Tonna Joseph E, Anderson-Bell Dustin, Peckham Miriam E, Hoareau Guillaume L, Drakos Stavros, DeHavenon Adam, Alexander Matthew D, Johnson Austin M, Steenblik Jacob, Youngquist Scott T
Department of Emergency Medicine, University of Utah Health, Salt Lake City, UT, USA.
Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health, Salt Lake City, UT, USA.
Resusc Plus. 2025 Aug 20;26:101072. doi: 10.1016/j.resplu.2025.101072. eCollection 2025 Nov.
Neuroprotective interventions after cardiac arrest are essential but largely lack evidence of efficacy. Early therapeutic hypothermia (TH) is the only intervention that has shown promise in humans. However, despite a consistent signal for efficacy in animal models, conflicting clinical data hamper clinical acceptance. Two potential causes for the lack of translation from animal studies to humans are the time to achieve target temperature in humans and the inability to cool to deep hypothermic states due to the inherent detrimental cardiac effects accompanying deep hypothermia. Given the observed inconsistent impact of TH on human patients with cardiac arrest despite animal data, we developed a perfusion-controlled, translational swine model to quantify the effects of rapid deep TH on HIBI, quantifying severity using magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) at a controlled time threshold.
Ten swine underwent cardiac arrest with 20 min of "no-flow" state, followed by resuscitation and controlled reperfusion using extracorporeal membrane oxygenation (ECMO). Animals were randomized to either control (normal temperature reperfusion) or rapid hypothermic reperfusion (RHR) (29 °C through ECMO-facilitated cooling). All swine underwent brain MRI with Diffusion Weighted Imaging (DWI) before cardiac arrest and then 2 h after ECMO reperfusion. Whole-brain gray and white matter apparent diffusion coefficient (ADC) values were compared pre- and post-ECMO cannulation and arrest in all animals.
At 45 min post-reperfusion, the mean temperature for RHR animals was 30.4 °C (95 % CI 29.6-31.1 °C), while for control animals it was 35.7 °C (95 % CI 34.9-36.5 °C, p < 0.0001). Whole brain ADC in RHR swine increased by a mean of 1.36 ± 4.09 %, while in control swine it decreased by a mean of 4.36 ± 4.50 % (Median difference of -5.91, 95 %CI -12.13 to -0.15; P value = 0.047).
Swine with induced cardiac arrest who underwent rapid ECMO-mediated cooling post-arrest had less cerebral hypoxic cellular injury, as quantified by changes on MRI DWI, than controls. These findings support the protective effect on neurologic injury of a rapid and brief period of induced deep hypothermia after cardiac arrest. Compared to prior translational models, our use of ECMO has the advantage of an ability to control important factors such as no-flow ischemic time and variability in post-arrest cardiac output as well as to mitigate complications of cardiac dysrhythmias that tend to arise from deep hypothermia. This portends a greater promise for translational success of ECMO-facilitated rapid cooling and potentially other ECMO-mediated models of cardiac arrest than experienced by previous attempts.
心脏骤停后的神经保护干预至关重要，但大多缺乏疗效证据。早期治疗性低温（TH）是唯一在人体中显示出前景的干预措施。然而，尽管在动物模型中疗效信号一致，但相互矛盾的临床数据阻碍了其在临床上的应用。动物研究未能转化至人体的两个潜在原因是人体达到目标温度的时间以及由于深度低温伴随的固有心脏有害影响而无法冷却至深度低温状态。鉴于尽管有动物数据，但观察到TH对心脏骤停人类患者的影响不一致，我们开发了一种灌注控制的转化猪模型，以量化快速深度TH对缺氧缺血性脑损伤（HIBI）的影响，并在受控时间阈值下使用磁共振成像（MRI）和扩散加权成像（DWI）对严重程度进行量化。
十头猪经历20分钟的“无血流”状态心脏骤停，随后使用体外膜肺氧合（ECMO）进行复苏和控制性再灌注。动物被随机分为对照组（常温再灌注）或快速低温再灌注（RHR）组（通过ECMO辅助冷却至29°C）。所有猪在心脏骤停前以及ECMO再灌注后2小时接受脑MRI和扩散加权成像（DWI）检查。比较所有动物在ECMO插管和心脏骤停前后全脑灰质和白质表观扩散系数（ADC）值。
再灌注后45分钟，RHR组动物的平均体温为30.4°C（95%可信区间29.6 - 31.1°C），而对照组动物为35.7°C（95%可信区间34.9 - 36.5°C，p < 0.0001）。RHR组猪的全脑ADC平均增加1.36±4.09%，而对照组猪平均下降4.36±4.50%（中位数差异为 - 5.91，95%可信区间 - 12.13至 - 0.15；P值 = 0.047）。
与对照组相比，经历心脏骤停后通过快速ECMO介导冷却的猪，通过MRI DWI变化量化显示，脑缺氧细胞损伤更少。这些发现支持心脏骤停后快速短暂诱导深度低温对神经损伤的保护作用。与先前的转化模型相比，我们使用ECMO的优势在于能够控制诸如无血流缺血时间和心脏骤停后心输出量变异性等重要因素，以及减轻往往由深度低温引起的心脏心律失常并发症。这预示着与先前尝试相比，ECMO辅助快速冷却以及潜在的其他ECMO介导的心脏骤停模型在转化成功方面更有前景。
