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 manage-
ment 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 electronic-
based discussion among subgroups and among the entire com-
mittee.
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
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 trans-
fusion should be targeted to maintain hemoglobin at 7.0 g/dL or
greater. Erythropoietin is not recommended as a specific treat-
ment 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)

B globin level ⬎12 g/dL (3). The time

lood products such as red
blood cells (RBCs), fresh-
frozen 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 recom-
mendations and practice for use of blood
products in sepsis are primarily based on
extrapolation of study results from heter-
ogeneous groups of critically ill patients,
studies in patients who are not critically
ill, and consensus guidelines. Further
clinical studies in septic patients are re-
quired to develop more definitive guide-
lines for transfusion of blood products.
Methods
A comprehensive Medline literature
search from May 1993 to May 2003 was
performed. The following terms were in-
dependently 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
plasma, erythropoietin, and antithrom-
bin. These terms were cross-searched
with the following: sepsis, severe sepsis,
sepsis syndrome, septic shock, critical
care, and intensive care. Additional refer-
ences were found by review of bibliogra-
phies 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 pa-
tients is also common but has not been
specifically characterized in patients with
sepsis. Although information on hemo-
globin levels and transfusions are fre-
quently collected in sepsis trials, it is
rarely reported. In a trial of early goal-
directed therapy for resuscitation of se-
vere 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 ob-
servational 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 inflamma-
tory response syndrome had a hemoglo-
bin level ⱕ8 g/dL and 21% had a hemo-
course and severity of anemia in sepsis
may be similar to other critically ill pa-
tients but confirmation is needed with
further study.
Anemia in septic patients, as in other
critically ill patients, may be due to mul-
tiple factors (5). Blood loss may be sec-
ondary to phlebotomy, overt or occult
hemorrhage, coagulation disorders, or
extracorporeal circuits. An increased de-
struction of red cells may be secondary to
nonimmune mechanisms, such as dis-
seminated intravascular coagulation
(DIC). A decrease in red cell production
may be due to marrow infiltration with
infection or malignancy or use of cyto-
toxic 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 pa-
tients. Inflammatory cytokines such as
tumor necrosis factor, interleukin-l,
transforming growth factor-␤, and pros-
taglandins have been demonstrated to in-
hibit hypoxia-induced erythropoietin pro-
duction (6).
The risks of blood transfusion are well
described (Table 1) and would be ex-
pected to be similar in patients with sep-
sis. Immunosuppression secondary to
blood transfusion may be particularly im-

S542 Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)

portant in septic patients. Although de-
bate continues (7), some studies in post-
operative and trauma patients have found
increased rates of infection and/or poor
outcomes in transfused patients (8 –12).
Recently, Taylor et al. (13) noted an in-
creased risk of nosocomial infection in a
retrospective study of 1,717 medical/
surgical ICU patients. Nosocomial infec-
tions were increased in transfused pa-
tients and demonstrated a dose response
pattern. A causal association is difficult to
establish due to confounding factors and
study design issues (7, 14). The Canadian
Critical Care Trials Group prospective
study of transfusion thresholds did not
find significant differences in infection
between the restrictive and liberal trans-
fusion groups (15). In a retrospective
study of 3,231 patients with severe sepsis,
the number of units transfused was found
to be similar in survivors and nonsurvi-
vors. However, mortality was associated
with older age of transfused blood (16).
Some studies suggest increased mortality
in critically ill patients is associated with
RBC transfusion (1).
Red Blood Cell Transfusion
Question: What is the appropriate hemo-
globin threshold for transfusion of
packed red blood cells in the patient with
severe sepsis?
Recommendation: Once tissue hypoper-
fusion has resolved and in the absence of
extenuating circumstances, such as sig-
nificant coronary artery disease, acute
hemorrhage, or lactic acidosis (see rec-
ommendations for initial resuscitation),
red blood cell transfusion should occur
only when hemoglobin decreases to ⬍7.0
Table 1. Risks of transfusion of blood products
Minor transfusion reactions
Fever, chills
Rash, 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. 32, No. 11 (Suppl.)
g/dL (⬍70 g/L) to target a hemoglobin of
7.0 –9.0 g/dL.
Grade B
Rationale: Although the optimum hemo-
globin for patients with severe sepsis has
not been specifically investigated, 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). A transfusion threshold of 7 g/dL
(70 g/L) was not associated with an in-
creased mortality rate. This recom-
mended 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 resus-
citation of septic shock.
Some groups of septic patients may
need a higher level of hemoglobin (Table
2). The transfusion threshold used in sep-
tic patients requires some individualiza-
tion and consideration of impaired phys-
iologic functions. Efforts should be made
to minimize phlebotomy, control hemor-
rhage, optimize oxygenation, and ade-
quately volume resuscitate patients be-
fore considering RBC transfusion.
Red blood cell transfusions are gener-
ally assumed to increase oxygen delivery
beneficially to tissues and prevent, mini-
mize, or improve ischemia. The effects of
RBC transfusion in septic patients have
been evaluated in several studies (Table
3) (17–25). In general, RBC transfusion
increases oxygen delivery in septic pa-
tients but does not increase oxygen con-
sumption. Blood transfusion consistently
increases pulmonary vascular resistance
and intrapulmonary shunt fraction.
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. Clinical
trials of blood transfusion to evaluate
physiologic effects over a longer time pe-
Table 2. 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.
The minimum hemoglobin tolerated
by healthy or ill individuals without ad-
verse effects is not known. A study of
acute isovolemic reduction of hemoglo-
bin to 5 g/dL (50 g/L) in healthy patients
and volunteers showed no evidence of
inadequate oxygen delivery or ischemia
(26). The TRICC study suggests that a
hemoglobin as low as 7 g/dL may be ad-
equate in a majority of critically ill pa-
tients (15, 27, 28). However, this study
may not adequately represent severe sep-
sis/septic shock patients. 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.
Infection was present at baseline in 27%
of the restrictive group and 26% of the
liberal group, but the proportion with
severe sepsis or septic shock is not spec-
ified. This study excluded patients with
chronic anemia who may be at higher
risk for sepsis due to underlying comor-
bidities. Neilipovitz and Hébert (29) sug-
gest 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. While it can be
postulated that septic patients with se-
vere disease are similar to the heteroge-
neous group of patients in the TRICC
study, that assumption is not well sup-
ported with existing information. The So-
ciety of Critical Care Medicine practice
parameters for hemodynamic support in
adults with sepsis recommend that he-
moglobin concentrations be maintained
above 8 –10 g/dL (80 –100 g/L), but the
limited data for decision-making is also
acknowledged (30). Specific groups of pa-
tients such as those with myocardial isch-
emia or severe hypoxemia may require
higher hemoglobin levels, but the effec-
tiveness of transfusion in these patients is
inadequately characterized (31, 32). Fur-
ther 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 recom-
mendations.
Erythropoietin Administration
Question: What is the role of erythropoi-
etin administration in the severe sepsis
patient with decreased hemoglobin?
Recommendation: Erythropoietin is not
recommended as a specific treatment for
S543
Table 3. Red blood cell transfusion studies in sepsis

Study Patients n RBC Transfusion Hgb Change, g/dL Findings

Gilbert et al. Septic adults 17 Estimated to achieve 8.6 ⫾ 1.9 to 10–12 1 DO2; 1 VO2 only in patients with
1986 (17) hemoglobin 10–12 g/dL increased lactate (thermodilution
measurements)
Mink and Pollack Septic shock (2 mos–6 8 8–10 mL/kg over 1–2 hrs 10.2 ⫾ 0.8 to 13.2 ⫾ 1.4 1 DO2 but VO2 not increased
1990 (18) yrs) (thermodilution measurements)
Lucking et al. Septic children (4 mos–15 7 10–15 mL/kg over 1–3 hrs 9.3 ⫾ 1.4 to 12.4 ⫾ 0.7 1 DO2 and 1 VO2 (thermodilution
1990 (19) yrs with VO2 ⬍ 180) measurements)
Conrad et al. Septic shock (1–77 yrs) 19 591 mL over 4.2 ⫾ 0.5 hrs 8.3 ⫾ 0.3 to 10.7 ⫾ 0.3 1 DO2; but VO2 not increased
1990 (20) (thermodilution measurements)
Steffes et al. Septic adults 21 (27 studies) 1 or 2 units at 2 hr/unit 9.3 ⫾ 1.1 to 10.7 ⫾ 1.5 1 DO2 in all; 1 VO2 only if normal
1991 (21) (postoperative or lactate; 1 intrapulmonary shunt
posttrauma) fraction (thermodilution
measurements)
Silverman and Tuna Septic adults 19 2 units 8.4 ⫾ 0.5 to 10.6 ⫾ 0.5 1 DO2; but VO2 not increased in
1992 (22) (normal pHi), 8.6 ⫾ 0.3 patients with normal or low pHi
to 10.8 ⫾ 0.3 (low pHi) (thermodilution measurements)
Marik and Sibbald Septic adults 23 3 units over 90–120 mins 9.0 ⫾ 7.8 to 11.9 ⫾ 9.0 1 DO2 but VO2 not increased; 1
1993 (23) SVR, 1 PVR, 1 intrapulmonary
shunt; 2 pHi with older bood
(thermodilution and indirect
calorimetry measurements)
Lorente et al. Severe sepsis adults 16 800 mL over 90 mins 9.6 ⫾ 0.3 to 11.6 ⫾ 0.3 1 DO2, but VO2 not increased; 1
1993 (24) SVR, 1 PVR; dobutamine 1 VO2
(thermodilution measurements)
Fernandes et al. Septic adults (Septic shock 10 (⫹5 control) 1 unit over 1 hr 9.4 ⫾ 0.5 to 10.1 ⫾ 0.8 DO2 and VO2 not increased; 1 PVR;
2001 (25) excluded) no change in lactate or pHi
(thermodilution and indirect
calorimetry measurements)

DO2, oxygen delivery; VO2, oxygen consumption; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; pHi, gastric intramucosal pH.

anemia associated with severe sepsis but
may be used when septic patients have
other accepted reasons for administration
of erythropoietin, such as renal failure-
induced compromise of red blood cell
production.
Grade B
Rationale: No specific information re-
garding erythropoietin use in septic pa-
tients is available, but clinical trials in
critically ill patients show some decrease
in red cell transfusion requirement with
no effect on clinical outcome (33, 34).
Erythropoietin may decrease the number
of units transfused per patient but has
minimal impact on avoiding transfusion
in critically ill patients.
Recombinant human erythropoietin
(rHuEPO) is widely used in anemic pa-
tients with chronic renal failure and can-
cer to improve the hematocrit, decrease
blood transfusions, and improve quality
of life. Erythropoietin (EPO) also has
pleiotropic effects on the body beyond
stimulation of erythropoiesis that are not
well understood, including neuroprotec-
tion and prevention of apoptosis.
Three questions need to be posed in
regard to the potential use of rHuEPO in
septic patients. The first question is
whether septic patients have low erythro-
poietin levels. Exogenous EPO is most
likely to be effective in patients with low
EPO levels based on the experience with
chronic renal failure patients. Studies in
heterogeneous groups of critically ill ane-
mic patients and trauma patients suggest
that erythropoietin levels are inappropri-
ately low (5, 35–38). Most studies had a
small number of patients with sepsis. Ro-
giers et al. (35) noted low erythropoietin
levels in 22 septic patients with and with-
out acute renal failure. However, Abel et
al. (39) described high EPO levels in sep-
tic patients and EPO levels rapidly in-
creased in nonsurvivors. The expected in-
verse relationship between EPO levels
and hemoglobin was present in survivors
but not in nonsurvivors. Higher levels of
EPO in nonsurvivors of septic shock were
also noted by Nakamura et al. (40) Non-
anemic children with sepsis and septic
shock have also been found to have in-
creased EPO levels (41).
The second question to consider is
whether septic patients will respond to
exogenous EPO. Relevant information to
answer this question definitively is not
available. 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). van Iperen et al. (43) demon-
strated that critically ill anemic patients
responded with higher reticulocyte
counts and transferrin receptor levels
when given folic acid, iron, and erythro-
poietin (300 IU/kg on days 1, 3, 5, 7, and
9) as compared with groups given folic
acid or folic acid plus iron. Group size
was small (12 in each treatment arm) and
the proportion of patients with sepsis var-
ied from 58% to 75%. It should be noted
that the reticulocyte count in the EPO
group was significantly different from
other groups beginning on day 8, which
is consistent with the pharmacologic ef-
fects of EPO on red cell maturation. In
two randomized clinical trials of rHuEPO
administration in critically ill patients,
information on response rates is not pro-
vided (33, 34). The appropriate dose and
frequency of administration of rHuEPO
has varied in clinical trials, and the opti-
mum regimen is not known.
The last question to pose is whether
EPO administration is beneficial in septic
patients. No clinical trials have been per-
formed with EPO in septic patients. Cor-
win et al. (33) evaluated rHuEPO admin-
istration compared with placebo in 160
critically ill patients but excluded pa-
tients with shock and severe respiratory
compromise. Only three of 80 patients in
each treatment group had sepsis. The to-
tal number of red blood cell units trans-
fused was lower in patients receiving
rHuEPO (p ⬍ .002), and the percentage
of patients transfused or who died on days
8 – 42 was not significantly reduced from

S544 Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)

55% to 45%. Corwin et al. (34) reported a
recent trial in 1,302 ICU patients who
received weekly rHuEPO. A large propor-
tion of ICU patients (71%) were not eli-
gible for the trial, and the majority of
patients were postoperative or trauma.
Sepsis was present in 7.1% of the placebo
group and 9.1% of the rHuEPO group.
Although there was a reduction in the
percentage of patients transfused and the
cumulative units transfused per patient,
no beneficial effects on morbidity or mor-
tality were noted with rHuEPO use. Dif-
ferences are not apparent until 1 wk after
initiation of treatment. Generalizing
these results to patients with sepsis is
difficult.
Due to the limited information avail-
able, the EPO response in sepsis cannot
be predicted. Response to rHuEPO in sep-
sis is unknown but may be less than other
critically ill patients due to the presence
of inflammatory cytokines (44). Further
studies are required to evaluate any ben-
efit of rHuEPO in decreasing transfusions
in septic patients. Studies suggest that
40% to 50% of transfusions occur in the
first week of critical illness, and approxi-
mately 70% of transfused patients receive
blood within the first 2 ICU days (1, 2, 5).
EPO administration would have no im-
pact on transfusions in the first 5– 6 days
of critical illness.
Fresh-Frozen Plasma
Transfusion
Question: When should FFP be trans-
fused 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.
FFP is indicated for coagulopathy due to
documented deficiency of coagulation
factors (increased prothrombin time, in-
ternational normalized ratio, or partial
thromboplastin time) in the presence of
active bleeding or before surgical or in-
vasive procedures.
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, such as dissemi-
nated intravascular coagulation (DIC).
Although clinical studies have not as-
sessed the impact of transfusion of FFP
on outcomes in critically ill patients,
guidelines for the use of FFP have been
Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)
proposed by several professional organi-
zations (45– 48). The triggering condition
must be aggressively treated. Routine use
of FFP to correct laboratory abnormali-
ties in the absence of bleeding is not
recommended. FFP transfusion is also
appropriate if reversal of the warfarin ef-
fect is needed immediately. Doses of FFP
should be chosen to achieve factor levels
ⱖ30% of normal values (usually 10 –15
mL/kg). Rapid infusion (not continuous
infusion) is needed to achieve effective
factor levels.
Antithrombin Administration
Antithrombin is a hepatically synthe-
sized glycoprotein that is an important
physiologic regulator of coagulation. An-
tithrombin functions as an anticoagulant
by 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 coagu-
lation pathway (49). Antithrombin may
also have anti-inflammatory effects (50,
51). Clotting inhibitors, including anti-
thrombin, are noted to have low func-
tional levels in sepsis, especially severe
sepsis and septic shock (52, 53).
Question: What is the role of antithrom-
bin in the treatment of severe sepsis?
Recommendation: Antithrombin admin-
istration is not recommended for the
treatment of severe sepsis and septic
shock.
Grade B
Rationale: Several open and double-blind
studies in a small number of patients
with sepsis suggested that high-dose an-
tithrombin may improve survival or or-
gan failure in the most severely ill (54 –
58). However, a large phase III clinical
trial of high-dose antithrombin did not
demonstrate any beneficial effect on 28-
day all-cause mortality in adults with se-
vere sepsis and septic shock. High-dose
antithrombin was associated with a sig-
nificantly increased risk of bleeding, es-
pecially when administered with heparin
(53). At this time, antithrombin is indi-
cated only for the very rare septic patient
with congenital antithrombin deficiency.
Platelet Transfusion
Thrombocytopenia occurs frequently
in critically ill patients and can be asso-
ciated with increased mortality (59 – 61).
Thrombocytopenia is also associated with
major bleeding and increased transfusion
requirements. Septic patients may have
decreased platelet production and/or in-
creased platelet destruction due to micro-
vascular injury and DIC.
Question: When should platelets be
transfused in the patient with severe sep-
sis?
Recommendation: In patients with severe
sepsis, platelets should be administered
when counts are ⱕ5000/mm3 (5 ⫻ 109/
L), regardless of apparent bleeding. Plate-
let 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
(ⱖ50,000/mm3 [50 ⫻ 109/L]) may be re-
quired for surgery or invasive procedures.
Grade E
Rationale: No clinical data exist in septic
patients to guide the use of platelet trans-
fusions. Most recommendations are
derived from consensus opinion and ex-
perience in patients undergoing chemo-
therapy (62). Guidelines for transfusion
of platelets in infants and children are
adapted from adult recommendations
(63). Recommendations take into ac-
count the etiology of thrombocytopenia,
platelet dysfunction, risk of bleeding,
planned invasive procedures, and the
presence of concomitant disorders (45,
47). The presence of active bleeding, fe-
ver, sepsis, coagulopathy, and platelet
dysfunction should be considered in as-
sessing the risk of serious hemorrhage.
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