Clinical Practice Guidelines in nephrology—for worse or for better

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application in nephrology, which ultimately aim at ... that may apply to a patient with multiple health .... Methods for guideline development have evolved over.

Nephrol Dial Transplant (2006) 21: 1145–1153 doi:10.1093/ndt/gfl084 Advance Access publication 6 March 2006

Editorial Comment

Clinical Practice Guidelines in nephrology—for worse or for better Katrin Uhlig, Ethan M. Balk, Joseph Lau and Andrew S. Levey National Kidney Foundation Center for Clinical Practice Guideline Development and Implementation, Tufts-New England Medical Center, Boston, USA

Keywords: clinical practice guidelines; systematic review; evidence grading; chronic kidney disease

Introduction Clinical practice guidelines (CPGs)* (throughout the text, terms marked with an asterisk are defined in Table 1 in alphabetical order) [1] have become important tools in shaping the care of individuals with chronic kidney disease (CKD). CPGs inform patient care, scientific debate, research agendas and policies. At the same time, CPGs have been criticized for restricting the care provided by physicians to patients. This article is intended as a review of selected topics related to guideline development and its application in nephrology, which ultimately aim at informing decision making and improving the quality of care.

What guidelines are and are not The primary purpose of CPGs is to improve patient care. As defined in the Institute of Medicine’s 1990 report, guidelines are ‘systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances’[1,2]. CPGs are evidence-based when they are derived from systematic reviews* of the pertinent literature. The evidence is interpreted by experts and forms the basis underlying concrete recommendations for care. A systematic review uses a protocol for identifying, synthesizing and appraising primary research articles. Meta-analyses* are systematic reviews where results of individual studies are quantitatively combined into a single effect estimate. Systematic tabulation of relevant literature facilitates comparison across studies and exploration of reasons for heterogeneity. A systematic approach to literature review Correspondence and offprint request to: Katrin Uhlig, Email: [email protected]

lends scientific rigour to guideline development and aims to reduce bias that can occur in narrative reviews*, where the selection of supporting references and their interpretation is at the discretion of the authors. Geographic variations in health care delivery are widely documented and demonstrate that there is no conformity of practice styles [3]. In nephrology, differences in dialysis care have been shown in different regional dialysis networks and in different countries [4,5]. In general, patient characteristics do not appear to account for all practice variability, which suggests that physician behaviour and system structures play contributing roles [6]. This highlights the need for CPGs to provide guidance on appropriate and effective care. CPGs can educate providers at a time when practitioners find it challenging to keep up with an increasing rate of scientific publications and look to guidelines as practically oriented, systematically developed literature updates. Yet, CPGs cannot be followed like cookbook recipes. They cannot be detailed enough to spell out an individualized approach, that takes into account all potentially important factors, such as patient needs, preferences, available resources, and limitations unique to an institution or type of practice [7]. They can, however, propel practitioners to the level of knowledge generated by an expert panel that has synthesized the relevant literature and arrived at a consensus* in its interpretation. ‘Expert panels’ in guideline development should consist of individuals who have advanced knowledge in the topic of interest, in methods of systematic review and in critical literature appraisal. CPGs often focus on improving the management of one particular disease. They have been criticized for not ranking the importance of different recommendations that may apply to a patient with multiple health care problems and for not providing guidance on how to integrate complex regimens for several diseases efficiently [8]. One explanation for this is that expert groups and professional societies naturally focus on issues of care primarily relevant for the patients they

ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: [email protected]


Nephrol Dial Transplant (2006) 21: Editorial Comments

Table 1. Glossary of terms Term


Algorithm Clinical practice guideline

Step-by-step problem-solving procedure.¼67 Systematically developed statement to assist practitioner and patient decisions about appropriate health care for special clinical circumstances. A tool to measure and report quality of care, primarily for the purpose of population-based quality improvement, rather than as a tool to evaluate care of specific patients, or for use as a standard for quality assurance. CPMs are constructed with a denominator that contains the cases meeting criteria for inclusion during the reporting period dates and a numerator that contains the subset meeting the medical review criteria for the health practice corresponding to the CPM. http:// Various forms of group judgment in which a panel of experts assesses an intervention and formulates findings by vote or other process to reach general agreement. This process may be informal or formal, involving such techniques as the nominal group and Delphi techniques. nichsr/hta101/ta101014.html A comparison of alternative interventions in which costs and outcomes are quantified in common monetary units. A comparison of alternative interventions in which costs are measured in monetary units and outcomes are measured in non-monetary units, e.g. reduced mortality or morbidity. nichsr/hta101/ta101014.html A form of cost–effectiveness analysis of alternative interventions in which costs are measured in monetary units and outcomes are measured in terms of their utility, usually to the patient, e.g. using quality-adjusted life years (QALYs). An approach to decision making under conditions of uncertainty that involves modelling of the sequences of multiple possible strategies (e.g. of diagnosis and treatment for a particular clinical problem) to determine which is optimal. It is based upon available estimates (drawn from the literature or from experts) of the probabilities that certain events and outcomes will occur and the values of the outcomes that would result from each strategy. The cost of different strategies can be compared in cost-benefit analysis, cost-effectiveness analysis, cost-utility analysis. http:// A systematic method that uses statistical techniques for combining results from different studies to obtain a quantitative estimate of the overall effect of a particular intervention or variable on a defined outcome. This combination may support a stronger conclusion than can be supported by any individual study. A literature review that provides an expert view of a topic in a narrative format without using a systematic review protocol. It is susceptible to bias in selecting and interpreting references. http:// A form of structured literature review that addresses a question that is formulated to be answered by analysis of evidence. It involves objective means of searching the literature, applying predetermined inclusion and exclusion criteria to this literature, critically appraising the relevant literature, and extraction and synthesis of data from the evidence base to formulate findings. http://

Clinical performance measure


Cost–benefit analysis Cost–effectiveness analysis Cost utility analysis Decision analysis


Narrative review Systematic review

care for or represent. Another explanation is that guidelines merely mirror the focus of the supporting evidence. Randomized controlled trials (RCTs), which generate the most rigorous evidence on treatment efficacy, generally examine only one type of intervention in a selected population with one dominant health problem. Evidence on how to integrate the management of several diseases in order to optimize competing health outcomes is sparse. To fill this gap, better methods are needed to stratify individual patients’ risks, to tailor interventions according to risk profile and to effectively deliver multi-factorial interventions. Currently, it is left to providers and their patients to integrate multiple guideline recommendations into a feasible and appropriate health care plan. While CPGs cannot provide an outline for complex disease management, they can provide best care recommendations for those aspects which they do address. CPGs contribute to continuous quality improvement when they are implemented and evaluated in clinical practice. It is important to distinguish guidelines from

the policies that are derived from them. Guidelines are used to develop clinical performance measures (CPMs)*, which are tools to measure and evaluate health care practices. Linkage of CPGs with CPMs has led to criticism that guidelines form the foundation for auditing and regulation [9]. There is distrust in the reliability and validity of CPMs, because they do not adequately adjust for patient factors or do not focus on central aspects of care. Coupling performance with financial incentives has worried physicians who feel that being measured against collective benchmarks overrides their professional autonomy and acumen. Still, guideline development provides an avenue for health care professionals to participate in the assessment of what is appropriate care, based on medical reasoning. Although guidelines can provide a foundation for policies, additional considerations need to be incorporated when creating policy decisions. One of these considerations is cost. How costs should be considered in guideline development is a controversial issue. When decision analyses* include estimates of costs as in cost–benefit*, cost–effectiveness* and cost–utility

Nephrol Dial Transplant (2006) 21: Editorial Comments

analyses*, different health practices can be compared regarding their returns. For this, the costs of the health practice are considered against the returns resulting from outcomes, which are expressed as monetary benefit, clinical effectiveness or utility. However, the conduct of decision analyses and incorporation of costs explicitly into guideline development requires special expertise. Further limitations are that costs are often based on assumptions and true costs can vary greatly in different contexts and over time. As a practical approach, it has been recommended that guideline panels primarily aim to determine the net medical benefit of a health practice from the patient perspective and that costs be considered separately [10]. Users can then distinguish the medical information and its interpretation from other considerations including costs. The goal for guideline development panels is not to decide what health services should be offered and how they should be paid for. This task falls on policy makers and local implementers. Guideline developers cannot resolve the tension that exists between the goal of optimizing health care for an individual and the goal of improving public health. At the same time, CPGs can be used as a tool to defend the provision of appropriate services against the pressure of other interests.

Methodological challenges for guideline development Evidence grading Methods for guideline development have evolved over the past several years. Checklists for quality criteria of CPGs have been proposed to provide instruction for guideline developers and help users evaluate the quality of a guideline [11–13] The following key attributes for well-developed guidelines are proposed: (i) An evidence-based approach is followed that involves systematic literature searches and comprehensive review of pertinent existing scientific evidence published in peer reviewed journals; (ii) Workgroup composition is interdisciplinary with representation of expertise in relevant clinical domains and in the methods of systematic literature review and appraisal; (iii) Workgroups are independent without the influence of organizations or industry and (iv) Guidelines undergo a review prior to publication which includes feed-back by representatives of patient organizations [7]. So far, guidelines do not consistently adhere to all quality criteria although they are improving [14,15]. One of the proposed quality criteria is that guidelines should be evidence-based and the strength of the recommendations should be graded. In guideline development, grading may occur at several levels: first, when grading the quality of an individual study; second, when grading an aggregate of studies that look at one health care practice and one type of outcome; third, when grading the composite of all studies that evaluate one health practice across all important outcomes; and fourth, when grading the strength of


a recommendation. Ideally, the grading at each level would be consistent and transparent and there would be an explicit linkage of the quality of the evidence and the strength of the recommendation. There are many different scales in use for grading the strength of recommendations and the quality of evidence [16]. However, none has been shown to be superior in direct comparisons. Nor has any been shown to reduce subjectivity in appraisal or predict how guidelines are accepted, implemented or improve clinical outcomes. It remains a sobering fact that translating evidence into a clinical context requires synthesis of facts as well as judgments, which are affected by values and opinions [17]. Nevertheless, grading schemes provide a structured approach to systematic evidence review and appraisal. They help make transparent how evidence and judgments are combined and clarify expectations for implementation. Although no single system may be ideal, harmonizing approaches to grading facilitates communication about the meaning of a guideline. Earlier systems, such as the evidence hierarchy of the Canadian Task Force on the Preventive Health Examination, have focused on the study design to assign a quality grade [18]. These systems are simple and make grading reproducible, but they do not consider the methodological quality of studies (i.e. the extent to which bias was minimized in each study), the quantity and consistency of studies or the magnitude of the effect. More recent systems, for example the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, incorporate additional dimensions in grading [10,19]. According to the GRADE approach, a collection of randomized clinical trials with serious limitations to the methodological quality of the studies or with inconsistent findings would not be assigned a composite quality grade of ‘high’, while an aggregate of highquality observational studies that consistently show a large effect size might be. For recent Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, grading of evidence has followed the GRADE approach with some modifications [10,19]. Overall, grading is a work in progress and methods for grading are expected to further evolve, in particular in the grading of evidence that looks at questions related to diagnosis, prognosis or harms. Quality of evidence in nephrology Evidence review in nephrology faces a number of challenges. The long and silent course of CKD makes it difficult and expensive to conduct studies that examine hard clinical outcomes. Therefore, surrogate outcomes are often used to shorten the necessary follow-up time. To study the progression of CKD, laboratory parameters, such as the level of glomerular filtration rate (GFR) or proteinuria, are commonly used. It remains an area of active investigation how changes in surrogate outcomes early in the disease predict subsequent changes in the risk for kidney failure. In addition, patients with CKD face an increased risk


of cardiovascular disease (CVD) [20,21]. Therefore, outcomes for CVD and interventions to reduce CVD risk need to be included in the study of patients with CKD. Despite the recognition of CKD as a public health problem, the recruitment of individuals with CKD in the stages of disease prior to kidney failure is difficult. These patients predominantly receive care by nonnephrologists (such as providers in family medicine, internal medicine, endocrinology and diabetes care, cardiology, vascular medicine and surgery). Until recently, the definition and staging of CKD in research studies was heterogeneous. Early stages of CKD were not recognized and large subpopulations with unrecognized CKD were included in studies of diabetes, hypertension or CVD. The use of the K/DOQI classification for CKD should result in a more consistent characterization of patients [22]. What remains unresolved is the problem of misclassification of the type of kidney disease since the aetiological diagnosis is often presumptive and a definitive histopathological diagnosis is usually not available. Still the type of kidney disease has important implications for the risk of progression and concomitant diseases. These methodological problems in the study of CKD may partly explain why the number of large, highquality clinical studies that examine hard clinical outcomes is relatively limited in nephrology [23]. This is relevant for guideline development since the quality of systematic reviews and the strength of the conclusions that can be drawn depend on the quality of the source literature. At present, many aspects of care for patients with earlier stages of CKD are largely based on extrapolating evidence from studies of individuals without kidney disease. Thus, guideline developers in nephrology face complex issues when integrating and appraising bodies of literature. Guidelines in nephrology have so far focused primarily on topics related to CKD, namely testing, evaluation and treatment for CKD, its complications and concomitant diseases (Table 2). There is a growing movement among experts to expand guideline development to the area of acute kidney injury (formerly acute renal failure). Expansion of CPGs to this area faces the challenge of lack of standardized definitions and limited understanding of the epidemiology and natural history of this entity.

Guideline development in nephrology Several professional societies in nephrology develop English language CPGs (Table 2). In addition, other agencies, committees and organizations issue guidelines that are relevant to the care of individuals with kidney diseases, for example on hypertension or diabetes. The authors participate in the development of guidelines for the National Kidney Foundation’s K/DOQI [24,25]. In the following section, the current process of K/DOQI guideline development is described as an

Nephrol Dial Transplant (2006) 21: Editorial Comments

example of what workgroup experts do when developing a guideline. However, discussion of all aspects of guideline methodology is beyond the scope of this review. Table 3 provides an overview of the process followed in the development of recent K/DOQI guidelines. A guideline is initiated after a topic relevant to clinical practice has been selected by the K/DOQI Chairs and Advisory Board. Workgroup chairs are appointed, who recruit workgroup members with expertise in the relevant areas and clinical disciplines. An evidence review team (ERT) consisting of a staff of methodology and nephrology experts is contracted to guide the workgroup through the systematic review and the critical literature appraisal. The timeline for development of a new guideline is approximately 2 years, with four in-person meetings of the workgroup and the ERT. An important step of guideline development is the generation of a comprehensive list of well-formulated questions that relate to important clinical problems. For each question the ‘PICO’ criteria are specified for population of interest, intervention or predictor of interest, comparison group and outcome(s) of interest [26]. In addition, desired study design, required duration of follow-up, and minimal number of subjects per study are specified for each question. These criteria are used for including studies when screening abstracts and articles. Data from eligible studies are extracted onto standardized forms and the methodological quality and applicability of each study is assessed. Summary tables are drafted that tabulate the information from each study in a condensed form. For each question the balance of benefits and harms of the health practice is summarized and the quality of the supporting evidence is judged. Thereafter, the workgroup implicitly considers additional issues such as availability of a service, special features of health systems and costs to determine whether a guideline recommendation can be issued and of what strength. Care is taken to make recommendations that are actionable and specific. They are written in the form of ‘what should be done in whom, when, where and how often’. Algorithms* are developed to organize recommendations into a logical sequence. Workgroup members are prompted to describe limitations of the evidence and to provide detailed recommendations for future research that will fill important gaps of knowledge. The CPG draft undergoes internal and public review. The workgroup then revises the guidelines in response to comments from reviewers and submits the guideline document for publication. When evidence is not sufficient to support an evidence-based guideline, K/DOQI workgroups have issued recommendations based on a consensus. In these cases, the literature has been reviewed and the evidence is not deemed to definitively answer the clinical question but the workgroup wishes to provide guidance to the practitioner. Distinguishing these workgroup consensus statements from evidence-based

Nephrol Dial Transplant (2006) 21: Editorial Comments


Table 2. Guidelines issued by nephrology organizations and societies


Organization or Society

Guideline titles (year first published, updated)

Canadian Society of Nephrology (CSN) 20practice/programmes/default.asp?s¼1

Principles of End-Stage Renal Disease Care (1997) CSN Clinical Practice Guidelines (1999) Elevated Levels of Serum Creatinine: Recommendations for Management and Referral (1999) CSN Position Paper on Care and Referral of Patients with Reduced Kidney Function (2006) Hemodialysis Clinical Practice Guidelines for the CSN (2006, in press) CSN Clinical Practice Guidelines on Peritoneal Dialysis Adequacy (2006) Management of Anemia in Patients with CKDc

Dialysis, Nephrology and Transplantation Subcommittee, a joint committee of the Australian and New Zealand Society of Nephrology (ANZSN) and Kidney Health Australia (KHA) – Caring for Australasians with Renal Impairment (CARI) guidelines.php

Part Part Part Part Part

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) – European Best Practice Guidelines (EBPG)

Transplantation, Part 1 (2000), Part 2 (2002) Haemodialysis Part 1 (2002), Part 2c Management of Anaemia in Patients with Chronic Renal Failure (2000, 2004) Peritoneal Dialysis (2005)

Kidney Disease Improving Global Outcomes (KDIGO)

Prevention, Diagnosis, Evaluation and Treatment of Hepatitis C in CKDc Bone and Mineral Metabolism in CKDc

National Kidney Foundation (NKF) – Dialysis Outcomes Quality Initiative (DOQI) and Kidney Disease Outcomes Quality Initiative (K/DOQI) http:// index.cfm

Hemodialysis Adequacy (1997, 2001)b Peritoneal Dialysis Adequacy (1997, 2001)c Vascular Access (1997, 2001)b Anemia of Chronic Renal Failure (1997, 2001)b Nutrition in Chronic Renal Failure (2001) CKD: Evaluation, Classification and Stratification (2002) Managing Dyslipidemias in CKD (2003) Managing Dyslipidemias in Kidney Transplant Recipients (2004) Hypertension and Antihypertensive Agents in CKD (2004) Bone Metabolism and Disease in CKD (2004) Cardiovascular Disease in Dialysis Patients (2005) Bone Metabolism and Disease in Children With CKD (2005) [34] Diabetes and Chronic Kidney Diseasec

Renal Association – Standards and Audit: Clinical Practice Guidelines Committee standards.html

Treatment of Adults and Children with Renal Failure: Standards and Audit Measures (2002)b

Joint Specialty Committee on Renal Disease of the Royal College of Physicians of London and Renal Association

Chronic Kidney Disease in Adults: UK Guidelines for Identification, Management and Referral (2005)

Renal Physicians Association (RPA) – Quality Safety and Accountability Committee

Adequacy of Hemodialysis (1993) Shared Decision Making in the Appropriate Initiation of and Withdrawal from Dialysis (1999) Appropriate Patient Preparation for Renal Replacement Therapy (2002) End-Stage Renal Disease Workgroup (2002)

1—Dialysis Guidelines (2000, 2005) 2—Early Renal Impairment Guidelinesb 3—Transplantation Guidelines (2005)b 4—Proteinuria, Peritonitis, and CMV Infection Guidelines (2004) 5—Kidney Stones/Calcineurin Inhibitors in Renal Transplantationc

a This table lists English language guidelines commissioned by nephrology organizations and societies. Guidelines pertaining to the management of individuals with kidney disease by other entities are not included. A list of subtopics covered by each guideline can be found at bUpdate under development. cNew guidelines under development.

guidelines clarifies that they are not meant to be used as a foundation for CPMs and should not obstruct future research on the topic. Guideline implementation After CPGs have been developed, they need to be implemented. Implementation aims at bridging the gap between best evidence and actual practice and to

shorten the delay encountered in the translation of new research findings [27]. Successful implementation is tailored to target practice settings. A first step is to analyse regional practice patterns and compare them against the recommendations in CPGs. Knowledge of local health priorities and structures forms the basis for decisions on how to adopt the guidelines. A growing body of empirical experience on which system changes produce better care and which strategies facilitate


Nephrol Dial Transplant (2006) 21: Editorial Comments

Table 3. Process of K/DOQI Guideline Development followed in recent guideline projects

Define scope of work and topics Define questions, draft mock guidelines Determine search criteria Develop search strategies and conductsearches, screen abstracts and articles Review existing guidelines Create data extraction forms and summary table templates Extract data. Grade quality and applicability of each study Check data. Create summary tables Grade quality of evidence for each outcome and assess overall quality of the evidence Write guideline recommendations and supporting rationale. Grade strength of the recommendations Write methods chapter Overall synthesis, develop algorithms, framework and background chapter Integrate guidelines into one document and prepare draft for public review Report to advisory board Respond to public review and submit for publication

Timeline (months 0–30) Workgroup meetings at 3, 9, 15 and 21 months

Workgroup chairs

Workgroup members


0–2 2–4 4–6 4–8

* * þ

þ þ þ

þ þ * *

4–6 6–8 6–12 12–18 18–20




* þ *

* * þ * þ




20–22 22–24



* þ





26 28–30

* *



* denotes primary and þ shared responsibility. Throughout the guideline project, the K/DOQI Co-Chairs and the K/DOQI Advisory Board provide oversight and feed-back. Staff of the National Kidney Foundation provides support for communication, coordination, meeting planning, editing of the draft, organization of public review. Workgroup chairs and workgroup members are volunteers. The Evidence Review Team (ERT) comprises a staff of domain and methods experts contracted by the National Kidney Foundation.

such changes can inform the design of implementation strategies [28]. The quality improvement cycle is closed by periodic updating of guidelines to incorporate new research findings and experience gained from evaluation of CPGs implementation. Figure 1 shows the feed-back loop between research, guideline development, implementation and evaluation. Guideline implementation is often not rigorously evaluated and it is difficult to attribute changes in practice solely to the issuance of a guideline. Table 4 shows a chronology of selected events in guideline development and implementation in nephrology. A temporal relationship does not establish what is cause or effect. It also remains to be demonstrated that these activities improve clinical patient outcomes. As can be seen in Table 4, the reaction to guidelines can vary. While some recommendations from CPGs have been widely adopted, others have been the topic of debate or have been contradicted by subsequent research. Evidence-based CPGs can only be definitive if they are supported by high-quality evidence. Yet the lifespan of medical knowledge is limited and even high-quality clinical research can be contradicted by subsequent studies [29]. This highlights the importance of updating CPGs to keep them current, especially when new scientific evidence becomes available. Challenges in international guideline development The coexistence of several independent guideline development programs in nephrology allows for diversity in development and tailoring of CPGs

Biomedical research (efficacy) Health services research (effectiveness)

Scientific research findings on efficacy and effectiveness

Systematic reviews of scientific evidence development of evidence reports

Dissemination of evidence reports

Development of evidencebased clinical practice guidelines Dissemination of guidelines

Use/Implementation of guidelines

Research agenda

Evaluation of guidelines, health care processes, outcomes and cost

Fig. 1. Flow of activity in evidence-based guidelines [41].

specific to particular settings. It also protects against monopolies in topic selection or bias from strong special interests. Yet as the list of CPGs published in Table 1 reveals, a number of topics have been dealt with in guidelines issued by several societies within

Nephrol Dial Transplant (2006) 21: Editorial Comments


Table 4. Selected Clinical Practice Guidelines and Quality Improvement Activities in Nephrology Guidelines


Renal Physicians Association guidelines on adequacy of dialysis are released.

1993 1994

Dialysis Outcomes Quality Initiative (DOQI) guidelines on dialysis adequacy, vascular access and anemia are released.

End Stage Renal Disease (ESRD) Core Indicators Project begins as part of the ESRD Health Care Quality Improvement Program and collects clinical information annually on four clinical performance measures (CPMs) (adequacy of dialysis, haematocrit value, nutritional status and blood pressure control).

1997 1999

Kidney Disease Outcomes Quality Initiative (K/DOQI) CPG on Chronic Kidney Disease (CKD): Evaluation, Classification and Stratification proposes new definition and classification for CKD and includes prevention of cardiovascular disease into action plan for CKD care.

Quality improvement activity

2000 2002

K/DOQI CPG Managing Dyslipidemias in CKD recommends Low Density Lipid (LDL) cholesterol target of
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