Currently in United States, there are no clinically-applicable hollow fiber extracorporeal membrane oxygenation (ECMO) oxygenators available. Therefore, our laboratory is in the process of developing a silicone hollow fiber membrane oxygenator for long-term ECMO usage. This oxygenator incorporates an ultrathin silicone hollow fiber. At this time, a specially-modified blood flow distributor (one chamber distributor) is centered in the module to prevent blood stagnation. An ex vivo long-term durability test for ECMO was performed using a healthy miniature calf for 2 weeks. Venous blood was drained from the left jugular vein of a calf, passed through the oxygenator and infused into the left carotid artery using a Gyro C1E3 centrifugal blood pump. A successful 2-week ex vivo experiment was performed. The O2 and CO2 gas transfer rates were maintained at the same value of 40 ml/min at a blood flow rate of 1 L/min flow and V/Q=3 (V=gas flow rate  Q=blood flow rate). The plasma free hemoglobin was maintained around 5 mg/dl. After the experiment, no blood clot formation was observed in the module and no abnormal necropsy findings were found. These data suggest that the performance of this newly-improved oxygenator was stable, reliable, and acceptable for long-term ECMO

Glueck, Julie

Hanazaki, Kazuhiro

Ichikawa, Seiji

Ishitoya, Hiroshi

Kawahito, Shinji

Linneweber, Joerg

Maeda, Tomohiro

Motomura, Tadashi

Nonaka, Kenji

Nose, Yukihiko

Sato, Koshiro

Takano, Tamaki

Tokushima University Institutional Repository

INTRODUCTIONAn effective microporous hollow fiber oxygenatorhas been developed for cardiopulmonary bypassprocedures ; however, since 1970, no improvementshave been made for an effective extracorporeal mem-brane oxygenation (ECMO) system (1). The Kolobowspiral coil membrane oxygenator (Medtronic Inc.,Anaheim, CA, U.S.A.) was developed in 1972 (2)and is the only practical available ECMO system inthe United States. This oxygenator is an old-fashioneddevice that is inefficient and difficult to handle.To solve this problem, our laboratory is develop-ing a new oxygenator using ultrathin silicone rub-ber hollow fibers (3-7). These devices have dem-onstrated better biocompatibility and higher gastransfer performances over and above the alreadyexisting ECMO oxygenator (6, 7). For further highperformance and antithrombogenicity, an oxygenatorwith an improved blood flow distributor was fabri-cated and evaluated with in vitro (8) and short termex vivo (9) testing. The purpose of this study wasto evaluate its clinical long-term feasibility for ECMOusing an animal model.ORIGINALFeasibility of a new hollow fiber silicone membrane oxygenatorfor long-term ECMO applicationShinji Kawahito, Tomohiro Maeda, Tadashi Motomura, Tamaki Takano,Kenji Nonaka, Joerg Linneweber, Seiji Ichikawa, Hiroshi Ishitoya,Kazuhiro Hanazaki, Julie Glueck, Koshiro Sato＊, and Yukihiko NoséMichael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA ;and ＊Fuji Systems, Inc., Tokyo, JapanAbstract : Currently in United States, there are no clinically-applicable hollow fiber extracorporealmembrane oxygenation (ECMO) oxygenators available. Therefore, our laboratory is in theprocess of developing a silicone hollow fiber membrane oxygenator for long-term ECMO usage.This oxygenator incorporates an ultrathin silicone hollow fiber. At this time, a specially-modifiedblood flow distributor (one chamber distributor) is centered in the module to prevent bloodstagnation. An ex vivo long-term durability test for ECMO was performed using a healthyminiature calf for 2 weeks. Venous blood was drained from the left jugular vein of a calf, passedthrough the oxygenator and infused into the left carotid artery using a Gyro C1E3 centrifugalblood pump. A successful 2-week ex vivo experiment was performed. The O2 and CO2 gastransfer rates were maintained at the same value of 40 ml/min at a blood flow rate of 1 L/minflow and V/Q=3 (V=gas flow rate ; Q=blood flow rate). The plasma free hemoglobin was main-tained around 5 mg/dl. After the experiment, no blood clot formation was observed in themodule and no abnormal necropsy findings were found. These data suggest that the per-formance of this newly-improved oxygenator was stable, reliable, and acceptable for long-termECMO. J. Med. Invest. 49 : 156-162, 2002Keywords : hollow fiber, silicone membrane, oxygenator, extracorporeal membrane oxygenation, long-term exvivo studyReceived for publication June 27, 2002 ; accepted July 31,2002.Address correspondence and reprint requests to Shinji Kawahito,M.D., Department of Anesthesiology, The University of TokushimaSchool of Medicine, Kuramoto-cho, Tokushima 770-8503, Japanand Fax : +81-88 -633-7182.The Journal of Medical Investigation Vol. 49 2002１５６METHODSAnimal preparationThe animal involved in this study received hu-mane care in compliance with the “Guiding Princi-ples in the Case and Use of Animals” approved by theCouncil of the American Physiological Society (re-vised 1980) and the “Guide for the Care and Use ofLaboratory Animals” published by the National In-stitutes of Health (NIH Publication No. 85-23, re-vised 1985). A healthy miniature female calf (Dex-ter strain) weighing 90 kg and 11 months old wasthe subject of this study. A calf of this age was es-sential for this study because an animal with normalphysiological adult circulation was needed, withoutabnormal anatomy due to the fetal circulation (i.e.atrial septal defect). Complete blood cell count (CBC),blood biochemistry, and plasma free hemoglobinwere examined before surgery.Surgical procedureAnesthesia was induced using 4% halothane with50% nitrous oxide through a special mask. Whenthe animal was anesthetized, endotracheal intubationwas performed and anesthesia was maintained by1-2% halothane with 100% oxygen. A 15 cm longitu-dinal incision was made along the jugular vein onthe left side of the neck, and the left carotid arteryand jugular vein were dissected. The arterial can-nula was inserted through a small arteriotomy andthreaded proximally into the artery ; the venouscannula was inserted through the jugular vein in theproximal direction in the same manner. After placingthe arterial and venous cannulae, both were exter-nalized and connected to the extracorporeal circuit,and the pump circuit was activated. The Gyro C1E3(Kyocera Corporation, Kyoto, Japan) was used forthe centrifugal pump. Mean arterial pressures weremaintained at more than 80 mmHg. Activated clottingtime (ACT) was maintained at approximately 400sec throughout the experiment using heparin. Whenthe calf completely recovered from the anesthesia,the ECMO study was started. At the end of experi-ment, euthanasia and necropsy were performed.Membrane OxygenatorA new silicone hollow fiber membrane oxygenator(Preproduction model PPM-04, Fuji Systems Inc.,Tokyo, Japan) was fabricated for long-term ECMOapplication based on the results of a previous mod-el (PPM-03) (8, 9). The major changes in the newimproved model (PPM-04) are an increase in thefiber length (from 100 to 150 mm) and the surfacearea (from 0.8 to 1.0 m2) to increase the gas trans-fer rate, a decrease in the packing density (from45 to 40%) to decrease the pressure drop, and aspecially-designed blood flow distributor (from 4chambers to 1 chamber) incorporated into the cen-ter of the module to prevent blood stagnation. Con-sequently, the new ECMO oxygenator module was220 mm long and contained in a silicone coatedacrylic housing. The priming volume of this modulewas 200 ml. This oxygenator was of the extracapillaryflow type, in which blood flows outside the hollowfibers (Fig. 1).MeasurementsGas transfer rate : At a blood flow rate of 1 L/minand V/Q=3 (V=gas flow rate ; Q=blood flow rate),the O2 and CO2 gas transfer rates were evaluatedfor 2 weeks (ECMO condition). Blood gas samples,taken from the inlet and outlet sampling ports, wereanalyzed every day using a System 1306 pH/blood gasanalyzer (Instrumentation Laboratories, Lexington,MA, U.S.A.). Three samples were measured for eachsampling time. The O2 content and O2 transfer rateand the CO2 content and transfer rates were cal-culated by the following standard formulas :O2 content (Vol%)=(Hb×1.34×%O2 saturation)/100+PO2×0.003Fig. 1. A photograph shows the new hollow fiber siliconemembrane oxygenator.The Journal of Medical Investigation Vol. 49 2002 １５７O2 transfer rate (ml/min)=(CaO2 - CvO2)×bloodflow rateTotal CO2 (mmol/L)=HCO3-+0.03×PCO2CO2 transfer rate (ml/min)=22.4×(tCO2v - tCO2a)×blood flow ratewhere Hb is hemoglobin (g/dl), PO2 is oxygen par-tial pressure (mmHg), CaO2 is arterial oxygen con-tent (Vol%), CvO2 is venous oxygen content (Vol%),the blood flow rate represents pump flow rate (L/min),HCO3 - is plasma bicarbonate ion concentration(mmol/L), PCO2 is CO2 partial pressure (mmHg),tCO2v is venous total CO2 (mmol/L), and tCO2a isarterial total CO2 (mmol/L).Hemolysis test : Plasma free hemoglobin wasmeasured every day. The method of measuringplasma free hemoglobin has been described byMizuguchi et al . (10).Pressure drop measurement : Pressure differencesbetween the inflow and outflow ports were monitoredto assess the pressure drop in the oxygenator through-out the experiment using a pressure monitor (LivingSystems Instrumentation, Burlington, VT, U.S.A.).CBC and biochemistry study : CBC, lactatedehydrogenase (LDH), aspartate aminotransferase(AST), alanine aminotransferase (ALT), blood ureanitrogen (BUN), creatinine, total billirubin (T. Bil),total protein (TP), and electrolytes (Na, K, Cl) weremeasured every two days postoperatively.RESULTSA 2-week ex vivo experiment was successfully per-formed without exchanging the oxygenator. Thestable and reliable performance of this new oxygenatorwas demonstrated for the entire experiment.Gas Transfer Performance : Fig. 2 shows the re-sults of gas exchange performance tests. The O2and CO2 gas transfer rates at a blood flow rate of1 L/min and V/Q=3 were maintained at 41.72±4.13(mean±SD) ml/min and 40.97±14.49 ml/min, re-spectively, for 2 weeks.Hemolysis test : As shown in Fig. 3, the plasmafree hemoglobin was maintained at 5.50±2.20 mg/dl for 2 weeks.Pressure drop study : The pressure drop in theblood chamber was kept from 20 to 40 mmHg. Ahigh pressure drop was sometimes observed, how-ever, this was not continuously observed (for only2 or 3 hours) (Fig. 4). The reason of this high pres-sure drop was unknown.CBC and biochemistry study : Table 1 shows theCBC and blood biochemistry data throughout theexperiment. All the mean values were within nor-mal limits except for anemia due to bleeding towardsthe end of the experiment. Just after the operation,abnormal levels of WBC, AST and TP were ob-served, however, they were normalized gradually.Also, the platelet count was maintained above200,000/µl.Visual inspection : After the experiment, the visu-al inspection of the oxygenator revealed no bloodclot or thrombus formation (Fig. 5).Necropsy findings : There were no thromboembolicfindings in major organs including liver, kidney,spleen, intestine, etc. in the macroscopic examina-tion. However, a huge hematoma in the chest cav-ity due to the high ACT level was observed.DISCUSSIONThe microporous membrane oxygenator that wasintroduced in the early 1960s has been successfullyused for cardiopulmonary bypass during cardiacsurgery. However, plasma leakage through the poresinto the gas phase is one of the limiting factors forlong-term use of these microporous membraneoxygenators (11-13). The plasma leakage is thoughtto be a result of the loss of the hydrophobic char-acteristics of the micropores by the adsorption ofprotein, and that is promoted by an increase in theoutlet blood pressure (14). Several techniques havebeen proposed to decrease the plasma leakage, in-cluding the use of a heated humiditied gas (11, 12,15), use of high gas flow rate (15), and developmentof a more uniform and smaller size porous mem-brane (16, 17). These techniques require addition-al complex and expensive devices. In contrast, thenonporous true membrane oxygenator can com-pletely prevent plasma leakage without any otherhardware.ECMO is now a standard treatment for respira-tory failure refractory to conventional pulmonarysupport techniques worldwide, and many patientsare treated with ECMO every year (18). The Kolobowspiral coil membrane oxygenator (2), the onlyECMO oxygenator approved in the U.S.A., employsa solid silicone membrane. However, because ofthe mechanically weak characteristics of silicone,manufacturing of hollow fibers from silicone elas-tomers is difficult and expensive. This author’sgroup developed a novel silicone material with suf-ficient mechanical strength, and a fine silicone hol-S. Kawahito et al. Long-term ECMOwith a New Oxygenator１５８low fiber with a diameter of 300 µm and wall thick-ness of 50 µm (3). Utilizing this hollow fiber, anoxygenator with an improved blood flow distributorwas fabricated. After satisfactory in vitro (8) andshort-term ex vivo (9) performances were achieved, a2-week ex vivo experiment was successfully performed.Other groups are also developing high-performanceECMO oxygenators, for example, Takewa et al.(19) reported long-term ECMO experiments usinga heparin bonded oxygenator. On the other hand,our oxygenator was made of silicone rubber withexcellent biocompatibility. This is the first all sili-cone rubber hollow fiber ECMO oxygenator in theworld.One of the limitations of conventional siliconehollow fiber compared with microporous membraneoxygenators is poor gas permeability. We solvedthe problem to some extent by using a novel fineultrathin silicone fiber. In this ex vivo experiment,the O2 and CO2 gas transfer rates were maintainedat the same value of 40 ml/min at a blood flow rateof 1 L/min flow and V/Q=3 for 2 weeks. Stable andreliable gas transfer performance under the ECMOcondition is advantageous for long-term usage. How-ever, O2 and CO2 transfer rates are still limitedcomparing the results of in vitro experiments (8).(A)(B)Fig. 2. Gas transfer performance changesof O2 transfer rate (A) and CO2 transferrate (B) for a 2-week ECMO study. Sta-ble and sufficient gas transfer levels wererevealed. Data are expressed as mean±SD.The Journal of Medical Investigation Vol. 49 2002 １５９Further improvements (further increase of the fiberlength and the surface area, etc.) are necessary.Additionally, the plasma free hemoglobin levelsand pressure drops were within acceptable levels,and no abnormalities during the blood examination ornecropsy were observed. Excellent biocompatibilityof our silicone membrane oxygenator was provenin this ex vivo experiment.The remaining problem is the bleeding compli-cation due to the anti-coagulant therapy. Becausethe preliminary study cases developed oxygenatorocclusion after several days, it was decided thatthe ACT level be increased from 200-250 sec to around400 sec. However, in this study, a huge hematomain the chest cavity due to the high ACT level wasobserved. During the next ECMO experiment, thisgroup is proposing the ACT level be in the range of250-300 sec. These results indicate that this oxygenatorcan be used for prolonged ECMO, although furtherimprovement in thrombo-resistant properties shouldbe achieved.In conclusion, a 2-week ex vivo experiment withthe silicone membrane hollow fiber oxygenator wassuccessfully completed. Stable and reliable perfor-mance of this oxygenator was proven. These datademonstrate the feasibility for long-term applicationof this newly improved silicone hollow fiber oxygenator.However, this manuscript is essentially the resultsof a single experiment, which confirms the feasi-bility of our newly-developed oxygenator. It is nota sufficient number of experiments to confirm theadvantages of our oxygenator. This oxygenator is stillFig. 3. The change of plasma free hemo-globin during the 2-week ECMO study.Fig. 4. The pressure drop in the bloodchamber during the 2-week ECMO study.S. Kawahito et al. Long-term ECMOwith a New Oxygenator１６０in the development stage, and further experimentsand improvements will be necessary.REFERENCES1. NosY, Motomura T, Kawahito S : Oxygenator-ArtificialLung-Past, present, and future. ICAOT/ICMTPress, Houston, 20012. Kolobow T, Spragg RG, Pierce JE, Zapol WM :Extended term (to 16 days) partial extracorporealblood gas exchange with the spiral membranelung in unanesthetized lambs. ASAIO Trans17 : 350-354, 19713. Funakubo A, Higami T, Sakuma I, Fukui Y,Kawamura T, Sato K, Sueoka A, NosY : De-velopment of a membrane oxygenator for ECMOusing a novel fine silicone hollow fiber. ASAIOJ 42 : M837-M840, 19964. Niimi Y, Yamane S, Yamaji K, Tayama E, SueokaA, NosY : Protain adsorption and platelet ad-hesion on the surface of an oxygenator mem-brane. ASAIO J 43 : M706-M710, 19975. Yamane S, Ohashi Y, Sueoka A, Sato K, KuwanaJ, NosY : Development of a silicone hollowfiber membrane oxygenator for ECMO appli-cation. ASAIO J 44 : M384-M387, 19986. Maeda T, Iwasaki A, Kawahito S, Nakata K,Nonaka K, Linneweber J, Schulte-Eistrup S,Takano T, Yoshikawa M, Sato K, Kuwana J,Murabayashi S, NosY : Preclinical evaluationof a hollow fiber silicone membrane oxygenatorfor extracorporeal membrane oxygenator ap-plication. ASAIO J 46 : 426-430, 20007. Kawahito S, Maeda T, Takano T, Nonaka K,Linneweber J, Mikami M, Motomura T, IchikawaTable 1. Complete blood cell count and biochemistry dataMean±SD RangeWBC (/µl)RBC (×104/µl)Ht (%)Plt (×104/µl)LDH (IU/L)AST (IU/L)ALT (IU/L)BUN (mg/dl)Creatinine (mg/dl)T. Bil (mg/dl)TP(g/dl)Na (mEq/L)K (mEq/L)Cl (mEq/L)11589±6214444±17118.9±6.335.7±6.2652±20264±3416±612±40.7±0.10.4±0.36.0±0.7136±34.6±0.596±74400-22000210-74010.0-30.022.3-43.6404-95537-12610-279-210.6-0.90.1 -1.14.8 -6.7133-1403.4-5.285-106All data are shown as mean±SD.WBC, white blood cell ; RBC, red blood cell ; Ht, hematocrit ;Plt, platelet ; LDH, lactate dehydrogenase ; AST, aspartateaminotransferase ; ALT, alanine aminotransferase ; BUN, bloodurea nitrogen ; T. Bil, total bilirubin ; TP, total protain ; Na, so-dium ; K, potassium ; Cl, chrorideFig. 5. A photograph taken of the oxygenator after the experiment.The Journal of Medical Investigation Vol. 49 2002 １６１S, Glueck J, Sato K, Kuwana J, NosY : Gastransfer performance of a hollow fiber siliconemembrane oxygenator : Ex vivo study. ArtifOrgans 25 : 498-502, 20018. Kawahito S, Maeda T, Motomura T, Takano T,Nonaka K, Linneweber J, Mikami M, IchikawaS, Kawamura M, Glueck J, Sato K, NosY :Development of a new hollow fiber siliconemembrane oxygenator : In vitro study. ArtifOrgans 25 : 494-498, 20019. Kawahito S, Maeda T, Motomura T, Takano T,Nonaka K, Linneweber J, Ichikawa S, Kawamura M,Ishitoya H, Glueck J, Sato K, NosY : Preclinicalevaluation of a new hollow fiber silicone mem-brane oxygenator for pediatric cardiopulmonarybypass : Ex-vivo study. Ann Thorac CardiovascSurg 8 : 7-11, 200210. Mizuguchi K, Damm GA, Aber GS, BozemanRJ, Bacak JW, Svejkovsky PA, Orime Y, OharaY, Naito K, Takai K, Makinouchi K, Takatani S,NosY : Does hematocrit affect in vitro hemolysistest results? Preliminary study with Baylor/NASA prototype axial flow pump. Artif Organs18 : 650-656, 199411. Palder SB, Shaheen KW, Whittelessy GC, NowlenTT, Kundu SK, Klein MD : Prolonged extracorporealmembrane oxtgenation in sheep with a hollowfiber oxygenator and a centrifugal pump. TransASAIO 34 : 820-822, 198812. Mottaghy K, Oedekoven H, Starmans H, MullerB, Kashefi A, Hoffmann B, Bohn S : Technical as-pects of plasma leakage prevention in microporouscapillary membrane oxygenators. ASAIO Trans35 : 640-643, 198913. Montoya JP, Shanley CJ, Merz SI, Bartlett RH :Plasma leakage through microporous mem-branes : Role of phospholipids. ASAIO J 38 :M399-M405, 199214. Tamari Y, Tortolani AJ, Lee-Sensiba KJ : Bloodlesstesting for microporous membrane oxygenatorfailure : A preliminary study. Int J Artif Organs14 : 154-160, 199115. Kawak AM, Gaylor JDS, Simpson K, Kirkland M :An in vitro technique to assess oxygenator po-tential for respiratory failure therapies. Int JArtif Organs 14 ; 234-238, 199116. Muramoto T, Tatebe K, Nogawa A, HagiwaraK, Seita Y, Fukasawa H, Takahashi K, SatohM, Inaba A, Takahashi A : Development of anew microporous hollow fiber membrane foroxygenators. Jpn J Artif Organs (in Japanese)19 ; 472-475, 199017. Hagiwara K, Innami K, Yokoyama K, Kitoh H,Nogawa A, Muramoto T, Tatebe K, Seita Y,Fukasawa H : An approach to the microporoushollow fiber for the ECMO oxygenator-microporecharacteristics of the gas exchange performance,plasma leakage, and hydrophilization of theinner surface of fibers. Jpn J Artif Organs (inJapanese) 21 ; 720-726, 199218. Ichiba S, Bartlett RH : Current status of extracorporealmembrane oxygenation for severe respiratoryfailure. Artif Organs 20 ; 120-123, 199619. Takewa Y, Tatsumi E, Taenaka Y, Nakatani T,Masuzawa T, Nishimura T, Nakamura M, EndoS, Takano H, Tanaka S : Long-term evaluationof a heparin bonded artificial lung-Continuoususe up to 36 days. Jpn J Artif Organs (in Japa-nese) 27 ; 379-383, 1998S. Kawahito et al. Long-term ECMOwith a New Oxygenator１６２

Feasibility of a new hollow fiber silicone membrane oxygenator for long-term ECMO application

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Feasibility of a new hollow fiber silicone membrane oxygenator for long-term ECMO application

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