Elsevier

Cytokine

Volume 60, Issue 3, December 2012, Pages 755-761
Cytokine

Effect of therapeutic hypothermia according to severity of sepsis in a septic rat model

https://doi.org/10.1016/j.cyto.2012.08.013Get rights and content

Abstract

Aim of study

The effects of therapeutic hypothermia (HT) during experimental sepsis may be influenced by disease severity. We experimentally investigated the effect of therapeutic HT on varying disease severity in a septic rat model.

Materials and methods

An adult male Sprague-Dawley rat model of intra-abdominal sepsis was used. To modify the disease severity, we used two different models; a moderate severe sepsis model (MSSM) and a severe septic shock model (SSSM). All rats were randomized to a hypothermia group (HT, 30–32 °C) or a normothermia group (NT, 36–38 °C) 1 h after sepsis induction in each model. HT was maintained for 4 h and rewarming was conducted for 2 h. Survival time was recorded for up to 12 h in the SSSM group and 24 h in the MSSM group. Acute lung and liver injury, cytokine, and malondialdehyde (MDA) levels were investigated 7 h after sepsis induction. Hemodynamic profiles were also evaluated.

Results

In the SSSM, there were survival benefits and reduced acute lung and liver injury with therapeutic HT. Therapeutic HT was also associated with significantly reduced levels of plasma interleukin-6 and tissue malondialdehyde (MDA) levels in the liver and lung compared with the NT group in the SSSM. There was a tendency for the mean arterial pressure to be higher in the HT group compared to the NT group in the SSSM. In MSSM, however, there was no such beneficial effect.

Conclusion

In this rat model of severe septic shock, therapeutic HT showed beneficial effects. In contrast, therapeutic HT did not show protective effect in the moderate sepsis model.

Highlights

► We examine the effects of the therapeutic hypothermia in sepsis model. ► We used sepsis model with two different severities. ► Therapeutic hypothermia has beneficial effects only in severe model of sepsis. ► The beneficial effects were shown by longer survival rate and less organ injury. ► The effects could be partly explained by anti-inflammatory effects of hypothermia.

Introduction

Current treatment of septic patients mainly consists of administration of broad-spectrum antibiotics, fluid resuscitation, assisting ventilation with mechanical support and general supportive care. This treatment protocol has essentially remained unchanged during the past decades. A sepsis-related inflammatory response may develop into septic shock and multiple organ dysfunction syndrome, which remains one of the leading causes of morbidity and mortality in critically ill patients [1]. This emphasizes the need for new therapeutic strategies.

Induced mild HT is recommended in patients with post-resuscitation syndrome to prevent ischemia–reperfusion injury, resulting in a better neurologic outcome and reduced mortality [2]. The dysregulated production of cytokines is the main feature of the post-resuscitation syndrome, which mimics the immunological disorders observed in sepsis [3], [4]. Since Blair et al. introduced the use of hypothermia in septic shock patients [5], several studies have reported the effects of HT during experimental sepsis. Unfortunately, the effects of HT on sepsis are less clear and still under debate [6], [7], [8], [9].

The severity of the disease may play an important role in influencing the efficacy of treatment. For example, a meta-analysis of clinical trials on anti-inflammatory agents in sepsis demonstrated a significant relationship between severity of illness and treatment effect. This relationship was characterized by beneficial effects in severely ill patient populations with no effector potentially harmful effects in less severely ill patient populations [10].

In this regard, we hypothesized that the effects of therapeutic HT would be dependent on sepsis severity. To examine this hypothesis, we used a cecal ligation and puncture (CLP) and a cecal ligation and incision (CLI) sepsis model for different levels of severity.

Section snippets

Animal preparation

This study was approved by the Institutional Review Board of our hospital for the care and use of laboratory animals. In total, eighty adult male Sprague-Dawley rats (310–360 g) were housed in a controlled environment with free access to food and water before the experiment. All procedures were performed by the same investigator in order to minimize variability.

Experimental model of sepsis

We developed two different sepsis models according to severity. In the moderate severe sepsis model (MSSM), we used a CLP model

The effects of therapeutic HT on survival

Survival time was significantly increased in the HT group compared to the NT group in the SSSM (Fig. 2B, p < 0.05). However, it was not different between groups in the MSSM (Fig. 2A, p = 0.928). In the SSSM, the mean survival time in the NT group and the HT group was 6.5 h and 8.4 h, respectively (p < 0.05).

Hemodynamics

In the MSSM, MAP did not differ significantly between groups (NT vs. HT group, p = 0.637, Fig. 3A). In the SSSM, all rats in the NT group died before 220 min and MAP was not significantly different

Discussion

Our study demonstrated that therapeutic HT increased survival time in the SSSM, but not in the MSSM. Lung and liver injury were also attenuated in the SSSM. In addition, therapeutic HT decreased serum IL-6, the ratio of IL-6 to IL-10, and the MDA levels of liver and lung tissues in the SSSM.

The effect of HT in sepsis is still under debate. Some authors reported that therapeutic HT would have protective effects via modulation of the inflammatory response, attenuation of lung injury, and a

Conclusion

This study shows that therapeutic HT had beneficial effects on survival in the SSSM. It may be associated with the modulation of the inflammatory response, antioxidant effects, and improved hemodynamics.

Acknowledgments

This study was partly supported by Grant No. 04-2011-007 from SNUBH Research Fund and by Grant No. 12-C07 from the Medical Research Laboratory of Seoul Medical Center.

References (29)

  • E. Blair et al.

    The use of hypothermia in septic shock

    JAMA J Am Med Assoc

    (1961)
  • A. Torossian et al.

    Mild preseptic hypothermia is detrimental in rats

    Crit Care Med

    (2004)
  • A. Torossian et al.

    Deleterious effects of mild hypothermia in septic rats are ameliorated by granulocyte colony-stimulating factor

    Anesthesiology

    (2003)
  • T. Taniguchi et al.

    Effects of hypothermia on mortality and inflammatory responses to endotoxin-induced shock in rats

    Clin Diag Lab Immunol

    (2003)
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