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

B

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.

Methods
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

S542

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. 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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. 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(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. 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