Introduction: Secondary injury, marked by delayed tissue damage hours to days after traumatic brain injury (TBI), influences outcome. A better understanding of the metabolic pathways and cellular damage that occurs during this phase could lead to therapeutic options. The Warburg Effect is an increase in cellular glucose uptake and lactate synthesis in the presence of Oxygen. We hypothesize that the energetic forces driving the immune responses are predominantly glycolytic persisting despite resuscitation and oxygen availability. Methods: After IRB approval (CHW 2021-096) and informed consent, pediatric patients (17 TBI with GCS ≤ 8, and 10 controls) aged ≥ 1 and ≤ 21 years were enrolled. Blood samples were collected at three timepoints after initial injury: 24±12 hours, 48±12 hours and on hospital day 9±12 hours, along with clinical variables from medical record. RNA was analyzed as paired-end 150 base pair reads of around 30 million reads per sample. Reads were aligned to the human transcriptome Gencode 45. Enriched pathways from significant genes determined using STRING. MiXCR mapped data processed using ImmunArch. We employed Nuclear Magnetic Resonance (NMR) to profile plasma. All data were combined using a variety of machine learning modalities. Results: Clinical data revealed a mean lactic acidemia of 3.2±2mmol/L and a serum glucose of 164.4±57mg/dL, white cell counts (WBC) of 16861±7425/uL, and absolute neutrophil count (ANC) at 11515±5194/uL upon admission. At day 2, WBC: 10949±4409/uL and ANC: 7447±2185/uL. Day 8, WBC: 10815±4534/uL and ANC: 6760±1356/uL. At admission, TBI patients had high-confidence transcripts elevated that returned to control levels by day 8. Glycolysis genes SLC2A3, HK3, HMGb2, HIF1A, LDHA, PKM and HK2 show statistically significant gene expression over controls. High lactate pyruvate (LP) ratios are indicative of increased glycolysis and we found LP ratios were elevated at 24.4 (P< 0.05) in TBI patients in the first 24 hours compared to 15.1 in control and 14.5 later. Conclusions: In severe TBI, RNA from circulatory WBC revealed increased glycolysis with those transcripts being elevated. This was further associated with an increased serum LP ratio. However, confounders such as hypoxia during resuscitation and tissue hypoxia secondary to local effects could confound findings.
Sanfilippo et al. (Sun,) studied this question.