Extracorporeal membrane oxygenation (ECMO) or extracorporeal lung assist (ECLA) are intensive medical techniques in which a machine takes over parts or all of the respiratory functions of a patient. Thus, they maintain gas exchange during insufficient respiratory functions providing diseased lungs with an optimal environment for recovering.1 During ECMO, venous blood is removed from the patient and guided through a membrane oxygenator, where oxygen is added and carbon dioxide removed, afterward blood is returned to the patient.2 Extracorporeal membrane oxygenation is a bridge to recovery for patients with severe respiratory and cardiac failure, such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), or graft failure after heart–lung transplantation with intractable hypoxemia and respiratory acidosis.3,4 Despite its life-saving potential, several complications may occur affecting the patients’ outcomes.
The Extracorporeal Life Support Organization (ELSO) registered 53,190 ECMO cases through January 2013 with a survival rate of 61%.5 Here, it needs to be emphasized that nearly 85% of these patients are neonates (children <30 days) and pediatric (30 days to 18 years) patients.5,6 In neonates, ECMO is mostly applied with respiratory failure resulting from meconium aspiration, sepsis, hypoplasia of the lung, or respiratory distress syndrome with a survival rate of 75%.7–9 Compared with neonatal patients less ECMO treatment is performed on pediatric patients with pulmonary failure, whereas it provides support for cardiac failure arising from anatomic abnormalities of the heart or cardiogenic shock.10 Here, the survival rates are less than 50%.5 In general, pediatric patients are very sensitive, and particular attention has to be paid to their small size and their hemostasiological differences compared with adult patients. Specific complications, such as inadequate flow and oxygen delivery, thromboembolism, brain injuries, or bleeding, may occur as a consequence of the large artificial surfaces of the ECMO devices in relation to the blood volume.11,12 In addition, the relatively high priming volume of the extracorporeal circulation (ECC) could cause hemostatic reactions.13,14 Currently, there are only few ECMO systems designed for pediatric use.
The basic ECMO normally consists of an oxygenator for blood gas exchange temporarily replacing the functions of the lung, as well as a centrifugal or roller pump with pulsatile or nonpulsatile flow.2,15,16 Arteriovenous or venovenous cannulae serve as vascular access. At first, silicone oxygenators with a large surface area were used but difficulties with the initial priming volumes and inflammatory responses caused by the large artificial surfaces occurred. Nowadays, most membrane oxygenators consist of polypropylene or polymethylpentene hollow fibers with an antithrombotic and anti-inflammatory coating surface.14,15,17–19
To minimize the priming volume and the artificial surface contact of the blood, an oxygenator with integrated pulsatile pump was developed especially for the use in neonatal and pediatric surgery. The pulsatile pump was incorporated into the hollow-fiber bundle of the oxygenator, called ExMeTrA (expansion mediated transport and accumulation). This was achieved by embedding thin-walled silicone tubes collapsing and expanding into the bundles.20–23 This ExMeTrA system can offer multiple advantages compared with conventional systems, such as minimal filling volume (27 ml), suitable for ECMO in neonatology, compact and combined design (integrated pump), short tubing routes to the patient, and a pulsatile flow.
In this study, the ExMeTrA oxygenator with integrated pulsatile pump was preclinically evaluated, according to its safe hemocompatibility, feasibility, and pump-efficiency in an in vivo animal model. Therefore, the activation of hemostatic and inflammatory parameters on the one hand and blood flow on the other hand were investigated.
The ExMeTrA oxygenators consist of an elliptical bundle made of polymethylpentene fibers (OXYPLUS, Membrana GmbH, Wuppertal, Germany) and 62 flexible silicone tubes (inner diameter = 2.0 mm; wall thickness = 0.3 mm; Deutsch & Neumann GmbH, Berlin, Germany), which are used as a pulsatile pump. These tubes were placed in an equidistant arrangement between the fibers to achieve a uniform flow across the fiber bundle and to avoid recirculation and shunt flow areas. A biocompatible, two-component silicone (Elastosil RT 625; Wacker Chemie AG, Munich, Germany) was used to seal the oxygenators on a centrifuge.
After assembling, each ExMeTrA oxygenator was tested regarding leakage and performance. Therefore, they were filled with distilled water and pressurized (static pressure 200 mm Hg) for 5 min, followed by an inspection for water leakage. Afterward, the pump-performance of each oxygenator was tested, where a maximum pump-capacity of less than 600 ml/min (distilled water) resulted in reassembling of this oxygenator. Finally, each oxygenator and corresponding extracorporeal circuit was CARMEDA coated, which is a bioactive surface heparin coating technology, allowing for lower activated clotting times (ACTs) during the in vivo tests.
The ECC used in this study consisted of a total tubing length of about 130 cm, resulting in a total priming volume of 72 ml, including the ExMeTrA oxygenator. Sampling points proximal and distal the oxygenator were integrated into the circuit as well as a 3/8″ tube to measure the blood flow distal the oxygenator, using a flow meter (Sono TT Ultrasonic Flowmeter; em-tec GmbH, Finning, Germany). Figure 1A shows a schematic sketch of the circuit and a sectional view of an ExMeTrA oxygenator.
During in vivo testing, only the pulsating silicone tubes inside the ExMeTrA oxygenators were used to generate a flow across the ECC. One pulse cycle proceeds as follows: the active magnetic pinch valve (Zimmer Automation, Rosengarten, Germany) at the oxygenator’s outlet closes, while the corresponding inlet valve opens. A negative pressure, generated by a custom-made pulsator, causes the silicone tubes inside the fiber bundle to collapse, so they actively draw blood into the fiber bundle, where gas exchange occurs. Afterward, the active valve at the inlet closes, while the outlet valve opens. A positive pressure generated by the pulsator expands the silicone tubes, which results in a blood flow out of the fiber bundle. Afterward, a new pulse cycle starts. The pulsator that generates the pressure pulses to collapse and expand the silicone tubes as well as the signals to open and close the active magnetic valves, was a custom-made device provided by BYTEC GmbH (Eschweiler, Germany). All silicone tubes, which are placed in an equidistant arrangement inside the oxygenator’s fiber bundle, collapse and expand during a pump cycle. This leads to a well-distributed flow across the bundle by means of reduced risk of shunt flows and recirculation areas. As a consequence, this results in a lower risk for thrombus formation and an efficient gas exchange.24,25 This proves the feasibility to use those pump tubes in venoarterial ECMO circuits.
According to European Union (EU) and German law, the study was approved by the responsible authority (Regional Council Tuebingen) and performed under supervision of the local animal welfare officer. In experimental heart surgery and regenerative medicine, the pig is an established large animal model, not least because of its physiological and anatomical similarities to humans. To simulate the body weight of children, six juvenile pigs weighing 37 kg (range 34.4–40.4 kg) were obtained from a local specific pathogen-free breeding facility. Piglets were unsuitable for this set of experiments, as their blood volume is limited for the amount of different parameters and time points to be determined.
All animals were fasted with water ad lib for 24 h before operation. On the day of intervention, animals were premedicated with a combination of atropine (0.05 mg/kg intramuscular [i.m.]) and azaperone (4 mg/kg i.m.; Stresnil, Elanco Animal Health; Bad Homburg, Germany), followed by midazolam (0.2 mg/kg i.m., 5 mg/ml, Ratiopharm GmbH, Ulm, Germany) and ketamine (14 mg/kg i.m.; Ursotamin, Serumwerke Bernburg, Bernburg, Germany) for sedation. A permanent vein catheter (20 G; Sarstedt, Nümbrecht, Germany) was placed in an ear vein serving as access for fluid (5–10 ml/kg/h), analgesics and anesthetics during operation. To facilitate endotracheal intubation and induce general anesthesia, an intravenous (i.v.) bolus injection of propofol (2–5 mg/kg i.v., vetofol 10 mg/ml; Bayer Vital GmbH, Leverkusen, Germany) was administered. Afterward, the animals were controlled ventilated, and general anesthesia was further maintained by the volatile anesthetic isoflurane (1.6–1.8 vol.%; Isofluran CP, CP-Pharma, Handelsgesellschaft GmbH, Burgdorf, Germany). To establish analgesia already in the early surgical phase, an i.v. bolus of fentanyl (0.02–0.15 mg/kg; Fentanyl-ratiopharm, Ratiopharm GmbH) was applied. Analgesia was carried out by i.v. administration of fentanyl at a dosage of 0.03–0.1 mg/kg/h. To prevent coagulation, heparin was systemically administered at a dose of 100 IU/kg (Heparin-Natrium-25000-ratiopharm, Ratiopharm GmbH). During anesthesia ECG, blood gas analyzes, pulse oximetry, and clinical inspection were monitored constantly. At the end of the experiment, the anaesthetized animals were euthanized by a lethal dose of potassium chloride i.v. (>2 mmol/kg i.v.).
The intervention was preceded by a bolus i.v. injection of 0.02–0.15 mg/kg fentanyl (Ratiopharm GmbH). After midline sternotomy, the pericardium was opened to prepare connection to the ExMeTrA oxygenator. According to standard procedure, an aortic cannula (arterial cannula outer diameter (OD) = 10 French (FR) [3.3 mm]; MAQUET Cardiopulmonary AG, Hirrlingen, Germany) was inserted into the ascending aorta and a venous cannula (thin-flex dual stage venous drainage cannula OD = 18 of 24 FR; Edwards Lifesciences, Unterschleißheim, Germany) was inserted into the right atrium of the heart. To prevent blood clotting within the ExMeTrA oxygenator, 500 IU/kg of heparin was systemically given. An ACT of 270–300 sec was desirable. Therefore, ACT was continuously ascertained—at least every 60 min—using Hemochrom Jr.II system (Whole blood Microcirculation System, ITC, Edison, NJ). If necessary, additional heparin (35 IU/kg; Heparin-Natrium-25000-ratiopharm, Ratiopharm GmbH) was given. Extracorporeal circulation was established with the ExMeTrA oxygenator containing inflow and outflow tubes from the oxygenator to the aortic and venous cannula. Blood flow within the ECC was achieved with the integrated pulsatile pump within the oxygenator as described above (Figure 1B). The priming solution of the ECC consisted of 20 ± 2.2 ml physiological saline solution. Extracorporeal circulation was performed with an average blood flow of 500 ml/min and 1.5 l/min of air were set inside the hollow fibers of the oxygenator. The heart was left beating throughout the whole procedure, and an aortic clamping was not performed.
Baseline blood samples were taken after positioning the venous cannula. Sequential blood sampling was performed at 1, 5, 10, 20, 30, 60, 120, 270, and 360 min after starting the ECC.
Whole Blood Cell Count
Whole blood cell count was performed using ABX Micros 60 blood analyzer (Axon Lab AG, Switzerland) from ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood (EDTA-Monovette, Sarstedt Nümbrecht, Germany).
Analysis of Hemostatic Activation
Changes in hematologic markers indicating an activation of the complement system and the coagulation cascade were measured by commercially available enzyme-linked immunosorbent assay (ELISA) kits. With the help of the pan-specific C3 converter kit (MicroVue Pan-Specific C3 kit, Tecomedical GmbH, Buende, Germany), the activity of C3 in the pig plasma was converted to be detectable with the traditional human sC5b-9 ELISA kit (Osteomedical GmbH, Buende, Germany). Hence, the kit provides a measurement of prior complement activation. To evaluate coagulation status, thrombin– antithrombin-III complex (TAT; Siemens healthcare, Erlangen, Germany) was investigated. Haptoglobin, an acute-phase protein, was analyzed for detection of inflammatory responses and as hemolysis marker by BioCheck Leipzig, Germany. Additionally, hemolysis was investigated by using a photometrical colorimetric test detecting the amount of plasma-free hemoglobin (Photometer PM 4 CHR, Carl Zeiss, Jena, Germany).
Scanning Electron Microscopy
After each experiment, hollow-fiber bundles were fixed overnight in 2% glutaraldehyde (Serva, Heidelberg, Germany) diluted with phosphate buffered saline (PBS) solution (PAA laboratories, Cölbe, Germany) at 4°C. After the fixation, samples were washed for 10 min in pure PBS and then dehydrated with an ascending ethanol series (40–100% ethanol; Merk, Darmstadt, Germany) in 10 min steps. In a critical point, drier (Polaron E3100, GaLa Instruments, Bad Schwalbach, Germany) bundles were dried and sputtered with gold palladium particles (Emitech K550X, GaLa Instruments, Bad Schwalbach, Germany) and subsequently analyzed by scanning electron microscopy (Zeiss Evo LS10, Zeiss, Oberkochen, Germany).
During operation, the pigs received infusions to stabilize their cardiovascular systems. Therefore, a hematocrit correction was performed by forming a quotient of the individual hematocrit value with the baseline value and using the derived factors for normalization of all subsequent data sets. Statistical analyzes were performed using the analysis software GraphPad Prism 6.0 (GraphPad Software, Inc., San Diego, CA). The results are shown as mean ± standard error of mean (SEM). After testing the homogeneity of variances by Grubbs, the data were tested for normal distribution by Kolmorgorov–Smirnov normality test. For not normally distributed data, the nonparametric Kruskal– Wallis test was applied followed by Dunn’s multiple comparison posttest. Values of p less than or equal to 0.05 were considered as being significant, and values of p more than 0.05 were considered as being not significant (n.s.).
Whole Blood Cell Count
Interaction of whole blood with artificial surfaces may lead to an activation of leukocytes and platelets. Here, a decrease in platelet count caused by sticking of platelets to the surface of the oxygenator and ECC tubing could not be observed. In addition, shear stress within ECC might result in a decrease of erythrocytes and hemolysis. No significant differences in platelet, white blood cell, and erythrocyte counts were observed during the time of ECC compared with the baseline value (Figure 2, A–C). The hematocrit, however, tended to decrease over time compared with the baseline (Figure 2D) because of rehydration of the animals and the priming of the ECC. Therefore, a hematocrit correction was performed as described in the “Methods” section. On that basis, the hemoglobin values were not influenced by the ECC (Figure 2E).
Analysis of Hemostatic Activation
During coagulation, the key event in formation of a fibrin clot is the conversion of prothrombin to thrombin. This clot formation is counteracted by the endogenous coagulation inhibitor antithrombin III neutralizing thrombin by forming the TAT complex. Hence, the coagulation activation can be indirectly detected by the TAT plasma concentration. In our investigations, blood circulation through the ExMeTrA leads to increasing values of TAT concentration. After initial 180 min of the experiment, a significant increase (p ≤ 0.05) in TAT complex formation was detected compared with the baseline (Figure 3A) that persisted until the end of the experiment.
The activation of the complement system is a pivotal event in response to foreign antigens. In our investigations, the consumption of C3 was measured compared with the baseline. No significant consumption of C3 was detected within 360 min of circulation through the ExMeTrA (Figure 3B).
Haptoglobin is an acute phase protein and acts as an antioxidant and high-affinity hemoglobin-binding protein with essential protective functions. Any inflammatory process may increase the haptoglobin concentration in plasma, whereas hemolysis might lead to a decrease in free haptoglobin. In this study, a time-dependent decrease in haptoglobin plasma concentration was observed, which became significant after 360 min (p ≤ 0.05; Figure 3C).
Hemolysis is caused by a destruction of erythrocytes and the release of hemoglobin into the plasma. In our investigation, only a slight but not significant trend in hemolysis was observed (Figure 3D).
Activated Clotting Times.
The point-of-care ACT test is the standard assay for monitoring anticoagulation during ECMO. In this set of experiments, the ACT baseline values were 100 sec and increased significantly in the first minute after the beginning of ECMO (p < 0.001). Afterward, the ACT was adjusted to levels of 220–250 sec (Figure 3E) by heparin injection (35 IU/kg, Heparin-Natrium-25000-ratiopharm, Ratiopharm GmbH).
The blood flow through the ExMeTrA oxygenator stayed stable throughout the whole experiment at a mean of 517.3 ± 22.54 ml/min (Figure 4).
Scanning Electron Microscopy
To visualize fibrin adsorption and cell adhesion to the hollow fiber bundles after blood contact, SEM was performed. Representative SEM images are shown in Figure 5. Blood contact during circulation lead to mild cellular deposition and adhesion of activated platelets (Figure 5, A–D).
ECMO is an accepted and commonly used rescue support for pulmonary and cardiac failure in pediatric patients. Especially as neonatal extracorporeal life support ECMO is applied, but it also often serves as bridge to transplant for adult patients with chronic cardiac or pulmonary failure.26–29 Most of the extracorporeal life support systems are associated with severe complications because of their inherent tendency toward hemolysis, hemorrhages, and thromboembolism.11,30,31 These feared complications may lead to renal failure, shock, sepsis, or neurological injuries and are associated with an increased mortality (<50%) and long-term morbidity rate.5,16,32,33 Therefore, advanced technologies in extracorporeal life support are urgently needed.
In this study, the in vivo feasibility and hemocompatibility of the new pediatric ExMeTrA oxygenator were examined. The experimental group consisted of six pigs that received ECC treatment for 6 h. This animal model was best suited for testing ExMeTrA oxygenator modules because of its physiological and anatomical similarities to humans.34,35 Blood samples were analyzed for hemostatic activation, and the oxygenator was tested for its blood flow rate. The integrated pulsatile pump reduced the priming volume by means of thin-walled symmetric silicone tubes inside the oxygenator to 27–72 ml for the whole ECC. During the ECC, the pulsatile blood flow was constantly at 517.3 ± 22.54 ml/min while using solely the silicone tubes as a pump.
Contact of blood with nonphysiological material surfaces of ECMO is known to cause complement activation,14,36 but in our experiments, the markers for inflammation and coagulation were only slightly influenced by the ExMeTrA oxygenator. Despite the observation that median sternotomy combined with a large tissue injury already leads to an increased sC5b-9 plasma level,37 an activation of the complement system by the ExMeTrA oxygenator was not observed. The measurement of the C3 consumption was performed with a newly developed kit from Tecomedical (MicroVue Pan-Specific C3 kit) that converted the C3 in the pig plasma to be detectable with a traditional human sC5b-9 ELISA kit. The results showed a marginal consumption of 20%. This consumption of C3 can be explained by the operation procedure with sternotomy for central cannulation of the ECC.
The activation of the intrinsic pathway of the coagulation cascade is a well-known phenomenon of the interaction of blood with artificial surfaces.38 In our study, the TAT levels showed a delayed but moderate increase after 180 min of ECC. During 360 min of ECC, very small thrombogenicity of the hollow fibers within the oxygenators could be detected. In general, a decrease in platelet count and an increase in leukocyte count would be expected by sticking of platelets to the artificial surface of the oxygenator and tubing system and inflammatory responses.14,39,40 During the entire experimental period, the concentration of total hemoglobin was on a very low level and extremely low red blood cell damage could be detected. Barrett et al31 reported an increase in ECMO complications including hyperbilirubinemia, acute renal failure, and hemolysis in pediatric patients receiving ECMO support with a centrifugal pump. The resulting hemolysis is attributed to the negative pressure and cavitations within the centrifugal pump.41 In roller pumps, hemolysis is also frequently seen and may be induced by shear stress generated by compression of the tubings by the roller pump valves.42 The levels of plasma free hemoglobin as a result of hemolysis may rise as much as twoflod to 25-fold during ECMO with all kind of pumps.43 In our investigations, the free plasma hemoglobin level did not increase significantly during the experiment. In contrast, the haptoglobin levels showed a decreasing trend during ECC, which was overall not significant (p > 0.05). Haptoglobin, an acute-phase protein, is a marker for inflammation as well as for hemolysis. Therefore, an increased level of haptoglobin is associated with inflammatory reactions, and a decreased level on the other hand is an indicator for hemolysis.44,45 Hence, ECC hemolysis may occur with an increase of free hemoglobin and decrease of haptoglobin.46 In this experiment, a slight to moderate hemolysis occurred induced by the ExMeTrA oxygenator using an integrated pulsatile pump by collapsing and expanding silicone tubes placed in the fiber bundle in combination with active valves.20,39,47,48
In conclusion, our study analyzed the feasibility and hemocompatibility of a novel pediatric oxygenator with integrated pulsatile pumping silicone tubes and reduced priming volume. With only slight influence of the hemostatic markers, such as coagulation and inflammation by the ExMeTrA oxygenator within 6 h of ECC, we could clearly demonstrate its hemocompatibility. In addition, the oxygenator showed an optimal quality of flow. Our findings provide necessary groundwork for further studies to evaluate the suitability and safety of the ExMeTrA modules for ECC procedures in infants.
Limitations and Outlook
Pigs represent an excellent animal model because their similarity to humans concerning anatomy, genetics, and physiology enables the study of various diseases or operation techniques.49
In this small initial study, observations were focused on hemocompatibility of the ExMeTrA oxygenator with integrated pulsatile pump. Therefore, the chosen parameters were investigated over a 6 h timeframe, as blood–material interactions trigger contact and immune system within minutes up to 24 h.28,38 The second activation period that can be observed after 72 h of ECMO treatment characterized by increased coagulation parameters was not investigated here.
The study demonstrated that the hemostatic markers such as coagulation and inflammation were only slightly influenced by the ExMeTrA oxygenator. In addition, the oxygenator showed an optimal quality of flow.
However, the obtained results cannot be transferred directly to the clinical situation on their own because our ECMO model differs in some points from a neonatal ECMO model:
- Animals weighing approximately 37 kg and were oversized for a neonatal ECMO model.
- The maximal flow of the ExMeTrA oxygenator is limited to 500 ml/min, thus full ECMO support was not achieved.
- Tubing and cannula size were adapted to the size of the used animals.
- No control group with an oxygenator with a pulsatile or roller pump was performed.
Nevertheless, the obtained parameters yield valid information on the general hemocompatibility of the new device. Especially, the suitability for infants will be investigated in further validation studies with a larger group of piglets with a body weight ranging from 3 to 10 kg on full ECMO support with infant tubing and cannula sizes.
This work was performed in the course of a research and development project with the “Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG, Schönefeld” (Germany) which is also the owner of the underlying international patent.
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