The present study demonstrates that intratracheal administration of porcine-derived surfactant to patients with ALI/ARDS induces a significant lung reaeration of poorly or nonaerated lung regions. This beneficial effect, however, is associated with a significant increase in lung tissue in normally aerated lung areas at day 7 whose mechanisms remain to be elucidated.
Distribution of surfactant within the lung is likely to be an important factor that determines the efficacy of surfactant therapy. Delivery technique and lung morphology influence surfactant distribution. In a previous randomized clinical trial [7
], the unsuccessful surfactant treatment was related to the technique of aerosolization that provided less than 10% distal lung deposition [21
]. Intratracheal instillation by a catheter positioned just above the carina has been shown to be much more effective in animals and patients with ARDS [6
]. In patients with ARDS/ALI, the loss of lung aeration does not have a uniform distribution and, in the supine position, dependent and caudal lung regions are virtually nonaerated as a result of external compression by the abdomen and heart [13
]. The distribution of exogenous surfactant in aerated and nonaerated parts of the distal lung has never been assessed and it is unknown whether instilled surfactant does penetrate into nonaerated lower lobes. In the present study, the CT scan at H39 in the surfactant group was performed within three hours following the third administration of HL-10. Based on the fact that the tissue volume did not change at H39 compared with its baseline value in the control group, we can assume that the increase in lung tissue between baseline and H39 in the surfactant group is representative of instilled exogenous surfactant. The present data show that the overall volume of instilled HL-10 was homogeneously distributed between upper and lower lobes and between normally and poorly or nonaerated lung regions (Figure ). This result demonstrates that the procedure of instillation (successive bolus in right and left lateral positions followed by consecutive recruitment maneuvers) resulted in uniform bilateral surfactant distribution. A predominant distribution of HL-10 in normally aerated lung regions can be ruled out.
Although several randomized trials have failed to demonstrated beneficial effects of exogenous surfactant in adults patients with ARDS in terms of mortality and ventilator-free days [7
], the effect of surfactant therapy on lung aeration had never been evaluated. In the present study, using CT regional analysis of normally and poorly or non-aerated lung regions, a significant higher lung reaeration was evidenced at day 7 in patients treated by surfactant replacement as compared with control patients (Figure ). This finding provides evidence that tracheal instillation of HL-10 induces a substantial and prolonged reaeration of poorly or nonaerated lung regions and more specifically of nonaerated lower lobes. This encouraging result supports the rationale for exogenous surfactant replacement as indication for lung reaeration in adult patients with ALI/ARDS.
HL-10-induced lung reaeration was, however, associated with a long lasting increase in lung tissue in previously normally aerated lung areas. Its mechanism remains unknown and several hypotheses can be discussed. A delayed alveolar clearance of the large doses of HL-10 administered to aerated lung regions, where endogenous surfactant is already present, is a possible mechanism that could explain the sustained increase in lung tissue. In newborn infants, the surfactant half life is around 35 hours [24
]. In patients with ARDS treated by recombinant surfactant, components of exogenous surfactant were retrieved in bronchoalveolar lavage (BAL) two days after initial administration, but were no longer detectable five days later [6
]. The dose of surfactant used in the present study was orders of magnitude beyond what was commonly used in neonates, older children and adults. The high volume of phospholipids administered may have prolonged the turn-over time, explaining the persistent increase in lung tissue. Another hypothesis explaining the increase of lung tissue could be an inflammatory reaction resulting from the interaction of HL-10 with active endogenous surfactant present in aerated lung regions [25
]. As illustrated in the present study, normally aerated lung regions in ARDS/ALI are characterized by an excess of lung tissue [15
] and an increased vascular permeability [26
], two abnormalities increasing the vulnerability of lung parenchyma to external aggressions. In these regions, saline diluted HL-10 could induce depletion of endogenous surfactant [27
], increased release of TNF and IL-6 in response to overinflation [28
] and a resulting increase in lung micovascular permeability. The consecutive influx of albumin into the alveolar space could inactivate further endogenous surfactant [29
], and aggravate lung injury. In addition, 720 ml of saline (4 ml/kg/bolus) containing HL-10 were instilled in both lungs over 36 hours. By itself, such an amount of liquid could induce lung injury in experimental normal lungs. Lastly, breakdown products of the phospholipids in surfactant, specifically lysophosphatidylcholine, can provoke inflammation. In this study, BAL after surfactant replacement was not performed. Further study is required to explore the correlation between the presence of inflammatory mediators, components of exogenous surfactant, protein and cells in BAL, and the CT increase in lung tissue in normally aerated lung areas.
Exogneous surfactant has strong immunomodulatory properties [30
]. In patients with ARDS, exogenous surfactant therapy decreases IL-6 concentrations in the plasma and BAL of patients with ARDS, suggesting either a direct anti-inflammatory effect or a reduction of ventilator-induced lung stretch [6
]. However, in the present study, despite surfactant-induced recruitment of poorly or nonaerated lung regions, CT lung hyperinflation was similar in both groups. Unexpectedly, HL-10-induced reaeration was not associated with a significant improvement in arterial oxygenation. Very likely, HL-10 instillation in normally aerated lung regions worsened regional ventilation/perfusion ratios through an increase in lung tissue. In other words, benefit in terms of aeration of poorly or nonaerated regions of the lung was likely to be counteracted by a negative impact of HL-10 on aeration of previously normally aerated lung.