the role of surfactant in the reduction of early reperfusion injury during lung transplantation has been widely investigated , but only recently have data become available for humans . ischemia reperfusion injury is characterized by pulmonary edema caused by endothelial dysfunction , platelet aggregation , and neutrophil activation and sequestration . particularly at the time of reperfusion , free radicals are produced in the endothelial cell membranes and in neutrophils causing an increase in cell membrane permeability . in addition , sludging of red blood cells , together with the obstruction by white blood cells , vasospasm and the narrowing of the vessel lumen as a result of the edema of the vascular endothelium , can cause blood flow from the arterioles into the capillaries to be markedly diminished ( i.e. the no - reflow phenomenon ) . moreover , inadequate surfactant function was found in all patients after lung transplantation . during respiratory distress syndrome of premature infants , these benefits have provoked interest in the use of surfactant in the treatment of acute respiratory distress syndrome ( ards ) . the surfactant alterations in ards are thought to contribute significantly to lung dysfunction . in several case reports , successful surfactant replacement has been demonstrated . exogenous surfactant therapy has been shown to be effective in severe animal models of acute lung injury . in this case report , we describe the effects of combined inhaled nitric oxide ( ino ) and surfactant replacement therapy in a patient with severe reperfusion injury during and after double lung transplantation for cystic fibrosis . a young woman ( 24 years old , weight 40 kg , height 150 cm ) , with end - stage lung disease from cystic fibrosis was admitted for double lung transplantation . a pulmonary artery catheter facilitating continuous cardiac output and mixed venous oxygen saturation ( svo2 ) ( vigilance intelicath baxter , irvine , ca , usa ) , was placed in the left or right subclavian or internal jugular vein . a 4fr catheter was inserted into the femoral artery and connected to the picco monitor ( pulse contour continuous cardiac output ; pulsion medical system , munich , germany ) ; this allowed evaluation of continuous cardiac output , intrathoracic blood volume and extra lung water index through the single indicator technique . transesophageal echocardiography ( sonos 2500hp , mc minville , oregon , usa ) and routine monitors were also attached . double lung transplantation was performed using the bilateral sequential single lung technique . the first lung transplantation ( left ) was successfully performed without cardiopulmonary bypass ( table 1 , reperfusion1 ) with 6 hours of ischemia time . the surgical procedure was complicated when the right pulmonary artery was clamped ( table 1 , clamping 2 ) . the transesophageal echocardiography showed evidence of right ventricular failure and of an increase in right ventricular chamber dysfunction with a mpap of 65 mmhg and a severe wall motion abnormality ; at this time a marked increase in pulmonary artery pressure was observed , in association with systemic hypotension and oxygen desaturation ( spo2 and svo2 ) and a decrease in cardiac output . at this time prostaglandin e1 ( 40 g / kg / min ) by continuous infusion and ino ( 40 ppm ) were administered . therefore , cardiovascular drugs such as dobutamine ( 10 g / kg / min ) , dopamine ( 7 g / kg / min ) , enoximone , norepi - nephrine ( 0.7 g / kg / min ) and ephedrine ( 25 mg ) were required to support the systemic pressure . ( right ) was reperfused after 35 min of cardiopulmonary bypass . soon after the reperfusion of the second lung , a severe lung injury developed . hemodynamic and oxygenation data from the preoperative period to the application of surfactant baseline , with both lungs mechanically ventilated ; 1,2 , 1st and 2nd lung ; mpap , mean pulmonary arterial pressure ; ci , cardiac index ; evlwi , extravascular lung water index ; itbvi , intrathoracic blood volume ; pre - surfactant , before surfactant administration ; post - surfactant , after surfactant replacement ( 3 days after end of surgical procedure ) ; cpb , cardiopulmonary bypass ; cvp , central venous pressure . oxygenation could be maintained using fio2 = 1 and high positive end - expiratory pressure ( peep = 10 cmh2o and inspiration : expiration [ i : e ] ratio = 1:1 ) . continuous main bronchial suction was performed to reduce fluids in the airways ( a total of 2000 ml ) . the patient received a bronchial lavage through a fiberoptic bronchoscope and was then transferred to the intensive care unit ( fig . 1 ) supported by the same regimen of cardiovascular drugs and pulmonary vasodilators . in the intensive care unit the patient was ventilated in control mode ventilation by a servo 900 c ventilator ( siemens elema , solna , sweden ) with pressure support ventilation of 20 cmh2o , a tidal volume of 8 ml / kg , fio2 = 1 , i : e = 1:1 , and peep of 10 cmh2o in the supine position then 400 mg / kg of porcine surfactant ( curosurf ; chiesi farmaceutici , parma , italy ) was delivered via the fiberoptic bronchoscope directly into the right and the left main bronchi . the instillation of surfactant was approved by the local ethics committee . during this application , the position of the patient ( supine ) and the ventilator settings were not changed . after 2.5 hours , in response to the surfactant application , we observed modifications of hemodynamic and oxygenation data ( table 1 , pre - surfactant and post - surfactant ) . the edema of the transplanted lungs on chest x - ray film was remarkably reduced the day after the surfactant replacement therapy still associated with ino administration . the patient was planned to be extubated when clinically indicated by the following criteria for discontinuation of mechanical ventilation : pao2 > 120 mmhg , where the fio2 was 0.4 and the ph > 7.37 , svo2 > 65% , hemodynamic stability and presence of spontaneous breathing . a tracheotomy was performed 7 days after the surgical procedure ( 5 days after surfactant replacement ) , and 2 days later the patient was extubated ( fig . the patient was discharged from the hospital 45 days after double lung transplantation , and 1 year later she is still enjoying good health . chest x - ray film 2 hours after double lung transplantation before surfactant replacement therapy , revealing edema of transplanted lungs . chest x - ray film 5 days after double lung transplantation following surfactant replacement therapy . lung reperfusion injury remains one of the major complications during the early postoperative course , with respiratory distress usually occurring 612 hours after lung transplantation . although the pathogenesis of reperfusion injury after lung transplantation is not completely understood , it is generally accepted that an inflammatory response as a result of activation of leukocytes and platelets may play an important role . additional signs are capillary leakage of the graft with an infiltrate on chest x - ray , pleural effusions and lung edema . one of the main symptoms is a steadily increasing oxygen demand on the ventilator , but the complete failure of the graft may also occur . in 1967 , ashbaugh and colleagues   first described ards and suggested that abnormalities of pulmonary surfactant could be involved in the pathophysiology of the lung injury . generally , the administration of surfactant after lung transplantation is based on experimental findings that indicate an alteration in surfactant composition and function after transplantation . in our case report the improvement of gas exchange and the amelioration of pulmonary edema that followed the administration of surfactant associated with ino , reversed a life - threatening situation . several studies described various strategies for surfactant administration and preparation , for the timing of the treatment , for the dosage and the frequency of administration , and for ventilator settings . among the strategies proposed in the literature for surfactant administration , we preferred the bronchoscopic instillation to aerosolized surfactant , based on recent findings showing the superiority of instilled surfactant . in addition , no significant effects have been found after the continuous administration of aerosolized surfactant . with respect to the ventilator strategies , it has been demonstrated in different animal models that for the same peak or mean airway pressure , ventilation with peep at lower tidal volumes results in less edema than would occur with ventilation using zero peep and ventilation with higher tidal volumes . the use of peep prevents alveolar flooding and reduces endothelial and epithelial injury . in our case , different studies have examined the beneficial effects of peep on the surfactant system . in 1975 , wyszogrodski et al . showed that peep prevents a decrease in lung compliance and surface activity of lung extract , indicating a preventive loss of alveolar surfactant function during lung overinflation . in addition , because peep prevents alveolar collapse , it maintains the end - expiratory volume of alveoli at a higher level , and prevents excessive loss of surfactant in the small airways by surfactant being ' squeezed out ' of the alveoli during expiration . more recent studies have shown that the rate of conversion of large surfactant into small aggregates is dependent on tidal volume and time , while respiratory rate or peep level did not affect surfactant conversion . these studies suggest that the preservation of the surfactant system by peep is a result of the reduction of cyclic changes in the surface areas of the alveoli . in our case , after the amelioration of gas exchange , peep was decreased from 10 to 5 cmh2o and then to zero before complete withdrawal of treatment . the frequency increases with increased duration of extracorporeal membrane oxygenation . the lung injury is mainly initiated by shear forces and from contact of the venous blood with non - physiological surfaces of the extracorporeal circuit , resulting in activated platelets and polymorphonuclear granulocytes , mediator release and activation of the complement and kallikrein  kinin system . found impaired surfactant function as indicated by deterioration in surface activity from day 0 to day 3 after bypass . in conclusion , our results show an amelioration of the lung injury as a result of surfactant replacement . the beneficial effect may be because of the replacement of surfactant when production is impaired after hypoxia . in an experimental lung transplantation model , normal surfactant function in the reperfusion period was found only after exogenous substitution . in the setting of continued use of ino shortly after transplant , it should be noted that the ino therapy itself did not produce any amelioration of the lung injury in the early period after transplantation . lung function improvement occurred only after surfactant replacement , which was used in combination with ino therapy . the combination of ino and surfactant has been used by struber et al . in one case of injury of the lung with an episode of ischemia and reperfusion , which can be considered similar to the reperfusion injury occurring after lung transplantation . during the continuous administration of ino , they applied synthetic surfactant through a bronchoscope into the left and right main bronchi , to improve gas exchange and lung compliance . they hypothesized that ino improves perfusion of well - ventilated alveoli , increasing the number of alveoli available for ventilation . , surfactant replacement therapy has not been used for lung injury reperfusion occurring in the early post - transplantation period . our data suggest a potential role for a combined therapy with ino and surfactant replacement in reperfusion injury after lung transplantation . combined therapy with inhaled nitric oxide , intravenous prostaglandin e1 plus surfactant replacement may play a role in the treatment of the reperfusion injury after lung transplantation . ards = acute respiratory distress syndrome ; i : e = inspiration : expiration ratio ; ino = inhaled nitric oxide ; peep = positive end - expiratory pressure ; svo2 = venous oxygen saturation .
aimto demonstrate the effects of combined inhaled nitric oxide and surfactant replacement as treatment for acute respiratory distress syndrome . 
 this treatment has not previously been documented for reperfusion injury after double lung transplantation.methoda 24-year - old female with cystic fibrosis underwent double lung transplantation . during implantation of the second lung a marked increase in pulmonary artery pressure associated with systemic hypotension , hypoxemia and low cardiac output were observed . 
 notwithstanding the patient received support from cardiovascular drugs and pulmonary vasodilators cardiopulmonary by - pass was necessary . in the intensive care unit the patient received the same drug support , 
 inhaled nitric oxide and two bronchoscopic applications of bovine surfactant.resultsa rapid improvement in pao2/fio2 within 23 hours of administration of surfactant was seen . 
 the patient is well at follow - up 1 year post-transplant.conclusionthere is a potential role for a combined therapy with inhaled nitric oxide and surfactant replacement in reperfusion injury after lung transplantation .