when the treatment of acute heart failure and respiratory failure is difficult with existing conventional methods , treatment with an extracorporeal membrane oxygenator ( ecmo ) has become an alternative ( 1 ) . although heparin has been used as an anticoagulant among a variety of methods to reduce bleeding complications during ecmo usage , bleeding complications still occur in 10%-30% of patients ( 1 - 4 ) . nafamostat mesilate , a synthetic protease inhibitor with a short half life , has been widely used as an anticoagulant for hemodialysis patients with a tendency to bleed ( 5 - 7 ) . it has been reported that nafamostat mesilate produces good results when it is applied for anticoagulation to cardiac surgery and ecmo ; however , different dosages were used in each study ( 8 - 12 ) . the present study investigated the ideal dosage and efficacy of nafamostat mesilate for use with ecmo in patients with acute cardiac or respiratory failure . we retrospectively reviewed the records of 73 consecutive patients who received ecmo due to acute cardiac or respiratory failure between january 2006 and december 2009 . tokyo , japan ) was used as an anticoagulant in 17 patients and 56 patients received heparin . we excluded 5 of the 56 heparin patients because they underwent an operation just after ecmo : 3 pulmonary artery thromboembolectomies due to acute pulmonary thromboembolism , 1 coronary artery bypass graft due to acute myocardial infarction , and 1 reoperation due to cardiac arrest at 10 hr after receiving a coronary artery bypass graft . we started to use nafamostat mesilate in october 2008 as an anticoagulant during ecmo support in patients with acute renal failure or with a high risk of bleeding due to antiplatelet medication . the criteria for venoarterial ecmo use was refractory cardiogenic shock , cardiac arrest , and septic shock that did not respond to conventional therapy . the inclusion criteria were a systolic blood pressure < 80 mmhg despite adequate intravascular volume replacement and the infusion of high dose catecholamines ( dopamine > 30 g / kg / min and/or norepinephrine > 0.2 g / kg / min ) . the inclusion criteria for venovenous ecmo were based on the lung dysfunction measured with a pao2/fio2 ratio < 100 for an fio2 of 1.0 , or an arterial blood gas ph < 7.25 due to hypercapnia despite receiving the optimal treatment . three types of centrifugal pumps were used for the ecmo system : capiox emergency bypass system ( terumo , inc . , tokyo , japan ) , bio - pump ( medtronic inc , minneapolis , mn , usa ) , and centrifugal rotaflow pump ( maquet inc . , hirrlingen , germany ) . we used 3 types of polypropylene hollow - fiber membrane oxygenators : capiox rx25 ( termo , inc . ) , d903 avant ( sorin group italia s.r.l . , mirandola modena , italy ) , and capiox emergency bypass system ( terumo , inc . ) . to enable ecmo , all patients received 17 - 21 fr arterial cannulae ( dlp : medtronic inc . , or rmi : edward 's lifescience llc , irvine , ca , usa ) and 17 - 28 fr venous cannulae ( dlp : medtronic inc . or rmi : edward 's lifescience llc ) according to the patient 's size . after the intravenous injection of 10 mg / kg heparin , the femoral artery and femoral vein were cannulated percutaneously using the seldinger method , except for 1 patient who was cannulated after an inguinal incision . in the case of venovenous ecmo , both femoral veins were cannulated . initially , 3 patients were observed for a high infusion rate of nafamostat mesilate ( 1.15 - 2.19 mg / kg / hr ) to maintain the activated clotting time ( act ) at 140 - 180 sec . from the 4th patient , nafamostat mesilate was adjusted at 0.41 - 0.93 mg / kg / hr according to the activated partial thromboplastin time ( aptt ; target range : 60 - 80 sec ) . the heparin patients received a continuous infusion at a rate of 1 - 2 mg / kg / hr to maintain the act at 140 - 180 sec . the patients with acute myocardial infarction ( ami ) who received percutaneous coronary intervention were administered aspirin ( 250 mg ) and clopidogrel ( 300 mg ) on the day of the procedure , and received aspirin ( 200 mg ) and clopidogrel ( 75 mg ) on the following day . we tried to maintain the hematocrit levels > 35% and the platelet count > 80,000 per l . if the hematocrit and platelet counts fell below these levels , we transfused blood products . in addition , fresh frozen plasma ( ffp ) and cryoprecipitate transfusion was performed once after 3 or 4 days according to the occurrence of hemorrhagic complications . after weaning was successfully performed , the cannulae were surgically removed in the operating room to avoid complications such as leg ischemia , aneurysm , or arteriovenous fistula . nafamostat mesilate was discontinued after removing the cannulae , while heparin was discontinued at 12 hr before the cannulae were removed . 4.1 ; dbstat co. , chuncheon , korea ) was used for all statistical analysis . categorical variables were expressed as percentages and evaluated with pearson 's chi - square test or fisher 's exact test . continuous variables were expressed as the mean and standard deviation and were evaluated with student 's t test or the mann whitney u - test . this study received institutional review board approval of the hallym university chuncheon sacred heart hospital ( irb no this study received institutional review board approval of the hallym university chuncheon sacred heart hospital ( irb no the clinical characteristics of the 17 patients treated with nafamostat mesilate during ecmo support are as follows . six , 3 , 5 , and 3 patients were diagnosed with ami , cardiac arrest , septic shock , and acute respiratory distress syndrome ( ards ) , respectively . the mean dosage of nafamostat mesilate was 0.64 mg / kg / hr to maintain an aptt of 60 - 80 sec . the mean duration of ecmo was 270.7 hr . seven patients survived and were discharged . to evaluate the efficacy of nafamostat mesilate , a clinical comparison between the nafamostat mesilate and heparin groups is shown in table 1 . the patients ' ages , sex , diagnosis , ecmo duration , and peak blood urea nitrogen , and total and direct bilirubin levels were found to be statistically significant variables ( p < 0.05 ) . the number of mortalities within 24 hr after applying ecmo in the heparin group was 14 , which was 1 in the nafamostat mesilate group ; however , this was not a significant difference ( p = 0.092 ) . the average time of oxygenator use in the nafamostat mesilate group was longer than in the heparin group ( p = 0.003 ) . the daily transfusion volume of packed rbcs , ffp , and cryoprecipitate was lower in the nafamostat mesilate group than in the heparin group ( p < 0.001 , p < 0.001 , p = 0.035 ) . the number of complications related to hemorrhage and thrombosis was higher in the heparin group ( 34 in 31 patients ) than in the nafamostat mesilate group ( 4 complications in 4 patients ) ( p = 0.011 ) . the long term survival and cause of death according to anticoagulants is shown in table 3 . the ecmo support of 8 patients in the heparin group was withdrawn because of uncontrolled bleeding . the nafamostat mesilate group provided a better survival rate than the heparin group ( p = 0.048 ) . the number of cases in which ecmo is used to treat cardiopulmonary failure is increasing . although the incidence of bleeding complications has decreased in various trials , bleeding remains one of the most fatal complications . nafamostat mesilate is a synthetic serine protease inhibitor with a very short half - life that inhibits coagulation , fibrinolysis , and platelet aggregation by inactivating the action of thrombin , activated coagulation factors xiia and xa , complement c1r and c1s , plasmin , trypsin , and kallikrein ( 13 - 15 ) . nafamostat mesilate has been used as an anticoagulant instead of heparin for extracorporeal oxygenation , left ventricular assist devices , cardiac surgery , and hemodialysis in patients at high risk of hemorrhage ( 5 , 8 , 9 , 16 ) . the anticoagulant effect of nafamostat mesilate , like heparin , is dependent on the dosage ; however , the ideal dosage of nafamostat mesilate for ecmo has not yet been determined . according to 2 case studies that administered nafamostat mesilate instead of heparin as an anticoagulant to treat pulmonary hemorrhage during ecmo use , daimon et al . ( 10 ) and kotani et al . ( 11 ) used a nafamostat mesilate infusion rate of 1.0 mg / kg / hr and 1.0 - 1.7 mg / kg / hr , and act was maintained at 150 sec in a 49-yr - old male patient and 190 - 200 sec in a 27-yr - old female patient , respectively . ( 8) successfully treated bleeding complications in 12 neonates on ecmo by administering nafamostat mesilate at 0.48 mg / kg / hr and heparin at 21.0 u / kg / hr , while act was maintained at 205.7 sec . in the present study , a nafamostat mesilate infusion rate of 1.15 - 2.19 mg / kg / hr was needed to maintain an act of 140 - 180 sec in 3 patients ; however , in the other patients , the infusion rate of nafamostat mesilate was lower ( 0.64 mg / kg / hr ) , while maintaining an aptt of 60 - 80 sec . the test results of act are affected by patient characteristics and technical factors ( 17 - 19 ) . in this study , the use of aptt monitoring in the nafamostat mesilate group might allow more precise control of anticoagulation than act monitoring . two cases of amputation due to leg ischemia occurred in patients who were diagnosed with septic shock ; however , these were related to the existing disease , disseminated intravascular coagulation , and not to the insertion of the cannula . a patient who was diagnosed with ami and acute aortic dissection died after 24 hr due to left hemothorax . pulmonary hemorrhagic complications occurred in another patient who was diagnosed with septic shock , and he was relieved by nafamostat mesilate ; however , the patient died after 404 hr on ecmo because of a previously existing disease . the incidence of bleeding complications in the nafamostat mesilate group was less than in the heparin group . transfusion with packed rbcs is needed because hemoglobin levels are decreased during ecmo due to thrombocytopenia , hemolysis , and hemodilution caused by continuous systemic heparinization ( 20 ) . ( 21 ) reported that a transfusion volume of 3.1 units / day was required . bakhtiary et al . ( 22 ) transfused 16.3 units of packed rbcs over an average of 6.3 day during ecmo . patients with post - cardiotomy and non - cardiotomy received transfusions of 23.3 and 17.3 units of packed rbcs over an average of 5.5 and 11.6 day on ecmo , respectively ( 23 ) . in the present study , the incidence of bleeding complications in the nafamostat mesilate group was significantly less than in the heparin group because 1.6 units / day of packed rbcs were transfused in the nafamostat mesilate group compared to 7.5 units / day in the heparin group . such a large transfusion volume was needed in the heparin group because bleeding complications occurred in 31 patients , and , in particular , the greatest transfusion volume was used in the 13 patients who died from bleeding . we had to change the circuit every 2 - 3 days due to failure of the oxygenator because we do not have access to long - term support ecmo oxygenators . the average time on ecmo oxygenators in the nafamostat mesilate group was 91.7 hr , which was longer than in the heparin group ( 41.6 hr ) because 14 patients ( 27.5% ) in the heparin group died within 24 hr . ( 24 ) , in which short - term support ecmo was replaced once by the use of an oxygenator for 2 - 3 days . the duration of ecmo for the nafamostat mesilate group was also longer than for the heparin group because 47% of the nafamostat mesilate patients underwent ecmo due to septic shock or ards , and 73% of the heparin patients underwent ecmo due to ami . therefore , the different existing diseases had differing recovery periods , resulting in the varying durations of ecmo ( 20 , 25 - 27 ) . ( 28 ) reported that complement and neutrophils were suppressed by nafamostat mesilate before reperfusion ; therefore , myocardial damage was decreased after reperfusion . the survival rate of the ami patients who were treated with nafamostat mesilate was 50% ( 3 of 6 patients ) , which was higher than in the patients who were treated with heparin ( 11% , 4 of 37 patients ) . however , additional studies are needed because the small number of patients is not sufficient to determine whether the survival rate is increased due to decreased myocardial damage by nafamostat mesilate . first , our data describe a retrospective analysis of our experience with mixed indication for ecmo implantation . therefore it is difficult to exclude that higher prevalence of ami and elderly in the heparin group influenced our results . second , this study is limited in its ability to suggest the ideal dosage of nafamostat mesilate because it is a retrospective examination of a small number of patients who underwent ecmo for various diagnoses . however , in the present study , the incidence of bleeding complications and transfusions in patients on ecmo decreased when a lower dosage of nafamostat mesilate was needed maintain the aptt than for the dosages used in previous studies to maintain the act . higher amounts of peak total and direct bilirubin were observed in the nafamostat mesilate patients than in the heparin patients ; however , additional studies are needed to examine whether this was caused by the long - term administration of nafamostat mesilate or existing diseases . in conclusion , nafamostat mesilate should be considered as an alternative anticoagulant to heparin to reduce bleeding complications during ecmo . use of nafamostat mesilate as an anticoagulant during extracorporeal membrane oxygenation sang jin han , hyoung soo kim , gun il kim , sung mi whang , kyung soon hong , won ki lee and sun hee lee we investigated the effective dosage and efficacy of nafamostat mesilate for use with extracorporeal membrane oxygenator ( ecmo ) in patients with acute cardiac or respiratory failure . the daily volume of transfused packed red blood cells , fresh frozen plasma , and cryoprecipitate was lower in patients treated with nafamostat mesilate than with heparin . also , the number of complications related to hemorrhage and thrombosis was lower than the heparin group .