body fat

INTRODUCTION — Methods for determining body composition have improved over the past 20 years, greatly increasing the accuracy and ease of making these measurements [1-4]. Body composition measurements may be useful in undernourished patients, or for identifying patients who do not have an increase in overall body fat, but who have an increase in visceral fat. This latter circumstance is associated with a substantially increased risk of heart disease and diabetes. Measurement of body composition is also instructive for assessing body changes associated with growth and development, aging (sarcopenia), and in certain disease states (eg, HIV, diabetes) [5-11].

Certain measurements, such as height, weight (to calculate body mass index), and waist circumference are the minimal clinical criteria for evaluating the overweight patient. This topic will review body composition and critique most methods available for its measurement. Other considerations when evaluating the overweight patient are discussed elsewhere. (See "Screening for and clinical evaluation of obesity in adults".)

MODELS OF BODY COMPOSITION — Body composition can be viewed from five perspectives (figure 1) [1,12]:

Atomic
Molecular
Cellular
Tissues
Whole body

Atomic composition — A reference human weighing 70 kg contains 61 percent oxygen, 23 percent carbon, 10 percent hydrogen, 2.6 percent nitrogen, 1.4 percent calcium, and less than 1 percent all other atoms (phosphorous, sulphur, potassium, sodium, chlorine, magnesium, and various trace elements). Thus, six elements - oxygen, carbon, hydrogen, nitrogen, calcium, and phosphorous - account for more than 98 percent of body mass, while less than 2 percent is contributed by the other 44 elements that are present [1].

Molecular composition — The molecular model is the most common form in which body composition is expressed. More than 100,000 chemical compounds can be identified in the human body, ranging from simple to very complex; water, lipid, and protein are the major components (figure 1) [1].

Water comprises 60 percent or more of the reference male (and 50 percent of the reference female), of which approximately 26 percent is extracellular and 34 percent intracellular.
Body fat ranges from under 10 percent in well-trained athletes to slightly over 50 percent in obese patients. Two to three percent of lipids in fat are essential structural lipids; the remainder are fat stores.
Protein comprises 15 percent of normal body composition.
Mineral comprises 5 percent of normal body composition.

Thus, water, lipid, protein, and minerals account for 99.4 percent of the molecular constituents of the body.

Cellular composition — The body is composed of cell mass, extracellular fluid, and extracellular solids. The 10(18) cells in the body of an adult can be divided into four major categories: connective tissue cells, epithelial cells, neural cells, and muscle cells. Fat cells, osteoclasts, osteoblasts, and the cellular elements of blood are components of connective tissue. Muscle cells include skeletal muscle, smooth muscle, and cardiac muscle. Epithelial cells include the cells lining a hollow viscus. The body content of potassium, measured as the naturally occurring isotope (40K) or as exchangeable potassium (42K), is the most widely used indicator of body cell mass because potassium is the principal intracellular cation [1].

Extracellular fluid is approximately 94 percent water. It is distributed into two main compartments, the plasma in the intravascular space and the interstitial fluid in the space outside of the vascular compartment. Plasma and interstitial fluid account for approximately 5 and 20 percent, respectively, of body weight in the reference human.

Tissue and organ components — Body weight represents the sum of the muscle tissue, connective tissue, epithelial tissue, and nervous tissue. Bone, adipose tissue, and muscle make up 75 percent of body weight (figure 1). The majority of body fat (80 percent in men, 90 percent in women) is subcutaneous. However, fat also accumulates around the abdominal organs (visceral fat). Visceral adipose tissue is more difficult to measure [13]. Visceral adiposity is associated with a greater risk of metabolic and cardiovascular disorders including insulin resistance, type 2 diabetes mellitus, hypertension, and coronary heart disease. (See "Health hazards associated with obesity in adults".)

Whole body — The whole body represents the final perspective on body composition. There are at least 10 different components of the whole body that may be measured, including stature, segment lengths, circumferences, skinfold thicknesses, body surface area, body volume, body weight, body mass index, and body density.

METHODS OF MEASURING BODY COMPOSITION — There are several methods for determining body composition. Each provides a different view of the body's components. The various methods include two compartment models (fat and non-fat, aqueous and non-aqueous), three compartment models (fat, lean, bone mineral), or four compartment models (body density, weight, water, and bone mineral mass) [14,15]. They differ in ease of determination, cost, accuracy, use of radiation, and utility for assessing regional body fat (table 1). The most useful techniques are described below.

Anthropometric measurements

Height and weight are the most commonly measured and can be determined with great accuracy. They are important in making clinical decisions regarding treatment of obesity [16]. Weight can be related to height by several methods, but the most widely used is the body mass index (BMI), which is weight (in kilograms) divided by the height (in meters) squared (table 2A-B). (See "Screening for and clinical evaluation of obesity in adults".)
Waist circumference is another essential anthropometric measurement. It is measured with a flexible tape placed on a horizontal plane at the level of the iliac crest as seen from the anterior view (figure 2). Increasing central adiposity, as measured by waist circumference, is associated with an increased risk of morbidity and mortality. (See "Screening for and clinical evaluation of obesity in adults", section on 'Waist circumference' and "The metabolic syndrome (insulin resistance syndrome or syndrome X)".)
Measurements of skinfold thickness are considerably less accurate than measurements of height or weight, particularly in obese subjects. Thus, they have little practical clinical value and are primarily used in epidemiological studies.

Dual-energy X-ray absorptiometry — Dual-energy X-ray absorptiometry (DXA) is one of the more commonly used methods for determining body composition. This method is based on the attenuation of signals from two energy sources to provide a three compartment model of body composition.

In a study comparing DXA with a four compartment model of body composition, estimates of mean percent body fat were similar between the two methods [15]. However, there was considerable intraindividual variability, ranging from -3.0 to +4.0 percent, with DXA. Thus, DXA is good for cross-sectional measurements, but is less reliable for individual measures.

Isotopic measurement of body water — Isotopic dilution with a tracer that measures body water (D20; 3H20) also provides an accurate assessment of body fat. In a study of children, three methods (DXA, isotopic measurement of body water, and densitometry) provided a similar estimate of body fat relative to a more complicated four-compartment model of body composition [1,14].

Body density and whole body plethysmography — Partitioning fat and fat-free components of the body can be done with hydrodensitometry (underwater weighing) or whole body plethysmography (Bod Pod). The first technique weighs the individual on dry land and then after complete submersion, preferably with a simultaneous measurement of lung volume. In contrast, whole body plethysmography uses air displacement rather than water displacement to measure body fat. It is similar in principle to hydrodensitometry or underwater weighing, but does not require submersion. In a study that compared air displacement (Bod Pod) versus water displacement (underwater weighing), the two methods were highly correlated (r = 0.94) with a standard error of the estimate of 0.0073 [17]. Air displacement appears to be an important new instrument for measurement of body fat.

Impedance measurement — Impedance measurement is widely used but has significant limitations. Impedance is measured by applying electrodes to one arm and one leg or by standing on the foot plates of a special scale. Impedance is proportional to the length of the conductor and inversely related to the cross-sectional area of the conductor. Accuracy in placement of electrodes is essential because even small variations can cause relatively large errors in the measurement of impedance and corresponding errors in the estimate of body water.

A variety of formulas have been developed to convert impedance, which measures body water, into an estimate of fat [18,19]. Most formulas for estimating fat from bioelectric impedance analysis underestimate body fat [14]. As an example, in a study comparing two bioelectric impedance devices with DXA for the measurement of body fat, percent body fat measured with both bioelectric impedance devices was 2 to 6 percent lower in men and women with normal BMI [18]. Among the overweight individuals, the values were lower in women but similar in men. When using bioelectric impedance devices, it is important to use validated formulas to estimate body fat [18].

Imaging techniques — Patterns of body fat distribution can be reliably determined by either computed tomography (CT) or magnetic resonance imaging (MRI) [1,20,21]. The most common technique is to obtain a single cross sectional image at the interspace between the fourth and fifth lumbar vertebrae. The image is used to quantitate subcutaneous and visceral fat. Images obtained between the second and third lumbar vertebrae provide similar information [22].

CT uses X-radiation and computer analysis to determine the structure of internal organs. It is possible to obtain an accuracy of less than 1 percent margin of error for body fat using a series of scans. To minimize radiation dose, however, a single cut at the L4-5 position is used clinically.
MRI requires the use of a powerful magnet that surrounds the subject. It has no risks, but takes considerably longer to perform than CT. Movement will blur the images.

The estimates of subcutaneous and visceral fat obtained by these two methods may differ in absolute terms, but the relative ranking of subjects is similar.

SUMMARY — Careful measurement of height, weight, and waist circumference are the minimal measurements needed to begin evaluation of overweight patients. (See "Screening for and clinical evaluation of obesity in adults".) If there is concern about whether fat is increased, particularly visceral fat, DXA may be beneficial. Although impedance measurements are used in many clinical settings, they do not contribute more than the methods outlined a

Meaningful use II a

Medicare and Medicaid Programs; Electronic Health Record Incentive Program--
Stage 2
AGENCY: Centers for Medicare & Medicaid Services (CMS), HHS.
ACTION: Proposed rule.
SUMMARY: This proposed rule would specify the Stage 2 criteria that eligible
professionals (EPs), eligible hospitals, and critical access hospitals (CAHs) must meet in
order to qualify for Medicare and/or Medicaid electronic health record (EHR) incentive
payments. In addition, it would specify payment adjustments under Medicare for
covered professional services and hospital services provided by EPs, eligible hospitals,
and CAHs failing to demonstrate meaningful use of certified EHR technology and other
program participation requirements. This proposed rule would also revise certain Stage 1
criteria, as well as criteria that apply regardless of Stage, as finalized in the final rule
titled Medicare and Medicaid Programs; Electronic Health Record Incentive Program
published on July 28, 2010 in the Federal Register. The provisions included in the
Medicaid section of this proposed rule (which relate to calculations of patient volume and
hospital eligibility) would take effect shortly after finalization of this rule, not subject to
the proposed 1 year delay for Stage 2 of meaningful use of certified EHR technology.
CMS-0044-P 2
Changes to Stage 1 of meaningful use would take effect for 2013, but most would be
optional until 2014.
DATES: To be assured consideration, comments must be received at one of the
addresses provided below, no later than 5 p.m. on [OFR--insert date 60 days after date of
publication in the Federal Register].
ADDRESSES: In commenting, please refer to file code CMS-0044-P. Because of staff
and resource limitations, we cannot accept comments by facsimile (FAX) transmission.
You may submit comments in one of four ways (please choose only one of the
ways listed):
1. Electronically. You may submit electronic comments on this regulation to
http://www.regulations.gov. Follow the "Submit a comment" instructions.
2. By regular mail. You may mail written comments to the following address
ONLY:
Centers for Medicare & Medicaid Services,
Department of Health and Human Services,
Attention: CMS-0044-P,
P.O. Box 8013,
Baltimore, MD 21244-8013.
Please allow sufficient time for mailed comments to be received before the close
of the comment period.
3. By express or overnight mail. You may send written comments to the
following address ONLY:
CMS-0044-P 3
Centers for Medicare & Medicaid Services,
Department of Health and Human Services,
Attention: CMS-0044-P,
Mail Stop C4-26-05,
7500 Security Boulevard,
Baltimore, MD 21244-1850.
4. By hand or courier. Alternatively, you may deliver (by hand or courier)
your written comments ONLY to the following addresses prior to the close of the
comment period:
a. For delivery in Washington, DC--
Centers for Medicare & Medicaid Services,
Department of Health and Human Services,
Room 445-G, Hubert H. Humphrey Building,
200 Independence Avenue, SW.,
Washington, DC 20201
(Because access to the interior of the Hubert H. Humphrey Building is not readily
available to persons without Federal government identification, commenters are
encouraged to leave their comments in the CMS drop slots located in the main lobby of
the building. A stamp-in clock is available for persons wishing to retain a proof of filing
by stamping in and retaining an extra copy of the comments being filed.)
CMS-0044-P 4
b. For delivery in Baltimore, MD--
Centers for Medicare & Medicaid Services,
Department of Health and Human Services,
7500 Security Boulevard,
Baltimore, MD 21244-1850.
If you intend to deliver your comments to the Baltimore address, call telephone
number (410) 786-1066 in advance to schedule your arrival with one of our staff
members.
Comments erroneously mailed to the addresses indicated as appropriate for hand
or courier delivery may be delayed and received after the comment period.
For information on viewing public comments, see the beginning of the
"SUPPLEMENTARY INFORMATION" section.
FOR FURTHER INFORMATION CONTACT:
Elizabeth Holland, (410) 786-1309, or Robert Anthony, (410) 786-6183, EHR Incentive
Program issues.
Jessica Kahn, (410) 786-9361, for Medicaid Incentive Program issues.
James Slade, (410) 786-1073, or Matthew Guerand, (410) 786 1450, for Medicare
Advantage issues.
Travis Broome, (214) 767-4450, Medicare payment adjustment issues.
Douglas Brown, (410) 786-0028, or Maria Durham, (410) 786-6978, for Clinical quality
measures issues.
Lawrence Clark, (410) 786-5081, for Administrative appeals process issues.
CMS-0044-P 5
SUPPLEMENTARY INFORMATION:
Inspection of Public Comments: All comments received before the close of the comment
period are available for viewing by the public, including any personally identifiable or
confidential business information that is included in a comment. We post all comments
received before the close of the comment period on the following Web site as soon as
possible after they have been received: http://www.regulations.gov. Follow the search
instructions on that Web site to view public comments.
Comments received timely will also be available for public inspection as they are
received, generally beginning approximately 3 weeks after publication of a document, at
the headquarters of the Centers for Medicare & Medicaid Services, 7500 Security
Boulevard, Baltimore, Maryland 21244, Monday through Friday of each week from 8:30
a.m. to 4 p.m. To schedule an appointment to view public comments, phone
1-800-743-3951.
Acronyms
ARRA American Recovery and Reinvestment Act of 2009
AAC Average Allowable Cost (of certified EHR technology)
AIU Adopt, Implement, Upgrade (certified EHR technology)
CAH Critical Access Hospital
CAHPS Consumer Assessment of Healthcare Providers and Systems
CCN CMS Certification Number
CFR Code of Federal Regulations
CHIP Children's Health Insurance Program
CMS-0044-P 6
CHIPRA Children's Health Insurance Program Reauthorization Act of 2009
CMS Centers for Medicare & Medicaid Services
CPOE Computerized Physician Order Entry
CY Calendar Year
EHR Electronic Health Record
EP Eligible Professional
EPO Exclusive Provider Organization
FACA Federal Advisory Committee Act
FFP Federal Financial Participation
FFY Federal Fiscal Year
FFS Fee-For-Service
FQHC Federally Qualified Health Center
FTE Full-Time Equivalent
FY Fiscal Year
HEDIS Healthcare Effectiveness Data and Information Set
HHS Department of Health and Human Services
HIE Health Information Exchange
HIT Health Information Technology
HITPC Health Information Technology Policy Committee
HIPAA Health Insurance Portability and Accountability Act of 1996
HITECH Health Information Technology for Economic and Clinical Health Act
CMS-0044-P 7
HMO Health Maintenance Organization
HOS Health Outcomes Survey
HPSA Health Professional Shortage Area
HRSA Health Resource and Services Administration
IAPD Implementation Advance Planning Document
ICR Information Collection Requirement
IHS Indian Health Service
IPA Independent Practice Association
IT Information Technology
MA Medicare Advantage
MAC Medicare Administrative Contractor
MAO Medicare Advantage Organization
MCO Managed Care Organization
MITA Medicaid Information Technology Architecture
MMIS Medicaid Management Information Systems
MSA Medical Savings Account
NAAC Net Average Allowable Cost (of certified EHR technology)
NCQA National Committee for Quality Assurance
NCVHS National Committee on Vital and Health Statistics
NPI National Provider Identifier
NPRM Notice of Proposed Rulemaking
ONC Office of the National Coordinator for Health Information Technology
CMS-0044-P 8
PAHP Prepaid Ambulatory Health Plan
PAPD Planning Advance Planning Document
PFFS Private Fee-For-Service
PHO Physician Hospital Organization
PHS Public Health Service
PHSA Public Health Service Act
PIHP Prepaid Inpatient Health Plan
POS Place of Service
PPO Preferred Provider Organization
PQRI Physician Quality Reporting Initiative
PSO Provider Sponsored Organization
RHC Rural Health Clinic
RPPO Regional Preferred Provider Organization
SAMHSA Substance Abuse and Mental Health Services Administration
SMHP State Medicaid Health Information Technology Plan
TIN Tax Identification Number
Table of Contents
I. Executive Summary and Overview
A. Executive Summary
1. Purpose of Regulatory Action
a. Need for the Regulatory Action
b. Legal Authority for the Regulatory Action
CMS-0044-P 9
2. Summary of Major Provisions
a. Stage 2 Meaningful Use Objectives and Measures
b. Reporting on Clinical Quality Measures (CQMs)
c. Payment Adjustments and Exceptions
d. Modifications to Medicaid EHR Incentive Program
e. Stage 2 Timeline Delay
3. Costs and Benefits
B. Overview of the HITECH Programs Created by the American Recovery and
Reinvestment Act of 2009
II. Provisions of the Proposed Regulations
A. Definitions Across the Medicare FFS, Medicare Advantage, and Medicaid
Programs
1. Uniform Definitions
2. Meaningful EHR User
3. Definition of Meaningful Use
a. Considerations in Defining Meaningful Use
b. Changes to Stage 1 Criteria for Meaningful Use
c. State Flexibility for Stage 2 of Meaningful Use
d. Stage 2 Criteria for Meaningful Use (Core Set and Menu Set)
B. Reporting on Clinical Quality Measures Using Certified EHRs Technology by
Eligible Professionals, Eligible Hospitals, and Critical Access Hospitals
1. Time Periods for Reporting Clinical Quality Measures
CMS-0044-P 10
2. Certification Requirements for Clinical Quality Measures
3. Criteria for Selecting Clinical Quality Measures
4. Proposed Clinical Quality Measures for Eligible Professionals
a. Statutory and Other Considerations
b. Clinical Quality Measures Proposed for Eligible Professionals for CY 2013
c. Clinical Quality Measures Proposed for Eligible Professionals Beginning with
CY 2014
5. Proposed Reporting Methods for Clinical Quality Measures for Eligible
Professionals
a. Reporting Methods for Medicaid EPs
b. Reporting Methods for Medicare EPs in CY 2013
c. Reporting Methods for Medicare EPs Beginning with CY 2014
d. Group Reporting Option for Medicare and Medicaid Eligible Professionals
Beginning with CY 2014
6. Proposed Clinical Quality Measures for Eligible Hospitals and Critical Access
Hospitals
a. Statutory and Other Considerations
b. Clinical Quality Measures Proposed for Eligible Hospitals and CAHs for FY
2013
7. Proposed Reporting Methods for Eligible Hospitals and Critical Access
Hospitals
a. Reporting Methods in FY 2013

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anemia

Initial Classification of Anemia

The functional classification of anemia has three major categories. These are: (1) marrow production defects (hypoproliferation), (2) red cell maturation defects (ineffective erythropoiesis), and (3) decreased red cell survival (blood loss/hemolysis). The classification is shown in Fig. 58-17. A hypoproliferative anemia is typically seen with a low reticulocyte production index together with little or no change in red cell morphology (a normocytic, normochromic anemia) (Chap. 98). Maturation disorders typically have a slight to moderately elevated reticulocyte production index that is accompanied by either macrocytic (Chap. 100) or microcytic (Chaps. 98, 99) red cell indices. Increased red blood cell destruction secondary to hemolysis results in an increase in the reticulocyte production index to at least three times normal (Chap. 101), provided sufficient iron is available. Hemorrhagic anemia does not typically result in production indices of more than 2.0–2.5 times normal because of the limitations placed on expansion of the erythroid marrow by iron availability.

Figure 58-17

The physiologic classification of anemia. CBC, complete blood count.

In the first branch point of the classification of anemia, a reticulocyte production index > 2.5 indicates that hemolysis is most likely. A reticulocyte production index < 2 indicates either a hypoproliferative anemia or maturation disorder. The latter two possibilities can often be distinguished by the red cell indices, by examination of the peripheral blood smear, or by a marrow examination. If the red cell indices are normal, the anemia is almost certainly hypoproliferative in nature. Maturation disorders are characterized by ineffective red cell production and a low reticulocyte production index. Bizarre red cell shapes—macrocytes or hypochromic microcytes—are seen on the peripheral blood smear. With a hypoproliferative anemia, no erythroid hyperplasia is noted in the marrow, whereas patients with ineffective red cell production have erythroid hyperplasia and an M/E ratio < 1:1.

Hypoproliferative Anemias

At least 75% of all cases of anemia are hypoproliferative in nature. A hypoproliferative anemia reflects absolute or relative marrow failure in which the erythroid marrow has not proliferated appropriately for the degree of anemia. The majority of hypoproliferative anemias are due to mild to moderate iron deficiency or inflammation. A hypoproliferative anemia can result from marrow damage, iron deficiency, or inadequate EPO stimulation. The last may reflect impaired renal function, suppression of EPO production by inflammatory cytokines such as interleukin 1, or reduced tissue needs for O2 from metabolic disease such as hypothyroidism. Only occasionally is the marrow unable to produce red cells at a normal rate, and this is most prevalent in patients with renal failure. With diabetes mellitus or myeloma, the EPO deficiency may be more marked than would be predicted by the degree of renal insufficiency. In general, hypoproliferative anemias are characterized by normocytic, normochromic red cells, although microcytic, hypochromic cells may be observed with mild iron deficiency or long-standing chronic inflammatory disease. The key laboratory tests in distinguishing between the various forms of hypoproliferative anemia include the serum iron and iron-binding capacity, evaluation of renal and thyroid function, a marrow biopsy or aspirate to detect marrow damage or infiltrative disease, and serum ferritin to assess iron stores. Occasionally, an iron stain of the marrow will be needed to determine the pattern of iron distribution. Patients with the anemia of acute or chronic inflammation show a distinctive pattern of serum iron (low), TIBC (normal or low), percent transferrin saturation (low), and serum ferritin (normal or high). These changes in iron values are brought about by hepcidin, the iron regulatory hormone that is increased in inflammation (Chap. 98). A distinct pattern of results is noted in mild to moderate iron deficiency (low serum iron, high TIBC, low percent transferrin saturation, low serum ferritin) (Chap. 98). Marrow damage by drugs, such as the antiretrovirals used to treat HIV infection, infiltrative disease such as leukemia or lymphoma, or marrow aplasia can usually be diagnosed from the peripheral blood and bone marrow morphology. With infiltrative disease or fibrosis, a marrow biopsy is required.

Maturation Disorders

The presence of anemia with an inappropriately low reticulocyte production index, macro- or microcytosis on smear, and abnormal red cell indices suggests a maturation disorder. Maturation disorders are divided into two categories: nuclear maturation defects, associated with macrocytosis and abnormal marrow development, and cytoplasmic maturation defects, associated with microcytosis and hypochromia usually from defects in hemoglobin synthesis. The inappropriately low reticulocyte production index is a reflection of the ineffective erythropoiesis that results from the destruction within the marrow of developing erythroblasts. Bone marrow examination shows erythroid hyperplasia.

Nuclear maturation defects result from vitamin B12 or folic acid deficiency, drug damage, or myelodysplasia. Drugs that interfere with cellular DNA metabolism, such as methotrexate or alkylating agents, can produce a nuclear maturation defect. Alcohol, alone, is also capable of producing macrocytosis and a variable degree of anemia, but this is usually associated with folic acid deficiency. Measurements of folic acid and vitamin B12 are key not only in identifying the specific vitamin deficiency but also because they reflect different pathogenetic mechanisms.

Cytoplasmic maturation defects result from severe iron deficiency or abnormalities in globin or heme synthesis. Iron deficiency occupies an unusual position in the classification of anemia. If the iron-deficiency anemia is mild to moderate, erythroid marrow proliferation is decreased and the anemia is classified as hypoproliferative. However, if the anemia is severe and prolonged, the erythroid marrow will become hyperplastic despite the inadequate iron supply, and the anemia will be classified as ineffective erythropoiesis with a cytoplasmic maturation defect. In either case, an inappropriately low reticulocyte production index, microcytosis, and a classic pattern of iron values make the diagnosis clear and easily distinguish iron deficiency from other cytoplasmic maturation defects such as the thalassemias. Defects in heme synthesis, in contrast to globin synthesis, are less common and may be acquired or inherited (Chap. 352). Acquired abnormalities are usually associated with myelodysplasia, may lead to either a macro- or microcytic anemia, and are frequently associated with mitochondrial iron loading. In these cases, iron is taken up by the mitochondria of the developing erythroid cell but not incorporated into heme. The iron-encrusted mitochondria surround the nucleus of the erythroid cell, forming a ring. Based on the distinctive finding of so-called ringed sideroblasts on the marrow iron stain, patients are diagnosed as having a sideroblastic anemia—almost always reflecting myelodysplasia. Again, studies of iron parameters are helpful in the differential diagnosis and management of these patients.

Blood Loss/Hemolytic Anemia

In contrast to anemias associated with an inappropriately low reticulocyte production index, hemolysis is associated with red cell production indices 2.5 times normal. The stimulated erythropoiesis is reflected in the blood smear by the appearance of increased numbers of polychromatophilic macrocytes. A marrow examination is rarely indicated if the reticulocyte production index is increased appropriately. The red cell indices are typically normocytic or slightly macrocytic, reflecting the increased number of reticulocytes. Acute blood loss is not associated with an increased reticulocyte production index because of the time required to increase EPO production and, subsequently, marrow proliferation. Subacute blood loss may be associated with modest reticulocytosis. Anemia from chronic blood loss presents more often as iron deficiency than with the picture of increased red cell production.

The evaluation of blood loss anemia is usually not difficult. Most problems arise when a patient presents with an increased red cell production index from an episode of acute blood loss that went unrecognized. The cause of the anemia and increased red cell production may not be obvious. The confirmation of a recovering state may require observations over a period of 2–3 weeks, during which the hemoglobin concentration will be seen to rise and the reticulocyte production index fall.

Hemolytic disease, while dramatic, is among the least common forms of anemia. The ability to sustain a high reticulocyte production index reflects the ability of the erythroid marrow to compensate for hemolysis and, in the case of extravascular hemolysis, the efficient recycling of iron from the destroyed red cells to support red cell production. With intravascular hemolysis, such as paroxysmal nocturnal hemoglobinuria, the loss of iron may limit the marrow response. The level of response depends on the severity of the anemia and the nature of the underlying disease process.

Hemoglobinopathies, such as sickle cell disease and the thalassemias, present a mixed picture. The reticulocyte index may be high but is inappropriately low for the degree of marrow erythroid hyperplasia (Chap. 99).

Hemolytic anemias present in different ways. Some appear suddenly as an acute, self-limited episode of intravascular or extravascular hemolysis, a presentation pattern often seen in patients with autoimmune hemolysis or with inherited defects of the Embden-Meyerhof pathway or the glutathione reductase pathway. Patients with inherited disorders of the hemoglobin molecule or red cell membrane generally have a lifelong clinical history typical of the disease process. Those with chronic hemolytic disease, such as hereditary spherocytosis, may actually present not with anemia but with a complication stemming from the prolonged increase in red cell destruction such as symptomatic bilirubin gallstones or splenomegaly. Patients with chronic hemolysis are also susceptible to aplastic crises if an infectious process interrupts red cell production.

The differential diagnosis of an acute or chronic hemolytic event requires the careful integration of family history, the pattern of clinical presentation and—whether the disease is congenital or acquired—by a careful examination of the peripheral blood smear. Precise diagnosis may require more specialized laboratory tests, such as hemoglobin electrophoresis or a screen for red cell enzymes. Acquired defects in red cell survival are often immunologically mediated and require a direct or indirect antiglobulin test or a cold agglutinin titer to detect the presence of hemolytic antibodies or complement-mediated red cell destruction.

Anemia: Treatment

An overriding principle is to initiate treatment of mild to moderate anemia only when a specific diagnosis is made. Rarely, in the acute setting, anemia may be so severe that red cell transfusions are required before a specific diagnosis is made. Whether the anemia is of acute or gradual onset, the selection of the appropriate treatment is determined by the documented cause(s) of the anemia. Often, the cause of the anemia may be multifactorial. For example, a patient with severe rheumatoid arthritis who has been taking anti-inflammatory drugs may have a hypoproliferative anemia associated with chronic inflammation as well as chronic blood loss associated with intermittent gastrointestinal bleeding. In every circumstance, it is important to evaluate the patient's iron status fully before and during the treatment of any anemia. Transfusion is discussed in Chap. 107; iron therapy is discussed in Chap. 98; treatment of megaloblastic anemia is discussed in Chap. 100; treatment of other entities is discussed in their respective chapters (sickle cell anemia, Chap. 99; hemolytic anemias, Chap. 101; aplastic anemia and myelodysplasia, Chap. 102).

Therapeutic options for the treatment of anemias have expanded dramatically during the past 25 years. Blood component therapy is available and safe. Recombinant EPO as an adjunct to anemia management has transformed the lives of patients with chronic renal failure on dialysis and made some improvements in the quality of life of anemic cancer patients receiving chemotherapy. Improvements in the management of sickle cell crises and sickle cell anemia have also taken place. Eventually, patients with inherited disorders of globin synthesis or mutations in the globin gene, such as sickle cell disease, may benefit from the successful introduction of targeted genetic therapy (Chap. 65).

Polycythemia

Polycythemia is defined as an increase in circulating red blood cells above normal. This increase may be real or only apparent because of a decrease in plasma volume (spurious or relative polycythemia). The term erythrocytosis may be used interchangeably with polycythemia, but some draw a distinction between them; erythrocytosis implies documentation of increased red cell mass, whereas polycythemia refers to any increase in red cells. Often patients with polycythemia are detected through an incidental finding of elevated hemoglobin or hematocrit levels. Concern that the hemoglobin level may be abnormally high is usually triggered at 170 g/L (17 g/dL) for men and 150 g/L (15 g/dL) for women. Hematocrit levels >50% in men or >45% in women may be abnormal. Hematocrits >60% in men and >55% in women are almost invariably associated with an increased red cell mass.

Historic features useful in the differential diagnosis include smoking history; living at high altitude; or a history of congenital heart disease, peptic ulcer disease, sleep apnea, chronic lung disease, or renal disease.

Patients with polycythemia may be asymptomatic or experience symptoms related to the increased red cell mass or an underlying disease process that leads to increased red cell production. The dominant symptoms from increased red cell mass are related to hyperviscosity and thrombosis (both venous and arterial), because the blood viscosity increases logarithmically at hematocrits >55%. Manifestations range from digital ischemia to Budd-Chiari syndrome with hepatic vein thrombosis. Abdominal thromboses are particularly common. Neurologic symptoms such as vertigo, tinnitus, headache, and visual disturbances may occur. Hypertension is often present. Patients with polycythemia vera may have aquagenic pruritus and symptoms related to hepatosplenomegaly. Patients may have easy bruising, epistaxis, or bleeding from the gastrointestinal tract. Patients with hypoxemia may develop cyanosis on minimal exertion or have headache, impaired mental acuity, and fatigue.

The physical examination usually reveals a ruddy complexion. Splenomegaly favors polycythemia vera as the diagnosis (Chap. 103). The presence of cyanosis or evidence of a right-to-left shunt suggests congenital heart disease presenting in the adult, particularly tetralogy of Fallot or Eisenmenger syndrome (Chap. 229). Increased blood viscosity raises pulmonary artery pressure; hypoxemia can lead to increased pulmonary vascular resistance. Together these factors can produce cor pulmonale.

Polycythemia can be spurious (related to a decrease in plasma volume; Gaisbock's syndrome), primary, or secondary in origin. The secondary causes are all associated with increases in EPO levels: either a physiologically adapted appropriate elevation based on tissue hypoxia (lung disease, high altitude, CO poisoning, high-affinity hemoglobinopathy) or an abnormal overproduction (renal cysts, renal artery stenosis, tumors with ectopic EPO production). A rare familial form of polycythemia is associated with normal EPO levels but hyperresponsive EPO receptors due to mutations.

Approach to the Patient: Polycythemia

As shown in Fig. 58-18, the first step is to document the presence of an increased red cell mass using the principle of isotope dilution by administering 51Cr-labeled autologous red blood cells to the patient and sampling blood radioactivity over a 2-h period. If the red cell mass is normal (<36 mL/kg in men, <32 mL/kg in women), the patient has spurious polycythemia. If the red cell mass is increased (>36 mL/kg in men, >32 mL/kg in women), serum EPO levels should be measured. If EPO levels are low or unmeasurable, the patient most likely has polycythemia vera. Ancillary tests that support this diagnosis include elevated white blood cell count, increased absolute basophil count, and thrombocytosis. A mutation in JAK-2 (Val617Phe), a key member of the cytokine intracellular signaling pathway, can be found in 70–95% of patients with polycythemia vera.

Figure 58-18

An approach to diagnosing patients with polycythemia. RBC, red blood cell; EPO, erythropoietin; COPD, chronic obstructive pulmonary disease; AV, atrioventricular; IVP, intravenous pyelogram; hct, hematocrit.

If serum EPO levels are elevated, one attempts to distinguish whether the elevation is a physiologic response to hypoxia or is related to autonomous production. Patients with low arterial O2 saturation (<92%) should be further evaluated for the presence of heart or lung disease, if they are not living at high altitude. Patients with normal O2 saturation who are smokers may have elevated EPO levels because of CO displacement of O2. If carboxyhemoglobin (COHb) levels are high, the diagnosis is smoker's polycythemia. Such patients should be urged to stop smoking. Those who cannot stop smoking require phlebotomy to control their polycythemia. Patients with normal O2 saturation who do not smoke either have an abnormal hemoglobin that does not deliver O2 to the tissues (evaluated by finding elevated O2-hemoglobin affinity) or have a source of EPO production that is not responding to the normal feedback inhibition. Further workup is dictated by the differential diagnosis of EPO-producing neoplasms. Hepatoma, uterine leiomyoma, and renal cancer or cysts are all detectable with abdominopelvic CT scans. Cerebellar hemangiomas may produce EPO, but they nearly always present with localizing neurologic signs and symptoms rather than polycythemia-related symptoms.

New in Hospital Med

HOSPITAL CARDIOVASCULAR MEDICINE

The role of supplemental oxygen in nonhypoxic patients with acute myocardial infarction patients has not been well studied. A systematic review of three trials found no significant difference in mortality, but a trend towards worse outcomes, for hypoxic or normoxic patients with acute myocardial infarction who were randomly assigned to oxygen or no supplemental oxygen [1]. The suggestion of harm with supplemental oxygen is of concern, particularly in patients with normoxia, as a pathophysiologic basis for such harm has been articulated [2]. (See "Overview of the acute management of acute ST elevation myocardial infarction", section on 'Oxygen'.)

In patients with heart failure (HF), an elevated heart rate is associated with worse cardiovascular outcomes. The SHIFT trial randomly assigned patients with HF due to systolic dysfunction to receive the selective sinus node inhibitor ivabradine or placebo [3]. At a median follow-up of 23 months, the primary endpoint of cardiovascular death or hospital admission for worsening HF was less frequent in the ivabradine group but there was no effect on all-cause mortality. (See "Possibly effective emerging therapies for heart failure", section on 'Sinus node inhibition'.)

Based on the results of small observational studies, prophylactic intraaortic balloon pumping (IABP) has been advocated for both stable patients and those with acute coronary syndromes undergoing high-risk or complicated percutaneous coronary intervention (PCI). However, the elective placement of an IABP was not found to improve outcomes in the randomized BCIS-1 trial that involved 301 high risk patients with severe left ventricular dysfunction and complex, multivessel coronary artery disease [4]. (See "Intraaortic balloon pump counterpulsation", section on 'High-risk PCI'.)

Whether patients who are receiving chronic clopidogrel therapy require an additional loading dose prior to PCI was evaluated in the ARMYDA-4 RELOAD trial [5]. Over 500 patients on chronic clopidogrel were randomly assigned to receive clopidogrel 600 mg or placebo four to eight hours before PCI. There was no significant difference in the primary combined endpoint (30 day incidence of death, MI, or target vessel revascularization). (See "Antithrombotic therapy for intracoronary stent implantation: General use", section on 'Patients already taking clopidogrel'.)

The optimal loading and maintenance dosing regimens for either clopidogrel or aspirin in patients with acute coronary syndromes (ACS) are not known. This issue was addressed in the CURRENT-OASIS 7 trial, which randomly assigned over 25,000 patients with an ACS who were referred for an invasive strategy to differing doses of aspirin and clopidogrel in a 2 by 2 factorial design [6]. Doses were clopidogrel 600 mg followed by 150 mg daily for 6 days (and 75 mg thereafter) or clopidogrel 300 mg followed by 75 mg daily and aspirin 300 to 325 mg or 75 to 100 mg daily [6]. The following findings were noted:

* With regard to the clopidogrel comparison, the rate of the primary outcome (cardiovascular death, MI, or stroke at 30 days) was not statistically different comparing high to low dose. Major bleeding occurred significantly more often in patients who received the higher clopidogrel dose.
* With regard to the aspirin comparison, there was no significant difference in the primary outcome between those who were randomly assigned to 300 to 325 mg compared to those given 75 to 100 mg [6]. While there was no significant difference in the rate of major bleeding, the rate of minor bleeding in the subgroup of patients who received percutaneous coronary intervention was significantly higher in those who received the higher dose of aspirin [7].

(See "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'Primary PCI' and "Coronary artery stent thrombosis: Prevention and management", section on 'Coronary artery stent thrombosis prevention'.)

Fondaparinux is one of four anticoagulants with demonstrated efficacy in patients with non-ST elevation ACS who undergo PCI. However, its use is limited by the fact that a second anticoagulant (unfractionated heparin [UFH]) is necessary to prevent catheter-related thrombi. The optimal dose of UFH was evaluated in the randomized FUTURA/OASIS 8, which found no difference in the rates of bleeding or access-site complications between standard and low dose UFH [8]. (See "Anticoagulant therapy in unstable angina and acute non-ST elevation myocardial infarction", section on 'Heparin dosing'.)

HOSPITAL GASTROENTEROLOGY AND HEPATOLOGY

Nonselective beta blockers are used routinely to prevent variceal bleeding in patients with cirrhosis and esophageal varices. However, a prospective observational study of patients with refractory ascites found increased mortality in patients who received beta blockers compared with those who did not, raising concerns over their safety in this population [9]. (See "Treatment of diuretic-resistant ascites in patients with cirrhosis", section on 'Safety concern with beta blockers'.)

A randomized trial of 77 patients who had bled from gastric varices confirmed a benefit of endoscopic cyanoacrylate injection [10]. Compared with the use of non-selective beta blockers, cyanoacrylate injection was associated with a significantly lower risk of rebleeding (15 versus 55 percent) and lower mortality (3 versus 25 percent). (See "Treatment of active variceal hemorrhage", section on 'Approach to patients with bleeding gastric varices'.)

HOSPITAL HEMATOLOGY

A study that examined agents possibly responsible for drug-induced thrombocytopenia (DITP) using three different methods (published case reports, documentation of drug-dependent platelet-reactive antibodies, and a search of the US Food and Drug Administration’s Adverse Event Reporting System database), identified 24 drugs that had evidence of an association with thrombocytopenia by all three methods [11]. This list of 24 identified drugs provides a valuable resource for the evaluation and management of patients with suspected DITP, although other agents that are not on this list may be causative in some patients. (See "Drug-induced thrombocytopenia", section on 'Multiple approaches for identifying drugs causing DITP'.)

Patients with multiple myeloma or the precursor lesion monoclonal gammopathy of undetermined significance (MGUS) have an increased incidence of venous thromboembolism. In addition, several studies suggest an increased risk of arterial thromboembolism in these populations as manifested by stroke, transient ischemic attack, myocardial infarction, or symptomatic peripheral arterial disease [12]. (See "Treatment of the complications of multiple myeloma", section on 'Thrombosis'.)

In a phase III trial conducted in adults with hematologic malignancies at risk for tumor lysis syndrome (TLS), normalization of serum uric acid was achieved by a significantly higher percentage of patients receiving rasburicase alone than allopurinol alone, and time to control serum uric acid was also shorter [13]. Although the study was not designed to demonstrate differences in clinical endpoints, the incidence of clinical tumor lysis syndrome was similar in both groups, as was the percentage of patients who experienced acute kidney injury following chemotherapy. There did not appear to be any benefit for combined therapy with both rasburicase and allopurinol. (See "Tumor lysis syndrome", section on 'Rasburicase'.)

HOSPITAL INFECTIOUS DISEASES

In September 2010, the US Food and Drug Administration (FDA) issued a safety announcement regarding increased mortality risk associated with the use of tigecycline compared with other drugs [14]. The increased risk was seen most clearly in patients treated for hospital-acquired pneumonia, but was also seen in patients with complicated skin and skin structure infections, complicated intraabdominal infections, and diabetic foot infections. (See "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults" and "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on 'MRSA'.)

An FDA review of cefepime safety data was initiated in 2007 following findings of a meta-analysis that raised concern regarding increased all-cause mortality associated with cefepime use [15]. The FDA reviewed these study data, conducted additional analyses based on other data, and determined that the data do not indicate a higher rate of death in cefepime-treated patients [16]. Cefepime remains an appropriate therapy for its approved indications. (See "Cephalosporins", section on 'Fourth generation'.)

Ceftaroline is a fifth generation cephalosporin that exhibits bactericidal activity against gram-positive organisms (including MRSA, vancomycin-intermediate S. aureus, and macrolide-resistant S. pyogenes) as well as gram-negative pathogens (including Enterobacteriaceae, but not Pseudomonas species or extended-spectrum beta-lactamase producers). In phase 3 trials including 1378 patients with complicated skin and skin structure infection who were randomly assigned to receive ceftaroline alone or vancomycin plus aztreonam, clinical cure rates and rates of adverse events were similar [17]. (See "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults", section on 'Cephalosporins'.)

Enterobacteriaceae isolates carrying a novel metallo-beta-lactamase gene, the New Delhi metallo-beta-lactamase (NDM-1), were first described in December 2009 in a patient hospitalized in India with an infection due to Klebsiella pneumoniae [18]. Subsequent cases have been reported elsewhere in Asia, Europe, and North America [19]. Clinicians should be aware of the possibility of NDM-1 producing Enterobacteriaceae in patients who have received medical care in India and Pakistan. In the United States, isolates may be forwarded through state public health laboratories to the Centers for Disease Control for further characterization [19]. Therapeutic options for infections due to these organisms are limited but may include tigecycline, colistin, and aztreonam. (See "Carbapenemases", section on 'Class B beta-lactamases'.)

Rapid testing using molecular techniques can greatly improve diagnosis and control of multidrug resistant tuberculosis infection. The assay Xpert MTB/RIF is an automated nucleic acid amplification test for M. tuberculosis and rifampin resistance (rpoB gene). In a study including 1730 patients with suspected tuberculosis, the test correctly identified 98 percent with smear positive tuberculosis and 72 percent with smear negative tuberculosis [20]. The accuracy for identification of rifampin resistance was 98 percent. The assay is simple to perform with minimal training, is not prone to cross-contamination, and requires minimal biosafety facilities. (See "Diagnosis, treatment, and prevention of drug-resistant tuberculosis", section on 'Rapid testing'.)

A revised version of the HIV treatment guidelines from the International AIDS Society-USA panel has several major changes [21]:

* Antiretroviral therapy (ART) is now recommended for patients with a CD4 count less than 500 cells
* ART is also recommended for HIV-infected patients with certain comorbidities, regardless of CD4 cell count
* Raltegravir is now considered an option for use within combination antiretroviral regimens for treatment-naive patients

These recommendations are largely in agreement with the treatment guidelines from the US Department of Health and Human Services (DHHS), which were released in December 2009. (See "When to initiate antiretroviral therapy in HIV-infected patients" and "Selecting antiretroviral regimens for the treatment naive HIV-infected patient".)

The Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America have endorsed a policy in which annual influenza vaccination is a condition of employment and/or professional privileges for healthcare workers [22,23]. (See "Infection control measures to prevent seasonal influenza in healthcare settings", section on 'Immunization of healthcare workers'.)

HOSPITAL NEPHROLOGY

A case-control study found that, in elderly patients being treated with an angiotensin-converting enzyme inhibitor (ACEi) or ARB, admission with hyperkalemia was associated with prior use of trimethoprim-sulfamethoxazole compared with other antibiotics [24]. (See "Etiology and treatment of hypoaldosteronism (type 4 RTA)", section on 'Antibiotics'.)

HOSPITAL NEUROLOGY

A meta-analysis of the three largest randomized trials comparing carotid artery stenting with carotid endarterectomy in patients with symptomatic carotid disease found that the proportion with stroke or death at 120 days after randomization was significantly higher for the stenting group [25]. The estimated risk of stroke or death for patients age 70 and older was approximately two-fold higher for the stenting group compared with the endarterectomy group. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Randomized trials' and "Management of symptomatic carotid atherosclerotic disease", section on 'Effect of age'.)

MRI and diffusion-weighted imaging (DWI) utilizing higher magnetic field strengths of 3 Tesla (T) units are increasingly available in clinical settings. A retrospective study found that diagnostic accuracy for early strokes, read by radiologists blinded to the machine used, was better for images taken with standard 1.5 T MRI scanners than for 3 T images [26]. Artifacts with higher magnetic field strengths may obscure early ischemic changes. (See "Neuroimaging of acute ischemic stroke", section on 'Diffusion-weighted imaging'.)

New guidelines published by the American Academy of Neurology refine the criteria for diagnosing brain death and emphasize that there are no published reports of neurologic recovery after a diagnosis of brain death using these or the 1995 criteria [27]. (See "Diagnosis of brain death".)

HOSPITAL ONCOLOGY

In a randomized trial, early integration of palliative care into the disease-specific therapies for patients with advanced non-small cell lung cancer resulted in improved quality of life and mood [28]. Although patients had less aggressive care at the end of life, median survival was significantly longer in patients who received earlier palliative care. (See "Overview of the treatment of advanced non-small cell lung cancer", section on 'Palliative care'.)

HOSPITAL PULMONARY AND CRITICAL CARE MEDICINE

Neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) has both desirable effects (improves oxygenation) and undesirable effects (prolonged neuromuscular weakness). A trial randomly assigned 340 patients with ARDS to receive cisatracurium besylate or placebo by continuous infusion for 48 hours [29]. The cisatracurium besylate group had lower 90-day mortality after adjustment for baseline risk and there was no difference in the frequency of prolonged neuromuscular weakness. (See "Supportive care and oxygenation in acute respiratory distress syndrome", section on 'Paralysis'.)

The potential for long-term psychological sequelae (eg, posttraumatic stress disorder [PTSD]) has slowed the incorporation of daily interruption of sedation into routine clinical practice for management of patients requiring mechanical ventilation. However, a randomized trial found that patients who underwent daily interruption of sedation had less cognitive impairment at three months and no increase in the frequency of PTSD at 3 or 12 months, compared to patients who did not undergo daily interruption of sedation [30]. (See "Sedative-analgesic medications in critically ill patients: Selection, initiation, maintenance, and withdrawal", section on 'Daily interruption'.)

The relative effects of high frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation in patients with ARDS are uncertain. A meta-analysis that compared HFOV to conventional mechanical ventilation (tidal volume <8 mL/kg) found a reduction in mortality with HFOV that was not statistically significant [31]. (See "High-frequency ventilation in adults", section on 'HF oscillatory ventilation'.)

In a randomized trial assessing treatment options for malignant pleural effusions, 58 patients were assigned to in-dwelling catheter drainage or talc pleurodesis [32]. The effusion recurrence rates were slightly lower and the quality of life scores slightly higher with catheter drainage than with pleurodesis; however, the success rate with talc pleurodesis in this trial (approximately 50 percent) was low compared with other published reports. (See "Management of malignant pleural effusions", section on 'In-dwelling pleural catheter'.)

A retrospective cohort study that evaluated follow-up computed tomography pulmonary angiograms (CT-PA) in patients with prior acute pulmonary embolism (PE) found that complete radiographic resolution of PE is common and occurs more quickly in the main and lobar pulmonary arteries than in the segmental pulmonary arteries [33]. (See "Diagnosis of acute pulmonary embolism", section on 'Time course of PE'.)

aki

Acute renal failure (ARF) has traditionally been defined as the abrupt loss of kidney function that results in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. The loss of kidney function is most easily detected by measurement of the serum creatinine which is used to estimate the glomerular filtration rate (GFR).

Three problems are associated with the use of the serum creatinine to quantitatively define ARF:

* Serum creatinine does not accurately reflect the GFR in a patient who is not in steady state. In the early stages of severe acute renal failure, the serum creatinine may be low even though the actual (not estimated) GFR is markedly reduced since there may not have been sufficient time for the creatinine to accumulate. (See "Assessment of kidney function: Serum creatinine; BUN; and GFR".)
* Creatinine is removed by dialysis. As a result, it is usually not possible to assess kidney function by measuring the serum creatinine once dialysis is initiated. One exception is when the serum creatinine continues to fall on days when hemodialysis is not performed, indicating recovery of renal function.
* Numerous epidemiologic studies and clinical trials have used different cut-off values for serum creatinine to quantitatively define ARF [1].

The lack of consensus in the quantitative definition of ARF, in particular, has hindered clinical research since it confounds comparisons between studies. Some definitions employed in clinical studies have been extremely complex with graded increments in serum creatinine for different baseline serum creatinine values [1,2]. As an example, in a classic study of the epidemiology of hospital-acquired acute renal failure, ARF was defined as a 0.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≤1.9 mg/dL, an 1.0 mg/dL increase in serum creatinine if the baseline serum creatinine was 2.0 to 4.9 mg/dL, and a 1.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≥5.0 mg/dL [2].

The Acute Dialysis Quality Initiative (ADQI) was created by a group of expert intensivists and nephrologists to develop consensus and evidence based guidelines for the treatment and prevention of acute renal failure [3]. Recognizing the need for a uniform definition for ARF, the ADQI group proposed a consensus graded definition, called the RIFLE criteria [4]. A modification of the RIFLE criteria was subsequently proposed by the Acute Kidney Injury Network, which included the ADQI group as well as representatives from other nephrology and intensive care societies [5-7].

Because of these initiatives, the term acute kidney injury (AKI) was proposed to represent the entire spectrum of acute renal failure. This topic review will address the current definitions of acute renal failure, particularly the RIFLE criteria and the AKIN modifications.

RIFLE CRITERIA — The RIFLE criteria consists of three graded levels of injury (Risk, Injury, and Failure) based upon either the magnitude of elevation in serum creatinine or urine output, and two outcome measures (Loss and End-stage renal disease). The RIFLE strata are as follows [4]:

* Risk — 1.5-fold increase in the serum creatinine or GFR decrease by 25 percent or urine output <0.5 mL/kg per hour for six hours
* Injury — Twofold increase in the serum creatinine or GFR decrease by 50 percent or urine output <0.5 mL/kg per hour for 12 hours
* Failure — Threefold increase in the serum creatinine or GFR decrease by 75 percent or urine output of <0.5 mL/kg per hour for 24 hours, or anuria for 12 hours
* Loss — Complete loss of kidney function (eg, need for renal replacement therapy) for more than four weeks
* ESRD — Complete loss of kidney function (eg, need for renal replacement therapy) for more than three months (figure 1)

The RIFLE criteria correlated with prognosis in a number of studies [8-14]. As an example, a systematic review of 13 studies demonstrated a stepwise increase in the relative risk of death in patients who met the RIFLE criteria for various stages of AKI [14]. Compared to patients who did not have AKI, patients in the RIFLE stages of "risk," "injury," and "failure" had increased relative mortality risks of 2.4 (CI 1.94-2.97), 4.15 (CI 3.14-5.48), and 6.37 (CI 5.14-7.9). Despite significant heterogeneity among studies, results from most individual reports were qualitatively similar.

Limitations — There are several important shortcomings to the RIFLE criteria:

* The "risk," "injury," and "failure" strata are defined by either changes in serum creatinine or urine output. The assignment of the corresponding changes in serum creatinine and changes in urine output to the same strata are NOT based on evidence. In the one assessment of the RIFLE classification that compared the serum creatinine and urine output criteria, the serum creatinine criteria were strong predictors of ICU mortality, whereas the urine output criteria did not independently predict mortality [12]. Thus, if the RIFLE classification is used to stratify risk, it is important that the criteria that result in the least favorable RIFLE strata be used [4].
* As mentioned above, the change in serum creatinine during acute renal failure does not directly correlate with the actual change in glomerular filtration rate, which alters the assignment of that patient to a particular RIFLE level. As an example, in a patient with an abrupt decline in renal function in the setting of severe ARF, the serum creatinine might rise from 1.0 to 1.5 mg/dL (88.4 to 133 micromol/L) on day one, 2.5 mg/dL (221 micromol/L) on day two, and 3.5 mg/dL (309 micromol/L) on day three. According to the RIFLE criteria, the patient would progress from "risk" on day one to "injury" on day two and "failure" on day three, even though the actual GFR has been <10 mL/min over the entire period. This issue is intrinsic to any assessment of acute renal failure based upon the serum creatinine level.
* It is impossible to calculate the change in serum creatinine in patients who present with ARF but without a baseline measurement of serum creatinine. The authors of the RIFLE criteria suggest back-calculating an estimated baseline serum creatinine concentration using the four-variable MDRD equation, assuming a baseline GFR of 75 mL/min per 1.73 m2 [4]. However, this approach has not been prospectively validated.

AKIN CRITERIA — Given these limitations, a modification of the RIFLE criteria has been proposed by the Acute Kidney Injury Network. The AKIN proposed both diagnostic criteria for ARF and a staging system that was based on the RIFLE criteria [5-7]. In addition, the term acute kidney injury (AKI) was proposed to represent the entire spectrum of acute renal failure.

Diagnostic criteria — The proposed diagnostic criteria for ARF are an abrupt (within 48 hours) absolute increase in the serum creatinine concentration of ≥0.3 mg/dL (26.4 micromol/L) from baseline, a percentage increase in the serum creatinine concentration of ≥50 percent, or oliguria of less than 0.5 mL/kg per hour for more than six hours (table 1).

The latter two of these criteria are identical to the RIFLE "risk" criteria. The addition of an absolute change in serum creatinine of ≥0.3 mg/dL is based on epidemiologic data that have demonstrated an 80 percent increase in mortality risk associated with changes in serum creatinine concentration of as little as 0.3 to 0.5 mg/dL [15]. Including a time constraint of 48 hours is based upon data that showed that poorer outcomes were associated with small changes in the creatinine when the rise in creatinine was observed within 24 to 48 hours [16,17].

Two additional caveats were proposed by the AKIN group:

* The diagnostic criteria should be applied only after volume status had been optimized
* Urinary tract obstruction needed to be excluded if oliguria was used as the sole diagnostic criterion.

A flaw with the last caveat is that, according to the current definition, AKI would still be used to describe the patient with acute urinary tract obstruction and an acute increase in serum creatinine. It is not clear whether the AKIN modifications to RIFLE have substantively changed the classification of patients with AKI or improved its ability to predict hospital mortality [18].

Staging system — The classification or staging system for ARF is comprised of three stages of increasing severity, which correspond to risk (stage 1), injury (stage 2), and failure (stage 3) of the RIFLE criteria. Loss and ESRD are removed from the staging system and defined as outcomes.

The clinical applicability of these staging systems is uncertain. However, they will likely have some utility in standardizing the definitions for epidemiologic studies and for establishing inclusion criteria and endpoints for clinical trials.

Ultimately these definitions are likely to be replaced by more sensitive and specific biomarkers of renal injury.

CLINICAL UTILITY — The RIFLE and AKIN criteria have helped to focus attention that decrements in renal function that result in small changes in serum creatinine concentration are associated with significant clinical consequences. However, the precise clinical utility of these criteria is uncertain. There is also an inherent confusion within these criteria as to whether prerenal and obstructive etiologies of ARF are subsumed in or are external to the definition of AKI.

We believe that these criteria have greatest utility in epidemiologic studies and in defining consistent inclusion criteria and/or endpoints for clinical studies. Their utility at the bedside is less clear and it seems likely that they will eventually be replaced at least in part by sensitive and specific biomarkers of renal tubular injury. The use of such biomarkers, analogous to troponin as a marker of myocardial injury, will permit development of a new paradigm for classifying acute kidney injury that is not solely dependent upon serum creatinine or other functional markers.

We do believe that adoption of the term acute kidney injury (AKI) to replace the older terminology of acute renal failure is highly appropriate. Just as acute lung injury is used to describe acute pulmonary injury that has not progressed to overt organ failure, we believe that AKI is more representative of the full spectrum of acute kidney dysfunction.

SUMMARY

* Acute renal failure (ARF) has traditionally been defined as the abrupt loss of kidney function resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. (See 'Introduction' above.)
* Although the loss of kidney function is most easily detected by measurement of the serum creatinine, several problems are associated with the use of this measure to quantitatively define ARF, particularly the lack of consensus in the quantitative definition. (See 'Introduction' above.)
* The Acute Dialysis Quality Initiative (ADQI) has proposed a graded definition of ARF called the RIFLE criteria. The Acute Kidney Injury Network (AKIN) modified the RIFLE criteria in order to include less severe ARF, to impose a time constraint of 48 hours, and to allow for correction of volume status and obstructive causes of ARF prior to classification. (See 'Rifle criteria' above and 'AKIN criteria' above.) These criteria have their greatest utility in epidemiologic studies.
* The AKIN proposed the term acute kidney injury (AKI) to represent the entire spectrum of acute renal failure. The proposed diagnostic criteria are an abrupt (within 48 hours) absolute increase in the serum creatinine concentration of ≥0.3 mg/dL (26.4 micromol/L) from baseline, a percentage increase in the serum creatinine concentration of ≥50 percent, or oliguria of less than 0.5 mL/kg per hour for more than six hours. These criteria will likely be revised, and possibly replaced, as biomarkers of tubular injury are developed. (See 'Diagnostic criteria' above.)
* We agree that adoption of the term acute kidney injury to replace the older terminology of acute renal failure is highly appropriate. AKI better represents the full spectrum of acute kidney dysfunction. (See 'Clinical utility' above

FLexner Report

The Flexner Report[1] is a book-length study of medical education in the United States and Canada, written by the professional educator Abraham Flexner and published in 1910 under the aegis of the Carnegie Foundation. Many aspects of the present-day American medical profession stem from the Flexner Report and its aftermath.

The Report (also called Carnegie Foundation Bulletin Number Four), called on American medical schools to enact higher admission and graduation standards, and to adhere strictly to the protocols of mainstream science in their teaching and research. Many American medical schools fell short of the standard advocated in the Report, and subsequent to its publication, nearly half of such schools merged or were closed outright. The Report also concluded that there were too many medical schools in the USA, and that too many doctors were being trained. A repercussion of the Flexner Report resulting from the closure or consolidation of university training, was reversion of American universities to male-only admittance programs to accommodate a smaller admission pool. Universities had begun opening and expanding female admissions as part of women's and co-educational facilities only in the mid-to-latter part of the 19th century with the founding of co-educational Oberlin College in 1833 and private colleges such as Vassar College and Pembroke College.

[edit] History

In 1904 the AMA created the Council on Medical Education (CME) whose objective was to restructure American medical education. At its first annual meeting, the CME adopted two standards: one laid down the minimum prior education required for admission to a medical school, the other defined a medical education as consisting of two years training in human anatomy and physiology followed by two years of clinical work in a teaching hospital. In 1908, the CME asked the Carnegie Foundation for the Advancement of Teaching to survey American medical education, so as to promote the CME's reformist agenda and hasten the elimination of medical schools that failed to meet the CME's standards. The president of the Carnegie Foundation, Henry Pritchett, a staunch advocate of medical school reform, chose Flexner to conduct the survey.

At that time, the 155 medical schools in North America differed greatly in their curricula, methods of assessment, and requirements for admission and graduation. Flexner visited all 155 schools and generalized about them as follows: "Each day students were subjected to interminable lectures and recitations. After a long morning of dissection or a series of quiz sections, they might sit wearily in the afternoon through three or four or even five lectures delivered in methodical fashion by part-time teachers. Evenings were given over to reading and preparation for recitations. If fortunate enough to gain entrance to a hospital, they observed more than participated." The Report became notorious for its harsh description of certain establishments, for example describing Chicago's 14 medical schools as "a disgrace to the State whose laws permit its existence... indescribably foul... the plague spot of the nation."

Nevertheless, several schools received praise for excellent performance, including Harvard, Western Reserve, Michigan, Wake Forest University School of Medicine, McGill, University of Toronto, and especially Johns Hopkins - the latter was described as 'model for medical education'. [2]

Wake Forest University School of Medicine was praised for: "The laboratories of this little school are, as far as they go, models in their way. Everything about them indicates intelligence and earnestness. The dissecting room is clean and odorless, the bodies undergoing dissection being cared for in the most approved modern manner. Separate laboratories, properly equipped, are provided for ordinary undergraduate work in bacteriology, pathology, and histology, and the instructor has a private laboratory besides. Chemistry is taught in the well equipped college laboratory; physiology is slight; there is no pharmacology. There is a small museum; animals, charts, and books are provided." [3]

It should be noted that Wake Forest University School of Medicine, formerly Bowman Gray School of Medicine, opened a in a new town as a four-year school in 1941.
[edit] Recommended changes

When Flexner researched his report, many American medical schools were "proprietary", namely small trade schools owned by one or more doctors, unaffiliated with a college or university, and run to make a profit. A degree was typically awarded after only two years of study. Laboratory work and dissection were not necessarily required. Many of the instructors were local doctors teaching part-time, whose own training left something to be desired. The regulation of the medical profession by state government was minimal or nonexistent. American doctors varied enormously in their scientific understanding of human physiology, and the word "quack" flourished. There is no evidence that the mass of Americans were dissatisfied with this situation.

Flexner looked this situation in the face. Using the Johns Hopkins University School of Medicine as the ideal[4], he boldly recommended that:

* Admission to a medical school should require, at minimum, a high school diploma and at least two years of college or university study, primarily devoted to basic science. When Flexner researched his report, only 16 out of 155 medical schools in the United States and Canada required applicants to have completed two or more years of university education (p 28). According to Hiatt and Stockton, by 1920 92% of U.S. medical schools required this of applicants.
* The length of medical education be four years, and its content should be what the CME agreed to in 1905.
* Proprietary medical schools should either close or be incorporated into existing universities. Medical schools should be part of a larger university, because a proper stand-alone medical school would have to charge too much in order to break even.

Less known is Flexner's recommendation that medical schools appoint full-time clinical professors. Holders of these appointments would become "true university teachers, barred from all but charity practice, in the interest of teaching." Flexner pursued this objective for years, despite widespread opposition from existing medical faculty.

Flexner was the child of German immigrants, and had studied and traveled in Europe. He was well aware that one could not practice medicine in continental Europe without having undergone an extensive specialized university education. In effect, Flexner was demanding that American medical education conform to prevailing practice in continental Europe.

By and large, medical schools in Canada and the United States have followed Flexner's recommendations down to the present day. Recently, however, schools have increased their emphasis on public health matters.
[edit] Consequences of the report

To a remarkable extent, the following present-day aspects of the medical profession in North America are consequences of the Flexner Report:

* A physician receives at least six, and preferably eight, years of post-secondary formal instruction, nearly always in a university setting;
* Medical training adheres closely to the scientific method and is thoroughly grounded in human physiology and biochemistry. Medical research adheres fully to the protocols of scientific research;[5]
* Average physician quality has increased significantly;[6]
* No medical school can be created without the permission of the state government. Likewise, the size of existing medical schools is subject to state regulation;
* Each state branch of the American Medical Association has oversight over the conventional medical schools located within the state;
* Medicine in the USA and Canada becomes a highly paid and well-respected profession;
* The annual number of medical school graduates sharply declined, and the resulting reduction in the supply of doctors makes the availability and affordability of medical care problematic. The Report led to the closure of the sort of medical schools that trained doctors willing to charge their patients less. Moreover, before the Report, high quality doctors varied their fees according to what they believed their patients could afford, a practice known as price discrimination. The extent of price discrimination in American medicine declined in the aftermath of the Report;
* Kessel (1958) argued that the Flexner Report in effect began the cartelization of the American medical profession, a cartelization enforced by the American Medical Association and backed by the police power of each American state. This de facto cartel restricted the supply of physicians, and raised the incomes of the remaining practitioners.

The Report is now remembered because it succeeded in creating a single model of medical education, characterized by a philosophy that has largely survived to the present day. "An education in medicine," wrote Flexner, "involves both learning and learning how; the student cannot effectively know, unless he knows how." Although the report is more than 99 years old, many of its recommendations are still relevant—particularly those concerning the physician as a "social instrument... whose function is fast becoming social and preventive, rather than individual and curative."
[edit] Closure of many medical schools

According to Hiatt and Stockton (p. 8), Flexner sought to shrink the number of medical schools in the USA to 31, and to cut the annual number of medical graduates from 4,400 to 2,000. A majority of American institutions granting M.D. or D.O. degrees as of the date of the Report (1910) closed within two to three decades. (No Canadian medical school was deemed inadequate, and none closed or merged subsequent to the Report.) In 1904, there were 160 M.D. granting institutions with more than 28,000 students. By 1920, there were only 85 M.D. granting institution, educating only 13,800 students. By 1935, there were only 66 medical schools operating in the USA.

Between 1910 and 1935, more than half of all American medical schools merged or closed. This dramatic decline was in some part due to the implementation of the Report's recommendation that all "proprietary" schools be closed, and that medical schools should henceforth all be connected to universities. Of the 66 surviving M.D. granting institutions in 1935, 57 were part of a university. An important factor driving the mergers and closures of medical schools was that all state medical boards gradually adopted and enforced the Report's recommendations.
[edit] American medicine becomes a less diverse profession

One of the consequences of Flexner's advocacy of university-based medical education was that medical education became much more expensive, putting such education out of reach of all but upper class white males. The small "proprietary" schools Flexner condemned, which were contended to be have been based in generations-old folk traditions rather than relatively recent western science, did admit African-Americans, women, and students of limited financial means. These students usually could not afford six to eight years of university education, and were often simply denied admission to medical schools affiliated with universities. At the same time, the Report tended to delegitimize existing women doctors and doctors of color. While many such doctors continued to practice, usually within underserviced clienteles, they did so under proscribed circumstances and for less pay. In general, the standardization of medical education advocated in the Report led to the domination of American medicine by well-off white males. It also made it more difficult for people of color, residents of rural areas, and for those of limited means generally to obtain medical care in any form. The Flexner report recommended the closure of several African American medical schools, including the Leonard Medical Center, the oldest four-year medical school in the country, of any persuasion, not just for African-Americans. Ironically one of the schools was located in his own hometown of Louisville, Kentucky, Louisville National Medical College.
[edit] Impact on alternative medicine

When Flexner researched his report, "modern" medicine faced vigorous competition from several quarters, including osteopathic medicine, eclectic medicine, physiomedicalism, naturopathy and homeopathy. Flexner clearly doubted the scientific validity of all forms of medicine other than biomedicine, deeming any approach to medicine that did not advocate the use of treatments such as vaccines to prevent and cure illness as tantamount to quackery and charlatanism. Medical schools that offered training in various disciplines including eclectic medicine, physiomedicalism, naturopathy, and homeopathy, were told either to drop these courses from their curriculum or lose their accreditation and underwriting support. A few schools resisted for a time, but eventually all complied with the Report or shut their doors.[citation needed]
[edit] Impact on osteopathic medicine

Although almost all the alternative medical schools listed in Flexner's report were closed, the American Osteopathic Association (AOA) were able to bring a number of osteopathic medical schools into compliance with Flexner's recommendations. As a result, American osteopathic medical schools today teach from an evidence-based, medicalised, scientific knowledge base. The curricula of DO and MD awarding medical schools differ only minimally, the chief difference being the additional instruction in osteopathic schools of manipulative medicine. This dramatic convergence of osteopathic and biomedical training demonstrates the sweeping effect the Flexner report had, not only in the closure of inadequate schools, but also in the standardization of the curricula of surviving schools.