Jenelle M. Izer

In Vivo Hemodynamic Performance Evaluation of Novel Electrocardiogram-Synchronized Pulsatile and Nonpulsatile Extracorporeal Life Support Systems in an Adult Swine Model

The primary objective of this study was to evaluate a novel electrocardiogram (ECG)-synchronized pulsatile extracorporeal life support (ECLS) system for adult partial mechanical circulatory support for adequate quality of pulsatility and enhanced hemodynamic energy generation in an in vivo animal model. The secondary aim was to assess end-organ protection during nonpulsatile versus synchronized pulsatile flow mode. Ten adult swine were randomly divided into a nonpulsatile group (NP, n = 5) and pulsatile group (P, n = 5), and placed on ECLS for 24 h using an i-cor system consisting of an i-cor diagonal pump, an iLA membrane ventilator, an 18 Fr femoral arterial cannula and a 23/25 Fr femoral venous cannula. Trials were conducted at a flow rate of 2.5 L/min using nonpulsatile or pulsatile mode (with assist ratio 1:1). Real-time pressure and flow data were recorded using a custom-based data acquisition system. To the best of our knowledge, the oxygenator and circuit pressure drops were the lowest for any available system in both groups. The ECG-synchronized i-cor ECLS system was able to trigger pulsatile flow in the porcine model. After 24-h ECLS, energy equivalent pressure, surplus hemodynamic energy, and total hemodynamic energy at preoxygenator and prearterial cannula sites were significantly higher in the P group than those in the NP group (P < 0.05). Urine output was higher in P versus NP (3379 ± 443 mL vs. NP, 2598 ± 1012 mL), and the P group seemed to require less inotropic support, but both did not reach statistical significances (P > 0.05). The novel i-cor system performed well in the nonpulsatile and ECG-synchronized pulsatile mode in an adult animal ECLS model. The iLA membrane oxygenator had an extremely lower transmembrane pressure gradient and excellent gas exchange capability. Our findings suggest that ECG-triggered pulsatile ECLS provides superior end-organ protection with improved renal function and systemic vascular tone.

The Clinical Importance of Pulsatile Flow in Extracorporeal Life Support: The Penn State Health Approach

Recent improvements in the safety and efficiency of components of the extracorporeal life support (ECLS) circuit have improved the mortality and morbidity of patients with severe, reversible cardiac and respiratory failure (1,2). Circuit improvements are primarily due to optimization of the components of the circuit, namely the efficiency of the oxygenators and pumps along with better veno-arterial and veno-venous cannulae (3,4). New ECLS systems have several advantages including significantly reduced set-up time (less than 10 min), a lower priming volume (<190 mL for pediatric and <400 mL for adult systems), and better safety and portability (3,4). However, most of these new generation ECLS systems produce only nonpulsatile flow. We at the Pediatric Cardiovascular Research Center at Penn State Health have conducted extensive translational research on the impact of pulsatile flow during ECLS for neonates, infants, and adult patients throughout the past 8 years (5–9). The objective of this editorial is to share the latest results using a novel electrocardiogram (ECG)-ECLS system in vitro and in vivo and to suggest further clinical research with pulsatile flow.

Ultrasound-guided vessel catheterization in adult Yorkshire cross-bred pigs.

OBJECTIVE To describe an ultrasound-guided approach for venous and arterial vascular access and catheterization in anesthetized adult Yorkshire cross-bred pigs. STUDY DESIGN Prospective experimental study. ANIMALS Ten adult female Yorkshire cross-bred pigs, weighing 78.4 ± 5.6 kg (mean ± standard deviation). METHODS Using ultrasound guidance and the Seldinger technique, a 7 Fr, 20 cm triple-lumen central venous catheter was placed in the external jugular vein and an 18 gauge, 16 cm catheter was placed in the femoral artery. The success rate of catheterization and the incidence of catheter patency over 24 hours of general anesthesia were recorded. RESULTS Catheterization of the external jugular vein was successful in 10 out of 10 pigs and catheterization of the femoral artery was successful in eight out of 10 pigs. A surgical dissection technique on the femoral artery was performed in two pigs. Venous and arterial catheter patency was maintained in all pigs over the 24 hour study period. CONCLUSIONS AND CLINICAL RELEVANCE Ultrasound guidance resulted in success rates of 100% for catheterization of the external jugular vein and 80% for catheterization of the femoral artery in anesthetized adult Yorkshire cross-bred pigs. This technique is a noninvasive, easily performed alternative to surgical exposure of the vessels in large pigs undergoing surgical instrumentation for biomedical device testing.

Spontaneous Lung Lesions in Aging Laboratory Rabbits (Oryctolagus cuniculus)

Spontaneous age-related lesions of laboratory rabbits are not well documented in the contemporary scientific literature. A retrospective study of diagnostic necropsies of 36 rabbits >2 years of age found a number of common lung lesions. Fibromuscular intimal hyperplasia affected medium and to a lesser extent large pulmonary arteries and was present to a variable extent in all 36 rabbits >2 years of age. The lesions were characterized by fragmentation and/or reduplication of the internal elastic lamina (IEL), proliferation of smoothelin+/alpha-smooth muscle actin (α-SMA)+/vimentin− smooth muscle cells and fewer smoothelin−/α-SMA+/vimentin+ myofibroblasts, and intimal deposition of collagen without thrombosis, embolism, or evidence of pulmonary hypertension. Pulmonary emphysema, present in 30/36 rabbits, was characterized by the loss of alveolar septa; most affected rabbits did not have clinical signs of respiratory disease. In 8/13 rabbits of the inbred EIII/JC audiogenic strain, we identified a unique syndrome of granulomatous pneumonia containing hyaline brown to gray, globular to ring-like acellular material that was Alcian blue and periodic acid-Schiff positive. The material was immunoreactive for surfactant protein-A and had the ultrastructural appearance of multilamellar vesicles, suggesting a genetic defect in surfactant metabolism. Additionally, we found small benign primary lung tumors (fibropapillomas, 5 rabbits) not previously described. Other findings included heterotopic bone (5 rabbits), subacute to chronic suppurative bronchopneumonia, pyogranulomatous pneumonia with plant material, and pulmonary artifacts from barbiturate euthanasia solution.

Development of a Pain Scoring System for Use in Sheep Surgically Implanted with Ventricular Assist Devices

ABSTRACT Purpose/Aim: In prey species, such as sheep, clinical signs of postoperative pain can manifest in subtle ways or may be concealed entirely. Previous publications describing pain assessment in ruminants focus on lameness and flock behavior, often in a farm environment. These indicators of pain may be difficult to assess in sheep housed in biomedical research settings. We have developed a novel pain scoring system for sheep undergoing thoracotomy for implantation of ventricular assist devices that are permanently housed in modified stanchions. Materials and Methods: The pain scoring system includes ruminant-specific behavioral signs of pain in addition to objective measurements that can be readily evaluated in a biomedical research setting. A numerical score is generated by the evaluator for each category. A decision tree is utilized to help guide further action following the generation of a cumulative score by the evaluator. A total score of 0–2 requires no intervention, 3–9 requires the consideration of additional analgesic administration, and a pain score ≥ 10 warrants the consideration of additional multimodal analgesia. Results: A novel pain scoring system and decision tree specifically designed for sheep undergoing thoracotomy in a biomedical research environment was developed and successfully utilized. Out of 102 postoperative pain scores measured, 86 scores were <2. There were 17/102 postoperative pain scores ≥3, which typically resulted in the administration of supplemental rescue analgesia in the immediate postoperative period. Conclusions: A novel pain scoring system was developed and utilized in a biomedical research environment for evaluating postoperative pain in sheep undergoing thoracotomy for implantation of a ventricular assist device. Further studies are necessary to validate the reliability of this novel pain scoring system.

Animal Models for Pediatric Mechanical Circulatory Support Research at Penn State Health

For nearly five decades, a variety of animal models have been utilized for in vivo testing of biomedical devices for mechanical circulatory support research at the Penn State Health Milton S. Hershey Medical Center (PSHMC), Penn State College of Medicine. Pediatric ventricular assist devices (PVAD), extracorporeal life support systems (ECLS), and total artificial hearts (TAHs) have been designed, developed, tested, and refined by a multidisciplinary team of bioengineers, scientists, surgeons, and veterinarians. Calves and adult sheep have been utilized for study of adult TAHs and ventricular assist devices (VADs), lambs have served as the model of choice for in vivo study of PVADs and pediatric TAHs, adult sheep are the preferred models for study of failed Fontan circulation pumps, and adult swine and piglets are often used for ECLS research. Each animal model encompasses its own unique set of challenges with anesthesia, surgery, postsurgical recovery, and long-term care. This editorial discusses methods that have been utilized at Penn State Health to refine in vivo mechanical circulatory support research to successfully meet study objectives. Unfortunately, there is no “perfect” animal model that satisfies all of the requirements for investigational and preclinical device testing. Substantial differences in anatomy and physiology exist between animal models and humans. Furthermore, many differences exist among animal species, including variations in hemodynamics, coagulation systems, thrombogenicity and response to anticoagulants, which may affect the overall response of animal models to mechanical circulatory support devices (1–4). Differences in body mass and cardiac index between animal models and humans may be a challenge in the development of mechanical circulatory support devices, and must be considered during the design phase. Because domestic farm animals are bred to maximize growth and are frequently in the growth phase during the time of device study, the animal model often outgrows the device, making chronic study of pediatric devices unfeasible. At our institution, there has been a recent change in ventricular assist device research from adult to pediatric applications. Current mechanical circulatory support device options for infants and children are limited, especially those available for long-term duration of support (5,6). Attempts to utilize calves, adult sheep, and pygmy goats at Penn State for study of an infant VAD with a dynamic stroke volume of 12–14 mL were largely unsuccessful. The cardiac output of a 50–90 kg calf is 8–10 L/min, which far exceeds that of the intended pediatric human patient (7). Postweaning Dorset-Finn crossbred lambs have been successfully used and are the preferred animal model for study of the Penn State PVAD, a pulsatile, pneumatically actuated blood pump (8). Surgical implantation of 20–25 kg lambs has more closely matched the hemodynamics of an infant or child. In comparison to calves and goats, the slower growth rate, docility and ability to readily acclimate lambs to modified stanchion housing have allowed us to successfully accomplish studies of up to 90 days or more. However, use of the lamb model for PVAD study has not been without its challenges. Early implantation studies had a success rate of 50% or less, largely due to intraoperative and postoperative respiratory complications such as irreversible atelectasis, pleural effusion with respiratory acidosis, pulmonary edema, and acute respiratory failure (8). Substantial changes to our respiratory management protocol were made in 2014 which significantly improved intraoperative and postoperative ventilation and the overall success of the PVAD studies (9). Several refinements were made to the anesthetic regimen to prevent bronchospasm, doi:10.1111/aor.13133

FATAL CLOSTRIDIUM SEPTICUM MYONECROSIS IN A CAPTIVE CANADA LYNX (LYNX CANADENSIS)

Abstract:  A 1-yr-old female Canada lynx (Lynx canadensis) presented for sudden onset of rapidly progressive bilateral pelvic limb paralysis. The lynx was chemically immobilized to perform a physical examination but expired shortly thereafter. On postmortem radiographs, there were myriad small irregular, round-to-spherical gas densities within the skeletal muscle of the right thigh and epaxial musculature. At gross necropsy, the muscles of the right thigh, right lateral abdominal wall, and epaxial region were emphysematous and necrohemorrhagic, with subcutaneous and muscular crepitant swelling. Multiple skin puncture wounds, consistent with bites, were present over the affected tissues. Clostridium septicum was isolated in pure anaerobic culture from the musculature of the right hind limb. Histopathologic examination confirmed the diagnosis of acute, severe necrohemorrhagic and gangrenous myositis and cellulitis. Gram stains demonstrated large gram-positive bacilli with subterminal spores. This is the first known documented case of C. septicum myonecrosis in a nondomestic felid.