http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.885941

ORIGINAL ARTICLE

Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm infants

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Dalal Taha1, Sharon Kirkby2, Ursula Nawab1, Kevin C. Dysart4, Linda Genen2,3, Jay S. Greenspan1, and Zubair H. Aghai1 1

Division of Pediatrics/Neonatology, Thomas Jefferson University/Nemours, Philadelphia, PA, USA, 2Alere Health, Atlanta, GA, USA, 3Department of Neonatology, Cohen Children’s Medical Center, New Hyde Park, NY, USA, and 4Department of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Abstract

Keywords

Objective: To determine if an early commencement of caffeine is associated with improved survival without bronchopulmonary dysplasia (BPD) in preterm infants. Methods: Retrospective data analysis from the Alere Neonatal Database for infants weighing 1250 g, and treated with caffeine within the first 10 days of life. The neonatal outcomes were compared between the infants who received early caffeine (0–2 days) with the infants who received delayed caffeine (3–10 days). Results: A total of 2951 infants met the inclusion criteria (early caffeine 1986, late caffeine 965). The early use of caffeine was associated with reduction in BPD (OR 0.69, 95% CI 0.58–0.82, p50.001) and BPD or death (OR 0.77, 95% CI 0.63–0.94, p ¼ 0.01). Other respiratory outcomes also improved with the early commencement of caffeine. The frequency of severe intraventricular hemorrhage and patent ductus arteriosus was lower and the length of hospitalization was shorter in infants receiving early caffeine therapy. However, early use of caffeine was associated with an increase in the risk of nectrotizing enterocolits (NEC) (OR 1.41, 95% CI 1.04–1.91, p ¼ 0.027). Conclusion: Early commencement of caffeine was associated with improvement in survival without BPD in preterm infants. The risk of NEC with early caffeine use requires further investigation.

BPD, NEC, neonates, premature, xanthine

Introduction Bronchopulmonary dysplasia (BPD) is a type of chronic lung disease associated with significant mortality and morbidity in premature infants. Despite the utilization of antenatal steroids, surfactant replacement therapy, and gentle ventilation, BPD remains a significant problem in premature infants [1]. The pathogenesis of BPD is complex with the interplay of genetic and environmental factors including sepsis (antenatal and/or post-natal), ventilator-induced lung injury and hyperoxia [1]. These factors (amongst others) have been shown to initiate a cascade of inflammatory cytokines leading to tissue injury, cell death and impaired alveolarization [1–4]. Lung inflammation during the first few days of life plays a key role in the development of BPD in preterm infants. Early increase in tracheal aspirate cytokines, chemokines and inflammatory cells are associated with the development of BPD in

Address for correspondence: Zubair H. Aghai, MD, Associate Professor of Pediatrics, Division of Neonatology, Thomas Jefferson University/ Nemours, 833 Chestnut Street, Suite 1237, Philadelphia, PA 19107, USA. Tel: 215-955-6523. Fax: 215-861-0408. E-mail: [email protected] nemours.org

History Received 18 July 2013 Revised 20 December 2013 Accepted 17 January 2014 Published online 17 February 2014

premature infants [5–9]. Using an anti-inflammatory agent during this critical time may ameliorate lung inflammation and prevent BPD in premature infants. Caffeine, a methylxanthine derivative, is commonly used for apnea of prematurity in preterm infants. Caffeine also has anti-inflammatory and immunomodulatory properties [10,11]. In the Caffeine for Apnea of Prematurity (CAP) trial, caffeine initiated during the first 10 days of life was associated with a reduction in the frequency of BPD and a decrease in the duration of assisted mechanical ventilation by one week in very low birth weight infants [12]. In a post hoc analysis of the CAP trial, Davis et al. performed a subgroup analysis and found that an early commencement (53 days) of caffeine may be associated with a greater reduction in respiratory morbidities [13]. A more recent retrospective analysis from a single center indicates that an early initiation of caffeine may improve survival without BPD in preterm infants [14]. Our objective was to determine if respiratory outcomes in preterm infants are better with an early use of caffeine based on information from a nationwide database. We hypothesized that an early initiation of caffeine therapy within 2 days of life will be associated with improved survival without BPD in preterm infants. In addition, we wanted to

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evaluate the impact of early caffeine therapy on other neonatal morbidities associated with prematurity.

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Table 1. The demographics and baseline clinical characteristics of the study population (mean ± SD).

Material and methods

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Study population This study is a retrospective data analysis from the Alere Neonatal Database for infants admitted to the Neonatal Intensive Care Unit (NICU) between June 2006 and May 2011, weighing 1250 g, treated with caffeine within the first 10 days of life. Alere’s NICU database is comprised of standardized clinical, socio-demographic and cost-related information pertaining to neonates admitted to the NICU in over 1000 hospitals nationwide. All demographic information was obtained prospectively from the neonatal chart and entered into this NICU database. All infants included in the study were admitted to the NICU (level II and level III), in both community and academic settings. The Institutional Review Board of Nemours approved this study. All infants less than or equal to 1250 g at birth and treated with caffeine within the first 10 days of life were included in the analysis. The baseline demographics, clinical characteristics and the neonatal outcomes were compared between the infants who received early caffeine (0–2 days) with the infants who received late caffeine (3–10 days). BPD was defined as requiring oxygen or a higher level of respiratory support at 36 weeks post-menstrual age. Other morbidities associated with prematurity such as patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), severe intraventricular hemorrhage (IVH) defined as grade 3 or 4, and severe retinopathy of prematurity (ROP) defined as stage 3 or 4, were also analyzed. The diagnosis of NEC was made if the infant was kept NPO, treated with antibiotics and radiographic findings were documented in the chart or infant required surgery for NEC. Statistical analysis Statistical analysis was performed using the Stata 12.0 software (StataCorp, College Station, TX). For bivariate comparisons of continuous variables, Student’s t-tests and Mann–Whitney U-tests were used. The categorical variables between the two groups were compared by using chi-square and Fisher’s exact tests. Clinical and demographic characteristics that were found to be significantly different between the two groups in bivariate analyses were then used as controls in multivariate regression models. Linear and logistic regression models controlling for gestational age, birth weight, centers and the prenatal steroids were used to test differences in outcomes between the groups. The difference was considered significant for p  0.05.

Results Characteristics of the study subjects A total of 2951 preterm infants met the inclusion criteria (BW 860 ± 201 g, GA 27.5. ± 2.3 weeks). Caffeine was initiated within 2 days after birth in 1986 infants and between days 3–10 in 965 infants. Clinical characteristics of the study population are summarized in Table 1. The median age of initiating caffeine therapy was 1 day (range 0–2 days)

Birth weight (g)* Gestational age (w)* Sex (Male) (%) Race White (%) Black (%) Hispanic (%) Other or unknown (%) Apgar 5 min (median, range) Chorioamnionitis (%) Prenatal steroids (%)* Ventilated on day 1 (%) Ventilated any time (%) Surfactant (%) Apnea (%) Caffeine started (day)* Days on caffeine

Early caffeine (0–2 days) (n ¼ 1986)

Late caffeine (3–10 days) (n ¼ 965)

938 ± 201 27.5 ± 2.0 979 (49.3)

899 ± 216 27.2 ± 2.1 462 (47.9)

806 (40.6) 428 (21.6) 303 (15.3) 449 (22.6) 8 (1–10) 96 (4.8) 956 (48.1) 1509 (76.0) 1614 (81.3) 1349 (67.9) 1776 (89.4%) 0.9 ± 0.8 50.0 ± 31.5

389 (40.3) 203 (21.0) 141 (14.6) 232 (24.0) 8 (1–10) 48 (5.0) 418 (43.3) 749 (77.6) 804 (83.3) 685 (71.0) 869 (90.5%) 5.3 ± 2.1 49.0 ± 33.1

*p50.05.

and 5 days (range 3–10 days) in early and late groups, respectively. The mean birth weight (BW) and gestational age (GA) were lower in the the late caffeine group. More infants received prenatal steroids in the early caffeine group. There were no significant differences in gender, race, 5-min Apgar score and chorioamnionitis between the two groups. The number of infants ventilated on day 1, the number of infants ventilated any time, and the use of surfactant were also similar in the two groups. There was no significant difference in the duration of caffeine therapy in infants who received early caffeine versus late caffeine. Respiratory outcomes The number of infants who developed BPD was significantly lower in the early caffeine group (Table 2). Early use of caffeine was also associated with improved survival without BPD in preterm infants. Similarly, age of first extubation, duration of ventilator support and post-menstrual age (PMA) to room air, were significantly lower with the use of early caffeine. The improvement in respiratory outcomes with early caffeine use remained significant even after adjusting for BW, GA and prenatal steroids. The early use of caffeine also reduced the number of infants going home on oxygen. The use of post-natal steroids was lower in the early caffeine group. This difference was not significant after adjusting for BW, GA and prenatal steroid use. Early caffeine and neonatal outcomes In a logistic regression model, when adjusted for BW, GA, centers and prenatal steroids, early caffeine therapy reduced the odds of developing BPD (OR 0.69, 95% CI 0.58–0.82, p50.001) and BPD or death (OR 0.77, 95% CI 0.62–0.94, p ¼ 0.01) in preterm infants (Table 3). Similarly, the odds of developing severe IVH and PDA were lower in the early caffeine group. However, the odds of developing NEC was higher (OR 1.41, 95% CI 1.04–1.91, p ¼ 0.027) with early caffeine therapy. When PDA was added to this model,

Early caffeine and BPD

DOI: 10.3109/14767058.2014.885941

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Table 2. Respiratory outcomes in infants treated with early versus late caffeine. Early caffeine (0–2 days) (n ¼ 1986)

Late caffeine (3–10 days) (n ¼ 965)

p

16.7 ± 21.7 34.7 ± 3.8 7.1 ± 13.6 366 (18.4) 217 (10.9) 716 (36.1) 904 (45.5) 72.5 ± 33.8

23.7 ± 23.7 35.6 ± 4.3 10.8 ± 14.2 235 (24.4) 131 (13.6) 451 (46.7) 530 (54.9) 79.0 ± 34.8

50.001 0.002 50.001 50.01 0.04 50.01 50.01 0.001

Days on ventilator (mean ± SD)* PMA to room air (weeks) (mean ± SD)* First extubation (age in days) (mean ± SD)* Discharged home on oxygen (%) Post-natal steroids (%) BPD (%) BPD or died (%) Length of stay (days) (mean ± SD)*

*Remains significant after adjusting for BW, GA prenatal steroids and centers (linear regression).

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Table 3. Multivariate logistic regression analysis of early caffeine therapy and neonatal outcomes. Odd ratio (OR) adjusted for gestational age, birth weight, prenatal steroids and centers.

BPD BPD or died Severe IVH PDA Home on oxygen NEC Post natal steroids ROP requiring laser

OR

95 CI

p

0.692 0.767 0.722 0.727 0.724 1.411 0.940 0.737

0.581–0.825 0.625–0.940 0.522–0.999 0.620–0.851 0.545–0.959 1.040–1.914 0.712–1.239 0.515–1.055

50.001 0.01 0.05 50.001 0.025 0.027 0.66 0.098

Table 4. Clinical characteristics and demographics of infants who developed NEC in early and late caffeine groups.

Gestational age (w) Birth weight (g) Male sex (%) White race (%) Apgar at 5 min (median, range) Prenatal steroid (%) Day feed started Only breast milk (%) Breast milk ± formula (%) PDA (%) Day NEC developed Surgery for NEC (%) Died (%) Length of stay (days)

NEC Early caffeine (n ¼ 144)

NEC Late caffeine (n ¼ 57)

p

26.7 ± 1.8 855 ± 200 84 (58) 46 (40) 8 (1–9) 74 (51) 6.0 ± 8.0 12 (8.3) 135 (93.8) 67 (46) 27.2 ± 15.8 52 (36) 51 (35) 86.2 ± 56.0

25.9 ± 1.8 774 ± 206 28 (49) 18 (40) 8 (1–9) 23 (40) 10.6 ± 12.7 5 (8.8) 53 (92.9) 32 (56) 32.2 ± 21.0 22 (39) 18 (31) 98.9 ± 54.7

0.006 0.001 0.24 0.99 0.56 0.16 50.01 0.87 0.9 0.22 0.035 0.87 0.61 0.15

the odds of having NEC remained significant with early caffeine use (OR 1.40, 95% CI 1.01–1.93, p ¼ 0.041). Table 4 depicts the clinical characteristics of the infants who developed NEC in the early and late caffeine groups. Birth weight and gestational age were higher in infants with NEC in the early caffeine group. Enteral feeds were started earlier and the mean time to develop NEC was shorter in infants of the early caffeine group when compared to the late caffeine group. The number of infants who received exclusive breast milk or any breast milk was similar in the two groups.

Discussion Caffeine is routinely used in premature infants for the prevention and treatment of apnea of prematurity [12,15].

Since the CAP study, the use of caffeine has significantly increased to prevent BPD in premature infants. Due to its antiinflammatory and immunomodulatory properties, an early commencement of caffeine may ameliorate lung inflammation and reduce the frequency and/or severity of BPD in preterm infants. In the current retrospective analysis from a large database, we tested a hypothesis that the early use of caffeine may reduce BPD and improve respiratory outcomes in premature infants. The result from this study demonstrates that an early commencement of caffeine was associated with improved survival without BPD in preterm infants. The early use of caffeine was also associated with reduction in other neonatal morbidities including severe IVH and PDA. However, an early initiation of caffeine may potentially increase the risk of NEC in preterm infants. Although multiple factors contribute to the development of BPD in premature infants, early inflammation induced by oxidative stress, ventilator-induced lung injury and perinatal infection play a key role in its pathogenesis. Tracheal aspirate cytokines/chemokines and inflammatory cells are increased very early during the course of BPD. Tracheal aspirate TNF-a, IL-1b, IL-6, IL-8 [7–9], high mobility box-1 protein (HMGB1) [6], and angiopoetien 2 [5] are elevated either at birth or during the first few days of life in preterm infants who developed BPD. Tracheal aspirate neutrophils are also increased immediately after birth in preterm infants who later developed BPD [16]. Caffeine, a trimethylxanthine, is a non-specific adenosine receptor antagonist and is known for its anti-inflammatory and immunomodulatory properties. Caffeine decreases TNF-a release from cord blood monocytes by blocking adenosine A1 receptors [10]. In an animal model of hyperoxia, caffeine reduced the influx of inflammatory cells into the lungs and attenuated hyperoxia-induced upregulation of proinflammatory mediators [11]. In a similar study, acute high dose and chronic use of caffeine ameliorated oleic acid induced acute lung injury in mice and reduced the production and release of TNF-a and IL-1b [17]. Premature infants are most susceptible to acute lung injury during the first few days of life. Hyperoxia and ventilator-induced acute lung injury leads to a local as well as systemic inflammatory response [18]. It is likely that caffeine, due to its anti-inflammatory properties, is protective during this critical phase of lung injury. In addition, caffeine also improves lung function and pulmonary mechanics by stimulating the respiratory center and improving respiratory muscle contractility [19–21]. Similarly, caffeine given at 1 and 12 h of age resulted in improved pulmonary function

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at 12 and 24 h in immature baboons with respiratory distress syndrome [22]. In the past, caffeine was used solely to treat or prevent apnea of prematurity. For extremely low birth weight infants who required ventilator support, caffeine therapy was delayed until the infants were ready for extubation. The data from the current study indicates that early commencement of caffeine in very low birth weight infants substantially improves survival without BPD and reduces the days on assisted ventilation, days on oxygen and length of hospitalization. A post hoc analysis from the CAP trial suggests that an early initiation of caffeine may be associated with a greater reduction in time on mechanical ventilation [13]. However, authors have cautioned in interpreting their findings, as infants who started caffeine early were likely to be seen by their clinician as less sick and ready to wean from respiratory support. After the publication of results from the CAP trial, some experts have advocated the use of caffeine for the prevention of BPD in premature infants [23,24]. A large number of centers have adopted potentially better practices for the reduction of chronic lung diseases, which include caffeine on admission for extremely premature infants. This practice is encouraged in quality initiatives presented in the 2012 iNICU respiratory series by the Vermont Oxford Network. The trend over the last six years in the Alere database confirms an increase in early use of caffeine for premature infants. The early use of caffeine in preterm infants (BW  1250 g) has significantly increased from 48% in 2006 to more than 61% in 2011 according to this database. In the current study, the increase in early caffeine was noted after the publication of the results from the CAP trial and the likely indication was prevention of BPD. Moreover, the severity of respiratory illness appears similar in early and late caffeine groups in our cohort. The number of infants who required mechanical ventilation on day 1, the number of infants who ventilated at anytime during their hospital course, and the number of infants who received surfactant therapy were similar in the early versus late caffeine groups. A recent retrospective study from a single center confirms our finding of reduced frequency of BPD in preterm infants with early caffeine therapy [14]. Patel et al. compared 83 preterm infants who received early caffeine (53 days) with 57 infants who received delayed caffeine (43 days). They found significant improvement in survival without BPD and reduction in the duration of ventilatory support with an early caffeine therapy. However, this was a retrospective analysis from a single center with a small sample size in a predominantly African– American population. Early commencement of caffeine was not only associated with reduction in the rate of BPD and other respiratory morbidities, it also decreased severe IVH and PDA in preterm infants. Patel et al. also reported a decrease in the occurrence of PDA in infants treated with early caffeine. They postulated that the decrease in incidence of PDA with early caffeine therapy is likely due to diuresis and improved cardiac and pulmonary functions [14]. However, the decrease in a systemic inflammatory response from caffeine therapy may also contribute to the reduction of the frequency of PDA. Interestingly, we noted a decline in severe IVH with early caffeine therapy. The CAP trial did not find a significant

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change in the frequency of severe brain injury with caffeine therapy [12]. However, more than 90% of IVH in premature infants occurs during the first 3 days of life [25]. In the CAP trial, it is likely that caffeine was started after infants already developed IVH, as the median age of initiating caffeine therapy was 3 days (range 1–10 days). The likely mechanisms for the reduction of severe IVH with early caffeine can be attributed to the improvement in cardiac output, stable blood pressure, lower incidence of PDA, lower respiratory support and decreased systemic inflammatory response with an early initiation of caffeine. Our data also indicate that early caffeine use may increase the risk of NEC in preterm infants. The odds of developing NEC were significantly higher with early caffeine use when corrected for BW, GA and prenatal use of steroids. Those infants who developed NEC with an early caffeine therapy were presumably at a lower risk for NEC than their counterparts, based on higher birth weight, increased gestational age and earlier initiation of enteral feeding. Although not statistically significant, there were trends towards increased prenatal steroid use and lower incidence of PDA, both of which have been associated with a decrease in NEC. No significant difference in breast milk use was noted between the two groups. The potential mechanisms for increased risk for NEC with early caffeine use include decreased superior mesenteric artery (SMA) blood flow and increased oxygen consumption [26,27]. Hoecker et al. studied 16 preterm neonates at postnatal ages between 24 and 72 h [27]. The mean SMA and celiac artery blood flow significantly decreased 1 and 2 h after oral loading dose of caffeine. In a similar study, Lane et al. reported a significant reduction in peak systolic velocity in SMA and celiac artery after a high intravenous loading dose of caffeine in 12 preterm neonates [28]. In a more recent study, a single loading dose of intravenous caffeine (10 mg/kg base) reduced peak systolic velocity in SMA by 18% in 18 preterm infants. However, this difference was not statistically significant and the authors concluded that a single dose of intravenous caffeine does not cause a significant reduction in SMA blood flow velocity [29]. In the past, methylxanthines have been linked to the development of NEC in preterm infants [30]. Five cases of NEC were reported by Robinson et al. after oral aminophyline [30]. In a double-blind, placebo-controlled clinical trial, six out of 85 preterm infants developed NEC [15]. Five of the six infants with NEC were randomized to or had been exposed to caffeine. When the caffeine citrate was approved by the Food and Drug Administration, a warning was included in the label about NEC as a possible side effect [31]. The CAP trial failed to show the increased risk for NEC with the caffeine therapy. However, caffeine was used in more stable infants with less severe lung disease. Moreover, the median age of starting caffeine was 3 days. Similarly, a retrospective analysis from a single center did not find an increased risk for NEC with an early caffeine therapy, but the small number of subjects may have limited the statistical power [14]. The major strength of this current study is the large sample size. The data included infants from 1000 NICUs across the nation in both academic and community settings. We recognize some important limitations of this study. This is a retrospective study and the indication of using early caffeine

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DOI: 10.3109/14767058.2014.885941

cannot be determined. It is possible that caffeine was initiated early due to less severe respiratory illnesses. However, the initial severity of respiratory illness appears similar amongst the two groups as there were no differences in the number of infants who required mechanical ventilation on the first day of life or were treated with surfactant. Our data indicates an association between NEC and the early commencement of caffeine therapy yet, it does not establish a causal relationship. The data from this study should be used with caution and the results can only be used to generate hypothesis for future clinical trials. In conclusion, our data indicates that an early use of caffeine was associated with improved survival without BPD and other morbidities associated with prematurity. The benefits of early caffeine should be weighed against an increase risk for NEC. A large randomized multicenter prospective study is needed to confirm these findings before encouraging early use of caffeine in extremely premature infants.

Declaration of interest The authors report no conflicts of interest.

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Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm infants.

To determine if an early commencement of caffeine is associated with improved survival without bronchopulmonary dysplasia (BPD) in preterm infants...
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