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Biphasic Release of the Alarmin High Mobility Group Box 1 Protein Early After Trauma Predicts Poor Clinical Outcome

Ottestad, William MD1,2; Rognes, Ingrid N. MD2; Pischke, Soeren E. MD, PhD1,3; Mollnes, Tom E. MD, PhD3,4,5; Andersson, Ulf MD, PhD6; Eken, Torsten MD, PhD1,2

doi: 10.1097/CCM.0000000000003800
Online Clinical Investigations

Objectives: The causal role of the prototype alarmin high mobility group box 1 protein in systemic inflammation and remote organ injury after trauma and shock is established in animal models but not in humans. Our aim was therefore to determine high mobility group box 1 protein concentration kinetics with high time resolution during the first hours after trauma in individual patients and investigate the association with outcome.

Design: Prospective single-center observational study.

Setting: University hospital Level I trauma center.

Patients: Convenience recruitment of 136 trauma patients.

Interventions: None.

Measurements and Main Results: Total plasma high mobility group box 1 protein levels were analyzed with enzyme-linked immunosorbent assay in repeated samples. Relationships between predefined predictor variables and outcome were examined in multivariable linear regression models. Ventilator-free days was used as primary outcome measure. Two distinct high mobility group box 1 protein release phases were identified. An initial exponential decay phase with half-life 26 minutes was not correlated with outcome. In contrast, a second high mobility group box 1 protein wave peaking 3–6 hours after trauma in the most severely injured and physiologically deranged patients was consistently the most important predictor of outcome in our multivariable models, rendering all other predictor variables insignificant except for smaller contributions from age and sex, and of admission base excess for maximal creatinine concentration.

Conclusions: High mobility group box 1 protein was released in two consecutive phases. Only the second high mobility group box 1 protein wave was a significant predictor of outcome. Patients with a high high mobility group box 1 protein concentration between 3 and 6 hours after trauma might hypothetically benefit from high mobility group box 1 protein-specific antagonist therapy.

1Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway.

2Division of Critical Care, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

3Department of Immunology, Oslo University Hospital, and K.G. Jebsen IRC, University of Oslo, Oslo, Norway.

4Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.

5Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.

6Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Dr. Eken conceived the study and was responsible for overall design; Drs. Pischke and Mollnes contributed to study design. Drs. Ottestad, Rognes, and Eken collected the data. Dr. Rognes performed the enzyme-linked immunosorbent assay analyses with support from Drs. Pischke and Mollnes. Drs. Ottestad and Eken designed the statistical analyses and did the initial data interpretation; Drs. Ottestad, Rognes, Andersson, and Eken finalized analyses and interpretation. Drs. Ottestad, Andersson, and Eken wrote the first version of the article, and all authors critically revised and approved the final version.

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This study was financially supported by Oslo University Hospital, the University of Oslo, South-Eastern Norway Regional Health Authority, the Karolinska Institutet, The Research Council of Norway, The Norwegian Council on Cardiovascular Disease, and the European Community’s Seventh Framework Programme under grant agreement n° 602699 (Disarming the intravascular innate immune response to improve treatment modalities for chronic kidney disease [DIREKT]).

Dr. Ottestad’s institution received funding from South-Eastern Norway Regional Health Authority. Dr. Mollnes’ institution received funding from The Norwegian Council on Cardiovascular Disease and the European Community’s Seventh Framework Programme under grant agreement n° 602699 (DIREKT). The remaining authors have disclosed that they do not have any potential conflicts of interest.

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