SCCM Resource Library-ACCM Distinguished Investigator Presentation: Anemia in the ICU: Current Concepts and Future Treatments

Video Transcription

you  Welcome to this presentation on Anemia in the ICU, Current Concepts and Future Treatments. I'm Lina Napolitano, Director of Surgical Critical Care at the University of Michigan.  I would like to provide my most sincere thanks to the American College of Critical Care Medicine and its awards committee for the honor of being selected as  a recipient of the 2021 ACCM Distinguished Investigator Award. I'm truly humbled by this great honor. I have no disclosures.  Anemia is common in critical illness with anemia present in 97 percent of patients in the ICU at day 8, and is commonly treated with allogeneic red blood cell transfusion.  Optimal diagnosis and management of anemia in critical illness is an area of much controversy and ongoing research. The etiology of anemia in the ICU is multifactorial,  including blood loss due to diagnostic phlebotomy, bleeding, and hemolysis. In addition, decreased red cell production due to  bone marrow suppression related to inflammatory cytokines, erythropoietin or iron deficiency, renal dysfunction, and drugs is common.  Anemia in the ICU is associated with increased risk of mortality, cardiovascular morbidity, prolonged requirement for mechanical ventilation, reduced physical function,  and global cognitive decline. With a growing awareness of the functional limitations in critical illness survivors, the potential associations between  persistent anemia and functional recovery in this high-risk group must be considered and investigated further, particularly with regard to targeted anemia management strategies.  Anemia is highly prevalent amongst survivors of critical illness with 77 percent of patients still anemic at hospital discharge. In ICU patients who required mechanical ventilation,  50 percent remained anemic at six months after ICU discharge. This is in part an unintended consequence of restrictive transfusion practices in the ICU.  Most patients have red blood cell morphology of anemia of chronic disease or anemia of inflammation, AI. A recent population-based cohort study of  almost 7,000 ICU patients confirmed that 41 percent had anemia preceding their hospitalization, and 80 percent had anemia at hospital discharge. Anemia persisted in 45 percent of  these patients at 12 months after hospital discharge. Anemia recovery at 12 months was 58 percent for mild anemia and only 24 percent for severe anemia.  Interestingly, higher hemoglobin concentration at hospital discharge was associated with significantly decreased mortality after multivariable adjustment with a hazards ratio of  0.95 per one gram per deciliter increase in hemoglobin. Importantly, ICU patients with moderate or severe anemia at hospital discharge had significantly higher mortality and  much higher rates of persistent anemia.  Normal erythropoiesis requires inadequate iron supply in an absence of inflammation. The main mechanism of iron homeostasis centers on  the interaction between the iron regulatory hormone hepcidin produced by hepatocytes and ferroportin, which is both the hepcidin receptor and the sole cellular iron exporter through  which iron is transferred to blood plasma. There are substantial changes in iron homeostasis with anemia of inflammation. Inflammatory cytokines, particularly IL-6,  upregulates hepcidin. Iron restriction in anemia of inflammation is mediated by the interaction of increased levels of hepcidin with the iron exporter ferroportin.  Hepcidin excess is further exacerbated if renal function is impaired, which is common in our ICU patients, since hepcidin renal clearance is reduced.  Increased hepcidin levels then reduce iron availability via two mechanisms, decreased absorption of iron across the GI tract, and decreased release of iron from  the reticular endothelial system.  Any inflammatory stimulus, including infection and trauma, increases hepcidin and decreases erythropoietin, resulting in functional iron deficiency,  anemia, and reduced erythropoiesis. We have confirmed that serum hepcidin levels are high in anemia of inflammation in ICU patients and low in iron deficiency anemia patients.  Our research group was the first to report in 144 ICU trauma patients that over 90% acquire anemia during their ICU stay, and that hepcidin levels are markedly increased.  Increased injury severity measured by ISS was associated with significantly higher hepcidin levels.  Systemic inflammation with high levels of cytokines biases hematopoiesis towards myeloid cell production, depicted here by the large green arrow,  rather than erythropoiesis, depicted by the red arrow. It also inhibits erythroid precursor proliferation. It activates macrophages for erythrophagocytosis,  and thereby shortens the erythrocyte lifespan, and lastly inhibits the release of recycled iron from macrophages, causing hypothermia.  Hypothermia then inhibits erythroblast proliferation, resulting in anemia.  40 to 70% of ICU patients will receive a red blood cell transfusion for anemia treatment, but this will further impair recovery of endogenous erythropoiesis by multiple mechanisms,  including increased iron sequestration by increased hepcidin,  direct inhibition of red cell production by the bone marrow, direct inhibition of the erythroid precursor cell response to EPO,  and inhibition of EPO gene transcription in the kidney.  Erythropoiesis is tightly regulated by erythropoietin, the levels of which are normally increased with anemia. However, during critical illness,  circulating EPO concentrations fall quickly and remain inappropriately low because of a combination of decreased renal function  and pro-inflammatory cytokine inhibition of EPO production. The additional inflammatory stimulus of allogeneic red blood cell transfusion for the treatment of anemia in the ICU  further down-regulates EPO production, impairing normal endogenous erythropoiesis.  New emerging treatments for anemia of inflammation directly address the hepcidin pathway. There are multiple approaches to decrease hepcidin overexpression.  These targeted mechanisms are designed to reverse hypopharemia in anemia of inflammation by one, decreasing the level of hepcidin with the use of hepcidin binders,  or two, by hindering the access of hepcidin to its target feroportin, or three, antagonizing the signaling pathways that stimulate hepcidin production during inflammation.  Pharmacologic regulation of hepcidin activity with clinically relevant drugs that modulate the hepcidin-feroportin access are currently being evaluated in randomized clinical trials  for treatment of hepcidin-related disorders, including anemia of inflammation.  Recently, vitamin D deficiency has also been identified as a risk factor for anemia, particularly anemia of inflammation. The hepcidin antimicrobial peptide gene  contains a vitamin D response element, making the observed association between vitamin D deficiency and anemia biologically plausible. A novel way to reduce hepcidin  to increase hemoglobin is via vitamin D, which has been documented to reduce pro-inflammatory cytokines and suppress hepcidin transcription,  thereby resolving functional iron deficiency and increasing endogenous erythropoiesis. In this study of mechanically ventilated critically ill adults,  treatment with 500,000 international units of vitamin D3 increased hemoglobin and acutely reduced serum hepcidin concentrations.  A new hormone and erythroid regulator, erythroferon or ERFI, has been identified. Importantly, erythroferon suppresses hepcidin, which augments iron delivery  for intensified endogenous erythropoiesis, so high ERFI levels are desired. Erythroferon production by erythroblast should be increased in response to anemia.  Erythroferon is also secreted by erythroblast in response to stimulation by erythropoietin, either endogenous or exogenous.  In converse, erythroferon levels are suppressed with red blood cell transfusion and inflammation.  In response to anemia, increased EPO production by the kidney stimulates erythroblast to increase the production of ERFI, both because EPO increases the number of erythroblasts  and because EPO increases the synthesis of erythroferon by each erythroblast. Circulating ERFI then acts directly on hepatocytes to suppress hepcidin production,  leading to reduced plasma concentration of hepcidin. These low levels of circulating hepcidin then allow the efflux of stored iron, primarily from macrophages and hepatocytes,  as well as increased dietary iron absorption so that more iron is loaded onto transferrin.  Increased flow of plasma holotransferrin then delivers iron to erythroblasts for augmented heme and hemoglobin synthesis.  Erythroferon, or ERFI, plays a significant role on the pathophysiology of anemia of inflammation. In this study, comparing AI ICU patients  to septic or non-septic patients with high hemoglobin  striking differences are noted.  Anemia of inflammation in the black bars is characterized by high levels of IL-6, hepcidin, and ferritin, and very low levels of iron, transferrin, and erythroferon.  ERFI, which regulates hepcidin, showed a rapid decrease in anemia of inflammation ICU patients resulting in high hepcidin levels and iron-restricted erythropoiesis.  We have confirmed similar findings in a study of 147 trauma ICU patients. The profile of this trauma patient who was in the ICU for 28 days  with persistent anemia with hemoglobins of seven to eight had persistently high hepcidin levels, low erythropoietin levels, and low erythroferon levels.  This resulted in iron-restricted erythropoiesis.  Another important regulator of erythropoiesis in anemia is hypoxia-inducible factors, or HIF. The Nobel Prize in Physiology or Medicine in 2019  was awarded jointly to Drs. Kalin, Ratcliffe, and Semenza for their discoveries of how cells sense and adapt to oxygen availability via HIF. This research laid the foundation  for understanding the mechanistic basis for the cellular response to hypoxia and paved the way for the therapeutic targeting of this response pathway to treat conditions  including cancer and anemia.  The erythropoietic effects of HIF are numerous, as listed here, so stabilization of HIF is of paramount importance for optimal human erythropoiesis.  Erythropoietin production in the kidney is regulated by the oxygen-sensing transcription factor HIF1-alpha, which is degraded under normoxic conditions by HIF prolohydroxylase,  here depicted as HIF-PHD.  Inhibition of HIF-PHD by HIF-PH inhibitors leads to increased erythropoietin production, better iron absorption, and amelioration of anemia by complete erythropoiesis.  HIF prolohydroxylase inhibitors are HIF stabilizers that stimulate the production of erythropoietin and also act directly on the intestinal mucosa  to increase iron absorption and thereby ameliorate iron restriction.  Recent studies confirm that the HIF pathway can be activated to coordinate a comprehensive erythropoietic response via HIF-PH inhibition to ensure effective erythropoiesis.  There are some potential significant advantages to the use of HIF stabilizers for anemia treatment in both CKD and ICU patients listed here  compared to recombinant human erythropoietin. And a number of these HIF stabilizer agents are currently in clinical trials.  Some ICU patients will have iron deficiency as the etiology of their anemia. It is very challenging to determine the etiology of anemia in ICU patients  and differentiate iron deficiency versus anemia of inflammation by blood biomarkers. Percent hypochromic red blood cells cannot be used  if the ICU patient received a blood transfusion, which is a common treatment for anemia in the ICU.  Two other proposed biomarkers are a high ratio of soluble transferon receptor in the log ferritin or a low level of pepsidin.  A recent multicenter observational cohort study of ICU patients confirmed that iron deficiency anemia was diagnosed in 37% by low hepcidin levels.  And this was an independent predictor of increased one-year mortality with an odds ratio of 1.51.  The hepcidin study also used hepcidin levels to diagnose iron deficiency anemia with treatment with iron or iron and erythropoietin  dependent on the hepcidin levels in the ICU patients. Preliminary data confirm that 37% of ICU patients had true iron deficiency and 23% had functional iron deficiency.  This emerging strategy of hepcidin guided management of anemia in the ICU patients is quite promising.  In this study of ICU patients with anemia, baseline hepcidin concentrations predicted red blood cell transfusion requirement. In addition, patients with low hepcidin levels  responded significantly to IV iron therapy with a substantial decrease, 52% reduction in red blood cell transfusion requirement.  The 2020 clinical practice guidelines from the French SFAR and SRLF critical care groups on management and prevention of anemia in adult critical care have now recommended  the use of erythropoiesis stimulating agents, ESAs, in anemic and trauma ICU patients in the absence of contraindications to reduce both red blood cell use and decrease mortality.  This new recommendation for ESAs to treat ICU-acquired anemia in part comes from the data on EPO and its impact on trauma outcomes. Importantly, in two large RCTs  which evaluated the use of the ESA epoetin alpha for anemia treatment as a red cell transfusion sparing agent in critically ill patients,  a post hoc pooled analysis confirmed lower mortality in the critically ill trauma patient cohort.  Similarly, the recent erythropoietin and traumatic brain injury study, the EPO-TBI trial, also confirmed a reduction in six-month mortality.  A systematic review and meta-analysis of nine RCTs that compared ESA to placebo or no ESA in critically ill trauma patients has confirmed that ESA treatment was associated  with a significant reduction in trauma mortality with a risk ratio of 0.63 depicted here.  Based on these important findings, the EPO trauma randomized control trial has just begun enrollment a few months ago. The primary aim is to evaluate the effect  of epoetin alpha compared to placebo in critically ill mechanically ventilated trauma patients on mortality and severe disability.  Professors Craig French and Elzer Nickel are the PIs and we are hopeful to be able to initiate U.S. clinical sites for this important clinical trial in the future.  In summary, all potential strategies to prevent anemia in the ICU should be implemented. Additional strategies for ICU-acquired anemia treatment  include accurate identification of iron deficiency versus anemia of inflammation and consideration of treatment with iron, erythropoiesis-stimulating agents, anti-hepcidin agents,  anti-hypoxia-inducible factor hip stabilizers.  Thank you again for the wonderful opportunity to present today. Good evening. ♪♪

Video Summary

Anemia is a common condition in critically ill patients in the ICU, with 97% of patients having anemia by day 8. The causes of anemia in the ICU are multifactorial, including blood loss, decreased red cell production, and inflammation. Anemia is associated with increased mortality and morbidity, as well as reduced physical function and cognitive decline. Anemia often persists even after hospital discharge, with 77% of patients still anemic and 50% still anemic at 6 months post-ICU discharge. Current treatments for anemia, such as red blood cell transfusion, can further impair recovery of the body's own red blood cell production. Future treatments for anemia in the ICU are focused on targeting the hepcidin pathway, which regulates iron availability and erythropoiesis. Other potential treatments include vitamin D supplementation and HIF stabilizers. Accurate diagnosis and targeted management of anemia in ICU patients is crucial to improve outcomes and prevent long-term complications.

Asset Subtitle

Hematology, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Anemia in the ICU: Current Concepts and Future Treatments

Lena M. Napolitano

Meta Tag

Content Type Presentation

Knowledge Area Hematology

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Anemia

Tag Transfusion

Year 2021

Keywords

anemia

critically ill patients

ICU

causes of anemia

mortality and morbidity

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