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",isbn:"978-1-83962-547-3",printIsbn:"978-1-83962-546-6",pdfIsbn:"978-1-83962-548-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"e5ba02fedd7c87f0ab66414f3b07de0c",bookSignature:"Dr. John P. Tiefenbacher",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10765.jpg",keywords:"Managing Urbanization, Managing Development, Managing Resource Use, Drought Management, Flood Management, Water Quality Monitoring, Air Quality Monitoring, Ecological Monitoring, Modeling Extreme Natural Events, Ecological Restoration, Restoring Environmental Flows, Environmental Management Perspectives",numberOfDownloads:18,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 12th 2021",dateEndSecondStepPublish:"February 9th 2021",dateEndThirdStepPublish:"April 10th 2021",dateEndFourthStepPublish:"June 29th 2021",dateEndFifthStepPublish:"August 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A geospatial scholar working at the interface of natural and human systems, collaborating internationally on innovative studies about hazards and environmental challenges. Dr. Tiefenbacher has published more than 200 papers on a diverse array of topics that examine perception and behaviors with regards to the application of pesticides, releases of toxic chemicals, environments of the U.S.-Mexico borderlands, wildlife hazards, and the geography of wine.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"73876",title:"Dr.",name:"John P.",middleName:null,surname:"Tiefenbacher",slug:"john-p.-tiefenbacher",fullName:"John P. Tiefenbacher",profilePictureURL:"https://mts.intechopen.com/storage/users/73876/images/system/73876.jfif",biography:"Dr. John P. Tiefenbacher (Ph.D., Rutgers, 1992) is a professor of Geography at Texas State University. His research has focused on various aspects of hazards and environmental management. Dr. Tiefenbacher has published on a diverse array of topics that examine perception and behaviors with regards to the application of pesticides, releases of toxic chemicals, environments of the U.S.-Mexico borderlands, wildlife hazards, and the geography of wine. More recently his work pertains to spatial adaptation to climate change, spatial responses in wine growing regions to climate change, the geographies of viticulture and wine, artificial intelligence and machine learning to predict patterns of natural processes and hazards, historical ethnic enclaves in American cities and regions, and environmental adaptations of 19th century European immigrants to North America's landscapes.",institutionString:"Texas State University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"Texas State University",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"12",title:"Environmental Sciences",slug:"environmental-sciences"}],chapters:[{id:"76073",title:"Integrating Ecological Site Descriptions with Soil Morphology to Optimize Forest Management: Three Missouri Case Studies",slug:"integrating-ecological-site-descriptions-with-soil-morphology-to-optimize-forest-management-three-mi",totalDownloads:18,totalCrossrefCites:0,authors:[{id:"185895",title:"Dr.",name:"Michael",surname:"Aide",slug:"michael-aide",fullName:"Michael Aide"},{id:"269286",title:"Dr.",name:"Christine",surname:"Aide",slug:"christine-aide",fullName:"Christine Aide"},{id:"269287",title:"Dr.",name:"Indi",surname:"Braden",slug:"indi-braden",fullName:"Indi Braden"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"194667",firstName:"Marijana",lastName:"Francetic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/194667/images/4752_n.jpg",email:"marijana@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. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"600",title:"Approaches to Managing Disaster",subtitle:"Assessing Hazards, Emergencies and Disaster Impacts",isOpenForSubmission:!1,hash:"e97caba8487382025a1e70eb85e4e390",slug:"approaches-to-managing-disaster-assessing-hazards-emergencies-and-disaster-impacts",bookSignature:"John Tiefenbacher",coverURL:"https://cdn.intechopen.com/books/images_new/600.jpg",editedByType:"Edited by",editors:[{id:"73876",title:"Dr.",name:"John P.",surname:"Tiefenbacher",slug:"john-p.-tiefenbacher",fullName:"John P. 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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"}}]},chapter:{item:{type:"chapter",id:"67646",title:"Retinoblastoma Management: Advances in Chemotherapy",doi:"10.5772/intechopen.86820",slug:"retinoblastoma-management-advances-in-chemotherapy",body:'\nThe treatment of retinoblastoma is challenging, as the governing objectives are preserving life, protecting from pineoblastoma, decreasing the lifetime incidence of secondary tumors and salvaging useful vision without exposing the patient to significant and serious side effects that may endanger the patient’s survival and quality of life. The treatment of retinoblastoma evolved steadily during the past decades, and multiple modalities of treatment were introduced including chemotherapy. At one time, chemotherapy was used mainly to manage metastatic retinoblastoma, but later the interest of scientists and clinicians shifted to the use of this treatment strategy for non-metastatic retinoblastoma. As the interest of experts grew and the demand for better overall outcome increased, multiple interesting treatment strategies were developed and refined. Now, four main routes of administration of chemotherapy are present, and these are: intravenous chemotherapy (IVC), intra-arterial chemotherapy (IAC), intravitreal chemotherapy (IVitC) and periocular chemotherapy (POC).
\nToday, chemotherapy is regarded as one of the indispensable pillars of treatment of retinoblastoma. In fact, retinoblastoma is currently one of the most commonly curable childhood malignant tumors universally. In developed countries, the rates of expected survival exceed 95% whereas the rates in developing countries are lower due to the limited healthcare resources [1]. The different chemotherapy treatment strategies outlined above will be discussed thoroughly in the upcoming sections.
\nThe era of chemotherapeutic treatment for retinoblastoma began in 1953 when Carl Kupfer reported the successful use of intravenous nitrogen mustard along with irradiation to treat a child with recurrent retinoblastoma [2]. Thereafter, the use of triethylene melamine, a chemotherapeutic alkylating agent, via different routes (oral, intramuscular, intravenous and intra-arterial) became more widespread between clinicians until the late 1960s given that it allowed the reduction of radiotherapy dose which was associated with multiple potential side effects [3, 4, 5, 6]. In the following years, the use of systemic chemotherapy fluctuated until the early 1990s when the use of systemic chemotherapy was popularized and strongly advocated by the leading retinoblastoma treatment centers worldwide and the use of external beam radiation was restricted in favor of chemotherapy due to the considerable risk of secondary tumors in patients receiving radiotherapy.
\nThe management of retinoblastoma should be carried out by an experienced team as these children need meticulous bilateral ocular examination, usually under anesthesia, in parallel with systemic evaluation by a pediatric oncologist with experience in ocular oncology and appropriate systemic imaging by magnetic resonance imaging (MRI) must be standardly performed to rule out metastasis. These steps are vital to accurately classify the disease in accordance with the more recent International Classification of Retinoblastoma (ICRB). This will direct the treatment to either systemic chemotherapy or local therapies (thermal, cryotherapy and chemotherapy) or a combination of both.
\nUnderstating the effect of systemic chemotherapy on the different forms of retinoblastoma (solid tumor, subretinal tumor and vitreous seeds) is essential as it helps in guiding the treatment. Moreover, the likely complications and systemic toxicities of IVC are important to be looked at carefully before commencement as this will help in individualizing the treatment in this vulnerable subset of patients so as to reduce systemic morbidities without jeopardizing the treatment success [7]. In this section, we will highlight the principal characteristics of this treatment modality.
\nThe use of IVC varies slightly between different treatment centers worldwide; but generally speaking, the umbrella of IVC usage encompasses its use in patients with intraocular disease only and in patients with or at high risk of extraocular disease. When the disease is limited to the eyes, IVC aims at shrinking the size of the tumor to expedite cure and lessen the damage induced by consolidating local therapies to follow, especially when the tumor involves sensitive retinal areas such as the macula. This has been termed chemoreduction and it had been shown to achieve adequate tumor control (alone or along with focal consolidating therapies) and eliminate the need for enucleation or external beam radiation (EBR) in more than 75% of patients in a large series (n = 457, group A–D). The risk of recurrence in this series was 22% and these were usually detected in the first year after starting the treatment; yet; none occurred by 4 years of follow up [8, 9]. This is probably the most important concern arising with the use of chemoreduction; though continuous surveillance of these children partly helps in overcoming this shortcoming. Moreover, one study suggested that the administration of chemoreduction might minimize the risk of pineoblastoma where none of the children (n = 147) receiving this therapy developed trilateral retinoblastoma [10].
\nIVC is used also as an adjuvant therapy after enucleation in patients with extraocular disease (metastasis) as well as patients with intraocular disease associated with high-risk histopathological features (e.g., optic nerve invasion beyond the lamina cribrosa and choroid invasion >3 mm) demonstrated on histopathological examination of the enucleated eye [11]. It is speculated that patients with high-risk features might presumably have micro-metastasis and administering systemic chemoprophylaxis helps in improving their prognosis. Evidence in the literature supports the use of prophylactic IVC in high-risk patients where it was shown that it is safe and effective in decreasing the risk of metastasis [12, 13].
\nPatients with extraocular disease receiving IVC can be divided into three categories: those with orbital and/or regional spread to the preauricular lymph nodes or optic nerve cut, those with central nervous system (CNS) dissemination and those with distant extracranial metastasis [14]. In patients presenting with orbital retinoblastoma, IVC is a valuable treatment. This holds true when it is predominantly administered in combination with other therapies (multimodal therapy: surgery, radiotherapy and chemotherapy) as its effect is usually inadequate when given alone [15]. Patients who have CNS involvement usually have a very poor prognosis with low survival rate. The usual approach to these patients consists of platinum-based IVC with agents having good CNS penetration along with focal CNS treatments such as radiotherapy. Some studies suggested using high doses of IVC followed by autologous hematopoietic progenitor cell rescue; yet, this technique is controversial [16]. Distant metastasis usually occurs to the bone and a small series (n = 14) on stage 4A patients showed promising results using intense induction chemotherapy followed by high dose consolidating chemotherapy and autologous hematopoietic progenitor cell rescue [17].
\nOver the past decades, multiple chemotherapeutic agents were used, and multiple chemotherapy protocols were implemented, some of which are now outdated. In the meantime, the most commonly employed IVC therapy is the VEC protocol consisting of three main chemotherapeutic agents (Vincristine, Etoposide, Carboplatin) in standard doses based on the body weight. Higher doses may be used in patients with more advanced disease (bilateral group D or E) [7, 18]. This three-drug regimen is the most popular combination preferred by many experts and this stems from its proven effect on neuronal tumors in the pediatric age group as well as its good penetration into the eye [19]. The patient usually receives 6–9 cycles on a monthly basis and once the tumor shrinks in size, then focal consolidating treatments can follow [7].
\nCommon side effects, which are usually observed with any systemic chemotherapy, include transient pancytopenia owing to bone marrow suppression, fever and alopecia. The occurrence of these side effects is usually limited to the treatment period. Although carboplatin, a platinum based agent, had been linked to ototoxicity and nephrotoxicity, these serious side effects are rare as they are dose-dependent [20, 21]. There was an underlying concern that etoposide may induce acute myelogenous leukemia especially with high multiple doses; yet, the results of several studies on this topic were reassuring [7, 22]. With regards to secondary tumors, it does not seem that IVC increases the risk ominously. A long term follow-up study demonstrated that the rate of secondary tumors in germline retinoblastoma patients treated with systemic chemotherapy was 4%, which is less than expected for this vulnerable subset of patients [23].
\nThe introduction of systemic chemotherapy resulted in an improved eye salvage rate, not to mention the enhanced visual outcome. Chemoreduction success can be predicted in patients with retinoblastoma following the ICRB classification as following: 100% in group A, 93% in group B, 90% in group C and <50% in group D and E [24]. The success rate in the advanced stages can be augmented when combining IVC with other modalities of treatment such as IAC or IVitC. Long-term studies have shown that chemotherapy with or without adjunctive therapies maintains ambulatory vision of ≥6/60 in almost two-thirds of the patients, particularly those with multiple tumors and/or no foveolar tumors [25]. Furthermore, IVC seems to exert a protective effect against pineoblastoma as its occurrence is usually very low in patients receiving it [26].
\nThe effect of systemic chemotherapy as a monotherapy appears to be satisfactory especially in patients with less advanced disease whereas in patients with advanced disease, its remedial action is complementary to the selective recent therapies. A recently published meta-analysis comparing IVC to the more selective IAC revealed that both methods are equivalent in terms of tumor recurrence and metastasis. IAC evidently had a higher total success rate and ocular sparing effect in group D patients compared to IVC [27]. Despite this, we believe that IVC will continue to be an integral part of the treatment regimen of retinoblastoma.
\nIntra-arterial chemotherapy (IAC), also known as ophthalmic artery chemosurgery (OAC), is an important treatment strategy for retinoblastoma that evolved rapidly and gained popularity worldwide. Today, this modality of treatment is being performed in many retinoblastoma treatment centers located in more than 45 countries across the globe [28]. This treatment modality was initially explored by Reese et al. [3] who directly injected the alkylating agent triethylene melamine (TEM) into the internal carotid artery; nevertheless, it was not until 2006 when Abramson and Gobin introduced the novel technique of super-selective ophthalmic artery catheterization via transfemoral artery approach which allowed immediate and effectual delivery of the administered agent (melphalan) into the diseased eye [29]. Thereafter, many oncology centers adopted this technique and started publishing their experience. In this section, we will be shedding the light on the important aspects and most recent results of IAC.
\nIAC opened the door to a new era in the treatment of retinoblastoma. The key exciting factor behind this local therapy is its ability to achieve adequate therapeutic intraocular concentrations of the delivered chemotherapeutic agents while minimizing the systemic toxicity induced by these infused drugs such as neutropenia and secondary tumors [30]. In view of this, IAC is utilized mainly in treating patients with intraocular disease without local or systemic spread. Previous studies on IAC have shown that it can be used successfully as a primary retinoblastoma treatment in naïve eyes (no previous therapy employed) or as a secondary treatment in eyes with recurrent or residual tumor after trying other treatment modalities such as systemic chemotherapy, external beam radiotherapy and others [29, 31, 32, 33, 34, 35, 36, 37]. Currently, the common indications for IAC in retinoblastoma patients include unilateral retinoblastoma that cannot be halted by local treatments alone (e.g., cryotherapy or laser photocoagulation) and advanced unilateral retinoblastoma (such as group D and E based on the ICRB) [30]. Several studies had previously reported the following advantages of using IAC in patients with group D retinoblastoma: better eye conservation rates and greater visual acuity compared to systemic chemotherapy, shorter treatment period and ability to repeat the therapy several times using multiple agents without endangering the patients’ life and vision [28, 38]. It is also noteworthy to mention that IAC can save naïve eyes with advanced retinoblastoma from enucleation particularly when subretinal seeding is present (2 year ocular survival rate of 83%) [39]. Furthermore, IAC has a proven benefit even in patients presenting with advanced disease such as those having retinoblastoma-induced total or partial retinal detachment in which it can successfully achieve retinal re-attachment and thus help in preserving the eye and the life with the least possible side effects [40, 41].
\nSimultaneous IAC (tandem therapy) to both eyes consecutively is also a valuable and safe treatment method in patients with bilateral germline retinoblastoma whether used primarily or secondarily. This was demonstrated in two recent studies, which reported excellent globe salvage rates (ocular survival rate > 90%) even in patients with advanced disease. Despite that the safety profile of this simultaneous therapy was considerably high where no treatment-associated deaths occurred, these children were still at risk of secondary tumors such as pineoblastoma and this is probably attributed to their inherent genetic predisposition [42, 43].
\nThe technique of IAC is carried out on patients who are generally anesthetized and is usually coordinated by a specialized and experienced oncology/radiology team. The common femoral artery on the ipsilateral treatment side is usually used to gain access to the internal carotid artery and then the ophthalmic artery (OA) is selectively catheterized under fluoroscopic guidance at its ostium (origin) while heparin is infused intravenously to prevent coagulation. Then, in order to verify the proper placement of the microcatheter, selective angiography is done by contrast infusion to delineate the vascular anatomy and ocular perfusion. Due to the variability of vascular territory anatomy and blood flow patterns, OA catheterization might fail and other routes are available, however, this is out of the scope of this chapter [34].
\nThe most commonly used intra-arterial chemotherapeutic agent is melphalan, a potent alkylating agent. Melphalan is by far the strongest chemotherapeutic drug acting effectually against human retinoblastoma cells [44]. It is very safe when administered locally but very toxic when infused systemically due to the resultant severe myelosuppression [45]. In fact, it is currently considered an ideal agent due to its favorable safety profile, short half-life and ability to be used in combination with other agents to achieve greater tumor control when needed [34, 46]. Topotecan, a topoisomerase inhibitor, and carboplatin, an alkylating agent, are other agents that have been used alone or as a part of a multi-drug regimen in advanced cases that fail to respond to melphalan solitarily or in bilateral tandem therapy where the dose of melphalan is decreased to prevent systemic side effects [34].
\nDespite being a less invasive therapeutic intervention, IAC does carry some risk of complications, as it would be expected with any medical interventional procedure. Complications occurring after IAC are attributed either to the procedure itself or to the chemotherapeutic agent/agents or both. Complications developing from the procedure include endovascular complications occurring intraoperative, allergy to iodine and hematoma at the site of entry into the femoral artery. Systemic thromboembolic and hemorrhagic events (stroke, limb ischemia) are possible but their current reported overall occurrence is extremely scarce [30, 44]. Up to date, no procedure-related deaths had been reported. Theoretically speaking, since IAC targets chiefly the intraocular pathology, the risk of metastasis and secondary neoplasms remains unchanged or even might be increased, as this treatment is not intended to reach the systemic circulation in high concentrations. Experts studied the incidence of death due to retinoblastoma-associated metastasis in a cohort of patients treated over a 10-year period by IAC primarily or secondarily and found it to be negligible (<1%) [47]. Likewise, IAC was not associated with an increased rate of second primary malignancies (SPM) in a group of patients with germline retinoblastoma from one treatment center studied over a 10-year period (2006–2016) [48]. However, IAC is relatively a recent therapy; therefore, it is still premature to derive definite conclusions regarding the potential risk and studies with longer follow up periods are required.
\nNeutropenia is another important complication that should be recognized and managed early to prevent devastating complications. The local distribution of the drug has helped in limiting its occurrence to <15% [34, 49]. On the other hand, minor ocular side effects are common and these include: lids edema, blepharoptosis, temporary loss of the eyelashes and forehead hyperemia along the distribution of the supratrochlear artery [50]. Ocular vascular complications are among the universally feared local side effects. A recent review of 16 published studies reported that <2.5% had ophthalmic artery obstruction or occlusion, choroidal ischemia or atrophy and vasospasm [49]. These vascular events should be interpreted in the context of the clinical case given that these are usually sick eyes that might have received other local treatments that might contribute to the occurrence of such events. A recently published study looked at the incidence of vascular events and the variability of their occurrence when IAC is given primarily or secondarily and reported the following: overall vascular complications occur in 5% of eyes per infusion and no difference was observed when IAC is used as a primary or secondary therapy [51].
\nThe body of evidence in the literature supporting the use of IAC has been growing persistently in the past decade. Impressively, the reported globe salvage rate is currently exceeding 90% without compromising patient’s survival and the enucleation rate dropped to <10% [35, 52, 53, 54]. Even the rate of orbital recurrence was significantly higher in patients with advanced disease treated with enucleation compared to IAC and this further emphasizes the gainful outcome of IAC [55].
\nA major concern about the risk of recurrence after IAC treatment remains in spite of the success achieved by this treatment modality. A recent study from one of the pioneering centers utilizing IAC with 10 years experience reported that around 25% of eyes treated primarily with IAC might develop recurrence. The recurrence of the disease was observed to occur mainly in the first 12 months post-treatment; and therefore, close follow up with serial meticulous examination is recommended during this period. Surprisingly, the rate of recurrence was higher in eyes that received the drug through routes other than OA and in eyes with widely spaced treatments more than 4 weeks. The risk of recurrence was <10% by 2 years in eyes remaining disease free in the first year after IAC [52].
\nIntravitreal chemotherapy (IVitC) is another well-established targeted therapy accounting for one of the important current treatment modalities for retinoblastoma manifesting vitreous seeds. Initial reports on IVitC date back to the 1960s where thiotepa was injected into the vitreous cavity of six eyes with retinoblastoma; yet the results were inconclusive due to the limited number of treated eyes [56]. Later, this method was revived by Kaneko and Suzuki who injected melphalan intravitreally in 41 eyes along with ocular hyperthermia to cure vitreous seeding with a notable resultant eye preservation rate of 51.3% [57]. The choice of melphalan was essentially based on in-vitro testing of 12 anti-neoplastic drugs, and melphalan proved to be the most effective against retinoblastoma cells [45]. Implementing this technique into current practice took several years and perhaps the major limiting factor was the fear of disseminating the cancer cells during injection with the risk of subsequent extraocular spread causing metastasis and death. This section will elaborate on the key qualities of this relatively new therapy.
\nThis local therapeutic technique is intended essentially to achieve the highest concentration of the delivered tumoricidal drug into the confined intraocular space adjacent to the tumor. IVitC is used as an adjunctive therapy to chemoreduction with systemic chemotherapy and IAC. The main indications for this treatment modality are the presence of active vitreous seeds that are either refractory to standard therapy or recurrent after pervious standard therapy [7]. The use of IVitC had also expanded lately to include patients with retinal and subretinal tumors where it had been shown to be successful in salvaging the globe of such patients [58].
\nOn the other hands, contraindications preventing the execution of this procedure include tumors involving the ciliary body or extending up to the anterior segment, tumors filling the globe, retinal detachment and vitreous hemorrhage.
\nBefore proceeding with this treatment, it is critical to meticulously evaluate the pars plana clinically in all quadrants 360° looking for any tumor foci as that could pose a threat to safety if present due to the risk of spread while injecting. If visualization is difficult, then ultrasound biomicroscopy can be used to help in detection and affirmation [59].
\nThe procedure is usually carried out in the operating room under sterile conditions while the child is under general anesthesia. The anti-cancerous drug, typically melphalan, is injected through the pars plana 3–3.5 mm from the limbus into the vitreous cavity using a small needle, preferably a 32 gauge-needle. This creates the smallest needle track that helps in reducing the risk of dissemination. The injection is rather done in a seed-free quadrant, 2 o’clock hours away from vitreous seeds to prevent the undesirable exteriorization of tumor cells. Furthermore, some experts advocate reducing the pressure inside the eye by paracentesis before inserting the needle to prevent the possible risk of microscopic tumor seeding. After injecting the drug and before exiting the tumor-harboring globe, triple freeze-thaw cryotherapy should be carried out concurrently at the injection site while withdrawing the needle. Then, uniform intraocular distribution of the drug is achieved by gentle shaking of the eye using forceps. Examination is usually performed at the end of the procedure to rule out possible acute complications such as retinal detachment and bleeding. The ocular surface is then washed with balanced salt solution to remove any remnant chemotherapeutic agent that could be toxic. The child is usually discharged in the same day and the family is instructed to avoid touching the eye [59]. The procedure may vary minimally between different specialized treatment centers.
\nMelphalan hydrochloride is the principal drug injected into the vitreous cavity in retinoblastoma patients. It is a cytotoxic nitrogen mustard derivative that inhibits the synthesis of DNA and RNA together [59]. Its effective dosage range was studied and set at 20–30 μg per injection as low doses (8 μg) were not adequate to control and eradicate the disease while high doses (50 μg) controlled the disease but resulted in local toxicity (cataract, posterior segment hemorrhage, hypotony and phthisis bulbi) [60]. The number of injections is governed by the response. In general, Shields et al. proposed giving a total of six injections weekly or every 2 weeks [7].
\nTopotecan, a topoisomerase-1 inhibitor, is another potent intravitreal agent that had been employed in the treatment of retinoblastoma with vitreous seeds. Experimental animal studies showed that topotecan produce high and stable levels in the vitreous [61]. One of the distinguishable advantages of topotecan is its ability to attain a vitreous-to-plasma concentration five times more than melphalan [62]. Previous studies have shown that it is an effective anti-tumor drug with good safety profile and low ocular toxicity [63]. It had been used intravitreally in combination with melphalan in humans with encouraging results where this multi-agent regimen managed to achieve notable vitreous seeds regression with fewer injections [64]. Topotecan can also be used effectively in patients with recurrent or resistant viable vitreous seeds according to a recent study on 17 eyes which demonstrated control of these seeds in all treated eyes (100%) in the absence of ocular or systemic side effects and with a lower number of injections [65].
\nExtraocular tumor dissemination through the needle track with subsequent metastasis was perhaps the most feared serious event limiting the use of this treatment modality in the past. However, a meta-analysis examining published studies on this matter revealed that the risk of systemic spread is very low (two cases out of 1304 injections, proportion of extraocular spread secondary to injections was 0.007) especially when the appropriate safety enhancing injection techniques are applied. Therefore, IVitC can be utilized unreservedly whenever needed after proper patient selection [66].
\nOcular side effects are generally uncommon in patients receiving IVitC. The major factor influencing the risk of complications and local ocular toxicity is the dose of administered medication where toxicity is more likely with melphalan doses higher than 30 μg [67]. Among the most frequent side effects is retinal pigment epithelium changes (salt and pepper retinopathy), which is believed to represent a form of chemical burn to the retinal at the area where the drug is concentrated the most [68, 69]. Retinal function decline due to toxicity, usually highlighted on electroretinography (ERG), is a possible complication of melphalan although the results are conflicting in the literature where one study showed no effect on ERG (dose: 20–30 μg) while another reported non-progressive decreased ERG amplitudes of approximately 5 μV (equivalent to 5% retinal response) with every 30 μg melphalan injection [70, 71, 72]. ERG can actually be a useful tool to monitor these patients for cumulative retinal toxicity.
\nOther major ocular complications that were highlighted in a systematic review with a total of 1287 intravitreal injections given to 306 eyes include: iris depigmentation and atrophy, chorioretinal atrophy with vitreous hemorrhage and retinal detachment [67]. Fortunately, there are no reports of endophthalmitis after IVitC; nonetheless, all protective measures should be taken to prevent this possible devastating complication.
\nWith regards to serious systemic side effects, namely significant neutropenia of grade 3 and 4, these were not observed when analyzing 46 blood samples withdrawn from patients receiving IVitC (despite some patients received concurrent IAC) [71]. Again, this accentuates the benefit of local therapies in these young children.
\nTreating retinoblastoma with vitreous seeding can be really challenging due to the avascular nature of the vitreous; and therefore, drug delivery through systemic routes may not be sufficient sometimes. Besides this, it tends to be resistant to external radiation and systemic chemotherapy [68, 73]. In the past two decades, a quantum leap forward in the management of advanced retinoblastoma was reached with the help of IVitC. The reported vitreous seeding control rates of IVitC (melphalan with or without topotecan) ranges between 60 and 100% [60, 68, 71, 72, 74]. Additionally, the attained globe salvage rates are also impressive reaching up to 100% as reported in one study on 11 eyes receiving a total of 55 intravitreal melphalan injections [69].
\nPeriocular chemotherapy (POC) administration was designed to allow delivery of a higher concentration of the tumoricidal drugs locally. This route was firstly tested in retinoblastoma animal models using carboplatin and it had been shown that this route produces vitreous concentrations 8–10 folds more than the intravenous route [75, 76]. These preclinical results led to the conduction of a trial in which children with retinoblastoma were treated using subconjunctival carboplatin and the results were promising [77]. Thereafter, POC grew in popularity and it was consequently incorporated into the multimodal treatment algorithm of retinoblastoma. Currently, it is a part of the prospective multicenter Children’s Oncology Group trials for retinoblastoma. In this section, POC will be tackled comprehensively.
\nPOC is used predominantly as an adjunctive therapy to systemic chemotherapy as presently there is no evidence promoting it as a stand-alone therapy [78]. It is indicated principally in patients with recurrent localized tumor and in advanced disease (group D and E) where chemotherapy can be desirably infused in higher concentrations without exposing the patient to increased systemic toxicity [7]. It can also be utilized in patients who are not fit to receive systemic chemotherapy as well as patients with recurrent or persistent viable non-calcified vitreous seeds [78].
\nThe common chemotherapeutic agents that are mostly used are carboplatin and topotecan. Experimental work showed that carboplatin peaks in the vitreous after 30 min of periocular injection and lasts for hours. Its concentration in the vitreous is approximately seven times more than that achieved by intravenous chemotherapy [76]. Several periocular drug administrative devices were explored and these include: plain liquid, Lincoff balloon, fibrin sealant, nanoparticles and iontophoresis [76, 79, 80, 81].
\nThis treatment modality fortunately has no systemic side effects. Ocular complications do occur, and these mostly affect the periorbital tissue possibly owing to local toxicity. The most common observed side effects are lid edema, lid erythema, periorbital pseudocellulitis, ptosis, orbital fat atrophy, optic nerve atrophy and muscle fibrosis causing ocular motility changes [7, 77, 78, 82, 83]. Concerns were raised regarding the toxic effect on the extraocular muscles; yet, a study examining the effect of sub-tenon topotecan on the extraocular muscles of 10 eyes concluded that it had no toxic effect on the muscles and it is a safe and effective alternative [84].
\nAlthough the number of studies on POC is limited overall, it had been shown that POC is principally effective when combined with other modalities of anti-neoplastic therapies. One long-term follow up study demonstrated that 39% (n = 33 eyes) of the enrolled eyes were saved when treated with POC in addition to other concurrent treatment modalities. The same report indicated that two eyes treated by POC as monotherapy were cured and remained disease free on follow up [82].
\nIn the last two decades, significant new approaches have been employed in the treatment of retinoblastoma which is a curable disease when diagnosed early. Modalities to avoid enucleation and minimize the short and long term effects of exposure to systemic chemotherapy and radiation therapy continue to evolve and now set the platform in the treatment of retinoblastoma. Despite new techniques such as selective intra-arterial and intravitreal chemotherapy, it is paramount to individualize therapy according to multiple factors including patient age, tumor location, stage of disease, size, and extension, along with realistic visual expectations. Personalized medicine will be able to tailor therapy with the best response and safety in children with retinoblastoma.
\nWe would like to thank the College of Medicine Research Center, Deanship of Scientific Research, and Ophthalmology Department at King AbdulAziz University Hospital under King Saud University, Riyadh, Saudi Arabia for funding and supporting this chapter.
\nThe authors have no conflict of interest to disclose.
The popularization of general anesthesia by William Morton in the 1840’s and the concept of antisepsis introduced by Joseph Lister would lead to a paradigm shift and the emergence of modern surgery [1, 2]. The mastery of surgery was no longer associated with speed or flamboyance, but instead focused on meticulous dissection, careful handling of tissues, hemostasis, and correct approximation of tissue planes to promote adequate healing. Among operative specialties, this transition from “art” to “science” of surgery was most profound in the neurosurgical field, enabling rapid advances to occur.
\nEarly in the evolution of modern surgery, the issue of hemostatic control became prominent, as the heavily vascularized central nervous system and its propensity to bleed resulted in limitations of procedures and posed significant challenges [3, 4, 5]. Surgical ligation was utilized sparingly for fear of vessel rupture or vascular occlusion that may compromise entire vascular distributions. The instruments and techniques in neurosurgical armamentarium therefore relied predominately on application of pressure with gauze to combat bleeding [3, 6]. As a result, a search and incorporation of novel alternatives in hemostatic techniques would effectively lead to the development of modern neurosurgery as represented by Horsley’s use of bone wax and other pioneering hemostatic maneuvers [7, 8] and the introduction of electrosurgery by Cushing and Bovie in the 1920’s [9, 10]. Later in the revolutionary era of neurosurgery, biosurgical materials were introduced [6, 11].
\nIn its broadest sense, the term biosurgery relates to the utilization of biomaterials that are defined as systemically and pharmacologically inert substances designed for implementation within or incorporation with living systems [12, 13, 14]. In the context of the current chapter, biosurgical materials (BSMs) are defined as biomaterials that are intended as adjuncts in attaining surgical hemostasis [15, 16]. The gradual development of hemostatic techniques has greatly impacted not only the field of neurosurgery, but all of surgery. The application of biosurgical agents first developed in the neurosurgical theater proved immensely valuable across virtually all surgical applications.
\nOne of the earliest neurosurgical applications of biosurgical hemostats involved the control of bleeding in inaccessible areas with difficult tissue topography and in situations where use of electrocautery, sutures, or clips may simply not be feasible [4, 13, 17]. This chapter will review the categories, mechanism of action, efficacy, advantages, disadvantages, and complications of the various biological materials currently available for hemostasis in neurosurgery.
\nThe abundance of biosurgical materials available for use requires a system of categorization. These agents can be divided into specific categories based on their mechanism of action, including passive or active hemostatics, flowable agents, and sealants [18, 19, 20]. Passive or mechanical agents act through contact with the site of bleeding to promote platelet aggregation [21, 22]. They form a matrix type network at the site of bleeding, thereby activating the coagulation pathway to provide a platform for platelet aggregation and clot formation. At the same time, these agents will be ineffective if used on patients with known coagulopathies due to factor deficiencies or platelet dysfunction. These products include gelatins, collagens, cellulose, and polysaccharide spheres. They require no special storage, minimal or no preparation, and are relatively inexpensive [23, 24].
\nActive hemostatic agents act biologically and directly participate in the coagulation cascade to stimulate fibrinogen at the site of bleeding to produce a fibrin clot [21, 25]. These agents primarily include the different forms of thrombin, and are useful in patients with coagulopathies or platelet dysfunction [18, 26]. However, they rely on the presence of fibrinogen in the patient’s blood to be effective. In general, they control bleeding more effectively than passive agents, are more costly, and are prepared/available in various forms and formulations.
\nFlowable hemostatic agents consist of various combinations of active and passive components within a single application [20, 27]. This category includes products that work by providing a physical barrier to blood flow while actively converting fibrinogen in blood into fibrin at the bleeding site [26, 28]. Finally, sealants work by the formation of a barrier impervious to flow [24, 29]. There are several types of sealants currently available for use. Our subsequent discussion will focus on each of the various types of biosurgicals utilized, with emphasis on neurosurgical applications.
\nThis material contains 1-μm microcrystals of purified bovine dermal collagen available as flour-like or sheet-like format [30, 31]. The microcrystalline collagenous network provides surface for platelets to aggregate while coagulation factors are released [30, 31]. The effectiveness of microfibrillar materials may be decreased in cases of severe thrombocytopenia (<10,000 mL) [32]. The material should be kept dry prior to use because moisture may decrease its activity and the hydrophilic nature of product results in adherence to surgical gloves and possible mis-application. Consequently, the material is best handled with sterile forceps. As with other biologic hemostats, optimally the smallest amount required to arrest bleeding should be utilized, although this may not be precisely known in every situation.
\nOf importance, microfibrillar collagen is considered a foreign substance and can therefore serve as a nidus for infection and/or foreign body reaction [33]. The small particles of the flour-like material are useful for arresting bleeding from cancellous bone. In this setting, it has demonstrated superior efficacy when compared with other agents, such as thrombin alone or thrombin combined with gelfoam [7]. It also does not seem to interfere with bone healing in contrast to oxidized cellulose or bone wax [34]. It is recommended to firmly pack product into bone surface followed by direct pressure for 5–10 minutes. In terms of clinical application considerations, it should not be used in areas where it may exert pressure on adjacent structures because of fluid absorption and expansion. Also, excessive expansion along a dural sinus may lead to occlusion after bone flap replacement. Although collagen is relatively less antigenic and only results in minor inflammation there remains the very small risk of allergic reactions [35, 36]. Finally, it can also lead to infection, abscess, pseudo-abscess or granuloma formation [37, 38, 39].
\nThis type of biomaterial was developed in the 1940’s to help facilitate hemostasis [40, 41]. It is available as pads, strips or powder [40, 42, 43]. It can absorb seven to ten times its own weight [44]. This ubiquitous hemostatic agent is one of the most frequently used. Upon contact with blood, the material reacts to form a reddish black gelatinous mass containing hematin (accounts for the color change) [45]. The oxidation of cellulose results in a product of low pH with resultant bacteriostatic properties [46, 47]. Despite the antimicrobial properties the rates of infection do appear to correlate with the amount of retained product [48]. Consequently, though often left in place in surgical beds, excess amounts should be removed prior to wound closure. Of note, the addition of saline or thrombin to oxidized regenerated cellulose may decrease its effectiveness in addition to inactivating thrombin as a result of the acidic environment [49]. It may also interfere with bone healing and may cause blood vessel compression [49]. Finally, there are reports of excessive postoperative swelling of this type of biomaterial [50].
\nAlso introduced in the 1940’s this type of hemostatic material consists of water-insoluble sponges prepared from purified porcine skin gelatin [11]. It provides hemostasis by absorbing up to 45x its weight in fluid, thus restricting blood flow and providing stable matrix for clot formation [51]. Gelfoam with gentle pressure can tamponade and treat most dural sinus bleeding without occlusion of the sinus. Although hemostatically beneficial, this capacity to expand physically can lead to compression of neural (and vascular) structures [52]. Absorbable gelatin material is considered relatively nonreactive, however there have been case reports of giant-cell granuloma formation at the implantation site [53, 54]. Although generally non-antigenic, this type of biosurgical material is considered a foreign body and can serve as a nidus for infection [55].
\nThis is a relatively new category of biosurgicals, derived from vegetable starch containing no animal or human components [56, 57, 58]. It is available in powder form with a bellows-type applicator [56, 59]. The material requires no mixing and is available for immediate use. It produces a hydrophilic effect to dehydrate blood and concentrate solid components to increase barrier formation [59, 60]. It poses little risk to patients since it lacks any human or animal components and should not be used in closed spaces because of physical expansion / swelling.
\nThere are three forms of thrombin products differentiated based on type of plasma used to provide concentrated thrombin to rapidly convert fibrinogen to fibrin clot [61, 62, 63]. This class of biosurgicals should be used in cases of mild to moderate bleeding, mainly because such products tend to be easily washed off in the setting of brisk arterial bleeding or surgical irrigation [64]. In addition, thrombin-based hemostatic agents may be less effective in situations of severe fibrinogen deficiency [15]. Finally, thrombin products should not be allowed to enter the vascular system as intravascular thrombosis can occur [65].
\nAntibody formation represents a risk with the use of bovine thrombin, leading to coagulopathy and even death in rare cases [66, 67]. In fact, there is a “Black Box” warning associated with this complication. The use of bovine thrombin is contraindicated if the patient is allergic or has known sensitives to materials of bovine origin [23, 68]. On the other hand, pooled human plasma carries a potential risk of viral or prion disease transmission since multiple units of blood are required to manufacture each lot of product [69, 70].
\nThese products represent a combination of absorbable passive and active hemostatic components [71, 72]. One of the flowables currently available is a combination of bovine gelatin particles and pooled human thrombin [73, 74], while the other consist of absorbable porcine gelatin particles combined with stand-alone thrombin [27, 75]. In order to become effective, the flowables require direct contact with blood as fibrinogen source [76]. Reconstitution is required, with these products having a paste-like consistency and the ability to “remain in place” compared to liquid thrombin [43]. Flowables are applied with a syringe-like applicator and require 2–3 minutes of preparation time [28, 77]. Direct injection into emissary veins or venous sinuses should be avoided to decrease the risk of dural venous sinus thrombosis and post-operative venous stroke.
\nThis group of agents consists of concentrated fibrinogen and thrombin. They increase the rate of blood clot formation by providing higher concentrations of both fibrinogen and thrombin [78]. There are three available types: (a) Pooled human plasma [79, 80]; (b) Individual human plasma, bovine collagen, and bovine thrombin [81]; and (c) Pooled human plasma and equine collagen [82].
\nSealants may be used in coagulopathic patients with insufficient fibrinogen [64, 78, 83]. These agents can also be used in heparinized patients since they do not rely on host factors for hemostasis [84, 85, 86]. Typical indications are hemostasis during cardiopulmonary bypass, splenic injuries, and a number of less commonly utilized general surgical applications [23]. However, they are widely used as hemostatic adjuncts and sealants during neurosurgical procedures, including the prevention of cerebrospinal fluid (CSF) leaks [87, 88].
\nThere are three different product types in this class of biosurgicals [89, 90]. They tend to be most efficacious when used on a relatively dry field to allow sufficient time for polymerization [91]. One type of polyethylene glycol polymers (PGPs) consists of a combination of 2 polyethylene glycol (PEG) polymers that cross-link to each other and contact tissue following application [92]. In effect, the PGP-based network acts as a sealant to tissue fluids as well as barrier to cell ingrowth and adhesion formation [92, 93].
\nAnother type of PGP material consists of a combination of PEG polymer, trilysine amine, and blue dye [94, 95]. This particular component mix produces a hydrogel able to help with dural closure because of its ability to form a watertight seal [96]. A modified derivative using a reduced molecular weight PEG component can be used in sutured dural repair during spinal surgery [96, 97]. The built-in blue dye is used to provide accurate placement of sealant [98, 99]. Some concerns about this particular material being associated with cases of postoperative spinal cord compression have been voiced [94, 100, 101, 102]. As such, specific non-expanding formulations exist for usage in the spinal canal [103].
\nThe third class of PEG polymer compound consists of a combination with human serum albumin. This substance is biodegradable and fairly well studied in terms of safety and effectiveness [104]. It provides a strong barrier, as evidenced by the FDA approval for use on visceral pleura to close air leaks of >2 mm during pulmonary surgeries [105]. There may also be associated economic benefits of using this type of biologic sealant [106].
\nIt is important to realize that biosurgical agents are adjuncts to hemostasis when standard methods like direct pressure, suturing, or cautery are impractical or ineffective [107, 108]. Good knowledge of the mechanism of action of different available biosurgical hemostats is critical, with multiple considerations including the patient’s anticoagulation status, the rate of bleeding, the presence of thrombocytopenia, fibrinogen level assessment, and many other factors. The choice of a specific biosurgical product should be dependent on the type of surgery, site of bleeding, other anatomic considerations, cost, and preference of the operating neurosurgeon [3, 16, 32, 109, 110].
\nThe continuous oozing encountered from dilated varicose intraspinal veins and bone during spinal surgery can be effectively managed with topical hemostats [111, 112]. With that said, such materials should not be left in contact with intra or extradural nerve roots due to possibility of granuloma formation [39, 53, 54, 113]. There have been reports of paraplegia from use of oxidized cellulose during thoracotomy from passage of material through the intervertebral foramen resulting in spinal cord compression [114, 115]. Therefore, it is recommended to use only the minimum required amount and any excess material should be removed once adequate hemostasis is attained.
\nBiosurgical materials are increasingly applied during spinal cord surgery to help with hemostasis since opportunities for electrocautery use are limited in this setting. Bipolar cautery, although more focused than monopolar cautery, can also allow dissipation of heat from the tips inducing thermal injury to vascular and neural structures. Fibrin glues are commonly used as hemostatic agents in neurosurgical procedures, including the management of epidural, cortical, and dural sinus bleeding [116].
\nDuring surgical resection of brain tumors, from craniotomy to extradural hemostasis following dural closure, one will find that these agents are generally used throughout the procedure. For example, oxidized regenerated cellulose is widely used during ablation of lesion(s) and at the end to prevent and abate any bleeding in the remaining cavity. However, excess agent should not be left along the surgical cavity. A single layer of oxidized regenerated cellulose should be sufficient for hemostasis without significant risk. Evaluations of the efficacy and safety of polysaccharide hemospheres reported no adverse events after use in brain surgery. There have been several reports of signal anomalies on post-operative imaging mimicking residual tumor or early recurrence, or even abscess when oxidized regenerated cellulose or gelatin sponges are left in the operative field. A pediatric case series of 3 patients who underwent intracerebral surgery with use of microfibrillar collagen reported that all required second surgery for new or recurrent seizures [38]. An MRI of preoperatively suspected tumor recurrence or abscess subsequently confirmed to be microfibrillar collagen-centric necrotizing granuloma surrounded with macrophages and eosinophils. One must remain aware of the above considerations and remove any local hemostatic agent prior to dural closure.
\nBleeding during surgery on the pituitary via a transsphenoidal approach may significantly impede visualization while not being conducive of the use of electrocautery [117]. The use of oxidized cellulose and Floseal (Baxter, Deerfield, IL) can be useful in this situation. Mild persistent oozing from brain tissue following excision can be controlled with application of oxidized regenerated cellulose followed by its removal from the remaining cavity prior to closure. Defects of the skull base in some cases require filling of the defect with bone graft, followed by suture and/or grafting of the dura reinforced with fibrin sealant. A minimally invasive treatment of spontaneous supratentorial intracerebral hemorrhage was also described using Floseal. Floseal was placed in 31 patients without evidence of vascular anomalies or coagulopathy following evacuation of hematoma from a 3 cm craniotomy. Hemostasis was achieved in all but 1 patient who required re-exploration [118].
\nA multicenter, prospective randomized study with 237 patients undergoing elective cranial surgery demonstrated PEG hydrogel (DuraSeal, Integra LifeSciences, Princeton, NJ) similarly safe when used with common dural sealing techniques (eg, sutures, autologous grafts, gelatin or collagen sponges, fibrin glues) or when used as dural closure augmentation in cranial surgery [99]. The incidences of neurosurgical complications, surgical site infections and CSF leaks were similar between treatment groups using PEG hydrogel and the control group using standard dural sealing techniques. DuralSeal was also found to be statistically significantly superior to fibrin sealant at preventing CSF leaks following posterior fossa craniotomy or craniectomy [119]. However, the special formulation of DuraSeal Exact should be used in areas where expansion can lead to neurologic compromise – such as the spinal canal [120]. This is because neurologic compromise after expansion has been described in the literature [101, 121]. This again emphasizes mindfulness to use to least amount of material to achieve closure and/or hemostasis while precluding migration or expansion of any excess materials.
\nHemostasis in neurosurgery – more so that many other surgical disciplines – is challenged by the closed space environment of the brain, spinal cord, and other critical structures [3, 122, 123]. Unlike other areas in which the “bulk” or space-occupying characteristics of biosurgicals may represent a potential benefit as they expand, this is less desirable in neurosurgical applications. In the closed environment of the skull, brain, or the spinal cord – even if bone is removed to help minimize the effect of swelling from edema – a relatively small amount of compression, especially in critical areas, like the brain stem, can have devastating consequences. As discussed in previous sections of this chapter, such compressive complications, if left untreated can result in irreversible neurologic damage [94, 100, 101, 102], with resultant “Black Box” warnings clearly outlining biomaterial-specific restrictions.
\nOf growing concern in all aspects of surgery is the increasing utilization of anticoagulants and anti-platelet therapies – and often various combinations of both [124, 125]. While the indications for such therapies are outside of the scope of this review, it is clear that more and more patients are being prescribed agents belonging to these broad medication classes. This is of special significance in the elderly population, where anticoagulants and antiplatelet drugs are used for stroke reduction (e.g., in non-valvular atrial fibrillation); various prophylaxis indications (e.g., orthopedic surgery); and of most concern, being used without any clear indications [126]. However, many clinical factors that prompt physicians to initiate antiplatelet or anticoagulant use also increase the neurosurgical risk associated with even minor traumatic events (e.g., falls and minor head injuries). Under such circumstances, even minor neurological injuries can quickly evolve into bleeding-related catastrophes when patients are anticoagulated [127, 128, 129].
\nNeurosurgical interventions in the setting of traumatic (or even spontaneous) subdural, epidural, and intraventricular hemorrhage, when confounded by drugs that inherently interfere with hemostasis can compound the difficulties and risks of an already complex clinical scenario [130, 131]. The overall challenge can be magnified even further as acute reversal agents tend to be expensive, may not always be available, reliable/effective, and could result in thrombotic complications in high-risk scenarios such as multi-trauma or massive transfusion [131, 132, 133, 134]. Furthermore, reversal algorithms and guidelines, while helpful do not always definitively address the acute problem once significant bleeding starts, and regardless of the mechanism and defect in the clotting cascade, a consumptive process may be triggered that might require a multi-faceted approach to effectively and timely manage the associated coagulopathy [134, 135, 136, 137]. Similar to other surgical scenarios, such as major trauma and cardiothoracic surgery, at times the best way of managing bleeding is via a timely and aggressive operative intervention. The above concepts are critical in the setting of neurosurgical applications of biosurgical hemostats in that it must be recognized that “bleeding” is a complex problem and often requires a combination of tools to control. Such basic tools require an understanding of the primary question – why is this patient bleeding?
Other patient factors and comorbidities can have unpredictable effects on hemostasis, but must be considered in the bleeding neurosurgical patients. Elderly, debilitated, and frail patients might be malnourished and hence have impaired protein stores which contribute to diminished clotting factor reserves – even in the setting of normal clotting tests. Patients might be taking herbal supplements (which might not even be reported in a medical record or medication lists) that have been correlated with bleeding risks [140, 141, 142].
Each of the above considerations requires a focused approach and highly specific management strategy. It is important to recognize that good surgical technique must be augmented with a broader understanding of the biologic mechanisms that contribute to the overall disease process and that there is no single tool that is ideal for all circumstances [108, 138]. Conversely, it must be recognized that there is a growing concern that using the wrong or inappropriate therapy for a given clinical scenario can be just as problematic, if not intrinsically ineffective or potentially dangerous. More so than ever in the past, optimal management of the neurosurgical patient (especially one who is bleeding) requires an in-depth and comprehensive understanding of the complex mechanisms of hemostasis pathways and the clotting cascade while also recognizing those variables, such as pharmaceutical therapies, that might adversely impact the normal balance between clotting and bleeding.
\nIn summary, in the setting of neurosurgical bleeding management, several key concepts must be recognized:
Use the right tool for the right job
Sometimes more than one approach is necessary to control bleeding
Different types of bleeding might require different management strategies
Difficult to access areas
Risk for post-operative re-bleeding
Compressive or expanding agents can cause devastating complications
Recognizing the differences between arterial and venous bleeding and how management of each might be different
Understanding the specific reasons why bleeding is occurring and what interventions – such as biosurgical agents – should be central to the overall hemostatic management.
Sometimes the best approach to managing bleeding is preventing it in the first place with strict attention to surgical technique and anatomy. It might sound inherently obvious, but the best way to avoid a dural sinus bleeding is to avoid injury in the first place.
Uncontrolled or difficult to control bleeding in neurosurgery is a challenging clinical problem and one that is becoming more common with wider use of anti-coagulant and anti-platelet agents in a population that is aging, becoming more frail, has more co-morbidities, and is at increasingly greater risk for neurotrauma. In addition, as more patients are undergoing major surgical interventions and re-interventions for complex neuro-axial pathologies the risks for bleeding complications also increase. Effective management of bleeding and bleeding related morbidity requires a thorough understanding of the mechanisms of bleeding and potential biologic defects in the normal hemostatic process. With such an understanding, management can be more focused and targeted towards the specific problem. Hence, an understanding of the adjuvant therapies, such as the full-spectrum of biosurgical agents that can be used to manage bleeding is imperative in achieving optimal patient outcomes.
\nThe authors would like to acknowledge Dr. Roy S. Hwang, for his support and expertise during the preparation of this manuscript.
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He registered 2 patents, wrote 12 international books, published more than 90 SCI journal papers and 45 conference presentations, and served as the technique committee member as well as chair in many international conferences and the editor in BMC Genomics as well as in Current Issues in Molecular Biology, and also a reviewer for more than 25 SCI cited journals. He received several awards, including State Prize awarded from the Academy of Science, Egypt (2004); Young Arab Researcher Prize awarded from Schuman Foundation, Jordan (2005); State Excellence Prize from the Academy of Science, Egypt (2011 and 2018); and Cairo University Prizes (2007, 2010, and 2014). He served as an expert for African Regional Center for Technology, Dakar, Senegal, plus a visiting professor at Pan African University, African Union, Nairobi, Kenya. He was appointed acting vice president of the Academy of Science and Technology from November 2013 to November 2014, Egypt. 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