After successful cardiopulmonary resuscitation (CPR), the ensuing post-cardiac arrest syndrome (PCAS) becomes the main cause of death in cardiac arrest (CA) victims (1). Currently, the post-CA care mainly includes the identification and treatment of the precipitating cause of CA, and the assessment and mitigation of ischemia–reperfusion injury to multiple organ systems (2). Although therapeutic hypothermia (TH) has been confirmed to provide the effective protection for PCAS (3, 4); however, less than half of the patients can obtain a favorable outcome after hypothermic treatment (5, 6). Recently, another investigation further demonstrated that similar outcomes were achieved when applying 33°C of hypothermia or 36°C of normothermia (NT) (7). These disappointing results might be partly attributed to a lower cooling efficacy with conventional techniques (8). Surface blanket cooling which is considered as a representative of conventional cooling methods in the clinical setting, usually requires several hours to achieve the target temperature in patients (9, 10).
Based on the current evidence, early induction of hypothermia and rapid achievement of target temperature are the key factors to optimize the protective effects of hypothermia (8). Those newly developed, faster cooling techniques have been shown to produce a significantly better outcome when compared with conventional techniques. Earlier, 2 investigations demonstrated that transpulmonary hypothermia by total liquid ventilation exerted potent cardiac, neurologic, and renal protection after resuscitation in rabbit (11, 12). Recently, fast induction of hypothermia using continuous automated peritoneal lavage obtained a high proportion of survival with excellent neurologic outcome in human (13). However, all these novel cooling techniques require special equipments, which hamper them to be translated into clinical practice.
Currently, 2 clinical cases reported that rapid hypothermia through continuous renal replacement therapy (CRRT) was feasible and furthermore facilitated the recovery of cardiac and neurologic function (14, 15). Considering that CRRT is a conventional, well-performed technique in the clinical setting, it may become a promising method for rapid cooling in post-CA patients. In this study, we investigated the efficacy of cooling by CRRT and its effectiveness in alleviating the severity of PCAS in a porcine model. We hypothesized that CRRT cooling initiated early after resuscitation would induce fast hypothermia, and therefore yield better protective effects against post-resuscitation multiple organ injuries when compared with conventional surface cooling (SC).
MATERIALS AND METHODS
This was a prospective, randomized, controlled experimental study. A porcine model of CA and resuscitation was utilized. The protocol of this study was approved by the Institutional Animal Care and Use Committee of the Zhejiang University School of Medicine (approval number: IACUC-P201601). Thirty-two healthy male domestic pigs (4–6-month-old, 33–41 kg) were supplied by Shanghai Jiagan Biotechnology Inc. (Shanghai, China), and were fed under the conditions of standard atmospheric pressure, 12-h light/dark cycle, room temperature (20–25°C), humidity (60%–80%), closed cage, spontaneous water intake, regular feeding, regular cleaning, and disinfection. All animals received humane care in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources.
All animals were fasted overnight except for free access to water. Anesthesia was initiated by i.m. injection of ketamine (20 mg/kg) and completed by an ear vein injection of sodium pentobarbital (30 mg/kg). Thereafter, sodium pentobarbital (8 mg/kg/h) and fentanyl (2 μg/kg/h) were intravenously infused to maintain anesthesia. A cuffed endotracheal tube was advanced into the trachea. The animals were mechanically ventilated with a volume-controlled ventilator (SynoVent E5, Mindray, Shenzhen, China) with a tidal volume of 12 mL/kg, peak flow of 40 L/min, and FiO2 of 0.21. End-tidal carbon dioxide (ETCO2) was continuously monitored with a handheld ETCO2/SPO2 monitor (PMSH-300, SunLife Science Inc., Shanghai, China). Respiratory frequency was adjusted to maintain ETCO2 between 35 mmHg and 40 mmHg. The conventional lead II electrocardiogram was continuously monitored.
For the measurements of stroke volume (SV) and global ejection fraction (GEF), a 7 Fr central venous catheter was inserted into the left external jugular vein for the injection of iced saline, and another 4 Fr thermistor-tipped arterial catheter was inserted into the left femoral artery, both of which were connected to the PiCCO Monitor system (PiCCOplus, Pulsion Medical Systems, Munich, Germany). For the establishment of vascular access of CRRT, an 11 F double-lumen catheter (GDK-1120, Gambro Kathetertechnik Hechingen, Hechingen, Germany) was inserted into the left femoral vein. For the measurement of aortic pressure, a fluid-filled 8 Fr catheter (Model 6523, C.R. Bard Inc., Salt Lake, UT) was advanced from the right femoral artery into the thoracic aorta. For the measurements of right atrial pressure and blood temperature, a 7 Fr pentalumen, thermodilution-tipped catheter (Abbott Critical Care # 41216, Chicago, IL) was advanced from the right femoral vein into the right atrium. All catheters were intermittently flushed with saline containing 5 IU bovine heparin per mL. For inducing ventricular fibrillation (VF), a 5 F pacing catheter (EP Technologies Inc., Mountain View, CA) was advanced from the right external jugular vein into the right ventricle. The position of catheters was confirmed by characteristic pressure morphology and with fluoroscopy. Body temperature for all animals was maintained at 38.0 ± 0.5°C during the preparation.
Following a 10-min stabilization, baseline measurements were obtained. The animals were then randomized into 4 groups: sham control (Control, n = 5), NT (n = 9), SC (n = 9), or CRRT (n = 9). In the Control and NT groups, a normal temperature of 38.0 ± 0.5°C was maintained by the Blanketrol III (Cincinnati Sub-Zero, Cincinnati, OH). In the 2 hypothermic groups, TH was initiated at 5 min after resuscitation and maintained at 33 ± 0.5°C. The cooling was induced by either the combination of an earlier 8-h CRRT and later 16-h SC or the whole 24-h SC, followed by a rewarming period at a rate of 1°C/h. SC was performed by the Blanketrol III. CRRT was implemented with the Prisma system (Gambro Dasco S.p.A., Medolla, Italy) using an AN69ST hemofilter (Gambro Industries, Meyzieu, France).
The CRRT mode was continuous venovenous hemofiltration. Blood flow rate was initially set at 180 mL/min with the circuit submerged in 4°C of ice water to rapidly decrease blood temperature. Once the target temperature of 33°C was reached, blood flow was set at 120 mL/min and the circuit was wrapped by an adjustable heating device to maintain the temperature. The rate of replacement liquid and ultrafiltration was consistently set at 30 mL/kg/h and 0 mL/kg/h, respectively. The composition of replacement liquid included 4.91 mmol/L of potassium, 139.7 mmol/L of sodium, 1.16 mmol/L of calcium, 1.74 mmol/L of magnesium, 117.4 mmol/L of chloride, 27.2 mmol/L of bicarbonate, and 10 mmol/L of glucose. Coincident with the start of CRRT, the anticoagulation was performed with a 1000-IU loading dose of heparin, and then 150 IU for the first hour, 300 IU for the second hour, 450 IU for the third hour, 600 IU/h for the remaining 5 h.
Sham animals only underwent surgical preparation including endotracheal intubation and all venous and arterial catheterizations without experiencing CA and resuscitation. In the other 3 groups, VF was induced by 1 mA alternating current. Mechanical ventilation was discontinued after onset of VF. After 8 min of untreated VF, CPR was manually performed by a ratio of 30:2 of compression to ventilation. The compression quality was monitored by an E Series Monitor Defibrillator (ZOLL Medical Corporation, Chelmsford, MA) to guarantee a compression depth of 50–60 mm at a rate of 100–120 per minute. The ventilation was performed using a bag respirator attached to the endotracheal tube with room air. After 2.5 min of CPR, the first bolus of epinephrine was administered at a dose of 20 μg/kg. After 5 min of CPR, defibrillation was attempted with a single 150-J biphasic waveform electrical shock. If an organized rhythm with a mean arterial pressure (MAP) of greater than 50 mmHg persisted for 5 min or more, the animal was regarded as return of spontaneous circulation (ROSC). With failure to achieve ROSC, chest compression and ventilation were immediately resumed for 2 min prior to another defibrillation. The protocol was repeated until successful resuscitation or for a total of 15 min. Additional doses of epinephrine were administered at an interval of 3 min after the first bolus injection. Following ROSC, mechanical ventilation was continued for 30 h. Additionally, compound sodium chloride solution (2 mL/kg/h) was continuously infused to maintain fluid balance. Cisatracurium besylate (0.2 mg/kg/h) was intravenously administered to avoid shivering. Antibiotics (amoxicillin sodium and clavulanate potassium, 1.2 g) was intramuscularly injected every 12 h to prevent infection. At the end of 30 h post resuscitation, the animals were euthanized with an i.v. injection of 150 mg/kg sodium pentobarbital, and then a necropsy was routinely performed for documentation of potential injuries to thoracic and abdominal viscera resulting from the surgical or CPR intervention or the presence of obfuscating diseases. The experimental outline was summarized in Figure 1.
Hemodynamics, electrocardiogram, and blood temperature were continuously measured and recorded by a patient monitoring system (BeneView T6, Mindray, Shenzhen, China). Coronary perfusion pressure (CPP) was calculated as the difference between decompression diastolic aortic and time-coincident right atrial pressures. Tympanic and rectal temperatures were detected by the thermal probe, respectively.
Myocardial function, including SV and GEF, were evaluated with the PiCCO system at baseline and at 1, 3, 6, 12, 24, and 30 h post resuscitation. Venous and arterial blood samples were collected at the same time points. The serums were separated from venous blood samples and then stored at −80°C until analysis. The levels of cardiac troponin I (cTnI), neuron-specific enolase (NSE), S100B protein (S100B), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in serum were measured with enzyme-linked immunosorbent assay kits (Meixuan Biotechnology Inc., Shanghai, China) according to the manufacturer's instructions. Additionally, venous blood samples were used to measure coagulation parameters including prothrombin time (PT) and activated partial thromboplastin time (APTT) with an automatic blood coagulation analyzer (STA compact, Diagnostica Stago, Asnieres-Sur-Seine, France). Arterial blood samples were used for the measurements of blood gas, lactate, and electrolyte concentrations with a Blood Gas/Electrolyte Analyzer (Model 5700, Instrumentation Laboratory, Lexington, MA).
For the evaluation of inflammatory and oxidative injuries in the heart and brain, left ventricular myocardium and cerebral cortex were harvested immediately after animal euthanasia at 30-h post resuscitation. Subsequently, cardiac and brain tissues were washed in 4°C of cold saline, then frozen in liquid nitrogen, and finally stored at −80°C for further analysis. All specimens were homogenized with normal saline on ice, and centrifuged at 4000 rpm at 4°C for 15 min. The supernatants were collected for measuring the levels of TNF-α, IL-6, and malondialdehyde (MDA) and the activities of superoxide dismutase (SOD). The inflammatory cytokines were measured with enzyme-linked immunosorbent assay kits (Meixuan Biotechnology Inc., Shanghai, China) according to the manufacturer's instructions. The contents of MDA were determined by the thiobarbituric acid reactive substances assay and the activities of SOD were determined by the xanthine oxide assay based on the previously reported methods (16). The MDA assay kit and SOD assay kit were purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Total protein concentration was determined using a standard BCA protein assay kit (Nanjing Jiancheng Bioengineering Institute). All the results were expressed as per microgram of protein.
The rates of apoptotic cells in the heart and brain at 30 h post resuscitation were measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. First, cardiac and brain specimens were fixed in 4% paraformaldehyde for 24 h. Second, all specimens were embedded in paraffin, and then cut in a 5-μm section. Third, the sections were stained using a TUNEL assay kit (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer's instructions. The analysis of cell apoptosis was performed by an experienced pathologist who was blinded to the study. In each section, 6 views were randomly chosen to count the numbers of TUNEL-positive cells and total cells at 200× magnification under an optical microscope (biological microscope CX31, Olympus, Japan). The rate of apoptotic cells was calculated as the percentage of TUNEL-positive cells/total cells. The expression levels of cleaved caspase-3 protein were evaluated with the method of immunohistochemistry. After the sections were prepared by the abovementioned method, they were incubated with primary anticleaved caspase-3 (1:200; Cell Signaling Technology Inc., Danvers, MA), then treated with the secondary antibody, and finally reacted with diaminobenzidine (Boster Biological Technology Co. Ltd., Wuhan, China). Hematoxylin was used as the counterstain. The Olympus CX31 biological microscope was used to randomly capture 6 images of immunohistochemical staining under 200× magnification. The semiquantitative analysis of the intensity of cleaved caspase-3-positive staining was performed through integrated optical density using the Image-Pro Plus 6.0 software (Media Cybernetics, Silver Spring, MD) according to the method of Xing et al. (17).
Continuous variables were shown as mean ± SD for normally distributed data or as median (25th–75th percentiles) for non-normally distributed data. Normal distribution was confirmed with the Kolmogorov–Smirnov test. Variables were compared with one way analysis of variance or the Kruskal–Wallis test for nonparametric data. If there was a significant difference in the overall comparison of groups, comparisons between any other 2 groups were made by the Bonferroni test. For the comparison of categorical variables such as ROSC, the Fisher's exact test was used. A value of P < 0.05 was considered significant.
Thirty-two studies were performed and completed. Baseline hemodynamics, body temperature, myocardial function, and blood analytical measurements did not differ among the 4 groups (Tables 1 and 2, Figs. 2–6). During CPR, CPP was maintained at an even level in all animals experiencing CA and resuscitation. Consequently, 8 of the 9 animals were successfully resuscitated in the NT, SC, and CRRT groups. No differences were observed in the rate of ROSC, duration of CPR, number of defibrillation, dosage of epinephrine among the 3 groups. In addition, the absolute time of hypoperfusion from CA to ROSC was also statistically insignificant among the 3 groups (Table 3).
After resuscitation, the temperatures were normally maintained in the Control and NT groups. However, the temperatures were progressively decreased to 33°C, followed by stable maintenance and rewarming in the 2 hypothermic groups (Fig. 2). In the animals receiving the CRRT, blood temperature decreased very rapidly with a cooling rate of 9.8°C/h requiring only 28 min to achieve target temperature. However, a significantly slower cooling was observed with a rate of 1.5°C/h requiring 185 min to fall below 33°C in the animals receiving the SC (P < 0.01). For tympanic and rectal temperatures, the cooling rates of 3.9°C and 3.3°C/h were achieved in the CRRT group, which were also significantly faster than those with the rates of 1.6°C and 1.7°C/h in the SC group (both P < 0.01).
After resuscitation, heart rate was rapidly decreased and maintained at a near-baseline level in the 2 hypothermic groups, which was significantly slower than that in the NT group (P < 0.05). The decrease in MAP was also observed but maintained at a normal physiological level of greater than 98 mmHg in all hypothermic animals (Fig. 3).
After resuscitation, decreased pH and increased lactate were observed in the CRRT, SC, and NT groups, in which the differences were significant at 1 and 3 h compared to the Control group (all P < 0.05). Post-resuscitation PO2 was also decreased in the 3 groups, however, PO2 was gradually increased and significantly greater in the 2 hypothermic groups than in the NT group (both P < 0.05). There were no significant differences in arterial PCO2, potassium, sodium, and calcium among the 4 groups (Fig. 4, Table 1).
After resuscitation, the serum levels of TNF-α and IL-6 were significantly increased in all resuscitated animals compared to the Control group (all P < 0.05). However, the increases in TNF-α and IL-6 were significantly slower starting 6 h after resuscitation in the 2 hypothermic groups than in the NT group (all P < 0.05). Additionally, both of them were significantly decreased starting 12 h after resuscitation in the CRRT group than in the SC group (both P < 0.05, Table 2).
After resuscitation, abnormal blood coagulation was observed in the NT, SC, and CRRT groups. Especially in animals treated with CRRT, significantly greater increase in APTT was observed due to the application of heparin. However, both PT and APTT were almost normalized at 24 and 30 h post resuscitation in the 3 groups (Table 2).
After resuscitation, the values of SV and GEF were significantly decreased and the serum levels of cTnI, NSE, and S100B were significantly increased in all resuscitated animals compared to the Control group (all P < 0.05). However, all of them were improved faster in the 2 hypothermic groups than in the NT group, in which the differences were significant starting 12 h after resuscitation (all P < 0.05). Additionally, myocardial and brain damage were further significantly alleviated starting 24 h after resuscitation in the CRRT group when compared with the SC group (all P < 0.05, Figs. 5 and 6).
At 30 h post resuscitation, no significant abnormalities were observed on gross examination at necropsy in all animals. However, the levels of TNF-α, IL-6, and MDA and the activities of SOD in the heart and brain were significantly changed in the NT, SC, and CRRT groups compared to the Control group (all P < 0.05). Similarly, the rates of apoptotic cells and the levels of cleaved caspase-3 expression in the heart and brain were significantly increased in the 3 groups (all P < 0.05). However, all of these changes were significantly milder in the 2 hypothermic groups than in the NT group (all P < 0.05). Additionally, CRRT cooling further significantly decreased tissue inflammation, oxidative stress and cell apoptosis in the heart and brain compared with the SC group (all P < 0.05, Figs. 7 and 8).
The present study systematically investigated the efficacy and safety of CRRT cooling and its protective effects against PCAS in a porcine model. We demonstrated that fast hypothermia was successfully induced by CRRT, and its cooling efficacy was significantly superior to SC. No adverse events were observed in all hypothermic animals. Post-resuscitation myocardial dysfunction, brain injury, and systemic inflammation were significantly alleviated in the 2 hypothermic groups compared to the NT group. Most importantly, the cooling by CRRT produced significantly more potent protection against post-resuscitation multiple organ injuries through the inhibition of tissue inflammation, oxidative stress, and cell apoptosis when compared with the SC group.
In 2005, 1 investigation first demonstrated that the cooling by CRRT was a feasible approach to induce TH in CA victims (18). Recently, 2 clinical cases reported that CRRT cooling alleviated neurological dysfunction after CPR and acute heart failure after cardiovascular surgery (14, 15). Currently, optimizing the strategy of CRRT cooling might provide an effective method for the implementation of TH in the clinical setting. In this study, we initially set a higher rate of blood flow with the circuit submerged in ice water to rapidly extract the heat from the blood. The cooling rates of 9.8°C, 3.9°C, and 3.3°C/h in blood, tympanum, and rectum were achieved in the CRRT group, which were significantly faster than those in the SC group. Subsequently, we applied a lower rate of blood flow with the circuit wrapped by an adjustable heating device, and observed that TH was stably maintained in these sites. To reduce the risk of adverse events, we chose a duration of CRRT cooling of 8 h followed by 16 h of SC based on a previous study (18). Additionally, a systemic heparin-based anticoagulation was applied according to our clinical experience. No adverse events including hemodynamic instability, electrolyte disturbance, and visceral hemorrhage were observed in animals treated with CRRT. Thus, CRRT cooling might become an easily-performed, high-efficiency, and safe method to implement TH.
Recently, there is increasing evidence that the protective effects produced by TH are strongly dependent on the time to target temperature. In a rabbit model of CA, Chenoune et al.(11) demonstrated that fast cooling with 10 min to target temperature exerted potent cardiac and neurologic protection after resuscitation, whereas the protective effects were disappeared when applying conventional cooling requiring 30 min to target temperature. In the clinical setting, Sendelbach et al.(19) found that a 17% greater of poor neurologic outcome in CA survivors was increased with every 30-min delay in the achievement of target temperature. Currently, a clinical meta-analysis concluded that rapid cooling with the attainment of target temperature of 34°C within 3.5 h post resuscitation was beneficial to yield a good neurologic recovery (8). Similarly, the present study demonstrated that fast hypothermia induced by CRRT significantly alleviated the severity of PCAS when compared with SC. The potent organ protection produced by CRRT was further confirmed by pathologic evaluation, which indicated that tissue inflammation, oxidative stress, and cell apoptosis in the heart and brain after resuscitation were significantly milder compared to the SC group.
Currently, it has been suggested that CRRT itself has hemodynamics-stabilizing and anti-inflammatory effects (20), and systemic heparinization during CRRT treatment can inhibit the process of coagulation disorder (21). Therefore, the benefits afforded by CRRT cooling might be a result of synergistic protective effects produced by the combined TH and CRRT. However, the hemodynamics was normally maintained in the 2 hypothermic groups so that the hemodynamics-stabilizing effect of CRRT was not observed in this study. Additionally, previous investigations manifested that CRRT could not alleviate post-resuscitation systemic inflammation in clinical and experimental CA events (18, 22). Another recent clinical investigation demonstrated that systemic anticoagulation via any agent failed to improve the severity of illness and survival to discharge in CA patients (23). Thus, the protective effects produced by CRRT cooling might be mainly attributed to its rapid induction of hypothermia in the present study.
There were several limitations in our study. First, the equipment for CRRT cooling was prepared in advance and its performance was timely initiated once ROSC was achieved. However, all the preparation will be carried out after ROSC in the clinical setting, and a longer duration of at least 15 min is needed to run CRRT in our clinical experience. Second, a higher rate of rewarming of 1°C/h was applied based on our previous study (24). However, the patients should be rewarmed at a rate of 0.25–0.5°C/h according to the current guidelines (25). Third, all animals were continuously monitored under anesthesia throughout the experiment. We failed to evaluate post-resuscitation neurologic function in this study.
In a porcine model of CA, fast hypothermia was successfully induced by CRRT and produced significantly greater protection against PCAS compared with conventional SC.
We thank Moli Wang and Wenlong Tang for their contribution in the animal preparation. Additionally, we appreciate Zafar ullah Khan's help in the proofreading of this manuscript.
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