The role of fetal hemoglobin in the artificial placenta: A premature ovine model.

INTRODUCTION: A radical paradigm shift in the treatment of premature infants failing conventional treatment is to recreate fetal physiology using an extracorporeal Artificial Placenta (AP). The aim of this study is to evaluate the effects of changing fetal hemoglobin percent (HbF%) on physiology and circuit function during AP support in an ovine model. METHODS: Extremely premature lambs (n = 5) were delivered by cesarean section at 117-121 d estimated gestational age (EGA) (term = 145d), weighing 2.5 ± 0.35 kg. Lambs were cannulated using 10-14Fr cannulae for drainage via the right jugular vein and reinfusion via the umbilical vein. Lambs were intubated and lungs were filled with perfluorodecalin to a meniscus with a pressure of 5-8 cm H2O. The first option for transfusion was fetal whole blood from twins followed by maternal red blood cells. Arterial blood gases were used to titrate AP support to maintain fetal blood gas values. RESULTS: The mean survival time on circuit was 119.6 ± 39.5 h. Hemodynamic parameters and lactate were stable throughout. As more adult blood transfusions were given to maintain hemoglobin at 10 mg/dL, the HbF% declined, reaching 40% by post operative day 7. The HbF% was inversely proportional to flow rates as higher flows were required to maintain adequate oxygen saturation and perfusion. CONCLUSIONS: Transfusion of adult blood led to decreased fetal hemoglobin concentration during AP support. The HbF% was inversely proportional to flow rates. Future directions include strategies to decrease the priming volume and establishing a fetal blood bank to have blood rich in HbF.

Extracorporeal life support without systemic anticoagulation: a nitric oxide-based non-thrombogenic circuit for the artificial placenta in an ovine model.

BACKGROUND: Clinical translation of the extracorporeal artificial placenta (AP) is impeded by the high risk for intracranial hemorrhage in extremely premature newborns. The Nitric Oxide Surface Anticoagulation (NOSA) system is a novel non-thrombogenic extracorporeal circuit. This study aims to test the NOSA system in the AP without systemic anticoagulation. METHODS: Ten extremely premature lambs were delivered and connected to the AP. For the NOSA group, the circuit was coated with DBHD-N2O2/argatroban, 100 ppm nitric oxide was blended into the sweep gas, and no systemic anticoagulation was given. For the Heparin control group, a non-coated circuit was used and systemic anticoagulation was administered. RESULTS: Animals survived 6.8 ± 0.6 days with normal hemodynamics and gas exchange. Neither group had any hemorrhagic or thrombotic complications. ACT (194 ± 53 vs. 261 ± 86 s; p < 0.001) and aPTT (39 ± 7 vs. 69 ± 23 s; p < 0.001) were significantly lower in the NOSA group than the Heparin group. Platelet and leukocyte activation did not differ significantly from baseline in the NOSA group. Methemoglobin was 3.2 ± 1.1% in the NOSA group compared to 1.6 ± 0.6% in the Heparin group (p < 0.001). CONCLUSIONS: The AP with the NOSA system successfully supported extremely premature lambs for 7 days without significant bleeding or thrombosis. IMPACT: The Nitric Oxide Surface Anticoagulation (NOSA) system provides effective circuit-based anticoagulation in a fetal sheep model of the extracorporeal artificial placenta (AP) for 7 days. The NOSA system is the first non-thrombogenic circuit to consistently obviate the need for systemic anticoagulation in an extracorporeal circuit for up to 7 days. The NOSA system may allow the AP to be implemented clinically without systemic anticoagulation, thus greatly reducing the intracranial hemorrhage risk for extremely low gestational age newborns. The NOSA system could potentially be applied to any form of extracorporeal life support to reduce or avoid systemic anticoagulation.

A Pumpless Pediatric Artificial Lung Maintains Function for 72 h Without Systemic Anticoagulation Using the Nitric Oxide Surface Anticoagulation System.

BACKGROUND: Children with end-stage lung disease are commonly managed with extracorporeal life support (ECLS) as a bridge to lung transplantation. A pumpless artificial lung (MLung) is a portable alternative to ECLS and it allows for ambulation. Both ECLS and pumpless artificial lungs require systemic anticoagulation which is associated with hemorrhagic complications. We tested the MLung with a novel Nitric Oxide (NO) Surface Anticoagulation (NOSA) system, to provide local anticoagulation for 72 h of support in a pediatric-size ovine model. METHODS: Four mini sheep underwent thoracotomy and cannulation of the pulmonary artery (inflow) and left atrium (outflow), recovered and were monitored for 72hr. The circuit tubing and connectors were coated with the combination of an NO donor (diazeniumdiolated dibutylhexanediamine; DBHD-N2O2) and argatroban. The animals were connected to the MLung and 100 ppm of NO was added to the sweep gas. Systemic hemodynamics, blood chemistry, blood gases, and methemoglobin were collected. RESULTS: Mean device flow was 836 ± 121 mL/min. Device outlet saturation was 97 ± 4%. Pressure drop across the lung was 3.5 ± 1.5 mmHg and resistance was 4.3 ± 1.7 mmHg/L/min. Activated clotting time averaged 170 ± 45s. Methemoglobin was 2.9 ± 0.8%. Platelets declined from 590 ± 101 at baseline to 160 ± 90 at 72 h. NO flux (x10-10 mol/min/cm2) of the NOSA circuit averaged 2.8 ± 0.6 (before study) and 1.9 ± 0.1 (72 h) and across the MLung 18 ± 3 NO flux was delivered. CONCLUSION: The MLung is a more portable form of ECLS that demonstrates effective gas exchange for 72 h without hemodynamic changes. Additionally, the NOSA system successfully maintained local anticoagulation without evidence of systemic effects.

Ultrasound-Guided Enteropexy for Repair of Ostomy Prolapse.

Background: Enterostomies provide fecal diversion for numerous conditions, but anatomical complications-prolapse, stricture, and retraction-occur in up to 25%. Given up to 76% of these complications require surgical intervention, effective minimally invasive repair techniques for their management are needed. This article describes a new technique for prolapse repair utilizing image-guided surgery for incisionless repair of ostomy prolapse. Methods: To perform the procedure, the prolapsed bowel is reduced and evaluated for feasibility for ultrasound repair. Under direct ultrasound guidance sutures are used to pexy the bowel loop to the overlying fascia. Sutures are tied with knots and sutures buried below the skin to securely tack the bowel to the abdominal wall. Results: Four patients aged 2-10 years underwent ultrasound-guided enteropexy for repair of major prolapse of an end ileostomy (2 patients), loop colostomy, and end colostomy. All patients remained free of major prolapse for 3-10 months after the procedure, 2 of whom have progressed to ostomy takedown without complications. Conclusions: Ultrasound-guided enteropexy is a noninvasive effective way to manage ostomy prolapse.

Prolonged (24-hour) Normothermic ex vivo Heart Perfusion Facilitated by Perfusate Hemofiltration.

Currently, normothermic ex vivo heart perfusion (NEVHP) is limited to 6-12 hours. NEVHP for 24 hours or more would allow organ treatment, assessment of organ function, and near-perfect recipient matching. We present a model of NEVHP using continuous hemofiltration (HFn) with sustained myocardial viability up to 24 hours. Twenty hearts from 6-10 kg piglets were procured and maintained on our NEVHP circuit. HFn hearts (n = 10) underwent NEVHP with HFn, whereas controls (n = 10) used NEVHP alone. All HFn vs. four controls were viable at 24 h (p = 0.004). At end perfusion, HFn hearts had higher left ventricular systolic pressure (51.5 ± 6.8 mm Hg, 38.3 ± 5.2 mm Hg, p = 0.05), lower coronary resistance (0.83 ± 0.11 mm Hg/mL/min, 1.18 ± 0.21mmHg/mL/min, p < 0.05), and lower serum lactate levels (2.9 ± 0.4 mmol/L, 4.1 ± 0.6 mmol/L, p < 0.0001) when compared to control hearts. HFn hearts also had less extensive myocardial damage and significantly less edema than control hearts with lower weight gain and wet-dry ratios. Using our circuit, NEVHP for 24 hours is possible with HFn and allows for preservation of myocardial function, improved tissue viability, decreased tissue edema, and less myocardial injury.

Seven-day in vivo testing of a novel, low-resistance, pumpless pediatric artificial lung for long-term support.

INTRODUCTION: For children with end-stage lung disease that cannot wean from extracorporeal life support (ECLS), a wearable artificial lung would permit extubation and provide a bridge to recovery or transplantation. We evaluate the function of the novel Pediatric MLung-a low-resistance, pumpless artificial lung developed specifically for children-in healthy animal subjects. METHODS: Adolescent "mini sheep" weighing 12-20 kg underwent left thoracotomy, cannulation of the main pulmonary artery (PA; inflow) and left atrium (outflow), and connection to the MLung. RESULTS: Thirteen sheep were studied; 6 were supported for 7 days. Mean PA pressure was 23.9 ± 6.9 mmHg. MLung blood flow was 633±258 mL/min or 30.0 ± 16.0% of CO. MLung pressure drop was 4.4 ± 3.4 mmHg. Resistance was 7.2 ± 5.2 mmHg/L/min. Device outlet oxygen saturation was 99.0 ± 3.3% with inlet saturation 53.8 ± 7.3%. Oxygen delivery was 41.1 ± 18.4 mL O2/min (maximum 84.9 mL/min) or 2.8 ± 1.5 mL O2/min/kg. Platelet count significantly decreased; no platelet transfusions were required. Plasma free hemoglobin significantly increased only on day 7, at which point 2 of the animals had plasma free hemoglobin levels above 50 mg/dL. CONCLUSION: The MLung provides adequate gas exchange at appropriate blood flows for the pediatric population in a PA-to-LA configuration. Further work remains to improve the biocompatibility of the device. LEVEL OF EVIDENCE: N/A.

Novel Left Atrial Cannulation Technique for Attachment of a Pumpless Artificial Lung.

A pumpless artificial lung has the potential to provide a bridge to recovery or transplantation in children with respiratory failure. Pulmonary artery inflow and left atrial outflow are necessary for low-gradient, pumpless systems; however, long-term cannulation of the fragile left atrium remains problematic. In this technique, the left atrium and pulmonary artery were exposed through a left anterior thoracotomy. Inflow to the artificial lung was created using an end-to-side anastomosis with the pulmonary artery. Device outflow was established through the left atrium. A single-stage venous cannula was passed through a free PTFE graft. Using polypropylene with pledgets, two concentric purse-string sutures were placed in the dome of the left atrium. The venous cannula was inserted. The graft was slid down the cannula and circumferentially secured to the adjacent left atrial tissue and pledgets. The other end of the graft was secured to the cannula with silk ties. The procedure was successful in 10 sheep. Initial device blood flow was 969 ± 222 ml/min, which remained stable for up to 7 days with no anastomotic complications. This is an effective method of achieving secure, long-term left atrial cannulation without cardiopulmonary bypass for use in a low-resistance, pumpless artificial lung. And, most importantly, improves the ease and safety of cannula replacement and final decannulation when AL support is no longer required.

Ultrasound-guided percutaneous central venous access in a neonatal porcine model.

Percutaneous catheterization is currently utilized for central venous access in adult and adolescent porcine models; however, neonatal models require a cut down to gain venous access. This approach requires general anesthesia and can result in systemic inflammation, which can confound studies investigating other inflammatory triggers. Here we present the first successful series of percutaneous, ultrasound-guided, durable central venous access in newborn piglets weighing 1 kg with a novel method of tunneling the catheter subcutaneously using a needle. Catheters (3-5 Fr, single- or double-lumen) were successfully placed in the right jugular vein of eight piglets weighing 1.3 ± 0.4 kg (mean ± standard deviation) with an average duration of catheter patency of 4.5 ± 2.1 days. There were no adverse events from catheter placement, though one catheter was inadvertently removed. This technique is a safe, minimally invasive method for obtaining secure central venous access in a neonatal porcine model.

Hepatic Function in Premature Lambs Supported by the Artificial Placenta and Total Parenteral Nutrition.

The artificial placenta (AP) promotes organ development and reduces organ injury in a lamb model of extreme prematurity. This study evaluates hepatic outcomes after AP support with total parenteral nutrition (TPN) administration. Premature lambs (116-121 days estimated gestational age; term = 145) were cannulated for 7 days of AP support. Lambs received TPN with SMOFlipid (n = 7) or Intralipid (n = 5). Liver function and injury were compared between the two groups biochemically and histologically. Groups were compared by ANOVA with Tukey's multiple comparisons or linear-mixed effects models. From baseline to day 7, total bilirubin (Intralipid 2.6 ± 2.3 to 7.9 ± 4.4 mg/dl; SMOFlipid 0.3 ± 0.1 to 5.5 ± 2.3 mg/dl), alanine aminotransferase, and gamma-glutamyl transferase increased in both groups ( p < 0.001 for all). Direct bilirubin (0.3 ± 0.2 to 1.8 ± 1.4 mg/dl; p = 0.006) and AST (27 ± 5 to 309 ± 242 mg/dl; p < 0.001) increased in SMOFlipid group (not measured in Intralipid group). On liver histology, Intralipid showed more cholestasis than SMOFlipid; both groups showed more than tissue controls. The Intralipid group alone showed hepatocyte injury and had more congestion than controls. Lambs supported by the AP with TPN administration maintain normal hepatic function and sustain minimal hepatic injury. SMOFlipid is associated with decreased cholestasis and hepatic injury versus Intralipid.

A pumpless artificial lung without systemic anticoagulation: The Nitric Oxide Surface Anticoagulation system.

BACKGROUND: Artificial lungs have the potential to serve as a bridge to transplantation or recovery for children with end-stage lung disease dependent on extracorporeal life support, but such devices currently require systemic anticoagulation. We describe our experience using the novel Nitric Oxide (NO) Surface Anticoagulation (NOSA) system-an NO-releasing circuit with NO in the sweep gas-with the Pediatric MLung-a low-resistance, pumpless artificial lung. METHODS: NO flux testing: MLungs (n = 4) were tested using veno-venous extracorporeal life support in a sheep under anesthesia with blood flow set to 0.5 and 1 L/min and sweep gas blended with 100 ppm NO at 1, 2, and 4 L/min. NO and NO2 were measured in the sweep and exhaust gas to calculate NO flux across the MLung membrane. Pumpless implants: Sheep (20-100 kg, n = 3) underwent thoracotomy and cannulation via the pulmonary artery (device inflow) and left atrium (device outflow) using cannulae and circuit components coated with an NO donor (diazeniumdiolated dibutylhexanediamine; DBHD-N2O2) and argatroban. Animals were connected to the MLung with 100 ppm NO in the sweep gas under anesthesia for 24 h with no systemic anticoagulation after cannulation. RESULTS: NO flux testing: NO flux averaged 3.4 ± 1.0 flux units (x10-10 mol/cm2/min) (human vascular endothelium: 0.5-4 flux units). Pumpless implants: 3 sheep survived 24 h with patent circuits. MLung blood flow was 716 ± 227 mL/min. Outlet oxygen saturation was 98.3 ± 2.6%. Activated clotting time was 151±24 s. Platelet count declined from 334,333 ± 112,225 to 123,667 ± 7,637 over 24 h. Plasma free hemoglobin and leukocyte and platelet activation did not significantly change. CONCLUSIONS: The NOSA system provides NO flux across a gas-exchange membrane of a pumpless artificial lung at a similar rate as native vascular endothelium and achieves effective local anticoagulation of an artificial lung circuit for 24 h.

Development of an artificial placenta for support of premature infants: narrative review of the history, recent milestones, and future innovation.

Over 50 years ago, visionary researchers began work on an extracorporeal artificial placenta to support premature infants. Despite rudimentary technology and incomplete understanding of fetal physiology, these pioneering scientists laid the foundation for future work. The research was episodic, as medical advances improved outcomes of premature infants and extracorporeal life support (ECLS) was introduced for the treatment of term and near-term infants with respiratory or cardiac failure. Despite ongoing medical advances, extremely premature infants continue to suffer a disproportionate burden of mortality and morbidity due to organ immaturity and unintended iatrogenic consequences of medical treatment. With advancing technology and innovative approaches, there has been a resurgence of interest in developing an artificial placenta to further diminish the mortality and morbidity of prematurity. Two related but distinct platforms have emerged to support premature infants by recreating fetal physiology: a system based on arteriovenous (AV) ECLS and one based on veno-venous (VV) ECLS. The AV-ECLS approach utilizes only the umbilical vessels for cannulation. It requires immediate transition of the infant at the time of birth to a fluid-filled artificial womb to prevent umbilical vessel spasm and avoid gas ventilation. In contradistinction, the VV-ECLS approach utilizes the umbilical vein and the internal jugular vein. It would be applied after birth to infants failing maximal medical therapy or preemptively if risk stratified for high mortality and morbidity. Animal studies are promising, demonstrating prolonged support and ongoing organ development in both systems. The milestones for clinical translation are currently being evaluated.

Membrane Lung and Blood Pump Use During Prolonged Extracorporeal Membrane Oxygenation: Trends From 2002 to 2017.

Extracorporeal life support (ECLS) has grown in its application since its first clinical description in the 1970s. The technology has been used to support a wide variety of mechanical support modalities and diseases, including respiratory failure, cardiorespiratory failure, and cardiac failure. Over many decades and safety and efficacy studies, followed by randomized clinical trials and thousands of clinical uses, ECLS is considered as an accepted treatment option for severe pulmonary and selected cardiovascular failure. Extracorporeal life support involves the use of support artificial organs, including a membrane lung and blood pump. Over time, changes in the technology and the management of ECLS support devices have evolved. This manuscript describes the use of membrane lungs and blood pumps used during ECLS support from 2002 to 2017 in over 65,000 patients reported to the Extracorporeal Life Support Organization Registry. Device longevity and complications associated with membrane lungs and blood pump are described and stratified by age group: neonates, pediatrics, and adults.

Pediatric and neonatal extracorporeal life support: current state and continuing evolution.

The use of extracorporeal life support (ECLS) for the pediatric and neonatal population continues to grow. At the same time, there have been dramatic improvements in the technology and safety of ECLS that have broadened the scope of its application. This article will review the evolving landscape of ECLS, including its expanding indications and shrinking contraindications. It will also describe traditional and hybrid cannulation strategies as well as changes in circuit components such as servo regulation, non-thrombogenic surfaces, and paracorporeal lung-assist devices. Finally, it will outline the modern approach to managing a patient on ECLS, including anticoagulation, sedation, rehabilitation, nutrition, and staffing.

Salvage Laparoscopic-Assisted Anorectoplasty after Failed Vestibular Fistula Repair Using Magnetic Resonance Image Guidance.

Patients with vestibular fistula have a good functional outcome after posterior sagittal anorectoplasty (PSARP). While continence is often preserved, close follow-up and management of constipation are often required. Redo anorectal surgery has been associated with worse functional outcomes compared with primary procedures, possibly due to injury and scarring of the pelvic floor musculature and sphincter complex. Our group has a growing experience in the use of intraoperative real-time magnetic resonance imaging (MRI) for anorectal malformation repairs. We present a case of salvage operation of a failed PSARP for vestibular fistula.

Efficacy and risk profile of self-expandable stents in the management of pediatric esophageal pathology.

PURPOSE: The purpose of this study was to evaluate the efficacy and risk profile of esophageal stents in the management of complicated pediatric esophageal disease. METHODS: An IRB-approved, single-center, retrospective review was performed on all pediatric patients (n = 13) who underwent esophageal stent placement (2005-2017). Demographic, perioperative, and outcome data were analyzed (p < 0.05). RESULTS: Forty-one stents were placed due to recalcitrant strictures (n = 36), perforations (n = 2), and/or fistulae (n = 3). Median age at initial stent placement was 23.8 months (range, 50 days to 16 years), and median stent duration was 36 days (range, 3-335). The recurrence rate for strictures after initial stent removal was 100%. Four (31%) children subsequently underwent definitive operative repair. There were 5 deaths, including 2 related to stent placement. Seventy-one percent of stents were associated with an adverse event, most commonly intraluminal migration (56%). Younger children experienced an increased risk for airway compression and retching (p = 0.010). CONCLUSION: These data suggest that stents are associated with high complication rates and are not effective as definitive therapy for recalcitrant strictures in children. Although there may be a temporizing role for stents in selected patients, further refinements in stent technologies are needed to help manage this difficult patient population. LEVEL OF EVIDENCE: Level IV.

Routine Use of Distal Arterial Perfusion in Pediatric Femoral Venoarterial Extracorporeal Membrane Oxygenation.

Lower-extremity ischemia is a significant complication in children on femoral venoarterial extracorporeal membrane oxygenation (VA ECMO). Our institution currently routinely uses distal perfusion catheters (DPCs) in all femoral arterial cannulations in attempts to reduce ischemia. We performed a single-center, retrospective review of pediatric patients supported with femoral VA ECMO from January 2005 to November 2015. The outcomes of patients with prophylactic DPC placement at cannulation (prophylactic DPC) were compared to a historical group with DPCs placed in response only to clinically evident ischemic changes (reactive DPC). Ischemic complication requiring invasive intervention (fasciotomy or amputation) was the primary outcome. Twenty-nine patients underwent a total of 31 femoral arterial cannulations, 17 with prophylactic DPC and 14 with reactive DPC. Ischemic complications requiring invasive intervention developed in 2 of 17 (12%) prophylactic DPC patients versus 4 of 14 (29%) reactive DPC. In the reactive DPC group, 7 of 14 (50%) had ischemic changes postcannulation, six underwent DPC placement, and three out of six of these patients still required invasive intervention. One of the seven patients had ischemic changes, did not undergo DPC, and required amputation. While a greater percentage of patients in the prophylactic group was cannulated during extracorporeal cardiopulmonary resuscitation (ECPR), statistical significance was not otherwise demonstrated. We demonstrate feasibility of superficial femoral artery (SFA) access in pediatric patients. We note fewer ischemic complications with prophylactic DPC placement, and observe that salvaging a limb with a reactive DPC was only successful 50% of the time. Although there was no statistical difference in the primary outcome between the two groups, limitations and confounding factors include small sample size and a greater percentage of patients in the prophylactic DPC group cannulated with ECPR in progress.

The Marker State Space (MSS) method for classifying clinical samples.

The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines "marker states" based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three-marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications.