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Ann Thorac Surg 1996;61:800-804
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Surgical Repair of Transposition of the Great Arteries in Neonates With Persistent Pulmonary Hypertension

Divisions of Cardiothoracic Surgery and Cardiology, Childrens Hospital Los Angeles, and Departments of Surgery and Pediatrics, University of Southern California School of Medicine, Los Angeles, California

Accepted for publication October 11, 1995.

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
Background. Pulmonary hypertension due to persistent fetal circulation is rarely associated with transposition of the great arteries and intact ventricular septum. Previous attempts at management of affected neonates using prostaglandin E₁ and balloon atrial septotomy followed by surgical repair have been largely unsuccessful.

Methods. Between September 1992 and April 1995, 45 neonates underwent repair of transposition of the great arteries with the arterial switch operation. Two patients (4%) with transposition of the great arteries and intact ventricular septum presented with profound reversed differential desaturation and right-to-left shunting at the level of the ductus arteriosus after balloon atrial septotomy. A diagnosis of persistent pulmonary hypertension was established and both neonates entered an experimental management protocol using inhaled nitric oxide and rapid arterial switch operation.

Results. Preoperative hemodynamic stabilization was achieved in 1 patient using 40 parts per million of inhaled nitric oxide, whereas the other required in addition extracorporeal membrane oxygenation for severe biventricular dysfunction. Both underwent successful surgical repair 4 to 5 days after admission, but received postoperatively 1 week of inhaled nitric oxide therapy for persistent pulmonary hypertension. Follow-up echocardiography at 3 months showed good biventricular function and normal geometry of the ventricular septum, suggesting low pulmonary artery pressure, in both.

Conclusions. A management protocol using inhaled nitric oxide and extracorporeal membrane oxygenation followed by the arterial switch operation was successfully used in neonates with transposition of the great arteries, intact ventricular septum, and persistent pulmonary hypertension. Wider use of preoperative and postoperative inhaled nitric oxide may improve the surgical outcome of this difficult subset of patients.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
See also page 805.

The results of the surgical repair of transposition of the great arteries (TGA) with intact ventricular septum (IVS) using the arterial switch operation (ASO) are well documented, with a perioperative mortality of 2% to 5% and a neglegible late mortality [1]. Aside from anatomic variables, there exist physiologic variables that represent incremental risk factors for early mortality [1, 2]. Among these is the presence of pulmonary hypertension (PHT) due to persistent fetal circulation, which is associated with about 1% to 2% of all cases of TGA/IVS [2–5]. Management of these patients using balloon atrial septotomy (BAS) and prostaglandin E₁ (PGE₁) infusion alone has yielded uniformly poor results [3–5]. Recent attempts at hemodynamic stabilization by decreasing the pulmonary vascular resistance with alkalinization and early surgical correction with the ASO have been more encouraging [5, 6]. We report our preliminary clinical experience with 2 neonates presenting with TGA/IVS and PHT who did not respond to previously proposed medical treatment. The use of inhaled nitric oxide (NO) and extracorporeal membrane oxygenation (ECMO) allowed for adequate preoperative and postoperative support and successful surgical repair with the ASO.

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
Between September 1992 and April 1995, 45 neonates with TGA underwent surgical repair with the ASO. Twenty-six patients presented with TGA/IVS, whereas 19 had TGA and ventricular septal defect. All patients with TGA/IVS (26) and 10 with TGA/ventricular septal defect underwent BAS at birth to establish adequate atrial level mixing.

During this study period, 2 neonates (4%) who presented with profound cyanosis and were diagnosed with TGA/IVS at birth remained profoundly cyanotic after BAS (arterial oxygen saturation [SaO₂] = 40% to 50% on an inspired oxygen fraction of 1.0). Given the echocardiographic evidence of unidirectional right-to-left shunting at the ductal level in both, the diagnosis of TGA/IVS/PHT was reached.

Nitric Oxide Investigative Protocol
Evidence of unidirectional right-to-left shunting at the ductal level and profound desaturation on mechanical ventilation with an inspired oxygen fraction of 1.0, PGE₁ infusion, narcotic anesthesia, and neuromuscular blockade was used as indication for a trial of NO therapy. Measurements of hemodynamic profile (heart rate, mean arterial blood pressure, central venous pressure, and mean pulmonary arterial pressure) as well as arterial and mixed venous blood gases were made at baseline and during the induction phase of the NO inhalation therapy. The protocol for induction consisted of progressive increments of the NO dose (5, 20, 40, and 80 ppm) every 15 minutes for the first hour. After induction, weaning back to the maintenance dose was rapidly done. The maintenance dose was identified as the dose at which an appreciable (20% change from baseline) hemodynamic benefit (increase in SaO₂ or increase in mean systemic pressure or decrease in mean pulmonary artery pressure or decrease in metabolic acidosis) could be derived. During this study period, no ventilator changes were made and no drug infusions were altered. An attempt to wean the NO to the lowest effective dose was routinely made every 24 hours if hemodynamic stability and arterial oxygenation were maintained.

Monitoring of toxicity was done by surveillance of the methemoglobin level and the percentage of inhaled nitrogen dioxide. Methemoglobin levels, expressed as percent of total hemoglobin, were measured every 3 hours during the therapy with a cooximeter (AV Laboratories, Graz, Austria). The chemiluminescence analyzer (Thermoenvironmental Instruments, Franklin, MA) used to continuously monitor inhaled NO was also used to assess levels of nitrogen dioxide. The protocol dictated suspension of inhaled NO therapy if the methemoglobin level was 5% or greater, or if the nitrogen dioxide level was 5 ppm or greater.

Methods of Operation
All ASOs were performed using previously published techniques [1], under deep hypothermic (20°C core temperature) low-flow perfusion (50 mL•kg^-1•min^-1). Cold (4°C) sanguineous cardioplegia (12 to 15 mL/kg) and continuous cold (4°C) saline pericardial irrigation were used for myocardial protection. Infusion of cold cardioplegia in the neo-aortic root was routinely repeated only once, upon completion of the coronary translocation and anastomosis of the ascending aorta to the pulmonary root. Separation from cardiopulmonary bypass was aided by the use of inotropic agents (dopamine, 5 µg • kg^-1 • min^-1, and dobutamine, 5 µg • kg^-1 • min^-1). Intraoperative transesophageal echocardiography (TEE) was routinely performed before and after the ASO to assess the adequacy of the repair.

Methods of Extracorporeal Membrane Oxygenation
Venoarterial perfusion with gravity drainage was used in all neonates with TGA who required preoperative or postoperative ECMO support. Standard cannulation involved surgical dissection of the internal jugular vein and carotid artery, with direct-vision catheterization of both vessels. Transesophageal echocardiography was used to evaluate the recovery of ventricular function upon weaning from ECMO support.

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
There was only one operative death in the entire series, giving an early (<30 days) mortality of 2%. The patient was a neonate with TGA/VSD and parachute mitral valve who was judged to have postoperative severe left ventricular dysfunction. There was one late death (2%), occurring 4 months after successful ASO, in 1 of the 2 reported patients who presented with TGA/IVS/PHT. The overall 1-month, 12-month, and 24-month survival was 97%, 95%, and 95%, with a total follow-up of 610 patient-months and mean of 13.8 ± 9.7 months (range, 1 to 31 months).

Clinical Course of Patients With Transposition of the Great Arteries, Intact Ventricular Septum, and Pulmonary Hypertension
PATIENT 1.
Patient 1 was a 4-day-old boy with TGA/IVS who presented with reversed differential cyanosis and systemic hypotension, which persisted after two BAS procedures on PGE₁ infusion (fig 1). Emergency transfer to our institution for NO therapy and possible surgical treatment was prompted. On arrival, the patient required resuscitation with atropine and epinephrine boluses and a short period of closed chest compression for profound hypotension (40/20 mm Hg) and bradycardia (40 beats/min). Admission pH was 6.69, with an arterial oxygen tension of 21 mm Hg, arterial carbon dioxide tension of 68 mm Hg, and base excess of -28 on full mechanical ventilatory support. Right-to-left ductal and atrial level shunting with profound biventricular dysfunction were evident at echocardiography.

View larger version (20K): [in this window] [in a new window]   Fig 1. . Preoperative and postoperative clinical course of patient 1 and the response to nitric oxide (NO) and extracorporeal membrane oxygenation (ECMO). (ASO = arterial switch operation; BE = base excess; PAP = pulmonary arterial pressure; SaO2 = arterial oxygen saturation; SAP = systemic arterial pressure.)

After 5 days, the patient was transferred to the operating room and underwent ASO repair of TGA/IVS while on ECMO. Intraoperative TEE demonstrated satisfactory biventricular function on high inotropic support (dopamine, 10 µg • kg^-1 • min^-1; dobutamine, 10 µg • kg^-1 • min^-1; and epinephrine, 0.05 µg • kg^-1 • min^-1) and pge₁ infusion (0.05 µg • kg^-1 • min^-1). cardiopulmonary bypass could therefore be discontinued; the sternotomy wound was left open to allow for cardiocirculatory stabilization. postoperatively, anuria, systemic hypotension (52/38 mm hg), pulmonary hypertension (38/22 mm hg), systemic venous hypertension (central venous pressure, 20 to 22 mm hg), and mixed venous desaturation (myocardial oxygen consumption, 50% to 52%) persisted. in an attempt to control the right ventricular failure due to increased pulmonary vascular resistance, inhaled no was restarted (second trial). using 40 ppm of inhaled no, the hemodynamics temporarily stabilized (systemic pressure, 63/42 mm hg; pulmonary pressure, 28/14 mm hg; central venous pressure, 18 mm hg; and myocardial oxygen consumption, 61%), but metabolic acidosis and oliguria persisted. given the evidence of left ventricular dysfunction at tee, despite maximal inotropic support, ecmo support was restarted 6 hours after surgical repair. on this occasion, it was felt that both pulmonary hypertension and left ventricular ``deconditioning,'' due to preoperative total cardiopulmonary bypass, were responsible for the hemodynamic deterioration.

Discontinuation of ECMO was achieved after 6 days of support, using high-dose inotropic support (dopamine, 8 µg • kg^-1 • min^-1; dobutamine, 10 µg • kg^-1 • min^-1; and epinephrine, 0.05 µg • kg^-1 • min^-1) and inhaled no (third trial). indications for no therapy were persistence of mild pulmonary hypertension (32/16 mm hg) and, more importantly, profound arterial desaturation (sao₂, 65%), thought to be due to pulmonary microatelectasis and edema resulting in ventilation/perfusion mismatch. improvement in sao₂ (86% to 89%) and decrease in pulmonary arterial pressure (24/15 mm hg) were observed using 10 ppm of inhaled no. delayed sternal closure was possible 3 days after restarting the no therapy and 8 days after the aso. support with no at 10 ppm was prolonged for 10 days, until clinical (arterial oxygen tension from 34 to 94 mm hg) and radiologic improvement of the adult respiratory distress syndrome was obtained.

After weaning from the NO therapy, the patient's recovery progressed slowly but steadily; extubation was possible on postoperative day 41 and transfer from the intensive care unit 2 days later. The infant was discharged on postoperative day 51 in good clinical condition on oral digitalis and furosemide therapy. A follow-up echocardiogram 4 months after discharge showed good biventricular function and normal geometry of the ventricular septum, suggesting less than half systemic pulmonary artery pressure.

PATIENT 2.
The patient was a full-term female infant, cyanotic at birth, diagnosed with TGA/IVS, who, after a first unsuccessful BAS, was transferred to our hospital for further medical and surgical management (Fig 2). Shortly after admission, she underwent a second BAS, which resulted in creation of a large interatrial communication. The patient remained profoundly cyanotic (upper limb pulse oxymeter SaO₂, 35% to 50%; lower limb, 55% to 65%) despite full mechanical ventilatory support under neuromuscular blockade with narcotic (fentanyl, 5 µg • kg^-1 • min^-1) and pge₁ infusion (0.5 µg • kg^-1 • min^-1). Systemic hypotension (55/30 mm Hg), peripheral vasoconstriction, and metabolic acidosis (base excess, -8), were also present. A repeat echocardiogram showed an adequate-sized atrial septal defect but unidirectional shunt at the atrial and ductal level.

View larger version (19K): [in this window] [in a new window]   Fig 2. . Preoperative and postoperative clinical course of patient 2 and the response to nitric oxide (NO). (ASO = arterial switch operation; BE = base excess; PAP = pulmonary arterial pressure; SaO2 = arterial oxygen saturation; SAP = systemic arterial pressure.)

Recovery of the patient was slowed by repeated episodes of aspiration of gastric contents, due to gastroesophageal reflux, and respiratory failure, due to coexistent bronchopulmonary dysplasia, resulting in intermittent need for ventilatory support. Transthoracic echocardiography 1 month after the ASO showed brisk biventricular function with no flattening of the ventricular septum, suggesting normal pulmonary artery pressure. The further clinical course of the patient was complicated by multiple episodes of sepsis, the last of which resulted in irreversible hepatic and renal failure, ultimately leading to death of the infant 4 months after the successful ASO.

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
The analysis of a decade of surgical experience with the ASO for transposition of the great arteries has shown very low (2% to 5%) early mortality and negligible late mortality [1, 2]. Our early results with 45 neonates undergoing this operative procedure continue to support this treatment modality. The wider application of the BAS and the earlier timing of anatomic repair, as well as the evolution of preoperative and postoperative intensive care and surgical techniques, have been responsible for the improved survival and quality of life after the ASO. However, there remain anatomic, a few physiologic, and procedural variables that have been identified as incremental risk factors for perioperative morbidity and mortality [1, 2]. Among such factors, the rare association of TGA with persistent fetal circulation, responsible for neonatal pulmonary hypertension, has been shown to be extremely unfavorable [3–5].

The exact prevalence of TGA/IVS/PHT is not well established. Review of the scattered reports of affected patients suggests that 1% to 3% of all neonates with TGA/IVS will present with persistent fetal circulation [1, 3, 4]. The pathologic substrate of TGA/IVS/PHT has been shown to be the increased thickness of the wall of the pulmonary arterioles (<150 µm diameter), due to extension of smooth muscle to the peripheral vessels [3, 5]. Based on experimental evidence, intrauterine hypoxia has been proposed as one mechanism accounting for the increase in distal muscularity [3]. The pathophysiology of TGA/IVS/PHT is rather complicated. Although infusion of PGE₁ (initially) and creation of a large interatrial communication by means of a BAS (subsequently) seem rational in a neonate presenting with TGA/IVS and profound cyanosis, inability of the patient to improve after these maneuvers is to be expected in the presence of PHT [4, 5]. Due to the increased atrial and ductal anatomic right-to-left shunting promoted by BAS and PGE₁ infusion, the amount of blood bypassing the pulmonary circulation increases, making the systemic oxygen desaturation more profound [5].

Analysis of the overall experience with the management of TGA/IVS/PHT underlines the uniformly poor response to PGE₁ infusion and BAS alone, with half of the reported patients requiring multiple septotomies or surgical septectomy (Table 1). In addition, hemodynamic instability persisted in the majority of patients, leading to death before surgical repair or to the need for emergent physiologic repair using the ASO (see Table 1). Although application of the atrial switch procedure to neonates with TGA/IVS/PHT has proved unsuccessful [3–5], more recent attempts at preoperative stabilization of these critically ill infants and early anatomic repair with the ASO have yielded encouraging results (5) (see Table 1). In an analysis of 2 such cases, Chang and associates [6] recommended use of BAS to increase O₂ delivery and narcotic anesthesia with neuromuscular blockade to reduce O₂ consumption as first-line measures to improve the hemodynamics. Control of the pulmonary vascular resistance by alkalinization (hyperventilation, sodium bicarbonate infusion) or by infusion of vasodilators (PGE₁) was also advised to further ameliorate the circulatory instability. Despite these maneuvers, however, the 2 neonates reported continued to show intermittent crises of profound desaturation and systemic hypotension until the time of the ASO [6].

Even though the ultimate outcome of 1 infant was compromised by the presence of associated lesions [2], the present experience validates the use of inhaled NO and ECMO to achieve preoperative and postoperative control of PHT. With the above treatment modality, both neonates underwent a successful repair with the ASO and showed echocardiographic evidence of normal pulmonary pressure 2 to 3 weeks after operation.

In conclusion, PHT due to persistent fetal circulation should be suspected whenever profound cyanosis persists despite PGE₁ infusion and successful BAS in neonates with TGA/IVS. We recommend preoperative and postoperative stabilization with inhaled NO combined with early anatomic surgical repair by means of the ASO. Extracorporeal membrane oxygenation support may be needed when PHT is associated with severe ventricular dysfunction.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
Address reprint requests to Dr Luciani, Division of Cardiovascular Surgery, University of Verona, OCM Piazzale Stefani 1, Verona, 37126, Italy.

	References

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 

1. Wernovsky G, Mayer JE, Jonas RA, et al. Factors influencing early and late outcome of arterial switch operation for transposition of the great arteries. J Thorac Cardiovasc Surg 1995;109:289–302.[Abstract/Free Full Text]
2. Kirklin JW, Blackstone EH, Tchervenkov CI, Castañeda AR, Congenital Heart Surgeon Society. Clinical outcomes after the arterial switch operation for transposition. Patient, support, procedural, and institutional risk factors. Circulation 1992;86:1501–15.[Abstract/Free Full Text]
3. Dick M, Heidelberger K, Crowley D. Quantitative morphometric analysis of the pulmonary arteries in two patients with D-transposition of the great arteries and persistent fetal circulation. Pediatr Res 1981;15:1397–401.[Medline]
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.[Abstract/Free Full Text]
6. Chang AC, Wernovsky G, Kulik TJ, Jonas RA, Wessel DL. Management of the neonate with transposition of the great arteries and persistent pulmonary hypertension. Am J Cardiol 1991;68:1253–5.[Medline]
7. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;2002-12.
8. Di Donato RM, Fujii AM, Jonas RA, Castañeda AR. Age-dependent ventricular response to pressure overload. Considerations for the arterial switch operation. J Thorac Cardiovasc Surg 1992;104:713–22.[Abstract]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Giovanni Battista Luciani Vaughn A. Starnes Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Luciani, G. B. Articles by Starnes, V. A. Search for Related Content PubMed PubMed Citation Articles by Luciani, G. B. Articles by Starnes, V. A.