Persistent Pulmonary Hypertension of the Newborn
`With Transposition of the Great Arteries
`Marcus T. R. Roofthooft, MD, Klasina A. Bergman, MD, Tjalling W. Waterbolk, MD,
`Tjark Ebels, MD, PhD, Beatrijs Bartelds, MD, PhD, and Rolf M. F. Berger, MD, PhD
`Departments of Paediatric Cardiology and Neonatology, Beatrix Children’s Hospital, and Department of Thoracic Surgery,
`University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
`
`CARDIOVASCULAR
`
`Background. Persistent pulmonary hypertension of the
`newborn (PPHN) in patients with transposition of the
`great arteries (TGA) is reported to be a high-risk and
`often therapy-resistant condition, associated with a high
`mortality. However, data on its incidence and prognosis
`are scarce and originate mostly from the era before
`introduction of inhaled nitric oxide (iNO) therapy for
`PPHN.
`Methods. This is a retrospective study of consecutive
`newborns with TGA, admitted to a tertiary cardiac and
`neonatal intensive unit over a 10-year period. In this
`period, iNO therapy was available.
`Results. Fourteen out of 112 patients with TGA (12.5%)
`presented with associated PPHN. The PPHN occurred
`more frequently in patients with TGA and intact ventric-
`ular septum (IVS) compared with those with TGA and
`ventricular septal defect (13 out of 83 patients versus one
`out of 29 patients, respectively; p ⴝ 0.06, Fisher exact test).
`
`Of those newborns, six presented with severe PPHN,
`whereas eight presented with mild-to-moderate PPHN.
`Despite currently available treatment modalities, includ-
`ing iNO, four out of 14 patients died before corrective
`surgical procedures were considered to be an option
`(TGA/PPHN preoperative mortality 28.6%). These in-
`cluded three out of six patients (50%) with severe PPHN
`and one out of eight (12.5%) with mild-to-moderate
`PPHN.
`Conclusions. The combination of TGA with PPHN is a
`serious and often fatal condition. It may jeopardize the
`usually favorable outcome of newborns with TGA. De-
`spite the introduction of iNO therapy, the combination of
`TGA and PPHN remains a condition with unacceptable
`high mortality (in our series). Additional treatment strat-
`egies need to be investigated.
`(Ann Thorac Surg 2007;83:1446 –50)
`© 2007 by The Society of Thoracic Surgeons
`
`Transposition of the great arteries (TGA) is the most
`
`common cyanotic congenital heart defect presenting
`in the neonate. Transposition of the great arteries is
`present in 5% to 7% of patients with congenital heart
`disease. The TGA has a 60% to 70% male predominance
`[1, 2]. Hallmark is a discordant ventriculoarterial connec-
`tion. In TGA the systemic and pulmonary circulation are
`separated, resulting in hypoxemic systemic and hyperox-
`emic pulmonary flow. Mixing opportunities, like persis-
`tent ductus arteriosus (PDA), atrial septal defect (ASD),
`or ventricular septal defect (VSD), are obligatory for early
`survival. Untreated, TGA is a fatal congenital heart defect
`due to progressive hypoxia and acidosis.
`The combination of persistent pulmonary hyperten-
`sion of the newborn (PPHN) and TGA has serious impli-
`cations on treatment and prognosis, with often deleteri-
`ous outcome [3– 6]. Limited data concerning the
`incidence and prognosis of this condition are available.
`The estimated incidences are based mainly on case
`reports or small series in the period before introduction
`of inhaled nitric oxide (iNO), and range from 1% to 3% in
`
`Accepted for publication Nov 1, 2006.
`
`Address correspondence to Dr Roofthooft, Department of Paediatric
`Cardiology, Beatrix Children’s Hospital, University Medical Centre Gro-
`ningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands; e-mail:
`m.t.r.roofthooft@bkk.umcg.nl.
`
`patients with TGA and intact ventricular septum (IVS)
`[3–7].
`Persistent pulmonary hypertension of the newborn
`(PPHN) is defined as failure of normal pulmonary vas-
`cular adaptation at or soon after birth, resulting in
`increased pulmonary vascular resistance, which exceeds
`systemic vascular resistance such that pulmonary blood
`flow is diminished and unoxygenated blood is shunted to
`the systemic circulation. This condition, usually diag-
`nosed on clinical features, is confirmed by echocardiog-
`raphy [8]. We present the results of a single-center
`experience concerning the incidence and treatment of
`PPHN in TGA, with or without ventricular septal defects
`(VSD/IVS).
`
`Patients and Methods
`In a retrospective study, a cohort of consecutive patients
`with TGA was studied for the presence of associated
`PPHN. All patients were admitted to a tertiary cardiac
`and neonatal intensive unit (Beatrix Children’s Hospital,
`Groningen, The Netherlands) over a 10-year period (Jan-
`uary 1995 to January 2005). Our Institutional Medical
`Ethics committee waived the need of patient consent in
`this retrospective study, because individual patients were
`not identified.
`
`© 2007 by The Society of Thoracic Surgeons
`Published by Elsevier Inc
`
`0003-4975/07/$32.00
`doi:10.1016/j.athoracsur.2006.11.001
`
`Ex. 2027-0001
`
`

`
`Ann Thorac Surg
`2007;83:1446–50
`
`ROOFTHOOFT ET AL
`PPHN IN PATIENTS WITH TGA
`
`1447
`
`CARDIOVASCULAR
`
`Results
`Incidence
`Between January 1995 and January 2005, 112 neonates
`were diagnosed with TGA. Eighty-three patients pre-
`sented with TGA/IVS, whereas 29 had TGA with VSD.
`Fourteen patients (12.5%) fulfilled our criteria for PPHN.
`Of these, 13 had TGA with IVS, whereas one had a small,
`muscular VSD. Six patients were defined as having
`severe PPHN and eight had mild-to-moderate PPHN. In
`the group of severe PPHN the right arm (preductal)
`oxygen saturation ranged from 30% to 50% (mean ␦-SO2
`⫽ 21%). In the patients with mild-to-moderate PPHN
`preductal oxygen saturation was observed between 70%
`and 85% (mean ␦-SO2 ⫽ 12%).
`
`Medical Treatment
`All 14 newborns with TGA and PPHN were treated with
`intravenous prostaglandins E1 (PGE1). Each of these
`infants had PPHN despite optimal mechanical ventila-
`tion and 100% inspired O2. All patients were sedated and
`paralyzed. In 13 patients (93%) a balloon atrioseptostomy
`was performed, compared with 53 of the 98 TGA patients
`without PPHN (54%) (p ⱕ 0.01, ␹2 test). Additional iNO
`therapy (5 to 40 ppm) was started in 11 patients with TGA
`and PPHN (six with severe PPHN and five with mild-to-
`moderate PPHN). The remaining three patients (all with
`mild-to moderate PPHN) responded well to maximal
`conservative therapy and did not need iNO. Additional
`therapy in the PPHN patients consisted of inotropics
`(isoprenaline [n ⫽ 6], dopamine [n ⫽ 9], dobutamine
`[n ⫽ 4] and norepinephrine [n ⫽ 3]) and intravenous
`vasodilators (epoprostenol [n ⫽ 5], tolazoline [n ⫽ 2], and
`enoximone [n ⫽ 1]).
`
`Outcome
`Overall mortality (preoperative, operative, in-hospital [30
`days] and late mortality) in this cohort of TGA patients
`was 15 out of 112 (13.4%). Seven of these patients (6.3%)
`were considered not eligible for corrective surgery be-
`cause of various comorbidity; therapy-resistant PPHN
`(n ⫽ 4), necrotizing enterocolitis (n ⫽ 1), prematurity
`
`Fig 1. Surgical characteristics of transposition of the great arteries
`(intact ventricular septum/ ventricular septal defect). (ASO ⫽ arte-
`rial switch operation; PPHN ⫽ persistent pulmonary hypertension
`of the newborn.)
`
`At presentation, after optimal ventilation with 100%
`inspired oxygen, two groups of patients with pulmonary
`hypertension were defined. Group 1 (severe PPHN),
`presenting with profound cyanosis and associated with
`echocardiographic continuous right-to-left shunting (ie,
`pulmonary to systemic circulation) through a PDA on
`color flow Doppler and pulsed wave Doppler, or a
`predominant right-to left shunt through the PDA associ-
`ated with a preductal to postductal difference in transcu-
`taneous oxygen saturation (␦-SO2) 15% or greater, as
`measured between the right arm and a leg. Group 2,
`mild-to-moderate PPHN, presenting with echocardio-
`graphic bidirectional shunting through the PDA associ-
`ated with ␦-SO2 between 5% and 15%.
`During the study period, a standard approach was
`used toward patients with PPHN in combination with a
`TGA. Intravenous prostaglandin E1 (PGE1) was started
`as soon as possible. In patients with insufficient mixing at
`the level of the open foramen ovale a balloon atriosep-
`tostomy was performed. Therapies for PPHN in this
`group of patients were aimed at lowering pulmonary
`vascular resistance and improving mixing at the level of
`the atria and PDA. The ventilator strategy used is meant
`to reduce pulmonary vascular resistance by improving
`oxygenation, while aiming for a pH of 7.4 and an arterial
`CO2 pressure (pCO2) between 4.0 and 5.5 kPa. Ventilator
`settings were adjusted according to the patient’s pulmo-
`nary condition, tidal volume, and arterial blood gas
`determination. Patients received sedation with morphine
`and, if necessary, neuromuscular blockade with vecuro-
`nium. Inotropic agents (isoprenaline, dopamine, dobut-
`amine, and noradrenaline) and intravenous volume re-
`placement were used aggressively to maintain an
`adequate arterial blood pressure. During iNO therapy,
`nitric oxide was introduced into the inspiratory limb of
`the ventilator (5–40 ppm). In case of failure, intravenous
`vasodilators (tolazoline, epoprostenol, enoximone) were
`started in the absence of contraindications (hypotension,
`renal failure, hemorrhage). During the study period,
`newborns with major congenital heart defects were not
`eligible for preoperative cardiac extracorporeal mem-
`brane oxygenation (ECMO) in the Netherlands.
`
`Statistical Methods
`To compare patients (TGA/PPHN) with VSD versus IVS,
`a Fisher exact test was used. The same statistic test was
`used to compare patients with or without PPHN and
`delayed sternal closure, as well as to compare the mor-
`tality in patients (TGA/PPHN) treated with or without
`iNO therapy. By a ␹2 test, differences in the incidence of
`a balloon atrioseptostomy in patients with TGA (PPHN
`vs non-PPHN) were tested. Differences in length of
`intensive care unit (ICU) stay or days on ventilatory
`support after the arterial switch operation (ASO) (PPHN
`vs non-PPHN) were tested by the Mann-Whitney U test.
`In all tests, a p value of 0.05 or less was considered
`significant.
`
`Ex. 2027-0002
`
`

`
`1448
`
`ROOFTHOOFT ET AL
`PPHN IN PATIENTS WITH TGA
`
`Ann Thorac Surg
`2007;83:1446–50
`
`Table 1. Postoperative Characteristics of Persistent Pulmonary Hypertension of the Newborn (PPHN)/Transposition of the
`Great Arteries Patients
`
`Patient
`
`1. Female
`2. Male
`3. Male
`4. Male
`5. Male
`6. Male
`7. Female
`8. Female
`9. Female
`10. Male
`
`PPHN
`
`Mild-moderate
`Mild-moderate
`Mild-moderate
`Mild-moderate
`Mild-moderate
`Mild-moderate
`Mild-moderate
`Severe
`Severe
`Severe
`
`Coronary
`Anatomy
`
`I LAD-CX II RCA
`I LAD-CX II RCA
`I LAD-CX II RCA
`I LAD-CX II RCA
`I LAD-CX II RCA
`I LAD II RCA-CX
`I LAD-CX II RCA
`I LAD-CX II RCA
`I LAD-CX II RCA
`I LAD-CX II RCA
`
`Postoperative Complications
`
`Uncomplicated
`Uncomplicated
`Pulmonary edema/atelectasis
`Atelectasis
`Chylothorax
`Pulmonary hypertension
`Cardiac infarction eci
`Uncomplicated
`Junctional ectopic tachycardia
`Open chest/obstruction left coronary ostium
`
`Mechanical
`Ventilation
`
`ICU Stay
`
`2 days
`2 days
`5 days
`5 days
`9 days
`10 days
`14 days
`2 days
`10 days
`23 days
`
`3 days
`3 days
`6 days
`6 days
`10 days
`11 days
`15 days
`3 days
`11 days
`33 days
`
`CX ⫽ circumflex coronary artery;
`
`ICU ⫽ intensive care unit;
`
`LAD ⫽ left anterior descending artery;
`
`RCA ⫽ right coronary artery.
`
`CARDIOVASCULAR
`
`(gestational age 28 1/7 weeks)(n ⫽ 1) and associated
`debilitating coloboma of the eye, heart anomaly, choanal
`atresia, retardation, and genital and ear anomalies
`(CHARGE) syndrome (n ⫽ 1).
`In 99 of the remaining 105 patients a primary ASO was
`performed. Six patients underwent alternative surgery;
`Senning procedure [n ⫽ 1], banding of the pulmonary
`artery ⫾ atrioseptectomy ⫾ modified Blalock-Taussig
`shunt (n ⫽ 5). In four of the latter five patients an ASO
`was performed at a later stage (see Fig 1). In the surgi-
`cally treated patients we observed a 30-day mortality of
`four patients out of 105 (3.9%). Two of these children died
`operatively from heart failure due to impaired coronary
`artery perfusion. In the first child the circumflex coronary
`artery (CX) originated from the right coronary artery
`(RCA):(I LAD [left anterior descending artery], II RCA-
`CX), the second child showed a I LAD-RCA, II CX
`pattern. The third patient developed therapy-resistant
`pulmonary hypertensive crises postoperatively and died
`fourteen days after operation (I LAD, II RCA-CX). The
`fourth patient survived the ASO, despite associated com-
`plex coronary anatomy (I ramus descendens anterior, II
`RCA-CX); however, the patient suffered from cerebral
`edema and died due to cerebral herniation. In the re-
`maining group of 99 patients who underwent a successful
`ASO we observed an unusual pattern of the coronary
`
`Fig 2. Characteristics of transposition of the great arteries and per-
`sistent pulmonary hypertension of the newborn (TGA/PPHN)
`patients.
`
`anatomy in 26 patients (p ⫽ 0.006 compared with the four
`out of four patients who died perioperatively) [9].
`Four patients died during long-term postoperative
`follow-up (late mortality). One of
`these patients 16
`months after uneventful ASO due to progressive idio-
`pathic-unexplained pulmonary vascular disease not re-
`lated to left ventricular dysfunction (usual coronary pat-
`tern I LAD-CX,
`II RCA). Three patients died
`unexpectedly at, respectively, 0.5, 1.5, and 3.75 years of
`age due to unknown cause, although two of these chil-
`dren had associated complex coronary anatomy and had
`shown temporary perioperative ischemia (I intramural
`LAD-CX, II RCA and I two right conal arteries, II LAD-
`CX-RCA) [9]. Of the 99 patients who underwent a pri-
`mary ASO, ten had a history of PPHN (group A), whereas
`89 had no PPHN (group B).
`Considering the postoperative characteristics of ASO
`in both groups, we observed remarkable differences:
`patients with PPHN needed significantly longer ventila-
`tory support (mean 8.2 days vs 3.9 days, p ⫽ 0.02), and
`their ICU stay was significantly longer (mean 10.4 days vs
`5.5 days, p ⫽ 0.03) (Mann-Whitney U test). Delayed
`sternal closure was observed in one patient of group A
`and in two patients of group B (p ⫽ 0.03, Fisher exact test).
`In both groups one patient needed iNO therapy (p ⫽ 0.2
`Fisher exact test). The characteristics of the complicated
`postoperative course of group A are shown in Table 1. As
`mentioned, group B showed a 30-day mortality of four
`patients and a late mortality of four patients. In contrast
`to group B all patients of group A have survived thus far.
`Four out of the 14 patients with TGA and PPHN died
`(29%) preoperatively, despite optimal conventional ther-
`apy including iNO therapy and adequate balloon atrio-
`septostomy. (see Fig 2). The PPHN that did not resolve
`despite that this therapy was considered a contraindica-
`tion to ASO. In the group with severe PPHN the mortality
`was 50% (three out of six patients). All patients in this
`group received iNO therapy (10 to 40 ppm) for a median
`duration of 51 hours (range, 24 to 120 hours). The remain-
`ing three patients recovered successfully from PPHN and
`subsequently underwent an ASO. In the group with
`
`Ex. 2027-0003
`
`

`
`Ann Thorac Surg
`2007;83:1446–50
`
`ROOFTHOOFT ET AL
`PPHN IN PATIENTS WITH TGA
`
`1449
`
`Table 2. Management of Neonates with Transposition of The Great Arteries/Intact Ventricular Septum and
`Pulmonary Hypertension
`
`First Author
`
`Year
`
`No. of
`Patients
`
`PGE1
`(Patients)
`
`BAS/BAH
`(Patients)
`
`NO
`(Patients)
`
`ECMO
`(Patients)
`
`Repair
`(Patients)
`
`Surgical
`Outcome
`
`Follow-up
`
`CARDIOVASCULAR
`
`None
`1
`2
`3
`2
`3
`13
`
`4/1
`2b/1
`2/none
`3b/2
`2b/none
`3b/none
`13/none
`
`None
`None
`None
`None
`2c
`3c
`11
`
`None
`None
`None
`None
`2c
`None
`None
`
`2 atrial/2 none 3 dead/1 alivea Lost to follow-up
`1 atrial/1 none 2 dead
`None
`2 ASO
`2 alive
`2 alive (2 mo)
`2 atrial/2 ASO 3 dead
`none
`2 ASO
`2 alive
`1 alive/1 dead
`3 ASO
`3 alive
`3 alive
`9 ASO/4 none
`9 alive
`9 alive
`
`Hawker [4]
`Dick [3]
`Chang [11]
`Kumar [5]
`Luciani [6]
`El-Segaier [12]
`Roofthooft
`[this article]
`
`1974
`1981
`1991
`1993
`1996
`2005
`2006
`
`4
`2
`2
`3
`2
`3
`13
`
`a Patient who underwent only a Blalock-Hanlon atrial septectomy.
`ASO ⫽ arterial switch operation;
`atrial ⫽ atrial switch operation;
`ECMO ⫽ extracorporeal membrane oxygenation;
`NO ⫽ nitric oxide;
`
`b Multiple atrial septotomies.
`c Preoperative and postoperative support.
`BAS ⫽ balloon atrial septostomy;
`BH ⫽ Blalock-Hanlon atrial septectomy;
`PGE1 ⫽ prostaglandin E1.
`
`mild-to-moderate PPHN, the mortality was 12.5 % (one
`out of eight). Five of these patients received iNO therapy
`(10 to 40 ppm) for a median duration of 50 hours (range,
`20 to192 hours). One patient, who was severely asphyxi-
`ated, died within 24 hours after starting iNO. In a
`deviation from the standard approach at our institution,
`a successful rescue ASO was performed in one patient 24
`hours after the start of iNO therapy, although the PPHN
`had not resolved at that time. The remaining six patients
`in this group underwent a successful ASO after complete
`recovery of the PPHN.
`
`Comment
`Untreated, TGA is a fatal congenital heart defect due to
`progressive hypoxia and acidosis. Heart failure usually
`develops within the first weeks of life. Patients with
`reduced mixing opportunities (eg, TGA with IVS and
`restrictive open foramen ovale and [or] closure of the
`arterial duct), are the patients who become symptomatic
`with cyanosis early after birth. This group of patients
`usually responds well to PGE1 infusion and balloon
`atrioseptostomy. Patients with TGA and VSD show less
`cyanosis and usually present at a later time. In general,
`patients diagnosed as TGA and VSD/IVS have good
`prognosis after an ASO [10].
`Sixteen patients with TGA/IVS and PPHN have been
`described previously (see Table 2) [3–6, 11]. In total, eight
`of those patients died in the neonatal period (50%).
`Inhaled nitric oxide therapy was not available in 11 of
`these patients. Five patients did receive iNO and sur-
`vived. They underwent a successful ASO although addi-
`tional perioperative ECMO was considered necessary in
`two patients. These limited data may suggest that the
`introduction of iNO therapy for PPHN may have im-
`proved the prognosis of newborns with TGA associated
`with PPHN (Table 2).
`Ten years after the introduction of iNO in our institu-
`tion, we reviewed our patient data concerning patients
`with TGA and PPHN. The incidence of PPHN in our
`cohort was higher than reported in previous reports in
`the literature (12.5% vs 3%) but compatible with the data
`
`by El-Segair and colleagues [12]. If only the patients with
`severe PPHN were considered (group 1; n ⫽ 6), an
`incidence of 5.3% (6 of 112) was found. In this latter group
`all patients had TGA/IVS; three patients survived with
`iNO therapy (maximum duration 48 hours). The three
`nonsurvivors showed therapy-resistant PPHN with early
`(n ⫽ 2; maximum 48 hours) or intermediate mortality
`(n ⫽ 1, after eight days iNO). In these patients, additional
`treatment with enoximone (Perfan; Hoechst Marion
`Roussel, Höchst am Main, Germany), epoprostenol (Flo-
`lan; GlaxoSmithKline, Boronia, Australia), and isoprena-
`line was attempted unsuccessfully. The incidence and
`clinical outcomes in our series are comparable to those in
`the report of Luciani and colleagues [6]. In contrast to
`their treatment approach, preoperative cardiac ECMO
`was not used in the Netherlands during the study period.
`Its role in the management of TGA and PPHN is still
`unclear. The international experience with postoperative
`cardiac ECMO is limited but promising. So far, four cases
`of TGA/PPHN in which ECMO was used have been
`described in the literature. The results in those cases
`were promising; however, the high incidence of cerebral
`hemorrhage, associated with ECMO, may limit the use of
`mechanical cardiopulmonary support in those patients
`[13, 14]. One patient in our series successfully underwent
`a so-called “rescue switch,” in which the ASO was
`performed in the presence of clinical PPHN. However,
`due to our limited experience we are not able to draw any
`conclusions regarding the place of such a procedure in
`the treatment of TGA/PPHN. The role of this approach
`needs further exploration.
`Although iNO is considered to be the first choice
`therapy in neonates with PPHN, it is also known that
`about 30% of these patients are nonresponders to iNO
`[15]. This lack of response may be explained by the fact
`that PPHN is a complex, multifactorial disorder associ-
`ated with a wide array of cardiopulmonary disorders.
`Airway obstruction or edema may decrease the response
`to iNO and atelectasis may cause intrapulmonary shunt-
`ing and hypoxia, which is not remedied by vasodilators.
`A variety of cellular mechanisms is involved in the
`complex process of perinatal pulmonary adaptation and,
`
`Ex. 2027-0004
`
`

`
`1450
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`ROOFTHOOFT ET AL
`PPHN IN PATIENTS WITH TGA
`
`Ann Thorac Surg
`2007;83:1446–50
`
`consequently, in disturbances of this process. Persistent
`pulmonary hypertension of the newborn is associated
`with pulmonary endothelial and vascular smooth muscle
`cell dysfunction that may be caused by multiple factors,
`including hypoxia, inflammation, and mechanical forces.
`These vascular cells are crucially important in both
`pulmonary vascular adaptation and homeostasis. Its dys-
`function may lead to a disturbed vasoconstrictor-
`vasodilator balance in the pulmonary vasculature.
`Animal experiments have suggested a role for various
`vasoactive pathways in the pathogenesis of PPHN, in-
`cluding the endothelin-1 pathway with its A and B
`receptors, the prostacyclin-cGMP and the nitric oxide-
`cAMP pathway, and, finally, the vascular endothelial
`growth factor- fetal liver kinase receptor-1- kinase insert
`domain receptor pathway [16–18]. Treatment solutions
`are likely to be found also on multiple levels. Further
`studies are needed to unravel the cellular mechanisms of
`PPHN and to identify new treatment targets for new-
`borns with this devastating disease.
`The surgical mortality in our series is low (3.9%) and
`congruent with other reported series on the ASO for TGA
`[19,20]. However, preoperative mortality due to various
`comorbidity, a number that is usually not reported in
`surgical series, was 6% in our series. It should be noted
`that such a number importantly affects the overall sur-
`vival rate in newborns with TGA.
`The combination of TGA with PPHN is a serious and
`often fatal condition. It may jeopardize the usually favor-
`able outcome of newborns with TGA. Its mechanism is,
`to a great extent, still unsolved. Restrictive patent fora-
`men ovale and (or) premature closure of the ductus
`arteriosus have been suggested as potential causes of
`PPHN. Fetal echocardiography might play a role in
`identifying these fetuses with TGA at risk for PPHN. Our
`data do not allow conclusions on the value of prenatal
`echocardiography in these patients because none of the
`PPHN patients was diagnosed antenatally. Because of the
`retrospective nature of this study, and incomplete data
`regarding restriction of the PFO in the total patient
`group, it was not possible to determine the relative risk
`for PPHN in patients with restrictive PFO.
`Despite the introduction of iNO therapy, the combina-
`tion of TGA and PPHN remains a serious and often fatal
`condition. Newborns in which the PPHN could be suc-
`cessfully treated preoperatively, underwent ASO with
`good operative results and survival. However, the role of
`additional treatment modalities in patients with therapy-
`resistant PPHN, including new pulmonary vasoactive
`drugs, the perioperative use of ECMO, and the “rescue
`switch procedure,” needs further investigation.
`
`References
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`tion of the great arteries: patterns of congenital heart disease
`in familial precurrence. Circulation 2001;104:2809.
`
`2. Samanek M. Boy:girl ratio in children born with different
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`Pediatr Cardiol 1994;15:53–7.
`3. Dick M, Heidelberger K, Crowley D. Quantitative morpho-
`metric analysis of pulmonary arteries in two patients with
`d-transposition of the great arteries and persistent fetal
`circulation. Pediatr Res 1981;15:1397–401.
`4. Hawker RE, Freedom RM, Rowe RD. Persistence of fetal
`pattern of circulation in transposition of the great arteries.
`Hopkins Med 1974;134:107–17.
`5. Kumar A, Taylor GP, Sandor GG, Patterson MW. Pulmonary
`vascular disease in neonates with transposition of the great
`arteries and intact ventricular septum. Br Heart J 1993;69:
`442–5.
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`CARDIOVASCULAR
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`Ex. 2027-0005