Reinhold Schmidt

Surfactant alteration and replacement in acute respiratory distress syndrome

The acute respiratory distress syndrome (ARDS) is a frequent, life-threatening disease in which a marked increase in alveolar surface tension has been repeatedly observed. It is caused by factors including a lack of surface-active compounds, changes in the phospholipid, fatty acid, neutral lipid, and surfactant apoprotein composition, imbalance of the extracellular surfactant subtype distribution, inhibition of surfactant function by plasma protein leakage, incorporation of surfactant phospholipids and apoproteins into polymerizing fibrin, and damage/inhibition of surfactant compounds by inflammatory mediators. There is now good evidence that these surfactant abnormalities promote alveolar instability and collapse and, consequently, loss of compliance and the profound gas exchange abnormalities seen in ARDS. An acute improvement of gas exchange properties together with a far-reaching restoration of surfactant properties was encountered in recently performed pilot studies. Here we summarize what is known about the kind and severity of surfactant changes occuring in ARDS, the contribution of these changes to lung failure, and the role of surfactant administration for therapy of ARDS.

Time-dependent changes in pulmonary surfactant function and composition in acute respiratory distress syndrome due to pneumonia or aspiration

BackgroundAlterations to pulmonary surfactant composition have been encountered in the Acute Respiratory Distress Syndrome (ARDS). However, only few data are available regarding the time-course and duration of surfactant changes in ARDS patients, although this information may largely influence the optimum design of clinical trials addressing surfactant replacement therapy. We therefore examined the time-course of surfactant changes in 15 patients with direct ARDS (pneumonia, aspiration) over the first 8 days after onset of mechanical ventilation.MethodsThree consecutive bronchoalveolar lavages (BAL) were performed shortly after intubation (T0), and four days (T1) and eight days (T2) after intubation. Fifteen healthy volunteers served as controls. Phospholipid-to-protein ratio in BAL fluids, phospholipid class profiles, phosphatidylcholine (PC) molecular species, surfactant proteins (SP)-A, -B, -C, -D, and relative content and surface tension properties of large surfactant aggregates (LA) were assessed.ResultsAt T0, a severe and highly significant reduction in SP-A, SP-B and SP-C, the LA fraction, PC and phosphatidylglycerol (PG) percentages, and dipalmitoylation of PC (DPPC) was encountered. Surface activity of the LA fraction was greatly impaired. Over time, significant improvements were encountered especially in view of LA content, DPPC, PG and SP-A, but minimum surface tension of LA was not fully restored (15 mN/m at T2). A highly significant correlation was observed between PaO2/FiO2 and minimum surface tension (r = -0.83; p < 0.001), SP-C (r = 0.64; p < 0.001), and DPPC (r = 0.59; p = 0.003). Outcome analysis revealed that non-survivors had even more unfavourable surfactant properties as compared to survivors.ConclusionWe concluded that a profound impairment of pulmonary surfactant composition and function occurs in the very early stage of the disease and only gradually resolves over time. These observations may explain why former surfactant replacement studies with a short treatment duration failed to improve outcome and may help to establish optimal composition and duration of surfactant administration in future surfactant replacement studies in acute lung injury.

Patients with ARDS show improvement but not normalisation of alveolar surface activity with surfactant treatment: putative role of neutral lipids

Background: Extensive biochemical and biophysical changes of the pulmonary surfactant system occur in the acute respiratory distress syndrome (ARDS). Methods: The effect of intrabronchial administration of a recombinant surfactant protein C-based surfactant preparation (Venticute) on gas exchange, surfactant composition and function was investigated in 31 patients with ARDS in a randomised controlled phase I/II clinical pilot trial. Bronchoalveolar lavage fluids for surfactant analysis were obtained 3 h before and 48 and 120 h after the first surfactant application. Potentially deleterious effects of surfactant neutral lipids in patients with ARDS were also identified. Results: Before treatment all patients had marked abnormalities in the surfactant phospholipid and protein composition. In response to surfactant treatment, gas exchange improved and surfactant phospholipid and protein content were almost normalised. Alveolar surface activity was dramatically impaired before treatment and only partially improved after surfactant administration. Further analysis of the bronchoalveolar lavage fluids revealed a twofold increase in neutral lipid content and altered neutral lipid profile in patients with ARDS compared with healthy controls. These differences persisted even after administration of large amounts of Venticute. Supplementation of Venticute or natural surfactant with a synthetic neutral lipid preparation, mimicking the profile in ARDS, caused a dose-dependent deterioration of surface activity in vitro. Conclusion: Intrabronchial surfactant treatment improves gas exchange in ARDS, but the efficacy may be limited by increased concentration and altered neutral lipid profile in surfactant under these conditions.

Host defence lectins in preterm neonates.

AIM Deficiency in collectins is discussed as a risk factor for pulmonary and systemic infections in children and adults. The objective of this study was to determine serum concentrations of surfactant protein D (SP-D) and mannose-binding lectin (MBL) in preterm and term infants at birth. METHODS 47 preterm infants below 32 wk gestational age (GA) and 19 healthy, term newborn infants at birth have been included in the study, and SP-D as well as MBL concentrations have been determined in umbilical cord blood samples using sandwich ELISA technique. In addition, SP-D concentrations were assessed in tracheal aspirates (TA) of 24 mechanically ventilated preterms and in infants without pulmonary complications before elective surgery. RESULTS MBL serum concentrations were significantly lower in preterms <32 wk GA (756.7 ng/ml; 14.6-11 184 ng/ml) compared to term newborns (3168.9 ng/ml; 282.3-7679.5 ng/ml; p=0.005; median and range, respectively). Serum SP-D concentrations were significantly decreased in preterms between 28 and 32 wk GA (1.4 ng/ml; 0-4.6 ng/ml; n=26) compared to term infants (2.2 ng/ml; 1.2-3.3 ng/ml; p=0.05) and were found to positively correlate with history of antenatal corticosteroids and chorioamnionitis. SP-D concentrations in TA were increased in preterm infants between 28 and 32 wk GA with respiratory distress syndrome (RDS) (25.0 ng/ml; 0.9-44.7 ng/ml; n=12) compared to control subjects (6.6 ng/ml; 0.5-30.4 ng/ml; n=12) in contrast to extremely immature infants <28 wk GA suffering from RDS (4.4 ng/ml; 0.8-78.4 ng/ml; n=12). CONCLUSION In preterm infants, significant changes occur in collectin umbilical cord blood concentrations and pulmonary SP-D levels. Functional aspects of these findings need to be addressed further.

Sequential analysis of surfactant, lung function and inflammation in cystic fibrosis patients

BackgroundIn a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time.MethodsAs part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV1 94% of predicted) at three times over a three year period.ResultsThere was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV1, MEF75/25%VC, and MEF25%VC. The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period.ConclusionOur findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease.

Synthetic and natural surfactant differentially modulate inflammation after meconium aspiration.

ObjectiveMeconium aspiration syndrome remains a relevant cause of neonatal respiratory failure and is associated with severe pulmonary changes including surfactant inactivation and pronounced inflammatory changes. The present study investigated the effect of two different surfactant preparations—recombinant surfactant protein C surfactant (rSP-C Surf) and natural bovine surfactant—on pulmonary gas exchange and inflammatory response.Design and subjectsTwenty-three newborn piglets were intubated, mechanically ventilated, received 5 ml/kg 20% sterile meconium for induction of lung injury, and were randomized thereafter for controls (n=7), rSP-C Surf (n=8), or natural surfactant (n=8). Surfactants were given as an intratracheal bolus (75 mg/kg) and animals were further ventilated.Measurements and resultsLung function variables, arterial blood gas samples and lung tissues were obtained. Histological evaluation was performed in right lung tissue using an established score. Cytokine mRNA expression (left lung tissue) was quantified using TaqMan real-time PCR (ΔΔCT method, normalized to controls). In addition to significant improvement in gas exchange and lung function, histological evaluation showed significantly lower sum scores in the rSP-C Surf group than in controls). Cytokine mRNA expression of IL-1β in whole lung tissue was significantly lower after administration of rSP-C Surf than in natural surfactant and controls whereas IL-10 mRNA expression was significantly induced in both surfactant groups.ConclusionsSurfactant administration improved both gas exchange and pulmonary inflammatory cytokine transcription. Mechanisms underlying the differential inflammatory response in both surfactant preparations need to be further addressed.

Pulmonary surfactant in patients with Pneumocystis pneumonia and acquired immunodeficiency syndrome.

Objective:Pneumocystis pneumonia (PCP) is a severe infection of the immunocompromised host, resulting in diffuse alveolar damage and life-threatening respiratory failure. We analyzed pulmonary surfactant composition and function in bronchoalveolar lavage fluid (BALF) from ventilated and spontaneously breathing HIV-positive patients with PCP. Design:Prospective clinical trial. Setting:University hospital intensive care unit. Patients:Thirty-four spontaneously breathing (SB-PCP) and 20 ventilated HIV-positive patients with PCP (V-PCP), ten patients with acute respiratory distress syndrome (ARDS), 11 spontaneously breathing patients with bacterial pneumonia (PNEU), and 22 healthy volunteers. Interventions:None. Measurements and Main Results:Total phospholipid in BALF did not differ between any category vs. controls, whereas total protein increased approximately 14-fold in V-PCP and five-fold in SB-PCP compared with controls (p < .001). The relative content of large surfactant aggregates (LA) was reduced in SB-PCP and V-PCP compared with controls (p < .05). The phospholipid and fatty acid profiles showed a significant reduction in the relative content of phosphatidylcholine (PC), phosphatidylglycerol, and palmitic acid in PC in all patient categories compared with controls, with more in V-PCP (p < .001) compared with SB-PCP (p < .05). The neutral lipid-to-phospholipid ratio in LA was three-fold elevated in V-PCP (p < .01 compared with control) but not in SB-PCP. Analysis of neutral lipid classes showed a significant increase in the relative content of triglycerides and a reduction in free fatty acids in V-PCP compared with controls. BALF surfactant protein (SP)-A and SP-D significantly increased in V-PCP and SB-PCP, but not in ARDS and PNEU, compared with controls (p < .05). SP-B and SP-C content in LA remained unchanged in PCP compared with controls but decreased significantly in ARDS and PNEU. The minimum surface tension of LA was impaired (p < .001) in V-PCP more than in SB-PCP and was strongly correlated with the reduction in palmitic acid levels in PC LA (r = −.81). Reductions in phosphatidylglycerol strongly correlated with decreased Pao2/Fio2 values (r = .72). Conclusions:We conclude that severe alterations in surfactant function and composition occur in patients with PCP and are even more pronounced in ventilated patients than in nonventilated patients. Surfactant lipid changes in PCP, but not surfactant protein profiles, closely resemble those found in ARDS.

Host defence lectins in preterm neonates: Host defence lectins in preterm neonates

Aim: Deficiency in collectins is discussed as a risk factor for pulmonary and systemic infections in children and adults. The objective of this study was to determine serum concentrations of surfactant protein D (SP‐D) and mannose‐binding lectin (MBL) in preterm and term infants at birth. Methods: 47 preterm infants below 32 wk gestational age (GA) and 19 healthy, term newborn infants at birth have been included in the study, and SP‐D as well as MBL concentrations have been determined in umbilical cord blood samples using sandwich ELISA technique. In addition, SP‐D concentrations were assessed in tracheal aspirates (TA) of 24 mechanically ventilated preterms and in infants without pulmonary complications before elective surgery. Results: MBL serum concentrations were significantly lower in preterms <32 wk GA (756.7 ng/ml; 14.6–11 184 ng/ml) compared to term newborns (3168.9 ng/ml; 282.3–7679.5 ng/ml; p=0.005; median and range, respectively). Serum SP‐D concentrations were significantly decreased in preterms between 28 and 32 wk GA (1.4 ng/ml; 0–4.6 ng/ml; n=26) compared to term infants (2.2 ng/ml; 1.2–3.3 ng/ml; p=0.05) and were found to positively correlate with history of antenatal corticosteroids and chorioamnionitis. SP‐D concentrations in TA were increased in preterm infants between 28 and 32 wk GA with respiratory distress syndrome (RDS) (25.0 ng/ml; 0.9–44.7 ng/ml; n=12) compared to control subjects (6.6 ng/ml; 0.5–30.4 ng/ml; n=12) in contrast to extremely immature infants <28 wk GA suffering from RDS (4.4 ng/ml; 0.8–78.4 ng/ml; n=12).