Acta Paediatrics, 2005; 94: 912-916
`
`Taylorléi Francis
`lsylatnrrmmii (xnup
`
`Nitric oxide in neonatal transposition of the great arteries
`
`MILAD EL-SEGAIER', LENA HELLSTROMAWESTAS2 & GORAN WETTRELL'
`
`Divisions of ‘Paediatric Cardiology, and 2Neonatol'ogy, Children 's Hospital, Limd Unitrersity Hospital, Ltmd, Sweden
`
`Abstract
`Three newborn infants with transposition of the great arteries (TGA) and intact ventricular septum (IVS) developed postnatal
`persistent pulmonary hypertension of the newborn (PPHN) and were successfully treated with inhaled nitric oxide (iNO).
`Intervention with balloon atrial septostomy (BAS) was performed in two of the infants before the iNO treatment, but they
`continued to be severely hypoxic with metabolic acidosis. However, the iNO immediately improved oxygenation and the
`clinical condition. The third neonate had a moderately large atrial communication and echocardiographic signs of PPHN. He
`received iNO before BAS with dramatic clinical improvement, which therefore postponed BAS.
`
`Conclusion: Early diagnosis of PPHN and treatment with iNO may improve final outcome in neonates with TGA and IVS.
`In the presence of moderately large atrial communication and PPHN, treatment with iNO might be considered before BAS.
`
`Key Words: Atrial’ septostorny, intact ‘ventricular septum, nitric oxide, persistent pulmonary hypertension of the newborn,
`transposition of the great arteries
`
`Inlxoducfion
`
`Persistent pulmonary hypertension of the newborn
`(PPI-IN)
`is a well-known cause of morbidity and
`mortality in full—terrn and near-term infants. Manage-
`ment of this condition has been greatly improved by
`the use of inhaled nitric oxide (iNO), especially when
`limited to patients with severe extrapulmonary shunt-
`ing [I-5]. Transposition of the great arteries (TGA)
`and intact ventricular septum (IVS) is associated with
`development of neonatal pulmonary hypertension in
`4% of cases [6]. Preoperative mortality in neonates
`with TGA has been reported to be 4%, and among
`these, PPHN was a contributing factor in 17% of
`preoperative deaths [7]. Preoperative management
`with prostaglandin E,
`(PGE1) and balloon atrial
`septostorny (BAS) is not sufficient to improve oxy-
`genation in some infants with TGA and PPHN [6].
`Luciani et al.
`reported a successful management
`protocol using iNO and extracorporeal membrane
`oxygenation in two neonates with TGA and PPHN [6] .
`Previous reports have stressed the risks associated
`with PPHN in infants with TGA,
`including high
`mortality, but fewer reports have discussed possible
`treannent strategies [7]. To illustrate possible pre-
`operative strategies in infants with TGA, IVS and
`
`PPHN, we report three infants who did not respond
`to BAS and the usual supportive managements. In
`all three infants, administration of iNO resulted in
`prompt
`improvement
`in oxygenation and clinical
`condition.
`
`Patients and methods
`
`The Children’s Hospital at Lund University Hospital
`is one of two Swedish referral centres for paediatric
`cardiac surgery. During an 18-mo period, between
`January 2001 and June 2002, 22 neonates with TGA
`were referred for preoperative and surgical manage-
`ment. Thirteen of the 22 infants (59%) had TGA and
`IVS, and nine (41%) had TGA with ventricular septal
`defect (VSD). Seven of the 13 infants with TGA and
`IVS underwent BAS. Three babies (14%) had a
`complicated course with profound hypoxia
`and
`acidosis. They developed pulmonary hypertension
`early after delivery and were successfully treated with
`iNO (AGA Medical system).
`
`Case I
`
`On his first day of life, a full-term male infant, born at
`42 wk of gestation, with a birthweight (BW) of 3765 g
`
`Correspondence: Milad El-Segaicr, Division of Paediatric Cardiology, Department of Paediatrics, Ciii1drcn‘s Hospital, Lund University Hospital, SE-22] 35
`Lund, Sweden. Tel: +46 46 178266. Fax: +46 61-6 178150. E-mail: mi|ad.ei-scgaiurfias1-zanesc
`
`(Received 4 flriarelr 2004; revised 1.? Septemoer 2004 and i‘3}a:mai3' 2005; accepted 26 }'amtar:\' 2005)
`ISSN 0803-5253 prinb"ISSN 1651-222? unline 1- 2005 Taylor 8: Francis Group Ltd
`DOI: 10.10-301080352505 10032664
`
`Mallinckrodt Hosp. Prods. IP Ltd.
`Exhibit 2025
`Praxair Distrib., Inc. et al., v. Mallinckrodt Hosp. Prods. IP Ltd.
`Case |PR2016-00779
`
`Ex. 2025-0001
`
`

`
`and normal Apgar scores, developed cyanosis with
`oxygen saturation 60%, arterial pH 7.1 and base ex-
`cess (BE) — 10.4. Cardiac echocardiography demon-
`strated TGA and IVS and a small patent foramen
`ovale (PFO). Intravenous infusion with PGE1 was
`started (50 ng/kg/min). He was transported without
`complications to the cardiac centre. On admission, he
`was clinically stable, with oxygen saturation 70%, and
`ongoing PGE,
`infusion. There was no cardiac mur-
`mur, and neurological status was normal. A repeated
`echocardiographic examination confirmed the diag-
`nosis TGA and IVS. Soon after arrival, his clinical
`condition deteriorated with increasing respiratory
`distress, and mechanical ventilation was
`started.
`Despite the ventilatory support, oxygen saturation
`declined from 70% to 50%. An emergency BAS was
`done with maximum balloon size 2 ml, but there was
`no clear improvement in oxygenation, which remained
`around 60%. After a few hours, oxygen saturation
`deteriorated to less than 50% and metabolic acidosis
`
`developed (BE -8.4). Cardiac echocardiography
`showed signs of PPHN with shunt flow through the
`patent ductus arteriosus (PDA) from the pulmonary
`artery to the descending aorta. In spite of supportive
`measures, no improvement occurred in oxygen satu-
`ration, which remained around 55%, and the infant
`also developed arterial hypotension. Volume support
`with transfusions of blood and fresh frozen plasma
`was given, and dopamine infusion (2-5 pg/kg/min)
`was
`started. These changes
`rendered some im-
`provement in the oxygen saturation (65%). Muscle
`tone increased but there were no convulsions, ampli-
`tude-integrated EEG monitoring (Cerebral Function
`Monitor, CFM, Lectromed, Letchworth, UK) showed
`normal
`electrocortical
`background
`activity
`[8].
`Midazolam and morphine infusions were given for
`sedation.
`
`Several hours later, oxygenation deteriorated again.
`A new echocardiography of the heart showed signs
`of continued pulmonary hypertension. Inhaled nitric
`oxide was started with 20 parts per million (ppm), and
`oxygen saturation rose immediately and stabilized at
`85% within 4 h. A repeated cardiac echocardiography
`showed that the flow through the PDA was now com-
`pletely reversed, i.e. from the descending aorta to the
`pulmonary artery. The iNO treatment could therefore
`be decreased and was discontinued within 24 h. As no
`
`more neurological symptoms were noted, no further
`neurological investigations were performed, and the
`midazolam and morphine infusion were discontinued.
`Corrective surgery was performed at 7 d with an
`arterial switch operation (A80). The postoperative
`course was uncomplicated,
`and the infant was
`discharged home on postoperative day 10. He has
`developed normally on follow-up at 3 y of age, and
`no cardiac or neurological complications have been
`reported.
`
`Clinical observation
`
`9 13
`
`Case 2
`
`Initial clinical examination after birth of a full-term
`
`male baby, with BW 3680 g and normal Apgar scores,
`showed cieft lip, cyanosis, and oxygen saturation of
`50% in the arms and 75% in the feet. On cardiac aus-
`
`cultation, there was no munnur. A cardiac malfor-
`mation was suspected, PGE, infusion was started and
`the baby was transported with ongoing mechanical
`ventilation to the cardiac centre at 8 h postnatal age.
`On admission, he was clinically stable with oxygen
`saturation 60%, pH 7.2 and BE -8. Cardiac echo-
`cardiography revealed TGA and IVS, a patent foramen
`ovale with left-to-right shunting, and a large PDA with
`bi—directional shunt flow, mainly from the aorta to the
`pulmonary artery. An emergency BAS, with achievable
`balloon size 3.5 ml, was performed since oxygen
`saturation had deteriorated to 45%. Immediately after
`BAS, oxygen saturation increased to 80% and mean
`arterial blood pressure rose from 35 mmHg to
`54 mmHg. Five hours later, oxygen saturation dete-
`riorated to 45% again. A repeat echocardiography of
`the heart showed a large atrial septal defect (ASD) with
`left-to-right shunt, and a large PDA with shunting from
`the pulmonary artery to the descending aorta, indi-
`cating PPHN. Inhaled NO was started with 20 ppm
`resulting in immediate improvement in oxygen satu-
`ration, which increased to 80%. Two hours later, repeat
`cardiac assessment by echocardiography showed shunt
`direction through the PDA fi“om the descending aorta
`to the pulmonary artery. The iN0 treatment was
`gradually decreased and could be withdrawn after 8 h
`without complication. An ASO was performed at 5 d
`postnatal age. The infant continued to be stabie after
`surgery, and he was discharged home at 2 wk of age.
`On follow-up control at 1 y of age, he had developed
`normally and no cardiac or neurological complications
`had been reported.
`
`Case 3
`
`In a full—term male infant, with BW 3630 g and normal
`Apgar scores, cyanosis was evident 15 min after de-
`livery. Oxygen saturation was 80%, pH 7.18 and BE
`— 6. He was admitted to the neonatal unit and received
`
`treatment with continuous positive airway pressure
`(CPAP), FiO2 50% and sodium bicarbonate buffer.
`However, there was no improvement in his oxygen
`saturation, which initially remained at 80%, and 2 h
`later decreased to 50%. Mechanical ventilation and
`PGE, infusion was started. The initial PGE1 dose was
`50 nglkg/min, but since this dose did not result in
`improved oxygenation the dose was increased to
`100 ngfkgjmin. However, oxygen saturation remained
`around 65%, and the baby was transported to our
`cardiac centre by an emergency team.
`On admission, his oxygen saturation was 80%
`with 100% inspired oxygen. Cardiac and pulmonary
`
`Ex. 2025-0002
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`9 14
`
`Clinical obsemariorz
`
`auscultation was normal, as were peripheral pulses and
`a chest X-ray.
`The PGE, dose was reduced to 50 ngjkgfmin.
`Cardiac echocardiography demonstrated a TGA and
`IVS and a moderately large atrial communication with
`diameter 7 mm. During preparation for BAS, at 5 h of
`age, his condition deteriorated with poor peripheral
`circulation, hypothermia (body temperature 35°C),
`and oxygen saturation decreased to 50%. He also de-
`veloped “reversed differential cyanosis”, i.e. a demar-
`cation line on the chest at the level of the nipple, with
`darker skin colour on the upper part of the body and
`paler skin colour on the lower part of the body. A new
`cardiac evaluation by echocardiography revealed signs
`of PPHN with shunt flow through the PDA from the
`pulmonary artery to the descending aorta. Inhaled
`nitric oxide was started with an initial dose of 10 ppm
`and then increased to 20 ppm. Oxygen saturation rose
`from 50% to 60% within 20 min, and then gradually
`increased to 80-85%. The differential cyanosis dis-
`appeared gradually, and the baby‘s general condition
`stabilized. A repeat echocarcliography showed that
`shunt direction through the PDA was bi—directional
`with flow dominance from the descending aorta to the
`pulmonary artery. With this improvement, it was con-
`cluded that BAS was not vitally needed since an ASO
`was planned within a few days. The iNO treatment was
`gradually withdrawn and discontinued after 12 h. The
`PGE1 dose was reduced to 20 ng/kgfmin with main-
`tained oxygen saturation around 85-88%. One day
`later, the baby had increased muscle tone but no signs
`of clinical convulsion. EEG showed normal back-
`
`ground activity with some sharp waves. A CT scan
`of the brain showed ischaemic changes,
`indicating
`focal infarctions in the left hemisphere of the brain.
`Clinical
`convulsions occurred and were
`treated
`with phenobarbitone and phenytoin. At
`this stage,
`
`a cardiopulmonary bypass operation was concluded to
`imply too much risk on brain function, and surgery was
`consequently postponed. Oxygenation and haemo-
`dynamic variables
`stabilized, and the infant was
`extubated from mechanical ventilation. BAS was
`
`performed at 9 d of age. At 18 postnatal days, a new
`CT scan and brain MRI showed no new cerebral
`
`ischaemic lesions, and no progress in those previously
`described. It was possible to perform ASO at 25 d of
`age with good result. Postoperatively,
`the baby
`continued with phenobarbitone treatment for 3 mo.
`Both cardiac and neurological status were normal on
`later follow-up at 3 y of age.
`
`Results
`
`Details of the clinical courses, e.g. oxygen saturation
`and shunting directions, for the three infants are given
`in Table I and Figure 1. Arterial blood gases, including
`methaemoglobin levels, were checked frequently at a
`few—hour intervals. None of the infants developed
`methaemoglobinaemia. There were no rebound
`effects in oxygen saturation after withdrawal of iNO
`treatment.
`
`Discussion
`
`We have described the positive effects of iNO in
`three neonates with TGA and IVS who developed
`PPHN. The addition of iNO to the conventional
`
`treatment gave an immediate and striking improve-
`ment in oxygenation.
`It is well known that the combined effect of acidosis
`
`and hypoxaemia may cause intense pulmonary vaso-
`constriction, raise pulmonary vascular resistance, and
`in newborns with TGA and IVS this may result
`in PPHN. Despite early PGE1 treatment, which keeps
`
`Table I. Clinical and diagnostic details of patients.
`
`N0.
`
`1
`
`Clinical
`
`Echo finding
`
`Cyanosis, acidosis
`
`TGA 8i IVS PFO
`
`Cyanosis, acidosis
`
`TGA 61 IVS PFO
`
`Cyanosis, acidosis
`
`TGA 8: IVS
`PFOJ-‘ASD
`(T mm)
`
`Before
`BAS
`
`After BAS
`
`Before iNO After iNO
`
`Comments
`
`Sat 60%
`Sat 50%
`P2102 2.0
`Pa0;: 1.9
`BE -8.4
`BE -3.9
`PGE1, PDA flow PA-DA
`Sat 45%
`Sat 80%
`P802 2.9
`Fat), 2.?
`BE -7.3
`BE 1.6
`PGE1, PDA flow PA—~DA
`
`Not done
`
`PGEI, FDA flow PA~>DA
`
`Sat 85%
`Sat 50%
`PaO=_: 4.?
`P303 3.8
`BE ]
`BE 1.9
`PDA flow DA-PA
`
`Sat 35%
`Sat 45%
`Pao, 4.5
`P210, 2.7
`BE (0.9
`BE —l.9
`PDA flow DA-PA
`
`Sat 85%
`Sat 50%
`PaO2 4.?
`13303 2.8
`BE -1.3
`BE -6.2
`PDA flow DA—>PA
`
`Rcsponsc to iNO <4 h.
`Operated at 7 cl.
`
`Immediate response to
`iNO. Operated at 5 :1.
`
`Immediate response to
`iNO. Operated at 25 d.
`
`BAS: balloon atrial septostomy; iNO: inhaled nitric oxide; TGA: transposition of the great arteries,’ IVS: intact ventricular septum; PFO:
`persistent foramen ovalc; ASD: atrial septal sefcct; Sat: oxygen saturation; P3023 partial pressure of oxygen in arterial blood in kPa; BE: base
`excess; PGE1: prostaglandin E1; PDA: patent ductus arteriosus; PA: pulmonary artery; DA: descending aorta.
`
`Ex. 2025-0003
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`
`on
`
`______-_________E,
`
`A~vI'
`
`.--.-------..-.2
`
`55 Patient I (O)
`35 Patient 2 (I)
`
`sit Patient} in
`
`Figure 1. Blood oxygen saturation before and after BAS and iNO.
`Oxygen saturation was persistently improved only after iNO treat-
`ment.
`
`the ductus arteriosus open, and BAS, which may create
`large interatrial communications, some of the newborn
`infants with TGA have limited intercirculatory mixing.
`As iNO creates pulmonary vascular relaxation, more
`blood reaches the pulmonary capillaries. This changes
`haernodynaniics through facilitated interatrial mixing
`and thus increases arterial oxygenation. Inhaled nitric
`oxide does not change cerebral blood flow, or cerebral
`oxygen consumption [9].
`The use of iNO in treatment of PPHN with severe
`
`extrapulmonary shunting was reported in two previous
`studies [4,5]. In newborn infants with PPHN,
`the
`clinical response to iNO seems to be most dramatic
`in patients with the most severe hypoxaemia when
`initiating the treatment [10].
`The three infants in the present report developed
`cyanosis early after delivery, and further investigations
`confirmed the diagnosis of TGA and IVS. They were
`all outborn, and after initial stabilization, including
`PGEI, they were transported to our cardiac centre.
`The clinical condition of newborns with cardiovascular
`
`and} or pulmonary disease may deteriorate during long-
`distance transportation. During a 5-y period, almost
`50% of infants with TGA arrived with oxygen satu-
`ration less than 65% [11]. To improve outcome from
`emergency transfers, urgent bedside balloon atrial
`septostomy in the local neonatal intensive units might
`be performed by a mobile specialist cardiac team [12].
`This management would probably also reduce the risks
`for development of PPHN in some of the infants, since
`early BAS is likely to improve oxygenation and thus
`prevent prolonged acidosis and hypoxaemia.
`Reversed differential cyanosis, i.e. a line of demar-
`cation on the chest wall at the nipple level where the
`cyanosis of the upper body was greater than that of the
`lower body, was present in one of the infants. In infants
`with TGA and IVS, the presence of reversed difi’er-
`ential cyanosis indicates that the blood flow through
`
`Clinical observation
`
`9 15
`
`the ductus arteriosus is directed from the pulmonary
`artery to the aorta, and consequently that PPI-IN may
`be present. However, reversed differential cyanosis is
`not specific for PPHN in infants with TGA; it can also
`be found in more complex cardiac malformations with
`aortic anomalies [13].
`Two of the presented infants developed clinical
`neurological symptoms.
`In one infant,
`there was
`mild muscle rigidity with spontaneous regress within
`4 to 5 h. In the other infant,
`there was increased
`muscle rigidity and clinical convulsion; EEG showed
`increased sharp wave activity but no seizure activity,
`and CT and MRI showed cerebral infarction. It is likely
`that the cerebral ischaemic lesions developed during
`the initial severe hypoxaemia and acidosis, before iNO
`treatment was started.
`After the initial critical course, all three infants were
`treated surgically with ASO without any perioperative
`complications. None of the babies developed post-
`operative pulmonary hypertension, which is a de-
`scribed rislt [14]. Furthermore, long-term neurological
`follow—up was normal in all three children.
`In conclusion, the acute management of neonates
`with TGA and IVS, early diagnosis of PPHN and
`treatment with iNO may improve outcome in these
`infants.
`In the presence of moderately large atrial
`communication and PPHN,
`treatment with iNO
`should be considered before BAS.
`
`Acknowledgements
`
`We wish to thank our research nurse Laura O’Sullivan Darcy
`for language correction.
`
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