Your patient has been in the surgical ICU for three days with multiple long-bone fractures and contusions sustained in a motor vehicle accident. His hemoglobin and hematocrit are 10 gm/dL and 30%, respectively. Does the patient need to be transfused with packed red blood cells (PRBCs)? Should he receive epoetin alfa (Epogen) instead? Why is the patient anemic, and what is anemia of critical illness?

ACI is present in a majority of patients admitted to ICUs. With this diagnosis, the patient’s hemoglobin level can be expected to decrease an average of 0.5 gm/dL per day.¹ By the third day of an ICU admission, 95% of patients are anemic.^1,2,3 Recent studies report that 37% to 44% of patients receive at least one transfusion of PRBCs during their ICU stay.^2,4 Several prospective studies have linked higher mortality rates in ICU patients to those who received at least one blood transfusion during their stay compared to those not transfused. This finding remained after adjustment for acuity levels and individual patient factors.⁴

This module reviews the overall pathophysiology of ACI and examines the risk factors of and treatment options for this condition. It also addresses the potential complications of blood transfusions and the nurse’s role in caring for the patient with ACI. It’s important for the critical care nurse to recognize ACI as a distinct clinical entity that can be prevented through a multifaceted approach, which includes improving the nutritional status of ICU patients and decreasing phlebotomy-related blood loss.   

Pathophysiology and etiology

Anemia is not considered a separate disease entity but is rather a manifestation of an underlying disease process. The clinical consequences of anemia relate to the duration and intensity of the condition. Chronic anemias develop gradually and produce more subtle symptoms, such as lethargy, pallor, and anorexia. In contrast, acute anemias do not allow the body sufficient time to make physiologic adjustments, and patients are more likely to be symptomatic with shortness of breath, extreme fatigue, and cardiac discomfort.^1,2 

In general, anemia is attributable to three main causes: decreased production of red blood cells (RBCs) in the bone marrow, increased systemic destruction of RBCs, and acute or chronic blood loss. However, the specific etiology of ACI involves a unique pathophysiologic mechanism in which acquired nutritional risk factors play a role.¹

The pathophysiology of ACI resembles the process observed in anemia of chronic inflammatory illness and results in an inappropriately low production of RBCs by the bone marrow.¹ In this process, inflammatory mediators, also known as acute phase reactants, are triggered. Such acute phase reactants include fibrinogen, haptoglobin, and C-reactive protein.

The regulation of these mediators causes widespread systemic effects. One of the distinguishing features in ACI is that the kidney decreases erythropoietin production and the body’s response to circulating erythropoietin decreases. This results in decreased bone marrow production of mature RBCs and a subsequent anemia. Furthermore, iron transport from macrophage storage pools is blocked, resulting in the abnormal metabolism of iron in ACI.^5,6 This mechanism is likely responsible for low serum iron levels, an increased total iron binding capacity (TIBC), and elevated serum ferritin levels in more than 90% of ICU patients.¹ About 2% are also vitamin B12 and folate deficient.³ Decreased responsiveness of erythroid progenitor cells affects efforts to treat ACI as well. The reticulocyte response to exogenously administered erythropoiesis-stimulating agents (ESAs), such as epoetin alfa and darbepoetin alfa (Aranesp), is blunted in the face of ACI. Increased levels of circulating cytokines, stimulated in response to bacteria, viruses, and neoplasms affecting the critically ill patient, may also inhibit the action of ESAs.¹ Overall, the inflammatory response pattern of ACI may not be dissimilar to that in systemic inflammatory response syndrome.⁵

Risk factors

The acquired risk factors for ACI development are multifaceted and often overlapping. Such factors include blood loss from frequent phlebotomy or invasive procedures (placement of peripheral or central indwelling catheters and arterial monitoring devices); GI bleeding (acute or occult); acquired coagulation disorders (e.g., disseminated intravascular coagulopathy); multiple organ dysfunction; renal failure; nutritional deficiencies; and primary bone marrow disorders.⁶

Of these risk factors, blood loss through excessive phlebotomy particularly pertains to nursing care for the critically ill. More specifically, arterial blood gas (ABG) analysis is the most frequently ordered laboratory test in the ICU, followed by the chemistry profile, complete blood count, and coagulation studies.⁷ The frequency of phlebotomy positively correlates with the patient’s severity of illness.^2,4 In patients on whom ABGs are obtained, the procedure may account for up to 40% of the patient’s acute daily blood loss.⁷ In an ICU setting, the average blood loss per day from phlebotomy alone is 41 ml to 65 ml.^4,8 The average total blood loss per patient can vary from 762 ml to 944 ml depending on procedures performed, if an indwelling arterial catheter is in place, and if at least three ABGs are collected per day.⁸ As an alternative, using pulse oximetry and end-tidal carbon dioxide monitoring to evaluate a patient’s oxygenation and ventilation status can dramatically reduce blood loss through ABG analysis.   

Diagnosis of ACI

In ACI, a microcytic anemia (mean corpuscular volume less than 80 fL) is typically present, though macrocytic anemias are possible if folate or vitamin B12 deficiencies are coexistent or premorbid. Men are considered to be anemic when the hemoglobin level is less than 14 gm/dL (or hematocrit below 42%) and in women when the hemoglobin is less than 12 gm/dL (or hematocrit below 37%).⁹

The initial laboratory evaluation of anemia includes a complete blood count (CBC) with white blood cell (WBC) differential, a reticulocyte count (RC), a serum ferritin level, and a peripheral blood smear. In a CBC, the hemoglobin, hematocrit, RBC indices (MCV, MCH, MCHC, and stained exam of RBCs), and either a machine- or hand-counted differential count of WBCs are obtained. The RC is the percentage of new RBCs released into the peripheral circulation from the bone marrow on a daily basis; the normal amount released varies from approximately 0.5% to 2%.⁹ The serum ferritin level measures the iron stores in the reticuloendothelial system (monocytes and macrophages). It’s a more sensitive measure of total body iron than a serum iron level or TIBC. Inflammatory cytokines associated with ACI may increase the serum ferritin level threefold.¹ Therefore, the assessed value should be divided by three to obtain an accurate measure of iron stores.¹ The TIBC measures the amount of iron bound to transferrin, a transport protein synthesized by the liver that regulates iron absorption. 

Lastly, the peripheral blood smear allows visualization of the type, size, and shape of the RBCs, WBCs, and platelets present and indicates the effectiveness of erythropoiesis and overall bone marrow function. The lymphocyte count is useful as a measure of the body’s immune function. T-lymphocytes are responsible for cellular immunity, while B-lymphocytes (immunoglobins) are indicative of humoral immunity. Circulating levels of interleukin-1 and T-lymphocytes are also elevated in ACI.¹ Increased haptoglobin levels (greater than 25 mg/dL), considered an acute phase reactant, is another result of regulated cytokine production.¹⁰ Serum creatinine levels tend to rise when erythropoietin is underproduced by the kidney. However, elevated creatinine levels must be evaluated with regard to the patient’s age, sex, race, fluid status, and history of preexistent renal insufficiency. 

Management of ACI

In the management of ACI early recognition of the underlying etiology is necessary to individualize patient therapy. The goal of ACI treatment is to support the patient’s hematopoietic function and prevent iatrogenic complications (complications resulting from prescribed therapy). Interventions frequently include the administration of blood or blood products; the use of exogenous erythropoietin (epoetin alfa or darbepoetin alfa) to stimulate RBC production; maintaining adequate nutrition and iron supplementation; and minimizing blood loss from phlebotomy, diagnostic procedures, and monitoring devices.^10,11 Recommended practices include using small-volume phlebotomy tubes (pediatric tubes) and conserving blood with in-line “cell-savers” while obtaining blood samples, which reduce blood loss in critically ill patients by 50%.¹¹ Moreover, replacing standing orders for daily blood draws with individualized orders also helps to conserve blood.¹¹ 

ACI has traditionally been treated with PRBC transfusions when the hemoglobin concentration dips below 10 gm/dL or the hematocrit is less than or equal to 30% (i.e., 10/30). However, emerging evidence of decreased survival in critically ill patients who received blood transfusions has led to an initiative to reduce the number of transfusions in ICU patients.¹² National Institutes of Health blood transfusion guidelines recommend the use of a lower transfusion threshold, such as a hemoglobin level of 6 gm/dL to 8 gm/dL, and emphasize the importance of clinical decision-making based on assessment of the patient’s bleeding characteristics.¹² These guidelines also suggest transfusing patients when a higher hemoglobin level improves oxygen delivery. The critically ill patient with cardiac disease and a hemoglobin level of less than 9.5 gm/dL constitutes a gray area. Lower hemoglobin levels in patients with ischemic heart disease are associated with poorer outcomes.⁹ Studies have indicated a survival benefit when blood transfusion occurs with the usual 10/30 trigger in such patients.⁹ 

The administration of blood is not without risk. Potential complications include anaphylactic shock, infection, immunosuppression, impairment of the microcirculation, and 2,3-diphosphoglycerate deficiency related to PRBC storage.⁸ The age of transfused blood is another concern and has been associated with a decline in gastric pH, the development of pneumonia, increased RBC fragility, and decreased ability of hemoglobin to offload oxygen.⁸ Blood stored for more than 14 days is an independent risk factor for the development of multiple organ failure.¹² Transfusion-related acute lung injury (TRALI) is a well-documented though relatively rare complication of blood transfusion.¹⁴ The reported incidence is approximately 1 per 5,000 units of transfused blood.¹⁴ TRALI may be misdiagnosed as anaphylaxis, circulatory overload, or cardiac failure unrelated to transfusion.⁸ (See table for potential complications related to RBC transfusion.) To prevent transfusion-related reactions (rash, rigors, fever, or swelling of the face or airway structures), patients may be premedicated with acetaminophen (Tylenol) and diphenhydramine hydrochloride (Benadryl).

Additional management of ACI may include the use of ESAs. ESAs are growth factors that stimulate stem cells to increase RBC production. The benefits of ESA therapy that have been observed in other patient populations include a decreased need for transfusion by 50% of treated cancer patients, improved quality of life scores in patients with chronic renal failure, decreased intraoperative transfusion requirements in orthopedic patients, and decreased prevalence of anemia in patients with HIV.¹⁵ Furthermore, ESAs stimulate RBC production in ACI and reduce the need for transfusion. Administration of epoetin alfa for five days at a dose of 300 U/kg, followed by every-other-day dosing, reduces transfusion need by 50% and significantly increases hematocrit levels.¹⁵ Researchers analyzed subgroup survival in surgical trauma patients and in surgical and medical nontrauma ICU patients.¹⁶ They identified a trend toward higher mortality in the surgical trauma and nontrauma patients (10.4%) who had received RBC transfusions compared to patients who received epoetin alfa therapy plus transfusion (4.8%).¹⁶  However, to date, no large-scale study has definitively established a survival benefit in patients receiving epoetin alfa therapy vs. blood transfusion.

Although the benefits of ESA therapy are many, recent studies of ESAs also have shown a higher chance of serious and life-threatening side effects and greater number of deaths in patients treated with these agents.¹⁷

Maintaining adequate nutrition is also required to prevent and manage ACI. It is imperative to meet the patient’s required caloric and protein needs and to preserve sufficient body stores of iron, folate, niacin, thiamine, zinc, and vitamins B12, C, A, and K. For patients with normal GI tract functioning and who are not intubated or sedated, providing a complete diet is important. If unable to accept oral intake, enteral feeding through a gastrostomy or jejunostomy tube is the preferred route. Nutritional preparations are tailored for the patient’s individual needs based on preexisting disease, such as chronic renal failure, diabetes mellitus, and cardiopulmonary disease, that may require dietary adjustments. Nutritional preparations for critically ill and stressed patients are rich in protein, glutamine, arginine, selenium, and vitamins C, E, and A.¹⁷ Total parenteral nutrition (TPN) administered through a central venous catheter may be required, either as the sole source of nutrition when the GI tract is nonfunctioning or as a supplement to enteral feedings. TPN contains a highly concentrated dextrose solution mixed with amino acids, lipids, electrolytes, vitamins, mineral, and trace elements.¹⁸ 

Preventing ACI in the preoperative and intraoperative patient is also an emerging concept. Autologous blood donation to reduce postoperative anemia may be an option for patients undergoing elective surgery. Furthermore, preadmission treatment of anemic patients with erythropoietin and the intraoperative use of blood substitutes and “cell saver” devices reduce postoperative and ICU mortality and morbidity in surgical patients. Intraoperative cell salvage techniques are regularly used and have reduced allogeneic transfusion requirements by 23% in elective surgery.¹⁹

Nursing interventions

Critical care nurses play an important role as advocates for the most severely ill patients in a hospital setting. As such, recognition of a progressive ACI falls within the domain of critical care nurses, as they often are responsible for daily monitoring of patients’ hemograms (hemoglobin and hematocrit). Nursing documentation of blood loss during phlebotomy and procedures is essential for preventing worsening ACI in these high-risk patients. The amount of blood drawn and estimates of incidental blood loss should be documented on the critical care flow sheet. Early intervention to minimize acute and preventable blood loss via procedures and reminding fellow care providers of the importance of exogenous erythropoietin are important nursing functions. 

Furthermore, nurses frequently interact with family members and can use these opportunities to inform them about bloodless treatment options, such as epoetin alfa and darbepoetin alfa, used to improve patient outcomes. In addition, activity tolerance is monitored by symptom assessment, pulse and respiratory rate measurement, and oxygen requirements as patients progress. Patients with weakness and fatigue and those unable to ambulate should be assisted with active or passive range of motion exercises. The patient and family should be cautioned about the risk of fainting or near-syncopal episodes that may occur as a result of weakness and fatigue after ICU discharge. 

Patients with ACI are at risk for inadequate tissue oxygenation, secondary to decreased red blood cell mass. Nursing assessment of these patients focuses on assessing for shortness of breath, palpitations, dizziness, and chest pain, and monitoring for neurological signs that may be evident in anemic patients, such as difficulty concentrating, gait disturbances, and irritability.

The reliance on indwelling arterial catheters to obtain frequent ABGs on stable patients requires scrutiny by nurses as part of the health care team. Noninvasive pulse oximetry for monitoring oxygen saturation levels and end-tidal carbon dioxide monitoring should be integral components of an ICU blood conservation program. Transitioning patients from mechanical ventilation to T-pieces, face masks, and nasal cannula therapy reduces extraneous blood loss because ABG analysis is less frequent.

It’s also the nurse’s responsibility to understand that ICU patients often suffer from iron deficiency and other nutritional abnormalities that contribute to the development of ACI. Addressing the patient’s nutritional needs requires a multidisciplinary approach to avoid factors that increase the patient’s risk of malnutrition. Such risk factors include delayed and insufficient monitoring of a patient’s nutritional parameters and inadequate use of nutritional supplements, tube feedings, and TPN. Recording daily weights and assessing serum albumin, prealbumin, and lymphocyte counts are particularly important in detecting nutritional imbalances. The nutritional status of critically ill patients can decline in as quickly as three days because of the physiologic effects and metabolic demands of fever, infection, trauma, respiratory failure, and wound healing.¹⁸ Enteral feeding is an effective means of providing nutrition if patients have a functioning GI tract and are continually re-evaluated.

Astute critical care nurses should alert other providers of the presence of medications in the patient’s regimen that have the potential for bone marrow toxicity and inhibition of bone marrow activity. These medications alone or in combination with other risk factors can contribute to ACI. Nurses and other health care providers must assess the risks and benefits of continuing the offending medication. (See table for selected medications with potential for bone marrow suppression). 

ACI occurs frequently and is considered a distinct clinical entity. The quality of life experienced by patients discharged from an ICU is significantly reduced for many months, but information concerning the long-term impact of ACI is lacking.²² Decreased use of blood transfusions and increased use of other treatment measures, such as exogenous erythropoietin, limiting blood loss through phlebotomy and procedures, improved nutrition, pulse oximetry rather than exclusive reliance on ABGs, and use of blood substitutes may improve outcomes of patients with ACI. Preventing anemia will likely decrease overall morbidity and mortality and improve the functional status of the patient. As the best practices for the prevention and management of ACI continue to emerge, critical care nurses must incorporate evidence-based research findings into practice and participate in future research endeavors to learn more about this condition.