Papers by Alvaro Rojas-Pena
Critical care explorations, May 1, 2023
OBJECTIVE: Prolonged cardiac arrest (CA) causes microvascular thrombosis which is a potential bar... more OBJECTIVE: Prolonged cardiac arrest (CA) causes microvascular thrombosis which is a potential barrier to organ reperfusion during extracorporeal cardiopulmonary resuscitation (ECPR). The aim of this study was to test the hypothesis that early intra-arrest anticoagulation during cardiopulmonary resuscitation (CPR) and thrombolytic therapy during ECPR improve recovery of brain and heart function in a porcine model of prolonged out-of-hospital CA. DESIGN: Randomized interventional trial. SETTING: University laboratory. SUBJECTS: Swine. INTERVENTIONS: In a blinded study, 48 swine were subjected to 8 minutes of ventricular fibrillation CA followed by 30 minutes of goal-directed CPR and 8 hours of ECPR. Animals were randomized into four groups (n = 12) and given either placebo (P) or argatroban (ARG; 350 mg/kg) at minute 12 of CA and either placebo (P) or streptokinase (STK, 1.5 MU) at the onset of ECPR. MEASUREMENTS AND MAIN RESULTS: Primary outcomes included recovery of cardiac function measured by cardiac resuscitability score (CRS: range 0–6) and recovery of brain function measured by the recovery of somatosensory-evoked potential (SSEP) cortical response amplitude. There were no significant differences in recovery of cardiac function as measured by CRS between groups (p = 0.16): P + P 2.3 (1.0); ARG + P = 3.4 (2.1); P + STK = 1.6 (2.0); ARG + STK = 2.9 (2.1). There were no significant differences in the maximum recovery of SSEP cortical response relative to baseline between groups (p = 0.73): P + P = 23% (13%); ARG + P = 20% (13%); P + STK = 25% (14%); ARG + STK = 26% (13%). Histologic analysis demonstrated reduced myocardial necrosis and neurodegeneration in the ARG + STK group relative to the P + P group. CONCLUSIONS: In this swine model of prolonged CA treated with ECPR, early intra-arrest anticoagulation during goal-directed CPR and thrombolytic therapy during ECPR did not improve initial recovery of heart and brain function but did reduce histologic evidence of ischemic injury. The impact of this therapeutic strategy on the long-term recovery of cardiovascular and neurological function requires further investigation.
Circulation, Nov 14, 2017
Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) is a feasible and effective res... more Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) is a feasible and effective resuscitation strategy for refractory cardiac arrest, but often fails to restore heart and brain functi...
The Annals of Thoracic Surgery, Jul 1, 2014
Background-Centrifugal pumps are increasingly used for temporary mechanical support for the treat... more Background-Centrifugal pumps are increasingly used for temporary mechanical support for the treatment of cardiogenic shock. However, centrifugal pumps can generate excessive negative pressure and are afterload-sensitive. A previously developed modified roller pump mitigates these limitations both in vitro and in preliminary animal experiments. We report the results of intermediate-term testing of our evolving pump technology, known as BioVAD. Methods-The BioVAD was implanted in 6 adult male sheep (62.5 ± 3.9 kg), with drainage from the left atrium and reinfusion into the descending aorta. The sheep were monitored for 5 days. Heparin was given during the initial implantation, but no additional anti-coagulation was given. Data collected included hemodynamic status, pump flow and pressures, laboratory values to monitor end-organ function and hemolysis, pathologic specimens to evaluate for thromboembolic events and organ ischemia, and explanted pump evaluation. Results-All animals survived the planned experimental duration and there were no pump malfunctions. Mean BioVAD flow was 3.57 ± 0.30 L/min (57.1 cc/kg/min) and mean inlet pressure was-30.51 ± 4.25 mmHg. Laboratory values, including plasma free hemoglobin, creatinine, lactate, and bilirubin levels, remained normal. Three animals had small renal cortical infarcts, but there were no additional thromboembolic events or other abnormalities seen on pathologic examination. No thrombus was identified in the BioVAD blood flow path.
Journal of Pediatric Surgery, 2022
Background:Artificial lungs have the potential to serve as a bridge to transplantation or recover... more 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 hours 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 hours 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 seconds. Platelet count declined from 334,333±112,225 to 123,667±7,637 over 24 hours. 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 hours.
Biomicrofluidics, Mar 1, 2017
Artificial lungs have been used in the clinic for multiple decades to supplement patient pulmonar... more Artificial lungs have been used in the clinic for multiple decades to supplement patient pulmonary function. Recently, small-scale microfluidic artificial lungs (lAL) have been demonstrated with large surface area to blood volume ratios, biomimetic blood flow paths, and pressure drops compatible with pumpless operation. Initial small-scale microfluidic devices with blood flow rates in the ll/min to ml/min range have exhibited excellent gas transfer efficiencies; however, current manufacturing techniques may not be suitable for scaling up to human applications. Here, we present a new manufacturing technology for a microfluidic artificial lung in which the structure is assembled via a continuous "rolling" and bonding procedure from a single, patterned layer of polydimethyl siloxane (PDMS). This method is demonstrated in a small-scale four-layer device, but is expected to easily scale to larger area devices. The presented devices have a biomimetic branching blood flow network, 10 lm tall artificial capillaries, and a 66 lm thick gas transfer membrane. Gas transfer efficiency in blood was evaluated over a range of blood flow rates (0.1-1.25 ml/min) for two different sweep gases (pure O 2 , atmospheric air). The achieved gas transfer data closely follow predicted theoretical values for oxygenation and CO 2 removal, while pressure drop is marginally higher than predicted. This work is the first step in developing a scalable method for creating large area microfluidic artificial lungs. Although designed for microfluidic artificial lungs, the presented technique is expected to result in the first manufacturing method capable of simply and easily creating large area microfluidic devices from PDMS. [
Asaio Journal, 2013
Vascular access cannulas for extracorporeal life support are characterized by French (Fr) size al... more Vascular access cannulas for extracorporeal life support are characterized by French (Fr) size alone, which affords limited information on pressure (P) and flow (Q) performance, making their selection difficult. Previously, we developed an accurate metric of cannula performance, the M number, but its complexity and the need of a nomogram hindered its utility. We propose adoption of an easier and clinically useful metric to assess cannula performance: Q at 100 mm Hg P, the updated M number, or the "UM number." A circuit was created using a centrifugal pump, Tygon tubing, and a reservoir. A total of 74 cannulas (arterial, venous, and double lumen) ranging from 6 to 50 Fr size were studied. Glycerol solution with a viscosity of 3 cP was used to mimic blood. A Biopac system and ultrasonic flow probe was used to collect P/Q data across a cannula's performance range. The UM number describes the pressure-flow characteristics of any given cannula. It can be used to select access cannulas based on performance and to determine if flow matches expected flow during use.
PLOS ONE, Dec 10, 2020
Background Current limitations in the supply of ventilators during the Covid19 pandemic have limi... more Background Current limitations in the supply of ventilators during the Covid19 pandemic have limited respiratory support for patients with respiratory failure. Split ventilation allows a single ventilator to be used for more than one patient but is not practicable due to requirements for matched patient settings, risks of cross-contamination, harmful interference between patients and the inability to individualize ventilator support parameters. We hypothesized that a system could be developed to circumvent these limitations. Methods and findings A novel delivery system was developed to allow individualized peak inspiratory pressure settings and PEEP using a pressure regulatory valve, developed de novo, and an inline PEEP 'booster'. One-way valves, filters, monitoring ports and wye splitters were assembled in-line to complete the system and achieve the design targets. This system was then tested to see if previously described limitations could be addressed. The system was investigated in mechanical and animal trials (ultimately with a pig and sheep concurrently ventilated from the same ventilator). The system demonstrated the ability to provide ventilation across clinically relevant scenarios including circuit occlusion, unmatched physiology, and a surgical procedure, while allowing significantly different pressures to be safely delivered to each animal for individualized support. Conclusions In settings of limited ventilator availability, systems can be developed to allow increased delivery of ventilator support to patients. This enables more rapid deployment of ventilator capacity under constraints of time, space and financial cost. These systems can be smaller,
Asaio Journal, Jun 1, 2023
Transplantation Journal, 2012
Introduction: During the last decade Israel´s organ donation rate has been among the lowest in We... more Introduction: During the last decade Israel´s organ donation rate has been among the lowest in Western countries. Cultural and religious objection towards recognition of brain death among parts of the society, combined with "free riding" behavior of these elements regarding accepting organs for transplants, as well as generous reimbursement of transplant tourism by insurance agencies, have all contributed to these lower donation rates. A unique new Organ Transplantation Law, drafted to counterbalance these phenomena, and a law defining brain death determination, made a marked impact on the Israeli organ transplantation scene. Methods: In March 2008 Israel´s Parliament passed into legislation two laws relevant to organ transplantation: (A) The Brain Death Law which defines the precise circumstances and mechanisms to determine brain death; (B) The Organ Transplantation Law which includes several unique clauses: (1)Total ban of reimbursing transplants performed abroad if they are performed under the definitions of organ trade or against local laws; (2) Granting prioritization in organ allocation to candidates for organ transplantation who have previously signed a donor card or have given their consent for actual organ donation of their deceased next of kin; (3) Removing disincentives for living donation by providing modest insurance reimbursement and some social supportive services. The impact of the gradual implementation of these new laws has finally been witnessed in the 2011 annual results of Israel's National Transplant Center. Results: In 2011 there were 89 deceased organ donors compared to 60 in 2010, which represents an increase in organ donation rate from 7.8 donors per million population to 11.4 (p< 0.0001). In 2011 267 organ transplantations from deceased donors were performed compared to 157 in 2010. Consent rate for organ donation from deceased donors has risen from 49% in 2010 to 55% in 2011. Kidney transplantations from living donors have risen from 71 in 2010 to 117 in 2011. Total number of candidates waiting for an organ transplant has dropped for the first time in decade from 1117 in January 2011 to 1041 in January 2012. Similarly, the total number of candidates who died while waiting for transplants has dropped from 124 in 2010 to 105 in 2011. The annual number of new signatories on the donor card has risen from a steady number of 45,000 to 70,000 in 2011, representing an increase in donor card holders' rate from 10% to 12% of the adult population. The annual number of patients who underwent kidney transplantation abroad has sharply dropped since 2008 from 155 in 2006 to the lowest ever number of 26 in 2011. Conclusions: The implementation of the new Israeli Organ Transplantation Law, along with the Brain Death Law, has resulted in a significant increase in organ transplantations both from deceased donors, by prioritizing holders of donor cards, and from living donors, by removing disincentives for living donation. In addition transplant tourism from Israel was brought to an almost complete halt by banning its reimbursement.
Asaio Journal, Apr 5, 2022
The artificial placenta (AP) promotes organ development and reduces organ injury in a lamb model... more 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 &lt; 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 &lt; 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.
Asaio Journal, Jun 1, 2023
Talanta, Dec 1, 2019
Implantable medical devices are an integral part of primary/critical care. However, these devices... more Implantable medical devices are an integral part of primary/critical care. However, these devices carry a high risk for blood clots, caused by platelet aggregation on a foreign body surface. This study focuses on the development of a simplified approach to create intravascular electrochemical oxygen (O2) sensors with increased biocompatibility and analytical accuracy via polymers that release nitric oxide (NO). The implantable sensors are prepared by embedding S-nitroso-N-acetylpenacillamine (SNAP) as the NO donor molecule in the walls of the catheter type sensors. The SNAP-impregnated catheters were prepared by swelling silicone rubber tubing in a tetrahydrofuran solution containing SNAP. Control and SNAP-impregnated catheters were used to fabricate the Clark-style amperometric PO2 sensors. The SNAP-impregnated sensors release NO under physiological conditions for 18 d as measured by chemiluminescence. The analytical response of the SNAP-impregnated sensors was evaluated in vitro and in vivo. Rabbit and swine models (with sensors placed in both veins and arteries) were used to evaluate the effects on thrombus formation and analytical in vivo PO2 sensing performance. The SNAP-impregnated PO2 sensors were found to more accurately measure PO2 levels in blood continuously (over 7 and 20 h animal experiments) with significantly reduced thrombus formation (as compared to controls) on their surfaces.
Analytical Chemistry, Aug 5, 2015
A novel electrochemically controlled release method for nitric oxide (NO) (based on electrochemic... more 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 (PO 2) in blood. The on-demand electrochemical NO generation/release method is shown to be fully compatible with amperometric PO 2 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 PO 2 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.
Pediatric Research, Apr 22, 2023
Transplantation, Apr 1, 2018
C over 116 500 patients are waiting for a lifesaving organ in the United States. A promising alte... more C over 116 500 patients are waiting for a lifesaving organ in the United States. A promising alternative to increase the source of organs is the use of grafts from donors after Circulatory death (DCD). At present, DCD lungs, livers, and kidneys with minimal warm ischemic time are considered and successfully used for transplantation. However, it has been documented that liver grafts from DCD (compared with donors after brain death) have a higher incidence of primary nonfunction and aworse 1and 3-year graft survivals. Current research is directed at techniques to improve practices for organ preservation, storage, and assessment of organ viability pretransplantation. One of them is ex situ perfusion of organs, a concept introduced in the early 1900s by Charles Lindbergh and Alexis Carrel, when Locke’s solution was used to preserve kidneys and vessels. Kakizaki et al describe the results of a subnormothermic ex vivo liver perfusion (SELP) rat model and concluded that even 30 minutes of room temperature (22.5 ± 2.5°C) perfusion after cold storage resuscitated DCD liver grafts from ischemia-reperfusion injury and improved the viability of livers. This conclusion wasmade on liver function parameter measurements in the perfusate and pro/inflammatory cytokine studies. This study adds support to the growing practice of ex-vivo organ perfusion at the time of organ procurement or after cold storage. Future studies should evaluate longer perfusionwith oxygen delivery tomatch oxygen requirements. Perfusion for hours allows assessment of function, which is particularly important in DCD organs subjected to prolonged ischemia during the agonal period. In addition, ex vivo perfusion “washes out” toxic products of ischemic and reperfusion injury, as postulated by the authors. Although this study used clear perfusate, prolonged ex vivo organ perfusion to document organ function (and likelihood of transplant success) must be done at normothermia (37 ± 0.5°C) and requires an oxygen carrier, “Red blood cells (RBC)” are the best oxygen carrier in our experience.
Analytical Chemistry, Sep 21, 2020
In this letter, the innate ability of nitric oxide (NO) to inhibit platelet activation/adhesion/t... more In this letter, the innate ability of nitric oxide (NO) to inhibit platelet activation/adhesion/thrombus formation is employed to improve the hemocompatibility and in vivo accuracy of an intravascular (IV) potentiometric PCO 2 (partial pressure of carbon dioxide) sensor. The catheter-type sensor is fabricated by impregnating a segment of dual lumen silicone tubing with a proton ionophore, plasticizer, and lipophilic cation-exchanger. Subsequent filling of bicarbonate and strong buffer solutions and placement of Ag/AgCl reference electrode wires within each lumen, respectively, enables measurement of the membrane potential difference across the inner wall of the tube, with this potential changing as a function of the logarithm of sample PCO 2. The dual lumen device is further encapsulated within a S-nitroso-N-acetyl-DL-penicillamine (SNAP)doped silicone tube that releases physiological levels of NO. The NO releasing sensor exhibits near-Nernstian sensitivity toward PCO 2 (slope = 59.31 ± 0.78 mV/decade) and low drift rates (<2 mV/24 h after initial equilibration). In vivo evaluation of the NO releasing sensors, performed in the arteries and veins of anesthetized pigs for 20 h, shows enhanced accuracy (vs non-NO releasing sensors) when benchmarked to measurements of discrete blood samples made with a commercial blood gas analyzer. The accurate, continuous monitoring of blood PCO 2 levels achieved with this new IV NO releasing PCO 2 sensor configuration could help better manage hospitalized patients in critical care units.
Asaio Journal, Feb 1, 2019
Ex-situ perfusion (ESP) is a promising method in preserving vascularized composite tissue allogra... more Ex-situ perfusion (ESP) is a promising method in preserving vascularized composite tissue allografts (VCA) with potential to widen donor procurement to larger geographic areas. To optimize the method of preservation, we developed a small animal model to conduct biomolecular investigations. Twenty rat hind limbs (18.2±1.3 gr) were procured and connected to our custommade ESP system. Perfusion pressure and flow parameters were measured with hourly blood gas analysis under near-normothermic (30-35°C) conditions. Perfusate was prepared with swine hemoglobin (6-9 g/dL) and STEEN Solution ™. After 6 hours of perfusion, gastrocinemius muscles were evaluated for their histology and metabolomic profiling. Following 3 sets of experiments, perfusion was maintained at an average flow of 0.9±0.24 mL/min and resulted in lactate levels of 3.78±1.02mmol/L. Metabolomic analysis revealed maintained cellular energy stores (total adenylates perfusion 0.698±0.052 vs. baseline 0.685±0.091umols/ug, p=0.831), and histologic analysis revealed no evidence of barotrauma or myodegeneration. Rat hind limbs were viable after 6 hours of ex-situ perfusion on our miniaturized ESP system. This study is the first to document the ex-situ hind limb perfusion platform on a rodent model. These experimental findings have potential to guide future research to extend the viable duration of VCA preservation.
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Papers by Alvaro Rojas-Pena