PostOperative Anemia What is the Appropriate Transfusion Threshold

Post-Operative Anemia: What is the Appropriate Transfusion Threshold?

Objectives • Describe the physiology of oxygen delivery • List risks and benefits of red blood cell transfusions • Discuss the evidence regarding thresholds for red blood cell transfusion • Explain methods to prevent the need for intra- and post-operative transfusions

Case • A 14 year old female with adolescent idiopathic scoliosis is POD 2 after posterior spinal fusion. She is otherwise healthy. You are co-managing her care with the orthopaedic surgery team. • In the OR her EBL was 1 L, and she received 5 L of crystalloid, 500 m. L of albumin, and 400 m. L of cell saver blood. Her hemoglobin levels have been as follows: - Pre-op: 12. 5 - Immediately post-op: 8. 6 - POD 1: 7. 8 - POD 2: 7. 2 • Her post-operative course has been unremarkable so far except for intermittent tachycardia and difficult to control pain. On POD 2, the orthopaedic surgery team asks you whether a red blood cell transfusion is indicated for this patient. • The content of this module should help you provide an evidence-based recommendation for this patient.

Why Transfuse? To maintain adequate oxygen delivery to tissues DO 2 = (Oxygen delivery) CO x arterial oxygen content (Cardiac Output) DO 2 = CO x [(1. 3 x Hgb x arterial O 2 sat %)+(Pa. O 2 x 0. 003)] Increasing Hgb has a direct effect on oxygen delivery (Kleinman, et al. 2013)

Compensation • In healthy patients at rest oxygen delivery is 4 x greater than oxygen consumption • Theoretically, for an adult, if intravascular volume and cardiovascular function are preserved, oxygen delivery is adequate until hematocrit is <10% (hgb <3. 5 g/d. L). This is due to: – increase cardiac output – rightward shift of the oxygen-hgb dissociation curve – increased oxygen extraction (Kleinman, et al. 2013)

Signs/Symptoms of Acute Anemia • Some of the signs/symptoms of acute anemia are related to compensation – Tachycardia (which may have other causes in post-op patients) – Pallor – Dizziness, headaches – Fatigue, weakness, exercise intolerance • Consider risk factors in past medical history and in operative report – Look for record of prior Hgb levels – Check the estimated blood loss during procedure – Risk factors for baseline anemia (heavy periods, iron deficiency, family history)

Risk of not Transfusing Mortality in adult patients with very low postoperative Hgb levels who declined blood transfusion (adapted from Carson, et al. 2002)

Risks of Transfusing Potential Transfusion Complications • Risk of infection following transfusion of whole blood or red blood cell products Infection Risk Hepatitis B 1: 58, 000 to 1: 269, 000 Hepatitis C 1: 1, 000 to 1: 2, 000 Human Immunodeficiency Virus (HIV) 1: 1, 500, 000 to 1: 2, 000 Human T-Cell Lymphotropic Virus (HTLV) 1: 1, 900, 000 (Teruya, 2013)

Risks of Transfusing • Transfusion reactions – Febrile – Hemolytic (acute or delayed) – Transfusion-related acute lung injury (TRALI) • Metabolic derangements – Hyperkalemia, hypocalcemia (especially in neonates) • Immunologic complications – Allergic reactions, including anaphylaxis – Graft-versus-host disease (rare, but mortality is 80 -90%) • Volume overload – Dyspnea, tachycardia, HTN with a wide pulse pressure (Teruya, 2013)

Preventing Transfusions Techniques to reduce transfusions during/after spinal fusion surgery • Peri-operative blood salvage (cell saver) • Acute normovolemic (intraoperative) hemodilution (ANH) – (Copley, et al. , 1999) Eglin AFB, Florida • Preoperative autologous donation (PAD) – (Anand, et al. , 1998) Bronx Pharmacologic interventions: • Epsilon Aminocaproic acid (EACA) – (Florentino-Pineda, et al. , 2001) Cleveland • Tranexamic Acid – (Neilipovitz, et al. , 2001) Ottawa • Erythropoietin (with pre-operative autologous donation) – (Franchini, et al. , 2004) Verona, Italy • Recombinant Factor VIIa – (Sachs, et al. , 2007) Plano, Texas

When to Transfuse (Adults) RCT in adult ICU patients (Hebert et al. , 1999) • Patients were randomized to receiving a transfusion, if – Hemoglobin was <10 (liberal), or – Hemoglobin was <7 (conservative, restrictive) • Among patients with Apache II scores <20 (healthier) – 16. 1% mortality for those transfused at <10 – 8. 7% mortality for those transfused at <7 • Criticisms: – not using leukocyte reduced blood; – excluding about 87% of eligible patients – Post-hoc stratification

When to Transfuse (Kids) • • Recommendations vary somewhat Good evidence is scarce Recommendations are based mostly on expert opinion Some address children < 4 months and > 4 months of age separately • The best evidence about transfusion thresholds comes from the TRIPICU study From La. Croix, et al. (2007) and Rouette, et al. (2010)

TRIPICU Study Transfusion Requirements in the Pediatric ICU (TRIPICU) Study • 648 subjects, 19 centers (including CCHMC) in 4 countries • Recruitment from November, 2001 to August, 2005 • Randomized with stratification by center and by age ≤ 28 days, 29 -364 days, ≥ 365 days (up to 14 years) Restrictive strategy Liberal strategy Transfusion Threshold Hgb Goal < 7 g/d. L 8. 5 – 9. 5 < 9. 5 g/d. L 11 - 12 • Used leukocyte reduced units of RBCs • Protocol was followed for 28 days, or until d/c from PICU

TRIPICU Study • Primary outcomes – Multiple (≥ 2) organ dysfunction syndrome (MODS) – 28 day mortality • Secondary outcomes – Pediatric Logistic Organ Dysfunction (PELOD) score, sepsis, transfusion reactions, infections, length of stay (ICU & hospital) • Non-inferiority trial design – 626 subjects to detect a 10% change in MODS with 90% power • Temporary suspensions of protocol (attending discretion) – For active and clinically significant blood loss, surgery, severe hypoxemia, or hemodynamic instability • Blinding not possible Lacroix, et al. , 2007

Lacroix, et al. , 2007

TRIPICU Study Results <7 g/d. L • • <9. 5 g/dl No significant difference in major outcomes between the two strategies Twice as many patients (p<0. 001) getting transfusions and twice as many transfusion reactions (p=0. 34) in the liberal strategy (<9. 5 g/d. L) group (La. Croix, et al. 2007)

Postsurgical Subgroup Rouette, et al. , 2010

Surgical Sub-Group Results (Rouette, et al. , 2010)

TRIPICU Surgical Subgroup • Weaknesses – Subgroup analysis – Power calculations for a non-inferiority design require 560 patients to conclude non-inferiority • Strengths – There is a strong, but statistically not significant, trend toward a longer PICU length of stay for the liberal strategy group – There is no clinical explanation for the difference except for the RBC transfusion strategy – This trend is suggestive of harm to the post-op patient due to the liberal strategy, but it is not statistically significant Rouette, et al. , 2010

Guidelines • For children > 4 months of age – Transfuse for Hgb levels <7 g/d. L. – Do not transfuse for Hgb >10 – For Hgb levels 7 -10, depends on the clinical situation • signs and symptoms of anemia • active bleeding, etc. • This is approach is consistent with findings from TRIPICU • Hgb of ≥ 10 is recommended prior to anesthesia / surgery – Based on evidence from sickle cell patients (Teruya, 2012)

More Guidelines (Roseff et al. 2002)

Key Points • Understanding the physiology of oxygen delivery and how the body compensates for anemia is important in order to make decisions about giving blood transfusions. • Treating acute anemia with red blood cell transfusions comes with risks, which include transfusion reactions, fluid overload, and serious infections (e. g. Hep B). • The TRIPICU study suggests for asymptomatic children with acute anemia that it is safe to use a hemoglobin of <7 g/d. L as the red blood cell transfusion threshold and that there no benefits to transfusing if the hemoglobin is 7. 0 or greater.

Questions for Review • Consider the patient you were consulted on earlier. Her exam is normal, she is not actively bleeding. Her mom still thinks she would feel better if she weren’t so anemic. What are some of the possible complications of RBC transfusion? • Which are rare? Serious?

Further Discussion • Based on the TRIPICU study, are you comfortable not transfusing until Hgb < 7? – In which clinical situations would you want to transfuse before the Hgb falls below 7?

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