Transfusion of 35-Day Stored RBCs in the Presence of Endotoxemia Does Not Result in Lung Injury in Humans*

Peters, Anna; Hezel, Maike E. van; Cortjens, Bart; Boer, Anita M Tuip de; Bruggen, Robin van; Korte, Dirk de; Jonkers, René E.; Bonta, Peter I.; Lutter, René; Juffermans, Nicole P.; Vlaar, Alexander P.J.

doi:10.1097/ccm.0000000000001614

Cited by 27 publications

(47 citation statements)

References 36 publications

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“…81,82 However, the dose of endotoxin (2 ng/kg; 40-50 pg/mL) used in these experiments was much less than the IV doses (1 mg) for the treatment of neurosyphilis, which was completed in most cases without significant mortality. 33,70,81,82 Aside from becoming febrile with a mild increase in the respiratory rate, the subjects were not as ill as the LPS-treated rats. 33,70,81,82 Moreover, LPS does not induce proinflammatory changes in human PMNs and HMVECs at concentrations of less than 20 ng/mL in vitro, which is orders of magnitude higher than the in vivo dosing.…”

Section: Discussionmentioning

confidence: 92%

“…Longer storage was required for lipid accumulation in AS‐3–stored LR‐RBCs. Finally, the two‐event model of ALI employed has been questioned because humans who received endotoxin did not manifest injury when transfused with older, stored blood RBCs . However, the dose of endotoxin (2 ng/kg; 40‐50 pg/mL) used in these experiments was much less than the IV doses (≥1 mg) for the treatment of neurosyphilis, which was completed in most cases without significant mortality .…”

Section: Discussionmentioning

confidence: 99%

“…Finally, the two‐event model of ALI employed has been questioned because humans who received endotoxin did not manifest injury when transfused with older, stored blood RBCs . However, the dose of endotoxin (2 ng/kg; 40‐50 pg/mL) used in these experiments was much less than the IV doses (≥1 mg) for the treatment of neurosyphilis, which was completed in most cases without significant mortality . Aside from becoming febrile with a mild increase in the respiratory rate, the subjects were not as ill as the LPS‐treated rats .…”

Section: Discussionmentioning

confidence: 99%

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Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation

et al. 2017

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Background Although transfusion is a life-saving intervention, it may be associated with significant morbidity in injured patients. We hypothesize that stored red blood cells induce pro-inflammatory activation of human pulmonary microvascular endothelium (HMVECs) resulting in neutrophil (PMN) adhesion and predisposition to acute lung injury (ALI). Methods Ten units of red blood cells (RBCs) were collected and 50% (by weight) were leukoreduced (LR-RBCs) and the remainder was unmodified and stored in additive solution-5 (AS-5). Another 10 units of RBCs were collected, leukoreduced, and stored in AS-3. HMVECs were incubated with [10–40%]FINAL of the supernatants day (D)1-D42 of storage, lipid extracts and purified lipids. Endothelial surface expression of ICAM-1, IL-8 release, and PMN adhesion to HMVECs were measured. HMVEC signaling via the BLT2 receptor was evaluated. Supernatants and lipids were also employed as the first event in a two-event model of ALI. Results The supernatants [10–40%]FINAL from D21 LR-RBCs and D42 RBCs and LR-RBCs and the lipids from D42 stored in AS-5 induced increased ICAM-1 surface expression on endothelium, IL-8 release, and PMN adhesion. In addition, the supernatants [20–40%]FINAL from D21 and D42 RBCs in AS-5 also increased endothelial surface expression of ICAM-1. D42 supernatants and lipids also caused co-precipitation of β-arrestin-1 with BLT2, PKCβI, and PKCδand served as the first event in a two-event rodent model of ALI. In conclusion, lipids that accumulate during RBC storage activate endothelium and predispose to ALI, which may explain some of the adverse events associated with the transfusion of critically injured patients.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation

et al. 2017

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“…However, these randomized controlled trials did not compare maximally stored RBCs to standard stored RBCs . Therefore, we recently performed a randomized trial in endotoxin‐primed healthy volunteers that specifically investigated pulmonary function after transfusion of maximally stored RBCs . In this study we did not detect any relation between storage time of RBCs and pulmonary function.…”

Section: Non–antibody‐mediated Trali Versus Hit From the Bench‐side Pmentioning

confidence: 85%

Redefining transfusion‐related acute lung injury: don't throw the baby out with the bathwater

Peters

Vlaar

2016

Transfusion

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Recently two articles have been published in TRANSFUSION in which the authors propose to change the current definition on transfusion-related acute lung injury (TRALI). It was proposed to view TRALI from the perspective of detectability versus nondetectability of leukoreactive alloantibodies (Transfusion 2015;55:1128-34). The authors argue that only cases in which leukoreactive alloantibodies can be detected should be defined as "true" TRALI in analogy with the understanding of the pathophysiology of heparin-induced thrombocytopenia. In the other article (Transfusion 2015;55:947-52), the authors propose to redefine possible TRALI to transfused acute respiratory distress syndrome (ARDS) as their study in intensive care unit patients did not show a relation between the number of transfusions and possible TRALI.We discuss these two propositions in light of the current evidence on pathophysiology of TRALI and possible TRALI. We argue that it is too early to redefine TRALI, as 1) factors, such as storage time of platelets, which induce TRALI in preclinical studies, have not yet been properly investigated in humans. Further research is needed on these agents before it is concluded that antibody-mediated TRALI is the only "true" TRALI. 2) In light of the current knowledge, it makes perfect sense that multiple transfusion is not related to possible TRALI: ARDS risk factors in these patients result in a very sensitive equilibrium in which even only one transfusion induces TRALI. Excluding possible TRALI from the TRALI definition would result in further underrecognition of TRALI induced by alloantibodies and interferes with exclusion of donors related to TRALI cases and thus TRALI prevention.

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“…The two‐event model of TRALI has been recently criticized because of the inability of volunteers injected with 2 ng/kg Escherichia coli lipopolysaccharide (LPS) to manifest TRALI when transfused with autologous RBC units stored for 35 days . Injection of E. coli LPS induced fevers of more than 38°C, pulses or more than 90 beats/min, and mild tachypnea (>20 breaths/min) without evidence of pulmonary endothelial activation or PMN sequestration in the lung, a prerequisite for the two‐event model of TRALI .…”

Section: Discussionmentioning

confidence: 99%

A comparison of different methods of red blood cell leukoreduction and additive solutions on the accumulation of neutrophil‐priming activity during storage

et al. 2018

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Transfusion of 35-Day Stored RBCs in the Presence of Endotoxemia Does Not Result in Lung Injury in Humans*

Abstract: Transfusion of 35-day stored autologous RBCs in the presence of endotoxemia does not result in lung injury in humans.

Cited by 27 publications

References 36 publications

Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation

Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation

Redefining transfusion‐related acute lung injury: don't throw the baby out with the bathwater

A comparison of different methods of red blood cell leukoreduction and additive solutions on the accumulation of neutrophil‐priming activity during storage

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