Prehospital plasma is associated with distinct biomarker expression following injury

Abstract

BACKGROUNDPrehospital plasma improves survival in severely injured patients transported by air ambulance. We hypothesized that prehospital plasma would be associated with a reduction in immune imbalance and endothelial damage.METHODSWe sampled blood from 405 trauma patients enrolled in the Prehospital Air Medical Plasma (PAMPer) trial upon hospital admission (0 hours) and 24 hours post admission across 6 U.S. sites. We assayed samples for 21 inflammatory mediators and 7 markers associated with endothelial function and damage. We performed hierarchical clustering analysis (HCA) of these biomarkers of the immune response and endothelial injury. Regression analysis was used to control for differences across study and to assess any association with prehospital plasma resuscitation.RESULTSHCA distinguished two patient clusters with different injury patterns and outcomes. Patients in cluster A had greater injury severity and incidence of blunt trauma, traumatic brain injury, and mortality. Cluster A patients that received prehospital plasma showed improved 30-day survival. Prehospital plasma did not improve survival in cluster B patients. In an adjusted analysis of the most seriously injured patients, prehospital plasma was associated with an increase in adiponectin, IL-1β, IL-17A, IL-23, and IL-17E upon admission, and a reduction in syndecan-1, TM, VEGF, IL-6, IP-10, MCP-1, and TNF-α, and an increase in IL-33, IL-21, IL-23, and IL-17E 24 hours later.CONCLUSIONPrehospital plasma may ameliorate immune dysfunction and the endotheliopathy of trauma. These effects of plasma may contribute to improved survival in injured patients.TRIAL REGISTRATIONNCT01818427.FUNDINGDepartment of Defense; National Institutes of Health, U.S. Army.

Keywords: Cellular immune response; Cytokines; Immunology; Inflammation; endothelial cells.

Conflict of interest statement

Conflict of interest: YV reports funding from Immunetrics Inc. BGH reports grants, personal fees, and nonfinancial support from Haemonetics; grants and personal fees from Janssen Pharmaceuticals; grants from Instrument Laboratories; grants from Noveome; support from Haima Therapeutics; and personal fees from CSL Behring.

Figures

Figure 1. Consort diagram.

Screening, randomization, follow-up, and biomarker sampling.

Figure 2. Circulating inflammatory and endothelial marker concentrations measured at 0 and 24 hours for 30-day survivors and nonsurvivors.

Lines within the bars represent medians. The lower and upper hinges correspond to the first and third quartiles (the 25th and 75th percentiles). The whiskers extend from the hinge to the smallest and largest values, no further than 1.5× IQR from the hinge (where IQR is the interquartile range). The asterisks denote significantly different (P < 0.05) time points as calculated by the Mann-Whitney U test. All inflammatory mediators are reported in pg/mL, except IL-23, which is reported in ng/mL. We report adiponectin, S100A10, suPAR, syndecan-1, and TM, in ng/mL, and VEGF in pg/mL. DNA (histone-complexed) is reported as relative units. 0h inflammatory mediators, n = 361; 24h inflammatory mediators, n = 312; 0h endothelial markers n = 359; 24h endothelial markers, n = 316.

Figure 3. Heatmap of scaled hospital admission marker concentrations corresponding to patients (n = 337) in the cluster dendrogram.

Clusters are denoted by A and B. Dark gray lines next to patients correspond to patients who received prehospital plasma, and light gray lines correspond to patients who received standard care resuscitation. Markers of inflammation (circles) and endothelial damage (triangles) form clusters (denoted 1 and 2) along the top and are labeled along the bottom of the heatmap. Higher-scaled values are represented by darker red lines, and lower-scaled values are represented by darker blue lines.

Figure 4. Kaplan Meier survival curves for cluster A and cluster B.

Cluster A, n = 158, log-rank, P = 0.016. Cluster B, n = 179, log-rank, P = 0.66. Time is in hours (to 30 days).

Figure 5. Early (0 hours) inflammatory and endothelial marker concentrations plotted against injury severity score (ISS) in patients who survived to 30 days.

Gray triangles represent patients in the standard care arm, and red circles represent patients in the prehospital plasma arm. Shading represents the 95% CI. Inflammatory mediators IL-6 and MCP-1 are reported in pg/mL (n = 263). Endothelial marker syndecan-1 is reported in ng/mL, and VEGF is reported in pg/mL (n = 262).

Figure 6. Illustration depicting the dynamic immune and endothelial responses to traumatic injury.

The gray bars at the top of the figure define the time period, with hospital admission occurring within approximately 1 hour of injury or initial emergency response. The hypothesized effects of prehospital fluid administration as reported in this study are delineated by the red (plasma) and gray (standard care) panels. The endothelium is represented as previously depicted (10).