Serum RIPK1, Acute Lung Injury, and Outcomes in Severe Traumatic Brain Injury: A Multicenter Prospective Study

Liang Cai,1,* Xianghong Dou,2,* Wensheng Dong,1 Kangqin Zou,1 Lixin Zhang,3 Huayong Hong,3 Xiaole Zhang,3 Jin Liu,4 Da Tian,4 Xiaoyu Wu,4 Jianhua Zhang1 1Department of Neurosurgery, The second People’s Hospital of Lianyungang Affiliated to Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, 222000, People’s Republic of China; 2Department of Neurology, Donghai County People’s Hospital, Lianyungang, Jiangsu, 222300, People’s Republic of China; 3Department of Neurosurgery, The Hangzhou Ninth People’s Hospital, Hangzhou, Zhejiang, 311225, People’s Republic of China; 4Department of Neurosurgery, The Lishui People’s Hospital, Lishui, Zhejiang, 323000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua Zhang, Email [email protected]: Receptor-interacting protein kinase-1 (RIPK1), a regulator of necroptosis, is involved in acute brain injury and acute lung injury (ALI). Here, serum RIPK1 levels were measured after severe traumatic brain injury (sTBI), with an endeavor to unveil its prognostic implications and mediation effects of ALI.Methods: In this multicenter prospective study, serum RIPK1 levels were gauged in 100 healthy individuals and 158 sTBI patients in need of decompressive craniectomy for brain herniation. The collected materials encompassed the Glasgow Coma Scale (GCS), pupil enlargement status, basal cisternal shapes, ALI, etc. The extended Glasgow outcome scale (GOSE) was employed for estimating neurological impairments at posttraumatic 180-day mark. Multifactorial analytical methods were applied to assess relevancies.Results: Patients, as opposed to controls, had markedly raised serum RIPK1 levels, with the even substantially higher levels in those with lower GCS scores, bilateral pupil enlargement or obliterated basal cisterns. Using restricted cubic spline, RIPK1 levels were linearly related to occurrent risks of the four outcome variables of interest, that is 180-day death, overall survival, poor prognosis (GOSE scores 1– 4) and ALI. RIPK1 levels independently predicted these outcome variables. RIPK1 levels had noninteractional effects with age, sex, hypertension, diabetes, smoking and alcohol habits in terms of its association with these outcome variables. RIPK1 levels exhibited high discriminatory efficiency for these outcome variables under the receiver operating characteristic curve. RIPK1 levels, via partial mediation by ALI, were associated with death and poor prognosis of patients.Conclusion: Elevated serum RIPK1 levels of patients with sTBI may be highly related to trauma severity, and risks of poor outcomes and ALI; and ALI partially explains the links between serum RIPK1 levels, death and poor prognosis, substantializing serum RIPK1 as a serological prognostic predictor of good prospect in sTBI.Keywords: traumatic brain injury, RIPK1, outcomes, biomarkers, mediations