Shock-induced systemic hyperfibrinolysis is attenuated by plasma-first resuscitation

Abstract

Background: We developed a hemorrhagic shock animal model to replicate an urban prehospital setting where resuscitation fluids are limited to assess the effect of saline versus plasma in coagulopathic patients. An in vitro model of whole blood dilution with saline exacerbated tissue plasminogen activator (tPA)-mediated fibrinolysis, while plasma dilution did not change fibrinolysis. We hypothesize that shock-induced hyperfibrinolysis can be attenuated by resuscitation with plasma while exacerbated by saline.

Methods: Sprague-Dawley rats were hemorrhaged to a mean arterial pressure of 25 mm Hg and maintained in shock for 30 minutes. Animals were resuscitated with either normal saline (NS) or platelet-free plasma (PFP) with a 10% total blood volume bolus, followed by an additional 5 minutes of resuscitation with NS to increase blood pressure to a mean arterial pressure of 30 mm Hg. Animals were observed for 15 minutes for the assessment of hemodynamic response and survival. Blood samples were analyzed with thrombelastography paired with protein analysis.

Results: The median percentage of total blood volume shed per group were similar (NS, 52.5% vs. PFP, 55.7; p = 0.065). Survival was 50% in NS compared with 100% in PFP. The change in LY30 and tPA levels from baseline to shock was similar between groups (LY30 PFP, 10; interquartile range [IQR], 4.3-11.2; NS, 4.5; IQR, 4.1-14.2; p = 1.00; tPA PFP, 16.6 ng/mL; IQR, 13.7-27.8; NS, 22.4; IQR, 20.1-25.5; p = 0.240). After resuscitation, the median change in LY30 was greater in the NS group (13.5; IQR, 3.5-19.9) compared with PFP (-4.9%; IQR, -9.22 to 0.25 p = 0.004), but tPA levels did not significantly change (NS, 1.4; IQR, -6.2 to 7.1 vs. PFP, 1.7; IQR, -5.2 to 6.8; p = 0.699).

Conclusion: Systemic hyperfibrinolysis is driven by hypoperfusion and associated with increased levels of tPA. Plasma is a superior resuscitation fluid to NS in a prehospital model of severe hemorrhagic shock as it attenuates hyperfibrinolysis and improves systemic perfusion.

Figures

Figure 1. Schematic of profound shock model

Animals after cannulation underwent hemorrhage form 5 minutes reduce blood pressure to a mean arterial pressure of less than 35 mmHg, 30 minutes of shock, 5 minutes of resuscitation, and 15 minutes of observation. During resuscitation animals were randomized to either plasma or saline with an initial 10% estimated blood volume bolus followed by an addition as needed saline resuscitation to obtain a mean arterial pressure greater than 30. MAP= mean arterial pressure in mmHG

Figure 2. Saline resuscitation improves blood pressure

The median mean arterial blood pressure is represented on the Y axis. The X axis represents time points at which blood pressure were measured. Animals in both experimental arms had similar blood pressure during the hemorrhage and shock period. After initial bolus of resuscitation plasma increased blood pressure greater than saline, and continued to have a higher blood pressure during the observation period. NS= normal saline; PFP = platelet free plasma; ng = nanogram

Figure 3. Kaplan Meyer curve

Y axis represents cumulative survival, and X axis represents observation times in minutes. NS= normal saline; PFP= platelet free plasma; ng= nanogram

Figure 4

A, LY30 increased with shock: Y Axis represents the change in LY30 from baseline to shock. Both experimental groups had an increase in LY30 following 30 minutes of hemorrhagic shock. B, tPA levels increased with shock: Y axis represents the change in tPA from baseline to shock. Both experimental groups had an increase in tPA following shock. NS= normal saline; PFP = platelet free plasma; MAP = mean arterial pressure; Hem = hemorrhage; Obs = Observation; *= P

Figure 5

A, LY30 after NS resuscitation and was attenuated with plasma. Y Axis represents the change in LY30 from shock to partial resuscitation and 15 minutes of observation. NS resuscitation increased LY30 while plasma resuscitation tended to decrease LY30. B, tPA levels similar regardless of resuscitation. Y axis represents the change in tPA from shock to partial resuscitation and 15 minutes of observation. Both experimental groups showed a similar distribution of change in tPA. PFP= platelet free plasma; NS= normal saline