National indicators of higher quality palliative care. From 2015 quality of death index of the Economist [1].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"604",leadTitle:null,fullTitle:"Earth Observation",title:"Earth Observation",subtitle:null,reviewType:"peer-reviewed",abstract:"Today, space technology is used as an excellent instrument for Earth observation applications. 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It discusses the industrial uses of some minerals as raw materials and in electrical firms and gemology. The book also introduces several works on synthesis of some compounds and applications of mineralogy in biomedicine, including iron oxide nanoparticles and nannocomposites, and their biomedical applications as diagnostic and drug delivery tools for treatment of cancer and many other diseases.",isbn:"978-1-78985-826-6",printIsbn:"978-1-78985-825-9",pdfIsbn:"978-1-83880-738-2",doi:"10.5772/intechopen.83247",price:119,priceEur:129,priceUsd:155,slug:"mineralogy-significance-and-applications",numberOfPages:174,isOpenForSubmission:!1,hash:"5149699e666cbb61c220646173769f18",bookSignature:"Ali Ismail Al-Juboury",publishedDate:"May 27th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9247.jpg",keywords:null,numberOfDownloads:3050,numberOfWosCitations:2,numberOfCrossrefCitations:7,numberOfDimensionsCitations:8,numberOfTotalCitations:17,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 13th 2019",dateEndSecondStepPublish:"September 17th 2019",dateEndThirdStepPublish:"November 16th 2019",dateEndFourthStepPublish:"February 4th 2020",dateEndFifthStepPublish:"April 4th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"58570",title:"Prof.",name:"Ali",middleName:"Ismail",surname:"Al-Juboury",slug:"ali-al-juboury",fullName:"Ali Al-Juboury",profilePictureURL:"https://mts.intechopen.com/storage/users/58570/images/system/58570.png",biography:"Ali Ismail Al-Juboury is a professor in the Geology Department, University of Mosul, Iraq. He obtained his BSc in Geology and MSc in Sedimentology in 1980 and 1983, respectively, and his PhD from Comenius University, Slovakia, in 1992. He has published more thah 100 papers in local and peer-reviewed journals in the fields of mineralogy, petroleum geology, sedimentology, and geochemistry. He is a member of numerous international societies and serves on the editorial board of the Iraqi Geological Journal and International Sedimentology and Stratigraphy Journal of Oil and Gas Basins, Azerbaijan, and International Journal of Geophysics and Geochemistry (American Association of Science and Technology). He has received several awards, such as the Distinguished Scholars Award from the Arab Fund for Economic and Social Development, Kuwait, in 2009, and the Science and Technology (Geology) Award from the Islamic States in 2014.",institutionString:"University of Mosul",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"University of Mosul",institutionURL:null,country:{name:"Iraq"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"651",title:"Mineralogy",slug:"geology-and-geophysics-mineralogy"}],chapters:[{id:"64824",title:"Hematite Spherules on Mars",slug:"hematite-spherules-on-mars",totalDownloads:546,totalCrossrefCites:0,authors:[{id:"257657",title:"Dr.",name:"Anupam",surname:"Misra",slug:"anupam-misra",fullName:"Anupam Misra"},{id:"272258",title:"Dr.",name:"Tayro",surname:"Acosta-Maeda",slug:"tayro-acosta-maeda",fullName:"Tayro Acosta-Maeda"}]},{id:"69780",title:"Mineral Chemistry of Chalki Basalts in Northern Iraq and Their Petrological Significance",slug:"mineral-chemistry-of-chalki-basalts-in-northern-iraq-and-their-petrological-significance",totalDownloads:265,totalCrossrefCites:0,authors:[{id:"58570",title:"Prof.",name:"Ali",surname:"Al-Juboury",slug:"ali-al-juboury",fullName:"Ali Al-Juboury"},{id:"219752",title:"Dr.",name:"Mohsin",surname:"Ghazal",slug:"mohsin-ghazal",fullName:"Mohsin Ghazal"},{id:"300008",title:"MSc.",name:"Sabhan",surname:"Jalal",slug:"sabhan-jalal",fullName:"Sabhan Jalal"}]},{id:"68291",title:"Titanite from Titanite-Spots Granodiorites of the Moldanubian Batholith (Central European Variscan Belt)",slug:"titanite-from-titanite-spots-granodiorites-of-the-moldanubian-batholith-central-european-variscan-be",totalDownloads:367,totalCrossrefCites:0,authors:[{id:"142108",title:"Dr.",name:"Miloš",surname:"René",slug:"milos-rene",fullName:"Miloš René"}]},{id:"69711",title:"Investigation of the Usability of Pseudoleucites in Central Anatolia Alkali Syenites as Industrial Raw Materials",slug:"investigation-of-the-usability-of-pseudoleucites-in-central-anatolia-alkali-syenites-as-industrial-r",totalDownloads:195,totalCrossrefCites:0,authors:[{id:"299081",title:"Dr.",name:"Zeynel",surname:"Başıbüyük",slug:"zeynel-basibuyuk",fullName:"Zeynel Başıbüyük"},{id:"299082",title:"Dr.",name:"Gökhan",surname:"Ekincioğlu",slug:"gokhan-ekincioglu",fullName:"Gökhan Ekincioğlu"}]},{id:"71848",title:"Mineralogical-Petrographical Investigation and Usability as the Gemstone of the North Anatolian Kammererite, Tokat, Turkey",slug:"mineralogical-petrographical-investigation-and-usability-as-the-gemstone-of-the-north-anatolian-kamm",totalDownloads:207,totalCrossrefCites:0,authors:[{id:"299081",title:"Dr.",name:"Zeynel",surname:"Başıbüyük",slug:"zeynel-basibuyuk",fullName:"Zeynel Başıbüyük"},{id:"299082",title:"Dr.",name:"Gökhan",surname:"Ekincioğlu",slug:"gokhan-ekincioglu",fullName:"Gökhan Ekincioğlu"},{id:"317737",title:"Dr.",name:"İlkay",surname:"Kaydu Akbudak",slug:"ilkay-kaydu-akbudak",fullName:"İlkay Kaydu Akbudak"}]},{id:"71052",title:"Enhanced Humidity Sensing Response in Eu3+-Doped Iron-Rich CuFe2O4: A Detailed Study of Structural, Microstructural, Sensing, and Dielectric Properties",slug:"enhanced-humidity-sensing-response-in-eu-sup-3-sup-doped-iron-rich-cufe-sub-2-sub-o-sub-4-sub-a-deta",totalDownloads:221,totalCrossrefCites:7,authors:[{id:"266255",title:"Dr.",name:"Jagadeesh",surname:"Angadi V",slug:"jagadeesh-angadi-v",fullName:"Jagadeesh Angadi V"},{id:"321561",title:"Dr.",name:"I.C.",surname:"Sathisha",slug:"i.c.-sathisha",fullName:"I.C. 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Ultimately, it is in clinical practice, the collective activities of health care providers, that the majority of critical activities bearing on actual patient palliative care experiences occur. To a great degree, the broad area indicators reviewed reflect community and political interest as well as financial investment. Unquestionably, such attention can, over time, lead to higher-quality palliative care, but throughout the world what governs the experience of individual patients needing palliation is primarily determined by the organization of medical practice, the attention of clinicians, and the focus of health systems. In the United States, as Emanuel has suggested in identifying key directions for the future of medical practice, effective organizations are those that transform provider interactions in palliative care [2]. It is in this context that the goals of this communication are addressed: more immediately than can occur to address the broad national and community indicators, how can general clinical practice globally be favorably affected to provide efficient and more effective palliative care for all patients needing such service? We describe here an information technology tool-facilitated basic system we believe is easily implemented and widely adaptable to clinical practice circumstances in many countries. By addressing common major barriers to provision of palliative care, we can increase practitioner engagement in such care at significant patient-benefiting levels.
\nNational policies addressing palliative care | \n
Higher levels of public spending | \n
Extensive training of health professionals | \n
Patient care subsidies | \n
Availability of opiate drugs | \n
Public awareness | \n
National indicators of higher quality palliative care. From 2015 quality of death index of the Economist [1].
Three-quarters of patients with advanced cancer are reported to suffer from pain and “85% of patients (with pain) can be well palliated with the use of simple, inexpensive, ‘low technology’ oral analgesics” [3, 4]. Unfortunately, however, there is little evidence supporting the long-term benefit of these analgesics and other symptom-alleviating interventions [5]. What and where are the barriers to closing these gaps? (Table 2).
\nPractitioners lack current patient data on symptom presence and severity | \n
Practitioners lack practical, quickly accessed information on palliative interventions | \n
Lack of efficient local systems for providing palliative care, particularly at home | \n
Insufficient numbers of health professionals | \n
Higher level interventions with no practical effect in the short- or medium-term, including increasing numbers of hospices, specialists, or specialist training activities | \n
Barriers to effective palliative care in clinical practice.
A primary barrier to provision of adequate symptom treatment for patients is a clinical practice failure sequence: under-appreciation from under-assessment by clinicians of the types and intensities of symptoms patients are experiencing, which then logically is associated with very limited or absence of interventions to address these or the consequent helplessness and hopelessness that are root causes of suffering [4, 5, 6]. To provide optimal care for patients with cancer and other life-threatening illnesses, practitioner-available accurate, complete, and timely information about symptoms, daily information if possible, is necessary. Specifically, repeated failure among physicians worldwide to use validated symptom assessment tools prevents communication between patients and health-caregivers that could bring attention to symptom issues [7]. The usual way such information is obtained is through direct questioning or information provided in completing paper instruments during patients’ relatively infrequent (and typically very brief) office visits with medical practitioners. If symptomatic status information could be obtained regularly, for example on a daily basis, and brought to the attention of the caring practitioners, this would be expected to improve symptom management and decrease suffering. This kind of activity is what characterizes comprehensive hospice programs and contributes significantly to their effectiveness for patients and their positive image for family members. Additionally, the development of regularly obtained symptom data would provide the basis for measuring, reporting, and improving the quality of palliative care, all absent in general current practice [2].
\nA second major palliative care practice barrier is the absence of immediately-accessible information on locally practical, affordable, and effective interventions. A generally useful approach to more widespread use of effective interventions across the board in medicine has been the development and promotion of clinical practice guidelines. Academic approaches to such palliative care guidelines have been comprehensive, but overwhelming in their dimension and their lengths, and thus impractical for over-scheduled clinicians everywhere. The American NCCN clinical practice guidelines for palliative care are 106 pages in length [8]. Increasingly, attempts are underway to create succinct and practical palliative care clinical practice guidelines specific to each country to address all of the common symptoms, and that are well-grounded in local conditions and circumstances. There has been, however, even more limited attention to facilitating access to such guidelines and employment of their recommendations.
\nA third major palliative care practice barrier worldwide is the absence of efficient systems and processes to facilitate physicians’ engagement in successful palliative care. Components of this situation are the understandable interest of patients and families in home care over institution or medical facility care, a dearth of practitioners in low- and middle-income countries comfortable with palliative care problem-solving and practice, and general clinical practice circumstances in which physicians are overburdened. Further, even if physicians were to have patient symptom and applicable intervention information readily available, their practice systems are not organized to allow them to provide home care as part of the workload for which they can be appropriately compensated financially. Worldwide, the palliative care manpower shortage situation cannot be realistically addressed by scaling-up training of adequate numbers of palliative care specialists. The practical approach is to facilitate engagement of physicians across all practice specialties in basic palliative care, under cost-effective and efficient locally-acceptable systems. The Economist investigation recognizes this need in emphasizing that training for all doctors and nurses is essential [1].
\nIn general, there is a lack of approaches that consider whole populations in a public health perspective that addresses clinical-practice systems to provide for palliative care needs. Calls for increasing manpower of palliative care specialists, residential hospices, or educational activities regarding palliative care, even if successful, can simply not be expected to address adequately the large numbers of patients needing palliative care. These calls stem from the usual starting point—a provider-centric model of health care that needs to be replaced by a more patient-centric model. Simplistically speaking, the evolution of our health systems, particularly in the United States, has been grounded in addressing how things can and should ideally work for providers fixing problems, not supporting patients. This has led to organizational functioning and operations that produce fragmented care oriented to a disease; patient goals, wishes, perspectives and, most importantly, needs are regularly ignored. Addressing palliative care better can logically start by focusing on these patient-centered factors. In many ways, articulating an approach to palliative care is a tabula rasa, because, according to the Economist report documents, it is only in some high-income countries that apparently reasonable levels of palliative care for those in need are being provided [1]. Our personal experiences over the last 15 years in multiple health care settings across Asia, most particularly in Bangladesh (ranked 79 out of 80 countries in the Economist report), support the general conclusion that for the majority of global citizens, palliative care, at even the most basic levels, is nonexistent. It is within this broad perspective that the authors present the current innovations. Under the premise that information technology (IT) tools could contribute constructively to creation of patient-centered, effective, and cost-effective palliative care systems feasible within diverse health care systems in low- and middle-income countries (LMICs), we have been working for several years to develop practical, user-friendly, affordable IT tools and systems which address these afore-stated barriers [9, 10, 11].
\nIf, instead of seeking paper questionnaire data on symptoms at the times of office visits, symptomatic status information could be obtained regularly on the day’s experience from home by use of patient cell phones and delivered to attentive and responding physicians and caregivers in real-time in a well-organized way that complements prevailing overburdened physician practice with appropriate financial compensation, we could expect to improve symptom management and decrease suffering. Changing the collection and recording of patient symptom data from a medical staff task, currently done inefficiently and irregularly, if at all, to a patient task and responsibility has multiple major consequences [7]. First, it obviously simplifies and eases the operations of often hectic and overburdened clinic staff. In circumstances where electronic medical records have been extensively implemented, a well-described scenario occurs: the addition of more and more features makes the software system progressively more frustrating to use, developing it into what is called a “Tar Pit”. Second, it allows creation of a legible standardized record of symptoms, which can be permanently filed in some patient record system. Simple standardization of a rating system enhances clinical staff interpretation of those records and easily notices and responds to a (sudden) increase in any one symptom. Third, critically, it engages the patients and their family members in openly identifying in detail the breadth of common symptoms. Fourth, and perhaps even more critically, the process of recording and submitting symptom reports by cell phone sets the stage for increased patient and family expectations about attention to those very symptoms.
\nExperienced clinicians report that when they have provided such means for patients to report specific data, expectations are high that there will be a closing of the loop with a clinician’s response. In the circumstances of serious symptom report, for example a high level of pain, particularly if sudden and/or new, such empowered patients and family members react strongly if there are not prompt clinician responses. The perception is that if clinicians allow such information submission, they should have the capacity to process and act on it. The kinds of unhappy conversations that follow when patient reports do not elicit health professional or system responses can easily be imagined. In fact, when a patient computer-submitted report study that involved multiple practitioners did not train the practitioners beforehand in the creation of response systems, the clinicians experienced angry communications from patients and families in the absence of prompt responses to reports that demanded intervention. The practitioners quickly developed their own response systems to meet patient expectations, an example of a patient-driven change driven by enabling patients to communicate their needs.
\nWe have first developed a basic cell phone symptom-status application, the reliability, feasibility, and validity of which we have established in studies in Bangladesh and Nepal [9, 10, 11]. The Marquette Symptom Assessment Survey (MSAS) is a 15-item questionnaire covering 12 symptoms; 4 items address pain dimensions. It is constructed using time-tested items from two well-validated and reliable instruments, the Edmonton Symptom Assessment Survey and the Brief Pain Inventory, and three additional items from prevailing palliative care practice: constipation, sleep quantity, and sleep quality [11, 12, 13] (Table 3). Current forms of this questionnaire in English, Bengali, or Nepali are presented on an Android cell-phone platform and display the questions in sequential fields in legible and audio-presented modes, allowing the patient, including those who are illiterate, to answer each question by moving a cursor along a Likert scale, which is a unidimensional 10-point visual analogue scale (Figure 1, top rating scale).
\nNausea1 | \n
Tiredness1 | \n
Depression1 | \n
Anxiety1 | \n
Drowsiness1 | \n
Appetite1 | \n
Well-being1 | \n
Shortness of breath1 | \n
Current pain1 | \n
In last 24 hours: worst level of pain2 | \n
lowest level of pain2 | \n
usual level of pain2 | \n
Constipation | \n
Quantity of sleep | \n
Quality of sleep | \n
Laminated symptom scale and symptoms-to monitor pocket ruler.
In a pilot study, 10 women with advanced breast cancer provided inter-rater and intra-rater reliabilities of >0.73, and patients or their caretakers were able to successfully submit reports despite progressive terminal illnesses [10]. These women and their families willingly and regularly submitted reports over several months. In <3 minutes, with minimal training, patients could and did answer the questions to indicate the presence and intensities of their symptoms. Subsequent extensive field testing and a large cross-sectional study of over 1000 patients with advanced cancers in Bangladesh and Nepal have established that this application is reliable, valid, and user-friendly, and can be employed by almost 100% of patients from a broad spectrum of socioeconomic circumstances. Specifically, in 640 adult Bangladeshi patients with advanced cancers under regular care in tertiary level institutions, all but two patients recruited agreed to study participation; all of these 638 patients had no trouble completing the questionnaire, despite the fact that some of the patients did not personally possess their own Android/smart phone [11, 14]. Only 2 patients out of the 640 said they would not choose to provide future monitoring data using this application [11]. Among 383 similarly recruited patients with advanced malignancies in Nepal, no patients refused study participation, all were able to complete the questionnaire rapidly, and none said they would refuse to provide future monitoring data with this questionnaire. Cell phone penetrance in Bangladesh is >90%; our Bangladeshi colleagues estimate that perhaps 50% of Dhaka residents have Android phones. In Nepal, more than 90% of families have access to cell phones, 2/3rds of which are estimated to be Android phones.
\nAssuming that patients can understand the symptom-intensity Likert scale and that there are no major cultural factors which influence specific patient reports such as language interpretations of the end-points, for example, or beliefs that there are “right” answers, which might lead to mid-scale scores, it is important to ask how we should define mild, moderate, and severe scores, and what unit changes in scores might be truly meaningful for patients. We have explored some of these cultural issues in our data from Bangladesh and have concluded that our data present a true picture of patients’ symptoms [14]. With respect to word definitions in English for describing symptom intensity, we have chosen to consider as “mild” symptom scores of 3–4; otherwise our definitions are similar to those widely used. It is important to note that the scales are graphically as well as verbally defined. Regarding clinically significant score changes, for pain, it is reported that changes of 1–2 units, or down from moderate (5–6 score) to mild 1–4 scores, are, for patients, clinically significant [15].
\nIn summary, we have developed a reliable and validated symptom assessment tool, specifically tailored to palliative care by adding questions about constipation and sleep because these issues are frequently of importance for such patients. This tool has been easily and rapidly used by essentially all studied patients (together over 1000) in two low-middle income countries. Importantly, ongoing repeated use was favorably perceived by patients and family members, even in the face of suboptimal patient symptom relief. After the deaths of relatives, family members repeatedly told staff members receiving the symptom reports how grateful they were for the opportunities to regularly engage the staff in assisting their loved ones. To them, often the most important matter was that everyone was paying attention to their relatives’ symptoms. Thus, requesting and recording patient experience can be validated even when no intervention is possible—the opposite of clinician abandonment.
\nWhile the foregoing barrier considerations are all valid and should be the focus of interventions, successful palliative care management must begin with some understanding of the numbers, levels, and types of symptoms experienced by patients with limited life expectancy and the implications of that experience. Thus, we began as Cleeland did some 25 years ago in the United States, investigating the symptom picture for patients with advanced malignancy in two low- and middle-income country (LMIC) sites [11, 16]. The cross-sectional study described above allowed such evaluation for populations in Bangladesh and Nepal [11, 14, 17].
\nIn Bangladesh, usual pain scores were ≥5 in two thirds of patients, but few patients had very high or minimal scores [11, 14]. Majorities of patients reported moderate scores for tiredness, nausea, depression, anxiety, drowsiness, poor appetite, and poor sleep [14]. The reported high intensity levels of these symptoms were not surprising to our Bangladeshi clinician colleagues. Collectively these symptoms contributed significantly to the suffering of these patients. For example, pain scores were correlated significantly with scores for nausea, anxiety, and poor sleep [14]. The patient population studied here might be expected to have a lesser symptom burden than that of the broad population of palliative care-needing patients in the country, because these patients were able to travel and seek care in tertiary care institutions. Overall, we interpret these data to suggest that there is high level and multi-symptom suffering among patients needing palliative care in Bangladesh, despite access to tertiary level care. The moderate pain scores for the majority of patients studied, along with minimal frequencies of high-score levels, suggest partial- and under-treatment. These conclusions are consistent with the Economist report assessment for the country, and with, for pain, the low level of narcotic consumption per capita [1, 18]. More important for the current communication is the practical usefulness of the tool used and these data in developing and targeting interventions [14]. Specifically, it is reasonable to suggest that under-treatment might be partially addressed by physicians having more symptom information in real time, the very issue our cell phone system seeks to address.
\nIn Nepal, among the 383 studied patients, 37% reported maximal pain scores of 7 or greater [17]. Disturbingly, 5% of patients reported maximal pain scores of 10 [17]. A total of 59% of subjects however reported minimal pain. Again, the majority of patients reported moderate or greater levels of tiredness, depression, anxiety, poor appetite, and poor sleep. Alarmingly, 15% and 19%, respectively, reported severe depression and anxiety scores [17]. Our interpretation of these data is that again the cell phone questionnaire tool was very useful in developing reliable and informative data. Here, in contrast to Bangladesh, it appeared that a major fraction of the population had no pain management intervention at all.
\nIn summary, in two LMIC settings, we have been able to demonstrate that our cell phone questionnaire tool can be used to develop important, clinically-useful patient symptom data.
\nAs discussed above, a practical barrier for clinicians to effectual palliative care is having easy and quick access to information about evidenced-based interventions. For LMIC settings, the first issue is creating such guidelines. Ideally, such guidelines would involve, as they have in high-income countries, comprehensive, rigorous, and transparent local processes involving a large cross section of local stake-holders and experts. The challenge, of course, is that such activities are expensive. Recognizing that the perfect is the enemy of the good, and that having some credible palliative care clinical practice guidelines in each of our pilot LMIC sites would be better than having none, we have created local guidelines in each country. Using the limited resources and experts available, we grounded these documents on local and international sources [8]. The 7-page document for Bangladesh is available at
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Clinical Practice Palliative Care Guidelines.
To integrate the cell phone questionnaire patient data and the clinical practice guidelines for practitioners in a system that will facilitate provision of palliative care interventions, we have created websites in Bangladesh and Nepal (
Entering this section, physicians can access the following:
The Clinical Practice Palliative Care Guidelines.
Basic descriptive instructions for patient symptom report review.
A menu of types of the different reports that can be generated with one click.
A list of specific patients registered to each clinician.
Current or most recent MSAS reports for their patients.
An historical graph of any score for last 14 or 28 days.
Individual demographic and medical summary data for their patients, as outlined in Tables 5 and 6.
A link to specific Clinical Practice Guideline intervention suggestions if any moderate or greater symptom score is reported.
Twice-weekly alerts by text and/or email, by physician’s preference, if any patient reports symptoms with an increase in the level of an individual item score by more than 2 units, or a pain score of level 7 or greater results.
A follow-up alert after a phone call has prompted a patient to send a confirmatory duplicate report to correct for patient entry errors.
A prescription-writing field, with links to specific Clinical Practice Guideline intervention suggestions, and a menu of commonly prescribed drugs, standard indications, recommended doses, and standard use instructions. When an individual menu item is selected, drug, dose, and usage instructions automatically fill the individual patient’s prescription field. When the patients’ field is clicked on, their name and the date and other data required for prescriptions, as well as the physician’s name, are also automatically entered into the prescription field. A prescription cannot be completed without independent physician identity confirmation digital delivery is available.
Name | \n
Date of birth | \n
National identity number | \n
Home address | \n
Patient mobile phone | \n
Patient email address | \n
Patient facial photograph | \n
Family or closest friend contact information: | \n
1. Name | \n
Contact information | \n
2. Name | \n
Contact information | \n
Notes: | \n
Patient demographic dashboard.
Name | \n
Major medical problems and diagnoses | \n
Current major symptoms (most recent MSAS report) | \n
Symptom MSAS score Date | \n
Current medications (most recent prescription) | \n
Notes: | \n
Patient medical summary dashboard.
At least every 2 weeks, there will be a visit to the responsible physician. In recognition that repeated clinic visits may be a burden to family or patients, may worsen the very symptoms that are the target of care, and may even not be possible, the clinician will see either the patient or a family member. If the patient is not physically present at the clinic, the physician will call him or her during the visit, and confirm the information shared by a family member. This will also discreetly serve to avoid opioid theft and diversion, as well as to confirm that the patient is alive and receiving medication. Further benefit of the clinic visits is continuity of record keeping, so that the palliative care website can remain auxiliary and does not need to match or duplicate any one facility’s medical record system. These visits will also coordinate palliative care with the facility billing procedure, ensuring that physicians will be compensated at their usual rates for their time and expertise and encouraging their participation in the palliative care program. Palliative care is therefore insulated from the economic, administrative, and political concerns of a facility and does not interfere with the compensatory concerns of the physicians.
\nUse of the cell phone symptom questionnaire “app” described in Section 2.1 and the website described in section 2.4 by physicians and patients is managed under the following system: patients or physicians contact the local system operating organization to learn about and register for system use. In Bangladesh, this is a nongovernmental organization, Amader Gram, and in Nepal, this organization is The Nepal Association for Palliative Care (NAPCare).
\nThe local organization:
Educates patients and families (and physicians) about the system. An essential requirement is that ongoing use of the system requires a clinic visit to the responsible physician at a maximum of every 14 days by the patient or a family member.
Registers the patient and doctor in the website system so that cell-phone submitted patient symptom reports will be accepted and filed, associated with the responsible physician.
Provides the physician with a website doctor’s password and obtains a fingerprint for prescription writing verification/security.
Provides the physician with a pocket-sized paper copy of the local Palliative Care Clinical Practice Guidelines as described in Section 2.3 and a laminated symptom-scale and symptoms-to-monitor pocket ruler (Figure 1).
Encourages conduct of a baseline palliative care assessment clinical visit to clarify and codify breadth of patient medical diagnoses, specific symptoms and their likely pathophysiology, patient and family goals, and an overall palliative care plan (Table 7).
Completes, along with the patient, the demographic “dashboard” database for that patient (Table 5) and identifies the responsible physician who agrees to provide care for that patient using the system.
Works with the responsible physician using the baseline assessment data to create the medical summary “dashboard” database, and posts this database on the website.
Assists patients in obtaining the cell-phone patient symptom questionnaire application from the Google store.
Trains the patient and family in making symptom assessments, and then recording, and submitting them to the website.
Arranges for payment (or waiving) of modest monthly fee to the local organization for submission of the reports and their availability on the system website. Use of an online payment system like PayPal can facilitate these transactions. Note that this fee can remain small because it covers the administration of the efficient palliative care system, not medical care compensation.
Provides a text and telephone trouble-shooting “hotline” for patients and physicians and insures coverage.
Maintains smooth operation, security, and accuracy of the website system. Reviews and updates the clinical practice guidelines periodically.
Acts as an intermediary with responsible physicians for patient crises.
Seeks feedback from the patient, families, and physicians regularly on system operations and problems and vigorously seeks to extend the use of the system, by marketing, to as large a patient population as possible.
Seeks peer review of anonymized patient data and management for quality assurance to evaluate quality of care.
Seeks to develop and conduct a rigorous evaluation of the entire system to determine the impact of the system on patients’ symptoms, quality of life, and survival.
Seeks, from the start-up phases on, to develop an operational business model that secures local system sustainability.
Date of evaluation: | \n
All major medical diagnoses | \n
(For cancer, list primary site of origin and sites of known clinical metastases) | \n
1. | \n
2. | \n
3. | \n
Performance status (ECOG scale 1–4) | \n
Vital signs: Blood pressure, pulse, respiratory rate, temperature | \n
Weight BMI | \n
Height | \n
Results of the most recent examination showing disease status: | \n
Physical examination (+findings) | \n
Imaging tests: | \n
Hemoglobin | \n
Current symptoms by Marquette Symptom Assessment Survey | \n
Pain: Maximal pain score | \n
Minimal pain score | \n
Usual pain score | \n
Current pain score | \n
Major site(s) of pain and presumed causes (Inflammation, neuropathic, diffuse or focal bone, other) | \n
MSAS score | \n
Tiredness | \n
Nausea | \n
Depression | \n
Anxiety | \n
Drowsiness | \n
Anorexia | \n
Illness | \n
Shortness of breath | \n
Constipation | \n
Sleep quantity | \n
Sleep quality | \n
Patient major goals | \n
Family concerns and goals | \n
Management plan | \n
Problem/symptom Intervention/treatment | \n
Palliative care baseline assessment checklist.
In 2013–2014, the cross-sectional study described above was done in both Bangladesh and Nepal [11]. As detailed earlier in this chapter, considerable developmental work with the tools and on the system described here has been done in Bangladesh. By the end of 2017, the website and software had been developed and we were ready to launch the system as a business with Amader Gram. Unfortunately, various Amader Gram personnel and broad political uncertainty in the country have subsequently prevented further activities as of the end of 2018.
\nDuring the last half of 2018, we have been setting up the website and the operational system for this palliative care service model in Nepal. During the first 6 months of 2019, major clinical piloting experience with this system will be underway at a major cancer hospital outside of Kathmandu.
\nHow to respond meaningfully to the data from reports like those of the Economist and to general calls for addressing palliative care globally is challenging [1, 19]. In this chapter, we argue that there can be a constructive way forward with immediate impact by taking a patient-centric, bottom-up approach to clinical practice systems, their barriers to palliative care, and the potential of IT tools and software. The system we present can in part and wholly be adapted to other country’s circumstances, through a relatively minor investment of resources. High-income countries are beginning to develop and use such tools and systems in palliative care, and integration of such systems into established electronic medical record systems is achievable when the control issues can be worked out [2]. Until then, this system can economically function as a program auxiliary to facilities with medical records and those without. The system we present is particularly important in being directed at engaging clinicians/physicians who might otherwise avoid, refer, or somehow abandon their patients who now need palliative care. It can also be employed in noncancer specialties other than oncology that deal with chronic pain, and even be a resource for clinicians with less frequent need for palliation, or those in rural areas with fewer resources. Because our system is patient-centric and relies on and facilitates greater patient and family engagement and control, it also encourages stronger family support.
\nThe entire system focus on palliative care might be expected to generally lower the total care costs, with minimal patient family expenses for submission of symptom reports and clinical office visits. In general, while limited, the available data suggest that facilitating home palliative care is effective for symptomatic relief of patients and is grief-limiting for families, while the overall cost efficacy remains to be well-understood [20]. We believe that after being extensively piloted, our system in Nepal and Bangladesh should be rigorously evaluated in a randomized clinical trial to document the impact on symptoms over time and overall patient survival.
\nThe increasing use of IT technologies in patient care, including the use of video images and consultations, offer many ways of adding to the capacities of the system we describe. It would very much seem that affordable, efficient, and effective home care/palliative care should be within the reach of many more countries and global citizens.
\nThe authors wish to acknowledge very helpful discussions about the development of the system discussed in this chapter with Reza Salim, Tahmina Ferdousy, Arunangshu Das, Bishnu Paudel, Deepak Shrestha, and Roshni Gautam.
\nThis chapter focuses on the treatment of acute cerebral ischemia and intracranial hemorrhage, which are two types of stroke. Stroke is characterized by a sudden loss of brain function with no established cause other than vascular origin. This applies to both ischemic stroke and intracranial hemorrhage.
\nAcute stroke suggests the following signs:
Sudden onset of symptoms and development of the clinical picture in a few seconds or minutes with further stabilization or improvement.
Focal neurological symptoms associated with damage to certain parts of the brain: motor deficits (weakness or immobility of the limbs on one side of the body (hemiplegia or hemiparesis) or an isolated limb), loss of sensitivity (decreased sensitivity in various parts of the body), aphasia, agnosia, and vision disorders.
Symptoms suggesting a loss of function: limb tremors, convulsions, paresthesias, visual hallucinations, and flashes before the eyes.
Headache, nausea and vomiting, dysphagia, dysarthria, dysphonia, diplopia, ataxia, hiccups, one-sided acute hearing loss, respiratory disorder, convulsive syndrome, and transient loss of consciousness may be clinical manifestations of a stroke localized in the brain stem.
Symptoms such as loss of consciousness, dizziness, general weakness, confusion, urinary incontinence, syncopal condition, and tinnitus do not indicate the development of a stroke if they are not associated with focal neurological symptoms.
For the differential diagnosis of ischemic and hemorrhagic strokes, it is necessary to conduct a neuroimaging study [1]. This is the most important stage of diagnosis, because patients with ischemic and hemorrhagic strokes require different therapies in the acute period and various measures of secondary prevention [2].
\nMagnetic resonance imaging (MRI) is the most appropriate diagnostic method for patients with acute cerebral circulation disorders due to the following reasons [3]:
T1- and T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences allow the differentiation of old foci and foci of nonvascular origin.
Diffusion-weighted images allow the identification of new ischemic foci. Low brain blood flow causes the development of cytotoxic cell edema and, as a result, a decrease in the movement of extracellular fluid, which is displayed as a hyperintensive signal on diffusion-weighted images, and a decrease in the water diffusion coefficient. These changes appear earlier than changes in T1 and T2 and FLAIR.
T* sequences are used to detect hemorrhages.
Time-of-flight (TOF) MR angiography can be used to visualize the occlusion of extra- and intracranial arteries.
When MRI is not available in an emergency or cannot be performed due to contraindications (established rhythm driver, claustrophobia, psychomotor agitation), an emergency computed tomography (CT) scan of the brain is performed without contrast. CT scan reveals an intracranial hemorrhage in the form of a hyperintensive zone in the brain parenchyma. Figure 1 shows a non-contrast CT scan with a spontaneous hyperdensity of the right cerebral hemisphere, due to a deep intracerebral hemorrhage (ICH). In the early stages of acute cerebral ischemia, CT signs of ischemia may be absent. But within 3 hours, you can see signs of ischemia, for example, the disappearance of a clear border of gray and white matter. With the occlusion of the middle cerebral artery, CT signs will appear in the form of a hyperintensive zone. CT with contrast allows you to visualize the anatomy of the arteries and perfusion.
\nNon-contrast CT scan shows a spontaneous hyperdensity of the right cerebral hemisphere.
The most common causes of ischemic stroke are common atherosclerosis, atrial fibrillation (AF), occlusion of small perforating arteries of the brain, pathology of heart valves, and infectious diseases, in young patients—cerebral artery dissection.
\nIntracerebral hemorrhages in most cases are the result of the damage to small cerebral vessels due to chronic arterial hypertension or amyloid angiopathy.
\nFor all patients in the acute stage, the following examinations should be carried out, which will determine the treatment plan: a thorough collection of anamnesis to determine the presence of hypertension, medications used, alcohol abuse, and substance abuse and a family history of stroke, oncology, and trauma; a clinical examination; blood test to detect polycythemia and plateletemia, erythrocyte sedimentation rate (ESR) to detect vasculitis, and the level of glycemia to detect diabetes or hypoglycemia, and coagulation tests. Cardiac assessment including electrocardiogram (ECG) and echocardiography (EchoCG) is quite important in all cases and Holter in selected cases. ECG recording to detect heart attacks, atrial fibrillation, continuous ECG monitoring to detect arrhythmias; monitoring of systolic, diastolic, and mean blood pressure (BP) by noninvasive method; dopplerography to detect stenoses and dissections of cervical and intracranial vessels; transthoracic EchoCG to detect blood clots, tumors, valve pathology, vegetations on the valves, reduction of ejection fraction, and the presence of an open oval window. Neuroimaging methods include MRI and CT of the brain to detect caverns, intracranial venous thromboses, cerebral microhemorrhages, arteriovenous malformations (AVM), tumors, and indirect signs of unknown injuries. Additional examinations are prescribed depending on the initial results obtained, the patient’s age, and the presumed etiology of the stroke: angiography (usually MR, CT angiography) and specific biological tests when it comes to specific causes, such as antinuclear antibodies, etc.
\nThere are neurological complications that occur in the acute phase of stroke in any type in the form of convulsive syndrome; hyper- and hypoactive delirium, especially with a pre-existing decrease of cognitive functions and the development of metabolic or infectious complications; as well as intracranial hypertension.
\nNonspecific complications include bedsores, pneumonia, urinary tract infection, hyponatremia due to inadequate secretion of antidiuretic hormone (ADH), deep vein thrombosis, and pulmonary thromboembolism. They are more likely to develop in patients with severe neurological deficits. Hyponatremia is a common accompaniment during the acute stage of stroke. Its relevance to the clinical presentation, treatment and prognosis should be mentioned.
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Hypernatremia: Na >145 mmol/l (the main reason—central DI)
Criteria: polyuria: rate of diuresis >3 ml/kg/hour
Hypernatremia: >145 mmol/l
Urine specific gravity: <1005
\nInfusion therapy:
Base 75–100 ml/hour monitoring of sodium concentration every 6 hours.
Fluid deficit replenishment: in case of polyuria—compensation of fluid loss.
\nIf ineffective, symptoms of diabetes insipidus (DI) persist—ADH\n
Desmopressin: 2–4 mcg per 24 hours
Vasomirin (nasal spray): 10 mcg
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Total body fluid = 0.6 × body weight
Free water deficit = (0.6 × body weight) − (0.6 × body weight) × (140/Na act)
Example: body weight = 75 kg, Na = 154 mmol/l
Free water deficit = 0.6 × 75 − [0.6 × 75 × (140/154)] = 45 − 40.9 = 4.1 l
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Hyponatremia: Na < 135 mmol/l
If Na <125 mmol/l, there is a high risk of neurological disorders.
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
No neurological deterioration
Acute neurological deterioration
Hyponatremia: no longer than 24 hours acute not prolonged reducing the level of sodium
Negative fluid balance: IV 3% NaCl—4 ml/kg during 15–30 min
2/3 of physiological need for fluid + furosemide 1 mg/kg
Intravenous (IV): only sodium solutions
Monitoring: fluid balance, diuresis, sodium in plasma/urine, and urine specific gravity
Central salt wasting syndrome
Restoring of fluid deficit
Positive sodium balance
Rehydration
HyperHAES: 0.25 ml/kg/hour or 0.9%NaCl
Fludrocortisone: 0.4 mg per 24 hours
Acute hyponatremia correction rate (<48 h): ≤24 mmol/l/24 hours
Chronic hyponatremia correction rate (>48 h): ≤0.5 mmol/l/hour, but ≤10 mmol/l/24 hours
In the presence of an accompanying potassium deficit: ≤4 mmol/l/25 hours
Stroke patients should be treated in specialized departments. For every 24 patients treated in a specialized rather than general ward, one death and one disability are prevented [4]. This does not depend on the age, type, and severity of stroke [4, 5]. Therefore, specialized departments are very important for the treatment of stroke patients [1, 4]. For all strokes with persistent neurological deficits, the treatment aimed at stabilizing the patient’s condition, controlling vital functions, and actively curating problems that may worsen recovery is indicated. This is the main component of the stroke treatment program [6, 7].
\nIn the detection and treatment of emergency life-threatening conditions (risk of aspiration, epileptic status, respiratory failure, etc.), the patency of the upper respiratory tract should be ensured in the case of deprivation of consciousness to the level of coma, respiratory failure of central origin, or local causes leading to respiratory disorders.
\nThe stabilization of most physiological parameters, blood pressure, saturation (more than 93%), glycemic level (less than 180 mg), body temperature (below 37.50°C), and hydration, is necessary in the first few days to prevent negative dynamics in the penumbra zone.
\nA normal respiratory function with adequate blood oxygenation is necessary in the acute period of stroke to maintain an adequate oxygen delivery to brain cells, but there is no conclusive evidence that all patients with stroke receive oxygen therapy with a positive result [4]. In cases of hypoxemia, improved blood oxygenation is achieved by oxygen therapy via a nasal catheter and noninvasive or invasive ventilation.
\nComplications of acute stroke include neurogenic stressful cardiomyopathy, paroxysmal sympathetic hyperactivity, atrial fibrillation, acute heart failure, myocardial infarction, and sudden death [1, 2]. The frequency of these complications explains the need for a constant monitoring for 2–3 days.
\nMany stroke patients are in a state of dehydration, which leads to a worse outcome of the disease [1, 2]. Despite limited clinical data, the administration of infusion therapy (0.9% sodium chloride solution) is considered part of the overall treatment of stroke, especially in patients with an increased risk of dehydration due to depression of consciousness or respiratory disorders. Experience in the treatment of hyperglycemia recommends avoiding the introduction of glucose solutions in the early period of stroke and strict control of the level of glycemia [4].
\nAccording to the literature, there are no mechanisms for autoregulation of cerebral blood flow in the penumbra zone. Therefore, a decrease in blood pressure in the first hours after a stroke before the penumbra zone appears can cause significant hypoperfusion, which worsens the development of the ischemia zone. Therefore, in the acute period, it is not necessary to aggressively treat arterial hypertension if there are no concomitant life-threatening conditions, such as aortic dissection or intracranial hematoma [2, 4].
\nIn practice, blood pressure correction is usually started when the systolic blood pressure exceeds 220 mm Hg and diastolic blood pressure exceeds 120 mm Hg. However, in many clinics, antihypertensive therapy is performed only in cases of heart failure, acute renal failure, aortic arch dissection, or malignant hypertension. When conducting a thrombolytic therapy (TLT), it is common practice to maintain blood pressure below 185 mm Hg. The intravenous administration of labetalol (10 mg bolus, followed by an infusion of 0.1–0.3 mg/kg/hour) or urapidil (12.5 mg bolus for 20 seconds, followed by an infusion of 6–30 mg/hour) is often used.
\nHyperglycemia occurs in 60% of stroke patients who have not previously suffered from diabetes [2, 7]. Hyperglycemia after a stroke is usually associated with a large volume of infarction and cortical damage and is associated with an adverse outcome of the disease [4]. Currently, the routine use of insulin infusions in patients with moderate hyperglycemia is not recommended. The European Stroke Association recommends maintaining glycemia below 180 mg/dl (10 mmol/l) [4].
\n\nBody temperature control: hyperthermia is associated with an increase in the size of the infarction zone and a worsening of the outcome of the disease [8]. Fever is associated with a worse clinical outcome [9]. When the body temperature increases, it is necessary to quickly exclude concomitant infections and, if necessary, treat them.
\nThe prevention of trophic disorders in the form of bedsores is carried out by establishing an early enteral nutrition through a nasogastric probe with an adequate calorie of nutritional mixtures: early mobilization, anti-bedsore mattresses, suitable beds, and nursing care.
\n\nAspiration pneumonia: diagnosis of dysphagia (special examination of the function of swallowing by doctors, nurses, or speech therapists) [10, 11] or use of a nasogastric probe if necessary.
\nDeep vein thrombosis and pulmonary embolism: low-molecular-weight heparins (LMWH) in prophylactic doses reduce the risk of thromboembolic complications without affecting mortality [2]. Their use slightly increases the risk of intracranial hemorrhages. The use of LMWH is recommended only if the patient has risk factors for deep vein thrombosis and pulmonary embolism, such as lower limb immobilization, in the first few hours after a stroke [2], and not earlier than 24 hours in patients with intracranial hemorrhage [9]. A recent study of Clots in Legs Or sTockings after Stroke (CLOTS) [12] has shown that an intermittent pneumatic compression reduces the risk of deep vein thrombosis and can improve stroke survival in patients who cannot go to the toilet with an assistant.
\n\nRehabilitation: it is an important issue both in acute phase and in chronic phase. Points to be covered are position turning to avoid pressure sores, chest physiotherapy to minimize lung complication, swallowing assessment and training, limb movements to prevent deep vein thrombosis, speech therapy, early mobilization, etc. All should be started as early as possible. Rehabilitation should begin as soon as the patient’s condition stabilizes: passive measures to minimize contractures, bedsores, and pneumonia. A coordinated multidisciplinary approach to patient management with the help of constantly trained staff is important, which leads to a reduction in mortality and disability.
\nThe intravenous administration of a recombinant tissue plasminogen activator (tPA) increases the chances of a favorable outcome approximately 8 times within 3 months if performed in the first 90 minutes, 2 times when performed within 91–180 minutes after a stroke, and 1.4 times when performed in 181–270 minutes [6, 13]. The mortality does not change when administered up to 270 min after stroke onset, but increases with later administration of tPA [6]. Indications and contraindications for thrombolytic therapy are noted in Tables 1 and 2, respectively.
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Indications for thrombolytic therapy.
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Contraindications for thrombolytic therapy.
Hemorrhagic transformation is more often observed in patients with large strokes and of old age [7]. The earlier the tPA is introduced, the more likely the beneficial effect is, and despite the fact that the probability of a favorable effect is also present when used later than 3 hours from a stroke, it is significantly reduced. The dose is 0.9 mg/kg (10% intravenous bolus, 90%—within an hour microjet). In Japan, the recommended dose is lower—0.6 mg/kg. Thus, thrombolytic therapy is recommended as early as possible after the onset of a stroke, no later than 4.5 hours. Restrictions apply both to contraindications [increased risk of hemorrhage, delay of more than 4.5 hours, blood pressure (BP) above 185 mm Hg, blood glucose above 4 G/l] and strict rules of use (only by a doctor trained in the management of stroke patients and only in the stroke department) [6].
\nOther ways to achieve rapid recanalization are currently being investigated and do not change the existing recommendations: other thrombolytic drugs, MRI patient selection criteria, intra-arterial thrombolytic therapy, and ultrasound-assisted intravenous thrombolysis. Mechanical thrombextraction is considered a promising technique in addition to intravenous thrombolysis in patients with proximal occlusions. In patients receiving oral anticoagulants, mechanical thrombectomy is often the only recommended recanalization strategy.
\nAspirin at a starting dose of 300 mg and then 75–150 mg daily prevents 9 cases of disability and death per 1000 patients. Aspirin should be prescribed 24 hours after any thrombolytic therapy. Recently, a Clopidogrel in High-Risk Patients with Acute Nondisabling of Cerebrovascular Events (CHANCE) study showed that patients with small strokes and transient ischemic attack (TIA) who received a loading dose of clopidogrel for 24 hours, against the background of aspirin, and then for 90 days on 75 mg of aspirin and 75 mg of clopidogrel had better outcomes without the risk of bleeding.
\nLow-molecular-weight heparins do not have advantages, because a decrease in the frequency of early recurrent strokes is balanced by an increase in the frequency of hemorrhagic transformations. There is no reason to recommend heparin in the acute stage of ischemic stroke, even in patients with atrial fibrillation.
\nExperimental studies have shown that potential neuroprotectors are effective, but this is not confirmed in the human population. Many neuroprotective agents have been developed based on a cascade of biochemical events leading to cell death. We report below the current clinical status of drugs that have been developed as neuroprotective agents (Table 3) [14].
\nCategory, mechanism | \nDrug name, name of multicenter study, and its results | \nCategory, mechanism | \nDrug name, name of multicenter study, and its results | \n
---|---|---|---|
Ca2+ channel blocker | \nNimodipine: no benefit (VENUS) | \nNoncompetitive NMDA antagonist | \nDizocilpine, discontinued Dextrorphan, no benefit | \n
Na+ channel blocker | \nLifarizine, no benefit; lubeluzole, no benefit; fosphenytoin, discontinued | \nCompetitive NMDA antagonist | \nSelfotel: discontinued | \n
GABA agonist | \nClomethiazole: no effect | \nAMPA/KA receptor antagonist | \nNBQX, discontinued YM872, RCT | \n
Free radical scavenger | \nEdaravone, clinical use; ebselen, phase III; NXY059: phase III; tirilazad, discontinued | \nMetabotropic receptor antagonist | \nGroups I, II, and III: RCT being planned | \n
Growth factor | \nbFGF: abandoned AX200 (filgrastim, G-CSF analogue), phase II | \nLMWH-CoA reductase inhibitor | \nLovastatin, phase II; simvastatin, phase III | \n
Growth factors, oxygen delivery | \nHuman chorionic gonadotropin (hCG)/erythropoietin (Ntx-265): phase II | \nHemodiluting agent | \nAlbumin: phase III (ALIAS) | \n
Ganglioside | \nNo benefit | \nMembrane stabilizer | \nCiticoline (CDP choline): phase III | \n
MgSO4\n | \nFAST-MAG: ongoing (IMAGE) | \nIron chelator | \nDeferoxamine mesylate: phase II | \n
Opioid receptor antagonist | \nNalmefene: no benefit | \nMetal ion chelator | \nDP-b99: phase III | \n
Polyamine receptor antagonist | \nEliprodil: discontinued | \nAntibiotic, pleiotropic protective effects | \nMinocycline: phase III | \n
Glycine antagonist | \nACEA-1021, no benefit; gavestinel, no benefit | \nOthers | \nPiracetam: phase III | \n
Neuroprotective drugs developed so far and results of clinical trials.
VENUS, very early nimodipine use in stroke; NMDA, N-methyl-D-aspartic acid; GABA gamma-aminobutyric acid; AMPA, amino-hydroxy-methyl-isoxalone propionic acid; KA, kainate; NBQX, 2,3dihydroxy-6-nitro-7-sulfamoyl-benzo [f]quinoxaline-2,3-dione; RCT, randomized controlled trial; bFGF basic fibroblast growth factor; ALIAS, albumin in acute stroke; FAST-MAG, Field Administration of Stroke Therapy—Magnesium; ACEA-1021, 5-nitro-6,7-dichloro-1,4dihydro-2,3-quinoxalinedione.
Hypothermia is a potential opportunity to provide neuroprotection, but due to side effects and the need for intensive therapy, it can only be used in severe cases, especially in patients with malignant heart attacks, and currently requires randomized trials [8, 15].
\nDecompressive neurosurgery (hemispherectomy) reduces mortality and disability in patients younger than 60 years old who recently suffered a massive stroke in the middle cerebral artery basin [16]. In order to be effective, the operation must be performed before the development of a malignant brain attack. The best selection criterion is the volume of damage on a diffusion-weighted MRI within 24 hours; a volume greater than 145 cm3 is a good predictor of malignant infarction. Therefore, the best candidates for surgical treatment are patients younger than 60 years with a lesion volume of more than 145 cm3 on diffusion-weighted MRI (6.50). The effectiveness of hemispherectomy is great—every second death is prevented. Results of the Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II (DESTINY II) study also showed effectiveness in patients over 60 years of age [3].
\nIt is necessary to control blood pressure (BP). Lowering blood pressure in the first hours can prevent or slow down the growth of hematoma, as well as reduce the risk of repeated hemorrhage.
\nAn early decrease in blood pressure can cause cerebral ischemia in low-perfused and hypometabolic regions of the brain adjacent to the hematoma.
\nEuropean recommendations are based on the evidence of a low level of significance (class 4) [9]:
No specific drug is recommended.
In patients with a history of primary arterial hypertension or signs (ECG, changes in the fundus vessels) of chronic hypertension, systolic pressure above 180 mm Hg or diastolic pressure above 105 mm Hg and in patients without a history of hypertension, the target blood pressure is 170/100 or average 125 mm Hg.
In patients without a history of arterial hypertension (systolic blood pressure above 160 mm Hg and/or diastolic blood pressure above 95 mm Hg), the target blood pressure is 150/90 mm Hg or BP mean 110 mm Hg.
Avoid lowering blood pressure by more than 20%. These targets should be revised for patients who are being monitored for intracranial pressure (ICP) and are experiencing intracranial hypertension in order to maintain adequate cerebral perfusion pressure (greater than 70 mm Hg).
The INTERACT 2 study recently showed that in patients with intracerebral hematoma, an intensive reduction in blood pressure with targets below 140 mm Hg within an hour slightly improves the outcome and is well tolerated by the patient.
\nIn patients with intracerebral hematoma, complications such as deep vein thrombosis and pulmonary embolism are feared. A small study conducted on patients with intracerebral hematoma showed that the use of intermittent pneumatic compression is more effective than the use of compression knitwear alone [17]. The CLOTS study [12] showed that the use of compression knitwear is ineffective, but only 232 patients with intracerebral hematoma were included out of 2518 stroke patients. The expediency of using heparin and low-molecular-weight heparins is justified only in cases where the probability of bleeding risk is less than the possible benefit of prescribing drugs. In clinical practice, low doses of fractionated or low-molecular-weight heparin can be prescribed after 24 hours [16]. According to the results of the CLOTS 3 study [12], intermittent pneumatic compression is effective.
\nICP negatively affects the functional outcome. The superiority of invasive ICP monitoring over clinical observation and neuroimaging has not been proven. Ways to reduce ICP by medication help to buy time to prepare for surgical decompression, if it is planned. In the acute phase of intracranial hemorrhage, it is recommended to avoid corticosteroids. These recommendations are based on low confidence data. For the medical treatment of ICH, glycerol, mannitol, HAES, and short-term hyperventilation (confidence class 4) are used. For example, mannitol (20%) at a dose of 0.75–1.0 g/kg can be administered as an intravenous bolus followed by 0.25–0.5 g/kg every 3–6 hours, depending on the neurological status and fluid balance.
\nIn the acute stage, every patient with intracranial hemorrhage and an INR greater than 1.4 should receive intravenous vitamin K and drugs that replace the deficiency of clotting factors, despite the reason for taking oral anticoagulants (including patients with artificial valves). The goal is to prevent the growth of hematoma volume. In European protocols, it is recommended to use a concentrated prothrombin complex or SPP together with the intravenous administration of vitamin K [18]. Doses of concentrated prothrombin complex: 10–20 U/kg, if the INR is less than 3.5; or 20–30 units/kg, if the INR exceeds 3.5; together with 10 mg of vitamin K in/B.
\nRecombinant factor VIIa is not recommended for routine use outside of clinical trials.
\nThere is currently no antidote for patients with intracranial hematoma receiving new oral anticoagulants. This limits the use of these drugs.
\nThere are no specific recommendations for the treatment of hemorrhage on the background of antiplatelet drugs. Studies of the use of thrombosis have not proved its effectiveness [6, 13].
\nIn patients with intracranial hemorrhage with increased ventricles and obstruction of the third and fourth ventricles, according to some data, it is recommended to use a recombinant tissue plasminogen activator inserted directly into the ventricular system, which can improve the functional outcome [9].
\nThe removal of a blood clot should be considered in cases where there is neurological dysfunction or neuroimaging data about occlusion of cerebrospinal fluid spaces subtentorially. According to European recommendations, ventricular drainage and hematoma removal should be performed when the size of the hematoma is more than 2–3 cm in diameter or in the presence of hydrocephalus, even if the favorable outcome is doubtful due to old age or coma.
\nDynamic monitoring and conservative medical treatment are the first stage in the treatment of patients with intracranial hematoma. A special analysis of subgroups from the STICH study and a recent meta-analysis showed that craniotomy should be considered as a treatment option in cases of depression of consciousness (from 12 to 9 points on the Glasgow scale) [19] or in cases of superficial intracranial hemorrhage (less than 1 cm from the surface and does not reach the basal ganglia) [20, 21, 22]. With deep-seated hematomas, craniotomy does not bring a positive result. The STICH II study showed that early surgical treatment did not increase mortality and disability within 6 months, but slightly improved survival in patients with spontaneous intracranial hemorrhage in the absence of intraventricular hemorrhage.
\nSinus thrombosis is the cause of approximately 1% of strokes. It occurs due to the occlusion of the venous sinuses and/or cortical veins. This can lead to a venous infarction with petechial hemorrhages or a perivascular venous infarction. Usually, the cause of sinus thrombosis is congenital and acquired prothrombotic disorders, such as pregnancy and infections, including infections of the central nervous system as well as ear, sinuses, mouth, face, or neck. Also the predisposing factors are various diagnostic and therapeutic procedures, such as surgery, lumbar puncture, jugular vein catheterization, and administration of certain medications, especially oral contraceptives, hormone replacement therapy, steroids, and antitumor drugs [23].
\nThe clinical picture may be different, but sinus thrombosis should be excluded in young patients with recent headache and stroke-like symptoms, transient neurological deficits, convulsions, or lobar intracranial hemorrhages. This is especially true for patients with intracranial hypertension and patients with signs of hemorrhagic infarctions, especially if they are numerous and correspond to certain vascular pools.
\nThe gold standard for diagnosing sinus thrombosis is MRI, which provides direct visualization of occluded veins, sinuses, and blood clots [23]. Sometimes CT is used for diagnostics, but if MRI is available, this is not the method of choice for diagnostics. On CT, you can see a hyperintensive shadow of a blood clot in the occluded sinus, the so-called cord symptom.
\nThe available research data on the treatment of venous thrombosis recommend the use of heparin, as it reduces the risk of death and severe disability without the risk of intracranial hematoma. It has been shown that anticoagulant therapy leads to an absolute reduction in the risk of death and disability by 13% and a relative reduction in the risk by 54%, as well as a positive effect of using heparin without increasing the risk of intracranial hemorrhage.
\nAccording to European recommendations [18], venous thrombosis should be treated with low-molecular-weight heparins subcutaneously or intravenous heparin; doses are selected by body weight. The presence of intracranial hemorrhage accompanying venous thrombosis is not a contraindication to a heparin therapy [18].
\nThere is no data from randomized controlled trials on the efficacy and safety of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. A recently published systematic review of thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis suggests a favorable effect in comatose patients [24].
\nAccording to European protocols [18], there is insufficient data to recommend the use of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. Thrombolytic therapy may be an option if the patient’s condition worsens despite an adequate anticoagulant therapy.
\nAfter the acute phase, they switch to oral anticoagulant therapy. The Target INR is 2.0–3.0. In cases of cerebral vein thrombosis and sinus thrombosis during pregnancy, oral anticoagulants are not prescribed due to their possible teratogenic effects and the ability to penetrate the placenta. In these cases, anticoagulant therapy is continued with heparin. There is no available data from controlled studies concerning the optimal duration of anticoagulant therapy in patients with cerebral vein thrombosis and sinus thrombosis. MRI data from 33 patients showed that recanalization occurs within 4 months after cerebral vein thrombosis and sinus thrombosis, regardless of further anticoagulation therapy [25].
\nAccording to European protocols [18], anticoagulants can be prescribed for 3 months if cerebral vein thrombosis occurred due to transient factors and for 6–12 months in patients with idiopathic thrombosis and congenital “moderate” thrombophilia.
\nThe preventive use of anticonvulsants is controversial. Some studies have shown that sensory and motor deficits, parenchymal lesions on MRI/CT, and cortical vein thrombosis can be independent predictors of early symptomatic epileptic seizures [26]. According to European recommendations [18], prophylactic administration of anticonvulsants is possible for patients with local neurological deficits and foci of parenchymal lesions. Treatment can be continued for a year. Despite the fact that 50% of patients with venous thrombosis experience brain edema, mild edema can be relieved by isolated administration of heparin to restore venous outflow. Steroids are not recommended for the treatment of intracranial hypertension due to their unproven effectiveness. In severe cases, with the threat of transtentorial dislocation, surgical decompression is considered the only lifesaving method of treatment.
\nThe incidence of strokes in the postoperative period in patients with coronary artery bypass grafting (CABG) is about 2%, and a higher incidence of strokes is observed in patients after valve replacement operations and other cardiac surgeries [3]. The causes of stroke after cardiac surgery include perioperative embolism from the aortic arch or heart chambers, systemic hypoperfusion, ischemia associated with occlusion of large vessels, or a combination of these factors [3]. Risk factors for stroke after cardiac surgery are old age; a history of strokes, hypertension, and diabetes mellitus; the presence of noise in the projection of the carotid arteries; the use of bronchodilators and diuretics; high serum creatinine levels; recovery of large vessels; the use of inotropes after artificial circulation; and the duration of artificial blood circulation.
\nCurrently, there are no special recommendations for the treatment of patients with stroke after CABG [3]. Moreover, patients with stroke after CABG are treated as patients with acute stroke with loading doses of aspirin (160–320 mg) [3].
\nCarotid endarterectomy is the standard method for treating carotid artery stenosis [3]. It is recommended for 70–99% of patients with symptomatic stenosis. It is confirmed that surgical treatment of asymptomatic stenosis reduces the risk of ipsilateral stroke; however, the absolute advantage of this method has not been proven. Currently, stenting is not recommended for revascularization of the carotid arteries.
\nThe pathophysiological mechanism of stroke in carotid revascularization may be associated with hemodynamic cerebral ischemia or arterio-arterial embolism. The latter mechanism may be more frequent during stenting due to endovascular access.
\nIntracranial hemorrhage can be a severe side effect of thrombolytic therapy in ACS. The risk of intracranial hemorrhage depends on the previous episodes in the history, age, and mode of thrombolytic therapy. Usually, the risk of intracranial hemorrhage during thrombolytic therapy of acute myocardial infarction is 0.5–1%.
\nThere are no special recommendations for the treatment of ischemic stroke in ACS in European protocols. In the presence of ACS, the protocols of the European Stroke Organization recommend lowering blood pressure [4, 6]. An anticoagulant therapy is not recommended, while a combination of clopidogrel and aspirin is recommended in terms of cardiac causes [4, 7].
\nCardio-cerebral embolism is considered to be the cause of at least 20% of ischemic strokes, and non-valvular AF is the most common cause, associated with a fivefold increase in the risk of stroke, and accounts for 25% of all strokes in patients older than 80 years [3]. Long-term thromboprophylaxis is necessary to prevent strokes in patients with AF. Recently, for patients who cannot be treated with warfarin and clopidogrel, it has been shown that clopidogrel and aspirin therapy reduces the risk of vascular accidents [7]. Oral direct thrombin inhibitors such as dabigatran have been shown to be effective in preventing stroke and systemic embolism with a risk of intracranial hemorrhage comparable to that of warfarin. Stroke in patients with AF can be divided into three groups:
Ischemic stroke in patients with insufficient therapy, i.e., not receiving anticoagulants, despite scores on the CHADS2 scale greater than 2 [3]
Ischemic stroke that developed despite warfarin therapy
Intracranial hemorrhage that occurred in a patient receiving anticoagulants
The incidence of intracranial hemorrhage increases 7–10 times compared to patients who do not receive oral anticoagulants and is 1.8% per year in patients at risk of stroke [7].
\nIn the acute phase of stroke, heparin is not recommended; its use leads to a slight decrease in repeated strokes, an indefinite decrease in mortality, and a disability with an increase in the frequency of intracranial hemorrhages [7].
\nThe connection between the brain and the heart reflects a complex multidirectional complex regulation of systemic hemodynamics and organ autoregulation of local perfusion, which is especially pronounced in a cerebral catastrophe. Arrhythmias, in particular AF, often accompany the development of stroke, while myocardial infarction, Takotsubo syndrome, and sudden death are rare, although they are also described in strokes [27, 28, 29]. Sometimes stroke patients are found to have high levels of troponin, indicating myocardial damage.
\nTo ensure adequate treatment, a rapid diagnosis of stroke and its nature and cause is necessary. Specialized stroke departments allow for effective treatment and specific therapy.
\nThe authors declare no conflict of interest.
\nWe would like to thank our teachers—neurologists, anesthesiologists, and neurosurgeons—of Russian Polenov’s Neurosurgical Institute, the first institute of neurological surgery in the world founded in 1926 in St. Petersburg (Petrograd) in Russia.
\nACS | acute coronary syndrome |
AF | atrial fibrillation |
ADH | antidiuretic hormone |
aPTT | activated partial thromboplastin time |
AVM | arteriovenous malformation |
BP | blood pressure |
CT | computed tomography |
CABG | coronary artery bypass grafting |
DI | diabetes insipidus |
DWI | diffusion-weighted imaging |
ECG | electrocardiogram |
EchoCG | echocardiography |
ESR | erythrocyte sedimentation rate |
LMWH | low-molecular-weight heparins |
ICH | intracranial hemorrhage |
ICP | intracranial pressure |
INR | international normalized ratio |
MCA | medium cerebral artery |
MRI | magnetic resonance imaging |
NIHSS | National Institutes of Health Stroke Scale |
SAH | subarachnoid hemorrhage |
SIADH | syndrome of inappropriate antidiuretic hormone secretion |
tPA | tissue plasminogen activator |
TLT | thrombolytic therapy |
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