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Previous work in a 4 h rabbit thrombogenicity model has shown that a nitric oxide- (NO) generating polymer extracorporeal circuits (ECC) with infusion of S- nitroso- N -acetyl-penicillamine (SNAP) preserved platelets eventhough platelets were activated as shown by an increase in the glycoprotein, p-selectin. The platelet preservation mechanism was shown to be due to a changing fibrinogen structure leading to attenuation of platelet aggregation. Understanding the effects that SNAP, another RSNO, S- nitroso-glutathione (GSNO) as well as the non-RSNO, sodium nitroprusside (SNP), may have on human fibrinogen polymerization, this in vitro study evaluated the released NO effects on the thrombin-mediated fibrin formation and fibrinogen structure. Thrombin-induced fibrin formation at 300 μM SNAP (50 + 11% of baseline) was significantly reduced compared to SNAP's parent, N-acetyl-penicillamine (NAP) (95 + 13%) after 1 h of RSNO exposure. GSNO, its parent, glutathione (GSH) and 1000 ppm NO gas did not attenuate the thrombin-mediated fibrin formation. SNAP, NAP and SNP exposure for 1 h, however, did not decrease thrombin activity by directly inhibiting thrombin itself. Changes in fibrinogen conformation as measured by intrinsic tryptophan fluorescence significantly decreased in the 300 μM SNAP (38057 + 1196 mean fluorescence intensity (MFI) and SNP (368617 + 541 MFI) groups versus the NAP control (47937 + 1196 MFI). However, infused 1000 ppm NO gas had no direct effect on the ITF after 1 h incubation at 37°C. High performance liquid chromatography (HPLC) showed that fibrinogen degradation by 0.03 U/ml thrombin was concentration-dependently reduced after 1 h with SNAP but not with NAP or SNP. Western blotting showed RSNOs, SNAP, NAP and the non-RSNO, SNP-incubated fibrinogen solutions showed that the percent level of the Aγ dimer to total Aγ dimer + γ monomer was significantly reduced in the case of the SNAP group when compared to SNP group. These results suggest that NO donors such as SNAP and SNP induce fibrinogen conformational changes by potentially nitrosating fibrinogen tyrosine residues. These NO-mediated fibrinogen changes induced via NO donors may provide another mechanism of NO for improving thromboresistance in ECC.

A new portable gas phase nitric oxide (NO) generator is described for potential applications in inhaled NO (INO) therapy and during cardiopulmonary bypass (CPB) surgery. In this system, NO is produced at the surface of a large-area mesh working electrode by electrochemical reduction of nitrite ions in the presence of a soluble copper(II)-ligand electron transfer mediator complex. The NO generated is then transported into gas phase by either direct purging with nitrogen/air or via circulating the electrolyte/nitrite solution through a gas extraction silicone fiber-based membrane-dialyzer assembly. Gas phase NO concentrations can be tuned in the range of 5-1000 ppm (parts per million by volume for gaseous species), in proportion to a constant cathodic current applied between the working and counter electrodes. This new NO generation process has the advantages of rapid production times (5 min to steady-state), high Faraday NO production efficiency (ca. 93%), excellent stability, and very low cost when using air as the carrier gas for NO (in the membrane dialyzer configuration), enabling the development of potentially portable INO devices. In this initial work, the new system is examined for the effectiveness of gaseous NO to reduce the systemic inflammatory response (SIR) during CPB, where 500 ppm of NO added to the sweep gas of the oxygenator or to the cardiotomy suction air in a CPB system is shown to prevent activation of white blood cells (granulocytes and monocytes) during extracorporeal circulation with cardiotomy suction conducted with five pigs.

Purpose: Extracorporeal life support (ECLS) is usually reserved for infants ≥34weeks estimated gestational age (EGA) owing to concerns about increased mortality and incidence of intracranial hemorrhage (ICH). We sought to characterize survival, rates of ICH, and complications in <34week EGA neonates placed on ECLS., Methods: 752 neonates of EGA 29-34weeks were identified in the Extracorporeal Life Support Organization (ELSO) Registry (1976-2008). Data analyzed included birthweight, survival, pre-ECLS conditions, ventilatory parameters and complications (including ICH and other neurological outcomes). Data were compared using t-test, Chi-square and logistic regression analyses., Results: When compared to survival rates of 34week EGA neonates (58%), survival was statistically different for 29-33week EGA (48%, p=0.05). No significant difference in ICH incidence was seen between the 29-33week and 34week groups (21% vs. 17%, respectively), but a significant difference was seen in the incidence of cerebral infarct between groups (22% for 29-33weeks vs. 16% for 34weeks; p=0.03). ICH and survival did not correlate with EGA during logistic regression analysis., Conclusions: Though rates of survival and cerebral infarction were worse at 29-33weeks EGA compared with 34weeks, these differences were modest and may be clinically acceptable. This suggests that EGA<34weeks may not be an absolute contraindication to use of ECLS., Level of Evidence: III., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Prolonged normothermic ex vivo heart perfusion could transform cardiac transplantation. To help identify perfusate components that might enable long-term perfusion, we evaluated the effects of cross-circulated whole blood and cross-circulated plasma from a live paracorporeal animal on donor porcine hearts preserved via normothermic ex vivo heart perfusion. Standard perfusion (SP; n = 40) utilized red blood cell/plasma perfusate and Langendorff technique for a goal of 12 hours. Cross-circulation groups used a similar circuit with the addition of cross-circulated venous whole blood (XC-blood; n = 6) or cross-circulated filtered plasma (XC-plasma; n = 7) between a live paracorporeal pig under anesthesia and the perfusate reservoir. Data included oxygen metabolism, vascular resistance, lactate production, left ventricular function, myocardial electrical impedance, and histopathologic injury score. All cross-circulation hearts were successfully perfused for 12 hours, compared with 22 of 40 SP hearts (55%; p = 0.002). Both cross-circulation groups demonstrated higher oxygen consumption and vascular resistance than standard hearts from hours 3-12. No significant differences were seen between XC-blood and XC-plasma hearts in any variable, including left ventricular dP/dT after 12 hours (1478 ± 700 mm Hg/s vs. 872 ± 500; p = 0.17). We conclude that cross circulation of whole blood or plasma from a live animal improves preservation of function of perfused hearts, and cross-circulated plasma performs similarly to cross-circulated whole blood.

The first successful neonatal extracorporeal membrane oxygenation case (1975) is important in the development of extracorporeal life support, but the case report was never published. This is the report of that case with commentary on the evolution of extracorporeal membrane oxygenation since 1975.

Current hollow fiber membrane lungs feature a predominantly straight blood path length across the fiber bundle, resulting in limited O2 transfer efficiency because of the diffusion boundary layer effect. Using computational fluid dynamics and optical flow visualization methods, a hollow fiber membrane lung was designed comprising unique concentric circular blood flow paths connected by gates. The prototype lung, comprising a fiber surface area of 0.28 m, has a rated flow of 2 L/min, and the oxygenation efficiency is 357 ml/min/m. The CO2 clearance of the lung is 200 ml/min at the rated blood flow. Given its high gas transfer efficiency, as well as its compact size, low priming volume, and propensity for minimal thrombogenicity, this lung design has the potential to be used in a range of acute and chronic respiratory support applications, including providing total respiratory support for infants and small children and CO2 clearance in adults.

In the past the only option for the treatment of respiratory failure due to acute exacerbation of chronic obstructive pulmonary disease (aeCOPD) was invasive mechanical ventilation. In recent decades, the potential for extracorporeal carbon dioxide (CO 2 ) removal has been realized. We review the various types of extracorporeal CO 2 removal, outline the optimal use of these therapies for aeCOPD, and make suggestions for future controlled trials. We also describe the advantages and requirements for an ideal long-term ambulatory CO 2 removal system for palliation of COPD.

Stable and long-term nitric oxide (NO) releasing polymeric materials have many potential biomedical applications. Herein, we report the real-time observation of the crystallization process of the NO donor, S -nitroso- N -acetylpenicillamine (SNAP), within a thermoplastic silicone-polycarbonate-urethane biomedical polymer, CarboSil 20 80A. It is demonstrated that the NO release rate from this composite material is directly correlated with the surface area that the CarboSil polymer film is exposed to when in contact with aqueous solution. The decomposition of SNAP in solution (e.g. PBS, ethanol, THF, etc.) is a pseudo-first-order reaction proportional to the SNAP concentration. Further, catheters fabricated with this novel NO releasing composite material are shown to exhibit significant effects on preventing biofilm formation on catheter surface by Pseudomonas aeruginosa and Proteus mirabilis grown in CDC bioreactor over 14 days, with a 2 and 3 log-unit reduction in number of live bacteria on their surfaces, respectively. Therefore, the SNAP-CarboSil composite is a promising new material to develop antimicrobial catheters, as well as other biomedical devices.

Management of gas exchange using extracorporeal membrane oxygenation (ECMO) in respiratory failure is very different than management when the patient is dependent on mechanical ventilation. All the gas exchange occurs in the membrane lung, and the arterial oxygenation is the result of mixing the ECMO blood with the native venous blood. To manage patients on ECMO, it is essential to understand the physiology described in this essay.

Nitric oxide (NO) has many important physiological functions, including its ability to inhibit platelet activation and serve as potent antimicrobial agent. The multiple roles of NO in vivo have led to great interest in the development of biomaterials that can deliver NO for specific biomedical applications. Herein, we report a simple solvent impregnation technique to incorporate a nontoxic NO donor, S -nitroso- N -acetylpenicillamine (SNAP), into a more biocompatible biomedical grade polymer, CarboSil 20 80A. The resulting polymer-crystal composite material yields a very stable, long-term NO release biomaterial. The SNAP impregnation process is carefully characterized and optimized, and it is shown that SNAP crystal formation occurs in the bulk of the polymer after solvent evaporation. LC-MS results demonstrate that more than 70% of NO release from this new composite material originates from the SNAP embedded CarboSil phase, and not from the SNAP species leaching out into the soaking solution. Catheters prepared with CarboSil and then impregnated with 15 wt % SNAP provide a controlled NO release over a 14 d period at physiologically relevant fluxes and are shown to significantly reduce long-term (14 day) bacterial biofilm formation against Staphylococcus epidermidis and Pseudonomas aeruginosa in a CDC bioreactor model. After 7 h of catheter implantation in the jugular veins of rabbit, the SNAP CarboSil catheters exhibit a 96% reduction in thrombus area (0.03 ± 0.01 cm 2 /catheter) compared to the controls (0.84 ± 0.19 cm 2 /catheter) ( n = 3). These results suggest that SNAP impregnated CarboSil can become an attractive new biomaterial for use in preparing intravascular catheters and other implanted medical devices.

Lung disease in children often results in pulmonary hypertension and right heart failure. The availability of a pediatric artificial lung (PAL) would open new approaches to the management of these conditions by bridging to recovery in acute disease or transplantation in chronic disease. This study investigates the efficacy of a novel PAL in alleviating an animal model of pulmonary hypertension and increased right ventricle afterload. Five juvenile lambs (20-30 kg) underwent PAL implantation in a pulmonary artery to left atrium configuration. Induction of disease involved temporary, reversible occlusion of the right main pulmonary artery. Hemodynamics, pulmonary vascular input impedance, and right ventricle efficiency were measured under 1) baseline, 2) disease, and 3) disease + PAL conditions. The disease model altered hemodynamics variables in a manner consistent with pulmonary hypertension. Subsequent PAL attachment improved pulmonary artery pressure (p = 0.018), cardiac output (p = 0.050), pulmonary vascular input impedance (Z.0 p = 0.028; Z.1 p = 0.058), and right ventricle efficiency (p = 0.001). The PAL averaged resistance of 2.3 ± 0.8 mm Hg/L/min and blood flow of 1.3 ± 0.6 L/min. This novel low-resistance PAL can alleviate pulmonary hypertension in an acute animal model and demonstrates potential for use as a bridge to lung recovery or transplantation in pediatric patients with significant pulmonary hypertension refractory to medical therapies.

Background: Vascularized composite allografts, particularly hand and forearm, have limited ischemic tolerance after procurement. In bilateral hand transplantations, this demands a 2 team approach and expedited transfer of the allograft, limiting the recovery to a small geographic area. Ex situ perfusion may be an alternative allograft preservation method to extend allograft survival time. This is a short report of 5 human limbs maintained for 24 hours with ex situ perfusion., Methods: Upper limbs were procured from brain-dead organ donors. Following recovery, the brachial artery was cannulated and flushed with 10 000 U of heparin. The limb was then attached to a custom-made, near-normothermic (30-33°C) ex situ perfusion system composed of a pump, reservoir, and oxygenator. Perfusate was plasma-based with a hemoglobin concentration of 4 to 6 g/dL., Results: Average warm ischemia time was 76 minutes. Perfusion was maintained at an average systolic pressure of 93 ± 2 mm Hg, flow 310 ± 20 mL/min, and vascular resistance 153 ± 16 mm Hg/L per minute. Average oxygen consumption was 1.1 ± 0.2 mL/kg per minute. Neuromuscular electrical stimulation continually displayed contraction until the end of perfusion, and histology showed no myocyte injury., Conclusions: Human limb allografts appeared viable after 24 hours of near-normothermic ex situ perfusion. Although these results are early and need validation with transplantation, this technology has promise for extending allograft storage times.

A pediatric artificial lung (PAL) is under development as a bridge to transplantation or lung remodeling for children with end-stage lung failure (ESLF). To evaluate the efficiency of a PAL, a disease model mimicking the physiologic derangements of pediatric ESLF is needed. Our previous right pulmonary artery (rPA) ligation model (rPA-LM) achieved that goal, but caused immediate mortality in nearly half of the animals. In this study, we evaluated a new technique of gradual postoperative right pulmonary artery occlusion using a Rummel tourniquet (rPA-RT) in seven (25-40 kg) sheep. This technique created a stable model of ESLF pathophysiology, characterized by high alveolar dead space (58.0% ± 3.8%), pulmonary hypertension (38.4 ± 2.2 mm Hg), tachypnea (79 ± 20 breaths per minute), and intermittent supplemental oxygen requirement. This improvement to our technique provides the necessary physiologic derangements for testing a PAL, whereas avoiding the problem of high immediate perioperative mortality.

Objectives: To assess the current attitudes of extracorporeal membrane oxygenation (ECMO) program directors regarding eligibility for ECMO among children with cardiopulmonary failure., Study Design: Electronic cross-sectional survey of ECMO program directors at ECMO centers worldwide within the Extracorporeal Life Support Organization directory (October 2015-December 2015)., Results: Of 733 eligible respondents, 226 (31%) completed the survey, 65% of whom routinely cared for pediatric patients. There was wide variability in whether respondents would offer ECMO to any of the 5 scenario patients, ranging from 31% who would offer ECMO to a child with trisomy 18 to 76% who would offer ECMO to a child with prolonged cardiac arrest and indeterminate neurologic status. Even physicians practicing the same specialty sometimes held widely divergent opinions, with 50% of pediatric intensivists stating they would offer ECMO to a child with severe developmental delay and 50% stating they would not. Factors such as quality of life and neurologic status influenced decision making and were used to support decisions for and against offering ECMO., Conclusions: ECMO program directors vary widely in whether they would offer ECMO to various children with cardiopulmonary failure. This heterogeneity in physician decision making underscores the need for more evidence that could eventually inform interinstitutional guidelines regarding patient selection for ECMO., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Robert Bartlett, emeritus Professor of surgery at the University of Michigan in Ann Arbor, USA, transformed classical works of world literature (Charles Dickens: A Christmas Carol, Lewis Carroll: Alice in Wonderland) into teaching aids for advanced training in intensive care medicine. He recently turned his hand to the well-known work of Ernest Hemingway: the Nobel Prize winning novel The Old Man and the Sea. Subsequent to Robert Bartlett's essay this article provides background information and comments on the current problems in modern intensive care medicine addressed in his essay.

Blood-contacting devices, such as intravascular catheters, suffer from challenges related to thrombus formation and infection. Nitric oxide (NO) is an endogenous antiplatelet and antimicrobial agent. Exogenous release of NO from various polymer matrices has been shown to reduce thrombosis and infection of/on implantable medical devices. However, the clinical applications of such materials have been hindered due to factors such as NO donor leaching and thermal instability. In this study, a novel approach is demonstrated in which one lumen of commercial dual lumen catheters is dedicated to the NO release chemistry, allowing the other lumen to be available for clinical vascular access. A composite consisting of poly(ethylene glycol) (PEG) and S-nitroso-N-acetylpenicillamine (SNAP) is used to fill the NO-releasing lumen of commercial 7 French silicone catheters. Physiological levels of NO are released from the SNAP-PEG catheters for up to 14 d, as measured by chemiluminescence NO analyzer (in PBS buffer at 37 °C). PEG facilitates the NO release from SNAP within the lumen by increasing the water absorption and slowly dissolving the solid SNAP-PEG composite. In a CDC biofilm bioreactor, the SNAP-PEG catheters are found to reduce >97% bacterial adhesion as compared to the PEG controls for single bacterial species including E. coli and S. aureus. SNAP-PEG and PEG control catheters were implanted in rabbit veins for 7 h (single lumen) and 11 d (dual lumen) to evaluate their hemocompatibility properties. Significant reductions in thrombus formation on the SNAP-PEG vs PEG controls were observed, with ca. 85% reduction for 7 h single lumen catheters and ca. 55% reduction for 11 d dual lumen catheters.

Unlabelled: Two major problems with implanted catheters are clotting and infection. Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion/activation and an antimicrobial agent, and NO-releasing polymers are expected to have similar properties. Here, NO-releasing central venous catheters (CVCs) are fabricated using Elast-eon™ E2As polymer with both diazeniumdiolated dibutylhexanediamine (DBHD/NONO) and poly(lactic-co-glycolic acid) (PLGA) additives, where the NO release can be modulated and optimized via the hydrolysis rate of the PLGA. It is observed that using a 10% w/w additive of a PLGA with ester end group provides the most controlled NO release from the CVCs over a 14d period. The optimized DBHD/NONO-based catheters are non-hemolytic (hemolytic index of 0%) and noncytotoxic (grade 0). After 9d of catheter implantation in the jugular veins of rabbits, the NO-releasing CVCs have a significantly reduced thrombus area (7 times smaller) and a 95% reduction in bacterial adhesion. These results show the promise of DBHD/NONO-based NO releasing materials as a solution to achieve extended NO release for longer term prevention of clotting and infection associated with intravascular catheters., Statement of Significance: Clotting and infection are significant complications associated with central venous catheters (CVCs). While nitric oxide (NO) releasing materials have been shown to reduce platelet activation and bacterial infection in vitro and in short-term animal models, longer-term success of NO-releasing materials to further study their clinical potential has not been extensively evaluated to date. In this study, we evaluate diazeniumdiolate based NO-releasing CVCs over a 9d period in a rabbit model. The explanted NO-releasing CVCs were found to have significantly reduced thrombus area and bacterial adhesion. These NO-releasing coatings can improve the hemocompatibility and bactericidal activity of intravascular catheters, as well as other medical devices (e.g., urinary catheters, vascular grafts)., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The veno-venoarterial (VVA) mode of extracorporeal membrane oxygenation (ECMO) is defined by having both venous and arterial reinfusion cannulas. It is purposed to improve upper body oxygenation as the venous reinfusion cannula is typically placed in the upper body. We performed a single-center retrospective review to better characterize the patients placed on this mode. Adults (n = 23) were 40.4 ± 14.7 years old and were supported with ECMO for a median of 141 (97, 253) hours, with VVA support 110 (63, 179) hours. Ten (43%) were initially cannulated VVA; reasons for conversion included cardiac failure (46%), North-South syndrome (38%), and worsening hypoxia (15%). Survival was 39% and neurological complications 13%. Pediatrics (n = 8) were 13.0 ± 2.4 years old and were supported with ECMO for a median of 258 (168, 419) hours, with VVA support 131 (98, 161) hours. One (12.5%) was initially cannulated VVA; reasons for conversion were North-South syndrome (42%), cardiac failure (29%), and worsening hypoxia (29%). Survival was 71% and neurological complications 29%. We concluded that there was neither survival advantage nor complication reduction with the VVA mode in this cohort; however, VVA does have value for unique clinical situations when conventional ECMO modes do not meet support needs.

Biomedical devices are essential for patient diagnosis and treatment; however, when blood comes in contact with foreign surfaces or homeostasis is disrupted, complications including thrombus formation and bacterial infections can interrupt device functionality, causing false readings and/or shorten device lifetime. Here, we review some of the current approaches for developing antithrombotic and antibacterial materials for biomedical applications. Special emphasis is given to materials that release or generate low levels of nitric oxide (NO). Nitric oxide is an endogenous gas molecule that can inhibit platelet activation as well as bacterial proliferation and adhesion. Various NO delivery vehicles have been developed to improve NO's therapeutic potential. In this review, we provide a summary of the NO releasing and NO generating polymeric materials developed to date, with a focus on the chemistry of different NO donors, the polymer preparation processes, and in vitro and in vivo applications of the two most promising types of NO donors studied thus far, N-diazeniumdiolates (NONOates) and S-nitrosothiols (RSNOs).

Clinical research to evaluate the effectiveness of life support systems in acute fatal illness has unique problems of logistics, ethics, and consent. There have been 10 prospective comparative trials of extracorporeal membrane oxygenation in acute fatal respiratory failure, utilizing different study designs. The trial designs were prospective controlled randomized, prospective adaptive randomized, sequential, and matched pairs. The trials were reviewed with regard to logistics, ethics, consent, statistical methods, economics, and impact. The matched pairs method is the best study design for evaluation of life support systems in acute fatal illness., (© The Author(s) 2014.)

Although total body perfusion with extracorporeal life support (ECLS) can be maintained for weeks, individual organ perfusion beyond 12 hours has yet to be achieved clinically. Normothermic ex situ heart perfusion (ESHP) offers the potential for prolonged cardiac preservation. We developed an ESHP system to study the effect of perfusate variables on organ preservation, with the ultimate goal of extending organ perfusion for ≥24 hours. Forty porcine hearts were perfused for a target of 12 hours. Hearts that maintained electromechanical activity and had a <3× increase in vascular resistance were considered successful preservations. Perfusion variables, metabolic byproducts, and histopathology were monitored and sampled to identify factors associated with preservation failure. Twenty-two of 40 hearts were successfully preserved at 12 hours. Successful 12 hour experiments demonstrated lower potassium (4.3 ± 0.8 vs. 5.0 ± 1.2 mmol/L; p = 0.018) and lactate (3.5 ± 2.8 vs. 4.5 ± 2.9 mmol/L; p = 0.139) levels, and histopathology revealed less tissue damage (p = 0.003) and less weight gain (p = 0.072). Results of these early experiments suggest prolonged ESHP is feasible, and that elevated lactate and potassium levels are associated with organ failure. Further studies are necessary to identify the ideal perfusate for normothermic ESHP.

Objective: The objective of this report is to review the physiology and management of anemia in critical care. Selected publications on physiology and transfusion related to anemia and critical care, including the modern randomized trials of conservative versus liberal transfusion policy, were used. Anemia is compensated and tolerated in most critically ill patients as long as oxygen delivery is at least twice oxygen consumption. There are risks to blood transfusion which can be minimized by blood banking practice. The availability of cultured red cells may allow correction of anemia without significant risk. The benefit of transfusion in anemia must be weighted against the risk in any specific patient., Conclusion and Recommendation: In a criticially ill patient, anemia should be managed to avoid oxygen supply dependency (oxygen delivery less than twice comsumption) and to maintain moderate oxygen delivery reserve (DO2/VO2 > 3)., (© The Author(s) 2015.)

Objective: To develop and validate the Neonatal Risk Estimate Score for Children Using Extracorporeal Respiratory Support, which estimates the risk of in-hospital death for neonates prior to receiving respiratory extracorporeal membrane oxygenation (ECMO) support., Study Design: We used an international ECMO registry (2008-2013); neonates receiving ECMO for respiratory support were included. We divided the registry into a derivation sample and internal validation sample, by calendar date. We chose candidate variables a priori based on published evidence of association with mortality; variables independently associated with mortality in logistic regression were included in this parsimonious model of risk adjustment. We evaluated model discrimination with the area under the receiver operating characteristic curve (AUC), and we evaluated calibration with the Hosmer-Lemeshow goodness-of-fit test., Results: During 2008-2013, 4592 neonates received ECMO respiratory support with mortality of 31%. The development dataset contained 3139 patients treated in 2008-2011. The Neo-RESCUERS measure had an AUC of 0.78 (95% CI 0.76-0.79). The validation cohort had an AUC = 0.77 (0.75-0.80). Patients in the lowest risk decile had an observed mortality of 7.0% and a predicted mortality of 4.4%, and those in the highest risk decile had an observed mortality of 65.6% and a predicted mortality of 67.5%., Conclusions: Neonatal Risk Estimate Score for Children Using Extracorporeal Respiratory Support offers severity-of-illness adjustment for neonatal patients with respiratory failure receiving ECMO. This score may be used to adjust patient survival to assess hospital-level performance in ECMO-based care., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Blood-contacting devices, including extracorporeal circulation (ECC) circuits, can suffer from complications due to platelet activation and thrombus formation. Development of nitric oxide (NO) releasing polymers is one method to improve hemocompatibility, taking advantage of the ability of low levels of NO to prevent platelet activation/adhesion. In this study a novel solvent swelling method is used to load the walls of silicone rubber tubing with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). This SNAP-silicone rubber tubing exhibits an NO flux of ca. 1×10(-10)molcm(-2)min(-1), which mimics the range of NO release from the normal endothelium, which is stable for at least 4h. Images of the tubing before and after swelling, obtained via scanning electron microscopy, demonstrate that this swelling method has little effect on the surface properties of the tubing. The SNAP-loaded silicone rubber and silicone rubber control tubing are used to fabricate ECC circuits that are evaluated in a rabbit model of thrombogenicity. After 4h of blood flow, the SNAP-loaded silicone rubber circuits were able to preserve the blood platelet count at 64% of baseline (vs. 12% for silicone rubber control). A 67% reduction in the degree of thrombus formation within the thrombogenicity chamber was also observed. This study demonstrates the ability to improve the hemocompatibility of existing/commercial silicone rubber tubing via a simple solvent swelling-impregnation technique, which may also be applicable to other silicone-based blood-contacting devices., Statement of Significance: Localized nitric oxide (NO) release can be achieved from biomedical grade polymers doped with S-nitroso-N-acetylpenicillamine (SNAP). Despite the promising in vitro and in vivo biocompatibility results reported for these NO releasing polymers, many of these materials may face challenges in being translated to clinical applications, especially in the areas of polymer processing and manufacturing. In this study, we report a solvent swelling-impregnation technique to incorporate SNAP into extracorporeal circuit (ECC) tubing. These NO-releasing ECCs were able to attenuate the activation of platelets and maintain their functionality, while significantly reducing the extent of thrombus formation during 4h blood flow in the rabbit model of thrombogenicity., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: To develop and validate the Pediatric Risk Estimation Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS). Ped-RESCUERS is designed to estimate the in-hospital mortality risk for children prior to receiving respiratory extracorporeal membrane oxygenation (ECMO) support., Methods: This study used data from an international registry of patients aged 29 days to less than 18 years who received ECMO support from 2009 to 2014. We divided the registry into development and validation datasets by calendar date. Candidate variables were selected for model inclusion if the variable independently changed the mortality risk by at least 2 % in a Bayesian logistic regression model with in-hospital mortality as the outcome. We characterized the model's ability to discriminate mortality with the area under curve (AUC) of the receiver operating characteristic., Results: From 2009 to 2014, 2458 non-neonatal children received ECMO for respiratory support, with a mortality rate of 39.8 %. The development dataset contained 1611 children receiving ECMO support from 2009 to 2012. The model included the following variables: pre-ECMO pH, pre-ECMO arterial partial pressure of carbon dioxide, hours of intubation prior to ECMO support, hours of admission at ECMO center prior to ECMO support, ventilator type, mean airway pressure, pre-ECMO use of milrinone, and a diagnosis of pertussis, asthma, bronchiolitis, or malignancy. The validation dataset included 438 children receiving ECMO support from 2013 to 2014. The Ped-RESCUERS model from the development dataset had an AUC of 0.690, and the validation dataset had an AUC of 0.634., Conclusions: Ped-RESCUERS provides a novel measure of pre-ECMO mortality risk. Future studies should seek external validation and improved discrimination of this mortality prediction tool.

We are fortunate to live in an age in which biomedical technology has provided us with unprecedented ability to supplant the functions of organs and support the physiologic processes of the human body. Ingenious doctors, physiologists, and engineers helped create these advances with new and innovative ideas. One of these pioneers was Dr. Theodor Kolobow. He is best known for one of his earliest inventions, the spiral coil membrane lung. His contributions to medical innovation, however, are diverse, as he also contributed to advances in hemodialysis, improvements in extracorporeal life support technology/circuit components, and through his laboratory experiments helped shape our current understanding of cardiopulmonary pathophysiology. In retrospect, much of Kolobow's work was unified by the theme of preventing iatrogenic lung injury caused by mechanical ventilation. This tenet became more obvious as his later studies progressed to developing techniques and devices intended to limit ventilator pressures, and prevent bacterial colonization of the lungs. Although he formally retired from his research endeavors in 2009, the impact of his contributions remains prominent in our everyday use of techniques and equipment that he either originated or helped to develop.

Objective: To examine the outcomes of prolonged (≥14 days) extracorporeal membrane oxygenation (P-ECMO) for adult severe respiratory failure and to assess characteristics associated with survival., Background: The use of ECMO for treatment of severe respiratory adult patients is associated with overall survival rates of 50% to 70% with median ECMO duration of 10 days. No prior multi-institutional studies have examined outcomes of P-ECMO for severe respiratory failure., Methods: Data on all adult (≥18 years) patients who required P-ECMO for severe respiratory failure from 1989 to 2013 were extracted from the Extracorporeal Life Support Organization international multi-institutional registry. We examined outcomes over 23 years and compared the 2 more recent time periods of 1989 to 2006 versus 2007 to 2013., Results: Up to 974 patients, mean age 40.2 (18-83) years, had ECMO duration of mean 25.2 days/median 21.0 days (range: 14-208 days). Venovenous ECMO support was most common (venovenous: 79.5%, venoarterial: 9.9%). Reason for ECMO discontinuation included native lung recovery (54%), organ failure (23.7%), family request (6.7%), hemorrhage (2.7%), and diagnosis incompatible with life (5.6%). Forty patients (4.1%) underwent lung transplant with 50% postoperative in-hospital mortality. Increased prevalence of P-ECMO was noted with 72% (701/974) of all cases reported since 2008. Survival to hospital discharge was 45.4% (443/974) and did not vary with ECMO duration. Multivariate logistic regression analysis confirmed that P-ECMO patients 2007 to 2013 had a lower risk of death [odds ratio (OR): 0.650; 95% confidence interval (CI), 0.454-0.929; P = 0.010] compared with 1989 to 2006. Factors independently associated with survival were younger age (OR: 0.983; 95% CI, 0.974-0.993; P < 0.001) and lower PaCO2 (OR, 0.991; 95% CI, 0.986-0.996; P < 0.001)., Conclusions: Prolonged ECMO use for adult respiratory failure was associated with a lower (45.4%) hospital survival rate, compared with prior reported survival rates of short duration ECMO. Prolonged ECMO survival significantly increased in recent years, and increasing ECMO duration did not alter the survival fraction in the 1989 to 2013 study cohort. Although P-ECMO survival rates are less than short ECMO runs, P-ECMO support is justified.

Objective: To investigate the effects of the combination of extracorporeal cardiopulmonary resuscitation and thrombolytic therapy on the recovery of vital organ function after prolonged cardiac arrest., Design: Laboratory investigation., Setting: University laboratory., Subjects: Pigs., Interventions: Animals underwent 30-minute untreated ventricular fibrillation cardiac arrest followed by extracorporeal cardiopulmonary resuscitation for 6 hours. Animals were allocated into two experimental groups: t-extracorporeal cardiopulmonary resuscitation (t-ECPR) group, which received streptokinase 1 million units, and control extracorporeal cardiopulmonary resuscitation (c-ECPR), which did not receive streptokinase. In both groups, the resuscitation protocol included the following physiologic targets: mean arterial pressure greater than 70 mm Hg, cerebral perfusion pressure greater than 50 mm Hg, PaO2 150 ± 50 torr (20 ± 7 kPa), PaCO2 40 ± 5 torr (5 ± 1 kPa), and core temperature 33°C ± 1°C. Defibrillation was attempted after 30 minutes of extracorporeal cardiopulmonary resuscitation., Measurements and Main Results: A cardiac resuscitability score was assessed on the basis of success of defibrillation, return of spontaneous heart beat, weanability from extracorporeal cardiopulmonary resuscitation, and left ventricular systolic function after weaning. The addition of thrombolytic to extracorporeal cardiopulmonary resuscitation significantly improved cardiac resuscitability (3.7 ± 1.6 in t-ECPR vs 1.0 ± 1.5 in c-ECPR). Arterial lactate clearance was higher in t-ECPR than in c-ECPR (40% ± 15% vs 18% ± 21%). At the end of the experiment, the intracranial pressure was significantly higher in c-ECPR than in t-ECPR. Recovery of brain electrical activity, as assessed by quantitative analysis of electroencephalogram signal, and ischemic neuronal injury on histopathologic examination did not differ between groups. Animals in t-ECPR group did not have increased bleeding complications, including intracerebral hemorrhages., Conclusions: In a porcine model of prolonged cardiac arrest, t-ECPR improved cardiac resuscitability and reduced brain edema, without increasing bleeding complications. However, early electroencephalogram recovery and ischemic neuronal injury were not improved.

Purpose of Review: The purpose is to review the development and current application of extracorporeal life support [ECLS, extracorporeal membrane oxygenation (ECMO)] in acute severe respiratory failure., Recent Findings: Extracorporeal support (ECMO) is used for acute severe respiratory failure in advanced ICUs. The current survival rate is 60-70%. Three controlled trials all demonstrated 20-30% improvement in survival compared to conventional care. Patients may now be maintained awake and ambulatory with spontaneous breathing., Summary: ECMO is the next step in the algorithm for management of severe respiratory failure unresponsive to conventional care.

End-stage lung disease (ESLD) causes progressive hypercapnia and dyspnea and impacts quality of life. Many extracorporeal support (ECS) configurations for CO2 removal resolve symptoms but limit ambulation. An ovine model of pumpless ECS using subclavian vessels was developed to allow for ambulatory support. Vascular grafts were anastomosed to the left subclavian vessels in four healthy sheep. A low-resistance membrane oxygenator was attached in an arteriovenous (AV) configuration. Device function was evaluated in each animal while awake and spontaneously breathing and while mechanically ventilated with hypercapnia induced. Sweep gas (FiO2 = 0.21) to the device was increased from 0 to 15 L/min, and arterial and postdevice blood gases, as well as postdevice air, were sampled. Hemodynamics remained stable with average AV shunt flows of 1.34 ± 0.14 L/min. In awake animals, CO2 removal was 3.4 ± 1.0 ml/kg/min at maximum sweep gas flow. Respiratory rate decreased from 60 ± 25 at baseline to 30 ± 11 breaths per minute. In animals with induced hypercapnia, PaCO2 increased to 73.9 ± 15.1. At maximum sweep gas flow, CO2 removal was 3.4 ± 0.4 ml/kg/min and PaCO2 decreased to 49.1 ± 6.7 mm Hg. Subclavian AV access is effective in lowering PaCO2 and respiratory rate and is potentially an effective ambulatory destination therapy for ESLD patients.

Purpose: To test the potential for the ex situ limb perfusion system to prolong limb allograft survival up to 24 hours., Methods: We used 20 swine for the study. In group 1 (control), 4 limbs were perfused with heparin solution and preserved at 4°C for 6 hours. In group 2, 4 limbs were perfused with autologous blood at 27°C to 32°C for 24 hours. In both groups, limbs were transplanted orthotopically to recipients and monitored for 12 hours. In addition to perfusion parameters, we recorded perfusate gases and electrolytes (pH, pCO2, pO2, O2 saturation, Na, K, Cl, Ca, HCO3, glucose, and lactate) and obtained functional electrostimulation hourly throughout the experiment. Histology samples were obtained for TUNEL staining and single-muscle fiber contractility testing., Results: In both groups, hemodynamic variables of circulation remained stable throughout the experiment. Neuromuscular electrical stimulation remained intact until the end of reperfusion in group 2 vs no response in group 1. In group 2, a gradual increase in lactate levels during pump perfusion returned to normal after transplantation. Compared with the contralateral limb in group 2, single-muscle fiber contractility testing showed no significant difference at the end of the experiment., Conclusions: We demonstrated extended limb survival up to 24 hours using normothermic pulsatile perfusion and autologous blood., Clinical Relevance: Successful prolongation of limb survival using ex situ perfusion methods provides with more time for revascularization of an extremity., (Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Since its introduction to bedside clinical practice over 40 years ago, extracorporeal life support (ECLS) has been continually changing and improving as a life-saving technology. Extracorporeal life support disrupts the normal finely maintained balance of coagulation and fibrinolysis by exposing large amounts of blood to nonendothelial surfaces. This leads to an inflammatory response with activation of the coagulation cascade and the need for systemic anticoagulation. Unfractionated heparin (UNFH) is currently the standard anticoagulant in ECLS. Alternative anticoagulants have been recently developed with improved safety profiles and reliable monitoring. Within this group of agents are the direct thrombin inhibitors (DTIs) bivalirudin and argatroban. The purpose of this article is to compare these DTIs to the current standard of UNFH anticoagulation during ECLS, to evaluate the current literature surrounding the use of these drugs in ECLS, and finally to propose therapeutic guidelines for their use in ECLS.

The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-D-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC-MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer-crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4-4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.

Background: Organ perfusion systems have successfully been applied in solid organ transplantations. Their use in limb transplantation and replantation has not been widely investigated. In this study, we tested the potential for ex situ perfusion system to prolong limb allograft viability in a swine forelimb amputation/replantation model., Methods: Fourteen swine were used. In group 1 (n = 4), we perfused 4 amputated limbs for 12 hours using warm (27 °C-32 °C) autologous blood. Group 2 (n = 3) served as a cold preservation control group, preserving limbs for 6 hours at 4 °C. All limbs were transplanted into healthy swine (n = 7) and observed for another 12 hours. Hemodynamic variables of circulation, as well as perfusate gases and electrolytes (pH, pCO2, pO2, O2 saturation, Na(+), K(+), Cl(-), Ca(2+), HCO3(-), glucose, lactate) were measured. Muscle samples were used to measure single-muscle fiber contractility., Results: In the control group, no microcirculation was observed after 6 hours of cold storage. In the pump perfusion group, all limbs displayed a gradual increase in lactate levels (P < 0.05) during ex situ perfusion that returned to normal after transplantation and reperfusion (P = 0.05). The pH and potassium remained stable throughout the experiment. Single-muscle fiber contractility testing showed near normal contractility at the end of the reperfusion period (P > 0.05). Limb weight did not increase significantly between the end of pump perfusion and reperfusion (P > 0.05)., Conclusions: We demonstrated the potential to preserve limb allograft using ex vivo circulation. This approach promises to extend the narrow time frame for revascularization of procured extremities in limb transplantation.

A novel electrochemically controlled release method for nitric oxide (NO) (based on electrochemical reduction of nitrite ions) is combined with an amperometric oxygen sensor within a dual lumen catheter configuration for the continuous in vivo sensing of the partial pressure of oxygen (PO2) in blood. The on-demand electrochemical NO generation/release method is shown to be fully compatible with amperometric PO2 sensing. The performance of the sensors is evaluated in rabbit veins and pig arteries for 7 and 21 h, respectively. Overall, the NO releasing sensors measure both venous and arterial PO2 values more accurately with an average deviation of -2 ± 11% and good correlation (R(2) = 0.97) with in vitro blood measurements, whereas the corresponding control sensors without NO release show an average deviation of -31 ± 28% and poor correlation (R(2) = 0.43) at time points >4 h after implantation in veins and >6 h in arteries. The NO releasing sensors induce less thrombus formation on the catheter surface in both veins and arteries (p < 0.05). This electrochemical NO generation/release method could offer a new and attractive means to improve the biocompatibility and performance of implantable chemical sensors.

Inexpensive nitric oxide (NO) release strategies to prevent thrombosis and bacterial infections are desirable for implantable medical devices. Herein, we demonstrate the utility of electrochemically modulated NO release from a catheter model using an inner copper wire working electrode and an inorganic nitrite salt solution reservoir. These catheters generate NO surface fluxes of >1.0 × 10(-10)mol min(-1) cm(-2) for more than 60 h. Catheters with an NO flux of 1.1 × 10(-10)mol min(-1) cm(-2) are shown to significantly reduce surface thrombus formation when implanted in rabbit veins for 7h. Further, the ability of these catheters to exhibit anti-biofilm properties against bacterial species commonly causing bloodstream and urinary catheter infections is examined. Catheters releasing NO continuously during the 2d growth of Staphylococcus aureus exhibit a 6 log-unit reduction in viable surface bacteria. We also demonstrate that catheters generating NO for only 3h at a flux of 1.0 × 10(-10)mol min(-1) cm(-2) lower the live bacterial counts of both 2d and 4d pre-formed Escherichia coli biofilms by >99.9%. Overall, the new electrochemical NO-release devices could provide a cost-effective strategy to greatly enhance the biocompatibility and antimicrobial properties of intravascular and urinary catheters, as well as other implantable medical devices., (Copyright © 2014 Elsevier B.V. All rights reserved.)

An implantable pediatric artificial lung (PAL) may serve as a bridge to lung transplantation for children with end-stage lung failure (ESLF); however, an animal model of pediatric lung failure is needed to evaluate the efficacy of PAL before it can enter clinical trials. The objective of this study was to assess ligation of the right pulmonary artery (rPA) as a model for pediatric ESLF. Seven lambs weighing 20-30 kg underwent rPA ligation and were recovered and monitored for up to 4 days. Intraoperatively, rPA ligation significantly increased physiologic dead space fraction (Vd/Vt; baseline = 48.6 ± 5.7%, rPA ligation = 60.1 ± 5.2%, p = 0.012), mean pulmonary arterial pressure (mPPA; baseline = 17.4 ± 2.2 mm Hg, rPA ligation = 28.5 ± 5.2 mm Hg, p < 0.001), and arterial partial pressure of carbon dioxide (baseline = 40.4 ± 9.3 mm Hg, rPA ligation = 57.3 ± 12.7 mm Hg, p = 0.026). Of the seven lambs, three were unable to be weaned from mechanical ventilation postoperatively, three were successfully weaned but suffered cardiorespiratory failure within 4 days, and one survived all 4 days. All four animals that were successfully weaned from mechanical ventilation had persistent pulmonary hypertension (mPPA = 28.6 ± 2.2 mm Hg) and remained tachypneic (respiratory rate = 63 ± 21 min). Three of the four recovered lambs required supplemental oxygen. We conclude that rPA ligation creates the physiologic derangements commonly seen in pediatric ESLF and may be suitable for testing and implanting a PAL.

Donation from uncontrolled circulatory determination of death donors (uDCD) is impractical in United States because of the time needed to organize procurement before irreversible organ damage. Salvaging organs after prolonged warm ischemic time (WIT) may address this limitation. We evaluated the combination of extracorporeal support (ECS) and thrombolytics in a porcine uDCD renal transplant model. Nonanticoagulated uDCD sustained 60 min of WIT, and two groups were studied. Rapid recovery (RR)-uDCD renal grafts procured using the standard quick topical cooling and renal flush, and ECS-assisted donation (E-uDCD), 4 hr ECS plus thrombolytics for in situ perfusion before procurement. All kidneys were flushed and cold stored, followed by transplantation into healthy nephrectomized recipients without immunosuppression. Delayed graft function (DGF) was defined as creatinine more than 5.0 mg/dl on any postoperative day. Twelve kidneys in E-uDCD and 6 in RR-uDCD group were transplanted. All 12 E-uDCD recipients had urine production and adequate function in the first 48 hr, but two grafts (16.7%) had DGF at 96 hr. All six recipients from RR-uDCD group had DGF at 48 hr and were killed. Creatinine and blood urea nitrogen (BUN) levels were significantly lower in E-uDCD compared with RR-uDCD group at 24 hr (2.9 ± 0.7 mg/dl vs. 5.2 ± 0.9 mg/dl) and 48 hr (3.2 ± 0.9 mg/dl vs. 7.2 ± 1.0 mg/dl); BUN levels at 24 and 48 hr were 28.3 ± 6.7 mg/dl vs. 39.5 ± 7.5 mg/dl and 23.9 ± 5.0 mg/dl vs. 46 ± 12.9 mg/dl, respectively. Thrombolytics plus ECS precondition organs in situ yielding functional kidneys in a porcine model of uDCD with 60 min of WIT. This procurement method addresses logistical limitations for uDCD use in the United States and could have a major impact on the organ donor pool.

Historically, patients on extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome have received ventilatory "lung rest" with conventional or high-frequency oscillating ventilators. We present a series of adults treated with high-frequency percussive ventilation (HFPV) to enhance recovery and recruitment during ECMO. Adult respiratory patients, treated between January 2009 and December 2012 were cared for with a combination of standard ECMO practices and a protocol of recruitment strategies, including HFPV. Data are reported as mean ± standard error of the mean, percentage, or median. Comparisons are made by χ for categorical variables and by t-test and Mann-Whitney test for continuous variables. Significance is noted at the 95% confidence level (p < 0.05). There were 39 HFPV patients. They were 39.9 ± 2.2 years of age and had 3.0 ± 0.37 days of mechanical ventilation before the initiation of ECMO. Their pre-ECMO PaO2 to FiO2 ratio (PF ratio) was 52.3 ± 3.0 and their pCO2 was 50.22 ± 2.4. HFPV patients required a mean of 143.1 ± 17.6 hours and a median of 106 hours (range 45.75-350.25) of ECMO support and had a 62% survival to discharge. The post-ECMO PF ratio in the HFPV cohort was 301.8 ± 16.7. A protocolized practice of active recruitment that includes HFPV is associated with reduced duration of ECMO support in adults with respiratory failure.

Rationale: Recent pediatric studies suggest a survival benefit exists for higher-volume extracorporeal membrane oxygenation (ECMO) centers., Objectives: To determine if higher annual ECMO patient volume is associated with lower case-mix-adjusted hospital mortality rate., Methods: We retrospectively analyzed an international registry of ECMO support from 1989 to 2013. Patients were separated into three age groups: neonatal (0-28 d), pediatric (29 d to <18 yr), and adult (≥18 yr). The measure of hospital ECMO volume was age group-specific and adjusted for patient-level case-mix and hospital-level variance using multivariable hierarchical logistic regression modeling. The primary outcome was death before hospital discharge. A subgroup analysis was conducted for 2008-2013., Measurements and Main Results: From 1989 to 2013, a total of 290 centers provided ECMO support to 56,222 patients (30,909 neonates, 14,725 children, and 10,588 adults). Annual ECMO mortality rates varied widely across ECMO centers: the interquartile range was 18-50% for neonates, 25-66% for pediatrics, and 33-92% for adults. For 1989-2013, higher age group-specific ECMO volume was associated with lower odds of ECMO mortality for neonates and adults but not for pediatric cases. In 2008-2013, the volume-outcome association remained statistically significant only among adults. Patients receiving ECMO at hospitals with more than 30 adult annual ECMO cases had significantly lower odds of mortality (adjusted odds ratio, 0.61; 95% confidence interval, 0.46-0.80) compared with adults receiving ECMO at hospitals with less than six annual cases., Conclusions: In this international, case-mix-adjusted analysis, higher annual hospital ECMO volume was associated with lower mortality in 1989-2013 for neonates and adults; the association among adults persisted in 2008-2013.

The usual duration of extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome is 7-10 days. Prolonged duration ECMO (defined as greater than 14 days) is increasingly being documented with native lung recovery or as a bridge to lung transplantation. We report a case of prolonged duration ECMO (6,364 hours, 265 days) requiring no complete circuit exchange. As critical care improves, prolonged ECMO will continue to pose unique technological and ethical challenges that test our expectations of this treatment modality. There is a critical need for diagnostic modalities to provide objective assessment of native lung recovery in patients requiring prolonged duration ECMO.

Thrombosis and infection are two common problems associated with blood-contacting medical devices such as catheters. Nitric oxide (NO) is known to be a potent antimicrobial agent as well as an inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5~4×10 -10 mol cm -2 min -1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, NO-releasing catheters were fabricated by incorporating S -nitroso- N -acetylpenicillamine (SNAP) in the Elast-eon E2As polymer. The SNAP/E2As catheters release physiological levels of NO for up to 20 d, as measured by chemiluminescence. Furthermore, SNAP is stable in the E2As polymer, retaining 89% of the initial SNAP after ethylene oxide (EO) sterilization. The SNAP/E2As and E2As control catheters were implanted in sheep veins for 7 d to examine the effect on thrombosis and bacterial adhesion. The SNAP/E2As catheters reduced the thrombus area when compared to the control (1.56 ± 0.76 and 5.06 ± 1.44 cm 2 , respectively). A 90% reduction in bacterial adhesion was also observed for the SNAP/E2As catheters as compared to the controls. The results suggest that the SNAP/E2As polymer has the potential to improve the hemocompatibility and bactericidal activity of intravascular catheters, as well as other blood-contacting medical devices (e.g., vascular grafts, extracorporeal circuits).

This is a review of the University of Michigan experience with extracorporeal life support (ECLS) also known as extracorporeal membrane oxygenation (ECMO). Two thousand patients were managed with ECMO from 1973 to 2010. The first 1,000 patients were reported previously. Of the 2,000 patients, 74% were weaned from ECLS, and 64% survived to hospital discharge. In patients with respiratory failure, survival to hospital discharge was 84% in 799 neonates, 76% in 239 children, and 50% in 353 adults. Survival in patients with cardiac failure was 45% in 361 children and 38% in 119 adults. ECLS during extracorporeal cardiopulmonary resuscitation was performed in 129 patients, with 41% surviving to discharge. Survival decreased from 74 to 55% between the first and second 1,000 patients. The most common complication was bleeding at sites other than the head, with an incidence of 39%, and the least frequent complication was pump malfunction, with a 2% incidence. Intracranial bleeding or infarction occurred in 8% of patients, with a 43% survival rate. This is the largest series of ECLS at one institution reported in the world to date. Our experience has shown that ECLS saves lives of moribund patients with acute pulmonary and cardiac failure in all age groups.

During veno-venous extracorporeal membrane oxygenation (VV-ECMO) support, optimization of oxygenation can be achieved by therapeutic interventions on both patient physiological variables and adjustment of ECMO settings. Based on the physiology of oxygen delivery during VV-ECMO support, we established the mathematical relationship between the variables which define the oxygenation state: hemoglobin (Hb), extracorporeal blood flow (ECBF), cardiac output (Q), and systemic oxygen consumption (VO2). Assuming constant values for Q and VO2, the model was applied to elucidate the interplay between Hb and ECBF in determining arterial oxygen saturation (SaO2), and the resultant systemic oxygen delivery (DO2) and native venous oxygen saturation (SvO2) in static conditions. At constant VO2 and Q, an inverse relationship exists between Hb and ECBF in determining SaO2 and SvO2. Despite the same value of SaO2, the DO2 resulting from the different combinations of Hb and ECBF progressively decreases with decreasing Hb. By demonstrating the quantitative relationship between Hb and ECBF as determinants of oxygenation during VV-ECMO support, this mathematical model could provide a theoretical basis for a rational approach to strategies to optimize oxygenation in patients on VV-ECMO.

Hemocompatibility is the goal for any biomaterial contained in extracorporeal life supporting medical devices. The hallmarks for hemocompatibility include nonthrombogenicity, platelet preservation, and maintained platelet function. Both in vitro and in vivo assays testing for compatibility of the blood/biomaterial interface have been used over the last several decades to ascertain if the biomaterial used in medical tubing and devices will require systemic anticoagulation for viability. Over the last 50 years systemic anticoagulation with heparin has been the gold standard in maintaining effective extracorporeal life supporting. However, the biomaterial that maintains effective ECLS without the use of any systemic anticoagulant has remained elusive. In this review, the in vivo 4-h rabbit thrombogenicity model genesis will be described with emphasis on biomaterials that may require no systemic anticoagulation for extracorporeal life supporting longevity. These novel biomaterials may improve extracorporeal circulation hemocompatibility by preserving near resting physiology of the major blood components, the platelets and monocytes. The rabbit extracorporeal circulation model provides a complete assessment of biomaterial interactions with the intrinsic coagulation players, the circulating platelet and monocytes. This total picture of blood/biomaterial interaction suggests that this rabbit thrombogenicity model could provide a standardization for biomaterial hemocompatibility testing., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Nitric oxide (NO) has many biological roles (e.g. antimicrobial agent, promoter of angiogenesis, prevention of platelet activation) that make NO releasing materials desirable for a variety of biomedical applications. Localized NO release can be achieved from biomedical grade polymers doped with diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) and poly(lactic-co-glycolic acid) (PLGA). In this study, the optimization of this chemistry to create film/patches that can be used to decrease microbial infection at wound sites is examined. Two polyurethanes with different water uptakes (Tecoflex SG-80A (6.2±0.7wt.%) and Tecophilic SP-60D-20 (22.5±1.1wt.%)) were doped with 25wt.% DBHD/N2O2 and 10wt.% of PLGA with various hydrolysis rates. Films prepared with the polymer that has the higher water uptake (SP-60D-20) were found to have higher NO release and for a longer duration than the polyurethane with the lower water uptake (SG-80A). The more hydrophilic polymer enhances the hydrolysis rate of the PLGA additive, thereby providing a more acidic environment that increases the rate of NO release from the NO donor. The optimal NO releasing and control SG-80A patches were then applied to scald burn wounds that were infected with Acinetobacter baumannii. The NO released from these patches applied to the wounds is shown to significantly reduce the A. baumannii infection after 24h (∼4 log reduction). The NO release patches are also able to reduce the level of transforming growth factor-β in comparison to controls, which can enhance re-epithelialization, decrease scarring and reduce migration of bacteria. The combined DBHD/N2O2 and PLGA-doped polymer patches, which could be replaced periodically throughout the wound healing process, demonstrate the potential to reduce risk of bacterial infection and promote the overall wound healing process., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Interfacility transport of patients on extracorporeal membrane oxygenation (ECMO) has been performed in large numbers at only a few programs. Limited data are available on outcomes after ECMO transport to justify expanding or discontinuing these programs., Methods: This was a retrospective review of a 20-year, single-institution experience with interhospital ECMO transport as well as a systematic review of reports of transfers of patients on ECMO. Results of both were compared with historical data from the international registry of the Extracorporeal Life Support Organization (ELSO)., Results: Between 1990 and 2012, ECMO was used to facilitate transport of 221 patients to our institution, and 135 (62%) survived to discharge. Review of an additional 27 case series describing ECMO transport of 643 patients showed an overall survival of 61%. After stratifying by age and primary indication for ECMO, survival of transported patients was not significantly different compared with all ECMO patients in the ELSO registry, with the exception of pediatric patients treated for respiratory failure (transported patients in this category had higher survival than those in the ELSO registry)., Conclusions: Interfacility transport on ECMO is feasible and can be accomplished safely in the critically ill. Survival of transported patients is comparable to age-matched and treatment-matched ECMO patients at large., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)