**Table 11.**

*Coronary Embolectomy Catheters.*

interventions (**Table 11**). They share the same principle of mechanical aspiration embolectomy that depends on manual or machine assisted aspiration of the clot. Multiple passes might be required for some cases. No blood return while aspirating is a sign of either poor flow triggered by clot occluding the catheter or suctioning against the vessel wall. When no blood return is seen, the catheter should be withdrawn till blood return is seen. If blood return still not seen, the catheter should be removed out of the body and examined for clot at the tip. It is very important to keep negative pressure while withdrawing the catheter out of the GC followed by

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

Aspiration thrombectomy can aspirate the clots from the coronaries and displace it to systemic circulation. The data of using aspiration embolectomy is controversial. Most recent guidelines recommend against their routine use due to increased risk of embolic strokes and no clinical outcome benefit. However, some cases with signif-

Upsizing or exchanging GC to provide more support during procedure is challenging after crossing a difficult lesion or any case where guide wire position is critical. The risk of losing guide wire position while loading the new GC is high. Long guide wire or adding extension wire is first step. More support with additional buddy wire and/or using micro catheter inside the new GC could be helpful.

bleed back of the GC to remove any potential clot left within the GC.

Coronary micro-catheters are small catheters compatible with 0.014″ coronary wires. There is a wide spectrum of micro-catheters with different designs (**Table 12**). They provide operators with significant ability to provide wire exchanges, crossing difficult lesions, assist wiring difficult angulated lesions (**Table 13**) and many other technical advantages especially in CTO

**Manufacturer Catheter name Compatibility Length Note**

Export AP 6.0 Fr 140 cm

Fetch 2 6Fr 135 cm

Pronto 5.0 to 10 Fr Pronto V4 (138 cm)

Pronto V3 (140 cm) Pronto LP (138 cm)

Medtronic Export Advance 6.0 Fr 140 cm

Terumo Priority one 6 and 7FR 140 cm Spectranetics Quick Cat 6Fr 145 cm Atrium Xpress-Way 6 and 7 Fr 140 cm

Stron Medical Vmax 5, 6 and 7Fr 135–141 cm Tsuna Med Emax 5, 6 and 7Fr 136.5–141 cm

Pneumbra Indigo CAT RX 5.3 Fr 140 cm Aspiration catheter of

CAT RX SEPC4 catheter can be used to break the clots (200 cm)

Pronto V4 and V3 are available with 5.5, 6, and 8Fr Pronto LP available with 5, 6 Fr Pronto 0.03 is peripheral catheter 10 Fr, 120° angled 4 cm tip

icant thrombosis cannot be resolved without their use.

interventions.

Vascular solutions/ Teleflex

Boston Scientific

**Table 11.**

**220**

*Coronary Embolectomy Catheters.*

#### **Table 12.**

*Coronary micro catheters.*


3.3.1. Cytokines

Cytokines are polypeptides or glycoproteins that cause growth, differentiation and inflammatory or anti-inflammatory signals to different types of cells, which are released at a particular time in response to a specific stimulus and have a limited half-life time in the circulation [77]. Target cells of cytokines express high affinity membrane receptors, which activate intracellular signalling when they bind to cytokines, producing modifications in gene transcription that will determine the cellular response. The receptors receive information about the concentration and time of exposure to different cytokines, which implies a high degree of complexity. Due to all these features, cytokines play important roles as modulating agents that are involved in immune homeostasis by regulating inflammatory response, specific immune response, tolerance mechanisms, and promoting effective pathogen control. Hence,

the administration of cytokines allows for the manipulation of the immune system in auto-immune disorders, infectious diseases, increasing the efficiency of the vaccines (due to inherent adjuvants disorders) and in the therapy of cancer [78].

**Figure 6.** Schematic classification of immunotherapies designed for cancer.

The ability of cytokines to enhance the immune response against cancer and the development of recombinant DNA technology has allowed for preclinical and clinical investigation of the anti-tumoral activity of several recombinant human cytokines since the 1980s [77]. Several cytokines, among others including IL-2, IL-12, IL-15, IL-21, GM-CSF and INF-α, have demonstrated efficacy in preclinical models of murine cancer [79]; however, cytokines have shown limitations, such as their short half-life and narrow therapeutic framework, with low anti-tumour efficacy in their use as monotherapy agent. So far, only a few cytokines showed clinical benefit, which were IL-2 and IFN-α, being approved by the Food and Drug Administration (FDA) as anti-tumoral therapies. In the case of IL-2, it was approved for the treatment of advanced renal cell carcinoma and metastatic melanoma; regarding IFN-α, it was approved for the treatment of hairy cell leukemia, follicular non-Hodgkin's lymphoma, melanoma, and AIDS-related Kaposi's sarcoma [77].

In the case of IL-2, which has been approved by FDA for the treatment of advanced renal cell carcinoma and metastatic melanoma. The identification of IL-2 as a therapeutic agent began in the 1960s, when a factor capable of stimulating lymphocyte division in antigen-activated leukocyte culture supernatants was discovered. In 1969, it was demonstrated that human lymphocyte media contained this factor and could be used to maintain T-cell cultures for more than nine months without the need for repetitive antigenic stimulation. This technique was used to cultivate tumour-reactive cytotoxic T cells. This allowed a more in-depth study of this lymphocyte growth factor, thus giving it the name IL-2 [80], which was approved for the treatment of metastatic renal cell cancer in 1992 and advanced melanoma in 1998. IL-2 has opposite functions, acting as a T-cell growth factor during the initiation of the immune response, but is also essential for terminating the T-cell response, maintaining self-tolerance. This cytokine acts as a growth factor for T CD4+ cells and NK cells and promotes the clonal expansion of antigen activated CD8 T cells. In addition, it facilitates the production of antibodies by B cells that have been previously stimulated by factors such as CD40L. With respect to its immune response attenuation function, IL-2 plays an essential role in the maintenance of peripheral Tregs cells, as well as in the Activation-Induced Cell Death (AICD) of Fas-mediated T CD4+ cells. In IACD, receptor-mediated stimulation of T CD4+ cells with high antigen concentrations induces the expression

of IL-2 and their receptors, which interacts and activate the T cell cycle. This antigen activation in turn increases transcription and expression of Fas Ligand (FasL), resulting in T cell death [79].

Regarding IFN-α, it was approved for the treatment of hairy cell leukemia, follicular non-Hodgkin's lymphoma, melanoma, and AIDS-related Kaposi's sarcoma. IFN-α belongs to IFN type I, a family of cytokines synthesized by different cells in response to viral infections and immune stimulation [79]. IFNs of this type induce the expression of MHC class I molecules in tumour cells, involved in the maturation of DCs, activate B and T cells and increase the number of cytotoxic cells. Specifically, IFN-α has pro-apoptotic and anti-proliferative activity, but also presents anti-angiogenic activity on the tumour vasculature. The use of IFN-α was approved in 1986 for the treatment of hairy cell leukemia [77], as it produced a sustained improvement in granulocyte, platelet count and hemoglobin levels in 77% of LCH patients treated [81] and has since been used in the treatment of hematologic malignancies and solid tumours [77], such as chronic myeloid leukemia, AIDS-related Kaposi's sarcoma, renal cell cancer, and in the case of stage II and III melanoma has been used as adjuvant therapy [79].

In contrast, administration of IL-2 and IFN-α has a low response rate and high toxicity associated with high doses, making targeted therapy and checkpoint inhibitors a better option currently for these tumours [77].

A drawback of treatments with cytokines is that, for some of them, positive actions are accompanied by the induction of immune checkpoint cytokines, such as the inhibitory factors IL-10 or TGFβ [79]. IL-10 is released by innate and adaptive immune cells to regulate the activity of pro-inflammatory cytokines; but also as an immunosuppressive cytokine, because it decreases the antigen-presenting activity of dendritic cells (DCs) and inhibits cytotoxic function and cytokine release from T and NK cells (depending on the microenvironment). In chronic infections and cancer, CD8+ T cells exhibit autocrine activity mediated by IL-10, inhibiting their antigen-induced apoptosis, thus prolonging the efficacious activity of cytotoxic lymphocytes. TGFβ has a dual role in the tumour process, since at the beginning of tumorigenesis, TGFβ is an inhibitor of tumour development by blocking the cell cycle; nevertheless, in later stages, the cells develop mechanisms of resistance against the TGFβ´s effects. This resistance mechanism begins to promote tumour progression and mediates the epithelium-mesenchyme transition. In addition, TGFβ promotes the release of angiogenic factors (such as vascular endothelial growth factor (VEGF)), and the recruitment of Treg cells, neutrophils, macrophages (with pro-tumour polarization), myeloid-derived suppressor cells (MDSC) and tolerogenic DCs, in turn decreasing the functions of NK cells and CD8 T lymphocytes [77].

In summary, cytokines have demonstrated anti-tumour therapeutic activity in murine models and in the clinical treatment of certain specific human cancers. Moreover, IL-2 and IFN-α have been approved for the treatment of selected malignancies. In contrast, cytokines in monotherapy have not met all the expectations efficiency as has been observed in preclinical experiments. This is because they are often associated with severe dose-limiting toxicities, and are known to induce immunosuppressive humoral factors, suppressive cells and immune checkpoints. Normally, soluble cytokines act over short distances, in a paracrine or autocrine manner; therefore, to achieve effective intra-tumoral concentrations they must be administered parenterally at high doses, which increases the potential for systemic toxicities, such as hypotension, acute renal failure, respiratory failure and neuropsychiatric symptoms in severe situations. They also do not induce a tumour-specific immune response. To avoid these drawbacks, new mutant engineered cytokines (supercins), chimeric antibody-cytokine fusion proteins (immunocins) or even the combination of cytokines with other therapies such as checkpoint inhibitors, among other novel strategies, are being investigated in an attempt to increase their anticancer efficacy [82]. However, due to these limitations, it has been necessary to develop more tumour-specific immunotherapeutic agents with greater effectiveness and less associated toxicity that are currently being used with better results, and the employment of cytokines in immunotherapy has taken a back seat.


**Author details**

Cristina Gaio\* and Rita Henriques Advance/CSG, ISEG - Lisbon School of Economics and Management, Universidade de Lisboa, Portugal

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Social Responsibility and Financial Performance: The Case of STOXX Europe Index DOI: http://dx.doi.org/10.5772/intechopen.93573*


**5.2 Specific prevention**

To date, there is no immunization option available to prevent or treat any fungal infection. Although there have been numerous attempts to develop a potential vaccine against histoplasmosis, these candidates have only been tested on murine models. Various strategies have been used in the search for an effective vaccine for histoplasmosis. The active immunization approaches used in the research consisted of administration of recombinant heat shock protein rHsp60 or only the small protein fragment F3 of rHsp60, the surface protein H antigen, or auto-transplantation into a murine model of dendritic cells, primed *in vitro*, with apoptotic macrophages obtained by phagocytizing *H. capsulatum* yeast, inactivated by heat.

Research studies based on passive immunization methods have focused on the administration of monoclonal antibodies (mAbs Ig.M against histone 2B, mAbs Ig.G against rHsp60) or therapeutic pan-anti-fungal antibodies.

Immune system modulation strategies targeting the programmed cell death receptor-1 (PD-1) and its ligand (PD-L) have suggested that selective blockade of the PD-1/PD-L pathway may play a key therapeutic role in fungal immunity, not only for histoplasmosis but also for other mycoses [142].

The latest research in this field, approaching revolutionary methods of reverse vaccinology, comparative genomics, and molecular docking, have identified some candidate targets to produce both vaccines and new drugs against *H. capsulatum*. The most promising candidate vaccine target appears to be beta-1,3-glucanosyl transferase, the enzyme involved in the elongation of beta-(1-3)-glucans in the fungal cell wall, but further *in vivo* research is needed to test its efficacy and safety [143].

Recently, the WHO has released the fungal priority pathogen list (FPPL) to strengthen the global response against fungal infections. The FPPL highlights the need for actions, interventions, and strategies that focus on three main areas: surveillance, research and development, and public health actions [40].


**4.5 I-124 PET/CT**

I-124 is a positron emitter with a half-life of 4.18 days, produced by a cyclotron. It can be used to directly image thyroid cancer using PET scanner. Van Nostrand et al. compared I-124 PET with I-131 DxWBS in detecting residual thyroid tissue and/or metastatic lesion. They reported that I-124 PET identified as many as 50% more foci of radioiodine uptake suggestive of additional residual thyroid tissue and/or metastasis (Van Nostrand et al., 2010). They suggest that I-124 PET produced superior results because the PET scanner provides images with reduced background noise and enhanced spatial and contrast resolution compared with I-131 DxWBS. The longer half-life of I-124 is useful for dose monitoring over an extended time period (Surti et al., 2009). It can be also used for lesionspecific dosimetry. I-131 mean absorbed dose distributions can be calculated from serial I-124 PET image (Erdi et al., 1999; Larson & Robbins, 2002).


Regional Anesthesia in Times of COVID-19

*Víctor M. Whizar-Lugo, Karen L. Iñiguez-López and Guillermo Castorena-Arellano*

#### **Abstract**

The globalized coronavirus pandemic 2019 has kept us on our toes. Although confusion is widespread and there is a trend toward normalization of almost all human activities, outbreaks remain frequent. The majority of patients with COVID-19 have a trivial to moderate clinical course; a small group develops severe pneumonia and other life-threatening complications. Vaccination against this virus has contributed to better control of the pandemic, but there are no antiviral drugs that have demonstrated efficacy; therefore, the management of surgical patients confirmed or suspected of this disease is a challenge for health care workers, including the anesthesiologists, as well as the non-COVID-19 patients who at a given moment could become carriers or sick. General anesthesia produces aerosols and risks medical and technical personnel being infected, especially those who manage the airway. On the other hand, regional anesthesia has advantages over general anesthesia because the airway is not handled; however, its limited duration is the most important concern. It is reasonable that regional anesthesia occupies a preponderant place in the safe management of all patients, as long as the type of surgery allows it, the anesthesiologist has sufficient skills and patients accept the proposed technique. At this time of globalized crisis due to COVID-19, the intrapandemic anesthetic management of patients undergoing surgery continues to be a changing task, a challenge that has been solved as new data based on solid scientific evidence arise, besides the development of drugs, safer vaccines, equipment, and health prophylactic methods. There is a clear tendency to use regional anesthesia whenever this is possible.

**Keywords:** COVID-19, regional anesthesia, safety

#### **1. Introduction**

In early December 2019, the first cases of coronavirus disease 2019 (COVID-19) were reported in Wuhan, a city located in the Chinese province of Hubei. Most of these patients stated exposure to the Huanan seafood wholesale market selling several alive animals. On the eve of 2020, the WHO office in China was informed of cases of atypical pneumonia with mysterious etiology. Three days later, the first 44 patients with this new pathology were notified and a new member of enveloped RNA coronavirus was identified in bronchoalveolar lavage fluid from a patient in Wuhan and subsequently confirmed as the cause of this infection by the Chinese Center for Disease Control and Prevention. On January 7, 2020, the WHO named

this virus a 2019 novel coronavirus (2019-nCoV). On February 11, 2020, the WHO named the illness associated with 2019-nCoV the 2019 novel coronavirus disease (COVID-19). On January 23, 2020, the central government of China imposed a lockdown in Wuhan and other cities in Hubei in an effort to quarantine the center of an outbreak of COVID-19; this action is commonly referred to as the Wuhan lockdown. The Huanan seafood market became recognized worldwide as the "Ground Zero" site of COVID-19. Since then, the disease has spread rapidly to all countries and territories of the planet—with the exception of Turkmenistan, North Korea, Tuvalu, and Nauru, which have reported no cases—becoming a pandemic that has devastated the world in all its activities and collapsing all health systems [1–5].

Although the available global statistics are approximations, as December 31, 2021; 287,574,670 cases had been recorded, with 5,449,965 deaths and 253,516,625 people recovered [6]. These data are changing every moment in relation to the virulence of the new strains, the worldwide resources for the comprehensive care of the population, and the attitude of the people. As COVID-19 spreads across the planet, perioperative medical and surgical personnel must prepare for the challenges associated with the best care for the pandemic. Rapid suspicion, diagnosis and isolation, proper clinical management, and prevention of disease transmission are vital not only for COVID-19 patients but also for other patients and healthcare workers (HCWs) who are at risk of transmission.

Professionals in perioperative areas, such as other specialties, have been developing timely guidelines based on experiences acquired since the beginning of this pandemic in such a way that peri anesthetic care is the safest and most effective for patients and health personnel. Care policies must be endorsed by hospital administrators, medical societies involved, governments, and the third-party payer, to establish an adequate consensus that can adapt to the frequent changes that are necessary for such a way that the infrastructure and available supplies are optimized.

At this time of the COVID-19 pandemic, we must consider five large groups of patients [7]—people with active COVID-19, patients with a history of remission of SARS-CoV-2, potential carriers, vaccinated and unvaccinated patients, and patients without COVID-19. The pre-anesthetic evaluation and perioperative anesthesiological management are based on these groups according to the type of urgent or scheduled surgery, the available resources, and, of course, the experience of each anesthesiologist.

This chapter reviews the actual role of regional anesthesia in the era of COVID-19, considering the different clinical scenarios that this pandemic has generated. Nowadays, there is no information on how regional anesthesia could affect patients with active COVID-19, those with the post-COVID-19 syndrome, carriers, or recently vaccinated people. Practical recommendations that guarantee both the safety of each patient and also of HCWs are addressed, as well as the protection of the equipment. More research is needed to justify the design of management guidelines in regional anesthesia based solidly on global scientific evidence.

### **2. SARS-CoV-2 virus**

COVID-19 or coronavirus disease is caused by the SARS-CoV-2 virus that belongs to the betacoronavirus genus and shares high homology to the severe acute respiratory syndrome coronavirus (SARS-CoV) that occurred in 2003. This virus is closely related to SARS-CoV-1 and possibly originated either from bats or pangolins. Pneumonia and acute respiratory distress syndrome are the primary complications, although there are other disorders such as cardiovascular, hematological with lethal thrombotic complications, renal, gastrointestinal, hepatic, endocrine,

#### *Regional Anesthesia in Times of COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.104977*

and central nervous system diseases, just to mention a few. This sequence of events is due to the activation of immune responses that trigger uncontrolled massive inflammatory responses mediated by elevated serum levels of pro-inflammatory cytokines that can cause localized and systemic tissue damage. Eosinopenia and lymphopenia with reduction of CD4 + and CD8 + T cells, B cells, and natural killer (NK) cells have been identified in severe cases, severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells. A higher ratio of neutrophils to lymphocytes has also been reported, being an indicator of inflammation and infection. COVID-19 patients display high levels of inflammatory cytokines and chemokines (IL-1, IP-10, MCP-1), with severe cases showing elevation in TNF alfa, IL-1, IL-6, IL-8, IL-10, MCP-1, and MIP-1A, leading to severe pulmonary damage and IL-1 has also been linked to the expression of thromboxane-A2 resulting in increased platelet activation and aggregation [8–11].


**3. Chemical and hydrodynamics activation of gases using corona microdischarge**

### **3.1 Introduction**

During the past two decades several studies have shown that non-thermal plasmas reactor working in ambient air are very efficient sources of active species like charged particles, radicals and excited species. In fact, and as already explained in the previous sections, in the non-thermal plasma reactor, the majority of the injected electrical energy goes into the generation of energetic electrons, rather than into gas heating. The energy in the microplasma is thus directed preferentially to electron-impact dissociation, excitation and ionization of the background gas to generate active species that, in turn, induce the chemical activation of the medium. As a consequence, the non-thermal plasma reactors at atmospheric pressure are used in many applications such as flue gas pollution control (Fridman et al., 2005, Urashima et Chang, 2010), ozone production (Ono & Oda b, 2004), surface decontamination (Clement et al., 2001, Foest et al., 2005) and biomedical field (Laroussi, 2002, Villeger et al., 2008, Sarrette et al., 2010). For many applications, particularly in the removal of air pollutants, decontamination or medicine field, the non-thermal plasma approach would be most appropriate because of its energy selectivity and its capability for simultaneous treatment of pollutants, bacteria or cells for example.

In micro-discharges the active species are created by energetic electrons during the primary and the secondary streamer propagation that last some hundred of nanoseconds. Despite these very fast phenomena, the energy transferred to the gas can initiate shock waves starting from the stressed high voltage electrodes. Furthermore, a part of the electronic energy is stored in the vibrational energy that relaxes in thermal form after some tens of microseconds. Anyway, it is worth to notice, that all the initial energy (chemical, thermal, among others) is transferred inside a very thin discharge filament i.e. in a very small volume compared with the volume of the plasma reactor. Therefore, the efficiency of the processes is correlated to the radical production efficiency during the discharge phase, the number of micro-discharges that cross the inter-electrode gap, the repetition frequency of the discharge and how the radicals are diffused and transported from the micro-discharge towards the whole reactor volume.

In the following sections, the discharge and the post-discharge phase are simulated using the hydrodynamics models presented in section 2.5 in the case of a DC positive pin-to-plan corona reactor in dry air at atmospheric pressure.


**5. Eurocentric vs. afrocentric knowledge systems**

This section deliberates on the two streams of knowledge systems and worldviews as espoused by various scholars. There are ongoing and raging debates by African scholars over the relevance of these knowledge systems and their relevance for development. The dominance of Eurocentric knowledge systems over Afrocentric systems has renewed the academic and epistemological search for indigenous knowledge systems for African development. At the center of knowledge society, economy, and information age, production, management, and dissemination of scientific knowledge are what differentiate developed and developing nations. The Eurocentric Systems and their stories of control and oppression have always dominated Afrocentric Knowledge Systems between Africa and the rest of the world [72]. The systems' two main effects are: (1) the first is that they deliberately degraded African thought, disparaged African culture, and fabricated African history [73]. The concept of Africans as "savages, inferior, uncivilized, backward, lacking knowledge and culture and possessing bad qualities and desire" was created and spread by the proponents of Eurocentric narratives [74]. The conceptual framework of the narratives was oppressive, and it maintained the relation of domination and subjugation. Unfortunately, Eurocentric Knowledge Systems led Africans to search outside of themselves for self-actualization and sustainable growth. They began to think less highly of themselves and their place in the grand scheme of things. The second is that the stories distorted Westerners' anthropological and philosophical analyses of African Knowledge System and kept future generations from having a true understanding of African existential and cultural reality [75]. It somewhat constrained their field of comprehension and warped their idea of the subjective other.

On the other hand, Afrocentricity or Afrocentric Knowledge Systems offer a philosophical, esthetic, and rational vision of reality from an African perspective [23, 76]. It is a theoretical foundation for comprehending African people, ideas, and values provided by Afrocentric thought. It is fruitful to be preoccupied with and try to define African identity, metaphysics, and knowledge [72]. In order to achieve social reconstruction in Africa, Afrocentric system is a keen awareness of African cultural orientations and an empathic evaluation of its fundamental values, beliefs, and ideas [73]. Afrocentric systems advocate using a logical grasp of African cultural concepts to address difficulties relating to human life [77]. It also involves giving our cultural differences and potentials thoughtful, sympathetic evaluation. It has the ability to respect cultural differences and function within African culture.


*Article* **An Integrative Simulation for Mixing Different Polycarbonate Grades with the Same Color: Experimental Analysis and Evaluations**

**Jamal Alsadi \*, Rabah Ismail and Issam Trrad**

Engineering College, University of Jadara, Irbid 21110, Jordan<EMAIL_ADDRESS>(R.I<EMAIL_ADDRESS>(I.T.)

**\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** The processing parameters' impact such as temperature (Temp.), feed rate (F.R.), and speed (S.) at three distinct grades of the same color was explored in this study. To investigate the effect of the characteristics on color formulations, they were each adjusted to five different levels. For these grades, which were all associated with the same color, an intermeshing twin-screw extruder (TSE) was used. The compounded materials were molded into flat coupons then evaluated with a spectrophotometer for their CIE (L\*, a\*, b\*, and dE\*) values. A spectrophotometer was used to determine the color of a compounded plastic batch, which measured three numbers indicating the tristimulus values (CIE L\*a\*b\*). The lightness axis, which ranged from 0 (black) to 100 (white), is known as the L\*-axis (white). Redness-greenness and yellowness-blueness were represented by the other two coordinates, a\* and b\*, respectively. The color difference deviation (Delta E\*) from a target was dimensionless, when dE\* approached zero. However, the most excellent favorable color difference value occurred and different processing impact factors on polycarbonate grade were investigated. Using the response service design (RSD) software of Stat-Ease Design-Expert® (Minneapolis, MN, USA), historical data were gathered and evaluated. To reduce the value of dE\*, the impacts of these processing factors were investigated with the three processing parameters. The whole tristimulus color value could be simulated. Parameters were adjusted on 45 different treatments, using a five-level controlled response method to investigate their impact on color and detect non-optimal responses. The ANOVA for each grade was used to build the predicted regression models. The significant processing parameters were subjected to experimental running to simulate the regression models and achieve the best color, reducing waste.

**Keywords:** different grades; RSD; simulate r egression models; processing and parameters; analysis of variance; resin pigment blends


**2.1 Sacral anterior root stimulation**

Though this mode of urological neuromodulation is almost of historical interest in the face of current advances in the field and the dominance of sacral neuromodulation, it yet deserves honorable mention as it paved the way to utilize the sacral region for restoration of bladder function. Through stimulation of the anterior sacral nerve, both bladder parasympathetic efferents and somatic motor fibers to the external urethral sphincter are activated. This ventral activation facilitates intermittent bladder emptying [1].

Brindley in 1976 implanted intradurally and bilaterally on the ventral roots from S2 to S5 subcutaneous cables that were externally powered and would provide ondemand electromagnetic stimulation to facilitate voiding [5–7]. He later modified his procedure by performing posterior rhizotomy at the S2–S3 level during implantation of the stimulator to improve the continence outcome by eliminating the effect C-fiber bladder afferents had on amplifying the micturition reflex. This is what was later named the Brindley procedure, and its popularity phased out years later as more studies and reports demonstrated debilitating and unacceptable complications such as sacral dermatome hyperalgesia, cerebrospinal fluid leak, and damage to the anterior nerve root. The procedure, however, remains indicated for patients with complete spinal cord injury (SCI) with maintained bladder reflexes [1, 7–9].

### **2.2 Sacral neuromodulation**

The first reports describing the application of sacral neuromodulation were by Schmidt and Tanagho, the latter concentrating on its application in neurogenic lower urinary tract dysfunction [2, 3]. Since then, both experimental and approved applications and research aiming to understand the mechanism of action by which sacral neurostimulation, or more appropriately now termed sacral neuromodulation (SNM), affects and rehabilitates the functions of the lower urinary tract, both in facilitating bladder storage and voiding, has expanded. Researchers also embarked

on assessing its efficacy, particularly cost-effectiveness, when compared to other modes of treatment for its indications. SNM is, perhaps, the best studied mode of neuromodulation in urology [5].

Compared to the Brindley procedure, SNM posed numerous advantages and technical differences. The SNM procedure involves extradural electrode implantation usually in one of the paired S3 foramens. It does not require posterior rhizotomy either. This minimized the risks of nerve root injury or cerebrospinal fluid leakage. It provides continuous electrical stimulation to the nerves in its proximity and is controlled remotely without the need for subcutaneous cables as it has a built in-battery and antenna. It also modulates for restoration of normal micturition and suppresses bladder overactivity, which made it applicable to non-neurogenic voiding dysfunctions as well [1, 3].

The first SNM device made commercially available was the Interstim® (Medtronic Neuromodulation, Minneapolis USA). It was first approved in 1997 by the US Food & Drug Administration (FDA) for use in refractory urge incontinence, and later in 1999 its approval was expanded to include significant urgency, frequency, and idiopathic urinary retention. The US market was the most enthusiastic to adopt it, and back then and by the year 2004 15,000 units were implanted, the majority of which were in the USA [10, 11]. Since then, the rates of SNM implantations increased by at least 10 to 20-folds [12, 13].

Sacral neuromodulation is dedicated to the S3 foramen, targeting the S3 nerve root which is identified as the most relevant home for impulses, containing sensory fibers from the pelvic floor and parasympathetic neural fibers affecting the detrusor muscle of the bladder. This differs from the target of other neuromodulation modalities, and provides a distinct pattern of identification during implantation, which will be discussed later [14, 15].

### *2.2.1 Mechanism of action*

The goal of SNM is to modulate abnormal bladder sensations the patient may have, as well as involuntary uncontrollable reflexes in the lower urinary tract to restore the patient's voluntary control and facilitate normal function [16]. The theories on how it actually achieves these goals are vast, and expanding to date, and remain complex. This is perhaps in part due to the sophisticated interaction of higher central voiding centers in the brain and spinal cord and the peripheral nervous system in facilitating the functions of the lower urinary tract.

Investigators have assessed a multitude of concepts, from the molecular neurophysiological level to broader neurocirculatory behaviors in the brain and spine, in both animal models and human studies. Yet to date, no single theorem has been solely agreed upon. Some studies have even shown dual or multiple mechanisms through different channels by which SNM exerts its modulatory effect on the lower urinary tract, partly by studying its different effects in many neuro-urological conditions ranging from bladder overactivity to chronic pelvic pain.

SNM therapeutic effects are speculated to arise through electric stimulation of both afferent and efferent neural circuits in the pelvic viscera and connections with spinal interneurons. The stimulator produces an electrical charge in close proximity to the sacral root nerves, regenerating propagational axonal action potentials in the region. This in turn stimulates somatic afferents which modulate higher center control of micturition including the prefrontal cortex and insula, by restoring normal bladder function and perhaps suppressing reflex bladder activity such as that seen in overactive bladder (OAB). This indirect effect both on the bladder and the urinary sphincter is achieved through adaptive neural plasticity, and thus, an intact neural system, at least distally, is a neural requirement for SNM to successfully restore

**213**

*Neuromodulation in Urology: Current Trends and Future Applications*

overactivity mediated by supraspinal GABAA receptors [30].

bladder function [15–21]. The SNM device can provide different levels of stimulation, which may further modulate efferents to the bladder-sphincter complex; however, it does not have any direct effect on urethral resistance [16, 22].

Several studies have proved that SNM has modulatory effects in the brain. Earlier work has demonstrated stimulatory and inhibitory effects in specific brain regions including those responsible for alertness, sensation of bladder filling, and timing of micturition [23, 24]. Utilizing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) of the brain, researchers were able to identify decreased function after SNM in areas like the orbitofrontal cortex, angulate gyrus, and thalamus, while stimulating the dorsolateral prefrontal cortex, and the therapeutic effect of SNM corresponded to pre-implantation increased activity in the angulate and inferior frontal gyri, insula and thalamus. Such patterns of activity in the brain were shown to predict response to SNM treatment in females with OAB. Furthermore, investigators were able to show that different SNM stimulus intensities had varied brain responses, which may have differential

On the neurophysiological level, much has been investigated to understand which neural receptors and neurotransmitters may be affected by neuromodulation, SNM in particular. Opiod receptors are shown to be inhibited by SNM, and this inhibitory effect is augmented by tramadol and other opiod receptor agonists [28]. From animal models, blockade of opiod receptors with naloxone significantly reduced bladder capacity during sacral neuromodulation for reflex bladder activity. Blockade of beta-2 receptors, however, showed the opposite response during SNM [29]. Also mediated by opiod receptors are the SNM inhibitory effects of bladder

The US Food and Drug Administration has approved four main indications for SNM application, three of which are urological: refractory urinary urgency and frequency, urge urinary incontinence (UUI), non-obstructive urinary retention (NOUR), and lastly, fecal incontinence. This has been agreed upon and resounded by multiple authorities including the International Continence Society in their best practice statements, among other bodies [4]. However, FDA approval does not indicate level of recommendation, and authoritarians and experts in the field have built on this approval to debate and set the grade and the line of therapy at which SNM serves for a number of conditions, as well as argue for and against other indications or applications the FDA has not seen the benefit of SNM for eye-to-eye with available literature and results. There are, moreover, conditions that must be met prior to justifying an implantation regardless of the aforementioned indications

The International Continence Society (ICS) assessed the evidence available for SNM in different pathological genitourinary conditions and published its recommendations based on available literature. In summary, the ICS panel found grade A evidence to support the efficacy of SNM in overactive bladder and non-obstructive urinary retention including Fowler's syndrome and voiding dysfunction; however, this high level evidence did not change their recommendation of maintaining SNM as a second or third-line mode of therapy in these disorders. For other conditions including interstitial cystitis/bladder pain syndrome (IC/BPS) and neurogenic lower urinary tract symptoms, SNM remained an option based on lower levels of

*DOI: http://dx.doi.org/10.5772/intechopen.92287*

therapeutic implications [23–27].

*2.2.2 Indications and contraindications*

and contraindications that must be observed.

evidence (grade C evidence/level III recommendations) [4, 31].

*<IP_ADDRESS> FDA approved indications*

### *Neuromodulation in Urology: Current Trends and Future Applications DOI: http://dx.doi.org/10.5772/intechopen.92287*

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

neuromodulation in urology [5].

dysfunctions as well [1, 3].

which will be discussed later [14, 15].

*2.2.1 Mechanism of action*

20-folds [12, 13].

on assessing its efficacy, particularly cost-effectiveness, when compared to other modes of treatment for its indications. SNM is, perhaps, the best studied mode of

Compared to the Brindley procedure, SNM posed numerous advantages and technical differences. The SNM procedure involves extradural electrode implantation usually in one of the paired S3 foramens. It does not require posterior rhizotomy either. This minimized the risks of nerve root injury or cerebrospinal fluid leakage. It provides continuous electrical stimulation to the nerves in its proximity and is controlled remotely without the need for subcutaneous cables as it has a built in-battery and antenna. It also modulates for restoration of normal micturition and suppresses bladder overactivity, which made it applicable to non-neurogenic voiding

The first SNM device made commercially available was the Interstim® (Medtronic Neuromodulation, Minneapolis USA). It was first approved in 1997 by the US Food & Drug Administration (FDA) for use in refractory urge incontinence, and later in 1999 its approval was expanded to include significant urgency, frequency, and idiopathic urinary retention. The US market was the most enthusiastic to adopt it, and back then and by the year 2004 15,000 units were implanted, the majority of which were in the USA [10, 11]. Since then, the rates of SNM implantations increased by at least 10 to

Sacral neuromodulation is dedicated to the S3 foramen, targeting the S3 nerve root which is identified as the most relevant home for impulses, containing sensory fibers from the pelvic floor and parasympathetic neural fibers affecting the detrusor muscle of the bladder. This differs from the target of other neuromodulation modalities, and provides a distinct pattern of identification during implantation,

The goal of SNM is to modulate abnormal bladder sensations the patient may have, as well as involuntary uncontrollable reflexes in the lower urinary tract to restore the patient's voluntary control and facilitate normal function [16]. The theories on how it actually achieves these goals are vast, and expanding to date, and remain complex. This is perhaps in part due to the sophisticated interaction of higher central voiding centers in the brain and spinal cord and the peripheral

Investigators have assessed a multitude of concepts, from the molecular neurophysiological level to broader neurocirculatory behaviors in the brain and spine, in both animal models and human studies. Yet to date, no single theorem has been solely agreed upon. Some studies have even shown dual or multiple mechanisms through different channels by which SNM exerts its modulatory effect on the lower urinary tract, partly by studying its different effects in many neuro-urological

SNM therapeutic effects are speculated to arise through electric stimulation of both afferent and efferent neural circuits in the pelvic viscera and connections with spinal interneurons. The stimulator produces an electrical charge in close proximity to the sacral root nerves, regenerating propagational axonal action potentials in the region. This in turn stimulates somatic afferents which modulate higher center control of micturition including the prefrontal cortex and insula, by restoring normal bladder function and perhaps suppressing reflex bladder activity such as that seen in overactive bladder (OAB). This indirect effect both on the bladder and the urinary sphincter is achieved through adaptive neural plasticity, and thus, an intact neural system, at least distally, is a neural requirement for SNM to successfully restore

nervous system in facilitating the functions of the lower urinary tract.

conditions ranging from bladder overactivity to chronic pelvic pain.

**212**

bladder function [15–21]. The SNM device can provide different levels of stimulation, which may further modulate efferents to the bladder-sphincter complex; however, it does not have any direct effect on urethral resistance [16, 22].

Several studies have proved that SNM has modulatory effects in the brain. Earlier work has demonstrated stimulatory and inhibitory effects in specific brain regions including those responsible for alertness, sensation of bladder filling, and timing of micturition [23, 24]. Utilizing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) of the brain, researchers were able to identify decreased function after SNM in areas like the orbitofrontal cortex, angulate gyrus, and thalamus, while stimulating the dorsolateral prefrontal cortex, and the therapeutic effect of SNM corresponded to pre-implantation increased activity in the angulate and inferior frontal gyri, insula and thalamus. Such patterns of activity in the brain were shown to predict response to SNM treatment in females with OAB. Furthermore, investigators were able to show that different SNM stimulus intensities had varied brain responses, which may have differential therapeutic implications [23–27].

On the neurophysiological level, much has been investigated to understand which neural receptors and neurotransmitters may be affected by neuromodulation, SNM in particular. Opiod receptors are shown to be inhibited by SNM, and this inhibitory effect is augmented by tramadol and other opiod receptor agonists [28]. From animal models, blockade of opiod receptors with naloxone significantly reduced bladder capacity during sacral neuromodulation for reflex bladder activity. Blockade of beta-2 receptors, however, showed the opposite response during SNM [29]. Also mediated by opiod receptors are the SNM inhibitory effects of bladder overactivity mediated by supraspinal GABAA receptors [30].

### *2.2.2 Indications and contraindications*

### *<IP_ADDRESS> FDA approved indications*

The US Food and Drug Administration has approved four main indications for SNM application, three of which are urological: refractory urinary urgency and frequency, urge urinary incontinence (UUI), non-obstructive urinary retention (NOUR), and lastly, fecal incontinence. This has been agreed upon and resounded by multiple authorities including the International Continence Society in their best practice statements, among other bodies [4]. However, FDA approval does not indicate level of recommendation, and authoritarians and experts in the field have built on this approval to debate and set the grade and the line of therapy at which SNM serves for a number of conditions, as well as argue for and against other indications or applications the FDA has not seen the benefit of SNM for eye-to-eye with available literature and results. There are, moreover, conditions that must be met prior to justifying an implantation regardless of the aforementioned indications and contraindications that must be observed.

The International Continence Society (ICS) assessed the evidence available for SNM in different pathological genitourinary conditions and published its recommendations based on available literature. In summary, the ICS panel found grade A evidence to support the efficacy of SNM in overactive bladder and non-obstructive urinary retention including Fowler's syndrome and voiding dysfunction; however, this high level evidence did not change their recommendation of maintaining SNM as a second or third-line mode of therapy in these disorders. For other conditions including interstitial cystitis/bladder pain syndrome (IC/BPS) and neurogenic lower urinary tract symptoms, SNM remained an option based on lower levels of evidence (grade C evidence/level III recommendations) [4, 31].