Use of blood products in sepsis: An evidence-based review

Janice L. Zimmerman, MD, FCCM

Objective: In 2003, critical care and infectious disease experts
representing 11 international organizations developed management guidelines for the use of blood products in sepsis that would
be of practical use for the bedside clinician, under the auspices of
the Surviving Sepsis Campaign, an international effort to increase
awareness and to improve outcome in severe sepsis.
Design: The process included a modified Delphi method, a
consensus conference, several subsequent smaller meetings of
subgroups and key individuals, teleconferences, and electronicbased discussion among subgroups and among the entire committee.
Methods: The modified Delphi methodology used for grading
recommendations built on a 2001 publication sponsored by the
International Sepsis Forum. We undertook a systematic review of
the literature graded along five levels to create recommendation


lood products such as red
blood cells (RBCs), freshfrozen plasma (FFP), and
platelets are commonly used
in septic patients as in other critically ill
patients. Appropriate use is necessary in
view of the limited supply and potential
risk to patients. There are few clinical
trials that specifically evaluate the use of
blood products in patients with severe
sepsis or septic shock. Current recommendations and practice for use of blood
products in sepsis are primarily based on
extrapolation of study results from heterogeneous groups of critically ill patients,
studies in patients who are not critically
ill, and consensus guidelines. Further
clinical studies in septic patients are required to develop more definitive guidelines for transfusion of blood products.

A comprehensive Medline literature
search from May 1993 to May 2003 was
performed. The following terms were independently searched: transfusion, blood
transfusion, platelets, fresh-frozen

From Baylor College of Medicine, Houston, TX.
Copyright © 2004 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000145906.63859.1A


grades from A to E, with A being the highest grade. Pediatric
considerations to contrast adult and pediatric management are in
the article by Parker et al. on p. S591.
Conclusion: In the absence of extenuating circumstances and
following resolution of tissue hypoperfusion, red blood cell transfusion should be targeted to maintain hemoglobin at 7.0 g/dL or
greater. Erythropoietin is not recommended as a specific treatment for sepsis-associated anemia. Fresh-frozen plasma should
be given for documented deficiency of coagulation factors and in
the presence of active bleeding or before surgical or invasive
procedures. Antithrombin administration is not recommended.
Specific platelet transfusion thresholds are based on the presence
or absence of bleeding, significant risk for bleeding, plans for
surgery or invasive procedures, and platelet count <5,000/mm3.
(Crit Care Med 2004; 32[Suppl.]:S542–S547)

plasma, erythropoietin, and antithrombin. These terms were cross-searched
with the following: sepsis, severe sepsis,
sepsis syndrome, septic shock, critical
care, and intensive care. Additional references were found by review of bibliographies of articles.

Red Blood Cell Transfusion
Transfusion of RBCs in the critically
ill is common and increases with the
length of stay in the intensive care unit
(ICU) (1–3). Anemia in critically ill patients is also common but has not been
specifically characterized in patients with
sepsis. Although information on hemoglobin levels and transfusions are frequently collected in sepsis trials, it is
rarely reported. In a trial of early goaldirected therapy for resuscitation of severe sepsis and septic shock, the baseline
hematocrit was reported as 34.7 ⫾ 8.5%
in the standard therapy group and 34.6 ⫾
8.3% in the goal-directed therapy group
(4). The mean admission hemoglobin in
septic shock patients in the European observational study was 10.4 g/dL, and 6.6%
had been transfused in the prior 24 hrs
(2). In the United States observational
study, 11% of patients with an admission
diagnosis of sepsis or systemic inflammatory response syndrome had a hemoglobin level ⱕ8 g/dL and 21% had a hemo-

globin level ⬎12 g/dL (3). The time
course and severity of anemia in sepsis
may be similar to other critically ill patients but confirmation is needed with
further study.
Anemia in septic patients, as in other
critically ill patients, may be due to multiple factors (5). Blood loss may be secondary to phlebotomy, overt or occult
hemorrhage, coagulation disorders, or
extracorporeal circuits. An increased destruction of red cells may be secondary to
nonimmune mechanisms, such as disseminated intravascular coagulation
(DIC). A decrease in red cell production
may be due to marrow infiltration with
infection or malignancy or use of cytotoxic drugs. Nutrient deficiencies (iron,
B12, folate) are also possible but less
common. Impaired iron utilization and
inadequate erythropoietin production
may be important factors in septic patients. Inflammatory cytokines such as
tumor necrosis factor, interleukin-l,
transforming growth factor-␤, and prostaglandins have been demonstrated to inhibit hypoxia-induced erythropoietin production (6).
The risks of blood transfusion are well
described (Table 1) and would be expected to be similar in patients with sepsis. Immunosuppression secondary to
blood transfusion may be particularly imCrit Care Med 2004 Vol. 32, No. 11 (Suppl.)

Conditions in septic patients that may require a higher hemoglobin Acute instability Cardiovascular disease Coronary artery disease Low cardiac output Pulmonary disease Severe arterial hypoxemia Organ or tissue ischemia Severe mixed venous desaturation Elevated lactate level riod or impact on outcomes have not been performed in septic patients. A causal association is difficult to establish due to confounding factors and study design issues (7.0 Table 1. The transfusion threshold used in septic patients requires some individualization and consideration of impaired physiologic functions. Red Blood Cell Transfusion Question: What is the appropriate hemoglobin threshold for transfusion of packed red blood cells in the patient with severe sepsis? Recommendation: Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances. or lactic acidosis (see recommendations for initial resuscitation). chills Rash. However. some studies in postoperative and trauma patients have found increased rates of infection and/or poor outcomes in transfused patients (8 –12). optimize oxygenation. that assumption is not well supported with existing information. or improve ischemia. These short-term physiologic studies of blood transfusion in sepsis suggest flow or tissue or cellular factors may be more important than arterial oxygen content in improving tissue oxygenation. but the proportion with severe sepsis or septic shock is not specified. 14). 27. The TRICC study suggests that a hemoglobin as low as 7 g/dL may be adequate in a majority of critically ill patients (15. The Canadian Critical Care Trials Group prospective study of transfusion thresholds did not find significant differences in infection between the restrictive and liberal transfusion groups (15). 11 (Suppl. Some groups of septic patients may need a higher level of hemoglobin (Table 2). Further studies to characterize the course of anemia in sepsis and to assess the impact of a specific transfusion strategy are needed to provide more definitive recommendations. 32). Although debate continues (7).717 medical/ surgical ICU patients.231 patients with severe sepsis. Red blood cell transfusions are generally assumed to increase oxygen delivery beneficially to tissues and prevent. minimize. While it can be postulated that septic patients with severe disease are similar to the heterogeneous group of patients in the TRICC study. 32. Infection was present at baseline in 27% of the restrictive group and 26% of the liberal group. Blood transfusion consistently increases pulmonary vascular resistance and intrapulmonary shunt fraction. control hemorrhage. This study excluded patients with chronic anemia who may be at higher risk for sepsis due to underlying comorbidities. this study may not adequately represent severe sepsis/septic shock patients. Erythropoietin Administration Question: What is the role of erythropoietin administration in the severe sepsis patient with decreased hemoglobin? Recommendation: Erythropoietin is not recommended as a specific treatment for S543 . urticaria Major transfusion reactions Acute hemolysis Delayed hemolysis Anaphylaxis Transmission of infection Human immunodeficiency virus Human T-cell lymphotrophic virus I and II Hepatitis B and C Cytomegalovirus Bacterial contamination Graft-versus-host disease Acute lung injury Volume overload Hypothermia Immunomodulation/immunosuppression Crit Care Med 2004 Vol. Clinical trials of blood transfusion to evaluate physiologic effects over a longer time pe- Table 2. Sepsis was listed as the primary diagnosis in 6% of patients in the restrictive strategy group and 4% of patients in the liberal strategy group. Efforts should be made to minimize phlebotomy. The effects of RBC transfusion in septic patients have been evaluated in several studies (Table 3) (17–25). No.0 –9. but the limited data for decision-making is also acknowledged (30). Nosocomial infections were increased in transfused patients and demonstrated a dose response pattern. A transfusion threshold of 7 g/dL (70 g/L) was not associated with an increased mortality rate. Risks of transfusion of blood products Minor transfusion reactions Fever. This recommended transfusion threshold contrasts with the target of a hematocrit of 30% in patients with low central venous oxygen saturation during the first 6 hrs of resuscitation of septic shock. such as significant coronary artery disease. Specific groups of patients such as those with myocardial ischemia or severe hypoxemia may require higher hemoglobin levels. In general. Neilipovitz and Hébert (29) suggest that the results of the TRICC trial are applicable to patients with sepsis but also recommend a more liberal transfusion practice for septic patients compared with nonseptic patients. The minimum hemoglobin tolerated by healthy or ill individuals without adverse effects is not known. the number of units transfused was found to be similar in survivors and nonsurvivors.0 g/dL. Grade B Rationale: Although the optimum hemoglobin for patients with severe sepsis has not been specifically investigated. RBC transfusion increases oxygen delivery in septic patients but does not increase oxygen consumption. The Society of Critical Care Medicine practice parameters for hemodynamic support in adults with sepsis recommend that hemoglobin concentrations be maintained above 8 –10 g/dL (80 –100 g/L). Recently. (13) noted an increased risk of nosocomial infection in a retrospective study of 1. acute hemorrhage. A study of acute isovolemic reduction of hemoglobin to 5 g/dL (50 g/L) in healthy patients and volunteers showed no evidence of inadequate oxygen delivery or ischemia (26). In a retrospective study of 3.) g/dL (⬍70 g/L) to target a hemoglobin of 7. 28). Some studies suggest increased mortality in critically ill patients is associated with RBC transfusion (1).portant in septic patients. However. data from the Transfusion Requirements in Critical Care (TRICC) trial suggests that a hemoglobin of 7–9 g/dL (70 –90 g/L) is adequate for most critically ill patients (14). but the effectiveness of transfusion in these patients is inadequately characterized (31. Taylor et al. mortality was associated with older age of transfused blood (16). red blood cell transfusion should occur only when hemoglobin decreases to ⬍7. and adequately volume resuscitate patients before considering RBC transfusion.

decrease blood transfusions. 1990 (20) Steffes et al. 3.6 ⫾ 1. and the optimum regimen is not known.3 Fernandes et al.5 Silverman and Tuna 1992 (22) Septic adults 19 2 units Marik and Sibbald 1993 (23) Septic adults 23 3 units over 90–120 mins 8. 7.002).5 to 10. (33) evaluated rHuEPO administration compared with placebo in 160 critically ill patients but excluded patients with shock and severe respiratory compromise.3 to 10. 1 SVR. pHi. and 9) as compared with groups given folic acid or folic acid plus iron.2 ⫾ 0. 1 intrapulmonary shunt fraction (thermodilution measurements) 1 DO2.3 to 10. (39) described high EPO levels in septic patients and EPO levels rapidly increased in nonsurvivors.) . However. Studies in heterogeneous groups of critically ill anemic patients and trauma patients suggest that erythropoietin levels are inappropriately low (5. but clinical trials in critically ill patients show some decrease in red cell transfusion requirement with no effect on clinical outcome (33.5 hrs 8. Only three of 80 patients in each treatment group had sepsis. Rogiers et al.7 ⫾ 1.4 ⫾ 0.6 ⫾ 0. pulmonary vascular resistance. 8. 35–38).Table 3.0 ⫾ 7. Relevant information to answer this question definitively is not available.6 ⫾ 0.3 (low pHi) 9. Most studies had a small number of patients with sepsis. including neuroprotection and prevention of apoptosis. It should be noted that the reticulocyte count in the EPO group was significantly different from other groups beginning on day 8.2 ⫾ 1. PVR.6 ⫾ 0. which is consistent with the pharmacologic effects of EPO on red cell maturation. Group size was small (12 in each treatment arm) and the proportion of patients with sepsis varied from 58% to 75%.7 ⫾ 0.1 ⫾ 0. 1 intrapulmonary shunt. 1990 (19) Conrad et al. 1993 (24) Severe sepsis adults 16 800 mL over 90 mins 9.2 ⫾ 0. Erythropoietin may decrease the number of units transfused per patient but has minimal impact on avoiding transfusion in critically ill patients. The total number of red blood cell units transfused was lower in patients receiving rHuEPO (p ⬍ .3 ⫾ 1.5 to 10. gastric intramucosal pH.0 Lorente et al. but VO2 not increased. 34). A placebo-controlled trial in 21 surgical or trauma patients with multiple organ dysfunction found a significantly increased reticulocyte count in the EPO group (600 IU/kg three times weekly) at 3 wks (42). Three questions need to be posed in regard to the potential use of rHuEPO in septic patients.8 to 11.8 ⫾ 0.3 to 11. but VO2 not increased in patients with normal or low pHi (thermodilution measurements) 1 DO2 but VO2 not increased.8 to 13. Abel et al. The first question is whether septic patients have low erythropoietin levels.4 ⫾ 0. In two randomized clinical trials of rHuEPO administration in critically ill patients.5 (normal pHi). The second question to consider is whether septic patients will respond to exogenous EPO. The expected inverse relationship between EPO levels and hemoglobin was present in survivors but not in nonsurvivors.4 7 10–15 mL/kg over 1–3 hrs 9. and improve quality of life.9 to 10–12 17 Estimated to achieve hemoglobin 10–12 g/dL 8 8–10 mL/kg over 1–2 hrs 10. Red blood cell transfusion studies in sepsis Study Patients Gilbert et al.3 ⫾ 0. 34). van Iperen et al. oxygen consumption.9 ⫾ 9. and the percentage of patients transfused or who died on days 8 – 42 was not significantly reduced from Crit Care Med 2004 Vol. Erythropoietin (EPO) also has pleiotropic effects on the body beyond stimulation of erythropoiesis that are not well understood. Recombinant human erythropoietin (rHuEPO) is widely used in anemic patients with chronic renal failure and cancer to improve the hematocrit. dobutamine 1 VO2 (thermodilution measurements) DO2 and VO2 not increased. information on response rates is not provided (33. SVR. 1 VO2 only if normal lactate. Grade B Rationale: No specific information regarding erythropoietin use in septic patients is available.8 Findings 1 DO2.3 Septic adults (postoperative or posttrauma) 21 (27 studies) 1 or 2 units at 2 hr/unit 9. Higher levels of EPO in nonsurvivors of septic shock were also noted by Nakamura et al.7 19 591 mL over 4. 5. g/dL 8.6 ⫾ 0. (40) Nonanemic children with sepsis and septic shock have also been found to have increased EPO levels (41). No clinical trials have been performed with EPO in septic patients. (43) demonstrated that critically ill anemic patients responded with higher reticulocyte counts and transferrin receptor levels when given folic acid. 1 SVR. 1 PVR. The last question to pose is whether EPO administration is beneficial in septic patients.4 to 12. The appropriate dose and frequency of administration of rHuEPO has varied in clinical trials. 11 (Suppl. 1 PVR. and erythropoietin (300 IU/kg on days 1.1 to 10. 1 VO2 only in patients with increased lactate (thermodilution measurements) 1 DO2 but VO2 not increased (thermodilution measurements) 1 DO2 and 1 VO2 (thermodilution measurements) 1 DO2. anemia associated with severe sepsis but may be used when septic patients have other accepted reasons for administration of erythropoietin.4 ⫾ 0. VO2.3 ⫾ 1. 32. such as renal failureinduced compromise of red blood cell production. 2 pHi with older bood (thermodilution and indirect calorimetry measurements) 1 DO2. Corwin et al. 1 PVR. 2001 (25) Septic adults (Septic shock excluded) 10 (⫹5 control) 1 unit over 1 hr 9. oxygen delivery. iron. No. Exogenous EPO is most likely to be effective in patients with low S544 EPO levels based on the experience with chronic renal failure patients. 1991 (21) Septic shock (2 mos–6 yrs) Septic children (4 mos–15 yrs with VO2 ⬍ 180) Septic shock (1–77 yrs) n RBC Transfusion Hgb Change. (35) noted low erythropoietin levels in 22 septic patients with and without acute renal failure. 1986 (17) Septic adults Mink and Pollack 1990 (18) Lucking et al. but VO2 not increased (thermodilution measurements) 1 DO2 in all. systemic vascular resistance. no change in lactate or pHi (thermodilution and indirect calorimetry measurements) DO2.

platelet dysfunction. Response to rHuEPO in sepsis is unknown but may be less than other critically ill patients due to the presence of inflammatory cytokines (44).302 ICU patients who received weekly rHuEPO.55% to 45%. Differences are not apparent until 1 wk after initiation of treatment. Baron J-F. Rivers E. Grade E Rationale: No clinical data exist in septic patients to guide the use of platelet transfusions. Crit Care Med 1999. REFERENCES 1. A large proportion of ICU patients (71%) were not eligible for the trial. guidelines for the use of FFP have been Crit Care Med 2004 Vol. 32. Pearl RG. antithrombin is indicated only for the very rare septic patient with congenital antithrombin deficiency. FFP transfusion is also appropriate if reversal of the warfarin effect is needed immediately.1% of the placebo group and 9. Sepsis was present in 7. Parsonnet KC. no beneficial effects on morbidity or mortality were noted with rHuEPO use. and the presence of concomitant disorders (45. Question: What is the role of antithrombin in the treatment of severe sepsis? Recommendation: Antithrombin administration is not recommended for the treatment of severe sepsis and septic shock. 27:2630 –2639 6. Gettinger A: RBC transfusion in the ICU: Is there a reason? Chest 1995. Müller C. N Engl J Med 2001. coagulopathy. international normalized ratio. the EPO response in sepsis cannot be predicted. 53). et al: Important role of nondiagnostic blood loss and blunted erythropoietic response in anemia of medical intensive care patients. Guidelines for transfusion of platelets in infants and children are adapted from adult recommendations (63). Septic patients may have decreased platelet production and/or increased platelet destruction due to microvascular injury and DIC. Most recommendations are derived from consensus opinion and experience in patients undergoing chemotherapy (62). sepsis. Antithrombin functions as an anticoagulant by inhibiting factors XIa and IXa of the intrinsic pathway. Platelet Transfusion Thrombocytopenia occurs frequently in critically ill patients and can be associated with increased mortality (59 – 61). Further studies are required to evaluate any benefit of rHuEPO in decreasing transfusions in septic patients. Grade E Rationale: FFP is often used in critically ill and septic patients to correct factor deficiencies that occur as a result of an acquired coagulopathy. Fresh-Frozen Plasma Transfusion Question: When should FFP be transfused in patients with severe sepsis? Recommendation: Routine use of FFP to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures is not recommended.000/mm3 [50 ⫻ 109/L]) may be required for surgery or invasive procedures. JAMA 2002. Due to the limited information available.000/mm3 (5–30 ⫻ 109/L) and there is a significant risk of bleeding. et al: Anemia and blood transfusion in critically ill patients. Goldberg MA: Effect of inflammatory cytokines on hypoxia- S545 .) proposed by several professional organizations (45– 48). et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. Thrombocytopenia is also associated with major bleeding and increased transfusion requirements. Corwin et al. and platelet dysfunction should be considered in assessing the risk of serious hemorrhage. 108:767–771 3. Platelet transfusion may be considered when counts are 5. Doses of FFP should be chosen to achieve factor levels ⱖ30% of normal values (usually 10 –15 mL/kg). von Ahsen N. Vincent JL. risk of bleeding. 47). Nguyen B. platelets should be administered when counts are ⱕ5000/mm3 (5 ⫻ 109/ L). Grade B Rationale: Several open and double-blind studies in a small number of patients with sepsis suggested that high-dose antithrombin may improve survival or organ failure in the most severely ill (54 – 58). Generalizing these results to patients with sepsis is difficult. 51). 2. At this time. No. Serke S. Question: When should platelets be transfused in the patient with severe sepsis? Recommendation: In patients with severe sepsis. fever. Corwin H. et al: The CRIT study: Anemia and blood transfusion in the critically ill—Current clinical practice in the United States. 288:1499 –1507 2.000 –30. or partial thromboplastin time) in the presence of active bleeding or before surgical or invasive procedures. EPO administration would have no impact on transfusions in the first 5– 6 days of critical illness. 11 (Suppl. such as disseminated intravascular coagulation (DIC). Antithrombin may also have anti-inflammatory effects (50. 345:1368 –1377 5. (34) reported a recent trial in 1. including antithrombin. a large phase III clinical trial of high-dose antithrombin did not demonstrate any beneficial effect on 28day all-cause mortality in adults with severe sepsis and septic shock. and factor Xa and thrombin of the common coagulation pathway (49). Although clinical studies have not assessed the impact of transfusion of FFP on outcomes in critically ill patients.1% of the rHuEPO group. are noted to have low functional levels in sepsis. Rapid infusion (not continuous infusion) is needed to achieve effective factor levels. However. Recommendations take into account the etiology of thrombocytopenia. planned invasive procedures. Faquin WC. The triggering condition must be aggressively treated. Havsted S. Crit Care Med 2004. 32: 39 –52 4. and approximately 70% of transfused patients receive blood within the first 2 ICU days (1. Studies suggest that 40% to 50% of transfusions occur in the first week of critical illness. Clotting inhibitors. Although there was a reduction in the percentage of patients transfused and the cumulative units transfused per patient. Antithrombin Administration Antithrombin is a hepatically synthesized glycoprotein that is an important physiologic regulator of coagulation. Gettinger A. Reinhart K. Corwin HL. High-dose antithrombin was associated with a significantly increased risk of bleeding. regardless of apparent bleeding. Routine use of FFP to correct laboratory abnormalities in the absence of bleeding is not recommended. 5). FFP is indicated for coagulopathy due to documented deficiency of coagulation factors (increased prothrombin time. Schneider TJ. Higher platelet counts (ⱖ50. and the majority of patients were postoperative or trauma. The presence of active bleeding. tissue factor bound VIIa of the extrinsic pathway. especially when administered with heparin (53). especially severe sepsis and septic shock (52.

48. 21. 42. et al: Antithrombin inhibits lipopolysaccharideinduced tissue factor and interleukin-6 production by mononuclear cells. 156:S1–S24 American Society of Anaesthesiologists Task Force on Blood Component Therapy: Practice guidelines for blood component therapy. 17. et al: Efficacy of recombinant human erythropoietin in the critically ill patient: A randomized double-blind. 639 – 660 Wu W-C. Chaten FC. 29. 45. 23: 159 –162 Hobisch-Hagen P. et al: Human cardiovascular response to acute. protein C. SM Opal (Eds). O’Brien J. Wells G. Blajchman MA. 36. Manganaro L. is associated with worse outcome in trauma. et al: Response of erythropoiesis and iron metabolism to recombinant erythropoietin in intensive care unit patients. 32. Gaillard CAJM. Society of Critical Care Medicine: Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. 12. Wang Y. Zhang H. Chest 1992. J Trauma 2003. Levinson MA: Blood transfusion and oxygen consumption in S546 22. Nephrol Dial Transplant 2002. 27:2346 –2350 Corwin HL. Hebert CA. JL Vincent. Can J Anaesth 1997. et al: Changes in plasma erythropoietin and interleukin-6 concentrations in patients with septic shock after hemoperfusion with polymyxin B-immobilized fiber. 24: 1455–1459 Gabriel A. 24. 15. et al: Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? Crit Care Med 2001. 73:138 –142 Hill GE. Pollack MM: Effect of blood transfusion on oxygen consumption in pediatric septic shock.7. human umbilical vein endothelial cells. Intensive Care Med 1997. Circ Shock 1990. 30: 2249 –2254 Vamvaka EC. et al: Effect of antithrombin III supplementation on inflammatory response in patient with severe sepsis. placebo-controlled trial. Eur J Haematol 1996. Yetisir E. Sibbald WJ: Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. 19. Crit Care Med 1990. 340:409 – 417 Purdy FR. Tweeddale MG. DeMarco FVC. Merrick PM: Association of mortality with age of blood transfused in septic ICU patients. 46. et al: Dependence of oxygen consumption on oxygen delivery in children with hyperdynamic septic shock and low oxygen extraction. Semin Thromb Haemost 1998. No. 134:873– 878 Mink RB. In: The Sepsis Text. et al: A multicenter. JAMA 1993. 35. vol 23. 27. Mandanas RY. et al: Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Tracy JK. Wiedermann F. et al: Do blood transfusions improve outcomes related to mechanical ventilation? Chest 2001. Crit Care Med 1994. 51. N Engl J Med 2001. Bray GL. Blajchman MA: Deleterious clinical effects of transfusion-associated immunomodulation: Fact or fiction? Blood 2001. 11 (Suppl. 2002. 29:134 –139 Inthorn D. 348:1055–1060 Corwin HL. J Carlet. 271:777–781 Guidelines for red blood cell and plasma transfusion for adults and children. 49. 101: 816 – 823 Warren BL. Crit Care 2003. Viele MK. 22:821– 826 Elliott JM. dePablo R. pp 401– 410 Task Force of the American College of Critical Care Medicine. Am Surg 2002. National Blood Transfusion Council: Guideline for the use of fresh-frozen plasma. 269:3024 –3029 Lorente JA. et al: Association of bacterial infection and red blood cell transfusion after coronary artery bypass surgery. et al: Blood transfusions correlate with infections in trauma patients in a dose-dependent manner. Prato S. 24:1272–1276 Krafte-Jacobs B. Ebihara I. Sawyer RG. 40. Mayr A. 38. et al: Blunted erythropoietic response to anemia in multiply traumatized patients. Dunne J. Goudemand J. Eid A. 20. Crit Care 2001. Cox PM. 25. Crit Care Med 1999. Gettinger A. 53. 41. GarcíaCuriel A. et al: Red blood cell transfusion does not increase oxygen consumption in critically ill septic patients. 88:1344 –1347 Mammen EF: Antithrombin III: Its physiologic importance and role in DIC. 279:217–221 Hébert PC. 119: 1850 –1857 Neilipovitz D.) . 31:419 – 429 Steffes CP. et al: Serum erythropoietin levels in patients with sepsis and septic shock. and whole blood. 18: 1087–1091 Lucking SE. surgical sepsis. 31. 14. et al: Erythropoietin response to critical illness. independent of shock severity. JAMA 2002. 54:898 – 807 Leal-Noval SR. 44. Can Med Assoc J 1999. Martin C. Hartl WH. Schulman AM. JAMA 1998. 30. 16. 26. et al: Septic shock. Dietrich KA. 10. 23. 68:566 –572 Chelemer SB. 102:184 –188 Marik PE. induced erythropoietin production. 28:2773–2778 Macdougall IC. 57:359 –363 Nakamura T. et al: Allogeneic blood transfusion increases the risk of postoperative bacterial infection: A metaanalysis. 18:1316 –1319 Conrad SA. Intensive Care Med 1998. 8. Tuna P: Gastric tonometry in patients with sepsis. et al: Blood transfusion in elderly patients with acute myocardial infarction. et al: The effect of fluid loading. Thomas S. Bock GH: Circulating erythropoietin and interleukin-6 concentrations increase in critically ill children with sepsis and septic shock. Chest 2001. and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. 24:19 –25 Souter PJ. Leeman M. multiple organ failure. Carven JH: RBC transfusion and postoperative length of stay in the hospital or the intensive care unit among patients undergoing coronary artery bypass graft surgery: The effects of confounding factors. Gettinger A. Fandrey J. Kraaijenhagen RJ. Chopin C. Bender JS. Spannbrucker N. sponse in critical illness. Crit Care Med 1991. Crit Care Med 2001. Feiner J. Shimada N. Rathore SS. Hubbard AR. J Trauma 1998. 84:732–747 Medical Directors Advisory Committee. effects of dobutamine infusions and packed red blood cell transfusions. 10:90 –96 Fourrier F. and platelets. Crit Care Med 1999. Hoffmann JN. 21:1312–1318 Fernandes CJ. Lancet 1996. 37. Blajchman MA. Shock 1998. 11. Blood 1992. 79:1987–1994 Vamvakas EC. Crit Care Med 1996. Anesthesiology 1996. et al: Impact of allogenic packed red cell transfusion on nosocomial infection rates in the critically ill patient. 7:R35–R40 Abel J. Crit Care Med 2000. Frawley WH. et al: Erythropoietin mimics the acute phase re- 39. 33. 119:1461–1468 Taylor RW. blood transfusion. 13. et al: Effect of red cell transfusion on oxygen consumption following fluid resuscitation in septic shock. Poses RM. 43. and disseminated intravascular coagulation: Compared patterns of antithrombin III. 54:908 –914 Malone DL. Rincón-Ferrari MD. Cook DJ. N Engl J Med 1999. JAMA 1994. 40:832– 839 Hébert PC. Transfusion 2000. Hébert PC: Blood transfusion and sepsis. 32. Pearl RG. 9. Rodriguez RM. et al: High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome. 47. severe isovolemic anemia. Crit Care Med 2002. et al: Transfusion of blood components and postoperative infection in patients undergoing cardiac surgery. 97:1180 –1195 Claridge JA. Virankabutra T. Akamine N. cryoprecipitate. 17(Suppl 11):39 – 43 College of American Pathologists: Practice parameter for the use of fresh-frozen plasma. et al: High-dose Crit Care Med 2004 Vol. Crit Care Med 2001. et al: Erythropoietin response is blunted in critically ill patients. Landín L. et al: Blood transfusion. Crit Care Med 1990. 5:362–367 Weiskopf RB. Cooper AC: Erythropoietin resistance: The role of inflammation and proinflammatory cytokines. Williams TM. 345:1230 –1236 Carson JL. and protein S deficiencies. Crit Care Med 1993. J Trauma 2003. S Afr Med J 1998. 28: 2827–2835 Rogiers P. 29:743–747 Krafte-Jacobs B. 28. Singer P. randomized. 18. Haupt MT. Chest 1992. 34. 44:1256 –1261 Gilbert EM. 44:361–367 van Iperen CE. 29:227–234 Hébert PC. Kozek S. Am Rev Resp Dis 1986. 52. Jones S. 50. et al: Efficacy of recombinant human erythropoietin in critically ill patients. Griffith KE. controlled clinical trial of transfusion in critical care. Chiari A. Duff A. 19: 512–517 Silverman HJ. Klurver Academic Publishers. Levetown ML. Ann Thorac Surg 2002. et al: Effects of blood transfusion on oxygen transport variables in severe sepsis.

28: 1871–1876 Akca S. Mehler K. placebo-controlled. Fourrier F. randomized. et al: Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. 30: 753–756 Rebulla P: Trigger for platelet transfusion. Intensive Care Med 1998. Crit Care Med 2002. 63. et al: Antithrombin III in patients with severe sepsis: A randomized. de Mendonca A. double-blind trials with antithrombin III in severe sepsis. 104:882– 888 Crit Care Med 2004 Vol. Strauss R.) 56. Hartl WH.antithrombin III in severe sepsis: A randomized controlled trial. Intensive Care Med 1998. 8:328 –334 57. placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. placebo-controlled. Crit Care Med 2000. doubleblind multicenter trial plus a meta-analysis on all randomized. Eisele B. et al: Double-blind. Vox Sang 2000. Chopin C. 24:336 –342 58. Crit Care Med 2002. Hoffmann JM. Haji-Michael P. deCataldo F. Chest 1993. 28:S38 –S43 59. Crit Care Med 2000. 24:663– 672 55. 42: 1398 –1413 S547 . Lamy M. Heart J-J. Manno CS: Guidelines for assessing appropriateness of pediatric transfusion. et al: Thrombocytopenia and prognosis in intensive care. Wehler M. 30:1765–1771 Vanderschueren S. Luban NLC. and outcome. Baudo F. JAMA 2001. 11 (Suppl. et al: Antithrombin III (AT III) replacement therapy in patients with sepsis and/or post surgical complications: A double-blind. Inthorn D. Jourdain M. Thijs LG. multicenter trial. Fourrier F. et al: Time course of platelet counts in critically ill patients. Malbrain M. DeWeerdt A. 32. 62. Caimi TM. Transfusion 2002. Shock 1997. 286: 1869 –1878 54. et al: Thrombocytopenia in patients in the medical intensive care unit: Bleeding prevalence. transfu- 60. No. 78:179 –182 Roseff SD. Tournoys A: Clinical trial results with antithrombin III in sepsis. 61. sion requirements.