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• W2017120411 abstract "The National Heart, Lung, and Blood Institute (NHLBI) convened a meeting of NIH contractors funded under the Pediatric Circulatory Support program in February 2008. Working groups were formed on major areas of common interest, including a group discussing animal models used for pediatric VAD testing. Animal testing is typically a component of pre-clinical assessment of circulatory support devices. In the case of devices intended for the pediatric population, the choice of animal model is especially important and challenging. The choice of animal model and the test protocol are dictated by the objectives of the study, which may be multi-factorial. The working group outlined the important factors to consider in designing the animal study. Compromises are required, and no single animal model or study design was recommended for all groups. This report discusses important general study objectives, issues related to specific animal models, and methods that may be utilized to meet study objectives. Introduction The National Heart, Lung, and Blood Institute (NHLBI) convened a meeting of NIH contractors funded under the Pediatric Circulatory Support program in February 2008. As part of that meeting, working groups were formed on major areas of common interest. This manuscript summarizes the findings of the working group on animal models. Animal testing is typically a component of pre-clinical testing for circulatory support devices. In the case of devices intended for the pediatric population, the choice of animal model is especially important and challenging. The choice of animal model and the test protocol are dictated by the objectives of the study, which may be multi-factorial. The working group outlined the important factors to consider in designing the animal study. Compromises are required, and no single animal model or study design was recommended for all groups. Important general study objectives are discussed, along with issues related to specific animal models1 and methods which may be utilized to meet the objectives. Thrombogenicity In most cases, the primary study objective in animal testing of circulatory support devices is to assess throm-bogenicity. If the study is intended to support an Investigational Device Exemption (IDE) application, the anti-coagulation protocol is usually chosen to emulate the expected clinical protocol. However, differences between the animal and human system in regard to the coagulation system, complement system, platelet function, and response to anticoagulants and platelet inhibitors, may require specialized protocols. In addition, a number of assays, (e.g., fibrin split products and thrombin-anti-thrombin complex) may not be available or practical in animal studies. It is important to note that, in the case of a scientific study in contrast to a regulatory study, the study objective may dictate that the anticoagulation protocol deviate from expected clinical practice. For example, it may be desirable to compare devices and blood-contact materials, to study the coagulation system response, or to study the effect of anticoagulants or platelet therapies on animals. The objectives should be clearly defined and the anticoagulation protocol should be justified. The methods for assessing thrombogenicity include the documentation of thrombi and fibrin depositions on the device surfaces2 (e.g., location, size, composition, and adherence), necropsy examination of end organs for evidence of embolic infarcts, and assessment of clinical indicators of embolization (neurologic function, renal function). Confounding factors include infection, bleeding and transfusions, cannulae malposition, and VAD flow rates outside of the target range. Coagulation systems vary considerably among species.3 Comparative studies of coagulation and platelet function in animals are relatively few, especially in response to a biomaterial or shear stress stimulus. More recent studies have utilized flow cytometry to assess platelet activation in animals with VADs.4,5 Species variability in blood viscoelasticity may have implications for assessing thrombogenesis, as well as sub-lethal damage in red blood cells.6 The response to anticoagulants and platelet inhibitors varies as well.7 For example, the presence of a functional rumen in the calf and juvenile sheep may affect the absorption of oral anticoagulants.8 Differences in the platelet activation and aggregation pathways result in different sensitivities to platelet agonists and inhibitors.9–13 Further research is needed to understand the sensitivity of anti-coagulation and anti-platelet therapy in the relevant species, so that these studies will yield the highest possible predictive accuracy in humans. The choice of the model based solely on hematologic similarity is not always feasible, since thrombogenesis and blood flow are interdependent, and a good hematological model with poor hemodynamics complicates the analysis of thrombosis. Hemodynamics The objectives of the animal study will determine the importance of matching the hemodynamics (cardiac output, preload and afterload pressures, heart rate, vascular impedances, cannulae length and placement) of the animal model to that of the intended patients. Also, they will dictate whether a heart failure model is required. In most cases, the objective of a pre-IDE animal chronic study is not to demonstrate efficacy of VAD support in the failing heart. As such, a chronic heart failure model may not be necessary. However, there are a number of models of diminished cardiac function that have been used. The most commonly used models involve producing some sort of ischemic insult to the myocardium, thereby weakening it, or using a pharmacologic agent to diminish cardiac function. It is beyond the scope of this summary to discuss the individual models; however, it is important to understand the target population prior to producing the reduced function. Thus, an ischemic model of diminished cardiac function may not be appropriate for a pediatric population, where there is little ischemic disease. A more appropriate model is likely one where the heart is globally weakened. The development of congenital heart defect models, such as single or hypo-plastic ventricle anomalies, for the purpose of VAD testing, may not be practical. Alternatively, in vitro models of heart failure and VAD interaction may be used in conjunction with more well-established in vivo models with normal cardiac function. The animal study does provide an opportunity to observe the VAD and control system function with an actively contracting ventricle, and documentation of VAD performance and any anomalies should be provided. The size of the animal relative to the intended human patient may be important in that the volume of the cannulated ventricle affects control system response and the sensitivity to ventricular collapse due to VAD filling. Separate acute studies may be included, with pressure and flow instrumentation, and pharmacologic manipulation of preload, afterload, and ventricular contractility. These studies may be used to complement and/or validate in vitro modeling studies. Hemolysis Hemolysis is usually assessed by measuring the plasma free hemoglobin. Factors to consider in interpreting in vivo hemolysis results include the differences in mechanical and osmotic fragility between the red blood cells of animals and humans. Furthermore, a clinically-significant increase in plasma free hemoglobin may not be detectable in a large, healthy, animal (relative to the intended patient) because of the high clearance rate relative to the production rate of free hemoglobin. In vitro measurements of the normalized index of hemolysis may be used to complement the animal study findings. Response to Implanted Components The response of the animal to the device (and of the device to the animal) is assessed during the animal study. The susceptibility of the device components to corrosion may also be tested in saline solutions during durability testing. The tissue response is affected by leachable components (e.g., plasticizing agents) and corrosion byproducts. Elevated temperature of the surrounding tissues due to heat dissipation from VAD components is a function of implantation location and VAD flow rate, tissue perfusion, and external air flow. Compressive and tensile forces on the tissue surrounding the implanted components and percutaneous cables and tubes may lead to inflammation, necrosis, and infection. In ruminants, VADs placed in the preperitoneal location are subject to compression due to the animal’s weight on the device when the animal is lying down. Devices placed intrathoracically may be more protected. The thickness and vascularity of subcutaneous and muscular layers also differs among species, which may dictate a different implantation site in animals compared to humans. Study Duration Choice of an animal model may vary based on the expected length of VAD support time. Piglets (6–10 kg) are often used for acute hemodynamic studies, modeling use of the VAD in neonates.14 However, managing a VAD-implanted piglet chronically is challenging from a husbandry and developmental standpoint, impairing the ability to obtain suitable data. There are no known reports of chronic survival of a piglet with a heart assist device. Sheep (10–30 kg) are commonly used for pediatric VAD testing, and unlike the piglet, can be maintained long-term.15 Sheep are docile and can be easily restrained for longer term studies. Because of husbandry and physiologic issues (namely lambs not being weaned and fragility of lungs in sheep weighing < 20 kg), most groups have tested their devices in juvenile sheep (>25 kg). Calves have been used for decades for cardiac studies, including adult VAD testing. They are docile and can be managed long-term. Limitations to the use of the calf model in pediatric VAD testing are discussed later in this paper. The duration of a chronic VAD study has typically ranged from 4 to 8 weeks, although the objectives may require shorter or longer durations. Factors to consider are the growth of the animal, post-operative recovery time and normalization of blood studies, and the risk of infection. Animal Size and Growth Rate When attempting to match the animal model’s cardiac output with that of the human, the piglet and lamb are the best fit for pediatrics. Calves, weighing 50–90 kg, have a cardiac output of 8–10 L/min and growth rate of 0.5–1.0 kg/day. These parameters are much higher than that of a pediatric human patient. Other animal models, including dogs, rabbits, and pygmy goats, have been used to test VADs due to their appropriate size and growth rate. However, these models have had limited use, and therefore regulatory familiarity is also limited, requiring thorough justification if used. Anatomy The anatomy of the aortic arch and arterial branch vessels differs among species, with a single branch (bra-ciocephalic trunk) in ruminants, two branch vessels in piglets (braciocephalic and left subclavian artery), and three in humans (additional left common carotid). In humans, the VAD outlet cannulae is usually connected to the ascending aorta, but in ruminants, surgical access to the ascending aorta is poor, and the descending aorta is usually used instead. Additionally, the ruminant and pig models are quad-rupeds with keel-shaped chests. The implantation of the pediatric VAD in this type of chest cavity spatially differs from how the device will fit in the human. In this regard, the nonhuman primate may represent a better animal model. However, managing this animal chronically would be exceedingly difficult, and the use of this model invokes greater cost, increased scrutiny, and stricter regulations from an animal care and use standpoint. The animal study provides the opportunity to work with surgeons and cardiologists to develop cannulae, tools, and procedures for implantation. Ideally, human-sized cannulae would be suitable for use in the animal studies, but this is not always the case. In spite of the anatomical differences, results obtained with special animal-sized cannulae are generally predictive of the results in humans. Durability The animal study provides an invaluable near - ‘real world’ environment for assessing durability, not only of the pump, but also of the associated components. In assessing durability data from animal studies, and predicting system reliability, it is important to document the expectation or ‘release level’ of the components. Failure of a prototype component and failure of a final configuration component may be treated differently. Due to the limited duration and limited number of most animal studies, in vitro durability studies (real time and/or accelerated) are required to provide longer test times and a larger number of units, but under controlled and simulated conditions. The animal study exposes the system to a larger range of users, conditions, and failure modes. Source of Animals Obtaining animals from a reputable, local source that can provide the required size/age of animal, free from disease, can be a challenge. Sheep are seasonal breeders, and to have a year-round supply of animals, specific breeds (e.g., Finn, Dorset, Romanov, Merino, and Rambouillet) known to be less affected by length of daylight need to be used. Sheep also carry a zoonotic risk (Q-fever) that can be fatal in immunocompromised people; testing of sheep prior to arrival is highly recommended. Calves are more readily obtained year-round; contracting with a dairy farmer to purchase male calves that would otherwise be sent to auction has been a successful means to secure healthy animals on a regular basis. Anesthesia and Analgesia Choosing an anesthesia regimen is largely based on the species of animal undergoing surgery. It is beyond the scope of this paper to discuss the many options for sedation and induction of anesthesia.16 Following intubation, general anesthesia is typically maintained using isoflurane, delivered in oxygen. Newer agents, such as sevoflurane, may also be used but are more expensive. Reduction of gas flow can be accomplished by adding a continuous infusion of fentanyl during the operation, providing significant analgesia. Although caution is warranted when using opioids in ruminants, both fentanyl and buprenorphine can be used safely (i.e., without causing rumenal atony) in both calves and sheep. Ruminants under anesthesia will bloat and must be managed with an orogastric tube. Careful monitoring of tidal volume, end tidal CO2, and peak inspiratory pressure and the use of peak end expiratory pressure (PEEP) will lead to successful respiratory function. Analgesia in the post-operative period is an important consideration. The thoracotomy, chest tubes, and pump itself may all be sources of pain. Signs of pain include increased respiratory rate, which may lead to acid-base disturbances, and increased blood pressure, which can interfere with data collection. Aside from being good animal care, regulatory bodies (including USDA) are increasingly expecting to see incorporation of analgesia in perceived painful procedures, such as VAD implantation. Post-operative Management in Chronic Studies Controlling infection in the post-operative period is critical. In many cases, there are multiple points of entry in the animal’s body for bacteria, namely chest tubes, long-term intravenous catheters, an arterial line, and the drive line for the pump. Fastidious care of these sites, including sanitizing and application of topical antibiotic treatment, must be practiced to prevent infection. Respiratory infections are also a potential complication in the post-operative period. The animal must fairly quickly resume eating and drinking in order to thrive, and in the case of ruminants, prevent die-off of rumen flora and a “dry” rumen. Dehydration also has the potential to adversely affect pump filling. Quality Control Important factors to be included in pre-IDE animal studies are: use of final device configurations, controlled protocols, consistent quality of animals, quality control of monitoring and data recording, training, and assurances such as AAALAC and/or PHS. Pilot studies and/or base-line studies are frequently required to establish outcome variability and the required number of studies. Acknowledgments The authors thank the eighteen members of the working group who represented the contractors and contributed to these recommendations. Report Authors: *Elizabeth Carney, D.V.M, †Kenneth Litwak, D.V.M., Ph.D., *‡William Weiss, Ph.D. *Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Department of Comparative Medi-cine, ‡Department of Pediatrics, Hershey, PA †Lerner Research Institute, Cleveland Clinic Foundation, Veterinary Services, Cleveland, OH" @default.
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• W2017120411 title "Animal Models for Pediatric Circulatory Support Device Pre-Clinical Testing" @default.
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