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Diastolic arterial pressures (DAP) during cardiopulmonary resuscitation (CPR). Application of 20 ppm inhaled nitric oxide (iNO) during CPR significantly increased DAP in comparison to untreated controls; † p <0.05 for 20 ppm iNO vs. control; mean ± standard error of the mean. Data based on 10 animals in each group
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Introduction:
Inhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA).
Methods:
Thirty male Sprague-Dawley rats were subjected to 10...
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Aim
This study investigates the potentially adverse association between extracorporeal cardiopulmonary resuscitation (ECPR) after cardiac arrest on weekends versus weekdays.
Methods
Single-centre, retrospective, stratified (weekday versus weekend) analysis of 318 patients who underwent in-hospital ECPR after out-of-hospital and in-hospital cardiac...
Citations
... In comparison, manual chest compressions can only generate approximately 20% of the native cardiac output [27]. The ROSC rate of 75% in this small trial was satisfactory, although below the results of 100% from our previous trials [7,28]. Overall, we conclude that sufficient resuscitation could be achieved using the Impella ECP. ...
The survival rate of cardiac arrest (CA) can be improved by utilizing percutaneous left ventricular assist devices (pLVADs) instead of conventional chest compressions. However, existing pLVADs require complex fluoroscopy-guided placement along a guidewire and suffer from limited blood flow due to their cross-sectional area. The recently developed self-expandable Impella CP (ECP) pLVAD addresses these limitations by enabling guidewire-free placement and increasing the pump cross-sectional area. This study evaluates the feasibility of resuscitation using the Impella ECP in a swine CA model. Eleven anesthetized pigs (73.8 ± 1.7 kg) underwent electrically induced CA, were left untreated for 5 min and then received pLVAD insertion and activation. Vasopressors were administered and defibrillations were attempted. Five hours after the return of spontaneous circulation (ROSC), the pLVAD was removed, and animals were monitored for an additional hour. Hemodynamics were assessed and myocardial function was evaluated using echocardiography. Successful guidewire-free pLVAD placement was achieved in all animals. Resuscitation was successful in 75% of cases, with 3.5 ± 2.0 defibrillations and 1.8 ± 0.4 mg norepinephrine used per ROSC. Hemodynamics remained stable post-device removal, with no adverse effects or aortic valve damage observed. The Impella ECP facilitated rapid guidewire-free pLVAD placement in fibrillating hearts, enabling successful resuscitation. These findings support a broader clinical adoption of pLVADs, particularly the Impella ECP, for CA.
... When it comes to brain injuries, a deficiency in NO could contribute to secondary brain damage, while NO possesses neuroprotective qualities in animal models of ischemia/reperfusion, including stroke. Interestingly, NO inhalation has been suggested as a neuroprotective intervention during cardiopulmonary resuscitation [102]. Consequently, extensive research is needed to better understand its mechanisms and potential therapeutic effects. ...
The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species (RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain's vascular tone's vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or those presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, potentially impacting cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. RNS, particularly NO and perox-ynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone under conditions of high oxidative stress. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, and explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.
... Indeed, some animal studies of NO and H 2 S supplementation have shown benefit. 27,28 Nevertheless, restoring optimal NO and H 2 S balance is challenging because of lack of available drug and delivery systems, as well as unknown impacts on the gut microbiome. ...
Background
Every year the American Heart Association's Resuscitation Science Symposium (ReSS) brings together a community of international resuscitation science researchers focused on advancing cardiac arrest care.
Methods and Results
The American Heart Association's ReSS was held in Chicago, Illinois from November 4th to 6th, 2022. This annual narrative review summarizes ReSS programming, including awards, special sessions and scientific content organized by theme and plenary session.
Conclusions
By exploring both the science of resuscitation and important related topics including survivorship, disparities, and community‐focused programs, this meeting provided important resuscitation updates.
... Such a neuroprotective effect was also demonstrated in both hyperoxic and hypoxic models of brain damage [37][38][39]. iNO reduces the inflammatory response and TNF signaling at low doses [40,41]. The main biological effect of NO-an increase in cGMP concentration-can also be achieved by sildenafil, a highly potent selective inhibitor of phosphodiesterase type-5 (PDE5i). ...
Inhaled nitric oxide (iNO) is a therapy used in neonates with pulmonary hypertension. Some evidence of its neuroprotective properties has been reported in both mature and immature brains subjected to injury. NO is a key mediator of the VEGF pathway, and angiogenesis may be involved in the reduced vulnerability to injury of white matter and the cortex conferred by iNO. Here, we report the effect of iNO on angiogenesis in the developing brain and its potential effectors. We found that iNO promotes angiogenesis in the developing white matter and cortex during a critical window in P14 rat pups. This shift in the developmental program of brain angiogenesis was not related to a regulation of NO synthases by exogenous NO exposure, nor the VEGF pathway or other angiogenic factors. The effects of iNO on brain angiogenesis were found to be mimicked by circulating nitrate/nitrite, suggesting that these carriers may play a role in transporting NO to the brain. Finally, our data show that the soluble guanylate cyclase/cGMP signaling pathway is likely to be involved in the pro-angiogenetic effect of iNO through thrombospondin-1, a glycoprotein of the extracellular matrix, inhibiting soluble guanylate cyclase through CD42 and CD36. In conclusion, this study provides new insights into the biological basis of the effect of iNO in the developing brain.
... Several preclinical studies showed that NO inhalation following resuscitation improved survival rate and neurological outcome while reducing brain edema, neuronal apoptosis and cerebral inflammatory cytokines levels [136,137]. Furthermore, iNO increased the proportion of ROSC [138,139], allowing for superior hemodynamics and higher cerebral blood flow [140] when administered during cardiopulmonary resuscitation (CPR) in a pediatric pig model of shock associated-CA [139,140]. Of particular interest for translation from experimental to clinical setting, NO inhalation during CPR has been observed also in a high proportion (~80%) of pediatric in-hospital CA subjects with PH [141]. ...
Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss innovative proposed strategies to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO.
... While iNO has been used to improve oxygenation and hemodynamic parameters in the setting of pulmonary hypertension, right ventricular failure, acute respiratory distress syndrome, peri-or post-operatively following heart or lung transplantation, coronary artery bypass graft surgery, and left ventricular assist device placement [6,16,17], its use in adults with CA has not been explored until now. Multiple animal models have demonstrated clinical benefit of iNO following cardiac arrest [10,11,[18][19][20]. Brucken and colleagues reported that iNO at 20 ppm administered at the time of CPR up until 30 min post ROSC was associated with increased diastolic arterial pressure and reduced time to ROSC in the rat model, alongside with a less pronounced rise in lactate and inflammatory cytokines, improved neurologic outcomes, and attenuated cardiac damage [20]. ...
... Multiple animal models have demonstrated clinical benefit of iNO following cardiac arrest [10,11,[18][19][20]. Brucken and colleagues reported that iNO at 20 ppm administered at the time of CPR up until 30 min post ROSC was associated with increased diastolic arterial pressure and reduced time to ROSC in the rat model, alongside with a less pronounced rise in lactate and inflammatory cytokines, improved neurologic outcomes, and attenuated cardiac damage [20]. Furthermore, use of iNO at 20 ppm with mild therapeutic hypothermia in rats was associated with significant decrease in lactate levels and tumor necrosis factor-alpha release than compared with therapeutic hypothermia alone [18]. ...
... While higher rates of survival to discharge were noted in our study with iNO administration, no significant difference in favorable neurologic outcomes was noted. Animal studies demonstrating attenuation of neurologic dysfunction with iNO administration primarily utilized neurological deficit score (NDS) [18,20], neurologic function score [11], overall performance categories (OPC) [19], a visual spatial memory task [19], neurohistopathological evaluation [18,20], and assessment of focal lesions and cerebral blood flow measurement on magnetic resonance imaging (MRI) [10]. All scores have been validated in prior studies, including the GOS score used in our study. ...
Background:
While inhaled nitric oxide (iNO) has revealed benefit in cardiac arrest in an animal model, no published data has yet demonstrated the impact of iNO in humans with cardiac arrest.
Methods:
In this pilot study, we administered iNO, along with standard post-resuscitative care, in adults with in-hospital cardiac arrest (IHCA) following achievement of return of spontaneous circulation (ROSC) at an academic tertiary medical center. Patients receiving iNO were compared to age-matched controls with IHCA receiving standard care from an institutional registry. The primary outcome was survival to discharge; secondary outcome was favorable neurologic outcome, defined by a Glasgow Outcome Score of 4 or 5. Propensity-score (PS) matching analysis was performed between patients receiving iNO versus controls.
Results:
Twenty adults with IHCA receiving iNO were compared to 199 controls with IHCA. Similar age, Charlson comorbidity score, and initial rhythm were noted in both groups. Patients receiving iNO had higher rates of survival to discharge compared to controls (35% vs 11%, p<0.0001) but no difference in favorable neurologic outcome (15% vs 9%, p=0.39) in the unmatched population. In the PS-matched analysis, patients receiving iNO had higher survival to discharge (35% vs 20%, p=0.0344) than the control group but no difference in favorable neurologic outcome (15% vs 20%, p=0.13) were noted between both groups.
Conclusions:
In this pilot study, iNO was associated with significantly higher rates of survival to discharge but not favorable neurologic outcome among patients with IHCA compared to controls, this benefit was also observed in the PS-matched analysis. A large scale randomized controlled trial comparing standard of care supplemented with iNO to standard of care alone is warranted in patients with cardiac arrest. (Funded by Stony Brook University, ClinicalTrials.gov number, NCT04134078).
... In adult male mice, iNO after CA reduce water diffusion abnormality, caspase-3 activation, cytokine induction in the brain, and increase serum nitrate/nitrite levels, show the protective effects on the outcome (65). Following 10 minutes CA in rats, 40 ppm iNO improve seven-day neurological outcomes and survival, and 20 ppm iNO with mild therapeutic hypothermia had similar results (66,67). iNO during CPR and with a percutaneous LVAD can improve transpulmonary blood flow, and clinical neurological outcomes in pigs (68). ...
Pulmonary hypertension (PH) is a severe disease that affects people of all ages. It can occur as an idiopathic disorder at birth or as part of a variety of cardiovascular and pulmonary disorders. Inhaled pulmonary vasodilators (IPV) can reduce pulmonary vascular resistance (PVR) and improve RV function with minimal systemic effects. IPV includes inhaled nitric oxide (iNO), inhaled aerosolized prostacyclin, or analogs, including epoprostenol, iloprost, treprostinil, and other vasodilators. In addition to pulmonary vasodilating effects, IPV can also be used to improve oxygenation, reduce inflammation, and protect cell. Off-label use of IPV is common in daily clinical practice. However, evidence supporting the inhalational administration of these medications is limited, inconclusive, and controversial regarding their safety and efficacy. We conducted a search for relevant papers published up to May 2020 in four databases: PubMed, Google Scholar, EMBASE and Web of Science. This review demonstrates that the clinical using and updated evidence of IPV. iNO is widely used in neonates, pediatrics, and adults with different cardiopulmonary diseases. The limitations of iNO include high cost, flat dose-response, risk of significant rebound PH after withdrawal, and the requirement of complex technology for monitoring. The literature suggests that inhaled aerosolized epoprostenol, iloprost, treprostinil and others such as milrinone and levosimendan may be similar to iNO. More research of IPV is needed to determine acceptable inclusion criteria, long-term outcomes, and management strategies including time, dose, and duration.
... Potential mechanisms responsible for the beneficial effects of NO on the outcomes of PACS are shown in Figure 1. It has been reported that the administration of NO through inhalation (13,58,68,69) or with an NO-donating compound (70) improves outcomes after CA in multiple species. Additionally, in mice lacking the NO synthase 3 gene, the protective effect of TH after CA/CPR is abolished (71), suggesting that NO may play an important role in TH. ...
... These observations suggest that the protective effects of inhaled NO on outcomes after ROSC are largely mediated by GC-1α-dependent mechanisms. Another research group showed that NO inhalation starting at initiation of CPR until 30 min after ROSC prevented myocardial injury and improved neurologic function and survival in rats (68). It was also shown that NO breathing, starting with the left ventricular assist devicesupported CPR for 5 h, increased the transpulmonary blood flow by reducing the pulmonary artery pressure and improving neurological outcomes in pigs (69). ...
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 (H 2), and xenon (Xe) have attracted much attention. Herein, we summarize recent literature on the application of NO, H 2 , 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.
... Most current animal models use short durations of CA [8][9][10][11][12] , which may be unable to produce a considerable ischemic or reperfusion injury to accurately represent the majority of human CA patients. Short duration CA animals are able to recover and survive for several days without much treatment 13,14 . However, most human patients suffer longer durations of CA and as a result, succumb to the severe injuries within a few days, thus requiring a long duration CA rat model. ...
Cardiac arrest (CA) is a leading cause of death and there is a necessity for animal models that accurately represent human injury severity. We evaluated a rat model of severe CA injury by comparing plasma metabolic alterations to human patients. Plasma was obtained from adult human control and CA patients post-resuscitation, and from male Sprague–Dawley rats at baseline and after 20 min CA followed by 30 min cardiopulmonary bypass resuscitation. An untargeted metabolomics evaluation using UPLC-QTOF-MS/MS was performed for plasma metabolome comparison. Here we show the metabolic commonality between humans and our severe injury rat model, highlighting significant metabolic dysfunction as seen by similar alterations in (1) TCA cycle metabolites, (2) tryptophan and kynurenic acid metabolites, and (3) acylcarnitine, fatty acid, and phospholipid metabolites. With substantial interspecies metabolic similarity in post-resuscitation plasma, our long duration CA rat model metabolically replicates human disease and is a suitable model for translational CA research.
... Most current animal models use short durations of CA [8][9][10][11][12] , which may be unable to produce a considerable ischemic or reperfusion injury to accurately represent the majority of human CA patients. Short duration CA animals are able to recover and survive for several days without much treatment 13,14 . However, most human patients suffer longer durations of CA and as a result, succumb to the severe injuries within a few days, thus requiring a long duration CA rat model. ...
Cardiac arrest (CA) is a leading cause of death and there is a necessity for animal models that accurately represent human injury severity. We evaluated a rat model of severe CA injury by comparing plasma metabolic alterations to human patients. Plasma was obtained from adult human control and CA patients post-resuscitation, and from male Sprague-Dawley rats at baseline and after 20 min CA followed by 30 min cardiopulmonary bypass resuscitation. An untargeted metabolomics evaluation using UPLC-QTOF-MS/MS was performed for plasma metabolome comparison. Here we show the metabolic commonality between humans and our severe injury rat model, highlighting significant metabolic dysfunction as seen by similar alterations in (1) TCA cycle metabolites, (2) tryptophan and kynurenic acid metabolites, and (3) acylcarnitine, fatty acid, and phospholipid metabolites. With substantial interspecies metabolic similarity in post-resuscitation plasma, our long duration CA rat model metabolically replicates human disease and is a suitable model for translational CA research.
