INTRODUCTION

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The acute respiratory distress syndrome (ARDS) is a life-threatening disorder characterized by noncardiogenic pulmonary edema and refractory hypoxemia, with a case fatality rate as high as 40-60% (1). The pathophysiology of ARDS involves injury to the alveolar-capillary barrier, lung inflammation, atelectasis, surfactant dysfunction, and intrapulmonary shunting. The disorder typically appears within 12 to 24 h of an identifiable clinical event and may be due to direct lung injury, such as with gastric content aspiration, pneumonia, near-drowning, toxic gas inhalation, or chest/lung trauma. In addition, ARDS may be associated with systemic processes such as sepsis, nonthoracic trauma, acute pancreatitis, major surgery, multiple blood transfusions, fat embolism, or shock. No specific therapy for ARDS currently exists. To date, the numerous treatment strategies for the disorder that have been studied have not reduced associated morbidity or mortality.

Pulmonary surfactant lines the alveolar epithelium of mature animal lungs. It is a lipoprotein complex that reduces surface tension to assist alveoli expansion, allowing gas exchange. The endogenous surfactant system of patients with ARDS may be compromised in several ways (7, 8): the inciting disorder may directly damage type II pneumocytes and decrease the synthesis, secretion, and composition of surfactant or produce abnormal surfactant aggregate forms; plasma proteins in the pulmonary edema fluid may inhibit surfactant properties; and the products of inflammation, such as proteases and reactive oxygen species, may interfere with surfactant function, as well as processing of the substance in the alveolus (7, 8).

The major pulmonary consequences of ARDS are decreased compliance, decreased oxygenation, loss of lung volume, and intrapulmonary shunting of blood flow (8). Each of these physiologic abnormalities may be directly influenced by surfactant dysfunction. In addition, damaged alveoli are filled with fluid containing inflammatory cells, protein, and various mediators. It would be a logical approach to cleanse and remove injurious substances and debris from the lungs of patients with ARDS and to restore functional surfactant.

This investigation was performed to assess the safety and tolerability of sequential bronchopulmonary segmental lavage via bronchoscopy of a dilute, exogenous, synthetic surfactant, Surfaxin, in adults with acute respiratory distress syndrome.

	METHODS

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Patients

This was an open label, uncontrolled Phase 1b trial in which 12 subjects with ARDS received one of three dosing regimens of dilute Surfaxin by lavage through a bronchoscope wedged into bronchopulmonary segments. Patients in intensive care units were enrolled at five academic teaching hospitals in the United States between August 15, 1997 and December 8, 1997. At each participating site, the study was approved by the Institutional Review Board for human studies. Informed written consent was obtained for each patient from appropriate surrogates. Since the therapy was expected to affect only lung function, an attempt was made to exclude patients who were unlikely to survive despite an improvement in lung function. The general entry criteria are included in Table 1.

Treatment

Surfaxin is a surfactant in which the chemically synthesized KL₄ peptide is combined with the phospholipids dipalmitoylphosphatidylcholine (DPPC) and palmitoyl-oleoyl phosphatidylglycerol (POPG), as well as palmitic acid, in an isotonic aqueous dispersion (9). Surfaxin (development name, KL₄-Surfactant) was provided by Discovery Laboratories (Doylestown, PA). Patients were assigned to one of three treatment regimens with Surfaxin in an escalating dose manner, a schematic of which is depicted in Figure 1. Three to five patients per treatment group were administered one of the three different dosing regimens. Data were reviewed after all patients had been entered into each treatment group. The procedure and the drug had to have been considered tolerated and safe before enrollment into the next (higher dose) group was permitted. There was no comparative agent or control group in this safety study.

View larger version (39K): [in this window] [in a new window]   Figure 1.   Schematic of the escalating dose regimen for administration of Surfaxin.

The subject vital signs, peripheral oxygen saturation (Sp_O2), and ventilator parameters were monitored continuously during the bronchoscopic lavage. The procedure could not begin until the patient met all of the following criteria: (1) Sp_O2  90%; (2) systolic blood pressure  100 mm Hg; (3) heart rate  140 beats/min; and (4) ventilator peak inspiratory pressure (PIP)  60 cm H₂O while the bronchoscope was out of the patient. A pass-through valve was placed at the end of the endotracheal tube to allow passage of the bronchoscope without loss of delivered tidal volume or positive end expiratory pressure (PEEP). Additional doses of sedative or analgesic agents could be adminstered as needed. During the procedure, the delivered FI_O2 was set at 1.0 and if PEEP was < 10 cm H₂O, it was increased to  10 cm H₂O. If PEEP was already  10 cm H₂O, it could either be left at those levels or increased. The protocol required investigators to maintain PEEP  10 cm H₂O for 24 h after the lavage was initiated. A size 4.8 to 5.5-mm (o.d.) bronchoscope was inserted through the endotracheal tube and used to inspect the distal airways to assure patency and absence of mucous plugging from all airways to the subsegmental level. Topical lidocaine (1% solution) was instilled via the bronchoscope to provide airway anesthesia. A maximum of 400-mg of lidocaine could be used during the entire procedure. Any visible mucous plugs or secretions were removed by suctioning and saline lavage before proceeding. In all treatment groups, Surfaxin application proceeded sequentially from the lower to the upper segments in the right lung, followed by the lower to the upper segments in the left lung. In the event of anatomic variation, up to two additional segmental airways could be lavaged. Within each bronchopulmonary segment, suctioning was performed 10-30 s after instillation of individual Surfaxin aliquots. The volume of fluid recovered was recorded. Up to four suctioning attempts could be made in an effort to remove at least 50% of the instilled volume. During the lavage procedure, the following were considered to be abnormal safety parameters:

1. Systolic arterial blood pressure < 100 mm Hg

2. Heart rate > 140 beats/min

3. Sp_O2 < 90%

4. Peak inspiratory pressure (PIP) > 60 cm H₂O while bronchoscope was out of the patient

5. Greater than a 25% increase from baseline in minute ventilation

If any of these changes in safety parameters occurred during the lavage procedure, the bronchoscope was removed and steps were taken by the medical staff to rectify the event(s). If the parameter(s) did not return to acceptable limits within 30 min, investigators were instructed to discontinue dosing.

The first dosing regimen (treatment Group 1) consisted of two 30-ml aliquots: the initial aliquot was a 2.5-mg/ml concentration of Surfaxin, while the second consisted of a 10-mg/ml concentration. Three patients were enrolled in this first group. Data from these three patients were reviewed by the medical monitor. After the procedure was considered to have been safe and well tolerated, progression to the second group was approved. The second dosing regimen (Group 2) consisted of administration of three 30-ml aliquots of Surfaxin: the first two aliquots were of the 2.5-mg/ml concentration, while the third aliquot was of the 10-mg/ml concentration. Four subjects were enrolled into this dose group. Data from these four patients were similarly reviewed by the medical monitor for safety and tolerability. Progression to the third group was permitted. Subjects in Group 3 received the same dosing regimen as the second group except that a second set of lavages was permitted between 6 and 24 h after completion of the first set provided: (1) there was no radiographic evidence of barotrauma; (2) the patient had a Pa_O2/FI_O2 ratio < 300 mm Hg; and (3) the patient still met the other criteria for ARDS (Table 1). Five patients were enrolled into the third dosing group. One of these subjects did not receive a second treatment because her Pa_O2/FI_O2 ratio was > 300 mm Hg within the 6 to 24-h time period.

Parameters

Pulmonary function indicators, including ventilator settings and arterial blood gas results, were recorded at baseline (just before treatment), at completion of the procedure, and 3, 6, 12, 24, 48, 72, and 96 h after administration of the first aliquot of Surfaxin. From the pulmonary function indicators, a Pa_O2/FI_O2 ratio and a modified oxygenation index were calculated, where modified oxygenation index (OI) = (FI_O2 × PEEP × 100)/Pa_O2. We developed the modified OI to assess oxygenation in critically ill patients. The parameter reflects how well a patient is able to oxygenate and how that degree of oxygenation is influenced by the manner in which oxygen is administered to them (the concentration of oxygen [FI_O2] and the positive end expiratory pressure [PEEP]). Because this is an inverse relationship, the lower the modified OI, the better the oxygenation.

Chest radiographic assessment was performed at baseline, after treatment (Group 3 only), and on Days 2, 3, 4, and 5 after treatment, as well as on Day 28 or the day of discharge. Laboratory evaluations were performed within 8 h of initiation of therapy and on Days 2, 3, 4, and 5 after treatment, as well as on the day of discharge or Day 28. These consisted of a white blood cell (WBC) count with percentage of neutrophils, platelet count, prothrombin time (PT), partial thromboplastin time (PTT), creatinine, total bilirubin, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), and blood urea nitrogen (BUN). The presence of any new organ failure was noted at 24, 48, 72, and 96 h after the start of the procedure, and throughout the remainder of the trial. The occurrence of adverse experiences was recorded from the initiation of therapy through the end of the 28-d period. On Day 28 or on the day of discharge, it was noted whether patients had died, when and if they had been extubated and taken off mechanical ventilation, and whether rescue therapies (e.g., inhaled nitric oxide) had been used.

Statistical Methods

Descriptive statistics were used to summarize the baseline information, the bronchoscopic safety information, changes in various parameters during the 96 h after treatment initiation, and major outcome variables (mortality, duration of mechanical ventilation, and discharge).

	RESULTS

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Twelve patients at five sites were enrolled into Group 1 (n = 3), Group 2 (n = 4), and Group 3 (n = 5). Baseline characteristics of the study population are listed in Table 2. No patients were discontinued from the study after enrollment. All patients entered and completed the treatment phase of the study. The associated causes of ARDS in this population are listed in Table 3. All 12 patients were subjected to an initial lavage. Four of the five Group 3 patients had a second lavage that occurred approximately 24 h after the first lavage. One Group 3 patient did not have a second lavage because her Pa_O2/FI_O2 ratio was > 300 during the period she was eligible for retreatment. The median duration of the lavage procedure (n = 16) was 92.5 min. In no patient did the procedure take longer than 2.5 h. Overall, 43% of the fluid was retrieved with suctioning (41% from the initial lavage of all 12 patients and 49% from the 4 patients who were retreated). Thus, approximately 57% of the instilled fluid remained in the lungs after suctioning. There was no apparent deterioration in lung compliance during the 96 h after the procedure. Adequate gas exchange was maintained during and after Surfaxin lavage. Serial chest radiographs did not worsen during the 4 d after the procedure.

In 5 of 12 patients, at least one of the safety parameters fell outside the acceptable range during the lavage procedure. This occurred during the first lavage in these five subjects, one of whom also had a recurrence during the second lavage. As a result, the bronchoscope was temporarily removed and efforts were made to rectify the condition. These efforts were successful in all instances. In most cases, the affected parameter was an Sp_O2 value < 90% lasting 2-3 min. The patients generally responded to temporary removal of the bronchoscope or to hand ventilation. No patient had a safety parameter out of acceptable range for a duration of more than 30 min (definition of procedure intolerance).

In Table 4 we present the patient baseline ventilator settings and oxygenation status and compare these with the values 96 h after initiation of treatment. In general, the greatest decreases in ventilator support over time were seen among patients in treatment Group 3. Subjects in the latter group also had the greatest improvement in the modified oxygenation index. The time course of the Pa_O2/FI_O2 ratios is presented in Figure 2. This ratio declined at 3 h after treatment and generally rose therafter. In addition, the time course of the modified oxygenation index values is depicted in Figure 3. This parameter, which includes the effect of PEEP levels, initially rose at 3 h after treatment and declined thereafter (i.e., improved oxygenation). As specified in the protocol, PEEP levels were maintained at  10 cm H₂O for 24 h after the lavage procedure was initiated. PEEP levels declined dramatically thereafter (Figure 4). The disposition of the study patients through the 28-d period is provided in Table 5. Three subjects died, while all nine survivors were extubated by Day 28. Five of the 12 patients were considered by the principal investigator at their respective sites to have "sepsis" contributing to ARDS at the time of enrollment. The diagnosis of "sepsis" was not further defined. Over the initial 96 h after Surfaxin treatment, the "nonsepsis" patients had a greater decline in ventilator support (FI_O2, PEEP, and PIP) than did the "sepsis" patients. Moreover, the nonsepsis patients had a greater degree of reduction in the modified OI (i.e., improved oxygenation). The three patients who died (on Days 19, 22, and 28, respectively) all had sepsis initially contributing to their ARDS. In all three cases the families of the patients either elected to discontinue all support or to not have aggressive resuscitative efforts performed because of progressive deterioration unresponsive to any therapies. None of the deaths were felt by the principal investigators to be related to therapy. In addition, the number of days alive and off mechanical ventilation through Day 28 was considerably greater in the nonsepsis group of patients (20.1 versus 2.8 d, respectively). All seven nonsepsis patients had been discharged by Day 28, while neither of the surviving sepsis patients was discharged by Day 28. 

View larger version (22K): [in this window] [in a new window]   Figure 2.   Values of the PaO2/FIO2 ratio over time. Generally, the values declined 3 h after the procedure and increased thereafter.

View larger version (24K): [in this window] [in a new window]   Figure 3.   Values of the modified oxygenation index (OI) ratio over time. This variable takes into account the effect of different PEEP levels. The modified OI increased 3 h after the procedure and declined substantially thereafter.

View larger version (21K): [in this window] [in a new window]   Figure 4.   As required by the protocol, PEEP levels were maintained  10 cm H2O for the first 24 h after initiation of therapy. PEEP levels declined substantially thereafter, particularly among Group 3 patients.

Multiple hemodynamic parameters were monitored during the clinical course of the study. At baseline, the mean systolic blood pressure of the patients was 116.3 ± 11.6 mm Hg. Mean values subsequently varied between 111 and 121 mm Hg during the procedure itself, and between 116 and 122 mm Hg for the remainder of the 96-h period. The mean cardiac output at baseline was 7.6 ± 2.3 liters/min, rose to 8.6 ± 2.5 liters/min at 3 h after lavage initiation, and remained between 7.0 and 7.9 liters/min thereafter. The mean pulmonary artery wedge pressure was 15.0 ± 2.9 mm Hg at baseline and ranged between 15.8 and 17.1 mm Hg through 48 h. The latter parameter declined at 72 and 96 h after initiation of the lavage procedure (13.0 ± 9.8 and 11.5 ± 2.1 mm Hg, respectively).

Three patients had air leaks that occurred between 4 and 26 d after the procedure. New organ failure developed in a total of four patients: transient liver dysfunction resolved in three patients, while a single patient developed both renal failure and cardiac failure. No neurological failure was noted in any of the assessed patients. None of the new organ failure was attributed to the drug or the procedure. In addition, there were no persistently abnormal laboratory values that were attributed to the therapy. None of the 12 subjects received rescue therapies with inhaled nitric oxide, high-frequency ventilation, or extracorporeal membrane oxygenation.

We were able to perform protein analysis of the fluid retrieved from the four Group 3 patients who had a second course of bronchopulmonary segmental lavage (Table 6). Retreatment occurred approximately 24 h after the initial therapy. Fluid for analysis was withdrawn by suctioning after instillation of the third aliquot. Material retrieved from individual bronchopulmonary segments in each lobe was combined for purposes of the analysis (e.g., the fluid from all segments in the right lower lobe [RLL] was combined to become the RLL specimen for analysis). In 18 of the 22 fluid specimens analyzed, the protein concentration was lower at the time of retreatment.

Of 59 reported adverse experiences, 12 were considered by the principal investigator to be remotely related to therapy and 44 were considered to be unrelated to therapy. The sole highly probable related adverse experience consisted of transient oxygen desaturation (Sp_O2 < 90%), which occurred in the first patient enrolled in the study. This patient responded favorably within several minutes to immediate removal of the bronchoscope and hand-bagging. Two possibly related adverse experiences occurred in the first two patients enrolled in the trial, and consisted of suspected mucous plugging of the airways 2 and 4 d, respectively, after the procedure. The most common adverse experience was skin rash, which occurred in 9 of the 12 patients. However, in none of the cases did the investigator consider the skin rash to be related to therapy. In only one patient did the skin rash occur on the day of therapy. In the remaining patients, the rash initially appeared an average of 8.3 d after initial lavage. The second most common adverse experience was the occurrence of urinary tract infection (UTI) in four patients. Onset of UTI also occurred an average of 8.3 d after initial lavage.

	DISCUSSION

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In this investigation, we have demonstrated that bronchopulmonary segmental lavage can be safely administered and be well tolerated by a patient population with acute respiratory distress syndrome (ARDS). To our knowledge, this is the first time total lung bronchopulmonary segmental lavage with dilute surfactant has been used to treat ARDS. This unique therapeutic approach was an attempt to both "cleanse" the lungs of these patients and to provide sufficient functional surfactant to assist gas exchange. In all cases, the enrolled patients were able to tolerate the entire bronchoscopic lavage procedure, including both Surfaxin administration and suctioning of segmental fluid. On average, the procedure took 1.5 h. In no cases did the procedure last more than 2.5 h. The duration of the procedure decreased as individual investigators became more experienced with total lung bronchopulmonary segmental lavage. In no cases did any of the abnormal safety parameters extend beyond acceptable limits, i.e., for longer than 30 min during the administration procedure (the definition of intolerance for this trial). Although several patients required transient removal of the bronchoscope for a short period of time, each of the investigators who enrolled patients felt that the procedure and drug were safe and that every enrolled patient tolerated the procedure and the Surfaxin. In addition, there were no serious adverse events or deaths that appeared to be associated with either the drug or the procedure. We believe the improved oxygenation (modified OI) and lower ventilator settings 96 h after treatment intitiation, as well as the lower protein concentrations of retrieved fluid at the time of retreatment, indicate that this therapy may have efficacy in the treatment of ARDS.

Surfaxin is a surfactant in which the synthetic KL₄ peptide (U.S. adopted name [USAN], sinapultide) is combined with the phospholipids dipalmitoylphosphatidylcholine (DPPC) and palmitoyl-oleoyl phosphatidylglycerol (POPG), as well as palmitic acid, in an isotonic aqueous dispersion (9). The KL₄ peptide, created by C. G. Cochrane and S. D. Revak at The Scripps Research Institute (La Jolla, CA), is a chemically synthesized peptide of the sequence KLLLLKLLLLKLLLLKLLLLK, where "K" denotes the hydrophilic amino acid lysine and "L" represents the hydrophobic amino acid leucine (10, 11). The KL₄ peptide mimicks the hydrophobic and hydrophilic pattern of human surfactant protein B (SP-B). When combined with phospholipids, SP-B has the strongest capacity of any of the pulmonary surfactant proteins to reduce surface tension and induce pulmonary expansion (12, 13). In vitro, Surfaxin resists inhibition by plasma proteins, as well as by oxidants released during the inflammatory process, to a greater extent than Survanta, a bovine-derived surfactant (14). As Survanta contains relatively low amounts of SP-B, these differences may be due in part to the similarity of the KL₄ peptide to SP-B. Seeger and coworkers (17) have found surfactant inhibition by different plasma proteins to be influenced by the varying levels of SP-B contained in the three bovine and one porcine surfactant they evaluated. Surfaxin has been shown to be safe and efficacious in premature human infants with idiopathic respiratory distress syndrome (18). In addition, Cochrane and colleagues (19, 20) have performed a series of experiments to assess the efficacy of lung lavage with dilute Surfaxin in animal models of acute lung injury akin to ARDS. Pulmonary lavage with dilute Surfaxin removed the inflammatory exudate and produced generalized expansion of the animal lungs, resulting in greatly improved oxygenation. Balaraman and colleagues (21) assessed lavage administration of three different surfactants (including Surfaxin, Infasurf, and Exosurf) in a neonatal piglet model of acute lung injury. These investigators described improvements in several parameters of pulmonary function, as well as better oxygenation after this therapy with dilute preparations of the three surfactants. The latter authors speculated that dilute surfactant doses in the range of 20-40 mg of phospholipid per kilogram body weight would be effective in treating humans with ARDS. Finally, an exploratory feasibility study to examine the safety and efficacy of dilute Surfaxin when administered by segmental lavage via bronchoscopy was conducted in an adult pig model of ARDS (R. M. Smith and C. G. Cochrane, unpublished data, 1997). The procedure was well tolerated by the animals and resulted in sustained improvement in oxygenation and lung expansion.

Steinberg and coworkers (22) led an investigation in which the safety of bronchoalveolar lavage (BAL) with saline in adults with ARDS was evaluated. The investigators found the bronchoscopy procedure and BAL in a limited number of bronchopulmonary segments to be well tolerated in their population. The work of these authors led us to hypothesize that a lavage procedure with Surfaxin in all of the bronchopulmonary segments might also be tolerated by patients with ARDS. Nicholas and colleagues (7) speculated that such an approach might be beneficial to patients with ARDS: bronchoscopic lavage could remove plasma proteins, inflammatory mediators, and other debris, while instillation of a functional surfactant could enhance lung expansion and function. Willson and colleagues (23) used Infasurf to treat 29 children with hypoxemic respiratory failure. Infasurf is a calf lung surfactant extract containing substantially more SP-B than Survanta. Their patients were treated with up to four bolus doses of Infasurf over a 24-h period. Twenty-four of the 29 exhibited improved oxygenation after the initial dose. There was less of a response after subsequent doses.

Surfactant dysfunction is a major component in the pathophysiology of ARDS. Such dysfunction potentiates a vicious cycle of atelectasis and edema, factors that adversely affect gas exchange and further compromise surfactant. Surfactant administration to patients with ARDS has been previously assessed in a variety of ways. Anzueto and coworkers (24) performed a collaborative trial in which an aerosolized synthetic surfactant was administered to patients with sepsis-induced ARDS. Surfactant-treated patients received continuously administered Exosurf (at a concentration of 13.5-mg of DPPC per milliliter) in an aerosolized form for up to 5 d. No significant beneficial effects of this therapy were found in the major outcome variables (mortality, duration of mechanical ventilation, length of stay in the intensive care unit and in the hospital). The authors estimated that less than 5 (mg/kg)/d of the administered 112 (mg/kg)/d of aerosolized DPPC was actually delivered to the lungs. Gregory and colleagues (25) gave varying bolus doses of Survanta to 43 patients with ARDS (up to 8 doses of 50 mg of phospholipids per kilogram, up to 8 doses of 100 mg of phospholipids per kilogram, and up to 4 doses of 100 mg of phospholipids per kilogram, respectively). The interval between doses was approximately 8 h in each group. The amount of fluid instilled (as much as 2,240 ml total over approximately 48 h in a 70-kg patient) "was generally well tolerated." These investigators found suggestions of improved oxygenation and lower mortality in those patients who received four doses of this surfactant (~ 400 mg of phospholipid per kilogram over a 24-h period). Spragg and colleagues (26) gave a single dose of porcine surfactant (a total of 4 g in 50 ml) to each of six subjects with ARDS. Aliquots of the fluid were delivered via bronchoscopy to each of the lobar bronchi. Assuming an average patient weight of 70 kg, the total amount of phospholipid administered was 57 mg/kg. These authors noted a modest transient improvement in gas exchange after therapy. Finally, to 10 patients with ARDS, Walmrath and co-workers (27) administered a total of 300 mg of bovine surfactant (Alveofact) per kilogram in divided doses into bronchopulmonary segments via bronchoscopy. The surfactant was mixed in approximately 313 ml of fluid, all of which was left in the lungs. The investigators did not perform a lavage procedure; rather, separate doses of the Alveofact were instilled and left in each segment. Five patients received a second dose of 200 mg/kg 18 to 24 h later. The authors noted improved oxygenation during and after surfactant administration. Five of 10 patients survived.

In the current investigation, complete lung lavage was performed. Dilute aliquots of Surfaxin were instilled into each bronchopulmonary segment, followed by immediate suctioning. Group 1 patients received 7.125 g of Surfaxin in 1,140 mg of fluid (81.9 mg/kg), of which 35% was retrieved via suctioning. Group 2 patients received 8.55 g of Surfaxin in 1,710 ml of fluid (94.0 mg/kg), of which 38% was recovered. Group 3 patients similarly received 8.55 g of Surfaxin in 1,710 ml of fluid (113.7 mg/kg), 48% of which was retrieved. The second, identical dose of Surfaxin was administered to four of five Group 3 patients approximately 24 h later, 49% of which was retrieved. All subjects appeared to tolerate the fluid volume that remained in their lungs. Lung compliance did not worsen in the 96 h after the procedure, adequate gas exchange was maintained during and after the procedure, and serial chest radiographs did not deteriorate. The Surfaxin that remained in the lungs after suctioning likely served to replace the patient endogenous dysfunctional surfactant. The modest decline in oxygenation 3 h after lavage initiation may have been a response both to increased airway fluid volume and to the bronchoscopy procedure itself. Moreover, investigators had lowered the FI_O2 in two-thirds of the subjects at the 3-h time point. As one notes from isoshunt curves, in patients with severe shunts (e.g., those seen in patients with ARDS), at higher FI_O2 levels there is an out-of-proportion decline in Pa_O2 relative to FI_O2. This phenomenon may have been reflected in the transiently lower mean Pa_O2/FI_O2 ratios at 3 h, although oxygen saturations remained > 90% in all patients (mean, 95.1%). In addition, by 24 h after lavage initiation, the overall mean Pa_O2/FI_O2 ratio had increased substantially from baseline (from 143 to 185 mm Hg).

The oxygenation index (OI) is a pulmonary index commonly used by neonatologists to assess the severity of respiratory illness and the likelihood of mortality as an outcome (28). The OI is calculated by multiplying the ventilator mean airway pressure by 100 times the FI_O2 and dividing this by the Pa_O2. Fort and colleagues (29) reported use of the OI in an adult ARDS trial and speculated that it may better reflect ARDS severity than indices based only on various oxygen tensions (e.g., the Pa_O2/FI_O2 ratio). We modified the OI calculation by substituting PEEP for mean airway pressure, as we believe adjustments of PEEP more directly influence the oxygenation of a patient with ARDS. We found this modified OI to better reflect the degree of pulmonary insufficiency and the degree of improvement than the Pa_O2/FI_O2 ratio.

It was not surprising that subjects with sepsis did not fare as well as nonsepsis patients after bronchopulmonary segmental lavage with Surfaxin. The former patients are more prone to multiple organ failure and generally do not do as well as ARDS patients with direct lung injury (2). Moreover, bronchopulmonary segmental lavage would be expected to have more dramatic efficacy in patients with direct lung injury because the procedure focuses on the lung as its site of action. No specific therapy for ARDS currently exists. Numerous treatments for ARDS have not been successful in reducing morbidity or mortality (1, 30). The approach we have taken may mitigate the fundamental mechanisms of early ARDS and provide a rational basis for treating affected patients. Moreover, this therapy could shorten the course of potentially injurious mechanical ventilation, a factor that may play a pivotal role in the inflammatory response of patients with ARDS (31). We believe that data from this trial support further clinical study of bronchopulmonary segmental lavage with Surfaxin in patients with ARDS.