Long-Term Effects of Induced Hypothermia on Local and Systemic Inflammation - Results from a Porcine Long-Term Trauma Model.

K Horst,F Hildebrand,S Ruchholtz,N Vogt,R Pfeifer,H Wulf,M Frink,M Sassen,D Eschbach,H C Pape,B Relja,T Steinfeldt

doi:10.1371/journal.pone.0154788

Abstract

BackgroundHypothermia has been discussed as playing a role in improving the early phase of systemic inflammation. However, information on the impact of hypothermia on the local inflammatory response is sparse. We therefore investigated the kinetics of local and systemic inflammation in the late posttraumatic phase after induction of hypothermia in an established porcine long-term model of combined trauma.Materials & MethodsMale pigs (35 ± 5kg) were mechanically ventilated and monitored over the study period of 48 h. Combined trauma included tibia fracture, lung contusion, liver laceration and pressure-controlled hemorrhagic shock (MAP < 30 ± 5 mmHg for 90 min). After resuscitation, hypothermia (33°C) was induced for a period of 12 h (HT-T group) with subsequent re-warming over a period of 10 h. The NT-T group was kept normothermic. Systemic and local (fracture hematoma) cytokine levels (IL-6, -8, -10) and alarmins (HMGB1, HSP70) were measured via ELISA.ResultsSevere signs of shock as well as systemic and local increases of pro-inflammatory mediators were observed in both trauma groups. In general the local increase of pro- and anti-inflammatory mediator levels was significantly higher and prolonged compared to systemic concentrations. Induction of hypothermia resulted in a significantly prolonged elevation of both systemic and local HMGB1 levels at 48 h compared to the NT-T group. Correspondingly, local IL-6 levels demonstrated a significantly prolonged increase in the HT-T group at 48 h.ConclusionA prolonged inflammatory response might reduce the well-described protective effects on organ and immune function observed in the early phase after hypothermia induction. Furthermore, local immune response also seems to be affected. Future studies should aim to investigate the use of therapeutic hypothermia at different degrees and duration of application.

Highlights

Multiple injuries in trauma patients have been associated with severe systemic and local complications [1,2,3,4]
Hypothermia has been discussed as playing a role in improving the early phase of systemic inflammation
Induction of hypothermia resulted in a significantly prolonged elevation of both systemic and local HMGB1 levels at 48 h compared to the NT-T group

Summary

Introduction

Multiple injuries in trauma patients have been associated with severe systemic and local complications [1,2,3,4]. There is evidence for a higher incidence of delayed fracture healing and nonunion in multiple trauma patients compared to those who sustain an isolated fracture [5,6,7] These local and systemic complications have been associated with the posttraumatic immune response. Beside the well-known consequences of an overwhelming systemic inflammatory response on the development of remote organ damage, a profound local inflammation has been assumed to negatively affect the early phase of bone repair thereby impairing fracture healing [6] In this context, the immunologic milieu of local fracture hematoma in particular is supposed to be crucial for adequate initiation of repair processes (e.g. stimulation of angiogenesis, regulation of osteoclast activity) [8]. We investigated the kinetics of local and systemic inflammation in the late posttraumatic phase after induction of hypothermia in an established porcine long-term model of combined trauma.

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