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Conservation of Blood A Precious Resource

Conservation of Blood A Precious Resource. James P. AuBuchon, MD E. Elizabeth French Professor and Chair of Pathology Professor of Medicine Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire. Conservation of Blood A Precious Resource. Why? Availability Expense Outcomes

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Conservation of Blood A Precious Resource

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  1. Conservation of Blood A Precious Resource James P. AuBuchon, MD E. Elizabeth French Professor and Chair of Pathology Professor of Medicine Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

  2. Conservation of Blood A Precious Resource Why? Availability Expense Outcomes Reactions How? Indications Alternatives Source

  3. NOT INR = 1.5

  4. Abnormality ≠ Clinical Deficiency Procoagulant ?Consumed Concentration Procoagulant ?Consumed Concentration in Coagulation Normal Necessary in Coagulation Normal Necessary Fibrinogen Yes 200-400 mg/d 50-100 mg/dL Fibrinogen Yes 200-400 mg/d 50-100 mg/dL Factor V Yes 1 U/mL 5-25% Factor V Yes 1 U/mL 5-25% Factor VIII Yes 1 U/mL 15-25% Factor VIII Yes 1 U/mL 15-25% Factor VII No 1 U/mL 5-20% Factor VII No 1 U/mL 5-20%

  5. 1:1 Mix 50% FV 50% FVII 1:1 Mix 50% FV 50% FVII (75% each ) (75% each ) Plasma Plasma Problems Using Coagulation Tests Problems Using Coagulation Tests as Transfusion Triggers as Transfusion Triggers 15 15 PT (sec) PT (sec) 10 10 5 5 Burnset al. AJCP 1993;100:94-8. Burnset al. AJCP 1993;100:94-8.

  6. Plasma Plasma Effect of Mildly-Abnormal Coagulation Parameters Effect of Mildly-Abnormal Coagulation Parameters Test Group n Bleeding Hb Change Test Group n Bleeding Hb Change Complications (g/dL) Complications (g/dL) PT Normal 100 4% -0.3±0.9 PT Normal 100 4% -0.3±0.9  1.3*ULN 43 6% -0.2±0.8 43 6% -0.2±0.8 PTT Normal 103 5% -0.3±0.9 PTT Normal 103 5% -0.3±0.9  1.3*ULN 34 3% -0.1±0.6 34 3% -0.1±0.6 Diagnosis of malignancy: 18x risk of bleeding Diagnosis of malignancy: 18x risk of bleeding Platelet count > 50,000/µL adequate Platelet count > 50,000/µL adequate McVay PA et al. AJCP 1990;94:747-53. McVay PA et al. AJCP 1990;94:747-53.

  7. Plasma Plasma Effect of Coumadin Treatment on Surgical Blood Loss Effect of Coumadin Treatment on Surgical Blood Loss Gastrectomy Patient Group Gastrectomy Patient Group 1000 1000 RBC Loss Controls (n=20) RBC Loss Controls (n=20) (mL) (mL) 800 800 Coumadin (therapeutic; n=20) Coumadin (therapeutic; n=20) 600 600 RANGE RANGE 400 400 200 200 24 h 72 h 24 h Operative 72 h Operative Total Total Total Total Rustad H et al. Acta Med Scand 19 63 ;173:115-9. Rustad H et al. Acta Med Scand 19 63 ;173:115-9.

  8. Plasma Plasma Effect of Coumadin Treatment on Post-Op Blood Loss Effect of Coumadin Treatment on Post-Op Blood Loss Group n Post-Op Blood Loss (mL) Group n Post-Op Blood Loss (mL) Controls 26 813 (125-2125) Controls 26 813 (125-2125) Coumadin 26 624 (210-1650) Coumadin 26 624 (210-1650) (therapeutic) (therapeutic) Procedure: Mitral commissurotomy Procedure: Mitral commissurotomy Storm O et al. Circ 19 55; 12:981-5. Storm O et al. Circ 19 55; 12:981-5.

  9. Plasma Plasma PT as a Predictor of Bleeding PT as a Predictor of Bleeding LL RR LL RR 16 16 Liver Liver 12 12 Bleeding Bleeding Time (min) Time (min) 8 8 Mean Mean 4 4 30 50 60 70 80 90 100 10 20 40 30 50 60 70 80 90 100 10 20 40 PT (% normal activity) PT (% normal activity) Note: 10% change in activity = approximately 1 sec Note: 10% change in activity = approximately 1 sec Ewe K. Dig Dis Sci 1981;26:388-93. Ewe K. Dig Dis Sci 1981;26:388-93.

  10. Ansell J. Chest.2001;119:22S-38S. Correcting Over-Coumadinization Recommendations of American College of Chest Physicians CLINICAL SITUATION CLINICAL SITUATION GUIDELINES GUIDELINES Ansell J et al. Chest 2004;126(3Suppl):204S-233S.

  11. An Analysis of the Literature Normal vs. Abnormal Coagulation Tests RISK DIFFERENCE Angiography Angiography Bronchoscopy Liver biopsy Liver biopsy Liver laparoscopy Liver laparoscopy Transjugular liver biopsy Transjugular liver biopsy Transjugular liver biopsy Para/thoracentesis Transjugular kidney biopsy Kidney biopsy -0.25 0 0.25 FAVORS NO TRANSFUSION FAVORS TRANSFUSION Segal and Dzik. Transfusion 2005;45:1413-25.

  12. Plasma vs. Saline in Severe Head Trauma Glasgow coma scale ≤ 8 FFPSaline 10-15 mL/kg 10-15 mL/kg N 44 46 CT: Worse 32% 15% p = 0.06 CT: Better 2.3% 2.2% Delayed hematoma 17% 0% p = 0.007 Mortality 63% 35% p = 0.006 Note: < 2% with INR > 1.4 Etemadrezaie H et al. Clin Neurol Neurosurg 2007;109:166-71.

  13. Mean change: -0.03/unit And what if plasma is transfused? 3.0 2.5 Pretransfusion INR 2.0 1.5 1.0 +0.5 0 -0.5 -1.0 -1.5 Change in INR post-transfusion Holland LL et al. Transfusion 2005;45:1234-5.

  14. And what if plasma is transfused? INR Change after Transfusion Cheng CK, Sadek I. Transfusion 2007;47:748-9.

  15. 78 patients had repeat PT within 8h of transfusion And what if plasma is transfused? 723 patients, PT 13-17sec  transfused Outcome PT decreased at least halfway to normal: 14.5% PT decreased to normal: 0.9% Mean decrease: 0.2 sec No correlation of PT with RBC usage Abdel-Wahab et al. Transfusion 2005;45:141A.

  16. What is Gained with Plasma? And…as more plasma is given, greater plasma volume in which to increase factor concentration 50% And…the half-life of Factor VII is 5h! Factor activity 30% 10% SMALL GAIN LARGE GAIN 13s 15 s 20 s PT (seconds)

  17. How much plasma should be transfused to correct a significant procoagulant deficiency? “Therefore, transfusion for patients not meeting current FFP guidelines does not reliably reduce the INR and exposes patients to unnecessary risk.” Calculations from Holland LL and Brooks JP. Am J Clin Pathol 2006; 126:133-9.

  18. NORMAL NORMAL CIRRHOTIC CIRRHOTIC BALANCED REDUCTION IN CIRRHOTICS EQUAL OUTCOME procoagulants Protein C activation Protein C Why Don’t Cirrhotic Patients Bleed? Thrombin Generation (ETP as FU/mL) REDUCED SYNTHESIS Actually, Fib:Prot C ratio increases by 20% Tripodi A et al. Hepatology 2005;41:553-8.

  19. Cryoprecipitate Fibrinogen: < 100 mg/dL or 120 mg/dL and falling rapidly vWF: If unresponsive to DDAVP Factor VIII: (None) Topical: As needed

  20. Unselected adults: Carson. Lancet 1988. Anemia: What is the Limit? Baboons: Hct = 4% Wilkerson. Surgery , 1988. Dogs: Hct = 7% Crystal. Am J Phsyiol , 1988. Healthy adults: Hb = 5 g/dL Botero. J Clin Anesth , 1996. van Woerkens. Anesth Analg , 1996. Peds card surg: Hb  3 g/dL Henling. J Thorac Cardiovasc Surg , 1985. Hb > 8 g/dL  mortality = 6% Hb < 6 g/dL  mortality = 61%

  21. Anemia: What is the Limit? Vasodilator Reserve Ratio Vasodilator Reserve Ratio 6 6 Cardiac Response Cardiac Response 5 5 During Hemodilution During Hemodilution 4 4 Control 3 Control 3 2 2 Stenosis Stenosis 1 1 20 40 10 30 20 40 10 30 Hct (%) Hct (%) Levy et al. Am J Physiol 1993;265:H340. Levy et al. Am J Physiol 1993;265:H340.

  22. BUT 25% fatality at 9 g/dL Anemia: What is the Limit? 19 dogs with critical stenosis of LAD  Lowest tolerated Hgb: 7.5 g/dL Spahn et al. J Thorac Cardiovasc Surg 1993;105:694. Spahn et al. J Thorac Cardiovasc Surg 1993;105:694.

  23. Effect of Co-Morbidities on Mortality Effect of Co-Morbidities on Mortality Adjusted odds ratio for Adjusted odds ratio for perioperative mortality perioperative mortality 16 16 13 13 Cardiovascular disease present Cardiovascular disease present 10 10 7 7 4 4 Cardiovascular disease absent Cardiovascular disease absent 1 1 11 12 7 8 10 + 6 9 11 12 7 8 10 + 6 9 Preoperative hemoglobin (g/dL) Preoperative hemoglobin (g/dL) Carson JL et al. Lancet 1996;348:1055-60. Carson JL et al. Lancet 1996;348:1055-60.

  24. Effect of Post-CABG Transfusion Strategy Effect of Post-CABG Transfusion Strategy Parameter Transfusion Strategy Parameter Transfusion Strategy "Liberal" (Hct = 32%) "Conservative" (Hct = 25%) "Liberal" (Hct = 32%) "Conservative" (Hct = 25%) Patients 18 20 Patients 18 20 Post-op Transfusion 37 units/18 pts 20 units/15 pts Post-op Transfusion 37 units/18 pts 20 units/15 pts Length of Stay Length of Stay ICU 3.3±3.4 d 3.2±0.7 d ICU 3.3±3.4 d 3.2±0.7 d Total post-op 7.6±1.9 d 7.9±4.3 d Total post-op 7.6±1.9 d 7.9±4.3 d Exercise Testing Exercise Testing Mean duration #1 4.5±1.7 min 4.1±1.7 min Mean duration #1 4.5±1.7 min 4.1±1.7 min Mean duration #2 5.4±1.5 min 5.1±2.1 min Mean duration #2 5.4±1.5 min 5.1±2.1 min Johnson RG et al. J Thorac Cardiovasc Surg 1992;104:307-14. Johnson RG et al. J Thorac Cardiovasc Surg 1992;104:307-14.

  25. Effects of Post-CABG Transfusion Strategy Liberal: 9 g/dL Conservative: 8g/dL or bleeding > 750 mL acute respiratory failure inadequate cardiac output + pressors No difference in morbidity, mortality, LOS Same fatigue assessment Liberal: 1.4±1.8 units Conservative: 0.9±1.5 units Bracey AW et al. Transfusion 1999; 39:1070-77.

  26. Effect of Post-CABG Hematocrit Effect of Post-CABG Hematocrit Post-Operative Hematocrit <24% 24-33%>33% Patient distribution: 15% 68% 17% Q-wave MI: 3.6% 5.5% 8.3% LV dysfunction: 5.7% 7.4% 11.7% Spiess BD et al. J Thorac Cardiovasc Surg 1998;116:460-7.

  27. Cardiovascular Effects of Isovolemic Anemia Lactate concentrations: Unchanged. Weiskopf R et al. JAMA 1998;279;217-21.

  28. Effects of Severe Anemia Changes in Cognitive Function in Normal Subjects 40% * Changes in Error Rate 20% 7.2 6.0 5.1 7.2 Hemoglobin, g/dL Similar results: Reaction time Weiskopf R et al. Anesthesiology 2000;92:1646-52.

  29. Anemia: What is the Target? EPO in ESRD patients with CHF 0.6 0.5 Hct 42% RR: 1.3 (0.9 - 1.9) 0.4 Probability of Death or MI 0.3 Hct 30% 0.2 0.1 6 12 18 24 30 Months after Intervention Besarab A et al. NEJM 1998;339:584-90.

  30. Anemia: What is the Limit? Acute Myocardial Infarction Mortality in the Elderly 1.0 Admission hematocrit 0.9 Hct > 39% 0.8 Proportion Surviving Hct 30-33% 0.7 Hct <24% 0.6 For two-day survivors: Benefit of transfusion if Hct < 30% 0.5 20 30 10 Days after Admission Wu W-C et al. NEJM 2001;345:1230-6.

  31. Anemia: What is the Limit? Acute Myocardial Infarction Induced in Rats Hb 7-9 g/dL (compared to 14-15): Mortality doubled Transfusion immediately after MI: to 10 g/dL  No excess mortality to 12 g/dL  No improvement At 24h, anemic rats had ↑ extent of infarct compared to area at risk ↓ LV contractility Transfusion immediately after MI: to 10 g/dL  Return to control to 12 g/dL  No further improvement Xenocostas A et al. Blood 2007;110:140a.

  32. Anemia: What is the Limit? Transfusion in Acute Coronary Syndromes Secondary analysis of 24,112 enrollees 2,401 transfusion recipients from GUSTO IIb, PURSUIT and PARAGON B trials Transfusion recipients: - Older - More co-morbidities at presentation Rao SV et al. JAMA 2004;292:1555-62.

  33. Anemia: What is the Limit? Transfusion in Acute Coronary Syndromes Adjusted Probability of Death (at 30 d) With and Without Transfusion by Nadir Hematocrit Hct = 20% Probability = 1.6 25% 1.1 30% 169 35% 292 “We could not identify a hematocrit below which transfusion was beneficial…” Rao SV et al. JAMA 2004;292:1555-62. JAMA 2005;293:673-4.

  34. Anemia: What is the Limit? Associations of Anemia in Angioplasty Analysis from the CADILLAC Study – 2,027 patient Multivariate Predictors of In-Hospital Mortality Ejection Fraction (lower) 1.10 (p<0.0001) Creatinine clearance (lower) 1.03 (0.02) Baseline anemia 3.26 (0.048) Anemia but may be bad – but is transfusion good? Nikolsky E et al. J Am Coll Cardiol 2004;44:547-53.

  35. Anemic Morbidity in High-Risk Anemic Morbidity in High-Risk Vascular Patients Vascular Patients 100% 100% Myocardial ischemia Myocardial ischemia 80% 80% Morbid cardiac event Morbid cardiac event 60% 60% 40% 40% 20% 20% (0) (0) (0) (0) (0) (0) (0) (0) 23-25% 26-28% 29-31% 32-34% 35-37% 23-25% 26-28% 29-31% 32-34% 35-37% POD#1 Hct POD#1 Hct Nelson AH et al. Crit Care Med 1993;21:860-66. Nelson AH et al. Crit Care Med 1993;21:860-66.

  36. Anemic Morbidity in High-Risk Anemic Morbidity in High-Risk Vascular Patients Vascular Patients Hct, POD#1 n Cardiac Events Hct < 28%* 13 non Q-wave MI 25.1 (24-25) 27.5 (27-28) 24.9 (23-26) 27.6 (26-29) unstable angina 26.2 (22-30) ischemic pulm edema 25.2 (22-29) ≥ 28% 14 (none) *Note: More cases of pre-op anemia/ischemia *Note: More cases of pre-op anemia/ischemia *All with prior EKG changes. Nelson AH et al. Crit Care Med 1993;21:860-66. Nelson AH et al. Crit Care Med 1993;21:860-66.

  37. Anemia and Silent Myocardial Ischemia Patients undergoing arthroplasty – EKG monitoring “Conservative”“Liberal” Patients 109 109 Hb trigger (g/dL) 8 10 Mean postop Hb 9.87 11.09 Transfused 34% - 89 units 43% - 119 units Silent ischemia 19% 24% Length of ischemia 0.48 min/h 1.51 min/h* Median post-op LOS 7.3 7.5 * p<0.05 Grover et al. Vox Sang 2006;90:105-12.

  38. Assessing Red Cell Needs Assessing Red Cell Needs in Critically Ill Patients in Critically Ill Patients Multicenter, prospective, randomized study Multicenter, prospective, randomized study 838 patients in 25 centers 838 patients in 25 centers > 24 h ICU stay expected > 24 h ICU stay expected Hb < 9.0 g/dL within 72 h Hb < 9.0 g/dL within 72 h Volume resuscitated or normovolemic Volume resuscitated or normovolemic Restrictive: Maintain 7-9 g/dL (APACHE II: 20.8) Restrictive: Maintain 7-9 g/dL (APACHE II: 20.8) Liberal: Maintain 10-12 g/dL (APACHE II: 21.3) Liberal: Maintain 10-12 g/dL (APACHE II: 21.3) Transfusion Requirements in Critical Care Cooperative Study Transfusion Requirements in Critical Care Cooperative Study

  39. Assessing Red Cell Needs Assessing Red Cell Needs in Critically Ill Patients in Critically Ill Patients Liberal Restrictive p Liberal Restrictive p Units transfused 5.2±4.9 2.5±3.8 .0001 Units transfused 5.2±4.9 2.5±3.8 .0001 Mean Hb 10.7±7.3 8.5±7.2 .0001 Mean Hb 10.7±7.3 8.5±7.2 .0001 Avoiding transfn 0 33% .0001 Avoiding transfn 0 33% .0001 ICU mortality 15% 12% .27 ICU mortality 15% 12% .27 30 d mortality 24% 18% .05 30 d mortality 24% 18% .05 MODS 11.9 10.7 .02 MODS 11.9 10.7 .02 Hébert PC et al. NEJM 1999;340:409-17.

  40. Assessing Red Cell Needs Assessing Red Cell Needs in Critically Ill Patients in Critically Ill Patients with Ischemic Heart Disease LiberalRestrictive p Patients 147 111 30-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 9.3+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.

  41. Assessing Red Cell Needs Assessing Red Cell Needs in Critically Ill Patients in Critically Ill Patients Ventilation Outcomes LiberalRestrictive p Patients requiring ventilation 356 357 Length of ventilation (d) 8.3+8.1 8.3+8.1 NS Ventilator-free days 16.1+11.4 17.5+10.9 NS Successful extubation 78% 82% NS Hebert PC et al. Chest 2001;119:1850-7.

  42. Assessing Red Cell Needs Assessing Red Cell Needs in Critically Ill Patients Less- in Critically Ill Patients Less- APACHE II < 20 APACHE II < 20 Liberal Restrictive p Liberal Restrictive p ICU mortality 8.8% 4.4% .03 ICU mortality 8.8% 4.4% .03 30 d mortality 16.5% 9.2% .08 30 d mortality 16.5% 9.2% .08 MODS 10.1 8.4 .01 MODS 10.1 8.4 .01 Hébert PC et al. NEJM 1999;340:409-17.

  43. Assessing Red Cell Needs Assessing Red Cell Needs in Critically Ill Patients in Critically Ill Patients With a restrictive trigger (Hb = 7 g/dL): With a restrictive trigger (Hb = 7 g/dL): • 52% reduction in red cell transfusion • 52% reduction in red cell transfusion • Treat 12 patients => save 1 life • Treat 12 patients => save 1 life • Largest effect in healthier patients • Largest effect in healthier patients Hébert PC et al. NEJM 1999;340:409-17.

  44. Assessing Red Cell Needs Assessing Red Cell Needs in Critically Ill Patients in Critically Ill Patients with Cardiovascular 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.

  45. Liberal vs. Restrictive Triggers in Neonates 100 infants – 500-1300 g “Phase” Intubated 34% 46% Supplemental O2 28% 38% No respiratory support 22% 30% RestrictiveLiberal Study transfusions 2.7±2.4 4.8±4.1 u * Donor exposures 1.8±1.8 2.5±2.5 Survival 96% 98% IV hemorrhage, Gr. 4 12% 0 >1 apneic episode/d 43% 20% * - requiring stim (median) 0.42 0.42 * * p<0.05 Bell EF et al. Pediatrics 2005;115:1685-91.

  46. Pediatric Transfusion Strategies 637 critically ill children LiberalRestrictive 9.5 g/dL 7 g/dL Transfused 98% 46%p<0.001 Total transfusions 542 301 units p<0.001 Death (all cause-28d) 4% 4% p=0.98 Nosocomial infections 25% 20% p=0.16 Mechanical ventilation 6.0±5.4 6.2±5.9 d p=0.76 ICU LOS 9.9±7.4 9.5±7.9 p=0.39 Lacroix J et al. NEJM 2007;356:1609-19.

  47. Hb 7.5 – 8.5 g/dL Alternatives in O2 Delivery RANDOMIZE: 1 unit RBC 2 units RBC 100% O2 Post-op CABG (intubated) Outcome measures: O2 delivery and consumption Deltoid tissue O2 monitor Vascular and ventilatory parameters Suttner S et al. Anesth Analg 2004;99:2-11.

  48. ptiO2 DO2 400 40 30 300 20 Lactate Cardiac index 200 10 60 60 60 120 120 120 180 min 180 min 180 min VO2 1 RBC 140 2 RBC 100% O2 120 100 80 Alternatives in O2 Delivery Unit age: 10d (5-14) Suttner S et al. Anesth Analg 2004;99:2-11.

  49. Transfusion Guidelines Hb < 7 g/dL Transfusion often necessary Hb < 7 g/dL Transfusion often necessary Hb > 10 g/dL Transfusion rarely necessary Hb > 10 g/dL Transfusion rarely necessary

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