In-Vivo Evaluation of a Novel Integrated Pediatric Pump Lung in a 30 Day Ovine Animal Model.

Recently there has been increased use of mechanical circulatory support in pediatric patients as a bridge to cardiopulmonary recovery or transplantation. However, there are few devices that are optimized and approved for use in pediatric patients. We designed and prototyped a novel integrated pediatric pump lung (PPL) that underwent 30 day in-vivo testing in seven juvenile Dorset Hybrid sheep. Devices were implanted in a right atrial to pulmonary artery configuration. Six of seven sheep survived with a device functioning for 25-35 days. The device flow rate was maintained at 2.08 ± 0.34 to 2.54 ± 0.16 L/min with oxygen transfer of 109.8 ± 24.8 to 151.2 ± 26.2 ml/min over the study duration. Aside from a postoperative drop in hematocrit, all hematologic and blood chemistry test values returned to normal ranges after 1-2 weeks postoperatively. Similarly, lactate dehydrogenase increased postoperatively and returned to baseline. In two sheep, there were early device failures due to oxygenator thrombosis on postoperative days zero and five; they then had oxygenator exchanges with subsequent devices performing stably for 30 days. This study demonstrated that the integrated PPL device exhibited stable performance and acceptable biocompatibility in a 30 day ovine model.

Pulmonary thromboendarterectomy in hospitalized versus elective patients with chronic thromboembolic pulmonary hypertension.

OBJECTIVE: We sought to characterize outcomes in patients undergoing pulmonary thromboendarterectomy electively versus after acute presentation. METHODS: This is a retrospective analysis of patients who underwent pulmonary thromboendarterectomy from October 2015 to April 2022. Patients were divided into 2 groups depending on elective surgery or surgery during the same hospitalization as their presentation. RESULTS: In total, 69 patients were included: 45 in the hospitalized group and 24 in the elective group. Patients in the hospitalized group were less likely to have chronic lung disease, history of pulmonary embolism and hypertension, be on anticoagulation and medication for pulmonary hypertension, and present with >1 month of respiratory symptoms. They were more likely to have worse preoperative right ventricular function. Among other demographics, risk factors for venous thromboembolism were similar between both groups. Thirteen patients in the hospitalized group required preoperative extracorporeal membrane oxygenation. There was no difference in disease classification and operative, cardiopulmonary bypass, and hypothermic circulatory arrest durations between both groups. Postoperative complications were similar between both groups, except for greater frequency of deep vein thrombosis in the hospitalized group (26.7% vs 4.2%, P = .03). In-hospital and intensive care unit length of stay were similar between both groups. Overall, in-hospital mortality was 4.3% and was similar between both groups; P = .28. CONCLUSIONS: Our series shows that pulmonary thromboendarterectomy can be safely performed in patients presenting acutely, with comparable postoperative complications and in-hospital mortality to an elective setting. Such patients present with worse right ventricular function, sometimes requiring temporary mechanical support.

High protein intake and nitrogen balance in patients receiving venovenous extracorporeal membrane oxygenation: A descriptive cohort study.

BACKGROUND: This retrospective cohort study sought to describe the ability of high protein regimens to achieve nitrogen equilibrium in patients receiving venovenous extracorporeal membrane oxygenation (VV ECMO). METHODS: Patients aged ≥18 years with a documented nitrogen balance study (NB) on VV ECMO between February 2018 and December 2021 were included. Studies with incomplete 24-h urine collections or changes in blood urea nitrogen ≥10 mg/dl were excluded. Data were summarized, correlation between first NB and potentially contributing variables was assessed with Kendall tau. Subanalysis described findings after stratifying for weight class (obese vs nonobese) and duration of VV ECMO at the time of NB. RESULTS: A total of 68 NBs in 30 patients were included; 47% of the cohort had obesity. The number of NBs per patient was 2.2 ± 1.1, which were completed on a median of 31.5 (interquartile range: 16, 53.8) days receiving ECMO. Nitrogen equilibrium or positive balance was achieved in 72% of studies despite elevated nitrogen excretion. Patients received 87.9 ± 16.8% of prescribed protein on NB days for average intakes of 2.4 ± 0.4 g/kg of actual weight per day and 2.4 ± 0.5 g/kg of ideal weight per day in patients without and with obesity. Median NB in patients without obesity was -1.46 (-8.96, 2.98) g/day and -0.21 (-10.58, 4.04) g/day in patients with obesity. A difference in median NB after stratification for timing was observed (P = 0.029). CONCLUSION: Nitrogen equilibrium can be achieved with high protein intake in adults receiving VV ECMO. NB monitoring is one tool to individualize protein prescriptions throughout the course of VV ECMO.

Evaluating the Safety of Transcarotid Artery Revascularization under Local Anesthesia Prior to Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Controversy exists regarding the timing of intervention for patients with critical coronary artery disease (CAD) awaiting coronary artery bypass and severe carotid artery stenosis (CAS). Transcarotid artery revascularization (TCAR) is a minimally invasive revascularization alternative through direct transcervical carotid access that minimizes the chance of arch manipulation and consequent antegrade embolic stroke rate. While the TCAR procedure can be performed under local anesthesia (monitored anesthesia care [MAC]) versus general anesthesia, the hemodynamic benefits of local anesthesia in patients with severe CAD are significant. Patients receiving staged TCAR-coronary artery bypass grafting (CABG) have high-risk cardiovascular disease and require accurate perioperative neurological and hemodynamic evaluation that can be safely provided with local anesthesia. METHODS: In this retrospective single-center study, 14 patients were systematically identified to have undergone staged TCAR prior to CABG surgery from December 2018 to October 2021. All patients underwent TCAR with local anesthesia and minimal sedation. Relevant patient demographics, medical and surgical history, preoperative covariates, and type of anesthesia administered were obtained from patients' charts. CAD was confirmed by either carotid duplex imaging or computed tomography angiography (CTA) of the head/neck. RESULTS: Staged TCAR-CABG interventions were performed on 14 patients (64% male; mean age 65.0 years). No major adverse cardiac events were reported including transient ischemic attack (TIA), stroke, myocardial infarction (MI), or TCAR-related death in the interval between their TCAR and CABG as well as in a 12-month follow-up period. One patient required to return to the operating room (OR) for evacuation of a neck hematoma. CONCLUSIONS: This study demonstrated high success rate of TCAR under local anesthesia prior to CABG (100%) with no incidence of perioperative stroke, MI, or death at 1-month, 6-month, and 12-month follow-up intervals. The authors support the use of staged TCAR-CABG with local anesthesia as a safe and promising treatment option for patients with high-grade cardiac disease, high risk of stroke, or multiple comorbidities that preclude a carotid endarterectomy (CEA).

Computational fluid dynamics analysis and experimental hemolytic performance of three clinical centrifugal blood pumps: Revolution, Rotaflow and CentriMag.

Centrifugal blood pumps have become popular for adult extracorporeal membrane oxygenation (ECMO) due to their superior blood handling and reduced thrombosis risk featured by their secondary flow paths that avoid stagnant areas. However, the high rotational speed within a centrifugal blood pump can introduce high shear stress, causing a significant shear-induced hemolysis rate. The Revolution pump, the Rotaflow pump, and the CentriMag pump are three of the leading centrifugal blood pumps on the market. Although many experimental and computational studies have focused on evaluating the hydraulic and hemolytic performances of the Rotaflow and CentriMag pumps, there are few on the Revolution pump. Furthermore, a thorough direct comparison of these three pumps' flow characteristics and hemolysis is not available. In this study, we conducted a computational and experimental analysis to compare the hemolytic performances of the Revolution, Rotaflow, and CentriMag pumps operating under a clinically relevant condition, i.e., the blood flow rate of 5 L/min and pump pressure head of 350 mmHg, for adult ECMO support. In silico simulations were used to characterize the shear stress distributions and predict the hemolysis index, while in vitro blood loop studies experimentally determined hemolysis performance. Comparative simulation results and experimental data demonstrated that the CentriMag pump caused the lowest hemolysis while the Revolution pump generated the highest hemolysis.

Role of thrombin to non-physiological shear stress induced platelet activation and function alternation.

OBJECTIVE: Non-physiological shear stress (NPSS) and thrombin have two distinct mechanisms for activating platelets. NPSS in mechanically assisted circulation (MAC) devices can cause platelet dysfunction, e.g., by shedding its key receptors. In addition, patients with heart failure have increased levels of thrombin generation, which may further affect the NPSS-induced platelet dysfunction, resulting in device-associated complications. This study aimed to assess the combined effect of NPSS and thrombin in platelet activation, expression of adhesion receptors on the platelet surface, and alterations of platelet aggregation. METHODS: Fresh human blood from healthy donors was divided into two groups; one group was treated by adding 0.01 U/mL thrombin, and another group not treated with thrombin served as a control comparison. They were then pumped through a novel blood shearing device which produces similar shear stress conditions to those in the MAC devices. Three levels of NPSS (i.e., 75, 125, and 175 Pa) with a 1.0 s exposure time were selected for the shearing conditions. Expression of platelet activation markers (PAC-1, activated GPIIb/IIIa and CD62P, platelet surface P-selectin) were investigated along with the shedding of platelet receptors (GPIb, GPIIb/IIIa, and GPVI), generation of platelet microparticles, and Phosphatidylserine (PS)-positive platelets detected by flow cytometry. Platelet aggregation (induced by collagen/ristocetin) was measured by Lumi-aggregometry. RESULTS: Platelet receptors were shed after exposure to NPSS showing a positive correlation with the level of shear stress. The generation of platelet microparticles and PS-positive platelets also increased with greater NPSS. Elevated NPSS decreased the platelet aggregation capacity. Platelet activation level increased with greater NPSS. Being treated by thrombin can further exacerbate these characteristics under same level of NPSS, except that platelet activation level drastically dropped after the exposure to 175 Pa NPSS in the thrombin-treated blood. CONCLUSION: After being treated by thrombin, platelets became more susceptible to NPSS, resulting in more receptor shedding, platelet microparticles, and PS-positive platelets, thus limiting platelet aggregation capacity after exposure to NPSS. Platelet activation, in terms of PAC-1 and P-selectin, is an interim status competing between the expression and shedding of these makers/receptors. When platelets have reached a saturation level of activation, exposure to excessive NPSS can potentially impair activation.

Inferior Vena Cava Filter Placement Through a Venovenous Extracorporeal Membrane Oxygenation Circuit.

We present a technique for performing endovascular procedures by obtaining vascular access directly through a venovenous extracorporeal membrane oxygenation (VV ECMO) circuit. This technique is demonstrated in a lung transplant recipient, supported on VV ECMO, whose course was complicated by an extensive right femoral vein and inferior vena cava deep venous thrombosis. The patient was successfully managed by the placement of an inferior vena cava filter using the VV ECMO circuit as a point of access to the circulatory system before cessation of VV ECMO support and decannulation.

A Single Dose of Dietary Nitrate Increases Maximal Knee Extensor Angular Velocity and Power in Healthy Older Men and Women.

BACKGROUND: Aging results in reductions in maximal muscular strength, speed, and power, which often lead to functional limitations highly predictive of disability, institutionalization, and mortality in elderly adults. This may be partially due to reduced nitric oxide (NO) bioavailability. We, therefore, hypothesized that dietary nitrate (NO3-), a source of NO via the NO3- → nitrite (NO2-) → NO enterosalivary pathway, could increase muscle contractile function in older subjects. METHODS: Twelve healthy older (age 71 ± 5 years) men and women were studied using a randomized, double-blind, placebo-controlled, crossover design. After fasting overnight, subjects were tested 2 hours after ingesting beetroot juice containing or devoid of 13.4 ± 1.6 mmol NO3-. Plasma NO3- and NO2- and breath NO were measured periodically, and muscle function was determined using isokinetic dynamometry. RESULTS: N O 3 - ingestion increased (p < .001) plasma NO3-, plasma NO2-, and breath NO by 1,051% ± 433%, 138% ± 149%, and 111% ± 115%, respectively. Maximal velocity of knee extension increased (p < .01) by 10.9% ± 12.1%. Maximal knee extensor power increased (p < .05) by 4.4% ± 7.8%. CONCLUSIONS: Acute dietary NO3- intake improves maximal knee extensor angular velocity and power in older individuals. These findings may have important implications for this population, in whom diminished muscle function can lead to functional limitations, dependence, and even premature death.

Dietary nitrate-induced increases in human muscle power: high versus low responders.

Maximal neuromuscular power is an important determinant of athletic performance and also quality of life, independence, and perhaps even mortality in patient populations. We have shown that dietary nitrate (NO3- ), a source of nitric oxide (NO), improves muscle power in some, but not all, subjects. The present investigation was designed to identify factors contributing to this interindividual variability. Healthy men (n = 13) and women (n = 7) 22-79 year of age and weighing 52.1-114.9 kg were studied using a randomized, double-blind, placebo-controlled, crossover design. Subjects were tested 2 h after ingesting beetroot juice (BRJ) either containing or devoid of 12.3 ± 0.8 mmol of NO3- . Plasma NO3- and nitrite (NO2- ) were measured as indicators of NO bioavailability and maximal knee extensor speed (Vmax ), power (Pmax ), and fatigability were determined via isokinetic dynamometry. On average, dietary NO3- increased (P < 0.05) Pmax by 4.4 ± 8.1%. Individual changes, however, ranged from -9.6 to +26.8%. This interindividual variability was not significantly correlated with age, body mass (inverse of NO3- dose per kg), body mass index (surrogate for body composition) or placebo trial Vmax or fatigue index (in vivo indicators of muscle fiber type distribution). In contrast, the relative increase in Pmax was significantly correlated (r = 0.60; P < 0.01) with the relative increase in plasma NO2- concentration. In multivariable analysis female sex also tended (P = 0.08) to be associated with a greater increase in Pmax. We conclude that the magnitude of the dietary NO3- -induced increase in muscle power is dependent upon the magnitude of the resulting increase in plasma NO2- and possibly female sex.

Dietary Nitrate Increases VO2peak and Performance but Does Not Alter Ventilation or Efficiency in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) exhibit lower efficiency, dyspnea, and diminished peak oxygen uptake (VO2peak) during exercise. Dietary nitrate (NO3-), a source of nitric oxide (NO), has improved these measures in some studies of other populations. We determined the effects of acute NO3- ingestion on exercise responses in 8 patients with HFrEF using a randomized, double-blind, placebo-controlled, crossover design. METHODS AND RESULTS: Plasma NO3-, nitrite (NO2-), and breath NO were measured at multiple time points and respiratory gas exchange was determined during exercise after ingestion of beetroot juice containing or devoid of 11.2 mmol of NO3-. NO3- intake increased (P < .05-0.001) plasma NO3- and NO2- and breath NO by 1469 ± 245%, 105 ± 34%, and 60 ± 18%, respectively. Efficiency and ventilation during exercise were unchanged. However, NO3- ingestion increased (P < .05) VO2peak by 8 ± 2% (ie, from 21.4 ± 2.1 to 23.0 ± 2.3 mL.min-1.kg-1). Time to fatigue improved (P < .05) by 7 ± 3 % (ie, from 582 ± 84 to 612 ± 81 seconds). CONCLUSIONS: Acute dietary NO3- intake increases VO2peak and performance in patients with HFrEF. These data, in conjunction with our recent data demonstrating that dietary NO3- also improves muscle contractile function, suggest that dietary NO3- supplementation may be a valuable means of enhancing exercise capacity in this population.

Acute Dietary Nitrate Intake Improves Muscle Contractile Function in Patients With Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Trial.

BACKGROUND: Skeletal muscle strength, velocity, and power are markedly reduced in patients with heart failure, which contributes to their impaired exercise capacity and lower quality of life. This muscle dysfunction may be partially because of decreased nitric oxide (NO) bioavailability. We therefore sought to determine whether ingestion of inorganic nitrate (NO3 (-)) would increase NO production and improve muscle function in patients with heart failure because of systolic dysfunction. METHODS AND RESULTS: Using a double-blind, placebo-controlled, randomized crossover design, we determined the effects of dietary NO3 (-) in 9 patients with heart failure. After fasting overnight, subjects drank beetroot juice containing or devoid of 11.2 mmol of NO3 (-). Two hours later, muscle function was assessed using isokinetic dynamometry. Dietary NO3 (-) increased (P<0.05-0.001) breath NO by 35% to 50%. This was accompanied by 9% (P=0.07) and 11% (P<0.05) increases in peak knee extensor power at the 2 highest movement velocities tested (ie, 4.71 and 6.28 rad/s). Maximal power (calculated by fitting peak power data with a parabola) was therefore greater (ie, 4.74±0.41 versus 4.20±0.33 W/kg; P<0.05) after dietary NO3 (-) intake. Calculated maximal velocity of knee extension was also higher after NO3 (-) ingestion (ie, 12.48±0.95 versus 11.11±0.53 rad/s; P<0.05). Blood pressure was unchanged, and no adverse clinical events occurred. CONCLUSIONS: In this pilot study, acute dietary NO3 (-) intake was well tolerated and enhanced NO bioavailability and muscle power in patients with systolic heart failure. Larger-scale studies should be conducted to determine whether the latter translates into an improved quality of life in this population. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01682356.

Effect of acute dietary nitrate intake on maximal knee extensor speed and power in healthy men and women.

Nitric oxide (NO) has been demonstrated to enhance the maximal shortening velocity and maximal power of rodent muscle. Dietary nitrate (NO3(-)) intake has been demonstrated to increase NO bioavailability in humans. We therefore hypothesized that acute dietary NO3(-) intake (in the form of a concentrated beetroot juice (BRJ) supplement) would improve muscle speed and power in humans. To test this hypothesis, healthy men and women (n = 12; age = 22-50 y) were studied using a randomized, double-blind, placebo-controlled crossover design. After an overnight fast, subjects ingested 140 mL of BRJ either containing or devoid of 11.2 mmol of NO3(-). After 2 h, knee extensor contractile function was assessed using a Biodex 4 isokinetic dynamometer. Breath NO levels were also measured periodically using a Niox Mino analyzer as a biomarker of whole-body NO production. No significant changes in breath NO were observed in the placebo trial, whereas breath NO rose by 61% (P < 0.001; effect size = 1.19) after dietary NO3(-) intake. This was accompanied by a 4% (P < 0.01; effect size = 0.74) increase in peak knee extensor power at the highest angular velocity tested (i.e., 6.28 rad/s). Calculated maximal knee extensor power was therefore greater (i.e., 7.90 ± 0.59 vs. 7.44 ± 0.53 W/kg; P < 0.05; effect size = 0.63) after dietary NO3(-) intake, as was the calculated maximal velocity (i.e., 14.5 ± 0.9 vs. 13.1 ± 0.8 rad/s; P < 0.05; effect size = 0.67). No differences in muscle function were observed during 50 consecutive knee extensions performed at 3.14 rad/s. We conclude that acute dietary NO3(-) intake increases whole-body NO production and muscle speed and power in healthy men and women.