Abstract
Introduction
Congenital heart diseases (CHD) have been reported to be responsible for 30 to 50% of infant mortality caused by congenital disabilities. In critical cases, survival of newborns with CHD depends on the patency of the ductus arteriosus (PDA), for maintaining the systemic or pulmonary circulation. The aim of the study was to assess the efficacy and side effects of PGE (prostaglandin E) administration in newborns with critical congenital heart disease requiring maintenance of the ductus arteriosus.
Material and method
All clinical and paraclinical data of 66 infants admitted to one referral tertiary level academic center and treated with Alprostadil were analyzed. Patients were divided into three groups: Group 1: PDA dependent pulmonary circulation (n=11) Group 2: PDA dependent systemic circulation (n=31) Group 3: PDA depending mixed circulation (n=24)
Results
The mean age of starting PGE1 treatment was 2.06 days, 1.91 (+/-1.44) days for PDA depending pulmonary flow, 2.39 (+/-1.62) days for PDA depending systemic flow and 1.71 (+/1.12) for PDA depending mixing circulation. PEG1 initiation was commenced 48 hours after admission for 72%, between 48-72 hours for 6%, and after 72 to 120 hours for 21% of newborns detected with PDA dependent circulation. Before PEG1 initiation the mean initial SpO2 was 77.89 (+/- 9.2)% and mean initial oxygen pressure (PaO2) was 26.96(+/-6.45) mmHg. At the point when stable wide open PDA was achieved their mean SpO2increased to 89.73 (+/-8.4)%, and PaO2 rose to 49 (+/-7.2) mmHg. During PGE1 treatment, eleven infants (16.7%) had apnea attacks, five children (7.5%) had convulsions, 33 (50%) had fever, 47 (71.2%) had leukocytosis, 52 (78.8%) had edema, 25.8% had gastrointestinal intolerance, 45.5% had hypokalemia, and 63.6% had irritability.
Conclusions
For those infants with severe cyanosis or shock caused by PDA dependent heart lesions, the initiation and maintenance of PGE1 infusion is imperative. The side effects of this beneficial therapy were transient and treatable.
Keywords: prostaglandins, patent ductus arteriosus, congenital heart disease
Introduction
Congenital heart diseases are the most common birth defects in newborns. Nearly 1% of newborns have congenital heart defects, and approximately one-quarter of those defects are associated with a critical condition [1,2,3]. Most of these heart defects require ductal patency for survival, and may not have been visible clinical signs immediately after birth until constriction of the duct occurred [4].
Congenital heart diseases are responsible for 30-50% of infant mortality caused by birth defects. According to the NBDPN surveillance data, these deaths occurred most commonly in critical cases of hypoplastic left heart syndrome, transposition of the great arteries, or tetralogy of Fallot [5].
Prenatal diagnosis of cardiac malformations is crucial to initiate the most appropriate therapeutic strategy and depends on largely upon the echocardiography recognition of the structural heart defects during the second trimester [6,7].
According to Cochrane Database of Systemic Reviews 2014, infants with critical congenital heart defects that are dependent on the patency of the ductus arteriosus (PDA) for survival can be categorized into three groups. The first group is characterized by severe restriction of the pulmonary blood flow e.g. pulmonary atresia, tricuspid atresia or tetralogy of Fallot with pulmonary atresia. In these cases, pulmonary circulation is dependent on the patency of the ductus arteriosus and postnatal constriction of the ductus causes severe hypoxemia, cyanosis and death 8]. Group two includes conditions with severe restriction of the systemic blood flow e.g. severe aortic stenosis, coarctation of the aorta, interrupted aortic arch or left hypoplastic syndrome. In these cases, the systemic circulation is dependent on the patency of the ductus arteriosus and postnatal constriction of the ductus may cause systemic hypoperfusion, circulatory deterioration, metabolic acidosis, shock, and death [9]. The third group includes cardiac anomalies e.g. transposition of the great arteries, where adequate mixing of pulmonary and systemic blood flow is necessary for maintaining a circulation in series [10].
Due to its importance in the maintenance of the ductus patency during fetal life, prostaglandin is the elective therapy (PEG1) indicated for the temporary management of the neonate with ductus dependent congenital heart disease to maintain ductal patency until surgery can be performed [11]. PEG1 promotes vasodilatation by the direct effect on the vasculature and smooth muscle of the ductus arteriosus. Four PGE1 receptors have been identified. EP2 and EP4 receptor subtypes mediate PGE1-induced relaxation of the ductus arteriosus in human neonates through a cyclic AMP-dependent mechanism. PEG1 was approved by the Food and Drug Administration in 1981 for use in infants with a congenital cardiac defect but is not without limitation and side effects [12]. Sixty to eighty percent of PEG1 is metabolized on first passing through the lungs and so must be administered by continuous infusion. At a starting dose of 0.025 to 0.1 microgram/ kg/minute, the ductus usually reopens within thirty minutes to two hours of initiating PGE1, with the clinical response usually being instant [11,13,14,15].
The aim of the study was to assess the efficacy and the effects of PGE administration in newborns with critical congenital heart disease requiring maintenance of ductus arteriosus.
Method
The clinical case reports of sixty-six infants admitted to one tertiary level academic center and treated with Alprostadil for critically congenital cardiac malformations from 1st January 2014 to 30st June 2016 were reviewed.
Patients were divided into three groups: Group 1: PDA dependent pulmonary circulation (n=11) Group 2: PDA dependent systemic circulation (n=31) Group 3: PDA depending mixing circulation (n=24)
A critical congenital heart defect was defined as a structural malformation of the heart present at birth, was life threatening and required interventions in the first months of life. Adverse medical events were defined as any unanticipated or undesirable incident that occurred during the treatment, or preparatory stabilization time before surgical treatment and might have necessitated an alteration in therapy.
Descriptive statistics including mean (+/-SD) were presented for continuous variables and frequencies for categorical variables. Univariate analyses with independent samples t-test and λ2 test for categorical variables were performed to evaluate differences between group using SPSS 10.0 for Windows.
The significant level was set at α=0.05.
The study was conducted by the principles stipulated in the Declaration of Helsinki and informed consent for future data processing was obtained from the parents prior to data collection.
Results
During the study period, sixty-six neonates with congenital heart disease with PDA dependent PGE1 infusion were admitted to the neonatal intensive care unit. Eleven (16.7%) had a PDA dependent pulmonary circulation, thirty-one (47%) had a PDA dependent systemic circulation and twenty-four (36.4%) a PDA dependent mixing circulation (Table 1).
Table 1.
Type of critical congenital heart disease
| Disease | number |
|---|---|
| Heart disease with PDA dependent pulmonary circulation | |
| Pulmonary atresia/stenosis Complete atrioventricular canal | 8 |
| Complete atrioventricular canal | 1 |
| Tetralogy of Fallot with pulmonary atresia | 1 |
| Double outlet right ventricle | 1 |
| Overall | 11 |
| Heart disease with PDA dependent systemic circulation | |
| Coarctation of the Aorta | 18 |
| Complete atrioventricular canal | 1 |
| Hypoplastic left ventricle | 3 |
| Hypoplastic aortic arch | 8 |
| Total anomalous pulmonary venous return | 1 |
| Overall | 31 |
| Heart disease with PDAdepending mixing circulation | |
| Transposition of the great artery | 24 |
Antenatal diagnosis, intervention and perinatal outcomes among infants detected with congenital heart disease are presented in Table 2. Fifty-six infants (84.8%) were followed during pregnancy, thirty-three (50%) were diagnosed antenatally with critical CHD, fifty-seven (83.55%) were born in the tertiary level unit, and nine (13.63%) were transferred from other tertiary level maternities. Thirty-five (53%) infants were born vaginally and thirty-three (47%) by elective caesarean section. There were no significant differences in clinical findings at the onset of disease in the study groups. 60.6% of neonates presented with cyanosis, 74.2% of cases with respiratory distress. Cardiac murmur was present in 100% of newborns with critical CHD.
Table 2.
Antenatal diagnosis, intervention and perinatal outcomes among infants detected with congenital heart disease
| PDA dependent Pulmonary circulation N=11 | PDA dependent Systemic circulation N= 31 | PDA dependent Mixing circulation N=24 | Overall N=66 | p | |
|---|---|---|---|---|---|
| Antenatal care | 11 (100%) | 26 (83.87%) | 19 (79.16%) | 56 (84.8%) | 0.129 |
| Antenatal diagnosis | 7 (63.33%) | 16(51.61%) | 10 (41.66%) | 33 (50%) | 0.329 |
| Concordance antenatal/postnatal diagnosis | 4 (36.36%) | 15 (48.38%) | 10 (41.66%) | 29 (43.9%) | 0.586 |
| Birth in the tertiary level care center | 3 (27.27%) | 2 (6.45%) | 5 (20.83%) | 9 (13.6%) | 0.226 |
| Cesarean section | 2 (18.18%) | 18 (58.06%) | 11 (45.83%) | 31 (47%) | 0.037 |
| Apgar score less than 7 at 1 minute | 2 (18.18%) | 2 (6.45%) | 3 (12.5%) | 7 (10.6%) | 0.379 |
| Apgar score less than 7 at 5 minute | 0 | 0 | 2 (8.33%) | 2 (3%) | 0.528 |
| Cyanosis | 6(54.54%) | 13 (41.93%) | 21 (87.5%) | 40 (60.6%) | 0.658 |
| Respiratory distress | 7 (63.63%) | 19 (61.29%) | 23 (95.83%) | 49 (74.2%) | 0.386 |
| Systolic murmur | 11 | 31 | 24 | 66 | |
| Grade I | 1 (9.09%) | 3 (9.67%) | 0 | 4 (6.06%) | |
| Grade II | 4 (36.36%) | 9 (29.03%) | 8 (33.33%) | 21 (31.8%) | 0.652 |
| Grade III | 4 (36.36%) | 14 (45.16%) | 12 (50%) | 30 (45.5%) | |
| Grade IV | 2 (18.18%) | 5 (16.12%) | 4 (16.66%) | 11 (16.7%) | |
| Echocardiography evaluation, number (SD) | 5.27 (±2.1) | 6.26 (±3.09) | 5.46 (±2.5) | 5.8 (±2.7) | 0.489 |
The mean age of starting PGE1 treatment was 2.06 days with 1.91 (+/-1.44) days for PDA depending pulmonary flow, 2.39 (+/-1.62) days for PDA depending systemic flow and 1.71 (+/-1.12) for PDA depending mixing circulation. The initiation of PEG1 treatment was commenced before 48 hours postpartum in 72%, between 48 to 72 hours in 6%, and after 72 to 120 hours in 21% of neonates detected with PDA dependent circulation (Figure 1). The maxim dose of PEG1 was 0.0378 (+/-0.03) μgrams/kg/minute for PDA depending pulmonary flow group, 0.0521 (+/-0.04) µgrams/kg/minute for PDA-dependent systemic flow group and 0.050 (+/-0.03) for PDA dependent mixing circulation group (p<0.05). PGE1 doses and condition of treatment initiation are shown in Table 3.
Figure 1.
Level of PGE1initiation dose in accordance with the time of starting infusion and heart defect type
∗Boxes are interquartile ranges, the midpoints are medians, whiskers are range and circles are outliers.
Table 3.
PGE1 doses, condition of treatment initiation in the study groups
| PDA dependent Pulmonary circulation N=11 | DA dependent Systemic circulation N=31 | PDA dependent Mixing circulation N=24 | Overall N=66 | p | |
|---|---|---|---|---|---|
| Mean age at PG initiation days (SD) | 1.91 (±1.44) | 2.39 (±1.62) | 1.71 (±1.12) | 2.06 (±1.44) | 0.709 |
| Initiation PGE1 | |||||
| 0-48 hours | 8 (72.7%) | 19 (61.29%) | 21 (87.5%) | 48 (72.7%) | |
| 48-72 hours | 1 (9.09%) | 3 (9.67%) | 0 | 4 (6.1%) | 0.908 |
| 72-120 hours | 2 (18.18%) | 9 (29.03%) | 3 (12.5%) | 14 (21.2%) | |
| Length of PGE1 treatment | |||||
| Sum (days) | 207 | 603 | 384 | 1194 | |
| Mean (SD) | 18.82 (±9.15) | 19.45 (±12.69) | 16.00 (±9.8) | 18.09 (±11.15) | 0.815 |
| PEG1 initial dose | |||||
| μgrams/kg/minute, Mean, (SD) | 0.0356 (±0.026) | 0.0390 (±0.0398) | 0.0429 (±0.027) | 0.0398 (±0.033) | 0.648 |
| PEG1 minimdose | |||||
| μgrams/kg/minute, Mean, (SD) | 0.0161 (±0.0119) | 0.0167 (±0.0139) | 0.0123 (±0.1129) | 0.0150 (±0.0126) | 0.216 |
| PEG1 maximdose | |||||
| μgrams/kg/minute, Mean, (SD) | 0.0378 (±0.027) | 0.0521 (±0.037) | 0.050 (±0.0288) | 0.0490 (±0.0329) | 0.752 |
PGE1 efficacy
Before PEG1 treatment initiation the mean initial SpO2 was 77.89 (+/-9.2)% and mean initial oxygen pressure (PO2) was 26.96 (+/-6.45) mmHg. At the point when the echocardiography indicated a stable open PDA with free blood flow under, the mean SpO2increased to 89.73 mm Hg and PO2 rose to 49 mmHg (p<0.001). The PGE1 treatment responses are indicated in table 4.
Table 4.
PGE1 treatment responses
| PDA dependent Pulmonary circulation N=11 | PDA dependent Systemic circulation N= 31 | PDA dependent Mixing circulation N=24 | Overall N=66 | p | |
|---|---|---|---|---|---|
| FiO2 after PG initiation | 24% | 22% | 28% | 25% | 0.788 |
| pO2(mmHg) before PG initiation | 26.96 | 31.26 | 27.26 | 29.09 | 0.418 |
| pO2(mmHg) after PG initiation | 39.91 | 59.01 | 40.50 | 49.09 | 0.200 |
| SpO2(mmHg) before PG initiation | 71.55 | 85.16 | 71.42 | 77.89 | 0.116 |
| SpO2(mmHg) after PG initiation | 88.36 | 92.26 | 87.08 | 89.73 | 0.387 |
During PGE1 treatment, eleven infants (16.7%) had apnea attacks, five infants (7.5%) had convulsions, thirty-three (50%) had a fever, and forty-seven (71.2%) had leukocytosis (more than 20.000/mm3), and fiftytwo (78.8%) had edema. Other complications possibly related to PGE1 therapy were listed as 25.8% had gastrointestinal intolerance, 45.5% had hypokalemia, and 63.6% had irritability. Additional complications like ectropion, cardiac arrest, and antral hyperplasia were recorded in fewer than 5% of the neonates.
Only one mortality related to PEG1infusion was recorded. A male neonate detected with left ventricle hypoplasia at the five dayspostpartum, died. An initial dose of PEG1, 0.06-0.15 μgrams/kg/minute by continuous infusion had been administered. Table 5 details the side effects during PGE1 infusion.
Table 5.
Side effects during PGE1 treatment
| PDA dependent Pulmonary circulation N=11 | PDA dependent Systemic circulation N= 31 | PDA dependent Mixing circulation N=24 | Overall N=66 | p | |
|---|---|---|---|---|---|
| Apnea | 2 (18%) | 4 (13%) | 5 (21%) | 11 (16.7%) | 0.885 |
| Convulsion | 0 | 2 (6.44%) | 3 (13%) | 5 (7.5%) | 0.301 |
| Irritability | 7 (64%) | 18 (58.06%) | 17 (71%) | 42 (63.6%) | 0.988 |
| Fever | 5 (45%) | 14 (45%) | 14 (58%) | 33 (50%) | 0.746 |
| Gastrointestinal disturbances | 1 (9%) | 7 (23%) | 9 (38%) | 17 (25.8) | 0.171 |
| Antral hyperplasia | 0 | 1 (3.22%) | 1 (4%) | 2 (3%) | 0.658 |
| Cardiac arrest | 0 | 2 (6%) | 0 | 2 (3%) | 0.528 |
| Bradicardia | 2 (18%) | 5 (16%) | 6 (25%) | 13 (19.7%) | 0.892 |
| Leukocytosis | 7 (64%) | 23 (77%) | 16 (67%) | 47 (71.2%) | 0.550 |
| Hipopotasemia | 3 (27%) | 16 (51.61%) | 11 (46%) | 30 (45.5%) | 0.190 |
| Edema | 9 (82%) | 22 (71%) | 21 (88%) | 52 (78.8%) | 0.792 |
| Ectropion | 0 | 1 (3.22%) | 1 (4%) | 2 (3%) | 0.528 |
| Hyperextension of the neck | 1 (9%) | 2 (6.44%) | 0 | 3 (4.5%) | 0.436 |
| CRP Mean (SD) | 27.72 (62.60) | 35.91 (58.93) | 12.3 (18.12) | 25.96 (49.38) | 0.898 |
Echocardiography indicated that all remaining sixty-five newborns had widened PDAs with unrestricted blood flow were bridged to surgical interventions.
Discussion
PGE1 is the currently recommended temporary initial therapy for infants with isolated defects that restrict pulmonary blood flow, poor arterial-venous mixing and conditions that interfere with systemic circulation. This treatment allows the ductus arteriosus to remain patent, maintaining pulmonary and systemic circulation and oxygenation until appropriate surgical intervention can proceed. The policy of administrating PEG1 therapy for neonates with PDA dependent congenital heart disease consisted of an initial dose of PEG1, 0.03-0.05 μgrams/kg/minute. This is a regime suggested by Doblec and should be combined with early a pediatric cardiology consultation, which has been shown to improve outcomes [16].
Yaffe and Aranda suggested that an initial PEG1 infusion of 0.05μgrams/kg/minute may be decreased to 0.01 μgrams/kg/minute for maintenance [17].
In addition to standard parameters like PaO2 and pulse oximetry, echocardiography was also employed to provide information about the effect of PEG1 on the patency of the ductus arteriosus and on-going monitoring of the size of the PDA allowed PEG1 infusion to be decreased a lower level where stable oxygenation has been achieved. This regime is in accordance with reports which have demonstrated it to be crucial in the management of critical congenital heart disease [18].
When no improvement in oxygenation was obtained after the initial dosage, this increased incrementally by 0.05 μgrams/kg/minute until no further increase of oxygenation was needed. This is in accordance with Chamberlin and Lozynski, who state that the ductus arteriosus should be patent within thirty minutes to two hours after the initiation of a continuous infusion of PGE1, who also recommend that it is appropriate to wean the patient off medication after the appropriate level PaO2 has been achieved [19].
There were numerous reports about the side effects of PEG1 under the current dosage schedule, and it has been demonstrated that side effects increased with increasing dosages [20,21,22,23]. In our patients the incidence of the side effects due to PEG1 infusion such as fever, convulsion, apnea and hyperirritability was high compared to Huang et al, this probably being explained by the longer length of PEG1 treatment [24]. This has also been suggested as a cause in other studies, where the same tendencies have been reported when neonates were treated with PEG1 for more than two weeks [25,26].
There were some limitations in the current study which was based solely on the information from chart reviews and record bias may exist. The number of cases was relatively small, but it is considered that the study can provide useful information about perioperative management of neonates with critical congenital heart disease and PDA dependent pulmonary, systemic and mixed blood flow.
Conclusions
For those infants with severe cyanosis or shock caused by PDA dependent heart lesions, initiating and maintaining PGE1 infusion is imperative. The side effects of this beneficial therapy were transient and could be treated.
Footnotes
Conflicts of interest: The authors have nothing to disclose.
References
- 1.Hoffman JI, Kaplan S.. The incidence of congenital heart disease. J Am Coll Cardiol. 2002(39):1890–900. doi: 10.1016/s0735-1097(02)01886-7. [DOI] [PubMed] [Google Scholar]
- 2.Oster ME, Lee KA, Honein MA, Riehle-Colarusso T, Shin M, Correa A.. Temporal trends in survival among infants with critical congenital heart defects. Pediatrics. 2013;131:e1502–8. doi: 10.1542/peds.2012-3435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A.. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr. 2008(153):807–13. doi: 10.1016/j.jpeds.2008.05.059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Yun SW.. Congenital heart disease in the newborn requiring early intervention. Korean J Pediatr. 2011(54):183–91. doi: 10.3345/kjp.2011.54.5.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Olney RS, Ailes EC, Sontag MK.. Detection of critical congenital heart defects: Review of contributions from prenatal and newborn screening. Semin Perinatol. 2015(39):230–7. doi: 10.1053/j.semperi.2015.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.American Institute of Ultrasound in Medicine. AIUM practice guideline for the performance of an antepartum obstetric ultrasound examination. J Ultrasound Med. 2003(22):1116–25. doi: 10.7863/jum.2003.22.10.1116. [DOI] [PubMed] [Google Scholar]
- 7.AIUM practice guideline for the performance of obstetric ultrasound examinations. J Ultrasound Med. 2010(29):157–66. doi: 10.7863/jum.2010.29.1.157. [DOI] [PubMed] [Google Scholar]
- 8.Momma K, Uemura S, Nishihara S, Ota Y.. Dilatation of the ductus arteriosus by prostaglandins and prostaglandin’s precursors. Pediatr Res. 1980(14):1074–7. doi: 10.1203/00006450-198009000-00011. [DOI] [PubMed] [Google Scholar]
- 9.Heymann MA, Rudolph AM.. Ductus arteriosus dilatation by prostaglandin E1 in infants with pulmonary atresia. Pediatrics. 1977(59):325–9. [PubMed] [Google Scholar]
- 10.Benson LN, Olley PM, Patel RG, Coceani F, Rowe RD.. Role of prostaglandin E1 infusion in the management of transposition of the great arteries. Am J Cardiol. 1979;44:691–6. doi: 10.1016/0002-9149(79)90289-3. [DOI] [PubMed] [Google Scholar]
- 11.Hundalani SG, Kulkarni M, Fernandes CJ, Cabrera AG, Shivanna B, Pammi M.. Prostaglandin E1 for maintaining ductal patency in neonates with ductus-dependent cardiac lesions (Protocol) Cochrane Database of Systematic Reviews. 2014;12:CD011417. doi: 10.1002/14651858.CD011417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kobayashi T, Narumiya S.. Function of prostanoid receptors: studies on knockout mice. Prostaglandins Other Lipid Mediat. 2002;68-69:557–73. doi: 10.1016/s0090-6980(02)00055-2. [DOI] [PubMed] [Google Scholar]
- 13.Reese J, Veldman A, Shah L, Vucovich M, Cotton RB.. Inadvertent relaxation of the ductus arteriosus by pharmacologic agents that are commonly used in the neonatal period. Semin Perinatol. 2010(34):222–30. doi: 10.1053/j.semperi.2010.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Buck ML.. Prostaglandin E1 treatment of congenital heart disease: use prior to neonatal transport. DICP. 1991(25):408–9. doi: 10.1177/106002809102500413. [DOI] [PubMed] [Google Scholar]
- 15.Moldovan E, Cucerea M.. Drug Closure of a Patent Ductus Arteriosus in An Extremely Low Birth Weight Premature Newborn. A Case Report. J Crit Care Med. 2015(1):28–32. doi: 10.1515/jccm-2015-0006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Dolbec K.. Congenital heart disease. Emerg Med Clin North Am. 2011(29):811–27. doi: 10.1016/j.emc.2011.08.005. [DOI] [PubMed] [Google Scholar]
- 17.Yaffe SJ, Aranda JV. Neonatal and Pediatric Pharmacology 4e: Therapeutic Principles In Practice. Lippincott Williams & Wilkins; Philadelphia, PA.: 2011. [Google Scholar]
- 18.Toganel R.. Critical Congenital Heart Diseases as Lifethreatening Conditions in the Emergency Room. Journal of Cardiovascular Emergencies. 2016(2):7–10. doi: 10.1515/jce-2016-0002. [DOI] [Google Scholar]
- 19.Chamberlin M, Lozynski J.. To go against nature: manipulating the neonatal ductusarteriosus with prostaglandin. Newborn and Infant Nursing Reviews. 2006(6):158–62. doi: 10.1053/j.nainr.2006.05.001. [DOI] [Google Scholar]
- 20.Elliott RB, Starling MB, Neutze JM.. Medical manipulation of the ductus arteriosus. Lancet. 1975:1, 140e2. doi: 10.1016/s0140-6736(75)91432-4. [DOI] [PubMed] [Google Scholar]
- 21.Nelson textbook of paediatrics. Arch Dis Child. 1983:58–942. doi: 10.1136/adc.58.11.942-b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Olley PM, Coceani F, Bodach E.. E-type prostaglandins: a new emergency therapy for certain cyanotic congenital heart malformations. Circulation. 1976;53:728 e31. doi: 10.1161/01.cir.53.4.728. http://dx.doi.org/10.1161/01.CIR.53.4.728 [DOI] [PubMed] [Google Scholar]
- 23.Heymann MA, Rudolph AM.. Ductus arteriosus dilatation by prostaglandin E1 in infants with pulmonary atresia. Pediatrics. 1977;59:325e9. [PubMed] [Google Scholar]
- 24.Huang FK, Lin CC, Huang TC. et al. Reappraisal of the prostaglandin E1 dose for early newborns with patent ductus arteriosus-dependent pulmonary circulation. Pediatr Neonatol. 2013(54):102–6. doi: 10.1016/j.pedneo.2012.10.007. [DOI] [PubMed] [Google Scholar]
- 25.Talosi G, Katona M, Túri S.. Side-effects of long-term prostaglandin E(1) treatment in neonates. Pediatr Int. 2007(49):335–40. doi: 10.1111/j.1442-200X.2007.02380.x. [DOI] [PubMed] [Google Scholar]
- 26.Middleton P, Kelly AM, Brown J, Robertson M.. Agreement between arterial and central venous values for pH, bicarbonate, base excess, and lactate. Emerg Med J. 2006(23):622–4. doi: 10.1136/emj.2006.035915. [DOI] [PMC free article] [PubMed] [Google Scholar]