TRICC study: No benefit and possibly harm for transufusions in the less ill and the young. No benefit but no arm in other categories. Rec. transfuse unstable angina and myocardial infarction at less than 10, other groups less than 7 to keep between 7 and 9 (NEJM 1999;340 (6):409)
subgroup analysis in trauma patients showed both groups did the same
Subgroup of cardiac patients reported from above trial (Crit Care Med 2001;29(2):227) folks did better with restrictive policy unless active ACS/MI
In 1999, Hebert et al. (1) published the results of a randomized controlled study that compared the outcomes of critically ill patients managed with a liberal blood transfusion strategy (hemoglobin concentration kept at >10 g/dL as was general practice at the time) with a restrictive transfusion practice (hemoglobin concentration maintained at >7 g/dL). Patients in the liberal group received a mean of 5.6 units of RBCs, compared with 2.6 units in the restrictive group (p < .01). ICU and hospital mortality rates were lower in the restrictive group, but the differences were only significant for hospital mortality (22 vs. 28%, p = .05). In the subgroups of patients with lower Acute Physiology and Chronic Health Evaluation II scores (<20) and younger age (<55 yrs), mortality rates were notably lower in the restrictive group than the liberal group. The authors concluded that hemoglobin concentrations should be maintained between 7.0 and 9.0 g per deciliter (1). Indeed, this study provided the kick-start to a complete rethink of transfusion strategies in the ICU, further fuelled by data from observational studies that suggested worse outcomes in patients who received blood transfusions (2, 3). The ABC study (2) reported higher ICU (19 vs. 10%, p < .001) and overall (29 vs. 15%, p < .001) mortality rates in patients who had received a blood transfusion than in those who had not. Additionally, in matched patients in a propensity analysis, the 28-day mortality rate was 22.7% among patients with transfusions and 17.1% among those without (p = .02). The CRIT study showed that the number of RBC transfusions a patient received during the study was independently associated with longer ICU and hospital lengths of stay and an increase in mortality (3).
Interestingly, just as the intensive care world had begun to get used to the idea that smaller may be better in terms of hemoglobin concentrations, the SOAP study, evaluating 3,147 patients in 198 ICUs across Europe in May 2002, reported that, unlike the earlier ABC (2) and CRIT (3) studies, blood transfusion was not associated with increased mortality in multivariate analysis or by propensity case matching (20). The ABC and SOAP studies were very similar in design and analysis, so what could explain these apparently conflicting results from two similar studies conducted just 3 yrs apart.
One possible explanation is the increased use of deleukocyted blood since the ABC study was conducted. Blood transfusions are associated with various risks linked to the white blood cell component of the transfusion, and if this is removed could some of these risks be reduced? Leukoreduction is a process in which the white cells are intentionally reduced in number through centrifugation or filtration. Leukocyte counts can be reduced by >99%, and the technique is effective in reducing the transmission of cell-associated viruses, especially cytomegalovirus, herpes viruses, and Epstein-Barr virus (34). Leukoreduction may also reduce parasite and prion transmission, transfusion-related febrile reactions, and transfusion-related acute lung injury. Several randomized controlled studies have evaluated the effects of leukoreduction in various groups of patients (Table 3), although no randomized controlled trial has compared leukoreduced blood with nonleukoreduced blood in critically ill patients. In a before-after cohort study of 14,786 patients who received RBC transfusions following cardiac surgery or repair of hip fracture, or who required intensive care following a surgical intervention or multiple trauma, transfusion of leukoreduced blood was associated with fewer febrile reactions and reduced posttransfusion antibiotic use (35). In a meta-analysis of 14 randomized controlled trials comparing standard blood with leukoreduced or autologous blood, Vamvakas (36) reported no consistent effect of leukoreduction on long-term mortality. In another meta-analysis of ten randomized controlled trials, the authors concluded that patients who were transfused leukoreduced RBCs might benefit from a decrease in postoperative infections (37). Many countries have now adopted routine leukoreduction based on its supposed benefits, although it makes blood transfusion more expensive and whether it should be used in all a patients is a matter of ongoing debate (38).
Transfusion trigger of 8 was just as good as 9 in post CABG patients (Transfusion 1999;39:1070)
In a SR, transfusion above 7 seems beneficial only in ST elevation MI, but not other cardiac disorders (Crit Care Med 2008;36:1068)
If the patient has high levels of inflammatory cytokines and is septic or under inflammation secondary to trauma, hepcidin, a protein known to interfere in iron absorption, will prevent any absorption from the gastrintestinal tract with average iron sulphate and polidroxilated iron. Ferrochelate is only slightly better (in Brazil – Neutrofer 500 mg – the equivalent of 4mg/kg of elemental iron daily). We don´t give iron per oral route in inflammed patients. However if the patient is anemic and needs erythropoietin, you need to evaluate his iron stores, and iron metabolism through serum ferritin, serum iron, and transferrin saturation. If you have very low levels of serum iron, and ferritin is low, that means that the patient might benefit from intravenous iron supplementation. However one must be aware that iron might impair phagocytosis and saturate cells from phagocytic mononuclear lineage, increasing risks of sepsis – so the ammount given must be the smallest needed to give substrate for erythropoietin – not the full ammount to correct completely the hemoglobin difference described in the products´ especifications. Erythropoietin doses are also to be higher than in average schemes for renal patients since trauma and septic patients usually are resistant to this hormone and already have high circulating levels of endogenous erythropoietin – then doses must start from 40000 units a week , if we are speaking of rHuepo, epoietin. The responses shall be monitored with reticulocytes count 10 days after the beginning of therapy with iron – to see if the patient is responding. Causes of blunted response are additional vitamin deficiencies – B12, folate, piridoxin, overt inflammation, sepsis, low thyroid hormone or suprarenal hormones levels, drug induced marrow depression and myelodysplastic alterations. I usually perform folate and B12 serum dosage, besides ferrokinetics tests. I don´t administer erythropoietin without being sure that there is enough substrate for the marrow to work with.
Transfusion Practice in the Critically Ill
Anemia is very common in the critically ill; almost 95% of patientsadmitted to the ICU have a hemoglobin level below normal byICU day 3.45 As a consequence of this anemia, critically illpatients receive a large number of RBC transfusions. Two cross-sectionalstudies67 conducted in Europe and the United States observedthat RBC transfusions were administered in approximately 40%of all patients studied. On average, critically ill patientsreceived almost 5 U of RBCs. This has changed little over thepast decade despite the scrutiny of transfusion practice.4
The best evidence available regarding the efficacy of RBC transfusionamong critically ill patients is from a randomized controlled trial, the Transfusion Requirements in Critical Care (TRICC)trial, conducted by the Canadian Critical Care Trials Group.8 In this study, a liberal transfusion strategy (hemoglobin 100 to 120 g/L, with a transfusion trigger of 100 g/L) was comparedto a restrictive transfusion strategy (hemoglobin 70 to 90 g/L,with a transfusion trigger of 70 g/L) in a general medical andsurgical critical care population. Patients who were euvolemicafter initial treatment who had a hemoglobin concentration <90 g/L within 72 h were enrolled. The TRICC trial8 documentedan overall nonsignificant trend toward decreased 30-day mortalityin the restrictive group; however, there was a significant decreasein mortality in the restrictive group among patients who were less acutely ill (APACHE [acute physiology and chronic health evaluation] II scores < 20) and among patients who were <55 years of age. Patients in the restrictive group received54% less RBC units than those in the liberal group. Based onthe results of the study, the authors8 recommended that critically ill patients receive allogeneic RBC units when hemoglobin concentrationsfall < 70 g/L and maintained at hemoglobin concentrationsfrom 70 to 90 g/L. The diversity of patients enrolled in thetrial and the consistency of the results suggest that the conclusionsmay be generalized to most critical care patients, with thepossible exception of patients with active coronary ischemicsyndromes.
Since the publication of the TRICC trial,8 Carson et al9 performeda systematic review of the literature to document all of theclinical trial evidence examining transfusion triggers. Theyidentified 10 randomized clinical trials of adequate methodologicquality in which different RBC transfusion triggers were evaluated.Included were a total of 1,780 surgery, trauma, and ICU patientsenrolled in trials conducted over the past 40 years. The transfusiontriggers evaluated in these trials varied from 70 to 100 g/L.Data on mortality or hospital length of stay were only availablein six of these trials. Conservative transfusion triggers werenot associated with an increase in mortality; on average, mortalitywas one fifth lower (relative risk, 0.80; 95% confidence interval[CI], 0.63 to 1.02) with conservative compared with liberaltransfusion triggers. Likewise, cardiac morbidity and lengthof hospital stay did not appear to be adversely affected bythe lower use of RBC transfusions. From the 1,780 patients,892 patients (50%) had cardiovascular disease. Using metaanalytictechniques, there were no differences in the combined odds ofdeath or cardiac events using restrictive strategies as comparedto more liberal approaches. There were insufficient data onpotentially relevant clinical outcomes such as stroke, thromboembolism,multiorgan failure, delirium, infection, or delayed wound healingto perform any pooled analysis. Carson and colleagues9 concludedthere were insufficient data to address the full range of risksand benefits associated with different transfusion thresholds,particularly in patients with coexisting disease. They alsonoted that their metaanalysis was dominated by a single trial:the TRICC trial,8 which enrolled 838 patients and was the onlyindividual trial identified that was adequately powered to evaluatethe impact of different transfusion strategies on mortalityand morbidity.
The observational studies,67 in combination with the TRICC trial,8 have raised questions regarding the validity of the historicalassumption that RBC transfusion was beneficial for criticallyill patients with anemia. Few studies have attempted to determinewhether clinical practice has changed following the publicationof the TRICC trial. Hébert and colleagues10 reportedthe results of a repeat of a 1993 survey of Canadian criticalcare physicians to examine transfusion practice in criticallyill patients. There were important changes observed betweenresponses to the 2002 and 1993 surveys of transfusion practice.A threshold of 70 g/L was adopted 34% of the time in 2002, ascompared to 15% of the time in 1993 (p < 0.001). Thresholds> 100 g/L were reported in 6% of all responses in 2002 ascompared to 29% in 1993 (p < 0.0001). Indeed, 85% of physiciansstated that they had modified their approach to transfusionfollowing the publication of the TRICC. However, there stillremains variation in RBC transfusion practice patterns.67 Despite the apparent change in attitudes of Canadian critical care physicians,we are unsure if these attitudes prevail elsewhere. In addition,the survey demonstrated persistence of practice variations.
To date, there are no convincing data to support the routineuse of RBC transfusion to treat anemia in hemodynamically stable critically ill patients without evidence of acute bleeding.The data available would suggest that, in the absence of acutebleeding, hemoglobin levels of 70 to 90 g/L are well toleratedby most critically ill patients and that a transfusion thresholdof 70 g/L is appropriate. There is still some controversy asto what the appropriate transfusion threshold should be forcritically ill patients with acute ischemic cardiac diseaseor in the early resuscitation of the septic patient.
Transfusion Practice in Patients With Cardiac Disease
A number of risk factors for adverse outcomes associated with anemia have been identified in clinical practice guidelines1212 and reviews.31314 Anemia is believed to be less well toleratedin older patients, in the severely ill, and in patients withclinical conditions such as coronary, cerebrovascular or respiratorydisease. However, the clinical evidence confirming that thesefactors are independently associated with an increased riskof adverse outcome is lacking. One small case-control study15 following high-risk vascular surgery suggested an increase inpostoperative cardiac events with increasing severity of anemia.In perioperative16 and critically ill patients,17 two largecohort studies have documented that increasing degrees of anemiawere associated with a disproportionate increase in mortality rate in the subgroup of patients with cardiac disease. In 1958 Jehovahs Witness patients,16 the adjusted odds of deathincreased from 2.3 (95% CI, 1.4 to 4.0) to 12.3 (95% CI, 2.5to 62.1) as preoperative hemoglobin concentrations declined from the range of 100 to 109 g/L to 60 to 69 g/L in patientswith cardiac disease. A significant increase in mortality innoncardiac patients was not observed at comparable levels ofanemia. In a separate study17 of critically ill patients, patientswith cardiac disease and hemoglobin concentrations < 95 g/Lalso had a trend toward an increased mortality (55% vs 42%,p = 0.09) as compared to anemic patients with other diagnoses.Although both cohort studies were retrospective in nature andmay not have controlled for a number of important confounders,available studies suggest that anemia increases the risk ofdeath in patients with significant cardiac disease.
Two additional observational studies have explored the clinical consequences of anemia in patients with acute coronary syndromesor an acute myocardial infarction. Wu et al18 used Medicarerecords in a retrospective study of 78,974 patients > 65years old who were hospitalized with a primary diagnosis of acute myocardial infarction. The authors then categorized patients according to their admitting hematocrit. Although anemia definedin the study18 as a hematocrit < 39% was present in nearlyhalf the patients, only 3,680 patients received an RBC transfusion.Lower hospital admission hematocrit values were associated withincreased 30-day mortality, with a mortality rate approaching50% among patients with a hematocrit 27% who did not receivean RBC transfusion. This study was among the first to demonstratethat RBC transfusion may be beneficial in patients with acutemyocardial infarction. However, a number of potential biasesseverely limited any inferences made from this study. Specificconcerns include a very low rate of exposure to RBCs, limitedstatistical adjustments made in the multivariable analysis,an analysis based on the admitting hematocrit rather than the hematocrit value associated with the transfusion, no consideration for the time dependent use of RBCs, and residual confoundingbecause the use of RBCs are intimately linked to hematocritvalues (confounding by indication). Moreover, the observed benefitsof RBC transfusion did not persist for patients with admittinghematocrit levels between 30.1% and 33% in a secondary analysisthat removed patients who died within 2 days of hospital admission.Despite these limitations, the authors and an accompanying editorialstated there was sufficient evidence from this publication torecommend the transfusion of RBCs below a hematocrit of 33%in elderly patients following an acute myocardial infarction.
The second study by Rao and colleagues19 attempted to overcomethe limitations of the study by Wu et al18 by using detailedand accurate prospectively collected data, by focusing on apatient population that required aggressive interventions anda greater exposure to blood products, and by using a numberof multivariable statistical techniques that might better adjustfor the influence of many baseline characteristics as well astime. In their analysis,19 they noted that RBC transfusionswere not associated with improved survival when nadir hematocritvalues were in the range of 20% or 25% and were clearly associatedwith worsened outcomes when values were > 30%. Despite superiormethods, some limitations still remain. The study by Rao etal19 only had 2,400 patients (10%) who received RBC transfusions,a small number of exposed individuals given an average mortalityof 4%. Indeed, an overall mortality difference as large as 2%may not have been detected, and larger differences would havebeen missed in some of the strata, as suggested by the disproportionatehigh odd ratios at higher hematocrit levels.
Importantly, over and above apparent differences, both studies1819 consistently demonstrate that patients who receive RBCs at a higher hematocrit appear to be harmed by the transfusions. At hematocrit values < 30%, it is possible that the interpretationgiven by the authors represent aspects of the true effects,especially since there are many differences between studies.Wu et al18 derived observations from a wide population of allelderly patients who had an acute myocardial infarction, whereasRao and colleagues19 only included younger individuals who requiredaggressive interventional management. It is plausible that ahigher transfusion threshold would benefit elderly patientsbecause of the greater degree of diffuse vascular disease, thepresence of additional comorbid illnesses, and the inabilityto augment cardiac output as a means of compensation for anemia.However, younger patients may derive less benefit from RBC transfusionsbecause of widespread use of aggressive revascularization procedures,statins, new antiplatelet agents, and other therapies that havebeen shown to save lives. In addition to more elaborate treatmentfor the primary lesion, collateral blood flow is either adequateor treated as part of cardiovascular management strategy. Itis also possible that younger patients can better adapt to anemia.If this interpretation holds, clinicians should consider adoptinga higher transfusion strategy in all elderly patients whileallowing patients who are aggressively treated for their acutecoronary syndromes to be treated according to a more restrictiveapproach to transfusions. It is also plausible that there islimited incremental benefit of RBC transfusion in patients followinga myocardial infarction with a hematocrit > 20% or a hemoglobinconcentration > 70 g/L as suggested by the findings of Raoet al.19 Ideally, further evidence from randomized controlledtrials would provide the needed evidence to determine optimaltransfusion strategies in this high-risk patient population.
Table 1. Transfusion Recommendations
Variables Transfusion Trigger, g/dL* Goal, g/dL General critically ill (no acute bleeding) 7 79 Critically ill with septic shock (> 6 h) 7 79 Critically ill with septic shock (< 6 h) 810 10 Critically ill with chronic cardiac disease 7 79 Critically ill with acute cardiac disease 810 10
* Administer 1 U of RBCs at a time and remeasure hemoglobin concentrations.
((Chest. 2007; 131:1583-1590)
(Hebert Chest 2007)
Anemia in the Critically Ill Iron Metabolism Iron Absorption and Excretion.
Dietary Fe is absorbed via the divalent metal transporter 1 protein located on the apical membrane of duodenal enterocytes (11). Through incompletely understood mechanisms, Fe absorption is enhanced under conditions of decreased dietary Fe intake, reduced Fe stores, increased erythropoiesis, and acute hypoxia (12). Whereas Fe absorption is regulated, Fe excretion is not. Small amounts of Fe are lost daily in sweat, mucosal sloughing, and feces. However, the removal of larger amounts of Fe requires serial phlebotomy or Fe chelation therapy, which remain the mainstays of treatment for Fe-overload states such as hemochromatosis and aceruloplasminemia (13).
Distribution of Total Body Iron.
Whereas there is abundant Fe within the human body, the total amount of circulating free Fe is well below 1 mg, and serum Fe concentration is kept remarkably constant in the face of both increased and decreased total body Fe stores. The majority of Fe thus exists bound to heme and serum proteins. Hemoglobin and myoglobin contain Fe bound to a porphyrin ring, in which it plays a crucial role in oxygen transport. Within mitochondria, the enzymes of the cytochrome system use Fe to transfer electrons during aerobic respiration. The remaining Fe is bound to the Fe-binding proteins ferritin, transferrin, and lactoferrin. Ferritin is the principal storage protein for Fe, maintaining it in a soluble, nontoxic, biologically useful form. Sites of Fe storage are predominantly within hepatocytes and reticuloendothelial macrophages. Transferrin serves to transport Fe among sites of absorption, storage, and use. Circulating transferrin is usually 30% saturated with Fe, and empty binding sites buffer against the rapid influx of free Fe into the circulation during trauma, infection, and parenteral Fe supplementation (14). Lactoferrin is found in milk, mucosal secretions, and granules within polymorphonuclear leukocytes. Apolactoferrin (Fe-free lactoferrin) is released at sites of inflammation, where it binds Fe and is taken up by macrophages. The primary role of lactoferrin seems to be scavenging and sequestration of Fe from microorganisms as they invade the host and establish an infection (1518).
Alterations During Critical Illness.
During the inflammatory response that accompanies critical illness, ferritin and lactoferrin synthesis are up-regulated (acute-phase reactants), whereas transferrin synthesis and saturation are decreased (negative acute-phase reactant) (13). Fe is thus trafficked into storage, resulting in hypoferremia, despite normal-to-elevated total body Fe. It has been suggested that these alterations have evolved to withhold Fe from invading microorganisms (4, 1921). Although this response may afford protection against infection, less Fe is made available for erythropoiesis, resulting in a functional Fe deficiency and ultimately anemia.
Iron Deficiency Anemia and the Anemia of Inflammation
Fe deficiency anemia and the anemia of inflammation constitute the two Fe-related anemias encountered most commonly in the treatment of critically ill patients. Central to both diseases is a decreased availability of Fe to erythroid progenitor cells, resulting in Fe-deficient erythropoiesis (Fig. 1). Irrespective of pathogenesis, Fe-deficient erythropoiesis is present in up to 35% of critically ill patients at admission to the intensive care unit (ICU) (9, 10).
[Help with image viewing] [Email Jumpstart To Image] Figure 1. Schematic of iron (Fe) trafficking in relation to erythropoiesis under normal conditions, iron deficiency anemia, and anemia of inflammation. Under normal conditions, Fe moves freely between storage and sites of erythropoiesis. During Fe deficiency, storage Fe is mobilized. However, an inadequate supply of total body Fe ultimately results in iron-deficient erythropoiesis. During the anemia of inflammation, Fe stores are increased. However, mobilization of these Fe stores is blocked, also resulting in iron-deficient erythropoiesis. Iron-deficient erythropoiesis is characterized by an increased percentage of hypochromic erythrocytes and increased erythrocyte zinc protoporphyrin concentration. aAlthough each ferritin molecule contains >2,000 Fe atoms, only nine are pictured for simplification purposes. bBoth diferric transferrin and apotransferrin (Fe-free transferrin) are pictured.
Fe deficiency anemia is characterized by total body Fe depletion and may occur secondary to blood loss or inadequate dietary Fe, both of which are common in the ICU setting. Indeed, blood loss from phlebotomy alone may exceed 70 mL/day in critically ill patients, resulting in continual Fe depletion (22). Signs and symptoms indicative of Fe deficiency anemia (fatigue, pallor, pica, glossitis, and koilonychias) are usually absent, nonspecific, or impossible to assess in the ICU patient. Prevalence estimates of Fe deficiency in critical illness based on hypoferritinemia or increased serum transferrin receptor concentration (discussed below) range from 13% to 23% (23, 24).
The anemia of inflammation is the manifestation of synergistic pathologic processes of altered Fe trafficking and impaired erythropoietin synthesis and function (7). Once believed to occur over the course of weeks to months, decreases in hemoglobin concentration secondary to the anemia of inflammation have been shown to occur in <1 wk (25), thus accounting for the abandonment of the term anemia of chronic disease.
The inhibitory effects of inflammatory cytokines on erythropoiesis mediate the anemia of inflammation. Interleukin-1, tumor necrosis factor-[alpha], and transforming growth factor-[beta] inhibit erythropoietin synthesis and action (2629). Recombinant tumor necrosis factor-[alpha] induces anemia and hypoferremia associated with decreased Fe release from the reticuloendothelial system and incorporation into red blood cells (30, 31). Furthermore, interleukin-1 and tumor necrosis factor-[alpha] induce ferritin production, sequestering Fe that might otherwise be available for erythropoiesis (32).
Critically ill patients demonstrate both an attenuated response of erythropoietin synthesis to anemia (3337) and a functional Fe deficiency (9, 10, 36, 38). As a result, the majority of patients develop the anemia of inflammation (24). In turn, the anemia of inflammation prolongs both ICU length of stay and duration of systemic inflammatory response syndrome (9, 10). Because malabsorption, serial phlebotomy, and inflammation are all common within critically ill patients, Fe deficiency anemia and the anemia of inflammation may coexist. Munoz et al. (24) reported a 21% prevalence of Fe deficiency in patients with the anemia of inflammation.
Diagnosis of Iron-Related Anemias
To differentiate between Fe deficiency anemia, the anemia of inflammation, and a mixed-factor anemia in critical illness, an assessment of total body Fe stores must first be made. The abundance of available laboratory markers reflects the complexity of Fe metabolism. The response of these markers to both Fe deficiency and inflammation are discussed below, summarized in Table 1, and illustrated in Figure 1.
[Help with image viewing] [Email Jumpstart To Image] Table 1. Serum markers of total body iron in iron deficiency anemia (IDA) and anemia of inflammation (AoI)
Serum Fe concentration is an unreliable marker for total body Fe stores. Burns et al. (39) found the serum Fe concentration 77.5% sensitive and only 35.6% specific in diagnosing Fe deficiency anemia when compared with Prussian Bluestained bone marrow smears. A variety of conditions other than Fe deficiency, such as inflammation, infection, neoplasia, alcoholism, and liver disease, may cause hypoferremia, accounting for this low specificity (13).
Small amounts of ferritin circulate within serum; changes in serum ferritin concentration correlate well with changes in total body ferritin (40, 41). Ferritin synthesis is induced by a variety of stimuli, including hyperferremia, oxidative stress, and neoplasia (42, 43). Most importantly, ferritin behaves as an acute-phase reactant (33, 44). Plasma concentrations of ferritin may thus increase sharply in the absence of any change in total body Fe stores, rendering an elevated ferritin concentration ambiguous in the setting of critical illness. However, a low serum ferritin concentration is highly suggestive of Fe deficiency (45).
Serum Transferrin, Total Serum Iron Binding Capacity, and Transferrin Saturation.
Hepatic synthesis of transferrin is up-regulated during Fe deficiency, increasing both serum transferrin concentration and the total serum Fe-binding capacity. However, inflammation, infection, malignant disease, and malnutrition all decrease both serum transferrin concentration and total serum Fe-binding capacity (13). Critically ill patients may thus manifest normal to depressed values, despite the presence of Fe deficiency. Low transferrin saturation may be suggestive of Fe deficiency. However, both Burns et al. (39) and Kalandar-Zadeh et al. (46) found it to be only 40% specific. This is likely because serum transferrin saturation is also decreased during inflammation, increased in bone marrow dysfunction due to alcohol, chemotherapy, or megaloblastic processes, and exhibits a diurnal variation (47).
Erythrocyte Zinc Protoporphyrin.
During normal erythropoiesis, Fe is chelated to protoporphyrin IX to form heme. In the absence of Fe or inadequate Fe delivery to the bone marrow, zinc is substituted for Fe, forming zinc protoporphyrin (Fig. 2). Increased erythrocyte zinc protoporphyrin concentration has been shown to accurately diagnose Fe deficiency anemia in the absence of inflammation (4850). Moreover, in contrast to traditional measures of Fe metabolism, erythrocyte zinc protoporphyrin concentration is not directly affected by inflammation (51). However, any pathologic process that limits the transfer of Fe to the bone marrow or that stimulates porphyrin synthesis can lead to an increased concentration of erythrocyte zinc protoporphyrin (52). Hastka et al. (53) studied 19 patients with the anemia of inflammation based on hypoferremia, decreased transferrin saturation, and increased ferritin concentration. Coexisting Fe deficiency was excluded by documenting adequate bone marrow Fe stores. All patients showed significantly elevated erythrocyte zinc protoporphyrin concentrations, despite having increased Fe stores. Increased erythrocyte zinc protoporphyrin concentration in the critically ill patient is thus best interpreted to signify Fe-deficient erythropoiesis rather than to specify Fe deficiency anemia.
[Help with image viewing] [Email Jumpstart To Image] Figure 2. Relationship between zinc protoporphyrin and ferrous protoporphyrin metabolism. Proportions of the three forms of protoporphyrin found in erythrocytes of healthy persons are shown in µmol. Zinc protoporphyrin plays a prominent role in the catabolism of heme (dotted arrow). Adapted from Labbe et al (102).
Hypochromic erythrocytes are the result of erythroid precursors that mature in the absence of adequate Fe. Normally, the circulation contains <2.5% hypochromic erythrocytes, and values of >10% are highly sensitive for Fe-deficient erythropoiesis (54). However, the percentage of hypochromic erythrocytes is an indirect marker of Fe reaching the bone marrow rather than total body Fe stores. Inflammation both decreases Fe supply to the bone marrow and slows erythropoiesis. Significantly reduced erythropoiesis may actually decrease Fe requirements and thus artificially lower the percentage of hypochromic erythrocytes, despite possible Fe deficiency (55).
Serum Transferrin Receptor.
The transferrin receptor is a cell-surface protein found mainly on erythroid progenitors (80%) but also on circulating hematopoietic cells within the blood. Transferrin receptor synthesis is increased under conditions of both enhanced erythropoiesis and Fe deficiency (56), and patients with Fe deficiency anemia possess increased levels of serum transferrin receptors (5759). The accuracy of the transferrin receptor assay in differentiating Fe deficiency anemia from the anemia of inflammation has been studied. Ferguson et al. (60) demonstrated an increased mean serum transferrin receptor concentration in patients with Fe deficiency anemia as compared with patients with acute infection, anemia of inflammation (with normal bone marrow Fe stores), and normal controls. More recently, Punnonen et al. (61) and Margetic et al. (62) used receiver operating characteristic analyses to document the utility of the serum transferrin receptor assay in detecting underlying Fe deficiency in patients with the anemia of inflammation. In these two studies, calculation of the ratio of transferrin receptor/log ferritin concentration provided a highly sensitive and specific variable for the detection of Fe deficiency.
It is important to note that, to diagnose Fe deficiency anemia, serum transferrin receptor concentration must be measured before initiating therapy with recombinant human erythropoietin. This is because erythropoietin therapy also increases serum transferrin receptor concentration (33).
A proposed algorithm for the diagnosis of and differentiation between Fe deficiency anemia and the anemia of inflammation in critical illness is shown in Figure 3. Determination of erythrocyte zinc protoporphyrin concentration provides a simple, relatively inexpensive method for diagnosing Fe-deficient erythropoiesis. If normal, other pathogeneses of anemia are pursued. If erythrocyte zinc protoporphyrin concentration is elevated, serum ferritin concentration may be determined; if it is depressed, the diagnosis of Fe deficiency anemia can be made. However, if serum ferritin concentration is normal or elevated, serum transferrin receptor concentration may be used to reveal coexisting Fe deficiency.
[Help with image viewing] [Email Jumpstart To Image] Figure 3. Algorithm for the diagnosis of and differentiation between iron deficiency anemia (IDA) and the anemia of inflammation (AoI) in critical illness. ZPP, zinc protoporphyrin; IDE, iron-deficient erythropoieses; TfR, transferrin receptor.
Although the results of these tests may provide valuable information, certain limitations bear recognition. In many instances, diagnostic test characteristics were determined in outpatients with longstanding anemia secondary to chronic diseases rather than hospitalized, critically ill patients, raising the possibility of spectrum bias. Even in the former patient population, no single test is invariably accurate when compared with the gold standard of stained bone marrow smears. Further, the serum transferrin receptor assay suffers from a lack of standardization. Finally, erythrocyte zinc protoporphyrin and serum transferrin receptor assays are often not available routinely or, alternatively, may require secondary laboratory analysis, substantially prolonging time to diagnosis. As such, both the final assessment of Fe stores and the pathogenesis of anemia in critical illness should involve the interpretation of many of these tests relative to each other and in conjunction with trends and clinical circumstances.
Treatment of Iron-related Anemias
Fe replacement and recombinant human erythropoietin therapy offer targeted treatment options for Fe-related anemias. A detailed discussion of more general treatment strategies for ICU anemia, such as red blood cell transfusion, is beyond the scope of this review.
Iron Replacement Therapy.
Fe replacement therapy is usually initiated with enteral ferrous sulfate. Ferrous Fe is best absorbed in a mildly acidic medium, necessitating the co-administration of ascorbic acid to optimize Fe absorption. Absorption of enteral Fe may be down-regulated in patients with increased Fe stores as a result of inflammation (12, 63). Furthermore, patients may be unable to tolerate enteral Fe supplementation at adequate doses due to marked gastrointestinal side effects. Alternatively, enteral nutrition may be contraindicated secondary to coexisting pathology. In these cases, parenteral Fe replacement therapy with Fe saccharate, Fe gluconate, or Fe dextran may be considered.
Although Fe replacement in the treatment of outpatient Fe deficiency anemia is invaluable (6467), the effect of Fe supplementation on morbidity and mortality in critically ill patients with Fe deficiency has not been well studied. As mentioned previously, the inflammatory response associated with critical illness may limit the amount of supplemental Fe ultimately available for erythropoiesis.
It follows that Fe supplementation in the anemia of inflammation is also ineffective. Van Iperen et al. (33) studied critically ill patients with the anemia of inflammation based on anemia, hypoferremia, low transferrin concentration and transferrin saturation, high serum ferritin concentration, and normal serum transferrin receptor concentration. Patients were randomized to receive no treatment (control group), intravenous Fe saccharate (Fe group), or intravenous Fe saccharate plus recombinant human erythropoietin (epo group). After 21 days, serum Fe concentration had increased in all three study groups, and serum ferritin concentration had increased in those groups receiving Fe supplementation. However, reticulocyte concentration and serum transferrin receptor concentration had increased in only the epo group, suggesting that supplemental Fe alone had no effect on erythropoiesis. Interestingly, in the epo group, erythrocyte zinc protoporphyrin concentration had also significantly increased as compared with baseline and also the control and Fe groups, indicating Fe-deficient erythropoiesis, despite parenteral Fe supplementation. Finally, hemoglobin concentration remained identical in the three study groups.
Beyond a questionable benefit, Fe replacement therapy in critical illness poses certain risks. Because Fe excretion is not regulated, caution must be exercised during parenteral supplementation, which bypasses normal gastrointestinal regulation of Fe absorption. Specifically, clinically meaningful amounts of free Fe may be released from both the Fe saccharate and Fe gluconate complex, resulting in acute Fe toxicity (hypotension, cardiovascular collapse, and in some instances, cardiac arrest), especially during rapid administration. Furthermore, anaphylactic reactions to Fe dextran may occur because many patients have preformed antibodies against dextran. For these reasons, a test dose must be administered before initiating supplementation, and facilities for cardiopulmonary resuscitation must be readily available (13, 68).
The use of Fe replacement therapy in critical illness has also been questioned because of the possible link between Fe and infection (2). This notion is supported mainly by evolutionary mechanisms developed by both host and pathogen to sequester Fe during infection (6974), research documenting in vitro inhibition of Fe-overloaded macrophages and neutrophils (7578), human and animal studies documenting increased virulence of microorganisms in the presence of Fe (7985), and retrospective data in hemodialysis patients documenting a relationship between hyperferritinemia and both impaired immunity and increased likelihood of infection (8692).
Data addressing the relationship between Fe and infection in critical illness are sparse. One may speculate that the observed relationship between increased length of storage of transfused blood and infection in critical illness (93) may be in part due to the extent of in vitro hemolysis and subsequent liberation of free Fe (4). However, two recent retrospective studies did not observe a relationship between parenteral Fe replacement therapy and likelihood of infection. Torres et al. (94) followed 863 patients who underwent cardiopulmonary bypass surgery. Patients chose to enroll in a blood conservation program, in which they received parenteral Fe gluconate and recombinant human erythropoietin as indicated, or to receive blood transfusions as indicated. After controlling for age, sex, diabetes mellitus, blood transfusion, and type and duration of surgery, likelihood of infection was not significantly different in patients who received Fe vs. those who did not. A retrospective cohort study of 27 surgical ICU patients who received intravenous Fe from 2000 to 2004 reported a 22% prevalence of bacteremia in the Fe group compared with a 13% prevalence of bacteremia in the control group (p = .29) (95). Although this study suggested an association, the observed difference was not statistically significant, and the authors concluded that intravenous Fe did not increase the risk of bacteremia.
Recombinant Human Erythropoietin.
Because endogenous erythropoietin synthesis and function are preserved in Fe deficiency anemia, treatment of this disorder with recombinant human erythropoietin is not necessary (96, 97). However, the anemia of inflammation may benefit from the administration of recombinant human erythropoietin. As mentioned previously, the anemia of inflammation is characterized by an inappropriate response of endogenous erythropoietin synthesis to anemia. Furthermore, the bone marrow of critically ill patients responds to the administration of recombinant human erythropoietin with increased generation of reticulocytes and transferrin receptor (33). However, investigations into the clinical significance of this response have yielded mixed results.
In the study of Van Iperen et al. (33), an observed increase in reticulocytes and transferrin receptor in response to recombinant human erythropoietin therapy was not met by an increase in hemoglobin concentration at the end of the 3-wk study period. Moreover, despite the addition of parenteral Fe supplementation to the epo group, Fe-deficient erythropoiesis ensued as evidenced by a significant increase in erythrocyte zinc protoporphyrin concentration. A second randomized trial of 21 patients with multiple organ dysfunction syndrome and the anemia of inflammation also demonstrated an increased reticulocyte count relative to the control group after 3 wks of treatment with recombinant human erythropoietin (98). Both groups also received supplemental Fe. However, no difference existed between study groups in either final hemoglobin concentration or red blood cell transfusion requirement. A third randomized, multiple-center trial of 40 critically ill burn patients with anemia, hypoferremia, and hyperferritinemia documented no change in hemoglobin concentration or transfusion requirement relative to the control group after 30 days of treatment with recombinant human erythropoietin (99).
Two recent, larger trials have found significant differences in both final hemoglobin concentration and transfusion requirement in critically ill subjects treated with recombinant human erythropoietin compared with placebo. Corwin et al. (100) first randomized 160 critically ill patients with anemia and without hypoferritinemia to receive either recombinant human erythropoietin or placebo (both groups also received supplemental Fe). Compared with the placebo group, the recombinant human erythropoietin group realized both fewer red blood cell transfusions and an increased final hemoglobin concentration for up to 42 days postrandomization. Corwin et al. (101) next randomized 1,302 critically ill, anemic patients from 65 institutions to receive either recombinant human erythropoietin or placebo. Again, both groups received supplemental Fe. After 28 days of follow-up, subjects in the recombinant human erythropoietin group had received fewer red blood cell transfusions and realized a larger increase in hemoglobin concentration compared with the control group. However, mortality and number of adverse events were not significantly different between study groups in either trial.
Incorporation of Fe metabolism during critical illness into this literature is warranted. Specifically, in the aforementioned trials, variable laboratory measurements were used to both diagnose the anemia of inflammation and exclude Fe deficiency anemia. Moreover, treatment with concomitant recombinant human erythropoietin and Fe has not been shown to prevent Fe-deficient erythropoiesis. Finally, whether the benefits of recombinant human erythropoietin therapy for the anemia of inflammation are preserved in the absence of Fe supplementation remains unclear.
In summary, the treatment of Fe-related anemias in critical illness involves weighing clinical benefit against risk. Fe replacement therapy alone has not been shown to affect anemia in this setting. Further, there exists a plausible, although as of yet incompletely investigated, increased risk of infection as a result of Fe therapy during critical illness. Recombinant human erythropoietin therapy has been shown to stimulate erythropoiesis, increase hemoglobin concentration, and decrease transfusion requirements in anemic, critically ill patients. However, a consequent decrease in morbidity and mortality was not demonstrated. Furthermore, markers of both Fe deficiency and Fe-deficient erythropoiesis were not obtained routinely. As an understanding of the full effect of these treatments evolves, the importance of both minimizing phlebotomy and treating underlying inflammatory processes in critically ill patients cannot be overstated.
Crit Care Med. 2006 Jul;34(7):1898-905.
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