Original Article
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Comparison of Two Natural Surfactants for Pulmonary Hemorrhage in Very Low-BirthWeight Infants: A Randomized Controlled Trial Dilek Dilli, MD2
Tülin Gökmen, MD3
1 Department of Neonatology, Umraniye Research and Training
Hospital, İstanbul, Turkey 2 Department of Neonatology, Dr Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey 3 Department of Neonatology, Bağcılar Research and Training Hospital, İstanbul, Turkey 4 Department of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey 5 Department of Pediatrics and Neonatology, Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
Uğur Dilmen, MD4,5
Address for correspondence Dilek Dilli, MD, Dr Sami Ulus Maternity and Children Research and Training Hospital, Babür street, zip code: 06080, Altjndag/Ankara/Turkey (e-mail: [email protected]).
Am J Perinatol 2015;32:211–218.
Abstract
Keywords
► premature ► pulmonary hemorrhage ► surfactant
Objective To compare the efficacy of two natural surfactants for pulmonary hemorrhage in very low-birth-weight (VLBW) infants. Study Design A prospective randomized controlled trial was conducted on 42 infants who were divided into two groups, poractant alfa (n ¼ 21) and beractant (n ¼ 21). Results In both the groups, the mean standard deviation (SD) birth-weight and gestational age were similar (p ¼ 0.33 and 0.89, respectively). Although, the mean oxygenation index (OI) increased after pulmonary hemorrhage compared with baseline value and decreased after surfactant in both groups, variations in OI were more prominent in poractant alfa group (before hemorrhage: 11.9, after hemorrhage: 22.7, 1 hour of surfactant: 14.6, 8th hour of surfactant: 7.8, 24th hour of surfactant: 8.5, p ¼ 0.007 vs. before pulmonary hemorrhage:11.1, after pulmonary hemorrhage: 17.9, 1 hour of surfactant: 12.8, 8th hour of surfactant: 12.8, 24th hour of surfactant: 9.7, p ¼ 0.02). There was no significant difference between the groups for OI values at all time points (p > 0.05). The rates of bronchopulmonary dysplasia (BPD) and mortality related to pulmonary hemorrhage were similar in both the groups. Conclusion Both natural surfactants improved oxygenation when administered for pulmonary hemorrhage in VLBW infants. The type of surfactant seems to have no effect on BPD and mortality rates in these patients.
Pulmonary hemorrhage is a life-threatening condition that associates with many predisposing factors, including low gestational age, vaginal birth, male sex, and the presence of respiratory distress syndrome (RDS), patent ductus arteriosus (PDA), sepsis, as well as pulmonary hemorrhage, hypoxia, severe hypothermia, and congenital heart disease (CHD).1,2
The mortality rate of pulmonary hemorrhage remained about 50%, despite recent improvements in the treatment of pulmonary hemorrhage.2 There are a variety of treatment options for pulmonary hemorrhage, with outcomes varying from country to country and hospital to hospital. Pulmonary hemorrhage results in an
received June 27, 2013 accepted after revision July 19, 2013 published online September 21, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1389090. ISSN 0735-1631.
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Şenol Bozdağ, MD1
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acute deterioration reflected by an increase in the fraction of inspired oxygen (FIO2) and ventilatory support.2,3 Surfactant therapy is a well-established role in the management of neonates with RDS, where there is a surfactant deficiency. Pulmonary hemorrhage may be associated with surfactant therapy for RDS, and, therefore, there is conflict on the use of surfactant to treat respiratory failure due to pulmonary hemorrhage.1 However, it is also hypothesized that exogenous surfactant can be useful in neonates with respiratory disorders where surfactant inactivation, rather than surfactant deficiency, may occur. In pulmonary hemorrhage, severe leaking of blood components into the alveolar space occurs in pulmonary hemorrhage.4 The presence of hemoglobin, red cell membrane lipids, and serum proteins increases the surface tension, leading to secondary surfactant deficiency or surfactant dysfunction.5 In a complementary pulmonary hemorrhage physiological experiment, the authors have shown that instillation of hemoglobin, membrane lipids, or albumin into excised rat lungs leads to a decrease in respiratory system compliance. The increase in surface tension can be overcome by increasing the concentration of surfactant and this is the rationale for the use of surfactant in pulmonary hemorrhage. Although, both natural and synthetic surfactant preparations reduce the incidence of neonatal mortality in premature infants with RDS,6 natural surfactants improve oxygenation and lung function more rapidly than synthetic surfactants.4 Within the group of natural surfactants, a differential response has also been reported—either as differences in the a: A PO2 ratio during the first 24 hours7,8 or as a difference in ventilatory requirement during the first 24 hours, following administration for RDS. Two retrospective studies evaluating the effect of surfactant therapy after pulmonary hemorrhage showed that administration of exogenous surfactant was a useful adjunctive therapy in newborns with clinically significant pulmonary hemorrhage.9,10 However, there is no prospective randomized controlled trial (RCT) comparing the efficacy of different surfactants for pulmonary hemorrhage in this age group. We, therefore, conducted a prospective RCT comparing the effects of two natural surfactants on outcomes of very low-birthweight (VLBW) infants with pulmonary hemorrhage.
Study Design This was a prospective RCT conducted in the neonatal intensive care unit (NICU) of Zekai Tahir Burak Maternity and Children Research and Training Hospital, Ankara, Turkey, between March 2010 and February 2011. During the study period, 446 VLBW infants with a gestational age of < 32 weeks or birth-weight of < 1,500 g were born. Among them, infants having pulmonary hemorrhage within the first 2 weeks of life were considered for the study. Pulmonary hemorrhage was determined by the symptom of a nontraumatic gush of bloody secretion from the endotracheal tube, which was associated with clinical deterioration or a need of increased ventilatory support.9,11 American Journal of Perinatology
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Initially, 52 infants (11.6%) were eligible for the study. Ten patients were not included because four died within the first 2 hours of pulmonary hemorrhage, two had congenital anomalies (one with trisomy 18 and another with gastroschisis), and in the remaining four the parental consents could not be obtained. Finally, 42 infants were randomized for the study.
Randomization Randomization was performed using a computer-generated random numbers algorithm. Allocation to receive either surfactant A or surfactant B was performed for each eligible newborn using a sealed opaque envelope. Poractant alfa, which is from porcine lung extract, was given for surfactant A at a dose of 100 mg/kg (1.25 mL/kg). Beractant, which is from beef lung extract, was given for surfactant B at a dose of 100 mg/kg (4 mL/kg). Surfactant was given as a single dose after the 2nd hour of pulmonary hemorrhage to eliminate improvement either spontaneously or due to changes in ventilatory management.
Patient Characteristics and Clinical Outcomes Maternal (age, multiple birth, chorioamnionitis, antenatal steroid, and cesarean delivery) and infant (gestational age, birth weight, Apgar score at 5 minutes, gender, and the age at pulmonary hemorrhage) characteristics were extracted from the patients’ sheet. Interval between pulmonary hemorrhage and surfactant, hemoglobin values before and after pulmonary hemorrhage, and severity of pulmonary hemorrhage were recorded. Pulmonary hemorrhage was classified as mild if FIO2 increased by < 0.1, moderate if it increased by 0.1 to 0.3, and severe if the increase was > 0.3 from the baseline. Type of respiratory support and presence of pneumothorax were noted. Respiratory variables collected were Fio2, peak inspiratory pressure (PIP), mean airway pressure (MAP), partial arterial carbon dioxide (Paco2), and oxygenation index (OI). OI was defined as OI ¼ (Fio2 MAP 100)/Pao2.12 For basal values of respiratory parameters, the nearest data within the last 6 hours before pulmonary hemorrhage was assumed to be representative. These parameters were also recorded at the 1st, 8th, and 24th hours of surfactant administration. Data on RDS (with signs of hyaline membrane disease on the chest X-ray examination), PDA (characteristic murmur or echocardiographic confirmation), intraventricular hemorrhage (IVH) (grade 2),13 proven sepsis (bacteria cultured from blood or tracheal aspirate accompanied by clinical deterioration and increased C-reactive protein concentrations), necrotizing enterocolitis (NEC) (grade 2),14 bronchopulmonary dysplasia (BPD) (the need for oxygen at 36 weeks of postmenstrual age),15 and retinopathy of prematurity (ROP) (stage > 3)16 were recorded. Data on late outcomes, such as NEC, BPD, and ROP, were analyzed for those neonates who survived until discharge from hospital. Duration of mechanical ventilation, length of NICU stay, and mortality were noted. The effects of the two surfactants on clinical outcomes were compared.The primary outcome measures were a
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change in respiratory status following surfactant therapy, as reflected by change in OI and other respiratory variables. Secondary outcome measures were BPD and mortality related to pulmonary hemorrhage (within 72 hours after pulmonary hemorrhage).
Ethics Informed consent was obtained from the parents before administration of the surfactant. This study was approved by the institutional review board and strictly followed the institution’s ethical guidelines.
Power Analysis and Statistics According to the results from observational data in 20 neonates who were receiving two surfactants after pulmonary hemorrhage, the mean (standard deviation [SD]), OI after poractant alfa were 14.7 (10.1) and 11.0 (4.8) after beractant. A sample size of 42 could detect 3.7 point change in OI with 80% power and 5% type I error (https://www.dssresearch.com).
Statistics Comparisons of variables in infants who received poractant alfa versus those who received beractant were analyzed. SPSS 16.0 (SPSS, IBM Inc., Chicago IL) was used for statistical analysis. Kolmogorov–Smirnov test was used to analyze the distribution of data. Data were expressed as the arithmetic mean (SD) or median (range). Differences between the two groups were tested using Student t-test or Mann– Whitney U test, as appropriate. Chi-square tests were performed for categorical variables. Wilcoxon or Friedman tests were used to analyze repeated measurements. Associations were analyzed using odds ratios (OR) and 95% confidence intervals (CIs). A two-tailed p value of < 0.05 was accepted as significant.
Results A total of 42 newborns who had their pulmonary hemorrhage within the first 2 weeks of life and treated by surfactant were evaluated. In 19 patients (45.2%), pulmonary hemor-
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rhage developed within the first 48 hours of life. All received conventional therapy for the pulmonary hemorrhage before administration of surfactant. Management of pulmonary hemorrhage included an increase in respiratory support, administration of fluids, medications, and antibiotics. Eight patients who were previously nonventilated were entubated and connected to the ventilator after the development of pulmonary hemorrhage. Four infants switched to high frequency oscillation after pulmonary hemorrhage. Epinephrine was diluted 10,000 times and administered via endotracheal tube to all infants. Vasopressors and vitamin K were given to all neonates. The patients were randomized to receive poractant alfa or beractant; 21 patients were included in each group. The median surfactant administration time was 4 hours (2–8). The characteristics of the study patients are shown in ►Table 1. The mean (SD) birth weight and gestational age were similar in groups. Birth weight was less than 1,000 g in nine patients (42.9%) in each group. ►Table 2 shows clinical outcome of the patients studied. Pulmonary hemorrhage was severe in 14 (33.3%), moderate in 22 (52.4%), and mild in 6 (14.3%). The severity of pulmonary hemorrhage did not differ between the groups. All patients with RDS, but none of the others, had previously received surfactant. Paired hemoglobin (Hb) values were available for 39 patients. In both groups, the median Hb was significantly decreased after pulmonary hemorrhage (p ¼ 0.01 vs. p ¼ 0.01). Coagulation screens were performed in 32 patients. International normalized ratio was > 1.5 in 10 patients (47.6%) in poractant alfa group and 14 (66.7%) in beractant group (p ¼ 0.71). Packed red blood cells (n ¼ 32, 76.1%) and fresh frozen plasma of AB blood type (n ¼ 10, 23.8%) were given to patients if necessary. Respiratory variables recorded before and after pulmonary hemorrhage are documented in ►Table 3. ►Fig. 1 shows the response to surfactant therapy as assessed by OI in both groups. Although the mean OI increased after pulmonary hemorrhage compared with baseline value and decreased after surfactant in both groups,
Table 1 Characteristics of the study patients according to type of surfactant Variables
Poractant alfa (n ¼ 21)
Beractant (n ¼ 21)
p-Value
Maternal age, y
26.4 (5.2)
26.6 (6.6)
0.93
Multiple birth, n (%)
10 (47.6)
11 (52.4)
0.75
Chorioamnionitis, n (%)
4 (19.0)
0 (0)
0.10
Antenatal steroid, n (%)
11 (52.4)
13 (61.9)
0.75
Cesarean delivery, n (%)
12 (57.1)
14 (66.7)
0.52
Gestational age, wk
27.9 (2.3)
27.2 (2.3)
0.36
Birth-weight
1,051 (236)
1,074 (242)
0.76
Apgar score at 5 min, median (range)
7 (1–9)
8 (3–9)
0.66
Male, n (%)
13 (61.9)
10 (47.6)
0.53
Age at pulmonary hemorrhage, h
46 (24–324)
96 (24–310)
0.05
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Table 2 Clinical outcomes of the study patients according to type of surfactant Variables
Poractant alfa (n ¼ 21)
Beractant (n ¼ 21)
p-Value
Early outcomes Interval between pulmonary hemorrhage and surfactant, h
3 (2–8)
4 (3–6)
Hb before pulmonary hemorrhage, (g/dl) median (range)
11.9 (5.7–15.2)
10.8 (6.7–17.6)
0.58
Hb after pulmonary hemorrhage, (g/dl), median (range)
10.3 (4.2–13.8)
9.4 (5.2–16.1)
0.55
Severity of pulmonary hemorrhage, n (%) Mild, Moderate, Severe
4 (19) 11 (52.4) 6 (28.6)
2 (9.5) 11 (52.4) 8 (38.1)
0.62
RDS, n (%) Poractant alfa, n (%) Beractant, n (%)
5 (23.8) 14 (66.7)
5 (23.8) 15 (71.4)
0.83
PDA, n (%)
8 (38.1)
12 (57.1)
0.44
IVH (> grade 2), n (%)
1 (4.8)
7 (33.3)
0.04
Sepsis, n (%)
2(9.5)
8 (38.0)
0.06
Pneumothorax, n (%)
3 (14.3)
0 (0)
0.23
Duration of mechanical ventilation,
5 (1–12)
5 (2–14)
0.16
NICU stay, median (range)
5 (1–90)
8 (2–84)
0.47
Death age after pulmonary hemorrhage, h, median (range)
4 (1–36)
6 (1–36)
0.75
Mortality, related to pulmonary hemorrhage, n (%)
12 (57.1)
11 (52.4)
0.75
Overall mortality, n (%)
15 (71.4)
14 (66.7)
0.73
Poractant alfa (n ¼ 6)
Beractant (n ¼ 7)
NEC (> stage 2), n (%)
4 (66.7)
2 (28.6)
0.28
BPD, n (%)
2 (33.3)
3 (42.9)
0.72
ROP (> stage 3), n (%)
2 (33.3)
1 (16.7)
0.50
Late outcomes
Abbreviations: BPD,bronchopulmonary dysplasia; Hb, hemoglobin; IVH, ıntraventricular hemorrhage; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; OI, oxygenation index; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; SD, standard deviation.
variations in OI were more prominent in poractant alfa group (before hemorrhage: 11.9, after hemorrhage: 22.7, 1 hour of surfactant: 14.6, 8th hour of surfactant: 7.8, 24th hour of surfactant: 8.5, p ¼ 0.007 vs. before pulmonary hemorrhage: 11.1, after pulmonary hemorrhage: 17.9, 1 hour of surfactant: 12.8, 8th hour of surfactant: 12.8, 24th hour of surfactant: 9.7, p ¼ 0.02). There was no significant difference between the groups for OI values at all time points (p > 0.05). In survived patients, OI gradually decreased at 8th and 24th hours of surfactant, without significant difference between the groups. Among the 20 neonates who had a clinical and echocardiographic diagnosis of PDA, 10 had this diagnosis made before the pulmonary hemorrhage. Of the 42 patients, 23 (54.7%) died within 72 hours after pulmonary hemorrhage and 17 of these 23 patients (73.9%) died within the first 6 hours of pulmonary hemorrhage. Mortality rates did not differ in groups. Of the survived patients, six died during the neonatal period (first 28 days of life): four died from severe sepsis, one from severe IVH, and American Journal of Perinatology
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another one from acute renal failure. Among the survived ones, five patients (38.4%, 5/13) developed BPD with characteristic clinical and X-ray features. No difference was found between the survivor and the death groups in the following variables: gender, gestational age, birth weight, age at pulmonary hemorrhage, and the incidences of RDS, PDA, sepsis, NEC, BPD, and ROP. Apgar score at 5 minutes was lower (7 [1–9] vs. 8 [4–9], p ¼ 0.01) and OI value after surfactant was higher (24.5 [11–30] vs. 8.5 [4.5–14], p ¼ 0.01) in infants who could not survive compared with the survivors (p ¼ 0.01 and 0.001, respectively). Independent risk factors, which significantly increased the mortality of pulmonary hemorrhage, were further analyzed using multivariable logistic regression analysis (forward stepwise). A seven-variable logistic regression model was generated, which included gestational age, antenatal steroid, PDA, Apgar score at 5 minutes, sepsis, IVH, and type of surfactant. It was found that only low Apgar score at 5 minutes has increased the risk of mortality (OR: 2.2, 95% CI: 1.2–4.0).
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Table 3 Respiratory variables of the study patients according to type of surfactant Variables, mean (SD)
Poractant alfa (n ¼ 21)
Beractant (n ¼ 21)
p-Value
Before pulmonary hemorrhage 57.7 (20.1)
54.8 (22.1)
0.71
14.4 (1.9)
16.5 (2.4)
0.04
MAP
9.5 (1.1)
10.7 (0.9)
0.007
PaCO2
50.8 (21.5)
56.1 (17.8)
0.41
OI
11.9 (5.5)
11.1 (5.5)
0.74
74.2 (18.9)
0.05
After pulmonary hemorrhage FIO2
85.5 (12.5)
PIP
17.4 (3.05)
20.4 (3.3)
0.01
MAP
11.5 (1.4)
12.2 (1.4)
0.21
PaCO2
62.7 (17.2)
55.2 (35.2)
0.40
OI
22.7 (9.4)
17.9 (8.6)
0.20
1 h after surfactant administration FIO2
65.7 (19.6)
71.5 (25.7)
0.52
PIP
16.5 (2.3)
19.5 (3.6)
0.02
MAP
10.4 (1.3)
11.7 (1.6)
0.05
PaCO2
49.8 (12.0)
49.3 (25.2)
0.94
OI
14.6 (8.7)
12.8 (7.0)
0.59
8 h after surfactant administration FIO2
59.5 (24.9)
60.2 (25.1)
0.95
PIP
16.4 (3.9)
18.3 (4.8)
0.35
MAP
10.2 (1.3)
10.9 (1.5)
0.32
PaCO2
70.1 (15.6)
43.1 (11.0)
0.001
OI
7.8 (4.2)
12.8 (7.1)
0.29
24 h after surfactant administration FIO2
45 (22.0)
49 (22.7)
0.71
PIP
15 (3.9)
16.7 (4.6)
0.41
MAP
10 (1.5)
10 (1.6)
0.62
PaCO2
60 (15.1)
43.8 (9.6)
0.03
OI
8.5 (10.0)
9.7 (10.4)
0.84
Abbreviations: FiO2, fraction of inspired oxygen; MAP, mean airway pressure; OI, oxygenation index; PaCO2, partial arterial carbon dioxide; PIP, peak inspiratory pressure; SD, standard deviation. Note: Values are expressed as mean (SD).
Discussion The results of this prospective RCT indicate that neonates exhibiting a respiratory deterioration following a pulmonary hemorrhage have at least a short-term improvement in oxygenation and ventilation, as determined by OI, following therapy with surfactant. Both natural surfactants improved the OI from before surfactant (22.7 vs. 17.9) to after surfactant (at 1 hour) (14.6 vs. 12.8). Although the latter value was
Fig. 1 Oxygenation index (OI) before and after surfactant in study groups.
higher than the prehemorrhage baseline OI values (11.9 vs. 11.1), it may be said that exogenous surfactant appears to be a useful adjunctive therapy in newborns with pulmonary hemorrhage. In spite of the lack of a placebo group, improvement of the oxygenation was apparently prompt and seemed to be related to the surfactant application. The incidence of pulmonary hemorrhage among infants with RDS reported in some of the larger surfactant trials varies from 1 to 11%.1,17 However, this incidence may not be accurate as there is no generally accepted method of grading its severity. Some investigators have defined pulmonary hemorrhage in the presence of small amounts of blood in the endotracheal tube that could have been due to trauma, following suction, others may have reported only massive pulmonary hemorrhage. Therefore, this may have led to overreporting.1 In our study, traumatic hemorrhage was excluded and severity of pulmonary hemorrhage was defined. The incidence of pulmonary hemorrhage among VLBW infants was 11.6% and there was no significant difference for severity of pulmonary hemorrhage between the groups. In pulmonary hemorrhage, death may occur despite attempts at resuscitations. It was reported that over 60% of newborns who have a severe pulmonary hemorrhage die, usually within the first 72 hours of life.11 Furthermore, 60% of those who survive develop BPD. In survived patients this is likely to be related to an increased need of oxygen support which may lead to further lung injury. In our study, mortality rate (54.7%) was also higher within 72 hours after pulmonary hemorrhage. Six infants died during neonatal period and BPD developed in five of 13 survived infants (38.4%). BPD rates were similar in groups. There are conflicts on the decision to treat (or not to treat) with surfactant after pulmonary hemorrhage and timing of the therapy.1,18,19 In both in vitro and animal studies, it has been shown that surfactant inhibition may be overcome at least partially by exogenous surfactant replacement. It is likely that surfactant inhibition may occur in several respiratory conditions. Pandit et al2 reported the clinical outcomes of neonates who had developed pulmonary hemorrhage and were treated by surfactant, 38% of the neonates died and 62% of the survivors developed pulmonary hemorrhage. In the current study, the lower rate of BPD may be explained by higher rate of mortality. There are inherent differences in the American Journal of Perinatology
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biochemical composition and physiological properties of the various types of exogenous surfactants that have been used. Surfactants derived from animal lungs appear to have greater surface tension reducing properties, a greater ability to improve lung compliance, and a more rapid action than synthetic surfactants.2,4 Therefore, natural surfactants were preferred in our study. Both poractant alfa and beractant have improved oxygenation when given for pulmonary hemorrhage. Studies showed that mortality of pulmonary hemorrhage was primarily associated with VLBW.9,11 Alfaleh et al17 reported the mortality rate of pulmonary hemorrhage as 47.2% in infants with birth weight of 500 to 999 g. In Li et al’s20 study, this rate was very high (74.5%) among infants with pulmonary hemorrhage. The authors defined the risk factors as birth weight, IVH, heart failure, and sepsis. In another report, it was found that the incidence of massive pulmonary hemorrhage in VLBW infants was 5.9% (20/340) with a mortality rate of 85.2%.21 The authors reported that this high mortality rate might be related to poor treatment of pulmonary hemorrhage in their NICU. They also stated that their study population had higher risk for one or more severe illnesses and medical complications, such as RDS, IVH, and sepsis. In our study, we evaluated VLBW infants with pulmonary hemorrhage with an incidence of 11.6% and found the pulmonary hemorrhage-related mortality as 54.7%. Mortality was associated to low Apgar score at 5 minutes. The type of surfactant given for pulmonary hemorrhage has no effect on the mortality rate. There are several limitations of our study. First of all, the size of our study groups does not allow us to make inferences regarding changes, if any, in mortality and long-term morbidity. Furthermore, we did not control specifically for severity of illness. However, this study is the first RCT comparing the effect of natural surfactants in VLBW infants with pulmonary hemorrhage. In conclusion, exogenous natural surfactants may be used for adjunctive therapy in VLBW infants with pulmonary hemorrhage. We suggest that this may be further investigated by larger RCTs.
of the version to be published, Clinical Trials registry: “Comparison of Two Different Natural Surfactants in the Treatment of Pulmonary Hemorrhage” www.clinicaltrials. gov NCT01860014.
Conflict of Interest There is no conflict of interest.
References 1 Raju TNK, Langenberg P. Pulmonary hemorrhage and exogenous
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5
6 7
8 9
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Funding There is no support from any foundation.
Author’s Contribution Şenol Bozdağ: Conception and design, acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, final approval of the version to be published. Dilek Dilli: Conception and design, acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, final approval of the version to be published. Tülin Gökmen: Conception and design, acquisition of data, or analysis and interpretation of data. Uğur Dilmen: Conception and design, acquisition of data, or analysis and interpretation of data, final approval American Journal of Perinatology
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13
14 15 16
17
surfactant therapy: a metaanalysis. J Pediatr 1993;123(4): 603–610 Pandit PB, Dunn MS, Colucci EA. Surfactant therapy in neonates with respiratory deterioration due to pulmonary hemorrhage. Pediatrics 1995;95(1):32–36 Trompeter R, Yu VYH, Aynsley-Green A, Roberton NRC. Massive pulmonary haemorrhage in the newborn infant. Arch Dis Child 1975;50(2):123–127 Horbar JD, Wright LL, Soll RF, et al; National Institute of Child Health and Human Development Neonatal Research Network. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. J Pediatr 1993;123(5):757–766 Holm BA, Notter RH. Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity. J Appl Physiol 1987;63(4): 1434–1442 Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328(12):861–868 Speer CP, Robertson B, Curstedt T, et al. Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single versus multiple doses of Curosurf. Pediatrics 1992;89(1):13–20 Ramanathan R. Choosing a right surfactant for respiratory distress syndrome treatment. Neonatology 2009;95(1):1–5 Tomaszewska M, Stork E, Minich NM, Friedman H, Berlin S, Hack M. Pulmonary hemorrhage: clinical course and outcomes among very low-birth-weight infants. Arch Pediatr Adolesc Med 1999;153(7): 715–721 Amizuka T, Shimizu H, Niida Y, Ogawa Y. Surfactant therapy in neonates with respiratory failure due to haemorrhagic pulmonary oedema. Eur J Pediatr 2003;162(10):697–702 Pandit PB, O’Brien K, Asztalos E, Colucci E, Dunn MS. Outcome following pulmonary haemorrhage in very low birthweight neonates treated with surfactant. Arch Dis Child Fetal Neonatal Ed 1999;81(1):F40–F44 Ortiz RM, Cilley RE, Bartlett RH. Extracorporeal membrane oxygenation in pediatric respiratory failure. Pediatr Clin North Am 1987;34(1):39–46 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92(4):529–534 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33(1):179–201 Northway WH Jr. Observations on bronchopulmonary dysplasia. J Pediatr 1979;95(5 Pt 2):815–818 An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. [No authors listed]. Arch Ophthalmol. 1984;102(8):1130–1134 Alfaleh K, Smyth JA, Roberts RS, Solimano A, Asztalos EV, Schmidt B; Trial of Indomethacin Prophylaxis in Preterms Investigators. Prevention and 18-month outcomes of serious pulmonary hemorrhage in extremely low birth weight infants: results from the
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20 Li L, Yu J, Wang J, et al. A prediction score model for risk factors of
mortality in neonate with pulmonary hemorrhage: the experience of single neonatal intensive care unit in Southwest China. Pediatr Pulmonol 2008;43(10):997–1003 21 Lin TW, Su BH, Lin HC, et al. Risk factors of pulmonary hemorrhage in very-low-birth-weight infants: a two-year retrospective study. Acta Paediatr Taiwan 2000;41(5):255–258
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trial of indomethacin prophylaxis in preterms. Pediatrics 2008; 121(2):e233–e238 18 Strauss T, Rozenzweig N, Rosenberg N, et al. Surfactant impairs coagulation in-vitro: a risk factor for pulmonary hemorrhage? Thromb Res 2013;132(5):599–603 19 Rogers D. Pulmonary haemorrhage, surfactant, and low-birthweight babies. Lancet 1993;341(8846):698
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Comparison of Two Natural Surfactants for Pulmonary Hemorrhage in Very Low-BirthWeight Infants: A Randomized Controlled Trial Dilek Dilli, MD2
Tülin Gökmen, MD3
1 Department of Neonatology, Umraniye Research and Training
Hospital, İstanbul, Turkey 2 Department of Neonatology, Dr Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey 3 Department of Neonatology, Bağcılar Research and Training Hospital, İstanbul, Turkey 4 Department of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey 5 Department of Pediatrics and Neonatology, Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
Uğur Dilmen, MD4,5
Address for correspondence Dilek Dilli, MD, Dr Sami Ulus Maternity and Children Research and Training Hospital, Babür street, zip code: 06080, Altjndag/Ankara/Turkey (e-mail: [email protected]).
Am J Perinatol 2015;32:211–218.
Abstract
Keywords
► premature ► pulmonary hemorrhage ► surfactant
Objective To compare the efficacy of two natural surfactants for pulmonary hemorrhage in very low-birth-weight (VLBW) infants. Study Design A prospective randomized controlled trial was conducted on 42 infants who were divided into two groups, poractant alfa (n ¼ 21) and beractant (n ¼ 21). Results In both the groups, the mean standard deviation (SD) birth-weight and gestational age were similar (p ¼ 0.33 and 0.89, respectively). Although, the mean oxygenation index (OI) increased after pulmonary hemorrhage compared with baseline value and decreased after surfactant in both groups, variations in OI were more prominent in poractant alfa group (before hemorrhage: 11.9, after hemorrhage: 22.7, 1 hour of surfactant: 14.6, 8th hour of surfactant: 7.8, 24th hour of surfactant: 8.5, p ¼ 0.007 vs. before pulmonary hemorrhage:11.1, after pulmonary hemorrhage: 17.9, 1 hour of surfactant: 12.8, 8th hour of surfactant: 12.8, 24th hour of surfactant: 9.7, p ¼ 0.02). There was no significant difference between the groups for OI values at all time points (p > 0.05). The rates of bronchopulmonary dysplasia (BPD) and mortality related to pulmonary hemorrhage were similar in both the groups. Conclusion Both natural surfactants improved oxygenation when administered for pulmonary hemorrhage in VLBW infants. The type of surfactant seems to have no effect on BPD and mortality rates in these patients.
Pulmonary hemorrhage is a life-threatening condition that associates with many predisposing factors, including low gestational age, vaginal birth, male sex, and the presence of respiratory distress syndrome (RDS), patent ductus arteriosus (PDA), sepsis, as well as pulmonary hemorrhage, hypoxia, severe hypothermia, and congenital heart disease (CHD).1,2
The mortality rate of pulmonary hemorrhage remained about 50%, despite recent improvements in the treatment of pulmonary hemorrhage.2 There are a variety of treatment options for pulmonary hemorrhage, with outcomes varying from country to country and hospital to hospital. Pulmonary hemorrhage results in an
received June 27, 2013 accepted after revision July 19, 2013 published online September 21, 2014
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DOI http://dx.doi.org/ 10.1055/s-0034-1389090. ISSN 0735-1631.
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Şenol Bozdağ, MD1
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acute deterioration reflected by an increase in the fraction of inspired oxygen (FIO2) and ventilatory support.2,3 Surfactant therapy is a well-established role in the management of neonates with RDS, where there is a surfactant deficiency. Pulmonary hemorrhage may be associated with surfactant therapy for RDS, and, therefore, there is conflict on the use of surfactant to treat respiratory failure due to pulmonary hemorrhage.1 However, it is also hypothesized that exogenous surfactant can be useful in neonates with respiratory disorders where surfactant inactivation, rather than surfactant deficiency, may occur. In pulmonary hemorrhage, severe leaking of blood components into the alveolar space occurs in pulmonary hemorrhage.4 The presence of hemoglobin, red cell membrane lipids, and serum proteins increases the surface tension, leading to secondary surfactant deficiency or surfactant dysfunction.5 In a complementary pulmonary hemorrhage physiological experiment, the authors have shown that instillation of hemoglobin, membrane lipids, or albumin into excised rat lungs leads to a decrease in respiratory system compliance. The increase in surface tension can be overcome by increasing the concentration of surfactant and this is the rationale for the use of surfactant in pulmonary hemorrhage. Although, both natural and synthetic surfactant preparations reduce the incidence of neonatal mortality in premature infants with RDS,6 natural surfactants improve oxygenation and lung function more rapidly than synthetic surfactants.4 Within the group of natural surfactants, a differential response has also been reported—either as differences in the a: A PO2 ratio during the first 24 hours7,8 or as a difference in ventilatory requirement during the first 24 hours, following administration for RDS. Two retrospective studies evaluating the effect of surfactant therapy after pulmonary hemorrhage showed that administration of exogenous surfactant was a useful adjunctive therapy in newborns with clinically significant pulmonary hemorrhage.9,10 However, there is no prospective randomized controlled trial (RCT) comparing the efficacy of different surfactants for pulmonary hemorrhage in this age group. We, therefore, conducted a prospective RCT comparing the effects of two natural surfactants on outcomes of very low-birthweight (VLBW) infants with pulmonary hemorrhage.
Study Design This was a prospective RCT conducted in the neonatal intensive care unit (NICU) of Zekai Tahir Burak Maternity and Children Research and Training Hospital, Ankara, Turkey, between March 2010 and February 2011. During the study period, 446 VLBW infants with a gestational age of < 32 weeks or birth-weight of < 1,500 g were born. Among them, infants having pulmonary hemorrhage within the first 2 weeks of life were considered for the study. Pulmonary hemorrhage was determined by the symptom of a nontraumatic gush of bloody secretion from the endotracheal tube, which was associated with clinical deterioration or a need of increased ventilatory support.9,11 American Journal of Perinatology
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Initially, 52 infants (11.6%) were eligible for the study. Ten patients were not included because four died within the first 2 hours of pulmonary hemorrhage, two had congenital anomalies (one with trisomy 18 and another with gastroschisis), and in the remaining four the parental consents could not be obtained. Finally, 42 infants were randomized for the study.
Randomization Randomization was performed using a computer-generated random numbers algorithm. Allocation to receive either surfactant A or surfactant B was performed for each eligible newborn using a sealed opaque envelope. Poractant alfa, which is from porcine lung extract, was given for surfactant A at a dose of 100 mg/kg (1.25 mL/kg). Beractant, which is from beef lung extract, was given for surfactant B at a dose of 100 mg/kg (4 mL/kg). Surfactant was given as a single dose after the 2nd hour of pulmonary hemorrhage to eliminate improvement either spontaneously or due to changes in ventilatory management.
Patient Characteristics and Clinical Outcomes Maternal (age, multiple birth, chorioamnionitis, antenatal steroid, and cesarean delivery) and infant (gestational age, birth weight, Apgar score at 5 minutes, gender, and the age at pulmonary hemorrhage) characteristics were extracted from the patients’ sheet. Interval between pulmonary hemorrhage and surfactant, hemoglobin values before and after pulmonary hemorrhage, and severity of pulmonary hemorrhage were recorded. Pulmonary hemorrhage was classified as mild if FIO2 increased by < 0.1, moderate if it increased by 0.1 to 0.3, and severe if the increase was > 0.3 from the baseline. Type of respiratory support and presence of pneumothorax were noted. Respiratory variables collected were Fio2, peak inspiratory pressure (PIP), mean airway pressure (MAP), partial arterial carbon dioxide (Paco2), and oxygenation index (OI). OI was defined as OI ¼ (Fio2 MAP 100)/Pao2.12 For basal values of respiratory parameters, the nearest data within the last 6 hours before pulmonary hemorrhage was assumed to be representative. These parameters were also recorded at the 1st, 8th, and 24th hours of surfactant administration. Data on RDS (with signs of hyaline membrane disease on the chest X-ray examination), PDA (characteristic murmur or echocardiographic confirmation), intraventricular hemorrhage (IVH) (grade 2),13 proven sepsis (bacteria cultured from blood or tracheal aspirate accompanied by clinical deterioration and increased C-reactive protein concentrations), necrotizing enterocolitis (NEC) (grade 2),14 bronchopulmonary dysplasia (BPD) (the need for oxygen at 36 weeks of postmenstrual age),15 and retinopathy of prematurity (ROP) (stage > 3)16 were recorded. Data on late outcomes, such as NEC, BPD, and ROP, were analyzed for those neonates who survived until discharge from hospital. Duration of mechanical ventilation, length of NICU stay, and mortality were noted. The effects of the two surfactants on clinical outcomes were compared.The primary outcome measures were a
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change in respiratory status following surfactant therapy, as reflected by change in OI and other respiratory variables. Secondary outcome measures were BPD and mortality related to pulmonary hemorrhage (within 72 hours after pulmonary hemorrhage).
Ethics Informed consent was obtained from the parents before administration of the surfactant. This study was approved by the institutional review board and strictly followed the institution’s ethical guidelines.
Power Analysis and Statistics According to the results from observational data in 20 neonates who were receiving two surfactants after pulmonary hemorrhage, the mean (standard deviation [SD]), OI after poractant alfa were 14.7 (10.1) and 11.0 (4.8) after beractant. A sample size of 42 could detect 3.7 point change in OI with 80% power and 5% type I error (https://www.dssresearch.com).
Statistics Comparisons of variables in infants who received poractant alfa versus those who received beractant were analyzed. SPSS 16.0 (SPSS, IBM Inc., Chicago IL) was used for statistical analysis. Kolmogorov–Smirnov test was used to analyze the distribution of data. Data were expressed as the arithmetic mean (SD) or median (range). Differences between the two groups were tested using Student t-test or Mann– Whitney U test, as appropriate. Chi-square tests were performed for categorical variables. Wilcoxon or Friedman tests were used to analyze repeated measurements. Associations were analyzed using odds ratios (OR) and 95% confidence intervals (CIs). A two-tailed p value of < 0.05 was accepted as significant.
Results A total of 42 newborns who had their pulmonary hemorrhage within the first 2 weeks of life and treated by surfactant were evaluated. In 19 patients (45.2%), pulmonary hemor-
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rhage developed within the first 48 hours of life. All received conventional therapy for the pulmonary hemorrhage before administration of surfactant. Management of pulmonary hemorrhage included an increase in respiratory support, administration of fluids, medications, and antibiotics. Eight patients who were previously nonventilated were entubated and connected to the ventilator after the development of pulmonary hemorrhage. Four infants switched to high frequency oscillation after pulmonary hemorrhage. Epinephrine was diluted 10,000 times and administered via endotracheal tube to all infants. Vasopressors and vitamin K were given to all neonates. The patients were randomized to receive poractant alfa or beractant; 21 patients were included in each group. The median surfactant administration time was 4 hours (2–8). The characteristics of the study patients are shown in ►Table 1. The mean (SD) birth weight and gestational age were similar in groups. Birth weight was less than 1,000 g in nine patients (42.9%) in each group. ►Table 2 shows clinical outcome of the patients studied. Pulmonary hemorrhage was severe in 14 (33.3%), moderate in 22 (52.4%), and mild in 6 (14.3%). The severity of pulmonary hemorrhage did not differ between the groups. All patients with RDS, but none of the others, had previously received surfactant. Paired hemoglobin (Hb) values were available for 39 patients. In both groups, the median Hb was significantly decreased after pulmonary hemorrhage (p ¼ 0.01 vs. p ¼ 0.01). Coagulation screens were performed in 32 patients. International normalized ratio was > 1.5 in 10 patients (47.6%) in poractant alfa group and 14 (66.7%) in beractant group (p ¼ 0.71). Packed red blood cells (n ¼ 32, 76.1%) and fresh frozen plasma of AB blood type (n ¼ 10, 23.8%) were given to patients if necessary. Respiratory variables recorded before and after pulmonary hemorrhage are documented in ►Table 3. ►Fig. 1 shows the response to surfactant therapy as assessed by OI in both groups. Although the mean OI increased after pulmonary hemorrhage compared with baseline value and decreased after surfactant in both groups,
Table 1 Characteristics of the study patients according to type of surfactant Variables
Poractant alfa (n ¼ 21)
Beractant (n ¼ 21)
p-Value
Maternal age, y
26.4 (5.2)
26.6 (6.6)
0.93
Multiple birth, n (%)
10 (47.6)
11 (52.4)
0.75
Chorioamnionitis, n (%)
4 (19.0)
0 (0)
0.10
Antenatal steroid, n (%)
11 (52.4)
13 (61.9)
0.75
Cesarean delivery, n (%)
12 (57.1)
14 (66.7)
0.52
Gestational age, wk
27.9 (2.3)
27.2 (2.3)
0.36
Birth-weight
1,051 (236)
1,074 (242)
0.76
Apgar score at 5 min, median (range)
7 (1–9)
8 (3–9)
0.66
Male, n (%)
13 (61.9)
10 (47.6)
0.53
Age at pulmonary hemorrhage, h
46 (24–324)
96 (24–310)
0.05
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Table 2 Clinical outcomes of the study patients according to type of surfactant Variables
Poractant alfa (n ¼ 21)
Beractant (n ¼ 21)
p-Value
Early outcomes Interval between pulmonary hemorrhage and surfactant, h
3 (2–8)
4 (3–6)
Hb before pulmonary hemorrhage, (g/dl) median (range)
11.9 (5.7–15.2)
10.8 (6.7–17.6)
0.58
Hb after pulmonary hemorrhage, (g/dl), median (range)
10.3 (4.2–13.8)
9.4 (5.2–16.1)
0.55
Severity of pulmonary hemorrhage, n (%) Mild, Moderate, Severe
4 (19) 11 (52.4) 6 (28.6)
2 (9.5) 11 (52.4) 8 (38.1)
0.62
RDS, n (%) Poractant alfa, n (%) Beractant, n (%)
5 (23.8) 14 (66.7)
5 (23.8) 15 (71.4)
0.83
PDA, n (%)
8 (38.1)
12 (57.1)
0.44
IVH (> grade 2), n (%)
1 (4.8)
7 (33.3)
0.04
Sepsis, n (%)
2(9.5)
8 (38.0)
0.06
Pneumothorax, n (%)
3 (14.3)
0 (0)
0.23
Duration of mechanical ventilation,
5 (1–12)
5 (2–14)
0.16
NICU stay, median (range)
5 (1–90)
8 (2–84)
0.47
Death age after pulmonary hemorrhage, h, median (range)
4 (1–36)
6 (1–36)
0.75
Mortality, related to pulmonary hemorrhage, n (%)
12 (57.1)
11 (52.4)
0.75
Overall mortality, n (%)
15 (71.4)
14 (66.7)
0.73
Poractant alfa (n ¼ 6)
Beractant (n ¼ 7)
NEC (> stage 2), n (%)
4 (66.7)
2 (28.6)
0.28
BPD, n (%)
2 (33.3)
3 (42.9)
0.72
ROP (> stage 3), n (%)
2 (33.3)
1 (16.7)
0.50
Late outcomes
Abbreviations: BPD,bronchopulmonary dysplasia; Hb, hemoglobin; IVH, ıntraventricular hemorrhage; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; OI, oxygenation index; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; SD, standard deviation.
variations in OI were more prominent in poractant alfa group (before hemorrhage: 11.9, after hemorrhage: 22.7, 1 hour of surfactant: 14.6, 8th hour of surfactant: 7.8, 24th hour of surfactant: 8.5, p ¼ 0.007 vs. before pulmonary hemorrhage: 11.1, after pulmonary hemorrhage: 17.9, 1 hour of surfactant: 12.8, 8th hour of surfactant: 12.8, 24th hour of surfactant: 9.7, p ¼ 0.02). There was no significant difference between the groups for OI values at all time points (p > 0.05). In survived patients, OI gradually decreased at 8th and 24th hours of surfactant, without significant difference between the groups. Among the 20 neonates who had a clinical and echocardiographic diagnosis of PDA, 10 had this diagnosis made before the pulmonary hemorrhage. Of the 42 patients, 23 (54.7%) died within 72 hours after pulmonary hemorrhage and 17 of these 23 patients (73.9%) died within the first 6 hours of pulmonary hemorrhage. Mortality rates did not differ in groups. Of the survived patients, six died during the neonatal period (first 28 days of life): four died from severe sepsis, one from severe IVH, and American Journal of Perinatology
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another one from acute renal failure. Among the survived ones, five patients (38.4%, 5/13) developed BPD with characteristic clinical and X-ray features. No difference was found between the survivor and the death groups in the following variables: gender, gestational age, birth weight, age at pulmonary hemorrhage, and the incidences of RDS, PDA, sepsis, NEC, BPD, and ROP. Apgar score at 5 minutes was lower (7 [1–9] vs. 8 [4–9], p ¼ 0.01) and OI value after surfactant was higher (24.5 [11–30] vs. 8.5 [4.5–14], p ¼ 0.01) in infants who could not survive compared with the survivors (p ¼ 0.01 and 0.001, respectively). Independent risk factors, which significantly increased the mortality of pulmonary hemorrhage, were further analyzed using multivariable logistic regression analysis (forward stepwise). A seven-variable logistic regression model was generated, which included gestational age, antenatal steroid, PDA, Apgar score at 5 minutes, sepsis, IVH, and type of surfactant. It was found that only low Apgar score at 5 minutes has increased the risk of mortality (OR: 2.2, 95% CI: 1.2–4.0).
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Table 3 Respiratory variables of the study patients according to type of surfactant Variables, mean (SD)
Poractant alfa (n ¼ 21)
Beractant (n ¼ 21)
p-Value
Before pulmonary hemorrhage 57.7 (20.1)
54.8 (22.1)
0.71
14.4 (1.9)
16.5 (2.4)
0.04
MAP
9.5 (1.1)
10.7 (0.9)
0.007
PaCO2
50.8 (21.5)
56.1 (17.8)
0.41
OI
11.9 (5.5)
11.1 (5.5)
0.74
74.2 (18.9)
0.05
After pulmonary hemorrhage FIO2
85.5 (12.5)
PIP
17.4 (3.05)
20.4 (3.3)
0.01
MAP
11.5 (1.4)
12.2 (1.4)
0.21
PaCO2
62.7 (17.2)
55.2 (35.2)
0.40
OI
22.7 (9.4)
17.9 (8.6)
0.20
1 h after surfactant administration FIO2
65.7 (19.6)
71.5 (25.7)
0.52
PIP
16.5 (2.3)
19.5 (3.6)
0.02
MAP
10.4 (1.3)
11.7 (1.6)
0.05
PaCO2
49.8 (12.0)
49.3 (25.2)
0.94
OI
14.6 (8.7)
12.8 (7.0)
0.59
8 h after surfactant administration FIO2
59.5 (24.9)
60.2 (25.1)
0.95
PIP
16.4 (3.9)
18.3 (4.8)
0.35
MAP
10.2 (1.3)
10.9 (1.5)
0.32
PaCO2
70.1 (15.6)
43.1 (11.0)
0.001
OI
7.8 (4.2)
12.8 (7.1)
0.29
24 h after surfactant administration FIO2
45 (22.0)
49 (22.7)
0.71
PIP
15 (3.9)
16.7 (4.6)
0.41
MAP
10 (1.5)
10 (1.6)
0.62
PaCO2
60 (15.1)
43.8 (9.6)
0.03
OI
8.5 (10.0)
9.7 (10.4)
0.84
Abbreviations: FiO2, fraction of inspired oxygen; MAP, mean airway pressure; OI, oxygenation index; PaCO2, partial arterial carbon dioxide; PIP, peak inspiratory pressure; SD, standard deviation. Note: Values are expressed as mean (SD).
Discussion The results of this prospective RCT indicate that neonates exhibiting a respiratory deterioration following a pulmonary hemorrhage have at least a short-term improvement in oxygenation and ventilation, as determined by OI, following therapy with surfactant. Both natural surfactants improved the OI from before surfactant (22.7 vs. 17.9) to after surfactant (at 1 hour) (14.6 vs. 12.8). Although the latter value was
Fig. 1 Oxygenation index (OI) before and after surfactant in study groups.
higher than the prehemorrhage baseline OI values (11.9 vs. 11.1), it may be said that exogenous surfactant appears to be a useful adjunctive therapy in newborns with pulmonary hemorrhage. In spite of the lack of a placebo group, improvement of the oxygenation was apparently prompt and seemed to be related to the surfactant application. The incidence of pulmonary hemorrhage among infants with RDS reported in some of the larger surfactant trials varies from 1 to 11%.1,17 However, this incidence may not be accurate as there is no generally accepted method of grading its severity. Some investigators have defined pulmonary hemorrhage in the presence of small amounts of blood in the endotracheal tube that could have been due to trauma, following suction, others may have reported only massive pulmonary hemorrhage. Therefore, this may have led to overreporting.1 In our study, traumatic hemorrhage was excluded and severity of pulmonary hemorrhage was defined. The incidence of pulmonary hemorrhage among VLBW infants was 11.6% and there was no significant difference for severity of pulmonary hemorrhage between the groups. In pulmonary hemorrhage, death may occur despite attempts at resuscitations. It was reported that over 60% of newborns who have a severe pulmonary hemorrhage die, usually within the first 72 hours of life.11 Furthermore, 60% of those who survive develop BPD. In survived patients this is likely to be related to an increased need of oxygen support which may lead to further lung injury. In our study, mortality rate (54.7%) was also higher within 72 hours after pulmonary hemorrhage. Six infants died during neonatal period and BPD developed in five of 13 survived infants (38.4%). BPD rates were similar in groups. There are conflicts on the decision to treat (or not to treat) with surfactant after pulmonary hemorrhage and timing of the therapy.1,18,19 In both in vitro and animal studies, it has been shown that surfactant inhibition may be overcome at least partially by exogenous surfactant replacement. It is likely that surfactant inhibition may occur in several respiratory conditions. Pandit et al2 reported the clinical outcomes of neonates who had developed pulmonary hemorrhage and were treated by surfactant, 38% of the neonates died and 62% of the survivors developed pulmonary hemorrhage. In the current study, the lower rate of BPD may be explained by higher rate of mortality. There are inherent differences in the American Journal of Perinatology
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FIO2 PIP
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biochemical composition and physiological properties of the various types of exogenous surfactants that have been used. Surfactants derived from animal lungs appear to have greater surface tension reducing properties, a greater ability to improve lung compliance, and a more rapid action than synthetic surfactants.2,4 Therefore, natural surfactants were preferred in our study. Both poractant alfa and beractant have improved oxygenation when given for pulmonary hemorrhage. Studies showed that mortality of pulmonary hemorrhage was primarily associated with VLBW.9,11 Alfaleh et al17 reported the mortality rate of pulmonary hemorrhage as 47.2% in infants with birth weight of 500 to 999 g. In Li et al’s20 study, this rate was very high (74.5%) among infants with pulmonary hemorrhage. The authors defined the risk factors as birth weight, IVH, heart failure, and sepsis. In another report, it was found that the incidence of massive pulmonary hemorrhage in VLBW infants was 5.9% (20/340) with a mortality rate of 85.2%.21 The authors reported that this high mortality rate might be related to poor treatment of pulmonary hemorrhage in their NICU. They also stated that their study population had higher risk for one or more severe illnesses and medical complications, such as RDS, IVH, and sepsis. In our study, we evaluated VLBW infants with pulmonary hemorrhage with an incidence of 11.6% and found the pulmonary hemorrhage-related mortality as 54.7%. Mortality was associated to low Apgar score at 5 minutes. The type of surfactant given for pulmonary hemorrhage has no effect on the mortality rate. There are several limitations of our study. First of all, the size of our study groups does not allow us to make inferences regarding changes, if any, in mortality and long-term morbidity. Furthermore, we did not control specifically for severity of illness. However, this study is the first RCT comparing the effect of natural surfactants in VLBW infants with pulmonary hemorrhage. In conclusion, exogenous natural surfactants may be used for adjunctive therapy in VLBW infants with pulmonary hemorrhage. We suggest that this may be further investigated by larger RCTs.
of the version to be published, Clinical Trials registry: “Comparison of Two Different Natural Surfactants in the Treatment of Pulmonary Hemorrhage” www.clinicaltrials. gov NCT01860014.
Conflict of Interest There is no conflict of interest.
References 1 Raju TNK, Langenberg P. Pulmonary hemorrhage and exogenous
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5
6 7
8 9
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Funding There is no support from any foundation.
Author’s Contribution Şenol Bozdağ: Conception and design, acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, final approval of the version to be published. Dilek Dilli: Conception and design, acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, final approval of the version to be published. Tülin Gökmen: Conception and design, acquisition of data, or analysis and interpretation of data. Uğur Dilmen: Conception and design, acquisition of data, or analysis and interpretation of data, final approval American Journal of Perinatology
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13
14 15 16
17
surfactant therapy: a metaanalysis. J Pediatr 1993;123(4): 603–610 Pandit PB, Dunn MS, Colucci EA. Surfactant therapy in neonates with respiratory deterioration due to pulmonary hemorrhage. Pediatrics 1995;95(1):32–36 Trompeter R, Yu VYH, Aynsley-Green A, Roberton NRC. Massive pulmonary haemorrhage in the newborn infant. Arch Dis Child 1975;50(2):123–127 Horbar JD, Wright LL, Soll RF, et al; National Institute of Child Health and Human Development Neonatal Research Network. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. J Pediatr 1993;123(5):757–766 Holm BA, Notter RH. Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity. J Appl Physiol 1987;63(4): 1434–1442 Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328(12):861–868 Speer CP, Robertson B, Curstedt T, et al. Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single versus multiple doses of Curosurf. Pediatrics 1992;89(1):13–20 Ramanathan R. Choosing a right surfactant for respiratory distress syndrome treatment. Neonatology 2009;95(1):1–5 Tomaszewska M, Stork E, Minich NM, Friedman H, Berlin S, Hack M. Pulmonary hemorrhage: clinical course and outcomes among very low-birth-weight infants. Arch Pediatr Adolesc Med 1999;153(7): 715–721 Amizuka T, Shimizu H, Niida Y, Ogawa Y. Surfactant therapy in neonates with respiratory failure due to haemorrhagic pulmonary oedema. Eur J Pediatr 2003;162(10):697–702 Pandit PB, O’Brien K, Asztalos E, Colucci E, Dunn MS. Outcome following pulmonary haemorrhage in very low birthweight neonates treated with surfactant. Arch Dis Child Fetal Neonatal Ed 1999;81(1):F40–F44 Ortiz RM, Cilley RE, Bartlett RH. Extracorporeal membrane oxygenation in pediatric respiratory failure. Pediatr Clin North Am 1987;34(1):39–46 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92(4):529–534 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33(1):179–201 Northway WH Jr. Observations on bronchopulmonary dysplasia. J Pediatr 1979;95(5 Pt 2):815–818 An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. [No authors listed]. Arch Ophthalmol. 1984;102(8):1130–1134 Alfaleh K, Smyth JA, Roberts RS, Solimano A, Asztalos EV, Schmidt B; Trial of Indomethacin Prophylaxis in Preterms Investigators. Prevention and 18-month outcomes of serious pulmonary hemorrhage in extremely low birth weight infants: results from the
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mortality in neonate with pulmonary hemorrhage: the experience of single neonatal intensive care unit in Southwest China. Pediatr Pulmonol 2008;43(10):997–1003 21 Lin TW, Su BH, Lin HC, et al. Risk factors of pulmonary hemorrhage in very-low-birth-weight infants: a two-year retrospective study. Acta Paediatr Taiwan 2000;41(5):255–258
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trial of indomethacin prophylaxis in preterms. Pediatrics 2008; 121(2):e233–e238 18 Strauss T, Rozenzweig N, Rosenberg N, et al. Surfactant impairs coagulation in-vitro: a risk factor for pulmonary hemorrhage? Thromb Res 2013;132(5):599–603 19 Rogers D. Pulmonary haemorrhage, surfactant, and low-birthweight babies. Lancet 1993;341(8846):698
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No. 3/2015
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Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
