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Use of blood products in sepsis

Use of blood products in sepsis. Transfusion practice in the ICU: When to transfuse?. 台中榮民總醫院 加護中心 李博仁醫師. Use of blood products in sepsis. Blood products such as red blood cells (RBCs) Erythropoietin Antithrombin Fresh-frozen plasma (FFP) Platelets. extrapolation of study

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Use of blood products in sepsis

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  1. Use of blood products in sepsis Transfusion practice in the ICU: When to transfuse? 台中榮民總醫院 加護中心 李博仁醫師

  2. Use of blood products in sepsis • Blood products such as red blood cells (RBCs) • Erythropoietin • Antithrombin • Fresh-frozen plasma (FFP) • Platelets

  3. extrapolation of study heterogeneous groups of critically ill patients studies in patients who are not critically ill consensus guidelines Further clinical studies in septic patients Medline literature search from May 1993 to May 2003 few clinical trials that specifically evaluate the use of blood products in patients with severe sepsis or septic shock

  4. baseline hematocrit : 34.7 ± 8.5% in the standard therapy group 34.6 ± 8.3% in the goal-directed therapy group The ABC (anemia and blood transfusions in the critically ill) study involving 3,534 patients in 146 western European ICUs The mean Hb : 11.3 g/dl, 29% < Hb 10 g/dl inversely related to age,organ dysfunction related to a neoplasm than to chronic bleeding, a hematological disorder, renal dysfunction, or severe hepatitis Anemia is a common problem among critically ill patients Rivers E, Nguyen B, Havsted S, et alearly goal-directed therapy for resuscitation in sepsis N Engl J Med 2001; 345:1368–1377 JAMA 2002;288:1499-507

  5. Anemia is a common problem among critically ill patients • Increases with the length of stay in the intensive care unit (ICU) By 48 hrs after ICU admission 70% the ICU had a baseline hemoglobin level of <12 g/Dl half of these had a level of <10 g/dL More than 50% of patients admitted to the ICU receive RBC transfusions during their ICU stay Corwin L, Parsonnet KC, Gettinger A: RBC transfusion in the ICU: Is there a reason? Chest 1995; 108: 767

  6. Hebert et al:a study of 5,298 ICU patients in Canada 25% of patients received a transfusion during their ICU stay In the US : 16% of patients in a medical ICU and 27% in a surgical ICU the ABC study: 37% of patients in western European ICUs 1)57% of patients undergoing emergency surgery 2)47% of trauma patients 3)42% of patients undergoing a scheduled surgical intervention 4)32% of medical ICU patients Transfusion Practice

  7. Blood loss secondary to phlebotomy overt or occult hemorrhage coagulation disorders extracorporeal circuits increased destruction decrease in red cell production marrow infiltration with infection or malignancy use of cytotoxic drugs Nutrient deficiencies (iron, B12, folate) Impaired iron utilization inadequate erythropoietin production : cytokines(TNF, interleukin-l, transforming growth factor-[beta], prostaglandins) Hemoglobin concentrations fell by 0.52 ± 0.69 g/dl/day,the first three days, more marked in septic (Time course of hemoglobin concentrations in non-bleeding ICU patients. Crit Care Med 2003;31:406-10) Cause of anemia in septic patients

  8. Risks of blood transfusion • 1.increased rates of infection and/or poor outcomes in transfused postoperative and trauma patients • 2.increased risk of nosocomial infection 1.Transfusion of blood components and postoperative infection in patients undergoing cardiac surgery. Chest 2001; 119:1461 2.Taylor RW, Manganaro L Crit Care Med 2002; 30:2249 retrospective studyin 1,717 medical/surgical ICU patients

  9. Transfusion practice in the ICU: When to transfuse?( transfusion ′trigger′) • If septic shock patient (no cardiac ischemia) low hemoglobulinemia , which level index is your expect after blood tranfusion • 1.<7 2.7-9 3.10-12 4 .>12 Hebert PC : A multicenter, randomized,controlled clinical trial of transfusion requirements in critical care N Engl J Med. 1999 Feb 11;340(6):409-17

  10. Transfusion and Outcome ?transfusion requirements in critical care • hemoglobin concentrations usually range between 7 and 10 g/dL (Hct:30%)in patients with septic shock • The mortality rate during hospitalization was significantly lower in the restrictive-strategy group 7-9g/dL (22.3 percent vs. 28.1 percent, P=0.05).compare to liberal-strategy group10-12g/dL Hebert PC :A multicenter, randomized,controlled clinical trial of transfusion requirements in critical care N Engl J Med. 1999 Feb 11;340(6):409-17

  11. as low as 7.0 g of hemoglobin per deciliter, combinedwith maintenance of hemoglobin concentrations in the range of7.0 to 9.0 g per deciliter, was at least as effective as andpossibly superior to a liberal transfusion strategy (threshold,10.0 g per deciliter; maintenance range, 10.0 to 12.0) in criticallyill patients with normovolemia Hebert PC :A multicenter, randomized,controlled clinical trial of transfusion requirements in critical care N Engl J Med. 1999 Feb 11;340(6):409-17

  12. overall mortality was 13.5% 18.5% for transfused patients compared to 10.1% for those who were not transfused (p < 0.001) A transfusion during the ICU stay increased the risk of death by a factor of 1.37 (95% CI: 1.02-1.84). transfusion rather than anemia was an independent prognostic factor the ABC study

  13. The CRIT Study: Anemia and blood transfusion in the critically ill • prospective, multiple center, observational study of ICU patients (U.S.A) • August 2000 through April 2001 • within 48 hrs of ICU admission, A total of 284 ICUs in 213 hospitals participated 4,892 patients in the study. • To quantify the incidence of anemia and red blood cell (RBC) transfusion practice in critically ill patients and to examine the relationship of anemia and RBC transfusion to clinical outcomes Crit Care Med 2004; 32:39–52

  14. The CRIT Study

  15. The CRIT Study • The mean hemoglobin level at baseline was 11.0 ± 2.4 g/dL. • Hemoglobin level decreased throughout the duration of the study. • 44% of patients received one or more RBC units while in the ICU (mean, 4.6 ± 4.9 units) • The mean pretransfusion hemoglobin was 8.6 ± 1.7 g/dL

  16. The CRIT Study The number of RBC units transfused is an independent predictor of worse clinical outcome a nadir hemoglobin level of <9 g/dL was a predictor of increased mortality and length of stay. .

  17. The CRIT Study RBC transfusion remained statistically significantly associated with an increased risk for death

  18. Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? (?) whether anemic, ill patientswith cardiovascular disease mightbe at increased risk of adverse outcomesfrom the anemia?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. Hébert PC Crit Care Med 2001; 29:227

  19. hemoglobin tolerated in septic patient • Hypothesis: acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport • Does not produce evidence of inadequate systemic TO2, as assessed by lack of change of VO2 and plasma lactate concentration Weiskopf RB, Viele MK, Feiner J, et al: Human cardiovascular response to acute, severe isovolemic anemia. JAMA 1998; 279:217

  20. postoperative and trauma & RBC transfusion • increased rates of infection and poor outcomes in transfused patients • increased risk of nosocomial infection 1.Claridge JA: Blood transfusions correlate with infections in trauma patients in a dose-dependent manner. Am Surg 2002; 68:566–572 2.Leal-Noval SR: Transfusion of blood components and postoperative infection in patients undergoing cardiac surgery. Chest 2001; 119:1461–1468 3. Malone DL: Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 2003; 54:898–807

  21. What is the appropriate hemoglobin threshold for transfusion of packed red blood cells in the patient with severe sepsis? • Recommendation : red blood cell transfusion should occur only when hemoglobin decreases to <7.0 g/dL (<70 g/L) to target a hemoglobin of 7.0–9.0 g/dL • Some groups of septic patients may need a higher level of hemoglobin :coronary artery disease ,acute hemorrhage , lactic acidosis Grade B

  22. Rationale • Transfusion Requirements in Critical Care (TRICC) trial • transfusion threshold of 7 g/dL (70 g/L) was not associated with an increased mortality rate • first 6 hrs of resuscitation of septic shock: hematocrit of 30% Vamvaka EC: RBC transfusion and postoperative length of stay in the hospital or the intensive care unit among patients undergoing coronary artery bypass graft surgery:The records of 421 consecutive patients undergoing coronary artery bypass graft (CABG) operations at the Massachusetts General Hospital were reviewedTransfusion 2000; 40:832–839 Allogeneic blood transfusion was independently associated with longer postoperative stays in the hospital or the ICU

  23. Conditions in septic patients require a higher hemoglobin • • Impaired pulmonary function • • Increased oxygen consumption (fever, chills) • • Coronary artery disease • • Unstable coronary syndromes • Uncontrolled/unpredictable bleeding

  24. Hb level is determinant of oxygen transport ( the cardiac output and the PaO2) increasing the number of red blood cells can increase blood viscosity, which in turn can decrease cardiac output, and hence, limit oxygen delivery increases pulmonary vascular resistance intrapulmonary shunt fraction beneficial effects on the microcirculation, with oxygen extraction capacities being greater when the hematocrit is reduced during sepsis Normovolemic hemodilution improves oxygen extraction capabilities in endotoxic shock. J Appl Physiol 2001;91:1701 not increase oxygen consumption Good tolerance to anemia is due to increases in cardiac index (CI) and oxygen extraction ratio (O2ER), which maintain oxygen consumption (VO2) Red blood cell transfusions increase oxygen delivery ? Low Hb in sepsis

  25. The aim is not to achieve a predetermined oxygen delivery but to assess whether the oxygen delivery is adequate by examining urine output, skin temperature, and the severity of lactic acidosis

  26. 感染性休克病人 Hb含量常在8~10g/dl之間 • 感染性休克病人 Hb含量常在7~9g/dl之間可以很好耐受 • Hb下降與以下因素有關，包括紅細胞生成不足和血液稀釋 • 在用晶體液和膠體液對感染性性進行液體復蘇的過程中Hb常下降1~3g/dl。 • 貧血相關的血液粘滯度下降降低後負荷，增加靜脈回流，因而增加搏出量和心輸出量，因而可能增加微血管血流 • 對重危病人輸血Hb至8~10g/dl，並未證明對維持組織灌注有益

  27. What is the role of erythropoietin administration in the severe sepsis patient with decreased hemoglobin? • Not recommended as a specific treatment for anemia associated with severe sepsis • may be used ,as renal failure-induced compromise of red blood cell production. Grade B

  28. the potential use of rHuEPO in septic patients • 1.is whether septic patients have low erythropoietin levels ? low erythropoietin levels in 22 septic patients with and without acute renal failure (Rogiers P, Zhang H, Leeman M, et al: Erythropoietin response is blunted in critically ill patients. Intensive Care Med 1997; 23:159–162) • 2. is whether septic patients will respond to exogenous EPO ? not provided(Corwin HL, Gettinger A, Pearl RG, et al: Efficacy of recombinant human erythropoietin in critically ill patients. JAMA 2002; 28:2827–2835) • 3. is whether EPO administration is beneficial in septic patients ? No clinical trials have been performed with EPO in septic patients

  29. Efficacy of recombinanthuman erythropoietin in the critically ill patient A randomized, double-blind, placebo-controlled trial Corwin HL. Crit Care Med 1999; 27:2346–2350

  30. Efficacy of recombinant human erythropoietin in the critically ill patient Survival percentage blood transfused was lower in patients receiving rHuEPO (p < .002)

  31. the EPO response in sepsis cannot be predicted • Response to rHuEPO in sepsis is unknown but may be less than other critically ill patients due to the presence of inflammatory cytokines • EPO administration would have no impact on transfusions in the first 5–6 days of critical illness.

  32. FFP be transfused in patients with severe sepsis? • Routine use of FFP to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures is not recommended • Doses of FFP should be chosen to achieve factor levels >=30% of normal values (usually 10–15 mL/kg). Rapid infusion (not continuous infusion) is needed to achieve effective factor levels • FFP transfusion is also appropriate if reversal of the warfarin effect is needed immediately Grade E

  33. FFP be transfused in patients with severe sepsis? • FFP is indicated for coagulopathy due to documented deficiency of coagulation factors (increased PT,INR,PTT) in the presence of active bleeding or before surgical or invasive procedures Guidelines for red blood cell and plasma transfusion for adults and children. Can Med Assoc J 1999; 156:S1–S24 Medical Directors Advisory Committee, National Blood Transfusion Council: Guideline for the use of fresh-frozen plasma. S Afr Med J 1998; 88:1344–1347

  34. What is the role of antithrombin in the treatment of severe sepsis? • Anticoagulant:important physiologic regulator of coagulation(inhibiting factors XIa and IXa of the intrinsic pathway, tissue factor bound VIIa of the extrinsic pathway, and factor Xa and thrombin of the common coagulation pathway) • low functional levels in sepsis • Antithrombin may also have anti-inflammatory effects • Antithrombin administration is not recommended for the treatment of severe sepsis and septic shock. • Grade B High-dose antithrombin III in severe sepsis: A randomized controlled trial. JAMA 2001; 286:1869–1878

  35. High-Dose Antithrombin III in Severe Sepsis: A Randomized Controlled Trial JAMA. 2001;286:1869-1878

  36. Thrombocytopenia increased mortality(When should platelets be transfused in the patient with severe sepsis? ) • platelets should be administered when counts are <=5000/mm3 (5 × 109/L), regardless of apparent bleeding • Platelet transfusion may be considered when counts are 5,000–30,000/mm3 (5–30 × 109/L) and there is a significant risk of bleeding • Higher platelet counts (>=50,000/mm3 [50 × 109/L]) may be required for surgery or invasive procedures Grade E

  37. Thrombocytopenia and prognosis in intensive care Crit Care Med 28(6), June 2000, pp 1871-1876

  38. the etiology of thrombocytopenia, platelet dysfunction, risk of bleeding, planned invasive procedures, and the presence of concomitant disorders. • The presence of active bleeding, fever, sepsis, coagulopathy, and platelet dysfunction should be considered in assessing the risk of serious hemorrhage

  39. ER:key role in the chain of survival for acute and highly prevalent diseases • 387,616 patients with severe sepsis and septic shock initially present to the emergency department (ED) each year • incidence of more than 1 million cases annually by 2020

  40. Surviving Sepsis Campaign (SSC) • (phase I) :global effort to improve patient care worldwide (achieve a mortality reduction of 25% in 5 years and secure funding for research and improvements in patient care) • (phase II) :Creation of the guidelines ,ACEP has taken a major leadership role of the campaign • (phase III) converting guidelines to clinical practice change and improvement in outcome -- 2005

  41. Hypothesis: Implementation of a 6-hour SS Bundle specific to the ED setting will lead to improvement in the uniformity of care. Methods: 1) CVP/ScvO2 monitoring within 2 hrs 2) Broad spectrum antibiotics within 4 hrs 3) Hemodynamic goals(CVP> = 8 mmHg, MAP> = 65 mmHg, ScvO2> = 70%) within 6 hrs 4) Lactate monitoring 5) corticosteroid given if patient was vasopressor dependent the 6-hour Strategies to Timely Obviate the Progression of Sepsis (STOP Sepsis) Conclusion:24/208 patient complete bundle component,the mortality rate was 12.5%(P=0.008)compare with non-compete bundle group( 34.2%) H. Bryant Nguyen:SCCM 34th Critical Care Congress: Abstract 44. Presented Jan. 17,2005

  42. Preliminary 6,24-hour severe sepsis/septic shock bundle The 6-hour bundle includes 1.Early indentification 2.Early antibiotics and culture 3.Early goal Tx The 24-hour bundle includes administration of drotrecogin alfa (Xigris) per hospital guidelines, administration of steroids if vasopressors are required for 6 hours, administration of glucose control (150 mg/dL) and lung protective strategies (maximum plateau pressure of 30 cm/H2O).

  43. the SSC and Institute forHealthcare Improvement • Blood Cultures Obtained Before Broad-Spectrum Antibiotics • CVP ≥ 8 mm Hg Achieved for Septic Shock or Lactate > 4 mmol/L (36 mg/dl) within 6 Hours • Drotrecogin Alfa (Activated) Administered as per a Standardized ICU Policy within 24 Hours • Glucose Control ≥ Lower Limit of Normal and with Median < 150 mg/dl (8.3 mmol/L) within 24 Hours • Low-Dose Steroids Administered for Septic Shock as per a Stardardized ICU Policy within 24 Hours • Median Inspiratory Plateau Pressure < 30 cm H20 for Mechanically Ventilated Patients within 24 Hours • Median Time to Broad-Spectrum Antibiotic Administration • Overall Mortality – Severe Sepsis, Septic ShockScvO2 ≥ 70% (SvO2 ≥ 65%) for Septic Shock or Lactate > 4 mmol/L (36 mg/dl) within 6 Hours • Sepsis Management Bundle Reliability • Sepsis Resuscitation Bundle Reliability

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