This study evaluated the efficacy and safety of bronchoalveolar lavage (BAL) with diluted porcine surfactant in 8 mechanically ventilated term infants with acute respiratory distress syndrome (ARDS) due to meconium aspiration syndrome (MAS). Infants received BAL with 15 mL/kg of diluted porcine surfactant. BAL improved oxygenation and chest x-ray findings at 3 and 6 hours post-treatment without adverse effects. Radiological improvement was seen in all infants by 6 hours. Oxygenation parameters including a/ApO2 ratio and oxygenation index significantly improved. BAL was well tolerated and no adverse events occurred.

1. Clin Drug Invest 2006; 26 (1): 13-19
1173-2563/06/0001-0013/$39.95/0
ORIGINAL RESEARCH ARTICLE
 2006 Adis Data Information BV. All rights reserved.
Bronchoalveolar Lavage with Diluted
Porcine Surfactant in Mechanically
Ventilated Term Infants with
Meconium Aspiration Syndrome
Gianluca Lista, Silvia Bianchi, Francesca Castoldi, Paola Fontana and
Francesco Cavigioli
Neonatal Intensive Care Unit, Vittore Buzzi Children’s Hospital, Istituti Clinici di
Perfezionamento, Milan, Italy
Abstract
Background: To evaluate the efficacy and safety of bronchoalveolar lavage
(BAL) with diluted porcine surfactant in mechanically ventilated term infants
with severe acute respiratory distress syndrome (ARDS) due to meconium aspiration syndrome (MAS).
Methods: Eight consecutive mechanically ventilated term infants with severe
ARDS due to MAS underwent BAL with 15 mL/kg of diluted (5.3mg phospholipid/mL) surfactant saline suspension (porcine surfactant [Curosurf]). Treatment
was administered slowly in aliquots of 2.5mL. The mean age of neonates at
treatment was 3.5 (range 1–8) hours. Heart rate, systemic blood pressure and
oxygen saturation were monitored continuously. Arterial blood gases were measured immediately before treatment, and again at 3 and 6 hours post-treatment.
Chest x-rays were taken 6 and 24 hours after treatment.
Results: Radiological improvement was evident in all eight patients 6 hours
post-treatment. Compared with pre-BAL values, significant improvements
(p < 0.05) in mean values for partial pressure of oxygen in arterial blood, partial
pressure of carbon dioxide in arterial blood, pH, arterial/alveolar O2 ratio and
oxygenation index were documented at 3 and 6 hours after BAL. In all patients,
tracheal fluids that had been meconium-stained prior to BAL were clear of
meconium after BAL. Only one patient required nitric oxide therapy for transient
pulmonary hypertension. No adverse sequelae of treatment occurred during the
study.
Conclusions: BAL with dilute porcine surfactant administered slowly in 2.5mL
aliquots improved oxygenation and chest x-ray findings, without causing major
adverse effects, in mechanically ventilated term infants with ARDS due to MAS.

2. 14
Lista et al.
Introduction
Meconium aspiration syndrome (MAS) is a common cause of severe respiratory distress in neonates,
particularly term and post-term infants. Meconiumstained amniotic fluid occurs in 5–10% of all deliveries, with up to approximately 30% of neonates
born after 42 weeks’ gestation being affected.[1] In
ball-valve fashion, aspirated meconium can provoke
partial airway obstruction (leading to air trapping
and a high risk of air leak) or complete obstruction
of small airways (leading to regional atelectasis).
About 30% of babies with MAS will require
mechanical ventilation; some will also require nitric
oxide (NO) therapy or extracorporeal membrane
oxygenation because of persistent pulmonary hypertension of the newborn in association with severe
acute respiratory distress syndrome (ARDS).[2]
Progression of meconium into distal airspaces
frequently results in development of chemical pneumonia. Moreover, meconium in the alveoli inactivates the surfactant system, contributing to a deterioration in lung mechanics and decreased lung compliance.[3,4] Thus, an optimal approach to treatment
of MAS would be to remove residual meconium
from the lung, thereby preserving surfactant activity. Studies have shown that administration of diluted
surfactant solution by bronchoalveolar lavage
(BAL) enables residual meconium to be washed out
from the bronchial tree, resulting in enhanced
surfactant activity and lung function both in animal
models and in human newborns with MAS.[5-12]
The positive effects of modified porcine
surfactant on lung function in animal models with
MAS have been described in the literature.[13,14]
Based on these findings, we evaluated the efficacy
and safety of BAL with diluted surfactant saline
suspension (porcine lipid extract surfactant
[Curosurf, Chiesi Farmaceutici SpA, Parma, Ita1
ly])1 in mechanically ventilated term infants with
severe ARDS due to MAS.
Materials and Methods
Patients
The study was conducted at the Neonatal Intensive Care Unit of the Vittore Buzzi Children’s Hospital, Milan, Italy. Participants in the study consisted
of eight consecutive term infants requiring mechanical ventilation during the first 6 hours of life because
of severe ARDS (arterial-alveolar oxygen tension
ratio [a/ApO2] <0.2) due to MAS: ventilation criteria were fraction of inspired oxygen (FiO2) requirement >0.4; arterial partial pressure of carbon dioxide
(PaCO2) >60mm Hg, and arterial partial pressure of
oxygen (PaO2) <50mm Hg. Subjects were recruited
over a 2-year period (from August 2001 to August
2003). The diagnosis of ARDS due to MAS was
made according to radiological and clinical criteria
(coarse infiltrates and areas of hyperaeration on
chest x-ray, and tachydyspnoea with hypercapnia
and hypoxia in the newborn with meconium-stained
fluid in the airways). Infants with lethal congenital
anomalies were excluded from the study. Mechanical ventilation consisted of synchronised intermittent positive-pressure ventilation with the option of
volume guarantee (volume-targeted ventilation)
[Dr¨ ger Babylog 8000 Plus, software version 5.0,
a
Dr¨ ger Medical, Vienna, Austria].
a
The study was conducted with the approval of the
Vittore Buzzi Children’s Hospital Ethics Committee. Subjects were included in the study only after
written informed parental consent had been obtained.
Study Design
All study participants underwent BAL, consisting of 15 mL/kg of surfactant saline suspension
The use of trade names is for product identification purposes only and does not imply endorsement.
 2006 Adis Data Information BV. All rights reserved.
Clin Drug Invest 2006; 26 (1)

3. Bronchoalveolar Lavage in Meconium Aspiration Syndrome
(porcine lipid extract surfactant 80mg phospholipid/
mL, diluted to a concentration of 5.3mg phospholipid/mL). As a result of this dilution, study participants received 80mg surfactant phospholipid/kg.
BAL was administered in 2.5mL aliquots delivered
to the end of the endotracheal tube. In cases of
severe oxygen desaturation (arterial oxygen saturation [SaO2] <80%), BAL was halted and subjects
underwent manual bagging until SaO2 returned to
normal (>90%). After delivery of each aliquot of
BAL, suctioning of meconium debris was conducted
via a catheter (French size 8), using a negative
pressure of 80–90mm Hg, until the tracheal fluids
were clear of meconium.
Heart rate, systemic blood pressure and SaO2
were monitored continuously. Samples for arterial
blood gas tension measurement (Radiometer Copenhagen, ABL700) were collected from an indwelling
catheter immediately before BAL, and again at 3
and 6 hours after treatment. Ventilator settings (tidal
volume, mean airway pressure and FiO2) were recorded at the time of arterial blood gas sampling.
Chest x-rays were conducted before BAL, and at
6 and 24 hours after treatment. Echocardiography
was performed daily to detect and monitor persistent
pulmonary hypertension of the newborn.
15
For all subjects, tidal volume was set at 5 mL/kg,
positive end-expiratory pressure at 4–5cm H2O, and
inspiratory time at 0.3–0.4 seconds. Within the
ranges stated, these parameters were adjusted to
maintain SaO2 (as measured by pulse oximetry) at
91–96%, PaO2 at 40–75mm Hg, PaCO2 at
45–65mm Hg, and pH >7.25.
Statistical Methods
ANOVA with the Bonferroni post hoc test was
used for statistical analysis. The significance level
was taken as p < 0.05. Data are reported as means ±
SD.
Results
The clinical characteristics of the study population are listed in table I. The mean age of study
participants at administration of BAL was 3.5 (range
1–8) hours. The mean duration of the procedure was
35 ± 10 minutes.
Efficacy
Radiological improvement was observed in all
subjects 6 hours after BAL (air leak resolved in 2/8
patients; good reductions in coarse infiltrates and
Table I. Baseline characteristics of the study population (n = 8)
Characteristic
Value
Sex
male (n)
4
female (n)
4
Gestational age (wks) [mean ± SD (range)]
39 ± 1 (38–41)
Birth weight (g) [mean ± SD (range)]
3486 ± 415 (3030–4220)
Delivery mode (no.)
vaginal
4
Caesarean section
4
APGAR score
1 minute
5
5 minutes
7
a/APO2 (mean ± SD)
0.11 ± 0
OI (mean ± SD)
16.2 ± 11.7
a/APO2 = arterial/alveolar partial pressure of oxygen ratio; OI = oxygenation index.
 2006 Adis Data Information BV. All rights reserved.
Clin Drug Invest 2006; 26 (1)

4. 16
Lista et al.
Table II. Respiratory and ventilatory parameters before and 3 and 6 hours after bronchoalveolar lavage (BAL) [values are given as
mean ± SD]
Parameter
Pre-BAL
3 hours post-BAL
FiO2
0.55 ± 0.28
0.37 ± 0.19
6 hours post-BAL
0.38 ± 0.15
MAP (cm H2O)
9 ± 3.9
8.3 ± 3.8
8.2 ± 4.2
Vt (mL/kg)
5±0
5±0
5±0
a/APO2
0.11 ± 0
0.2 ± 0.13
0.3 ± 0.2*
OI
16.2 ± 11.7
7.0 ± 6.6
5.1 ± 3.1*
pH
7.16 ± 0.1
7.34 ± 0.01*
7.37 ± 0.01*
PaCO2 (mm Hg)
53.9 ± 8.3
40.2 ± 11.5*
37.2 ± 9.1*
PaO2 (mm Hg)
34.4 ± 15.1
55.4 ± 14.2
66.6 ± 21.6*
a/APO2 = arterial/alveolar PO2 ratio; FiO2 = fraction of inspired oxygen; MAP = mean airway pressure; OI = oxygenation index;
PO2 = partial pressure of oxygen; PaO2 = arterial PO2; PaCO2 = partial pressure of carbon dioxide; Vt = tidal volume. * p < 0.05 vs pre-BAL.
areas of hyperaeration on chest x-ray were observed
in 6/8 patients).
Improvements in mean PaO2, PaCO2, pH, a/
APO2 and oxygenation index (OI) were also observed 3 and 6 hours after BAL compared with preBAL values (p < 0.05 for pH and PaCO2 at 3 hours,
p < 0.05 for all parameters at 6 hours [table II]).
The mean length of mechanical ventilation was
2.88 ± 1.25 (range 1–5) days. The mean duration of
oxygen supplementation was 4.25 ± 2.05 (range
3–8) days. Only one patient required NO therapy (5
ppm for 12 hours) for transient pulmonary hypertension. In two patients with pneumothorax prior to
BAL, the lesions were no longer evident on the
6-hour post-treatment chest x-ray. In all babies, recovery of tracheal fluid during suctioning was incomplete (30–65% of the total lavage fluid volume
instilled into the lung). However, all recovered
tracheal fluids were clear of meconium at the end of
BAL.
Safety and Tolerability
BAL was well tolerated by all subjects. No
changes in blood pressure or episodes of bradycardia were observed during the procedure. No episodes of pulmonary haemorrhage occurred. No patients died during the study or had adverse sequelae
of any kind.
 2006 Adis Data Information BV. All rights reserved.
Discussion
The aim of this preliminary study was to evaluate
the efficacy and safety of BAL with diluted porcine
surfactant in mechanically ventilated term infants
with ARDS due to MAS. Our results showed that
slow administration of diluted surfactant in small
amounts by BAL improved oxygen status and chest
x-ray findings, and reduced the length of both
mechanical ventilation and oxygen supplementation, without any major adverse effects, in this patient population.
Several factors account for the pathophysiology
of MAS. First, high-molecular weight mucous glycoproteins in meconium give the substance adhesive
properties, making it more likely to cause airway
obstruction when inhaled. Secondly, meconium can
cause chemical injury to the respiratory epithelium.
Thirdly, many components of meconium, such as
lipids, proteins and bilirubin, potently inhibit
surfactant activity, contributing to severe respiratory
failure in MAS.[15,16]
These findings have prompted research into the
possible benefits of exogenous surfactant therapy in
the treatment of ARDS due to MAS. One important
finding from this research is that the mode of administration of such therapy contributes to its efficacy.
In one study performed in an acute lung injury
animal model, for example, bolus administration of
surfactant was not as effective as the same surfactant
Clin Drug Invest 2006; 26 (1)

5. Bronchoalveolar Lavage in Meconium Aspiration Syndrome
administered by lung lavage.[17] The reason for this
appears to be that exogenously administered
surfactant is not distributed uniformly throughout
the lung following bolus or aerosol administration.[18,19]
Numerous animal and clinical studies have
shown that early lavage with surfactant solution
significantly improves respiratory function in animals and neonates with acute lung injury and with
MAS.[5,8,20,21] The procedure generally involves the
initial administration of a relatively large volume of
surfactant solution, but the excess fluid is drained
immediately, leaving only a small residual volume
of lavage fluid in the lungs (about 15%).[5,8] Repeated lavage followed by suctioning removes meconium and lung debris responsible for both airway
obstruction and surfactant inactivation. Even if only
about 15% of the administered surfactant is retained,[5,8] the improvement in lung compliance and
better gas exchange indicate that surfactant administration was effective and distribution of the
surfactant particles was homogenous.[5,8,17,21]
It is now known that the endogenous surfactant
pool in humans is smaller than first estimated: the
alveolar wash contains about 2 mmol/kg of saturated
phosphatidylcholine/kg, which is equivalent to
about 4 mg/kg surfactant, a relatively small pool size
compared with other species.[22] Recognition of this
fact has prompted evaluation of much lower doses
of exogenous surfactant than had previously been
used in surfactant deficiency/dysfunction. Both
animal and human studies have now confirmed that
BAL with a diluted surfactant solution first reduces
the airway obstruction by removing meconium and
airway proteinaceous debris, thereby reducing the
risk of airway obstruction and subsequent surfactant
inactivation, then, with the subsequent doses of the
lavage fluid, achieves a homogeneous alveolar distribution of the surfactant particles.[5,7,8,20,23,24]
In neonatal piglets with acute lung injury, lavage
administration of a variety of artificial and natural
 2006 Adis Data Information BV. All rights reserved.
17
diluted surfactant preparations (4–4.5mg phospholipid/mL) improved oxygenation and other parameters of pulmonary function as effectively as undiluted surfactant (13.5mg phospholipid/mL).[19] It is
likely that acute lung injury with surfactant deficiency could be effectively treated even with a simple
surfactant administration, while the efficacy of treatment of MAS with diluted surfactant is probably
more linked to removal of meconium and debris. In
confirmation of that, tracheobronchial lavage with
15 mL/kg of diluted surfactant solution (5mg phospholipid/mL) administered in 2mL aliquots significantly improved oxygen status and reduced duration
of ventilation and oxygen therapy, without adverse
effects, in six neonates with severe MAS.[7] In another pilot study of 22 neonates with severe MAS,
diluted surfactant BAL (15 mL/kg; 5mg phospholipid/mL) was associated with a lower OI and higher
PaO2 at 1 hour, reduced duration of mechanical
ventilation and less time in hospital, compared with
historical controls.[20] Finally, a previous retrospective clinical study of 54 infants with MAS showed
generally modest therapeutic effects with porcine
surfactant.[25]
Our results also provide evidence that smaller
doses of surfactant (i.e. 80 mg/kg of diluted porcine
lipid extract surfactant, compared with the usual
dosages of 200 or 100 mg/kg) are effective when
administered as BAL in neonates with ARDS due to
MAS.
Our study also showed that administration of
surfactant solution in small (2.5mL) aliquots was
well tolerated. Importantly, this approach would
also be appropriate in patients with MAS-related
haemodynamic instability, in whom BAL with large
fluid volumes can overload the cardiorespiratory
system.[26] Furthermore, patients in our study did not
experience pulmonary haemorrhage, an event that
has been reported in an earlier study.[27] It is well
known that pulmonary haemorrhage is an event
strictly linked to perinatal hypoxia, but our ‘gentler’
Clin Drug Invest 2006; 26 (1)

6. 18
Lista et al.
small-volume procedure probably does not increase
the risk of injury to the pulmonary epithelium. There
was also no increase in the incidence of pulmonary
hypertension (only one patient needed a short course
of inhaled NO for transient pulmonary hypertension
revealed by an increased velocity of the tricuspid
regurgitation jet at the ecochardiographic control
without clinical significance), a condition frequently
associated with MAS.[26]
Because of its low potential to cause fluid overload and severe hypoxaemia, the BAL regimen used
in our study could be administered even to infants
with very high baseline OI scores. Indeed, BAL with
diluted surfactant (using small-volume aliquots)
could be used in all newborns (including preterm
infants receiving prolonged mechanical ventilation,
who might benefit from BAL fractionated in very
small amounts because this minimises the risks of
interrupting mechanical ventilation during the lavage procedure) in whom accumulation of lung debris inhibits surfactant activity. Our results confirm
that such treatment would be expected to facilitate
weaning from ventilator and oxygen therapy.
The small number of subjects and the lack of
controls are limitations of this study. Recent
changes in the approach to mechanical ventilation of
the neonate with MAS mean that supportive management in historic controls differs from current
practice, making comparisons difficult.
Conclusion
Our preliminary study suggests that BAL with
diluted porcine surfactant (phospholipid concentration 5.3 mg/mL), administered slowly and in small
amounts, improved oxygen status, resolved chest xray abnormalities, and facilitated weaning from
mechanical ventilation in infants with ARDS due to
MAS. These benefits were achieved without adverse
effects. Our findings suggest that BAL with diluted
surfactant would be a reasonable adjunct to ventilation, antibacterials, chest physiotherapy, haemody 2006 Adis Data Information BV. All rights reserved.
namic support and treatment of pulmonary hypertension (if indicated) in the management of MAS.
However, larger randomised studies are required to
validate the use of this procedure in the neonatal
setting.
Acknowledgements
We are grateful for the assistance and support of the
nursing staff at the Neonatal Intensive Care Unit, Vittore
Buzzi Children’s Hospital, involved in this study. No external
sources of funding were used to assist in the preparation of
this manuscript and the authors have no potential conflicts of
interest regarding the content of the study.
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Correspondence and offprints: Dr Gianluca Lista, Neonatal
Intensive Care Unit, Vittore Buzzi Children’s Hospital, Istituti Clinici di Perfezionamento, 32 Via Castelvetro, Milan,
20153, Italy.
E-mail: intensivist@tiscali.it
Clin Drug Invest 2006; 26 (1)