Evaluation of Chronic Heart Failure

July 12, 2017 Cardiology, Critical Care, Differential Diagnosis, Laboratory Medicine No comments , , , ,

Table 28-3 and 28-4, taken from the European Society of Cardiology heart failure guideline, recommend a routine assessment to establish the diagnosis and likely cause of heart failure. Once the diagnosis of heart failure has been made, the first step in evaluating heart failure is to determine the severity and type of cardiac dysfunction, by measuring ejection fraction through two-dimensional echocardiography and/or radionuclide ventriculography. Measurement of ejection fraction is the gold standard for differentiating between the two forms of heart failure, systolic and diastolic, and is particularly important given that the approaches to therapy for each syndrome differ somewhat. The history and physical examination should include assessment of symptoms, functional capacity, and fluid retention.


Functional capacity is measured through history taking or preferably an exercise test. Analysis of expired air during exercise offers a precise measure of the patient’s physical limitations. However, this test is uncommonly performed outside of cardiac transplant centers. The NYHA has classified heart failure into four functional classes that may be determined by history taking. The NYHA functional classification should not be confused with the stages of heart failure described in the American College of Cardiology/American Heart Association heart failure guideline. The NYHA classification describes functional limitation and is applicable to stage B through stage D patients, whereas the staging system describes disease progression somewhat independently of functional status.

Assessment of fluid retention through measurement of jugular venous pressure, auscultation of the lungs, and examination for peripheral edema is central to the physical examination of heart failure patients.

Given the limitation of physical signs and symptoms in evaluating heart failure clinical status, a number of noninvasive and invasive tools are under development for the assessment of heart failure. One such tool that has proven useful in determining the diagnosis and prognosis of heart failure is the measurement of plasma B-type natriuretic peptide (BNP) levels. Multiple studies demonstrate the utility of BNP measurement in the diagnosis of heart failure. The diagnostic accuracy of BNP at a cutoff of 100 pg/mL was 83.4 percent. The negative predictive value of BNP was excellent. At levels less than 50 pg/mL, the negative predictive value of the assay was 96%.


Based largely on the findings of the BNP Multinational Study, clinicians were advised that a plasma BNP concentration below 100 pg/mL made the diagnosis of congestive heart failure unlikely, while a level above 500 pg/mL made it highly likely. For BNP levels between 100 pg/mL and 500 pg/mL, the use of clinical judgement and additional testing were encouraged.

Additionally, plasma BNP is useful in predicting prognosis in heart failure patients. However, serial measurement of plasma BNP as a guide to heart failure management has not yet been proven useful in the management of acute or chronic heart failure.

Evidence-Based Medicine – How to Ask A Question

August 11, 2015 Clinical Trials, Evidence-Based Medicine, Pharmacy Informatics No comments , , , , ,

Foreground questions can be categorized into 5 types, including:

1.Therapy: determining the effect of interventions on patient-important outcomes (symptoms, function, morbidity, mortality, and costs)

2.Harm: ascertaining the effects of potentially harmful agents (including therapies from the first type of question) on patient-important outcomes

3.Differential diagnosis: in patients with a particular clinical presentation, establishing the frequency of the underlying disorders

4.Diagnosis: establishing the power of a test to differentiate between those with and without a target condition or disease

5.Prognosis: estimating a patient’s future course

Clinical questions often spring to mind in a form that makes finding answers in the medical literature a challenge. Dissecting the question into its component parts to facilitate finding the best evidence is a fundamental skill.

One can divide questions of therapy or harm into 4 parts following the PICO framework: patients or population, intervention(s) or exposure(s), comparator, and outcome. For questions of prognosis, you can use 1 of 2 alternative structures. One has only 3 elements: patients, exposure (time), and outcome. An alternative focuses on patient-related factors, such as age and sex, that can modify prognosis: patients, exposure (e.g., older age or male), comparison (e.g., younger age or female), and outcome. For diagnostic tests, the structure we suggest is patients, exposure (test), and outcome (criterion standard).

You need to correctly identify the category of study because, to answer your question, you must find an appropriately designed study. If you look for a randomized trial to inform the properties of a diagnostic test, you will not find the answer you seek.

Different structures or design of studies can investigate different foreground questions. To answer the foreground question that of interest, one should know these different structure or design of clinical studies. Because different study designs can correspond different type of foreground questions, I arrange following discussion due to the type of foreground questions.

Therapy and Harm

To answer questions about a therapeutic issue, we seek studies in which a process analogous to flipping a coin determines participant’s receipt of an experimental treatment or a control or standard treatment: a randomized trial. Once investigator allocate participant to treatment or control groups, they follow them forward in time to determine whether they have, for instance, a stroke or myocardial infarction – what we call the outcome of interest.

When randomized trials are not available, we look to observational studies in which – rather than randomization – clinician or patient preference, or happenstance, determines whether patients receive an intervention or alternative.

Ideally, we would also look to randomized trials to address issues of harm. For most potentially harmful exposures, however, randomly allocating patients is neither practical nor ethical. For instance, one cannot suggest to potential study participants that an investigator will decide by the flip of a coin whether or not they smoke during the next 20 years. For exposures such as smoking, the best one can do is identify observational studies (often sub classified as cohort or case-control studies) that provide less trustworthy evidence than randomized trials.

Differential Diagnosis

For sorting out differential diagnosis, we need a different study design. Here, investigators collect a group of patients with a similar presentation (e.g., painless jaundice, syncope, or headache), conduct an extensive battery of tests, and, if necessary, follow patients forward in time. Ultimately, for each patient the investigators hope to establish the underlying cause of the symptoms and signs with which the patient presented.


Establishing the performance of a diagnostic test (i.e., the test’s properties or operating characteristics) requires a slightly different design. In diagnostic test studies, investigators identify a group of patients among whom they suspect a disease or condition of interest exists (such as tuberculosis, lung cancer, or iron-deficiency anemia), which we call the target condition. These patients undergo the new diagnostic test and a reference standard (also referred to as gold standard or criterion standard). Investigators evaluate the diagnostic test by comparing its classification of patients with that of the reference standard.


A final type of study examines a patient’s prognosis and may identify factors that modify that prognosis. Here, investigators identify patients who belong to a particular group (such as pregnant women, patients undergoing surgery, or patients with cancer) with or without factors that my modify their prognosis (such as age or comorbidity). The exposure here is time, and investigators follow up patients to determine whether they experience the target outcome, such as an adverse obstetric or neonatal event at the end of a pregnancy, a myocardial infarction after surgery, or survival in cancer.

Diagnosis of Myelofibrosis

February 22, 2013 Hematology No comments ,

Current diagnosis of PMF is based on the 2008 World Health Organization (WHO) criteria, which enlist histopathologic, morphologic, clinical, and molecular-cytogenetic variables. The diagnosis of post-PV or post-ET MF is according to IWG-MRT criteria.

Table 1 Diagnostic Criteria of Myelofibrosis

In all 3 MF variants, typical laboratory features include anemia, peripheral blood leukoerythroblastosis, dacryocytosis, leukocytosis/thrombocytosis, increased lactate dehydrogenase (LDH), excess circulating blasts or CD34+ cells, and bone marrow fibrosis, osteosclerosis, and angiogenesis.

Occasionally, overt bone marrow fibrosis might be absent (ie, prefibrotic PMF) and, in the presence of thrombocytosis, a spurious diagnosis of ET is made. The possibility of prefibrotic PMF, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and marked splenomegaly. It is underscored that the distinction between ET and prefibrotic PMF is clinically relevant because both OS and leukemia-free survival are significantly inferior in the latter.

The differential diagnosis of PMF should also include bone marrow fibrosis associated with noneoplastic or other neoplastic conditions, including metastatic cancer, lymphoid neoplasm, or another myeloid malignancy, especially CML, MDS, chronic myelomonocytic leukemia (CMML), or AML. The presence of JAK2 or MPL mutation reliably excludes reative bone marrow fibrosis or a nonmyeloid malignancy.

Pharmacotherapy Options in the Treatment of Obstructive Sleep Apnea

October 10, 2012 Pharmacotherapy, Respirology 4 comments , , ,

Sleep Apnea Multiparameter Record

Obstructive sleep apnea (OSA) is a form of sleep-disordered breathing that is characterized by frequent episodes of snoring and a cessation in breathing for greater than 10 seconds, resulting in disrupted sleep. OSA results from decreased motor tone of either the tongue or airway dilator muscles, causing complete or partial obstruction of the upper airway during sleep. Patients with OSA frequently suffer from daytime sleepiness and reduced quality of life, as well as cardiac, metabolic, and psychiatric disorders.  Obesity is the primary risk factor and contributes to the other disorders commonly diagnosed in this population.

Symptoms and Diagnosis

Untreated OSA is an independent risk factor for increased comorbidities, making it imperative to evaluate common signs and symptoms such as disruptive snoring, daytime sleepiness, obesity, and large neck circumference (>42 cm in men). Diagnostic criteria for OSA include either an apnea-hypopnea index (AHI) of greater than five events per hour plus symptoms of excessive daytime sleepiness or an AHI greater than 15 events per hour regardless of symptoms.

OSA is independently associated with disorders of the cardiovascular, endocrine, and central nervous systems. A study by Peppard et al examined the association between OSA and hypertension.[5] The investigators found OSA to be an independent risk factor for hypertension, and that treatment with continuous positive airway pressure (CPAP) improved blood pressure. A prospective study by Marin et al found that untreated OSA increased the odds by 2.87 for a fatal and 3.17 for a nonfatal cardiovascular event.[6] Studies have found a relationship between OSA and increased incidence of stroke (hazard ratio 2.86–3.56) and a prevalence of seizures in 10% to 45% in patients with OSA.[7,8] Central nervous system (CNS) disorders result from the fatigue and hypersomnolence associated with OSA.[1] Patients with OSA frequently develop insulin resistance that leads to a diagnosis of diabetes. Studies have confirmed that patients with moderate-to-severe OSA are likely to have an elevated fasting glucose level and 2-hour glucose tolerance.[9,10]

Treatment Options

Current treatment options for OSA include both non-pharmacologic and pharmacologic modalities (Table 1). CPAP is the treatment of choice, eliminating episodes of apnea and hypopnea by maintaining airway patency and creating a pneumatic splint.[11,12] Patient compliance with CPAP is estimated at 40% to 60% secondary to the cumbersome equipment required for therapy. Alternative therapies include weight loss, oral appliances, surgery, and drug treatment. Treatment goals include reducing risk factors for OSA, correcting underlying metabolic disorders, treating the consequences, and preventing episodes of apnea and hypopnea.

Tricyclic Antidepressants

It is thought that tricyclic antidepressants (TCAs) improve OSA by increasing rapid eye-movement (REM) sleep latency while decreasing the overall amount of time spent in REM sleep. This modification to sleep architecture possibly improves OSA since the condition worsens during REM sleep, especially in overweight patients.

Serotonin Agents

The selective serotonin reuptake inhibitors (SSRIs) are thought to increase upper airway muscle tone in addition to increasing the amount of serotonin in the brain, which can improve sleep apnea by stimulating the hypoglossal motoneurons.

Nicotine Products

In addition to respiratory stimulation, nicotine can possibly improve OSA by increasing the activity of muscles that dilate the upper airway.

Methylxanthine Derivatives

Although methylxanthine derivatives are also respiratory stimulants, these agents work by blocking adenosine receptors and stimulating ventilatory drive.

Inhaled Corticosteroids

Inhaled nasal corticosteroids can be used to improve airway patency. (more…)

The dignosis of diabetes mellitus

April 9, 2012 Diabetes No comments , , ,

There are many types of diabetes mellitus. In general there are four types of diabetes. They are type 1 diabetes, type 2 diabetes, other specific types of diabetes, and gestational diabetes.

American Diabetes Association.

Type 1 diabetes results from β-cell destruction, usually leading to absolute insulin deficiency. Type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistance. Other specific types of diabetes due to other causes, e.g. genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas etc. And the gestational diabetes mellitus is diagnosed during pregnancy that is not clearly overt diabetes.

There also are three criterias for the diagnosis of diabetes. They are the fasting plasma glucose (FPG) [≥126 mg/dL (7.0 mmol/L)] which is defined as no caloric intake for at least 8 hours, the 2-h value in the 75-g oral glucose tolerance test (OGTT) [≥200 mg/dL (11.1 mmol/L).] which uses a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water, and the A1C test [≥6.5%].

But note that all the three criterias above should be repeated for confirmation before the diagnosis is clear, unless that the patient has classic symptoms of hyperglycemia or hyperglycemic crisis, and simultaneously his or her random plasma glucose ≥200 mg/dL (11.1 mmol/L). It is that the diagnosis of diabetes shall be clear.

A1C assay is a good way for the diagnosis of diabetes.It has many advantages compared to the FPG and OGTT, including greater convenience, evidence to suggest greater preanalytical stability, and less day-to-day perturbations during periods of stress and illness. But A1C assay is not perfect. It costs more, and the there is incomplete correlation between A1C and average glucose in certain individuals.

Also A1C inaccurately reflects glycemia with certain anemias and hemoglobinopathies. For example in conditions with abnormal red cell turnover, such as pregnancy, recent blood loss or transfusion, or some anemias, the diagnosis of diabetes must employ glucose criteria exclusively rather than A1C.

As we discussed above there are four different types mothod to diagnose diabetes and the test should be repeated to rule out laboratory error. Unless the diagnosis is clear on clinical grounds, such as a patient with a hyperglycemic crisis or classic symptoms of hyperglycemia and a random plasma glucose ≥200 mg/dL.

It is preferable that the same test be repeated for confirmation, since there will be a greater likelihood of concurrence in this case. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of diabetes is confirmed. However, if two different tests are both above the diagnostic thresholds, the diagnosis of diabetes is also confirmed. On the other hand, if two different test are available in an individual and the results are discordant, the test whose result is above the diagnostic cut point should be repeated, and the diagnosis is made on the basis of the confirmed test. That is, if a patient meets the diabetes criterion of the A1C (two results ≥6.5%) but not the FPG (≤126 mg/dL or 7.0 mmol/L), or vice versa, that person should be considered to have diabetes.

Also it is possible that when a test whose result was above the diagnostic threshold is repeated, the second value will be below the diagnostic cut point. This is least likely for A1C, somewhat more likely for FPG, and most likely for the 2-h PG. Barring a laboratory error, such patients are likely to have test results near the margins of the threshold for a diagnosis. The health care professional might opt to follow the patient closely and repeat the testing in 3-6 months.