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Fresh frozen plasma attenuates lung injury in a novel model of prolonged hypotensive resuscitation - PubMed

Fresh frozen plasma attenuates lung injury in a novel model of prolonged hypotensive resuscitation

Amanda M Chipman et al. J Trauma Acute Care Surg. 2020 Aug.

Abstract

Background: Hemorrhagic shock remains a leading cause of early death among severely injured in both civilian and military settings. As future military operations will require strategies allowing prolonged field care of the injured, we sought to develop an in vivo model of prolonged hypotensive resuscitation (PHR) and to evaluate the role of plasma-based resuscitation in this model. We hypothesized that resuscitation with fresh frozen plasma (FFP) would mitigate lung injury when compared with Hextend in a rodent model of PHR.

Methods: Mice underwent laparotomy and hemorrhagic shock (mean arterial blood pressure, 35 ± 5 mm Hg × 90 minutes) followed by PHR with either FFP or Hextend to maintain a mean arterial blood pressure of 55 mm Hg to 60 mm Hg for 6 hours. Sham animals underwent cannulation only. At the end of 6 hours, animals were euthanized, and lung tissue harvested for measurement of histopathologic injury, inflammation and permeability using hematoxylin and eosin staining, myeloperoxidase immunofluorescence staining and Evans Blue dye. Pulmonary syndecan-1 immunostaining was assessed as an indicator of endothelial cell integrity.

Results: All animals in the FFP, Hextend, and sham groups survived to the end of resuscitation. Resuscitation with FFP mitigated lung histopathologic injury compared with Hextend (histologic injury score of 4.38 ± 2.07 vs. 7.5 ± 0.93, scale of 0-9, p = 0.002) and was comparable to shams (histologic injury score of 4.0 ± 1.93, scale of 0-9, p = 0.99). Fresh frozen plasma also reduced lung inflammation (0.116 ± 0.044 vs. 0.308 ± 0.054 relative fluorescence of myeloperoxidase, p = 0.002) and restored pulmonary syndecan-1 (0.514 ± 0.061 vs. 0.059 ± 0.021, relative syndecan-1 fluorescence, p < 0.001) when compared with Hextend. Consistently, FFP mitigated lung hyperpermeability compared with Hextend (7.30 ± 1.34 μg vs. 14.91 ± 5.55 μg Evans blue/100 mg lung tissue, p = 0.005).

Conclusion: We have presented a novel model of PHR of military relevance to the prolonged field care environment. In this model, FFP maintains its pulmonary protective effects using a PHR strategy compared with Hextend, which supports the need for further development and implementation of plasma-based resuscitation in the forward environment.

Level of evidence: Basic science.

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Conflict of interest statement

The authors have no conflicts of interest. The views expressed in this manuscript are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S government. Some of the authors are military Service members and employees of the U.S. Government. This work was prepared as part of their official duties. Title 17, U.S.C., §105 provides that copyright protection under this title is not available for any work of the U.S. Government. Title 17, U.S.C., §101 defines a U.S. Government work as a work prepared by a military Service member or employee of the U.S. Government as part of that person’s official duties.

Figures

Figure 1:
Figure 1:. Mean Arterial Pressure Over Time

Mice underwent 90 minutes of hemorrhagic shock followed by prolonged hypotensive resuscitation with either FFP or Hextend® to maintain a mean arterial pressure (MAP) of 55–60mmHg for six hours and were compared to sham mice. Sham animals had a significantly higher MAP than FFP or Hextend® animals at all time-points. FFP and Hextend® animals had similar MAP for all time points except PHR hour 4 and PHR hour 5, which are denoted by an asterisk. Data is reported as mean ± SD with n=6–8/group; two-way ANOVA. Abbreviations: Hex=Hextend®, FFP=fresh frozen plasma, HS=hemorrhagic shock, PHR=prolonged hypotensive resuscitation.

Figure 2:
Figure 2:. Lung histopathologic injury was reduced by FFP

Mice underwent 90 minutes of hemorrhagic shock followed by prolonged hypotensive resuscitation with either FFP or Hextend® to maintain a MAP of 55–60mmHg for six hours and were compared to sham mice. Shown are representative images and the corresponding lung injury scores. Table with scoring system for lung histopathologic injury modified from Hart et al., 2005(18). Data is reported as mean ± SD with n=8/group and was analyzed by one-way ANOVA with Bonferroni post hoc. Abbreviations: Hex=Hextend, FFP=fresh frozen plasma.

Figure 3:
Figure 3:. Pulmonary inflammation was reduced by FFP

Mice underwent 90 minutes of hemorrhagic shock followed by PHR with either FFP or Hextend® to maintain a MAP of 55–60mmHg for six hours and were compared to sham mice. Myeloperoxidase immunostaining was assessed as an indicator of neutrophil infiltration. Shown are representative images and the corresponding quantitation. Data is reported as mean ± SD with n=4/group and was analyzed by one-way ANOVA with Bonferroni post hoc. Abbreviations: Hex=Hextend®, FFP=fresh frozen plasma.

Figure 4:
Figure 4:. Pulmonary hyperpermeability was reduced by FFP

Mice underwent 90 minutes of hemorrhagic shock followed by PHR with either FFP or Hextend® to maintain a MAP of 55–60mmHg for six hours and were compared to sham mice. Pulmonary permeability was assessed with an Evans blue dye assay. Data is reported as mean±SD with n=6–8/group and was analyzed by one-way ANOVA with Bonferroni post hoc. Abbreviations: Hex=Hextend®, FFP=fresh frozen plasma, EB=Evans Blue.

Figure 5:
Figure 5:. Pulmonary syndecan-1 immunostaining was increased by FFP

Mice underwent 90 minutes of hemorrhagic shock followed by PHR with either FFP or Hextend® to maintain a MAP of 55–60mmHg for six hours and were compared to sham mice. Pulmonary syndecan-1 immunostaining was assessed. Shown are representative images and the corresponding quantitation. Data is reported as mean±SD with n=4/group and was analyzed by one-way ANOVA with Bonferroni post hoc. Abbreviations: Hex=Hextend®, FFP=fresh frozen plasma.

Figure 6:
Figure 6:. Cytokine and chemokine profiles differed among FFP and Hextend® treated groups

Mice underwent 90 minutes of hemorrhagic shock followed by PHR with either FFP or Hextend® to maintain a MAP of 55–60mmHg for six hours and were compared to sham mice. A. Plasma and B. Bronchoalveolar lavage was obtained from mice at time of sacrifice and assayed on a mouse cytokine and chemokine array pro-inflammatory Luminex Immunoassay. Selected cytokine and chemokine profiles are shown. *indicates p<0.05 when compared to sham group, #indicates p<0.05 when compared to Hextend® group. Abbreviations: IL=interleukin, TNF=tumor necrosis factor, KC=keratinocyte chemoattractant, IP=induced protein, MIP=macrophage inflammatory protein, MCP=monocyte chemoattractant protein.

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