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1.  Major Burden of Severe Anemia from Non-Falciparum Malaria Species in Southern Papua: A Hospital-Based Surveillance Study 
PLoS Medicine  2013;10(12):e1001575.
Ric Price and colleagues use hospital-based surveillance data to estimate the risk of severe anemia and mortality associated with endemic Plasmodium species in southern Papua, Indonesia.
Please see later in the article for the Editors' Summary
Background
The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia.
Methods and Findings
Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81–9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16–9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44–9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49–9.57]); p-value for all comparisons <0.001. Severe anemia (hemoglobin <5 g/dl) was present in 8,151 (3.7%) patients. Compared to patients without malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99–3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00–2.23), 1.87 (95% CI 1.74–2.01), and 2.18 (95% CI 1.76–2.67), respectively, p<0.001. Overall, 12.2% (95% CI 11.2%–13.3%) of severe anemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%–16.3%) for P. falciparum monoinfections. Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17–6.50]; p<0.001). Not all patients had a hemoglobin measurement, thus limitations of the study include the potential for selection bias, and possible residual confounding in multivariable analyses.
Conclusions
In Papua P. vivax is the dominant cause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria—a mosquito-borne parasitic disease—is a global public health problem. Five parasites cause malaria—Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Of these, P. vivax is the commonest and most widely distributed, whereas P. falciparum causes the most deaths—about a million every year. All these parasites enter their human host when an infected mosquito takes a blood meal. The parasites migrate to the liver where they replicate and mature into a parasitic form known as merozoites. After 8–9 days, the merozoites are released from the liver cells and invade red blood cells where they replicate rapidly before bursting out and infecting more red blood cells. Malaria's recurring flu-like symptoms are caused by this cyclical increase in parasites in the blood. Malaria needs to be treated promptly with antimalarial drugs to prevent the development of potentially fatal complications. Infections with P. falciparum in particular can cause anemia (a reduction in red blood cell numbers) and can damage the brain and other vital organs by blocking the capillaries that supply these organs with blood.
Why Was This Study Done?
It is unclear what proportion of anemia is attributable to non-falciparum malarias in regions of the world where several species of malaria parasite are always present (Plasmodium co-endemicity). Public health officials in such regions need to know whether non-falciparum malarias are a major cause of anemia when designing malaria control strategies. If P. vivax, for example, is a major cause of anemia in an area where P. vivax and P. falciparum co-exist, then any malaria control strategies that are implemented need to take into account the biological differences between the parasites. In this hospital-based cohort study, the researchers investigate the burden of severe anemia from the endemic Plasmodium species in southern Papua, Indonesia.
What Did the Researchers Do and Find?
The researchers used hospital record numbers to link clinical and laboratory data for patients presenting to a referral hospital in southern Papua over an 8-year period. The hemoglobin level (an indicator of anemia) was measured in about a quarter of hospital presentations (some patients attended the hospital several times). A third of the presentations who had their hemoglobin level determined (67,696 presentations) had clinical malaria. Patients with P. malariae infection had the lowest average hemoglobin concentration. Patients with mixed species, P. falciparum, and P. vivax infections had slightly higher average hemoglobin levels but all these levels were below the normal range for people living in Papua. Among the patients who had their hemoglobin status assessed, 3.7% had severe anemia. After allowing for other factors that alter the risk of anemia (“confounding” factors such as age), patients with mixed Plasmodium infection were more than three times as likely to have severe anemia as patients without malaria. Patients with P. falciparum, P. vivax, or P. malariae infections were about twice as likely to have severe anemia as patients without malaria. About 12.2% of severe anemia was attributable to non-falciparum infections, 15.1% was attributable to P. falciparum monoinfections, and P. vivax was the dominant cause of severe anemia in infancy. Finally, compared to patients without anemia, patients with severe anemia had nearly a 6-fold higher risk of death.
What Do These Findings Mean?
These findings provide a comparative assessment of the pattern of anemia associated with non-falciparum malarias in Papua and an estimate of the public health importance of these malarias. Although the accuracy of these findings may be affected by residual confounding (for example, the researchers did not consider nutritional status when calculating how much malaria infection increases the risk of anemia) and other limitations of the study design, non-falciparum malarias clearly make a major contribution to the burden of anemia in southern Papua. In particular, these findings reveal the large contribution that P. vivax makes to severe anemia in infancy, show that the hematological (blood-related) impact of P. malariae is most apparent in adulthood, and suggest, in contrast to some previous reports, that mixed P. vivax/P. falciparum infection is associated with a higher risk of severe anemia than monoinfection with either species. These findings, which need to be confirmed in other settings, highlight the public health importance of implementing integrated malaria control strategies that aim to control all Plasmodium species rather than a single species in regions of Plasmodium co-endemicity.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001575.
This study is further discussed in a PLOS Medicine Perspective by Gosling and Hsiang
Information is available from the World Health Organization on malaria (in several languages); the 2012 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including information on different Plasmodium species and a selection of personal stories about malaria
The Malaria Vaccine Initiative has fact sheets on Plasmodium falciparum malaria and on Plasmodium vivax malaria
MedlinePlus provides links to additional information on malaria and on anemia (in English and Spanish)
Information is available from the WorldWide Antimalarial Resistance Network on antimalarial drug resistance for P. falciparum and P. vivax
doi:10.1371/journal.pmed.1001575
PMCID: PMC3866090  PMID: 24358031
2.  Threshold Haemoglobin Levels and the Prognosis of Stable Coronary Disease: Two New Cohorts and a Systematic Review and Meta-Analysis 
PLoS Medicine  2011;8(5):e1000439.
Anoop Shah and colleagues performed a retrospective cohort study and a systematic review, and show evidence that in people with stable coronary disease there were threshold hemoglobin values below which mortality increased in a graded, continuous fashion.
Background
Low haemoglobin concentration has been associated with adverse prognosis in patients with angina and myocardial infarction (MI), but the strength and shape of the association and the presence of any threshold has not been precisely evaluated.
Methods and findings
A retrospective cohort study was carried out using the UK General Practice Research Database. 20,131 people with a new diagnosis of stable angina and no previous acute coronary syndrome, and 14,171 people with first MI who survived for at least 7 days were followed up for a mean of 3.2 years. Using semi-parametric Cox regression and multiple adjustment, there was evidence of threshold haemoglobin values below which mortality increased in a graded continuous fashion. For men with MI, the threshold value was 13.5 g/dl (95% confidence interval [CI] 13.2–13.9); the 29.5% of patients with haemoglobin below this threshold had an associated hazard ratio for mortality of 2.00 (95% CI 1.76–2.29) compared to those with haemoglobin values in the lowest risk range. Women tended to have lower threshold haemoglobin values (e.g, for MI 12.8 g/dl; 95% CI 12.1–13.5) but the shape and strength of association did not differ between the genders, nor between patients with angina and MI. We did a systematic review and meta-analysis that identified ten previously published studies, reporting a total of only 1,127 endpoints, but none evaluated thresholds of risk.
Conclusions
There is an association between low haemoglobin concentration and increased mortality. A large proportion of patients with coronary disease have haemoglobin concentrations below the thresholds of risk defined here. Intervention trials would clarify whether increasing the haemoglobin concentration reduces mortality.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary artery disease is the main cause of death in high-income countries and the second most common cause of death in middle- and low-income countries, accounting for 16.3%, 13.9%, and 9.4% of all deaths, respectively, in 2004. Many risks factors, such as high blood pressure and high blood cholesterol level, are known to be associated with coronary artery disease, and prevention and treatment of such factors remains one of the key strategies in the management of coronary artery disease. Recent studies have suggested that low hemoglobin may be associated with mortality in patients with coronary artery disease. Therefore, using blood hemoglobin level as a prognostic biomarker for patients with stable coronary artery disease may be of potential benefit especially as measurement of hemoglobin is almost universal in such patients and there are available interventions that effectively increase hemoglobin concentration.
Why was This Study Done?
Much more needs to be understood about the relationship between low hemoglobin and coronary artery disease before hemoglobin levels can potentially be used as a clinical prognostic biomarker. Previous studies have been limited in their ability to describe the shape of this relationship—which means that it is uncertain whether there is a “best” hemoglobin threshold or a continuous graded relationship from “good” to “bad”—to assess gender differences, and to compare patients with angina or who have experienced previous myocardial infarction. In order to inform these knowledge gaps, the researchers conducted a retrospective analysis of patients from a prospective observational cohort as well as a systematic review and meta-analysis (statistical analysis) of previous studies.
What Did the Researchers Do and Find?
The researchers conducted a systematic review and meta-analysis of previous studies and found ten relevant studies, but none evaluated thresholds of risk, only linear relationships.
The researchers carried out a new study using the UK's General Practice Research Database—a national research tool that uses anonymized electronic clinical records of a representative sample of the UK population, with details of consultations, diagnoses, referrals, prescriptions, and test results—as the basis for their analysis. They identified and collected information from two cohorts of patients: those with new onset stable angina and no previous acute coronary syndrome; and those with a first myocardial infarction (heart attack). For these patients, the researchers also looked at all values of routinely recorded blood parameters (including hemoglobin) and information on established cardiovascular risk factors, such as smoking. The researchers followed up patients using death of any cause as a primary endpoint and put this data into a statistical model to identify upper and lower thresholds of an optimal hemoglobin range beyond which mortality risk increased.
The researchers found that there was a threshold hemoglobin value below which mortality continuously increased in a graded manner. For men with myocardial infarction, the threshold value was 13.5 g/dl: 29.5% of patients had hemoglobin below this threshold and had a hazard ratio for mortality of 2.00 compared to those with hemoglobin values in the lowest risk range. Women had a lower threshold hemoglobin value than men: 12.8 g/dl for women with myocardial infarction, but the shape and strength of association did not differ between the genders, or between patients with angina and myocardial infarction.
What Do These Findings Mean?
These findings suggest that there are thresholds of hemoglobin that are associated with increased risk of mortality in patients with angina or myocardial infarction. A substantial proportion of patients (15%–30%) have a hemoglobin level that places them at markedly higher risk of death compared to patients with lowest risk hemoglobin levels and importantly, these thresholds are higher than clinicians might anticipate—and are remarkably similar to World Health Organization anemia thresholds of 12 g/dl for women and 13 g/dl for men. Despite the limitations of these observational findings, this study supports the rationale for conducting future randomized controlled trials to assess whether hemoglobin levels are causal and whether clinicians should intervene to increase hemoglobin levels, for example by oral iron supplementation.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000439.
Wikipedia provides information about hemoglobin (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Health Organization provides an overview of the global prevalence of coronary artery disease, a factsheet on the top ten causes of death, as well as information on anemia
doi:10.1371/journal.pmed.1000439
PMCID: PMC3104976  PMID: 21655315
3.  Dose of Erythropoiesis-Stimulating Agents and Adverse Outcomes in CKD: A Metaregression Analysis 
Background
Targeting higher hemoglobin with erythropoiesis-stimulating agents (ESAs) to treat anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.
Study Design
Meta-regression analysis examining the association of ESA dose with adverse outcomes, independent of target or achieved hemoglobin.
Setting and Population
Patients with anemia of CKD, irrespective of dialysis status.
Selection Criteria for Studies
We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for treatment of anemia in adults with CKD, with minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.
Predictors
ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.
Outcomes
All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression or transfusion requirement.
Results
31 trials (12,956 patients) met criteria. All-cause mortality was associated with higher (per epoetin-alfa–equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10–1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02–1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin (IRR, 1.48; 95% CI, 1.02- 2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin (IRR, 2 1.41; 95% CI, 1.08–1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction but not statistically significant. Higher total-study-period mean ESA dose was also associated with increased rate of hypertension, stroke, and thrombotic events including dialysis vascular access-related thrombotic events.
Limitations
use of study-level aggregated data; use of epoetin alfa–equivalent doses; lack of adjustment for confounders.
Conclusions
In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin.
doi:10.1053/j.ajkd.2012.07.014
PMCID: PMC3525813  PMID: 22921639
erythropoietin; ESA; epoetin; darbepoetin; anemia; CKD; dose; mortality; cardiovascular morbidity; meta-regression
4.  The effects of iron deficiency anemia on p wave duration and dispersion 
Clinics  2010;65(11):1067-1071.
OBJECTIVES:
The association between P wave dispersion and iron deficiency anemia has not been documented in the literature. In this study, we evaluated P wave dispersion in patients with iron deficiency anemia and the possible relationships between P wave dispersion and other echocardiographic parameters.
INTRODUCTION:
The iron status of an individual may play an important role in cardiovascular health. Anemia is an independent risk factor for adverse cardiovascular outcomes. P wave dispersion is a simple electrocardiographic marker that has a predictive value for the development of atrial fibrillation. Apart from cardiovascular diseases, several conditions, such as seasonal variation, alcohol intake and caffeine ingestion, have been demonstrated to affect P wave dispersion.
METHODS:
The study included 97 patients who had iron deficiency anemia and 50 healthy subjects. The cases were evaluated with a clinical examination and diagnostic tests that included 12‐lead electrocardiography and transthoracic echocardiography.
RESULTS:
Compared to the control group, patients with iron deficiency anemia showed significantly longer maximum P wave duration (Pmax) (91.1±18.0 vs. 85.8±6.7 msec, p = 0.054), P wave dispersion (PWD) (48.1±7.7 vs. 40.9±5.6 msec, p<0.001), mitral inflow deceleration time (DT) (197.5±27.9 vs. 178.8±8.9 msec, p<0.001) and isovolumetric relaxation time (IVRT) (93.3±9.2 vs. 77.4±8.2 msec, p<0.001); they also showed increased heart rate (85.7±16.1 vs. 69.0±4.4, p<0.001) and frequency of diastolic dysfunction (7 (7.2%) vs. 0). Correlation analysis revealed that PWD was significantly correlated with IVRT, DT, heart rate, the presence of anemia and hemoglobin level.
CONCLUSIONS:
Iron deficiency anemia may be associated with prolonged P wave duration and dispersion and impaired diastolic left ventricular filling.
doi:10.1590/S1807-59322010001100001
PMCID: PMC2999696  PMID: 21243273
Diastolic dysfunction; Electrocardiogram; Iron deficiency; Anemia; P wave; Dispersion
5.  Anemia and Associated Clinical Outcomes in Patients with Heart Failure Due to Reduced Left Ventricular Systolic Function 
Clinical cardiology  2013;36(10):611-620.
Background
Anemia is associated with decreased functional capacity, reduced quality of life, and worsened outcomes among patients with heart failure (HF) due to reduced left ventricular ejection fraction (HFREF). We sought to evaluate the independent effect of anemia on clinical outcomes among those with HFREF.
Methods
The HF-ACTION trial was a prospective, randomized trial of exercise therapy versus usual care in 2331 patients with HFREF. Patients with New York Heart Association class 2–4 HF and left ventricular ejection fractions of ≤ 35% were recruited. Hemoglobin (Hb) was measured up to one year prior to entry and was stratified by quintile. Anemia was defined as baseline Hb < 13 g/dl and <12 g/dl in men and women, respectively. Hb was assessed in two models; a global prediction model that had been previously developed and a modified model including variables associated with anemia and the studied outcomes.
Results
Hemoglobin was available at baseline in 1763 subjects (76% of total study population); their median age was 59.0 years, 73% were male, and 62% were Caucasian. The prevalence of anemia was 515/1763 (29%). Older age, female gender, African American race, diabetes, hypertension, and lower estimated glomerular filtration rates were all more frequent in lower Hb quintiles. Over a median follow-up of 30 months, the primary outcome of all-cause mortality or all-cause hospitalization occurred in 78% of those with anemia and 64% in those without, p<0.001. The secondary outcomes of all-cause mortality alone, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization occurred in 23 % vs 15%, 67% vs 54%, and 44 vs 29%, respectively, p<0.001. Heart failure hospitalizations occurred in 36% vs 22%, and urgent outpatient visits for HF exacerbations occurred in 67% and 55%, respectively, p<0.001. For the global model, there was an association observed for anemia and all-cause mortality or hospitalization, adjusted hazard ratio (HR)=1.15, 95% CI 1.01–1.32, p=0.04, but other outcomes were not significant at p<0.05. In the modified model, the adjusted HR for anemia and the primary outcome of all-cause mortality or all-cause hospitalization was 1.25, 95% CI 1.10–1.42, p<0.001. There were independent associations between anemia and all-cause death, HR=1.11, 95% CI 0.87–1.42, p=0.38; cardiovascular death or cardiovascular hospitalization, HR=1.16, 95% CI 1.01–1.33, p=0.035; and cardiovascular death and heart failure hospitalization, HR=1.27, 95% CI 1.06–1.51, p=0.008.
Conclusions
Anemia modestly is associated with increased rates of death, hospitalization, and HF exacerbation in patients with chronic HFREF. After adjusting for other important covariates, anemia is independently associated with an excess hazard for all-cause mortality and all-cause hospitalization. Anemia is also associated with combinations of cardiovascular death and cardiovascular/heart failure hospitalizations as composite endpoints.
doi:10.1002/clc.22181
PMCID: PMC4008125  PMID: 23929781
heart failure; chronic kidney disease; anemia; glomerular filtration rate; renal insufficiency; hospitalization; mortality
6.  Preoperative anemia increases mortality and postoperative morbidity after cardiac surgery 
Background
Anemia is an established adverse risk factor in cardiovascular disease. However, the effect of preoperative anemia is not well defined in heart surgery. This study evaluates the effect of preoperative anemia on early clinical outcomes in patients undergoing cardiac surgery.
Methods
A retrospective, observational, cohort study of prospectively collected data was undertaken on 7,738 consecutive patients undergoing heart surgery between April 2003 and February 2009. Of these, 1,856 patients with preoperative anemia were compared to 5,882 patients without anemia (control group). According to the World Health Organization, anemia was defined as hemoglobin level < 13 g/dl for men and <12 g/dl for women. Selection bias not controlled by multivariable methods was assessed with propensity-adjustment method.
Results
Overall mortality was 2.1%. Preoperative anemia was associated with tripling in the risk of death (4.6% vs 1.5%, p < 0.0001) and postoperative renal dysfunction (18.5% vs 6.5%, p < 0.0001). There was also a significant difference between the anemic and non-anemic group in the risk of postoperative stroke (1.9% vs 1.1%, p = 0.008), atrial fibrillation (36.7% vs 33%, p = 0.003) and length of hospital stay > 7 days (54% vs 36.7%, p < 0.0001). In propensity-adjusted, multivariable logistic regression, preoperative anemia was an independent predictor of mortality (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.02 to 2.03), postoperative renal dysfunction (OR 1.73, 95% CI 1.43 to 2.1) and length of hospital stay > 7 days (OR 1.3, 95% CI 1.15 to 1.47).
Conclusion
In patients undergoing heart surgery, preoperative anemia is associated with an increased risk of mortality and postoperative morbidity.
doi:10.1186/1749-8090-9-137
PMCID: PMC4237817  PMID: 25096231
Anemia; Cardiac surgery; Outcome
7.  Anemia and the onset of gout in a population-based cohort of adults: Atherosclerosis Risk in Communities study 
Arthritis Research & Therapy  2012;14(4):R193.
Introduction
There is a growing prevalence of gout in the US and worldwide. Gout is a recognized risk factor for cardiovascular disease (CVD). It is unclear whether other risk factors for CVD are also associated with increased risk of gout. Anemia is one such CVD risk factor. No studies have evaluated the relationship between anemia and gout. We tested whether anemia was associated with incident gout independent of comorbid conditions in Atherosclerosis Risk in the Communities.
Methods
This population-based cohort recruited 15,792 individuals in 1987 to 1989 from four US communities and contained nine years of follow-up. Anemia was defined as hemoglobin <13.5 g/dL for men and <12 g/dL for women. Using a Cox Proportional Hazards model, we estimated the hazard ratio (HR) and confidence intervals (CI) of incident gout by baseline anemia, adjusted for confounders (sex, race, estimated glomerular filtration rate, body mass index and alcohol intake) and clinical factors (coronary heart disease, congestive heart failure, diabetes, hypertension, diuretic use and serum urate level).
Results
Among the 10,791 participants, 10% had anemia at baseline. There were 271 cases of incident gout. Patients with anemia had a two-fold increased risk of developing gout over nine years (HR = 2.01, 95% CI: 1.46, 2.76). Anemia was associated with incident gout independent of known gout risk factors, confounders and clinical risk factors (HR = 1.73, 95% CI: 1.24, 2.41). This association persisted after additionally adjusting for serum urate level (HR = 1.83, 95% CI: 1.30, 2.57).
Conclusion
We identified anemia as a novel risk factor for gout. Anemia was associated with an approximately two-fold increased risk of gout-independent kidney function and serum urate. These findings suggest that anemia is a risk factor for gout on par with other chronic conditions such as obesity and diabetes. The biological mechanism linking anemia to gout remains unclear.
doi:10.1186/ar4026
PMCID: PMC3580590  PMID: 22906142
8.  Diminished Quality of Life and Physical Function in Community-Dwelling Elderly with Anemia 
Medicine  2009;88(2):107-114.
The occurrence of anemia in older adults has been associated with adverse outcomes including functional decline, disability, morbidity and mortality. It is not clear to what extent these outcomes are the result of the anemia or concurrent illness. We performed a cross-sectional, observational study to determine whether lower hemoglobin concentrations in older adults are associated with reduced health-related quality of life, functional status, depression, disability, and physical strength, independent of chronic disease. Three sites participated in this research; an academic geriatric practice, a hospital based geriatric out patient unit, and a community-based multi-specialty internal medicine group. Health-related quality of life and functional status were measured using the Short Form-36 Health Survey (SF-36) and the Functional Assessment of Chronic Illness Therapy-Anemia (FACIT-An). Disability and depression were assessed using the Instrumental Activities of Daily Living (IADL) and the Geriatric Depression Scale (GDS) questionnaires, respectively. Handgrip strength was used as a physical performance measure. Anemia was defined as hemoglobin < 13 g/dL for men or < 12 g/dL for women. The mean SF-36 physical health component summary scores were 38.9 (with anemia) and 44.1 (without anemia), (P < 0.001). Anemia was associated with greater fatigue (P < 0.001), lower handgrip strength (P = 0.014), increased number of disabilities (P = 0.005) and more depressive symptoms (P = 0.002). Multivariate regression analysis, adjusted for demographic and clinical characteristics, demonstrated strong associations for reduced hemoglobin, even within the “normal” range, and poorer health-related quality of life across multiple domains. Thus, anemia was independently associated with clinically significant impairments in multiple domains of health-related quality of life, especially in measures of functional limitation. Mildly low hemoglobin levels, even when above the WHO anemia threshold, were associated with significant declines in quality of life among the elderly.
doi:10.1097/MD.0b013e31819d89d5
PMCID: PMC2893336  PMID: 19282701
9.  Prevalence, severity, and related factors of anemia in HIV/AIDS patients 
Objective:
The prevalence of anemia in HIV infected patients has not been well characterized in Iran. This study aimed to describe the prevalence of anemia and related factors in HIV positive patients.
Materials and Methods:
In a cross-sectional study, anemia prevalence and risk factors of 212 HIV positive patients were assessed, at the behavioral disease consulting center in Isfahan. The relationship between anemia, demographic variables, and clinical histories were analyzed. Mild to moderate anemia was defined as hemoglobin 8–13 g/dL for men and 8–12 g/dL for women. Severe anemia was defined as hemoglobin, 8 g/dL.
Results:
A total of 212 HIV positive patients with a mean±SD age of 36.1 ± 9.1 years were assessed. We found that hemoglobin levels were between 4.7 and 16.5 gr/dL. In this study, the overall prevalence of anemia was 71%, with the majority of patients having mild to moderate anemia. Mild to moderate anemia and severe anemia occurred in 67% and 4% of patients, respectively. The mean absolute CD4 count was 348 ± 267.8 cells/cubic mm. Sixty one of 212 patients were at late stage of HIV infection (males=51 and female=10). Of the 212 HIV positive patients enrolled, 17 (8%) had a positive history of tuberculosis. We found a strong association between anemia and death.
Conclusion:
Normocytic anemia with decreased reticulocyte count was the most common type of anemia in overall. Prevalence of anemia in this study is relatively higher than other similar studies. Such a high prevalence of anemia needs close monitoring of patients on a zidovudine-based regimen. Better screening for anemia and infectious diseases, and modified harm reduction strategy (HRS) for injection drug users are primary needs in HIV seropositive patients.
PMCID: PMC3525030  PMID: 23264786
AIDS; anemia; HIV positive
10.  Preoperative Anemia in Total Joint Arthroplasty: Is It Associated with Periprosthetic Joint Infection? 
Background
Anemia is common in patients undergoing total joint arthroplasty (TJA). Numerous studies have associated anemia with increased risk of infection, length of hospital stay, and mortality in surgical populations. However, it is unclear whether and to what degree preoperative anemia in patients undergoing TJA influences postoperative periprosthetic joint infection (PJI) and mortality.
Questions/Purposes
We therefore (1) determined the incidence of preoperative anemia in patients undergoing TJA; (2) assessed the possible association between preoperative anemia and subsequent PJI; and (3) explored the relationship between preoperative anemia with postoperative mortality.
Methods
We identified 15,722 patients who underwent TJA from January 2000 to June 2007. Anemia was defined as hemoglobin < 12 g/dL in women and hemoglobin < 13 g/dL in men. We determined the effect of preoperative anemia, demographics, and comorbidities on postoperative complications.
Results
Of the 15,222 patients, 19.6% presented with preoperative anemia. PJI occurred more frequently in anemic patients at an incidence of 4.3% in anemic patients compared with 2% in nonanemic patients. Thirty-day (0.4%), 90-day (0.6%), and 1-year (1.8%) mortality rates were not higher in patients with preoperative anemia. Forty-four percent of anemic patients received an allogenic transfusion compared with only 13.4% of nonanemic patients. Anemic patients had increased hospital stays averaging 4.3 days compared with 3.9 days in nonanemic patients. Anemia did not predict cardiac complications.
Conclusion
Our data demonstrate that preoperative anemia is associated with development of subsequent PJI. Preoperative anemia was not associated with 30-day, 60-day, or 1-year mortality in this cohort.
Level of Evidence
Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-012-2435-z
PMCID: PMC3442010  PMID: 22773393
11.  Anemia and blood transfusion in a surgical intensive care unit 
Critical Care  2010;14(3):R92.
Introduction
Studies in intensive care unit (ICU) patients have suggested that anemia and blood transfusions can influence outcomes, but these effects have not been widely investigated specifically in surgical ICU patients.
Methods
We retrospectively analyzed the prospectively collected data from all adult patients (>18 years old) admitted to a 50-bed surgical ICU between 1st March 2004 and 30th July 2006.
Results
Of the 5925 patients admitted during the study period, 1833 (30.9%) received a blood transfusion in the ICU. Hemoglobin concentrations were < 9 g/dl on at least one occasion in 57.6% of patients. Lower hemoglobin concentrations were associated with a higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score, greater mortality rates, and longer ICU and hospital lengths of stay. Transfused patients had higher ICU (12.5 vs. 3.2%) and hospital (18.3 vs. 6.5%) mortality rates (both p < 0.001) than non-transfused patients. However, ICU and in-hospital mortality rates were similar among transfused and non-transfused matched pairs according to a propensity score (n = 1184 pairs), and after adjustment for possible confounders in a multivariable analysis, higher hemoglobin concentrations (RR 0.97[0.95-0.98], per 1 g/dl, p < 0.001) and blood transfusions (RR 0.96[0.92-0.99], p = 0.031) were independently associated with a lower risk of in-hospital death, especially in patients aged from 66 to 80 years, in patients admitted to the ICU after non-cardiovascular surgery, in patients with higher severity scores, and in patients with severe sepsis.
Conclusions
In this group of surgical ICU patients, anemia was common and was associated with higher morbidity and mortality. Higher hemoglobin concentrations and receipt of a blood transfusion were independently associated with a lower risk of in-hospital death. Randomized control studies are warranted to confirm the potential benefit of blood transfusions in these subpopulations.
doi:10.1186/cc9026
PMCID: PMC2911729  PMID: 20497535
12.  Erectile Dysfunction Severity as a Risk Marker for Cardiovascular Disease Hospitalisation and All-Cause Mortality: A Prospective Cohort Study 
PLoS Medicine  2013;10(1):e1001372.
In a prospective Australian population-based study linking questionnaire data from 2006–2009 with hospitalisation and death data to June 2010 for 95,038 men aged ≥45 years, Banks and colleagues found that more severe erectile dysfunction was associated with higher risk of cardiovascular disease.
Background
Erectile dysfunction is an emerging risk marker for future cardiovascular disease (CVD) events; however, evidence on dose response and specific CVD outcomes is limited. This study investigates the relationship between severity of erectile dysfunction and specific CVD outcomes.
Methods and Findings
We conducted a prospective population-based Australian study (the 45 and Up Study) linking questionnaire data from 2006–2009 with hospitalisation and death data to 30 June and 31 Dec 2010 respectively for 95,038 men aged ≥45 y. Cox proportional hazards models were used to examine the relationship of reported severity of erectile dysfunction to all-cause mortality and first CVD-related hospitalisation since baseline in men with and without previous CVD, adjusting for age, smoking, alcohol consumption, marital status, income, education, physical activity, body mass index, diabetes, and hypertension and/or hypercholesterolaemia treatment. There were 7,855 incident admissions for CVD and 2,304 deaths during follow-up (mean time from recruitment, 2.2 y for CVD admission and 2.8 y for mortality). Risks of CVD and death increased steadily with severity of erectile dysfunction. Among men without previous CVD, those with severe versus no erectile dysfunction had significantly increased risks of ischaemic heart disease (adjusted relative risk [RR] = 1.60, 95% CI 1.31–1.95), heart failure (8.00, 2.64–24.2), peripheral vascular disease (1.92, 1.12–3.29), “other” CVD (1.26, 1.05–1.51), all CVD combined (1.35, 1.19–1.53), and all-cause mortality (1.93, 1.52–2.44). For men with previous CVD, corresponding RRs (95% CI) were 1.70 (1.46–1.98), 4.40 (2.64–7.33), 2.46 (1.63–3.70), 1.40 (1.21–1.63), 1.64 (1.48–1.81), and 2.37 (1.87–3.01), respectively. Among men without previous CVD, RRs of more specific CVDs increased significantly with severe versus no erectile dysfunction, including acute myocardial infarction (1.66, 1.22–2.26), atrioventricular and left bundle branch block (6.62, 1.86–23.56), and (peripheral) atherosclerosis (2.47, 1.18–5.15), with no significant difference in risk for conditions such as primary hypertension (0.61, 0.16–2.35) and intracerebral haemorrhage (0.78, 0.20–2.97).
Conclusions
These findings give support for CVD risk assessment in men with erectile dysfunction who have not already undergone assessment. The utility of erectile dysfunction as a clinical risk prediction tool requires specific testing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Erectile dysfunction is the medical term used when a man is unable to achieve or sustain an erection of his penis suitable for sexual intercourse. Although a sensitive topic that can cause much embarrassment and distress, erectile dysfunction is very common, with an estimated 40% of men over the age of 40 years experiencing frequent or occasional difficulties. The most common causes of erectile dysfunction are medications, chronic illnesses such as diabetes, and drinking too much alcohol. Stress and mental health problems can also cause or worsen erectile dysfunction. There is also increasing evidence that erectile dysfunction may actually be a symptom of cardiovascular disease—a leading cause of death worldwide—as erectile dysfunction could indicate a problem with blood vessels or poor blood flow commonly associated with cardiovascular disease.
Why Was This Study Done?
Although previous studies have suggested that erectile dysfunction can serve as a marker for cardiovascular disease in men not previously diagnosed with the condition, few studies to date have investigated whether erectile dysfunction could also indicate worsening disease in men already diagnosed with cardiovascular disease. In addition, previous studies have typically been small and have not graded the severity of erectile dysfunction or investigated the specific types of cardiovascular disease associated with erectile dysfunction. In this large study conducted in Australia, the researchers investigated the relationship of the severity of erectile dysfunction with a range of cardiovascular disease outcomes among men with and without a previous diagnosis of cardiovascular disease.
What Did the Researchers Do and Find?
The researchers used information from the established 45 and Up Study, a large cohort study that includes 123,775 men aged 45 and over, selected at random from the general population of New South Wales, a large region of Australia. A total of 95,038 men were included in this analysis. The male participants completed a postal questionnaire that included a question on erectile functioning, which allowed the researchers to define erectile dysfunction as none, mild, moderate, or severe. Using information captured in the New South Wales Admitted Patient Data Collection—a complete record of all public and private hospital admissions, including the reasons for admission and the clinical diagnosis—and the government death register, the researchers were able to determine health outcomes of all study participants. They then used a statistical model to estimate hospital admissions for cardiovascular disease events for different levels of erectile dysfunction.
The researchers found that the rates of severe erectile dysfunction among study participants were 2.2% for men aged 45–54 years, 6.8% for men aged 55–64 years, 20.2% for men aged 65–74 years, 50.0% for men aged 75–84 years, and 75.4% for men aged 85 years and over. During the study period, the researchers recorded 7,855 hospital admissions related to cardiovascular disease and 2,304 deaths. The researchers found that among men without previous cardiovascular disease, those with severe erectile dysfunction were more likely to develop ischemic heart disease (risk 1.60), heart failure (risk 8.00), peripheral vascular disease (risk 1.92), and other causes of cardiovascular disease (risk 1.26) than men without erectile dysfunction. The risks of heart attacks and heart conduction problems were also increased (1.66 and 6.62, respectively). Furthermore, the combined risk of all cardiovascular disease outcomes was 1.35, and the overall risk of death was also higher (risk 1.93) in these men. The researchers found that these increased risks were similar in men with erectile dysfunction who had previously been diagnosed with cardiovascular disease.
What Do These Findings Mean?
These findings suggest that compared to men without erectile dysfunction, there is an increasing risk of ischemic heart disease, peripheral vascular disease, and death from all causes in those with increasing degrees of severity of erectile dysfunction. The authors emphasize that erectile dysfunction is a risk marker for cardiovascular disease, not a risk factor that causes cardiovascular disease. These findings add to previous studies and highlight the need to consider erectile dysfunction in relation to the risk of different types of cardiovascular disease, including heart failure and heart conduction disorders. However, the study's reliance on the answer to a single self-assessed question on erectile functioning limits the findings. Nevertheless, these findings provide useful information for clinicians: men with erectile dysfunction are at higher risk of cardiovascular disease, and the worse the erectile dysfunction, the higher the risk of cardiovascular disease. Men with erectile dysfunction, even at mild or moderate levels, should be screened and treated for cardiovascular disease accordingly.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001372.
Wikipedia defines erectile dysfunction (note that Wikipedia is a free online encyclopedia that anyone can edit)
MedlinePlus also has some useful patient information on erectile dysfunction
The Mayo Clinic has patient-friendly information on the causes of, and treatments for, erectile dysfunction, and also includes information on the link with cardiovascular disease
The National Heart Foundation of Australia provides information for health professionals, patients, and the general public about how to prevent and manage cardiovascular disease, including assessment and management of cardiovascular disease risk
doi:10.1371/journal.pmed.1001372
PMCID: PMC3558249  PMID: 23382654
13.  How low is too low? Cardiac risks with anemia 
Critical Care  2004;8(Suppl 2):S11-S14.
Despite the increasing availability of data supporting more restrictive transfusion practices, the risks and benefits of transfusing critically ill patients continue to evoke controversy. Past retrospective and observational studies suggested that liberal transfusion strategies were more beneficial in patients whose hematocrit levels fell below 30%. An expanding body of literature suggests that an arbitrary trigger for transfusion (the '10/30 rule') is ill advised. A recent randomized controlled trial provided compelling evidence that similar, and in some cases better, outcomes result if a restrictive transfusion strategy is maintained. The impact of this accumulating evidence on clinical practice is evident in large reports, which show that the average transfusion trigger in critically ill patients was a hemoglobin level in the range 8–8.5 g/dl. Based on the available evidence, transfusion in the critically ill patient without active ischemic heart disease should generally be withheld until the hemoglobin level falls to 7 g/dl. Transfusions should be administered as clinically indicated for patients with acute, ongoing blood loss and those who have objective signs and symptoms of anemia despite maintenance of euvolemia. The hemoglobin level at which serious morbidity or mortality occurs in critically ill patients with active ischemic heart disease is a subject of continued debate but it is likely that a set transfusion trigger will not provide an optimal risk–benefit profile in this population.
doi:10.1186/cc2845
PMCID: PMC3226154  PMID: 15196315
anemia; blood; cardiac disease; critically ill patients; hemoglobin; transfusion trigger
14.  Effect of anemia correction on left ventricular structure and filling pressure in anemic patients without overt heart disease 
Background/Aims
There are few data on the effects of low hemoglobin levels on the left ventricle (LV) in patients without heart disease. The objective of this study was to document changes in the echocardiographic variables of LV structure and function after the correction of anemia without significant cardiovascular disease.
Methods
In total, 34 iron-deficiency anemia patients (35 ± 11 years old, 32 females) without traditional cardiovascular risk factors or cardiovascular disease and 34 age- and gender-matched controls were studied. Assessments included history, physical examination, and echocardiography. Of the 34 patients with anemia enrolled, 20 were followed and underwent echocardiography after correction of the anemia.
Results
There were significant differences between the anemia and control groups in LV diameter, left ventricular mass index (LVMI), left atrial volume index (LAVI), peak mitral early diastolic (E) velocity, peak mitral late diastolic (A) velocity, E/A ratio, the ratio of mitral to mitral annular early diastolic velocity (E/E'), stroke volume, and cardiac index. Twenty patients underwent follow-up echocardiography after treatment of anemia. The follow-up results showed significant decreases in the LV end-diastolic and end-systolic diameters and LVMI, compared with baseline levels. LAVI, E velocity, and E/E' also decreased, suggesting a decrease in LV filling pressure.
Conclusions
Low hemoglobin level was associated with larger cardiac chambers, increased LV, mass and higher LV filling pressure even in the subjects without cardiovascular risk factors or overt cardiovascular disease. Appropriate correction of anemia decreased LV mass, LA volume, and E/E'.
doi:10.3904/kjim.2014.29.4.445
PMCID: PMC4101591  PMID: 25045292
Anemia; Ventricular remodeling
15.  Mapping the Risk of Anaemia in Preschool-Age Children: The Contribution of Malnutrition, Malaria, and Helminth Infections in West Africa 
PLoS Medicine  2011;8(6):e1000438.
Ricardo Soares Magalhães and colleagues used national cross-sectional household-based demographic health surveys to map the distribution of anemia risk in preschool children in Burkina Faso, Ghana, and Mali.
Background
Childhood anaemia is considered a severe public health problem in most countries of sub-Saharan Africa. We investigated the geographical distribution of prevalence of anaemia and mean haemoglobin concentration (Hb) in children aged 1–4 y (preschool children) in West Africa. The aim was to estimate the geographical risk profile of anaemia accounting for malnutrition, malaria, and helminth infections, the risk of anaemia attributable to these factors, and the number of anaemia cases in preschool children for 2011.
Methods and Findings
National cross-sectional household-based demographic health surveys were conducted in 7,147 children aged 1–4 y in Burkina Faso, Ghana, and Mali in 2003–2006. Bayesian geostatistical models were developed to predict the geographical distribution of mean Hb and anaemia risk, adjusting for the nutritional status of preschool children, the location of their residence, predicted Plasmodium falciparum parasite rate in the 2- to 10-y age group (Pf PR2–10), and predicted prevalence of Schistosoma haematobium and hookworm infections. In the four countries, prevalence of mild, moderate, and severe anaemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The mean Hb was lowest in Burkina Faso (89 g/l), in males (93 g/l), and for children 1–2 y (88 g/l). In West Africa, severe malnutrition, Pf PR2–10, and biological synergisms between S. haematobium and hookworm infections were significantly associated with anaemia risk; an estimated 36.8%, 14.9%, 3.7%, 4.2%, and 0.9% of anaemia cases could be averted by treating malnutrition, malaria, S. haematobium infections, hookworm infections, and S. haematobium/hookworm coinfections, respectively. A large spatial cluster of low mean Hb (<80 g/l) and maximal risk of anaemia (>95%) was predicted for an area shared by Burkina Faso and Mali. We estimate that in 2011, approximately 6.7 million children aged 1–4 y are anaemic in the three study countries.
Conclusions
By mapping the distribution of anaemia risk in preschool children adjusted for malnutrition and parasitic infections, we provide a means to identify the geographical limits of anaemia burden and the contribution that malnutrition and parasites make to anaemia. Spatial targeting of ancillary micronutrient supplementation and control of other anaemia causes, such as malaria and helminth infection, can contribute to efficiently reducing the burden of anaemia in preschool children in Africa.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Global estimates for the time period 1993–2005 suggest that that worldwide, nearly 300 million children had anemia, that is, hemoglobin levels less than 110 g/l. In sub-Saharan Africa, two-thirds of all children were anemic, representing 83.5 million children. These statistics are important because anemia in infancy and childhood is associated with poor cognitive development, reduced growth, problems with immune function—and ultimately, decreased survival. Malnutrition (including micronutrient deficiency, especially of iron, vitamin A, vitamin C, and folate), undernutrition, and infectious diseases, particularly HIV, malaria, and helminth infections (caused by hookworm and Schistosoma haematobium—which causes urinary schistosomiasis), are major causes of anemia in children. Although iron supplementation can often correct anemia, in some circumstances, iron deficiency can protect against common infectious agents, and giving iron can, on occasion, increase the severity of infectious disease in some children. Focusing on the treatment and prevention of infectious diseases that cause anemia is therefore an important alternative strategy in the treatment of anemia.
Why Was This Study Done?
Control tools for targeting interventions for malaria and helminth infection in sub-Saharan Africa include modern spatial risk prediction methods that combine statistical models with geographical information systems (similar to those used in car navigation systems). However, to date no studies have used these tools to spatially predict the risk of anemia. Furthermore, the contribution that malnutrition and infections make to the overall anemia burden in Africa is largely unknown. In this study the researchers used these tools to predict the prevalence of anemia in three West African countries and to estimate the attributable risk of anemia due to malnutrition, malaria, and helminth infections.
What Did the Researchers Do and Find?
The researchers used geographically linked data from the most recent Demographic and Health Surveys (DHS) in Burkina Faso (2003), Ghana (2003), and Mali (2006), which included capillary blood sampling and testing and detailed anthropometric (height and weight) measurements. A total of 7,147 children aged 1–4 years (3,477 girls and 3,670 boys) in the three countries were included in the analysis. The researchers mapped DHS survey locations in the three study countries using DHS cluster coordinates in a geographic information system. Using data from the Malaria Atlas Project, the researchers extracted spatially predicted values of Plasmodium falciparum parasite rate for each DHS cluster using a geographical information system and used previously reported parasitological survey data of hookworm and S. haematobium infections to predict helminth infection risk across the region. Then the researchers developed spatial prediction models using Bayesian statistics to estimate of the population attributable fraction for specific predictors for anemia. Data from the DHS showed that the prevalence of mild, moderate, and severe anemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The prevalence of stunting, wasting, and being underweight in the study area was 87.8%, 89.7%, and 71.2%, respectively, and the mean P. falciparum parasite rate, and rates of S. haematobium infection, hookworm infection, and S. haematobium/hookworm coinfection for the study area were 52.0%, 26.8%, 8.2%, and 3.6%, respectively. The overall results indicate that in the three countries, approximately 6.7 million children aged 1–4 years have anemia. Severe malnutrition, P. falciparum infection, hookworm infection, S. haematobium infection, and hookworm/S. haematobium coinfection were responsible for an estimated 2.5 million, 1.0 million, 250,000, 285,000, and 61,000 anemia cases, respectively. Central Burkina Faso and southern Ghana had the highest number of anemic children.
What Do These Findings Mean?
These results add insight and detail to anemia prevalence and anemia severity within different geographical areas in three West African countries. The combination of anemia and mean hemoglobin predictive maps identifies communities in West Africa where preschool-age children are at increased risk of morbidity. The use of anemia maps has important practical implications for targeted control in these countries, such as guiding the efficient allocation of nutrient supplements and fortified foods, and enabling risk assessment of anemia due to different causes, which would in turn constitute an evidence base to calculate the best balance between interventions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000438.
This study is further discussed in a PLoS Medicine Perspective by Abdisalan Noor
The WHO Web site has comprehensive information on the worldwide prevalence of anemia
More information on Demographic Health Surveys is available
More information on global predictions of malaria is available
doi:10.1371/journal.pmed.1000438
PMCID: PMC3110251  PMID: 21687688
16.  Anemia and red blood cell transfusion in critically ill cardiac patients 
Anemia and red blood cell (RBC) transfusion occur frequently in hospitalized patients with cardiac disease. In this narrative review, we report the epidemiology of anemia and RBC transfusion in hospitalized adults and children (excluding premature neonates) with cardiac disease, and on the outcome of anemic and transfused cardiac patients. Both anemia and RBC transfusion are common in cardiac patients, and both are associated with mortality. RBC transfusion is the only way to rapidly treat severe anemia, but is not completely safe. In addition to hemoglobin (Hb) concentration, the determinant(s) that should drive a practitioner to prescribe a RBC transfusion to cardiac patients are currently unclear. In stable acyanotic cardiac patients, Hb level above 70 g/L in children and above 70 to 80 g/L in adults appears safe. In cyanotic children, Hb level above 90 g/L appears safe. The appropriate threshold Hb level for unstable cardiac patients and for children younger than 28 days is unknown. The optimal transfusion strategy in cardiac patients is not well characterized. The threshold at which the risk of anemia outweighs the risk of transfusion is not known. More studies are needed to determine when RBC transfusion is indicated in hospitalized patients with cardiac disease.
doi:10.1186/2110-5820-4-16
PMCID: PMC4085735  PMID: 25024880
Blood; Cardiac; Critical care; Erythrocyte; Hemoglobin; Intensive care; Practice; Risk factors; Surgery; Transfusion
17.  Nadir hemoglobin is associated with poor outcome from intracerebral hemorrhage 
SpringerPlus  2013;2:379.
Objective
Examine the relationship between anemia and outcomes from intracerebral hemorrhage (ICH).
Methods
Patients admitted with spontaneous ICH between July 2008 and December 2010 were identified from our prospective stroke registry. Patients were divided into two groups based on admission hemoglobin (low vs. normal based on laboratory reference range for gender). Baseline characteristics were compared between groups using Chi-square, t-tests and Wilcoxon Rank Sum tests. Primary outcome was functional status at discharge, with modified Rankin Scale (mRS) 5–6 considered a poor outcome. Cumulative logit and logistic regression models were used to assess the relationships between baseline hemoglobin, nadir hemoglobin, and transfusion with outcomes.
Results
Of the 109 patients, 28% (n = 30) were anemic on admission. Baseline anemia did not predict the primary outcome. Nadir hemoglobin was associated with poor functional outcome at discharge (OR = 1.58, 95% CI 1.31-1.90, p < 0.0001) and remained significant after adjusting for age, baseline NIHSS, transfusion, and length of stay (OR = 1.43, 95% CI 1.06-1.94, p = 0.02). Patients who received a transfusion had 9 times greater odds of having a discharge mRS 5–6 (OR 9.37, 95% CI 2.84-30.88, p = 0.0002) compared with patients who did not receive transfusion. This was no longer statistically significant after adjusting for other factors impacting outcome (OR 4.01, 95% CI 0.64-25.32, p = 0.1392). Neither nadir hemoglobin nor transfusion was found to be independent predictors of in-hospital mortality.
Conclusion
This study suggests that nadir hemoglobin, not admission hemoglobin, can be used to predict poor functional outcome. Transfusion was not an independent predictor of poor outcome from ICH.
doi:10.1186/2193-1801-2-379
PMCID: PMC3755802  PMID: 24010037
Intracerebral hemorrhage; Anemia; Hemoglobin; Transfusion; Outcome
18.  Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD 
Anemia is prevalent in patients with chronic kidney disease (CKD) and is associated with a lower quality of life and a higher risk of adverse outcomes including cardiovascular disease and death. Anemia management in CKD patients currently revolves around the use of erythropoiesis-stimulating agents (ESAs) and supplemental iron. However, many patients do not respond adequately and/or require high doses of these medications. Furthermore, recent clinical trials have shown that targeting higher hemoglobin levels with conventional therapies leads to increased cardiovascular morbidity and mortality, particularly when higher doses of ESAs are used, and in patients who are poorly responsive to therapy. One explanation for the poor response to conventional therapies in some patients is that these treatments do not fully address the underlying cause of the anemia. In many CKD patients, like patients with other chronic inflammatory diseases, poor absorption of dietary iron and inability to utilize the body's iron stores contributes to the anemia. Recent research suggests that these abnormalities in iron balance may be caused by elevated levels of the key iron regulatory hormone hepcidin. This article reviews the pathogenesis of anemia in CKD, the role and regulation of hepcidin in systemic iron homeostasis and the anemia of CKD, and the potential diagnostic and therapeutic implications of these findings.
doi:10.1053/j.ajkd.2009.12.030
PMCID: PMC2905036  PMID: 20189278
Anemia; chronic kidney disease; dialysis; inflammation; hepcidin
19.  Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol 
Trials  2010;11:70.
Background
Anemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are commonly used to increase hemoglobin levels in this population. In observational studies, higher hemoglobin levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to hemoglobin levels around 9-10 g/dL. A systematic review of randomized trials found that targeting higher hemoglobin levels with ESA causes an increased risk of adverse vascular outcomes. It is possible, but has never been formally tested in a randomized trial, that ESA dose rather than targeted hemoglobin concentration itself mediates the increased risk of adverse vascular outcomes. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) trial will assess the benefits and harms of a high versus a low fixed ESA dose for the management of anemia in patients with end stage kidney disease.
Methods/Design
This is a randomized, prospective open label blinded end-point (PROBE) trial due to enrol 2204 hemodialysis patients in Italy. Patients will be randomized 1:1 to 4000 IU/week versus 18000 IU/week of intravenous epoietin alfa or beta, or any other ESA in equivalent doses. The dose will be adjusted only if hemoglobin levels fall outside the 9.5-12.5 g/dL range. The primary outcome will be a composite of all-cause mortality, non fatal stroke, non fatal myocardial infarction and hospitalization for cardiovascular causes. Quality of life and costs will also be assessed.
Discussion
The C.E.DOSE study will help inform the optimal therapeutic strategy for the management of anemia of hemodialysis patients, improving clinical outcomes, quality of life and costs, by ascertaining the potential benefits and harms of different fixed ESA doses.
Trial registration
Clinicaltrials.gov NCT00827021
doi:10.1186/1745-6215-11-70
PMCID: PMC2903576  PMID: 20534124
20.  A retrospective study: the prevalence and prognostic value of anemia in patients undergoing radiotherapy for esophageal squamous cell carcinoma 
Background
The relationship between anemia and outcomes after radiotherapy has not been systematically addressed. The study aimed to assess the prevalence and prognostic value of anemia in patients receiving primary radiotherapy for esophageal squamous cell carcinoma (ESCC).
Methods
A total of 103 patients with ESCC were retrospectively reviewed. Anemia was defined as a hemoglobin level <12 g/dl for men and <11 g/dl for women. The 3-year and 5-year overall survival (OS) and disease-free survival (DFS) were analyzed between the anemic and non-anemic groups using the Kaplan-Meier method and the Cox proportional hazards model.
Results
No significant differences were observed in patient characteristics between the anemic and non-anemic groups. The prevalence of anemia was 29.1%. The 3-year and the 5-year OS were 43% and 37%, respectively, in the non-anemic group, and 20% and 17%, respectively, in the anemic group. The 3-year and the 5-year DFS were 37% and 26%, respectively, in the non-anemic group, and 13% and 10%, respectively, in the anemic group. Survival analysis using the Kaplan-Meier method showed that there was significant difference between anemia and non-anemia (P < 0.02). In a multivariate analysis, anemia was identified as a highly significant prognostic factor for 3-year OS (hazard ratio 1.916; P = 0.012) and 3-year DFS (hazard ratio 1.973; P = 0.007), independent of T stage and the status of lymph nodes, and 5-year OS (hazard ratio 1.705; P = 0.027) and 5-year DFS (hazard ratio 1.980; P = 0.005), independent of TNM stage and the status of lymph nodes.
Conclusions
Anemia before primary radiotherapy was associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic factor for ESCC.
doi:10.1186/1477-7819-12-244
PMCID: PMC4126388  PMID: 25085112
Anemia; Survival; Prevalence; Esophageal neoplasms; Squamous cell carcinoma; Radiotherapy
21.  The development of anemia is associated to poor prognosis in NKF/KDOQI stage 3 chronic kidney disease 
BMC Nephrology  2013;14:2.
Background
Anemia is a common condition in CKD that has been identified as a cardiovascular (CV) risk factor in end-stage renal disease, constituting a predictor of low survival. The aim of this study was to define the onset of anemia of renal origin and its association with the evolution of kidney disease and clinical outcomes in stage 3 CKD (CKD-3).
Methods
This epidemiological, prospective, multicenter, 3-year study included 439 CKD-3 patients. The origin of nephropathy and comorbidity (Charlson score: 3.2) were recorded. The clinical characteristics of patients that developed anemia according to EBPG guidelines were compared with those that did not, followed by multivariate logistic regression, Kaplan-Meier curves and ROC curves to investigate factors associated with the development of renal anemia.
Results
During the 36-month follow-up period, 50% reached CKD-4 or 5, and approximately 35% were diagnosed with anemia (85% of renal origin). The probability of developing renal anemia was 0.12, 0.20 and 0.25 at 1, 2 and 3 years, respectively. Patients that developed anemia were mainly men (72% anemic vs. 69% non-anemic). The mean age was 68 vs. 65.5 years and baseline proteinuria was 0.94 vs. 0.62 g/24h (anemic vs. non anemic, respectively). Baseline MDRD values were 36 vs. 40 mL/min and albumin 4.1 vs. 4.3 g/dL; reduction in MDRD was greater in those that developed anemia (6.8 vs. 1.6 mL/min/1.73 m2/3 years). These patients progressed earlier to CKD-4 or 5 (18 vs. 28 months), with a higher proportion of hospitalizations (31 vs. 16%), major CV events (16 vs. 7%), and higher mortality (10 vs. 6.6%) than those without anemia. Multivariate logistic regression indicated a significant association between baseline hemoglobin (OR=0.35; 95% CI: 0.24-0.28), glomerular filtration rate (OR=0.96; 95% CI: 0.93-0.99), female (OR=0.19; 95% CI: 0.10-0.40) and the development of renal anemia.
Conclusions
Renal anemia is associated with a more rapid evolution to CKD-4, and a higher risk of CV events and hospitalization in non-dialysis-dependent CKD patients. This suggests that special attention should be paid to anemic CKD-3 patients.
doi:10.1186/1471-2369-14-2
PMCID: PMC3623844  PMID: 23295149
Chronic kidney disease; Anemia; Cardiovascular risk; Non-dialysis CKD patients; Epidemiology
22.  Anemia and 90-day mortality in COPD patients requiring invasive mechanical ventilation 
Clinical Epidemiology  2010;3:1-5.
Background
There are data to suggest that anemia is associated with increased mortality in patients with chronic obstructive pulmonary disease (COPD). In contrast, critically ill patients with low hemoglobin levels (4.3–5.5 mmol/L, 7.0–9.0 g/dL) in general do not appear to have a worsened clinical outcome. The effects of anemia in critically ill patients with COPD remain to be clarified. We examined the association between anemia (hemoglobin <7.4 mmol/L, <12.0 g/dL) and 90-day mortality in COPD patients with acute respiratory failure treated with invasive mechanical ventilation in a single-institution follow-up study.
Method
We identified all COPD patients at our institution (n = 222) admitted for the first time to the intensive care unit (ICU) requiring invasive mechanical ventilation in 1994–2004. Data on patient characteristics (eg, hemoglobin, pH, blood transfusions, and Charlson Comorbidity Index), and mortality were obtained from population-based clinical and administrative registries and medical records. We used Cox’s regression analysis to estimate mortality rate ratios (MRR) in COPD patients with and without anemia.
Results
A total of 42 (18%) COPD patients were anemic at time of initiating invasive mechanical ventilation. The overall 90-day mortality among anemic COPD patients was 57.1% versus 25% in nonanemic patients. The corresponding adjusted 90-day MRR was 2.6 (95% confidence interval 1.5–4.5). Restricting analyses to patients not treated with blood transfusions during their intensive care unit stay did not materially change the MRR.
Conclusion
We found anemia to be associated with increased mortality among COPD patients with acute respiratory failure requiring invasive mechanical ventilation.
doi:10.2147/CLEP.S12885
PMCID: PMC3035601  PMID: 21326654
anemia; mortality; chronic obstructive pulmonary disease; intensive care
23.  Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery 
The New England Journal of Medicine  2011;365(26):2453-2462.
BACKGROUND
The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture.
METHODS
We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up.
RESULTS
A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, −3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, −0.9%; 99% CI, −3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, −1.9 to 4.0). The rates of other complications were similar in the two groups.
CONCLUSIONS
A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.)
doi:10.1056/NEJMoa1012452
PMCID: PMC3268062  PMID: 22168590
24.  The prevalence of anemia and its association with 90-day mortality in hospitalized community-acquired pneumonia 
Background
The prevalence of anemia in the intensive care unit is well-described. Less is known, however, of the prevalence of anemia in hospitalized patients with lesser illness severity or without organ dysfunction. Community-acquired pneumonia (CAP) is one of the most frequent reasons for hospitalization in the United States (US), affecting both healthy patients and those with comorbid illness, and is typically not associated with acute blood loss. Our objective was to examine the development and progression of anemia and its association with 90d mortality in 1893 subjects with CAP presenting to the emergency departments of 28 US academic and community hospitals.
Methods
We utilized hemoglobin values obtained for clinical purposes, classifying subjects into categories consisting of no anemia (hemoglobin >13 g/dL), at least borderline (≤ 13 g/dL), at least mild (≤ 12 g/dL), at least moderate (≤ 10 g/dL), and severe (≤ 8 g/dL) anemia. We stratified our results by gender, comorbidity, ICU admission, and development of severe sepsis. We used multivariable logistic regression to determine factors independently associated with the development of moderate to severe anemia and to examine the relationship between anemia and 90d mortality.
Results
A total of 8240 daily hemoglobin values were measured in 1893 subjects. Mean (SD) number of hemoglobin values per patient was 4.4 (4.0). One in three subjects (33.9%) had at least mild anemia at presentation, 3 in 5 (62.1%) were anemic at some point during their hospital stay, and 1 in 2 (54.5%) survivors were discharged from the hospital anemic. Anemia increased with illness severity and was more common in those with comorbid illnesses, female gender, and poor outcomes. Yet, even among men and in those with no comorbidity or only mild illness, anemia during hospitalization was common (~55% of subjects). When anemia was moderate to severe (≤ 10 g/dL), its development was independently associated with increased 90d mortality, even among hospital survivors.
Conclusions
Anemia was common in hospitalized CAP and independently associated with 90d mortality when hemoglobin values were 10 g/dL or less. Whether prevention or treatment of CAP-associated anemia would improve clinical outcomes remains to be seen.
doi:10.1186/1471-2466-10-15
PMCID: PMC2848211  PMID: 20233445
25.  Anemia in Heart Failure Patients 
ISRN Hematology  2012;2012:246915.
Heart failure is a very common disease, with severe morbidity and mortality, and a frequent reason of hospitalization. Anemia and a concurrent renal impairment are two major risk factors contributing to the severity of the outcome and consist of the cardio renal anemia syndrome. Anemia in heart failure is complex and multifactorial. Hemodilution, absolute or functional iron deficiency, activation of the inflammatory cascade, and impaired erythropoietin production and activity are some pathophysiological mechanisms involved in anemia of the heart failure. Furthermore other concomitant causes of anemia, such as myelodysplastic syndrome and chemotherapy, may worsen the outcome. Based on the pathophysiology of cardiac anemia, there are several therapeutic options that may improve hemoglobin levels, tissues' oxygenation, and probably the outcome. These include administration of iron, erythropoiesis-stimulating agents, and blood transfusions but still the evidence provided for their use remains limited.
doi:10.5402/2012/246915
PMCID: PMC3319993  PMID: 22536520

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