A retrospective study on the trends in surgical aortic valve replacement outcomes in the post-transcatheter aortic valve replacement era.

Background and Aims: Transcatheter aortic valve replacement (TAVR) is the mainstay of treatment of inoperable and severe high-risk aortic stenosis and is noninferior to surgical aortic valve replacement (SAVR) for low-risk and intermediate-risk patients as well. We aim to compare the valve size, area, and transaortic mean gradients in SAVR patients before and after the implementation of TAVR since being approved by the Food and Drug Administration  in 2011. Methods: Patients who underwent a bioprosthetic SAVR placement were divided into two groups based on the date of procedure: the early pre-TAVR implementation group (years 2011-2012) and the contemporary post-TAVR group (years 2019-2020). The primary endpoint was the mean gradient across the aortic valve within 16 months of surgery. The secondary endpoints included the difference in valve size and various aortic valve echocardiographic variables. Results: One hundred and thirty patients had their valves replaced in the years 2011-2012 and 134 in the years 2019-2020. The early group had a significantly higher mean gradient (median of 13 mmHg [interquartile range, IQR: 9.3-18] vs. 10 mmHg [IQR: 7.5-13.1], p = 0.001) and a smaller median effective orifice area index (0.8 cm2/m2 [IQR: 0.6-1] vs. 1.1 cm2/m2 [IQR: 0.8-1.3], p < 0.001). The median valve size was significantly smaller in the early group (median of 21 mm [IQR: 21-23] vs. 23 mm [IQR: 22.5-25], p < 0.001). Conclusion: In the contemporary era, surgical patients receive larger valves which translates into lower mean gradients, larger valve area, and lower rates of patient-prosthesis mismatch than in previous years before the routine introduction of TAVR.

Patients treated with venoarterial extracorporeal membrane oxygenation have different baseline risk and outcomes dependent on indication and route of cannulation.

OBJECTIVES: To investigate the baseline risk of patients treated with Extracorporeal Cardiopulmonary Membrane Oxygenation (ECMO) in relation to cannulation strategy and indication for ECMO as well as the relation of cannulation strategy with survival and secondary hospitalization outcomes. METHODS: Severity of illness and predicted mortality risk were assessed in 317 patients. Central cannulation was used in 52 patients unable to wean off cardiopulmonary bypass after cardiac surgery. Peripheral cannulation was used in 179 patients for extracorporeal cardiopulmonary resuscitation (eCPR) and in 86 patients who received ECMO for refractory cardiogenic shock (RCS). RESULTS: Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were significantly worse (P < 0.01) for peripheral ECMO eCPR (23.2) vs central ECMO (14.6) and vs peripheral ECMO for RCS (18.9). Survival After Venoarterial ECMO (SAVE) scores were significantly worse for peripheral ECMO for eCPR (-7.85) and RCS (-10.38) vs central ECMO (-3.97), and P < 0.01. Peripherally cannulated patients had significantly worse renal function. No significant difference existed for survival to discharge (peripheral ECMO for eCPR, 31%; central ECMO, 44%; peripheral ECMO for refractory cardiac shock, 39.5%; and P = 0.176), although centrally cannulated patients had significantly longer treatment durations compared with peripheral ECMO for eCPR. CONCLUSIONS: Peripherally cannulated patients with eCPR had significantly worse APACHE II and SAVE scores compared to peripherally cannulated RCS or patients with central ECMO, despite having similar mortality.

Generation of human endothelium in pig embryos deficient in ETV2.

The scarcity of donor organs may be addressed in the future by using pigs to grow humanized organs with lower potential for immunological rejection after transplantation in humans. Previous studies have demonstrated that interspecies complementation of rodent blastocysts lacking a developmental regulatory gene can generate xenogeneic pancreas and kidney1,2. However, such organs contain host endothelium, a source of immune rejection. We used gene editing and somatic cell nuclear transfer to engineer porcine embryos deficient in ETV2, a master regulator of hematoendothelial lineages3-7. ETV2-null pig embryos lacked hematoendothelial lineages and were embryonic lethal. Blastocyst complementation with wild-type porcine blastomeres generated viable chimeric embryos whose hematoendothelial cells were entirely donor-derived. ETV2-null blastocysts were injected with human induced pluripotent stem cells (hiPSCs) or hiPSCs overexpressing the antiapoptotic factor BCL2, transferred to synchronized gilts and analyzed between embryonic day 17 and embryonic day 18. In these embryos, all endothelial cells were of human origin.

Etv2 transcriptionally regulates Yes1 and promotes cell proliferation during embryogenesis.

Etv2, an Ets-transcription factor, governs the specification of the earliest hemato-endothelial progenitors during embryogenesis. While the transcriptional networks during hemato-endothelial development have been well described, the mechanistic details are incompletely defined. In the present study, we described a new role for Etv2 as a regulator of cellular proliferation via Yes1 in mesodermal lineages. Analysis of an Etv2-ChIPseq dataset revealed significant enrichment of Etv2 peaks in the upstream regions of cell cycle regulatory genes relative to non-cell cycle genes. Our bulk-RNAseq analysis using the doxycycline-inducible Etv2 ES/EB system showed increased levels of cell cycle genes including E2f4 and Ccne1 as early as 6 h following Etv2 induction. Further, EdU-incorporation studies demonstrated that the induction of Etv2 resulted in a ~2.5-fold increase in cellular proliferation, supporting a proliferative role for Etv2 during differentiation. Next, we identified Yes1 as the top-ranked candidate that was expressed in Etv2-EYFP+ cells at E7.75 and E8.25 using single cell RNA-seq analysis. Doxycycline-mediated induction of Etv2 led to an increase in Yes1 transcripts in a dose-dependent fashion. In contrast, the level of Yes1 was reduced in Etv2 null embryoid bodies. Using bioinformatics algorithms, biochemical, and molecular biology techniques, we show that Etv2 binds to the promoter region of Yes1 and functions as a direct upstream transcriptional regulator of Yes1 during embryogenesis. These studies enhance our understanding of the mechanisms whereby Etv2 governs mesodermal fate decisions early during embryogenesis.

Surviving refractory out-of-hospital ventricular fibrillation cardiac arrest: Critical care and extracorporeal membrane oxygenation management.

BACKGROUND: Resuscitation of refractory out-of-hospital ventricular fibrillation/ventricular tachycardia (VF/VT) cardiac arrest using extracorporeal membrane oxygenation (ECMO) establishes a complex patient population. We aimed to describe the critical care strategies and outcomes in this population. METHODS: Between December 1, 2015 and January 1, 2018, 100 consecutive adult patients with refractory VF/VT out-of-hospital cardiac arrest and ongoing CPR were transported to the cardiac catheterization laboratory. ECMO, coronary angiography, and percutaneous coronary intervention were performed. Patients achieving an organized cardiac rhythm were admitted to the cardiac intensive care unit (CICU). All patients were considered eligible for necessary intervention/surgery until declaration of death. RESULTS: Of 100 appropriately transported patients, 83 achieved CICU admission. 40/83 (48%) discharged functionally intact. Multi-system organ failure occurred in all patients. Cardiac, pulmonary, renal, and liver injury improved within 3-4 days. Neurologic injury caused death in 26/37 (70%) patients. Poor neurologic outcomes were associated with anoxic injury or cerebral edema on admission head CT, decline in cerebral oximetry over the first 48 h, and elevated neuron specific enolase on CICU admission. For survivors, mean time to ECMO decannulation was 3.5 ± 0.2 days, following commands at 5.7 ± 0.8 days, and hospital discharge at 21 ± 3.2 days. 41/83 (49%) patients developed infections. CPR caused traumatic injury requiring procedural/surgical intervention in 22/83 (27%) patients. CONCLUSIONS: Multi-system organ failure is ubiquitous but treatable with adequate hemodynamic support. Neurologic recovery was prolonged requiring delayed prognostication. Immediate 24/7 availability of surgical and medical specialty expertise was required to achieve 48% functionally intact survival.

Outcomes of intermediate-risk patients treated with transcatheter and surgical aortic valve replacement in the Veterans Affairs Healthcare System: A single center 20-year experience.

BACKGROUND: Transfemoral transcatheter aortic valve replacement (TAVR) was superior to surgical aortic valve replacement (SAVR) in the placement of aortic transcatheter valves (PARTNER) 2A trial (P2). The generalizability of the trial results to the broader population of patients with intermediate surgical risk remains unknown. OBJECTIVE: To compare the outcomes of SAVR and TAVR among patients with intermediate surgical risk treated in the VA Healthcare System. METHODS: We retrospectively analyzed the clinical characteristics and outcomes on all SAVR (1987-2014) and TAVR procedures (2015-2017) performed at the Minneapolis VA Healthcare System. Patients were divided into three groups based on their estimated 30-day mortality risk. The primary outcome was a composite of death or stroke at 30-days. RESULTS: A total of 1,049 patients underwent SAVR with (n = 468, 45%) or without CABG (n = 581, 55%) and 110 underwent TAVR during the study period. Intermediate-risk patients represented 29.4% and 40% of patients undergoing SAVR and TAVR, respectively. The predicted 30-day mortality risk of intermediate-risk patients was 5.5% for the SAVR group and 5.2% for the TAVR group (P = 0.54). The observed combined rate of stroke or death at 30-days for intermediate-risk patients treated with SAVR and TAVR was 11% and 2.2%, respectively (P = 0.05). The results for SAVR and TAVR at the VA were comparable to the P2 trial and STS database (all P = NS). The results did not change when the analysis was restricted to a more contemporary (2005-2014) surgical cohort or isolated SAVR. The number needed to treat to prevent one death/stroke with TAVR was 10. CONCLUSIONS: Adoption of TAVR as the preferred treatment modality in intermediate-risk patients may result in significant improvements in morbidity and mortality.

Improving cannulation time for extracorporeal life support in refractory cardiac arrest of presumed cardiac cause - Comparison of two percutaneous cannulation techniques in the catheterization laboratory in a center without on-site cardiovascular surgery.

BACKGROUND: Cardiac arrest (CA) without return of spontaneous circulation can be treated with veno-arterial extracorporeal membrane oxygenation (vaECMO) implemented surgically or percutaneously. We performed a study assessing time for vaECMO percutaneous cannulation in the catheterization laboratory. METHODS: Single-centre retrospective study in a University hospital without on-site cardiovascular surgery, including patients aged >18 receiving vaECMO for out- or in-hospital refractory CA of presumed cardiac cause between 2010 and 2016, cannulated by interventional cardiologists. Cannulation time using anatomic landmarks vessel puncture and conventional wires (first period) was compared with ultrasound guidance puncture and stiff wires (second period). Data are expressed as medians (interquartile range) and percentages. RESULTS: Forty-six patients were included, age 56 (49-62), 34 in the first period. Shockable initial rhythm occurred in 29 (63%), 36 (78%) had ischemic heart disease and 26 (57%) acute myocardial infarction (AMI). Out-of-hospital refractory CA occurred in 27 (59%) patients. Time from out-of-hospital refractory CA to admission was 100 (80-118) min. Cannulation was successful in 42 (91%) patients. Cannulation time was 14 (10-21) min, 17 (12-26) (first) and 8 (6-12) min (second period), p<0.001. Survival to discharge was 9%. In out-of-hospital versus in-hospital, time from CA to vaECMO was 120 (115-140) versus 82 (58-102) min, p=0.011, survival was 7% (two patients) versus 11% (two patients), p=0.35 respectively. All survivors had shockable initial rhythm. CONCLUSION: In these refractory CA patients with high prevalence of AMI and good feasibility of percutaneous vaECMO in the catheterization laboratory, cannulation time was shorter using ultrasound guidance and stiff wires.

PEO-PPO Diblock Copolymers Protect Myoblasts from Hypo-Osmotic Stress In Vitro Dependent on Copolymer Size, Composition, and Architecture.

Poloxamer 188, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), protects cellular membranes from various stresses. Though numerous block copolymer variants exist, evaluation of alternative architecture, composition, and size has been minimal. Herein, cultured murine myoblasts are exposed to the stresses of hypotonic shock and isotonic recovery, and membrane integrity was evaluated by quantifying release of lactate dehydrogenase. Comparative evaluation of a systematic set of PEO-PPO diblock and PEO-PPO-PEO triblock copolymers demonstrates that the diblock architecture can be protective in vitro. Short PPO blocks hinder protection with >9 PPO units needed for protection at 150 µM and >16 units needed at 14 µM. Addition of a tert-butyl end group enhances protection at reduced concentration. When the end group and PPO length are fixed, increasing the PEO length improves protection. This systematic evaluation establishes a new in vitro screening tool for evaluating membrane-sealing amphiphiles and provides mechanistic insight to guide future copolymer design for membrane stabilization in vivo.

Coronary artery spatial distribution of chronic total occlusions: Insights from a large US registry.

OBJECTIVE: To assess the spatial distribution of chronic total occlusions (CTOs) within the coronary arteries and describe procedural strategies and outcomes during CTO percutaneous coronary intervention (PCI). BACKGROUND: Acute occlusions due to plaque rupture tend to cluster within the proximal third of the coronary artery. METHODS: We examined the clinical and procedural characteristics of 1,348 patients according to lesion location within the coronary tree. RESULTS: A total of 1,369 lesions in 1,348 patients (mean age 66 ± 10 years, 85% male) were included. CTO PCI of proximal segments (n = 633, 46%) was more common than of mid (n = 557, 41%) and distal segments (n = 179, 13%). Patients undergoing CTO PCI of proximal segments were more likely to be smokers (P < 0.01), have prior coronary artery bypass graft surgery (P = 0.03) and lower ejection fraction (P = 0.04). CTOs occurring in proximal segments had longer length (P <0.01), proximal cap ambiguity (P < 0.01), and moderate/severe calcification (P < 0.01) compared to mid or distally located CTOs. Interventional collaterals were more often present in CTO PCI of proximal segments (64%, 53%, 56%, P < 0.01) consistent with the higher use of retrograde approach (47%, 33%, 37%, P < 0.01) relative to antegrade wire escalation (67%, 82%, 82%, P < 0.01). Procedural complexity was higher in CTO PCI of proximal segments (vs. mid and distal): contrast volume= 275 ml (200-375), 260 ml (200-350), 250 ml (175-350), P = 0.01; fluoroscopy time 53 minutes (32-83), 39 minutes (24-65), 40 minutes (22-72), P < 0.01. However, procedural success (87%, 90%, 85%, P = 0.1), technical success (89%, 91%, 88%, P = 0.24), and complications rates (2.8%, 2.5%, 2.2%, P = 0.88) were not different. CONCLUSIONS: The most common target vessel location for CTO PCI is the proximal coronary segment. PCI of proximal occlusions is associated with adverse clinical and angiographic characteristics and often requires use of the retrograde approach, but can be accomplished with high procedural and technical success and low complication rates. © 2016 Wiley Periodicals, Inc.

Early Access to the Cardiac Catheterization Laboratory for Patients Resuscitated From Cardiac Arrest Due to a Shockable Rhythm: The Minnesota Resuscitation Consortium Twin Cities Unified Protocol.

BACKGROUND: In 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis-St. Paul. METHODS AND RESULTS: Eleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07-3.72], P=0.03). CONCLUSIONS: Early access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome.

Complete versus incomplete coronary revascularization of patients with multivessel coronary artery disease.

OPINION STATEMENT: The treatment of patients with multivessel coronary artery disease in need of a revascularization procedure is influenced by the clinical situation (stable vs. unstable), comorbid conditions (diabetes mellitus), and anatomical variables (proximal left anterior artery stenosis, left ventricular dysfunction). Given the invasive nature of coronary artery bypass graft (CABG) operations, surgeons have embraced the concept of complete anatomical revascularization in one procedural stage since the inception of CABG surgery. However, achieving complete coronary revascularization has been more challenging with percutaneous coronary intervention (PCI), and as a result, incomplete procedures are far more common than complete ones. Data continue to emerge on the potential benefits of complete revascularization on clinical outcomes and suggest that complete revascularization should be the goal of therapy whenever possible. The heart team should carefully review the degree to which each revascularization modality can achieve this goal during procedural planning.

Post-conditioning to improve cardiopulmonary resuscitation.

PURPOSE OF REVIEW: Despite decades of advances in prehospital and in-hospital medical care, patients with out-of-hospital cardiac arrest continue to have poor neurologic and cardiac function following otherwise successful resuscitation. This review examines the mechanisms and therapeutic strategies currently under development to activate the post-conditioning pathways and thereby improve survival and function. RECENT FINDINGS: Post-conditioning utilizes the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways as common avenues to promote cell survival and function. Ischemic post-conditioning and multiple medications activate these pathways resulting in improved cardiac and neurological function in animal models of cardiac arrest. SUMMARY: Detailed knowledge of the RISK and SAFE pathways can be used for further drug development. Human studies are now underway to test some of these strategies, but further clinical trials are necessary to translate these therapies to clinical practice.

Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies.

OBJECTIVES: This study sought to perform a systematic review and meta-analysis of studies comparing complete revascularization (CR) versus incomplete revascularization (IR) in patients with multivessel coronary artery disease. BACKGROUND: There are conflicting data regarding the benefits of CR in patients with multivessel coronary artery disease. METHODS: We identified observational studies and subgroup analysis of randomized clinical trials (RCT) published in PubMed from 1970 through September 2012 using the following keywords: "percutaneous coronary intervention" (PCI); "coronary artery bypass graft" (CABG); "complete revascularization"; and "incomplete revascularization." Main outcome measures were total mortality, myocardial infarction, and repeat revascularization procedures. RESULTS: We identified 35 studies including 89,883 patients, of whom 45,417 (50.5%) received CR and 44,466 (49.5%) received IR. IR was more common after PCI than after CABG (56% vs. 25%; p < 0.001). Relative to IR, CR was associated with lower long-term mortality (risk ratio [RR]: 0.71, 95% confidence interval [CI]: 0.65 to 0.77; p < 0.001), myocardial infarction (RR: 0.78, 95% CI: 0.68 to 0.90; p = 0.001), and repeat coronary revascularization (RR: 0.74, 95% CI: 0.65 to 0.83; p < 0.001). The mortality benefit associated with CR was consistent across studies irrespective of revascularization modality (CABG: RR: 0.70, 95% CI: 0.61 to 0.80; p < 0.001; and PCI: RR: 0.72, 95% CI: 0.64 to 0.81; p < 0.001) and definition of CR (anatomic definition: RR: 0.73, 95% CI: 0.67 to 0.79; p < 0.001; and nonanatomic definition: RR: 0.57, 95% CI: 0.36 to 0.89; p = 0.014). CONCLUSIONS: CR is achieved more commonly with CABG than with PCI. Among patients with multivessel coronary artery disease, CR may be the optimal revascularization strategy.

Ischemic post-conditioning and vasodilator therapy during standard cardiopulmonary resuscitation to reduce cardiac and brain injury after prolonged untreated ventricular fibrillation.

AIM OF THE STUDY: We investigated the effects of ischemic postconditioning (IPC) with and without cardioprotective vasodilatory therapy (CVT) at the initiation of cardiopulmonary resuscitation (CPR) on cardio-cerebral function and 48-h survival. METHODS: Prospective randomized animal study. Following 15 min of ventricular fibrillation, 42 Yorkshire farm pigs weighing an average of 34 ± 2 kg were randomized to receive standard CPR (SCPR, n=12), SCPR+IPC (n=10), SCPR+IPC+CVT (n=10), or SCPR+CVT (n=10). IPC was delivered during the first 3 min of CPR with 4 cycles of 20s of chest compressions followed by 20-s pauses. CVT consisted of intravenous sodium nitroprusside (2mg) and adenosine (24 mg) during the first minute of CPR. Epinephrine was given in all groups per standard protocol. A transthoracic echocardiogram was obtained on all survivors 1 and 4h post-ROSC. The brains were extracted after euthanasia at least 24h later to assess ischemic injury in 7 regions. Ischemic injury was graded on a 0-4 scale with (0=no injury to 4 ≥ 50% neural injury). The sum of the regional scores was reported as cerebral histological score (CHS). 48 h survival was reported. RESULTS: Post-resuscitation left ventricular ejection (LVEF) fraction improved in SCPR+CVT, SCPR+IPC+CVT and SCPR+IPC groups compared to SCPR (59% ± 9%, 52% ± 14%, 52% ± 14% vs. 35% ± 11%, respectively, p<0.05). Only SCPR+IPC and SCPR+IPC+CVT, but not SCPR+CVT, had lower mean CHS compared to SCPR (5.8 ± 2.6, 2.8 ± 1.8 vs. 10 ± 2.1, respectively, p<0.01). The 48-h survival among SCPR+IPC, SCPR+CVT, SCPR+IPC+CVT and SCPR was 6/10, 3/10, 5/10 and 1/12, respectively (Cox regression p<0.01). CONCLUSIONS: IPC and CVT during standard CPR improved post-resuscitation LVEF but only IPC was independently neuroprotective and improved 48-h survival after 15 min of untreated cardiac arrest in pigs.

Controlled pauses at the initiation of sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitate neurological and cardiac recovery after 15 mins of untreated ventricular fibrillation.

OBJECTIVE: A multipronged approach to improve vital organ perfusion during cardiopulmonary resuscitation that includes sodium nitroprusside, active compression-decompression cardiopulmonary resuscitation, an impedance threshold device, and abdominal pressure (sodium nitroprusside-enhanced cardiopulmonary resuscitation) has been recently shown to increase coronary and cerebral perfusion pressures and higher rates of return of spontaneous circulation vs. standard cardiopulmonary resuscitation. To further reduce reperfusion injury during sodium nitroprusside-enhanced cardiopulmonary resuscitation, we investigated the addition of adenosine and four 20-sec controlled pauses spread throughout the first 3 mins of sodium nitroprusside-enhanced cardiopulmonary resuscitation. The primary study end point was 24-hr survival with favorable neurologic function after 15 mins of untreated ventricular fibrillation. DESIGN: Randomized, prospective, blinded animal investigation. SETTING: Preclinical animal laboratory. SUBJECTS: Thirty-two female pigs (four groups of eight) 32±2 kg. INTERVENTIONS: After 15 mins of untreated ventricular fibrillation, isoflurane-anesthetized pigs received 5 mins of either standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine. After 4 mins of cardiopulmonary resuscitation, all animals received epinephrine (0.5 mg) and a defibrillation shock 1 min later. Sodium nitroprusside-enhanced cardiopulmonary resuscitation-treated animals received sodium nitroprusside (2 mg) after 1 min of cardiopulmonary resuscitation and 1 mg after 3 mins of cardiopulmonary resuscitation. After 1 min of sodium nitroprusside-enhanced cardiopulmonary resuscitation, adenosine (24 mg) was administered in two groups. MEASUREMENTS AND MAIN RESULTS: A veterinarian blinded to the treatment assigned a cerebral performance category score of 1-5 (normal, slightly disabled, severely disabled but conscious, vegetative state, or dead, respectively) 24 hrs after return of spontaneous circulation. Sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, and controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine resulted in a significantly higher 24-hr survival rate compared to standard cardiopulmonary resuscitation (7 of 8, 8 of 8, and 8 of 8 vs. 2 of 8, respectively p<.05). The mean cerebral performance category scores for standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine were 4.6±0.7, 3±1.3, 2.5±0.9, and 1.5±0.9, respectively (p<.01 for controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine compared to all other groups). CONCLUSIONS: Reducing reperfusion injury and maximizing circulation during cardiopulmonary resuscitation significantly improved functional neurologic recovery after 15 mins of untreated ventricular fibrillation. These results suggest that brain resuscitation after prolonged cardiac arrest is possible with novel, noninvasive approaches focused on reversing the mechanisms of tissue injury.