Anemia and Transfusion Practice John M. Harlan, M.D. Harborview Medical Center University of Washington Seattle, WA
Anemia and RBCs Inadequate O 2 delivery with severe anemia RBC transfusion improves O 2 delivery Critically ill patients more susceptible to adverse effects of oxygen depletion impairs oxygen delivery to critical organs cardiovascular system must compensate RBC transfusion should improve outcomes
The very first requirement in a hospital is that it should do the sick no harm. Florence Nightingale
Oxygen Delivery (DO 2 ) DO 2 = Hb X %SaO 2 X CO Hb is normally nearly fully saturated with O 2 Baseline extraction of O 2 in resting tissue ~25% can increase to ~60% with exercise Increase CO by HR or stroke volume Hct Viscosity CO and SV DO 2 is increased at Hct of 30% and normal at Hct of 20% 2,3-DPG (chronic) increases release of O 2 from Hb to tissue
RBC Transfusion: Indications Chronic anemia: symptomatic (or at risk) (Hb < 8g/dL) other Rx ineffective or too slow Chronic Anemia Normal Red Cell Mass Plasma Volume Hess and AuBuchon, Clinical Transfusion Medicine Cmte, AABB, 2003
Compensation in Chronic Anemia 2,3-DPG decreases affinity of Hb for O2 shifts curve to right increased delivery of O2 to tissue
Compensation in Chronic Anemia 46 yo woman with c/o fatigue: BP 114/87, P117, R 18 25-dec-2003 at 14:03 Hemoglobin * <3.0 g/dl 25-dec-2003 at 14:03 Hematocrit * 6 % * identical results on second venipuncture
RBC Transfusion: Indications Large volume acute blood loss Symptomatic anemia occurs or anticipated after fluid replacement Acute Blood Loss Normal + Fluids Intravascular volume Red Cell Mass Plasma Hess and AuBuchon, Clinical Transfusion Medicine Cmte, AABB, 2003
Cardiovascular Effects of Isovolemic Anemia 16 14 12 10 8 6 4 2 0 77 76 75 74 73 72 71 70 69 68 Oxygen transport (ml/kg/min) 5 6 8 10 12 14 SvO2 (%) 5 6 8 10 12 14 100 Lactate concentrations: Unchanged. 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 HR (BPM) 6 8 10 12 14 Heart Rate (BPM) Stroke Volume Index (ml/m^2) 6 8 10 12 14 Weiskopf R et al. JAMA 1998;279: 217-21.
Effects of Severe Anemia Changes in Cognitive Function in Normal Subjects Similar results: Reaction time Changes in Error Rate 40% 20% * 7.2 6.0 5.1 7.2 Hemoglobin, g/dl Weiskopf R et al. Anesthesiology 2000;92:1646-52.
Effect of Post-Op Hemoglobin on Mortality Retrospective study of 300 patients with postoperative Hb < 8 who refused transfusion: mortality morbidity Hb 7-8 (99) 0% 9% Hb 6-7 (56) 9% Hb 5-6 (54) 9% Hb 4-5 (32) 34% 57% Hb 3-4 (25) 25% Carson et al, Transfusion 2002 Jul;42(7):812-8
Transfusion Trigger Transfusion trigger is Hb/Hct at which risks of decreased O 2 carrying capacity exceed the risks of transfusion
Risks of Transfusion Transfusion reactions Febrile, non-hemolytic Hemolytic TRALI Alloimmunization Infectious GVHD Other Immune modulation?
RBC Transfusion in Surgery and Critical Care Is a restrictive strategy better than a liberal strategy in surgical and critically ill patients?
Restrictive versus Liberal Twelve RCTs: Restrictive: transfusion threshold between Hb 7-8 g/dl Reduced # of RBCs transfused in all Not associated with adverse clinical outcomes Transfusion and Apheresis Science 2004;31:55
TRICC Study: Transfusions in the ICU Transfusion Requirements in Critical Care Cooperative Study Multi-center, Multicenter, prospective, randomized study 838 patients in 25 centers > 24 h ICU stay expected Hb < 9.0 g/dl within 72 h Volume resuscitated or normovolemic Restrictive: Maintain 7-9 g/dl (APACHE II: 20.8) Liberal: Maintain 10-12 g/dl (APACHE II: 21.3) Hébert PC et al. NEJM 1999;340:409-17.
TRICC Study: Transfusions in the ICU MODS and cardiac complication rates significantly less with restrictive RBC transfusions reduced by 52% Reduced exposure to any RBCs by 33% Hébert PC et al. NEJM 1999;340:409-17.
TRICC Study: Transfusions in the ICU Hébert PC et al. NEJM 1999;340:409-17.
TRICC: Subgroup Analysis Apache II <20 Age <55 Number needed to treat to save 1 life = 12 Hebert et al. New Engl J Med 1999; 340:409-417
Mortality Rates in Critically Ill Patients Retrospective, database review of 1717 ICU patients in a single institution Percent of Patients 25 20 15 10 5 0 P <.05 13.6 24 All Patients Transfused Patients Non-transfused Patients 10.2 N = 1,717 n = 416 n = 1,301 Taylor RW et al, Crit Care Med 2002;30:2249-54.
ABC Study-Transfusions in the ICU Prospective, observational study in 3534 patients in 176 western European ICUs 30% of patients with Hb <10 g/dl 37% percent of patients transfused in ICU If stay greater than 1 week 73% transfused Mean pre-transfusion Hb = 8.4 g/dl Transfused patients had higher mortality rates at every admitting Hb level when compared to non-transfused Dose-dependent relationship with number of units transfused and mortality 28 day mortality 22.7% in transfused versus 17.1 in nontransfused (p = 0.05) Vincent et al, JAMA 2002:288: 1499
CRIT Study: Transfusions in the ICU Prospective, multi-center, observational cohort 4892 patients in 284 US ICUs 44% of patients transfused Mean pre-transfusion Hb was 8.6+/- 1.7 g/dl Number of RBC units transfused was independent predictor of worse clinical outcome Corwin et al, Crit Care Med 32:39, 2004
CRIT Study: Transfusions in the ICU % Mortality 4892 patients in 284 ICUs Transfused P < 0.001 Non-Transfused Days Corwin et al, Crit Care Med 32:39, 2004
The CRIT Study 4892 patients in 284 ICUs: Little evidence that transfusion practice has changed over the last decade as majority of transfusions given with Hb > 8-9g/dL Corwin et al, Crit Care Med 32:39, 2004
Anemia in Cardiovascular Disease Retrospective cohort study in 1958 surgical patients who refused blood transfusion 11% with Hb < 10 If pre-op Hgb < 9.5 g/dl = 30 day mortality with CVD Carson JL et al, Lancet 1996;348:1055-60
Blood Transfusion in Elderly Patients with Acute Myocardial Infarction Cooperative Cardiovascular Project 78,974 medicare recipients CMS ICD-9 discharge code for MI and anemia (Hct <39%) 30 day mortality 3324 (4.2%) had admission Hct less than 30% These patients had more trauma, surgery, internal bleeding, coexisting diseases, DNR, shock and less treatments (β blockers ASA etc.) 3680 (4.7%) of the cohort received transfusions Wu WC et al, NEJM 2001;345:1230-36
Anemia and CVD Transfusion associated with greater 30 day mortality if admission Hct < 30% Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 Admission Hct Hct > 39% Hct 30-33% 33% Hct < 24% 10 20 30 Days after Admission Wu W-C et al. NEJM 2001;345:1230-6.
TRICC Study: Subgroup Analysis of Patients with Ischemic Heart Disease Liberal Restrictive p Patients 147 111 30-d d mortality 21% 26% 0.38 ICU mortality 17% 23% 0.27 Hospital mortality 27% 29% 0.78 MODS 9.1+4.5 9.1+5.0 0.98 LOS-ICU (d) 10.4+10.3 10.3 9.3+9.7 9.7 0.19 LOS-total 30.6+18.8 28.8+19.5 0.30 Hébert PC et al. Crit Care Med 2001;29:227-34.
TRICC Study: Subgroup Analysis of Patients with Ischemic Heart Disease in patients with heart disease, the restrictive strategy [transfusion at Hb of 70 g/l] should be considered the approach of choice....most hemodynamically stable, critically ill patients with cardiovascular disease may receive a transfusion safely when hemoglobin concentrations decrease to below 70 g/l and may be maintained at hemoglobin concentrations between 70 and 90 g/l. [possible exception: unstable coronary ischemic syndromes] Hébert PC et al. Crit Care Med 2001;29:227-34.
Anemia and Acute Coronary Syndromes Retrospective analysis of 24,112 patients prospectively enrolled in 3 large international trials (GUSTOIIb, PURSUIT and PARAGON) 10% received RBC transfusion After correction for other predictive factors, transfusion (if nadir Hct >25%) was associated with increased mortality at 30 days Rao et al, JAMA 292:1555, 2004
Anemia and Acute Coronary Syndromes Transfused % Cumulative Mortality Non-Transfused Rao et al, JAMA 292:1555, 2004
CRUSADE Study: Transfusions in ACS National QI Initiative retrospective study of 74, 271 patients in 478 hospitals Had NSTE ACS but did not undergo CABG 10% received RBC, older and with renal failure Transfused patients had greater risk of death or re-infarction (13.4% versus 5.8%) Risk persisted after adjustment for adverse clinical factors Yang et al, J Am Coll Cardiol 2005; 46:1490-5
Anemia in STEMI and NSTE ACS Retrospective analysis of 39, 922 patients prospectively enrolled in 16 TIMI trials for STEMI or NSTE ACS With STEMI, mortality increased as baseline Hb fell Sabatine et, Circulation 2005; 46: 1490-5
Anemia in STEMI and NSTE ACS Retrospective analysis of 39, 922 patients prospectively enrolled in 16 TIMI trials for STEMI or NSTE ACS With NSTE ACS, mortality increased as baseline Hb fell Sabatine et, Circulation 2005; 46: 1490-5
Anemia in STEMI and NSTE ACS 4.6% of STEMI patients transfused Transfusion improved CV mortality if pretransfusion Hb < 12g/dl 2.7% of NSTE ACS patients transfused Transfusion was associated with increased risk of death or re-infarction Sabatine et, Circulation 2005; 46: 1490-5
Transfusion Trials FOCUS: Post-op hip fracture Hb 10 g/dl versus 8 g/dl CV complications CRIT Pilot: Within 72 hours of MI Liberal (Hct 30%) versus conservative (Hct 24%)
Deleterious Effects of RBC Transfusion Data on increased mortality in ICU patients (without CVD) is provocative Little direct evidence that increased O2 delivery with RBC transfusion actually improves tissue oxygenation Reason to be conservative in considering RBC transfusion in absence of CVD Potential mechanisms: TRIM Storage defect Unknown
Transfusion-Related Immuno-Modulation (TRIM) Immunologic effects of allogenic blood Tx: Decreased T-cell proliferation Decreased CD3, CD4, CD8 T-cells Increased soluble cytokine receptor (stnf-r, sil-2r) Increased serum neopterin Increased cell-mediated lympholysis Increased TNF-alfa Increased suppressor T-cell activity Reduced natural killer cell activity McAlister FA et al, Br J Surg 1998;85:171-8. Innerhofer P et al, Transfusion 1999;39:1089-96
Transfusion-Related Immuno-Modulation (TRIM) Consequences of TRIM: decreased host defense and immune surveillance pro-inflammatory Mechanisms of TRIM: leukocytes and leukocyte-derived mediators?
Allogeneic Blood Transfusion and Post-Operative Infections Numerous observational studies and a meta-analysis have suggested a relationship between peri-operative allogeneic blood transfusion and postoperative bacterial infection Dellinger and Anaya, Critical Care 2004:8:S18
Allogeneic Blood Transfusion and Post-Operative Infections TRIM due to allogeneic WBCs has been postulated as the likely mechanism However, analysis of the multiple RCTs comparing transfusion with WBC-containing versus WBC-depleted allogeneic blood does not establish a TRIM effect Vamvakas et al, Crit Care Med 2006;34:S151
Storage Lesion Effects of Blood Storage: Significant loss of 2,3-DPG Decrease RBC deformability Release of micro-particles Increased cell lysis with age free Hgb Generation of bioactive agents from WBCs
RBC Shape Change During Storage Red Cell Shape, Bessis M, Weed RI, Leblond PF, 1973 RBCs shed micro-vesicles becoming progressively smaller and more rigid
Effect of Storage on Red Cells % Day 0 Concentration 100 80 60 40 20 DPG ATP Transfusion 2 4 6 0 12 24 Storage Period (wks) Post-Transfusion Period (h) Hess and AuBuchon, Clinical Transfusion Medicine Cmte, AABB, 2003
Storage Lesion Potential consequences of blood storage: Fewer viable RBCs Decrease in RBC ability to release oxygen Inability of RBCs to pass through capillary lumen Procoagulant mediators released Proinflammatory mediators released Free Hb scavenges NO
Aged Blood Longer storage of transfused RBCs (>14days) has been retrospectively associated with: Higher incidence of post-op infections Development of MOF Postulated mechanisms: TRIM due to accumulation of leukocyte-generated mediators Decreased tissue oxygenation due to storage lesions
ARE FRESH RBCs BETTER? Double blind, randomized study in ICU patients RBCs < 5d old versus >20 days old Measures of regional and global tissue oxygenation Conclusion: Our data do not support the hypothesis that transfusing stored red cells adversely affects tissue oxygenation in anemic, euvolemic, critically ill patients with no evidence of bleeding. Walsh TS et al. Crit Care Med 2004; 32:364-371
Everything hinges on the matter of evidence. Carl Sagan
Conclusions If Hb < 6-7 g/dl transfusion is usually necessary If Hb between 7 and 10 g/dl transfusion may not be necessary -? In MI, ACS, UA - in septic shock if central venous O2 saturation < 70% (EGDT) Hb > 10 g/dl transfusion not indicated