Clinical trial NCT02164734
Conditions: Respiratory Distress Syndrome, Newborn
Keywords: surfactant
Sponsor: Albany Medical College
Start date: 2014-06-01; Completion date: 2020-12-31
Enrollment: 93 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study, newborn babies with respiratory distress syndrome (RDS), receiving oxygen via nasal continuous airway pressure (CPAP) modalities, and needing surfactant treatment will be randomized to standard delivery of surfactant via and endotracheal tube airway (inserted after pre-medication for pain with a short-acting narcotic), or to surfactant delivery via laryngeal mask airway (LMA). The intent is to remove the airways and return babies to non-invasive CPAP support, after surfactant is given. The primary outcome measure is the rate of failure of initial surfactant therapy. Standardized failure criteria are reached: a) early, if the baby is unable to be placed back on non-invasive CPAP (i.e., needs tracheal intubation and mechanical ventilation) or, b) late, if the baby requires ventilation, retreatment with surfactant within 8 hours or more than 2 doses of surfactant.

The objective of this protocol is to reduce the need for endotracheal intubation and mechanical ventilation in preterm neonates with RDS needing rescue surfactant therapy by instilling surfactant though an LMA, while achieving comparable efficacy of surfactant treatment.

The hypothesis is that surfactant treatment through an LMA will decrease the proportion of babies with RDS who require mechanical ventilation or subsequent intubation, when compared to standard surfactant treatment following endotracheal intubation with sedation.

Detailed description:
Respiratory Distress Syndrome (RDS) due to deficiency of pulmonary surfactant is common in preterm newborns. Early treatment with surfactant improves oxygenation, reduces the need for subsequent mechanical ventilation, decreases the incidence of pulmonary air leaks and chronic lung disease and it also reduces mortality in extremely premature newborns. Optimal treatment of RDS includes surfactant therapy and avoidance of invasive mechanical ventilation by using nasal continuous positive airway pressure modes (NCPAP or NIPPV). The current standard method of surfactant delivery requires tracheal intubation and at least brief positive-pressure ventilation, as in the INSURE (Intubation-Surfactant-Extubation) approach. Because tracheal intubation causes pain and vagal-mediated physiologic instability in neonates, premedication with atropine and a narcotic is recommended. However, narcotic premedication increases respiratory depression, which may require sustained mechanical ventilation, thus contributing to the failure of INSURE. In a recent trial at our center, standard pretreatment with morphine and atropine was associated with failure of INSURE in more than 2/3 of patients. Consequently, we have recently changed our standard premedication for INSURE to the combination of atropine and remifentanil (a rapid onset, short-acting narcotic). The Laryngeal Mask Airway (LMA) is a commercially available, less invasive artificial airway that does not need to be inserted into the trachea; it is FDA-approved for use in neonates; preliminary data suggest that it can be used for surfactant administration, which in our trial was associated with a lower failure rate than the morphine plus INSURE approach.

The main objective of this study protocol is reduce the need for endotracheal intubation and mechanical ventilation in preterm neonates with mild to moderate RDS needing rescue surfactant therapy by instilling surfactant though an LMA. A second objective is to compare the efficacy of surfactant administered via LMA versus endotracheal tube (ETT) in decreasing the severity of RDS. Additionally, we will further evaluate the safety of surfactant administration via LMA.

The primary hypothesis is that surfactant therapy delivered via LMA is not inferior to surfactant therapy delivered via transient intubation (INSURE technique) with short-acting narcotic premedication for mild to moderate RDS in preterm neonates.

This randomized controlled trial will include babies with mild-to-moderate RDS, less than 48 hours of age, with gestational age 27 0/7 to 36 6/7 weeks, treated with NCPAP (or other NIPPV modality) ≥ 5 cm H2O and FiO2 between 0.30 and 0.60 for at least 2 hours to maintain oxygen saturation by pulse oximetry (SpO2) 90-95%.

After informed consent is obtained, babies are randomly assigned (from sealed, opaque, consecutively numbered envelopes), to "ETT" or "LMA" groups. The "ETT" group is managed according to our current INSURE approach to surfactant therapy (endotracheal intubation following premedication with atropine + remifentanil), whereas the "LMA" group will be pre-medicated with atropine before LMA insertion for surfactant administration.

Both groups will receive Infasurf (3mL/kg) instilled in 2 aliquots via their respective airway, followed by PPV for at least 5 minutes. The artificial airway will be removed and the patient returned to NCPAP/NIPPV by 15 minutes, if spontaneous respirations are adequate. Indications for surfactant re-dosing and mechanical ventilation will be equivalent for both groups. Babies will continue or initiate assisted ventilation via ETT if any of the following occurs:

* Persistent apnea;
* Severe retractions;
* Inability to wean FiO2 \< 60%

Criteria for re-dosing with surfactant:

1. Within 8 hours after first dose of surfactant:

   • FiO2 20% higher than the baseline FiO2, after excluding other obvious causes of respiratory insufficiency such as pneumothorax.

   If early re-dosing of surfactant is needed in patients of either group, it will be administered via ETT (i.e., LMA patients will be intubated, and will receive the dose of surfactant via ETT)
2. Beyond 8 hours of the first dose of surfactant:

   * FiO2 is ≥ 60%, or;
   * FiO2 is ≥ 30% associated with worsening clinical signs of RDS.

If late re-dosing is needed in patients of the LMA group, use of the LMA is permitted for the second dose. In the ETT group, all doses are given via the ETT.

Arms: arm 1: Endotracheal intubation for surfactant administration, following remifentanil and atropine pre-medication arm 2: Laryngeal mask airway insertion for surfactant administration, following atropine pre-medication
Interventions: intervention 1: Endotracheal intubation intervention 2: Laryngeal mask airway intervention 3: remifentanil
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: additional premedication in the endotracheal intubation/INSURE arm

Protocol documents:
Prot_SAP_000.pdf: 
Study protocol (including SAP) for: 
 
Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE 
technique) versus laryngeal mask airway (LMA) for respiratory distress 
syndrome (RDS) in preterm neonates 
 
 
Original document, 14 April 2014 
 
NCT02164734 
NCT title: Surfactant via endotracheal tube vs. laryngeal mask airway (LMA) 
in preterm neonates with respiratory distress syndrome 
 
 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
Version date: 04/03/14 
Page 1 of 18 
 
 
 
Efficacy of rescue surfactant delivery via endotracheal 
intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome 
(RDS) in preterm neonates. 
 
 
 
 
 
 
 
 
Principal Investigator: 
 
 
Kelly E. Clements, MD  
 
 
Department of Pediatrics 
 
 
 
 
 
 
 
 
Albany Medical Center 
 
 
 
 
 
 
 
 
43 New Scotland Avenue 
 
 
 
 
 
 
 
 
Albany, NY 12208 
 
 
 
 
 
 
 
 
(518) 262-5421 
 
 
Co-Principal Investigator: 
 
 
Joaquim M.B. Pinheiro, MD, MPH 
 
Department of Pediatrics 
 
 
 
 
 
 
 
 
Albany Medical Center 
 
 
 
 
 
 
 
 
43 New Scotland Avenue 
 
 
 
 
 
 
 
 
Albany, NY 12208 
 
 
 
 
 
 
 
 
(518) 262-5421


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
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Page 2 of 18 
 
 
A. Study Background and Purpose 
 
Pulmonary surfactant deficiency manifested as respiratory distress syndrome (RDS) is common 
in preterm newborns and remains a major cause of neonatal morbidity and mortality. Surfactant 
replacement therapy improves clinical outcomes in preterm infants with RDS.  Multiple clinical 
trials and meta-analyses have shown that surfactant is immediately effective in improving the 
need for respiratory support (Stevens, Harrington, Blennow, & Soll, 2007). Surfactant 
administered prophylactically to infants at high risk of developing RDS (before 28 to 30 weeks' 
gestation) is most effective in diminishing mortality (Yost & Soll, 2000). Surfactant is also used 
as rescue therapy for clinically significant RDS, most often within 12 to 48 hours of life, but 
better outcomes are obtained when surfactant is administered relatively early in the disease 
course (Halliday, 2008).  Surfactant therapy is also effective in larger preterm infants with RDS 
(Engle, 2008; Kattwinkel et al., 1993); in placebo-controlled trials, larger and more mature 
preterm neonates have a lower incidence of death or bronchopulmonary dysplasia when treated 
with surfactant (Engle, 2008).  Early treatment with surfactant in larger preterm infants with 
RDS improves oxygenation, reduces the need for subsequent mechanical ventilation and 
decreases the risk of pneumothorax, while decreasing the incidence of bronchopulmonary 
dysplasia (Verder et al., 1999; Stevens et al., 2007). In recent years, optimal combinations of 
non-invasive ventilation (nasal CPAP or nasal IPPV) and surfactant have been sought in order to 
minimize the use of invasive mechanical ventilation, which increases the risk of developing 
chronic lung disease (Verder et al., 1999; Stevens et al., 2007). Thus, variations of the INSURE 
approach (transient INtubation, SURfactant administration, and immediate Extubation) have 
emerged in neonatal care (Welzing et al., 2009). 
 
The standard method of surfactant delivery involves tracheal intubation with positive pressure 
ventilation (PPV) (American Academy of Pediatrics & American Heart Association, 2006) 
(Infasurf package insert, ONY, Inc.; available at www.infasurf.com). Intubation causes pain and 
physiological instability in the neonate, leading to hypoxemia and bradycardia while increasing 
systemic and intracranial pressure (Dempsey, Al Hazzani, Faucher, & Barrington, 2006; Friesen, 
Honda, & Thieme, 1987; Marshall, Deeder, Pai, Berkowitz, & Austin, 1984).  The use of 
premedication to minimize pain and stress in neonates undergoing intubation is supported by 
evidence showing that intubations following premedication may be safer and more effective than 
awake intubations (Carbajal, Eble, & Anand, 2007; Shah & Ohlsson, 2002). However, 
premedication often leads to respiratory depression and persistent hypoventilation, precluding 
extubation to CPAP as intended after surfactant administration (Santana-Rivas, Pinheiro, & 
Pezzano, 2013); intubation with premedication may thus contribute to the need for invasive 
mechanical ventilation in some neonates, an outcome that surfactant therapy aims to prevent. It is 
notable that the American Academy of Pediatrics and the Canadian Paediatric Society have 
recommended premedication for neonatal intubation as intended for mechanical ventilation, but 
not specifically for INSURE, where intubation is only a transient route for surfactant delivery 
and ventilation is undesirable (Barrington & Canadian Paediatric Society, 2011; Kumar, Denson, 
Mancuso, & Committee on Fetus and Newborn, 2010). 
Furthermore, in a significant proportion of neonates, as high as 21%, (Hipolito, Milstein, & 
Sherman, 2001) the endotracheal tube (ETT) is initially placed in a mainstem bronchus, which 
promotes unequal distribution of surfactant between the lungs, a risky and undesirable condition. 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
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Esophageal intubation with gastric administration of surfactant is a less common, ineffective and 
unintended complication of the procedure.  Other complications of surfactant therapy, including 
airway obstruction with surfactant stasis in the ETT, have lead clinicians to modify the surfactant 
administration strategies used in research protocols, including dose, frequency and treatment 
procedure. The route of administration of surfactant has been a topic of research in the last 5 
years, particularly considering the use of the laryngeal mask airway. 
 
The laryngeal mask airway (LMA) is a supraglottic airway device used to administer positive 
pressure ventilation (PPV) in adult, pediatric and neonatal patients (Trevisanuto et al., 2005). It 
has been used since 1988 in over 200 million patients for routine and emergency procedures. The 
mask conforms to the contours of the hypopharynx with its lumen facing the laryngeal opening, 
and it is designed to be a minimally-stimulating device for anesthesia or airway support.  The 
LMA can be inserted easily and quickly with minimal training, and it results in less 
misplacement and failure of ventilation than endotracheal intubation, even when performed by 
pre-hospital providers (Chen & Hsiao, 2008); associated discomfort and trauma are minimal in 
comparison with tracheal intubation (Trevisanuto et al., 2004; Schmiesing & Bock-Utne, 1998). 
In neonatal resuscitation, the LMA is an alternative to manage the difficult neonatal airway, 
when intubation is difficult (American Academy of Pediatrics & American Heart Association, 
2006).   
 
The LMA has also been used as a conduit for the pulmonary administration of various drugs, but 
as noted in the Neonatal Resuscitation Program "There is insufficient evidence to recommend the 
laryngeal mask when intratracheal medications are required” (American Academy of Pediatrics 
& American Heart Association, 2006). After case reports and a small case series by Trevisanuto 
et al. demonstrated the feasibility and apparent effectiveness of minimally invasive 
administration of surfactant via LMA in preterm infants with RDS (Brimacombe, Gandini, & 
Keller, 2004; Trevisanuto et al., 2005), a controlled trial aiming to study the efficacy of 
surfactant administration by LMA was started at the University of Virginia (Stewart, Attridge, & 
Kattwinkel, 2008), but stopped early because of slow enrollment (personal communications to J. 
Pinheiro, by J. Kattwinkel and A. Paget-Brown, 2008 and 2009), with only 11 babies in the 
LMA arm (Attridge, Stewart, Stukenborg, & Kattwinkel, 2013). 
 
Contemporaneously, in the Albany Medical Center NICU, premedication with morphine and 
atropine was used for elective and semi-urgent intubations, including INSURE procedures. We 
thus undertook and recently completed a randomized trial on preterm newborns with mild-
moderate RDS, to compare the effectiveness of surfactant administration via LMA versus 
transient intubation (using our traditional INSURE technique, with morphine for premedication).  
We found that the LMA group had a significantly decreased rate of failure of non-invasive 
ventilatory support (30%) in comparison to the INSURE (ETT) group; further, the early timing 
and pattern of failure in the INSURE group strongly suggested that morphine premedication 
contributed to the respiratory depression and unintended need for invasive ventilation (Santana-
Rivas, Pinheiro, & Pezzano, 2013). 
Another recent randomized trial of intubation techniques in preterm neonates concluded that 
“Because of circulatory changes and neurophysiological depression found during and after the 
intubation in infants given morphine, premedication with morphine should be avoided” (Norman 
et al., 2011).  Based on current evidence, the Canadian Pediatric Society now recommends that 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
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an optimal protocol for premedication for neonatal intubation should include a vagolytic, a rapid-
acting analgesic and a short-duration muscle relaxant (Barrington & Canadian Paediatric Society, 
2011).  However, neither these nor other expert recommendations exist for premedication in the 
context of INSURE, and a variety of approaches – including no premedication – have been used. 
Based on our own data and on recent publications, our new preferred premedication for INSURE 
combines a vagolytic (atropine) with a rapid-acting, short-duration analgesic (remifentanil), 
while muscle relaxants and longer acting analgesics are avoided, as they might increase the need 
for ventilatory support. Remifentanil has been studied mostly in neonates undergoing persistent 
intubation, with demonstrated effectiveness but some risk of chest wall rigidity at higher doses 
(Choong et al., 2010). At lower doses of 2 µg/kg, remifentanil has been used successfully for 
INSURE, without adverse effects (Welzing et al., 2009). 
 
The results of our recent LMA trial indicate that surfactant delivery via LMA produces 
immediate improvements in oxygenation comparable to delivery via ETT, and decreased need 
for subsequent ventilatory support. However, because our previous INSURE approach for ETT 
delivery of surfactant included morphine, a slow-onset, long acting analgesic which likely 
contributed to the need for invasive ventilation, it remains unclear whether LMA delivery of 
surfactant is as effective as our new INSURE technique, which is designed to avoid respiratory 
depression.  
 
Since our last trial began, the results of a small randomized trial were published, where the 11 
babies who received surfactant via LMA showed improvements in oxygenation comparable to 
those in our study, whereas no change occurred in the surfactant-untreated (CPAP-only) group 
(Attridge, Stewart, Stukenborg, & Kattwinkel, 2013). In a piglet model of RDS, surfactant 
administered via LMA had physiologic effects similar to those of ETT administration (Roberts et 
al., 2010). The only ongoing clinical trial on delivery of surfactant via LMA to human neonates 
with RDS (Roberts et al., NCT01116921 at www.clinicaltrials.gov ) is examining the 
effectiveness of this procedure (versus no surfactant treatment) in decreasing the need for later 
mechanical ventilation. 
 
From the foregoing, it is apparent that clinical trials are still needed to address the relative 
efficacy of surfactant delivered via LMA versus optimized INSURE approaches. In this 
proposal, we extend our investigations of surfactant delivery by LMA to the current clinical 
context in which premedication for INSURE comprises atropine and remifentanil.  
 
Hypothesis: 
 
Surfactant therapy delivered via LMA is not inferior to surfactant therapy delivered via transient 
intubation (INSURE technique) with short-acting narcotic premedication for mild to moderate 
RDS in preterm neonates. 
 
Aims: 
 
 
1. To compare the rate of failure of surfactant therapy delivered via LMA to the rate of 
failure of surfactant therapy delivered via transient intubation (INSURE technique) in avoiding 
mechanical ventilation in neonates 27 to 36 weeks’ gestation with mild to moderate RDS. 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
Version date: 04/03/14 
Page 5 of 18 
 
 
 
1a. To evaluate the success of remifentanil as premedication for transient 
intubation (INSURE technique) as compared to morphine used in our previous trial. 
 
 
 
2. To further evaluate the safety of surfactant administration via LMA. 
 
 
B. Study Design/C. Subject Population 
 
 
• Multi-center, randomized controlled trial. The participating centers are Albany Medical Center, 
Bellevue Woman’s Center at Ellis Hospital, and Golisano Children’s Hospital. Each center 
will obtain approval from that center’s own Institutional Review Board. It is anticipated that 
the study will take 2 years to complete.  
 
Patient Enrollment: 
 
• The investigators and/or study coordinator will evaluate all infants admitted to the NICU who 
are less than 48 hours of life from 27 through 36 completed weeks’ gestation with mild-
moderate RDS.  
 
• If they meet the pre-defined inclusion criteria and informed consent is obtained, they will be 
randomized to either the INSURE group or LMA group for the initial surfactant 
administration. Patients will be block randomized in one of three gestational age groups:         
27 0/7 - 28 6/7 weeks, 29 0/7 - 32 6/7 weeks, 33 0/7 - 36 6/7 weeks.  
 
• Randomization process: An anticipated 130 patients will be enrolled in the study. Patients will 
be randomized into three groups using a blind randomization selection method. After 
computer-generated block randomization, the 130 numbered cards will be placed in sealed, 
numbered envelopes, and kept in a NICU nurse practitioner office. Each card will indicate 
LMA or INSURE group and include an identifier code number. After obtaining the signed 
consent form, the investigators or coordinator will open the next envelope in the appropriate 
gestational age block.  
 
 
• Inclusion Criteria:  
 
• Gestational age (GA) 27 0/7 weeks to 36 6/7 weeks 
• Age < 48 hours 
• Mild-moderate RDS as defined by an FiO2 requirement of 0.30 - 0.60 on either CPAP or 
nasal intermittent positive pressure ventilation (NIPPV) for at least two hours to maintain 
SpO2 90-95% 
• Written consent obtained 
 
• Exclusion Criteria: 
• Prior tracheal intubation 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
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• Prior surfactant therapy 
• Evidence of pneumothorax, pneumomediastinum, or pneumopericardium 
• FiO2 > 0.60 
• Craniofacial or other airway malformation 
• Major congenital malformation (cardiac and thoracic defects) 
• Apgar score of ≤ 3 at 5 minutes of life or evidence of encephalopathy  
• Weight less than 800 grams 
 
Study/Intervention: 
 
The diagram below is a graphic depiction of the study protocol. Criteria for assisted ventilation 
and other respiratory support will be the same for both groups.  
 
 
 
 
 
 
 
 
 
 
 
 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
Version date: 04/03/14 
Page 7 of 18 
• INSURE (control group): Atropine + remifentanil + intubation (ETT) + Infasurf 
 
• The neonates randomized to standard management will be given premedication with 
atropine (0.1 mg/kg) and remifentanil (2 mcg/kg) for endotracheal intubation according to 
the new standard AMC premedication order sheet. 
 
• A CO2 detector will be used to verify endotracheal intubation 
 
• Surfactant (Infasurf) therapy will be delivered via ETT, at a dose of 3mL/kg, in 2 aliquots. 
Surfactant is drawn up in a syringe with a Luer adaptor. 
 
• This is followed by positive pressure ventilation (PPV) for a minimum of 5 minutes before 
extubation to nasal CPAP (if possible) by 15 minutes after completion of surfactant 
therapy. 
 
• However, the baby will remain intubated and continue to mechanical ventilation via ETT if 
one or more of the following occurs: 
• Persistent apnea 
• If this is thought to be related to sedative medication, a one-time dose of naloxone (0.1 
mg/kg) may be administered as part of the study protocol 
• Severe retractions (as judged by an attending neonatologist or fellow) 
• Inability to wean FiO2 < 0.60 to maintain target SpO2 90-95% 
 
• Management of RDS, mechanical ventilation, concurrent neonatal issues, and any 
complications that may arise will be at the discretion of the clinical care team.  
 
 
 
• LMA group: Atropine + LMA + Infasurf 
 
• The neonates randomized to LMA management will be given atropine (0.1 mg/kg) before 
the insertion of the size 1 classic LMA. The LMA cuff will be inflated with 2-4 mL of air. 
 
• A CO2 detector will be used to verify the placement of the device. 
 
• Adequate PPV will be verified by observing adequate chest movements and SpO2 for at 
least 1 minute. 
 
• The tip of a T-connector (or, a 5-French catheter) will be cut to reach the distal end of the 
LMA, to instill a 3 mL/kg dose of Infasurf in 2 aliquots.  
 
• Surfactant will be drawn up in a syringe with a Luer-type adaptor. 
 
• Following surfactant therapy, manual PPV will be provided for a minimum of 5 minutes.  
 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
Version date: 04/03/14 
Page 8 of 18 
• After spontaneous respirations are judged adequate, the LMA will be removed and nasal 
CPAP resumed. 
 
• Indications for intubation to initiate assisted ventilation will be one or more of the 
following: 
• Persistent apnea 
• Severe retractions (as judged by an attending neonatologist or fellow) 
• Inability to wean FiO2 < 0.60 to maintain target SpO2 90-95% 
 
• Management of RDS, mechanical ventilation, concurrent neonatal issues, and any 
complications that may arise will be at the discretion of the clinical care team.  
 
Since surfactant administration procedures are already standardized in the AMC NICU, babies 
will have had at least one clinically indicated chest x-ray before the intervention, and a blood gas 
is obtained 30 to 60 minutes after the treatment, as per the routine surfactant administration 
protocol. The study does not alter these routine clinical protocols. Similarly, routine monitoring 
during the instillation of surfactant will continue, including monitoring of pulse rate, SpO2, 
colorimetric CO2 exhalation, chest wall rise and auscultation as indicated, in all subjects. 
 
Babies at risk for apnea of prematurity are routinely treated with caffeine. The two lower 
gestation age groups in this study will continue to undergo prophylactic caffeine therapy for 
apnea of prematurity. 
 
Only one routine procedure will be standardized due to the study protocol. Babies with RDS on 
nasal CPAP all have an indwelling orogastric tube; gastric residuals are aspirated and aspirate 
volumes are recorded, but not always at consistent time points. For this study, the gastric residual 
will be suctioned before surfactant therapy in each patient, and also 15 minutes after the 
treatment. The amount of new gastric residual will be recorded. 
 
Failures: 
 
The criterion for Early Failure is the need for mechanical ventilation within 1 hour of surfactant 
therapy due to either persistent apnea, apnea despite naloxone, severe retractions, or the inability 
to maintain FiO2 < 0.60 for target SpO2 90-95% 
 
The criteria for Late Failure are one or more of the following: 
• a sustained FiO2 > 0.60 required to maintain target oxygen saturation, 
• a second dose of surfactant within 8 hours of the first dose, 
• more than 2 doses of surfactant, or 
• the need for mechanical ventilation within the first 120 hours of life. 
 
• Re-dosing of surfactant 
• Criteria for re-dosing are defined as FiO2 > 0.60 or FiO2 > 0.30 with associated clinical signs 
of worsening RDS. 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
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• If re-dosing surfactant before 8 hours has elapsed from the time of initial administration, 
the dose will be administered via ETT for all study patients, regardless of the group to which 
they had been randomized. 
• If re-dosing surfactant more than 8 hours after the initial dose, patients in the LMA group 
will have a second dose given via the LMA; any surfactant doses beyond the second will be 
given via ETT. In the ETT group, all doses are given via the ETT. 
 
Although the study interventions are limited to the airway used for surfactant administration in 
the first 1 to 3 days of life, and clinical management or follow-up are not otherwise conditioned 
by the study, all subjects enrolled will continue in the study up to discharge from AMC, for the 
purposes of data collection. This will include: 
• the FiO2 and mode of respiratory support before enrollment and at 0, 1, 12, 24, and 48 hours, 
and 7 and 28 days after initial surfactant administration, 
• any need for additional doses of surfactant, 
• any need for intubation, and 
• any need for mechanical ventilation.  
 
D. Data Analysis  
 
A copy of the data collection sheet that will be used for the study is included. 
 
 
Primary Outcome Measures: The primary outcome will be success of the surfactant 
administration strategy in avoiding mechanical ventilation in the first 120 hours of life. 
 
Secondary Outcome Measures: 
• Number of surfactant doses 
• Days on assisted ventilation 
• Day on any noninvasive respiratory support (CPAP/NIPPV modes) 
• Days until off respiratory support (supplemental oxygen and/or pressure support) 
• Rate pneumothorax and/or pneumomediastinum 
• Rate of BPD as defined by oxygen dependence at later of 28 days or 36 weeks’ 
postmenstrual age 
• Complications during insertion of LMA or ETT 
• Mortality rate 
 
Planned post-hoc analyses include timing of failure by treatment group, which should illuminate 
the mechanisms of failure by treatment strategy. 
➢ Baseline comparability: 
Baseline differences between ETT group and LMA group will be compared using t-tests  
for continuous variables (birth weight, gestational age, age and FiO2 at enrollment) and 
chi-square test for categorical variables (race, sex, prenatal care, antenatal steroids, mode 
of delivery, multiple gestation) 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
Clements et al.,  
Version date: 04/03/14 
Page 10 of 18 
➢ Primary outcome measure:   
Our primary outcome for the study is the proportion of infants that will reach the early 
and/or late failure criteria. The incidence of the failure criteria will be compared using 
chi-square statistics. 
➢ Sample size/Power analysis: 
The sample size was estimated based on results from the recent study on this population, 
at the Albany Medical Center NICU. We will thus expect that 30% of the LMA group 
will meet failure criteria, i.e., the LMA success rate in avoiding later intubation and 
ventilation will be 70%. For a non-inferiority design, with a clinically relevant non-
inferiority margin of 20%, a sample of 130 patients (65 per group) will be needed to 
conclude non-inferiority of the LMA method compared to INSURE (calculated using a 
one-sided α=0.05, β error=0.20). 
➢ Secondary outcome measures:  
Groups will be analyzed for secondary outcome differences using chi-square statistics for 
categorical data, and t-test or non-parametric tests for continuous data, as appropriate for 
the distribution obtained. The FiO2 response to surfactant treatment strategies will be 
compared from baseline to 1 and 8 hours using repeated measures ANOVA and post-hoc 
Dunnett’s test. Time to wean off respiratory support will be compared between groups 
using Kaplan-Meier analysis, with censoring at discharge. 
➢ Interim Analyses: 
Reports for the IRB will be prepared after one year of initiation of the trial or enrollment 
of 50 patients, whichever comes first. Data on the primary outcome, mortality, and major 
adverse events on the first 50 patients, will be submitted to Dr. Ashar Ata for purposes of 
safety monitoring. A difference in primary outcome at the p<0.01 level, or a consistent 
trend towards differences in major adverse events will constitute criteria for 
recommending that the study be stopped. 
 
E. Risks 
• Risk category:   Greater than minimal.  
This study is considered as a greater than minimal risk study. The study design includes a 
decreased use of laryngoscopy for tracheal intubation, which is currently the standard method of 
surfactant delivery. Laryngoscopy is associated with apnea, minor abnormalities in cardiac 
rhythm, obstructed respiration, increase in systolic blood pressure, decreased heart rate and 
transcutaneous oxygen tension in preterm neonates during the laryngoscopy (Carbajal, 2007) 


Efficacy of rescue surfactant delivery via endotracheal intubation (INSURE technique) versus laryngeal mask 
airway (LMA) for respiratory distress syndrome (RDS) in preterm neonates. 
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(Marshall, 1984).  ETT insertion causes pain and discomfort, coughing, laryngospasm, and vagal 
responses including apnea and bradycardia; it may cause trauma to the airway including the 
vocal cords, subglottic edema, and stridor; more than one attempt at insertion is usually 
necessary, and esophageal intubation is common, requiring re-intubation. As many as 21% of 
"successful" tracheal tubes end up in a mainstem bronchus (Hipolito et al., 2001), which can 
cause trauma, hypoventilation, desaturation, pneumothorax, cardiac arrest, and asymmetric 
delivery of surfactant.  
The hemodynamic effects of laryngoscopy and intubation are expected in most subjects during 
the procedure; we will follow our current procedures for intubation; this includes continuous 
monitoring of heart rate and SpO2 throughout the procedure, and a post-intubation chest X-ray to 
verify the ETT position, if the ETT is to remain in place. 
The adverse physiologic consequences of laryngoscopy and intubation can be attenuated with the 
appropriate use of premedication (VanLooy, Schumacher, & Bhatt-Mehta, 2008; Sarkar, 
Schumacher, Baumgart, & Donn, 2006; Greenwood & Colby, 2009). Premedication with 
intravenous remifentanil and atropine will be used, as per current practice (standardized order 
set).  Remifentanil is a synthetic opioid with a half-life of only 3-5 minutes. It could cause 
adverse effects such as hypotension and bradycardia (Penido, 2010; Welzing, 2009). There have 
been reports in the literature of remifentanil causing chest wall rigidity (Choong, 2010), 
however, this was at higher doses. Remifentanil has successfully been used for INSURE at lower 
doses without any adverse effects (Welzing, 2009). If there is any concern of chest wall rigidity 
in this trial, the infant will be give naloxone, and, if necessary, vecuronium.  
Decreased exposure to endotracheal intubation-related procedures among study patients would 
be expected to decrease the risks and discomfort associated with this method. 
Atropine is an anticholinergic drug, used commonly in conjunction with other medications to 
reduce episodes of bradycardia by decreasing vagal responses.  Bradycardia can result from 
vagal stimulation during laryngoscopy, endotracheal intubation, or insertion of the LMA.  
Tachycardia, restlessness, impaired gastrointestinal motility and dry secretions could be potential 
secondary effects observed. 
LMA insertion may result in kinking or malposition of the device, which may result in 
obstruction at the base of the tongue. In this case the mask must be removed and the procedure 
restarted.  The overall incidence of complications after removal of the LMA is about 10-13%, 
including coughing, laryngospasm, retching, breath holding, vomiting, stridor, desaturation and 
excessive salivation (Trevisanuto, Micaglio, Ferrarese, & Zanardo, 2004; Schmiesing & Bock-
Utne, 1998). A survey of almost 12000 patients of all ages managed with LMA over a period of 
2 years reported only 0.15% (18) critical incidents related to airway management, and none 
required intensive care management (Trevisanuto et al., 2004). 


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We will use Infasurf®, sterile intratracheal suspension of calf lung surfactant extract, FDA 
approved for prophylaxis and treatment of RDS (Infasurf package insert, ONY, Inc.; available at 
www.infasurf.com). The most common adverse reactions with Infasurf dosing procedures are 
cyanosis (65%), airway obstruction (39%), bradycardia (34%), reflux of the surfactant into the 
ETT (21%), requirement of manual ventilation (16%) and re-intubation (3%). These events were 
generally transient in the controlled trials with Infasurf. If any one of these events occurs the 
administration of the surfactant will be interrupted until the neonate's condition is stabilized.  
Other conditions observed in trials of prophylaxis using Infasurf were incidence of 
pneumothorax (10%); the overall incidence of pneumothorax in our recent rescue treatment trial 
was 17%, similar in both groups. If a pneumothorax is suspected, transillumination and/or chest 
X-ray will be done, and the pneumothorax is managed according to the clinicians' judgment.  
 
Adverse events (AEs):   
An AE is any untoward clinical occurrence including sign(s), symptom (s), and/or laboratory 
finding(s) concurrent with the use of a drug or device in humans. AEs include worsening of any 
baseline symptoms. An AE need not have a causal relationship with the use of the drug or 
device. AEs may be detected by the investigators, or other competent observers. The 
investigators will also evaluate significant changes in laboratory values and imaging results; if 
they determine that a laboratory or imaging abnormality is clinically significant, it will be 
documented, along with a determination of whether or not the abnormal finding is consistent 
with the current diagnoses. 
Reporting period: AEs will be recorded from the time of informed consent until 72 hours 
following the last use of the LMA or ETT for non-serious AEs, and until 30 days after the last 
use of the LMA or ETT for serious AEs. Any AE that occurs between the time informed consent 
is obtained and the initial airway insertion, that is considered related to a protocol-specified 
procedure, must be reported. 
Procedures for assessing, recording and reporting AEs: Throughout the duration of the study, the 
investigators will closely monitor each subject for clinical evidence of device-related events, and 
monitor all clinically information for evidence of AEs. AEs not explained by the infant’s 
underlying illness which occur during the course of the study will be reported in detail on the 
appropriate forms to the IRB, and followed until resolved or stable. All serious AEs will be 
reported to the IRB within 24 hours.  
Grading of AEs: 
• Mild - sign or symptom noticeable, but easily tolerated by the patient, and not expected to have 
a clinically significant effect on the baby’s overall health and well-being. Not likely to require 
specific medical attention. 


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• Moderate - causes interference with usual function or affects clinical status. May require 
medical intervention. 
• Serious - incapacitating or significantly affecting clinical status. Likely requires medical 
intervention and/or close follow-up. 
Expected adverse events (AEs):   
The following AEs associated with prematurity, the clinical course of RDS, or treatments for 
these conditions, are expected with the approximate frequencies listed in the Table. These AEs 
are actually or may be potentially relevant to the LMA study protocol. 
Adverse events 
Expected %
During surfactant administration procedure
Desaturation > 1 min 
5% to 20%
Airway obstruction 
39%
Bradycardia 
34%
Surfactant reflux onto CO2 detector
5%
Re-intubation  
5%
LMA replacement 
5 to 10%
Others (observer, specify): 
  
Clinical complications of prematurity and RDS
Pneumothorax 
6 to 17%
Other pulmonary air leak 
15%
Pulmonary hemorrhage 
1 to 7%
Hypotension 
15%
Oliguria 
10%
Intraventricular hemorrhage (grade > 2)
0.5% to 10%
  
Relevant Outcomes 
Chronic lung disease 
5% to 15%
Mortality (depends on gestational age)
1% to 5%
 
 


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Serious adverse events (SAE):   
A SAE is defined as an adverse effect that meets any of the following serious outcomes: 
o Is fatal; 
o Is life-threatening; 
o Results in persistent or significant disability; 
o Is an important medical event for which the subject may require medical or 
surgical intervention to prevent the outcomes above described; 
o It requires or prolongs inpatient  hospitalization 
SAEs will be recorded from the time of informed consent until the baby is discharged or 
removed from the study. A Serious Adverse event form must be completed and signed by the 
principal investigator, and submitted to the IRB within 24 hours after the event. Furthermore, the 
investigator will complete and submit follow-up SAE information including diagnosis, outcome, 
and results of specific investigations.  
The intensity or severity of SAEs: 
• SAEs will be classified as possibly related (little or no relationship with the study), 
probably related (likely to be related to the study) or definitely related (a strong relationship 
with the study). 
•  If a SAE is believed to be at least possibly related to the study device, it will be 
additionally reported to the manufacturer and the FDA.  
F. Benefits:  
There are no economic benefits for subjects or their families for participating in the research. The 
medical benefits will be evaluated as result of the research.  
G. Confidentiality: 
Every subject will have an identification code number (ICN) after the randomization that will 
identify the therapeutic method. The data collection form will have the ICN. All the data will be 


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stored in password protected files on a computer in the Neonatology fellows' office.  There will 
be two password protected files. The final dataset for analysis will be de-identified, including 
only the subjects' ICN and the study data. The second dataset will include the subjects’ name, 
MR number, date of birth and the ICN; this file will be used for cross-verification only, if 
needed. 
The principal investigator and/or co-investigator or study coordinator will release the preliminary 
information only to the IRB. Significant device-related adverse event information will be 
communicated to the IRB, the LMA manufacturer, and the FDA. Final aggregate data will 
posted on clinicaltrials.gov, and submitted for publication. 
H. Options 
The subjects that could be potentially enrolled in the trial, but whose parents do not agree to 
participate will receive the standard of care for patients with RDS, as outlined in the ETT group, 
and including premedication, intubation, rescue surfactant therapy and respiratory support as 
needed. 
 
Sponsor/materials:     
1. LMA-classic:   One size 1 device was previously donated by LMA North America, and 
another purchased by AMC. These are reusable devices, which could be used up to 40 
times each. If these are unavailable, a disposable LMA from a neonatal resuscitation box 
may be used.   
 
2. Infasurf®: Infasurf is already a stock item in the AMC Pharmacy. If, at the end of the 
study, a significant excess of Infasurf doses are used in the LMA group, the manufacturer, 
ONY, Inc., will donate the excess doses to AMC Pharmacy. No other materials are 
donated or reimbursed. ONY, Inc. will support the study through an educational grant. 
 
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