Published online September 29, 2008
PEDIATRICS Vol. 122 No. 4 October 2008, pp. e917-e921 (doi:10.1542/peds.2007-3193)
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ARTICLE

Changing Use of Surfactant Over 6 Years and Its Relationship to Chronic Lung Disease

Euming Chong, MDa, Jay Greenspan, MDa,b, Sharon Kirkby, MSNc, Jennifer Culhane, PhDd and Kevin Dysart, MDa,b

a Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania
b Nemours Children's Clinic, Alfred I. du Pont Hospital for Children, Wilmington, Delaware
c Alere (formerly ParadigmHealth), Upper Saddle River, New Jersey
d Department of Obstetrics and Gynecology, Drexel Medical College, Philadelphia, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Our goals were to identify the trend of surfactant use over a 6-year period and to determine whether a relationship exists between the incidence of chronic lung disease in infants born weighing <1000 g who receive surfactant and those who do not.

METHODOLOGY. Data regarding surfactant use, incidence of chronic lung disease, nasal continuous positive airway pressure use and duration, and demographic data were collected from the Alere (formerly ParadigmHealth) database from 2001 to 2006 (n = 3086). Groups were compared by using {chi}2 test, analysis of variance, or Student's t test.

RESULTS. Use of surfactant has decreased over time from 67% in 2001 to 59.9% in 2006. Infants who received surfactant were more likely to develop chronic lung disease. Those who received >1 dose of surfactant were more likely to develop chronic lung disease when compared with infants treated with only 1 dose. Chronic lung disease rates have risen over time from 47.8% in 2001 to 57.8% in 2006. There was no difference in survival between groups.

CONCLUSIONS. Despite the findings that surfactant use decreased during the study period and the rate of chronic lung disease increased, the data do not support a connection. Infants who receive surfactant are more likely to develop chronic lung disease, and chronic lung disease rates are stable in those infants not treated with surfactant. It is concerning, however, that 60% of infants not receiving surfactant developed chronic lung disease.

Key Words: prematurity • morbidity • lung disease • surfactant

Abbreviations: CPAP—continuous positive airway pressure • CLD—chronic lung disease • PDA—patent ductus arteriosus • IVH—intraventricular hemorrhage • ROP—retinopathy of prematurity • SGA—small for gestational age

Surfactant has been used for treatment of respiratory distress syndrome in premature infants since the late 1980s. Since then, multiple clinical studies have been conducted looking at the efficacy of surfactant in preventing major morbidities associated with prematurity. A meta-analysis published in the Cochrane Review in 1999 concluded that prophylactic surfactant administration shows a trend toward reducing risk for bronchopulmonary dysplasia and death at 28 days of age.1 However, with the increasing knowledge regarding ventilator-induced lung injury,2–4 multiple studies have evolved with regards to the use of nasal continuous positive airway pressure (CPAP) for ventilation. CPAP use has been implicated in decreasing the incidence of chronic lung disease (CLD), secondarily decreasing ventilator-induced lung injury and promoting earlier tracheal extubation.5–7 However, other studies including a meta-analysis by Subramaniam et al,8 found conflicting results with regards to effects on incidence of CLD.8–10 As a result of these variable conclusions, multiple centers are applying the strategy of early nasal CPAP use11,12 with variable success, thus leading to a decreased use of surfactant. We hypothesize that the incidence of CLD has increased over time with the decreasing use of surfactant.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
This was a retrospective data analysis on a large cohort of infants. The Alere (formerly ParadigmHealth) database was queried for all surviving infants born weighing <1000 g between January 2001 and December 2006. All patients who died were excluded from the analysis. Patients were either in level II or III hospitals at both community and academic settings. The institutional review board at Thomas Jefferson University approved this study.

Information analyzed included gestational age, birth weight, length of hospital stay, use and number of doses of surfactant, days on conventional ventilator, and incidence of CLD. CLD was defined as the need for supplemental oxygen at 36 weeks’ postmenstrual age. Other comorbidities analyzed within these populations included patent ductus arteriosus (PDA); severe intraventricular hemorrhage (IVH), defined as grade 3 or higher; severe retinopathy of prematurity (ROP), defined as stage 3 or more; confirmed necrotizing enterocolitis; and bacterial sepsis acquired after 3 days of life. All infants who received surfactant were compared by year for demographics and outcomes. In addition, infants who received surfactant during this time period were compared with all infants who did not receive surfactant.

Organization of the Alere Database System
The Alere database concurrently collects clinical information for all patients who Alere follows for multiple health plans and self-insured employer groups. Currently, >1235 NICUs across the United States are represented in the database. Clinical information including basic demographics, maternal history, birth history, cost data, and level of intensity of care, as well as over 300 separate clinical variables, are documented 3 to 4 times/wk by Alere Care Managers who are experienced NICU nurses. The Alere database, therefore, includes a wide range of gestational ages and longitudinal in-hospital recording of morbidity, treatment, and costs, which has lead to a database with a significant amount of information for clinicians to access.

Statistics
Groups were compared by using analysis of variance, Student's t test, or {chi}2 test. Statistical analysis was conducted by using the SAS (JMP 5.1) statistical program (SAS Institute, Inc, Cary, NC). A P value of <.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During the 6-year period, there were 3086 infants who met inclusion criteria for analysis. The gestational age in this time period did not change significantly as the mean gestational age (± SD) at 26.1 ± 1.7 weeks in 2001 and 26.1 ± 1.5 weeks in 2006. It was statistically significant when compared between groups but was not clinically significant because mean gestational age only varied between 25.8 weeks and 26.1 weeks. The percentage of patients who developed pneumothorax was higher in 2001 at 7.2% compared with 2006 at 2.4%. This was statistically significant when compared between groups over the study period. Small for gestational age (SGA) status, percentage of infants with Apgar score <5 at 5 minutes of life, mean birth weight, length of hospital stay, and duration of mechanical ventilation were also not significantly different in this time period, indicating minimal to no change in the patient population's baseline demographic (Table 1).


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  		TABLE 1 Patient Demographics From 2001 to 2006

 
Demographic Variables Corrected for Surfactant Use
The data were analyzed with regards to surfactant use as shown in Table 2. Use of surfactant was associated with younger gestational age (25.7 weeks compared with 26.3 weeks), birth weight (771 vs 789 g), longer length of hospital stay, and increased days on mechanical ventilation (P < .01). Surfactant use was also associated with higher neonatal morbidity (as shown in Table 3) as a measure of severity of illness. Incidence of PDA, grade 3 or higher IVH, stage 3 or higher ROP, and sepsis were higher in patients who received surfactant.


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  		TABLE 2 Characteristics of Patients Stratified According to Surfactant Use

 

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  		TABLE 3 Neonatal Morbidity and Surfactant Use

 
Surfactant Use in the Study Time Period
The trend of surfactant use decreased over the 6-year study period from 67.6% in 2001 to 56.7% in 2005 (P < .05); however, the rate of surfactant use increased in 2006 (Fig 1) This trend was also noticed when the number of surfactant doses was analyzed in their respective year as well. In Fig 2, there is an increasing number of patients who did not receive any surfactant from 2001 (32.4%) to 2006 (40.1%). However, the percentage of patients who received only 1 dose of surfactant remained fairly stable from 2001 to 2005. In 2006, there was a significant decrease in the use of single-dose surfactant (33.6% vs 41.6%). In the first 5 years of the study period, use of 2 doses of surfactant from 20.4% to 12.3%. However, in 2006, the percentage of patients receiving 2 doses of surfactant increased to levels seen in the earlier time period (18% in 2006 compared with 20% in 2001).


Figure 1
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  		FIGURE 1 Trend of surfactant use over the 6-year study time period. Surfactant use was significantly higher in earlier years (2001 and 2002) and trended lower in the later study time period (2005 and 2006).

 

Figure 2
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  		FIGURE 2 Trend of number of doses of surfactant used in the study time period. From 2001 to 2006, the percentage of patients who did not receive surfactant (0) increased from 32% to 40%. The percentage of patients receiving only 1 dose of surfactant remained stable from 2001 to 2005 but decreased between 2005 and 2006. There was a trend toward decreasing use of 2 doses of surfactant in the first 5 year of the study period. However, in the year 2006, the use of 2 doses of surfactant increased from 12% to 18%. The use of >3 doses of surfactant remained stable in the 6-year study time period.

 
The trend of surfactant use and incidence of CLD was then analyzed by year in the infants’ respective gestational age (Fig 3). In Fig 3A, we again noted that the trend of surfactant use decreased over the study period for each gestational age strata. However, the incidence of CLD showed an increasing trend for each gestational age strata throughout the study period (Fig 3B).


Figure 3
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  		FIGURE 3 Trend of surfactant use and incidence of CLD according to gestational age over the 6-year study period. A, There was an overall trend toward decreasing use of surfactant in all gestational ages over the study period. B, The incidence of CLD, however, seemed to be increasing in almost all gestational ages from 2001 to 2006.

 
Rate of CLD in the Study Time Period and its Relationship to Surfactant Use
The incidence of CLD increased from 47.7% in 2001 to 57.8% in 2006 (P < .01; Fig 4). In the population of patients with CLD, the incidence was higher in the group who received surfactant (57.5%) compared with those not exposed to surfactant (49.4%; Fig 5) The data were then analyzed for the subset of patients with CLD and stratified according to the use of surfactant and gestational age. In Table 4, the percentage of infants with CLD in the group receiving surfactant was either stable or trends lowers for each gestational age, and the reverse was observed in the groups without surfactant. However, it was noted that percentage of infants with CLD who did not receive surfactant was consistently >40% in the gestational age groups of 27 (after 2003), 28, and 29 weeks throughout the study period.


Figure 4
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  		FIGURE 4 Incidence of CLD in the study time period. The rate of CLD increased significantly from 2001 to 2006, with a corresponding decrease in the percentage of patients who do not have CLD. a P < .01.

 

Figure 5
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  		FIGURE 5 Relationship of CLD and use of surfactant. The percentage of patients with CLD was significantly higher (57%) in the population who received surfactant (A) compared with those who were not exposed to surfactant (B). a P < .005.

 

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  		TABLE 4 Incidence of CLD Stratified According to Gestational Age and Surfactant Use Over the 6-Year Study Period

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Surfactant is the only medication in neonatal care proven to reduce mortality and associated ventilator-induced injury from respiratory distress syndrome.13 This has led to increasing use of early/prophylactic surfactant administration as opposed to surfactant rescue therapy. A meta-analysis by Stevens et al13 in the Cochrane Review concluded that early surfactant therapy with extubation to CPAP compared with rescue surfactant was associated with reduced need for mechanical ventilation, although the rate of CLD remained unchanged. Despite the lack of evidence for prophylactic CPAP use, it is being administered increasingly from the delivery room. This practice may explain the decreasing use of surfactant in the last 6 years as noted by our group. The decreasing use of surfactant was also noted by our group and was consistent when analyzed either by year or by gestational age. We note that single-dose surfactant administration remained fairly stable in our study time period. It is interesting to note that use of 2 doses of surfactant was decreasing in the first 5 years of our study period, but in 2006 use of multiple doses of surfactant increased followed by a corresponding decrease in single-dose use of surfactant. Factors attributing to this change in clinical practice remains to be elucidated. When prophylactic CPAP fails, the most common reason is increasing oxygen requirement or increasing episodes of apneas and bradycardia. These patients would then be intubated, and we speculate that clinicians are recognizing the need for surfactant, and possible multiple doses in this subset of population with CPAP failures after intubation. It would be interesting to evaluate data regarding the timing of mechanical ventilation, CPAP, and CPAP failures to tease out the above data. Unfortunately, our database did not contain data with regards to the use of prophylactic CPAP and rate of CPAP failures.

It is also concerning that common neonatal morbidities such as PDA, IVH, ROP, and sepsis were associated with surfactant use. We could argue that this may be a reflection of a sicker population with lower gestational age and birth weight. However, our baseline demographics reveal that in the past 6 years, our patient population has remained fairly stable. Gestational age, birth weight, and even length of hospital stay have remained unchanged from 2001 to 2006. There were not enough variables collected in our database to formulate either the clinical risk index for babies (CRIB) or score for neonatal acute physiology perinatal extension (SNAPE) scores as markers of disease severity. However, the percentage of infants with Apgar scores of <5 at 5 minutes of life and those who develop pneumothoraces were stable from 2001 to 2006. The percentage of infants who were SGA was also stable throughout the study period; however, when stratified according to gestational age, the incidence of patients who were SGA were higher in the older gestational age groups of 27 weeks and above. This probably reflects our inclusion criteria of infants weighing <1000 g and therefore, an infant at 28 weeks’ gestational age weighing <1000 g will be defined as SGA as opposed to an infant at 25 weeks’ of similar weight. Therefore, it seems that although clinicians are using surfactant less frequently, they may be selecting a sicker subset of the population with inherent increased risk of the earlier-stated morbidities.

It is concerning that despite advances in the past decade, with the introduction of surfactant, better understanding of ventilator management, and the use of antenatal steroids, the incidence of CLD has not changed but rather worsened, increasing to almost 60%. This was also noted by Genzel-Boroviczény et al,14 in that mortality and major morbidities did not change significantly in their center despite changes in neonatal and obstetric care in the 1990s. These results were repeated by the National Institute of Child Health and Human Development Neonatal Network in evaluating their outcome in the past 15 years from 1987 to 2000. Although they noted a decrease in mortality for the entire cohort from 23% in 1987–1988 to 14% in 1999–2000, within each birth weight cohort, major morbidities such as CLD did not change significantly.15 This was also noted in our cohort of patients who develop CLD and received surfactant from 2001 to 2006. Again, one could argue that this increase is reflective of an increasing survival of a sicker population. But as noted earlier, this is not the scenario, because even the duration of mechanical ventilation has remained unchanged in the past 6 years. Interestingly, the rate of CLD seems to be increasing in groups not receiving surfactant, especially at older gestational ages of 28 and 29 weeks. An average rate of 45% and 50% in infants who are 28 and 29 weeks’ gestational age, respectively, compared with the average rate of 30% to 35% in lower gestational age infants who are at higher risk of developing CLD is disturbing.


   CONCLUSIONS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Despite our findings that the incidence of CLD has increased in the last 6 years and seems to be associated with surfactant use, we do not believe that surfactant results in the development of CLD. Once again, is this association more a reflection of clinicians recognizing and therefore, treating, patients whom they attribute as those with increased risk of developing CLD?

However, we have to agree that the risk of CLD is multifactorial and, therefore, may not be solely related to trends in surfactant use. The cause of CLD has shifted from being predominantly associated with ventilator-induced injury to the "new bronchopulmonary dysplasia" secondary to inflammation.16,17 Multiple studies have looked at association between maternal chorioamnionitis and incidence of CLD.18,19 Neonatal infection after 3 days of life has also been implicated as a source of the increasing trend in CLD.20–22 With mounting knowledge regarding the pathogenesis of CLD, this will give rise to increasing studies required for treatment and prevention of CLD. It is important for clinicians to be aware of changes in clinical practice as a result of newer studies and their impact on CLD, 1 of the most prevalent neonatal morbidities.


   FOOTNOTES
 
Accepted Jun 4, 2008.

Address correspondence to Euming Chong, MD, Jefferson Medical College, Department of Pediatrics, 1025 Walnut St, 700 College Building, Philadelphia, PA 19107. E-mail: euming.chong{at}mail.tju.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Surfactant administration trends toward reducing the risk of bronchopulmonary dysplasia. However, increasing knowledge regarding ventilator-induced lung injury has led to increasing use of early nasal CPAP with variable success, therefore decreasing the rate of surfactant administration.

 

What This Study Adds

Use of surfactant has definitely decreased, and the incidence of chronic lung disease has increased to almost 60%. The incidence of chronic lung disease and comorbidities of prematurity is higher in the group receiving surfactant. However, this may reflect better patient selection by clinicians.

 


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2000;(2):CD001456
  2. Slutsky AS. Lung injury caused by mechanical ventilation. Chest. 1999;116 (1 suppl):9S –15S
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  7. Jansson B, Katz-Salamon M, Faxelius G, et al. Neonatal care of very-low-birthweight infants in special-care units and neonatal intensive-care units in Stockholm: early nasal continuous positive airway pressure versus mechanical ventilation: gains and losses. Acta Paediatr Suppl. 1997;419 :4 –10[Medline]
  8. Subramaniam P, Henderson-Smart DJ, Davis PG. Prophylactic nasal continuous positive airways pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst Rev. 2005;(3):CD001243
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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Changing incidence of chronic lung disease cannot be attributed to surfactant use alone.
Ambalika Das, et al.
Pediatrics Online, 25 Nov 2008 [Full text]
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