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Preoperative Anemia Lori Heller, MD Cardiac Anesthesiologist

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1 Preoperative Anemia Lori Heller, MD Cardiac Anesthesiologist
Medical Director, Blood Management Program Swedish Medical Center Seattle, WA

2 Outline Anemia/preoperative anemia – Outcomes Evaluation of Anemia
Treatment Iron ESA – safety/efficacy

3 Swedish Medical Center
Private, non-profit organization founded 1910 6 Hospitals 100 Primary and Specialty Care Clinics 2 Ambulatory Care Centers Level II Trauma Residency: Gen Surgery/Family Medicine/Podiatry Fellowships: MFM, Thoracic , Neuro, Robotic, Lap Active Robotic Surgery Program 11,000 employees in Greater Seattle

4 FH Main Campus Ballard Campus 163 beds 613 beds 385 beds Cherry Hill Campus

5 5 Swedish Orthopedic Institute Edmonds Campus 84 beds 217 beds
Issaquah Campus 5

6 Blood Management Began 1999 as Bloodless Program Manager 1.5 FTE RN
0.7 FTE data assistant Medical Director – 20 hrs month

7 Ortho transfusion rate decreased 83% over 6 years.
% Orthopedic Patients Transfused Ortho transfusion rate decreased 83% over 6 years.

8 % Hospitalists Patients Transfused
% Patients transfused decreased from 32 to 23

9 Autologous Blood Utilization

10 Anemia – it’s prevalent!
Estimated 3.5 million US Preoperative – 20-40% (Ortho, lung ca, colorectal, mixed) HCT < 39 – 25-30% HCT < 36 – 34% Elderly – 10-60% Hospitalized men HCT < % women HCT < % Community % Cardiac Surgery – 26% 10

11 Percent CV Pts Anemic Upon Admission 2011-2012

12 % Orthopedic Patients Anemic

13 Anemia It’s bad! Higher rates of hospitalization Decreased survival
5 yr survival 48 v. 67% (p<0.001) 8 year survival Salive J Am Geriatr Soc 1992;40:489-96 Kikuchi et al J Am Geriatr Soc 2001;49:1226-8 The American Journal of Medicine Volume 119 • Number 4 • April 2006 13

14 Anemia Survival Not Anemic Anemic
The American Journal of Medicine Volume 119 • Number 4 • April 2006

15 Preoperative Anemia It’s bad too!

16 Preoperative Anemia 227,425 pts RC 30 day outcome OR 1.42 mortality
Even Mild Anemia Mild 29-36 Mod less than 29 Background Preoperative anaemia is associated with adverse outcomes after cardiac surgery but outcomes after non-cardiac surgery are not well established. We aimed to assess the e ect of preoperative anaemia on 30-day postoperative morbidity and mortality in patients undergoing major non-cardiac surgery. Methods We analysed data for patients undergoing major non-cardiac surgery in 2008 from The American College of Surgeons’ National Surgical Quality Improvement Program database (a prospective validated outcomes registry from 211 hospitals worldwide in 2008). We obtained anonymised data for 30-day mortality and morbidity (cardiac, respiratory, CNS, urinary tract, wound, sepsis, and venous thromboembolism outcomes), demographics, and preoperative and perioperative risk factors. We used multivariate logistic regression to assess the adjusted and modifi ed (nine predefi ned risk factor subgroups) e ect of anaemia, which was defi ned as mild (haematocrit concentration >29–<39% in men and >29–<36% in women) or moderate-to-severe (29% in men and women) on postoperative outcomes. Findings We obtained data for patients, of whom (30·44%) had preoperative anaemia. After adjustment, postoperative mortality at 30 days was higher in patients with anaemia than in those without anaemia (odds ratio [OR] 1·42, 95% CI 1·31–1·54); this di erence was consistent in mild anaemia (1·41, 1·30–1·53) and moderate-to-severe anaemia (1·44, 1·29–1·60). Composite postoperative morbidity at 30 days was also higher in patients with anaemia than in those without anaemia (adjusted OR 1·35, 1·30–1·40), again consistent in patients with mild anaemia (1·31, 1·26–1·36) and moderate-to-severe anaemia (1·56, 1·47–1·66). When compared with patients without anaemia or a defi ned risk factor, patients with anaemia and most risk factors had a higher adjusted OR for 30-day mortality and morbidity than did patients with either anaemia or the risk factor alone. Interpretation Preoperative anaemia, even to a mild degree, is independently associated Lancet 2011; 378: 1396–407

17 Preop Anemia 300,000 age > 65 (RC)
Increased Mortality and Cardiac Events HCTS < 39 wu Jama, June Vol 297 (22)

18 Preop Anemia OR 2.29 Independently Increased Mortality
Retrospective Review 8000 /Non cardiac Surg Prevalence 40% (HCT 36, 39) Adjusted for other RF and Elimination of transfusion or severe anemia OR 2.29 Independently Increased Mortality Anemic Not Anemic Also associated with increased risk transfusion After adjustment for major confounders and elimination of patients who were transfused or who had severe anemia, anemia was associated with increased mortality (odds ratio, 2.29) Anesthesiology Issue: Volume 110(3), March 2009, pp

19 Issue: Volume 110(3), March 2009, pp 574-581
Preop Anemia Anesthesiology Issue: Volume 110(3), March 2009, pp

20 Preoperative Evaluation
A (reformed) internists perspective: Focused on cardiac status, pulmonary reserve CBC, chemistry, PFT’s, cardiac stress test “Coronary artery disease – consider beta blockade, perioperative nitrates and placement of Swan Ganz catheter.”

21 Confession continued…
Preoperative anemia  ~ 34 Check Iron studies, trial of oral iron, stool guaiac, send for colon exam “May need perioperative transfusion”

22 Preoperative Evaluation
It’s all relative CAD BE CAREFUL!!!

23 % Pts Anemic on Admission

24 Improved Preop Admission Anemia
Managing preop anemia

25

26 Improved Preop Admission Anemia
Managing preop anemia Showing Data Canceling cases Make it easy for surgeons

27 Preoperative Anemia Assessment
28-30 days in advance Flexible – finger stick hgb when convenient Helped mrsa testing Prenatal Oral Iron

28 Limited in Scope Not for full work up of anemia
Detection and treatment of preoperative anemia to improve surgical outcomes Always referred back to PMD!

29 Increased Destruction Chemo/Myelodysplastic
Anemia Decreased Production Increased Destruction Marrow Failure Intrinsic RBC Decreased B12/Folate/ Chemo/Myelodysplastic Decreased HEME Decreased Globin Marrow failure – Renal disease, endocrine red cell aplasia, tumor infiltration Named for the Greek words for iron and germ, sideroblastic anemia is one of the principal types of iron-utilization anemia. Abnormal, iron-saturated red cells are present in the blood of people who have this disease. Although the iron circulates normally from the plasma to the bone marrow, where new red blood cells are created, it is not properly incorporated into new red blood cells. Sideroblastic anemia can be inherited, but the disease is usually acquired as a result of illness or exposure to toxic substances. Sideroblastic anemia is a disease of adults. Iron Def ACD Sideroblastic Thalassemia

30 Increased Destruction Intravascular Hemolysis Extravascular Hemolysis
Anemia Decreased Production Increased Destruction Blood Loss Intravascular Hemolysis Extravascular Hemolysis Marrow failure – Renal disease, endocrine red cell aplasia, tumor infiltration Vasculitis DIC Prosthetic Valve HGB S, C, E G6PD Immune Hemolysis Hypersplenism

31 Iron Def Anemia Decreased B12/Folate/ Myelodysplastic Blah Blah Blah
Decreased Blah Blah Decreased Blah Blah Marrow failure – Renal disease, endocrine red cell aplasia, tumor infiltration Iron Def Thalassemia ACD Sidero something

32 Surgeon’s View Give Iron Refer to Hematologist

33 Preoperative Anemia – NATA
A multidisciplinary panel of physicians was convened by the Network for Advancement of Transfusion Alternatives (NATA) with the aim of developing practice guidelines for the detection, evaluation, and management of preoperative anaemia in elective orthopaedic surgery. British Journal of Anaesthesia 106 (1): 13–22 (2011)

34 Other Cell lines/abnormal cells?
Anemia Other Cell lines/abnormal cells? CBC MCV/RDW Retic Count Or normal Iron Studies B12/Folate c/w ACD B12 replacement IM/PO Folate IV Iron ESA + IV iron Marrow failure – Renal disease, endocrine red cell aplasia, tumor infiltration Retic count helpful if low (less than 0.3) or high (more than 3) Thyroid ?ETOH Prenatal B mcg

35 Iron Little use for oral iron as sole replacement Chromagen Forte
Limited pt compliance Months to improve stores Poor absorption – H2 blockers, PPI, inflammation Chromagen Forte Vitamin C B12 Folate Prenatal mcg B12 + Iron If time, ok absorption

36 IV Iron Iron Dextran – “Total dose” replacement - 1500 mg
Risk anaphylaxis Needs pretreatment Iron Gluconate/Sucrose Limited by dosing 125 mg QD Ferrlicet 200 mg 2-3 x week Venofer Ferumoxytol (Feraheme) 510 mg IV push (watch anaphylaxis x 30 min) 2 doses 3-8 days apart

37 Calculating Dose Normal hgb + decreased Ferritin
mg Iron for each gm/dl hgb deficit Plus mg to replace true iron stores if tsat < 10 OR tsat < 20 + ferritin < 100 ng/dl Normal hgb + decreased Ferritin [100 – ferritin] x 10 Acute blood loss – mg per cc

38 Anemia of Chronic Disease
FE Deficiency V. ACD FE Deficiency Anemia of Chronic Disease Serum FE Decreased Ferritin Nml or increased TIBC Nl or Increased % sat Nml or decreased

39 Anemia of Chronic Disease: Role of Hepcidin
Why is this? There are many reasons for anemia, and I'm going to touch on them, but one very important aspect, particularly for primary care doctors, is this inflammatory process. In terms of the anemia of chronic disease that we've come to know, we're just starting to get some better idea of why this is the case. This inflammatory process of CKD is more likely than not also responsible for many of the other comorbidities we see, particularly as they pertain to CVD and peripheral vascular disease. The macrophages, when stimulated, will produce interleukin-6, which causes the hepatocytes to produce hepcidin, which blocks macrophage iron release and intestinal iron absorption. That effectively creates a situation in which iron utilization is impaired and can contribute to the anemia that we see. Iron regulatory hormone that causes sequestration of iron in macrophages Andrews J Clin Invest 2004

40 Anemia Of Chronic Disease
Enteric uptake inhibited Release from Macrophages Inhibited

41 Anemia of Chronic Disease- Preoperative Treatment
ESA IV iron

42 ESA Use Effective Check CMS guidelines - WA Give iron with ESA
Elective Hips and Knees HCTS < 39 All others HCTS < 33 Not Iron deficient Give iron with ESA Goodnough Transfusion 34:66-71, 1994 J Thorac Cardiovasc Surg 2001;122: Sowade Blood :

43 ASA Statement on Transfusion 2006
Erythropoietin should be administered when possible to reduce the need for allogeneic blood in certain selectedpatient populations (e.g., renal insufficiency, anemia of chronic disease, refusal of transfusion).

44 STS 2011 Guidelines Class IIa. “It is reasonable to use preoperative erythropoietin(EPO) plus iron, given several days before cardiac operation, to increase red cell mass in patients with preoperative anemia, in candidates for operation who refuse transfusion (eg, Jehovah’s Witness), or in patients who are at high risk for postoperative anemia.” However, chronic use of EPO is associated with thrombotic cardiovascular events in renal failure patients suggesting caution for this therapy in persons at risk for such events (eg, coronary revascularization patients with unstable symptoms). (Level of evidence B)

45 Perioperative ESA’s Approved for use for pts undergoing autologous donation: Japan 1993 Europe 1994 Canada 1996 Approved for perisurgical adjuvant therapy w/o auto donation Canada/USA 1996

46 Preoperative ESA’s Canadian, (+2 US studies) – 208 orthopedic pts
300 u/kg SQ x 14 days, 9 days preoperatively + oral iron all groups ½ rate exposure to allogeneic blood Both groups Hgb > 130 g/L No adverse events in treatment groups BAbstract: Concern about the risk of transmission of viral infection has led to attempts to reduce transfusion requirements in patients undergoing surgery. To determine whether recombinant human erythropoietin decreases blood transfusion requirements in patients undergoing elective hip arthroplasty, a multicentre double-blind, randomised, placebo-controlled trial was conducted. 208 patients undergoing elective primary or revision hip arthroplasty were randomised to 3 groups. All received daily subcutaneous injections of either erythropoietin or placebo starting 10 days before surgery. Group 1 (78 patients) received 14 days of placebo, group 2 (77 patients) received 14 days of erythropoietin (300 units/kg to a maximum of 30,000 units), and group 3 (53 patients) received placebo for days 10 to 6 before surgery and erythropoietin for the next 9 days. A primary outcome event (any transfusion or a haemoglobin concentration < 80 g/L) occurred in 46% of patients in group 1, 23% in group 2, and 32% in group 3 (p = 0.003). The mean number of transfusions was 1.14 in group 1, 0.52 in group 2, 0.70 in group 3. The mean reticulocyte count the day before surgery was 72 x 10(9)/L in group 1, 327 in group 2, and 170 in group 3. Deep venous thrombi were detected in 5 patients in group 1, 8 patients in group 2, and 8 patients in group 3. Patients who had a haemoglobin concentration before randomisation of < 135 g/L benefited most from erythropoietin. Thus erythropoietin given for 14 days perioperatively decreases the need for transfusion in patients undergoing elective hip arthroplasty. asis of these studies approved for perisurgical use in canda and US Lancet 341: , 1993 De Andrade JR: Am J Orthop 25: , 1996 Faris: J Bone J Surg 78A:62-72, 1996

47 Canadian Orthopedic Erythropoietin Study Group – Elective Hips
Group 1 placebo 14 days Group u/kg EPO 9 days preop/14 days total Group 3 placebo days and 300 u/kg EPO next 9 days Lancet 341: , 1993

48 European Epoetin Alfa Surgery Trial
Multicenter trial EPO v routine (6 countries- 700 pts) Anemic pts – hgb g/dl EPO 40u/ kg/wk x 3 + DOS + iron both groups (oral treatment/iv or oral control) Results: higher hgb levels throughout 12% v. 46% transfusion No effect post op recovery (time ambulation, d/c, infection rate Time to ambulation, d/c longer in transfused v. non-transfused SE comparable Effects of epoetin alfa on blood transfusions and postoperative recovery in orthopaedic surgery: the European Epoetin Alfa Surgery Trial (EEST). - Weber EW - Eur J Anaesthesiol - 01-APR-2005; 22(4): (MEDLINE is the source for the citation and abstract of this record ) Abstract: BACKGROUND AND OBJECTIVE: Preoperative epoetin alfa administration decreases transfusion requirements and may reduce transfusion complications, such as postoperative infection due to immune suppression and thus hospitalization time. This study examined the impact of preoperative epoetin alfa administration on postoperative recovery and infection rate. METHODS: In an open randomized controlled multicentre trial in patients undergoing orthopaedic surgery, the effects of preoperative administration of epoetin alfa vs. routine care were compared in six countries. Haemoglobin (Hb) values, transfusions, time to ambulation, time to discharge, infections and safety were evaluated in patients with preoperative Hb concentrations 10-13g dL(-1) (on-treatment population: epoetin n = 460; control n = 235), from study entry until 4-6 weeks after surgery. Outcome was also compared in patients with and without transfusion. RESULTS: Epoetin-treated patients had higher Hb values from the day of surgery until discharge (P < 0.001) and lower transfusion rates (12% vs. 46%; P < 0.001). Epoetin treatment delivered no significant effect on postoperative recovery (time to ambulation, time to discharge and infection rate). However, the time to ambulation (3.8+/-4.0 vs. 3.1+/-2.2days; P < 0.001)and the time to discharge (12.9+/-6.4 vs /-5.0 days; P < 0.001) was longer in the transfused than in the non-transfused patients. Side-effects in both groups were comparable. CONCLUSIONS: Epoetin alfa increases perioperative Hb concentration in mild-to-moderately anaemic patients and thus reduces transfusion requirements. Patients receiving blood transfusions require a longer hospitalization than non-transfused patients. Weber, Eur J Anaesthesiol April 2005;22(4):

49 European Epoetin Alfa Surgery Trial
Weber, Eur J Anaesthesiol April 2005;22(4):

50 FDA Orders ESAs Safety Labeling Changes - 2008
July 30, 2008 – FDA issues Complete Response letters ordering safety labeling changes under FDAAA Cancer Patients on Chemotherapy ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure DOSAGE AND ADMINISTRATION Therapy should not be initiated at hemoglobin levels ≥10 g/dL, except where the patient is unable to tolerate this degree of anemia due to co-morbid conditions If the hemoglobin exceeds a level needed to avoid transfusion or exceeds 12 g/dL, withhold dose until the hemoglobin approaches a level where transfusion may be required U.S. Food and Drug Administration. Accessed August 7, 2008.

51 PROCRIT® (epoetin alfa) for Injection
WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Cancer: ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course. Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

52 EPO and Thrombosis RTC 680 spine pts 600 u/kg x 4 doses
Rate all DVT (doppler Day 4 + sx) Greater (4.7 v 2.1) Rate symptomatic same Post –hoc combined PE + DVT same RCT involving 680 patients randomized to 600 U/kg epoetin alfa weekly x 4 dose (days ‐21, ‐14, ‐7, and 0) vs. standard care – No baseline ultrasound scanning to exclude DVT – Only mechanical thromboprophylaxis allowed post‐op – Doppler screening for DVT on day 4 or if symptomatic • Rate of all DVT (doppler plus symptomatic) was greater in the treatment group (4.7% vs. 2.1%) • Rate of symptomatic acute DVT was the same – Post‐hoc analysis of combined PE and acute DVT identical in the two groups – Basis of recommendation for thromboprophylaxis Spine 2009; 34: 2479‐85 Spine 2009; 34: 2479‐85

53 EPO and Renal Disease 4 major RTC 1999-2009
 New Engl J Med2006;355: New Engl J Med2006;355: EPO and Renal Disease 4 major RTC Targeted HCTS (hgb 13-15) One underpowered Higher EPO dosing (3x) Not adequate iron replacement 11,000 v 5,000 Some underpowered ecause of the non-protocolized nature of dialysis start, and the fact that there were no differences in rate of decline of GFR, or actual GFR at the time of dialysis, this finding should not be over-interpreted. It is possible that the physicians caring for the patients who knew their Hgb values, would decide to commence dialysis when symptoms worsened, in the absence of other explanations for the symptoms, while those in the lower Hgb group, who complained of symptoms, might have delayed dialysis because the symptoms were attributed to anaemia rather than uraemia. Drueke NEJM 2006: 355 Singh AK et al N Engl J Med 2006;355:2085‐98

54 Epo and Cancer One meta analysis 51 studies ALL Targeted hgb > 13
O.R. VTE 1.57 Increased tumor progression/mortality Not indicated for patients undergoing treatment “for cure” qol also improved Bennett CL et al, JAMA. 2008;299 (8): 914‐924

55 EPO and Cancer Meta analysis 60 studies
No affect mortality (OR 1.06) or disease progression (OR 1.01) + VTE (OR 1.48) Glaspy J et al British Journal of Cancer 2010;102, 301‐315

56 Presurgical EPO - summary
Use with caution CKD, malignancy, h/o VTE Use Lowest dose (with IV iron!) Consider Thromboprophylaxis – high risk pts

57 Risks of Blood Transfusion include:
Informed Consent Risks of Blood Transfusion include: Increased Mortality, Hemolytic Transfusion Reactions, Postoperative Infection, Malignancy Recurrence, Immunosuppression, Viral transmission, Transfusion Related Acute Lung Injury, Circulatory Overload

58 Blood Conservation in Cardiac Patients
Pre surgical (including cath lab) Intraoperative Post operative

59 Presurgical/Cath Lab Blood Conservation
Baseline HCT/HGB Iron studies if HCT < 37 or MCV < 80 B12/Folate levels if MCV > 100 Radial Artery Cannulation Use of U/S or Doppler Use of groin closure device Measure hematoma size Contrast image post diagnose retroperitoneal bleed Recycle all lost blood Spring loaded introducer Post Cath HCT

60 CV Surgery Presurgical Anemia
If HCT < 37  Delay if possible Aggressive IV iron (venofer 200 mg x 3-5 doses) EPO if HCT less than 33 600 u / kg q week x 2-4 weeks + IV iron Prenatal vitamins B mcg PLAVIX/P2Y12 inhibitors – measure platelet inhibition

61 CV surgery – ESA not indicated use
182 pts RCT ESA Placebo, 300 u/kg, 150 u/kg 5 day prior, DOS and 2 d after CABG Trend toward increased mortality (p=0.6) 4/5 deaths thrombotic/vascular “possibly drug related” 2/4 > 3 months after No deaths placebo D’Ambra Ann Thor Surg 1997;64:1886‐93

62 Cladellas M, American Journal of Cardiology (Jul 2012)
Effects of Preoperative Intravenous Erythropoietin Plus Iron on Outcome in Anemic Patients After Cardiac Valve Replacement Cladellas M, American Journal of Cardiology (Jul 2012) 75 consecutive patients- EPO + IV iron x 5 doses 59 observational cohort Post op morbidity OR p = 0.008 In hospital mortality OR p = 0.04 Decreased postop renal failure OR p = 0.03 Transfusion rate v 93% p=0.01 LOS (median) v p- 0.01 Adjusted for Operative Risk Score, type of intervention, time of CPB, year of surgery Preoperative anemia is a risk factor for postoperative morbidity and in-hospital mortality in cardiac surgery. However, it is not known whether treatment of anemia before cardiac surgery by administering recombinant human erythropoietin (rhEPO) plus iron improves postoperative outcomes and decreases red blood cell transfusions in these patients. In 1998 a collection of consecutive data for patients who underwent valve replacement was initiated and the inclusion criterion was anemia. Treatment with rhEPO was given at a dose of 500 IU/kg/day every week for 4 weeks and the fifth dose 48 hours before valve replacement. During each rhEPO session, patients received intravenous iron sucrose supplementation. The intervention cohort (2006 to 2011) included 75 patients and the observation cohort was composed of 59 patients who did not receive any treatment (1998 to 2005). Multivariable logistic regression analysis showed that administration of combined therapy was independently associated with decreased postoperative morbidity (odds ratio [OR] 0.13, 95% confidence interval [CI]0.03 to 0.59 p = 0.008) and in-hospital mortality (OR 0.16, 95% CI 0.28 to 0.95 p = 0.04) after adjusting for logistic European System for Cardiac Operative Risk Evaluation score, type of intervention, time of cardiopulmonary bypass, and year of surgery. Individually, this treatment also decreased postoperative renal failure (OR 0.23, 95% CI 0.06 to 0.88, p = 0.03). Rate of red blood cell transfusion decreased from 93% in the observation cohort to 67% in the intervention cohort as did days of hospitalization (median, 15 days, 10 to 27, versus 10 days, 8 to 14, respectively, p = 0.01 for all comparisons). In conclusion, administration of intravenous rhEPO plus iron in anemic patients before valve replacement improves postoperative survival, decreases blood transfusions, and shortens hospitalization.

63 To Review

64 Other Cell lines/abnormal cells?
Anemic HGB 12/13 Other Cell lines/abnormal cells? Check Iron Studies Check Renal Function B12/Folate ? Retic Count Deficient Not Deficient No Obvious Source ESA Give IRON GI W/U NATA Guidelines, British J Anesthaesia, 106 (1) 13-22, 2011

65 Review IV iron important therapy IF po – give with vitamin C
Prenatal/Vit B12 Consider ESA (Procrit 600 u/kg x 4 weeks) IV iron with ESA Caution CKD, Cardiac Surgery Check CMS guidelines

66 Summary Preoperative Anemia – Prevalent
Associated with poorer outcome and should be evaluated and treated Iron Studies mainstay of lab testing Others CBC, Creat, Retic count, Thyroid Use of ESA and IV iron safe and effective May require delay of elective surgery All anemic patients need referral back to PMD


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