalyst for H2O2 reduction in the presence of either Na+ or K+ ions (Fiorito et al., 2006). The constructed biosensor shows excellent catalytic properties towards H2O2 detection, with a performance higher than those observed for Prussian Blue and other analogues due to the electronic conductivity of the polymeric matrix (Fiorito et al., 2006).
\n\t\t\t\t\tIn practical, it is important to find ways to obtain PPy polymers with desirable properties for biosensor applications by introducing various dopants. For instance, electrical conductivity can be achieved in polymer films by doping or inserting anionic or cationic species during the process of polymerization. Besides, the incorporation of a large size dopant anion, such as polyvinyl sulphonate (PVS),
Layer-by-layer assembled technology has been also used in PPy-based biosensors. An example is that layer-by-layer assembled PPy and CNTs multilayer films were fabricated on Pt coated Polyvinylidene fluoride membrane, where PPy film was prepared by electrochemical polymerization and CNTs layers were coated by a vacuum filtration technique (Shirsat et al., 2008). Such multilayer structure provided an excellent matrix for the immobilization of enzyme, which possessed the favorable features of both PPy and CNTs. Cross-linking was chosen for GOD immobilization, and such prepared biosensor showed enhanced linear range, response time and sensitivity (Gade et al., 2006).
\n\t\t\t\t\tInterestingly, soluble PPy synthesized by the incorporation of sulfonate dopant anion could be well incorporated into microscopic polyacrylamide particles for glucose biosensing by concentrated emulsion polymerization method (Retama et al., 2005). The novelty of this method over conventional emulsion polymerization lies in the large volume of the aqueous dispersed phase used. The PPy/polyacrylamide microparticles showed the semi- conductivity, and GOD was immobilized in the microparticles by incorporating the enzyme into the aqueous phase of the concentrated emulsion before starting polymerization. To construct the biosensor, the obtained microparticles layer was covered and flattened around the platinum electrode surface using a dialysis membrane (Retama et al., 2005), and it showed the great interest for the application in glucose detection.
\n\t\t\t\t\tOther types of PPy nanostructures, like PPy nanotubes have been also proposed for enhanced adsorption of glucose oxidase in glucose biosensors (Ekanayake et al., 2007), where PPy nanotube array was synthesized using a solution of pyrrole and NaPF6 at a fixed current density for 90 s. GOD was immobilized onto the electrode through physical adsorption. With this new approach, the constructed biosensor had exhibited remarkable improvement in the sensitivity, response time and linear range values.
\n\t\t\t\tThis chapter mainly presents intelligent nanomaterials (e.g ZnO, gold, CNT and polyrrole) for construction of enzyme-based electrochemical biosensors to show the development in this area. To construct a biosensor with promising applications, it should be carefully considered to modify electrode in an effective way. The immobilization of enzyme onto the electrodes should be considered as another key step due to the important roles of the amount and bioactivity of immobilized enzyme on the performance of biosensors.
\n\t\t\tThere are many challenges currently faced towards practical applications of biosensors. For example, the construction of a biosensor with a low cost is still essential when considering the commercial devices. The major application field of biosensors is medical diagnostics with commercial devices. The biosensors in other areas, such as food industry and ecology, needed to be explored deeply for more applications. Challenges also exist to find ways to improve the performance criteria including high sensitivity, wider linear range, low limit of detection, fast response and repetitive ability. Research work now still keeps continuing to investigate more effective ways to construct enzyme-based electrochemical biosensors with more perfect performance.
\n\t\t\tIn the future development of electrochemical biosensors, the demands for portable and cheap biosensors with multifunctions (e.g. to detect several target analytes) will keep increasing for practical applications. Many thanks to the emergence of nanotechnology, many researchers could incorporate this technology into the biosensor construction to obtain novel structures. Miniaturization will play an important role in the trend of biosensor development in the future. However, it may result in low current because of the decreased amount of immobilized enzyme onto the available active area. This can be overcom by the nanostructures, which enhance the sensitivity of a biosensor by one to two orders of magnitude, due to the large surface area per unit volume ration, which allows the immobilization of a larger amount of the enzyme. Overall, electrochemical biosensors with perfect performance towards commercial systems keep a main thrust in future research.
\n\t\tThis work was supported financially by National Natural Science Foundation of China (Grant No. 40971279) and Nature Science Foundation of Jiangsu province (Grant No. BK2009264).
\n\t\tAcute pancreatitis (AP) is the most serious emergent disease in the gastroenterology field. The most common cause of AP is naturally gallstones. The most cases have mild disease and the illness limits itself in a short time period. In 15–20% of cases, the severe form of AP develops. The triage of patients with AP in accordance with the severity of illness is the single most important factor affecting monitorisation and treatment protocol of these patients. Acute biliary pancreatitis (ABP) develops due to gall stones and or sludge mostly coming from gall bladder, impacted in ampulla Vateri (AV) leading to increased pancreatic ductal pressure, pancreatic edema, inflammation and possibly necrosis. A lot of human and animal studies displayed that biliary obstrucition lasting more than 48 hours creates pancreatic necrosis. Therefore, before the endoscopic retrograde cholangiography (ERCP) area, surgery was used to induce biliary decompression and impede progression into pancreatic necrosis, however, new quests started after facing high rate of morbidities and mortalities associated with surgery.
Introduction of ERCP and endoscopic sphincterotomy into the daily practice, endoscopic relieving of biliary obstruction has come into reality. Nevertheless, occurence of complications even mortalitiy in association with ERCP initiated new debate about its indications and timing in patients with ABP. Although for the last 30 years, there has been many ongoing studies about to whom and when ERCP will be perforrmed in ABP, a certain conclusion has not been encountered yet. There has been 2 main strategies on debate [1].
Early routine ERCP strategy: If acute gallstone pancreatitis is triggered by duct obstruction caused by a stone, it would be reasonable to suggest that early ERCP with removal of any residual stones might reduce the severity of pancreatitis. The strategy of early ERCP is strongly supported by results from experimental studies and human studies, which show that the duration of biliary obstruction is a major factor in determining the severity of pancreatitis and that decompression of the biliary system can prevent progression of the disease. In addition, patients with severe pancreatitis tended to have stones impacted in the ampulla, and early (within 48 hours) surgical decompression of the obstruction has been shown to decrease mortalite rates These observations lend support to the theory of using early ERCP to remove obstructing stones in acute gallstone pancreatitis.
Early conservative management with or without delayed or selective use of ERCP strategy: Proponents of early conservative management with selective use of ERCP argue that early routine ERCP may lead to many unnecessary ERCPs in the majority of patients as the offending gallstone has often passed before the diagnosis of pancreatitis is made. Also, it remains unclear whether early ERCP improves the prognosis of acute gallstone pancreatitis. The severity of the pancreatitis may be determined at its inception and may not be dependent on the duration of duct obstruction. Furthermore, performing ERCP in the setting of acute pancreatitis can be technically difficult because of swollen ampulla and duodenal wall. Thus, it may be prudent to identify patients with persistent duct obstruction who would benefit from ERCP after a period of conservative medical management in order to avoid unnecessary negative ERCPs.
Due to 2 different approaches, how an imminent ERCP will affect the existing clinical situation in patients with ABP holds its uncertainity. There has been also no agreement on the preference of an urgent ERCP (U-ERCP) within 24 hours of patients’admission or an emergent ERCP (E-ERCP) within 48–72 hours [2]. These terms; U-ERCP and E-ERCP have been used in recent reports and the first paper published by Neoptolemos and et al. defined U-ERCP and E-ERCP differently than the other papers; the first one within 72 hours and the later within 35 days after admission [3]. Later on, ERCP within first 72 hours was labeled as U-ERCP [4] and after the year of 2000, U-ERCP has been defined as ERCP within 24 hours and E-ERCP as ERCP within 24–72 hours [2]. In severe ABP, there are some risks such as patient’s bad general situation, technical difficulties due to pancreatic edema and potential interruption of aggressive fluid resuscitation during and after the ERCP procedure. Therefore, valid only for patients having persisting indication for biliary decompression, seveal authors and our clinical experience favor E-ERCP together with immense supportive treament of these patients rather than U-ERCP in the absence of life threatining cholangitis.
In severe cases with AP, there can be pain, fever, cholestasis, mental confusion and hypotension due to ongoing pancreatic inflammation and necrosis and under this circumstances, an imminent ERCP can make the situation even worser [5]. Although, if we scrutinize the real life data, we will see that there is some kind of pressure on ERCP physicians to perform ERCP at night and or at weekends by the physicians seeing these patients with ABP in the emergency room [6]. However, in severe ABP, it would be impossible to guarentee the co-existence of cholangitis only by looking at some clinical and biochemical parameters, the use of harmless non-invasive methods such as magnetic resonance cholangiography (MRCP) and or endoscopic ultrasonography (EUS) seems to be more reasonable. Hence, endoscopist who will perform ERCP should estimate the clinical situation of patient with ABP correctly and know very well to whom and when ERCP should be done. Thirty four years after the first report by Neoptolemus [3] suggesting wider application of ERCP with ES during AP, Schepers NJ [4] reported a multicentric article (APEC study) which underlined the fact that U-ERCP with ES does not reduce AP associated complications and mortality compated with conservative approaches. These authors supported a conservative strategy in severe ABP with ERCP indicated only in patients with cholangitis or persistant cholestasis.
In this chapter, we will mention about the role of ERCP during ABP in accordance with the clinical studies and meta-analysis published on this subject and we will add our self clinical experience and practice in this area. The order of titles will be as such,
The pathogenesis and natural history of ABP
The estimation of cholangitis and cholestasis
The treatment steps in the first 72 hours in reference to International Guideliness
To whom and when ERCP should be done during ABP?
In the setting of ABP, biliary stones or sludge material impacted in ampulla vateri induce transient obstruction in the biliary tree and pancreatic ductus, followed by reflux of bile into the pancreatic channel. Consequently, undraining pancreatic channel develops increased ductal pressure leading to backflow of activated pancreatic enzymes into the parenchyma. This starts a cascade of tissue injury with a spectrum of events starting with mild parencymal inflammation ending with loss of pancreatic parenchyma due to severe necrosis [7]. For sure, cholestasis and or cholangitis due to biliary obstruction in addititon to pancreatic inflammation can add into the clinical scenario. There are several evidences indicating the duration of obstruction correlates with te severity of pathology in the pancreas. These evidences reveal that persisting obstruction after 48 hours leads to different degrees of necrosis and if the ductal decompression is obtained before that time period, disease associated morbidity and mortality decreases significiantly [8, 9, 10, 11, 12, 13, 14, 15, 16]. Runzi et al. [8] used an animal model of AP by balloon obstructed biliopancreatic ductal system and they relieved the obstruction at 1th, 3rd and 5th days. The authors documented that the severity of parenchymal inflammation, fat necrosis, hemorrhage, acinar cell vacuolisaiton and necrosis were most prominent in animals with obstructed ductal sysytem at 5 th days of the experiment. On contrary, animals having decompressed ductal sysytem at 1th and 3 rd day of experiment, pancreatic injury was able to be avoided. Another report by Acosta et al. [11] investigating the same subject on a clinical study put forth that severe pancreatitis develops significantly more in patients with the obstruction lasting more than 48 hours compared to those having less than 48 hours of obstruction. These authors suggested to wait for 48 hours to implement an ERCP as the impacted stone may fall down spontaneously and if the signs of obstruction persists after 48 hours, then we should think about ERCP. On the grounds that at least half of the cases, the impacted stone in Ampulla Vateri will fall down spontaneously within 24–48 hours after ampullary and duodenal edema diminishes, we know that the pancreatitis in these patients will limit itself and recover within a few days. Acosta et al. [12] investigated the effects of early ductal decompression in a report and they compared 30 patients who underwent ERCP within first 48 hours with 31 patients who got only conservative treatment. Within the first group, 16 had passed the stone into the duodenum during 48 hours and only 14 patients underwent ERCP in whom 11 were shown to have impacted stones. In the second group of patients, 22 patients had got rid of obstuction spontaneously and 9 patients who had persistent signs of obstruction underwent ERCP and only 3 of them had impacted stone. As a result, %78 of patients passed stones spontaneously into the duodenum and E-ERCP was performed on the others within 48 hours without an uneventful clinical course and mortality. Another report by Cavdar et al. [13] indicated that 74% of patients with ABP passed stones into the duodenum within 72 hours of admission.
Based on all this data and our clinical experience about the natural progression of ABP, we suggest conservative approach during the first 24 to 48 hours to limitate the severity of pancreatitis by agressive fluid recessuation correction hypovolemia and organ hypoperfusion. This approach also allows us to evaluate the patients with regard to the presence of cholestasis and cholangitis and to find out which patients need ductal decompression.
APACHE II, Ranson, Glasgow veya Atlanta criteria are used to evaluate the severity of AP. Cholangitis and or cholestasis are assessed according to the presence or absence of severe pain, mental confusion, hipotansiyon, jaundice, elevated serum bilirubin ve liver enzymes and absence of bile in the aspirated gastric juice. Acosta and et al. [14] clearly demonstrated that absence of bile in the aspirated gastric juice hyperbilirubinemia and severe pain are the parameters most sensitive and spesific for the ongoing obstruction of AV. The authors concluded to apply ERCP to this subgroup of patients. However, these findings may also occur in patients with severe pancreatitis and do not indicate the existence of cholangitis. Thus, ERCP performed based only on these findings may worsen pancreatitis, even end up with death. Therefore, we need better methods to show the stone in the biliary tree. Before the area of MRCP and endoscopic ultrasonography (EUS), we would do diagnostic ERCP and endoscopic sphincterotomy in every patient with a diagnosis of ABP even if we did not detect gall stones in the bile duct. This policy has changed to ‘never do diagnostic ERCP in ABP’ and do first MRCP or if possible more sensitive EUS to decide if ERCP will be done or not.
On clinical practice, the presence of cholangitis and or cholestasis in a patient with ABP is estimated by clinical and biochemical parameters together with abdominal ultrasonography (USG) [15, 16, 17, 18, 19]. Severe abdominal pain, fever, mental confusion, hypotension and jaundice can be seen in severe acute pancreatitis even in the absence of cholangitis. In 20% of patients, the liver enzymes can be persistently normal. The sensitivity of abdominal USG is very low around 27–50% in the diagnosis of cholestasis and cholangitis. The bile duct diameter can persist several days after spontaneously passing stones. Thus, we need more sensitive methods to detect cholangitis and or cholestasis. Nearly 20 years ago, ERCP has been widely used for a diagnostic purpose. However, there have been important developments with the administration of MRCP and EUS into the gastroenterology practice [20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. EUS is better than MRCP to detect gall stones smaller than 5 mm and after detecting the stone by EUS and as an adavantage of this procedure, ERCP can be used to extract the stone from the bile duct at the same session after EUS procedure [21, 22, 23, 24, 25, 26, 27]. Moon and his collagues [28] reported the accuracy rates of USG, computed tomography, MRCP, ERCP and intraductal USG to detect bile duct stones are 20%, 40%, %80%, 90%, 95%, respectively. The authors underlined IDUS and ERCP as the most sensitive methods to detect a CBD stone and suggested to use MRCP to choose the suitable patient for ERCP. They also notified that the rate of agreement between ERCP and MRCP is 90.6% and the large common bile duct has been mentioned as a factor for MRCP to overlook the bile duct stones.
MRCP has a low diagnostic value compared to EUS in a patient with dilated CBD having small sized stones. Scheiman and his colleagues [29] investigated and compared the cost and clinical efficacy of EUS and MRCP done 24 hours before the ERCP procedure. The authors identified EUS as the best cost-effective modality to prevent unnecessary ERCP. Thus, this will protect patients from potential complications of ERCP. Furthermore, 20% of bile duct stones smaller than 8 mm and detected by MRCP were found to pass spontaneously into the duodenum until the time comes for an ERCP procedure. Thus, EUS will reliably help us to give final decision to do ERCP or not. Another advantage of EUS is its applicability on bed side for patients warded in intensive care units. Additionally, in patients with normal gall bladder evaluation on percutaneous USG, EUS can detect sludge in the gall bladder in the setting of ABP. We can also use a quick EUS examination performed within 72 hours of hospitalization to decide if patients can be discharged early from the hospital. This strategy can decrease the health expanses as well. Thus, it seems very rational to increase cost effectivity of caring for ABP patients by provoking the motivation of ERCP physicians to get learn how to do EUS and vice versa [25, 26, 27].
Severe cases with ABP should be hospitalized in spesific centers having MRCP, ERCP and preferably EUS facilities under the control of a team of physicians consisted of gastroenterologist, pancreatobiliary surgeon and invasive radiologist [30, 31, 32, 33, 34, 35]. First, the severity of AP in accordance with the international scoring models must be determined and the patient’s co-morbidities should be recorded. Thereafter, these patients should be vigorously hydrated to prevent the collapse of pancreatic circulation. Indeed, we will especially emphasize aggressive fluid replacement therapy in these patients in the first 3 days of admission with patients with AP. This issue is also very important for the prophylaxis of post-ERCP pancreatitis [36].
A meticiluos fluid replacement within this very 24 hours limits pancreatitis by correcting the hypovolemia and organ hypoperfusion, hinders local and systemic complications of AP by decreasing Systemic Inflammatory Response Syndrome (SIRS) and associated multiorgan failure and lowers inhospital mortality. This helps to improve the general status of the patient and decreases the risks of further invasive procedures like ERCP in these circumstance. During the first 24 hours, iv crystalloid and or colloid solutions can be given [30, 31, 32, 33, 34, 35, 37, 38]. Although a retrospective study depicted no difference between ringer lactate (RL) and normal saline (SF) infusion with regard to the severity and complications of pancreatitis [39], there are vast data from the experimental and clinical studies supporting the benefits of RL; such as RL infusion hampers hyperchloremic acidosis and other metabolic complications of AP and by improvinng intraparenchymal pH status, RL infusion inhibits zymogen activation and worsening of AP [40, 41]. For these reasons, RL has been suggested by many international guidelines as first choice to be used as fluid therapy in these patients with AP [30, 31, 32, 33, 34, 35, 36]. In the absence of heart and kidney failure, RL infusion at 5–10 ml/kg/hour dose within the first 24 hours is recommended to these patients as targeted fluid therapy. By this way, we aim to get normal hemodynamic parameters, urine output 0.5–1 ml/kg/hour and hematocrit value as between 35–44%. However, we need to be scrupulous to avoid hypervolemia in elderly patients during fluid recesutation. Therefore, it is important to limit the dose to 5 to 10 ml/kg/hour as more than 10 ml/kg/hr. infusion rate has been associated with mehcanical ventilation, abdominal compartment syndorme and increased mortality [42].
Before 1978 when Classen [43] first did ERCP and endoscopic sphincterotomy in acute pancreatitis, ERCP was considered as contraindicated in AP. Thereafter, this dogma has changed by Safrany and his collegeus [44] who did ERCP in 15 cases with ABP in 1980. They detected impacted stone at AV in 8 patients and in 7 of them, they showed choledochal stone and removed the stones in all the patients. None of the patients developed any complications and discharged withn a short period after ERCP procedure. After 1980, case series have been reported in this area and first randomized controlled study about this subject was published by Neoptolemos and his collegues in 1986 [3]. In 1993, Fan and et al. [45] published a report in which they investigated the effects of early ERCP on progression of AP. The authors showed that early ERCP was useful only in patients with biliary sepsis compared to conservative group if there is an existing biliary pathology both in mild and severe cases of AP. However, early ERCP did not introduce declined morbidity and mortality when all other etiologies of AP had been included in the study cohort.
Nonetheless, many complications associated with ERCP have been reported in the following years and when and to whom ERCP questions became subject to many researches. ERCP and endoscopic sphincteratomy can make the situation worse in a patient with AP since therapautic ERPC had been reported to have 10% morbidity and 0.1% mortality rates [46, 47]. Additioanlly in patients with AP, there is potential risk of technical failure in ERCP procedure due to edema in the AV and duodenum itself.
For this reason, both the timing of ERCP and detrmining the correct patient who needs this procedure carry the utmost importance. In 2013, International Pancreas Union and American Pancreas Union published together ‘the management guideliness of AP’ and the suggestions about biliary system problems were written as follows [31]:
“ERCP is not indicated in predicted mild biliary pancreatitis without cholangitis. (GRADE 1A, strong agreement). ERCP is probably not indicated in predicted severe biliary pancreatitis without cholangitis (GRADE 1B, strong agreement). ERCP is probably indicated in biliary pancreatitis with common bile duct obstruction (GRADE 1C,strong agreement) ERCP is indicated in patients with biliary pancreatitis and cholangitis (GRADE 1B, strong agreement)
Urgent ERCP (<24 hrs) is required in patients with acute cholangitis. Currently, there is no evidence regarding the optimal timing of ERCP in patients with biliary pancreatitis without cholangitis.(GRADE 2C, strong agreement)
MRCP and EUS may prevent a proportion of ERCPs that would otherwise be performed for suspected common bile duct stones in patients with biliary pancreatitis who do not have cholangitis, without influencing the clinical course. EUS is superior to MRCP in excluding the presence of small (<5 mm) gallstones. MRCP is less invasive, less operator-dependent and probably more widely available than EUS. Therefore, in clinical practice there is no clear superiority for either MRCP or EUS.(GRADE 2C, strong agreement)”
Therefore, we will discuss the subject of bliary tree management in patients with AP as subtitiles; 1-Mild pancreatitis in the absence of cholangitis and persistent cholestasis. 2- Severe pancreatitis in the absence of cholangitis and persistent cholestasis 3- Acute pancreatitis together with the presence of cholangitis and persistent cholestasis. We will also discuss; 4- U-ERCP versus E-ERCP and 5-the role of elective ERCP 3 days after patient’s admission to prevent recurrence of AP.
The first randomized controlled trial in this field is published by Neoptolemus et al. in 1986 [3]. No relationship was found related to pancreatitis complications and mortality between the conservative treatment group and the ERCP group in mild acute biliary pancreatitis patients in this study and in the meta-analysis which contains 4 randomized controlled studies of Sharma et al. [48]. The patients were stratified by the severity of pancreatitis in the study of Burstow et al. [49] but the patients with or without cholangitis were not analyzed separately and eventually, a strong tendency to decrease pancreatitis complications has been suggested in patients with mild acute biliary pancreatitis, although this is not statistically significant (OR 0.67; 95% CI, 0.43, 1.03; P = 0.06). Another meta-analysis of 5 randomized controlled studies including 702 patients, which compared the conservative treatment and E-ERCP in acute biliary pancreatitis patients by Morietti et al. [50] showed no effect on pancreatitis complications (1.8% (95% CI -5.6% to 9.3%); p = 0.6). Since there is no mortality in patients with mild pancreatitis, a comparison could not be made in this regard. Petrov et al. [51] did not demonstrate any statistically significant difference between the E-ERCP group and the conservative treatment group in terms of reducing complications of pancreatitis in neither mild nor severe acute pancreatitis in their meta-analysis of 5 randomized controlled studies including 717 patients. A systematic review by Geenen et al. that published in Pancreatology in 2013 [52] examined the guidelines and meta-analysis in this field till then, reported that U or E-ERCP±ES had no place in mild acute biliary pancreatitis. As we do in our clinical practice, Elective ERCP (EL-ERCP) might be performed before the cholecystectomy only in case, the stuck stones in AV have escaped back into the choledoc and if this is proved by MRCP or EUS.
As a result, there is consensus that U or E-ERCP±ES is not indicated in mild acute biliary pancreatitis without cholangitis [31, 33, 34, 35].
ERCP in acute biliary pancreatitis is still a controversial issue, and there no consensus about it. As mentioned before, clinical and animal studies showed that if the biliary obstruction is not terminated within 48 hours, the pathology progresses to necrosis and then organ failure occurs. Therefore, the first studies demonstrated that U or E-ERCP decreased the mortality and morbidity in severe acute pancreatitis patients compared to the control group [53]. In 1997, Fölsch et al. [54] reported that especially deaths due to respiratory failure were more common in the E-ERCP group than the control group in their randomized controlled trial about the role of E-ERCP in acute biliary pancreatitis. The APEC study [4] that includes 232 patients from 26 centers published in July 2020 compared U-ERCP and conservative treatment, and this study changed the paradigm. Besides, acute biliary pancreatitis patients with cholangitis excluded from the APEC study and no significant difference demonstrated between two groups in regard of local or systemic complications of pancreatitis. Whereas, the cholangitis and recurrent attacks of pancreatitis were more common in the U-ERCP group than the conservative treatment group. This is because the criteria for persistent cholestasis or cholangitis were fever, serum bilirubin levels greater than 2.3 mg / dl, commom bile duct width greater than 8 millimeters in patients younger than 75 years and 1 centimeter in patients older than 75 years, and the presence of stones in common bile duct in this study. Another cause of these findings were that it was unclear whether MRCP or EUS, which are the most sensitive methods in detecting stones in choledoc, were performed or not.
Some conflicting results were obtained in the meta-analysis of randomized controlled trials about the role of emergency ERCP in acute biliary pancreatitis, according to the including and excluding criteria of the involved randomized controlled trials and whether subgroup analysis is done or not. Petrov et al. [55] published a meta-analysis in 2008 including 7 randomized controlled trials with 450 patients about the effects of E-ERCP on acute biliary pancreatitis without cholangitis, and they indicated that emergency ERCP has no effect on local complications of pancreatitis in neither mild nor severe pancreatitis. Van Santvoort et al. [56] compared E-ERCP with conservative treatment in patients with and without cholangitis in their randomized controlled trial and demonstrated that in patients without cholestasis, ERCP (29/75 patients: 39%) was not associated with reduced complications (45% vs. 41%, P = 0.814, multivariate adjusted OR: 1.36; 95% CI: 0.49–3.76; P = 0.554) or mortality (14% vs. 17%, P = 0.754, multivariate adjusted OR: 0.78; 95% CI: 0.19–3.12, P = 0.734).
A meta-analysis by Tse et al. [1] which contains 5 randomized controlled studies, indicated that unweighted pooled mortality rates for participants were 9.6% in the early routine ERCP strategy and 4.9% in the early conservative management strategy in patients without cholangitis. Three years after this meta-analysis, Burstow et al. [49] analyzed 11 RCTs consisting of 1314 patients (conservative management = 662, ERCP = 652). There was a near significant decrease in mortality for the ERCP group compared with conservatively managed patients with severe pancreatitis [odds ratio (OR) 0.45; 95% confidence interval (CI), 0.19, 1.09; P = 0.08]. In patients with mild pancreatitis, mortality results were comparable for both groups (OR 0.66; 95% CI, 0.02, 28.75; P = 0.83). Overall complications were significantly reduced in the ERCP group in severe pancreatitis patients (OR 0.32; 95% CI, 0.17,0.61; P = 0.00). The authors’ comments about this meta-analysis are as follows: this meta-analysis demonstrates a significant decrease in complications in patients with severe ABP managed with early ERCP/ES compared with conservative management. As far as the mortality is concerned, no significant decrease was observed in mortality even in severe ABP patients treated with early ERCP/ES.
The meta-analysis and systematic review about the comparison of E-ERCP and conservative treatment in acute biliary pancreatitis by Coutinho et al. [57] reported that; the pain and fever resolved in a shorter time, the hospitalization time was shorter with reduced complications and hospital costs were lower in the E-ERCP group than the conservative treatment group. Uy et al. [58] performed a meta-analysis including 2 randomized controlled trials that compares the E-ERCP (n = 177) and the conservative treatment (n = 163) in acute biliary pancreatitis. This meta-analysis revealed low mortality rates for both mild and severe pancreatitis in the ERCP group (RR = 1.92, 95% CI: 0.86–4.32) whereas the morbidity rates were similar in both groups (RR = 0.95, 95% CI: 0.74–1.22). Moretti et al. [50] demonstrated that ERCP had no effect on complications in mild pancreatitis however, ERCP reduced the complications in severe pancreatitis but it did not have any effect on mortality rates in their meta-analysis including 5 prospective randomized trials with 702 patients. Geenen et al. [52] preformed a review including 12 international guidelines and 8 meta-analysis. Although 3 meta-analysis and 1 guideline recommended against ERCP in acute biliary pancreatitis, 7 out of 11 guidelines recommended routine E-ERCP in severe acute biliary pancreatitis regardless of the presence of cholangitis, and they agreed on the lack of consensus about routine E-ERCP in severe acute biliary pancreatitis. However, the 4 main international guidelines that we evaluated (2 out of them belonged the same group but published at different times) recommended against the emergency ERCP in acute biliary pancreatitis without cholangitis because it did not significantly reduce mortality and morbidity compared to the conservative treatment group [31, 33, 34, 35]. Contrary to these guidelines, another guideline of the United Kingdom publishe in 2005 [32] has controversial suggestions about E-ERCP in severe acute biliary pancreatitis without cholangitis as; “
Because of the lack of statically significant data about the reduction in local and systemic complications or mortality rates of pancreatitis by emergency ERCP in severe acute biliary pancreatitis from many RCTs and meta-analyzes until to date, international guidelines referring to these results indicated that U- or E-ERCP have no benefit in every patient with severe acute biliary pancreatitis unless cholangitis is present. The ESGE guideline published in 2018 [33] explains why ERCP should not be performed in a patient with severe pancreatitis without cholangitis: “
Certainly, biliopancreatic obstruction should be resolved immediately in patients with cholangitis or persistent cholestasis. The most effective method of this is undoubtedly the removal of stone or sludge that caused the obstruction by performing ERCP and ES [59]. The first study in this area was performed by Neoptolemos et al. and it demonstrated that E-ERCP and ES was the most useful method in acute biliary pancreatitis with cholangitis and cholangitis without pancreatitis [60]. Van Santvoort et al. [56] performed a study about the efficiency of ERCP in acute pancreatitis patient with or without cholestasis and findings as follows: In patients with cholestasis, ERCP (52/78 patients: 67%), as compared with conservative treatment, was associated with fewer complications (25% vs. 54%, P = 0.020, multivariate adjusted odds ratio [OR]: 0.35, 95% confidence interval [CI]: 0.13–0.99, P = 0.049). This included fewer patients with >30% pancreatic necrosis (8% vs. 31%, P = 0.010). Mortality was nonsignificantly lower after ERCP (6% vs. 15%, P = 0.213, multivariate adjusted OR: 0.44, 95% CI: 0.08–2.28, P = 0.330).
Tse et al. [1] performed a meta-analysis which included 5 randomized controlled trials with 644 participants with cholangitis and reported mortality rates, comprising a total of 200 participants in the early routine ERCP strategy and 215 in the early conservative management strategy. Unweighted pooled mortality rates for participants were 1.0% for the early routine ERCP strategy and 6.9% in the early conservative management strategy. In the trials that included participants with cholangitis, the early routine ERCP strategy significantly reduced mortality compared to the early conservative management strategy (RR 0.20, 95% CI 0.06 to 0.68; P = 0.010).
There is no consensus on timing of ERCP in the literature. In most publications, the ERCP preformed within 72 hours after the symptom onset is called emergency ERCP, but the emergency ERCP timing could be defined as within 48 hours in some other publications. Additionally, the ERCP which is performed within 72 hours named as U-ERCP in some publications. The only trial that compares the timing of ERCP (within 24 hours versus within 24–72 hours) in acute biliary pancreatitis is performed by Lee et al. [2]. Patients with acute biliary pancreatitis but without cholangitis was excluded retrospectively in this study, and they compared U-ERCP and E-ERCP in acute biliary pancreatitis. No significant difference was found in the total length of hospitalization or procedural-related complications, in patients with biliary pancreatitis and a bile duct obstruction without cholangitis, according to the timing of ERCP (< 24 h vs. 24–72 h). Although the definition is not U-ERCP, in one of Fan et al.’s studies [45] the ERCP which is performed within 24 hours is defined as E-ERCP and there was no significant difference between the ERCP group and the conservative treatment group in terms of local and systemic complications of pancreatitis whereas hospitalization time was a little shorter in the E-ERCP group. With these results, it was demonstrated that performing U-ERCP within 24 hours did not change the pancreatitis course, supporting the study of Lee et al. [2]. When considering the course of acute biliary pancreatitis, naming the ERCP performed within 24 hours as “URGENT” and the ERCP within 24–72 hours as “EARLY” by Lee et al. is the most appropriate definition [2]. When the literature and international guidelines are reviewed, ERCP is recommended to the acute biliary pancreatitis within 24 hours if the cholangitis is present and within 72 hours if the biliary obstruction is present, instead of this definition.
Although the naming does not resemble, recommendation of ESGE in this respect is as follows: “
Early laparoscopic or open cholecystectomy as soon as AP recovers completely is the only proven treatment modality to prevent recurrence of ABP. Index cholecystectomy is defined as cholecystectomy applied during the same hospitalization period of ABP and interval cholcystectonmy is cholecystectomy performed 6 weeks after patient’s recovery from AP [61].
Sinha and colleagues [61] reported that index cholecystectomy in a case suitable for surgery has similar results with elective cholecystectomy in a patient without AP and they also reported significant difficulty to do dissection during interval cholecystectomy. In 2019, Fu-ping Zhung and colleagues [62] published a meta-analysis of 19 studies enrolling 2639 who underwent index or interval cholecystectomy. They noted that there was no differences with ragard to intraoperative and postoperative complications, duration of operation and the rates of open cholecystectomy. However, index cholecystectomy cases had lesser hospitalization period, lower biliary complications due to surgery and lesser rates of ERCP.
In cases with severe pancreatitis, most of the time it is impracticable to perform index cholcystectomy. Therefore, interval cholcystectomy is obligatory in these cases. Infortunately, these patients reamit with AP attacks and ot biliary complications during this 6 weeks period. Thus some authors offer ERCP and endoscopic sphincteratomy to prevent AP recurrences and or biliary complications to ocur during this time period [63, 64].
In a retrospective study comparing index cholecystectomy and post ERCP/ES plus interval cholecystectomy, both group of patients did not reveal mortality. Only 2 patients (%5) developed AP recurrences and acute cholecystitis and hospitalized. The authors suggested that ERCP/ES is highly successful to prevent recurrences in patients with severe ABP who can not undergo index cholecystectomy. ES and interval cholecystectomy in severe ABP is considered a reasonable alternative to an index cholecystectomy in patients with severe ABP [64].
Another report by Dedemadi and his colleagues [65] published in 2016 noted that ERCP and ES in cases with AP who can not undergo cholecystectomy developed biliary events 0%–28.6%, recurrent pancreatitis 0%–8.2%, mortality 3%–4.7%. Other cases under conservative treatment had biliary events 9.4%–14.3%, recurrent pancreatitis 12%–23%, mortality 3.9%. Statistical evaluation showed that ERCP and ES group had significanly less biliary complications and less recurrent pancreatitis with no difference in mortality compared to conservative treatment group. The conservative group consisted of patients who were elderly persons with multiple comorbidites and complications of AP. These conditions may be responsible for similar mortality rates in both groups. Nevertheless, because of high rates of biliary events and pancreatitis in the ERPC/ES group, this approach should be reserved only for patients not suitaable for cholecystectomy.
The advice of IAP/APA about timing od cholecystectomy in a case with ABP is as follows [31]:
Moreover, If we consider surgery for pancreatic cystic collections, pseudocysyt and or walled off necrosis, it should be performed at the same time with cholecystectomy [65].
We want to finish with the conclsuive statement made by ESGE [35];
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