Perioperative Management of Iron Deficiency Anemia

Moises Auron MD FAAP, FACP Hospital Medicine

Regulation of Iron Metabolism

Normal body iron content ~ 3 to 4 g. - Hemoglobin ~ 2.5 g - Iron-containing proteins (eg, myoglobin, Ironcytochromes, catalase) ~ 400 mg - Transferrin-bound ~ 3 to 7 mg Transferrin- Storage iron (ferritin; hemosiderin) Storage varies according to gender - Men ~ 1 g (liver, spleen, and bone marrow). - Women depends on physiologic factors (menses, pregnancies, deliveries, lactation, and iron intake).

Regulation of Iron Metabolism

Muoz M. Vox Sanguinis. 2008; 94: 172183

Erythropoiesis in CKD

Kalantar-Zadeh K. Adv Chron Kid Dis. 2009; 16(2): 143-151.

Hemoglobin
64.4 kd tetramer 2 pairs of globin polypeptide chains - One pair alpha chains - One pair of non-alpha chains non Heme group single protoporphyrin IX bound to ferrous (Fe2+) ion linked covalently to each globin chain - If iron is oxidized [ferric state (Fe3+)] metHb Heme iron is linked covalently to histidine Oxygenation and deoxygenation Hb conformational

Diagnostic indicators of IDA

Soluble transferrin receptors(sTfRs) sTfR sTfRferritin index (sTfRF) (sTfR Zinc protoporphyrin/heme ratio (ZPP/H) Reticulocyte hemoglobin content (CHr) Selective endoscopy Hepcidin

Clark SF. Curr Opin Gastroent. 2009; 25:122128.

Tests to assess Iron deficiency

Muoz M. Vox Sanguinis. 2008; 94: 172183

Serum Transferrin Receptor (sTfR)

Skikne BS. Am J Hematol. 2008; 83:872875.

Indian J Pediatr 2010; 77 (2) : 179-183

Serum TfR/Ferritin Ratio

sTfR as body Fe stores TfR/ferritin - valuable measure of the extent of Fe deficiency TfR/log ferritin - superior to the TfR/ferritin ratio, sTfR or ferritin in correctly distinguishing IDA vs. ACD vs. ACD from ACD + IDA (COMBI). sTfR had a sensitivity of 71% and specificity of 74% for correctly identifying iron-depleted marrow iron Ferritin which had a sensitivity of 25%, but specificity of 99%.
Skikne BS. Am J Hematol. 2008; 83:872875. Means RT. Clin. Lab. Haem. 1999; 21:161167

Degree of Iron deficiency

Gasche C, et al. Inflamm Bowel Dis 2007;13:15451553

Mortality predictability in CKD

Kalantar-Zadeh K. Adv Chron Kid Dis. 2009; 16(2): 143-151.

Ganzonis formula
Total Fe deficit (mg) = [Wt (kg) x (14 - actual Hb) x 0.24] + 500 (iron depot) - Blood volume 70 ml/kg of BW ~7% of body weight - Fe content of Hb 0.34% - Factor 0.24 = 0.0034 x 0.07 x 1000 (g to mg).

70 kg; Hb 9 g/dL ~ deficit of 1400 mg. Underestimation of iron depot in males - ~ 700-900 mg. 700Muoz M, et al. World J Gastroenterol 2009; 15(37): 4666-4674 Ganzoni AM. Intravenous iron-dextran: therapeutic and experimental possibilities. Schweiz Med Wochenschr. 1970;100: 301303.

Calculation of Iron deficit

Blood volume (dL) = 65 (mL/kg) x body weight (kg) 100 (mL/dL) Hb deficit (g/dL) = 14.0 [patient Hb] Hb deficit (g) = Hb deficit (g/dL) x Blood volume (dL) Iron deficit (mg) = Hb deficit (g) x 3.3 (mg Fe/g Hb) Volume of parenteral Fe (mL) = Iron deficit (mg) C(mg/mL)

Schrier SL. Up To Date. Version 18.3

Calculation of Iron deficit

Hemoglobin iron deficit (mg) = BW x (14 - Hgb) x (2.145) Volume of product required (mL) = BW x (14 - Hgb) x (2.145) C C = The concentration of elemental iron: Iron dextran: 50 mg/mL Iron sucrose: 20 mg/mL Ferric gluconate: 12.5 mg/mL

Schrier SL. Up To Date. Version 18.3

Algorithm for IV Iron replacement

Muoz M. Vox Sanguinis. 2008; 94: 172183

What about IM iron?

Painful Associated with gluteal sarcomas Permanent discoloration of the skin No evidence of superiority over IV

Auerbach M. Am J Hematol. 2008; 83: 580588

Parenteral Iron

Gasche C, et al. Inflamm Bowel Dis 2007;13:15451553

Other iron preparations

Ferumoxytol (Feraheme ) - semi-synthetic carbohydrate-coated semicarbohydratesuperparamagnetic iron oxide nanoparticle - safe and effective when given as a rapid intravenous infusion of up to 510 mg (infusion rate: up to 30 mg/second) in patients with CKD and ESRD Safety concerns were hypotension and/or hypersensitivity reactions (anaphylaxis and/or anaphylactoid reactions). May transiently affect the diagnostic ability of MRI

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022180lbl.pdf

Difficult beginnings
Self limited arthralgias and myalgias ~ 50% - Only 1 in 87 patients had nonfatal anaphylaxis - Decreased with methylprednisolone (125 mg) before and after infusion (1998) - No relationship with infusion rate - Lack of efficacy of ASA and diphenhydramine Single case report in Lancet (1983) of meningismus - Patient with myalgia/arthralgia syndrome Oral iron - inexpensive and effective if tolerated - decreased interest in parenteral iron.

Auerbach M. Am J Hematol. 2008; 83: 580588

The evolution of iron preparations

HMWD (DexFerrum) 1111-fold serious AE vs. LMWD (InFeD) - Anaphylactic reactions Non-dextran preparations Non- Ferric gluconate Patients with reactions have no tryptase 125 mg IV push over 510 min 5 - Iron sucrose 200 mg IV push or 300 mg over 2 hr LMWD, ferric gluconate, and iron sucrose: similar AEs - Estimated incidence of <1:200,000.
Auerbach M. Am J Hematol. 2008; 83: 580588

Iron in ESRD
Eschbach (1987) 1g IV Fe dextran in dialysis patients failing to respond to EPO (standard dose of 50 U/kg 3 x wk) despite Ferritin > 500 ng/ ml. Fishbane IV Fe: - Decreased suboptimal response to EPO: 3040% to < 10% 30 - dosing and duration of EPO - Poor compliance and absorption avoid PO Fe - IV Fe 1g rapid improvement of erythropoiesis and replenishment of depleted stores. Administered over 10 doses. Serious AE ~ 0.7% ~ 0.3% - acute chest and back pain without BP, RR, HR, wheezing, stridor, or periorbital edema Self limited reactions.
Auerbach M. Am J Hematol. 2008; 83: 580588

Iron and ESRD

Hoen et al. - N = 998 hemodialysis patients - No association of ferritin levels or IV Fe administered with infections.

Clin Nephrol. 2002 Jun;57(6):457-61.

Iron in ESRD
NKF-KDOQI - IV iron in preference to p.o. iron - Serum ferritin >100 ng/ mL - Continue Fe as long as ferritin <800 ng/mL. - Halt iron therapy if the Tsat > 50% - IV iron can be administered: LMWD total infusion dose or repeated doses Ferric gluconate or iron sucrose repeated doses

Auerbach M. Am J Hematol. 2008; 83: 580588

IDA in non-dialysis CKD non-

MacDougall IC. Curr Med Res & Opin. 2010; 26(2):473482.

IV Iron in Non-dialysis CKD Non-

MacDougall IC. Curr Med Res & Opin. 2010; 26(2):473482.

Anemia of chronic disease

Disturbed iron homeostasis - absorption and Fe recycling from RES - hypoferremia (low transferrin-bound iron) transferrin IBD - I.V. Fe route of choice Potential of worsening IBD with P.O. Fe

Auerbach M. Am J Hematol. 2008; 83: 580588

Anemia of cancer and chemotherapy

Multiple studies of patients with different type of cancer on chemoradiation or chemotherapy on ESA - Randomized to ESA alone, p.o. vs. i.v. Iron IV iron - Increase in Hb > 2 g/dL - 45% decrease in allogenic blood transfusions - reduces ESA failure - Oncology no difference in tumor outcomes vs. ESA

Auerbach M. Am J Hematol. 2008; 83: 580588

Auerbach M. Am J Hematol. 2008; 83: 580588

Parenteral iron in surgery

N = 84 patients Major elective surgery (30 colon cancer resections, 33 abdominal hysterectomies, 21 lower limb arthroplasties) IV iron mean dose 1000 mg + 440 mg Hb > 2.0 g/dl Resolved anemia in 58% of patients. No life-threatening AEs lifeMuoz M. Med Clin (Barc). 2009 Mar 7;132(8):303-6.

Iron in Orthopedic surgery

Meta-analysis (N = 807) Meta IV iron significant decrease in: - transfusion rate [ RR: 0.60, 95% CI: 0.500.50-0.72, P < 0.001] - infection rate [RR: 0.45, 95% CI: 0.320.320.63, P < 0.001]
Garca-Erce JA. Anemia 2009; 2: 17-27.

Iron in Gynecologic surgery

N = 76 with Hb <9.0 g/dl due to menorrhagia IV Fe sucrose 3 times/wk vs. Daily P.O. Fe protein succinylate IV Fe: - Hb (3.0 vs. 0.8 g/dl; p < 0.0001) - Ferritin levels (170.1 vs. 4.1 microg/l; p < 0.0001) - Target Hb was also higher in the intravenous iron group than in the oral iron group (76.7% vs. 11.5%; p < 0.0001).
Kim YH. Acta Haematol. 2009;121(1):37-41. 2009;121(1):37-

Potential negative effects of intravenous iron

Pro-oxidant - might increase oxidative stress, Proinfections, mortality, tumor growth. - p.o. Iron - worsening IBD (Fenton reaction) Non-ESRD patients nephrotoxicity? Non- Transient increase in induced proteinuria and albuminuria with iron sucrose. - Ferric gluconate showed significant increases in lipid peroxidation.

Auerbach M. Am J Hematol. 2008; 83: 580588

Iron and infectious diseases

Weinberg ED. Emerg Infect Dis 1999;5:34652.

Body iron and disease

Weinberg ED. Emerg Infect Dis 1999;5:34652.

Identify patients at risk of receiving perioperative transfusions - patients red blood cell mass - transfusion trigger - expected blood loss Check Hb and iron status (serum iron, serum ferritin, transferrin saturation, and C-reactive protein) ~ 30 days before surgery. CFor patients > 60 yr old, vitamin B12 and folic acid should also be measured. Iron replacement per Ganzonis formula. Postoperatively 150 mg of i.v. iron per g/dl of Hb drop should be added to compensate iron loss due to perioperative bleeding.

Br J Anaesth 2008; 100: 599604

 Preoperative Fe administration in non-anemic patients: non- Ferritin < 100 ng/ml - Ferritin 100300 ng ml and Tsat < 20% 100 - Surgery with EBL > 1500 ml (Hb drop ~f 35 g/dl) 3 IV Fe should be avoided in: - Ferritin > 300 ng/ml and Tsat > 50%. - Acute infection.

Br J Anaesth 2008; 100: 599604

Iron Adverse drug events

FDA (2001 2003) - 30 million doses - 11 deaths - 1141 total ADEs Iron sucrose - 0.6 per million doses Ferric gluconate - 0.9 per million doses LMWD - 3.3 per million doses HMWD - 11.3 per million doses
Chertow GM. Nephrol Dial Transplant. 2006;21(2):378-82.

Cost of IV Iron vs. Transfusion

Bieber EJ. OBG Management. 2010;22(2):28-38. Silverstein SB. Am J Hematol. 2004; 76:7478.

Recommended Preoperative IV Iron replacement

Venofer (Iron sucrose) 200 mg (10 ml) administered over 10 minutes x 5 doses. Ferrlecit (Ferric gluconate) 125 mg iv over 1 hour x 8 doses (Inpatient).