Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis. METHODS: KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment. FINDINGS: Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6-47·8). 36-month overall survival estimates were 71% (95% CI 66-76) in the pembrolizumab group and 64% (58-69) in the placebo group (hazard ratio 0·72 [95% CI 0·56-0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8-22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48-0·72]). In the as-treated population, grade 3-5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group. INTERPRETATION: The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Effect of upper body venoarterial ECMO on systemic hemodynamics and oxygenation: A computational study.

BACKGROUND: This study seeks to quantify the effects of upper body veno-arterial extracorporeal membrane oxygenation (VA ECMO) on the anatomical distribution of oxygen delivery in the setting of hypoxic respiratory failure and provide new insights that will guide clinical use of this support strategy to bridge patients to lung transplant. METHODS: Employing a patient-specific vascular geometry and a quantitative model of oxygen transport, computational simulations were performed to determine hemodynamics and oxygen delivery in the ascending and descending aorta, left and right coronary arteries, and great vessels during upper body VA ECMO support. Oxygen content in ECMO circuit blood flow was varied while considering different degrees of lung failure severity. Using lumped parameter models to dynamically apply perfusion boundary conditions, hemodynamic parameters and oxygen content were analyzed to assess the effect of ECMO supply titration. RESULTS: The results emphasize the importance of anatomical distribution for tissue oxygen delivery in severe lung failure, with ECMO-derived flow primarily augmenting oxygen content in specific vascular beds. They also demonstrate that although cannulating the subclavian artery can enhance cerebral oxygen delivery, its ability to ensure sufficient oxygen delivery to the coronary circulation seems to be comparatively restricted. CONCLUSIONS: The oxygen delivery to a specific vascular area is primarily determined by the oxygen content in the source of perfusion. Caution is advised with upper body VA ECMO for patients with hypoxic respiratory failure and right ventricle dysfunction, due to potential coronary ischemia. Management of these patients is challenging due to disease progression and organ availability uncertainties.

Temporary Mechanical Circulatory Support after Cardiac Surgery.

Postcardiotomy shock in the cardiac surgical patient is a highly morbid condition characterized by profound myocardial impairment and decreased systemic perfusion inadequate to meet end-organ metabolic demand. Postcardiotomy shock is associated with significant morbidity and mortality. Poor outcomes motivate the increased use of mechanical circulatory support (MCS) to restore perfusion in an effort to prevent multiorgan injury and improve patient survival. Despite growing acceptance and adoption of MCS for postcardiotomy shock, criteria for initiation, clinical management, and future areas of clinical investigation remain a topic of ongoing debate. This article seeks to (1) define critical cardiac dysfunction in the patient after cardiotomy, (2) provide an overview of commonly used MCS devices, and (3) summarize the relevant clinical experience for various MCS devices available in the literature, with additional recognition for the role of MCS as a part of a modified approach to the cardiac arrest algorithm in the cardiac surgical patient.

Characterizing the Racial Discrepancy in Hypoxemia Detection in Venovenous Extracorporeal Membrane Oxygenation: An Extracorporeal Life Support Organization Registry Analysis.

PURPOSE: Skin pigmentation influences peripheral oxygen saturation (SpO2) compared to arterial saturation of oxygen (SaO2). Occult hypoxemia (SaO2 ≤ 88% with SpO2 ≥ 92%) is associated with increased in-hospital mortality in venovenous-extracorporeal membrane oxygenation (VV-ECMO) patients. We hypothesized VV-ECMO cannulation, in addition to race/ethnicity, accentuates the SpO2-SaO2 discrepancy due to significant hemolysis. METHODS: Adults (≥ 18 years) supported with VV-ECMO with concurrently measured SpO2 and SaO2 measurements from over 500 centers in the Extracorporeal Life Support Organization Registry (1/2018-5/2023) were included. Multivariable logistic regressions were performed to examine whether race/ethnicity was associated with occult hypoxemia in pre-ECMO and on-ECMO SpO2-SaO2 calculations. RESULTS: Of 13,171 VV-ECMO patients, there were 7772 (59%) White, 2114 (16%) Hispanic, 1777 (14%) Black, and 1508 (11%) Asian patients. The frequency of on-ECMO occult hypoxemia was 2.0% (N = 233). Occult hypoxemia was more common in Black and Hispanic patients versus White patients (3.1% versus 1.7%, P < 0.001 and 2.5% versus 1.7%, P = 0.025, respectively). In multivariable logistic regression, Black patients were at higher risk of pre-ECMO occult hypoxemia versus White patients (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI] = 1.18-2.02, P = 0.001). For on-ECMO occult hypoxemia, Black patients (aOR = 1.79, 95% CI = 1.16-2.75, P = 0.008) and Hispanic patients (aOR = 1.71, 95% CI = 1.15-2.55, P = 0.008) had higher risk versus White patients. Higher pump flow rates (aOR = 1.29, 95% CI = 1.08-1.55, P = 0.005) and on-ECMO 24-h lactate (aOR = 1.06, 95% CI = 1.03-1.10, P < 0.001) significantly increased the risk of on-ECMO occult hypoxemia. CONCLUSION: SaO2 should be carefully monitored if using SpO2 during ECMO support for Black and Hispanic patients especially for those with high pump flow and lactate values at risk for occult hypoxemia.

Impact of Extracorporeal Membrane Oxygenation Bridging Duration on Lung Transplant Outcomes.

BACKGROUND: We sought to characterize the association between venovenous extracorporeal membrane oxygenation (VV-ECMO) bridging duration and outcomes in patients listed for lung transplantation. METHODS: A retrospective observational study was conducted using the Organ Procurement and Transplantation Network (OPTN) database to identify adults (aged ≥18 years) who were listed for lung transplantation between 2016 and 2020 and were bridged with VV-ECMO. Patients were then stratified into groups, determined by risk inflection points, depending on the amount of time spent on pretransplant ECMO: group 1 (≤5 days), group 2 (6-10 days), group 3 (11-20 days), and group 4 (>20 days). Waiting list survival between groups was analyzed using Fine-Gray competing risk models. Posttransplant survival was compared using Cox regression. RESULTS: Of 566 eligible VV-ECMO bridge-to-lung-transplant patients (median age, 54 years, 49% men), 174 (31%), 124 (22%), 130 (23%), and 138 (24%) were categorized as groups 1, 2, 3, and 4, respectively. Overall, median duration of VV-ECMO was 10 days (interquartile range, 1-211 days), and 178 patients (31%) died on the waiting list. In the Fine-Gray model, compared with group 1, patients bridged with longer ECMO durations in group 2 (subdistribution hazard ratio [SHR], 2.95; 95% CI, 1.63-5.35), group 3 (SHR, 3.96; 95% CI, 2.36-6.63), and group 4 (SHR, 4.33; 95% CI, 2.59-7.22, all P < .001) were more likely to die on the waiting list. Of 388 patients receiving a transplant, pretransplant ECMO duration was not associated with 1-year survival in Cox regression. CONCLUSIONS: Prolonged duration of ECMO bridging was associated with worse waiting list mortality but did not impact survival after lung transplant. Prioritization of very early transplantation may improve waiting list outcomes in this population.

Differential Effects of Pharmacologic and Mechanical Support on Right-Left Ventricular Coupling.

BACKGROUND: Percutaneous ventricular assist devices are increasingly relied on to maintain perfusion for cardiogenic shock patients. Optimal medical management strategies however remain uncertain from limited understanding of interventricular effects. This study analyzed the effects of pharmacologic and left-sided mechanical support on right ventricular function. METHODS: A porcine model was developed to assess biventricular function during bolus pharmacologic administration before and after left-sided percutaneous ventricular assist and in cardiogenic shock. RESULTS: The presence of mechanical support increased right ventricular load and stress with respect to the left ventricle. This shifted and exaggerated the relative effects of commonly used vasoactive agents. Furthermore, induction of cardiogenic shock led to differential pulmonary vascular and right ventricular responses. CONCLUSIONS: Left ventricular ischemia and mechanical support altered interventricular coupling. Resulting impacts of pharmacologic agents indicate differential right heart responses and sensitivity to treatments and the need for further study to optimize biventricular function in shock patients.

Steady Flow Left Ventricle Unloading Is Superior to Pulsatile Pressure Augmentation Venting During Venoarterial Extracorporeal Membrane Oxygenation Support.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) shunts venous blood to the systemic arterial circulation to provide end-organ perfusion while increasing afterload that may impede left ventricle (LV) ejection and impair cardiac recovery. To maintain flow across the aortic valve and reduce risk of lethal clot formation, secondary mechanical circulatory support (MCS) devices are increasingly used despite limited understanding of their effects on cardiac function. This study sought to quantify the effects of VA-ECMO and combined with either intraaortic balloon pump (IABP) or percutaneous ventricular assist device (pVAD) on LV physiologic state and perfusion metrics in a porcine model of acute cardiogenic shock. Shock was induced through serial left anterior descending artery microbead embolization followed by initiation of VA-ECMO support and then placement of either IABP or pVAD. Hemodynamic measurements, LV pressure-volume loops, and carotid artery blood flow were evaluated before and after institution of combined MCS. The IABP decreased LV end-diastolic pressure by a peak of 15% while slightly increasing LV stroke work compared with decreases of more than 60% and 50% with the pVAD, respectively. The pVAD also demonstrated increased coronary perfusion and systemic pressure gradients in comparison to the IABP. Combined support with VA-ECMO and pVAD improves cardiovascular state in comparison to IABP.

Dynamic load modulation predicts right heart tolerance of left ventricular cardiovascular assist in a porcine model of cardiogenic shock.

Ventricular assist devices (VADs) offer mechanical support for patients with cardiogenic shock by unloading the impaired ventricle and increasing cardiac outflow and subsequent tissue perfusion. Their ability to adjust ventricular assistance allows for rapid and safe dynamic changes in cardiac load, which can be used with direct measures of chamber pressures to quantify cardiac pathophysiologic state, predict response to interventions, and unmask vulnerabilities such as limitations of left-sided support efficacy due to intolerance of the right heart. We defined hemodynamic metrics in five pigs with dynamic peripheral transvalvular VAD (pVAD) support to the left ventricle. Metrics were obtained across a spectrum of disease states, including left ventricular ischemia induced by titrated microembolization of a coronary artery and right ventricular strain induced by titrated microembolization of the pulmonary arteries. A sweep of different pVAD speeds confirmed mechanisms of right heart decompensation after left-sided support and revealed intolerance. In contrast to the systemic circulation, pulmonary vascular compliance dominated in the right heart and defined the ability of the right heart to adapt to left-sided pVAD unloading. We developed a clinically accessible metric to measure pulmonary vascular compliance at different pVAD speeds that could predict right heart efficiency and tolerance to left-sided pVAD support. Findings in swine were validated with retrospective hemodynamic data from eight patients on pVAD support. This methodology and metric could be used to track right heart tolerance, predict decompensation before right heart failure, and guide titration of device speed and the need for biventricular support.

Clinical Use of Bedside Portable Low-field Brain Magnetic Resonance Imaging in Patients on ECMO: The Results from Multicenter SAFE MRI ECMO Study.

Purpose: Early detection of acute brain injury (ABI) is critical for improving survival for patients with extracorporeal membrane oxygenation (ECMO) support. We aimed to evaluate the safety of ultra-low-field portable MRI (ULF-pMRI) and the frequency and types of ABI observed during ECMO support. Methods: We conducted a multicenter prospective observational study (NCT05469139) at two academic tertiary centers (August 2022-November 2023). Primary outcomes were safety and validation of ULF-pMRI in ECMO, defined as exam completion without adverse events (AEs); secondary outcomes were ABI frequency and type. Results: ULF-pMRI was performed in 50 patients with 34 (68%) on venoarterial (VA)-ECMO (11 central; 23 peripheral) and 16 (32%) with venovenous (VV)-ECMO (9 single lumen; 7 double lumen). All patients were imaged successfully with ULF-pMRI, demonstrating discernible intracranial pathologies with good quality. AEs occurred in 3 (6%) patients (2 minor; 1 serious) without causing significant clinical issues.ABI was observed in ULF-pMRI scans for 22 patients (44%): ischemic stroke (36%), intracranial hemorrhage (6%), and hypoxic-ischemic brain injury (4%). Of 18 patients with both ULF-pMRI and head CT (HCT) within 24 hours, ABI was observed in 9 patients with 10 events: 8 ischemic (8 observed on ULF-oMRI, 4 on HCT) and 2 hemorrhagic (1 observed on ULF-pMRI, 2 on HCT). Conclusions: ULF-pMRI was shown to be safe and valid in ECMO patients across different ECMO cannulation strategies. The incidence of ABI was high, and ULF-pMRI may more sensitive to ischemic ABI than HCT. ULF-pMRI may benefit both clinical care and future studies of ECMO-associated ABI.

Decreased LPS-induced lung injury in pigs treated with a lung surfactant protein A-derived nonapeptide that inhibits peroxiredoxin 6 activity and subsequent NOX1,2 activation.

This study addressed the efficacy of a liposome-encapsulated nine amino acid peptide [peroxiredoxin 6 PLA2 inhibitory peptide-2 (PIP-2)] for the prevention or treatment of acute lung injury (ALI) +/- sepsis. PIP-2 inhibits the PLA2 activity of peroxiredoxin 6 (Prdx6), thereby preventing rac release and activation of NADPH oxidases (NOXes), types 1 and 2. Female Yorkshire pigs were infused intravenously with lipopolysaccharide (LPS) + liposomes (untreated) or LPS + PIP-2 encapsulated in liposomes (treated). Pigs were mechanically ventilated and continuously monitored; they were euthanized after 8 h or earlier if preestablished humane endpoints were reached. Control pigs (mechanical ventilation, no LPS) were essentially unchanged over the 8 h study. LPS administration resulted in systemic inflammation with manifestations of clinical sepsis-like syndrome, decreased lung compliance, and a marked decrease in the arterial Po2 with vascular instability leading to early euthanasia of 50% of untreated animals. PIP-2 treatment significantly reduced the requirement for supportive vasopressors and the manifestations of lung injury so that only 25% of animals required early euthanasia. Bronchoalveolar lavage fluid from PIP-2-treated versus untreated pigs showed markedly lower levels of total protein, cytokines (TNF-α, IL-6, IL-1ß), and myeloperoxidase. Thus, the porcine LPS-induced sepsis-like model was associated with moderate to severe lung pathophysiology compatible with ALI, whereas treatment with PIP-2 markedly decreased lung injury, cardiovascular instability, and early euthanasia. These results indicate that inhibition of reactive oxygen species (ROS) production via NOX1/2 has a beneficial effect in treating pigs with LPS-induced ALI plus or minus a sepsis-like syndrome, suggesting a potential role for PIP-2 in the treatment of ALI and/or sepsis in humans.NEW & NOTEWORTHY Currently available treatments that can alter lung inflammation have failed to significantly alter mortality of acute lung injury (ALI). Peroxiredoxin 6 PLA2 inhibitory peptide-2 (PIP-2) targets the liberation of reactive O2 species (ROS) that is associated with adverse cell signaling events, thereby decreasing the tissue oxidative injury that occurs early in the ALI syndrome. We propose that treatment with PIP-2 may be effective in preventing progression of early disease into its later stages with irreversible lung damage and relatively high mortality.

Extracorporeal membrane oxygenation as a bridge to lung transplantation: Practice patterns and patient outcomes.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly relied on to bridge patients with respiratory failure to lung transplantation despite limited evidence for its use in this setting. This study evaluated longitudinal trends in practice patterns, patient characteristics, and outcomes in patients bridged with ECMO to lung transplant. METHODS: A retrospective review of all adult isolated lung transplant patients in the United Network for Organ Sharing database between 2000 and 2019 was performed. Patients were classified as "ECMO" if supported with ECMO at the time of listing or transplantation and "non-ECMO" otherwise. Linear regression was used to evaluate trends in patient demographics during the study period. Trends in mortality were evaluated using Cox proportional hazards modeling, with time period as the primary covariate (2000-2004, 2005-2009, 2010-2014, or 2015-2019) and age, time on the waitlist, and underlying diagnosis as covariates. RESULTS: The number of patients included were 40,866, of whom 1,387 (3.4%) were classified as ECMO and 39,479 (96.6%) as no ECMO. Average age and initial Lung Allocation Score increased significantly during the study period in both cohorts, but occurred at a slower rate in the ECMO population. The hazard of death was significantly lower in more recent years (2015-2019) for both the ECMO and non-ECMO cohorts (aHR (adjusted hazards ratio) 0.59, 95% confidence interval (CI) 0.37-0.96 and aHR 0.74, 95% CI 0.70-0.79) when compared to the early years (2000-2004) of the study period. CONCLUSIONS: Post-transplantation survival for patients bridged to transplantation with ECMO demonstrates ongoing improvement despite cannulation of progressively older and sicker patients.

Characterizing the Racial Discrepancy in Hypoxemia Detection in VV-ECMO: An ELSO Registry Analysis.

Importance: Skin pigmentation influences peripheral oxygen saturation (SpO2) measured by pulse oximetry compared to the arterial saturation of oxygen (SaO2) measured via arterial blood gas analysis. However, data on SpO2-SaO2 discrepancy are limited in venovenous-extracorporeal membrane oxygenation (VV-ECMO) patients. Objective: To determine whether there is racial/ethnical discrepancy between SpO2 and SaO2 in patients receiving VV-ECMO. We hypothesized VV-ECMO cannulation, in addition to race/ethnicity, accentuates the SpO2-SaO2 discrepancy due to significant hemolysis. Design: Retrospective cohort study of the Extracorporeal Life Support Organization Registry from 1/2018-5/2023. Setting: International, multicenter registry study including over 500 ECMO centers. Participants: Adults (≥ 18 years) supported with VV-ECMO with concurrently measured SpO2 and SaO2 measurements. Exposure: Race/ethnicity and ECMO cannulation. Main outcomes and measures: Occult hypoxemia (SaO2 ≤ 88% with SpO2 ≥ 92%) was our primary outcome. Multivariable logistic regressions were performed to examine whether race/ethnicity was associated with occult hypoxemia in pre-ECMO and on-ECMO SpO2-SaO2 calculations. Covariates included age, sex, temporary mechanical circulatory support, pre-vasopressors, and pre-inotropes for pre-ECMO analysis, plus single-lumen versus double-lumen cannulation, hemolysis, hyperbilirubinemia, ECMO pump flow rate, and on-ECMO 24h lactate for on-ECMO analysis. Results: Of 13,171 VV-ECMO patients (median age = 48.6 years, 66% male), there were 7,772 (59%) White, 2,114 (16%) Hispanic, 1,777 (14%) Black, and 1,508 (11%) Asian patients. The frequency of on-ECMO occult hypoxemia was 2.0% (N = 233). Occult hypoxemia was more common in Black and Hispanic versus White patients (3.1% versus 1.7%, P < 0.001 and 2.5% versus 1.7%, P = 0.025, respectively).In multivariable logistic regression, Black patients were at higher risk of pre-ECMO occult hypoxemia versus White patients (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI] = 1.18-2.02, P = 0.001). For on-ECMO occult hypoxemia, Black patients (aOR = 1.79, 95%CI = 1.16-2.75, P = 0.008) and Hispanic patients (aOR = 1.71, 95%CI = 1.15-2.55, P = 0.008) had higher risk versus White patients. Furthermore, higher pump flow rate (aOR = 1.29, 95%CI = 1.08-1.55, P = 0.005) and higher on-ECMO 24h lactate (aOR = 1.06, 95%CI = 1.03-1.10, P < 0.001) significantly increased the risk of on-ECMO occult hypoxemia. Conclusions and Relevance: Hispanic and Black VV-ECMO patients experienced occult hypoxemia more than White patients. SaO2 should be carefully monitored during ECMO support for Black and Hispanic patients especially for those with high pump flow and lactate values at risk for occult hypoxemia.

A recommended preclinical extracorporeal cardiopulmonary resuscitation model for neurological outcomes: A scoping review.

Background: Despite the high prevalence of neurological complications and mortality associated with extracorporeal cardiopulmonary resuscitation (ECPR), neurologically-focused animal models are scarce. Our objective is to review current ECPR models investigating neurological outcomes and identify key elements for a recommended model. Methods: We searched PubMed and four other engines for animal ECPR studies examining neurological outcomes. Inclusion criteria were: animals experiencing cardiac arrest, ECPR/ECMO interventions, comparisons of short versus long cardiac arrest times, and neurological outcomes. Results: Among 20 identified ECPR animal studies (n = 442), 13 pigs, 4 dogs, and 3 rats were used. Only 10% (2/20) included both sexes. Significant heterogeneity was observed in experimental protocols. 90% (18/20) employed peripheral VA-ECMO cannulation and 55% (11/20) were survival models (median survival = 168 hours; ECMO duration = 60 minutes). Ventricular fibrillation (18/20, 90%) was the most common method for inducing cardiac arrest with a median duration of 15 minutes (IQR = 6-20). In two studies, cardiac arrests exceeding 15 minutes led to considerable mortality and neurological impairment. Among seven studies utilizing neuromonitoring tools, only four employed multimodal devices to evaluate cerebral blood flow using Transcranial Doppler ultrasound and near-infrared spectroscopy, brain tissue oxygenation, and intracranial pressure. None examined cerebral autoregulation or neurovascular coupling. Conclusions: The substantial heterogeneity in ECPR preclinical model protocols leads to limited reproducibility and multiple challenges. The recommended model includes large animals with both sexes, standardized pre-operative protocols, a cardiac arrest time between 10-15 minutes, use of multimodal methods to evaluate neurological outcomes, and the ability to survive animals after conducting experiments.

Extracorporeal Membrane Oxygenation Physiological Factors Influence Pulse Oximetry and Arterial Oxygen Saturation Discrepancies.

BACKGROUND: Cannulation strategy, vasopressors, and hemolysis are important physiological factors that influence hemodynamics in extracorporeal membrane oxygenation (ECMO). We hypothesized these factors influence the discrepancy between oxygen saturation measured by pulse oximetry (Spo2) and arterial blood gas (Sao2) in patients on ECMO. METHODS: We retrospectively analyzed adults (aged ≥18 years) on venoarterial or venovenous ECMO at a tertiary academic ECMO center. Spo2-Sao2 pairs with oxygen saturation ≥70% and measured within 10 minutes were included. Occult hypoxemia was defined as Sao2 ≤88% with a time-matched Spo2 ≥92%. Adjusted linear mixed-effects modeling was used to assess the Spo2-Sao2 discrepancy with preselected demographics and time-matched laboratory variables. Vasopressor use was quantified by vasopressor dose equivalences. RESULTS: Of 139 venoarterial-ECMO and 88 venovenous-ECMO patients, we examined 20,053 Spo2-Sao2 pairs. The Spo2-Sao2 discrepancy was greater in venovenous-ECMO (1.15%) vs venoarterial-ECMO (-0.35%, P < .001). Overall, 81 patients (35%) experienced occult hypoxemia during ECMO. Occult hypoxemia was more common in venovenous-ECMO (65%) than in venoarterial-ECMO (17%, P < .001). In linear mixed-effects modeling, Spo2 underestimated Sao2 by 9.48% in central vs peripheral venoarterial-ECMO (95% CI, -17.1% to -1.79%; P = .02). Higher vasopressor dose equivalences significantly worsened the Spo2-Sao2 discrepancy (P < .001). In linear mixed-effects modeling, Spo2 overestimated Sao2 by 25.43% in single lumen-cannulated vs double lumen-cannulated venovenous-ECMO (95% CI, 5.27%-45.6%; P = .03). Higher vasopressor dose equivalences and lactate dehydrogenase levels significantly worsened the Spo2-Sao2 discrepancy (P < .001). CONCLUSIONS: Venovenous-ECMO patients are at higher risk for occult hypoxemia compared with venoarterial-ECMO. A higher vasopressor requirement and different cannulation strategies (central venoarterial-ECMO; single-lumen venovenous-ECMO) were significant factors for clinically significant Spo2-Sao2 discrepancy in both ECMO modes.

Racial and ethnical discrepancy in hypoxemia detection in patients on extracorporeal membrane oxygenation.

Objective: To determine whether there is racial/ethnical discrepancy between pulse oximetry (SpO2) and oxygen saturation (SaO2) in patients receiving extracorporeal membrane oxygenation (ECMO). Methods: This was a retrospective observational study at a tertiary academic ECMO center with adults (>18 years) on venoarterial (VA) or venovenous (VV) ECMO. Datapoints were excluded if oxygen saturation ≤70% or SpO2-SaO2 pairs were not measured within 10 minutes. The primary outcome was the presence of a SpO2-SaO2 discrepancy between different races/ethnicities. Bland-Altman analyses and linear mixed-effects modeling, adjusting for prespecified covariates, were used to assess the SpO2-SaO2 discrepancy between races/ethnicities. Occult hypoxemia was defined as SaO2 <88% with a time-matched SpO2 ≥92%. Results: Of 139 patients receiving VA-ECMO and 57 patients receiving VV-ECMO, we examined 16,252 SpO2-SaO2 pairs. The SpO2-SaO2 discrepancy was greater in VV-ECMO (1.4%) versus VA-ECMO (0.15%). In VA-ECMO, SpO2 overestimated SaO2 in Asian (0.2%), Black (0.94%), and Hispanic (0.03%) patients and underestimated SaO2 in White (-0.06%) and nonspecified race (-0.80%) patients. The proportion of SpO2-SaO2 measurements considered occult hypoxemia was 70% from Black compared to 27% from White patients (P < .0001). In VV-ECMO, SpO2 overestimated SaO2 in Asian (1.0%), Black (2.9%), Hispanic (1.1%), and White (0.50%) patients and underestimated SaO2 in nonspecified race patients (-0.53%). In linear mixed-effects modeling, SpO2 overestimated SaO2 by 0.19% in Black patients (95% confidence interval, 0.045%-0.33%, P = .023). The proportion of SpO2-SaO2 measurements considered occult hypoxemia was 66% from Black compared with 16% from White patients (P < .0001). Conclusions: SpO2 overestimates SaO2 in Asian, Black, and Hispanic versus White patients, and this discrepancy was greater in VV-ECMO versus VA-ECMO, suggesting the need for physiological studies.

Challenges in determining death by neurologic criteria in extracorporeal membrane oxygenation - A single center experience.

INTRODUCTION: Apnea test (AT) in patients on extracorporeal membrane oxygenation (ECMO) support is challenging, leading to variation in determining death by neurologic criteria (DNC). We aim to describe the diagnostic criteria and barriers for DNC in adults on ECMO in a tertiary care center. METHODS: A retrospective review of a prospective observational standardized neuromonitoring study was conducted in adult VA- and VV-ECMO patients at a tertiary center from June 2016 to March 2022. Brain death was defined according to the 2010 American Academy of Neurology guidelines and following the 2020 World Brain Death Project recommendations for performing AT in ECMO patients. RESULTS: Eight (2.7%) ECMO patients (median age = 44 years, 75% male, 50% VA-ECMO) met criteria for DNC, six (75%) of whom were determined with AT. In the other two patients who did not undergo AT due to safety concerns, ancillary tests (transcranial doppler and electroencephalography) were consistent with DNC. An additional seven (2.3%) patients (median age = 55 years, 71% male, 86% VA-ECMO) were noted to have absent brainstem reflexes but failed to complete determination of DNC as they underwent withdrawal of life-sustaining treatment (WLST) before a full evaluation was completed. In these patients, AT was never performed, and ancillary tests were inconsistent with either neurological exam findings and/or neuroimaging supporting DNC, or with each other. CONCLUSION: AT was used safely and successfully in 6 of the 8 ECMO patients diagnosed with DNC and was always consistent with the neurological exam and imaging findings, as opposed to ancillary tests alone.

Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone. METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety. RESULTS: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events. CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).

A case series evaluating the effect of esmolol therapy to treat hypoxemia in COVID-19 patients on VV-ECMO.

When COVID-19 ARDS abolishes pulmonary function, VV-ECMO can provide gas exchange. If oxygenation remains insufficient despite maximal VV-ECMO support, the addition of esmolol has been proposed. Conflict exists, however, as to the oxygenation level which should trigger beta-blocker initiation. We evaluated the effect of esmolol therapy on oxygenation and oxygen delivery in patients with negligible native lung function and various degrees of hypoxemia despite maximal VV-ECMO support. We found that, in COVID-19 patients with negligible pulmonary gas exchange, the generalized use of esmolol administration to raise arterial oxygenation by slowing heart rate and thereby match native cardiac output to maximal attainable VV ECMO flows actually reduces systemic oxygen delivery in many cases.

National Trends, Risk Factors, and Outcomes of Acute In-Hospital Stroke Following Lung Transplantation in the United States: Analysis of the United Network for Organ Sharing Registry.

BACKGROUND: Lung transplantation (LTx) is the definitive treatment for end-stage lung failure. However, there have been no large, long-term studies on the impact of acute in-hospital stroke in this population. RESEARCH QUESTION: What are the trends, risk factors, and outcomes of acute stroke in patients undergoing LTx in the United States? STUDY DESIGN AND METHODS: We identified adult first-time isolated LTx recipients from the United Network for Organ Sharing database, which comprehensively captures every transplant in the United States, between May 2005 and December 2020. Stroke was defined as occurring at any time after LTx but prior to discharge. Multivariable logistic regression with stepwise feature elimination was used to identify risk factors for stroke. Freedom from death in patients with a stroke vs those without a stroke was evaluated with Kaplan-Meier analysis. Cox proportional hazards analysis was used to identify predictors of death at 24 months. RESULTS: Of 28,564 patients (median age, 60 years; 60% male), 653 (2.3%) experienced an acute in-hospital stroke after LTx. Median follow-up was 1.2 (stroke) and 3.0 (non-stroke) years. Annual incidence of stroke increased (1.5% in 2005 to 2.4% in 2020; P for trend = .007), as did lung allocation score and utilization of post-LTx extracorporeal membrane oxygenation (P = .01 and P < .001, respectively). Compared with those without stroke, patients with stroke had lower survival at 1 month (84% vs 98%), 12 months (61% vs 88%), and 24 months (52% vs 80%) (log-rank test, P < .001 for all). In Cox analysis, acute stroke conferred a high hazard of mortality (hazard ratio, 3.01; 95% CI, 2.67-3.41). Post-LTx extracorporeal membrane oxygenation was the strongest risk factor for stroke (adjusted OR, 2.98; 95% CI, 2.19-4.06). INTERPRETATION: Acute in-hospital stroke post-LTx has been increasing over time and is associated with markedly worse short- and long-term survival. As increasingly sicker patients undergo LTx as well as experience stroke, further research on stroke characteristics, prevention, and management strategies is warranted.

Initial development and testing of an exhaled microRNA detection strategy for lung cancer case-control discrimination.

For detecting field carcinogenesis non-invasively, early technical development and case-control testing of exhaled breath condensate microRNAs was performed. In design, human lung tissue microRNA-seq discovery was reconciled with TCGA and published tumor-discriminant microRNAs, yielding a panel of 24 upregulated microRNAs. The airway origin of exhaled microRNAs was topographically "fingerprinted", using paired EBC, upper and lower airway donor sample sets. A clinic-based case-control study (166 NSCLC cases, 185 controls) was interrogated with the microRNA panel by qualitative RT-PCR. Data were analyzed by logistic regression (LR), and by random-forest (RF) models. Feasibility testing of exhaled microRNA detection, including optimized whole EBC extraction, and RT and qualitative PCR method evaluation, was performed. For sensitivity in this low template setting, intercalating dye-based URT-PCR was superior to fluorescent probe-based PCR (TaqMan). In application, adjusted logistic regression models identified exhaled miR-21, 33b, 212 as overall case-control discriminant. RF analysis of combined clinical + microRNA models showed modest added discrimination capacity (1.1-2.5%) beyond clinical models alone: all subjects 1.1% (p = 8.7e-04)); former smokers 2.5% (p = 3.6e-05); early stage 1.2% (p = 9.0e-03), yielding combined ROC AUC ranging from 0.74 to 0.83. We conclude that exhaled microRNAs are qualitatively measureable, reflect in part lower airway signatures; and when further refined/quantitated, can potentially help to improve lung cancer risk assessment.