Budesonide Mas Surfactante en DBP

8/19/2019 Budesonide Mas Surfactante en DBP

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Intra-tracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary

Dysplasia

Tsu F. Yeh1,2

, Chung M. Chen1,3,4

, Shou Y. Wu5, Zahid Husan

5, Tsai C. Li

6,7, Wu S. Hsieh

8,

Chang H. Tsai2,9

, and Hung C. Lin2

1Maternal Child Health Research Center, College of Medicine, Taipei Medical University, Taipei,

Taiwan;2Department of Pediatrics, Children’s Hospital, China Medical University, Taichung,

Taiwan;

3

Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan;4Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University,

Taipei, Taiwan;5Division of Neonatology, John Stroger’s Hospital of Cook County, Chicago,

USA;6Graduate Institute of Biostatistics, College of Public Health, China Medical University,

Taichung, Taiwan;7Department of Healthcare Administration, College of Health Science, Asian

University, Taichung, Taiwan;8Department of Pediatrics, College of Medicine, National Taiwan

University and Hospital, Taipei, Taiwan; and 9Department of Biotechnology, Asian University,

Taichung, Taiwan.

Correspondence and requests for reprints should be addressed to Tsu F. Yeh, M.D., Ph.D., 252

Wu-Hsing Street, Taipei 110 or 2 Yuh Der Rd. Taichung, 40447, Taiwan. E-mail:

[email protected] or [email protected]

This article has an online data supplement, which is accessible from this issue’s table of content

online at www.atsjournals.org

ge 1 of 48 AJRCCM Articles in Press. Published on 09-September-2015 as 10.1164/rccm.201505-0861OC

Copyright © 2015 by the American Thoracic Society


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Author Contributions: Conception and design: T.F.Y. Conduction and coordination: T.F.Y.,

S.Y.W., W.S.H., and H.C.L. Acquisition of the data and statistical analyses: Z.H., S.Y.W., T.C.L.,

and C.H.T. Drafting the manuscript for important intellectual content: T.F.Y., C.M.C. Review and

revision of manuscript: T.F.Y., S.Y.W., Z.H., T.C.L., W.S.H., C.H.T., H.C.L., and C.M.C.

Funding: This work was supported in part by National Health Research Institute, Taiwan

NHRI-EX98-9818PI, NHRI-EX99-9818PI, NHRI-EX100-9818PI, NHRI-EX101-9818PI

Running head: Intra-tracheal Budesonide/Surfactant Prevents BPD

Descriptor number: 14.7 Bronchopulmonary Dysplasia

Total word count for the body of the manuscript: 3491

At a Glance Commentary

Scientific Knowledge on the Subject: Bronchopulmonary dysplasia (BPD) is an important

complication of mechanical ventilation in preterm infants and no definite therapy can eliminate

this complication. Pulmonary inflammation plays a crucial role in its pathogenesis.

Glucocorticoid is one of the most effective therapies to treat or prevent BPD. However, systemic

glucocorticoid therapy is not generally recommended because of long-term adverse events.

What This Study Adds to the Field: Intra-tracheal administration of surfactant/budesonide

compared with surfactant alone significantly decreased the incidence of BPD or death in very

low birth weight infants with severe respiratory distress syndrome. The infants received intra-

tracheal surfactant/budesonide had significantly lower interleukin levels in tracheal aspirates

compared with infants received intra-tracheal surfactant alone during the study period.

Page 2AJRCCM Articles in Press. Published on 09-September-2015 as 10.1164/rccm.201505-0861OC



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Abstract

Rationale: Bronchopulmonary dysplasia (BPD) is an important complication of mechanical

ventilation in preterm infants and no definite therapy can eliminate this complication. Pulmonary

inflammation plays a crucial role in its pathogenesis and glucocorticoid is one potential therapy

to prevent BPD.

Objective: To compare intra-tracheal administration of surfactant/budesonide with that of

surfactant alone on the incidence of death or BPD.

Methods: A clinical trial was conducted in 3 tertiary neonatal centers in the United States and

Taiwan in which 265 very low birth weight infants with severe respiratory distress syndrome

who required mechanical ventilation and inspired oxygen ≥ 50% within 4 hours after birth were

randomly assigned into 2 groups. (131 intervention and 134 control) The intervention infants

received surfactant (100 mg/kg) and budesonide (0.25 mg/kg), and the control infants received

surfactant only (100 mg/kg), until the infant required inspired O2 < 30% or was extubated.

Measurements and Main Results: The intervention group had a significantly lower incidence

of BPD or death [55/131 (42.0%) vs 89/134 (66%); risk ratio 0.58, 95% CI: 0.44 to 0.77, P <

0.001; number needed to treat (NTT) 4.1 (95% CI: 2.8 to 7.8). Intervention group required

significantly fewer doses of surfactant than control group. The intervention group had

significantly lower interleukin levels (IL-1, IL-6, IL-8) in tracheal aspirates at 12 hours and

lower IL-8 at 3-5 and 7-8 days.

Conclusions: In very low birth weight infants with severe respiratory distress syndrome, intra-

tracheal administration of surfactant/budesonide compared with surfactant alone significantly

decreased the incidence of BPD or death without immediate adverse effect.




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Word count for the abstract: 248

Keywords: bronchopulmonary dysplasia; very low birth weight infants; surfactant; budesonide;

respiratory distress syndrome

Trial Registration: NCT-00883532.




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Bronchopulmonary dysplasia (BPD) is the most important pulmonary complication following

mechanical ventilation in preterm infants. Various strategies including the use of vitamin A and

caffeine have been reported to be beneficial for BPD (1-3). However, no definite therapy can

eliminate this complication.

Although the mechanism is not completely clear, pulmonary inflammation is believed to

play a central role for the pathogenesis. Dexamethasone is one of the most effective therapies to

treat or prevent BPD. However, systemic dexamethasone therapy is not generally recommended

because of long-term adverse effects (4-5). Administering inhaled glucocorticoids to preterm

infants is technically challenging and the effects are limited (6-8). It is therefore important to find

a therapeutic method that reduces the systemic adverse effects of glucocorticoids while at the

same time retaining local anti-inflammatory effects on the lungs. Budesonide is a glucocorticoid

with strong local anti-inflammatory effects. A pilot study showed that intra-tracheal instillation

of budesonide, using surfactant as a vehicle, significantly improved pulmonary status (9). A

multi-center, randomized clinical trial was therefore undertaken to determine whether early intra-

tracheal administration of budesonide/surfactant would reduce the incidence of BPD or death.

Some of the results of these studies have been previously reported in the form of abstracts and

platform presentation in Pediatric Academic Societies meeting, May 4-7, 2013; Washington D.C.

and in European Academy of Paediatric Societies, October 17-21, 2014; Barcelona (10, 11).

Methods

Study Populations

Between April 1, 2009 and March 1, 2013, all infants with respiratory distress shortly after birth

were assessed for eligibility for the study in 3 tertiary centers, John H. Stroger Jr. Hospital (JSH),

Chicago, National Taiwan University Hospital (NTUH), Taipei, and China Medical University




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Hospital (CMUH), Taichung, Taiwan. The inclusion criteria were determined within 4 hours after

birth and included: 1) birth weight < 1500 gm, 2) radiographic evidence of severe respiratory

distress syndrome (RDS) (grade III-IV) (12), 3) mechanical ventilation, 4) fractional inspired

oxygen (FIO2) ≥ 0.5, and 5) absence of severe congenital anomalies or lethal cardiopulmonary

disorder. These infants were considered to be at high risk for developing BPD. The study was

approved by the Institutional Review Board of each participating hospital. Verbal consent was

obtained from the mother before delivery and written consent was obtained within 4 hours after

birth when inclusion criteria were determined.

Intra-tracheal Budesonide/Surfactant Instillation

Infants were randomized into either the intervention or control group based on an assignment list

designed by a statistician (TCL). Concealed randomization was generated by a computer with

permuted blocks in random sizes of 2, 4, 6, and 8 to maintain balance. A list of patient

assignments was given to each participating hospital, with half of the infants assigned to

intervention and half to control at each hospital. When the first dose was to be prescribed, the

main investigator in the participating hospital would open the assignment list and prepare the

appropriate syringe. The control group received surfactant only (Survanta,100 mg or 4 ml/kg,

Abbott Laboratory) and the intervention group received surfactant (100 mg or 4 ml/kg) and

budesonide (Pulmicort neubulising suspension, Astra Zeneca) (0.25 mg or 1 ml/kg). This dosage

provided a concentration ratio of surfactant to budesonide of > 50:1, which was demonstrated in

vitro study in Surfactometer and in high-performance liquid chromatography that this mixture

did not affect the biophysical and chemical properties of surfactant (11) (see appendix). Except

for a difference in volume, the solution in either syringe was clear and indistinguishable. The

syringe was covered by adhesive tape so that the volume of the solution could not be identified.




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The main investigators were either division director (WSH, HCL) or senior consultant (TFY),

they supervised and rarely had taken a direct patient care responsibility in NICU. Before intra-

tracheal instillation, the syringe was gently vortex, and surfactant or surfactant/budesonide

mixture was administered in a manner similar to that of routine surfactant therapy. Repeated

administrations of surfactant/budesonide or surfactant only was given every 8 hours to infants in

the intervention or control groups, respectively, until they required < 0.3 of FIO2 or were

extubated or received a maximum of 6 doses.

Respiratory Care

During the study, only the main investigator was aware of the content of the syringe. The NICU

service attending, neonatology fellows, residents and nursing practitioner who were blinded to

study assignment were the primary physicians in charge of the daily care. A general guideline for

management of RDS and fluid therapy was followed as described previously (9). For infants who

had respiratory distress shortly after birth, a trial of nasal continuous positive airway pressure

(NCPAP) was initiated in the delivery room and infants with severe retraction or poor respiratory

effort or apnea were intubated. The goal of ventilation therapy in the NICU was to maintain O2

saturation at 90-95%, PCO2 ≤ 50 mmHg, and pH ≥ 7.20. Infants who failed to respond

adequately to NCPAP (FIO2 ≥ 0.6 and O2 saturation < 85%) were subsequently intubated. The

respiratory care guideline focused on indications for using O2 hood, nasal cannula, CPAP (nasal

or intubated), intermittent mandatory ventilation (IMV), high frequency oscillatory ventilation

(HFOV), and for weaning from mechanical ventilation. Infant who could not tolerate room air or

O2 therapy through hood was placed on nasal cannula or CPAP as needed. During the study, we

defined “assisted O2 therapy” as requirement of any of the followings: nasal cannula, CPAP,

IMV, or HFOV. Blood gases and acid-base measurements were obtained each morning before




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NICU round. Nitric oxide was not given to very low birth weight infants during the study period.

Indomethacin was given to infants who had significant patent ductus arteriosus (PDA), defined

and described previously (13). Postnatal systemic dexamethasone was reserved only for infants

who had severe underlying lung disease and had intractable respiratory failure (on IMV with

FIO2 1.0 or on HFOV). In such cases, a short course of dexamethasone (3 to 5 doses of 0.25

mg/kg every 12 hours) was given at the discretion of the attending physician.

Outcome Measurements

Diagnosis of BPD was made by the service attending if the infant continuously had respiratory

distress since birth and required supplemental oxygen (> 21% O2) at 36 weeks’ postmenstrual

age. The result was reported to an outside independent observer (CMC) who was blinded to the

patient assignment. This definition was used in this study because it was considered a better

predictor of abnormal pulmonary outcome for very low birth weight infants (14). At the time of

designing this study in early 2009, we used this definition because of two reasons: 1) this

definition has been used for many years in our units, our medical and nursing staffs were very

familiar with this definition; and 2) this definition would provide a chance to compare BPD

incidence with our previous study (9) and with those important studies reported from others (2,

3, 15-17). Because of the severe radiographic RDS shortly after birth and because of continuous

respiratory distress since birth, our infants most likely represented a well establish underlying

lung disease at the time of BPD diagnosis. At the end of study, a post hoc analysis was also done

based on the current definition by National Institute of Child Health and Human Development

(NICHD) in infants < 32 weeks gestation (1). This definition was a severity-based definition. In

this definition, infant who required supplemental oxygen therapy at 28 postnatal days but did not

require supplemental O2 therapy at 36 weeks’ postmenstrual age was considered having mild




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BPD. A moderate BPD was defined as the need for < 30% oxygen and severe BPD was defined

as the need for ≥ 30% oxygen at 36 weeks’ postmenstrual age. Tracheal aspirates were assayed

(18) for interleukins (IL-1, IL-6 and IL-8) using commercial ELISA kits at 12 hours, 24 hours

and between 3 to 5 days and 7-8 days after starting the study in the first 40 infants.

Follow-up study

Follow-up study was conducted at 2-3 years of age. At each visit, an interim medical history was

obtained and a physical and neurological examination including coordination, general reflex and

muscle tone were performed. Neuromotor dysfunction was classified as mild, moderate or severe

based on the mobility of the child as described by Costello et al (19). Psychomotor and mental

evaluations were performed using Bayley Scale of Infant Development (BSID-II).

Neurodevelopmental Impairment (NDI) was defined and described by Stoll et al (20).

Statistical Analysis

Before the data were analyzed, the outside independent observer (CMC) would assess and verify

again the inclusion and exclusion criteria and the diagnosis of BPD of each infant. The primary

outcome assessed was the incidence of BPD or death.

Our previous experience indicated that about 60% of infants who fulfilled the inclusion

criteria would develop BPD or die (9). We hypothesized that 60% in the control group and 40%

in the intervention group would develop BPD or die. Allowing a 5% chance of type I error and a

10% chance of type 2 error, the number required in each group would be 130 (21). An estimated

140 patients was considered an adequate number for each group.

The secondary outcomes assessed were anti-inflammatory mediators in the tracheal

aspirates. The immediate adverse effects, including changes in serum electrolytes, glucose, blood

urea nitrogen and blood pressure and changes in physical growth were evaluated. The incidence




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of intra-ventricular hemorrhage, necrotizing enterocolitis, severe retinopathy of prematurity

(≥grade III), and clinical sepsis or bacteremia were all assessed. Cranial ultrasounds and eye

ground were examined based on a routine schedule in NICU for all infants


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prenatal steroid, Apgar score and chorioamnionitis. For secondary outcomes and immediate side

effects, no adjustments were made. All P values were 2-sided and considered significant if P <

0.05.

Results

Patient Population

During the study period, 1215 very low birth weight infants were treated for respiratory distress

at birth; 858 infants required intubation within 4 hours and were admitted to NICU. The final

number included for analysis was 265; 131 in the intervention group and 134 in the control group

(Figure 1). Their baseline data were comparable (Table 1) between the groups.

Primary Outcomes

Infants in the intervention compared with controls had a lower incidence of BPD or death

(55/131 [42.0%] vs 89/134 [66%], risk ratio 0.58, 95% confidence interval 0.44 to 0.77, P <

0.001); NNT 4.1 (95% confidence interval 2.8 to 7.8) (Table 2).

Secondary Outcomes

Of the 40 infants studied for tracheal aspirate interleukins, 2 were excluded because of

incomplete sampling. The intervention was associated with significantly lower median values for

IL-1, IL-6, and IL-8 at 12 hours (all P < 0.05) and lower IL-8 on days 3-5 and days 7-8 as

compared with surfactant alone (Table 3).

The groups were comparable in blood pressure, serum glucose and electrolytes and in

physical growth during the study (Figure 2). The 2 groups were comparable in incidence of intra-

ventricular hemorrhage [53/131 (40.5%) vs 57/134 (42.5%), P = 0.80)], necrotizing enterocolitis

[4/131 (3.1%) vs 7/134 (5.2%), P = 0.56], severe retinopathy of prematurity [7/131 (5.2%) vs

9/134 (6.8%), P = 0.79], clinical sepsis and/or bacteremia [29/131 (22%) vs 38/134 (28%), P =




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Post Hoc Analyses

The post hoc analysis of the primary outcome adjusted for prenatal steroid, Apgar score and

chorioamnionitis also showed a significant difference between the intervention and control group

(odd ratio 0.37, 95% confidence interval 0.22 to 0.54, P < 0.01). Based on the NICHD definition,

infant in the intervention group had a significantly lower incidence of severe BPD than infant in

the control group (Table 2).

Follow-up study

Up to this time, 192 infants (85.0%) of the 226 survivals are followed. The perinatal

characteristics and the physical, neurological and cognitive outcomes were shown in Table 4.

Except lower incidence of BPD [25/85 (29.4%) vs 39/87 (4.8%), P = 0.04] in the intervention

group at time of discharge, there was no significant difference between the groups in any of these

follow–up variables. Frequent upper respiratory infection (>10 times/year) was seen less often in

the intervention than the control group [15/89 (16.9%) vs 24/87 (27.6%) P = 0.15], this

difference was not statistically significant.

Discussion

This study demonstrated that in very low birth weight infants with severe RDS, intra-tracheal

instillation of budesonide/surfactant significantly reduced the incidence of BPD or death

compared with surfactant alone. No serious adverse effects were seen. Budesonide plus

surfactant was associated with a better pulmonary status in the early course of therapy and a

decreased need for assisted O2 therapy subsequently. The improvement in these parameters in

the intervention group may account for the lower incidence of BPD.

The mechanism to use surfactant as a vehicle was based on a physical phenomenon, the

“marangoni effect” (23). This effect is basically the mass transfer along an interface between two




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fluids due to surface tension gradient. Thus, when surfactant is instilled into the lungs of infants

with RDS, a convection flow is generated that may facilitate the delivery of medications, such as

budesonide, to the lung periphery. Various animal studies indicated that intra-tracheal

administration of surfactant and corticosteroid improved lung function (24-27). Direct intra-

tracheal instillation of budesonide without using surfactant as vehicle has not been shown

effective (28). A recent randomized controlled trial showed reduction of death before 36 weeks

or BPD by inhaled budesonide in extremely-low-birth-weight infants was of borderline statistical

significance (29).

Our pilot study indicated that more than 80% of budesonide may remain in the lungs for up

to 8 hours after intra-tracheal instillation of survanta/budesonide (9). Besides using as a vehicle

surfactant may also enhance the solubility of budesonide and increase budesonide absorption

(30). Budesonide is not metabolized by lung cells; rather, it is conjugated extensively with fatty

acids, resulting in the formation of budesonide esters at the C21-hydroxyl group (31). This

conjugation process is reversible, and the conjugates can be hydrolyzed inside the cell, gradually

releasing free budesonide into the surrounding medium. This reversible conjugation may

improve airway selectivity and prolong its local anti-inflammatory action in the lungs, possibly

explaining why budesonide was effective for days, even though only 1 or 2 doses were

administered. Based on the pharmacokinetic data (9), we estimate that 5-10% of budesonide may

still remain in the lungs by one week. Budesonide that is absorbed into the circulation is rapidly

metabolized in liver to 16-α-hydroxyprednisolone, which has low glucocorticoid activity. The

elimination half-life of plasma budesonide is about 4 hours (9). The results of our study also

suggest that a similar therapeutic method may be applied to shock lung, pneumonia, severe acute

respiratory syndrome, or malignancy. The systemic adverse effects associated with steroids,




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antibiotics, and chemotherapeutic agents could be markedly reduced. Further studies are needed

for this clinical implication.

The mechanism responsible for the effectiveness of budesonide is most likely due to its

anti-inflammatory effects. The improvement was seen early after intra-tracheal

surfactant/budesonide instillation as opposed to 2-3 days following systemic administration of

dexamethasone (32). The direct local anti-inflammatory effect may have played an important

role for this rapid improvement. This rapid improvement may be also related to the higher

volume of instillation in the intervention group (5 ml/kg) as compared to the control infant (4

ml/kg) that might facilitate surfactant/budesonide delivery. However, the higher volume could

also dilute the surfactant concentration in the liquid-air surface and decrease the surface-tension

reducing property of surfactant. Although there were small changes in FIO2, PO2 and PCO2

during the first few days, the intervention group needed less assisted O2 therapy on days 3, 7, 21,

and 28 suggesting a longer effect on the lungs. Lung inflammation occurs very early following

mechanical ventilation and any therapy beneficial for BPD prevention has to be administered as

early as possible. The results from our study indicated that budesonide was effective early in the

course of therapy, which might translate to longer term effects on the lungs.

Corticosteroids are known to cause growth impairment. In this study we didn’t find any

immediate alteration in serum glucose, electrolytes, blood pressure, and physical growth with

budesonide therapy. Another major concern following glucocorticoid therapy is long-term

adverse effects. Budesonide has been used in children with asthma for years without significant

long term side effects (33-36).While the follow up study is still in progress, our preliminary data

on 84 % of the survival up to 2-4 years indicates no apparent long term adverse effect on

physical growth, and on neuromotor and cognitive function. Based on our previous follow-up




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study (33) and the current preliminary results, and in view of the fact that majority of the infant

(65%) in the intervention group received only one dose of budesonide and that there was no

immediate adverse effect, the long-term side effects are probably negligible. A complete and

longer follow-up study is needed before this therapeutic regimen can be generally recommended

This study was done in 3 tertiary centers in 2 countries, which may raise the question of its

general application. However, diagnostic criteria and assessment tools that have good predictive

accuracy and have been evaluated across different hospital settings were used. All the

participating hospitals followed a standard protocol for respiratory care. In addition, an

independent observer unaware of the treatment assignment monitored the outcome; this may

decrease the study bias.

In conclusion, in very low birth weight infants with severe RDS, intra-tracheal

administration of surfactant and budesonide compared with surfactant alone significantly

decreased the incidence of BPD or death. Further large sample, double blind trials are warranted.

Acknowledgement: The authors like to thank Roberta A. Ballard, MD, PhD, and Philip L.

Ballard, MD, PhD, from UCSF, California, and William Oh, MD, from Brown University, Rhode

Island, for their expertise comments; Ju C. Cheng, PhD, from Department of Biotechnology,

China Medical University, Taichung, Taiwan for interleukins assay. Mei H. Wang, PhD, from

Institute of Nuclear Energy Research (INER), Longtan, Taiwan for Nano/PET digital scan of F-

18 labeled budesonide in rats. We also thank Ms. Audrey Yeh, Yu C. Pan and Hsiang T. Chou for

manuscript preparation and all the NICU nursing staffs at John H. Stroger Jr. Hospital, Chicago,

and China Medical University Hospital, Taichung and National Taiwan University Hospital,

Taipei, Taiwan for their cooperation. None of the names listed in the acknowledgement received




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compensation for their contribution.




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event for all end points. Infants in the intervention group had a significantly higher chance to be

weaned to room air than infants in the control group.




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Table 1. Baseline Characteristics

Perinatal Characteristics Intervention (131) Control (134)

Birth weight (g) 882 (249) 935 (283)

500-749 46 (35%) 42 (31%)

750-999 50 (38%) 42 (31%)

1000-1499 35 (27%) 50 (38%)

Gestational age (postmenstrual weeks) 26.5 (2.2) 26.8 (2.2)

SGA

AGA

9 (6.8%)

122 (93.1%)

11 (8.2%)

123 (91.8%)

Gender

male

female

71 (54.2%)

60 (45.8%)

72 (53.7%)

62 (46.3%)

Prenatal steroid 112 (85%) 106 (79%)

Chorioamnionitis 11 (8.4%) 10 (7.4%)

Mode of delivery

Cesarean Section 83 (63%) 83 (62%)

Vaginal delivery 48 (37%) 51 (38%)

Apgar Score

1 min

≤3 41 (31%) 48 (36%)

4-6 68 (52%) 67 (50%)

>6 22 (17%) 19 (14%)

5 min

≤3 3 (2%) 7 (5%)

4-6 26 (20%) 36 (27%)

>6 102 (78%) 91 (68%)




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Table 1. (continued)

Clinical and Laboratory Characteristics at Time of Entry into Study

Age (hrs) 2.0 (1.5) 1.8 (1.4)

IMV 131 134

FIO2 0.61 (0.25) 0.63 (0.26)

MAP (cm H2O) 7.1 (4.8) 7.2 (1.5)

OI 8.0 (4.3) 8.1 (5.1)

PO2 (mm Hg) 70.6 (57.9) 68.5 (43.3)

PCO2 (mm Hg) 48.1 (10.5) 49.7 (18.5)

pH 7.25 (0.12) 7.24 (0.14)

Blood Pressure (mmHg)

Systolic 48.1 (11.9) 46.6 (9.2)

Diastolic 29.4 (9.6) 27.5 (8.4)

Hematocrit (%) 42.4 (6.6) 42.6 (6.7)

Data are expressed as mean (SD) or number (%).

IMV = intermittent mandatory ventilation; MAP = mean airway pressure; OI = oxygen index.

SGA and AGA was defined if the births weight less than 10th percentile and between 10th and

90th percentile in intrauterine growth chart, respectively.




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Table 2. Mortality and BPD Morbidity

Intervention

(131)

Control

(134)

Difference (95% CI) RR (95% CI) P

value

BPD or Death 55/131 (42%) 89/134 (66%) -0.24 (-0.36 to -0.13) 0.58 (0.44 to 0.77)


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Table 3. Interleukins Concentration (pg/ml/mg urea) in Tracheal Aspirates and Baseline

Characteristics

Intervention group Control group

(n=18) (n=20) P value

Birth weight (g) 809 (196) 886 (232) 0.56

Gestational age

(weeks)

26.2 (2.4) 26.3 (1.6) 0.86

FIO2 0.64 (0.19) 0.59 (0.20) 0.57

MAP (cm H2O) 6.9 (0.87) 6.9 (0.99) 0.94

OI 6.7 (3.7) 7.0 (4.0) 0.44

Death 2 (11.1%) 5 (25.0%) 0.41

BPD 6 (33.3%) 11 (55%) 0.21

Death or BPD 8 (44.4%) 16 (80%) 0.042

Interleukins (pg/ml/mg urea) Z value P value

IL-1

12 hours 2.0 (1.4-4.4) 16.5 (6.2-21.0) -2.33 0.02

24 hours 10.7 (1.5-15.0) 24.0 (2.3-53.0) -13.5 0.18

3-5 day 13.5 (9.2-23.0) 61.5 (18.0-86.0) -1.43 0.15

7-8 day 14.2 (7.1-29.0) 17.1 (9.2-26.2) -0.04 0.97

IL-6

12 hours 32.0 (2.1-60.0) 79.0 (65.0-112.0) -2.57 0.01

24 hours 27.0 (7.3-30.0) 27.5 (13.0-47.0) -0.94 0.35

3-5 day 20.0 (15.0-27.0) 44.5 (18.0-53.0) -1.47 0.14




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7-8 day 9.0 (3.4-12.0) 7.4 (4.0-10.0) -0.12 0.90

IL-8

12 hours 53.0 (20.0-86.0) 198.0 (56.0-405.0) -2.12 0.03

24 hours 40.0 (21.0-49.0) 152.0 (29.0-540.0) -1.72 0.09

3-5 day 60.0 (48.0-105.0) 422.0 (180.0-580.0) -2.49 0.01

7-8 day 146.0 (86.0-210.0) 785.0 (160.0-1200.0) -2.25 0.02

Data are expressed as mean (SD) of baseline characteristics on admission to study, or median

(Q1-Q3) of interleukins.

OI = oxygen index; MAP = mean airway pressure.




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Table 4. Follow-up study

Perinatal Characteristics Intervention (85) Control (87)

Birth weight (g) 907 (215) 920 (240)

Gestational age (weeks) 26.5 (1.8) 26.7 (2.1)

Gender

male 45 (53%) 41 (47%)

Female 40 (47%) 46 (53%)

Follow up study

Age (m) 30.1 (4.2) 30.1 (3.9)

Weight (kg) 11.7 (1.8) 11.8 (2.3)

HC (cm) 47.7 (2.7) 46.9 (2.8)

L (cm) 86.7 (5.2) 85.8 (5.4)

Neuromotor dysfunction 23 (27.1%) 20 (23.0%)

Moderate to severe 8 (9.4%) 8 (9.2%)

MDI 83.4 (18.7) 81.5 (2.8)

MDI (≤ 69) 18 (21.2%) 19 (21.8%)

PDI 77.9 (18.7) 77.6 (20.1)

PDI (≤ 69) 24 (28.2%) 26 (29.9%)

NDI 26 (30.6%) 34 (39.1%)

Data are expressed as mean (SD) or number (%)., URI: upper respiratory infection

HC = head circumference; L = length; MDI = mental developmental index; PDI = psychomotor

developmental index; NDI = neurodevelopmental impairment




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190x254mm (96 x 96 DPI)




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190x275mm (300 x 300 DPI)




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190x275mm (300 x 300 DPI)




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254x190mm (300 x 300 DPI)




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206x304mm (300 x 300 DPI)




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Intra-tracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary

Dysplasia

Online Data Supplement

Tsu F. Yeh, Chung M. Chen,. Shou Y. Wu, Zahid Ullah, Tsai C. Li, Wu S. Hsieh, Chang H.

Tsai, Hung C. Lin

1Maternal Child Health Research Center, College of Medicine, Taipei Medical University,

Taipei, Taiwan;2Department of Pediatrics, Children’s Hospital, China Medical University,

Taichung, Taiwan;3Department of Pediatrics, Taipei Medical University Hospital, Taipei,

Taiwan;4Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical

University, Taipei, Taiwan;5Division of Neonatology, John Stroger’s Hospital of Cook

County, Chicago, USA; 6Graduate Institute of Biostatistics, College of Public Health,China

Medical University, Taichung, Taiwan;7Department of Healthcare Administration, College of

Health Science, Asian University, Taichung, Taiwan;8Department of Pediatrics, College of

Medicine, National Taiwan University and Hospital, Taipei, Taiwan; and9Department of

Biotechnology, Asian University, Taichung, Taiwan.




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Introduction

Surfactant has been used as a vehicle to deliver steroid in animals (1, 2) and in preterm infants

with RDS in a pilot study (3). However, the stability associated with administering a

steroid/surfactant mixture have not been well studied. Budesonide (Pulmicort neubulising

suspension, Astra Zeneca, Lund, Sweden), a dehalogenic glucocorticoid, and survanta (Abbott,

Columbus, OH), a mixture of phospholipid and hydrophobic proteins, both are stable

compounds. However, budesonide, (22R,S)-16α, 17α-butylenedioxy-11β,

21-dihydroxypregna-1,4-diene-3, 20-dione, having a ring structure with a certain degree of

un-saturation and branching, may interfere with the structure of the surfactant monolayer at

the air-liquid interface and, thus, may affect the surface-tension property of survanta. We,

therefore, conducted an in vitro study if the mixture of survanta and budesonide is

biophysically stable; and if the survanta and budesonide mixture is chemically stable.

Method

Biophysical and Chemical Stability of Survanta/Budesonide Mixture

To test the biophysical stability of surfactant after addition of budesonide, a series of tests

were performed using a surfactometer. Competitive absorption behavior of a

survanta-budesonid suspension with different concentration ratios between these two

compounds was conducted in a surfactometer (Amherst Electronics, Buffalo, NY). The

dynamic surface tension behavior of survanta, budesonide, and their mixtures was evaluated




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by pulsating the air-liquid interfaces at a rate of 20 cycles per minute at 37℃.

To test the chemical stability of the survanta/budesonide mixture, high performance liquid

chromatography (HPLC) was performed (SGS, Taoyen, Taiwan Ltd) at 0, 1, 4, 8, 12, and 24

hours after mixture of survanta/budesonide, with a concentration ratio of 25:1, 50:1, and

100:1.

Animal Study

To investigate if surfactant can be used as a vehicle to facilitate budesonide delivery,

Sprague-Dawley rats were intratracheally injected with 50 µl

surfactant/18F-budesonidemixture (with a concentration ratio of 12.50:0.12 mg/ml by equal

volume mixing, n = 3) or with 50 µl18

F-budesonideonly (0.12 mg/ml, n = 3). The

18F-budesonidebiodistribution and radioactivity was visualized and measured at 15, 30, 45,

and 60 min after injection by a Nano/PET/CT digital scan.

Statistical Analysis

Data are expressed as means ± SD. Between-group comparisons were made using Student’s

t -tests. Differences were considered significant at P < 0.05.

Results

Biophysical and Chemical Stability of Survanta/Budesonide Mixture

When a survanta suspension was mixed with an equal volume of a budesonide suspension, at

a concentration ratio of 12.50:0.25 mg/ml (50:1) or greater, the dynamic surface activity of




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survanta suspension as shown in sufactometer was minimally affected (Table 1). Based on

these results, we decided that the dosage between survanta/budesonide ratio for neonates

should be ≥50:1. The results were reported previously (4).

The HPLC analysis revealed that no new compounds were identified at any of the time

points after mixing survanta and budesonide at various concentration ratios (Figure 1A to 1T).

Thus, the mixture of budesonide and survanta appears to be chemically stable.

Pulmonary Distribution of18

F-Budesonide

The radioactivityof18

F-budesonide was most strongly detected near the trachea at 15 min

after intra-tracheal injection (Figure S2A). Almost no radioactivity was seen in the lung

region of the rats injected with18

F-budesonide alone at 60 min. The radioactivity of

18F-budesonide was distributed more in the peripheral lung and stayed longer in rats

supplemented with surfactant than in the rats without surfactant. Rats injected with

surfactant/18

F-budesonide mixture exhibited an approximately 200% increase in radioactivity

compared with rats that received18

F-budesonide alone during the study period (Figure 2B).

The detail results will be published elsewhere.

Conclusion

Surfactant can be used as an effective vehicle to facilitate the delivery of budesonide into the

lungs. With a concentration ratio of survanta/budesonide ≥50, the mixture is biophysically and

chemically stable.




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References

1.

Fajardo C, Levin D, Garcia M, Adrams D, Adamson I. Surfactant versus saline as a

vehicle for corticosteroid delivery to the lungs of ventilated rabbits. Pediatr Res

1998;43(4 pt 1):542–547.

2.

Chen CM, Fang CL, Chang CH. Surfactant and corticosteroid effects on lung function in a

rat model of acute lung injury. Crit Care Med 2001;29:2169–2121.

3.

Yeh TF, Lin HC, Chang CH, Wu TS, Su BH, Li TC, Suma P, Tsai CH. Early intratracheal

instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in

preterm infants: a pilot study. Pediatrics 2008;121;e1310-e1318.

4.

Chang DH, Chang CH, Lin YJ, Yeh TF. Influence of budesonide (B) on the dynamic

surface tension behavior of surfactant (survanta) (s) at pulsating air–liquid interface.

Pediatr Res 2002;51:346A

5.

Hvizdos KM, Jarvis B. Budesonide inhalation suspension: a review of its use in infants,

children and adults with inflammatory respiratory disorders. Drugs 2000;60:1141–1145.




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Dynamic Surface Tension Behavior of Survanta, Budesonide, and Their Mixtures

System

Phospholipid

Concentration,

mg/mL

Budesonide

Concentration,

mg/mL

Ye,

mN/m

Ymin,

mN/m

Ymax,

mN/m

S suspension

25.00

-

19

-0

46

12.50

-

21

-0

51

1.00

-

22

5

49

B suspension

-

0.50

31

27

47

-

0.25

33

29

49

Mixed S/B

suspension

12.50

0.25

20

-0

41

1.00 0.25 28 20 45

S indicates survanta; B, budesonide; mN/m, milli-Newton/meter; Ye, equilibrium

surface tension; Ymin, minimum surface tension; Ymax, maximum surface tension

(from Yeh et al. Pediatrics 2008;121:e1310-e1318).




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Figure Legends

Figure 1. HPLC performed on budesonide, survanta, and survanta/budesonide mixture,

comprising different concentration ratio of mixture (25:1, 50:1, and 100:1) at 0, 1, 4, 8, 12,

and at 24 hours after mixing of the two drugs. There was no new compound identified during

these tests, indicating that budesonide/survanta mixtures are chemically stable.

Figure 2. The18

F-budesonide bio-distribution (A) and radioactivity (B) in the

Sprague-Dawley rats intra-tracheal injected with surfactant/18

F-budesonide (n = 3) or

18F-budesonide alone (n = 3). The

18F-budesonide was distributed more into the peripheral

lungs and the accumulated 18F-budesonide radioactivity was higher in the rats supplemented

with S than in the rats without S during the study period. B =18

F-budesonide, BS =

surfactant/18

F-budesonide.




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Fig-1 A

Budesonide (B) 0.5 mg/ml

Fig-1B

Survanta (S) 25 mg/ml




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Fig -1E

S/B: 50/1 at 4 hr

Fig -1F

S/B: 50/1 at 8 hr

AJRCCM Articles in Press. Published on 09-September-2015 as 10.1164/rccm.201505-0861OC



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Fig -1I

S/B: 25/1 at 0 hr

Fig -1J

S/B: 25/1 at 1 hr




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Fig -1M

S/B: 25/1 at 12 hr

Fig -1N

S/B: 25/1 at 24 hr

F

S

AJRCCM Articles in Press. Published on 09-September-2015 as 10.1164/rccm.201505-0861OC



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Fig -1Q

S/B: 100/1 at 4 hr

Fig -1R

S/B: 100/1 at 8 hr




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Figure 2


Budesonide Mas Surfactante en DBP

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