Michael A. Tall, MD

  • Chief, Magnetic Resonance Imaging
  • Wilford Hall Medical Center
  • Lackland AFB, Texas

Prolactin levels released during early breastfeeding have been correlated with maternal adaptations blood pressure equipment proven 40 mg sotalol, including: reduced anxiety prehypertension 126 sotalol 40 mg visa, aggression arteria temporal purchase sotalol 40 mg mastercard, and muscular tension; and increased social desirability (conformity) arrhythmia causes buy sotalol once a day, which may help mothers to prioritize infant care hypertension lowering foods generic sotalol 40mg on line. Epidurals may cause in-labor prolactin elevations and postpartum prolactin reductions arteria recurrens ulnaris cheap 40 mg sotalol mastercard, with unknown impacts. Following cesarean section, prolactin release with early breastfeeding may be reduced or absent. These and other factors may contribute to reduced breastfeeding success following prelabor cesarean section. Following cesarean section, newborns may have lower prolactin levels, possibly contributing to breathing difficulties and low temperature. Separation of mothers and their healthy newborns, which typically follows cesarean section, may also impact postpartum maternal prolactin levels. If separation interferes with early breastfeeding initiation and frequency, disruption to prolactin receptor formation may impact ongoing milk production and breastfeeding success. The recommendations that follow give guidance for educators, clinicians, researchers, policy makers, advocates, and childbearing families for safely optimizing the hormonal physiology of childbearing. While beneficial in selected circumstances, maternity care interventions may disrupt these beneficial processes. Because of the possibility of enduring effects, including via epigenetics, the Precautionary Principle suggests caution in deviating from these healthy physiologic processes in childbearing. This evidence also suggests that the benefits of physiologic childbearing for mothers and babies may extend into the future through successful breastfeeding and optimizing of mother-baby attachment, with substantial benefits for modern mothers and babies, as they have had for our evolutionary ancestors. Maternity care interventions are beneficial and even lifesaving in selected circumstances. This report provides considerable evidence that they can also cause significant disruptions to hormonal processes in mother and baby with unintended consequences, as summarized in Table 4. The hormonal physiology perspective provides additional information, germane to the well-being of women and offspring, for clinicians, women, and others to consider when weighing benefits and harms of maternity care practices and interventions, both for care of individual mothers and babies and at a policy level. Biologic principles and solid findings from animal studies suggest that hormonal system functioning in the perinatal period, whether optimal or disrupted, may have enduring impacts on offspring hormonal and other biologic systems. This may occur via epigenetic programing, with possible longer-term effects on development, behavior, and/or hormone system functioning, as seen in animal studies. The known unintended shorter-term hormonal and other impacts of perinatal interventions, and evolving evidence about their possible longer-term effects invoke a strong case for the Precautionary Principle. First, for all of the hormone systems examined in this report, greater elucidation is needed of the underlying innate hormonal physiology as it relates to the processes of childbearing, with a priority for research in humans whenever possible. Second, better understanding is needed of possible impacts of widely used maternity care interventions. Such impacts are plausible given the principles and processes described in this report, but poorly researched. Urgent as well are questions about whether perinatal interventions have enduring developmental, and possibly epigenetic, effects in humans, as found in animals. All who are involved in maternity care are committed the best possible care, with the least harm, to mothers and babies. The research results synthesized here, along with underlying hormonal physiology principles and understandings, clarify that promoting, supporting and protecting physiologic birth is a simple, low-technology approach to health and wellness that is applicable in the vast majority of maternity care settings. The perspective of hormonal physiology provides a new framework with which to view childbearing, and can contribute to a salutogenic foundation for the care of mothers and babies. This perspective can provide direction for promoting, supporting, and protecting: fi the physiologic onset of labor at term, with full prelabor physiologic preparations for mother and baby fi safe and effective labor and birth for mother and baby fi optimal maternal and newborn transitions fi breastfeeding, fi maternal-infant attachment the findings of this report are well summarized by the distinguished Dutch obstetrician-gynecologist, Professor Gerrit-Jan Kloosterman: Spontaneous labor in a normal woman is an event marked by a number of processes so complicated and so perfectly attuned to each other that any interference will only detract from the optimum character. The only thing required of the bystanders under these conditions is that they show respect for this aweinspiring process by complying with the first rule of medicine, that of nil nocere [do no harm]. Benefits of hormonal physiology accrue, so that any safe enhancement of hormonal physiology will likely benefit women and babies to some degree. Greater conformity with physiologic processes is likely to be more beneficial than less conformity. Additional benefits are also likely from averting potential harms associated with unneeded interventions. The synthesis presented in this report supports a series of recommendations for safely optimizing hormonal physiology within maternity care. Currently available research, as presented in this report, consistently finds that physiologic childbearing confers valuable benefits to women and their babies in the short, medium, and likely longer terms. The benefits that accrue from optimizing hormonal physiology for mother and baby extend along a continuum, according to this framework, with greater benefits likely for any mother and baby with greater experience of physiologic processes. Additional benefits from averting unneeded maternity care practices that have potential to harm women and babies, both known harms and any that are currently unknown, also likely extend along a continuum. Maternity care systems could be readily adapted to safely optimize hormonal physiology for mothers and babies. As detailed in this chapter, adaptations of the system could include: fi promoting factors such as professional education, competencies of personnel, protocols, performance measures, quality improvement initiatives, innovative payment and delivery systems, and research fi supportive practices directly available to women from pregnancy through the postpartum period, such as reducing pregnancy stress as far as possible, primarily using comfort measures for labor pain and progress, and keeping mothers and newborns together after birth fi protecting women and babies, whenever possible and safe, from practices that disturb healthy physiologic processes the following high-level recommendations are provided to encourage those who plan, provide, or receive maternity care to help women and newborns experience healthy physiologic processes. They do not exclude the timely, appropriate, and safe use of maternity care procedures, medications, and other interventions when needed for the well-being of women and babies, in which case the recommendations can help maximize hormonal physiology as far as possible, and safely move women and babies along the salutogenic continuum. The Appendix identifies selected resources that support implementation of these recommendations for professionals, and for women and childbearing families. This will foster provision of high-quality care, effective care teams, and more judicious use of maternity care interventions. This will enable a more complete and accurate assessment of possible benefits and harms. It is important for health professionals to be able to provide physiologic care to the extent safely possible for women and babies with special conditions, needs, and care requirements. This knowledge and associated skills, along with a meaningful practical experience of physiologic childbearing, should be a foundational component of all levels of professional education within all of the disciplines that care for childbearing women and newborns. These subjects should be introduced in entrylevel education, well represented during more advanced professional training, and prioritized within continuing education, including maintenance of certification programs. Policy Use effective quality improvement strategies to foster reliable access to physiologic childbearing. These include: addressing physiologic childbearing within quality collaboratives, developing relevant performance measures and using them for quality improvement, developing and implementing protocols that promote physiologic childbearing, using innovative payment and delivery systems to foster appropriate care practices, and implementing evidence-based clinical practice guidelines including those to safely reduce use of cesarean section and other consequential interventions. Strengthen and increase access to care models that foster physiologic childbearing and safely limit use of maternity care interventions. These and other models and maternity care providers that prioritize and support physiologic processes should be encouraged. Facilities, maternity care providers and/or models of care with good safety outcomes and low rates of maternity care interventions likely are skilled in promoting, supporting, and protecting physiologic birth. Professional development can help maternity care facilities and practitioners with limited ability to facilitate physiologic childbearing obtain the needed knowledge and skills to provide optimal care for healthy childbearing women and newborns. Maternity care providers with skills and expertise in the care of women and babies with higher-risk and/or specific conditions provide critical maternity care services. For example, women with challenging conditions would likely benefit from one-on-one care in labor and skin-to-skin contact after birth. Similarly, breastfeeding in the early sensitive postpartum period following cesarean section is a priority. Models of care and protocols that safely apply these principles to women at higher-risk should be developed. Engaging and supporting childbearing women Use effective consumer engagement strategies to inform women about physiologic childbearing and involve them in related aspects of their care. This booklet, and related resources that can help women understand the hormonal physiology of childbearing, should be widely distributed and recommended to pregnant women and women planning pregnancy. Childbearing women should also have access to publicly reported results of performance measures that provide relevant information for choosing a care provider or group and a birth setting. Priority decision aids for childbearing decisions of great consequence should include relevant information and be routinely incorporated into maternity care practice. All women should have access to care that safely supports physiologic childbearing and to care environments that promote such care and protect women from the harm of unneeded disturbance of physiologic processes, as described in this report. Where childbearing deviates from optimal hormonal physiology, or extra assistance or interventions are required, women should be fully supported to maximize hormonal physiology. Journalists have a role to play in informing childbearing women and the general public about these matters. Some aspects of prenatal care, including fetal testing, may contribute to , or fail to reduce, maternal stress and anxiety. Reduction of stress and anxiety in pregnancy may have significant and long-term benefits to offspring, and therefore substantial public health benefits. Evolving evidence suggests that some forms of relaxation and relaxation training may improve not only physiologic and hormone stress markers but also meaningful outcomes in mothers and babies. Current evidence suggests that effective relaxation techniques that reduce stress may favorably influence maternal emotional states, stress hormones, and responses; and fetal growth and behavior, premature birth rate, mode of birth, and newborn neurobehavior, among other impacts. Scheduled birth, whether by induction or prelabor cesarean, will foreshorten these processes in mothers and babies, with potentially significant consequences for their physiologic transitions. With a prelabor cesarean, mothers and babies also miss beneficial processes of labor that activate maternal and fetal hormonal systems to optimize postpartum transitions of both. From the perspective of hormonal physiology, when a scheduled cesarean is needed, waiting when possible for labor to start on its own may offer benefits to mothers and babies. Due to many currently unanswered questions about possible hormonally-mediated effects of scheduled birth, policies that support the physiologic onset of labor at term and discourage unneeded induction of labor or prelabor cesarean in healthy mothers and babies are prudent. In women who plan hospital birth, moving from the familiar environment of home to the unfamiliar environment of hospital may slow labor, especially before the positive feedback cycles that progress labor are fully established, making labor less vulnerable to disturbance. Waiting for active labor before moving from home to hospital may reduce the risk of physiologic disruptions and is associated with increased likelihood of vaginal birth. Providing telephone support and/or a caregiver who is available to attend and assess the laboring woman at home, if needed, could be a cost-effective way to enhance physiologic processes, especially in first-time mothers. Establishing a trusting relationship with caregivers is also likely to be beneficial. Make non-pharmacologic comfort measures for pain relief routinely available, and use analgesic medications sparingly. Disruption of the hormonal physiology in labor, birth, and the postpartum period by pharmacologic interventions and their co-interventions may also have detrimental effects on breastfeeding and maternal-infant attachment. When mother and baby are in good condition and coping well, it may be safer and preferable to offer non-pharmacologic comfort measures. This may reduce the need for pharmacologic interventions, with benefits for mother and baby. Make non-pharmacologic methods of fostering labor progress routinely available, and use pharmacologic methods sparingly. Disruption of the hormonal physiology in labor, birth, and the postpartum period by pharmacologic interventions may also have detrimental effects on breastfeeding and maternal-infant attachment. Routinely making non-pharmacologic measures to foster labor progress available may reduce the need for these interventions, with benefits for mother and baby. When mother and baby are in good condition, it may be safe and preferable to allow labor to progress at a slower rate, with attention to any source of stress that may inhibit contractions. In addition, doulas are generally skilled in providing non-pharmacologic measures to deal with stress and pain and to foster labor progress, thus addressing preceding recommendations and reducing the need for stronger interventions and potential hormonal disruption. This may be a cost-effective strategy for reducing stress and stress hormones, reducing interventions, and improving outcomes for mothers and babies. This report identifies many ways that cesareans may impede optimal postpartum transitions in women and newborns. Important resources to safely address cesarean overuse include evidence-based guidance documents and a national endorsed standardized cesarean section performance measure. This report identifies care pathways that can help women avoid unneeded cesareans. Care models that foster physiologic childbearing, noted above, are associated with reduced likelihood of cesarean section. Postpartum care Support early and unrestricted skin-to-skin contact after birth between mother and newborn. Conversely, evidence reviewed in this report suggests that separation of mothers and newborns may provoke newborn stress and be detrimental to breastfeeding initiation and maternal mood. The early days after birth may be a sensitive period for upregulation of the prolactin system in particular, with long-term impacts on breast-milk production. Gaps include the frequent omission of priority medium-term outcomes including breastfeeding, maternal-infant attachment, and maternal emotional well-being, which are hormonally mediated and potentially susceptible to disruption of hormone systems through prior interventions and/or maternal stress. A related concern is the lack of long-term follow-up for possible impacts on offspring health and development. Biologically plausible effects on hormonally-related functions inside and outside reproduction, as described in each hormone chapter, also require high-quality research and long-term follow-up. High-quality studies are particularly needed that investigate consequential and biologically plausible, but as-yet poorly examined, impacts of maternity care practices and interventions on the mediumand long-term health and well-being of mothers and babies. These include outcomes of labor induction, augmentation, opioid and epidural analgesia, and cesarean section, and of stress in childbearing. Effective strategies to reduce stress and incorporate stress reduction support into prenatal care are also needed.

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In this conception arteria tibialis anterior buy sotalol 40 mg without prescription, the wealth of data generated in the process of providing health care becomes readily available in a secure manner for incorporation into continuous improvement activities within the system and for research to advance health care delivery in general (Friedman et al heart attack 18 order sotalol amex. In this manner blood pressure 9260 cheapest sotalol, the value of the care that is delivered to any individual patient imparts benefit to the larger population of similar patients blood pressure medication heart rate generic sotalol 40mg online. Clearly listed as one the 10 priorities is involvement of patients and families arteria networks corp cheap sotalol 40mg on-line, which should occur in at least two critically important ways heart attack test cheap 40 mg sotalol amex. Although interventions to enhance shared decision making have not yet shown consistently beneficial effects, these applications are very early in development and have great potential (Legare et al. Performance transparency Increase transparency on health Make robust performance charcare system performance. Broad leadership Expand commitment to the Promote broad stakeholder goals of a continuously learning engagement and ownership in health care system. Relatedly, organizations will also need to consider other ethical issues associated with data use and data stewardship (Faden, 2013). Multiple publications and patient-led organizations have argued that the public is willing to share data for purposes that improve patient health and facilitate collaboration with data and medical expertise (Wicks et al. Of particular note is the fact that not all patients and/or family have the same level of literacy, privilege, and understanding of how their data might be used or monetized, and the potential unintended consequences of privacy and confidentiality. Interoperability Does the organization support and maintain data at rest and in motion according to national and local standards for interoperability. Regulatory issues Are there specific regulatory issues that must be addressed and, (see Chapter 7) if so, what type of monitoring and compliance programs will be necessaryfi These key considerations are listed in Table 6-2 and are expanded further in the following sections. Newer methods of quality improvement introduced since Deming represent variations or elaborations of this approach. All too often, however, quality improvement efforts frequently fail because they are focused narrowly on a given task or set of tasks using inadequate metrics without due consideration of the larger environment in which change is expected to occur (Muller, 2018). New technology promises to substantially alter how medical professionals currently deliver health care at a time when morale in the workforce is generally poor (Shanafelt et al. In recognition that basic quality improvement approaches are generally inadequate to produce large-scale change, the field of implementation science has arisen to characterize how organizations can undertake change in a systematic fashion that acknowledges their complexity. This requires detailed work on the part of users implementation plans that address changes in workflow, data streams, adoption or elimination of equipment if necessary, etc. Nearly all approaches integrate concepts of change management and incorporate the basic elements that should be familiar because they are routinely applied in health care improvement activities. It must be recognized that even when these steps are taken by competent leadership, the process may not proceed as planned or expected. These concepts of how to achieve desired changes successfully continue to evolve and increasingly acknowledge the powerful organizational factors that inhibit or facilitate change (Braithwaite, 2018). As discussed earlier, the process begins with clear identification of the clinical problem or need to be addressed. Often the problem will be one identified by clinicians or administrators as a current barrier or frustration or as an opportunity to improve clinical or operational processes. It is essential to delineate existing workflows, and this usually entails in-depth interviews with staff and direct observation that assist with producing detailed flowcharts (Nelson et al. It is also important to define the desired outcome state, and all feasible options for achieving that outcome should be considered and compared. In addition, to the greatest extent feasible, at each relevant step in the development process, input should be sought from other stakeholders such as patients, end users and members of the public. The hierarchy categorizes pilot data as the lowest level of evidence, followed by observational, risk-adjusted assessment results, and places results of clinical trials at the top of the classification scheme. For example, simply demonstrating a high level of predictive accuracy may not ensure improved clinical outcomes if effective interventions are lacking, or if the algorithm is predicting a change in the requirements of a process or workflow that may not have a direct link to downstream outcome achievements. Actions should generally not be merely improvements in information knowledge but should be defined by specific interventions that have been shown to improve outcomes. High-risk tools will likely require evidence from rigorous studies for regulatory purposes and will certainly require substantial monitoring at the time of and following implementation. In some instances, due to feasibility, costs, time constraints or other limitations, a randomized trial may not be practical or feasible. In these circumstances quasi-experimental approaches such as stepped-wedge designs or even carefully adjusted retrospective cohort studies, may provide valuable insights. Specifically, they trained a neural network to diagnose pneumonia from patient radiographs in one hospital system and evaluated its diagnostic ability on external radiographs from different hospital systems, with their results showing that performance on external datasets was significantly degraded. In this instance, Zech and colleagues (2018) showed that large differences in the prevalence of pneumonia between populations caused performance to suffer. However, even subtle differences between populations can result in significant performance changes (Saria and Subbaswamy, 2019). In the case of radiographs, differences between scanner manufacturers or type of scanner. As an example, consider the policy by which physicians order blood lactate measurements. Historically, it may have been the case that, at a particular hospital, lactate measurements were only ordered to confirm suspicion of sepsis. Alternatively, if the patient population shifts, for example, to include more drug users, then elevated lactate might become more common and the value of lactate being measured would again be diminished. There are many subtle ways that site-specific or dataset-specific bias can occur in real-world datasets. Validation using external datasets will show reduced performance for models that have learned patterns that do not generalize across sites (Schulam and Saria, 2017). Overall, when there are varying, imprecise measurements or classifications of outcomes. Label leakage is when information about a targeted task outcome leaks back into the features used to generate the model. It is more desirable to detect and prevent problems proactively to avoid failures prior to or during training. Doing so requires adjusting for confounding, which is only sometimes possible, for instance, when the data meet certain quality requirements. When they can be anticipated, these shifts can be prespecified by model developers and included in documentation associated with the application. By refraining from incorporating learning predictive relationships that are likely to change, performance is more likely to remain robust when deployed at new hospitals or under new policy regimes. Such tools have the potential to prevent failures if implemented during the initial phase of approval. In addition to monitoring overall measures of performance, evaluating performance on key patient subgroups can further expose areas of model vulnerability: High average performance overall is not indicative of high performance across every relevant subpopulation. By introducing a manual audit for these individual points, one can improve reliability during use. Traditionally, uncertainty assessment was limited to the use of specific classes of algorithms for model development. However, recent approaches have led to wrapper tools that can audit some black box models (Schulam and Saria, 2019). Deterioration of model performance can also occur within the same health care system over time, as clinical care environments evolve due to changes in background characteristics of the patients being treated, overall population rates of exposures and outcomes of interest, and clinical practice as new evidence is generated (Davis et al. These methods range from completely regenerating models on a periodic basis to recalibrating models using a variety of increasingly complex methods. However, there are evolving areas of research into how frequently to update, what volume and types of data are necessary for robust performance maintenance, and how to scale these surveillance and updating activities across what is anticipated to be a high volume of algorithms and models in clinical practice (Davis et al. In addition, there is a tendency to question whether observed associations utilized within the model can be used to identify specific clinical or system-level actions that should be taken, or whether they can reveal novel and unsuspected underlying pathophysiologies. These issues are particularly complex as they relate to risk prediction models that can readily be validated in terms of predictive accuracy but for which the inclusion of data elements may not be based upon biological relationships. Innovations include establishing new methods, such as parallel models where one is used for core computation and the other for interpretation (Hara and Hayashi, 2018; Krause, 2016; Turner, 2016). There remains a paradox, however, because machine learning produces algorithms based upon features that may not be readily interpretable. In the absence of absolute transparency, stringent standards for performance must be monitored and ensured. Although the most stringent criteria for transparency are within the point-of-care setting, there are likely circumstances under which accuracy may be desired over transparency. Although the need for algorithm transparency at a granular level is probably overstated, descriptors of how data were collected and aggregated are essential, comparable to the inclusion/exclusion criteria of a clinical trial. This will make informed decisions about the likely accuracy of use in specific situations possible and help implementers avoid introducing systematic errors related to patient socioeconomic or documentation biases. For example, implementers might consider whether or not the data were collected in a system similar to their own. This applies to potential generalizability limitations among models derived from patient data within one part of a health system and then spread to other parts of that system. Closer examination is required because these results are apt to be biased by the socioeconomic and system-related factors mentioned above as well as by well-described issues such as allocation and treatment biases, immortal time biases, and documentation biases. However, as the technology improves, the digital divide may widen the significant disparities that already exist between institutions. Health care delivery systems and hospitals will need to take a thoughtful approach in the evaluation, decision making, and adoption of these tools that incorporates considerations regarding organizational governance and postdevelopment technical issues. This includes determining cultural resistance and workflow limitations that may dictate key interpretability and actionability requirements for successful deployment. Systematic review shows no performance benefit of machine learning over logistic regression for clinical prediction models. Proposed Policy, Payment, and Quality Provisions Changes to the Medicare Physician Fee Schedule for Calendar Year 2019. Fostering implementation of health services research findings into practice: A consolidated framework for advancing implementation science. Calibration drift in regression and machine learning models for acute kidney injury. Neonatal nurses experience unintended consequences and risks to patient safety with electronic health records. An ethics framework for a learning health care system: a departure from traditional research ethics and clinical ethics. Proceedings of the Twenty-First International Conference on Artificial Intelligence and Statistics. Expert consensus survey on digital health tools for patients with serious mental illness: Optimizing for user characteristics and user support. The practical implementation of artificial intelligence technologies in medicine. Digital Infrastructure for the Learning Health System: the Foundation for Continuous Improvement in Health and Health Care: Workshop Series Summary. Predicting 30-day hospital readmission risk in a national cohort of patients with cirrhosis. Beyond Consent: Building Trusting Relationships With Diverse Populations in Precision Medicine Research. Beyond sigmoids: How to obtain well-calibrated probabilities from binary classifiers with beta calibration. Food and Drug Administration precertification pilot program for digital health software: Weighing the benefits and risks. Interventions for increasing the use of shared decision making by healthcare professionals. Patient-like-mine: A real time, visual analytics tool for clinical decision support. Storylines, tensions and the unintended consequences of technology-supported care. Application of contextual design methods to inform targeted clinical decision support interventions in sub-specialty care environments. Learning Is Not Enough: Earning Institutional Trustworthiness Through Knowledge Translation. Using predictive analytics to guide patient care and research in a national health system. Healthy People/Healthy Economy: An Initiative to Make Massachusetts the National Leader in Health and Wellness. Evaluation of semantic web technologies for storing computable definitions of electronic health records phenotyping algorithms. A review of human factors principles for the design and implementation of medication safety alerts in clinical information systems. Portal use among patients with chronic conditions: Patient-reported care experiences. Proceedings of the 22nd International Conference on Artificial Intelligence and Statistics, pp. Using text message reminders in health care services: A narrative literature review. Engagement and outcomes in a digital Diabetes Prevention Program: 3-year update.

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Calcium and vitam in D cannot replace H T and other therapies as a treatm ent for osteoporosis blood pressure chart good and bad sotalol 40 mg on-line, but they provide a first line of defence 01 heart attackm4a demi buy sotalol 40 mg fast delivery. Natural progesterone A natural progesterone cream has been widely prom oted in the m edia as a natural alternative to H T for preventing osteoporosis or as a supplem ent to estrogen28 hypertension remedies order sotalol 40 mg with amex. H owever arteria carotida externa order sotalol mastercard, there are no controlled data to support any clinical benefit and recent reports have shown that absorption into the circulation is m inim al29 arrhythmia lasting hours order sotalol 40 mg line,30 blood pressure medication for acne sotalol 40 mg for sale. The significance of adolescence and young adulthood as a tim e to build bone cannot be overem phasized. O ver 50% of the skeletal m ass is laid down during puberty, and after the age of 30 there is no opportunity to m ake up any deficit. Unfortunately, m odern lifestyles are not conducive for optim al bone growth during this period. The decline in m anual work, the ubiquity of the m otor car, and the downgrading of sport in the school curriculum m ean that only a m inority of adolescents exercise sufficiently to develop their bones to their full potential. In addition, m edia and peer pressures with regard to body weight cause m any young wom en to restrict their food intake to below that needed to provide an adequate supply of bone-building nutrients (children need up to 1000 m g and adolescent girls up to 1600 m g calcium daily). Sm oking, which reduces the beneficial effects of estrogen and hastens the m enopause by about 2 years, is also on the increase am ong young wom en. It is a sad fact that osteoporosis is rising at a faster rate than can be explained by longevity alone, and is affecting increasingly younger wom en. W hile adverse conditions have a greater effect on younger wom en, other contributory factors for osteoporosis apply at any age. These m ay be related to genetic inheritance, to an underlying m edical condition or to lifestyle (Table 5. The usual m ethod of diagnosing osteoporosis and following its progress is by m easuring bone density. This can be repeated every 2 years to m onitor either the effectiveness of treatm ent or the progress of the disease. Another m eans of m onitoring bone is to carry out blood tests for various biochem ical m arkers, which m easure the rate of bone resorption. Although these tests cannot diagnose low bone m ineral density, they m ay provide som e indication of whether treatm ent is working. W ithout it, however, m any wom en with lowered bone density would be not be diagnosed and treated. W om en with risk factors should be screened, but the question rem ains: does being m enopausal constitute a sufficient risk factor in itselffi As awareness of the risks of osteoporosis grows, fuelled by the work of organizations such as the National O steoporosis Society ( It would be tem pting to attribute this to non-com pliance but, taking this into account, one study has shown that 12% of the treated group continued to lose bone32. Ideally, this could be determ ined by a sim ple blood test, but these are not yet reliable enough. Should they be followed up at regular intervals to m onitor the progress of the disease or the effectiveness of treatm ent, as is routinely done with other potentially serious conditions, such as raised blood pressurefi The developm ent of cheaper and m ore m obile equipm ent such as ultrasound will m ake m onitoring m ore readily available and cost-effective. Suggestions from the British M enopause Society33 regarding screening are shown in Table 5. Sim ilar indications from the Am erican National O steoporosis Foundation can be found on the Internet ( D espite the debate, the current situation is that relatively few wom en are being referred, even those with known risk factors, and densitom eters are not utilized to their full capacity. Som e authorities recom m end that estrogen should be taken for at least 10 years, starting at the m enopause. This gives rise to three considerations: (1) There is an increased risk of breast cancer with long-term H T use (see Section 8. This can be avoided by use of the newer continuous com bined regim ens or tibolone, and it is the responsibility of doctors to offer these to their patients if appropriate. H owever, after 10 years, when the treatm ent is discontinued, the wom an will be about 60 years of age. Bone loss will advance inexorably and, by the tim e she is 75 years of age (after which m ost hip fractures occur), there will be little difference between her bones and those of a wom an who has never taken H T34. A solution m ight be to take H T for about 5 years to cover acute m enopausal sym ptom s, and then start the 10-year program m e between the ages of 60 and 65, by which tim e the breast cancer risk will have returned to baseline. Another option is to use raloxifene or one of the other available bone-preserving treatm ents such as bisphosphonates. There is no doubt that osteoporosis is a m ajor cause of fracture, but there is little scientific evidence that H T reduces the incidence of fractures36,37. H T does reduce bone loss but there has only been one properly controlled study (W H I) that has been continued for long enough to dem onstrate a significant reduction in fractures, especially of the hip38. Such studies are very expensive and difficult to organize, but further useful data m ay becom e available from other ongoing trials that are prim arily investigating the effects of H T on heart disease. Calcitonin and the calcium regulating hormones in postmenopausal women: effect of estrogens. Effects of estrogen/progestin regimens on heart disease risk factors in postmenopausal women. Effects of transdermal vs oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. The dose response of percutaneous estradiol implants on the skeletons of postmenopausal women. Additive effects of weight-bearing exercise and estrogen on bone mineral density in older women. Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial. Effect of calcitonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Systemic absorption of micronised progesterone from Progest cream in postmenopausal women. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern and plasma and salivary progesterone levels in postmenopausal women. Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss. A systematic review of the skeletal effects of estrogen therapy in postmenopausal women. Estrogen produces favorable changes in m any of the biochem ical processes associated with an increased risk of heart disease, particularly a reduction in cholesterol levels and a relaxant effect on the arteries. For wom en who do not have any apparent risk factors for cardiovascular disease, and who lead a healthy lifestyle, there is no evidence of any cardiovascular benefit from H T. In the year 2000, death due to coronary disease occurred in 1022 wom en below the age of 55, com pared with 4600 m en (Figure 6. Although the total num ber of coronary deaths in m en and wom en of all ages is about the sam e, and as atherosclerosis is a slowly progressive disease, m uch of this process will have been initiated prior to the m enopause2. It is surprising, though, that the public generally perceive that breast cancer is a far m ore com m on cause of death in wom en, whereas the reality is alm ost exactly opposite to the general perception (Figure 6. Som e risk factors m ay be m odified or altered by horm one therapy, and others by a change in lifestyle. In recent years, sm oking rates have significantly declined, but have done so less in wom en, and particularly in younger wom en (Figure 6. In addition, sm oking has a strong m ultiplicative effect on risk with other factors such as diabetes and hypertension2. H D L encourages the uptake of cholesterol to the liver, where it is m etabolized. Sm oking com pounds this risk, and with 15 or m ore cigarettes a day it is m ore than seven tim es greater9. Estrogen given by non-oral routes tends to cause a decrease in triglyceride (Figure 6. H om ocysteine is an am ino acid, an excess of which contributes to atherosclerosis. Transderm al treatm ent, estradiol and norethisterone acetate; oral treatm ent, conjugated equine estrogens and levonorgestrel; 3A, estrogen alone; 3B, com bined therapy; 6, com bined therapy. M ost of the studies relating to estrogen and cardiovascular disease have involved wom en who have used unopposed conjugated equine estrogens. Transderm al treatm ent, estradiol and norethisterone acetate; oral treatm ent, conjugated equine estrogens and levonorgestrel; 3A, estrogen alone; 3B, com bined therapy; 6, com bined therapy. Reproduced from reference 11 with perm ission endom etrium, and since they are known to counteract som e of the biochem ical and physiological effects of estrogen, there have been concerns that they would reduce or elim inate som e cardioprotective effects. Inform ation about the effect of progestogen addition is relatively sparse, and what there is, is confusing. H owever, two studies into the incidence of heart attacks in wom en using estrogen alone or in com bination with different progestogens, showed that the risk was reduced m ore than with unopposed estrogen1,16. It is well recognized that different progestogens have different m etabolic effects and this m ay be relevant for the com parison of different H T regim ens in their effect on cardiovascular disease risk. In the future, system ic exposure to progestogens m ay be reduced by using a locally acting intrauterine device (such as M irena), which releases progestogen into the endom etrial cavity with m inim al spill into the circulation17. In fact, there was a sm all increase in coronary deaths in the first year of treatm ent, and only a sm all fall in death rate in subsequent years. O ther lines of research have, however, indicated that estrogen could be useful in secondary prevention after a heart attack, or in the presence of coronary disease. It shows a beneficial effect on coronary oxygen lack brought on by exercise, and has a relaxant effect on atherosclerotic coronary arteries13,19. But, a recent pilot study of 100 postm enopausal wom en who were between 48 hours and 28 days following an acute m yocardial infarction, found a lower death rate and fewer further adm issions to hospital in those who were given low-dose H T with oral estradiol 1 m g daily and norethisterone acetate 0. The other m ajor concerns were an increase in coronary heart disease, with a hazard ratio (H R) of 1. Regrettably, the m edia chose to highlight these findings in percentage term s of relative risk, such that the increase in breast cancer was 26%, coronary heart disease 29%, stroke 41% and pulm onary em bolism 213%. H owever, when the figures are given as absolute risk, for 10 000 wom en taking H T each year, the findings represent an extra eight cases of breast cancer, seven heart attacks, eight strokes and eight pulm onary em bolism s. These figures put the risks into a m ore appropriate and understandable perspective. Nevertheless, the increased risk of cardiovascular disease is surprising and disappointing. It is not clear whether these findings can be extrapolated to all other com binations of estrogen and progestogen, and other routes of adm inistration. H owever, it is well established that progestogens have different m etabolic effects, and non-oral routes of horm one delivery also produce different changes to the oral route, so it would be inappropriate to extrapolate to all form s of horm one therapy. In clinical practice, m ost wom en are given H T at a m uch younger age in order to relieve m enopausal sym ptom s, and few will be starting H T in their m id-60s as in these studies. It is therefore difficult to establish the im plications of these study results for the m ajority of wom en who m ay be seeking or are prescribed H T for the benefits of im proved quality of life. Because raloxifene does not stim ulate the endom etrium, it is not necessary to use additional progestogen. At age 50 years, a wom an faces an estim ated 20% probability of developing a stroke within her lifetim e and an 8% probability of dying from a stroke30. For infarction, ischem ic injury occurs as a direct consequence of dim inished blood flow. For hem orrhagic, vascular rupture into the subarachnoid space or brain tissue causes neuronal death m ainly through tissue com pression and secondary vasospasm. Both infarction and hem orrhage are prim arily diseases of the arterial system and venous strokes are rare31. In W estern countries, stroke is the third leading cause of death, exceeded only by ischem ic heart disease and cancer. Awareness, perception, and knowledge of heart disease risk and prevention among women in the United States. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26 year follow up of the Framingham population.

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Study results 13 where available heart attack warning signs order sotalol with a visa, to detect unreported use of have shown that arteria bologna 8 marzo 2014 buy 40mg sotalol visa, when used in a primary care other medications blood pressure of 100/60 generic 40mg sotalol free shipping, such as opioid analgesics or setting heart attack 90 blockage trusted sotalol 40 mg, the single question was 82 percent sensitive 12 sedative-hypnotics heart attack 5 year survival rate purchase 40 mg sotalol mastercard, that may interact negatively in detecting individuals who had alcohol problems blood pressure medication beta blockers side effects best buy sotalol. The physical drawback as well as a strength, because examination should evaluate neurocognitive exposure to even small amounts of alcohol function, identify sequelae of alcohol use, and 14. However, use of appropriate have no specific abnormal findings on physical laboratory cutoffs make it more likely that a examination, when present, these abnormal positive test is an indication of recent alcohol 20 findings provide evidence of the severity of a use. For example, fi Phosphatidylethanol, another alcohol longstanding alcohol consumption may be metabolite, is a promising new biomarker that marked by many classic features, such as is highly sensitive in detecting chronic drinking physical manifestations of cirrhosis, (three or more drinks a day for 1 or 2 weeks). It can be detected in the blood for 2 to 4 16,20,21,22 Alcohol consumption may also provoke weeks after drinking has stopped. An assessment of hematologic heavy drinking and identify alcohol-related laboratory indices is useful when considering damage. Many people who are alcohol dependent have elevated corpuscular volume Laboratory Testing. Initial and followwith alcohol use disorder may not consume a up laboratory testing can help motivate patients 2 healthful diet, resulting in vitamin deficiencies and reinforce their progress in treatment. For Although no single laboratory test can definitively example, deficiencies in thiamine, folic acid, point to an alcohol use disorder diagnosis in the 14 and pyridoxine are seen in people with absence of other information, the following tests physiological alcohol dependence, and those can be helpful in identifying heavy drinking and 16,17 deficiencies contribute to abnormal cell possible alcohol-related abnormalities: function. Vitamin deficiencies may also lead to fi Blood alcohol levels are useful measures of Wernicke-Korsakoff/amnesic syndrome in recent alcohol consumption and can indicate patients whose alcohol consumption is very physical or legal incapacity to perform specific excessive. For example, naltrexone elevated in people who have chronically and disulfiram should be used with caution in 16 consumed significant amounts of alcohol. Therefore, hepatic and renal system testing 8 Medication for the Treatment of Alcohol Use Disorder: A Brief Guide should be done as part of the patient other substances, and women of childbearing assessment. This is best achieved through face-to-face discussions and the use of written 9 Medication for the Treatment of Alcohol Use Disorder: A Brief Guide educational materials (see Appendix B for Withdrawal generally begins within 24 to 48 sources of helpful information). Symptoms include Elements of effective patient education include 2,13 restlessness, irritability, anxiety, and agitation; the following points: anorexia, nausea, and vomiting; tremor; elevated fi Information about alcohol use disorder as a heart rate; increased blood pressure; insomnia, chronic medical disorder intense dreaming, and nightmares; poor fi A description of what to expect from treatment concentration and impaired memory and fi Information about the medication and the judgment; increased sensitivity to sound, light, reasons it was selected, including a and tactile sensations; auditory, visual, or tactile discussion of potential risks and benefits and hallucinations; delusions (usually of a paranoid or the time to full effect persecutory nature); grand mal seizures; fi For women of childbearing age, explanation of hyperthermia; delirium with disorientation the importance of using an effective birth concerning time, place, person, and situation; 25 control method and fluctuations in level of consciousness. The fact that a patient has received and understands this information should be Some benzodiazepines are effective in treating documented in the patient record. For are advised to obtain a written informed consent example, diazepam carries a labeled indication 13 from the patient before initiating treatment. Chlordiazepoxide also is Managed Detoxification frequently used for the management of alcohol Alcohol withdrawal syndrome can be severe and withdrawal symptoms. Patients who need medically supervised detoxification may need to be referred to an addiction specialist or addiction treatment program that can provide medically monitored withdrawal treatment. Providers should Nonpharmacologic Therapies encourage patients to try different group meetings until they find one that is a good fit. Some patients may respond to psychosocial Lists of local meetings to give to patients can be interventions and others to medication therapy obtained from. Offering the full range Addressing Co-Occurring Disorders of effective treatments increases patient choice and the potential for a positive outcome, as no Research studies show that the most effective 7 way to treat co-occurring disorders is through single approach is universally successful. Psychosocial any mechanism by which treatment interventions treatments can enhance adherence to the for multiple co-occurring disorders are delivered treatment plan, including use of prescribed within the context of a primary treatment medications, and thus improve treatment relationship or service setting. Conversely, to the extent that they co-occurring acknowledges the need for a unified reduce craving and help patients maintain treatment approach to meet the substance use, abstinence, medications may help patients be mental health, and related needs of a patient 2,28 2 more receptive to psychosocial interventions. Almost all studies of medications for the Integrated treatment assumes that each disorder treatment of alcohol use disorder have included is primary and in need of simultaneous care. When providers combined with use of a medication is an effective cannot provide a full range of onsite care, they 2,7,9 treatment for many patients in early recovery. In addition, the patient may need psychosocial therapies onsite, most clinicians assistance with obtaining a referral, securing an need to refer patients for individual or group initial appointment within a reasonable time 2 frame, and addressing issues with health therapy. Encouraging Participation in Mutual-Help When medication management and addiction Programs. The support of a mutual-help group treatment services are delivered by separate can be helpful to long-term recovery. The oldest, providers, close coordination and integration of best known, and most accessible mutual-help services is essential. Empirical validation of the value of medicationTreating Older Adults assisted treatment in adolescents is lacking. Therefore, younger adolescents in social problems that increase the risk of need of treatment should be referred to a hospitalization, nursing home placement, and clinician or program specializing in adolescent 41,42,43 1,33 death. There are no specific safety contraindications for older adolescents/young adults for the medications discussed here, and available Accurately diagnosing an alcohol use disorder in information supports the safe and judicious use an older adult can be done more effectively when 36 of medications in this population. This is clinicians are cognizant of the following particularly true of older adolescents and young 45 challenges faced by this population group: adults who have severe alcohol use disorder, as fi Shame: Older adults are more likely to hide well as those who have not achieved success their substance-related problems because with psychosocial interventions alone and those they are more likely to feel shame and less who exhibit more adult patterns of moderate and 37 likely to seek help or talk about it. In fact, research has not common among older adults, such as identified any safe level of drinking during 38 depression or dementia. Use of alcohol during pregnancy may result in miscarriage, stillbirth, or premature Pharmacotherapies for alcohol use disorder delivery. Complications seen in the infant may appear to be as effective and safe for older include fetal alcohol syndrome or fetal alcohol adults as for younger adults. Pregnant or nursing patients should be referred to an 12 Medication for the Treatment of Alcohol Use Disorder: A Brief Guide As a result, the following factors need to be Mechanism of Action. The disulfiram reaction considered when prescribing pharmacotherapy to is caused by a blockade of aldehyde 45,46 older adults: dehydrogenase, which causes an accumulation of acetaldehyde when alcohol is ingested. When fi Dose reductions and frequent renal function this occurs, the physical reaction can include tests may be necessary when prescribing 40 nausea, flushing, and heart palpitations. Unlike acamprosate to individuals in whom other medications approved to treat alcohol use decreased renal function (creatinine clearance 2 disorder, disulfiram does not directly affect rate <70 mL/min/1. Disulfiram dopamine-beta-hydroxylase in the brain, thereby interacts with multiple drugs, so caution increasing dopamine levels and reducing should be exercised in prescribing it to older 51 noradrenaline levels. It is supplied in 250 mg and 500 mg 50 (disulfiram, acamprosate, and naltrexone) and tablets for oral administration. The initial and injectable naltrexone) for the treatment of alcohol average maintenance dose is 250 mg per day dependence or the prevention of relapse to 7,24 (doses range from 125 mg to a maximum dose of alcohol use. Faulty bioactivation in some patients can beliefs and opinions about which yield too low a concentration of the active pharmacotherapy may be most helpful; level of metabolite needed to inhibit aldehyde motivation for abstinence; medical status and dehydrogenase, and the 500 mg dose may be contraindications for each medication; and 52 2 more effective in these patients. The effectiveness of disulfiram in the particular patient, information for matching prevention and limitation of relapse to alcohol patients to particular pharmacotherapies is 47,48 24,40,47,48,49 use is supported by multiple studies. In or observed, liver function tests should be particular, the level and quality of supervision a obtained. When clinical or laboratory patient receives while taking disulfiram are evidence of hepatic dysfunction is found, believed to be important components of its disulfiram should be discontinued 55,56 success. Some studies have found that courtimmediately and liver function and other ordered disulfiram therapy promotes efficacy by symptoms monitored closely. There is evidence that Use of incentives, patient contracts, the disulfiram interacts with a number of drugs, cooperation of a significant other in fostering including benzodiazepines, isoniazid, rifadin adherence, the use of regular reminders to the (Rifampin), metronidazole, oral anticoagulants patient, and patient behavioral counseling and such as warfarin, oral hypoglycemics, phenytoin, social support may enhance disulfiram efficacy and theophylline. Overall, methodologic drug interactions makes it essential that patients limitations and mixed results make it difficult to be cautioned to report all medications they are state with certainty what percentage of patients 1 taking and not to start any new medication benefit from disulfiram. However, disulfiram is a without checking with the disulfiram medication that should be considered for patients 14,53 prescriber. When effects are severe, palliative therapy for a patient in recovery who anticipates and supportive measures may be needed to 50 being in a situation that may trigger craving for restore blood pressure and treat shock. Naltrexone hydrochloride is a longthe first 2 weeks of therapy, include acting opioid antagonist. Naltrexone has affinity hepatitis, as well as hepatic failure: When for the mu, kappa, and delta opiate receptors. The oral consumption observed in alcohol-dependent naltrexone tablet is taken by mouth once a day. Preclinical the dose recommended for most patients is 50 data suggest the involvement of the endogenous 2,7 mg per day, given in a single dose. It is retained at the site of injection so that its active compound is released consistently Extended-release injectable naltrexone is 63 over approximately 4 weeks, and measurable metabolized in the liver to the opioid antagonist 61 levels may be observed for longer than 1 month. Two peak blood levels occur after injection: a transient initial peak occurs Efficacy. Oral naltrexone has been shown to approximately 2 hours after injection and a reduce relapse to heavy drinking, which is second peak occurs approximately 2 days later. The systematic review of 11 double-blind, placeboabsorption of extended-release naltrexone is controlled trials, researchers found that oral mediated by its gradual and prolonged release naltrexone, when combined with psychosocial for 2 to 4 weeks after injection through hydrolysis treatments, reduced relapse rates at 3 months in 7,24 59 of copolymer microspheres. Thus, it is of the active ingredient over a period of especially useful in patients who have a history of 62,63 65 approximately 4 weeks. A secondary must be mixed vigorously to prevent clumping, analysis found that patients who had 4 or more 63 which can clog the needle during injection. Potential drug interactions involve cough and cold preparations, A side effect unique to extended-release antidiarrheal medications, thioridazine, injectable naltrexone is injection-site yohimbine, and nonsteroidal anti-inflammatory reaction, which involves pain or tenderness drugs (which can elevate liver enzymes). Naltrexone generally is well tolerated, the discussion of Special Considerations in Pain 13,14,68,69 although it has the potential to precipitate severe Management on page 18. Common side effects include Oral naltrexone is most effective when prescribed nausea, vomiting, headaches, dizziness, for patients who are highly motivated and/or fatigue, anxiety, and somnolence, with supported with observed daily dosing and who nausea and vomiting the most frequently 70,71 59,60,64,65,66,67,68 are abstinent at the time treatment is initiated. Less common side effects Naltrexone also appears to be effective in the include diarrhea, constipation, chest pains, following patient populations: joint/muscle pain, rash, insomnia, excessive thirst, loss of appetite, perspiration, mild fi Patients who have a history of opioid use depression, increased tears, and delayed disorder and who are seeking treatment for an 2,24 ejaculation. Naltrexone reduces the reinforcing effects of and curbs cravings for More serious adverse reactions, with suggestions 59,60 both opioids and alcohol. These individual may withdrawal symptoms, discontinue experience greater medication benefit than naltrexone, provide supportive treatments patients with low levels of craving for 72. Watch for clonidine side effects, clinical trials suggest that patients with a including dizziness, hypotension, fatigue, and family history of alcohol problems may benefit headache. ExtendedContact a poison control center for current release injectable naltrexone benefits people information. Swelling, naltrexone has not been shown to be effective erythema, bruising, and pruritus may occur, in patients who are drinking at the time generally as the result of an inadvertent treatment is initiated. Serious reactions include induration, cellulitis, hematoma, abscess, sterile fi Patients who are seeking treatment for abscess, and necrosis. Rarely, these reactions moderate or severe alcohol use disorder while require surgical intervention, such as in recovery from co-occurring opioid use debridement of necrotic tissue, which can result disorder. To prevent problems, release injectable naltrexone in 2010 for the 16 Medication for the Treatment of Alcohol Use Disorder: A Brief Guide prevention of relapse to opioid dependence, the most common side effect is diarrhea, which following opioid detoxification. Less common side effects include release synthetic compound that is indicated for intestinal cramps and flatulence, headache, maintaining abstinence in patients who are increased or decreased libido, insomnia, anxiety, alcohol dependent and are abstinent at the time 75 muscle weakness, and dizziness. There are no known drug 14,24 the imbalance between the glutamatergic and interactions with acamprosate. Acamprosate is supplied as identified particular characteristics that would 7 predict which patients would benefit most from enteric-coated 333 mg tablets. Two 333 mg acamprosate may be most effective for the delayed-release tablets are taken by mouth three 59,79 following types of patients: times a day, with or without food (a lower dose may be effective with some patients and must be fi Patients who are abstinent from alcohol at the used with those with impaired renal function). Acamprosate has a good safety profile: drug interactions with acamprosate, so it can no development of tolerance has been reported, be a safe medication for many patients taking there appears to be no risk of overdose, and other medications. Breath or blood alcohol tests, if clinically would make the individual a poor candidate for indicated to confirm abstinence 1,2 treatment with a medication. Complete blood count and routine fi Educate the patient about medication-assisted chemistries, if clinically indicated treatment and the specific medication being d. A urine drug proposed medication and to other screen should be conducted to verify abstinence 80 medications. If patients are to be fi For women, assess reproductive status, treated for both alcohol and opioid substance including current pregnancy or plans to use disorder, they should be off all opioids, become pregnant or to breastfeed. Patients transitioning from opioid Disulfiram agonist therapy to extended-release injectable naltrexone may be vulnerable to precipitation of Steps in initiating treatment with disulfiram are as 2,55,56 withdrawal symptoms for as long as 2 weeks. A spare administration needle of advice on opioid overdose prevention should be each size is provided in case of clogging. This means Serious injection-site reactions, sometimes a previously tolerated amount of opioid could requiring extensive surgical debridement, result in opioid overdose. Patients discontinuing have been observed with extended-release opioid antagonist therapy in order to receive pain injectable naltrexone. It has been reported management with opioid analgesics should also that these severe reactions may be more be advised of this risk. Consider providing common if the product is inadvertently patients at risk of opioid overdose with a administered subcutaneously rather than prescription for naloxone.

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Overall pulse pressure below 20 buy 40 mg sotalol amex, modest reductions in smoking prevalence blood pressure over 60 buy generic sotalol 40 mg, systolic blood pressure prehypertension icd 9 code generic 40mg sotalol with amex, diastolic blood pressure arrhythmia treatments purchase 40 mg sotalol overnight delivery, and blood cholesterol were observed hypertension signs and symptoms 40mg sotalol with visa. The studies with the highest baseline levels of smoking prevalence blood pressure medication prices order 40 mg sotalol with visa, diastolic blood pressure or cholesterol levels demonstrated greater intervention-related reductions in these risk factors. The pooled effects of the ten trials with clinical event endpoints showed no significant effect on total or cardiovascular disease mortality; this is consistent with the extent of changes in risk factors. However, trials that focused on participants with elevated blood pressure, and those that used drug treatment, demonstrated significant reductions in coronary heart disease mortality and total mortality. Interventions using personal or family counselling and education, with or without drug treatment, were more effective in modifying risk factors and reducing mortality in people at high risk because of raised blood pressure. These results argue in favour of multiple risk factor interventions for prevention of cardiovascular disease in multifactorial high-risk groups. For the general low-risk population, policy measures that create a conducive environment which facilitates behavioural change may have a greater impact at lower cost than individual counselling and therapeutic approaches. Blood pressure lowering Issue Does lowering blood pressure reduce cardiovascular riskfi Evidence Raised blood pressure is estimated to cause about 7 million premature deaths throughout the world, and 4. It is a major risk factor for cerebrovascular disease, coronary heart disease, and cardiac and renal failure. Raised blood pressure often coexists with other cardiovascular risk factors, such as tobacco use, overweight or obesity, dyslipidaemia and dysglycaemia, which increase the cardiovascular risk attributable to any level of blood pressure. Almost all clinical trials have confirmed the benefits of antihypertensive treatment at blood pressure levels of 160 mmHg (systolic) and 100 mmHg (diastolic) and above, regardless of the pres40 Prevention of cardiovascular disease ence of other cardiovascular risk factors (264, 268). Observational data support lowering of these systolic and diastolic thresholds (269, 270). These trial results suggest that treatment for such high-risk patients should begin at the lower blood pressure thresholds. Although women are at lower total risk of cardiovascular disease for a given level of blood pressure, and randomized controlled trials generally include a greater proportion of men than women, the treatment thresholds for systolic and diastolic pressure should be the same in men and women (274). Total risk of cardiovascular disease for any given level of blood pressure rises with age. For now, the treatment threshold should be unaffected by age, at least up to 80 years. Thereafter, decisions should be made on an individual basis; in any case, therapy should not be withdrawn from patients over 80 years of age (275, 276). In people over 55 years of age, the systolic blood pressure is more important (281), so the primary goal of therapy is to lower systolic blood pressure to 140 mmHg or less. In patients with high or very high cardiovascular risk, including diabetes or established vascular or renal disease, therefore, blood pressure should be reduced to 130/80 mmHg or less. These trials have demonstrated reductions in both cardiovascular mortality and morbidity with all three drug classes. For the endpoint of total cardiovascular mortality, these meta-analyses showed no strong evidence of differences between drug classes. At the beginning of the study, there was a fourth group treated with an alpha-blocker; this treatment was stopped prematurely because of an increased risk of combined cardiovascular disease, to which heart failure was a major contributor. The benefits were largely attributable to protection against stroke, and were particularly striking in the diabetic group (290). The incidence of diabetes was also lower in the group on the amlodipine-based regimen. However, this difference could be largely explained by the difference in systolic blood pressure in the two groups (292). One such study included clinical trials in which a beta-blocker was used as the first-line antihypertensive drug in at least half of all patients in one treatment group, with outcome data for cardiovascular morbidity and mortality, and all-cause mortality. This analysis found no difference in all-cause mortality or myocardial infarction, but the risk of stroke was lower with other antihypertensive drug regimens. However, when beta-blockers were compared with placebo or no treatment, they were found to significantly reduce the risk of stroke. Beta-blockers are as efficacious as other classes of anti42 Prevention of cardiovascular disease hypertensive drugs in reducing all-cause mortality and myocardial infarction, but appear to be less effective in reducing the risk of stroke (293). Another meta-analysis (295) investigated the efficacy of beta-blockers in different age groups. The efficacy was found to be similar to that of other antihypertensive agents in younger patients, but lower in older patients, with the excess risk being particularly marked for stroke. A recent Cocharane review assessed the effect of beta-blockers on mortality and morbidity endpoints, compared with placebo or no therapy for hypertension (296). Results showed a relatively weak effect of beta-blockers in reducing stroke and no effect on coronary heart disease. In choosing an antihypertensive drug therapy, there are a number of specific compelling indications (Table 7). For the majority of patients in resource-constrained settings, if there is no compelling indication for another class of drug, a low dose of a thiazide-like diuretic should be considered as the first choice of therapy, on the basis of comparative trial data, availability and cost-effectiveness (286) (Table 7). As previously noted, for many patients, blood pressure should be reduced to lower levels than previously recommended, and more than one drug will often be required (75, 271, 272, 277, 284). It is important to increase gradually the dose of each drug to achieve optimum effect before adding another drug. Adherence to treatment is important to achieve the optimal reduction in blood pressure, and may be facilitated by a once-a-day dosage. If a second antihypertensive drug is added, it should be from a different drug class. In addition to the compelling indications listed in Table 7, other factors may favour the choice of certain drugs. Central alpha-agonists, such as clonidine, or peripheral adrenergic blockers may be used as inexpensive therapies, despite the absence of outcome data. In certain conditions, specific drugs are contraindicated or should be used with caution (Table 7). While certain drugs may be more likely to induce side-effects in particular patients, they may still be used if they are strongly indicated and if the patients are carefully monitored. Beta-blockers, such as carvedilol and metoprolol, are increasingly used to treat stable heart failure. However, they may worsen heart failure and should not be given to individuals with decompensated heart failure (302). Evidence Many studies have shown that the benefits of cholesterol-lowering therapy depend on the initial level of cardiovascular risk: the higher the total risk, the greater the benefit. This is because the relative reductions in risk as a consequence of lipid lowering are approximately the same at different levels of cardiovascular risk. The effectiveness of statins in patients with established atherosclerotic disease (principally coronary artery disease) is well established. Primary prevention trials, on the other hand, are more limited; however, the benefits seen in these trials, as demonstrated by meta-analyses, are consistent with the overall results for all statin trials. Those in the treatment group had 31% fewer primary cardiovascular events than those given placebo (P<0. There were also significant reductions in non-fatal myocardial infarction and death from all cardiovascular causes. In addition, the risks of myocardial infarction, unstable angina, coronary events, and cardiovascular events, and the need for coronary revascularization procedures, were significantly reduced in the treatment group. This was a mixed primary and secondary prevention trial, with 14% of patients having had prior coronary disease and 35% being diabetic. Thus, the difference in cholesterol levels in the two groups of patients was not as large as expected. Simvastatin reduced the rates of myocardial infarction, stroke and revascularization by about one-quarter. About one-third of the participants in this study were free of coronary heart disease. In this group, statin therapy reduced major vascular events by 22% compared with placebo (P = 0. All patients had at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. Patients (n = 2102) were randomly assigned to receive fiuvastatin or placebo, and followed up for 5. This was a mixed primary and secondary prevention study, designed to test the benefits of statin treatment in the elderly. Participants either had existing vascular disease (coronary, cerebral or peripheral) or were at risk of such disease (because of smoking, hypertension or diabetes). The primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal and nonfatal stroke. Four studies met these criteria: the Lipid Research Clinic Primary Prevention Trial, the Helsinki Heart Study, the West of Scotland Coronary Prevention Study, and the Air Force/Texas Coronary Prevention Study (318, 319, 327, 328). Lipid-lowering drug treatment reduced the odds of a coronary heart disease event by 30% (summary odds ratio 0. When the analysis was limited to trials that used statins a slightly stronger effect on all outcomes was found, but there was still no significant reduction in all-cause mortality (although none of these studies was individually powered for this endpoint). Another review of lipid-lowering treatment with statins found that coronary heart disease events and all-cause mortality were reduced in primary prevention populations (329). This review, unlike the meta-analysis mentioned above (326), did not include the large Air Force/Texas trial, which was conducted later. It included the Kuopio atherosclerosis prevention study, a trial in which about 10% of subjects had a history of myocardial infarction (330), and which was not included in the more recent meta-analysis. Data from 15 trials with 63 410 participants and a mean duration of treatment of 3. Overall, statin treatment reduced the relative risk of coronary events, cardiovascular disease mortality, non-fatal strokes and all-cause mortality. There was a 23% reduction in myocardial infarction and coronary death, a 24% reduction in the need for coronary revascularization, and a 17% reduction in fatal and non-fatal strokes, giving a 21% reduction overall in major cardiovascular events. In some trials, participants had high blood pressure, diabetes or ischaemic heart disease. Statins reduced ischaemic heart disease events at age 60 by an estimated 61% in the long term; there was little reduction in the first year but a 51% reduction by the third year. They also reduced the overall risk of stroke by 17%, preventing thromboembolic stroke but not haemorrhagic stroke. Any possible excess of haemorrhagic stroke was greatly outweighed by the protective effect against ischaemic heart disease events and thromboembolic stroke. Twelve randomized placebo-controlled double-blind trials, with a follow-up of at least 3 years, were included. The analysis confirmed that patients, whether diabetic or not, benefit from lipid-lowering in accordance with their absolute cardiovascular risk. The evidence for efficacy of other lipid-lowering agents in primary prevention is weak. This was a mixed primary and secondary prevention study, which randomly assigned 2131 patients with previ48 Prevention of cardiovascular disease ous cardiovascular disease and 7664 without to receive either fenofibrate or a placebo. At 5 years follow-up, fenofibrate did not significantly reduce the risk of coronary events. While statins and resins had a significant lipid-lowering effect, n-3 fatty acids did not significantly affect cholesterol levels. Although there is little reason to believe that the effects would be different in non-Europeans with similar baseline risks of cardiovascular disease and similar lipid profiles, research is needed to examine the effects of lipid-lowering treatment in other racial groups. Risks There is no evidence from the large studies that cholesterol-lowering therapy increases the risk of death from other causes (333, 337, 338). Meta-analysis of data from statin trials has not shown an excess of adverse symptoms, including muscle pain and various gastrointestinal symptoms, in the treated group. Rhabdomyolysis (indicated by serum creatine kinase fi10 times the upper limit of normal) was reported in 55 treated patients (0. Hepatitis (indicated by alanine aminotransferase fi3 times the upper limit of normal) was reported in 449 treated patients (1. Data from randomized trials of cholesterol reduction and disease events have not provided evidence that a low serum cholesterol concentration increases mortality from any cause, other than possibly haemorrhagic stroke.

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