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Original Investigation | Pacific Coast Surgical Association

Use of Metabolomics to Trend Recovery and Therapy After Injury in Critically Ill Trauma Patients Online Only

Brodie A. Parent, MD1; Max Seaton, MD1; Ravi F. Sood, MD, MS1; Haiwei Gu, PhD2; Danijel Djukovic, PhD2; Daniel Raftery, PhD2; Grant E. O’Keefe, MD, MPH1
[+] Author Affiliations
1Harborview Department of Surgery, University of Washington Medical Center, Seattle
2Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle
JAMA Surg. 2016;151(7):e160853. doi:10.1001/jamasurg.2016.0853.
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Published online

Importance  Metabolomics is the broad and parallel study of metabolites within an organism and provides a contemporaneous snapshot of physiologic state. Use of metabolomics in the clinical setting may help achieve precision medicine for those who have experienced trauma, where diagnosis and treatment are tailored to the individual patient.

Objective  To examine whether metabolomics can (1) distinguish healthy volunteers from trauma patients and (2) quantify changes in catabolic metabolites over time after injury.

Design, Setting, and Participants  Prospective cohort study with enrollment from September 2014 to May 2015 at an urban, level 1 trauma center. Included in the study were 10 patients with severe blunt trauma admitted within 12 hours of injury with systolic blood pressure less than 90 mm Hg or base deficit greater than 6 mEq/L and 5 healthy volunteers. Plasma samples (n = 35) were obtained on days 1, 3, and 7, and they were analyzed using mass spectrometry.

Main Outcomes and Measures  Principal component analyses, multiple linear regression, and paired t tests were used to select biomarkers of interest. A broad-based metabolite profile comparison between trauma patients and healthy volunteers was performed. Specific biomarkers of interest were oxidative catabolites.

Results  Trauma patients had a median age of 45 years and a median injury severity score of 43 (interquartile range, 34-50). Healthy fasting volunteers had a median age of 33 years. Compared with healthy volunteers, trauma patients showed oxidative stress on day 1: niacinamide concentrations were a mean (interquartile range) of 0.95 (0.30-1.45) relative units for trauma patients vs 1.06 (0.96-1.09) relative units for healthy volunteers (P = .02), biotin concentrations, 0.43 (0.27-0.58) relative units for trauma patients vs 1.21 (0.93-1.56) relative units for healthy volunteers (P = .049); and choline concentrations, 0.17 (0.09-0.22) relative units for trauma patients vs 0.21 (0.18-0.22) relative units for healthy volunteers (P = .004). Trauma patients showed lower nucleotide synthesis on day 1: adenylosuccinate concentrations were 0.08 (0.04-0.12) relative units for trauma patients vs 0.15 (0.14-0.17) relative units for healthy volunteers (P = .02) and cytidine concentrations were 1.44 (0.95-1.73) relative units for trauma patients vs 1.74 (1.62-1.98) relative units for healthy volunteers (P = .05). From trauma day 1 to day 7, trauma patients showed increasing muscle catabolism: serine levels increased from 42.03 (31.20-54.95) µM to 79.37 (50.29-106.37) µM (P = .002), leucine levels increased from 69.21 (48.36-99.89) µM to 114.16 (92.89-143.52) µM (P = .004), isoleucine levels increased from 20.43 (10.92-27.41) µM to 48.72 (36.28-64.84) µM (P < .001), and valine levels increased from 122.56 (95.63-140.61) µM to 190.52 (136.68-226.07) µM (P = .004). There was an incomplete reversal of oxidative stress.

Conclusions and Relevance  Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients.

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Figure 1.
Principle Component Analysis of Plasma Samples

Each data point represents an individual plasma sample. Points that are close together represent samples with similar metabolic phenotypes; points that are far away have dissimilar metabolic phenotypes. B, The large symbols represent the mean values of the sample scores for a given group. Dim indicates dimension.

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Figure 2.
Plasma Metabolome Heat Maps for Trauma Patients and Healthy Volunteers

The heat maps demonstrate (A) relatively decreased amino acids, with a rise over time, and (B) reduced vitamin and antioxidant substrates (niacinamide and biotin) and increased oxidative catabolites (propionate and 4-pyridoxic acid). The heat maps are generated using mass spectrometry–based metabolomics. Two trauma patients are omitted owing to high concentrations, which obscure all other relative concentrations.

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Figure 3.
Plasma Concentrations in Blunt Trauma Patients and Healthy Volunteers

Generated using mass spectrometry–based metabolomics. Box and whisker plots display median, interquartile range, maximum, and minimum values. Comparisons between trauma patients and healthy volunteers are based on multiple regression with adjustments for body mass index and processing batch. Comparisons between day-1 and day-7 trauma patients are based on paired t tests. Multiple testing is accounted for by a Benjamini-Hochberg false discovery rate method.23

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Figure 4.
Pathway Analyses of the Plasma Metabolome

Generated using mass spectrometry–based metabolomics. Each data point represents a biologic pathway with quantified plasma metabolites. Based on the available metabolite’s centrality and importance to the pathway of interest, a level of pathway impact is assigned. Larger pathway impact is communicated by moving rightward on the x-axis and by increasing diameter of circles. Based on paired differences in metabolite concentration between comparison groups, a P value is assigned to the pathway. A more significant result is communicated by moving upward on the y-axis and by a color scale, which goes from white (low significance) to yellow to orange to red (high significance).

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