Mechanical Valves

Significant progress has been made with mechanical valves since the introduction of the first mechanical valve in 1952. Currently manufactured mechanical valves have either a single tilting disc, such as the Medtronic Hall Valve, or a bileaflet design, such as the St. Jude (St. Jude Medical, St. Paul, MN), Carbomedics (Austin, TX), ATS (ATS Medical, Minneapolis, MN), or On-X Valves (Medical Carbon Research, Austin, TX) ( Fig. 13-8 A). Structural failure of prosthetic valves is currently rarely reported. To date, all mechanical valves are thrombogenic, and necessitate anticoagulation. As a result, patients with mechanical valves are at risk for thromboembolic and bleeding complications. The risk of such complications is present, even in patients with optimally managed anticoagulation, and is influenced by factors specific to the patient, along with the position of the valve.

A, A typical bileaflet mechanical valve. Such valves are at risk for thromboembolic complications and anticoagulation is necessary. B, Adherent thrombus in an explanted valve.

(Reproduced with permission from St. Jude Medical, Inc., St. Paul, Minnesota.)

In adults, the incidence of thromboembolic complications among patients with a mechanical valve in the aortic position varies between 1.4 to 2.7 per patient per year, and bleeding complications between 0.7 and 2.3 per patient per year. ⁷³ The risk of these complications with mechanical valves in the aortic position in children is less well known. In one report, the freedom from thromboembolic complications after 20 years was 93%. ⁷⁴ Another series reported no episodes of thromboembolic complications, and only one incident of anticoagulation-related haemorrhage at a mean follow-up of 12 ± 6 years. ⁷⁵ Although these two reports suggest that replacement of the aortic valve with mechanical prostheses in children has a low risk of anticoagulation-related complications, they summarise only relatively small experiences from single centres. The true risk probably falls between these reports and the larger adult experience.

The risk of complications related to anticoagulation is greatest for mechanical valves placed in atrioventricular position in the systemic circulation. Three separate reports summarising individual institutional experiences in children totaling 115 patients reported 10-year freedom from thromboembolic complications above 92%, and the risk of complications related to bleeding at between 76% and 97%. ^76–78 The true incidence of thromboembolic complications in children undergoing replacement of the mitral valve with a mechanical prosthesis is probably underestimated by those reporting from single centres. A multi-centre study found that 4 of 102 survivors of such replacement required re-replacement for thrombosis at a mean follow-up of 6.0 years. ⁷⁹ Prospective studies of adults, with combined enrollment of over 1000 patients, showed that bileaflet mechanical valves in the mitral position were associated with an incidence of both thromboembolic events and complications due to bleeding at a frequency between 1% and 3% per patient per year. ^80,81 Freedom from thromboembolic complications after 10 years was 85.5%, and freedom from bleeding was 81.7%. ⁸⁰

The most widely used prosthetic valve of the last decade is the St. Jude valve ( Fig. 13-8 B). It is a low profile, bileaflet valve constructed of pyrolytic carbon. In its most recent iteration, it has a rotatable valvar mechanism. Competing bileaflet designs include the ATS, On-X, and Carbomedics valves. There has been considerable interest of late in the potential of utilising the On-X valve with aspirin as the only anti-thrombotic agent. The manufacturer claims that the lack of silicon coating on the carbon used to construct the valve makes it less thrombogenic. Controlled trials are underway to evaluate the risk of thromboembolic complications using only an antiplatelet strategy with the On-X valve.

Another major problem with mechanical valves when used in children is the limited availability of small sizes. Modifications of the sewing ring of the 19-mm Carbomedics and the 19-mm St. Jude valve have resulted in prosthetic valves that can accommodate a native annulus between 16 and 18 mm. Oftentimes, there is insufficient orifice for placement of even the smallest valve designed. Surgical techniques of annular enlargement, such as the anterior enlargement of Konno, ⁸² or the posterior enlargement of Nicks ⁸³ or Manougian ^84,85 are used when the diameter of the native aortic root does not permit placement of a valve sufficiently large to meet the haemodynamic needs of the patient. In the mitral position, the anatomy does not lend itself as well to annular expansion. Other techniques must be utilised. Valves can be placed in the supra-annular position, or at angles, techniques that can permit placement of modestly larger prosthesis. Significant oversizing of mitral prostheses should be avoided, as this can result in subaortic obstruction.

Xenobioprosthetic Valves

Xenobioprosthetic valves include porcine aortic valves, either stented, as in the Hancock and Mosiac Valves (Medtronic, Minneapolis, MN) ( Fig. 13-9 ), or nonstented, as in the Freestyle (Medtronic, Minneapolis, MN), Toronto SPV valve (St. Jude Medical, St. Paul, MN) and valves manufactured from bovine pericardium such as the Perimount valve (Edwards Life Science, Irvine, CA). ^86,87 Xenobioprosthetic material has been treated with glutaraldehyde in order to decrease immunogenicity and improve durability. In children, xenobioprosthetic valves undergo rapid calcific degeneration, limiting their use in the systemic circulation. ⁸⁸ Recent efforts have been directed at newer techniques for preservation that limit this process of calcification. ⁸⁹ Xenobioprosthetic valved conduits have been used for apicoaortic conduits for relief of obstruction of the left ventricular outflow tract, and in other rare circumstances where anticoagulation must be avoided, but in general xenobioprosthetic valves are rarely used in children in the systemic circulation.

A, A typical xenobioprosthetic stented porcine valve. B, Such valves, when inserted in children, undergo rapid calcification and degeneration.

( A, Reproduced with permission from Edwards Lifesciences, Irvine, California.)

Homograft Valves

Valved homograft material can also be used for valvar replacement and reconstruction ( Fig. 13-10 ). The homograft is considered the conduit of choice for replacement of the aortic valve and aortic root in the face of endocarditis. ^90–95 Small homograft valved conduits are ideal for complex reconstruction in neonates and small infants, such as repair of common arterial trunk, and tetralogy of Fallot with pulmonary atresia. In North America, however, homografts in sizes suitable for neonates and small infants are becoming less and less available. The use of homografts to join the right ventricle to the pulmonary arteries is discussed more fully when considering selection of valves.

Aortic ( A ) and pulmonary ( B ) homografts. The valves are harvested along with a segment of the outflow tract and varying lengths of artery.

(Reproduced with permission of Cryolite, Inc., Kennesaw, Georgia.)

Pulmonary Autograft Valves

The pulmonary autograft used for replacement of the aortic valve (the Ross procedure) addresses some of the limitations in other options, and involves the harvest of the native pulmonary valve for replacement of the aortic valve. ⁹⁶ The native outflow tract from the right ventricle is then reconstructed with another conduit, usually a homograft. The pulmonary autograft is frequently chosen for infants and small children. Although the autograft does allow for growth, late dilatation of the neoaortic root with resultant aortic insufficiency has been identified in a subgroup of patients undergoing the Ross procedure. At least two mechanisms resulting in regurgitation appear to explain dysfunction of the autograft. Patients undergoing the Ross procedure for isolated aortic incompetence have been shown to have an increased risk for development of incompetence, primarily due to dilation of the left ventriculo-aortic junction. Patients undergoing the Ross procedure for congenital aortic stenosis have an increased incidence of ascending aortic dilation, with dilation of the sinutubular junction that also results in aortic insufficiency. Efforts to limit development of autograft dilation and insufficiency include the use of annuloplasty sutures, and placement of the autograft within a Dacron tube graft. ^97,98 Both of these techniques limit the potential for growth, and are only suitable in older patients.

The autograft compares favourably to other options for replacing the aortic valve in children, but concern persists over long-term durability. In 150 patients under the age of 21 years, freedom from autograft failure of 84% ± 4%, and freedom from all valve-related complications of 72% ± 6%, were reported at 8 years. ⁹⁹ Other series from Western Europe and North America, in which it is possible to differentiate the outcome for children, report freedom from reoperation of 83% to 88% at 5 to 6 years of follow-up. ^100–103 The long-term outlook of the pulmonary valve when used to replace the aortic valve remains unknown. Data from the Ross Procedure International Registry shows that the freedom from reintervention curve does not reach a plateau, and it seems likely that many of these patients will require additional procedures directed at the neoaortic valve, as well as the predictable need for reintervention on the right ventricular outflow tract. Although it is generally acknowledged that the pulmonary homograft placed during the Ross procedure has greater longevity than that used for reconstruction of the right ventricular outflow tract for other forms of congenital cardiac disease, presumably due to the orthotopic position, normal pulmonary arteries and pulmonary vascular resistance, recent data indicate that replacement still will be necessary. ^104,105 Additional studies have indicated that even a mild, and apparently acceptable, gradient across the right ventricular outflow tract will increase importantly during exercise, and that exercise-induced arrhythmias are common following the Ross procedure. ¹⁰⁶

Selection of Valves

No consensus has been reached on selection, but some generally accepted guidelines are presented. For use in the aortic position in neonates, infants and small children, the Ross procedure is commonly chosen, because it accommodates growth and anticoagulation is not required. Furthermore, the size of the autograft matches the size of the normal left ventricular outflow tract, and lesser degrees of enlargement of the aortic root are required compared to mechanical valves. Homografts can be used in the aortic position in infants and small children, either as a first choice, or if the pulmonary valve is deemed unsuitable for use in the aortic position. For older children, some continue to advocate the Ross procedure, although mechanical valves are also frequently used. Xenobioprosthetic valves within valved conduits have been used as conduits from the left ventricular apex to the aorta for relief of severe and complex obstruction in the left ventricular outflow tract.

Mechanical valves are generally used for the mitral (or systemic atrioventricular junction) position. Despite the need for anticoagulation, these valves have the necessary durability. Mortality after such replacement continues to be high in younger children. Results, however, seem to be improving, with one study showing reduction in operative mortality from 31% to 3.6% when comparing children receiving operations at the same institution before and after 1990. ⁷⁶ A recent report showed an early mortality rate of 13% in children under 2 years of age undergoing replacement of the mitral valve, ¹⁰⁷ a figure to be compared with a mortality rate as high as 52% in a report from 1990. ¹⁰⁸ Xenobioprosthetic valves are rarely used in the mitral position due to the high rates of calcification and failure. ^109,110 Exceptions can be made, however, in extreme circumstances, such as haematological disorders or pregnancy, when the need to avoid anticoagulation is more definitive. There are advocates for the use of the pulmonary autograft in the mitral position, a procedure now known as the Ross II. ¹¹¹ The autograft is placed within a Dacron tube graft. Although the viability may be good, and the need for anticoagulation diminished, there is no potential for growth. There has been some success in children, ¹¹² but follow-up is limited. ¹⁰⁴ More studies will be necessary to determine the long-term success of this technique.

For reconstruction of the right ventricular outflow tract, biologic valves including homograft valved conduits, and xenobioprosthetic valves, are most commonly used. Biologic valves have longer durability in the lower pressured pulmonary position compared to any position in the systemic circuit, favouring the use of biologic over mechanical valves. Furthermore, the risk of anticoagulation is avoided. Homograft conduits have excellent handling qualities, conform to the anatomy, and facilitate achievement of haemostasis. Limited durability, however, can be a problem. Homografts are commonly used for reconstruction of the right ventricular outflow tract. Early valvar insufficiency and obstruction have been reported. ^113–115 In some children, homografts undergo severe calcification, with accompanying shrinkage, that can result in obstruction. Calcification appears to be more accelerated in younger children. ^{114,116–118} Incompatibility between donor and recipient have been proposed as contributing factors to this calcification and failure of the graft. ^{116,119–121}

An alternative to homografts is use of the bovine jugular venous conduit (Contegra, Medtronic, Minneapolis, MN) ( Fig. 13-11 ). The Contegra graft has been used in reconstruction of the outflow tract in patients with common arterial trunk, tetralogy of Fallot, the Ross procedure, and pulmonary atresia. ^122–127 Early and mid-term haemodynamic results are favourable, ¹²⁷ with one study showing valvar regurgitation to be absent in almost half of patients at a mean follow-up of 26 months. ¹²⁵ In the largest series reported to date, with a mean follow-up of 2.1 years, there was no relevant gradient detected at the level of the valves, and minimal valvar insufficiency. ¹²⁷ In the large prospective multi-centre study conducted by the Congenital Cardiac Surgeon’s Society, the bovine jugular vein fared well, with a lower probability of progressing to more severe forms of severe regurgitation than other types of conduit. ^128,129 Aneurysmal formation, ^113,130 and a particular tendency for distal stenosis, ¹²³ however, have been reported, though it is difficult at the current time to determine if these incidences are higher than those seen with homografts.

A, A bovine jugular vein graft. Note the tricuspid venous valve. B, The valve is contained within a length of jugular vein that can be tailored to the specific anatomic requirements of the patient.

(Reproduced with permission from Medtronic, Inc., Minneapolis, Minnesota.)

The use of small conduits is not surprisingly a risk factor for failure, ^115,131 but interestingly oversizing the valve by more than a z score of 2.7 has also been shown to be a risk factor for early failure. ¹³¹ This trend was confirmed in the study coordinated by the Society of Congenital Heart Surgeons, where outcomes were better when sizes with z scores between 1 and 3 were chosen. ¹²⁹

There is general agreement that a bioprosthetic valve is the conduit of choice in the tricuspid position when the native valve cannot be repaired. ^132,133 Bioprosthetic valves appear to fair better in this position than in any other position, with freedoms of reoperation reported at 97.5% ± 1.9%, and 80.6% ± 7.6%, at 1 and 5 years, respectively.

Valvar Repair

As discussed in the preceding section, options for replacement of valves are limited during childhood. Repair, if feasible, preserves the potential for growth, avoids anticoagulation, and also the need for valvar re-replacement. The disadvantages of repair include residual lesions, such as stenosis and insufficiency, and limited durability. Decision-making regarding the suitability of a lesion for repair is complex, and must take into account the pros and cons outlined above, as well as the specific lesion and the ability of the surgeon. Repair of the mitral valve is commonly performed, and uses techniques that borrowed from the experience in adults, as well as techniques that have been developed from repair of atrioventricular septal defects. Repair of the mitral valve is frequently successful and durable. ^134,135 In contrast, replacement of the mitral valve necessitates a repeated replacement in almost three-quarters of patients. ¹³⁶ Mitral valvopathy amenable to surgical intervention may be the result of rheumatic heart disease, acquired and congenital cardiomyopathies, Marfan’s disease, Shone’s complex, and congenital mitral stenosis. Techniques for repair vary depending on the aetiology of the pathology. ¹³⁵ For repair of mitral stenosis, techniques include commissurotomy, valvoplasty, cordal fenestration, and splitting of papillary muscles. For mitral insufficiency, techniques include repair of clefts, resection, shortening, or augmentation of leaflets, cordal shortening, annuloplasty, and creation of a double orifice. ¹³⁷ In general, mortality is low with repair in the setting of biventricular circulations. ^138–141 In those with a functionally univentricular circulation, in contrast, repair carries a higher mortality. ¹³⁵

Repair of the aortic valve is less well accepted than that of the mitral valve, albeit that experience is accumulating. ^142–148 Over the last decade, experience and success with repair have improved. ^146–149 Techniques include repair of valvar perforations, suspension of prolapsed leaflets, annuloplasty and extension of leaflets with pericardium. ¹⁴⁶ In particular extension of the leaflets has been used with success in patients with rheumatic aortic valve disease, with 90% of patients free from valvar related complications at 7 years. Extension has also been applied to patients with congenital pathology with improving results. ^150,151

Oxygenators

Hollow fibre membranes are manufactured to mimic the pulmonary capillary bed by packing together microporous fibres in a spiral fashion. ¹⁵⁸ Gas delivered to the oxygenator can be manipulated by the perfusionist to optimise oxygenation and removal of carbon dioxide. Anaesthetic vapours are commonly delivered via the membrane oxygenator, although the specific function for transfer of different vapours and oxygenators is variable. Surfaces exposed to the blood can be coated with some form of a biomimetic treatment. Several types of treatments are available, all having the goal of increasing the biocompatibility of the circuit, reducing damage to blood, and minimising the impact of bypass on the inflammatory response. ¹⁵⁷

Reservoirs

Two types of reservoirs are utilised, venous and cardiotomy. The former is a collection chamber only for the venous blood. The latter collects all shed blood returning from the operative field via cardiotomy suction and the left ventricular vent. Both reservoirs are filtered. The cardiotomy filters are designed to remove debris such as tissue, fat, macrothrombi and suture material. ¹⁵⁸ Many reservoirs are available that combine the venous and cardiotomy suction as a single unit. In this configuration, the separation of the chambers is made internally. After the filtration process, their volumes combine into a single outlet, which simplifies connections and permits visualisation of air and the level of fluid in the reservoir. According to the latest published survey, nine-tenths of paediatric institutions in North America use hardshell venous reservoirs. ¹⁵⁹

Pumps

Although many types of pumps have been described in the literature, there are primarily two types of arterial pumps in use today, namely roller and centrifugal. Roller pumps contain a length of tubing located inside a curved raceway. This raceway is placed at the travel perimeter of rollers mounted on the ends of rotating arms positioned opposite each other. These rollers are mounted in such a way that one roller is compressing the tubing at all times. By compressing a segment of the blood-filled resilient tubing, the pump pushes blood ahead of the moving roller, producing continuous flow. The output of the roller pump is determined by the revolutions per minute of the pump, and the volume displaced with each revolution. This stroke volume depends on the internal diameter of tubing and the circumferential length of the raceway. ¹⁶⁰ The roller pump head is reusable. The flow rate is simple to determine, by multiplying stroke volume by the revolutions each minute, and multiple sizes of tubing can be used in the same pump, making it applicable to patients of all sizes. These pumps, however, do have disadvantages. The pump displaces in positive fashion, so it will pump air as well as blood, necessitating the need for a system to detect bubbles. It is an occlusive pump, so pressure transducers must be connected to the system to detect excessive pressures, reducing the risk of particulate microembolisation from tubing spallation, shear-induced blood damage or possible rupture. Establishment of the optimal setting for occlusion is imperative for accurate calculation of rates of flow, and to minimise blood trauma.

Centrifugal pumps consist of an impeller arranged with either vanes or a nest of smooth plastic cones inside a plastic housing. The sterile, disposable impeller is coupled magnetically with an electric motor spinning in the drive console. When the impeller rotates rapidly, it generates a pressure differential, causing blood to flow. ¹⁶⁰ Centrifugal pumps are non-occlusive and pressure dependent. They generate increased flow when either the preload increases, or the afterload decreases. The non-occlusive nature of the pump eliminates the possibility of tubing wear, spallation, and excessive pressure in the lines, but since they are pressure dependent, a flow transducer is necessary to determine accurate rates of flow. If the pump slows or stops, reverse flow can occur. Centrifugal pumps require more expensive disposable parts compared to the roller pump. As a result of the described limitations of centrifugal pumps, a recent survey found that roller pumps were the predominant pump device in nine-tenths of paediatric centers. ¹⁵⁹

Filters and Haemoconcentrators

In addition to the cardiotomy and venous reservoir filters mentioned previously, all but 2% of paediatric institutions use arterial line filters as a last line of defense against gaseous and particulate microembolisation. ¹⁵⁹ They come in a variety of sizes, with pre-established limits to rates of flow. They require additional volume to prime, but are excellent gross bubble traps. Because they are micropore filters, they are susceptible to obstruction. Manufacturers recommend placing a clamped bypass line around them that can be opened if the filter becomes obstructed.

Haemoconcentrators allow the perfusionist to remove water and other electrolytes, such as potassium, from the blood. They contain hollow fibres similar to those within a dialysis filter. Blood passes through the inside of hollow fibres and light vacuum is placed on the outside. Everything smaller than the size of the pores of the semipermeable membrane will be extracted, including water, electrolytes, some cytokines and drugs, and everything larger than the pores will remain in the blood stream, including red cells, platelets and most plasma proteins. Significant haemoconcentration can be achieved. Some heparin will be removed; thus adequacy of heparinisation must be monitored regularly. ¹⁶⁰ The haemoconcentrator can be used at any time during the case, provided there is sufficient volume in the venous reservoir. This is the same type of filter used to perform modified ultrafiltration.

Rates of Flow

Although the determinants of delivery of oxygen, namely concentration of haemoglobin, saturation of oxyhaemoglobin and rates of flow, are more easily measured during cardiopulmonary bypass that at any other time in the life of a neonate or infant, the adequacy of delivery of oxygen should always be continuously monitored and adjusted to avoid overt or occult injury to the organs throughout the perioperative period. ^161,162 Rates of flow have typically been guided by nomograms based on body weight or surface area, and Fick’s principles of delivery of oxygen and metabolism. ¹⁶³ The regional distribution of blood during cardiopulmonary bypass is related to host and technical factors, and the probability of adequate flow to the whole body or organs is related to the total rate of flow. ^{162,164–167} Typically, full flow refers to a perfusion index of 2.8 to 3.6 L/m ² /min, which corresponds to 150 to 200 mL/kg/min in a neonate. Low flow is delivered at varying hypothermic conditions to afford metabolic protection and typically refers to rates of between one-quarter and half of full flow. ¹⁶⁷ The rates of flow to the whole body necessary to maintain adequate cerebral perfusion range from 30 to 80 mL/kg/min. ^168,169 Isolated perfusion of organs during bypass is governed by the relative distribution of vascular resistance. Reduction in temperature to 16° C to 20° C allows termination of flow for a limited amount of time to permit unobscured access to the surgical field, a condition referred to as deep hypothermic circulatory arrest . The safe duration of deep hypothermic circulatory arrest in any individual patient is unknown and highly related to the determinants of delivery of oxygen. ¹⁷⁰ The deleterious effects of lowered flow may be more pronounced after hypothermic arrest, ¹⁷¹ when a higher perfusion pressure is necessary to re-establish cerebral flow. ¹⁷² Because of variability between patients and techniques it is advisable to measure indicators of cerebral oxygenation. Manipulation of the independent determinants of delivery of oxygen, such as haemoglobin, and partial pressures of carbon dioxide, can be used to restore cerebral oxygen delivery. ¹⁷³

Haemodilution

Haemodilution has almost universally accompanied cardiopulmonary bypass because of the desire to prime extracorporeal circuitry with products other than blood. Rheologic considerations for microvascular flow during hypothermia have supported this approach, and are thought to outweigh the reduction in delivery of oxygen associated with the anaemia produced by haemodilution. The weight of evidence, however, supports limiting haemodilution in neonates and children, targeting a haematocrit of at least 30% even during deep hypothermia. ^174–176 While variations in prime solutions are mainly targeted at manipulation of electrolytes, oncotic pressure, and haemoglobin, the effects on prothrombotic, procoagulant and anticoagulant factors should also be recognised as important effects of haemodilution, and calculated based upon estimated blood volume and circuit volume for each patient.

Temperature Regulation

Hypothermia reduces both the cerebral metabolic rate and the availability of oxygen for transfer to the brain. The effects on cerebral metabolism are complex. The metabolism of brain and other tissue is reduced with reduction in body temperature. ¹⁷⁷ Most data suggests an inverse exponential relationship, with as much as a 3.5-fold reduction in metabolism for a reduction of 10°C in temperature, the so-called Q10. ¹⁷⁸ Others have found a Q10 as low at 2.3. ¹⁷⁹ The bulk of evidence suggests a nearly-inverse exponential reduction in metabolism is reduced by an average of 2.8 fold for a 10° C change in temperature. ¹⁸⁰ The result of metabolic suppression with hypothermia is that cerebral oxygen extraction is reduced, while flow of blood is allowed to be autoregulated, whether measured by saturations in the jugular bulb ^180,181 or near-infrared spectroscopy. ^182,183 Because temperature affects the solubility of oxygen and carbon dioxide in solution, and their interaction with haemoglobin, changes in temperature are coupled with changes in gas tensions and pH. In a broad range of studies, the independent effect of pH is small compared to the effect of temperature, with a small reduction in oxygen consumption in more acidotic environments. ¹⁸⁰ Because pH responsiveness of the cerebral vasculature remains in effect at hypothermia, however, control and manipulation of pH is a critical part of temperature management.

The coupling between cerebral metabolism and blood flow seems to be reasonably maintained in the temperature range of 32° C to 37° C. ^184–189 Below 30° C, however, uncoupling is commonly demonstrated, regardless of pH, such that the metabolism is reduced more than blood ^{181,190–192} The solubility of oxygen in plasma, and the affinity of haemoglobin for oxygen, are both increased with hypothermia, such that availability of oxygen in the tissues is reduced at any given rate of flow, the Bohr effect. The increased ratio of cerebral flow to metabolism with hypothermia is commonly viewed as cytoprotective from an energetic viewpoint, ¹⁸⁰ but the decreased availability of oxygen may negate this apparent metabolic protection. ^193,194 The result of increased solubility and leftward oxyhaemoglobin shift is that the fall in cerebral oxygenation with ischaemia is not attenuated by hypothermia, even though saturations of haemoglobin are better maintained. ¹⁹⁵ Altogether the cytoprotective effects of mild hypothermia exceed measurable metabolic effects and likely involve other mechanisms including alterations in gene expression. ¹⁹⁶

In practical terms, schemes for cooling are relatively standardised in most institutions. The complexity of the defect to be corrected or palliated dictates the strategy for the temperature used during bypass, albeit that compounding anatomic features such as the presence of aortopulmonary collateral arteries may influence the strategy. Typically, mild hypothermia, at 37° C to 32° C, will be employed for simple defects such as atrial and ventricular septal defects. Moderate hypothermia, between 32° C and 28° C, is used for more complex lesions such as atrioventricular septal defect or tetralogy of Fallot. Deep hypothermia, from 28° C down to 18° C, is reserved for the most complex lesions requiring a period of circulatory arrest, such as palliation of hypoplasia of the left heart, repair of interrupted aortic arch or correction of discordant ventriculo-arterial connections.

Acid-Base Management

The management of blood gases during cardiopulmonary bypass is intertwined with that of temperature and has been widely investigated and debated. The complexity ensues because metabolic rate, the solubility of gases in blood, the ionisation of water, and therefore the pH of electroneutrality, the ionisation of intracellular buffers, and the affinity of both oxygen and carbon dioxide for haemoglobin are all dependent on temperature. ¹⁹⁷ There are two strategies developed for management. A pH-stat strategy maintains normal levels of carbon dioxide and hydrogen ions when measured at hypothermia, or temperature corrected. An alpha-stat strategy maintains normal gas tensions and acid base balance when measured at normothermia, or temperature uncorrected. The alpha-stat approach is associated with minimal metabolic suppression, and represents the physiologic situation in homeotherms with temperature gradients across parts of the body, but with thermoregulation maintained. The pH-stat approach is associated with metabolic suppression, and more closely mimics the metabolic milieu of hibernation with induction of metabolic suppression. ¹⁹⁸

The pH affects the ratio of flow of blood to metabolism. ¹⁸⁵ While levels of adenosine triphosphate in the brain are maintained during alpha-stat cooling, ^183,199 with pH-stat cooling there is evidence of luxury perfusion. At temperatures below 30° C, blood flow is pressure-passive over a wider range of metabolism, with overperfusion evidenced by the appearance of oedema. ²⁰⁰ The increased flow with pH-stat strategy is widely utilised to increase uniformity of cerebral cooling, oxygenation ^{174,183,201–205} and metabolic suppression. ^182,197,205 There is evidence of improved outcome in children subjected to deep hypothermic circulatory arrest ^206–208 or low-flow bypass when using the pH-stat strategy. ^209–211 Evidence also exists for improved myocardial function with pH-stat techniques. ²¹² The effects of pH on non-cerebral tissue are also important in determining the distribution of flow on cardiopulmonary bypass. A pH-stat strategy directs more blood to the brain in the presence of aortopulmonary collateral connections. ¹⁷⁴ Approaches which combine pH-stat strategy for cooling with alpha-stat strategy for maintenance of high-flow hypothermic perfusion may represent a compromise between inadequate delivery of oxygen and metabolic suppression, and overperfusion-related formation of oedema and post-acidotic increased cerebrovascular resistance. ^181,213

Cerebral Protection and Anaesthesia

Suppression of cerebral consumption of oxygen occurs with both vapour and barbiturate-based anaesthesia, and hypoxia tolerance, based upon lactate production, is enhanced. ²¹⁴ The suppression of metabolism by anesthetic vapours is accompanied by maintenance of high energy phosphates, indicating desirable energetic balance. ²¹⁵ Because vapour agents are also cerebral vasodilators, the ratio of cerebral flow to metabolism is higher with these agents, and the increase in cerebral flow may be maintained for hours. ^216–218 Suppression of thermoregulatory ²¹⁹ responses to hypothermia may be an important role for the salutary effect of lower-stress anaesthetic strategies on survival in complex repairs. ²²⁰ Inhibition of K-ATP channels by vapours may induce preconditioning, reduce reperfusion injury and reduce apoptosis in ischaemic models. ^221–223 The vasodilatory effects of vapour anesthetics can be expected to improve the uniformity of cerebral cooling and warming. Withdrawal of anaesthetic vapour is likely to induce cerebral vasoconstriction in a fashion parallel to the vasodilation seen on acute introduction. Because the neonatal brain is particularly vulnerable to apoptosis via excitotoxic injury, vapour anesthetics might be particularly indicated. ^{222,224–227}

Pathways of Cerebral Injury Related to Bypass

Cerebral injury is deterministically related to the delivery of oxygen, with irreversible necrotic cell death resulting from a sustained reduction in delivery below 20% of normal. ^227,228 Rates of delivery above half baseline typically do not result in injury, while delivery rates of one-quarter to half of the normal range result in cellular injury, whose outcome is modifiable by other factors, such as temperature and free-radical scavenging, even when applied after the insult. ²²⁹ Apoptotic cell death ensues hours to days after subnecrotic hypoxic-ischaemic injury in susceptible populations of cells, and there exists a spectrum of ischaemic and apoptotic death in both focal and global models of ischaemia. ^225,228,229 Amplification of injury through excitatory amino acid neurotransmitter-related calcium-dependent cascades of uncontrolled neuronal depolarisation may play a role in both necrotic and apoptotic cell death. ²²⁸ Modification of excitotoxicity can be demonstrated with glutamate receptor antagonists such as ketamine and dextromethorphan, receptor agonists such as anesthetic vapours and barbiturates, magnesium, and hypothermia. ²²⁸ Although therapeutic trials have generally been disappointing in profound ischaemia, an incremental effect is likely in more moderate injury. ^230,231

Although hypothermic circulatory arrest represents an obvious example of global ischaemia, it is likely that regional partial ischaemia exists during many phases of bypass and the perioperative period. In an animal model of tissue oxygenation during changing conditions of bypass, a range of levels of oxygen in the tissues was demonstrated using the phosphorescent quenching technique, even during high-flow bypass. More hypoxic regions appear during low flow and hypothermic circulatory arrest. ²³² The cerebral circulation is susceptible to hypoxic injury throughout the perioperative period, and partial ischaemia is possible even during high-flow bypass, with neuronal fate modifiable by postoperative factors. ^229,233,234

Myocardial Protection and Cardioplegia

Initiation of cardiopulmonary bypass often has myocardial protective effects if the heart is properly unloaded by enhancing the availability of oxygen delivered through the coronary arteries and reducing consumption of oxygen. Hypothermia is a core component of myocardial protection. It further decreases consumption of oxygen, and preserves stores of high energy phosphates. Myocardial work can be further reduced by inducing a hyperkalaemic arrest via the administration of cardioplegia. The coronary arteries are isolated from the distal aortic circulation by placement of an aortic crossclamp distal to the cannula used to deliver cardioplegia. Cold solutions are then immediately delivered at 4° C. Aortic valvar competence is necessary to ensure the cardioplegia flows to the coronary arteries and not into the left ventricle. If the aortic valve is not competent, the aortic root can be opened and cardioplegia can be delivered directly into the orifices of the coronary arteries. Cardioplegia can also be delivered in a retrograde fashion via a catheter placed in the coronary sinus, as long as the sinus is not receiving blood from a left superior caval vein. Retrograde cardioplegia is often used as a supplementary method of cardioplegia, even when antegrade cardioplegia is possible.

Localised myocardial hypothermia can be achieved with cooling jackets and placement of ice slush in the pericardial space. This technique should be judiciously used, however, as it can result in injury to the phrenic nerves. ¹⁵⁹ As an adjunct to hypothermia, the high concentration of potassium in the cardioplegia results in myocardial electromechanical silence and diastolic arrest. The initial arresting dose of cardioplegia at our institution is 35 mL/kg delivered at a pressure in the aortic root of 80 to 120 mm Hg. Maintenance doses of 15 mL/kg are given every 15 to 20 minutes thereafter until the repair is complete.

A crucial component of successful myocardial protection is ventricular decompression. Myocardial consumption of oxygen and impedance to subendocardial flow of blood is significantly reduced by lowering the ventricular mural tension. ²³⁵ Decompression is accomplished most commonly with the use of a catheter introduced through the right superior pulmonary vein and the left atrium. The catheter passes through the left atrium, across the mitral valve into the left ventricle. Constant suction is applied to the catheter with the use of a designated roller pump on the bypass machine. Blood returning from the venting catheter is recycled into the cardiotomy reservoir as discussed previously.

Anticoagulation

Although other anticoagulants have been used in special situations, ^236–238 heparin is overwhelmingly the most commonly administered anticoagulant. ^239,240 Heparin has a rapid onset of action, is easily reversed with protamine, and has important anti-inflammatory effects. ^241,242 Dosing regimes include simple weight-based schemes, titration to a functional endpoint depending on activated clotting time, and measurement of concentrations with more complicated predictions. Convincing evidence for superiority of approaches is lacking. The gold standard of determining adequate anticoagulation suitable for bypass has been the activated clotting time. This test, however, does not take into account the effects of volume of blood, previous exposure to heparin, deficiency of antithrombin III, hypothermia or haemodilution. The Hepcon heparin management system (Medtronic, Inc. Minneapolis, MN) uses a pre-bypass titration of protamine to determine a patient-specific concentration of heparin to be maintained throughout the bypass run. While on bypass, samples of blood are taken every 30 minutes to determine both concentrations of heparin and activated clotting times. Additional need for heparin is based on maintaining an adequate concentration regardless of an extended activated clotting time. The Hepcon device calculates the dose of protamine needed to reverse heparin based on the circulating concentration of heparin at the end of the bypass run. The thrombotic, embolic, and inflammatory complications of cardiopulmonary bypass are increased with lower heparin effect. Adequate anticoagulation is crucial, otherwise intravascular coagulation, thrombosis, oxygenator dysfunction, and consumption of clotting factors may occur. ¹⁶⁰ Heparin-induced thrombocytopenia, still an unusual complication in infants and children, may be more difficult to recognise. ²⁴³

Strategies for Cooling

Surface cooling can begin with induction of anaesthesia, which promotes loss of heat and impairs thermoregulatory responses. A reduction in temperature to 35° C is generally well tolerated, and may confer protection against ischaemia in the period prior to bypass by metabolic suppression and alteration of responses to cellular injury. Further cooling on bypass is targeted based upon the anticipated level of flow required to complete the surgical repair. If deep hypothermic circulatory arrest is anticipated, a nasopharyngeal temperature of 18° C is generally the target, with evidence for increased complications at significantly higher and lower temperatures. Active cooling should be accompanied by measures of the adequacy of uniform cerebral cooling, for which measurements of surface temperature are inadequate. ²⁴⁴ Other indicators include jugular venous saturation, the electroencephalogram, and near infrared spectroscopy, from which evidence of metabolic suppression can be more directly ascertained. ^245–249 At least 20 minutes of cooling is associated with improved outcome if hypothermic circulatory arrest is utilised. ^250,251 A high flow hard-cooling pump strategy is necessary to raise the jugular venous saturation above 95%. ¹⁸¹ Measures which increase cerebral blood flow, such as a pH stat strategy, can improve brain cooling as previously discussed. ¹⁸²

Recent evidence-based reviews cite no advantage to hypothermia in either neurosurgery or open heart operations. ^252,253 Since many operations can be completed without significant interruption in flow of blood, this finding may be unsurprising. ²⁵⁴ These meta-analytic reviews, nonetheless, fly in the face of overwhelming laboratory and clinical evidence of protection from ischaemic injury with hypothermia in global ischaemia. ^255–259 Because the metabolic benefit of cooling and hypothermia is lost during rewarming, which may be superimposed on a period of reduced delivery of oxygen, a greater risk of ischaemia to both heart and central nervous system occurs with rewarming. ²⁶⁰ Given the multiple factors that may cause unexpected disruption in perfusion at full flow, some emergent in nature, most centers continue to use mild or moderate hypothermia as a protective adjunct to cardiopulmonary bypass without planned reduction of flow or circulatory arrest. ^254,261 While the overall perioperative inflammatory response, although reduced during hypothermia, does not seem to be altered by strategies depending on temperature, ²⁶² moderate hypothermia probably induces cellular adaptations at the transcriptional and translational level that result in survival programming. ^263,264

Deep Hypothermic Circulatory Arrest

Deep hypothermic circulatory arrest was first developed as a neuroprotective strategy when continuous perfusion could not be maintained. Currently, there is intense debate over the degree of protection offered by hypothermic circulatory arrest compared to hypothermic perfusion. The Boston circulatory arrest trial demonstrated that a strategy utilising hypothermic circulatory arrest compared to even low-flow bypass is associated with more immediate cerebral brain injury. Patients undergoing hypothermic circulatory arrest had more seizures, an increased tendency to have abnormal electroencephalograms, ²⁶⁵ and lower developmental performance at 1 year. ¹⁶³ Both groups underperformed at 8 years. ¹⁶⁵ Prolonged hypothermic circulatory arrest, greater than 40 minutes at 18° C, is associated with impaired neurodevelopmental outcome. ^266,267 The relationship between a shorter duration of circulatory arrest and outcome is uncertain, but examination of the data from the Boston trial reveals a range of outcomes across the range of circulatory arrest intervals, indicating a multiplicity of determinants of outcome, including individual biologic susceptibility. ²⁶⁸ The safe duration of hypothermic circulatory arrest is related to the rate of use of oxygen from available stores, and can be predicted on the combination of haemoglobin, temperature, pH, and time. It is reflected uniformly by the cerebral saturation of oxygen as measured by near infrared spectroscopy. ^166,170,199 The distribution of tensions of oxygen in the brain during hypothermic circulatory arrest is higher, and apoptotic regulators are lower, with a pH-stat strategy for cooling, predicting a longer safe time for hypothermic circulatory arrest. ^171,269

In an individual, the use of near-infrared spectroscopy can guide the safe duration of hypothermic circulatory arrest by limiting the time of low cerebral oxygenation. ^173,174 With optimal cooling to 18° C and a circulatory arrest time of less than 30 minutes, cerebral injury is unlikely. ²⁶⁷ Moderate and profound hypothermia may initiate protective pro-apoptotic mechanisms that off-set the deleterious effects of sublethal ischaemic times. ²⁷⁰ During longer periods of circulatory arrest, intermittent reperfusion at intervals of 15 to 30 minutes has been demonstrated to maintain cytoarchitecture, cerebral distribution of oxygen, and indicators of excitotoxicity in animals. ^271–273

Selective Antegrade Cerebral Perfusion

Because of the variability in time necessary to complete repair, and the limited duration of deep hypothermic circulatory arrest, strategies have been employed to maintain continuous delivery of oxygen to the brain. Selective antegrade cerebral perfusion via the brachiocephalic artery has become widely used. ^274–279 The optimal strategy for this technique remains poorly characterised, because measurements of cerebral blood flow are not readily available, and autoregulation may be altered during cold cardiopulmonary bypass and selective perfusion. ²⁸⁰ Most centers use pH-stat cooling to a target of 20° C to 26° C as in anticipated circulatory arrest, followed by direct perfusion of the brachiocephalic artery. Flow rates of 10 to 80 mL/kg/min have been described. ¹⁷³ Flow rates of less than 30 mL/kg/min, however, are not likely to provide adequate cerebral blood flow to open all capillary beds. ^281,282 Moreover, the increased affinity of haemoglobin at hypothermia may limit availability of oxygen during perfusion, partially off-setting the anticipated reduction in metabolism. The optimal temperature is not known, and is undoubtedly related to strategies of flow, although evidence supports maintenance of a deep hypothermia should a period of circulatory arrest be necessary. ^283,284 Techniques to monitor adequacy of cerebral flow during this technique include trans-cranial Doppler and near infrared spectroscopy. ¹⁷³

Experimental models of continuous cerebral perfusion compared to hypothermic circulatory arrest show improved cerebral oxygenation, ^169,285 better post-perfusion haemodynamics, ²⁸⁶ reduced apoptosis ²³² with less ischaemic injury, and improved outcomes. ^284,287,288 A recent comparison of cerebral perfusion versus hypothermic circulatory arrest in neonates undergoing reconstruction of the aortic arch showed no difference in neurodevelopmental outcome at 1 year. The technique for cerebral perfusion in this study, however, used a rate of flow of only 5 to 20 mL/min, and measures of cerebral oxygenation were not reported. ²⁸⁹ Because the rates of flow in those receiving cerebral perfusion were not likely to result in adequate delivery of oxygen, the results are not surprising, showing no difference between complete ischaemia and inadequate perfusion. Outcomes utilising an alternative approach utilising high-flow perfusion of 50 to 70 mL/kg/min show no evidence of ischaemic injury on postoperative magnetic resonance imaging. ²⁹⁰

Because bypass exposes the body to a huge inflammatory stimulus, there may be a relative disadvantage of prolonged cerebral perfusion compared to circulatory arrest of shorter duration. ^291–293 At present, there exists no direct comparison between cerebral perfusion at rates of flow with measured adequate cerebral oxygenation and deep hypothermic circulatory arrest. The optimal pH strategy for continuous selective perfusion is also debatable and conflicting, with some evidence favouring an alpha-stat approach, ²⁹⁴ and other evidence favoring a pH-stat approach. ^171,269 Because of the inherent risk of prolonged ischaemia, and the unpredictable delayed effects of hypothermic cerebral perfusion and circulatory arrest on postoperative flow of blood to the brain, we favour strategies that rely both on measurement and maintenance of cerebral oxygenation throughout the operative period. ²⁹⁵

Corticosteroids

Pre-treatment with corticosteroids is widely used, with broad but conflicting evidence for alteration of outcome. Pretreatment in adults reduces postoperative levels of tumour necrosis factor-α, interleukin-6, the incidence of atrial fibrillation, and markers of myocardial ischaemia. ^296–299 Evidence exists for both exacerbation and amelioration of hypoxic and ischaemic cerebral damage. ^300–303 It was shown that two doses of 30 mg/kg methylprednisolone may ameliorate the inflammation-related delayed reflow and cerebral metabolism after hypothermic circulatory arrest. ³⁰⁴ The membrane-stabilising effect may reduce excitatory neurotoxicity, ³⁰² and perivascular oedema may be reduced, ³⁰⁵ but necrotic cell death appeared to be unaffected, and apoptotic cell death may be increased. ^306,307

Aprotinin

Aprotinin is a serine protease inhibitor with a wide range of enzymatic targets. It has approval from the Food and Drug Administration to reduce the loss of blood during reoperation in adults undergoing bypass, and is widely used for conservation of blood, and for its anti-inflammatory effects. ^{153,308–310} As with other therapies aimed at modification of the inflammatory response, both desirable and undesirable outcomes may result, including an apparent increase in renal dysfunction related to hypotension. ³¹¹ Studies in adults have shown a reduction in both cerebral and myocardial injury in patients receiving aprotinin. This finding has been linked putatively to the anti-inflammatory effect of endothelial protection. ^312,313 Administration of aprotinin to piglets undergoing hypothermic bypass and hypothermic circulatory arrest resulted in greater preservation of endothelial-dependent vasodilation, improved cerebral blood flow, and produced faster recovery of cerebral stores of high energy phosphate, ³¹⁴ underscoring the impact of inflammatory microvascular injury in the pathophysiology of organ dysfunction following bypass.

Alpha-Adrenergic Blockade

The distribution of cardiac output is strongly influenced by the sympathetic nervous system, mainly through α-adrenergic mechanisms. Although deep anaesthetic strategies can alter the neurohumoral stress response to surgery, ²²⁰ evidence exists for high levels of sympathetic response during cardiac surgery, regardless of the anaesthetic regimen. ³¹⁵ We have shown an improvement in whole-body economy of oxygen using phenoxybenzamine that permits and necessitates a strategy of bypass at high rates of flow. ^316,317 In the presence of milrinone, α-adrenergic blockade is more effective than nitrovasodilators in improving flow both on ³¹⁸ and off bypass. ^281,319,320 Although outcomes seem improved with this approach, ^317,321 a randomised outcome trial is lacking. ³²²

Control of Glucose

Evidence for a beneficial effect of glycaemic control in paediatric cardiac surgery is distinctly lacking. The neonatal brain and heart are poorly tolerant of hypoglycaemia, which has been related to seizure activity and poor outcome in a large retrospective study of intraoperative glycaemic patterns and neurologic outcome. ³²³ In contrast to findings in adults, post-hypoxic supplementation of glucose may reduce neurologic injury in the developing brain. ³²⁴ Insulin has anti-oxidative, anti-apoptotic pro-survival cell programming effects, independent of its glycaemic effects. ^294,325 Because deficiency of insulin is rare in infants and children, the role for exogenous insulin is not yet established.

Ultrafiltration

Modified ultrafiltration is a technique to remove excessive water from the body after restoration of the native circulation, but before removal of the cannulas used for bypass. ^326,327 As an incremental strategy in adults, modified ultrafiltration reduces morbidity and post-operative use of resources. ³²⁸ In children, benefits include improved haemodynamics, pulmonary mechanics, and cerebral metabolism. ^329–333 Some of these effects may be achieved by other strategies to reduce the deleterious effects of bypass-related haemodilution and activation of blood products, including conventional ultrafiltration and strategies for reduction of the prime. ^334–336 A direct effect of modified ultrafiltration on inflammatory mediators, and on ultimate clinical outcome, is uncertain. ^337,338 Extreme reduction in the volume of prime volume miniaturisation of the circuit may eventually replace ultrafiltration. ³³⁹ It is likely that a combination of ultrafiltration and incremental alterations in components of the circuit to improve biocompatibility can also improve outcomes. ^157,329

Preconditioning

Ischaemic preconditioning, or induction of tolerance to prolonged ischaemia by brief exposure to ischaemia, has been observed in the myocardium, brain, liver, kidney, intestine, and skeletal muscle, and probably is a feature of all mammalian cells. ³⁴⁰ The effect was first described by the observation of reduced size of infarcts after 40 minutes of coronary arterial occlusion if preceded by cycles of 5 minutes of occlusion. ³⁴¹ The early protective window occurs within minutes, and fades within a few hours. A later second window of protection, or delayed preconditioning, opens about 24 hours after some preconditioning stimuluses. ^340,342,343

Early protective responses to sublethal ischaemia induce alteration in the flow of blood and metabolism. Within hours, signaling systems involving hypoxia-inducible factors and heat shock proteins confer resistance to apoptotic transformation. ³⁴⁴ Features of this characteristic response can be induced by hypoxia-ischaemia, hyperthermia, hypothermia, hypoglycaemia, a range of drugs including K-ATP channel blockers, erythromycin, volatile anaesthetics, opioids, acetylsalicylic acid, glutamate, and erythropoietin, the latter having received much attention in recent clinical trials. ^345,346 The mediators of this response favouring survival can be released remotely from the target organ, and improved myocardial function has been demonstrated in humans after minimal ischaemia induced by a tourniquet placed on the leg. ³⁴⁷ Induction of a common signaling pathway for survival of cells, as opposed to apoptosis, has been suggested as the underlying mechanism for these findings. ^348,349

Altered Cerebral Flow of Blood and Metabolism

The increased relative flow of blood to the brain induced by hypothermia can result in a postoperative increase in cerebrovascular resistance and cerebral oedema, although responsiveness to carbon dioxide is maintained. ^350–353 Some of this impaired flow may be due to microvascular occlusion, and can be ameliorated by treatments that reduce aggregation and adhesion of platelets, such as donors of nitric oxide, antagonists of thromboxane, and antiplatelet drugs. ^354–357 Modified ultrafiltration also seems to improve cerebral blood flow and metabolism, presumably by reduction of inflammatory mediators. ³³²

Hypothermic circulatory arrest results in both loss of autoregulation and delayed reflow, with a prolonged suppression of flow of blood and uptake of oxygen. ^358–360 This delayed recovery of cerebral metabolism may exacerbate the neurologic injury related to circulatory arrest. ¹⁶⁴ Suppression of metabolism during hypothermic circulatory arrest using a pH-stat strategy, ²⁰¹ and maintenance of a higher postoperative haematocrit, ³⁶¹ can, in piglets, partially ameliorate this metabolic derangement occurring after circulatory arrest. Postoperative arterial hypoxaemia exacerbates the arrest-related injury, ³⁶² and maintenance of delivery of oxygen to the brain with mechanical assistance may be preferable to inadequate postoperative delivery. ^169,363 We have demonstrated that, following hypothermic circulatory arrest in neonates, inadequate postoperative economy for oxygen is related to poor late neurodevelopmental outcome, and that postoperative hypercapnia is protective in this setting. ²³⁴ Continuous cerebral perfusion does not eliminate the risk of postoperative cerebral desaturation, ^295,364 and the interaction between intraoperative management and post-operative flows of blood remains complex.

Postconditioning

Ischaemic postconditioning describes modification of injury by interventions applied just at the time of reperfusion, and was first observed with intermittent reperfusion. ³⁶⁵ This may be a form of modified reperfusion, and has been observed with a variety of agents, including erythropoietin, insulin, and isoflurane, which are commonly administered in the operating room around the time of cardiopulmonary bypass and other ischaemic challenges. ^340,366,367 While hypothermia and volatile anaesthetics amplify the protection afforded by preconditioning for tolerance of prolonged ischaemia, postconditioning seems to have limited effect after prolonged ischaemia. ^368–370 Remote postconditioning has been described via brief occlusion of leg or kidney perfusion just at the time of reperfusion of myocardium, yielding a reduction in the size of infarcts 48 to 72 hours later. ^345,371 While the application of these techniques may seem simple, and associated with minimal risk, the clinical utility remains to be elucidated. Inadvertent conditioning may result from aspects of stimulations providing pre- and postconditioning commonly present throughout the operative period. The technique of intermittent reperfusion during prolonged hypothermic circulatory arrest ²⁷³ may be a paradigm for both pre- and postconditioning. An acidotic perfusion milieu at the beginning of reperfusion may not only enhance flow, but may also be important in promoting ischaemic postconditioning and anti-apoptosis. ³⁷²

Post-operative hyperthermia is common after cardiopulmonary bypass, ³⁷³ and has been associated with poorer neurologic outcome. ^374,375 Attention to the control of temperature during rewarming, and immediately following bypass, can reduce the incidence of undesired hyperthermia. Induction of post-operative hypothermia should be strongly considered for patients experiencing uncontrolled or prolonged peri-operative ischaemia. ³⁷⁶ Hypothermia may afford protection independent of its effects on cerebral blood flow and metabolism. The effects of hypothermia post-injury are likely due to reduction in apoptotic cell death, and thus both intra-operative and post-operative hypothermia may provide anti-apoptotic programming. Reduction in apoptotic cell death has been demonstrated using cerebral perfusion as a supportive strategy as opposed to hypothermic circulatory arrest. ^287,288 Post-operative mild hypothermia, and administration of albumin, are simple clinical interventions commonly applied which may alter outcome after incomplete ischaemia. ^229,377 Evidence of focal ischaemia from gas embolism or other causes should prompt consideration of hyperbaric treatment with oxygen. ^378,379

Monitoring

Because a range of conditions can affect central haemodynamics, regional cerebral perfusion, cerebral metabolism, and flow metabolism coupling during cardiac surgery, cerebral oxygenation is likely altered in both predictable and unpredictable ways. Cerebral hypoxia, measured by jugular venous saturation or infrared spectroscopy, has been shown experimentally to be related to injury during ischaemia, ^174,380 with similar findings reported in humans. ^364,381 Hypoxic-ischaemic conditions cannot reliably be identified by standard haemodynamic monitoring. Because aggressive prevention of overt and occult hypoperfusion improves outcomes, ^161,317,382 measurement of global and regional oxygenation is recommended as a method to prevent and treat unanticipated and unappreciated hypoxic-ischaemic conditions. This is especially crucial in the immediate perioperative period, when intervention to improve outcome is possible. ^382–385

Intra-operative Echocardiography

Transoesophageal echocardiography has become a mainstay of intra-operative management of the patient undergoing cardiac surgery. Specific guidelines have been developed as to the indications for its use in children. There is general agreement that the technique is indicated in every child over 3 kg. Some centers use the system in any infant over 2.5 kg in whom a probe is easily placed. An echo is generally performed at the beginning of every case, both to confirm the anatomy previously detected by using transthoracic windows, and to obtain real-time orientation to dynamic structures. Intra-operatively, echocardiography can be important to verify that air has been cleared from cardiac chambers prior to allowing cardiac contractions and emergence from cardiopulmonary support. It can also be very useful in delineating the source of failure when a child is not able to be weaned from bypass (i.e., residual lesions). For instance, echocardiography is very useful when differentiating hypovolaemia from functional compromise and residual structural deficits. At the termination of the procedure, echocardiography is critical in verifying the adequacy of many repairs. ³⁸⁶

Post-operative Extracorporeal Support

Short-term mechanical support is occasionally necessary following complex cardiac operations. The use of extracorporeal membrane oxygenation carries a reasonable expectation of recovery for small patients in cardiopulmonary failure. In the current era, the technique is an essential component of programmes undertaking complex congenital cardiac surgery. ^387,388 The circuit used by most centres is a direct descendant of the circuit initially developed for support of the neonate with pulmonary hypertension and persistent fetal circulation, and has the advantage of being standardised and well understood by the specially trained staff who manage the circuit. ^389,390 Key to its success was the development of the silicone membrane oxygenator, which extended the safe duration of extracorporeal support from hours to days, providing enough time for recovery of most neonates with respiratory failure. More recently, hollow fibre membrane oxygenators have been adapted for use, and both the oxygenator and the circuit can be heparin bonded. ³⁹¹ As a result the requirement for heparin is reduced, which can be helpful in controlling bleeding. The technique is still of value only in the short term, but because myocardial dysfunction is likely to recover within 96 hours, this duration of support is suitable for the post-operative patient. Survival to discharge from hospital for patients who required extracorporeal support subsequent to the operation is in the range of 40%. ^392,393 Not surprisingly, among patients requiring such support, a lack of residual lesions favours survival. ³⁹³ Patients with a functionally univentricular circulation suffering acute thrombosis of a shunt are noteworthy for a high rate of survival. ³⁹³ Many centres have developed a rapid response system to permit rapid cannulation so as to salvage patients who sustained unexpected cardiac arrest. ³⁹⁴ The technique, however, is still suitable only for relatively short periods of treatment. The longest duration resulting in a hospital survivor without transplantation in a large series reported from the Children’s Hospital of Philadelphia was 15 days. Bridging to transplantation requires long-term, low-morbidity support.

Providing mechanical support for the failing heart over longer periods has become a clinical reality in adults. Although the devices are imperfect, being subject to infection, haemolysis, and thromboembolic complications, long-term support has been possible. Patients have been bridged to transplantation with improvement in end-organ function, and reduction in pulmonary vascular resistance, ultimately resulting in a better candidate and a less complicated course following transplantation. The Heartmate and Thoratec devices, both manufactured by Thoratec (Pleasanton, CA) have been used in children. The Thoratec device in particular, an external or paracorporeal pump, has been used in patients as small as 17 kg. ³⁹⁵

Devices are now available that are specifically designed for use in children. The DeBakey VAD Child (MicroMed Technology, Inc., Houston, TX) uses an axial flow pump, and is modified from a device designed for adults. The axial flow pump itself is identical to the one designed for adults, but the inflow and outflow cannulas and flow probe have been modified to accommodate smaller patients. This device was given exemption by the Food and Drug Administration for humanitarian use as a bridge to transplantation for children. It is totally implantable, and is approved for use in patients aged from 5 to 16 years, and with body surface areas greater than 0.7 m ² and less than 1.5 m ^{2 396,397} The device has now been used in six patients with an average age of 11 years, and body surface areas from 0.8 to 1.7 m ^{2 398} The average duration of support was 39 days, with 84 days being the longest duration of support. Half of the patients were successfully bridged to transplantation. There are three major shortcomings with the device. The smallest size available will ideally accommodate only larger children, limiting the application in smaller children. Additionally, the intracorporeal position complicates replacement if thrombus develops in the device. Furthermore, because it is an axial flow device, reverse flow, mimicking severe acute aortic insufficiency, may occur if the device stops, a condition that can occur with formation of thrombus.

The Berlin Heart (Berlin Heart AG, Berlin, Germany) is a paracorporeal pneumatic displacement pump. The pumping ventricle is available in a variety of sizes from 10 to 80 mL. The smallest size is suitable for support of infants. ³⁹⁹ The experience in North America of May 2007 includes just under 100 patients. The longest duration of support is 234 days. Death occurred in one-quarter of those placed on the device, with just over half undergoing transplantation, and one-tenth being weaned from the device and a further one-tenth still being supported (personal communication). Because of the paracorporeal or external position of the pump, and the range of available cannulas, the device accommodates a range of anatomic variances. It is even possible to support patients with functionally univentricular circulations. ⁴⁰⁰ Thrombus within the device can be identified by visual inspection, and the external position permits changing of the pump without reoperation.

Placement of any assist devices puts patients at risk for bleeding and thromboembolic complications. The risk appears to be greatest in the smallest patients. Presently both the DeBakey VAD Child and the Berlin Heart permit extubation and ambulation, both necessary conditions for rehabilitation ( Fig. 13-14 ). Although the paracorporeal pump may be more cumbersome, at present all devices in children are placed as bridges to transplantation, and not as permanent therapy. The ease of exchange of the pump, and the ability to accommodate anatomic variances and a greater range of size, favour the paracorporeal pump for use in children.

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