Congenital heart disease type in the studied groups.
\r\n\t
",isbn:"978-1-83881-111-2",printIsbn:"978-1-83880-992-8",pdfIsbn:"978-1-83881-112-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"acb2875b3bfc189c9881a9b44b6a5184",bookSignature:"Dr. Abdo Abou Jaoudé",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11865.jpg",keywords:"Linear Operators, Normal Operators, Spectral Theorem, Applications, Differential Operators, Integral Operators, Functional Calculus, Complex Variables, Complex Analysis, Theory, Recent Advances, Latest Trends",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 13th 2022",dateEndSecondStepPublish:"June 21st 2022",dateEndThirdStepPublish:"August 20th 2022",dateEndFourthStepPublish:"November 8th 2022",dateEndFifthStepPublish:"January 7th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Abdo Abou Jaoudé is a pioneering Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé. He holds two PhDs in Mathematics and Prognostics from the Lebanese University and Aix-Marseille University. His research interests are in the field of mathematics.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"248271",title:"Dr.",name:"Abdo",middleName:null,surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé",profilePictureURL:"https://mts.intechopen.com/storage/users/248271/images/system/248271.jpg",biography:"Abdo Abou Jaoudé has been teaching for many years and has a passion for researching and teaching mathematics. He is currently an Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé (NDU), Lebanon. He holds a BSc and an MSc in Computer Science from NDU, and three PhDs in Applied Mathematics, Computer Science, and Applied Statistics and Probability, all from Bircham International University through a distance learning program. He also holds two PhDs in Mathematics and Prognostics from the Lebanese University, Lebanon, and Aix-Marseille University, France. Dr. Abou Jaoudé's broad research interests are in the field of applied mathematics. He has published twenty-three international journal articles and six contributions to conference proceedings, in addition to seven books on prognostics, pure and applied mathematics, and computer science.",institutionString:"Notre Dame University - Louaize",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Notre Dame University – Louaize",institutionURL:null,country:{name:"Lebanon"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"15",title:"Mathematics",slug:"mathematics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"63157",title:"Impact of Modified Ultrafiltration in Congenital Heart Disease Patients Treated with Cardiopulmonary Bypass",doi:"10.5772/intechopen.80599",slug:"impact-of-modified-ultrafiltration-in-congenital-heart-disease-patients-treated-with-cardiopulmonary",body:'\nCardiopulmonary bypass (CPB) allowed the correction of several congenital heart diseases such as intracardiac malformations, but it is well known that this is not a harmless procedure because it can lead to a systemic inflammatory response syndrome (SIRS), with activation of complement, cytokines, coagulation, and fibrinolysis pathways. Factors that contribute to the development of SIRS include blood contact with the synthetic surface of cardiopulmonary bypass components, as well as leukocyte and endothelial activation after tissue ischemia and reperfusion [1, 2, 3, 4, 5]. If there is a severe inflammatory response, it could also develop a multiorgan dysfunction syndrome that increases morbidity and mortality of the patients at pediatric intensive care units (PICUs). Some of the methods used to quantify the magnitude of SRIS due to the use of CPB include measurement of blood cytokine concentrations (interleukins 1 and 6), complement activation products (C3d and C4d), and also coagulation activated factors (Von Willebrand, fibrinogen, and factor VIII) [6].
\nThere are several operative strategies for diminishing SRIS and its clinical repercussion, such as the use of steroids, modified tubular surfaces for CPB, and ultrafiltration. Despite the single or combined use of these strategies [7, 8, 9, 10, 11, 12], ultrafiltration is the one that probably removes a larger amount of pro-inflammatory agents, as well as water (volume) [13]. The two ultrafiltration technique modalities widely accepted for pediatric cardiac surgery are conventional ultrafiltration (CUF) and modified ultrafiltration (MUF). CUF is applied in CPB during the heart re-warming period and MUF right after ending CPB.
\nCurrently, there is no enough evidence that favor routinely use of MUF [14, 15, 16, 17, 18, 19], and we can still find some controversies regarding the benefits of this technique [20, 21, 22]. Additionally, most reports of the literature are focalized in adult cohorts of patients, and there is few information provided for pediatric population that shows the real impact of MUF in the remotion of pro-inflammatory agents due to CPB use. Therefore, we aimed to study the real utility of MUF for remotion of pro-inflammatory agents induced by CPB in operated pediatric patients with simple congenital heart disease. We made a special emphasis in hemodynamic variables, morbidity and mortality at the operative period.
\nA prospective, randomized, analytic, clinical case-control trial was designed at the Department of Pediatric Cardiac and Congenital Heart Surgery of a single center during a 1-year period of time. Inclusion criteria were: age ≤ 18 years and simple congenital heart disease that required elective surgical treatment with CPB use for at least 30 minutes. Exclusion criteria were preoperative renal failure, preoperative cardiogenic shock requiring the use of inotropes, preoperative sepsis, preoperative mechanical ventilatory support ≤48 hours, preoperative lactate concentration ≥ 3 mmol/L, and cardiac reoperation. Patients were randomized in two study groups: problematic group (with MUF) and control group (without MUF). With the use of an electronic URNA software, a statistical person randomized the patients and told the perfusionist who was the only surgical team person informed about the results of randomization. All patients included in this study were operated on with informed consent signed by their parents or tutors. The study was also approved by our institutional research and ethics committee.
\nPatients randomized to problematic group (with MUF), when informed to the perfusionist, were prepared for CPB with an additional MUF set. Once CPB was ended and hemodynamic stability of the patient was provided, the surgeon was told not to remove the venous cannula, and the venous line was clamped just before its connection to the reservoir. Arterial and venous line pathways were released in order to begin MUF with a 10–20 ml/kg/min flow. MUF continuous flow was achieved pumping the venous residual reservoir volume by means of the arterial line to the patient. A 150–200 mmHg venous vacuum was applied when needed. MUF lasted 10–20 minutes in order to reach a desired hematocrit level and obtain a suitable volume and electrolyte balance. MUF was stopped in case of hemodynamic instability. Once ended, MUF volume was restored to the patient from the hemofilter and venous cannula, allowing the surgeon for decannulation of the patient.
\nBiochemical and clinical results were compared between the two study groups at the operative period. Biochemical results were the concentration of cytokine (interleukin 6 and 10) and complement activated products (C3d and C4d). These concentrations were measured from blood samples at the following times: T0 (baseline, at the beginning of anesthesia induction), T1 (before CPB), T2 (immediately after CPB), and T3 (immediately after MUF, in the problem group). The same agents were measured in the MUF fluid concentrate of the problematic group after the procedure (T4). Clinical operative results were evaluated in terms of hemodynamic instability (>20% post-CPB variation respect to previous CPB values of at least three of the following five hemodynamic variables: heart rate, systolic, diastolic and mean blood pressure, and central venous pressure), operative morbidity, and mortality. Operative clinical end points of success were defined as hemodynamic stability, absence of morbidity, and lack of mortality.
\nAll patient samples were obtained from central or peripheral blood and collected in tubes without heparin (vacutainer, Becton Dickinson). A 3-ml blood sample was obtained for each of the study times (T0, T1, T2, and T3). The same volume of T4 samples were obtained from the ultrafiltration fluid concentrate. All of the samples were centrifugated at 3000 rpm during 15 minutes, 4°C, and cryopreserved in aliquots of 1.5 ml at −75°C. Interleukin concentrations (IL-6 and IL-10) were measured by means of an ELISA sandwich technique with the use of monoclonal antibodies (PeproTech, New Jersey, EUA). Complement activation products (C3d and C4d) were measured with the same technique, using commercial kits (Bachem, San Carlos, CA, EUA). Optical density was determined at 450 nm in the ELISA plate detector. Concentrations of IL-6, IL-10 (pg/ml) as well as C3d and C4d (ng/ml) were calculated by means of a GraphPad Software v. 4.2.
\nInformation was registered in evaluation sheets, stored in an electronic Excel page, and analyzed by means of a Prisma Graphics v 3.1 statistical software. Continuous variables are presented as a mean, standard deviation, and variability ranges (minimum and maximum). Categorical data are presented by means of frequency and percentages in relation to the population at risk. Comparison between the two study groups was made by means of a Student t test for continuous variables. A chi-square (χ2) test was used for comparing categorical variables with a 95% confidence interval (CI). A p value < 0.05 was considered as statistically significant.
\nA total of 31 patients were enrolled and randomized to this trial: 15 to the problematic group (with MUF) and 16 to the control group (without MUF).
\nTable 1 shows the type of congenital disease that was operated by means of CPB in both groups of study. There are no differences in the total number of congenital heart disease in the studied groups, but control group (without MUF) showed more patients with AV channel than the problematic group (with MUF).
\nCongenital heart disease type | \nTotal series (n = 31) n (%) | \nProblematic group (With MUF) (n = 15) n (%) | \nControl group (Without MUF) (n = 16) n (%) | \nP OR (95% CI) | \n
---|---|---|---|---|
Ventricular septal defect | \n13 (42%) | \n8 (52%) | \n5 (31%) | \nNS | \n
Balanced AV channel | \n8 (26%) | \n1 (7%) | \n7 (44%) | \n0.0373 0.09 (0.0096 – 0.8770) | \n
Congenital mitral valve disease | \n4 (13%) | \n3 (20%) | \n1 (6%) | \nNS | \n
Sub aortic membrane | \n3 (10%) | \n1 (7%) | \n2 (13%) | \nNS | \n
Right ventricular outflow tract obstruction | \n1 (3%) | \n1 (7%) | \n0 (0%) | \nNS | \n
Double chamber right ventricle | \n1 (3%) | \n1 (7%) | \n0 (0%) | \nNS | \n
Atrial septal defect | \n1 (3%) | \n0 (0%) | \n1 (6%) | \nNS | \n
Congenital heart disease type in the studied groups.
Table 2 shows the rest of preoperative characteristics in both studied groups. Note that there are no statistical differences in all variables analyzed between the two groups.
\nVariable | \nTotal series n (%) or mean ± SD (range) | \nProblematic group (with MUF) n (%) or mean ± SD (range) | \nControl group (without MUF) n (%) or mean ± SD (range) | \np | \n
---|---|---|---|---|
Age (years) | \n4.26 ± 4.11 (0.38–17.18) | \n37 ± 14 (18–76) | \n31 ± 11 (18–56) | \nNS | \n
Male | \n12 (39%) | \n8 (53%) | \n4 (25%) | \nNS | \n
Female | \n19 (61%) | \n7 (47%) | \n12 (75%) | \nNS | \n
Weight (kg) | \n14.9 ± 10.8 (4–47) | \n14.1 ± 10.4 (4–38.3) | \n15.9 ± 11.6 (5.3–47) | \nNS | \n
Height (cm) | \n90 ± 31.1 (12–159) | \n94.2 ± 31.2 (55–158) | \n86 ± 31.5 (12–159) | \nNS | \n
Body surface area (m2) | \n0.56 ± 0.27 (0.25–1.32) | \n0.58 ± 0.31 (0.25–1.32) | \n0.53 ± 0.18 (0.28–0.78) | \nNS | \n
Circulating blood volume (ml) | \n1032 ± 627 (343–2660) | \n1164 ± 756 (343–2660) | \n867 ± 385 (452–1560) | \nNS | \n
Previous surgery | \n0 (0%) | \n0 (0%) | \n0 (0%) | \nNS | \n
Previous catheterization | \n2 (6%) | \n0 (0%) | \n2 (6%) | \nNS | \n
Pre-operative infection | \n1 (3%) | \n0 (0%) | \n1 (6%) | \nNS | \n
Pulmonary artery hypertension | \n4 (13%) | \n0 (0%) | \n4 (25%) | \nNS | \n
None | \n26 (84%) | \n15 (100%) | \n11 (69%) | \nNS | \n
Down’s syndrome | \n3 (10%) | \n0 (0%) | \n3 (19%) | \nNS | \n
None | \n28 (90%) | \n15 (100%) | \n13 (81%) | \nNS | \n
I | \n8 (26%) | \n4 (27%) | \n4 (25%) | \nNS | \n
II | \n21 (68%) | \n9 (60%) | \n12 (75%) | \nNS | \n
III | \n2 (6%) | \n2 (13%) | \n0 (0%) | \nNS | \n
RACHS-1 score | \n2.4 ± 0.5 (1–3) | \n2.4 ± 0.5 (2–3) | \n2.4 ± 0.6 (1–3) | \nNS | \n
Basic Aristoteles | \n7.2 ± 1.5 (3–9) | \n7 ± 1.2 (6–9) | \n7.4 ± 1.9 (3–9) | \nNS | \n
Complete Aristoteles | \n8.1 ± 1.8 (4–11) | \n7.8 ± 1.5 (6–10) | \n8.4 ± 2.1 (4–11) | \nNS | \n
Mechanic ventilation | \n0 (0%) | \n0 (0%) | \n0 (0%) | \nNS | \n
Pre-operative inotropic support | \n0 (0%) | \n0 (0%) | \n0 (0%) | \nNS | \n
Pre-operative infection | \n1 (3%) | \n0 (0%) | \n1(6%) | \nNS | \n
None | \n30 (97%) | \n15 (100%) | \n15 (94%) | \nNS | \n
Lactate | \n1.2 ± 0.3 (0.6–1.7) | \n1.2 ± 0.3 (0.7–1.7) | \n1.1 ± 0.3 (0.6–1.5) | \nNS | \n
Creatinine | \n0.4 ± 0.1 (0.2–0.7) | \n0.4 ± 0.1 (0.2–0.7) | \n0.4 ± 0.1 (0.3–0.5) | \nNS | \n
Oxygenator type | \n\n | \n | \n | \n |
Baby Rx | \n14 (52%) | \n7 (47%) | \n7 (58%) | \nNS | \n
Terumo SX10 | \n6 (22%) | \n4 (27%) | \n2 (17%) | \nNS | \n
Terumo SX18 | \n1 (4%) | \n1 (7%) | \n0 (0%) | \nNS | \n
Mini max | \n5 (19%) | \n2 (13%) | \n3 (25%) | \nNS | \n
Safe Mini | \n1 (4%) | \n1 (7%) | \n0 (0%) | \nNS | \n
Arterial filter use | \n18 (67%) | \n12 (80%) | \n6 (50%) | \nNS | \n
CPB time (min) | \n81.9 ± 26.9 (40–131) | \n76.5 ± 23.7 (40–122) | \n87 ± 29.4 (41–131) | \nNS | \n
Aortic cross clamp time (min) | \n53.7 ± 23.6 (12–96) | \n49.5 ± 21.8 (18–90) | \n57.6 ± 25.2 (12–96) | \nNS | \n
Temperature (°C) | \n27 ± 1.6 (24–30) | \n27 ± 1.5 (24–29) | \n27.3 ± 1.8 (24–30) | \nNS | \n
Anterograde cardioplegia | \n29 (94%) | \n14 (93%) | \n15 (94%) | \nNS | \n
Blood cardioplegia | \n29 (94%) | \n14 (93%) | \n15 (94%) | \nNS | \n
Pre-operative characteristics of the studied groups.
Pro-inflammatory agent | \nT0 problematic group (with MUF) n = 15 Mean ± DE | \nT0 control group (without MUF) n = 16 Mean ± DE | \np | \n
---|---|---|---|
C3d (ng/ml) | \n368.66 ± 331.87 | \n413.248 ± 316.804 | \nNS | \n
C4d (ng/ml) | \n199.57 ± 201.56 | \n213.89 ± 116.72 | \nNS | \n
IL-10 (pg/ml) | \n239.698 ± 381.517 | \n299.618 ± 370.148 | \nNS | \n
Comparison between concentrations of pro-inflammatory agents in both groups of study (with and without MUF) at baseline (T0).
Although more random patients with AV channel in the control group, the rest of the preoperative data showed that both groups are absolutely comparable.
\nTable 3 compares the concentration of pro-inflammatory agents between groups before surgical correction (T0). Note a baseline elevated concentration of IL-6 in the problematic group (with MUF), without differences in both groups for the rest of pro-inflammatory agents (IL-10, C3d, and C4d).
\nOn the other hand, Table 4 shows a lack of statistical significant difference in the concentrations of pro-inflammatory agents at the control group before surgical correction (T0) and after CPB (T2).
\nPro-inflammatory agent | \nT0 control group (without MUF) n = 16 Mean ± SD | \nT2 control group (without MUF) n = 16 Mean ± SD | \np | \n
---|---|---|---|
C3d (ng/ml) | \n413.248 ± 316.804 | \n264.33 ± 198.12 | \nNS | \n
C4d (ng/ml) | \n213.89 ± 116.72 | \n210.65 ± 141.13 | \nNS | \n
IL-6 (pg/ml) | \n246.874 ± 365.69 | \n289.499 ± 301.913 | \nNS | \n
IL-10 (pg/ml) | \n299.618 ± 370.148 | \n387.26 ± 306.07 | \nNS | \n
Comparison between concentrations of pro-inflammatory agents at T0 (baseline) and T2 (after CPB) for the control group (without MUF).
Finally, Table 5 shows the comparison between concentration of pro-inflammatory agents in the problematic group before surgical correction (T0) and after MUF (T4). There is a statistically significant removal of IL-6, but no difference in the concentrations of the rest pro-inflammatory agents analyzed (IL-10, C3d, and C4d).
\nPro-inflammatory agent | \nT0 problematic group (with MUF) n = 15 Mean ± SD | \nT4 problematic group (without MUF) n = 15 Mean ± SD | \np | \n
---|---|---|---|
C3d (ng/ml) | \n368.66 ± 331.87 | \n379.99 ± 264.64 | \nNS | \n
C4d (ng/ml) | \n199.57 ± 201.56 | \n172.89 ± 139.64 | \nNS | \n
IL-10 (pg/ml) | \n239.698 ± 381.517 | \n230.453 ± 352.27 | \nNS | \n
Comparison between concentrations of pro-inflammatory agents at baseline (T0) and after MUF (T4) for the problematic group (with MUF).
Table 6 summarizes the comparison of clinical end point variables in both groups of study (with and without MUF). There is a statistically significant decrease of hemoglobin (Hb) in the problematic group after MUF compared with the baseline level, which is not observed in the control group.
\n\n | \n | Problematic group (with MUF) | \nControl group (without MUF) | \nProblem vs control groups (with vs without MUF) | \n||||||
---|---|---|---|---|---|---|---|---|---|---|
Operative clinical end point variable | \nControl group | \nProblematic group | \np | \nControl group | \nProblematic group | \np | \nProblematic group | \nControl group | \nP | \n|
Before CPB | \nAfter MUF | \nBefore CPB | \nAfter MUF | \nAfter MUF | \nAfter CPB | \n|||||
n/total n (%) or | \nn/total n (%) or | \nn/total n (%) or | \nn/total n (%) or | \nn/total n (%) or | \nn/total n (%) or | \n|||||
Mean ± SD | \nMean ± SD | \nMean ± SD | \nMean ± SD | \nMean ± SD | \nMean ± SD | \n|||||
Laboratory exams | \n\n | |||||||||
\n | Hematocrit (%) | \n38 ± 7 | \n34 ± 6 | \nNS | \n37 ± 5 | \n34 ± 7 | \nNS | \n34 ± 6 | \n34 ± 7 | \nNS | \n
12 ± 2 | \n11 ± 2 | \nNS | \n11 ± 2 | \n11 ± 2 | \nNS | \n|||||
CPB hematocrit (%) | \n\n | 26 ± 5* | \n24 ± 4* | \nNS | \n||||||
3.5 ± 1.4 | \n3.3 ± 1.2 | \nNS | \n||||||||
Hemodynamic variables | \n\n | |||||||||
\n | 113 ± 18 | \n112 ± 15 | \nNS | \n|||||||
Systolic blood pressure (mmHg) | \n85 ± 16 | \n89 ± 12 | \nNS | \n83 ± 10 | \n90 ± 20 | \nNS | \n89 ± 12 | \n90 ± 20 | \nNS | \n|
Diastolic blood pressure (mmHg) | \n53 ± 15 | \n52 ± 12 | \nNS | \n49 ± 7 | \n49 ± 12 | \nNS | \n52 ± 12 | \n49 ± 12 | \nNS | \n|
Mean blood pressure (mmHg) | \n64 ± 18 | \n61 ± 12 | \nNS | \n64 ± 13 | \n64 ± 17 | \nNS | \n61 ± 12 | \n64 ± 17 | \nNS | \n|
10 ± 8 | \n12 ± 7 | \nNS | \n12 ± 7 | \n10 ± 3 | \nNS | \n|||||
Operative morbidity and mortality | \n\n | |||||||||
\n | Morbidity | \n\n | 3 (20%) | \n1 (6%) | \nNS | \n|||||
Mortality | \n\n | 0 (0%) | \n0 (0%) | \nNS | \n
Comparison between operative clinical end point variables in both groups of study (with and without MUF).
CPB measured values (due to hemodilution).
Both groups show an increase in lactate levels and heart rate after surgery when comparing these values with the baseline ones before CPB. Control group (without MUF) showed a statistically significant increase in central venous pressure after CPB compared with the ones before CPB. There were no differences before and after CPB in the other hemodynamic variables (systolic, diastolic, and mean blood pressures), nor inoperative morbidity and mortality. Successful clinical operative endpoints were archived in both groups of study.
\nCardiopulmonary bypass (CPB) is able to trigger a systemic inflammatory response syndrome (SRIS) due to several factors that include: (1) cell activation secondary to contact with CPB synthetic surfaces, (2) mechanic stress, (3) tissue ischemia and reperfusion, (4) hypotension, (5) non-pulsatile flow, (6) hemodilution relative anemia, (7) blood and blood products transfusion, (8) heparin and protamine administration, and (9) hypothermic effects. CPB activates the vessels endothelium and releases pro-inflammatory agents such as tumoral necrosis factor α (TNF-α), interleukins, and endotoxins. These agents also activate the intracellular transcription factor that increases endothelial pro-inflammatory cytokines and the molecular expression of leukocyte adhesion.
\nIt is well known the fact that younger age increases even more the inflammatory effects of CPB. Some reasons include increased metabolic demand in these patients, hyperactivity of their pulmonary vessels, immaturity of their organs/systems, and altered homeostasis. The risk is particularly high in neonates and young infants due to mismatch between CPB and patient’s size, with CPB circuit volume usually 200–300% higher than that of the patient. Additionally, an increased metabolic demand requires elevated pump flow up to 200 ml/kg−1/min−1 in neonates. Combining a relative major size of CPB with an increased perfusion rate leads to a greater blood exposure to synthetic surfaces of the circuit components [23]. In our series, there was no age difference between the studied groups, and it is important to highlight that none of the groups included neonate patients for the reasons already discussed.
\nOne of the most involved cytokines in SRIS development is, indeed, IL-6. Increased concentrations of IL-6 have been reported in patients with postoperative complications, and a correlation with posterior left ventricular wall dyskinesia detected by means of transesophageal echocardiography has been established. IL-6 is also an endogenous pyrogen agent that activates acute phase reactant proteins. Concentration of IL-6 increases independently of the oxygenator type, degree of hypothermia, or heparin use in the CPB circuit surfaces [24, 25]. Although in our study IL-6 concentrations were significantly higher before surgery in the problematic group than in the control group, this agent is also the one that is significantly more removed by MUF. This is probably the most relevant fact of our study because it shows that the benefit of MUF in congenital heart disease surgery is the removal of IL-6, an important pro-inflammatory agent, particularly in patients that SRIS is enhanced because of the immaturity of their immune system. Another effect that is important to discuss is the fact that, if MUF benefits patients with simple congenital heart disease surgery as were the ones included in our study, it would indeed improve operative outcomes in those operated on for complex congenital heart disease [26]. This single fact justifies the routine use of MUF in all patients with congenital heart disease that is operated on with CPB.
\nThere are several additional methods, despite ultrafiltration, that had been developed in order to diminish SRIS secondary to CPB at surgical correction of congenital heart disease in pediatric population. Some of them are steroids (e.g., dexamethasone 10–30 mg/kg 6–12 hours before CPB) and modified tubular synthetic surfaces in the CPB circuit. However, none of these methods is as such as useful for this purpose as MUF, which is established right after ending the CPB and before decannulation of the patient [27]. Since 1973, different types of hemofilters have been developed in order to remove priming volume (water) following the principle of pressure gradient, particularly those made of polycarbonate. These filters have been replaced by the ones made out of polysulfonate in 1986 and later by the current generation of polyamide hemofilters. These are the most practical ones because of its greater biocompatibility, reduced surface, and more ultrafiltration effectiveness due to a less than physiological pressure.
\nThe effectiveness of ultrafiltration for removing pro-inflammatory agents depends also on the type of hemofilter and on the modality of ultrafiltration procedure used. Kosik et al comments Berdat´s study on the effectiveness of polysulfonate filters vs polyamide ones in the two ultrafiltration modalities for the removal of pro-inflammatory agents such as IL-6, IL-10, and TNFα [3]. They prove that IL-6 was better removed by conventional ultrafiltration (CUF) with poliariletersulfonate filter, while TNFα was better removed by modified ultrafiltration (MUF) and poliariletersulfonate filter. The rest of the pro-inflammatory agents was not modified neither for the ultrafiltration modality nor for the hemofilter type. Therefore, it seems that MUF with poliariletersulfonate hemofilter is the better strategy for removing pro-inflammatory agents in pediatric patients with congenital heart surgery. Our results are based on the ultrafiltration modality rather than the type of filter, since the material of hemofilters that we used was variable.
\nIt has been reported that MUF is not only useful for removing extracellular fluid excess, but also cytokines and other inflammatory agents triggered by CPB and surgical trauma. There is some controversy in the literature regarding the efficacy of filters in the removal of cytokines, as well as in the differences between the two ultrafiltration modalities [28]. Additionally, the comparative results between both ultrafiltration modalities are difficult to interpret due to variations in the ultrafiltration technique, equipment, definitions and objectives, and measurements of cytokines. Finally, it is still not known if the clinical benefits of MUF are due to the removal of cytokines and other inflammatory agents, or to the isolated reduction of tissue edema [29, 30, 31, 32, 33].
\nBased on the results of this study [34], we can say that although the baseline concentrations of IL-6 in the patients of the problematic group were higher in relation to those of the control group, the removal of this pro-inflammatory agent by MUF was statistically significant. This indicates that MUF is a procedure that can benefit pediatric patients with congenital heart disease undergoing CPB because it is able to decrease the concentration of IL-6. Therefore, we consider that the use of MUF in pediatric patients should be routinely recommended as long as hemodynamic conditions allow it.
\nWe thank the Cardio Slim Foundation for the financial support provided to carry out this study.
\nThe authors declare no potential conflicts of interest with respect to the research, authorship or publication of this manuscript.
The design of ultra-low-voltage (ULV) and low-power (LP) analog and mixed-signal ICs in modern nanotechnologies represents a real challenge for circuit designers and researches, since it introduces several limitations in numerous aspects. Firstly, since advanced nanoscale technologies offer a possibility to design analog, digital, and radio-frequency (RF) circuits as well as micro-electro-mechanical systems (MEMS) on a single chip, there is usually issue of a common value of the supply voltage. With the technology development, the value of the supply voltage is scaled down significantly. However, the threshold voltage (\n
From the IC design point of view, one of the main problems caused by a lowered \n
Scaling the supply voltage and threshold voltage in time.
The minimum power supply voltage of CMOS analog ICs designed without dedicated low-voltage (LV) techniques is limited by a value given by the sum of the turn-on voltage \n
In this section, the survey of low-voltage design techniques and approaches that can be used in a standard CMOS technology (no additional process steps) are presented. Generally, low-voltage design techniques can be divided into two groups: conventional methods and unconventional ones. Unconventional methods include bulk-driven (BD) approach, dynamic threshold technique, floating-gate method, quasi-floating gate, and bulk-driven quasi-floating gate approaches. However, only the circuits designed by the bulk-driven and dynamic threshold approaches can be implemented in the standard CMOS technologies without any modification of the fabrication process. On the other hand, the conventional techniques such as circuits with rail-to-rail input/output operating range, MOS transistors working in sub-threshold region, level shifter techniques or MOS transistor in self-cascode structure represent commonly used approaches in the area of low-voltage IC design.
\nSince only circuits designed by the bulk-driven approach can be implemented in pure CMOS technology, in this chapter, we focus on this LV circuit design technique. At the end of this chapter, some examples of experimental and silicon-proven analog/mixed-signal circuits designed by the BD approach are presented.
\nFirstly, it is vital to explain the operation regions of the MOS transistor, since this is the most important aspect for analog IC design. The optimum IC design is characterized by the minimum power consumption, minimum silicon area and sufficient frequency response, gain and other circuit specifications. Analog and mixed-signal circuit design procedure of systems using (ultra) low-power supply voltage introduces an extra layer of challenges for even seasoned circuit designers. The problems low supply voltage introduces, negatively influence several design considerations, circuit attributes and possible design options. The first and foremost is the substantially limited inversion level the MOS transistors operate in. This results, among others, in higher mismatch between transistor parameters, exponential temperature sensitivity, and drastically lowered operational frequency. We must not forget the increased silicon area requirements due to large transistors compensating for low transconductance values, increased noise and difficulties with precise secondary effects modeling. All of the above are typical drawbacks of low-voltage/low-power circuit design and their application [3]. The second issue is topological. It lies in constrained possible number of stacked transistors, in order to ensure their operation in saturation region. According to [4], the
The situation has been greatly improved by the development of design-oriented charge-sheet based EKV MOS transistor model (named after its authors—Enz-Krummenacher-Vittoz) [5]. EKV model defines the parameters of MOS device dependent on continuous range of inversion level unlike the industry-standard threshold voltage-based BSIM models. EKV model also introduced the so-called \n
where \n
The point when IC = 1 also determines the conditions when the drain diffusion current equals drain drift current. The interpolated dependency of
\nFigure 2 depicts the dependency of \n
\n
In the conventional approaches, MOS transistor is usually controlled by its gate potential. However, the current flowing through the device can also be modulated by the bulk-source voltage \n
The effect of the \n
where \n
Thus, changes in \n
In order to analyze the properties of a MOS transistor driven by the bulk terminal, the conventional gate-driven and bulk-driven single stage common-source amplifiers, depicted in Figures 3 and 4, have been investigated and compared.
\nGate-driven common-source amplifier. (a) Schematic diagram, and (b) Small-signal model.
Bulk-driven single stage amplifier. (a) Schematic diagram, and (b) Small-signal model.
From Figures 3 and 4, it can be observed that the input capacitance of the BD single stage amplifier will be higher than in the case of the GD amplifier. It is caused by a parasitic capacitance \n
The transconductance of the conventional GD transistor can be expressed by the following Eq. (4)\n
\nIt is important to point out that Eq. (4) is only valid when the MOS transistor operates in the strong inversion. In the weak inversion, the transconductance is proportionally dependent on the drain current, as given by Eq. (5).
\nThe relationship between the transconductance of a GD transistor \n
where \n
In order to determine the frequency performance of the BD transistor, schematic diagram, and small-signal model (depicted in Figure 5) have to be employed. Using small-signal model, the transition frequency \n
Schematic diagram and small-signal model for
The transfer function and current gain of the BD MOS transistor can be expressed by Eq. (8).
\nIf we consider that unity small-signal gain is obtained at frequency \n
As can be observed from Eq. (9), the transition frequency of the BD MOS transistor is about five times lower than in the case of a MOS transistor driven by gate terminal. Another important parameter of the amplifier is the noise introduced into the circuit by the active component. The input referred noise of the GD MOS transistor depends on the current \n
Similarly, the input referred noise of the BD MOS transistor is given by Eq. (11), where one can observe that the BD MOS transistor suffers from higher noise due to the lower transconductance \n
The small-signal output resistance for both GD and BD transistors is identical, and given by Eq. (12).
\nwhere \n
BD MOS transistor depletion characteristics significantly reduce the need to overcome the threshold voltage \n
Suitable for rail-to-rail voltage range.
Better linearity due to low, transconductance (\n
Possibility to operate with a low value of the power supply.
Easy to implement in a standard CMOS technology (twin-well process, both MOS devices available).
Unfortunately, if compared to traditional GD design approach, the bulk-driven design method also exhibits the following disadvantages:
Body transconductance \n
Input capacitance of the BD MOS transistor is greater, if compared to the traditional GD device.
Input noise of the BD MOS transistor is increased.
BD MOS transistors fabricated in a standard CMOS process are prone to the catastrophic latch-up effect.
The last drawback, however, can be effectively mitigated by lowering the power supply voltage below the threshold voltage of a PN junction or by usage of an expensive silicon-on-insulator (SOI) fabrication process. This step would prevent the turn-on of the parasitic bipolar transistor in the substrate.
\nIn this section, several design examples and circuit topologies of basic analog IC building blocks using bulk-driven approach are presented. The described blocks have been silicon-proven through fabrication in a standard CMOS nanotechnology and measurement evaluation of the chip prototypes.
\nOne of the most widely used circuit structures employed in IC design are arguably the current mirrors (CM). It is a two-port circuit, which processes the input current \n
Simple BD current mirror.
Bulk terminals of both MOS devices M1 and M2 are tied together and connected to the input branch. The gate terminals are biased by static voltage \n
Another widely and frequently implemented circuit topologies the differential amplifier is depicted in Figure 7; however, in the bulk-driven configuration. The devices M1 and M2 have their gate terminals tied to the lowest potential to guarantee the highest possible level of inversion. The traditional topology of the differential amplifier suffers from a limited input common-mode range (\n
BD differential pair.
The input BD transistors are used to obtain the rail-to-rail input voltage range, which is important for achieving a sufficient voltage swing when low supply voltage value is used, which greatly enhances the input common-mode range (ICMR). Additional benefit of employing the bulk-driven differential amplifier rather than conventional one lies in highly linear voltage-to-current conversion thanks to almost perfectly constant transconductance \n
\nFigure 8 shows the block diagram of a two-stage VGA. The first stage is formed by a variable-gain differential difference amplifier (DDA) designed using BD approach. The second stage has a fixed gain and is created by a BD common-source amplifier (CSA). For stabilization of the operational point of both stages, two BD common-mode feedback (CMFB) circuits have to be employed. To achieve good stability of the CMFB loop as well as the whole two-stage VGA, frequency compensation circuitry has been applied.
\nBlock diagram of VGA.
The schematic diagram of the low-voltage VGA circuit is depicted in Figure 9. The input stage of the proposed topology is formed by DDA with bulk-driven MOS transistors, in order to obtain rail-to-rail input voltage range. The negative aspect of this solution lies in the reduced voltage gain and the gain-bandwidth product (GBW) [8]. Therefore, it is safe to state, that the proposed approach is suitable for low-voltage and low-frequency applications.
\nSchematic diagram of VGA.
In general, the overall VGA voltage gain can be controlled by adjusting either the total conductance or the total output impedance [8]. Thus, transistors M5 and M6 were employed to control the VGA gain. Modification of control voltage \n
\nFigure 9 depicts the implemented frequency compensation circuit. The second amplification stage of the proposed VGA consists of devices M9–M12 and transistors M13–M16 along with capacitors \n
From the design point of view, it is important to ensure good stability and investigate the parameters that influence the gain of the proposed two-stage VGA. For this purpose, the small-signal model of VGA shown in Figure 10 was used. We have to note that the output capacitance of the first stage was neglected. Thanks to the overall symmetry of the topology, we can perform the small-signal analysis just for one half-circuit and investigate the influence of \n
Small-signal model of the VGA.
The resulting formula defining the total DC gain of the discussed VGA is follows:
\nwhere \n
\n\n
where \n
One can observe that the total transconductance of VGA (\n
Transconductance
Besides, the total transconductance \n
where \n
where \n
The known location of the poles and zeros present in the proposed topology and their analytical definition is crucial for stability evaluation. The small-signal model of the circuit (Figure 10) has been used again for the pole-zero analysis. The overall small-signal model for both stages of the discussed VGA can be simplified to a single voltage-controlled current source (VCCS) with their associated output resistances \n
where \n
The first pole defines the amplifier bandwidth (BW), and it is approximately given by Eq. (22).
\nIt was considered in the approximation that \n
To achieve a stable operation of the proposed VGA topology, the so-called
It is obvious, that for satisfactory amount of phase margin (PM), the numerator of Eq. (23) has to be greater than the denominator. It is widely accepted that PM = 60° is sufficient for maintaining a stable operation of amplifier circuits, which will be met when the ratio \n
In this section, we would like to describe the proposed topology of a voltage comparator operating with the power supply voltage (\n
The analog core of the proposed circuit is depicted in Figure 12 along with the devices’ dimensions. Let us discuss the topology of the ultra-low-voltage rail-to-rail voltage comparator. As one can observe, the input signal is processed by bulk-driven MOS transistors. This is an elegant way to solve the issues with the threshold voltage of respective devices. The most dreaded problem associated with rather exotic bulk-driven circuits is so-called
Analog core of ultra-low-voltage comparator.
The input PMOS devices \n
Digital control and output block of the ultra-low-voltage comparator.
The gate terminals of low-side devices employed in analog core are controlled by the digital part. The input devices can be cut-off when their gate terminals are pulled up—digital block issues logic one, when the circuit function is being inhibited. Otherwise, the gates are pulled down by logic zero, which sets their operation in to active, saturation, and region. The schematic diagram omits four pull-up and pull-down devices, which are responsible for ensuring a definite and known potential in the analog core nodes, when the circuit function is being disabled.
\nTransistors \n
The controlling block and output latch are depicted in Figure 13. The controlling block processes the input signals of enable and hysteresis functions and the feedback signal from the output latch and the differential voltage from the analog core. The combinatorial logic issues logic states for the gate terminals of transistors in the analog core accordingly. It is also responsible for protecting the output latch from simultaneous switching based on the feedback information. Such an event has been observed with highly rippled power supply voltage. The output signal from the latch is afterwards “buffered” by digital inverter(s) sized accordingly to the capacitance load and speed/slew-rate requirements.
\nLet us discuss the design considerations of the proposed comparator topology. Since the power supply voltage has already been set to \n
The final transistor sizes can be seen in Figures 12 and 13. From the designer’s point of view, the analog part has to be symmetrical, which decreases the overall effort required during the design period. One can observe, rather large MOS transistor dimensions. This choice has been done, in order to mitigate the process fluctuations associated with nanoscale CMOS processes. Furthermore, it also increases the level of inversion within the respective devices since higher the inversion coefficient, the lower current mismatch and process sensitivity.
\nThe small-signal model of the proposed topology is shown in Figure 14. Thanks to the overall symmetry of the analog core, we will greatly benefit from analyzing only one half of the circuit. We have chosen the left-hand side, for our analysis. Furthermore, the devices from both topology sides are mutually interchangeable for the sake of small-signal analysis, if needed. The nodes marked “A” and “B” in the transistor-level schematic (Figure 12) are also depicted in the small-signal model. Another analysis simplification is, that the overall voltage amplification can be expressed as a product of partial voltage amplifications (or as a sum of partial voltage gains) of respective stages. For even further simplification, we have also omitted the enable pull-up and pull-down devices, which do not affect the overall accuracy that much and can be therefore neglected.
\nSmall-signal model of the proposed ultra-low-voltage comparator.
The first stage is comprised of devices \n
The second amplification stage is consist of devices M2 and M4. The input port is the “A” node and the output port would be the node named “B.” The devices form a classic configuration of PMOS common-source amplifier with diode-connected transistor acting as a load. The small-signal model yields an Eq. (25), which defines the voltage amplification of the second stage.
\nThe third and final stage of the model is comprised of devices M3 and M9. However, due to already explained reasons, we can swap the MOS transistor M9 with device M5, if desired. The topology of this stage can be described as a common-source amplifier with MOS transistor acting as load with fixed-bias. The small-signal model also reveals the fact, that the final stage is driven by the first stage only. Hence, the second stage does not contribute to the overall amplification, at all. The analytical voltage amplification provided by the final stage is defined by Eq. (26).
\nAs we discussed earlier, the final voltage amplification is a product of partial amplification contributions of the respective stages. However, the final analytical formula is unnecessarily complex and can be significantly simplified, if the circuit designer follows some of the common sense rules. The most basic one is associated with the “reasonable” channel length and/or minimized channel length modulation along with saturation operation mode of the transistors employed in the analog core. If this requirement is met, the sum of output conductance \n
It is apparent that for the maximized voltage gain, one should increase the transconductance of M3 and minimize the output conductance of devices M3 and M9. Since the topology is symmetrical, the same applies for the counterparts of discussed transistors.
\nAnother important design consideration is the minimum power supply voltage the circuit can reliably operate with. The presented topology contains only two stacked transistors that need to be saturated for correct functioning. Therefore, we can express the
The expression is taken from the EKV MOS transistor model theory for deep weak inversion [4]. In real scenario, the saturation voltage dependence on the level of inversion is of square root trend. Furthermore, considering a non-ideal conditions, the more realistic expectation is about \n
CMOS realization of the conventional charge pump based on the cross-coupled voltage doubler is shown in Figure 15. This charge pump represents one of the highly efficient topologies suitable for on-chip implementation. Both types of MOS devices are employed in the cross-coupled charge pump. The proposed control approach mitigates the excessive voltage stress, which the thin gate oxide of the MOS transistor is exposed to. The voltage drop is comprised of the equivalent resistance of the switched capacitors and the voltage drop across the turned-on transistor [10].
\nConventional cross-coupled CP (one stage).
The cross-coupled charge pump (Figure 15) is based on two inverters connected in cross-couple fashion. The discussed topology, exhibits the same level of minimal input switching voltage \n
One of the possible alternatives is to employ an inverter with resistor acting as a load, which would create the so-called pseudo-inverter. However, the solution is unacceptable in low-power systems, since it notably increases the internal current consumption of the charge pump. Another possibility is to tie the bulk terminal of the MOS transistors to a fixed potential and lower their threshold voltage (Figure 16(b)). Unfortunately, this approach substantially increases the sub-threshold leakage of the MOS transistors and their bulk current, as well. Hence, it suffers from the same drawback as the solution mentioned previously. The most effective approach, as it seems, is the so-called dynamic threshold voltage control. The basic idea is depicted in Figure 16(c). As one can observe, the bulk terminals are connected to the input signal. This way, the cut-off transistor exhibits nominal threshold voltage and the turned-on transistor exhibits lowered threshold voltage level, which improves its drain current and switching speed. The trade-off of this method is increased leakage current of one transistor only.
\nDifferent topology inverters in CMOS technology.(a) CMOS inverter, (b) CMOS inverter: reduced VTH (c) CMOS inverter: dynamic VTH.
Dynamic threshold inverter topology (Figure 16(c)) can be considered as an appropriate building cell for ultra-low-power and low-voltage charge pump designs. A very important design consideration for such a system is inevitability of twin-well CMOS fabrication process, since both PMOS and NMOS devices have to be isolated from the common substrate by their own wells. Another consideration is restricted power supply voltage. Its level must not exceed 0.6 V (at room temperature). Otherwise, parasitic NPN and PNP bipolar transistors will turn on, which with the high probability may cause triggering of latch-up effect. These limitations have to be taken into account, if designing the charge pump with dynamic \n
The BD charge pump based on the cross-coupled topology is shown in Figure 17. The charge pump employing dynamic threshold CMOS inverter is able to process very low levels of input voltages. This also represents the main advantage of the proposed topology [10]. However, the drawback lies in the limited voltage range the charge pump can work with, because of the increased risk of latch-up triggering. Hence, the main application area of such charge pump topology is constrained to low-voltage and low-power systems.
\nBulk-driven cross-coupled CP (one stage).
Theoretical value of the output voltage can be expressed as follows:
\nwhere \n
Due to limited voltage headroom, the sub-threshold operation is usually chosen for low-voltage/low-power charge pump designs. Although, when the input voltage is lesser than threshold voltage of MOS transistors, the overall efficiency will be degraded, since the switching properties of the devices are drastically reduced. The dependence of MOS transistor turn-on resistance \n
It can be observed that effective voltage \n
In order to fully verify the design concepts discussed in this chapter, the proposed circuit topologies have been designed in general purpose twin-well 130 nm CMOS technology. Both types of fabricated long-channel devices exhibit the standard threshold voltage around \n
Micrograph and physical design of the prototype chip.
The selected parameters of the proposed VGA, voltage comparator, and charge pump are depicted in Figure 19. The graphs contain the measured and simulated results for direct comparison and evaluation.
\nMeasured and simulated parameters of the proposed circuit topologies on the prototype chip. (a) VGA frequency response, (b) Comparator transfer characteristics, (c) Charge-Pump efficiency.
The comparison of simulated and measured data of frequency response of the proposed VGA is depicted in Figure 19(a). We used the Monte-Carlo analysis results to obtain the borders of the expected gain range. As one can observe, the measured frequency response remains between the borders specified by the simulation and deviates only slightly from the Monte-Carlo mean curve. The measurement and simulation conditions were identical, the load capacitance of 10 pF, the control voltage \n
The transfer characteristics of the proposed rail-to-rail comparator are depicted in Figure 19(b). The simulated results correlate very well with measured curves for all input voltage conditions. In our experiments, the comparator exhibited correct function for all four levels of hysteresis and the rail-to-rail operation has been confirmed by setting the reference voltage only 3 mV from the power supply range. This test can be considered quite strict, since it would also reveal issues with the input offset voltage. Monte-Carlo simulations performed on 3000 samples in corner and ambient temperatures resulted in the mean value of input offset \n
\nFigure 19(c) shows dependence of the efficiency on the output current. This is the example where the comparison of different charge pumps based on GD and BD cross-coupled inverter were compared. The best efficiency for the given parameters can be observed for the output current of \n
Considering the current onset of ultra-low-voltage and ultra-low-power operation requirements for today’s CMOS analog/mixed-signal ICs and their fabrication, a promising alternative to standard design approach and circuit topologies are discussed in this chapter. We presented low-voltage and low-power design techniques, which are focused on driving the MOS transistor through its bulk terminal, as well as setting the operating point of employed MOS transistors within the sub-threshold (weak inversion) or moderate inversion region. The combination of described design techniques provides the significant power consumption minimization (nW feasible), while maintaining acceptable circuit performance and parameters. The motivation for research and development in given scientific field is enormous and new published results are expected to grow in upcoming years.
\nThe proposed circuit topologies of basic analog IC building blocks have been designed and fabricated in 130 nm twin-well general purpose CMOS technology with industrial operating temperature range taken into account. The experimental measurements performed on the prototype chip samples confirm a successful implementation and correct circuit operation with ultra-low-power supply voltage. Hence, we can state that the feasibility of presented IC design approach has been successfully demonstrated and the circuit topologies have been silicon-proven, which opens the door for even deeper gradual investigation and understanding of given scientific topic with promising future impact on the IC industry as well.
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\\n\\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
\\n"}]'},components:[{type:"htmlEditorComponent",content:"Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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As ceramics require very high processing temperatures compared to metals and polymers, these processes tend to be very energy intensive and result in higher production costs to the manufacturers. Therefore, new technologies known as nonconventional sintering techniques, such as microwave technology, are being developed in order to reduce energy consumption, while maintaining or even improving the characteristics of the resulting ceramic material. This novel and innovative technology aims at helping industrial sectors lower their production costs and, at the same time, lessen their environmental impact. On the other hand, it is interesting and necessary to know and explore the basic principles of microwaves to advance in the development of materials that demand, every day more, the different industrial sectors. 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In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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