Surfactantes prematuros

Clin Drug Invest 2006; 26 (1): 13-19ORIGINAL RESEARCH ARTICLE 1173-2563/06/0001-0013/$39.95/0

2006 Adis Data Information BV. All rights reserved.

Bronchoalveolar Lavage with DilutedPorcine Surfactant in MechanicallyVentilated Term Infants withMeconium Aspiration SyndromeGianluca Lista, Silvia Bianchi, Francesca Castoldi, Paola Fontana andFrancesco Cavigioli

Neonatal Intensive Care Unit, Vittore Buzzi Children’s Hospital, Istituti Clinici diPerfezionamento, Milan, Italy

Background: To evaluate the efficacy and safety of bronchoalveolar lavageAbstract(BAL) with diluted porcine surfactant in mechanically ventilated term infantswith severe acute respiratory distress syndrome (ARDS) due to meconium aspira-tion syndrome (MAS).Methods: Eight consecutive mechanically ventilated term infants with severeARDS due to MAS underwent BAL with 15 mL/kg of diluted (5.3mg phospholip-id/mL) surfactant saline suspension (porcine surfactant [Curosurf]). Treatmentwas administered slowly in aliquots of 2.5mL. The mean age of neonates attreatment was 3.5 (range 1–8) hours. Heart rate, systemic blood pressure andoxygen saturation were monitored continuously. Arterial blood gases were mea-sured 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 hourspost-treatment. Compared with pre-BAL values, significant improvements(p < 0.05) in mean values for partial pressure of oxygen in arterial blood, partialpressure of carbon dioxide in arterial blood, pH, arterial/alveolar O2 ratio andoxygenation 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 ofmeconium after BAL. Only one patient required nitric oxide therapy for transientpulmonary hypertension. No adverse sequelae of treatment occurred during thestudy.Conclusions: BAL with dilute porcine surfactant administered slowly in 2.5mLaliquots improved oxygenation and chest x-ray findings, without causing majoradverse effects, in mechanically ventilated term infants with ARDS due to MAS.

14 Lista et al.

Introduction ly])1 in mechanically ventilated term infants withsevere ARDS due to MAS.

Meconium aspiration syndrome (MAS) is a com-Materials and Methodsmon cause of severe respiratory distress in neonates,

particularly term and post-term infants. Meconium-Patientsstained amniotic fluid occurs in 5–10% of all deliv-

eries, with up to approximately 30% of neonatesThe study was conducted at the Neonatal Inten-

born after 42 weeks’ gestation being affected.[1] Insive Care Unit of the Vittore Buzzi Children’s Hos-

ball-valve fashion, aspirated meconium can provokepital, Milan, Italy. Participants in the study consisted

partial airway obstruction (leading to air trapping of eight consecutive term infants requiring mechani-and a high risk of air leak) or complete obstruction cal ventilation during the first 6 hours of life becauseof small airways (leading to regional atelectasis). of severe ARDS (arterial-alveolar oxygen tensionAbout 30% of babies with MAS will require ratio [a/ApO2] <0.2) due to MAS: ventilation crite-mechanical ventilation; some will also require nitric ria were fraction of inspired oxygen (FiO2) require-oxide (NO) therapy or extracorporeal membrane ment >0.4; arterial partial pressure of carbon dioxideoxygenation because of persistent pulmonary hyper- (PaCO2) >60mm Hg, and arterial partial pressure oftension of the newborn in association with severe oxygen (PaO2) <50mm Hg. Subjects were recruitedacute respiratory distress syndrome (ARDS).[2]

over a 2-year period (from August 2001 to AugustProgression of meconium into distal airspaces 2003). The diagnosis of ARDS due to MAS was

frequently results in development of chemical pneu- made according to radiological and clinical criteriamonia. Moreover, meconium in the alveoli inacti- (coarse infiltrates and areas of hyperaeration onvates the surfactant system, contributing to a deteri- chest x-ray, and tachydyspnoea with hypercapniaoration in lung mechanics and decreased lung com- and hypoxia in the newborn with meconium-stained

fluid in the airways). Infants with lethal congenitalpliance.[3,4] Thus, an optimal approach to treatmentanomalies were excluded from the study. Mechani-of MAS would be to remove residual meconiumcal ventilation consisted of synchronised intermit-from the lung, thereby preserving surfactant activi-tent positive-pressure ventilation with the option ofty. Studies have shown that administration of dilutedvolume guarantee (volume-targeted ventilation)surfactant solution by bronchoalveolar lavage[Drager Babylog 8000 Plus, software version 5.0,(BAL) enables residual meconium to be washed outDrager Medical, Vienna, Austria].from the bronchial tree, resulting in enhanced

The study was conducted with the approval of thesurfactant activity and lung function both in animalVittore Buzzi Children’s Hospital Ethics Commit-models and in human newborns with MAS.[5-12]

tee. Subjects were included in the study only afterThe positive effects of modified porcinewritten informed parental consent had been ob-surfactant on lung function in animal models withtained.MAS have been described in the literature.[13,14]

Based on these findings, we evaluated the efficacyStudy Design

and safety of BAL with diluted surfactant salinesuspension (porcine lipid extract surfactant All study participants underwent BAL, consist-[Curosurf, Chiesi Farmaceutici SpA, Parma, Ita- ing of 15 mL/kg of surfactant saline suspension

1 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)

Bronchoalveolar Lavage in Meconium Aspiration Syndrome 15

(porcine lipid extract surfactant 80mg phospholipid/ For all subjects, tidal volume was set at 5 mL/kg,positive end-expiratory pressure at 4–5cm H2O, andmL, diluted to a concentration of 5.3mg phospholip-inspiratory time at 0.3–0.4 seconds. Within theid/mL). As a result of this dilution, study partici-ranges stated, these parameters were adjusted topants received 80mg surfactant phospholipid/kg.maintain SaO2 (as measured by pulse oximetry) atBAL was administered in 2.5mL aliquots delivered91–96%, PaO2 at 40–75mm Hg, PaCO2 atto the end of the endotracheal tube. In cases of45–65mm Hg, and pH >7.25.severe oxygen desaturation (arterial oxygen satura-

tion [SaO2] <80%), BAL was halted and subjectsStatistical Methodsunderwent manual bagging until SaO2 returned to

normal (>90%). After delivery of each aliquot of ANOVA with the Bonferroni post hoc test wasBAL, suctioning of meconium debris was conducted used for statistical analysis. The significance levelvia a catheter (French size 8), using a negative was taken as p < 0.05. Data are reported as means ±pressure of 80–90mm Hg, until the tracheal fluids SD.were clear of meconium.

ResultsHeart rate, systemic blood pressure and SaO2

were monitored continuously. Samples for arterialThe clinical characteristics of the study popula-

blood gas tension measurement (Radiometer Copen-tion are listed in table I. The mean age of study

hagen, ABL700) were collected from an indwellingparticipants at administration of BAL was 3.5 (range

catheter immediately before BAL, and again at 31–8) hours. The mean duration of the procedure was

and 6 hours after treatment. Ventilator settings (tidal35 ± 10 minutes.

volume, mean airway pressure and FiO2) were re-corded at the time of arterial blood gas sampling. EfficacyChest x-rays were conducted before BAL, and at6 and 24 hours after treatment. Echocardiography Radiological improvement was observed in allwas performed daily to detect and monitor persistent subjects 6 hours after BAL (air leak resolved in 2/8pulmonary hypertension of the newborn. 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 ± 11.7a/APO2 = arterial/alveolar partial pressure of oxygen ratio; OI = oxygenation index.


16 Lista et al.

Table II. Respiratory and ventilatory parameters before and 3 and 6 hours after bronchoalveolar lavage (BAL) [values are given asmean ± SD]

Parameter Pre-BAL 3 hours post-BAL 6 hours post-BAL

FiO2 0.55 ± 0.28 0.37 ± 0.19 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 Discussionin 6/8 patients).

The aim of this preliminary study was to evaluateImprovements in mean PaO2, PaCO2, pH, a/the efficacy and safety of BAL with diluted porcineAPO2 and oxygenation index (OI) were also ob-surfactant in mechanically ventilated term infantsserved 3 and 6 hours after BAL compared with pre-with ARDS due to MAS. Our results showed thatBAL values (p < 0.05 for pH and PaCO2 at 3 hours,slow administration of diluted surfactant in smallp < 0.05 for all parameters at 6 hours [table II]).amounts by BAL improved oxygen status and chestThe mean length of mechanical ventilation wasx-ray findings, and reduced the length of both2.88 ± 1.25 (range 1–5) days. The mean duration ofmechanical ventilation and oxygen supplementa-oxygen supplementation was 4.25 ± 2.05 (rangetion, without any major adverse effects, in this pa-3–8) days. Only one patient required NO therapy (5tient population.ppm for 12 hours) for transient pulmonary hyperten-

Several factors account for the pathophysiologysion. In two patients with pneumothorax prior toof MAS. First, high-molecular weight mucous gly-BAL, the lesions were no longer evident on thecoproteins in meconium give the substance adhesive6-hour post-treatment chest x-ray. In all babies, re-properties, making it more likely to cause airwaycovery of tracheal fluid during suctioning was in-obstruction when inhaled. Secondly, meconium cancomplete (30–65% of the total lavage fluid volumecause chemical injury to the respiratory epithelium.instilled into the lung). However, all recoveredThirdly, many components of meconium, such astracheal fluids were clear of meconium at the end oflipids, proteins and bilirubin, potently inhibit

BAL.surfactant activity, contributing to severe respiratoryfailure in MAS.[15,16]

Safety and Tolerability These findings have prompted research into thepossible benefits of exogenous surfactant therapy in

BAL was well tolerated by all subjects. No the treatment of ARDS due to MAS. One importantchanges in blood pressure or episodes of brady- finding from this research is that the mode of admin-cardia were observed during the procedure. No epi- istration of such therapy contributes to its efficacy.sodes of pulmonary haemorrhage occurred. No pa- In one study performed in an acute lung injurytients died during the study or had adverse sequelae animal model, for example, bolus administration ofof any kind. surfactant was not as effective as the same surfactant



administered by lung lavage.[17] The reason for this diluted surfactant preparations (4–4.5mg phospho-appears to be that exogenously administered lipid/mL) improved oxygenation and other parame-surfactant is not distributed uniformly throughout ters of pulmonary function as effectively as undilut-the lung following bolus or aerosol administra- ed surfactant (13.5mg phospholipid/mL).[19] It istion.[18,19] likely that acute lung injury with surfactant deficien-

cy could be effectively treated even with a simpleNumerous animal and clinical studies havesurfactant administration, while the efficacy of treat-shown that early lavage with surfactant solutionment of MAS with diluted surfactant is probablysignificantly improves respiratory function in ani-more linked to removal of meconium and debris. Inmals and neonates with acute lung injury and withconfirmation of that, tracheobronchial lavage withMAS.[5,8,20,21] The procedure generally involves the15 mL/kg of diluted surfactant solution (5mg phos-initial administration of a relatively large volume ofpholipid/mL) administered in 2mL aliquots signifi-surfactant solution, but the excess fluid is drainedcantly improved oxygen status and reduced durationimmediately, leaving only a small residual volumeof ventilation and oxygen therapy, without adverseof lavage fluid in the lungs (about 15%).[5,8] Repeat-effects, in six neonates with severe MAS.[7] In an-ed lavage followed by suctioning removes meconi-other pilot study of 22 neonates with severe MAS,um and lung debris responsible for both airwaydiluted surfactant BAL (15 mL/kg; 5mg phospholip-obstruction and surfactant inactivation. Even if onlyid/mL) was associated with a lower OI and higherabout 15% of the administered surfactant is re-PaO2 at 1 hour, reduced duration of mechanicaltained,[5,8] the improvement in lung compliance andventilation and less time in hospital, compared withbetter gas exchange indicate that surfactant adminis-historical controls.[20] Finally, a previous retrospec-tration was effective and distribution of thetive clinical study of 54 infants with MAS showedsurfactant particles was homogenous.[5,8,17,21]

generally modest therapeutic effects with porcineIt is now known that the endogenous surfactant

surfactant.[25]

pool in humans is smaller than first estimated: theOur results also provide evidence that smalleralveolar wash contains about 2 mmol/kg of saturated

doses of surfactant (i.e. 80 mg/kg of diluted porcinephosphatidylcholine/kg, which is equivalent tolipid extract surfactant, compared with the usualabout 4 mg/kg surfactant, a relatively small pool sizedosages of 200 or 100 mg/kg) are effective whencompared with other species.[22] Recognition of thisadministered as BAL in neonates with ARDS due tofact has prompted evaluation of much lower dosesMAS.of exogenous surfactant than had previously been

used in surfactant deficiency/dysfunction. Both Our study also showed that administration ofanimal and human studies have now confirmed that surfactant solution in small (2.5mL) aliquots wasBAL with a diluted surfactant solution first reduces well tolerated. Importantly, this approach wouldthe airway obstruction by removing meconium and also be appropriate in patients with MAS-relatedairway proteinaceous debris, thereby reducing the haemodynamic instability, in whom BAL with largerisk of airway obstruction and subsequent surfactant fluid volumes can overload the cardiorespiratoryinactivation, then, with the subsequent doses of the system.[26] Furthermore, patients in our study did notlavage fluid, achieves a homogeneous alveolar dis- experience pulmonary haemorrhage, an event thattribution of the surfactant particles.[5,7,8,20,23,24]

has been reported in an earlier study.[27] It is wellIn neonatal piglets with acute lung injury, lavage known that pulmonary haemorrhage is an event

administration of a variety of artificial and natural strictly linked to perinatal hypoxia, but our ‘gentler’


18 Lista et al.

small-volume procedure probably does not increase namic support and treatment of pulmonary hyper-the risk of injury to the pulmonary epithelium. There tension (if indicated) in the management of MAS.was also no increase in the incidence of pulmonary However, larger randomised studies are required tohypertension (only one patient needed a short course validate the use of this procedure in the neonatalof inhaled NO for transient pulmonary hypertension setting.revealed by an increased velocity of the tricuspid

Acknowledgementsregurgitation jet at the ecochardiographic controlwithout clinical significance), a condition frequently We are grateful for the assistance and support of theassociated with MAS.[26]

nursing staff at the Neonatal Intensive Care Unit, VittoreBuzzi Children’s Hospital, involved in this study. No externalBecause of its low potential to cause fluid over-sources of funding were used to assist in the preparation ofload and severe hypoxaemia, the BAL regimen usedthis manuscript and the authors have no potential conflicts ofin our study could be administered even to infantsinterest regarding the content of the study.

with very high baseline OI scores. Indeed, BAL withdiluted surfactant (using small-volume aliquots)

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syndrome. Pediatr Int 2005 Jun; 47 (3): 237-41ray abnormalities, and facilitated weaning from11. Sevecova-Mokra D, Calkovska A, Drgova A, et al. Treatment ofmechanical ventilation in infants with ARDS due to

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Correspondence and offprints: Dr Gianluca Lista, Neonatal20. Kowalska K, Szymankiewicz M, Gadzinowski J. An effective-ness of surfactant lung lavage (SLL) in meconium aspiration Intensive Care Unit, Vittore Buzzi Children’s Hospital, Isti-syndrome (MAS) [in Polish]. Przegl Lek 2002; 59 Suppl. 1:

tuti Clinici di Perfezionamento, 32 Via Castelvetro, Milan,21-420153, Italy.21. Tanveer A, Antunes MJ, Cleary GM, et al. Lung mechanics and

inflammatory response in meconium injured rats following E-mail: [email protected]


Surfactantes prematuros

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