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Iron and anemia in CCM

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This slide show was presented in critical care physiology class at Sina Hospital, Tehran University of Medical Sciences.

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Iron and anemia in CCM

  1. 1. IRON AND ANEMIA IN CRITICAL CARE PHYSIOLOGY Reza Nejat, M.D., Anesthesiologist, FCCM, Former Assistant Professor, SBMU
  2. 2. IRON and ANEMIA(CCP) Part 1 IRON and Evolution
  3. 3. IRON and ANEMIA(CCP) Living objects are complex systems: have distinct components with distinct properties but related to each other and as a whole have nonlinearity, ability to emerge, have spontaneous order, adaptation, and feedback loops, …. Living objects increase their enthalpy and decrease entropy: 𝑯 = 𝑼 + 𝒑𝑽
  4. 4. IRON and ANEMIA(CCP)  Primitive living objects were acellular organisms (complex systems) :  drastically different from anything we know.  lacking of a mechanism for division, yet were able to grow.  lacking of enzymes or a mechanism for translation, but with an autocatalytic metabolism.  lacking of nucleic acids or any other template, yet with inheritance and selection.  with capacity for evolution.
  5. 5. IRON and ANEMIA(CCP) Three hypothesis to explain the origin of prebiotic molecules:  synthesis in a reducing atmosphere,  input in meteorites and  synthesis on metal sulfides in deep- sea vents It is unclear whether the RNA world was the first biological world or whether some simpler world preceded it.
  6. 6. IRON and ANEMIA(CCP) RNA world hypothesis  Self-replicating RNA molecules proliferated before the evolution of DNA and Proteins Iron-Sulfur world (Wächtershäuser proposed) hypothesis  early life may have formed on the surface of pyrite (𝑭𝒆𝑺 𝟐)
  7. 7. IRON and ANEMIA(CCP)  Central to the proposed theory is the idea that life at its early stage was:  autotrophic  consisted of an autocatalytic metabolism  confined to an essentially two dimensional monomolecular organic layer.  surface organisms or metabolists
  8. 8. IRON and ANEMIA(CCP)  Central to the proposed theory is the idea that life at its early stage was:  autotrophic  consisted of an autocatalytic metabolism  confined to an essentially two dimensional monomolecular organic layer.  surface organisms or metabolists
  9. 9. IRON and ANEMIA(CCP) Autotroph:  an organism that is able to form nutritional organic substances from simple inorganic substances such as carbon dioxide  The energy for carbon fixation on these surface metbolists is provided by: the redox process of converting ferrous ions and hydrogen sulfide into pyrite (𝑭𝒆𝑺 𝟐)
  10. 10. IRON and ANEMIA(CCP) RNA world hypothesis  Self-replicating RNA molecules proliferated before the evolution of DNA and Proteins Iron-Sulfur world (Wächtershäuser proposed) hypothesis  early life may have formed on the surface of pyrite (𝑭𝒆𝑺 𝟐)
  11. 11. IRON and ANEMIA(CCP)  Iron is required by most organisms to serve as a prosthetic group for metalloproteins involved in central cellular processes:  Respiration (electron transfer),  DNA synthesis and repairment,  Oxygen sensing and transport.
  12. 12. IRON and ANEMIA(CCP)  Iron is the catalytic element that allowed the formation of macromolecules from CO2 and H2  Wächtershäuser proposed:  an early form of metabolism predated genetics  Metabolism?
  13. 13. IRON and ANEMIA(CCP) Increasing ambient OXYGEN concentration after photosynthesis started and declined 𝑭𝒆+𝟐 concentration by reducing it to its insoluble oxidized form 𝑭𝒆+𝟑
  14. 14. IRON and ANEMIA(CCP) Fenton’s Reaction H.J.H Fenton discovered in 1894 that several metals have a special oxygen transfer properties which improve the use of 𝑯 𝟐 𝑶 𝟐. Actually, some metals have a strong catalytic power to generate highly reactive 𝑶𝑯−•. 𝑭𝒆 𝟐+ + 𝑯 𝟐 𝑶 𝟐 → 𝑭𝒆 𝟑+ + 𝑶𝑯 + 𝑶𝑯−• 𝑭𝒆 𝟑+ + 𝑯 𝟐 𝑶 𝟐 → 𝑭𝒆 𝟐+ + 𝑶𝑶𝑯−• + 𝑯+
  15. 15. IRON and ANEMIA(CCP)  Excess of iron in cells:  Generation of Free Radicals  Damage proteins, DNA, Lipids  Cirrhosis,Cardiomyopathy, DM,  NBIA (neurodegeneration with brain iron accumulation)  FA (Friedreich's ataxia)  Parkinson’s and Alzheimer's diseases  Deficiency of iron in cells:  Impaires cellular proliferation  Cognitive Disorders  Anemia
  16. 16. IRON and ANEMIA(CCP) Body Content of IRON:  3-4 g  2.0-2.5 g (within hemoglobin of erythrocytes)  Average 2.3 g in males  Average 2.1 g in females  0.5-1.0 g (deposited in ferritin within hepatocytes and macrophages)  0.5 g (myoglobin, ferritin and iron-containing enzymes)  3 mg (in serum as transferrin-bound)
  17. 17. IRON and ANEMIA(CCP)  Iron is biologically functional due to its chemical properties:  its capacity to form a variety of coordination complexes with organic ligands in a dynamic and flexible mode,  favorable redox potential to switch between the ferrous, Fe(II), and ferric, Fe(III)
  18. 18. IRON and ANEMIA(CCP) Iron Absorption:  1-3 mg/day  (through the gut) Iron Loss:  1-3 mg/day  through urine, sweating, desquamated enterocytes, menstruation)  23 mg/day  recycled (dying RBC to M𝛗 to BM)
  19. 19. IRON and ANEMIA(CCP) Iron Absorption:  1-3 mg/day  (through gut) Iron Loss:  1-3 mg/day  through urine, sweating, desquamated enterocytes, menstruation)  mammals lack a regulated physiological mechanism for iron excretion,  intestinal iron absorption is a tightly regulated process
  20. 20. IRON and ANEMIA(CCP) Iron Absorption by enterocytes:  Dietary non-heme 𝑭𝒆 𝟑+:  After being reduced to 𝑭𝒆 𝟐+:  by membrane bound ferrireductases  Duodenal cytochrome B  DMT 1 (divalent metal transporter 1)  Dietary heme Iron:  by enterocytes by an undefined mechanism?
  21. 21. IRON and ANEMIA(CCP)
  22. 22. IRON and ANEMIA(CCP)
  23. 23. IRON and ANEMIA(CCP)
  24. 24. IRON and ANEMIA(CCP)
  25. 25. IRON and ANEMIA(CCP) Body Iron:  Most of it is found within hemoglobin in red cells (the erythron),  A smaller amount being distributed in other tissues such as muscles and in deposits.
  26. 26. IRON and ANEMIA(CCP) Hepcidin (Liver-derived) Decreases Iron Availability:  blocks iron absorption  directs iron towards deposits Erythroferrone (erythroblast-derived) Increases Iron Availability  inhibits hepcidin synthesis
  27. 27. IRON and ANEMIA(CCP) Hepcidin  a peptide hormone made in the liver  the principal regulator of systemic iron homeostasis which controls:  plasma iron concentration  tissue distribution of iron by inhibiting: intestinal iron absorption, iron recycling by macrophages, iron mobilization from hepatic stores
  28. 28. IRON and ANEMIA(CCP) Hepcidin synthesis:  increased by iron loading,  decreased by anemia and hypoxia.  elevated during infections and inflammation (Inflammatory cytokines like IL-1, IL-6, IL-22, Oncostatin M):  causing a decrease in serum iron levels  the development of anemia of inflammation,  probably a host defense mechanism to limit the availability of iron to invading microorganisms
  29. 29. IRON and ANEMIA(CCP) Hepcidin acts by:  inhibiting cellular iron efflux through binding to and inducing the degradation of ferroportin.  Ferroportin: the sole known cellular iron exporter
  30. 30. IRON and ANEMIA(CCP) molecules involved in Iron metabolism: TfR1 &TfR2 IRE IRP1 & IRP2 divalent metal transporter-1 Dcytb heme carrier protein-1 ferroportin-1, FPN1 Hepcidin EPO & erythroferron hemojuvelin, HJV hemochromatosis gene product, HFE lactoferrin, Lf melanotransferrin, MTf
  31. 31. IRON and ANEMIA(CCP) Hepcidin deficiency:  the ultimate cause of most forms of hemochromatosis, either due to mutations in the genes encoding:  hepcidin  regulators of hepcidin synthesis.
  32. 32. IRON and ANEMIA(CCP) Part 2 ANEMIA
  33. 33. IRON and ANEMIA(CCP) WHO anemia afflicts 1.6 billion people worldwide about one-fourth of the world’s population
  34. 34. IRON and ANEMIA(CCP) Definition of Anemia:  Hb level  less than 13 g/dL for adult males range from 13 to 14.2 g/dL  less than 12 g/dL for adult nonpregnant females 11.6 to 12.3 g/dL in women  the exact cutoff to establish a diagnosis can be elusive
  35. 35. IRON and ANEMIA(CCP)  RBC formation:  under steady-state conditions  Basal rate of 15–20 ml/day  After hemolysis or heavy blood loss  Rises to 200 ml/day (in iron-replete healthy persons)
  36. 36. IRON and ANEMIA(CCP) Blood. 2006; 107(5): 1747-1750
  37. 37. IRON and ANEMIA(CCP)  RBC rheology:  contributes to vasoregulation, particularly at the microvascular level  has an influence on vascular tone by:  Altering wall shear stress  Modifying nitric oxide generation,  homogenizing flow distribution at capillary branch points
  38. 38. IRON and ANEMIA(CCP) RBCs and hemoglobin through three mechanisms match local flow and metabolic demand: 1. bioactive NO production is proportionated with deoxyhemoglobin acting as a nitrite reductase 2. NO is bound by oxyhemoglobin in the lungs and released by deoxyhemoglobin in the tissues, 3. Mechanical deformation of RBCs and desaturation of hemoglobin initiates vasodilation by release of ATP that binds to endothelial cell purinergic receptors and stimulates NO synthesis ⌂critical contribution of healthy RBCs to active vasoregulation.
  39. 39. IRON and ANEMIA(CCP) Deleterious effects of ANEMIA:  Cardiac Related:  Morbidity  Mortality  Generalized low 𝑶 𝟐 transport 𝑫𝑶 𝟐 = 𝑪𝑶 × 𝑪 𝒂 𝑶 𝟐 𝑫𝑶 𝟐 = 𝑪𝑶 × (𝟏. 𝟑𝟒 × 𝑯𝒈𝒃 × 𝑺 𝒂 𝑶 𝟐)
  40. 40. IRON and ANEMIA(CCP) anemia and adverse outcomes in  congestive heart failure  acute myocardial infarction  type 2 myocardial infarction  chronic kidney disease  mechanical ventilation weaning off  increased risk of death
  41. 41. IRON and ANEMIA(CCP)  Acute isovolemic  ↓ [Hb] →5 g/dl in resting healthy humans with no evidence of tissue hypoxia →progressive increases in:  heart rate,  stroke volume,  oxygen extraction, and  cardiac index  Chronic drop in Hb is more tolerable:  HIF
  42. 42. IRON and ANEMIA(CCP)  patients with acute respiratory failure with Hb<10 g/dL have more than five times risk to require reintubation after an initial successful spontaneous breathing trial and extubation
  43. 43. IRON and ANEMIA(CCP)  Anemia may overestimate serum glucose by point-of-care glucometers,  creating a risk of hypoglycemia if these values are used to calculate insulin needed.
  44. 44. IRON and ANEMIA(CCP)  A large proportion of critically ill patients are anemic on admission,  the majority of non-anemic patients becomes anemic during their ICU stay  The incidence of anemia at ICU is proportionally related to the duration of ICU stay
  45. 45. IRON and ANEMIA(CCP) in critically ill patients: ABC study Common occurrence of anemia Large use of BT ABC study revealed association between: BT and diminished organ function BT and Mortality JAMA. 2002; 288: 1499-1507
  46. 46. IRON and ANEMIA(CCP)  Anemia:  common in the critically ill and  results in a large number of RBC transfusions.  The number of transfused RBC units:  independent predictor of worse clinical outcome.  Crit Study;  Critical Care Medicine. 32(1):39-52, JAN 2004
  47. 47. IRON and ANEMIA(CCP) Etiology: Three pathophysiological pathways end up with ANEMIA:  Low production  Low EPO, ACD (IL1, IL6,TNFα), relative Iron Def.,  Destruction before maturation  Ineffective erythropoiesis  Destruction after maturation  Hemolysis, bleeding (GI), phlebotomy,…
  48. 48. IRON and ANEMIA(CCP) Classification of anemia cause Blood Loss Inadequate production Excessive destruction morphology Normocytic microcytic macrocytic
  49. 49. IRON and ANEMIA(CCP)
  50. 50. IRON and ANEMIA(CCP)
  51. 51. IRON and ANEMIA(CCP) Anemia in critical illness and injury results from:  a shortened RBC circulatory life span  hemolysis,  phlebotomy losses (“anemia of chronic investigation”)  oozing at injury sites,  invasive procedures,  GI bleeding  diminished RBC production  nutritional deficiencies  and the “anemia of inflammation.”
  52. 52. IRON and ANEMIA(CCP) Eryptosis and Neocytolysis
  53. 53. IRON and ANEMIA(CCP)  Eryptosis:  the premature death of mature RBCs,  triggered by excessive oxidant RBC injury, and other stressors  Is inhibited by EPO  excessive eryptosis may lead to the development of anemia  Neocytolysis:  removal of RBCs just released from the marrow
  54. 54. IRON and ANEMIA(CCP)  Eryptosis is characterized by:  a cascade of biochemical and biomechanical changes, leading to:  cell shrinkage,  dysregulation of normal membrane asymmetry  exposure of normally sequestered phosphatidylserine on the outer membrane leaflet,  the formation of membrane blebs and microparticles.
  55. 55. IRON and ANEMIA(CCP)  Neocytolysis:  the process of selectively removing young circulating RBCs,  initiates by a sudden fall in EPO levels  was first noted in the study of RBC mass reduction that occurs during spaceflight (microgravity) and after descent from high altitude;
  56. 56. IRON and ANEMIA(CCP)  Eryptosis and Neocytolysis:  are negatively regulated by EPO  acting at different points in the life span of the RBC,  provide flexibility and fine control in regulation of total RBC mass
  57. 57. IRON and ANEMIA(CCP) “Anemia of Inflammation”  Inflammatory processes leading to impaired:  RBC proliferation,  iron metabolism,  EPO production and signaling  evolutionary response to sequester and harness iron trafficking  invading micro-organisms cannot reach iron.
  58. 58. IRON and ANEMIA(CCP) proinflammatory cytokines  impair iron homeostasis and normal RES functioning:  IL-1,  IL-6,  tumor necrosis factor (TNF)-α,  Decrease regulatory feedback between body iron needs and intestinal iron absorption
  59. 59. IRON and ANEMIA(CCP)  Inflammation results in minimal response by the bone marrow due to:  reduced transcription of the EPO gene  IL-1,TNF-a,TGF-β  Inhibition of RBC production through direct interaction of mediators with erythroid progenitor cells
  60. 60. IRON and ANEMIA(CCP)  in the setting of shock, vasopressor at high concentrations directly inhibit hematopoietic precursor maturation  norepinephrine  phenylephrine
  61. 61. IRON and ANEMIA(CCP)  Key tests for a complete diagnosis of anemia of critical illness: 1. serum iron concentration, 2. serum transferrin concentration, 3. transferrin receptor protein concentration, 4. total iron binding capacity, 5. serum ferritin concentration,
  62. 62. IRON and ANEMIA(CCP) Serum iron levels:  the amount of circulating iron bound to transferrin. The total iron-binding capacity:  an indirect measure of the circulating transferrin concentration.
  63. 63. IRON and ANEMIA(CCP)  Serum ferritin level correlates with total body iron stores:  suitable laboratory estimate of iron store  Levels of transferrin receptor protein in circulation:  a quantitative measure of total erythropoiesis  can be used to measure the expansion of the erythroid marrow in response to rEPO therapy.
  64. 64. IRON and ANEMIA(CCP) EPO  tightly regulates erythropoiesis  normally increases with anemia,  circulating EPO concentrations fall quickly and remain low in critical illnesses:  decreased renal function  proinflammatory cytokine  a sudden and continued drop in EPO production promotes neocytolysis and eryptosis
  65. 65. IRON and ANEMIA(CCP) EPO  In critical illnesses EPO receptor downregulation:  limits the availability of iron for cell proliferation and hemoglobin synthesis  Its release by the kidneys in response to hypoxemia and anemia is suppressed by:  angiotensin-converting enzyme inhibitors,  angiotensin receptor blockers,  calcium channel blockers,  theophylline,  b-adrenergic blockers,
  66. 66. IRON and ANEMIA(CCP)  Hepcidin, an iron regulatory protein:  is up-regulated in inflammatory conditions and  Is suppressed by EPO,  decreases duodenal iron absorption  blocks iron release from macrophages.
  67. 67. IRON and ANEMIA(CCP)  Hepcidin, an iron regulatory protein:  limits iron availability  leading to iron restricted erythropoiesis  impairs heme biosynthesis  during systemic infection there is  up-regulation of the IL-6–hepcidin axis,  responsible for low serum iron levels observed in inflammation
  68. 68. IRON and ANEMIA(CCP) Erythroferrone, ERFE  A new hormone identified,  Mediates hepcidin suppression  Allows increased iron absorption and mobilization from iron stores.  Is produced by erythroblasts in response to erythropoiesis- stimulating agent (ESA) treatment
  69. 69. IRON and ANEMIA(CCP) ACritD Iron Def ↓ 𝐹𝑒 ↓ 𝐹𝑒 ↓ 𝑇𝐼𝐵𝐶 ↑ 𝑇𝐼𝐵𝐶 ↓ 𝑡𝑟𝑎𝑛𝑠𝑓𝑒𝑟𝑟𝑖𝑛 𝑠𝑎𝑡𝑢𝑟𝑎𝑡𝑖𝑜𝑛 = (𝑠𝑒𝑟𝑢𝑚 𝐹𝑒) 𝑇𝐼𝐵𝐶 ↓↓↓ 𝑡𝑟𝑎𝑛𝑠𝑓𝑒𝑟𝑟𝑖𝑛 𝑠𝑎𝑡𝑢𝑟𝑎𝑡𝑖𝑜𝑛 = (𝑠𝑒𝑟𝑢𝑚 𝐹𝑒) 𝑇𝐼𝐵𝐶 < 18% 𝑁𝑙 𝑠𝑇𝑓𝑅𝑃 ↑ 𝑠𝑇𝑓𝑅𝑃 𝑁𝑙 −↑ 𝐹𝑒𝑟𝑟𝑖𝑡𝑖𝑛 ↓ 𝐹𝑒𝑟𝑟𝑖𝑡𝑖𝑛 TfR-F<1 TfR-F>2 𝒃𝒐𝒅𝒚 𝑰𝒓𝒐𝒏 𝒎𝒈 𝒌𝒈 = −[𝐥𝐨𝐠 𝑻𝒇𝑹 𝒇𝒆𝒓𝒓𝒊𝒕𝒊𝒏 − 𝟐. 𝟖𝟐𝟐𝟗]/𝟎. 𝟏𝟐𝟎𝟕 TfR-F=(𝑻𝒇𝑹/ 𝐥𝐨𝐠 𝑭𝒆𝒓𝒓𝒊𝒕𝒊𝒏)
  70. 70. IRON and ANEMIA(CCP)
  71. 71. IRON and ANEMIA(CCP) In a teaching general hospital:  Of 520 BT episodes with 1218 units of packed red blood cells 88% were appropriate;  Of 106 episodes with 405 units of FFP 90% were deemed appropriate;  Of 187 episodes with 320 units of albumin given 64% were considered appropriate. CMAJ. 1989; 140: 812-815
  72. 72. IRON and ANEMIA(CCP)  The long-term ICU population receive a large number of BT.  No clear indication for a large number of the BT given.  Many BTs are administered due to:  an arbitrary "transfusion trigger"  not a physiologic need for blood. CHEST 1995; 108:767-71
  73. 73. IRON and ANEMIA(CCP)  Blood Transfusion:  A physiologic need? Or  A response to transfusion trigger  Trials:  ABC  Crit  Walsh and colleagues  the American Burn Association  North Thames Blood Interest Group  ↑ ICU stay and mortality??!!!
  74. 74. IRON and ANEMIA(CCP)  Blood transfusion is associated with an increased risk of:  death,  infectious complications,  acute respiratory distress syndrome (ARDS)  The only absolute indication for PRBC transfusion is in the therapy of hemorrhagic shock  Take care of ACS and MI
  75. 75. IRON and ANEMIA(CCP) Serious risks of BT:  Transmission of infectious diseases,  immune-mediated reactions:  acute or delayed hemolytic reactions,  febrile allergic reactions,  anaphylaxis,  graft-versus-host disease,  non–immune-related complications:  fluid overload,  electrolyte toxicity,  iron overload
  76. 76. IRON and ANEMIA(CCP)  The decision to transfuse blood must be based rather on the patient’s  intravascular volume status,  evidence of shock,  duration and extent of anemia,  cardiopulmonary physiologic parameters.  The only absolute indication for PRBC transfusion is in the therapy of hemorrhagic shock  Take care of ACS and MI
  77. 77. IRON and ANEMIA(CCP) Normal RBC aging leads to:  changes in membrane characteristics:  reduced fluidity and deformability,  loss of volume and surface area,  increased cell density and viscosity,  deleterious alterations in the intracellular milieu  decreased ATP and 2,3-DPG,  Lowered hexokinase  Low G6PD activity
  78. 78. IRON and ANEMIA(CCP)  Phosphatidylserine↑:  marks cells for engulfment by macrophages,  may carry important downstream effects related to:  inflammation,  coagulation,  cell signaling,  immune modulation
  79. 79. IRON and ANEMIA(CCP) Normal RBC aging leads to:  a fall in cellular energy level,  increased Hb–oxygen affinity,  reduced repair of oxidant injury,  diminished ability of cells to deform normally during microvascular transit  mark RBCs for removal by the spleen and RES  Alterations in rheology with normal aging in critically ill patients:  may occur sooner  may be associated with poor outcomes
  80. 80. IRON and ANEMIA(CCP) Potentially deleterious changes during preservation and storage of blood:  Decreased concentrations of ATP, 2,3-DPG, and S-nitrosylhemoglobin;  Accumulation of proinflammatory cytokines;  Release of hemoglobin and red cell arginase;  Accumulation of RBC membrane microparticles  Decreased RBC membrane inactivation of cytokines by Duffy antigen These changes may result in:  potent NO scavenging and vasoconstriction,  loss of normal RBC-mediated vasoregulation,  immunosuppression.
  81. 81. IRON and ANEMIA(CCP) Preventive measures  Reduction in phlebotomy  Use of pediatric or low-volume adult blood sampling tubes  Use of in-line closed blood conservation devices on arterial and central lines  Cell salvage during surgical procedures,
  82. 82. IRON and ANEMIA(CCP) Erythropoiesis-stimulating agents  indicated for treatment of critically ill patients with chronic kidney disease  ESAs are not currently recommended for treatment of anemia in critically ill patients  ESA use in trauma critically ill patients was associated with significantly increased survival in 2 large RCTs
  83. 83. IRON and ANEMIA(CCP) Iron Supplementation  A recent meta-analysis of 5 RCTs of iron supplementation:  no difference in RBC transfusion rates or Hb  no difference in secondary outcomes of mortality, in hospital infection, or length of stay.  IRONMAN  compared IV iron (500 mg ferric carboxymaltose,FCM) to placebo in 140 critically ill patients  no significant difference between the groups in any safety outcome.
  84. 84. IRON and ANEMIA(CCP)  www.rezanejat.com

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