Protective effects of therapeutic hypothermia on renal injury in an asphyxial cardiac arrest rat model

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Highlights

  • Cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) induced renal injury.

  • Therapeutic hypothermia (TH) treatment after CPR following CA reduced the renal injury.

Abstract

Cardiac arrest (CA) is a leading cause of mortality worldwide. Most of post-resuscitation related deaths are due to post-cardiac arrest syndrome (PCAS). After cardiopulmonary resuscitation (CPR), return of spontaneous circulation (ROSC) leads to renal ischemia-reperfusion injury, also known as PCAS. Many studies have focused on brain and heart injuries after ROSC, but renal failure has largely been ignored. Therefore, we investigated the protective effects of therapeutic hypothermia (TH) on asphyxial CA-induced renal injury in rats.

Thirty rats were randomly divided into five groups: 1) the control group (sham); 2) the normothermic CA (nor.); 3) a normothermic CA group that received TH immediately within 2 h after CPR (Hypo. 2 hrs); 4) a normothermic CA group that received TH within 4 h after CPR (Hypo. 4 hrs); and 5) a normothermia CA group that received TH within 6 h after CPR (Hypo. 6 h). One day after CPR, all rats were sacrificed. Compared with the normothermic CA group, the TH groups demonstrated significantly increased survival rate (P < 0.05); decreased serum blood urea nitrogen, creatinine, and lactate dehydrogenase levels; and lower histological damage degree and malondialdehyde concentration in their renal tissue. Terminal deoxynucleotidyl transferase dUTP nick end labeling stain revealed that the number of apoptotic cells significantly decreased after 4 h and 6 h of TH compared to the results seen in the normothermic CA group. Moreover, TH downregulated the expression of cyclooxygenase-2 in the renal cortex compared to the normothermic CA group one day after CPR. These results suggest that TH exerts anti-apoptotic, anti-inflammatory, and anti-oxidative effects immediately after ROSC that protect against renal injury.

Introduction

The morbidity and mortality rates from cardiac arrest (CA) have increased across the globe. The sudden cessation of normal blood flow due to loss of heart function is known as CA, cardiopulmonary arrest, or circulatory arrest (Girotra et al., 2015). CA commonly causes disability and mortality; the annual incidence of sudden cardiac arrest is about 3 million cases, while the SCA survival rate is less than 1% worldwide (Forman-Hoffman et al., 2015).

Robert et al. reported that dysfunction in various organs is common after return of spontaneous circulation (ROSC) in post-cardiac arrest syndrome (PCAS) (Roberts et al., 2013). In particular, renal injury resulting from ROSC after CA is a complicated process; for hospital patients admitted with heart failure, renal impairment is common and is also related to a high mortality rate (Damman et al., 2014). Acute renal injury occurred in 30–50% of patients who survived CA (Hasper et al., 2009). Geri et al. reported that acute renal injury complicates 12–40% of the conditions of hospitalized CA patients (Geri et al., 2015). However, many studies have focused on brain and heart injury after ROSC, while renal failure has largely not been studied (Greite et al., 2018).

In humans, the first success in using therapeutic hypothermia (TH) after CA was described in the late 1950s (Williams and Spencer, 1958). Since that time, the most successful treatment for patients with CA has been TH (Palmers et al., 2015). Mild TH has an improved survival rate and better neurologic outcomes in patients who achieve ROSC after CA (Hypothermia after Cardiac Arrest Study, 2002). TH was shown to have anti-apoptotic effects on the brain after ROSC in a CA swine model (Suh et al., 2014). A previous study of serum samples reported that TH also has anti-inflammatory (Fries et al., 2009) and anti-oxidative effects (Hackenhaar et al., 2017) after ROSC in CA patients. However, a different study showed that TH had no significant effect on neurological and survival outcomes after ROSC in CA patients (Legriel et al., 2016; Moler et al., 2017; Nielsen et al., 2013). The effect of TH after ROSC remains controversial in CA patients. Thus, we applied TH after ROSC in CA to confirm its effect.

Tujjar et al. reported that acute renal injury was observed after ROSC in a CA patient; however, the mechanism of renal injury after CA remains elusive (Tujjar et al., 2015). Several studies have identified increased expression of malondialdehyde (MDA) and cyclooxygenase-2 (COX-2) in renal ischemia-reperfusion (I/R) injury in animal models (Arias-Negrete et al., 1995; Chatterjee et al., 2001). Thus, we investigated these factors to assess the anti-inflammatory and anti-oxidative effects of TH in asphyxial CA-induced I/R renal injury after ROSC. This study aimed to evaluate the underlying mechanism of asphyxial CA-induced renal I/R injury after ROSC and investigate the ability of TH to protect from renal injury.

Section snippets

Experimental animals

Twelve weeks old male Sprague-Dawley (SD) rats (310 ± 10 g) were obtained from the Experimental Animal Center of Chonbuk National University (South Korea). They were housed in a conventional state under adequate temperature (24 ± 2 °C) and humidity (60 ± 10%) control with a 12-hrs light/12-hrs dark cycle. They were provided free access to food and water. All experimental protocols were approved by the Chonbuk National University-Institutional Animal Care and Use Committee based on ethical

Physiological variables

There was no significant difference in physiological parameters between sham and normothermia CA group (P < 0.05). The physiological parameters of normothermia CA group versus hypothermia 2 h, 4 h, 6 h groups also showed no significant difference (P < 0.05) (Table 1). Isoelectric ECG and SpO2 were used for confirming CA (Table 1).

Survival rate

The survival rate of rats was determined at 1 day after CA. Kaplan-Meier analysis demonstrated a survival rate (P < 0.05). The survival rate of rats was 46% for the

Discussion

The present study showed changes in inflammatory components, oxidative stress markers, and apoptosis markers in the kidney after asphyxial CA rat models that developed ROSC following CPR. Immediate application of TH significantly increased the survival rate and mitigated inflammation and renal apoptosis after ROSC compared to those recorded in normothermic CA rats.

Nielsen et al. reported that TH has no significant beneficial effects on survival in CA patients, but our CA animal model revealed

Conclusion

In the present study, we confirmed the presence of renal tubular inflammation, apoptosis, and oxidative stress one day after ROSC in an asphyxial CA animal model and concluded that immediate TH treatment increased the survival rate in a time-dependent manner. Our results also suggest that immediate TH treatment after CPR was protective against renal injury through anti-apoptotic, anti-inflammatory, and anti-oxidative pathways in a time-dependent manner in an asphyxial CA animal model. TH

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea, South Korea funded by the Ministry of Education (NRF-2017R1D1A1B03031998, NRF-2019R1C1C1002564 and NRF-2019R1F1A1062696) and Biomedical Research Institute of Jeonbuk National University Hospital, South Korea.

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    Co-firsts: Anowarul Islam and So Eun Kim have contributed equally to this article.

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