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The Effects of Pharmacological Hypothermia Induced by Neurotensin Receptor Agonist ABS 201 on Outcomes of CPR

Li, Hao∗,†; Hua, Tianfeng; Wang, Wei; Wu, Xiaobo; Miao, Changqing; Huang, Weiping; Xiao, Yan; Yang, Jin; Bradley, Jennifer L.; Peberdy, Mary Ann∗,‡; Ornato, Joseph∗,§; Dix, Thomas A.||,¶; Beck, Tyler||,¶; Tang, Wanchun∗,§,∗∗

Author Information
doi: 10.1097/SHK.0000000000001178

Abstract

INTRODUCTION

Cardiac arrest (CA) is a major public health issue worldwide. Each year 356,500 people experience CA in the United States and 418 per million people suffer CA in China (1, 2). Despite major efforts to improve outcomes from CA, survival rates remain low. A meta-analysis showed that only 7.6% of CA patients survived to hospital discharge (3). Many patients initially resuscitated from CA die before discharge due to postresuscitation syndrome, which includes postresuscitation myocardial–neurological dysfunction (4). Therefore, management of postresuscitation syndrome, especially myocardial–neurological dysfunction, is a crucial therapy to improve the prognosis of CA patients.

Multiple basic studies and clinical trials have demonstrated that therapeutic hypothermia is an effective therapy for postresuscitation syndrome. It can exert a protective effect on brain injury and prolong survival duration. The American Heart Association guidelines also recommend therapeutic hypothermia (32°C–34°C) for unconscious survivors of CA (4–6). However, currently available techniques for achieving hypothermia are mainly physical cooling methods, including water-circulating cooling blankets and intravascular catheters. These techniques are only practical in-hospital and are either labor-intensive for nursing staff or are an invasive procedure and have risk of skin injury and catheter-related thrombosis and infection (7). These limitations drive physicians to find an alternative or supplemental method to induce therapeutic hypothermia.

Recently, pharmacological hypothermia has drawn increased attention due to its significant hypothermia effect and protective effect on postresuscitation syndrome (8). Our previous studies demonstrated that pharmacological hypothermia induced by cannabinoid receptor agonist WIN 55,212-2 exerted an effective hypothermia effect and improved postresuscitation outcomes in a rat model of CA (8–10). Neurotensin is an endogenous tridecapeptide that binds to neurotensin receptors in the brain, which induces analgesia and hypothermia (11). However, because neurotensin does not cross the blood–brain barrier and is rapidly degraded by serum peptidases, peripheral administration is ineffective, which restricts the use of neurotensin (11). It has been demonstrated that the C-terminal hexapeptide of neurotensin, Arg8-Arg9-Pro10-Tyr11-Ile12-Leu13 (Neurotensin [8–13]), is the essential determinant of its biological activity (12). Based on this knowledge, we synthesized a novel compound ABS 201, which is a neurotensin [8–13] analog with the amino acid sequence: NH3-homolys-Arg-Pro-Tyr-tertLeu-Leu-COOH (12). It has been shown that ABS 201 is stable in the presence of rat serum peptidases for more than 24 h and has high affinity for neurotensin receptors (13). It can be easily dissolved in saline and administered by peritoneal injection or intravenous injection, and it penetrates the blood–brain barrier and binds to brain neurotensin receptors subtype 1 (NTS1) to induce hypothermia (14). After an intravenous injection of ABS 201 5.33 mg/kg to a healthy rat, the maximum temperature decrease was −2.87 ± 0.4°C, and time to maximum temperature decrease was 150 min (13). Previous studies have demonstrated that ABS 201 is a dose-dependent effective hypothermic strategy and improves neurological dysfunction after intracerebral hemorrhage, traumatic brain injury, and stroke (15–17). These results indicate that ABS 201 may be a potential agent for induction of therapeutic hypothermia in postresuscitation animals.

The purpose of this study was to determine whether ABS 201 induces hypothermia after resuscitation from CA. We hypothesized that ABS 201 induces therapeutic hypothermia and improves postresuscitation outcomes in a rat model of CA.

MATERIALS AND METHODS

Animal preparation

In this study, we used male Sprague–Dawley rats weighing between 450 g and 550 g, aged 7 to 10 months, supplied by a single-source breeder (Envigo Inc, Fredrick, Md). This study was approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals (18).

Animal preparation procedures have previously been published (8–10). Briefly, animals were anesthetized by intraperitoneal injection of pentobarbital (45 mg/kg), and additional doses (10 mg/kg) were administered at hourly intervals or when required to maintain anesthesia.

As shown in Figure 1, the trachea was orally intubated with a 14-G cannula (Abbocath-T; Abbott Hospital Products Division, North Chicago, Ill). End-tidal carbon dioxide (also called PetCO2) was continuously monitored with a side-stream infrared CO2 analyzer (200; Instrumentation Laboratories, Lexiongton, Mass). A PE-50 catheter (Becton Dickinson, Franklin Lakes, NJ) was inserted into the left femoral artery for measurement of arterial pressure. Another PE-50 catheter was inserted into the left external jugular vein for measurement of right atrial pressure. Aortic and right atrial pressures were measured by high-sensitivity transducers (model 42584-01; Abbott Critical Care Systems, North Chicago, Ill). An additional PE-50 catheter was inserted into the right femoral vein for infusion of ABS 201 or placebo. A thermocouple microprobe (9030-12-D-34; Columbus Instruments, Columbus, Ohio) was inserted into the right femoral artery for measurement of blood temperature. A 3 Fr PE catheter (C-PMS-301J; Cook Critical Care, Bloomington, Ind) was advanced through the right external jugular vein into the right atrium. A guide wire supplied with the catheter was then advanced through the catheter into the right ventricle to induce ventricular fibrillation (VF). The placement of the guidewire was confirmed by an endocardial electrocardiogram. All catheters were flushed intermittently with saline containing 2.5 IU/mL of crystalline bovine heparin. A conventional electrocardiogram lead II was continuously recorded.

F1
Fig. 1:
Schematic diagram of surgery and experimental procedure.

Body temperature was maintained at 37°C by adjusting the distance between the heating lamp and animals. When the temperature was stabilized at 37°C for 30 min, the distance between the heating lamp and animals was fixed throughout the remainder of the experiment (8–10).

Established rat model of CA

As shown in Figure 1, after the completion of animal preparation, VF was electrically induced with a progressive increase in 60-Hz current to a maximum of 3.5 mA delivered to the right ventricular endocardium. The current flow was maintained for 3 min to prevent spontaneous defibrillation. Mechanical ventilation was stopped after the onset of VF. Precordial compression began 6 min after the onset of untreated VF with a pneumatically driven mechanical chest compressor as previously described (19). Coincident with the start of precordial compression, the rats were mechanically ventilated at a frequency of 100 breaths/min with a FiO2 of 1.0. Precordial compression was maintained at a rate of 200 beats/min and synchronized to provide a compression/ventilation ratio of 2:1 with equal compression–relaxation duration (i.e., 50% duty cycle). Depth of compression was adjusted to maintain a coronary perfusion pressure (CPP) at 22 ± 2 mmHg. Resuscitation was attempted with up to three 2-J counter shocks after 8 min of cardiopulmonary resuscitation (CPR). Resuscitation was defined as the return of supraventricular rhythm with a mean aortic pressure of 50 mmHg for a minimum of 5 min. During resuscitation, no additional drug was administered.

Intravenous infusion of ABS 201

Thirty minutes after successful resuscitation, animals were randomized into two groups: ABS 201 and Control. The principal investigator was blinded to randomization. The ABS 201 group had ABS 201 continuously infused with a concentration of 4 mg/mL (8 mg/kg/h) to induce pharmacological hypothermia. ABS 201 was synthesized by previously described procedures (12–14). For the control group, animals received continuous infusion of the same volume of saline. The infusion time in both groups continued for 30 min. The infusate temperature for both groups was 23°C. After resuscitation, mechanical ventilation was continued with 100% oxygen for 90 min, 50% for the next 2 h, and then with 21% oxygen for the next 3 h. After postresuscitation 6 h, anesthesia was terminated and animals recovered consciousness; all catheters, including the endotracheal tube, were removed. Then, the animal was rewarmed at a rate of 0.5°C/h by a heating blanket for an additional 6 to 8 h. During the rewarming period, animals were continuously observed by investigators and rectal temperature was measured by a noninvasive rectal thermometer (7002H; Cole-Parmer Instrument Company, Vernon Hills, Ill) on an hourly basis until 37.0°C was reached.

Animals were then returned to their cages and closely monitored for 72 h. After observation for 72 h, animals were euthanized by intraperitoneal injection of Euthasol (150 mg/kg).

A necropsy was performed to inspect for gross abnormalities, including evidence of traumatic injuries consequent to cannulation, airway management, or precordial compression.

Measurements

Right atrial and aortic pressures, electrocardiographic tracings, and PetCO2 were continuously recorded for up to 6 h after resuscitation on a PC-based data acquisition system supported by WINDAQ software (DATAQ, Akron, Ohio). During resuscitation, the CPP was calculated as the difference between decompression diastolic aortic and time-coincident right atrial pressure. Myocardial function parameters, including ejection fraction (EF), cardiac output (CO), and myocardial performance index (MPI), were measured at baseline and at postresuscitation 1, 2, 5, and 6 h by a Philips ultrasound instrument using a 12.5 Hz probe (HD 11 XE; Philips Ultrasound, Bothell, Wash). MPI, which combines time intervals related to systolic and diastolic function and reflects the global cardiac function, calculated by the formula (ab)/b, where a = mitral closure-to-opening interval (time interval from cessation to onset of mitral inflow) and b = ET (aortic flow ejection time, obtained at the left ventricle outflow tract) (20).

Neurological deficit scores (NDS) ranging from 0 (normal) to 500 (coma/death) were measured to assess levels of consciousness, brain stem function, and overall performance at 24, 48, and 72 h (21).

Statistical methods

Statistical analysis was performed using SPSS version 16.0 (SPSS Inc., Chicago, Ill). Data are presented as mean ± SEM. Independent t test was used to compare means of two groups with normal distribution. For non-normally distributed data, differences between two groups were analyzed using the Mann–Whitney U test. Comparison between time-based measurements within each group was performed with analysis of repeated-measurement one-way analysis of variance (ANOVA). Intragroup differences between baseline and postresuscitation 60 min of cardiac function parameters were analyzed by paired t test. The level of significance for all statistical tests was P ≤ 0.05.

RESULTS

Baseline characteristics

Twelve rats were used in this study and all were successfully resuscitated. As shown in Table 1 and Figures 2 to 4, there was no difference in baseline body weight, heart rate, PetCO2, blood temperature, mean arterial pressure, and cardiac function parameters, including EF, CO, and MPI, between the two groups. During the process of resuscitation, there was no difference in CPP, PetCO2, and number of defibrillation between the two groups (Table 2).

T1
Table 1:
Characteristics in body weight, heart rate, PetCO2, and uretic output
F2
Fig. 2:
Change of blood temperature in both groups.
F3
Fig. 3:
Change of mean arterial pressure in both groups.
F4
Fig. 4:
Change of cardiac function in both groups.
T2
Table 2:
Coronary perfusion pressure, PetCO2, and number of defibrillation during resuscitation

Hypothermic effect of ABS 201 on postresuscitation rat

As expected, blood temperature decreased significantly from 37.10 ± 0.16°C to 35.07 ± 1.34°C after infusion of ABS 201 for 1 h, and reached 33.61 ± 1.37°C after administration for 3 h, then maintained at 33°C to 34°C for 2.5 h. Throughout the experiment, there was no significant change in blood temperature in the control group; it was maintained at 37.04 ± 0.27°C to 36.87 ± 0.15°C (Fig. 2).

Mean arterial pressure was significantly decreased in the ABS 201 group after 15 min of infusion (postresuscitation 45 min) (Fig. 3, P < 0.05 vs. Control). After 2.5 h of infusion (postresuscitation 3 h), mean arterial pressure in the ABS 201 group gradually increased. There was no difference in mean arterial pressure between the two groups. Furthermore, heart rate was significantly decreased in the ABS 201 group at postresuscitation 6 h (Table 1; P < 0.05 vs. Control). There was an elevation of PetCO2 in the ABS 201 group at postresuscitation 6 h, but no statistical difference between the two groups. Uretic output was measured at the end of the experiment (postresuscitation 6 h) and was significantly greater in the ABS 201 group than the control group (Table 1; P < 0.05 vs. Control).

The effect of ABS 201 on postresuscitation myocardial dysfunction

Cardiac function parameters of both groups, including EF, CO, and MPI, were significantly decreased at postresuscitation 60 min compared with baseline values (Table 3; P < 0.05 vs. Baseline). After infusion of ABS 201 for 1.5 h (postresuscitation 2 h), cardiac function in the ABS 201 group gradually recovered; however, there was no difference between the two groups. At the end of the experiment (postresuscitation 6 h), cardiac function recovered to 80% of the baseline value in the ABS 201 group, and significantly improved compared with the control group (Fig. 4; P < 0.05 vs. Control).

T3
Table 3:
Intragroup differences between the baseline and PR 60 min of the cardiac function parameters

The effect of ABS 201 on postresuscitation neurological dysfunction and survival duration

Three of the six ABS 201 treated animals survived for 24 h, two animals survived for 48 h, and one animal survived for 72 h. One rat in the ABS 201 group survived for 72 h and was in good condition. Before euthanasia, this rat was able to drink, eat, and crawl. The NDS of this rat was only 20 which was very close to a normal rat. If we did not euthanize this rat, it could have survived longer. Therefore, the 72-h survival rate of the ABS 201 group was 16.7%. In contrast, no animals in the control group survived more than 24 h. The postresuscitation survival duration in the ABS 201 group was significantly longer than the control group (Table 4; P < 0.05 vs. Control).

T4
Table 4:
Survival time and neurological deficit score

At postresuscitation 6 h, the NDS in the ABS 201 group was significantly lower than the control group (Table 4; P < 0.05 vs. Control). At the end of the experiment, a necropsy was performed to define cause of death and inspect for gross abnormalities. There was no evidence of compression trauma or cannulation injury in both groups.

DISCUSSION

This study demonstrated that the neurotensin receptor agonist ABS 201 can induce therapeutic hypothermia following resuscitation in a ventricular fibrillation cardiac arrest (VFCA) rat model. This pharmacological hypothermia process is associated with the significant improvement of postresuscitation myocardial–neurological dysfunction and an increased postresuscitation survival duration.

Before this study, another neurotensin analogue (NT 77) was assessed for its potential pharmacological hypothermia effects (11). It has been demonstrated that NT 77 can induce therapeutic hypothermia and improve the NDS in an asphyxia cardiac arrest (ACA) animal model. It is worth noting that our VFCA animal model is a different model from ACA. In human adults, the most common cause of out hospital cardiac arrest (OHCA) is VF, and our VFCA animal model mimics the clinical scenario of OHCA (22). We listed the difference between these two animal models in Supplemental Figure 1 and Supplemental Table 1 (see https://links.lww.com/SHK/A753). In comparison with the VFCA animal model, the postresuscitation extracerebral organ complications in the ACA animal model are not severe, which can achieve a reliable long survival duration (22). Therefore, Katz et al. only investigated the neurological outcome in the ACA animal model, and did not assess cardiac function and survival duration. In addition, compared with the VFCA animal model, the no blood flow time after apnea in the ACA animal model is not uniform, which influences the consistency of outcome values (23). Therefore, our present study is the first to demonstrate that ABS 201 can induce therapeutic hypothermia associated with an improvement of postresuscitation myocardial–neurological dysfunction and survival duration in an animal model of VFCA. This result indicates that ABS 201 may be an alternative method to induce therapeutic hypothermia with current cooling methods and could ameliorate postresuscitation myocardial–neurologic dysfunction.

In addition, both ABS 201 and NT 77 are neurotensin analogues (11, 12). Compared with NT 77, ABS 201 is a more stable, second-generation neurotensin 1 receptor agonist, with a different amino acid sequence (Supplemental Table 2, https://links.lww.com/SHK/A753). It has been demonstrated that repeated daily injections of NT 77 resulted in a diminished hypothermic response, and which may limit its further application (24). Previous studies have demonstrated that ABS 201 can exert a dose-dependent regulatory hypothermia effect (14, 16, 17). Recently, there are multiple papers published about the hypothermia effect of ABS 201, and indicated that ABS 201 can also improve neurological dysfunction in different animal models by its hypothermia effect, including intracerebral hemorrhage, traumatic brain injury, and stroke animal models (15–17). Therefore, compared with NT 77, ABS 201 has more advantages and potential for the development as a novel hypothermia drug candidate for treatment of comatose CA survivors.

In our present study, ABS 201 was continuously administered at 8 mg/kg/h for 30 min to induce hypothermia. Blood temperature was decreased to 35°C after infusion for 1 h and reached 33.61 ± 1.37°C after infusion for 2 h. The dosage and administration methods in this study were selected based on our preliminary studies that exerted the most valid hypothermia effect without compromising hemodynamics. In Gu et al.'s study, after a single peritoneal injection of 8 mg/kg of ABS 201, rectal temperature was decreased below 32°C after 15 min in a neonatal rat (17). Compared with Gu et al.'s study, our temperature reduction rate was slower. This may be due to body weight. Achieving a hypothermia effect in obese patients will take more time due to the insulating properties of adipose tissue (25). The body weight of the animal in Gu et al.'s study was not reported. However, they used a neonatal rat, whose body weight is smaller than an adult rat. Therefore, compared with Gu et al.'s study, more time was required to decrease blood temperature in our study.

After administration of ABS 201, a transient hypotension was observed; however, it does not seem to deteriorate postresuscitation outcomes. This phenomenon was not reported in previous studies. Choi et al.'s study demonstrated that ABS 201 induced hypothermia in a mouse model of focal cerebral ischemia, and there was no significant effect on mean arterial pressure after ABS 201 peritoneal injection (16). Furthermore, Lee et al. used another neurotensin receptor agonist named HPI-363 to induce therapeutic hypothermia on a traumatic brain injury mouse model; it was shown that HPI-363 also had no significant effect on mean arterial pressure (26). The transient hypotension mechanism of ABS 201 is unclear. As ABS 201 is a neurotensin receptor agonist, and neurotensin can activate mast cell degranulation and release histamine, we speculate the transient hypotension of ABS 201 may be caused by histamine release (27, 28). In addition, compared with the traumatic brain injury animal model, which was induced by right middle cerebral artery occlusion, our VFCA animal model observes postresuscitation cardiac dysfunction; therefore, ABS 201-induced histamine release may cause significant hypotension in our model. Future studies are necessary to use an antihistamine drug to prevent transient hypotension from ABS 201 administration.

As shown in Table 4, the postresuscitation survival duration in the ABS 201 group was significantly longer than the control group. Postresuscitation syndrome, which includes postresuscitation myocardial–neurological dysfunction, can continue for hours to several days after global ischemia–reperfusion injury. It is stimulated by fever and blocked by mild-to-moderate hypothermia (7). Therefore, ABS 201-induced hypothermia significantly improved postresuscitation syndrome and prolonged survival duration. The ABS 201 group did not shiver during the period of therapeutic hypothermia. As ABS 201 was initially developed as an analgesic and antipsychotic (12), we speculated that it may reduce shivering through its analgesic effect, and exert its protective effect to prolong survival duration. In addition, compared with our previous pharmacological hypothermia study, postresuscitation animal survival duration was reduced. In Sun et al.’ s study, cannabinoid receptor agonist WIN55, 212-2 was administered to postresuscitation rats to induce hypothermia; three of five WIN55, 212-2 treated rats survived for 72 h and the mean survival time was 61 ± 15 h (8). Furthermore, all five WIN55, 212-2-treated rats survived for 72 h in Ma and Weng's study (9, 10). We analyzed the cause of death of the ABS 201 group; the CPP of the animal during CPR in this study was lower than our previous studies (20–21 mmHg and 25–28 mmHg, respectively) (9). CPP is a surrogate for myocardial perfusion, and it has been demonstrated that low CPP during CPR is an excellent predictor of poor survival (29, 30). Therefore, we speculate that the longer survival duration in our previous study may be due to a slightly higher CPP during CPR. In addition, it should be noted that WIN55, 212-2 is a cannabinoid receptor agonist, which may increase the risk of drug addiction (31). WIN55, 212-2 is quite difficult to dissolve in saline; in previous studies, 2% tween-80 or commercially available soya oil/water emulsion was used to dissolve WIN55, 212 (8–10, 32). All of these factors may limit the use of WIN55, 212.

Cardiac function parameters were significantly improved in the ABS 201 group compared with the control group at postresuscitation 6 h (Fig. 4; P < 0.05 vs. Control). The cardioprotective mechanism of ABS 201 is still unclear. As mild hypothermia can increase myocardial contractility, ABS 201 may exert its cardioprotective effect via its hypothermia effect (33). ABS 201 binds with high selective affinity to the neurotensin receptors subtype 1 (NTS1) which is not only expressed in rat brain, but also in myocardial tissue (12–14). It has been demonstrated that neurotensin can increase rat isolated ventricular contractility via activation of NTS1(34). Therefore, we speculate that ABS 201 may elicit a positive inotropic response in the postresuscitation rat via activation of NTS1, and this response may be independent of its hypothermia cardioprotective effect. In future studies, we plan to add an additional group of ABS 201 with normal body temperature to investigate the cardioprotective mechanism of ABS 201.

There are some limitations in this study. First, the animal in this study was anesthetized with pentobarbital, which may have a synergistic hypothermia effect with ABS 201. Second, the rats used in this study were healthy animals without heart disease, whereas CA victims often have cardiovascular disease. Finally, the animal model used in the present study was too severe to demonstrate the benefits of treatment on survival. Further studies are needed to investigate the effects of ABS 201 on survival.

CONCLUSIONS

The present study demonstrated neurotensin receptor agonist ABS 201 can induce therapeutic hypothermia in a VFCA rat model. Improved outcomes of postresuscitation were observed after ABS 201-induced pharmacological hypothermia. ABS 201 may be an alternative method to induce therapeutic hypothermia with current cooling methods to ameliorate postresuscitation myocardial–neurological dysfunction as well as prolong survival duration.

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Keywords:

Cardiopulmonary resuscitation; myocardial–neurological dysfunction; neurotensin analogue; survival duration; therapeutic hypothermia

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