The Journal of Critical Care Medicine 2016;2(4):

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1 The Journal of Critical Care Medicine 206;2(4):85-9 RESEARCH ARTICLE DOI: 0.55/jccm Congenital Heart Disease Requiring Maintenance of Ductus Arteriosus in Critically Ill Newborns Admitted at a Tertiary Neonatal Intensive Care Unit Manuela Cucerea *, Marta Simon, Elena Moldovan 2, Marcela Ungureanu 3, Raluca Marian, Laura Suciu University of Medicine and Pharmacy Tirgu Mureș, Romania 2 Institute of Cardiovascular Disease and Translant Tirgu Mureș, Romania 3 Deartment of Neonatal Intensive Care,County Clinical Emergency Hosital Tirgu Mureş, Romania Abstract Introduction: Congenital heart diseases (CHD) have been reorted to be resonsible for 30 to 50% of infant mortality caused by congenital disabilities. In critical cases, survival of newborns with CHD deends on the atency of the ductus arteriosus (PDA), for maintaining the systemic or ulmonary. The aim of the study was to assess the efficacy and side effects of PGE (rostaglandin E) administration in newborns with critical congenital heart disease requiring maintenance of the ductus arteriosus. Material and method: All clinical and araclinical data of 66 infants admitted to one referral tertiary level academic center and treated with Alrostadil were analyzed. Patients were divided into three grous: Grou : ulmonary (n=) Grou 2: systemic (n=3) Grou 3: PDA deending mixed (n=24) Results: The mean age of starting PGE treatment was 2.06 days,.9 (+/-.44) days for PDA deending ulmonary flow, 2.39 (+/-.62) days for PDA deending systemic flow and.7 (+/.2) for PDA deending mixing. PEG initiation was commenced 48 hours after admission for 72%, between hours for 6%, and after 72 to 20 hours for 2% of newborns detected with. Before PEG initiation the mean initial SO2 was (+/- 9.2)% and mean initial oxygen ressure (PaO2) was 26.96(+/-6.45) mmhg. At the oint when stable wide oen PDA was achieved their mean SO2increased to (+/-8.4)%, and PaO2 rose to 49 (+/-7.2) mmhg. During PGE treatment, eleven infants (6.7%) had anea attacks, five children (7.5%) had convulsions, 33 (50%) had fever, 47 (7.2%) had leukocytosis, 52 (78.8%) had edema, 25.8% had gastrointestinal intolerance, 45.5% had hyokalemia, and 63.6% had irritability. Conclusions: For those infants with severe cyanosis or shock caused by heart lesions, the initiation and maintenance of PGE infusion is imerative. The side effects of this beneficial theray were transient and treatable. Keywords: rostaglandins, atent ductus arteriosus, congenital heart disease Received: 0 July 206 / Acceted: 5 Setember 206 Introduction Congenital heart diseases are the most common birth defects in newborns. Nearly % of newborns have congenital heart defects, and aroximately one-quarter of those defects are associated with a critical condition [-3]. Most of these heart defects require ductal atency for survival, and may not have been visible clinical signs immediately after birth until constriction of the duct occurred [4]. * Corresondence to: Manuela Cucerea: Str. Gheorghe MarinescuNr. 38, 54039, TirguMures, Romania. Tel: manuelacucerea@yahoo.com Marta Simon: Str. Gheorghe MarinescuNr. 38, 54039, TirguMures, Romania. Tel: Elena Moldovan: Str. Gheorghe MarinescuNr. 50, 54036, TirguMures, Romania. Tel: Marcela Ungureanu: Str. Gheorghe MarinescuNr. 50, 54036, TirguMures, Romania. Tel: Raluca Marian: Str. Gheorghe MarinescuNr. 38, 54039, TirguMures, Romania. Tel: Laura Suciu: Str. Gheorghe MarinescuNr. 38, 54039, TirguMures, Romania. Tel:

2 86 The Journal of Critical Care Medicine 206;2(4) Available online at: Congenital heart diseases are resonsible 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 hyolastic left heart syndrome, transosition of the great arteries, or tetralogy of Fallot [5]. Prenatal diagnosis of cardiac malformations is crucial to initiate the most aroriate theraeutic strategy and deends on largely uon the echocardiograhy recognition of the structural heart defects during the second trimester [6,7]. According to Cochrane Database of Reviews 204, infants with critical congenital heart defects that are deendent on the atency of the ductus arteriosus (PDA) for survival can be categorized into three grous. The first grou is characterized by severe restriction of the ulmonary blood flow e.g. ulmonary atresia, tricusid atresia or tetralogy of Fallot with ulmonary atresia. In these cases, ulmonary is deendent on the atency of the ductus arteriosus and ostnatal constriction of the ductus causes severe hyoxemia, cyanosis and death [8]. Grou two includes conditions with severe restriction of the systemic blood flow e.g. severe aortic stenosis, coarctation of the aorta, interruted aortic arch or left hyolastic syndrome. In these cases, the systemic is deendent on the atency of the ductus arteriosus and ostnatal constriction of the ductus may cause systemic hyoerfusion, circulatory deterioration, metabolic acidosis, shock, and death [9]. The third grou includes cardiac anomalies e.g. transosition of the great arteries, where adequate mixing of ulmonary and systemic blood flow is necessary for maintaining a in series [0]. Due to its imortance in the maintenance of the ductus atency during fetal life, rostaglandin is the elective theray (PEG) indicated for the temorary management of the neonate with ductus deendent congenital heart disease to maintain ductal atency until surgery can be erformed []. PEG romotes vasodilatation by the direct effect on the vasculature and smooth muscle of the ductus arteriosus. Four PGE recetors have been identified. EP2 and EP4 recetor subtyes mediate PGE-induced relaxation of the ductus arteriosus in human neonates through a cyclic AMP-deendent mechanism. PEG was aroved by the Food and Drug Administration in 98 for use in infants with a congenital cardiac defect but is not without limitation and side effects [2]. Sixty to eighty ercent of PEG is metabolized on first assing through the lungs and so must be administered by continuous infusion. At a starting dose of to 0. microgram/ kg/minute, the ductus usually reoens within thirty minutes to two hours of initiating PGE, with the clinical resonse usually being instant [,3-5]. 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 reorts of sixty-six infants admitted to one tertiary level academic center and treated with Alrostadil for critically congenital cardiac malformations from st January 204 to 30st June 206 were reviewed. Patients were divided into three grous: Grou : ulmonary (n=) Grou 2: systemic (n=3) Grou 3: PDA deending mixing (n=24) A critical congenital heart defect was defined as a structural malformation of the heart resent at birth, was life threatening and required interventions in the first months of life. Adverse medical events were defined as any unanticiated or undesirable incident that occurred during the treatment, or rearatory stabilization time before surgical treatment and might have necessitated an alteration in theray. Descritive statistics including mean (+/-SD) were resented for continuous variables and frequencies for categorical variables. Univariate analyses with indeendent samles t-test and λ 2 test for categorical variables were erformed to evaluate differences between grou using SPSS 0.0 for Windows. The significant level was set at α=0.05. The study was conducted by the rinciles stiulated in the Declaration of Helsinki and informed consent for future data rocessing was obtained from the arents rior to data collection. Results During the study eriod, sixty-six neonates with congenital heart disease with PGE infusion were admitted to the neonatal intensive care unit. Eleven (6.7%) had a ulmonary cir-

3 Available online at: culation, thirty-one (47%) had a systemic and twenty-four (36.4%) a mixing (Table ). Antenatal diagnosis, intervention and erinatal outcomes among infants detected with congenital heart disease are resented in Table 2. Fifty-six infants (84.8%) were followed during regnancy, thirty-three (50%) were diagnosed antenatally with critical CHD, fifty-seven (83.55%) were born in the tertiary level unit, and nine (3.63%) were transferred from other tertiary level maternities. Thirty-five (53%) infants were born The Journal of Critical Care Medicine 206;2(4) 87 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 grous. 60.6% of neonates resented with cyanosis, 74.2% of cases with resiratory distress. Cardiac murmur was resent in 00% of newborns with critical CHD. The mean age of starting PGE treatment was 2.06 days with.9 (+/-.44) days for PDA deending ulmonary flow, 2.39 (+/-.62) days for PDA deending systemic flow and.7 (+/-.2) for PDA deending mixing. The initiation of PEG treatment Table. Tye of critical congenital heart disease Disease number Heart disease with ulmonary atresia/stenosis 8 Comlete atrioventricular canal Tetralogy of Fallot with ulmonary atresia Double outlet right ventricle Heart disease with systemic Coarctation of the Aorta 8 Comlete atrioventricular canal Hyolastic left ventricle 3 Hyolastic aortic arch 8 Total anomalous ulmonary venous return 3 Heart disease with PDAdeending mixing Transosition of the great artery 24 Table 2. Antenatal diagnosis, intervention and erinatal outcomes among infants detected with congenital heart disease N= N= 3 Antenatal care (00%) 26 (83.87%) 9 (79.6%) 56 (84.8%) 0.29 Antenatal diagnosis 7 (63.33%) 6(5.6%) 0 (4.66%) 33 (50%) Concordance antenatal/ostnatal diagnosis 4 (36.36%) 5 (48.38%) 0 (4.66%) 29 (43.9%) Birth in the tertiary level care center 3 (27.27%) 2 (6.45%) 5 (20.83%) 9 (3.6%) Cesarean section 2 (8.8%) 8 (58.06%) (45.83%) 3 (47%) Agar score less than 7 at minute 2 (8.8%) 2 (6.45%) 3 (2.5%) 7 (0.6%) Agar score less than 7 at 5 minute (8.33%) 2 (3%) Cyanosis 6(54.54%) 3 (4.93%) 2 (87.5%) 40 (60.6%) Resiratory distress 7 (63.63%) 9 (6.29%) 23 (95.83%) 49 (74.2%) Systolic murmur Grade I Grade II Grade III Grade IV (9.09%) 4 (36.36%) 4 (36.36%) 2 (8.8%) 3 3 (9.67%) 9(29.03%) 4 (45.6%) 5 (6.2%) (33.33%) 2 (50%) 4 (6.66%) 66 4 (6.06%) 2 (3.8%) 30 (45.5%) (6.7%) Echocardiograhy evaluation, number (SD) 5.27 (±2.) 6.26 (±3.09) 5.46 (±2.5) 5.8 (±2.7)

4 88 The Journal of Critical Care Medicine 206;2(4) was commenced before 48 hours ostartum in 72%, between 48 to 72 hours in 6%, and after 72 to 20 hours in 2% of neonates detected with (Figure ). The maxim dose of PEG was (+/-0.03) µgrams/kg/minute for PDA deending ulmonary flow grou, (+/-0.04) µgrams/ kg/minutefor PDA-deendent systemic flow grou and (+/-0.03) for mixing grou (<0.05). PGE doses and condition of treatment initiation are shown in Table 3. PGE efficacy Before PEG treatment initiation the mean initial SO 2 was (+/-9.2)% and mean initial oxygen ressure (PO 2 ) was (+/-6.45) mmhg. At the oint when the echocardiograhy indicated a stable oen PDA with free blood flow under, the mean SO 2 increased to mm Hg and PO 2 rose to 49 mmhg (<0.00). The PGE treatment resonses are indicated in table 4. Available online at: During PGE treatment, eleven infants (6.7%) had anea attacks, five infants (7.5%) had convulsions, thirty-three (50%) had a fever, and forty-seven (7.2%) had leukocytosis (more than /mm 3 ), and fiftytwo (78.8%) had edema. Other comlications ossibly related to PGE theray were listed as 25.8% had gastrointestinal intolerance, 45.5% had hyokalemia, and 63.6% had irritability. Additional comlications like ectroion, cardiac arrest, and antral hyerlasia were recorded in fewer than 5% of the neonates. Only one mortality related to PEGinfusion was recorded. A male neonate detected with left ventricle hyolasia at the five daysostartum, died. An initial dose of PEG, µgrams/kg/minute by continuous infusion had been administered. Table 5 details the side effects during PGE infusion. Echocardiograhy indicated that all remaining sixty-five newborns had widened PDAs with unrestricted blood flow were bridged to surgical interventions. Table 3. PGE doses, condition of treatment initiation in the study grous N= N=3 Mean age at PG initiation days (SD).9 (±.44) 2.39 (±.62).7 (±.2) 2.06 (±.44) Initiation PGE 0-48 hours hours hours 8 (72.7%) (9.09%) 2(8.8%) 9(6.29%) 3(9.67%) 9(29.03%) 2(87.5%) 0 3 (2.5%) 48 (72.7%) 4 (6.%) 4 (2.2%) Length of PGE treatment Sum (days) Mean (SD) (±9.5) (±2.69) (±9.8) (±.5) 0.85 PEG initial dose µgrams/kg/minute, Mean, (SD) (±0.026) (±0.0398) (±0.027) (±0.033) PEG minimdose µgrams/kg/minute,mean, (SD) 0.06 (±0.09) (±0.039) (±0.29) (±0.026) 0.26 PEG maximdose µgrams/kg/minute, Mean, (SD) (±0.027) (±0.037) (±0.0288) (±0.0329) Table 4. PGE treatment resonses N= N= 3 FiO2 before PG initiation 40% 35% 37% 36% 0.69 FiO2 after PG initiation 24% 22% 28% 25% O2(mmHg) before PG initiation O2(mmHg) after PG initiation SO2(mmHg) before PG initiation SO2(mmHg) after PG initiation

5 Available online at: Fig.. Level of PGEinitiation dose in accordance with the time of starting infusion and heart defect tye *Boxes are interquartile ranges, the midoints are medians, whiskers are range and circles are outliers. Discussion PGE is the currently recommended temorary initial theray for infants with isolated defects that restrict The Journal of Critical Care Medicine 206;2(4) 89 ulmonary blood flow, oor arterial-venous mixing and conditions that interfere with systemic. This treatment allows the ductus arteriosus to remain atent, maintaining ulmonary and systemic and oxygenation until aroriate surgical intervention can roceed. The olicy of administrating PEG theray for neonates with congenital heart disease consisted of an initial dose of PEG, µgrams/kg/minute. This is a regime suggested by Doblec and should be combined with early a ediatric cardiology consultation, which has been shown to imrove outcomes [6]. Yaffe and Aranda suggested that an initial PEG infusion of 0.05µgrams/kg/minute may be decreased to 0.0 µgrams/kg/minute for maintenance [7]. In addition to standard arameters like PaO 2 and ulse oximetry, echocardiograhy was also emloyed to rovide information about the effect of PEG on the atency of the ductus arteriosus and on-going monitoring of the size of the PDA allowed PEG infusion to be decreased a lower level where stable oxygenation has been achieved. This regime is in accordance with reorts which have demonstrated it to be crucial in the management of critical congenital heart disease [8]. When no imrovement in oxygenation was obtained after the initial dosage, this increased incrementally by 0.05 µgrams/kg/minute until no further increase of Table 5. Side effects during PGE treatment N= N= 3 Anea 2 (8%) 4 (3%) 5 (2%) (6.7%) Convulsion 0 2 (6.44%) 3 (3%) 5 (7.5%) 0.30 Irritability 7 (64%) 8 (58.06%) 7(7%) 42 (63.6%) Fever 5 (45%) 4 (45%) 4(58%) 33 (50%) Gastrointestinal disturbances (9%) 7(23%) 9 (38%) 7 (25.8) 0.7 Antral hyerlasia 0 (3.22%) (4%) 2 (3%) Cardiac arrest 0 2(6%) 0 2 (3%) Bradicardia 2 (8%) 5(6%) 6 (25%) 3 (9.7%) Leukocytosis 7 (64%) 23 (77%) 6 (67%) 47 (7.2%) Hiootasemia 3 (27%) 6 (5.6%) (46%) 30 (45.5%) 0.90 Edema 9 (82%) 22 (7%) 2 (88%) 52 (78.8%) Ectroion 0 (3.22%) (4%) 2 (3%) Hyerextension of the neck (9%) 2 (6.44%) 0 3 (4.5%) CRP Mean (SD) (62.60) 35.9 (58.93) 2.3 (8.2) (49.38) 0.898

6 90 The Journal of Critical Care Medicine 206;2(4) oxygenation was needed. This is in accordance with Chamberlin and Lozynski, who state that the ductus arteriosus should be atent within thirty minutes to two hours after the initiation of a continuous infusion of PGE, who also recommend that it is aroriate to wean the atient off medication after the aroriate level PaO 2 has been achieved [9]. There were numerous reorts about the side effects of PEG under the current dosage schedule, and it has been demonstrated that side effects increased with increasing dosages [20-23]. In our atients the incidence of the side effects due to PEG infusion such as fever, convulsion, anea and hyerirritability was high comared to Huang et al, this robably being exlained by the longer length of PEG treatment [24]. This has also been suggested as a cause in other studies, where the same tendencies have been reorted when neonates were treated with PEG 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 rovide useful information about erioerative management of neonates with critical congenital heart disease and ulmonary, systemic and mixed blood flow. Conclusions For those infants with severe cyanosis or shock caused by heart lesions, initiating and maintaining PGE infusion is imerative. The side effects of this beneficial theray were transient and could be treated. Conflicts of interest The authors have nothing to disclose. References. Hoffman JI, Kalan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39: Oster ME, Lee KA, Honein MA, Riehle-Colarusso T, Shin M, Correa A. Temoral trends in survival among infants with critical congenital heart defects. Pediatrics. 203;3:e doi: 0.542/eds Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa Available online at: A. Prevalence of congenital heart defects in metroolitan Atlanta, J Pediatr. 2008;53: doi: 0.06/j. jeds Yun SW. Congenital heart disease in the newborn requiring early intervention.korean J Pediatr. 20;54:83 9.doi: /kj Olney RS, Ailes EC, Sontag MK. Detection of critical congenital heart defects: Review of contributions from renatal and newborn screening. Semin Perinatol. 205;39: doi: 0.053/j.semeri American Institute of Ultrasound in Medicine. AIUM ractice guideline for the erformance of an anteartum obstetric ultrasound examination. J Ultrasound Med. 2003;22: AIUM ractice guideline for the erformance of obstetric ultrasound examinations. J Ultrasound Med. 200;29: Momma K, Uemura S, Nishihara S, Ota Y. Dilatation of the ductus arteriosus by rostaglandins and rostaglandin s recursors. Pediatr Res. 980;4: DOI: 0.203/ Heymann MA, Rudolh AM. Ductus arteriosus dilatation by rostaglandin E in infants with ulmonary atresia. Pediatrics. 977;59: Benson LN, Olley PM, Patel RG, Coceani F, Rowe RD. Role of rostaglandin E infusion in the management of transosition of the great arteries. Am J Cardiol.979;44: Hundalani SG, Kulkarni M, Fernandes CJ, Cabrera AG, Shivanna B, Pammi M. Prostaglandin E for maintaining ductal atency in neonates with ductus-deendent cardiac lesions (Protocol). Cochrane Database of Systematic Reviews. 204;2:CD047. DOI: 0.002/ CD Kobayashi T, Narumiya S. Function of rostanoid recetors: studies on knockout mice. Prostaglandins Other Liid Mediat. 2002;68-69: Reese J, Veldman A, Shah L, Vucovich M, Cotton RB. Inadvertent relaxation of the ductus arteriosus by harmacologic agents that are commonly used in the neonatal eriod. Semin Perinatol. 200;34: doi: 0.053/j.semeri Buck ML. Prostaglandin E treatment of congenital heart disease: use rior to neonatal transort. DICP. 99;25: Moldovan E, Cucerea M. Drug Closure of a Patent Ductus Arteriosus in An Extremely Low Birth Weight Premature Newborn. A Case Reort. J Crit Care Med. 205;: DOI: 0.55/jccm Dolbec K. Congenital heart disease. Emerg Med Clin North Am. 20;29:8-27. doi: 0.06/j.emc Yaffe SJ, Aranda JV. Neonatal and Pediatric Pharmacology 4e: Theraeutic Princiles In Practice. Liincott Williams & Wilkins, Philadelhia, PA Toganel R. Critical Congenital Heart Diseases as Lifethreatening Conditions in the Emergency Room. Journal of Cardiovascular Emergencies. 206;2:7-0.DOI: 0.55/jce Chamberlin M, Lozynski J. To go against nature: maniulating

7 Available online at: the neonatal ductusarteriosus with rostaglandin. Newborn and Infant Nursing Reviews. 2006;6: DOI: 0.053/j. nainr Elliott RB, Starling MB, Neutze JM. Medical maniulation of the ductus arteriosus. Lancet.975;:40e2. 2. Nelson textbook of aediatrics. Arch Dis Child 983;58: Olley PM, Coceani F, Bodach E. E-tye rostaglandins: a new emergency theray for certain cyanotic congenital heart malformations. Circulation.976;53:728 e3.htt://dx.doi. org/0.6/0.cir Heymann MA, Rudolh AM. Ductus arteriosus dilatation by rostaglandin E in infants with ulmonary atresia. The Journal of Critical Care Medicine 206;2(4) 9 Pediatrics.977;59:325e Huang FK, Lin CC,Huang TC, et al. Rearaisal of the rostaglandin E dose for early newborns with atent ductus arteriosus-deendent ulmonary. Pediatr Neonatol. 203;54:02-6. doi: 0.06/j.edneo Talosi G, Katona M, Tu ri S. Side-effects of long-term rostaglandin E() treatment in neonates. Pediatr Int. 2007;49: DOI: 0./j X x 26. Middleton P, Kelly AM, Brown J, Robertson M. Agreement between arterial and central venous values for H, bicarbonate, base excess, and lactate. Emerg Med J. 2006;23: DOI: 0.36/emj