ORIGINAL ARTICLE

Severe airway obstruction during surfactant administration usinga standardized protocol: a prospective, observational studyA Tarawneh1, J Kaczmarek2, MN Bottino3 and GM Sant’Anna4

1Department of Pediatrics, McMaster University, Hamilton, Ontario and Mutah University, Karak, Jordan; 2Department ofExperimental Medicine, McGill University, Montreal, Quebec; 3Department of Pediatrics, McMaster University, Hamilton, Ontario and4Department of Pediatrics, Division of Neonatology, McGill University Health Center, Montreal, Quebec

Objective: The objective of this study was to evaluate the occurrence of

adverse effects during surfactant delivery, using a standardized protocol for

administration and management of complications.

Study Design: The protocol was developed, implemented and used for 6

months. Vital signs and ventilatory parameters were prospectively recorded

during the procedure. Infants were classified into three groups, based on

the occurrence and severity of complications: no, minor or major.

Result: A total of 39 infants received surfactant and 19 presented some

complication: 11 minor and 8 major. Six of the major complications were

episodes of severe airway obstruction (SAO) and five occurred in extreme

low birth weight (ELBW) infants that had more severe lung disease before

surfactant delivery. Two cases of persistent pulmonary hypertension

occurred in infants with birth weight>1000 g.

Conclusion: This study identified a high rate of SAO and provides data

to support changes in the protocol, which should include faster and more

robust increases in positive inspiratory pressures in ELBW infants

presenting with SAO.

Journal of Perinatology advance online publication, 7 July 2011;

doi:10.1038/jp.2011.89

Keywords: surfactant; airway obstruction; adverse effects

Introduction

Surfactant is a widely used and effective therapy for the treatmentof respiratory distress syndrome (RDS) in newborns, but has beenassociated with complications occurring during or following itsadministration. These complications have been reported with theuse of different techniques, protocols of administration and types ofsurfactant, making it difficult to generate any comparisons.1

In our neonatal intensive care unit, a bovine lipid extractsurfactant (bLES, Biochemicals, London, Ontario, CA) is the onlytype of surfactant routinely used since 2004. Over the last years, weobserved a number of adverse effects during its administration,with some infants presenting with severe airway obstruction (SAO).These episodes were characterized by sudden and significantdeterioration in oxygenation and ventilation, with completeabsence of chest movement despite significant increases inventilatory assistance. However, the incidence of this complicationand magnitude of the problem was difficult to assess and categorizedue to variations in the delivery techniques used in our unit andlack of a well-delineated monitoring and management process.

Given the nature of the problem, there was a general sense ofurgency to implement changes that could improve care andpractice. Although we recognized that a randomized controlled trialwould be a powerful and unequaled study design, this wouldrequire a long time and large sample size. Therefore, we developedand implemented a surfactant protocol to standardize theadministration, and actively and objectively studied the effects ofthis change. A period of 6 months was chosen as the time framebetween the implementation and analysis. The primary objective ofthis study was to evaluate the occurrence and management ofsignificant adverse effects during bLES surfactant administrationusing the standardized protocol.

Methods

From July 2005 to December 2007, the entire process of surfactantadministration within the neonatal intensive care unit setting wasre-examined. Actions included modification of the delivery system(in-line catheter adopted), contact other centers experienced withthe use of bLES and follow strictly the manufacturer’srecommendations. We contacted the manufacturer and a thoroughand detailed analysis of samples of bLES was conducted to verifyany problem in the composition, solubility and stability of thesubstance. In the interim, a protocol for bLES administration wasdeveloped by a multidisciplinary team composed of neonatologists,pharmacists, respiratory therapists, nurse practioners and neonatalReceived 7 February 2011; revised 26 April 2011; accepted 25 May 2011

Correspondence: Dr GM Sant’Anna, Department of Pediatrics, Division of Neonatology,

Montreal Children’s Hospital, McGill University, 2300 Tupper Street, Room C912, Montreal,

Quebec, Canada, H3H 1P3.

E-mail: guilherme.santanna@mcgill.ca

Journal of Perinatology (2011), 1–6

r 2011 Nature America, Inc. All rights reserved. 0743-8346/11

www.nature.com/jp

fellows. The protocol was based on the available scientificliterature, manufacturer’s recommendations, and includedindications for surfactant administration, method of delivery and amonitoring process. From January to June 2008, all infants thatreceived a first dose of bLES for treatment of RDS were included.Retreatment and surfactant given for other indications were alsoperformed according to the protocol, but was not included in thisanalysis. This study is a retrospective analysis of the dataprospectively collected during the 6-months period. The study wasapproved by the Hamilton Health Science Ethics Board.

Indications for surfactant administrationAccording to the protocol, prophylactic surfactant was given only toinfants with a gestational age (GA) X23 and <24 weeks (10 to30 min of life). Infants with a GA X24 weeks received surfactantas an early treatment (<2 h of age), if they were intubatedimmediately after birth, except if the infant was on room air andminimal ventilatory support following admission at the neonatalintensive care unit. These infants should be immediately extubatedto nasal ventilation or nasal continuous positive airway pressure. Ifthese infants were initially treated with nasal continuous positiveairway pressure, intubation and surfactant administration shouldbe performed in the presence of one of the following criteria: a)fraction of inspired oxygen (FiO2) >0.5 to maintain oxygensaturation (SpO2) >88% or a PO2>45 mm Hg (arterial), b) partialpressure of carbon dioxide (PCO2) >55 to 60 mm Hg (arterial)with a pH <7.25, c) apnea requiring bag and mask ventilation ord) evidence of significant work of breathing (retractions, gruntingand chest wall distortion). All infants were ventilated according tothe neonatal intensive care unit protocol.2

Surfactant administrationSurfactant was administered by a respiratory therapist, with aneonatal fellow present at the bedside during the whole procedurefor monitoring and intervention. During a period of 2 monthsbefore its implementation, all respiratory therapists and fellowsreceived instructions and training about the new protocol. Beforesurfactant administration, chest X-rays, endotracheal tube (ETT)suctioning and pre-oxygenation to achieve SpO2>95% wasperformed. Surfactant was delivered through an in-line catheterwith the tip located at the mid trachea level. After warming thesurfactant to room temperature and mixing the medication for20 min (without shaking), a dose of 5 ml kg�1 (135 mgphospholipids kg�1) of bLES was given as bolus infusion (10–20 s),divided into four aliquots, with infants kept in the horizontalposition during the whole procedure. A minimum period of 60 sbetween the aliquots was used if infants remained stable.

The multidisciplinary team decided to exclude the routine use ofventilatory recruitment maneuvers before bLES administration dueto the risks of lung injury. All infants stayed connected to theventilator before and during the procedure. However, when infants

presented with signs of clinical deterioration (SaO2 <80% and/orheart rate (HR) <100 beats per minute (bpm)), stepwise changesin ventilatory settings were to be made every 20 s and includedincreases in ventilatory rate by 10 bpm at a time (up to 60 bpm)and peak inspiratory pressure (PIP) by 2 cmH2O steps up to amaximum of 30 cmH2O for the first 2 min. These changes inpressure and rate could be done simultaneously. After this period, ifno improvement was noted, the infant was to be disconnected fromthe ventilator and manual bagging, using a flow-inflating bag witha positive end expiratory pressure valve that was pre-set at5 cmH2O, was performed for another minute. During thisprocedure, similar or even higher pressures and rates could beapplied to overcome a suspected obstruction. If despite all thesemaneuvers, no chest movement and clinical improvement wereobserved and surfactant was visualized inside the lumen, the ETTshould be suctioned. If no improvement, the ETT should beremoved and a new ETT inserted. All infants were ventilated withthe Servo-I ventilator (Maquet Critical Care AB, Solna, Sweden)using a pressure limited mode (assisted control ventilation orsynchronized intermittent mandatory ventilation). Tidal volumewas monitored and recorded during the procedure, but asignificant and variable leak was noted in several patients whoprecluded the use of this data for analysis.

Data collection and definitions of complicationsWe recorded the birth weight (BW), GA, use of antenatal steroids,mode of delivery, presence of chorioamnionitis, severity of RDS(based on chest X-ray3), the most recent blood gases before bLESadministration (arterial or capillary), type of initial ventilatorysupport and time of surfactant administration. SpO2, FiO2, PIP,positive end expiratory pressure, ventilator rate and heart rate weremonitored during the entire procedure, and recorded before andafter each aliquot.

SAO, persistent pulmonary hypertension (PPHN), pulmonaryhemorrhage and tension pneumothorax were classified as majorcomplications. SAO was defined as the complete absence ofvisualization of chest movement in infants that presented withsudden and severe desaturation (SpO2 <70%), bradycardia (HR<100 bpm), and did not respond to increases in ventilatorpressures or bagging for X3 min and required suctioning of thesurfactant or replacement of the ETT. PPHN was defined as anincrease in FiO2 to 1.0, presence of pre- to post-ductal SpO2

difference of X20% and echocardiogram findings on laterassessment. Pulmonary hemorrhage was defined as the presence offresh blood into the ETT lumen and tension pneumothorax wasdefined as the sudden deterioration with positive transilluminationof the chest or chest X-ray, showing free air into the thoracic cavitywith mediastinal structures shift.

Episodes of bradycardia, desaturation, reflux of surfactant andhypercapnia that recovered spontaneously or with minimalchanges in the ventilator settings (increases in rates of <20 bpm

Airway obstruction during surfactant deliveryA Tarawneh et al

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and PIP <25 cmH20) during the first 3 min following the deliveryof each aliquot were classified as minor complications. Bradycardiawas defined as HR <100 bpm and desaturation was defined asSpO2 <80%. Reflux of surfactant was defined by the visualpresence of surfactant into the ETT lumen. Hypercapnia wasdefined as an increase in transcutaneous PCO2 of more than 20%from baseline.

Statistical analysisContinuous variables are expressed as mean±s.d. and categoricalvariables are expressed as counts and percentages. The w2-testand the Fisher’s exact test were used for categorical variables andthe Student’s t-test was used for continuous variables, whencomparing differences between no, minor and major complicationgroups in the overall population and for the subgroup of extremelow birth weight (ELBW) infants. A P-value <0.05 was consideredstatistically significant. Analysis was performed with Stata SE 10.0(Stata, College Station, TX, USA).

Results

Investigations conducted by the manufacturer revealed noproblems related to the composition, solubility and stability of theproduct. During the 6-month period, all infants that received bLESas treatment for RDS were included in the study (n¼ 39), and themean BW and GA were 1443±141 g and 30.2±0.7 weeks,respectively. The majority of these infants were inborn (97%) and19 infants (49%) presented some type of complication during thedelivery of surfactant: 11 (28%) minor and 8 (20%) major. In the

overall population, infants that developed any type of complicationhad significantly lower BW (1193±222 g versus 1681±163 g;P<0.05) and GA (28.4±1.0 weeks versus 32.0±0.8 weeks;P<0.05), when compared with infants without complications.

The minor complications identified during the procedure werebradycardia, desaturation, reflux of surfactant into the ETT andhypercapnia. All these complications were transient (<30 s) andresolved spontaneously or with the use of the interventionsproposed in the protocol.

The major complications identified were SAO and PPHN. Theincidence of SAO in the overall population was 15%. Five of the sixcases occurred in ELBW infants. Amongst ELBW infants, theincidence of SAO was 31%. Indeed, SAO was the only majorcomplication occurring in these infants (Table 1), which had amore severe lung disease (based on chest X-ray scores) and higherventilatory rates, when compared with ELBW infants with minor orno complications (Tables 2 and 3). The average total volume ofbLES administered before the development of SAO was 3.5 ml kg�1

(range: 2 to 4.2 ml kg�1) and all infants were treated similarlywith regard to timing of surfactant administration (Table 3). Inthree out of four cases of SAO that required re-intubation, weobserved a complete or partial obstruction of the ETT due to thepresence of a plug. The rate of re-intubation was 50% (4/8) ininfants that experienced a major complication and 10% (4/39) inthe overall population.

The other type of major complication observed was thedevelopment of PPHN, which occurred in two infants with BW>1000 g. Baseline characteristics and management of all infantswith major complications are presented in more detail in Table 1.

Table 1 Patient characteristics and clinical management of infants who developed major complications during bLES administration

#1 #2 #3 #4 #5 #6 #7 #8

BW (g) 1010 1290 640 790 820 1050 830 560

GA (weeks) 27 30+6d 25+1d 25 25+4d 29+1d 26+5d 26

ETT (mm) 3.0 3.0 2.5 2.5 2.5 3.0 2.5 2.5

Mode of ventilation AC SIMV/PS AC AC SIMV/PS SIMV/PS SIMV/PS AC

Volume of bLES given

before complication (ml)

1 2.8 2.4 2 4 2.4 4.2 2.1

Number of aliquots

received before complication

1 2 3 2 4 2 4 2

Complication Severe drop

in SpO2

No chest

movement

No chest

movement

No chest

movement

No chest

movement

Severe drop

in SpO2

No chest

movement

No chest

movement

Management PIP¼ 30

HFOV+iNO

PIP¼ 32

PEEP¼ 8

PIP¼ 30

bLES suctioned

PIP¼ 30

re-intubation

PIP¼ 32

re-intubation

PIP¼ 30

HFOV+iNO+dopamine

PIP¼ 33

re-intubation

PIP¼ 31

re-intubation (� 2)

ETT plug after extubation F F F Complete F F Partial Complete (2� )

Final diagnosis PPHN SAO SAO SAO SAO PPHN SAO SAO

Abbreviations: AC, assisted control ventilation; bLES, bovine lipid extract surfactant; ETT, endotracheal tube; GA, gestational age; HFOV, high-frequency oscillatory ventilation; iNO, inhalednitric oxide; PEEP, positive-end expiratory pressure, cmH2O; PIP, peak inspiratory pressure, cmH2O; PPHN, persistent pulmonary hypertension of the newborn; SAO, severe airwayobstruction; SIMV/PS, synchronized intermittent mandatory ventilation/pressure support; SpO2, oxygen saturation.

Airway obstruction during surfactant deliveryA Tarawneh et al

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Journal of Perinatology

Discussion

Our study is the first to systematically report the occurrence ofadverse events during bLES surfactant delivery, using astandardized protocol for administration and monitoring. A highincidence of SAO was observed in ELBW infants that had worse

respiratory disease before surfactant administration. Previously tothis standardized approach, these events were usually identified asan isolated occurrence likely related to drug preparation,administration technique employed and /or lack of adequatemonitoring.

In this study, we used bLES, which is a chloroform:methanolextract of surfactant isolated by centrifugation from bronchoalveolarlavage of intact bovine lungs. The original form of this surfactantwas previously used in clinical studies without any SAO reportsduring delivery of the drug.4,5 The general processes of lavage,centrifugation and extraction methods of bLES are similar to thoseutilized in the preparation of other bovine extract surfactantssuch as Alveofact (Boehringer Ingelheim, Germany) and Infasurf(ONY, Amherst, NY, USA),6 which have been associated with a2 to 4% incidence of ETT obstruction in clinical trials.7,8 However,a study comparing synthetic surfactant (Exosurf, BurroughsWellcome, Research Triangle Park, NC, USA) with bovine surfactant(Infasurf), reported an incidence of obstruction between 20 to 50%.9

Specifically, bLES was evaluated only in one unpublishedrandomized, controlled, double-blind, multicenter trial10 and arandomized study comparing bLES with Survanta (Ross Laboratories,Columbus, OH, USA).11 The first trial reported a 6% rate of ETTobstruction (not defined), but the second study did not comment oncomplications related to surfactant delivery. None of the trials orstudies reported on the severity of ETT obstruction, specific subgroupsof infants at higher risk of SAO or management of these episodes.

Although the best method of surfactant delivery is still underdebate,12 bolus administration through an in-line catheter wasreported to result in better distribution and less dose-related adverseeffects.13,14 However, bolus administration has also been associatedwith airway obstruction15 and all infants in our study receivedsurfactant using this technique. Wheeler et al.16 used assistedcontrol volume guarantee ventilation during the administration ofa surfactant with a volume of 1.25 ml kg�1 (Curosurf, ChiesiFarmaceutici SpA, Parma, Italy). Complete obstruction of the flowdown the ETT was observed in 95% of the infants, but only 25%had prolonged episodes (>30 s and <52 s). Following surfactantadministration, PIP increased in all patients up to 27 (23 to 30)cmH2O to restore adequate ventilation.16 No episodes requiring ETTreplacement were reported. In our five ELBW infants with SAO, theaverage total volume of bLES administered before the complicationwas almost three times higher, and no improvement was observeddespite stepwise increases in PIP up to a maximum of 33 cmH2O(Table 1). Airway obstruction can occur as a consequence of ETTlumen blockage or blockage of the airways immediately below theETT. In three of the four cases that required ETT replacement, acomplete or partial obstruction of the lumen with a plug (white–gray gelatinous material) was noted.

As ELBW infants with SAO had worse baseline lung disease, it ispossible that a higher volume of surfactant:functional residualcapacity ratio could have contributed to the occurrence of

Table 2 Patient characteristics before bLES administration for infants with BWp1000 g, according to the type of complications

No+minor

(n¼ 11)

SAO

(n¼ 5)

P-value

BW (g) 753.2±169.9 728±121.1 0.39

Gestational age (weeks) 26.8±2.4 25.7±0.7 0.17

Antenatal steroids 5 (45) 3 (60) 1.0

Chorioamnionitis 5 (45) 1/4 (25) 0.60

Severe respiratory distress syndrome (X-ray) 7 (64) 5 (100) 0.25

Initial management with CPAP 3 (27) 1 (20) F

Age of intubation (h) 13.5±12.3 0.6 F

Age of administration (h) 14.1±12.5 1.0 F

Initial management with intubation 8 (63) 4 (80) F

Age of intubation (min) 2.1±1.2 1.5±0.3 0.19

Age of administration (h) 1.8±0.9 2.2±1.2 0.3

Abbreviations: bLES, bovine lipid extract surfactant; BW, birth weight; CPAP, continuouspositive airway pressure; SAO, severe airway obstruction.Values are expressed as mean±s.d. or n (%).

Table 3 Blood gases, ventilatory settings and vital signs before bLESadministration for infants with BWp1000 g, according to the type ofcomplications

No+minor

(n¼ 11)

SAO

(n¼ 5)

P-

value

Blood gases

pH 7.3±0.13 7.3±0.02 0.49

pCO2 (mm Hg)a 43.1±9.6 (6/5) 44.5±6.4 (2/3) 0.43

Ventilatory settings

Fraction of inspired oxygen 0.6±0.3 0.45±0.1 0.08

Peak inspiratory pressue (cmH2O) 20.0±2.2 20.0±2 0.47

Positive end expiratory pressure

(cmH2O)

6.5±0.7 6.8±1.1 0.23

Ventilator rate (bpm) 50.0±7.9 58.0±4.5 0.02

Vital signs

Heart rate (bpm) 148.6±12.4 152.2±14.8 0.31

Oxygen saturation (%) 89.1±6.3 86.0±1.4 0.26

Abbreviations: bLES, bovine lipid extract surfactant; BW, birth weight; SAO, severe airwayobstruction.P<0.05.aNumber of samples recorded using values from transcutaneous CO2 or arterial blood gas(n/n). Values are expressed as mean±s.d. or n (%).

Airway obstruction during surfactant deliveryA Tarawneh et al

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Journal of Perinatology

obstruction. Preterm rabbits treated with surfactant before thefirst breath had increased mortality when volumes exceeded 16% ofthe functional residual capacity.17 The functional residual capacityof preterm infants with RDS is significantly decreased and thereported values can vary from 6 to 10 ml kg�1.18,19 Future studiesshould address this potential risk factor. It is well known thatsmaller ETT have higher resistance,20 which can contribute todecreased or slower clearance of surfactant and subsequent ETTblock. Five out of six of these infants with SAO were intubatedwith a 2.5 mm endotracheal tube (outer diameter). However, allELBW infants studied were intubated with this size of ETT and 75%of them did not develop SAO.

In animal studies, alveolar recruitment before and duringsurfactant administration has been demonstrated to improve drugdistribution and the efficacy of treatment, but have not beencorrelated with the occurrence of SAO.21,22 Our protocol did notinclude the routine use of these maneuvers before surfactantadministration. During the monitoring process, we did not recordthe time intervals between patient deterioration and changes inventilator settings and/or initiation of bagging. Although allprofessionals involved in the procedure were familiar with the ‘new’protocol, it is possible that delays in performing ventilatoradjustments or that the response to a sudden deterioration, using‘stepwise increments in PIP’, instead of a more robust and fastintervention may have contributed to the occurrence of a severeobstruction. On the other hand, the lack of evidence with regard tothe appropriate time interval and magnitude of ventilatory changesthat should be initiated makes it difficult to determine theadequacy of this response. It is possible that a faster and morerobust increase in positive inspiratory pressures and/or rates mayovercome this problem and this should be investigated.

In conclusion, the use of a standardized protocol for surfactantdelivery and management of adverse effects allowed us to identifyin a systematic manner that SAO was a common complicationin ELBW infants with worse baseline lung disease. This highrate of SAO could have occurred due to a combination ofstepwise increments in PIP levels, lower maximum PIP levelsand use of higher volumes of surfactant. The study providesdata for targeted changes in the administration protocol whenusing this type of surfactant, which should include faster andmore robust increases in positive inspiratory pressures in ELBWinfants presenting with SAO.

Conflict of interest

The authors declare no conflicts of interests.

Acknowledgments

Dr Amjad Tarawneh was supported by a scholarship from the Jordanian

Government. Dr Marcela Bottino and Jennifer Kaczmarek were supported by

scholarships from McMaster Children’s Hospital, Hamilton, Ontario, Canada and

Dr GM Sant’ Anna received start-up funds from the McMaster Children’s Hospital,

Hamilton, Ontario, Canada for this research.

References

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Curstedt T et al. Comparison of rapid bolus instillation with simplified slow

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15 Hentschel R, Jorch G. Acute side effects of surfactant treatment. J Perinat Med 2002;

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16 Wheeler KI, Davis PG, Kamlin COF, Morley CJ. Assist control volume guarantee

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improvement in lung volume after exogenous surfactant: alveolar recruitment versus

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19 Dinger J, Topfer A, Schaller P, Schwarze R. Functional residual capacity and

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20 Manczur T, Greenough A, Nicholson GP, Rafferty GF. Resistance of pediatric and

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a u t u m n 2 0 1 4 • v o l u m e 5 0 • n u m b e r 3

message from the editor- in-chief / message du rédacteur en chef

Responding to Ebola: The role of medical journals during global public health emergencies / Réagir au virus Ebola : le rôle des revues médicales pendant les urgences mondiales de santé publique

commentary

The OSCILLATE trial: Implications for respiratory therapists then and now

editorial

Surfactant: The importance of documented policy and procedure

original article

Prediction of endotracheal intubation outcome in opioid-poisoned patients: A clinical approach to bispectral monitoring

reviews

To PAPR or not to PAPR?

Surfactant administration in neonates: A review of delivery methods

PM 40062595

Official Journal of / Journal officiel de la

Can J Respir Ther Vol 50 No 3 Autumn 2014 77

surfactant: the importance of documented policy and procedure

Ron Valotaire RRT

London Health Sciences Centre, Victoria Hospital, London, OntarioCorrespondence: Mr Ron Valotaire, London Health Sciences Centre, Victoria Hospital,

800 Commissioners Road East, London, Ontario N6A 5W9. Telephone 519-685-8500 ext 65666, e-mail ron.valotaire@lhsc.on.ca

The current issue of the Canadian Journal of Respiratory Therapy includes an excellent – and timely – review by Nouraeyan et al (1) (pages 91-95) on surfactant administration in the

neonatal population. Care of this fragile group has improved greatly since the early days of neonatology. Huge strides have been made on the obstetrical side, which makes our job in the neonatal intensive care unit (NICU) significantly easier than it once was. Advances in maternal screening for infection, drugs and congenital anomalies, among others, have led to earlier and improved treatment.

In the NICU, our grasp of the importance of nutritional needs in the low birth weight popu-lation has improved immensely over the past 10 to 15 years. The leaps in technology have enabled us to fine-tune conventional ventilation and synchronize very closely to the patients’ needs in all phases of the ventilatory cycle. The technology and expertise in high-frequency ventilation have also shown exponential growth. However, there is one area that has shown a remarkable lack of consistency in its application. Surfactant plays such a vital role in the reduc-tion of mortality and morbidity, and yet, after 30 years of widespread use, many facilities do not have a documented policy and procedure, let alone one based on current evidence.

We are all aware that one of the main components of increased work of breathing is low functional residual capacity (FRC). Positive pressure ventilation (PPV), in the form of appropri-ate peak inspiratory pressure and positive end-expiratory pressure, is required to achieve effect-ive FRC. However, one of the first things we are taught as respiratory therapists is that there is no safe level of PPV. If you are administering PPV, in whatever form that may take, you are causing damage to the lungs in varying degrees.

This is where surfactant enters the fray. When given early and effectively, surfactant can help establish FRC while allowing the practitioner to use lower pressures and, therefore, mitigate damage to the premature lung. The question once was: what is the best way to administer surf-actant via the endotracheal tube? Well, as this article by the group from the Montreal Children’s Hospital (Montreal, Quebec) shows, the question has been answered. Bolus administration, ideally in one aliquot if tolerated, via a multi-access catheter to a patient in supine position with head mid-line, is the way to go. The article explains the rationale for this quite nicely, and most Level III units adhere to this practice. There are outliers, however, and that is why we need a standardized protocol that is easily accessible and teachable. In India, the pharmaceutical com-pany that markets one type of surfactant will not allow practitioners to administer the surfactant until they have read and signed a comprehensive package based on the latest practices and lit-erature available. The Montreal groups’ efforts are a significant step in that direction.

In Canada, the Evidence-based Practice for Improving Quality (EPIQ) group has talked about putting their heads together and developing a best practice standard. EPIQ is essentially a representative collection of health care providers from neonatal units across the country striving to raise quality and continuity of care to the highest level by shared practices and use of bench-marking in a highly collaborative manner. Hopefully the article by Noureayan et al (1) and the Montreal groups’ efforts will help kick start such an endeavour.

editoriaL

©2014 Canadian Society of Respiratory Therapists. All rights reserved

REfEREnCE1. Noureayan N, Lambrinakos-Raymond A, Leone M, Sant’Anna G. Surfactacnt administration in

neonates: A review of delivery methods. Can J Respir Ther 2014;50:91-5.

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Can J Respir Ther Vol 50 No 3 Autumn 2014 91

surfactant administration in neonates: a review of delivery methods

Nina Nouraeyan MD1, Alicia Lambrinakos-Raymond MD1, Marisa Leone RRT2, Guilherme Sant’Anna MD PhD FRCPC3

1Department of Pediatrics; 2Department of Respiratory Therapy; 3Faculty of Pediatrics; McGill University Health Centre, Montreal, QuebecCorrespondence: Dr Guilherme Sant’Anna, 2300 Tupper Street, Room C-912, Montreal, Quebec H3H 1P3.

Telephone 514-412-4400 ext 22389, fax 514-412-4356, e-mail guilherme.santanna@mcgill.ca

Treatment with exogenous surfactant has saved the lives of thou-sands of premature babies in the past few decades (1). The thera-

peutic efficiency of a given surfactant preparation correlates with its lipid and protein composition (and other factors), but it is also highly dependent on the technique used for administration. It is important to use a delivery strategy that optimizes surfactant distribution into the pulmonary airways to maximize its beneficial effects (2). In 2014, the Committee on Fetus and Newborn – American Academy of Pediatrics published a clinical report on the use of surfactant replacement ther-apy for respiratory distress in the preterm and term neonate (1). Among several recommendations, the report stated that “the optimal method of surfactant administration in preterm infants has yet to be clearly proven”. Unfortunately, the scientific literature provides con-flicting and limited data regarding the methods or techniques of surf-actant administration. The majority of studies were performed long ago and tested in more mature infants (gestational age >28 weeks), which does not reflect the population of preterm infants that actually undergo endotracheal intubation and surfactant treatment. Moreover, respiratory care has changed substantially since these studies were conducted.

Exogenous surfactant preparations must spread rapidly and effi-ciently into the air-liquid interface once instilled in the proximal air-ways, with the goal of achieving a homogenous distribution throughout the lungs. However, rapid administration of liquid into the lungs may elicit transient oxygen desaturation and bradycardia, or significant complications such as severe airway obstruction, pulmonary hemor-rhage, pneumothoraces or pulmonary hypertension (3). Therefore, surfactant should be administered according to a well-established protocol under the supervision of clinicians and respiratory therapists experienced in tracheal intubation, ventilator management and gen-eral care of the premature infant.

The present article reviews several aspects of administration tech-niques that can influence the delivery of surfactant into the lungs: the bolus volume, injection rate, gravity and orientation, ventilation strat-egies and development of airway obstruction, alveolar recruitment, and viscosity and surface tension of the fluid instilled. A surfactant adminis-tration protocol that was developed and implemented in our unit, based on the best available evidence, is included in Appendix 1.

BOLUS aDMInISTRaTIOn anD InJECTIOn RaTEThere are two common modes of delivering surfactant into the pul-monary airways: bolus infusion (one or multiple aliquots); or continu-ous infusion (2) (Box 1). Surfactant has also been given by nebulization; however, because this method and preparation remain under investi-gation, it will not be reviewed here.

In general, slower techniques of surfactant bolus administration have been noted to be inferior to the rapid bolus technique (4). When rapid bolus infusions were compared with slow bolus or continuous

review

©2014 Canadian Society of Respiratory Therapists. All rights reserved

n nouraeyan, a Lambrinakos-Raymond, M Leone, G Sant’anna. Surfactant administration in neonates: a review of delivery methods. Can J Respir Ther 2014;50(3):91-95.

Surfactant has revolutionized the treatment of respiratory distress syn-drome and some other respiratory conditions that affect the fragile neona-tal lung. Despite its widespread use, the optimal method of surfactant administration in preterm infants has yet to be clearly determined. The present article reviews several aspects of administration techniques that can influence surfactant delivery into the pulmonary airways: the bolus volume, injection rate, gravity and orientation, ventilation strategies, alveolar recruitment, and viscosity and surface tension of the fluid instilled. Based on the present review, knowledge gaps regarding the best way to administer surfactant to neonates remain. From the available evidence, however, the most effective way to optimize surfactant delivery and obtain a more homogeneous distribution of the drug is by using rapid bolus instil-lation in combination with appropriate alveolar recruitment techniques.

Key Words: Neonatology; Preterm infant; Respiratory distress syndrome; Review; Surfactant administration; Ventilation

L’administration de surfactant chez les nouveau-nés : une revue des modes de libération

Le surfactant a révolutionné le traitement du syndrome de détresse respi-ratoire et d’autres troubles respiratoires qui endommagent le fragile pou-mon néonatal. Malgré l’utilisation généralisée du surfactant son mode optimal d’administration n’est pas clairement établi chez les nourrissons prématurés. Le présent article traite de divers aspects des techniques d’administration, qui peuvent influer sur la libération du surfactant dans les voies respiratoires : le volume du bolus, le rythme d’injection, la gravité et l’orientation, les stratégies de ventilation, le recrutement alvéolaire, ainsi que la viscosité et la tension de surface du liquide instillé. D’après la présente revue, il reste des lacunes quant au meilleur moyen d’administrer le surfactant aux nouveau-nés. Cependant, selon les données probantes, pour en optimiser l’administration et obtenir une distribution plus homogène, il est préférable de procéder à un bolus rapide, combiné à des techniques pertinentes de recrutement alvéolaire.

BOX 1Modes of delivering surfactant into the

pulmonary airways• Bolus administration

○ One dose: complete dose given within a single time frame ○ Multiple doses: total dose divided into two or more amounts

(aliquots) and given separately in time• Continuous infusion (slow administration of the surfactant

preparation)• Nebulization: suspension of aerosolized surfactant that is

subsequently inhaled

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Can J Respir Ther Vol 50 No 3 Autumn 201492

infusions in several animal studies, they were noted to be superior in terms of overall distribution of the surfactant and a faster rate of improvement of oxygenation and lung compliance (5,6). However, side effects, such as transient bradycardia and decreased blood pres-sure, were noted with rapid bolus administration. At present, the rapid bolus technique remains the recommended method of surfactant administration.

Cassidy et al (7) showed that the method of liquid instillation affects how the liquid distributes within the lung. The best method allowed the formation of a liquid plug in the trachea at the beginning of surfactant instillation. The liquid was then driven to the distal parts of the lung by ventilation, resulting in quicker spread in a few breaths and more uniform liquid distribution throughout the lungs. Transit and delivery times depend on plug volume, among other factors. Although the exogenous surfactant takes in the order of minutes to reach the alveoli, the lowering of surface tension at the distal ends occurs very rapidly – within seconds – as the result of the compression of the endogenous surfactant (8).

GRaVITY anD ORIEnTaTIOn When surfactant is administered slowly (slow infusion and/or slow rate of ventilation), the distribution is dependent on the orientation of the airways with respect to gravity (4,5,9). This could lead to overinflation of the parts of the lung receiving surfactant and result in bron-chopulmonary dysplasia (6). Improved homogeneity is achieved with supine compared with upright positioning. Animal models have also shown greater epithelial cell injury at slower propagating speeds (10). In a randomized control trial (11), there was no difference in clinical outcomes when two fractional doses of surfactant were given in two body positions, compared with four fractional doses given in four positions.

VEnTILaTIOn STRaTEGIES anD DEVELOPMEnT Of aIRWaY OBSTRUCTIOn

Surfactant has been administered either by disconnecting the infant from the ventilator and applying bagging, or by continuing ventilation during the procedure. Using beractant at a volume of 4 mL/kg, Zola et al (11) conducted a multicentre, randomized control trial comparing three different strategies of surfactant instillation: two doses, removing patient from the ventilator; two doses, continuing ventilation during the procedure; and four doses, removing patient from the ventilator. Ventilation during all three procedures was performed by using pre-treatment pressures: fraction of inspired oxygen (FiO2) = 1.0; respira-tory rate at least 60 breaths/min; and an inspiratory time of 0.5 s. There were no significant differences among the three procedures. A similar study was conducted by Valls-i-Soler et al (12), who compared two methods. The first was bolus delivery (two aliquots) of poractant alfa at a volume of 2.5 mL/kg, with the patient removed from the ventilator and hand-bagged for 1 min with the same FiO2 used before the procedure and adjusting the peak inflation pressure (PIP) for adequate chest expansion. The second method was delivery via a side hole, in which a full dose of surfactant was rapidly given in 60 s via a 3.5 Fr catheter introduced through a side hole. Mechanical ventilation was not interrupted, but PIP was increased by 10% for 5 min. Both procedures were equally effective, but a slight significant increase in the partial pressure of carbon dioxide (PCO2) at 5 min of dosing was observed in the side-hole group, indicating decreased minute ventila-tion, likely related to some degree of airway obstruction.

A prospective study was performed in smaller and more immature preterm infants receiving their first or second dose of surfactant while being ventilated in assist control volume guarantee mode (13). A small volume of poractant alfa (1.25 mL/kg) was given as a single bolus using a closed technique during ventilation (ventilation not inter-rupted during administration). Ventilator parameters were recorded before, during and after administration. A complete cessation (ie, obstruction) of flow down the endotracheal tube (ETT) was observed in 21 of 22 (95%) of infants. Following surfactant administration, PIP

increased from a mean of 19 cmH2O (range 16 cmH2O to 22 cmH2O) up to 27 cmH2O (range 23 cmH2O to 30 cmH2O), taking 30 min to 60 min to return to baseline. A significant and prolonged decrease in the delivered tidal volume (obstruction) was noted in the majority of the infants. Airway obstruction immediately after surfactant adminis-tration was also noted by Miedema et al (14) in 15 preterm infants receiving surfactant while on high-frequency oscillatory ventilation, despite a lung recruitment manoeuvre used before surfactant adminis-tration. Tarawneh et al (3) prospectively evaluated a standardized protocol for a bovine lipid extract surfactant administration using a dose of 5 mL/kg. According to the protocol, surfactant was given in four aliquots using a closed technique without removing the patient from the ventilator. A significant number of extreme low birth weight infants experienced episodes of severe airway obstruction, requiring removal of the ETT followed by reintubation.

Anderson et al (15) investigated the effects of breathing frequency on liquid distribution. At 60 breaths/min, the liquid is first deposited on the airway walls and then transmitted toward the gravity-dependent region of the lung over the ensuing breaths. A more uniform distribu-tion of liquid throughout the lung was obtained. This phase lasted only a few minutes and facilitated the transport of liquid to its target loca-tion. After this initial targeted instillation is achieved, normal ventila-tion using appropriate ventilation rate can be used. The implication for surfactant delivery is that a slow rate of ventilation could result in nonhomogeneous surfactant distribution. This is not the desired out-come because it may inflate parts of the lung receiving surfactant, resulting in lung injury.

aLVEOLaR RECRUITMEnTRecruitment of the lungs before surfactant treatment can minimize ventilation-induced lung injury and facilitate the distribution of surf-actant into the pulmonary airways. In newborn piglets, a volume recruitment manoeuvre using moderately increased tidal volume applied before, during and for an additional 5 min after surfactant administration led to a superior clinical response in terms of gas exchange and lung function, owing to a more homogeneous distribu-tion pattern (16). Surfactant distribution was also evaluated in a study in which a recruitment manoeuvre to determine the optimal peak end-expiratory pressure (PEEP) level was performed in newborn pig-lets before surfactant administration. In one-half of the animals, an additional recruitment manoeuvre was performed to define a new PEEP level after surfactant administration. Using electrical imped-ance tomography, an improved spatial distribution of regional lung ventilation was observed in animals that underwent a postsurfactant recruitment manoeuvre. This recruitment manoeuvre was then applied in 15 preterm infants receiving surfactant while on high-frequency oscillatory ventilation. A rapid increase (5 min) followed by stabilization of lung volume was observed, with the most prominent effect in the dependent (dorsal) lung regions, supporting the role of gravity in surfactant distribution.

VISCOSITY anD SURfaCE TEnSIOn Of ThE fLUID InSTILLED

Commercial surfactants also differ in surface viscosity. Viscosity is believed to influence the rate, extent and uniformity of distribution of surfactant in the lungs. Preparations with lower surface viscosity are preferred for endotracheal application because it allows a more uni-form and rapid distribution of the instilled surfactant with less loss due to coating of the upper airways. The viscosity of surfactant prepara-tions is directly dependent on phospholipid concentration and inversely related to temperature. After 15 min at a temperature of 37°C, viscosity increases exponentially. In fact, after 30 min at this temperature, the viscosity of calfactant and beractant were 20 times higher when compared with values measured at 10 min (17). In an animal experiment, Lewis et al (18) compared beractant and a bovine lipid extract surfactant. A significantly improved distribution was achieved with the bovine lipid extract surfactant, which was demon-strated to have a viscosity eight times lower than beractant.

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Can J Respir Ther Vol 50 No 3 Autumn 2014 93

A more viscous liquid yields a more homogeneous distribution, and a less viscous plug penetrates more deeply into the distal airways. There are several surfactant preparations available for use in neonates. A natural bovine lipid extract surfactant is used in the majority of Canadian neonatal units. The biochemical composition of each prep-aration generally reflects the composition of natural surfactant obtained from the alveolar spaces, at least with respect to the high content of phospholipids and the high proportion of disaturated dipalmitoyl phosphatidylcholine (DPPC). The production procedure should also, in principle, preserve the hydrophobic proteins SP-B and SP-C. Surfactants produced from bronchoalveolar lavage are, in prin-ciple, less contaminated with plasmatic and tissue components: bovactant, calfactant, bovine lipid extract surfactant, and a biological product produced from pig lungs in Cuba. Poractant alfa and beractant are examples of surfactant obtained from minced lungs. The resulting proportion of the main surface-active lipid component, DPPC, varies from 70% in beractant, 40% in calfactant, approximately 35% to 56% in poractant alfa, 41% in the bovine lipid extract surfactant and 45% in the biological product produced from pig lungs in Cuba.

OThER faCTORSExperimental studies have demonstrated that the level of endogenous surfactant can have important consequences in surfactant replacement therapy. Pre-existing surfactant can slow the spreading of new surfact-ant by diminishing the differential in tension between surfactant-rich and surfactant-poor areas (19). In addition, the new surfactant can induce a disturbance through the existing surfactant. Once a patient is treated with the first dose of surfactant, it could be more difficult for subsequent doses to reach the periphery, hindering the overall delivery and efficacy of the product. This could be the reason of the observed decrease in benefits of the administration of three or more doses, com-pared with one or two doses (20).

COnCLUSIOnThe present review discussed some of the mechanisms that influence the instillation of surfactants into the pulmonary airways. In light of the evidence from animal and human studies, we believe that the optimal method for surfactant delivery should include the use of bolus instilla-tion combined with ventilatory strategies before (lung recruitment), during (disconnection and bagging OR increase on ventilator settings to provide sufficient pressure and a rate of 60 breaths/min) and after surf-actant administration (lung recruitment). Extra care should be taken when giving surfactant to extreme low birth weight infants because this is a population at higher risk for side effects such as severe episodes of airway obstruction during the procedure (3). As for any protocol, each neonatal intensive care unit should develop a coherent administration strategy with the goal of achieving targeted delivery of surfactant that enhances safety and efficacy of this medication.

aPPEnDIX: PROTOCOL fOR SURfaCTanT REPLaCEMEnT aDMInISTRaTIOn aT MCGILL

UnIVERSITY hEaLTh CEnTRE, MOnTREaL, QUEBEC Patient population:● Patients with respiratory distress syndrome● Patients with conditions associated with surfactant deficiency such

as meconium aspiration syndrome, sepsis and pulmonary hemorrhage as per discussion with the most responsible physician. Although congenital diaphragmatic hernia is associated with surfactant deficiency, the administration of surfactant may result in significant deterioration and, therefore, should be used with caution.

CRITERIa fOR SURfaCTanT aDMInISTRaTIOn a. <24 weeks’ gestational age: these infants should be intubated

immediately after birth and surfactant given prophylatically (within the first 15 min to 30 min of life). Between intubation and surfactant administration, these infants should be ventilated very carefully with low tidal volume and pressures.

b. ≥24 weeks’ gestational age: b.1 For infants intubated immediately after birth, it is recommended that surfactant be given as early treatment (<2 h of age), except if the infant is on room air and minimal ventilatory support on neonatal intensive care unit admission. These infants should be immediately extubated to nasal ventilation or nasal continuous positive airway pressure. b.2 Infants initially treated with noninvasive ventilation, endotracheal intubation and surfactant administration is recommended under one the following circumstances:

a) Fraction of inspired oxygen (FiO2) >0.5 (21-23) to maintain oxygen saturation (SpO2) >88% or a partial pressure of arterial oxygen (PaO2) >45 mmHg

b) Partial pressure of arterial carbon dioxide (PaCO2) >55 mmHg to 60 mmHg with a pH <7.25

c) Apnea requiring bag and mask ventilation d) >6 apneas/6 he) Evidence of significant work of breathing (retractions, grunting

and chest wall distortion in infants presenting with increases in oxygen needs)

PROCEDURE Physician will assess patient eligibility for surfactant administration and write an order for surfactant to be given. Physician should be at bedside during surfactant administration. The registered respiratory therapist (RRT) will advise the bedside nurse that the patient will be receiving surfactant. The RRT and registered nurse will perform a baseline patient assessment, which should include: 1. Respiratory assessment: respiratory rate, ventilator pressures, tidal

volumes and transcutaneous PCO2 (TcPCO2)2. Chest assessment: air entry, adventitious sounds, symmetry of chest

expansion, secretions3. Vital signs: heart rate, oxygen saturation (SpO2), blood pressure 4. Patient status: awake, asleep, sedated5. Chest x-ray review to assess endotracheal tube (ETT) position and

lung volume

EQUIPMEnT SET-UPThe RRT should set up the equipment as followsa) Retrieve surfactant from the freezer and warm to room temperature

for no more than 30 min before its use. The vial can be rolled but DO NOT shake it.

b) Calculate the amount of surfactant needed. c) Swab the vial rubber cap with an alcohol swab before introducing

needle. Fill syringe with surfactant. d) Attached luer lock syringe with medication to luer fitting.e) Attach trach care mac cartridge to Y.f) Before attaching trach care mac to patient, prime the interval

volume of the catheter with medication.g) Attach trach care mac adaptor to ventilator circuit and ETT.

InTERVEnTIOn BEfORE SURfaCTanT DELIVERY

The RRT perform the following interventions1. Pre-oxygenation: the oxygen concentration should be increased to

achieve SpO2 >95% before surfactant delivery.2. Suction ETT and listen to the air entry. 3. Lung recruitment manoeuvre: Provide five to 10 inflations with

pressures 1 cmH2O to 2 cmH2O above previous ventilatory settings to assure some lung recruitment before administration, which would facilitate drug distribution into the pulmonary airways.

4. Record all vital signs (heart rate, blood pressure, SpO2 and TcPCO2).

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Can J Respir Ther Vol 50 No 3 Autumn 201494

SURfaCTanT aDMInISTRaTIOn: BaCKGROUnD InfORMaTIOn (2)

The magnitude of the distribution problem is generally not appre-ciated. There are approximately 20 generations (branch points) from the trachea to the respiratory bronchioles and saccules. Therefore, there are approximately 250,000 binary branch points and 500,000 distal airways leading to saccules in the preterm lung. If the distribu-tion is not proportionate to the number of saccules distal to each branch point, then surfactant distribution will not be uniform. Any nonuniformity at a proximal branch point will be amplified at subse-quent branch points.

When surfactant is instilled into a lung, the distribution results from the following principles:

Therefore, treatment techniques do matter. Surfactant will dis-tribute to the preterm lung more uniformly when given rapidly and at higher volumes (see Table above).

The slow infusion of surfactant into the lungs to minimize any acute physiological changes during treatment can result in very poor distribution. Using a slow rate of administration could result in a non-homogeneous surfactant distribution, which is not the desired outcome.

Administration of surfactant to extreme preterm infants using multiple aliquots and with the patient receiving mechanical ventila-tion at the same settings before delivery of the drug was associated with severe episodes of airway obstruction. (3)

The effect of surfactant to open the lungs results in a rapid increase in oxygenation that can occur almost instantaneously. The subsequent responses to surfactant treatment result from improved lung mechan-ics, which may change more gradually and will depend, in part, on the choice of ventilator styles.

SURfaCTanT aDMInISTRaTIOnThe RRT should administered surfactant as follows: 1. Surfactant should be delivered through an in-line catheter with

the tip located at the mid trachea level. 2. Because the surfactant actually available at the Units is the bovine

lipid extract surfactant and the dose should be 5 mL/kg (135 mg phospholipids/kg) divided into one or a maximum of two aliquots.

3. Mode of delivery: surfactant should be given as bolus infusion (10 s to 20 s).

4. Infant should be disconnected from the ventilator and bagged by a physician or another RRT with the flow inflating bag or T-piece device at a rate of 60 inflations/min and pressure necessary to push the surfactant effectively into the pulmonary airways.

5. Start the bagging approximately 5 s after initiation of surfactant administration (to give some time for the formation of a fluid plug or column of surfactant into the ETT). The flow rate of the flow inflating bag should be the minimum necessary to provide adequate pressures.

6. Infant should be kept in the horizontal position during the entire procedure.

7. When using more than one aliquot, a minimum period of 30 s to 60 s between the aliquots should be used if infants remained stable.

8. Vital signs and ventilator parameters should be monitored during the delivery process.

9. Details regarding surfactant administration given should be written in the medical records (time, number of aliquots, PIP and PEEP used, vital signs and complications).

10. The ETT should not be suctioned for following 2 h unless signs of significant airway obstruction occur.

POSTSURfaCTanT aDMInISTRaTIOn1. Registered nurse should record vital signs immediately after

administration is completed and every 10 min for the next hour.2. RRT should record ventilator parameters every 15 min for the next

hour.

Property EffectSurface activity Causes rapid adsorption and spreadingGravity Surfactant distributed by gravity in large airwaysVolume Higher volumes, cause better distributionsRate of administration Rapid administration improves distributionVentilator settings Pressure and PEEP help clear airways of fluidFluid volume in the lungs Higher volumes of fetal lung fluid or edema fluid

improves distribution

PEEP Positive end-expiratory pressure

REfEREnCES1. Polin RA, Carlo WA; Committee on Fetus and Newborn;

American Academy of Pediatrics. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 2014;133:156-63.

2. Jobe AH. Mechanisms to explain surfactant responses. Biol Neonate 2006;89:298-302.

3. Tarawneh A, Kaczmarek J, Bottino MN, Sant’Anna GM. Severe airway obstruction during surfactant administration using a standardized protocol: A prospective, observational study. J Perinatol 2012;32:270-5.

4. Fernandez-Ruanova MB, Alvarez FJ, Gastiasoro E, et al. Comparison of rapid bolus instillation with simplified slow administration of surfactant in lung lavaged rats. Pediatric Pulmonol 1998;26:129-34.

5. Segerer H, van Gelder W, Angenent FW, et al. Pulmonary distribution and efficacy of exogenous surfactant in lung-lavaged rabbits are influenced by the instillation technique. Pediatr Res 1993;34:490-4.

6. Ueda T, Ikegami M, Rider ED, Jobe AH. Distribution of surfactant and ventilation in surfactant-treated preterm lambs. J Appl Physiol 1994;76:45-55.

7. Cassidy KJ, Bull JL, Glucksberg MR, et al. A rat lung model of instilled liquid transport in the pulmonary airways. J Appl Physiol 2001;90:1955-67.

8. Halpern D, Jensen OE, Grotberg JB. A theoretical study of surfactant and liquid delivery into the lung. J Appl Physiol 1998;85:333-52.

9. Hentschel R, Brune T, Franke N, Harms E, Jorch G. Sequential changes in compliance and resistance after bolus administration or slow infusion of surfactant in preterm infants. Intensive Care Med 2002;28:622-8.

10. Ghadiali SN, Gaver DP. Biomechanics of liquid-epithelium interactions in pulmonary airways. Respir Physiol Neurobiol 2008;163:232-43.

11. Zola EM, Gunkel JH, Chan RK, et al. Comparison of three dosing procedures for administration of bovine surfactant to neonates with respiratory distress syndrome. J Pediatr 1993;122:453-9.

12. Valls-i-Soler A, Lopez-Heredia J, Fernandez-Ruanova MB, Gastiasoro E. A simplified surfactant dosing procedure in respiratory distress syndrome: The “side-hole” randomized study. Spanish Surfactant Collaborative Group. Acta Paediatr 1997;86:747-51.

13. Wheeler KI, Davis PG, Kamlin CO, Morley CJ. Assist control volume guarantee ventilation during surfactant administration. Arch Dis Childhood 2009;94:F336-8.

14. Miedema M, de Jongh FH, Frerichs I, van Veenendaal MB, van Kaam AH. Changes in lung volume and ventilation during surfactant treatment in ventilated preterm infants. Am J Respir Crit Care Med 2011;184:100-5.

The acute treatment response to surfactant results from the biophysical properties of surfactant anD depends on the rapid

distribution of surfactant to the lungs

The practical ways to improve distribution are to position the infant to minimize gravity, to give surfactant quickly in a reasonable volume and to give the infant enough ventilatory

support to quickly clear the airways of fluid

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Can J Respir Ther Vol 50 No 3 Autumn 2014 95

15. Anderson JC, Molthen RC, Dawson CA, et al. Effect of ventilation rate on instilled surfactant distribution in the pulmonary airways of rats. J Appl Physiol 2004;97:45-56.

16. Krause MF, Jakel C, Haberstroh J, Schulte-Monting J, Leititis JU, Orlowska-Volk M. Alveolar recruitment promotes homogeneous surfactant distribution in a piglet model of lung injury. Pediatr Res 2001;50:34-43.

17. Lu KW, Perez-Gil J, Taeusch H. Kinematic viscosity of therapeutic pulmonary surfactants with added polymers. Biochim Biophys Acta 20091788:632-7.

18. Lewis JF, Goffin J, Yue P, McCaig LA, Bjarneson D, Veldhuizen RA. Evaluation of exogenous surfactant treatment strategies in an adult model of acute lung injury. J Appl Physiol 1996;80:1156-64.

19. Grotberg JB, Halpern D, Jensen OE. Interaction of exogenous and endogenous surfactant: Spreading-rate effects. J Appl Physiol 1995;78:750-6.

20. Long W, Thompson T Fau, Sundell H, et al. Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome. The American Exosurf Neonatal Study Group I. J Pediatr 1999;118:595-605.

21. Ammari A, Suri M, Milisavljevic V, et al. Variables associated with the early failure of nasal CPAP in very low birth weight infants. J Pediatr 2005;147:341-7.

22. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008;358:700-8.

23. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362:1970-9.