Evidence on Effective hemoglobin thresholds for Red Cell Transfusions

1. Evidence on Effective hemoglobin thresholds for Red Cell Transfusions Dr Chitra James

2. Background • For decades, decision to transfuse RBCs based on 10/30 rule • Concern on transmission of pathogens ,efforts at cost containment Revision of Transfusion Practices • Subsequent years, Clinical evidence generated based on RCTs Guidelines generated • Common theme Balance benefits and risks of Transfusion

3. Evidence Review- Milestone RCTS • Transfusion Requirements in Septic Shock (TRISS) • Villanueva C, et al • Transfusion in Gastrointestinal Bleeding Trial (TRIGGER) • Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) • Transfusion Requirements In Frail Elderly (TRIFE) • Transfusion Requirements After Cardiac Surgery (TRACS) • Transfusion Indication Threshold Reduction (TITRe2) • De Zern EA, et al. • Transfusion Requirements in Surgical Oncology Patients

4. Evidence Review- Milestone Meta- analyses • Salpeter, 2014 • Curley, 2014 • Brunskill, 2015 • Holst, 2015 • Fominskiy, 2015 • RipollesMelchor, 2016 • Carson, 2016 • Estcourt, 2017 • Carson ,2018

5. EVIDENCE BASED GUIDELINES • American College of Physicians, 2013 • British Committee for Standards in Hematology (BCSH), 2013 • American Society of Anestesiologists, 2015 • The National Institute for Health and Care Excellence (NICE) blood transfusion guideline NG24, 2015 • UK National Clinical Guideline Centre (NCGC), 2015 • AABB (formerly American Association of Blood Banks), 2016 • European Society of Anaesthesiology (ESA), 2017 • The Pediatric Critical Care Blood Research Network (BloodNet) and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) NetworK Guidelines for RBC transfusion in critically ill children ,2018

6. THRESHOLDS FOR SPECIFIC PATIENT POPULATIONS

7. NEONATES Factors affecting threshold • Acuity of blood loss • Gestational age • Need for respiratory support • Major surgery within 72 hours A restrictive transfusion threshold compared with a liberal threshold (HCT >40 %) results in less exposure to transfusions with no increase in mortality or serious morbidity Pediatric Critical Care Transfusion and Anemia Expertise Initiative (TAXI), Pediatric Critical Care Blood Research Network (BloodNet), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PediatrCrit Care Med. 2018;19(9):884. 

8. NEONATES TRANSFUSION THRESHOLDS • HCT trigger <30 - Infants requiring moderate or significant mechanical ventilation • HCT trigger <25 - Infants requiring minimal mechanical ventilation • HCT trigger <25 Infants requiring supplemental low- or high-flow oxygen , tachycardia, tachypnea , doubling of oxygen requirement from the previous 48 hours, metabolic acidosis, weight gain <10 g/kg per day, major surgery within 72 hours. • HCT trigger <21 - Asymptomatic infants, with an absolute reticulocyte  (<2 percent). Guidelines on transfusion for fetuses, neonates and older children.AU New HV, Berryman J, Bolton-Maggs PH, Cantwell C, Chalmers EA, Davies T, Gottstein R, Kelleher A, Kumar S, Morley SL, Stanworth SJ, British Committee for Standards in Haematology Br J Haematol. 2016 Dec;175(5):784-828

9. Transfusion in Critically ill Children • Avoid transfusion in critically ill children who are hemodynamically stable, not severely hypoxic, Hb≥7 g/dL. • Exceptions Congenital heart disease, A/c brain injury, Sickle cell anemia, Malignancy, Recent HSC Transplant, A/c blood loss. Pediatric Critical Care Transfusion and Anemia Expertise Initiative (TAXI), Pediatric Critical Care Blood Research Network (BloodNet), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PediatrCrit Care Med. 2018;19(9):884. 

10. Special clinical settings • Congenital heart disease surgery Cyanotic Heart disease-Hb 9g/dl Noncyanotic disease – 7g/dl • Chronic kidney disease Target Hb 11-12g/dl (usually managed with Fe & erythropoetin) Red cell transfusion management for patients undergoing cardiac surgery for congenital heart disease.Wilkinson KL, Brunskill SJ, Doree C, Trivella M, Gill R, Murphy MF Cochrane Database Syst Rev. 2014; 

11. Symptomatic patient- Hb Transfusion Thresholds -10 g/dL • Myocardial ischemia • Orthostatic hypotension • Tachycardia unresponsive to fluid replacement • Marked dyspnea at rest. • Chronic anemia – Irritability, weakness, exercise intolerance  Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011; 365:2453. Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013; 165:96

12. Preexisting coronary artery diseaseHb transfusion Threshold - 8 g/dL • Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial - A restrictive (8g/dl) compared with liberal (10g/dl) was not associated with worse outcomes, with the exception of an increase in MI that was marginally statistically significant.  • Transfusion Requirements in Critical Care (TRICC) trial -Compared with a threshold of 10 g/dL, a restrictive strategy (7g/dl) was associated with lower mortality. Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013; 165:964.

13. Acute coronary syndromesHb transfusion Trigger - 8 to 10 g/dL • Optimal transfusion threshold in ACS setting unresolved. • CRIT Pilot trial of 110 patients with ACS- 10g/dl trigger associated with greater survival at 30 days than 8g/dl (98 % vs 87 %) Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013; 165:964. Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol 2011; 108:1108

14. Heart Failure • Anemia is a surrogate marker for poor prognosis in individuals with HF, rather than a therapeutic target. • A RCT of 2278 patients with systolic heart failure and anemia, in which increasing the hemoglobin concentration from 9-12 g/dL to 13 g/dL using erythropoietin did not improve outcomes • No large randomized, controlled trials have been published addressing Tx Thresholds Treatment of anemia with darbepoetinalfa in systolic heart failure. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O'Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ, RED-HF Committees, RED-HF Investigators SON Engl J Med. 2013;368(13):1210. Epub 2013 Mar 10. 

15. Critically ill(hemodynamically stable) Transfusion thresholds 7 g/dL • Transfusion Requirements in Critical Care (TRICC) trial- 30-day mortality favored the restrictive strategy but was not statistically significant (23 vs 19%) • 30-day mortality rates were lower with the restrictive strategy in two predefined subgroups: Patients who were less severely ill Patients <55 years of age Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group [see comments]. N Engl J Med 1999; 340:409. Lacroix J, Hebert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007; 356:1609.

16. Critically ill…. • The Transfusion Requirements in Septic Shock (TRISS) trial randomly assigned 998 patients with septic shock & Hb < 9 g/dL to a restrictive or a liberal transfusion strategy • Mortality at 90 days similar in both groups (43 vs 45%); relative risk [RR], 0.94, 95% CI 0.78-1.09) • Other outcomes like ischemic events, transfusion reactions, use of inotropes, need for mechanical ventilation) were also similar between the two groups.  Lower versus higher hemoglobin threshold for transfusion in septic shock.AUHolst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, TRISS Trial Group, Scandinavian Critical Care Trials Group SON Engl J Med. 2014;371(15):1381. Epub 2014 Oct 1.

17. Gastrointestinal bleeding (hemodynamically stable) transfusion threshold 7 g/dL • Two RCTs suggest restrictive strategy when there is access to rapid endoscopic treatment. • Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster trial randomised 936 patients with acute upper gastrointestinal bleeding to a restrictive or liberal threshold (8 g/dL vs 10 g/dL) •   No significant differences in clinical outcomes; fewer transfusions were given in the restrictive group (33 vs 16 %) Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11. trial.Jairath V, Kahan BC, Gray A, DoréCJ, Mora A, James MW, Stanley AJ, Everett SM, Bailey AA, Dallal H, Greenaway J, Le Jeune I, Darwent M, Church N, Reckless I, Hodge R, Dyer C, Meredith S, Llewelyn C, Palmer KR, Logan RF, Travis SP, Walsh TS, Murphy MF SOLancet. 2015 Jul;386(9989):137-44. Epub 2015 May 5. ,

18. Non Cardiac Surgery-Hb transfusion threshold 8g/dl • Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial - Liberal transfusion strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk Liberal or restrictive transfusion in high-risk patients after hip surgery.AUCarson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, Nemo G, Dragert K, Beaupre L, Hildebrand K, Macaulay W, Lewis C, Cook DR, Dobbin G, Zakriya KJ, Apple FS, Horney RA, Magaziner J, FOCUS Investigators SON Engl J Med. 2011 Dec;365(26):2453-62. Epub 2011 Dec 14. 

19. Cardiac surgery • Transfusion Requirements in Cardiac Surgery III (TRICS III) trial randomly assigned 5243 patients undergoing cardiac surgery to Hb 7.5 vs 8.5-9.5 g/dl • Incidence of a composite endpoint of death, non-fatal MI, stroke or Renal failure with dialysis was similar in both groups (12.3 vs 12.9%) • Mortality was also similar (3.0 vs 3.6 %); OR 0.85; 95% CI( 0.62-1.16). • Fewer people in the restrictive group received transfusions (52 vs 73 %) • People who were transfused received fewer units of blood (2 vs 3 units). .  Restrictive or liberal red-cell transfusion for cardiac surgery.Mazer CD, Whitlock RP, Fergusson DA, Hall J,, TRICS Investigators and Perioperative Anesthesia Clinical Trials Group SON Engl J Med. 2017;377(22):2133. Epub 2017 Nov 12.

20. Cardiac surgery contd.. • The Transfusion Indication Threshold Reduction (TITRe2) trial- • Incidence of a composite endpoint of infection or an ischemic event was similar in the restrictive and liberal groups (35 vs 33 %). • 90 day mortality was higher in restrictive group(4.2 vs 2.6%) • 30 day mortality was similar (2.6 vs 1.9 %) as was the incidence of pulmonary complications (13 vs 12 %) • Transfusions were significantly reduced with the restrictive strategy (median 1 vs 2 units per patient; transfusion avoided in 36 vs 5 % & transfusion costs were lower with restrictive transfusion Liberal or restrictive transfusion after cardiac surgery.Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, Reeves BC, TITRe2 Investigators SON Engl J Med. 2015;372(11):997. 

21. Cardiac Surgery… • Transfusion Requirements After Cardiac Surgery; TRACS – Liberal or restrictive ( Hct 30 or 24) • Primary outcome - composite endpoint of 30-day all-cause mortality, cardiogenic shock, acute respiratory distress syndrome, or acute renal injury requiring dialysis or hemofiltration. • No difference between the groups (10 liberal vs 11 % restrictive). • Independent of transfusion strategy, the number of transfusions correlated with clinical complications and death (HR 1.2 for each unit transfused). Transfusion requirements after cardiac surgery: The TRACS randomized controlled trial.AUHajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, Fukushima J, KalilFilho R, Sierra DB, Lopes NH, Mauad T, Roquim AC, Sundin MR, Leão WC, Almeida JP, Pomerantzeff PM, Dallan LO, Jatene FB, Stolf NA, Auler JO Jr SOJAMA. 2010;304(14):1559.

22. Cardiac Surgery Hb transfusion threshold 7.5-8 g/dL •  Meta-analysis of data – Carson et al • Restrictive transfusion strategy Hb 7.5-8 g/dl appears to be reasonable in patients undergoing cardiac surgery with cardiopulmonary bypass • Risk ratio for 30-day mortality for a restrictive compared with a liberal transfusion strategy was 0.99; 95% CI 0.74-1.33 Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease.Carson JL, Stanworth SJ, Alexander JH, Roubinian N, Fergusson DA, Triulzi DJ, Goodman SG, Rao SV, Doree C, Hebert PC SOAm Heart J. 2018;200:96. Epub 2018 Apr 7 Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med 2017; 377:2133.

23. Ambulatory outpatientOncology patient in treatment-7 to 8 g/dl • Meta analysis by Estcourt, 2017 etal – 3RCT /156 + 1/84 (NRS) -Patients with haematological disorders undergoing myelo suppressive chemotherapy or stem cell transplantation • No difference in 100 day mortality and bleeding ,duration of hospital stay in both groups • Restrictive strategy could reduce quality of life & risk of serious infection Estcourt LJ, Malouf R, Trivella M, et al. Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support. Cochrane Database of Syst Rev 2017; 1: CD011305.

24. Threshold hemoglobin of 7 or 8 g/dL • 2018 Systematic Review And Meta-analysis –Carson Et Al • 37 randomized clinical trials comparing higher versus lower transfusion thresholds in 19,049 medical and surgical patients (adults and children) • Decreased probability of receiving a transfusion (41 percent decrease; relative risk [RR] 0.59; 95% CI 0.53-0.66) • No difference in 30-day mortality (RR 1.0; 95% CI 0.86-1.16) • No difference in infection rate (RR 0.97; 95% CI 0.88-1.07) • No difference in functional recovery, or hospital or intensive care length of stay • No increased risk of myocardial infarction (RR 1.05; 95% CI 0.88-1.26) Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease.Carson JL, Stanworth SJ, Alexander JH, Roubinian N, Fergusson DA, Triulzi DJ, Goodman SG, Rao SV, Doree C, Hebert PC SOAm Heart J. 2018;200:96. Epub 2018 Apr 7. 

25. Major Exceptions to threshold of 7-8g/dl • Symptomatic patient • Traumatic hemorrhage • Acute Coronary Syndrome • Massive Transfusion • Severe thrombocytopenia in oncology patients at risk of bleeding • Chronic transfusion-dependent anemia.

26. 2016 Meta-analysis by Hovaguimian F et al -context-specific evaluation in adult surgical or critically ill patients, stratifying by patient characteristics and clinical settings • Restrictive transfusion associated with increased risk of a composite outcome in patients undergoing cardiac procedures and in older adult orthopedic patients • 2017 Meta-analysis by Simon et al -older patients were benefited by liberal transfusion Restrictive versus Liberal Transfusion Strategy in the Perioperative and Acute Care Settings: A Context-specific Systematic Review and Meta-analysis of Randomized Controlled Trials. Hovaguimian F, Myles PS SOAnesthesiology. 2016 Jul;125(1):46-61. Outcomes of restrictive versus liberal transfusion strategies in older adults from nine randomised controlled trials: a systematic review and meta-analysis.Simon GI, Craswell A, Thom O, Fung YL Lancet Haematol. 2017;4(10):e465. Epub 2017 Sep 11

27. Recent Guidelines on Transfusion Thresholds American Society of Anesthesiologists, 2015 – Hb level <6 g/dL The National Institute for Health and Care Excellence (NICE) blood transfusion guideline NG24, 2015- Hb level ≤7 g/dL Hb level ≤8 g/dL (ACS) UK National Clinical Guideline Centre (NCGC), 2015 - Hb level <7 g/dL Hb level <8 g/dL in ACS

28. Guidelines …. • Recommendations from the College of Intensive Care Medicine & the Australian and New Zealand Intensive Care Society on end-of- life care, invasive devices, anaemia, sedation & antibiotics, 2016 Hb level <7 g/dL • AABB 2016 Hb level<7g/dl

29. Evidence based RBC Transfusion Practices- Recommendations • Not indicated in hemodynamically stable adult hospitalized patients with a Hb level of 7 g/dL or more including critically ill. • Not indicated in patients undergoing orthopedic or cardiac surgery or in patients with underlying cardiovascular disease with a Hb level of 8 g/dL or more (AABB 2016) • Single-unit RBC transfusions followed by reassessment should be the standard of care for patients who are hemodynamically stable and not actively bleeding. Promoting High-Value Practice by Reducing Unnecessary Transfusions With a Patient Blood Management Program.Sadana D, Pratzer A, Scher LJ, Saag HS, Adler N, Volpicelli FM, Auron M, Frank SM SOJAMA Intern Med. 2018;178(1):116. 

30. Good Clinical Practice Statement • Transfusion decision based on overall clinical context and consideration of alternative therapies. • Rate of decline of Hb • Intravascular volume status • Shortness of breath • Exercise tolerance • Light headedness • Chest pain of cardiac origin • Hypotension / Tachycardia unresponsive to fluid challenge. Clinical Practice Guidelines From AABB , Jeffrey L Carson, Gordon Guyatt et al JAMA Special communication

31. Limitations • The hemoglobin transfusion thresholds assessed may not be optimal. • The use of hemoglobin transfusion thresholds may be an imperfect surrogate for oxygen delivery.

32. Patient Blood Management • Multidisciplinary, multimodal, individualised strategies • Aimed at minimising transfusion of allogeneic blood components & improving outcomes • Detection and Rx of peri-operative anaemia, reduction of surgical blood loss & peri-operative coagulopathy • Optimisation of physiological tolerance of anaemia, allowing restrictive use of RBC transfusion

33. Paradigm shift • Restrictive to optimal use • Transfusion of minimum volume to revert symptoms of hypoxia • Attain a safe Hb level based on patients clinical characteristics

34. Blood transfusion is like marriage: it should not be entered upon lightly, unadvisedly or wantonly or more often than is absolutely necessary. Robert Beal