Physiologic and anatomic considerations

The discordant relationship between the ventricles and great arteries in d-transposition of the great arteries creates parallel systemic and pulmonary circulations. This results in significant systemic hypoxaemia due to ineffective delivery of blood to the pulmonary circulation for oxygenation and increased cardiac workload.

The degree of hypoxaemia in d-transposition of the great arteries is dependent on the presence and patency of intercirculatory communications. These communications may be intracardiac – patent oval foramen, atrial septal defect, or ventricular septal defect – or extracardiac – patent arterial duct or bronchopulmonary collaterals. Effective systemic and pulmonary blood flow is dependent on the presence of the aforementioned communications and should be considered in the context of the following principles:Reference Wernovsky ⁸

• • Anatomic left-to-right shunting (effective systemic blood flow): net blood flow entering the systemic circulation from the pulmonary circulation;

• • Anatomic right-to-left shunting (effective pulmonary blood flow): net blood flow entering the pulmonary circulation from the systemic circulation;

• • Physiologic left-to-right shunting: volume of recirculating pulmonary venous blood flow;

• • Physiologic right-to-left shunting: volume of recirculating systemic venous blood flow.

The amount of intercirculatory mixing is the volume of anatomic left-to-right shunting (effective systemic blood flow), which is equal to the volume of anatomic right-to-left shunting (effective pulmonary blood flow).

Several anatomic considerations should be borne in mind when evaluating infants with d-transposition of the great arteries with respect to intercirculatory mixing and effective flow of blood. Infants with d-transposition of the great arteries and a ventricular septal defect may present with mild cyanosis due to increased intercirculatory mixing and may also present with signs of increased pulmonary blood flow and congestive cardiac failure. However, the presence of a ventricular septal defect does not ensure adequate intercirculatory mixing and these patients may still require pre-operative interventions to establish effective mixing.

Conversely, infants with d-transposition of the great arteries and an intact ventricular septum normally present with significant cyanosis early after birth. This is secondary to decreased intercirculatory mixing, which typically requires early intervention to establish adequate intercirculatory mixing. It should be noted, however, that a large patent arterial duct in this cohort of patients may confuse the clinical picture as increased pulmonary blood flow in this intercirculatory shunt will blunt the degree of cyanosis and mimic the clinical course of those with increased pulmonary blood flow. An example of this case and intentional restriction of the arterial duct was reported by Masutani et al.Reference Masutani, Seki, Taketazu and Senzaki ⁹ In d-transposition of the great arteries with obstruction of the left ventricular outflow tract obstruction – restricted effective pulmonary blood flow – the degree of cyanosis can be amplified and may not be affected by the degree of intercirculatory mixing due to a fixed restriction of pulmonary blood flow. If right ventricular outflow tract obstruction – restricted effective systemic blood flow – is present, pulmonary blood flow and oxygenation may be adequate but the infant will suffer from systemic hypoperfusion.

Pre-operative management

The pre-operative management of d-transposition of the great arteries focuses on ensuring adequate systemic perfusion and oxygen delivery that is dependent on adequate mixing of the systemic and pulmonary circulations. Depending on the initial presentation of the infant, all emergent resuscitative measures should be addressed immediately following standard neonatal advanced life support algorithms. Umbilical arterial and venous lines may be helpful for close surveillance of haemodynamics, acid–base status, and medication administration. Following stabilisation, prompt, directed cardiac evaluation starting with echocardiography should be initiated, especially for the cyanotic infant. Accordingly, in cases in which a prenatal diagnosis is available, it is preferable to deliver these infants in or near a surgical referral centre.Reference Hellstrom-Westas, Hanseus and Jogi ¹⁰

Initiation of prostaglandin E1 may temporarily improve severe cyanosis by improving intercirculatory mixing – effective systemic and pulmonary blood flow – at the level of the arterial duct. Infusion of prostaglandin E1 can be initiated immediately after birth while awaiting completion of diagnostic studies or during transfer to a surgical centre. Once a diagnosis of d-transposition of the great arteries is confirmed, the prostaglandin E1 infusion can be discontinued if there is adequate mixing at the atrial or ventricular level. In the case of intact ventricular septum, prostaglandin E1 is usually infused until balloon atrial septostomy, or, in some cases, until surgery. Factors predictive for the successful discontinuation of prostaglandin E1 after balloon atrial septostomy in infants with intact ventricular septum have yet to be determined.Reference Oxenius, Hug and Dodge-Khatami ¹¹ Pre-operative duration of prostaglandin E1 infusion has not been associated with adverse effects in post-operative outcomes.Reference Butts, Ellis and Bradley ¹²

Risks associated with prostaglandin E1 include apnoea, fever, and vasodilation (hypotension). In addition, long-term exposure to prostaglandin therapy has been associated with an increased incidence of pyloric stenosis. Although the risk of apnoea is of significant consequence, the administration of aminophylline or caffeine may ameliorate this risk.Reference Lim, Kulik and Kim ¹³ Elective intubation for infants being transported on prostaglandin E1 has been shown to be associated with an increased risk of major transport complications that outweigh any potential benefit.Reference Meckler and Lowe ¹⁴ In addition, shunting across the patent arterial duct may adversely increase pulmonary blood flow and cause symptoms related to pulmonary congestion. It should be noted, however, that mixing at the patent arterial duct alone may not be sufficient and that continued cyanosis may persist in the presence of a restrictive atrial septal defect.

Restriction to mixing at the atrial septum, particularly in infants with a patent arterial duct, may require prompt balloon atrial septostomy to relieve profound cyanosis until definitive surgical treatment can be performed. Recently, Punn and SilvermanReference Punn and Silverman ¹⁵ found that prenatal echocardiographic findings of a hypermobile atrial septum and reverse diastolic patent arterial duct flow were predictive of the need for balloon atrial septostomy. This percutaneous procedure may be performed under echocardiographic guidance at the bedside in an intensive care unit or under fluoroscopy in a cardiac catheterisation laboratory.Reference Martin, Rigby, Penny and Redington ^{16 ,} Reference Zellers, Dixon and Moake ¹⁷ The safety of balloon atrial septostomy with regard to brain injury has been debated. McQuillen et alReference McQuillen, Hamrick and Perez ¹⁸ published data on a series of infants with increased rates of brain injury associated with balloon septostomy. However, more recent data have shown balloon atrial septostomy to be safe and not related to pre-operative brain injury.Reference Petit, Rome and Wernovsky ^{19 –} Reference Applegate and Lim ²¹ In fact, in the series by Petit et alReference Petit, Rome and Wernovsky ¹⁹ , failure to achieve a pre-operative arterial oxygen content >40 mmHg was associated with brain injury. Although balloon atrial septostomy may be required in centres that cannot perform an immediate arterial switch operation, there are new data reporting successful arterial switch operation in the first few hours of life in infants, including those with intact ventricular septum and restrictive patent oval foramen.Reference Nevvazhay, Chernogrivov and Biryukov ^{22 ,} Reference Chasovskyi, Fedevych and Vorobiova ²³

Changes in pulmonary vasculature may result in persistent primary pulmonary hypertension of the newborn in infants with d-transposition of the great arteries. This finding is more frequent in uncorrected, older infants with advanced pulmonary disease, but may occur earlier in those with intact ventricular septum and a patent arterial duct.Reference Newfeld, Paul, Muster and Idriss ²⁴ The development of pulmonary vascular disease is most likely multi-factorial, resulting from increased pulmonary blood flow, pressure, and hypoxia. Mortality is high in this group of infants and mid-term post-operative outcomes are adversely affected.Reference Fan, Hu and Zheng ^{25 ,} Reference Roofthooft, Bergman and Waterbolk ²⁶ A number of medical management strategies have been proposed including the use inhaled nitric oxideReference El-Segaier, Hellstrom-Westas and Wettrell ²⁷ and bosentan.Reference Goissen, Ghyselen and Tourneux ²⁸ Successful surgical management utilising inhaled nitric oxide in conjunction with extracorporeal membrane oxygenation pre-operatively has also been reported.Reference Jaillard, Belli and Rakza ^{29 ,} Reference Luciani, Chang and Starnes ³⁰

Post-operative management

Several anatomic and physiologic factors influence the post-operative management and intensive care unit course after the arterial switch operation for d-transposition of the great arteries. Such factors may include low cardiac output syndrome, abnormal left ventricular compliance, mitral regurgitation, left atrial hypertension, and coronary ischaemia.

Post-operative low cardiac output syndrome was classically described in this patient populationReference Wernovsky, Wypij and Jonas ³¹ and can be due to a number of causes after the arterial switch operation. Similar to other cardiac operations requiring cardiopulmonary bypass and circulatory arrest, suboptimal myocardial preservation, mechanical disruption of the myocardium, and the post-inflammatory effects of bypass should be considered. Unique to the infant with d-transposition of the great arteries, especially in the setting of an intact ventricular septum and delayed surgical intervention, is an untrained left ventricle that must now perform against systemic afterload. This predisposes the infant to declining left ventricular function, which may result in increasing mitral regurgitation. Ultimately, increased left atrial pressure develops, putting the infant at risk for increased pulmonary venous pressure. Standard monitoring including urine output, heart rate and blood pressure trends, mixed venous saturation, and serial lactate measurement can help alert the practitioner to declining cardiac output.

Management of low cardiac output during the post-operative period varies depending upon the physiologic state of the infant. Successful management is often achieved by developing a low-pressure, high-flow state as the left ventricle adapts to the demands of systemic afterload. Inotropic agents such as milrinone, epinephrine, or calcium can be titrated accordingly to help improve cardiac output while systemic afterload reduction can be achieved with alpha blockade – phenoxybenzamine or phentolamine – milrinone, and nitroprusside. During resuscitation, volume must be used with caution owing to the possibility of left atrial distension, high left atrial pressure, mitral regurgitation, and ventricular dysfunction. In situations where adequate haemodynamics cannot be achieved, a brief period of extracorporeal membrane oxygenation may be required to allow for ventricular recovery or surgical revision of any residual anatomic defects. Lastly, the pre-operative administration of steroids has been shown to mitigate the inflammatory effects of cardiopulmonary bypass while providing myocardial protection.Reference Heying, Wehage and Schumacher ^{32 ,} Reference Schroeder, Pearl and Schwartz ³³

A vital component of the atrial switch operation includes implantation of the coronary arteries into the neo-aorta. Therefore, vigilant monitoring and heightened awareness for signs of coronary insufficiency is of utmost importance. An immediate post-operative electrocardiogram should be obtained and compared against a pre-operative electrocardiogram. In the event of coronary insufficiency, nitroglycerin may be used; however, echocardiography and/or coronary angiography should be performed immediately to better delineate coronary anatomy, as surgical revision may be required.

Pre-operative management

Patients with common arterial trunk have functionally univentricular physiology and typically present clinically on the basis of the degree of pulmonary blood flow restriction. Patients presenting with cyanosis will likely have increased resistance in the pulmonary circulation secondary to pulmonary artery stenosis, pulmonary artery hypoplasia, or persistently elevated pulmonary vascular resistance. Patients with well-balanced pulmonary-to-systemic blood flow will likely not present until pulmonary vascular resistance falls. Those patients will then present with cardiac failure symptoms secondary to left ventricular volume overload and resultant pulmonary vascular congestion. Neonates who present in early cardiac failure or cardiogenic shock may have severe truncal valve stenosis or insufficiency.Reference Russell, Pasquali and Jacobs ^{36 ,} Reference Elzein, Ilbawi and Kumar ³⁷ Common arterial trunk has been independently associated with necrotising enterocolitis in term neonates with congenital heart disease admitted to the cardiac intensive care unit.Reference McElhinney, Hedrick and Bush ⁴³ This is thought to be secondary to relative ischaemia of the gut due to excessive pulmonary blood flow resulting in insufficient systemic blood flow. Feeding intolerance and abdominal distension should be closely monitored for and promptly responded to with a low threshold to discontinue feedings. Neonates that develop necrotising enterocolitis but are identified early may not have increased mortality; however, it has been shown to significantly increase their hospital stay.Reference McElhinney, Hedrick and Bush ⁴³

Management of patients with 22q11.2 deletion syndrome in the critical care setting includes recognition of potential airway issues, feeding intolerance, immunodeficiency, and electrolyte abnormalities. Endotracheal intubation in these patients may be potentially difficult given their relative microstomia and retrognathia. In addition, laryngotracheomalacia may be present in these infants, and as surgery typically occurs at an early post-natal age this may complicate extubation. Vascular rings formed by a right aortic arch and aberrant left subclavian artery with left-sided ligamentum arteriosum can present with stridor and wheezing and should be assessed on pre-operative non-invasive imaging.Reference McElhinney, McDonald-McGinn and Zackai ⁴⁴ Feeding issues secondary to palatoschisis – cleft palate – and velopharyngeal incompetence should be anticipated in this patient population and an age-appropriate feeding plan should be formulated early. Given the increased risk of infectious complications secondary to T-cell immunodeficiency and hypogammaglobulinaemia, it is important that these patients receive irradiated blood products.Reference McDonald, Dodgen and Goyal ⁴⁵ In addition, immunologic evaluation by a Paediatric Allergy/Immunology specialist may be necessary in the peri-operative period as prophylactic antibiotics may be warranted. Knowledge of additional associated anomalies of 22q11.2 deletion syndrome, including renal anomalies, anal atresia, and tethered cord syndrome, is also important.

Post-operative management

Post-operative physiology of common arterial trunk depends on the extent of the repair and the degree of residual lesions. Post-operative management must also account for the detrimental effects of cardiopulmonary bypass resulting in alterations of pulmonary and systemic vasculature resistance and myocardial dysfunction. Low cardiac output syndrome following cardiopulmonary bypass is common and of significant concern.Reference Hoffman, Wernovsky and Atz ⁴⁶ Depressed myocardial function following cardiopulmonary bypass is commonly treated with vasoactive infusion support. Contributing to the difficulty in post-operative management is right ventricular diastolic dysfunction. This can result from cardiopulmonary bypass-induced injury, ventriculotomy-related injury, or elevated pulmonary arterial pressure, which results in insufficient preload of the right ventricle. In the absence of an atrial communication, the patient will subsequently develop low cardiac output owing to insufficient preloading of the left ventricle. Placement of a left atrial line to allow closer monitoring for pulmonary arterial hypertension and associated crises should be considered, particularly in patients with higher risk for morality. Agitation secondary to pain may trigger a life-threatening pulmonary hypertensive crisis; therefore, it is imperative to maintain adequate sedation and paralysis for the first 24 to 48 hours after repair. Maintaining a relative metabolic alkalosis and keeping the patient relatively normocapnic will lead to pulmonary arterial bed vasodilation and decreased pulmonary vascular resistance. In addition, inhaled nitric oxide can be used to decrease pulmonary vascular resistance, and delayed sternal closure can be used when needed until pulmonary vascular resistance recovers. Extracorporeal membrane oxygenation may be necessary for significant low cardiac output syndrome and/or pulmonary hypertension.

The most likely complication in critically ill neonates with 22q11.2 deletion syndrome is hypocalcaemia. Post-operative hypocalcaemia has been reported to occur in as high as 86% of patients with 22q11.2 deletion syndrome compared with 47% of patients without the deletion. A comparison of the two groups of patients with 22q11.2 deletion showed that those with post-operative hypocalcaemia were more likely to have significant complications and mortality.Reference Shen, Gu and Wang ⁴⁷ In addition, neonatal myocardium is more dependent on exogenous calcium because of an immature sarcoplasmic reticulum. Therefore, hypocalcaemia will have a greater effect on cardiac function, cardiac rhythm, and vasomotor tone in these patients, and more frequent monitoring of ionised calcium should be performed in post-operative neonates with 22q11.2 deletion.