Effect of therapeutic hypothermia according to severity of sepsis in a septic rat 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)
- et al.
The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis
Clin Microbiol Infect
(2009) - et al.
Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction
Anal Biochem
(1979) - et al.
Effects of hypothermia and re-warming on the inflammatory response in a murine multiple hit model of trauma
Cytokine
(2005) - et al.
Cerebrovascular reactivity during hypothermia and rewarming
Br J Anaesth
(2007) - et al.
Rapid rewarming after mild hypothermia accentuates the inflammatory response after acute volume controlled haemorrhage in spontaneously breathing rats
Resuscitation
(2003) - et al.
Effect of speed of rewarming and administration of anti-inflammatory or anti-oxidant agents on acute lung injury in an intestinal ischemia model treated with therapeutic hypothermia
Resuscitation
(2010) - et al.
The epidemiology of sepsis in the United States from 1979 through 2000
New Engl J Med
(2003) - The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after...
- et al.
Postresuscitation disease after cardiac arrest: a sepsis-like syndrome?
Curr Opin Crit Care
(2004) - et al.
Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome
Circulation
(2002)
The use of hypothermia in septic shock
JAMA J Am Med Assoc
Mild preseptic hypothermia is detrimental in rats
Crit Care Med
Deleterious effects of mild hypothermia in septic rats are ameliorated by granulocyte colony-stimulating factor
Anesthesiology
Effects of hypothermia on mortality and inflammatory responses to endotoxin-induced shock in rats
Clin Diag Lab Immunol
Cited by (24)
Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome
2023, Contemporary Clinical Trials CommunicationsEffect of hypothermia on splenic leukocyte modulation and survival duration in severely septic rats
2017, Journal of Surgical ResearchCitation Excerpt :Since then, there have been multiple studies supporting and/or condemning the use of therapeutic HT.7-12 In experimental studies, therapeutic HT is protective against inflammatory responses and improves survival in animals with severe septic shock.13 Recent studies have shown that splenectomized animals that undergo cecal ligation and incision (CLI) have improved survival compared with their intact counterparts.14,15
The effect of hypothermia on influx of leukocytes in the digital lamellae of horses with oligofructose-induced laminitis
2016, Veterinary Immunology and ImmunopathologyCitation Excerpt :Due to the complex nature of systemic inflammation leading to increases in tissue leukocyte infiltration (Wang et al., 2013) and pro-inflammatory cytokine expression in multiple disease processes, targeted therapy through hypothermia for these individual processes has been the focus in both human (Crouser, 2012; Coyan et al., 2014; Yuan et al., 2014) and now veterinary medicine (van Eps and Pollitt, 2004; van Eps, 2010; Kullmann et al., 2014; van Eps et al., 2014; van Eps and Orsini, 2016). Hypothermia has been documented to decrease leukocyte infiltration and cytokine expression, leading to decreased end organ inflammation and injury in multiple disease states in humans and animal models of human disease (Crouser, 2012; Rim et al., 2012; Yenari and Han, 2012; Coyan et al., 2014; Yuan et al., 2014). Continuous digital hypothermia in the equid, which has been documented histologically in SRL models to inhibit lamellar injury (van Eps et al., 2004; van Eps et al., 2014) and clinically to protect septic equine patients from the development of laminitis (Kullmann et al., 2014), has been documented in the OF model of SRL to result in remarkable decreases (up to 100-fold) in lamellar expression of a broad spectrum of inflammatory molecules including cytokines, chemokines, and endothelial adhesion molecules (van Eps et al., 2012).
Accompanying mild hypothermia significantly improved the prognosis of septic mice than artificial mild hypothermia
2015, American Journal of Emergency MedicineCitation Excerpt :Hypothermia therapy could reduce the bleeding and edema of blood vessels, prevent the infiltration of neutrophils, reduce the release of excitatory neurotransmitter, lower the intracellular calcium accumulation, prevent the generation of oxygen free radicals, decrease the expression of cytokines, and reduce the cellular apoptosis [6]. Studies in recent years have demonstrated that a mild hypothermia therapy could significantly reduce the mortality rate of sepsis [7–11] from different aspects including proinflammatory and anti-inflammatory factors [7], cell apoptosis [6], and functions of autonomic nerves and different organs [8–11]. Sepsis is a systemic inflammatory response syndrome caused by an infection.
Effect of mild hypothermia on the increase of CD11b<sup>+</sup> Gr-1<sup>+</sup> myeloid-derived suppressor cells induced by lipopolysaccharide in a mouse model of sepsis
2015, American Journal of Emergency Medicine