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Hydrogen Inhalation is Superior to Mild Hypothermia for Improving Neurological Outcome and Survival in a Cardiac Arrest Model of Spontaneously Hypertensive Rat

Chen, Gang*; Chen, Bihua*; Dai, Chenxi*; Wang, Jianjie*; Wang, Juan; Huang, Yuanyuan; Li, Yongqin*

doi: 10.1097/SHK.0000000000001092
Basic Science Aspects
Editor's Choice

Background: Postcardiac arrest syndrome is the consequence of whole-body ischemia–reperfusion events that lead to multiple organ failure and eventually to death. Recent animal studies demonstrated that inhalation of hydrogen greatly mitigates postresuscitation myocardial dysfunction and brain injury. However, the influence of underlying heart disease on the efficacy of hydrogen is still unknown. In the present study, we investigated the effects of hydrogen inhalation on neurological outcome and survival in a cardiac arrest model of spontaneously hypertensive rat (SHR).

Methods: Cardiopulmonary resuscitation was initiated after 4 min of untreated ventricular fibrillation in 40 SHRs. Immediately after successful resuscitation, animals were randomized to be ventilated with 98% oxygen and 2% nitrogen under normothermia (Ctrl), 2% nitrogen under hypothermia (TH), 2% hydrogen under normothermia (H2), or 2% hydrogen under hypothermia (H2+TH) for 2 h. Hypothermia was maintained at 33°C for 2 h. Animals were observed up to 96 h for assessment of survival and neurologic recovery.

Results: No statistical differences in baseline measurements were observed among groups and all the animals were successfully resuscitated. Compared with Ctrl, serum cardiac troponin T measured at 5 h and myocardial damage score measured at 96 h after resuscitation were markedly reduced in H2, TH, and H2+TH groups. Compared with Ctrl and TH, astroglial protein S100 beta measured during the earlier postresuscitation period, and neurological deficit score and neuronal damage score measured at 96 h were considerably lower in both H2 and H2+TH groups. Ninety-six hours survival rates were significantly higher in the H2 (80.0%) and H2+TH (90.0%) groups than TH (30.0%) and to Ctrl (30.0%).

Conclusions: Hydrogen inhaling was superior to mild hypothermia for improving neurological outcome and survival in cardiac arrest and resuscitation model of systemic hypertension rats.

*School of Biomedical engineering, Third Military Medical University, Chongqing, China

Emergency Department, Southwest Hospital, Third Military Medical University, Chongqing, China

Neurology Department, Southwest Hospital, Third Military Medical University, Chongqing, China

Address reprint requests to Yongqin Li, MSBME, PhD, School of Biomedical Engineering, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China. E-mail: leeoken@gmail.com, leeoken@hotmail.com

Received 21 October, 2017

Revised 20 November, 2017

Accepted 18 December, 2017

This study was supported by the National Nature Science Foundation of China (NSFC31771070) and the Natural Science Foundation Project of Chongqing (cstc2017jcyjBX0053).

The authors declare that they have no competing interests.

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INTRODUCTION

With an incidence ranging from 35 to 125 cases per 100,000 people, sudden cardiac arrest is a major public health problem all over the world (1) and accounts for almost 20% of the total mortality in the ages between 20 and 75 (2). Despite decades of research and investment in the field of cardiac arrest, the prognosis of out-of-hospital cardiac arrest (OHCA) remains disappointingly poor, with a survival to hospital discharge of 6% to 8% (3).

Among patients who achieve restoration of spontaneous circulation (ROSC), two-thirds die during the subsequent days due to postcardiac arrest syndrome (PCAS), a complex pathophysiological state that following a successful cardiopulmonary resuscitation (CPR) (4). The main components of the PCAS are severe myocardial dysfunction and brain damage that may lead to multiple organ failure and death (5). Epidemiological studies also revealed that approximately 65% to 82% of all individuals who suffer cardiac arrest have a cardiovascular etiology, such as myocardial infarction, hypertension, dilated cardiomyopathy, and heart failure (2, 13, 14). PCAS is therefore a multifactorial syndrome resulted from the insult due to cardiac arrest superimposed on that from preexisting cardiac pathology.

Therapeutic hypothermia (TH), or targeted temperature management, is recommended for comatose patients after cardiac arrest and has become a mainstay of postresuscitation care (6). However, beneficial effects of TH remain controversial because recent clinical studies failed to show significantly improvements on neurological outcome and survival (7, 8). Treatment of PCAS, therefore, is still a big challenge.

Molecular hydrogen has been reported to have anti-inflammatory, antioxidant, and antiapoptotic properties by selectively neutralizing hydroxyl radicals (9). Recent experimental studies revealed that inhalation of hydrogen improved postresuscitation cardiac function and neurological outcome, to an extent comparable or superior to TH in different cardiac arrest models in the rat (10–12). However, models in these studies used healthy animals and the influence of underlying heart disease on the efficacy of hydrogen inhalation is still unknown.

The aim of the present study was designed to elucidate whether inhalation of hydrogen could improve neurological outcome and survival in a cardiac arrest model of spontaneously hypertensive rat (SHR).

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MATERIALS AND METHODS

This prospective, randomized, observational animal study was approved by the animal investigation committee of Third Military Medical University. Forty male SHRs weighing between 247 and 315 g (10–12 weeks of age) that were supplied by single-source breeder (Vital River Laboratory Animal Technology Co. Ltd, Beijing, China) were used for this study. All animal experiments were performed in strict accordance with guidelines from the Regulations for the Administration of Affairs Concerning Experimental Animals and efforts were exerted to minimize the suffering of the animals.

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Animal Preparation

All animals were fasted overnight except for free access to water. Anesthesia was initiated with an intraperitoneal injection of pentobarbital (45 mg/kg). Additional doses of 10 mg/kg were administered at intervals of 1 h when required to maintain anesthesia. After placing on a surgical board in the supine position, the tracheas of the animals were intubated through a tracheotomy with a 14-gauge cannula and mechanically ventilated with a tidal volume of 6.5 mL/kg at a FiO2 of 0.21 (ALC-V8, Alcott Biotech Co. Ltd, Shanghai, China). A PE-50 catheter was advanced from the right femoral artery for measurement of arterial pressure and blood sampling. The left femoral vein was also cannulated with an additional PE-50 catheter to allow for administration of fluids and drugs. Arterial pressure and conventional lead II ECG was continuously measured by a multiparameter monitor (Model 90369; Spacelabs, Snoqualmie, Wash). Core temperature was monitored by a thermocouple probe (TH-212, Bjhocy science and technology Co. Ltd., Beijing, China) that was placed into the esophagus and maintained by a heating lamp throughout the experiment to ensure appropriate temperature management. All catheters were flushed intermittently with saline solution containing 2.5 IU/m’L heparin.

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Experimental procedures

After collection of baseline data, ventricular fibrillation (VF) was induced through 50 Hz transesophageal cardiac pacing with an alternating current of 3 to 5 mA for 2 min. Mechanical ventilation was discontinued when cardiac pacing was started.

CPR, including chest compression and ventilation, was begun after 4 min of untreated arrest. Mechanical chest compression was delivered by a pneumatically driven compressor at a stroke rate of 200/min with a depth of 25% to 30% of the anterior posterior diameter of the animal's chest. Coincident with the start of precordial compression, animals were mechanically ventilated at a frequency of 80/min with a tidal volume 6.0 mL/kg and a FiO2 of 1.0. A dose of epinephrine (0.02 mg/kg) was injected 1 min after the start of CPR. After 3 min of CPR, defibrillation was attempted with a single 2-J biphasic shock (M Series, Zoll Medical Corporation, Chelmsford, Mass). Chest compression was immediately resumed after the shock delivery until confirmation of spontaneous circulation. Successful ROSC was defined as the return of an organized rhythm with a mean arterial pressure (MAP) >60 mmHg for an interval >10 s.

Immediately after ROSC, animals were randomly assigned to four groups (n = 10 each) and monitored in an intensive care setting for 5 h: ventilation with 2% nitrogen/98% oxygen under normothermia (Ctrl), ventilation with 2% nitrogen/98% oxygen under hypothermia (TH), ventilation with 2% hydrogen/98% oxygen under normothermia (H2), and ventilation with 2% hydrogen/98% oxygen under hypothermia (H2+TH). For all animals, mechanical ventilation was continued with mixed gas for 2 h and then with room air for another 3 h. For animals subjected to TH and H2+TH groups, surface cooling was initiated immediately after ROSC with the aid of ice packs and an electrical fan. Once the target temperature reached 33.0°C, it was maintained over the first 2 h of postresuscitation and then gradually returned to 37.0°C over a rewarming period of 2 h. For those animals assigned to H2 and Ctrl groups, core temperature was maintained at 37.0 ± 0.3°C until the end of the experiment.

All catheters including endotracheal tube were removed and wounds were surgically sutured 5 h after resuscitation. Animals were then returned to their cages with a room temperature maintained at 21°C–25°C and observed for 96 h.

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Measurements

ECG and blood pressure were continuously recorded with a PC-based data acquisition system supported by WINDAQ hardware and software (DATAQ Instruments Inc., Akron, Ohio). Cardiac function was noninvasively measured with an echocardiograph system (DC-6; Mindray Medical International Limited, Shenzhen, China). Left ventricular ejection fraction (LVEF) served as quantitative measurements of myocardial contractile function.

Arterial blood samples were collected at baseline, 2 and 5 h after ROSC. Blood samples were centrifuged, and serum was separated and stored at −80°C. The serum concentration of cardiac troponin T (cTnT) and astroglial protein S100 beta (S100B), as sensitive markers of cardiac and cerebral injury, were quantified with Enzyme-linked immunosorbent assay (ELISA) kits (Cusbio Biotech Co. Ltd., Wuhan, China) according to the manufacturer's instructions (17).

Neurological deficit score (NDS) was examined and confirmed by two investigators blinded to the treatment. Consciousness and breathing, cranial nerve reflexes, motor function, sensory function, and coordination were scored according to an NDS system (0–500 scale; 0 no observed neurological deficit, 500 death or brain death) that was developed to evaluate neurological outcome after global cerebral ischemia for rats (18).

Four days after ROSC, after assessment of the final NDS, the survived animals were reanaesthetized with pentobarbital sodium. The hearts and brains were removed and immersion fixed in 10% neutral buffered formalin. Organs were embedded in paraffin and sectioned (5 μm) on a microtome. Sections were stained with hematoxylin and eosin (H&E) for histopathological evaluation. In each section, 10 random slide fields were examined under an optical microscope at × 400 magnification. Myocardial damage was assessed based on the prevalence of infiltration of immune cells, myocytolysis and contraction band necrosis of the selected LV sections. Neuronal damage was diagnosed based on the prevalence of dystrophic neurons, including nuclear pyknosis, karyorrhexis, and vacuolization in the CA1 region of the hippocampus. Lesions were graded as normal (score, 0), minimal (score, 1), mild (score, 2), moderate (score, 3), and severe (score, 4) respectively, as was previously described (19, 20). For statistical analysis, each n represented an individual rat.

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Statistical analyses

Normal distribution of the data was confirmed using the Kolmogorov–Smirnov test. Continuous variables are presented as mean ± standard deviation. Hemodynamic and biochemical variables were compared by a mixed-effects model for repeated measures analyses, followed by ANOVA with Bonferroni correction for post hoc comparisons. Categorical data were expressed as percentage and tested with Fisher exact test. Survival curves were obtained with a Kaplan–Meier analysis and compared among groups with a log-rank test. A P < 0.05 was regarded as statistically significant.

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RESULTS

There were no statistical differences in baseline physiological measurements among groups (Table 1). All animals were successfully resuscitated and there were also no significant differences in characteristics of CPR (Table 2).

Table 1

Table 1

Table 2

Table 2

Target core temperature was achieved within 15 min after ROSC, while normothermia (37.0°C) was restored after 2 h of rewarming, for rats assigned to TH and H2+TH groups (Fig. 1A). Heart rate was significantly lower during the hypothermic period for animals treated with hypothermia compared to Ctrl (Fig. 1B). MAP was significantly decreased after resuscitation for all of the animals compared with baseline measurement (Fig. 1C). Three hours after resuscitation, MAP was relatively higher in the TH group but comparatively lower in H2 group. LVEF was dramatically improved in TH, H2, and H2+TH groups during the entire postresuscitation monitoring period compared with Ctrl, except for the measurement of 1 h in the TH group (Fig. 1D). In addition, significantly higher LVEF was observed in both H2 and H2+TH groups compared with TH, except for measurements at 3 and 4 h in the H2 group.

Fig. 1

Fig. 1

Prearrest serum cTnT and S100B levels did not differ significantly among groups (Fig. 2). Compared with Ctrl, serum cTnT levels were suppressed after resuscitation in all the three experimental groups and reached statistical significance 5 h after ROSC. At the same time, serum S100 B levels in H2 and H2+TH groups measured 2 and 5 h after resuscitation were significantly lower than Ctrl and TH groups, but no differences were observed between TH and Ctrl.

Fig. 2

Fig. 2

No statistical difference was observed for NDS between TH and Ctrl group during the observational period. However, NDS was significantly better in the H2 and H2+TH groups compared with the othertwo groups (Table 3). Eight and 9 animals in the H2 and H2+TH groups survived to 96 h, this contrasted with 3 animals in both TH and Ctrl groups (Fig. 3). Compared with Ctrl (30.0%) and TH (30.0%), the cumulative 96 h survival rates were was significantly higher in the H2 (80.0%) and H2+TH (90.0%) groups.

Table 3

Table 3

Fig. 3

Fig. 3

A total of 12 animals (n = 3 in each group) underwent myocardial and neuronal sampling for histopathology analysis because only 3 animals survived to 96 h in both Ctrl and TH groups. Representative micrographs of the HE-stained left ventricular are shown in Figure 4. Animals in the Ctrl group exhibited distinctive contraction bands and infiltration of a large number of immune cells. Compared with control, minor irregularities and few immune cells were observed in the three experimental groups. Representative images of the hippocampal CA1 region are shown in Figure 5. Many degenerated neurons with hypereosinophilic cytoplasm and dark shrunken nuclei were detectable in the Ctrl and TH groups. On the contrary, only few degenerated neurons and a lot of remaining viable neurons were observed in H2 and H2+TH groups. The overall myocardial damage score was significantly lower in TH, H2 and H2+TH groups compared to Ctrl (Fig. 6A). In addition, the H2+TH group had significantly reduced myocardial damage score compared to TH group. The neuronal damage score was also markedly reduced in H2 and H2+TH groups (Fig. 6B), compared either with Ctrl, or with TH.

Fig. 4

Fig. 4

Fig. 5

Fig. 5

Fig. 6

Fig. 6

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DISCUSSION

The present study demonstrated that hydrogen inhalation improves 96-h survival by attenuating postresuscitation myocardial dysfunction and brain injury in a cardiac arrest model of rats with systemic hypertension. Our results also indicated that the protective effect of molecular hydrogen is superior to mild hypothermia and is independent of targeted temperature management.

Mild hypothermia is nowadays one of the most important interventions to improve outcome in patient with PCAS, when commenced early after cardiac arrest (21, 22). In the present study, although the postresuscitation myocardial injury was relatively mitigated for animals subjected to TH group, the severity of brain injury was not alleviated and 96-h neurological outcome was not significantly improved compared with that of normothermic control. This result contradicts previous laboratorial studies (10, 11, 24), but is consistent with recent clinical studies showing that mild hypothermia does not confer a significant benefit in survival for both out-of-hospital and in-hospital cardiac arrests (7, 8, 25). Different with healthy rats without underlying heart disease used in aforementioned animal studies, we used SHRs in the present study. This specific model was used because it is a suitable experimental model for the investigation of hypertension-related cardiovascular disease such as cardiac hypertrophy and heart failure (26, 27). The interaction between prearrest hypertensive complications and postarrest ischemia–reperfusion insults can, at least in part, explain the observed decreased efficacy of mild hypothermia (15, 16). Moreover, the controversy between clinical studies may be explained by improvements in postresuscitation patient care. Compared with the unmanaged temperature for “normothermic group” in earlier clinical trials, the targeted temperature was also well managed for patients assigned to normothermic control in recent studies. The improved outcome most probably is not the sole result of hypothermia, but rather of the controlled normothermia or active prevention of hyperthermia (7, 8, 25, 28).

As hydrogen was reported to reduce infarct size and to improve neurological function in a rat model of middle cerebral artery occlusion, the effects of hydrogen have been studied on other animal models cardiac arrest and CPR (9). Hayashida et al. (10) first reported that inhalation of mixed gas comprising 2% hydrogen and 98% oxygen for 2 h at the beginning of CPR improved brain and cardiac function to an extent comparable to mild hypothermia in VF model of rats. The authors subsequently observed that inhalation of mixed gas comprising 1.3% hydrogen and 26% oxygen after ROSC for 2 h also improved neurological recovery and survival (11). Consistent with these studies, we observed that 96-h survival was greatly improved by inhaling 2% hydrogen for 2 h immediately after ROSC in animals with intrinsic cardiac disease, either under normothermia or hypothermia. The improved outcome can be attributed to both ameliorated postresuscitation myocardial dysfunction and brain injury. Furthermore, our results suggested that the beneficial effects of hydrogen outperform mild hypothermia in rats with spontaneous hypertension. This result was in agreement with previous animal studies. In isolated perfused hearts, Hayashida et al. (29) demonstrated that inhalation of hydrogen gas reduced infarct size without altering hemodynamic parameters, preventing deleterious left ventricular remodeling. Moreover, inhalation of hydrogen also prevented PCAS-associated increases in left ventricular end-diastolic pressure and serum IL-6 (10), which was not observed in animals treated with hypothermia (30). In a rat model of asphyxial cardiac arrest, hydrogen inhalation was also demonstrated to be superior to mild hypothermia in improving cardiac function and neurological outcome in our previous study (12).

The observation that hydrogen was superior to hypothermia on reducing postresuscitation cerebral injury can be explained by the difference in potential mechanisms of action. On one side, the protective role of hydrogen is primarily through selective reactive oxygen species attenuation (27, 31), whereas the physiological effects of hypothermia are multiple mechanisms of action blocking the cascade of ischemia on many levels (23). Although both therapies protect the organs by suppressing free radicals, inflammatory and apoptotic processes associated with reperfusion injury, inhaled hydrogen acts more rapidly because it is permeable to cell membranes and diffuses into ischemic tissues and cells in a timely fashion (32, 32). In addition, hydrogen specifically quenches detrimental reactive oxygen species while maintaining the metabolic oxidation-reduction reaction (31, 32). In contrast, hypothermia reduces the production of radical oxygen species through diminishing tissue metabolism (23, 33). On the other side, hydrogen has low toxicity with little drug–drug interaction and there is no reported potential side effect up to now (31–35). On the contrary, a number of adverse effects have been reported in the majority of patients treated with hypothermia, including pneumonia, sepsis, arrhythmia, electrolyte imbalance, bleeding, shivering, and coagulopathy (25, 36, 37). These advantages together with its effectiveness, suggest that hydrogen may be a good candidate in the management of PCAS as an effective therapy.

We recognize several limitations in our study. First, even though SHR is widely used for experimental studies because of its reliable spontaneous development of hypertension and hypertensive complications, the essential hypertension and destructive process may be different in rats compared with human. Second, the animals did not receive active antihypertensive treatment before induction of cardiac arrest. The results therefore should be more carefully interpreted when applied into clinical practice. Third, although we showed that hydrogen inhalation was superior to mild hypothermia for neuroprotection, the exact mechanism is still undetermined.

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CONCLUSIONS

Hydrogen inhaling was superior to mild hypothermia in improving neurological outcome and survival in cardiac arrest and resuscitation model of SHRs. Hydrogen may be a good candidate for postresuscitation intervention, especially for cardiac arrest with underlying structural heart disease.

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Keywords:

Cardiac arrest; hydrogen inhalation; mild hypothermia; myocardial injury; neurological outcome; systemic hypertension

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