# Non-leukodepleted red blood cell transfusion in sepsis patients: beyond oxygenation, is there a risk of inflammation?

Olivier Garraud, Adrien Chabert, Bruno Pozzetto, Fabrice Zeni, Fabrice Cognasse, Hind Hamzeh-Cognasse

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Olivier Garraud, Adrien Chabert, Bruno Pozzetto, Fabrice Zeni, Fabrice Cognasse, et al. Non-leukodepleted red blood cell transfusion in sepsis patients: beyond oxygenation, is there a risk of inflammation?. Critical Care, 2014, 18 (6), pp.690. 10.1186/s13054-014-0690-y. hal-04995280

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LETTER

Non-leukodepleted red blood cell transfusion in
sepsis patients: beyond oxygenation, is there a
risk of inflammation?

Olivier Garraud<fnref n="1" />,<fnref n="2" />*, Adrien Chabert<fnref n="1" />, Bruno Pozzetto<fnref n="1" />,³, Fabrice Zeni<fnref n="1" />,⁴, Fabrice Cognasse<fnref n="1" />,⁵ and Hind Hamzeh-Cognasse<fnref n="1" />

See related research by Donati *et al*., http://ccforum.com/content/18/1/R33

Donati and colleagues [1] evaluated the benefits of fresh,
leukodepleted (LD) versus non-leukodepleted (nLD) ery-
throcyte transfusions on the microcirculation in sepsis
patients. Oxygenation appeared equal in both groups.
Differences between the two kinds of blood cells are pre-
sented in Table 1. In the reported study, there is a differ-
ence between the age of erythrocytes in the two groups
(1.5 to 3 days for nLD versus 3.5 to 5 days for LD erythro-
cytes; a U test indicates *P* < 0.05); this suffices to influence
oxygen delivery mediators (Figure 1). The content of
leukocytes prior to (and after) leukodepletion were
not tested, nor was the freeing - which is usually very
fast - of secreted or docked, soluble biological response
modifiers. Considering the dynamics of secreted biological
response modifiers in platelet components [2], there
must be differences within the two groups, which possibly

influenced sepsis conditions. Residual plasma within
erythrocytes given by female donors may include anti-
human leukocyte antigen (HLA) antibodies which attack
the recipient's lung alveolar epithelium neutrophils, and as
sepsis is characterized by the pathology of neutrophils that
release microparticles and neutrophil extracellular traps
that target lung epithelium [3], it may be feared here that
the nLD condition aggravates pulmonary lesions.

The re-evaluation of procedures is infrequent in trans-
fusion despite the rapid evolution of techniques and ma-
terials; for example, differential stresses are inflicted on
erythrocytes, depending on the collection process (aphaer-
esis versus conventional whole blood), with consequences
for neutrophils and (vascular) endothelial cells upon trans-
fusion [4]. Clinical investigations and registered trials such
as Donati and colleagues are valuable.

Authors' response

Abele Donati, Elisa Damiani, Erica Adrario, Rocco Romano, Paolo Pelaia and Can Ince

We thank Professor Garraud and colleagues for their
interest in our study [1]. As underlined, the difference in
the age of transfused red blood cells (RBCs) between the
nLD group (4 (3.5 to 5) days) and the LD group (3 (1.5 to
3) days) may have influenced the RBC oxygen-delivery
capacity. Stored RBCs lose their ability to release vasodila-
tors (nitric oxide, ATP) during hypoxia [5,6]. We showed
similar changes in microvascular reactivity (tissue oxygen
saturation (StO₂)-upslope) and oxygenation (StO₂) after
nLD or LD RBC transfusions [1]. This may indicate that
oxygen-delivery mediators were not sufficiently affected to
determine relevant variations in the response observed.

Alternatively, heterogeneity in the study population pre-
vented detection of subtle differences. Variability in
the response to treatments is common during sepsis. The
patient heterogeneity was underlined as a limitation of
our investigation [1].

LD RBCs showed a more favorable effect on microcir-
culatory convective flow [1]. This may depend on the
lower adhesiveness of LD RBCs to the endothelium [7].
The transfusion of nLD RBCs decreased blood flow
velocity and increased glycocalyx damage markers [1].
Similar effects may reasonably occur in the lungs. As
highlighted, anti-HLA antibodies in nLD blood from
female donors may contribute to aggravate pulmonary
lesions. Nonetheless, the evaluation of respiratory func-
tion went beyond our goals.

<footnote>* Correspondence: ogarraud@ints.fr</footnote>

<footnote n="1">¹Université de Lyon, GIMAP-EA3064, Saint Etienne 42023, France</footnote>

<footnote n="2">²Institut National de Transfusion Sanguine (INTS), Paris 75739, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
<table><caption>Table 1 Possible consequences of variation in transfusion conditions and the type of packed red blood cells administered</caption><thead><tr><th>Variable</th><th>Primary or immediate consequences (efficacy)</th><th>Secondary or delayed consequences (hazards)</th></tr></thead><tbody><tr><td>Total volume</td><td>Possibly needs to be adjusted according to the patient's needs</td><td>Possibly needs to be adjusted to correct for anemia</td></tr><tr><td>Hematocrit</td><td>Possibly needs to be adjusted according to the patient's needs</td><td>Possibly needs to be adjusted to correct for anemia</td></tr><tr><td rowspan="2">Residual plasma volume</td><td>Possibly includes anti-HLA antibodies (from female donors)</td><td>Increases the risk of TRALI</td></tr><tr><td>Possibly affects the amount of soluble, free biological response modifiers</td><td>Increases the risk of inflammation and aggravates the risk of TRALI</td></tr><tr><td rowspan="6">Leukocytes</td><td>No pre-test (possibly affects donor eligibility)</td><td></td></tr><tr><td>Pre-activation of leukocytes</td><td>Increases the risk of inflammation</td></tr><tr><td>Release of biological response modifiers</td><td></td></tr><tr><td>Release of microparticles and neutrophil extracellular traps</td><td>Aggravates sepsis</td></tr><tr><td>HLA antibody targets</td><td>Increases the risk of TRALI</td></tr><tr><td>Infectious risk (intracellular viruses)</td><td>Increases the risk of viral infections</td></tr><tr><td rowspan="6">Age of blood</td><td>Decreases the benefit of oxygen transport</td><td></td></tr><tr><td>Release of microparticles</td><td>Increases the risk of inflammation</td></tr><tr><td>Expression of stress signals on red blood cells</td><td></td></tr><tr><td>Free iron release</td><td>Potentiates the risk of TRALI by stressing target neutrophils</td></tr><tr><td>NO and iNOS release</td><td></td></tr><tr><td>Oxygenated lipid and lipid degradation</td><td>Possibly increases the risk of allo-immunization</td></tr></tbody></table>

HLA, human leukocyte antigen; iNOS, inducible nitric oxide synthase; NO, nitric oxide; TRALI, transfusion-related acute lung injury.

<figure><img src="image_3.png" /><figcaption>**Figure 1** ATP and 2,3-diphosphoglycerate (2,3-DPG) in packed red blood cells. (A) ATP and (B) 2,3-DPG in packed red blood cells measured after 1, 7, 14, 21, 28, 35 and 42 days (d) of storage were re-evaluated by one-way analysis of variance. Inter-experiment differences in ATP and 2,3-DPG concentrations at different time points were analyzed by Wilcoxon paired test (XLSTAT® 2010 software, Addinsoft, Paris, France). *P*-values ≤0.05 were considered to be significant (*n* = 10). PLT, platelet.</figcaption></figure>
The efficacy of blood transfusion depends on mul-
tiple RBC- and patient-related factors. Understanding
the response to transfusion during sepsis is a challenging
task. Targeting predetermined hemoglobin levels and/or
macrohemodynamics is clearly not sufficient. Monitoring
the microcirculation may get us closer to the answer [8].

**Abbreviations**

HLA: Human leukocyte antigen; LD: Leukodepleted; nLD: Non-leukodepleted;
RBC: Red blood cell; StO₂: Tissue oxygen saturation.

**Competing interests**

The authors declare that they have no competing interests.

**Author details**

¹Université de Lyon, GIMAP-EA3064, Saint Etienne 42023, France. ²Institut National de Transfusion Sanguine (INTS), Paris 75739, France. ³Département de Microbiologie Hôpital Nord, CHU de Saint-Etienne, Saint-Etienne 42055, France. ⁴Service de Réanimation Médicale et Polyvalente Hôpital Nord, CHU de Saint-Etienne, Saint-Etienne 42055, France. ⁵Etablissement Français du Sang Auvergne-Loire, Saint-Etienne 42100, France.

Published online: 08 December 2014

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doi:10.1186/s13054-014-0690-y

Cite this article as: Garraud et al.: Non-leukodepleted red blood cell transfusion in sepsis patients: beyond oxygenation, is there a risk of inflammation? *Critical Care* 2014 **18**:690.