negative diagnosis in which the correct diagnosis was
`made at 20 weeks’ gestation.
`Nuchal anomalies appeared in 14 of 22 fetuses (59%)
`with atrioventricular septal defect. This finding is in
`accordance with the high incidence of nuchal anomalies
`in fetuses with cardiac anomalies.1 Allan4 reported 49
`fetuses with atrioventricular septal defect. Heterotaxia
`syndromes or isomerism of the atrial appendages was
`noted in 22 of these cases. In our series, there was only
`1 fetus with heterotaxia syndrome. We have no expla-
`nation for the difference between the 2 studies.
`The ability to diagnose atrioventricular septal defect
`relies on the skill of the observer. Gembruch et al9 and
`Achiron et al10 detected this anomaly in early pregnancy.
`Allan4 recently estimated that only 50% of cases are
`detected in utero. In our series, the diagnosis was con-
`firmed in 11 of 13 fetuses in which a postmortem exam-
`ination was performed. The higher detection rate in our
`series may be attributed to the fact that all examinations
`were performed by the same experienced observer.
`We are aware of 2 possible drawbacks in our study.
`(1) Because not all of our patients delivered in our
`hospital, we only had our own data on pregnancy out-
`come in 72% of patients. In the other cases we relied on
`information provided by patients or their obstetricians.
`We cannot exclude the possibility that we were not
`informed about a case of a false-negative diagnosis of
`atrioventricular septal defect. (2) Because of the destruc-
`tive nature of the termination of pregnancy, a reliable
`postmortem examination was not possible in all cases.
`
`In summary, the data show that accurate sono-
`graphic diagnosis of fetal complete atrioventricular
`septal defect is possible in the first and early second
`trimesters of pregnancy. Many of these fetuses
`have associated abnormal sonographic findings;
`the most frequent was nuchal translucency. About
`2/3 of the fetuses in whom chromosomal analysis
`was available had an abnormal karyotype.
`
`1. Berdahl LD, Wenstrom KD, Hanson JW. Web neck anomaly and its associ-
`ation with congenital heart disease. Am J Med Genet 1995;56:304 –307.
`2. Marino B. Pattern of congenital heart disease and associated cardiac anomalies
`in children with Down syndrome. In: Marino B. Pueschel SM, eds. Heart Disease
`in Persons with Down Syndrome. Baltimore: Brooks, 1996:133–140.
`3. Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD, eds. Genetic and
`Environmental Risk Factors of Major Cardiovascular Malformations: The Balti-
`more-Washington Infant Study 1981–1989; Armonk, NY: Futura,1997:103–122.
`4. Allan LD. Atrioventricular septal defect in the fetus. Am J Obstet Gynecol
`1999;181:1250 –1253.
`5. Digilio MC, Marino B, Giannico S, Giannotti A, Dallapiccola B. Atrioven-
`tricular canal defect and hypoplastic left heart syndrome as discordant congenital
`heart defects in twins. Teratology 1999;60:206 –208.
`6. Allan L. Atrioventricular septal defect. In: Allan L, Hornberger LK, Sharland
`G, eds. Textbook of Fetal Cardiology. London: Greenwick Media, 2000:163–193.
`7. Pierpont MAM, Markwald RR, Lin AE. Genetic aspects of atrioventricular
`septal defect. Am J Med Genet 2000;97:289 –296.
`8. Bronshtein M, Coffler MS, Zimmer EZ. The cardiovascular system. In:
`Bronshtein M, Zimmer EZ, eds. Transvaginal Sonography of the Normal and
`Abnormal Fetus. New York: Parthenon, 2001:87–130.
`9. Gembruch U, Hansmann M, Redel DA, Bald R, Knopfle G. Fetal complete
`heart block: antenatal diagnosis, significance and management. Eur J Obstet
`Gynecol Reprod Biol 1989;31:9 –22.
`10. Achiron R, Rotstein Z, Lipitz S, Mashiach S. First trimester diagnosis of fetal
`congenital heart disease by transvaginal ultrasonography. Obstet Gynecol 1994;
`84:69 –72.
`
`Diagnostic and Therapeutic Uses of Inhaled Nitric
`Oxide in Neonatal Ebstein’s Anomaly
`Andrew M. Atz, MD, Ricardo A. Munoz, MD, Ian Adatia, MB, ChB, and
`David L. Wessel, MD
`Inhaled nitric oxide (NO) is a selective pulmonary
`
`vasodilator with few adverse effects using current
`delivery and monitoring techniques. Failure of the
`postoperative newborn with pulmonary hypertension
`to respond to NO has successfully discriminated ana-
`tomic obstruction to pulmonary blood flow from re-
`versible pulmonary vasoconstriction.1 Severe neonatal
`Ebstein’s anomaly is a rare lesion with high mortali-
`ty.2,3 However, occasionally survivors demonstrate
`spontaneous clinical improvement as pulmonary vas-
`cular resistance declines.4 The aim of this study was to
`determine whether a trial of NO could differentiate
`patients with functional pulmonary atresia5 from
`structural pulmonary atresia, and therefore quickly
`identify those who would require surgery. Further-
`
`From the Children’s Hospital, Harvard Medical School, Boston, Mas-
`sachusetts. Dr. Atz’s address is: The Children’s Heart Center of South
`Carolina, Medical University of South Carolina, 165 Ashley Avenue,
`PO Box 250915, Charleston, South Carolina 29425. E-mail:
`atzam@musc.edu. Manuscript received September 18, 2002; re-
`vised manuscript received and accepted December 11, 2002.
`
`more, we speculated that NO might therapeutically
`improve oxygenation in patients with a patent pulmo-
`nary valve by decreasing afterload on the right ven-
`tricle, causing improved cardiac output and reduced
`intracardiac shunt.
`
`• • •
`We identified all neonates presenting to a cardiac
`intensive care unit with echocardiographically diagnosed
`Ebstein’s anomaly (Table 1). Patients with associated
`complex congenital heart disease were excluded. Four-
`teen (7 female and 7 male) patients had maximal arterial
`oxygen tension (PaO2) ⬍65 mm Hg and all received a
`trial of inhaled NO. Prostaglandin E infusions were dis-
`continued before NO testing in an effort to further en-
`courage anterograde flow across the pulmonary valve.
`Hemodynamic variables were measured at (1)
`baseline—a stage in which patients were normother-
`mic and hemodynamically stable (steady heart rate
`and blood pressure and no change in inotropic or
`ventilatory requirement), and (2) at the end of a 15-
`minute trial of inhaled NO at 80 ppm. Ventilation pa-
`
`906
`
`©2003 by Excerpta Medica, Inc. All rights reserved.
`The American Journal of Cardiology Vol. 91 April 1, 2003
`
`0002-9149/03/$–see front matter
`doi:10.1016/S0002-9149(03)00036-5
`
`Ex. 2023-0001
`
`

`
`TABLE 1 Patient Characteristics
`
`Patient
`Number
`1
`2
`3
`4
`
`Age
`(d)
`4
`1
`2
`1
`
`Weight
`(kg)
`1.7
`2.3
`2.5
`2.7
`
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`
`1
`1
`1
`2
`1
`1
`1
`1
`2
`4
`
`3.1
`3.0
`3.1
`3.2
`4.5
`2.4
`2.8
`3.6
`3.8
`4.0
`
`Celermajer
`Ratio
`(index)
`0.79 (2)
`2.50 (4)
`0.95 (2)
`2.57 (4)
`
`1.58 (4)
`1.68 (4)
`1.20 (3)
`0.61 (2)
`0.63 (2)
`0.67 (2)
`0.41 (1)
`0.50 (2)
`0.95 (2)
`0.53 (2)
`
`Operation
`
`B-T shunt
`0
`B-T shunt, TV closed, ASD created
`B-T shunt, PV opened, TV closed,
`ASD created
`B-T shunt, PV opened, ASD created
`0
`0
`0
`0
`TV closed
`RVOT patch, VSD closed, ASD closed
`0
`0
`0
`
`Pulmonic
`Atresia
`⫹
`⫹
`⫹
`⫹
`
`⫹
`Functional
`Functional
`Functional
`Functional
`0
`0
`0
`0
`0
`
`PaO2
`Arterial
`Saturation (%)
`(mm Hg)
`Base
`NO Base NO
`Outcome
`83
`84
`49
`51 Died (17 d)
`53
`51
`24
`22
`Died (1 d)
`81
`72
`41
`34 Died (4 mo)
`70
`77
`40
`39
`Died (5 d)
`
`86
`58
`31
`47
`84
`51
`82
`91
`90
`83
`
`78
`70
`77
`66
`90
`81
`79
`95
`95
`84
`
`34
`31
`20
`26
`33
`30
`49
`61
`42
`43
`
`Died (2 d)
`30
`Alive
`36
`Died (2 d)
`46
`Alive
`34
`Alive
`36
`Died (6 d)
`36
`45 Died (4 mo)
`130
`Alive
`46
`Alive
`45
`Alive
`
`ASD ⫽ atrial septal defect; Base ⫽ before nitric oxide; B-T ⫽ Blalock-Taussig; PaO2 ⫽ systemic arterial oxygen tension; PV ⫽ pulmonic valve; RVOT ⫽ right
`ventricular outflow tract; TV ⫽ tricuspid valve; VSD ⫽ ventricular septal defect.
`
`significant. Written informed consent was obtained
`from parents of all patients under approved protocols.
`After all data were collected, the patients were
`divided into 2 groups: those with structural pulmonary
`atresia and those with a patent pulmonary valve as
`defined by echocardiographic evidence of anterograde
`flow after inhaling NO for 15 minutes. The first group
`included 5 patients in whom anterograde flow was
`never demonstrated by echocardiography either before
`or during treatment with NO; in all, atresia was con-
`firmed at either catheterization or at operation. The
`second group included 5 patients in whom anterograde
`flow was detected by echocardiography at baseline
`and during NO inhalation, and 4 patients with func-
`tional pulmonary atresia who had evidence of antero-
`grade flow only after inhaling NO.
`There was no statistical difference seen in either
`group after 15 minutes of breathing inhaled NO with
`respect to heart rate, arterial blood pressure, arterial pH,
`or arterial carbon dioxide pressure. There was a signifi-
`cant increase in PaO2 from baseline in the group with a
`patent pulmonary valve (39 to 53 mm Hg; p ⬍0.05) and
`in arterial oxygen saturation (71% to 84%; p ⬍0.05)
`after inhalation of NO at 80 ppm for 15 minutes. In the
`group with structural pulmonary atresia, there was no
`comparative change in arterial PaO2 (41 to 39 mm Hg)
`or in arterial saturation (80% to 78%) (Figure 1).
`In 6 patients with improvement in oxygenation by
`ⱖ10% during the initial trial of NO at 80 ppm, NO
`was reintroduced at 5 to 20 ppm. Patient 11 was the
`only patient with a patent pulmonary valve who did
`not have improvement in oxygenation, and he was
`found to have subpulmonic stenosis, which resulted in
`fixed obstruction to pulmonary blood flow. Nitrogen
`dioxide measured continuously in all patients re-
`mained at ⬍2 ppm and methemoglobin concentration
`remained at ⱕ1.2%
`Six infants underwent surgery: four with structural
`pulmonary atresia, the patient with fixed subpulmonic
`stenosis, and patient 10, who underwent surgery for
`
`BRIEF REPORTS 907
`
`FIGURE 1. Patients with a patent pulmonary valve (no pulmonary
`atresia) had improvement in systemic saturation (Sat) and PaO2—a
`mean percentage increase of 36% and 31%, respectively, after 15
`minutes of NO. Those with structural pulmonary atresia had no im-
`provement in oxygenation with NO. No change in heart rate or
`systemic blood pressure (BP) was seen in either group.
`
`rameters were kept constant throughout the 15-minute
`trial. Nitrogen dioxide was continuously monitored and
`methemoglobin levels were measured by co-oximetry
`(CIBA-Corning model 2500, Medfield, Massachusetts).
`Heart rate, blood pressure, and blood gases were mea-
`sured in all patients. Patients underwent echocardiogra-
`phy at baseline and at the end of the trial of NO to assess
`the presence or absence of forward flow across the pul-
`monary valve. Initial diagnostic echocardiograms were
`reviewed by a single investigator blinded to the results to
`determine the index of severity of Ebstein’s anomaly as
`described by Celermajer et al2 (ratio of the combined
`right atrial and atrialized right ventricular area to the area
`of the functional right ventricle and left heart.)
`All patients acted as their own controls. A paired
`nonparametric test (Wilcoxon signed-rank test) was
`used to compare the difference between baseline he-
`modynamic variables and after 15 minutes of inhaled
`NO. A p value ⬍0.05 was considered statistically
`
`Ex. 2023-0002
`
`

`
`rapidly progressive heart failure within 6 hours of life
`despite improved oxygenation with NO. The types of
`surgical procedure varied and are listed in Table 1.
`Only 2 of 6 postoperative patients survived to hospital
`discharge and neither survived beyond 4 months.
`Eight patients did not undergo surgical procedures.
`Two patients were believed to be unsuitable candidates
`for surgery. One had pulmonary atresia and diminutive
`(1.5 mm) branch pulmonary arteries and died of severe
`hypoxia at 2 days despite reinitiating prostaglandin E.
`One with functional pulmonary atresia had severe neo-
`natal hydrops and despite a positive response to NO had
`progressive acidosis and rapid onset multiorgan system
`failure. The other 6 patients remain alive during an
`average of 4.4 years (range 2.9 to 8.6) of follow-up.
`In an effort to maximally encourage anterograde flow
`across the pulmonary valve, all patients in this study had
`prostaglandin discontinued before initiation of NO. The
`ductuses were patent in these patients at the time of
`testing but qualitatively were no larger than moderate in
`size. It is unclear whether our results would have been
`similar
`if performed during prostaglandin infusion.
`There has been a report of a neonate with Ebstein’s
`anomaly with documented anterograde flow across the
`pulmonary valve in whom maintenance of a ductus ar-
`teriosus with prostaglandin resulted in worsened hypox-
`emia, acidosis, and systemic hypotension due to a steal
`phenomenon. Prolonged NO and closure of the ductus
`was speculated to help long-term right ventricular com-
`pliance and function.6 Treatment with inhaled NO during
`prostaglandin infusion to maintain a widely patent ductus
`may theoretically have a deleterious effect on Ebstein’s
`patients with excessive pulmonary blood flow by in-
`creasing the pulmonary-to-systemic flow ratio and wors-
`ening hemodynamics. We did not see this in our study
`patients, who were profoundly cyanotic and had prosta-
`glandin discontinued. The present study confirms the
`
`safe and beneficial therapeutic aspect of NO in a series of
`cyanotic patients with Ebstein’s anomaly and illustrates
`the previously undescribed role of NO as a diagnostic
`tool for this disease. Use of this management strategy
`may have valuable utility in other scenarios where func-
`tional pulmonary atresia may be encountered, such as
`congenital tricuspid regurgitation7 and Uhl’s anomaly.8
`
`In conclusion, inhaled NO rapidly and effec-
`tively discriminated functional
`from structural
`pulmonary atresia shortly after birth in severely
`affected neonates with Ebstein’s anomaly. Inhaled
`NO after discontinuation of prostaglandin may
`play an important diagnostic and therapeutic role
`in neonates with Ebstein’s anomaly and may mod-
`ify currently accepted prognostic indicators.
`
`1. Adatia I, Atz AM, Jonas RA, Wessel DL. Diagnostic use of inhaled nitric oxide
`after neonatal cardiac operations. J Thorac Cardiovasc Surg 1996;112:1403–
`1405.
`2. Celermajer DS, Cullem S, Sullivan ID, Speigelhalter DJ, Wyse RK, Deanfield
`JE. Outcome in neonates with Ebstein’s anomlay. J Am Coll Cardiol 1992;19:
`1041–1046.
`3. Yetman AT, Freedom RM, McCrindle BW. Outcome in cyanotic neonates
`with Ebstein’s anomaly. Am J Cardiol 1998;81:749 –754.
`4. Bush A, Busst CM, Haworth SG, Hislop AA, Knight WB, Corrin B, Shine-
`bourne EA. Correlations of lung morphology, pulmonary vascular resistance, and
`outcome in children with congenital heart disease. Br Heart J 1988;59:480 –485.
`5. Freedom RM, Culham JA, Moes CA, Olley PM, Rowe RD. Differentiation of
`functional and structural pulmonary atresia: role of angiography. Am J Cardiol
`1978;41:914 –920.
`6. Bruckheimer E, Bulbul Z, Pinter E, Gailani M, Kleinman, CS, Fahey JT.
`Inhaled nitric oxide therapy in a critically ill neonate with Ebstein’s anomaly.
`Pediatr Cardiol 1998;19:477–479.
`7. Andelfinger G, Shirali GS, Rauniker RA, Atz AM. Functional pulmonary
`atresia in neonatal Marfan’s syndrome: successful treatment with inhaled nitric
`oxide. Pediatr Cardiol 2001;22:525–526.
`8. Tumbarello R, Adatia I, Yetman A, Boutin C, Izukawa T, Freedom RM. From
`functional pulmonary atresia to right ventricular restriction. Long term follow up
`of Uhl’s anomaly. Int J Cardiol 1998;67:161–164.
`
`Early and Late Results of Thrombolytic Therapy Using
`Tissue-Type Plasminogen Activator to Restore Arterial
`Pulse After Cardiac Catheterization in Infants and
`Small Children
`Duraisamy Balaguru, MBBS, MRCP, Muhammad Dilawar, MD, Pamela Ruff, BS, RDCS, and
`Wolfgang A.K. Radtke, MD
`Pulse loss after cardiac catheterization has been
`
`reported to occur in 8% to 39% of infants weigh-
`ing ⬍14 kg1–3 despite prophylactic use of heparin,4
`notably after retrograde balloon angioplasty or valvu-
`loplasty.5 Impaired limb growth is a possible late com-
`plication6,7 and access is lost for future catheterization.
`
`From the Children’s Heart Center, Medical University of South Caro-
`lina, Charleston, South Carolina. Dr. Radtke’s address is: Pediatric
`Cardiology, Medical University of South Carolina, 165 Ashley Ave-
`nue, PO Box 250915, Charleston, South Carolina 29425. E-mail:
`radtkew@musc.edu. Manuscript received April 30, 2002; revised
`manuscript received and accepted November 27, 2002.
`
`Thrombolytic therapy using streptokinase5,8,9 and uroki-
`nase,10 and, recently, tissue-type plasminogen activator
`(t-PA)11–14 has been reported but without assessing long-
`term patency of the target vessel. The reports on t-
`PA11–14 were based on a variety of doses given ⬎24
`hours after catheterization and patient numbers were
`small. We report our experience using a uniform t-PA
`dosing protocol that began 4 to 6 hours after cardiac
`catheterization with regard to safety, efficacy, and long-
`term patency of the target vessel.
`• • •
`Medical records of patients who received throm-
`
`908
`
`©2003 by Excerpta Medica, Inc. All rights reserved.
`The American Journal of Cardiology Vol. 91 April 1, 2003
`
`0002-9149/03/$–see front matter
`doi:10.1016/S0002-9149(03)00037-7
`
`Ex. 2023-0003