INTRODUCTION Besides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats. METHODS After return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 μM, 0.13 mg/kg) or placebo as a 5 min infusion beginning at 5 min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured. After 15 min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed. RESULTS In an initial series of experiments, rats (n = 21) were randomized to 4 groups: VF-CPR and nitrite therapy (n = 6), VF-CPR and placebo therapy (n = 5), sham (n = 5), or sham plus nitrite therapy (n = 5). Whole blood nitrite levels increased during drug infusion to 57.14 ± 10.82 μM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ± 0.58 μM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups. CONCLUSIONS Nitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.

中文翻译：

---

实验性心室纤颤心脏骤停后亚硝酸盐的药代动力学，安全性和有效性。

引言除了治疗性低温或目标温度管理外，还没有开发出新的疗法来改善心脏骤停（CA）后患者的预后。最近的研究表明，亚硝酸盐减少窒息性CA后的神经系统损害。亚硝酸盐还被认为是由止血带通货紧缩引起的远程后处理的新介体，CA正在积极研究中。但是，关于脑渗透或药代动力学（PK）知之甚少。因此，为了确定该药物的最佳用途，需要研究实验性心室纤颤（VF）中亚硝酸盐的PK。我们测试了以下假设：从VF复苏后施用的亚硝酸盐可在脑脊液（CSF），大脑和其他器官组织中检测到，不会产生不利的血液动力学影响，并改善大鼠的神经功能。方法5分钟未经治疗的VF自发循环（ROSC）恢复后，成年雄性Sprague-Dawley大鼠在CA后5分钟开始接受5min静脉注射亚硝酸盐（8μM，0.13 mg / kg）或安慰剂。另外，还研究了有或没有亚硝酸盐处理的假手术组。连续测量全血亚硝酸盐水平。15分钟后，收集脑脊液，脑，心脏和肝组织。在第二系列中，使用随机和盲法治疗方案，逮捕后用亚硝酸盐或安慰剂治疗大鼠。每天和复苏后八天进行神经功能缺损评分（NDS），评估恐惧条件测试（FCT）和脑组织学。结果在最初的一系列实验中，将大鼠（n = 21）随机分为4组：VF-CPR和亚硝酸盐疗法（n = 6），VF-CPR和安慰剂疗法（n = 5），假手术（n = 5）或假手术加亚硝酸盐疗法（n = 5）。VF亚硝酸盐治疗组在复苏后11分钟（给药完成后1分钟）全血亚硝酸盐水平增加至57.14±10.82μM，而VF安慰剂组为0.94±0.58μM（p <0.001）。在开始心肺复苏后7.5至15分钟之间，治疗组和安慰剂组之间的血液中亚硝酸盐水平存在显着差异，而各组之间在脑脊液，脑，心脏和肝脏中的亚硝酸盐水平方面存在显着差异。在第二个系列中（n = 25，包括5个短毛），每20只动物中有19只存活到第8天。但是，NDS，FCT和脑组织学在两组之间没有统计学上的显着差异。结论亚硝酸盐是在VF的ROSC后早期给予的，被证明在VF心脏骤停5分钟后越过血脑屏障。我们对VF后静脉注射亚硝酸盐的PK进行了表征，并在此可行性研究中证明了亚硝酸盐的安全性。