journal in anemia and bt

7/27/2019 Journal in Anemia and BT

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SYSTEMS PLUS COLLEGE FOUNDATION

Balibago, Angeles City

College Of Nursing

A.Y. 2012-2013

In Partial Fulfillment

Of the Requirements in

NCM 106-RLE

Current Trends in Managementof

Diabetes MellitusSubmitted To:

Jessica C. Sanchez, RN, MAN

Submitted By:

Ma. Cresencia S. Buenafe

NUR70A

Date Of Submission:

August 16, 2013


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Diabetes Management- Future Trends

June 2, 2013 12:01:15 AM | By DR. SHASHANK R JOSHI

Free Press Journal

Research in the diabetes field has taken two main directions: innovations aimed at improving current

management methods, and exploring radical new approaches, writes DR. SHASHANK R JOSHI.

There has been a considerable rise in prevalence of Diabetes across the world. As per the world health

statistics 2012, one in every 10 adults is diabetic with figure increasingly rising among the youth due to

unhealthy lifestyle and lack of exercise in their daily routine.The rising trend of weight gain coupled with

lack of physical exercise and high level of mental stress in school going children acts as a precursor of

future diabetes in them at a younger age particularly in those children who also have a family history of

diabetes.

More than 346 million people worldwide are currently suffering from diabetes; and this malady is

predicted to become the seventh leading cause of death in the world by the year 2030.

Unfortunately, India has one of the largest number of diabetic patients in the world (62.4 million people

live with diabetes in India & there are 77.2 million people with pre-diabetes). Currently India is facing an

epidemic of diabetes, with a high prevalence in urban areas.

The need to better manage and control the rapid rise of diabetes has led to innovations in diabetes

monitoring and management therapies to help patients and physicians to better manage the chronic

disease with more scientific and accurate results.

People with type 1 diabetes and many people with type 2 disease require treatment with insulin to control

blood sugar and reduce the risks of complications, including blindness, heart disease and nerve damage
http://freepressjournal.in/diabetes-management-future-trends/diabetes-management-future-trends/


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leading to amputations. The main aim of treatment of diabetes is to achieve blood glucose in order to

prevent acute and chronic complications, improve quality of life and avoid premature diabetes associated

deaths.

Research in the diabetes field has taken two main directions: innovations aimed at improving current

management methods, and exploring radical new approaches. Improvements in current therapy includemaking glucose monitoring and insulin delivery less invasive and more patient-friendly, and many

significant advances have been made in this context in the past two decades.

Among these have been the developments of improved glucose monitoring techniques and minimally-

invasive techniques for sampling blood. New, fast-acting forms of insulin have also been introduced along

with novel, and more accurate, ways of insulin delivery through the use of insulin pumps. There has also

been considerable research in non-injection dosage forms for insulin, such as inhalable insulin, although

products are not approved and pending more clinical data.Once approved, this could herald a new era in

Insulin Therapy.

Recent Trends in Diabetes Monitoring and Diagnosis: Blood sugar of a person without diabetes is

maintained by the body within a normal range irrespective of the amount of food that is consumed by a

person. In patients having diabetes, blood sugar spikes within an hour after any meal. This process goes

on throughout the day. So the blood sugar of a person with diabetes is continuously changing every

minute of the day throughout the persons life.

Patients may use glucometers to check blood sugar, but this gives the value of blood sugar only at the

particular time when the test is done. However, since blood sugar levels of a patient are changing from

minute to minute, checking simply with Blood Glucose Meters may not be sufficient

However a more effective way to monitor sugar levels to understand how the blood sugar is changing

throughout the day is with the help of a technology called Continuous Glucose Monitoring System

(CGMS), which is now also available in India. CGMS is done with the monitor (like ipro 2 etc.) which is

attached to the abdominal wall. It reads the sugar levels of the person every 10 seconds and keeps a

record every five minutes so that we can get 288 readings per day during the CGMS study period. This

data is uploaded on a computer and the data is clearly visible in the form of a graph which any one can

understand.

The patient gets to see how his or her blood sugar has moved after each and every meal of the day. This

gives the person a clear idea as to how much the blood sugar has risen after a particular meal. The

patient can then take corrective measures regarding food intake. The doctor can make out how a

particular patients blood sugar is changing throughout the day. With this information the doctor can

modify the treatment to get better control of blood sugar throughout the day.

HbA1c (Glycosylated Hemoglobin) is a very useful test to detect how well blood sugar is controlled over

the previous three months. HbA1c indicates the average blood sugar and so it does not give a correct

picture of how much fluctuation occur. In fact, if a patient has frequent low blood sugar, it could result in

low HbA1c (because HbA1c denotes an average value) and a false sense of security to the patient and

doctor, even when the blood sugar is often high and is actually poorly controlled. CGMS is a useful tool to

detect this disease.


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Another new upcoming diabetes monitoring approach is the use of Implantable Chips. A microchip can

detect the amount of glucose in a persons blood and will then transmit this information to a wireless

scanner where it can be easily read by the patient. All it will require are some basic instructions, and

monitoring ones own glucose level with this product will be simple and accurate. This innovative little

device serves as an alternate for the aid of glucose monitoring.

Recent Trends in Diabetes Management: Insulin therapy is one of the cornerstones of diabetes

management, and its efficacy in early and in late-stage diabetes is well-established. Yet, the first choice

of doctors in India for most diabetics has so far been to attempt sugar control through OADs (Oral Anti-

Diabetics), diet control, exercise and lifestyle changes. One of the key reasons for delaying control

through insulin is the resistance and fear in patients, of taking injections daily, particularly self-

administering the same.

For Type 1 Diabetes where insulin is required to manage the condition, the traditional diabetes

management is done by delivering insulin through Multiple Daily Injection (MDI) through devices such as

Insulin pens and Insulin Injections are also available for self-management for Diabetes in India.

An excellent alternative to multiple daily injections is Insulin Pump Therapy. By using an insulin pump,

patients can match their insulin to their lifestyle rather than trying to adjust their lifestyle to their bodys

response to insulin injections. People of all ages, who require insulin to manage their diabetes, can get

benefit from this novel therapy.


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Reaction and Recommendations

When it comes to type 2 diabetes, the most common type of diabetes prevention is a big

deal. It's especially important to make diabetes prevention a priority if you're at increased risk of

diabetes, for example, if you're overweight or have a family history of the disease.

Diabetes prevention is as basic as eating more healthfully, becoming more physically

active and losing a few extra pounds and it's never too late to start. Making a few simple

changes in your lifestyle now may help you avoid the serious health complications of diabetes

down the road, such as nerve, kidney and heart damage.

I recommend people with DM should get more physical activity. There are many benefits

to regular physical activity. Exercise can help you lose weight, lower your blood sugar and boost

your sensitivity to insulin, which helps keep your blood sugar within a normal range

Research shows that both aerobic exercise and resistance training can help control

diabetes, but the greater benefit comes from a fitness program that includes both.

Another would be to get plenty of fiber, it's rough, it's tough but it may help you to reduce

your risk of diabetes by improving your blood sugar control and lower your risk of heart disease

and promote weight loss by helping you feel full. Foods high in fiber include fruits, vegetables,

beans, whole grains, nuts and seeds.

I also recommend going for whole grains. Although it's not clear why, whole grains may

reduce your risk of diabetes and help maintain blood sugar levels. Try to make at least half your

grains whole grains. Many foods made from whole grains come ready to eat, including various

breads, pasta products and many cereals. Look for the word "whole" on the package and

among the first few items in the ingredient list.

You may also have to lose extra weight. If you're overweight, diabetes prevention may

hinge on weight loss. Every pound you lose can improve your health, and you may be surprised

by how much. Participants in one large study who lost a modest amount of weight around 7

percent of initial body weight and exercise regularly reduced the risk of developing diabetes by

almost 60 percent.

And lastly, I recommend skipping fad diets and just making healthier choices. Low-carb

diets, the glycemic index diet or other fad diets may help you lose weight at first, but their

effectiveness at preventing diabetes isn't known nor is their long-term effects. And by excluding


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or strictly limiting a particular food group, you may be giving up essential nutrients. Instead, think

variety and portion control as part of an overall healthy-eating plan.

You also have to share your concerns about diabetes prevention with your doctor. He or she will

applaud your efforts to keep diabetes at bay, and perhaps offer additional suggestions based on your

medical history or other factors.


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SYSTEMS PLUS COLLEGE FOUNDATION

Balibago, Angeles City

College Of Nursing

A.Y. 2012-2013

In Partial Fulfillment

Of the Requirements in

NCM 106-RLE

Journal about Anemiaand

Blood TransfusionSubmitted To:

Jessica C. Sanchez, RN, MAN

Submitted By:

Ma. Cresencia S. Buenafe

NUR70A

Date Of Submission:

August 16, 2013


8/19


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A number of studies have identified potentially correctible nutritional deficienncies in critically ill patients,

including deficiencies of iron, B12, and folate. These deficiencies can lead to ineffective erythropoiesis with

resultant anemia [9, 10].

Decreased erythropoietin production and/or impaired bone marrow response to erythropoietin may also play an

important role in the development of anemia [11]. These effects are mediated by a variety of inflammatory

cytokines such as Interleukin-1 (IL-1) and tumor necrosis factor- (TNF-), which inhibit erythropoietin (EPO)

production. Furthermore IL-1, IL-6, and TNF- suppress erythropoiesis by direct inhibitory effects on bone marrow

[12].

The hyperadrenergic state following severe injury may also induce bone marrow dysfunction and failure of

erythropoiesis. This effect may be mediated by IL-6 and interferon- (IFN-), which are released following severe

injury and have been shown to inhibit the differentiation and proliferation of erythroid precursor cells [13].

In addition increased levels of hepcidin, an iron regulatory hormone, have been purported to play an important

role in the development of anemia of chronic disease (ACD) [1416]. The most common causes of ACD are acute or

chronic inflammatory conditions such as infections, cancer, autoimmune diseases, and chronic kidney disease

(CKD) [17]. It is characterized by sequestration of iron in macrophages, hypoferremia, and iron-restricted

erythropoiesis. ACD is associated with elevated levels of inflammatory cytokines, including IL-1, IL-6, and IFN- [18].

These cytokines induce excess hepcidin production, which has been shown to downregulate ferroportin, an iron

export protein on the cell surface of duodenal enterocytes, macrophages, and hepatocytes [19, 20]. Thus high

serum levels of hepcidin decrease intestinal iron absorption and block iron export from tissue stores, resulting in

functional iron deficiency [14, 21, 22].

3. Impact of Anemia on Outcomes in Critically Ill Patients

3.1. Anemia and Cardiac Disease

Numerous recent studies have shown anemia to be associated with worse outcomes in patients with coronary

artery disease. After reviewing the data on nearly 40,000 patients enrolled in trials on acute coronary syndrome

(ACS) Sabatine et al. found anemia to be associated with a greater likelihood of death in patients with ST-segment

elevation MI (STEMI) and non-ST-segment elevation MI (NSTEMI) [23]. These investigators also found an increased

association of anemia with recurrent ischemia or acute MI in patients with NSTEMI. Aronson et al. found that

lower nadir hemoglobins in hospitalized patients following MI were strongly associated with increased mortality

[24].

Kulier et al., in a study of 5065 patients who underwent coronary artery bypass grafting (CABG), found

preoperative anemia and intraoperative blood transfusion to both independently be associated with adverse

postoperative neurologic and renal outcomes [25]. In another study of over 6,000 patients undergoing

percutaneous intervention, anemia was found to be independently associated with both short-term cardiovascular

events and decreased 1-year survival [26].

3.2. Anemia and Respiratory Failure

Respiratory dysfunction has also been associated with anemia in the critically ill.

Rady and Ryan in a retrospective study of cardiac surgery patients found anemia (defined as a hematocrit 10 units of blood products) to be significantly associated with the need for

reintubation [27].
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Khamiees et al. in a prospective observational study found anemia (Hgb < 10 g/dL) to be associated with

extubation failure in a mixed medical-surgical ICU population [28]. Nevins and Epstein found anemia (mean

hematocrit 36) to be associated with poor outcomes in a retrospective study of 166 patients with chronic

obstructive pulmonary disease (COPD) receiving mechanical ventilation [29]. Although, data exists showing anemia

to be associated with poorer outcomes in mechanically ventilated patients, no significant literature supports the

transfusion of PRBC to facil itate weaning patients from mechanical ventilation [30].

3.3. Anemia and Sepsis

Anemia is also a common occurrence in the setting of sepsis [31]. This is in part because mediators of sepsis (e.g.,

TNF- and IL-1) decrease expression of the erythropoietin gene and protein [32]. The early-goal-directed therapy

trial reported by Rivers et al. and the transfusion requirement in critical care Trial (TRICC) performed by Hebert et

al. used two different transfusion strategies in critically ill patients [31, 33]. Rivers et al. showed that correcting

anemia by transfusing to a hematocrit >30% in early sepsis was associated with improved outcome when included

as part of a broader resuscitation regimen [33]. However, it must be remembered that this was one of a number of

interventions as part of an early goal directed protocol. It is unclear how much of the improvement in outcome can

be attributed to transfusion alone. In the TRICC trial, subgroup analyses of older or more severely ill patients

showed no difference in 30-day mortality between the restrictive-strategy and liberal strategy groups. Younger

and less ill patients had better outcomes if transfused in a more restrictive manner (i.e., at lower hemoglobin) [31].

4. Indications for Transfusion

4.1. Transfusion and Tissue Hypoxia

The goal of packed red blood cell transfusion in the critically ill is to increase oxygen delivery to and hence

consumption by tissues. An increase in hemoglobin should improve patients oxygen carrying capacity and help

deliver oxygen to hypoxic tissues. Lactate, a clinically used surrogate of tissue hypoxia, should decrease with

improved oxygen consumption. An abundance of literature over the past thirty years demonstrates that thisclinical benefit is frequently not realized with transfusion in the critically ill. Shah et al. described their experience

with 8 trauma patients who were transfused to a hemoglobin of 10 and had increased oxygen delivery but no

increase in oxygen consumption [34]. Dietrich et al. in a larger study in the early nineties transfused volume

resuscitated critically ill patients to a hemoglobin of 10 g/dL *35]. These patients again had increased calculated

oxygen delivery but no increased oxygen uptake, no decrease in lactate, and no increase in cardiac index.

Silverman and Tuma used intramucosal gastric pH, a marker for adequacy of tissue oxygenation, to demonstrate

that transfusion was inferior to dobutamine in improving oxygen delivery to the splanchnic circulation [36]. Marik

and sibbald evaluated 23 critically ill patients with sepsis in a prospective study and demonstrated that transfused

patients had no increase in oxygen uptake [37]. Furthermore, they demonstrated that blood older than 15 days

decreased patients gastric intramucosal pH, suggesting an impairment in systemic oxygen delivery at the cellularlevel. Mazza et al. in a prospective study in 2005 showed that transfusing patients to a hemoglobin above 9 g/dL

was not associated with a significantly decreased lactate or increased mixed venous oxygen saturation, indication

no benefit in meeting previously unmet tissue oxygen needs [38]. These studies raise the question: why does the

transfusion of packed red blood cells frequently not relieve tissue hypoxia?

The mean age of blood transfused in the USA is 17.9 days and extensive literature exists about age-related changes

of packed red blood cells [2]. Stored blood cells have decreased amounts of 2,3-diphosphoglycerate which shifts

the oxygen disassociation curve to the left, decreasing hemoglobins ability to unload oxygen at the tissue
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level.Stored erythrocytes have been shown to lose their deformability resulting in increased aggregation,

hemolysis, and the subsequent release of systemic factors associated with organ dysfunction [39, 40]. Fitzgerald et

al. demonstrated in rats that transfused blood which was less than 3 days old was associated with an increased

systemic oxygen uptake as opposed to blood that was 28 days old [41]. Zallen et al. demonstrated that an

increased mean age of blood, especially an age of stored blood greater than 2 weeks, was associated with multiple

organ failure [42].

5. Complications of Transfusion

5.1. Infection

Historically, the AIDS crisis forced the critical care community to revaluate the benefits of blood transfusion in the

ICU. Due to these concerns blood is now screened for a variety of viral and bacterial infections including HIV and

Hepatitis A, B, and C. In the United Kingdom, the risk of acquiring infection due HIV secondary to transfusion is less

than one in 2 million [43].

The transmission of infection is only one of the ways blood can affect its potential recipient. In the early seventies,

it was observed that renal transplant patients who received a transfusion prior to transplant had increased

allograft survival. This finding led to further postulation in the medical literature that the transfusion of blood

might affect the recipients immune system. Over the past forty years numerous studies have evaluated the affect

of transfusing on transplant survival, cancer recurrence, and host predisposition to infection [44].

Taylor et al., in a retrospective study of 1711 patients demonstrated that transfused patients were six times more

likely to develop a nosocomial infection than nontransfused patients [45]. In addition, each unit of PRBC transfused

increased patients odds of developing infection by 1.5. Claridge et al. demonstrated in a prospective study of 1593

trauma patients that 33.6% of transfused patients developed infection versus 7.6% patients who did not receive

transfusions [46]. They also showed that a linear, dose-response pattern existed, as patients who received more

PRBC were more likely to develop infection. Univariate analysis of their data showed that the strongest predictor

of developing infection was the transfusion of PRBC in the first 48 hours. Shorr et al. conducted an important

secondary analysis of the CRIT study involving 284 ICUs and 4,892 patients to evaluate for blood stream infections

(BSIS) in the critically ill [47]. These investigators demonstrated that three factors were associated with new BSI in

the ICU: the initial use of cephalosporins, higher sequential organ failure assessment score, and PRBC transfusion.

The importance of their work is that the data came from multiple ICUs unlike single-center studies mentioned

previous and the patient populations were heterogeneous. Shorr et al. did another secondary analysis of the CRIT

study and demonstrated that both small (1-2 units) and large (>2 units) volume transfusions were independent risk

factors for the development of ventilator-associated pneumonia [48]. In cardiac surgery patients the transfusion of

PRBC has been similarly associated with increased risk of infection [30]. However, Ali et al. in a prospective, single-

center study of 234 patients demonstrated that PRBC was not associated with increased risk of infection in

postoperative cardiac surgery patients [49]. Multiple large well-designed trials suggest that PRBC predispose

patients to infection likely to due the immunomodulation of the patients immune system, but as Ali et al. study

demonstrates that debate in this area still exists.

5.2. Transfusion-Related Acute Lung Injury (TRALI)

This is a clinical syndrome that presents as acute hypoxemia and noncardiogenic pulmonary edema generally

occurring within six hours of a transfusion [50]. The incidence varies and is estimated at 1 in 5,000 blood and blood

components [51]. According to an FDA report presented at the TRALI conference in 2004, it is now the leading
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cause of transfusion-related death in the United States. TRALI is characterized by increased pulmonary

microvascular permeability. Leukocyte antibodies and biologically active substances such as lipids and cytokines

are thought to be responsible for this increased permeability [52, 53].

6. Impact of Blood Transfusion on Clinical Outcomes

6.1. Large Studies about Transfusion Outcome

A growing body of evidence now suggests that correcting anemia by transfusion often either provides no benefit or

is harmful. The TRICC trial showed a significant increase in cardiac and pulmonary complications and a trend

toward increased mortality in the liberal transfusion group during patients intensive care stay. In subgroup

analysis, younger (age < 55 yrs) or less critically ill (APACHE II scores < 20) patients randomized to a liberal strategy

had a statistically significant increase in mortality [31].

The CRIT study found that the number of blood transfusions was independently associated with both length of stay

and mortality in ICU patients [2]. A cohort analysis within the CRIT study found blood transfusion to be

independently associated with development of acute respiratory distress syndrome (ARDS) [54].

In 2002, Vincent et al. published a prospective observational study (Anemia and Blood Transfusion in Critically Ill

Patients ABC) evaluating the blood sampling, hemoglobin levels, and transfusion rates in 146 Western European

ICUs [3]. They concluded that receipt of a blood transfusion increased a patients odds of dying and increased

patients length of stay in the ICU. In 2008, Vincent el al. published another prospective observational study that

included 198 European ICUs [55]. This study showed that transfused patients had a lower mortality than

nontransfused patients at 30 days when patient populations were matched by propensity scores. Significant

debate exists about the use of a propensity score for statistical analysis including the inability to balance

unmeasured clinical variables in the studied populations [56]. Vincent et al. have spurred further debate about the

need for another prospective trial comparing a liberal versus conservative blood transfusion strategy in the

critically ill, especially in the era of leukodepletion of PRBC transfusions.

6.2. Transfusion Impact on Cardiac Disease

Data from the initial TRICC trial demonstrated that patient in the liberal transfusion arm (i.e., those transfused at a

threshold hemoglobin of 9 g/dL versus 7 g/dL for the restrictive group) had a higher incidence of both pulmonary

edema and MI [31].Subsequently, a subgroup analysis of patients from the TRICC trial with heart disease failed to

demonstrate any significant mortality outcomes between groups. However, patients in the liberal transfusion

group had a greater incidence of organ dysfunction [57].

Wu et al. reviewed Medicare data on almost 79,000 patients aged >65 years admitted with a diagnosis of acute MI

[58]. They found an association between blood transfusion and improved survival when admission hematocrit was

33%, and patients with hematocrit >36% who were

transfused had an increased risk of death compared with nontransfused patients.Yang et al. found that blood transfusion was a risk factor for death and the combined end point of death or MI in

patients with non-ST-elevation ACS [59].

Rao et al. found a similar association with blood transfusion for patients with ACS for hematocrits more than 25%

[60]. Below this value there was no difference in mortality between transfused and nontransfused patients.

Sabatine et al. [23] found differing results for patients with STEMI and those with non-ST-elevation ACS. Patients

with STEMI and hemoglobin levels


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Numerous studies in cardiac surgery patients have identified blood transfusion to be independently associated

with increase in infectious complications, myocardial infarction (MI), stroke, renal failure, prolonged mechanical

ventilation, atrial fibrillation, hospital length of stay, and mortality [6163].

6.3. Blood Conservation

Patients in the ICU on average have 41ml of blood drawn over a 24-hour period with sicker patients requiring morefrequent blood draws leading to even greater blood loss [3]. Older literature has estimated that patients with an

arterial catheter could lose greater than 900 mL during their stay [64]. Educational programs about reduced

sampling, point of care testing, and closed arterial line system have all been recommended [3].

6.4. Alternatives to Transfusion

Ideally, mechanisms would exist to decrease or eliminate the need of blood transfusion altogether. Critically ill

patients with anemia have been shown to have an inappropriately low erythropoietin response to their disease

[65]. Corwin et al. in two studies demonstrated that transfusion requirements were decreased in critically patients

treated with erythropoietin. However, in their third study erythropoietin treatment did not significantly alter the

rate of transfusion in the critically ill. Mortality was nonsignificantly different in the medical population, but

significantly lower in trauma patients at 140 days, although this decrease in mortality was unrelated to any

difference in transfusion rates in the groups that received and did not receive erythropoietin. This observation led

the authors to hypothesize that erythropoietin decreases mortality in trauma patients by mechanisms other than

the reduction in PRBC requirements [66]. Erythropoietin is not recommended in critically ill medical patients unless

other medical indications exist and can be used in trauma patients who will be in the ICU for greater than 48 hours.

Another mechanism for reducing PRBC transfusion is artificial oxygen carriers or hemoglobin substitutes.

Hemoglobin substitutes can be divided into two categories, perfluorocarbons and modified hemoglobins.

Perfluorocarbons transport both oxygen and carbon dioxide but require patients to be on 100% oxygen. The

advantages of perfluorocarbons over PRBC are their lack of potential infection transmission and their long half-

lives. They have been shown to decrease the need for blood transfusions in patients with elective noncardiac

surgeries. Further studies need to be done to determine their utility in the critically ill [67].

Although, bovine, old human, and recombinant-based hemoglobin-based oxygen carriers (HBOC) have been

heavily researched for thirty years only one HBOC is approved for clinical use. Hemopure

(Biopure http://www.biopure.com/) was approved in 2001 to help reduce the amount of blood transfusion in

anemic surgical patients in South Africa. The utility of these hemoglobin-based blood products currently is thought

to be the ability to decrease allogenic PRBC transfusion and provide a blood substitute in situations where blood is

unavailable (combat). Significant debate exists as to whether there are more myocardial infarctions in patients

who receive HBOC as one meta-analysis suggested [68]. The National Heart, Lung, and Blood Institute in 2006

convened a conference to examine the difficulties with the development of HBOCS. The results of the conference

were that HBOC show potential to have clinical utility, but concerns over side effects have impeded their approval

by regulatory agencies [69].

Conflict of Interests

The authors declare that they have no conflict of interests.
http://www.hindawi.com/journals/jbt/2012/629204/#B61http://www.hindawi.com/journals/jbt/2012/629204/#B61http://www.hindawi.com/journals/jbt/2012/629204/#B63http://www.hindawi.com/journals/jbt/2012/629204/#B3http://www.hindawi.com/journals/jbt/2012/629204/#B64http://www.hindawi.com/journals/jbt/2012/629204/#B3http://www.hindawi.com/journals/jbt/2012/629204/#B65http://www.hindawi.com/journals/jbt/2012/629204/#B66http://www.hindawi.com/journals/jbt/2012/629204/#B67http://www.biopure.com/http://www.hindawi.com/journals/jbt/2012/629204/#B68http://www.hindawi.com/journals/jbt/2012/629204/#B69http://www.hindawi.com/journals/jbt/2012/629204/#B69http://www.hindawi.com/journals/jbt/2012/629204/#B68http://www.biopure.com/http://www.hindawi.com/journals/jbt/2012/629204/#B67http://www.hindawi.com/journals/jbt/2012/629204/#B66http://www.hindawi.com/journals/jbt/2012/629204/#B65http://www.hindawi.com/journals/jbt/2012/629204/#B3http://www.hindawi.com/journals/jbt/2012/629204/#B64http://www.hindawi.com/journals/jbt/2012/629204/#B3http://www.hindawi.com/journals/jbt/2012/629204/#B63http://www.hindawi.com/journals/jbt/2012/629204/#B61


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