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Schematic setup of cardiopulmonary bypass model with endoaortic cross-clamp and cardioplegia administration (arterial line via superficial caudal epigastric artery)
Source publication
Neurologic and neurocognitive complications after cardiac surgery have been reported repeatedly. To better understand its etiology and design protective strategies, small animal models have been developed. This study describes the development of a survival rat cardiopulmonary bypass (CPB) model, along with the introduction of an appropriately sized...
Context in source publication
Context 1
... we adapted the model to induce com- plete cardiac arrest by administration of anterograde cardioplegia solutions and endoaortic clamping. 40 In this model, a balloon catheter is positioned just above the aortic valve (Figure 2). While on CPB, cardioplegia can be injected and the balloon inflated to serve as an endoaortic crossclamp. ...
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Citations
... closed reservoirs and centrifugal pumps) in ECLS. For rodent models in CPB research, Ballaux et al. [9], Berner et al. [10], Samarska et al. [11], Jungwirth, de Lange [12], and Umei [13] provide excellent overviews of according publications. ...
The survival rate of extracorporeal life support (ECLS) remains overall at 60 %. Research and development is slow, partly due to the lack of sophisticated experimental models. This publication introduces a dedicated rodent oxygenator (“RatOx”) and shows preliminary in vitro classification tests. The RatOx has an adaptable fiber module size for various rodent models. Gas transfer performance over the fiber module for different blood flows and fiber module sizes were tested according to DIN EN ISO 7199.At the maximum possible amount of effective fiber surface and a blood flow of 100 ml/min, the oxygenator performance has been tested to a maximum of 6.27 ml O2/min and 8.2 ml CO2/min, respectively. The priming volume for this the largest fiber module is 5.4 ml, while the smallest possible configuration with a single fiber mat layer has 1.1 ml of priming volume. The novel RatOx ECLS system has been evaluated in-vitro to comply to a high degree with all predefined functionality criteria for rodent sized animal models. We intend for the RatOx to become a standard testing platform for scientific studies on ECLS therapy and technology.
... Many animal models have been useful in evaluating CPB and a variety of cardiovascular, kidney, respiratory, and neurologic outcomes (Davidson et al., 2019, Grocott et al., 1999, Hubert et al., 2003, Jungwirth and de Lange, 2010, Madrahimov et al., 2018. No animal models of CPB, however, have been utilized to evaluate changes to the microbiome, intestinal barrier dysfunction, or intestinal eicosanoids. ...
... PGE2 is known to induce acute inflammation through mast cell and Th-1 cell activation (Tsuge et al., 2019, Kawahara et al., 2015. PGD2, conversely, has been associated with anti-inflammatory signaling, but can promote or suppress inflammation depending on the inflammatory milieu (Joo andSadikot, 2012, Murata andMaehara, 2016). Valeric acid has been associated with regulation of blood pressure mechanisms through angiotensin-converting enzyme inhibition, as well as protection from bacterial translocation (Takagaki andNanjo, 2015, Peron et al., 2017). ...
The intestinal microbiome is essential to human health and homeostasis and is implicated in the pathophysiology of disease, including congenital heart disease and cardiac surgery. Improving the microbiome and reducing inflammatory metabolites may reduce systemic inflammation following cardiac surgery with cardiopulmonary bypass (CPB) to expedite recovery post-operatively. Limited research exists in this area and identifying animal models that can replicate changes in the human intestinal microbiome after CPB are necessary. We used a piglet model of CPB with 2 groups, CPB (n=5) and a control group with mechanical ventilation (n=7) to evaluate changes to the microbiome, intestinal barrier dysfunction, and intestinal metabolites with inflammation after CPB. We identified significant changes to the microbiome, barrier dysfunction, intestinal short chain fatty acids and eicosanoids, and elevate cytokines in the CPB/DHCA group compared to the control group at just four hours after intervention. This piglet model of CPB replicates known human changes to the intestinal flora and metabolite profile and can be used to evaluate gut interventions aimed at reducing downstream inflammation after cardiac surgery with CPB.
... Moreover, the establishment of CPB with nonhypothermic cardiac arrest is challenging in small animal models. 31 Finally, possibly because of the relatively small sizes of the treatment groups in our study, we repeatedly observed effects of AdipoRon treatment in our in vivo and in vitro experiments, which lacked statistical significance. ...
Background
Cardiac surgery using cardiopulmonary bypass (CPB) frequently provokes a systemic inflammatory response syndrome, which is triggered by TLR4 (Toll‐like receptor 4) and TNF‐α (tumor necrosis factor α) signaling. Here, we investigated whether the adiponectin receptor 1 and 2 agonist AdipoRon modulates CPB‐induced inflammation and cardiac dysfunction.
Methods and Results
Rats underwent CPB with deep hypothermic circulatory arrest and were finally weaned from the heart‐lung machine. Compared with vehicle, AdipoRon application attenuated the CPB‐induced impairment of mean arterial pressure following deep hypothermic circulatory arrest. During the weaning and postweaning phases, heart rate and mean arterial pressure in all AdipoRon animals (7 of 7) remained stable, while cardiac rhythm was irretrievably lost in 2 of 7 of the vehicle‐treated animals. The AdipoRon‐mediated improvements of cardiocirculatory parameters were accompanied by increased plasma levels of IL (interleukin) 10 and diminished concentrations of lactate and K ⁺ . In myocardial tissue, AdipoRon activated AMP‐activated protein kinase (AMPK) while attenuating CPB‐induced degradation of nuclear factor κB inhibitor α (IκBα), upregulation of TNF‐α, IL‐1β, CCL2 (C‐C chemokine ligand 2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and inducible nitric oxide synthase. Correspondingly, in cultured cardiac myocytes, cardiac fibroblasts, and vascular endothelial cells, AdipoRon activated AMPK, upregulated IL‐10, and attenuated activation of nuclear factor κB, as well as upregulation of TNF‐α, IL‐1β, CCL2, NADPH oxidase, and inducible nitric oxide synthase induced by lipopolysaccharide or TNF‐α. In addition, the treatment of cardiac myocytes with the AMPK activator 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside resulted in a similar inhibition of lipopolysaccharide‐ and TNF‐α–induced inflammatory cell phenotypes as for AdipoRon.
Conclusions
Our observations indicate that AdipoRon attenuates CPB‐induced inflammation and impairment of cardiac function through AMPK‐mediated inhibition of proinflammatory TLR4 and TNF‐α signaling in cardiac cells and upregulation of immunosuppressive IL‐10.
... Extracorporeal membrane oxygenation (ECMO) was first performed by Gibbon et al. in 1954, during cardiac surgery [1]. The potential risks during cardiopulmonary bypass (CPB) with extracorporeal membrane oxygenation include cerebral stroke, inflammatory response and contact activation of the coagulation system [2,3].Various CPB animal models have been described to investigate the adverse effects of CBP [4]. Large animal models of CPBin lambs, pigs and dogshave been established, but they are limited by personal requirements and high costs of operation and handling [4]. ...
... The potential risks during cardiopulmonary bypass (CPB) with extracorporeal membrane oxygenation include cerebral stroke, inflammatory response and contact activation of the coagulation system [2,3].Various CPB animal models have been described to investigate the adverse effects of CBP [4]. Large animal models of CPBin lambs, pigs and dogshave been established, but they are limited by personal requirements and high costs of operation and handling [4]. Thus, rodent models of CPB facilitate large sample sizes and can be conducted by a single experimenter. ...
... Subsequently, several modified models of CPB were established [6]. Most of them used oversized bubble or membrane oxygenators with large priming volumes [4]. Therefore, a priming of the extracorporeal circuit with the blood of donor rats was required. ...
Background:
Extracorporeal membrane oxygenation (ECMO) has gained widespread acceptance for the treatment of critically ill patients suffering from cardiac and/or respiratory failure. Various animal models have been developed to investigate the adverse effects induced by ECMO. Different membrane oxygenators have been used with varying priming volumes and membrane surfaces (Micro-1, small animal membrane oxygenator (SAMO)).
Methods:
Sixteen male Lewis rats (350-400 g) were randomly assigned to receive ECMO with Micro-1 or SAMO (n = 8, respectively). Venoarterial ECMO was established after cannulation of the femoral artery and the jugular vein. The cardiac output was measured using a left-ventricular conductance catheter. The oxygen fraction of the ECMO was set to 1.0, 0.75, 0.5 and 0.21 after a stabilisation period of 15 min. Further, arterial blood gas analyses were performed at baseline, and during the first hour every 15 min after commencing the ECMO, and subsequently every 30 min. Dilutional anaemia was calculated using haemoglobin concentration at baseline, and 15 min after the start of ECMO therapy. Moreover, inflammation was determined by measuring tumour necrosis factor alpha, interleukin-6 and -10 at baseline and every 30 min.
Results:
Animals of the Micro-1 group showed a significantly lower dilutional anaemia (ΔHaemoglobin t0 - t0.25: SAMO 6.3 [5.6-7.5] g/dl vs. Micro-1 5.6 [4.6-5.8] g/dl; p = 0.028). Further, significantly higher oxygen partial pressure was measured in the SAMO group, at an oxygen fraction of 0.75, 0.5 and 0.21 (380 [356-388] vs. 314 [263-352] mmHg, p = 0.002; 267 [249-273] mmHg vs. 197 [140-222] mmHg, p = 0.002; 87 [82-106] mmHg vs. 76 [60-79] mmHg, p = 0.021, respectively). However, no differences were found regarding the oxygen fraction of 1.0, in terms of carbon-dioxide partial pressure and cardiac output. Moreover, in the Micro-1 group tumour necrosis factor alpha was increased after 60 min and interleukin-6 after 120 min.
Conclusion:
While the dilutional anaemia was increased after commencing the ECMO, the oxygenation was augmented in the SAMO group. The inflammatory response was elevated in the Micro-1 group.
... To date, CPB has been modelled in sheep, pigs, dogs, rabbits and rats [3,4]. Animal models of CPB are essential to investigate the effects of CPB in relation to different insults (e.g. ...
OBJECTIVES: Cardiopulmonary bypass (CPB) is an essential component of many cardiac interventions, and therefore, there is an increasing critical demand to minimize organ damage resulting from prolonged extracorporeal circulation. Our goal was to develop the first clinically relevant mouse model of CPB and to examine the course of extracorporeal circulation by closely monitoring haemodynamic and oxygenation parameters.
METHODS: Here, we report the optimization of device design, perfusion circuit and microsurgical techniques as well as validation of physiological functions during CPB in mice after circulatory arrest and reperfusion. Validation of the model required multiple blood gas analyses, and therefore, this initial report describes an acute model that is incompatible with survival due to the need of repetitive blood draws.
RESULTS: Biochemical and histopathological assessment of organ damage revealed only mild changes in the heart and lungs and signs of the beginning of acute organ failure in the liver and kidneys.
CONCLUSIONS: This new CPB mouse model will facilitate preclinical testing of therapeutic strategies in cardiovascular diseases and investigation of CPB in relation to different insults and pre-existing comorbidities. In combination with genetically modified mice, this model will be an important tool to dissect the molecular mechanisms involved in organ damage related to extracorporeal circulation.
... factors: (1) the presence of other cardioprotective strategies such as cardioplegia and hypothermia; (2) the presence of concomitant medication which may potentially be cardioprotective such as inhaled anesthetics, nitrates and opioids; (3) the heart is subjected to a variety of different forms of injury including global I/R injury, direct injury from handling of the heart, coronary micro-embolization, and inflammatory injury from the CPB circuit. Therefore, in order to simulate the clinical setting of cardiac bypass surgery, a specific I/R injury model of CPB may be better suited to test novel cardioprotective therapies.55 In this regard, there are rat models of CPB which are well-established and have the following advantages when compared to larger animal models: rats are relatively cheap, easy to survive, and do not require intensive care units (ICU) after surgery. ...
Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.
... Occasionally, cases of massive CAGE due to malfunctioning of CPB machinery or human error in handling the system continue to be reported (106). A review on animal CPB models has been published recently (107). We do not report on studies in which air was passively generated by the oxygenator in a CPB system, since we only included studies in which air was actively administered to the circulation. ...
Determining the effects of cerebral arterial gas embolism on cerebral function, using invasive and non-invasive measurement. Treatment of cerebral arterial gas embolism with hyperbaric oxygen therapy in a swine model. Treatment of decompression illness with lidocaine.
... CPB/DHCA models in large animals such as dogs, cows, sheep and pigs have been established successfully in experimental studies [ 4,5]. Recently, a CPB/DHCA model in rats was proposed, which does not require a full scale operating environment and reduces the difficulty for model implementation [6,7]. There are several critical operation risks which might affect the neurologic recovery after CPB/DHCA, including the duration of arrest, duration of cooling and carbon dioxide tension during CPB before arrest, etc. ...
Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) are important techniques often used in complex cardiac surgery for neonates and infants heart diseases. Cerebral blood flow (CBF) serves as an important physiological parameter and provides valuable hemodynamic information during the surgery. Laser speckle imaging (LSI), as an optical imaging technique, can provide full-field CBF information with a high spatiotemporal resolution. In this preliminary study, we acquired the real-time CBF images with a self-developed miniaturized head-mounted LSI system during the whole CPB/DHCA rat model. Relative CBF velocity in veins and arteries in bilateral hemispheres dropped significantly during cooling period and reached to nearly zero during arrest period (n = 5). More interestingly, two rats showing more dramatic CBF variations in veins than in arteries during cooling period exhibited severe cerebral edema after surgery. The real-time full-field CBF imaging during the CPB/DHCA surgery could add more insights into the operation and be utilized to study the surgical protocols with the ultimate goal of reducing neurologic injury after surgery.
... Thus, testing of the HLM using a rabbit model would mean testing under more strict and difficult conditions. In contrast to the rat model, [8][9][10] the ascending aorta and the right atrium can be cannulated after sternotomy exactly as done in the case of a newborn, and it is possible to sustain adequate flows. Also, comparability of hemolysis, 4,11 as well as inflammatory 5,12,13 parameters between rabbits and humans has been reported. ...
The utilization of a heart-lung machine (HLM) for the correction of congenital heart defects can lead to various complications, which can culminate in multiorgan failure and death. To reduce the considerable risk of complications, we developed a miniaturized, highly integrated HLM (MiniHLM) for use in infants and children. For the purpose of testing the MiniHLM, we developed a new rabbit animal model. In all, surgery was performed on 32 rabbits. In the first series, 13 New Zealand white rabbits were placed on cardiopulmonary bypass (CPB) for 1 hour with the use of an initial version of the MiniHLM. In the second series, we operated on 19 Chinchilla Bastard rabbits using the further developed MiniHLM 02 or the Dideco Kids D100 system. While several adjustments had to be made to the operating protocol in the first series in order to lower the mortality rate, 15 of the 19 rabbits were successfully weaned from the HLM in the second series. Blood tests pertaining to hemolysis and the expression of inflammation were performed. In addition, tissue samples were taken from the right atrial auricle for the purpose of investigating the expression of inflammatory parameters. The newly developed MiniHLM prototype was tested successfully in an animal model in terms of technical function, hemolysis, and the expression of inflammation. On account of the comparability of their blood values, as well as their anatomy, Chinchilla Bastard rabbits serve as excellent models for the testing of CPB and support systems for infants and children that do not require the administration of foreign blood.
... Rats are among the most frequently used animals in pre-clinical experimental research. Rat CPB models are thought to be a good option to investigate the pathophysiology of CPB-related injuries and to enable preclinical evaluation of potential therapeutic interventions (Cresce et al., 2008;de Lange, Yoshitani, Podgoreanu, Grocott, & Mackensen, 2008;Gourlay & Modine, 2010;Jungwirth & de Lange, 2010). Such models should however meet several requirements. ...
... The third main aspect is the use of procedures that allow for prolonged survival in accordance with the principles of good animal practice. Aortic cannulation, as performed in humans, requires a sternotomy to open the chest, but is associated with a higher mortality and post-operative pain and has been used mainly for the experiments without prolonged survival of conscious animals (Cresce et al., 2008;de Lange, Yoshitani, et al., 2008;Gourlay & Modine, 2010;Jungwirth & de Lange, 2010;You et al., 2005). Thus, despite some successful attempts in the lasts years, the optimal clinically relevant rat CPB model with long-term survival is still unavailable. ...
... To further optimize the rat CPB model, we developed one that is a modification of a previously described model (Gourlay & Modine, 2010;Jungwirth & de Lange, 2010). The main modifications included (1) the reduction of volume by miniaturization of the extracorporeal circuit to 15 ml, a volume that we considered sufficiently low not to require blood priming while avoiding excessive hemodilution, and (2) employing arterial inflow via the left common carotid artery to the aortic arch (instead of inflow via the tail artery). ...
Introduction:
Rat models of cardiopulmonary bypass (CPB) have been used to examine the mechanisms of associated organ damage and to test intervention strategies. However, these models only partly mimic the clinical situation, because of the use of blood transfusion and arterial inflow via the tail artery. Thus a model using arterial inflow in the aorta and a miniaturized CPB circuit without need of transfusion was validated by examining intra-procedure characteristics, mortality and the effects of CPB on biomarkers of inflammation and cerebral injury during 5days follow-up.
Methods:
Male Wistar rats (n=95) were anesthetized with isoflurane (2.5%) and fentanyl/midazolam during CPB. Animals were assigned to Control (n=6), Sham (n=40) or normothermic CPB (n=49) groups. Both Sham and CPB were cannulated in the aorta via the left carotid artery and in the right common jugular vein for access into the right heart. Extracorporeal circulation (ECC) was instituted for 60min only in CPB at a flow rate of 120mLkg(-1)min(-1) employing a CPB circuit of 15ml primed with 6% hydroxyethyl starch 60mgml(-1) solution. Rats were sacrificed at either 1h or 1, 2 or 5days after Sham or weaning from CPB. Plasma IL-6 and s100Beta levels were measured and blood cell counts were performed.
Results:
Mortality in CPB animals (3 out of 49) and Sham (4 out of 40) did not differ (chi-square=0.46, dF=1, P>0.5). Compared to baseline (1.87±0.46∗10^9cells/L), Sham procedure (cannulation and anesthesia) significantly increased blood neutrophil count at the end of the period matching ECC (6.34±2.36∗10^9cells/L, P<0.05). CPB induced neutrophilia which persisted during 24h recovery. Also, CPB caused a rapid and prominent increase in plasma IL-6 from the first hour of the postoperative period (~1200pg/ml) with continuation (50-90pg/ml) up to 5th day of recovery. S100Beta levels were above detection level only in 3 out of 42 samples from CPB animals.
Discussion:
Our rat model of CPB without homologous blood transfusion produces a reproducible and reliable systemic inflammatory response, with low mortality rates on long term follow up. The model more closely mimics the human situation in respect to arterial inflow site and avoidance of blood transfusion. Thus, our CPB model is suitable to study its influence on systemic inflammation, ischemia-reperfusion injury, microcirculation and vascular dysfunction in vivo, and to evaluate potential therapeutic interventions.
