scholarly journals Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression

2020 ◽  
pp. 0271678X2094861 ◽  
Author(s):  
Qiang Zhao ◽  
Yuntian Shen ◽  
Ran Li ◽  
Jiangbo Wu ◽  
Jingjun Lyu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Hpa Axis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lymphoid Organ ◽  
Whole Body ◽  
Critical Systems ◽  
Glucocorticoid Treatment ◽  
Hypothalamic Pituitary Adrenal ◽  
Severe Immunosuppression

In patients who are successfully resuscitated after initial cardiac arrest (CA), mortality and morbidity rates are high, due to ischemia/reperfusion injury to the whole body including the nervous and immune systems. How the interactions between these two critical systems contribute to post-CA outcome remains largely unknown. Using a mouse model of CA and cardiopulmonary resuscitation (CA/CPR), we demonstrate that CA/CPR induced neuroinflammation in the brain, in particular, a marked increase in pro-inflammatory cytokines, which subsequently activated the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, this activation was associated with a severe immunosuppression phenotype after CA. The phenotype was characterized by a striking reduction in size of lymphoid organs accompanied by a massive loss of immune cells and reduced immune function of splenic lymphocytes. The mechanistic link between post-CA immunosuppression and the HPA axis was substantiated, as we discovered that glucocorticoid treatment, which mimics effects of the activated HPA axis, exacerbated post-CA immunosuppression, while RU486 treatment, which suppresses its effects, significantly mitigated lymphopenia and lymphoid organ atrophy and improved CA outcome. Taken together, targeting the HPA axis could be a viable immunomodulatory therapeutic to preserve immune homeostasis after CA/CPR and thus improve prognosis of post-resuscitation CA patients.

scholarly journals Pharmacological Approach for Neuroprotection After Cardiac Arrest—A Narrative Review of Current Therapies and Future Neuroprotective Cocktail

2021 ◽  
Vol 8 ◽  
Author(s):  
Rishabh C. Choudhary ◽  
Muhammad Shoaib ◽  
Samantha Sohnen ◽  
Daniel M. Rolston ◽  
Daniel Jafari ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Brain Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Global Scale ◽  
Narrative Review ◽  
Therapeutic Interventions ◽  
Endoplasmic Reticulum Stress Response ◽  
Whole Body ◽  
Extracorporeal Cardiopulmonary Resuscitation

Cardiac arrest (CA) results in global ischemia-reperfusion injury damaging tissues in the whole body. The landscape of therapeutic interventions in resuscitation medicine has evolved from focusing solely on achieving return of circulation to now exploring options to mitigate brain injury and preserve brain function after CA. CA pathology includes mitochondrial damage and endoplasmic reticulum stress response, increased generation of reactive oxygen species, neuroinflammation, and neuronal excitotoxic death. Current non-pharmacologic therapies, such as therapeutic hypothermia and extracorporeal cardiopulmonary resuscitation, have shown benefits in protecting against ischemic brain injury and improving neurological outcomes post-CA, yet their application is difficult to institute ubiquitously. The current preclinical pharmacopeia to address CA and the resulting brain injury utilizes drugs that often target singular pathways and have been difficult to translate from the bench to the clinic. Furthermore, the limited combination therapies that have been attempted have shown mixed effects in conferring neuroprotection and improving survival post-CA. The global scale of CA damage and its resultant brain injury necessitates the future of CA interventions to simultaneously target multiple pathways and alleviate the hemodynamic, mitochondrial, metabolic, oxidative, and inflammatory processes in the brain. This narrative review seeks to highlight the current field of post-CA neuroprotective pharmaceutical therapies, both singular and combination, and discuss the use of an extensive multi-drug cocktail therapy as a novel approach to treat CA-mediated dysregulation of multiple pathways, enhancing survival, and neuroprotection.

Abstract 14456: Rethinking The Treatment Of Cardiac Arrest To Include Non-oxygen Metabolite Supplementation: Plasma Lysophosphatidylcholine Level Maintenance After Cardiac Arrest Is Critical For Survival

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Muhammad Shoaib ◽  
Mitsuaki Nishikimi ◽  
Rishabh Choudhary ◽  
Tai Yin ◽  
Kei Hayashida ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Membrane Integrity ◽  
Whole Body ◽  
Strongly Correlated ◽  
Oxygen Metabolites ◽  
Subsequent Resuscitation

Cardiac arrest (CA) is a loss of circulation that curtails the supply of oxygen and non-oxygen metabolites to the whole body resulting in ischemia and death. Subsequent resuscitation is vital for survival, but also causes reperfusion injury. Oxygen deprivation as one arm of ischemia-reperfusion injury and its relationship with death is well-established, but its counterpart, metabolite dysfunction, is overlooked and poorly understood. We have previously shown that many metabolites are not normalized as efficiently or rapidly after resuscitation especially, particularly those that are severely decreased after CA. As such, we hypothesize that appropriate replenishment of certain metabolites is essential for survival. Lysophosphatidylcholine (LPC), an important family of phospholipids, is an example of such non-oxygen metabolites required post-CA. With multifactorial roles for maintaining homeostasis, such as acting as an energy substrate, maintaining membrane integrity, and functioning in inter- and intra-cellular signaling, decreased levels of LPC post-CA disrupts the various physiologic responsibilities resulting in profound systemic effects causing cellular and organ system injury. In this analysis, 1) phospholipid screening using HPLS-MS on plasma samples obtained from asphyxial-CA rats and human CA patients shows that LPC significantly decreases post-CA, especially during the reperfusion phase, and is strongly correlated with the duration of preceding CA and poor neurological/survival outcomes, and 2) individual supplementation of three species of LPC (LPC 18:0, LPC 18:1, and LPC 22:6) following resuscitation after 10 and 12 min rat CA helps improve survival and brain function as compared with vehicle. Overall, our study highlights that LPC is an essential, non-oxygen metabolite that is necessary to help promote survival after CA in rats that has therapeutic potential for human translation.

scholarly journals Inhaled Gases as Therapies for Post–Cardiac Arrest Syndrome: A Narrative Review of Recent Developments

2021 ◽  
Vol 7 ◽  
Author(s):  
Kei Hayashida ◽  
Santiago J. Miyara ◽  
Koichiro Shinozaki ◽  
Ryosuke Takegawa ◽  
Tai Yin ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiac Arrest ◽  
Reperfusion Injury ◽  
Protein Modification ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Whole Body ◽  
Gas Treatment ◽  
Neurologic Sequelae ◽  
Post Cardiac Arrest Syndrome

Despite recent advances in the management of post–cardiac arrest syndrome (PCAS), the survival rate, without neurologic sequelae after resuscitation, remains very low. Whole-body ischemia, followed by reperfusion after cardiac arrest (CA), contributes to PCAS, for which established pharmaceutical interventions are still lacking. It has been shown that a number of different processes can ultimately lead to neuronal injury and cell death in the pathology of PCAS, including vasoconstriction, protein modification, impaired mitochondrial respiration, cell death signaling, inflammation, and excessive oxidative stress. Recently, the pathophysiological effects of inhaled gases including nitric oxide (NO), molecular hydrogen (H2), and xenon (Xe) have attracted much attention. Herein, we summarize recent literature on the application of NO, H2, and Xe for treating PCAS. Recent basic and clinical research has shown that these gases have cytoprotective effects against PCAS. Nevertheless, there are likely differences in the mechanisms by which these gases modulate reperfusion injury after CA. Further preclinical and clinical studies examining the combinations of standard post-CA care and inhaled gas treatment to prevent ischemia–reperfusion injury are warranted to improve outcomes in patients who are being failed by our current therapies.

Abstract 138: Remote Ischemic Postconditioning Alleviates Postresuscitation Inflammatory Response and Pulmonary Edema in a Porcine Model of Cardiac Arrest

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jiefeng Xu ◽  
Sen Ye ◽  
Zilong Li ◽  
Moli Wang ◽  
Zhengquan Wang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Inflammatory Response ◽  
Pulmonary Edema ◽  
Porcine Model ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Limb Ischemia ◽  
Multiple Organ ◽  
Control Group ◽  
Lung Water

Introduction: Systemic ischemia-reperfusion injury produced by CA and resuscitation can result in severe post-cardiac arrest syndrome; which includes systemic inflammatory response and multiple organ dysfunction syndrome such as acute pulmonary edema. We previously demonstrated that remote ischemic post-conditioning (RIpostC) improved post-resuscitation myocardial and cerebral function in a rat model of CA. In this study, we investigated the effects of RIpostC on inflammatory response and pulmonary edema after CPR in a porcine model. Hypothesis: RIpostC would alleviate post-resuscitation inflammatory response and pulmonary edema in a porcine model of CA. Methods: Fourteen male domestic pigs weighing 37 ± 2 kg were utilized. Ventricular fibrillation was electrically induced and untreated for 10 mins. The animals were then randomized to receive RIpostC or control. Coincident with the start of CPR, RIpostC was induced by four cycles of 5 mins of limb ischemia and then 5 mins of reperfusion. Defibrillation was attempted after 5 mins of CPR. The resuscitated animals were monitored for 4 hrs and observed for an additional 68 hrs. Results: Six of the seven animals in each group were successfully resuscitated. After resuscitation, significantly lower levels of tumor necrosis factor-α and interleukin-6 were measured in the animals that received RIpostC when compared with the control group. Post-resuscitation extra-vascular lung water index was lower in the RIpostC group than in the control group; in which the differences were significant at 2,3 and 4 hrs (Table). Conclusion: In a porcine model of CA, RIpostC significantly alleviates post-resuscitation inflammatory response and pulmonary edema.

Abstract 293: Cardiac Arrest and Resuscitation Causes Immunodeficiency That Involves the Hypothalamic-Pituitary-Adrenal Axis

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Yuntian Shen ◽  
Qiang Zhao ◽  
Jiangbo Wu ◽  
Zhuoran Wang ◽  
Wei Yang
Keyword(s):  
Immune Response ◽  
Cardiac Arrest ◽  
Immune System ◽  
Hpa Axis ◽  
Time Course ◽  
Immune Cell ◽  
Infectious Complications ◽  
Hypothalamic Pituitary Adrenal ◽  
Immune Organs ◽  
High Incidence

Introduction: Cardiac arrest (CA) is associated with high mortality and morbidity, which is in part due to infectious complications developed in CA patients. Infection complications, particularly pneumonia, occur in approximately 60% of CA patients. Given this high incidence, we hypothesized that after CA, the immune system is impaired, which increases the susceptibility of CA patients to potential infections. Therefore, in this study, we systematically examined the immune response in the brain and peripheral immune organs after CA. Methods: Mice were subjected to CA and cardiopulmonary resuscitation (CA/CPR). Flow cytometry, ELISA, immunohistochemistry, and quantitative PCR were used to analyze the immune response in various post-CA organs. Results: First, we characterized the time course of the immune response in the spleen after CA/CPR. CA/CPR induced significant changes in all major immune cell populations. Notably, B cell frequencies decreased, while T cell frequencies increased, in various organs on day 3 post-CA. Further, the levels of pro-inflammatory cytokines, eg IL-6, were markedly increased in the blood and brain after CA. Critically, we found that the lymphocyte counts in the spleen and thymus were dramatically lower in CA mice than in sham mice. Interestingly, CA/CPR caused progressive atrophy of the spleen and thymus. Since it has been shown that CA/CPR alters activity of the hypothalamic-pituitary-adrenal (HPA) axis, we speculated that CA-induced atrophy of lymphoid organs is mediated by the HPA axis. Thus, we treated CA mice with RU486, a glucocorticoid receptor antagonist. Indeed, this treatment reversed CA-induced organ atrophy and mitigated immune cell depletion, both in the thymus and spleen. Conclusions: We provided for the first time evidence that CA/CPR rapidly induced a systemic inflammatory response followed by impairment of the immune system, which eventually led to a massive loss of immune cells in the peripheral immune organs. This CA-induced immunodeficiency appears to be mediated by dysregulation of the HPA axis. Our findings here may be of high clinical significance, considering the high incidence of infectious complications in CA patients and their detrimental effects on CA outcome.

Abstract 595: Functional, Histologic, and Radiographic Characteristics of Global Ischemia-reperfusion Brain Injury in a Mouse Model Of Cardiac Arrest

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Akshay Pendyal ◽  
Cameron Dezfulian ◽  
Luhua Zhang ◽  
Jeeva Munasinghe ◽  
Mark T Gladwin
Keyword(s):  
Cardiac Arrest ◽  
Rectal Temperature ◽  
Diffusion Mri ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Global Ischemia ◽  
Neurological Injury ◽  
Strong Trend ◽  
Enhanced Mri ◽  
Neurological Score

Cardiac arrest (CA) and subsequent CPR constitute a clinically relevant form of global ischemia-reperfusion injury (IR). Global IR often results in widespread ischemic brain damage and severe neurologic sequelae. In the present study, we sought to describe the functional, histologic, and radiographic brain changes that occur following CA/CPR. 8–10 week old C57BL/6 mice were subjected to 12 minutes of normothermic cardioplegic CA and resuscitated with chest compressions, mechanical ventilation, and epinephrine. Sham mice underwent surgery, but not CA. At 3 and 24 hours, 10-point functional neurological score and rectal temperature were assessed prior to trans-cardiac perfusion with PBS and 10% buffered formalin. Sectioned brains were stained using hematoxylin and eosin (H/E) and the terminal deoxyuridine triphosphate nick end-labeling (TUNEL) technique. An additional cohort of mice underwent quantitative diffusion MRI at 24 and 72 hours, gadolinium (Gd)-enhanced MRI at 24 hours, and quantitative T2 imaging at 72 hours. Compared to shams, mice undergoing CA/CPR displayed significantly lower functional neurological score at 3 hours (3±2 vs. 10±0; P<.001) and 24 hours (8±1 vs. 10±0, P<.05), and significantly higher rectal temperature at 3 hours (35.8±1.5 vs. 34.1±0.8, P<.001) and lower rectal temperature at 24 hours (33.8±2.5 vs. 37.1±0.8, P=.08). TUNEL and H/E staining revealed injury in the cortex, thalamus, hippocampus, and cerebellum, but neither a consistent pattern nor clear temporal progression was observed. Gd-enhanced MRI revealed increased signal intensity, particularly in the cortex, after CA (3.7×105±0.96×105 vs. 0.66×105±0.017×105, P<.05), consistent with breakdown of the blood-brain barrier. Diffusion MRI revealed a strong trend towards globally decreasing diffusion coefficients at 24 and 72 hours (P=0.14), consistent with widespread cell death. In our model of CA, global IR results in poor neurological function and global injury by MRI that is not reflected by early histology. MRI thus appears to be a more sensitive measure of visualizing neurological injury in the early stages after CA and may predict the delayed neuronal death remarked upon by other authors.

Abstract P15: Periodic Acceleration (pGz) Preconditioning in Swine Increases Endothelial Derived NO and Phosphorylated eNOS via Akt Pathway

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jose A Adams ◽  
Jaqueline Arias ◽  
Jorge Bassuk ◽  
Heng Wu ◽  
Arkady Uryash ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Myocardial Stunning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Spontaneous Circulation ◽  
Akt Pathway ◽  
Phosphorylated Akt ◽  
Manual Chest Compression ◽  
Periodic Acceleration ◽  
Pulsatile Shear Stress

Periodic acceleration (pGz) is the motion of the supine body using a motorized platform (3Hz & ±0.4G). pGz produces pulsatile shear stress increasing release of endothelial derived NO (eNO) which, also decreases myocardial stunning and improves outcomes from ventricular fibrillation (VF) cardiac arrest. Preconditioning with pGz (PRE-pGz) prior to VF cardiac arrest ameliorates global post resuscitation cardiac dysfunction and reduces arrhythmias. To test whether pGz and PRE-pGz increase eNOS and phosphorylated eNOS (p-eNOS) via the PI3-kinase-Akt pathway, anesthetized, intubated male swine (40 –50lbs) were studied. Five animals had no intervention (BL) and 5 received 1 hr pGz preconditioning (pGz) followed by Western Blot of myocardial tissue. Additional animals (10 per group) received 1 hr pGz (PRE-pGz) or no treatment (CPR-CONT). In the latter groups VF was electrically induced and unsupported for 8 min followed by continuous manual chest compression and defibrillation for 10 min or until return of spontaneous circulation (ROSC). PRE-pGz animals showed less hemodynamically significant arrhythmias after ROSC than CPR-CONT (35 vs 7; p<0.05) and less myocardial stunning. eNOS and phosphorylated-eNOS (p-eNOS) significantly increased after pGz and after CPR but were significantly higher in pGz preconditioned animals along with increased phosphorylated Akt (p-Akt). The graph below shows % changes relative to BL (M±SD). *p < 0.01 PRE-pGz vs CPR-CONT. Conclusion: pGz applied prior to ischemia reperfusion injury increases eNOS and p-eNOS expression and increased p-Akt. Thus, pGz preconditioning protects myocardium during I-R in part by activating eNOS through p-Akt

Abstract 10773: Curcumin Improves the Outcomes of Cardiopulmonary Resuscitation in a Rat Model of Cardiac Arrest

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Zhengfei Yang ◽  
Jiangang Wang ◽  
Lu Yin ◽  
Shen Zhao ◽  
Ziren Tang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Placebo Group ◽  
Rat Model ◽  
Myocardial Function ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Sprague Dawley ◽  
Successful Resuscitation ◽  
Pre Treatment

Introduction: Curcumin has been proven to provide potent protection of vital organs against regional ischemia reperfusion injury. In this study, we investigated the effects of curcumin on the outcomes of CPR in a rat model of cardiac arrest. Hypothesis: Curcumin reduces the severity of post-CPR myocardial dysfunction and prolong the duration of survival. Method: Sixteen male Sprague-Dawley rats weighing between 450-550g were randomized into two groups: 1) Placebo; 2) Curcumin (100 mg/kg) pre-treatment. Ventricular fibrillation (VF) was induced. After 8 mins of VF, CPR was initiated for 8 mins and defibrillation was then attempted. Myocardial function was measured by echocardiography at baseline and hourly for 4 hours following successful resuscitation. The duration of survival was observed for total 72 hours. Result: Six animals in the placebo group and seven in the curcumin group were successfully resuscitated. Post-resuscitation myocardial function was significantly impaired in all animals. However, myocardial function gradually improved 4 hours after resuscitation and was significantly better in the animals pre-treated with curcumin (Figure). Significantly shorter duration of survival of 40±29 hours was observed in the placebo group. Conclusion: In a rat model of cardiac arrest, curcuminim proves post-resuscitation myocardial dysfunction and prolongs the duration of survival.

Effect of 3-aminotriazole on hyperthermia-mediated cardioprotection in rabbits

1996 ◽  
Vol 270 (4) ◽  
pp. H1165-H1171 ◽  
Author(s):  
J. G. Kingma ◽  
D. Simard ◽  
J. R. Rouleau ◽  
R. M. Tanguay ◽  
R. W. Currie
Keyword(s):  
Reperfusion Injury ◽  
Catalase Activity ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Whole Body ◽  
Cellular Protection ◽  
Whole Body Hyperthermia ◽  
Tetrazolium Staining

Hyperthermia-induced cardioprotection during myocardial ischemia may involve increased activity of antioxidative enzymes. In this study we investigated the effects of 3-amino-1,2,4-triazole (3-AT), an irreversible catalase inhibitor, in heat-shocked (HS) rabbits subjected to ischemia-reperfusion injury. Rabbits underwent whole body hyperthermia at 42 degrees C for 15 min. Twenty-four hours later, rabbits were administered either saline vehicle or 3-AT (1 or 2 g/kg i.p.) 30 min before undergoing 30 min of regional coronary occlusion and 3 h reperfusion. Controls did not undergo whole body hyperthermia and were given either saline or 3-AT. Heart rate and left ventricular pressure were recorded continuously during these experiments. Infarct area (tetrazolium staining) was normalized to anatomic risk zone size (microsphere autoradiography). Expression of HSP 71 was verified using Western blot analysis; myocardial catalase activity was determined in tissue biopsies. Infarct size was significantly reduced in HS rabbits (25.1 +/- 2.8%, P = 0.2; means +/- SE) compared with controls (53.6 +/- 4.7%). Treatment with 1 g/kg 3-AT attenuated HS-mediated cardioprotection (36.9 +/- 4.9%, P = 0.063 vs. HS); protection was abolished with 2 g/kg 3-AT (48.9 +/- 6.6%). Myocardial catalase activities were higher in tissue biopsies from HS rabbits (47.0 +/- 4.5 U/mg protein, P < or = 0.02) compared with controls (33.4 +/- 1.9 U/mg protein); catalase activities were significantly reduced in rabbits treated with 3-AT. In conclusion, whole body hyperthermia increases expression levels of HSP 71; myocardial catalase activity is also significantly increased. Myocardial protection is HS rabbits subjected to ischemia-reperfusion injury was reversed with 3-AT. These data suggest that increased intracellular activities of catalase and possibly other antioxidant enzymes is an important mechanism for hyperthermia-mediated cellular protection.

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