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Neonatal Cardiac Care, a PerspectiveGanga Krishnamurthy,a Veniamin Ratner,a and Emile Bachab

Every year in the United States approximately 40,000 infants are born with congenital heartdisease. Several of these infants require corrective or palliative surgery in the neonatalperiod. Mortality rates after cardiac surgery are highest amongst neonates, particularlythose born prematurely. There are several reasons for the increased surgical mortality riskin neonates. This review outlines these risks, with particular emphasis on the relativeimmaturity of the organ systems in the term and preterm neonate.Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 16:21-31 © 2013 Elsevier Inc. All

rights reserved.

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Introduction

Congenital heart disease is the most common birth de-fect.1 Recent prevalence estimates range from 6 to 10 per

1,000 live births.2-4 Nearly 40,000 infants are born with acongenital heart defect each year in the United States; world-wide, over 1 million such babies are born every year.1,5 Manyf these infants require surgery to correct or palliate theireart defect during their lifetime; several require surgery inhe newborn period.

Between 2007 and 2010, approximately 80,000 patientsnderwent cardiac surgery for congenital heart disease across6 North American centers.6 Figure 1 depicts the age distri-ution of these patients. Although neonates comprised only5% of the total surgical volume, they accounted for morehan 50% of all deaths that occurred during this time periodFig. 2). Tremendous strides in congenital heart surgery, ad-ances in cardiopulmonary bypass techniques, and im-roved preoperative and postoperative management skillsave resulted in a general decline in operative mortalitycross all age groups.7 However, mortality rates after neonatal

cardiac surgery continue to be high.6,7

One in 10 neonates does not survive to discharge aftercardiac surgery.6 Multiple factors contribute. Premature birthand low birth weight add substantial risk.8,9 Lesions requir-ing surgery in the neonatal period are often quite complex.Performance of intricate surgical procedures in tiny hearts

aDepartment of Pediatrics, College of Physicians and Surgeons, ColumbiaUniversity, New York, NY.

bDepartment of Surgery, College of Physicians and Surgeons, ColumbiaUniversity, New York, NY.

ddress correspondence to Ganga Krishnamurthy, MBBS, Assistant Profes-sor of Pediatrics, Division of Neonatology, College of Physicians andSurgeons, Columbia University, 3959 Broadway, BH12 N, #1211, New

York, NY 10032. E-mail: gk2008@columbia.edu

1092-9126/13/$-see front matter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1053/j.pcsu.2013.01.007

requires superior technical skills and several years of experi-ence for mastery. Neonates pose technically challenging is-sues related to structure, cannulation, and cardiopulmonarybypass. Abnormal preoperative circulation and effects of car-diopulmonary bypass on immature organ systems are addi-tional factors that place neonates at greater risk for death aftersurgery.

Neonates born prematurely, ie, before 37 completedweeks of gestation, are at greater risk of death after cardiacsurgery than those born after 37 weeks.8,10 This dichotomousdistinction, although not untrue, makes an erroneous as-sumption that the risk of death after 37 weeks is uniformlyequivalent. Population and single-center studies have dis-proven this theory in babies born with congenital heart dis-ease and in those born without birth defects.11,12 There is anincremental decline in death rate from 37 to 40 weeks, withthe nadir at 39 to 40 weeks.8,10 Death rates increase again if

elivery is delayed beyond 41 weeks. Extension of pregnancyrom 37-38 weeks to 39-40 weeks provides a significant sur-ival benefit and reduces the risk of complications.8,10

The majority of babies with congenital heart disease areborn before 39-40 weeks of gestation.8 Many babies are elec-ively delivered before the due date, for better coordination ofelivery, catheter intervention if necessary, and to avoid in-tero demise. The recent spate of single-center and popula-ion studies have shown significant risk of mortality and mor-idity among near-term babies and should caution againsthis practice.8,10-12 Elective delivery of babies before 39 com-leted weeks of gestation should be discouraged, absent anybstetrical or fetal risk. Local, state, and regional initiatives toliminate non-medically indicated elective deliveries before9 weeks are critical endeavors that may help reduce neona-al death rate, including those after cardiac surgery.13

Why should birth that occurs only 2 to 3 weeks before the

due date confer such a disadvantage? The answer is un-

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22 G. Krishnamurthy, V. Ratner, and E. Bacha

known. Human gestation is called “full term” when it lasts280 days (or 40 completed weeks). Term gestation, delin-eated for statistical probability, ranges from 37 weeks to 42weeks. Hence, 37 weeks is an entirely arbitrary beginning forterm gestation and the period between the two limits repre-sents a continuum where organ maturity continues. There-fore, babies born in the “early term” period are physiologi-cally less mature than babies born in “late term.” The exactphysiological immaturity that places early term neonates atgreater risk of mortality is not known, but likely representsincomplete development of several organ systems. The au-thors extend the argument that organ maturity is not con-ferred, even at late term or “due date.” Maturation is a gradualprocess that continues for several months and years afterbirth. Neonates are disadvantaged in comparison to infantsand older children because organ systems are comparativelyless mature.

Fetal CirculationNeonates are recent occupants of a fetal environment wheredemands are few and there is dependence on the uteropla-cental unit for survival. At birth, the fetus transitions fromthis sheltered milieu to a place of high metabolic rate andself-dependence for gas exchange.

Fetal lungs do not serve a respiratory function; they aresolid, fluid filled, and collapsed. Placenta assumes the role oforgan for gas exchange in the fetus. Oxygenated blood isconveyed from the placenta to the fetal heart and systemicblood is routed through the ductus arteriosus and descend-ing aorta to the placenta.

Preferential streaming of oxygen-rich blood in the inferiorvena cava and across the foramen ovale to the left side of theheart facilitates delivery of blood with relatively higher oxy-gen content to the fetal myocardium and brain.14 Because theesistance in the fetal pulmonary vasculature is high, less than5% of right ventricular output is delivered to the lungs.15

The majority of right ventricular output flows through theductus arteriosus into the descending aorta to perfuse thelower body and the low-resistance placental bed. The parallel

Figure 1 Age distribution of patients who underwent cardiac surgeryor a congenital heart defect between 2007 and 2010 in 96 centers inorth America. Y axis represents the number of cardiac surgicalatients. (Adapted from the Society of Thoracic Surgeons Congen-

tal Heart Surgery Database, 14th Harvest, with permission.6).

fetal circulatory system promotes efficient oxygen redistribu-tion in a relatively hypoxic environment (Fig. 3).

Oxygen delivery to tissues depends on regional blood flowand oxygen content in the blood. Hemoglobin concentrationand oxygen saturation of hemoglobin are the major determi-nants of oxygen content. Despite the low fetal blood oxygen

Figure 2 Proportional distribution of cardiac surgical mortality byage group between 2007 and 2010 in 96 centers in North America.(Adapted from the Society of Thoracic Surgeons Congenital HeartSurgery Database, 14th Harvest, with permission.6).

Figure 3 Mammalian fetal circulation. Ao, aorta; DA, ductus arteri-osus; DV, ductus venosus; LA, left atrium; LV, left ventricle; PA,pulmonary artery; RA, right atrium, RV, right ventricle. (Reprintedwith permission from Rudolph AM: Congenital Diseases of theHeart. Clinical-Physiological Considerations. Ed 3. Wiley-Black-

well; 2009).

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Neonatal cardiac care, a perspective 23

tension, the cellular oxygen demands of the fetus are met bywell-designed oxygen transport and delivery mechanisms.16

Greater oxygen affinity of fetal hemoglobin permits efficientoxygen extraction from the placenta. High concentration ofhemoglobin, the presence of fetal hemoglobin, and a highcombined ventricular output maintain tissue oxygen deliveryunder unstressed conditions.16

The fetal circulation is forgiving to even the most severeforms of congenital heart disease. Intra- and extra-cardiacshunts allow fetal circulatory adaptations to abnormal heartanatomy.

Transitional CirculationMost of the circulatory changes occur in the first few mo-ments after birth.17 Additional circulatory adjustments occurover a period of several weeks. The primary event triggeringthe alteration in blood flow patterns is the establishment ofalveolar respiration.18 As a consequence, there is a substantial

ecline in pulmonary vascular resistance and a several-foldncrease in pulmonary blood flow. A rise in left atrial pressureaused by an increase in pulmonary venous return allowslosure of the foramen ovale and abolishes the atrial levelhunt. The higher oxygen tension in the blood initiates theostnatal closure of the ductus arteriosus, establishes com-lete separation of pulmonary and systemic blood flows, and

eads to a circulation in series (Fig. 4).

Perinatal Cardiovascular SystemPostnatal Increase in Left Ventricular OutputThe “inappropriately” low for size fetal metabolic rate is an

Figure 4 Adult circulation. Similar volumes of blood are ejected fromand returned to each ventricle postnatally. (Reprinted with permis-sion from Rudolph AM: Congenital Diseases of the Heart. Clinical-Physiological Considerations. Ed 3. Wiley-Blackwell; 2009).

adaptation to low oxygen tension.19 Heat regulation is not

eeded and significant fetal physical or respiratory activity isbsent. The metabolic rate in late-term fetus approximateshe low level of its adult mother.19 At birth, metabolic rate/xygen consumption increases several-fold because of thedditional demands imposed by heat conservation mecha-isms and respiratory activity.19-22 Oxygen delivery increases

n a similar proportion to maintain normal oxygen reserveapacity.17 Much of the increase in oxygen delivery is attrib-ted to a substantial increase in left ventricular output afterirth. Enhanced left ventricular output is caused by an in-rease in heart rate, an increase in left ventricular preload,nd a greater inotropic state.23-25 The exact mechanisms caus-

ing postnatal increase in cardiac output are not known, butthyroid hormone is believed to play a role.26 Fetal lambs inwhich the thyroid gland was removed 2 weeks before deliv-ery demonstrated low plasma levels of T3 and failed to dem-onstrate the expected postnatal increase in T3 levels and car-diac output.26 The same lambs had fewer �-adrenergicreceptors on myocardial surface and exhibited a blunted re-sponse to �-adrenergic stimulation.26 Elevation in cortisolevels, catecholamine surge, and relief from ventricular con-trainment at delivery also contribute to postnatal elevationn cardiac output.27-29

The transition to extra-uterine life depletes much of theneonate’s circulatory reserves and exposes it’s vulnerability toadditional challenges. In the weeks that follow, the newbornreplenishes some of these reserves as evidenced by a declinein resting heart rate, a reduction in basal inotropic state, andimproved response to exogenous catecholamines.30 As post-natal age advances, the cardiac output declines in relation tobody weight (Fig. 5).17 This decrease parallels a decline inxygen consumption in relation to body weight, an improvedfficiency in oxygen unloading at the tissue level, and a tran-ition to adult hemoglobin.16,17,21

Figure 5 Relationships between changes after birth in body weight,actual cardiac output (CO) and cardiac output in mL/min/Kg bodyweight. (Reprinted with permission from Rudolph AM: CongenitalDiseases of the Heart. Clinical-Physiological Considerations. Ed 3.

Wiley-Blackwell; 2009).

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24 G. Krishnamurthy, V. Ratner, and E. Bacha

Developmental Differences in MyocardialStructure and Excitation-Contraction CouplingGeneration of myocardial contractile force increases withmaturation.31-33 Developmental differences in contractilityare, in large part, caused by age-related differences in myo-cardial structure (Fig. 6).

Immature myocytes possess fewer myofilaments, the fun-damental units of cross-bridge formation.32-35 Increase in thenumber of myofilaments with age correlates with increase inmyocardial force generation.31-34,36 Isoform switching ofmyofibrillar proteins with development contributes to im-proved contractile efficiency with age.37,38 The immaturemyocyte is smaller and reveals intracellular spatial disorgani-zation.33 The myofibrils assume a random arrangementrather than the parallel arrangement seen in adult myo-cytes.32-35 A large proportion of the immature myocyte isnhabited by non-contractile organelles that do not contrib-te to force generation. Biophysical disadvantage to shorten-

ng is also imposed by the small, spherical structure of themmature myocyte and the central location of noncontractilelements.33

The calcium handling mechanism in the neonate is under-developed and inefficient.34,35 T- tubules and sarcoplasmiceticulum are scarce, intracellular calcium regulatory pro-eins exhibit functional immaturity.39-44 Therefore, cytosolic

calcium concentration is primarily dependent on trans-sar-colemmal flux of calcium.

A densely arborized plexus of sympathetic nerves inner-vates the adult myocardium.45 Sympathetic innervation ofhe heart is incomplete at birth and continues postna-ally.36,45,46 Cardiac norepinephrine stores, a reflection of

sympathetic innervation, is the lowest in late-term fetusesand increases postnatally to approach adult levels by 4 weeksof age.36,45,47

Maturation of adrenergic receptors predates myocardialsympathetic innervation.36 �-adrenergic receptors on myo-cardial cell surface increase in number during fetal develop-ment, with no significant quantitative difference betweennewborns and adults.48,49 However, functional uncoupling of� receptor-G protein-adenylate cyclase complex in the new-

Figure 6 Hematoxylin and eosin stained sec

born limits the effectiveness of catecholamine-modulated

contractility in this age group.50 Maturational changes inyocyte ultra structure, calcium handling, and sympathetic

nnervation contribute to improved myocardial performanceith age.

eonatal Ventricular Performanceentricular performance improves with age.23,31,51-53 Circu-

latory adaptation at birth is vital to meet the increased meta-bolic demands of extra-uterine life. An acute increase in heartrate, pulmonary venous return, and contractile state contrib-utes to the postnatal enhancement in cardiac output.17,23,24

High resting inotropism limits contractile reserve in new-borns. Immature hearts exhibit a blunted response to exog-enous catecholamines compared with mature hearts.30 Im-provement in contractile performance with maturationparallels several developmental changes in the myocardium,as described previously. Limitation in contractile reserve inneonates favors utilization of rate-dependent mechanisms toimprove cardiac output.

Increase in preload augments stroke volume; the Frank-Starling relationship.54 Immature hearts demonstrate aFrank-Starling relationship, albeit a modest one (Fig. 7).55-59

The mature heart shows an extension of the Frank-Starlingslope beyond that seen in immature hearts, ie, a more robustincrease in stroke volume after volume loading.59 Therefore,the immature heart has a lesser recruitable preload reserve.Limited response to volume loading may in part be caused by

f neonatal and adult human myocardium.

Figure 7 Relationship of left ventricular end diastolic volume and

stroke volume in immature and mature hearts.

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Neonatal cardiac care, a perspective 25

decreased compliance of immature hearts. Maturationalchanges in cytoskeleton and extracellular matrix improvemyocardial compliance with age.34,36,60-62

Decreased ventricular compliance exposes the deleteriouseffects of ventricular interdependence. Volume or pressureloading of one ventricle can impact filling of the contralateralventricle to a greater extent in immature hearts than in moremature ones.63 This restrictive effect is particularly evident in

eonates who have endured an unfavorable postnatal transi-ion and exhibit persistent fetal circulation. The pressure-oaded right ventricle alters septal dynamics and limits leftentricular filling and left ventricular stroke volume.

Increase in afterload profoundly diminishes ventricularerformance in the fetus and neonate (Fig. 8).17,36 When

exposed to similar afterloads, the immature myocyte short-ens to a lesser extent and more slowly than a mature myo-cyte.36 Developmental changes in myocyte architecture per-

its the adult heart to counteract afterload stressors moreffectively.34,36

Congenital Heart Disease and Postnatal CirculationMost babies with structural heart disease experience an un-remarkable transition to ex-utero conditions. However, ab-normal circulatory patterns in some forms of congenital heartdisease may impose immediate hemodynamic challenges atbirth, ie, babies with hypoplastic left heart syndrome with arestrictive atrial communication, d-transposed great vesselswith intact ventricular septum, and restrictive foramen ovale.In others with circulations dependent on ductal patency,symptoms emerge with constriction of the ductus arteriosus.

Inherent limitations in cardiac mechanics of the newbornheart are exposed in some forms of congenital heart disease.Neonates with severe aortic stenosis are limited in their abil-ity to increase myocardial performance in the face of an in-creased afterload. Lesions with left-to-right shunts require anincrease in left ventricular output to maintain adequate sys-temic flow. Recruiting the Frank-Starling mechanism andincreasing inotropic state accomplish much of the increasedstroke work. Large shunts may overwhelm the limited pre-load and contractile reserve of the newborn heart. Babieswith hypoplastic left heart syndrome are particularly vulner-

Figure 8 Relationship of afterload and stroke volume in mature andimmature hearts.

able. In these neonates, excessive pulmonary blood flow

through a patent ductus arteriosus can limit systemic flow.Right ventricular output must increase several-fold to main-tain systemic flow. Right ventricular functional reserves maybe insufficient to accomplish the stroke work needed tomaintain systemic flow.

Other Immature Organ SystemsOther organ systems may also be incompletely developed,even in the infant born at term. An extensive description isbeyond the scope of this review. A brief summation of criticalsystems or issues is described.

RespiratoryChest wall structure and limited diaphragmatic appositionintroduces mechanical inefficiencies in neonatal ventila-tion.64 Neonatal lungs and chest wall possess variable com-pliances.64,65 The lungs are less compliant, while the chest

all is extremely compliant. This uncoupling predisposes thehest wall to deformational forces and much of the respira-ory energy is expended in counteracting these forces.65 Theeonate compensates with a higher resting respiratory ratehan is seen in older children and adults. Diminished respi-atory reserves in the neonate are exposed with parenchymalung disease, fluid, or air accumulation in pleural space.hest wall structure and mechanics improve with age, mak-

ng the older child or adult more equipped to face challengesequiring an increase in respiratory work.65

RenalNephrogenesis is completed at 35 weeks of gestation.66

Structural and functional growth of the kidney continues forseveral months after birth. The biggest limitation in renalfunction in the neonate is the rate of glomerular filtration,which, in the first few days of life, is one third that seen inadults.67 Tubular and medullary renal function limit themaximal urine concentrating ability of the newborn infant tohalf that of an adult.68 These functional limitations make the

eonate more vulnerable to fluid overload or depletion.

emperature Regulationewborn infants, particularly those born prematurely are

usceptible to hypothermia.69,70 A large surface area in rela-tion to body weight permits greater heat loss in neonates thanin older children. Neonates are limited in their ability toconserve heat in the presence of cold stressors.69,70 Shiveringthermogenesis is limited in the first few weeks to months oflife.69,70 Non-shivering mechanisms, ie, brown fat metabo-ism, is recruited for heat production in neonates, but thisncreases oxygen consumption.69,70 Therefore, neonates ben-efit from care in a thermoneutral environment, which is thetemperature at which normal core temperature is maintainedwith minimal energy expenditure.

Immune SystemNeonates are susceptible to infections. Skin and mucosaserve as ineffective barriers. Immature cellular and humoralsystems limit their ability to mount an effective immune re-sponse.71 Neonates, particularly premature infants with long-

standing indwelling venous catheters, are particularly at risk.

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26 G. Krishnamurthy, V. Ratner, and E. Bacha

Effects of Cardiopulmonary Bypass on NeonatesThe damaging effects of cardiopulmonary bypass includinghemodilution, systemic inflammation and bleeding are morepronounced in neonates than in older children and adults.72

The total blood volume in term neonates is approximately80 mL/Kg.73 The priming volume of the extracorporeal cir-uit may be as high as two or three times the circulating bloodolume of the neonate. This disparity between the circulatinglood volume and bypass circuit size results in marked he-odilution causing anemia, hypoproteinemia, and a reduc-

ion in coagulation factors. Significant hypoprotenemia canead to greater transflux of fluid into the extracellular spacerom the intra vascular compartment.

Surgical trauma and extracorporeal circulation triggers anxuberant systemic inflammatory response.74,75 Neutrophil,

contact and complement activation, cytokine release, plateletaggregation, and activation of coagulation cascade are com-ponents of systemic inflammation. Systemic inflammatorymediators can cause cellular and organ dysfunction. Releaseof C3a increases vascular permeability, TNF-� and IL-1�depresses myocardial contractile function, TNF-� increasesvascular permeability and lung water content and decreasesglomerular filtration.75 The adverse effects of global inflam-mation are more pronounced on the immature organ systemsof neonates.

Several strategies have been used to counteract the dam-aging effects of cardiopulmonary bypass.72 Reducing the ex-racorporeal circuitry will decrease the artificial surface areaf exposure. Deploying tubes of smaller length and diameter,ecreasing distance of circuit from surgical table, and elimi-ating arterial filters and other components can miniaturizeircuits. Such small circuits have the additional advantage ofequiring a smaller priming volume. Other strategies includeaintenance of a higher oncotic pressure in the bypass cir-

uit, use of anti-inflammatory agents like corticosteroids, andemoval of inflammatory mediators by continuous or modi-ed ultrafiltration.72

Implications forPostoperative CareThe immature organ systems and the deleterious effects ofcardiopulmonary bypass have been described in previousparagraphs. Cardiac surgery exposes the limited reserves ofthe neonate.

Hemodynamic OptimizationMyocardial edema and ischemia–reperfusion injury after car-diac surgery decreases ventricular performance. The declinein contractility is usually transient, unless there is a signifi-cant residual surgical defect. Despite mounting a robust sym-patho-adrenal response during surgery, the immature neona-tal heart is limited in its ability to augment ventricularperformance.76,77 Therefore, exogenous infusions of ino-ropes are required to enhance the contractile state after sep-ration from cardiopulmonary bypass. The inotropic re-ponse with exogenous agents is lesser in neonates than in

lder children because of the high baseline adrenergic state.30

There are no clear advantages of one inotrope combinationover another, and institutional choices determine practice.Factors that may influence response to inotropic agents in theneonate are discussed.

Dopamine exerts its cardiovascular, renal, and hormonaleffects in a dose-dependent manner.78-81 Renal effects pre-

ominate at low doses in older children and adults. Moderateoses (5 to 10 mcg/kg/min) stimulate cardiac adrenergic re-eptors and increase cardiac output, while doses �10 mcg/g/min stimulate vascular �-adrenergic receptors and in-

crease systemic vascular resistance. Maturational differences inthe expression and sensitivity of �- and �-adrenergic receptorsin the neonate make the response to dopamine less predictable,particularly in the preterm neonate.78,81,82 Therefore, �-adren-ergic stimulation and increase in systemic vascular resistancemay become apparent at low doses.78,81,82 Metabolism and elim-nation of dopamine is a complex process and wide inter-indi-idual variations in clearance are noted.78,81-83Reduced dopa-

mine clearances in premature neonates and patients withhepatic and/or renal failure may make the cardiovascular re-sponse to conventional dosing more difficult to predict.82 Fi-nally, dopamine exerts its effects on the heart in part by releasingnorepinephrine from nerve terminals. Hence, it may be lesseffective when myocardial norepinephrine stores are depleted orlow, as seen in immature hearts.45

Effects of epinephrine on �- and �-adrenergic receptorsmake it a good choice for post cardiac surgery patients withdiminished cardiac function and vascular tone.

However, there is limited data on the cardiovascular effectsof epinephrine in neonates. Metabolic effects of epinephrine,like hyperlactatemia and hyperglycemia, warrant cautioususe.84 Neonates are more susceptible to myocardial damageand necrosis after prolonged high-dose infusions of epineph-rine.85 Milrinone has several positive modulating effects onventricular performance.81,86,87 Decreased milrinone clear-nce in the setting of renal insufficiency may cause systemicypotension. Neonates are particularly vulnerable becausehey have a low baseline glomerular filtration rate.

It is not uncommon for neonates to develop catechol-mine-resistant hypotension after cardiac surgery.88 Down-

regulation of adrenergic receptors and relative insufficiencyor resistance to corticosteroid action may contribute to cate-cholamine resistance.89 In these cases, hydrocortisone ad-

inistration induces a dramatic improvement in hemody-amics through its genomic and non-genomic effects.88,90-92

Non-adrenergic agents like arginine–vasopressin may also beused for vasodilatory shock when ventricular function is pre-served.93,94

Finally, exploiting the Frank-Starling relationship to im-prove stroke volume may be less effective in neonates be-cause of decreased myocardial compliance and mismatch ofafterload to contractile state.59

Adrenergic agents primarily exert their effects by increas-ing intracellular calcium levels.35 In neonates, intracellularcalcium levels are maintained through a trans-sarcolemmalflux of calcium. Hence, maintaining normal serum levels ofionized calcium is critical to optimize contractile function.

Trans-capillary fluid shifts, bleeding and osmotic diuresis can

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Neonatal cardiac care, a perspective 27

deplete circulating volume and decrease venous return. Dy-namic and static assessments of volume status and fluid respon-siveness are often used in older children and adults.95,96 Thereare no perfect measures to assess intravascular volume statusin neonates. Single-point measurements of right atrial pres-sure are uninformative of volume status.97 Despite this, mostintensivists use right atrial pressure or central venous pres-sure to guide fluid therapy.98,99 Hypovolemia and decreasedventricular end-diastolic volume is inferred from decliningtrends in right atrial pressure measures. In these cases, cor-rection of hypovolemia will increase venous return andstroke volume.

In the absence of bleeding, choice of replacement fluid forcorrection of hypovolemia is not clear.100 There is no convincingdata that 4% to 5% albumin secures sustained improvement inhemodynamics compared with 0.9% saline.101-103

Hemodynamic Monitoring and AssessmentAccurate indices of ventricular output that may guide therapyrequire devices that are too large for the neonate. Therefore,the clinician is dependent on clinical evaluation for the ade-quacy of cardiac output and on arterial blood gases for ade-quacy of global oxygen delivery. The first of these measures isgrossly unreliable in neonates; the second is sensitive only tosignificant declines in cardiac output.104,105

Tissue oxygen demands under conditions of reduced sys-temic flow are initially met by increasing oxygen extractionand/or redistribution of flow. Additional derangements insystemic oxygen transport can lead to decreased oxygen con-sumption and tissue utilization of anaerobic bioenergetics.

True mixed venous saturation (from the pulmonary artery)as an indicator for coefficient of global oxygen utilization isalmost never measured in neonates and a close proxy, rightatrial saturation, is unhelpful in mixing circulations. Someinstitutions place internal jugular lines or catheters for inter-mittent or continuous measures of central venous saturation;others use non-invasive technology to assess regional oxygenextraction.106,107 The focus on tissue oxygen delivery status asa measure of circulatory well-being is particularly importantin neonates. This constantly changing measure depends onoxygen delivery, demand, and consumption, and varies fromorgan to organ. It is impossible to measure oxygen deliverystatus to every tissue continuously. However, trends in proxymeasures of oxygen utilization in select regions (ie, kidney,brain) using near infra-red spectroscopy technology can pro-vide some information about circulatory health.108,109

Institutions, including ours, continue to follow arterial lac-tate levels. It is an easily available measure in point-of-caresystems. However, the utility of arterial lactate level as astand-alone measure of oxygen delivery status is question-able.110 Arterial lactate levels may rise for several reasons that

ave very little to do with ventricular performance (ie, “washut” from reperfusion, cellular/tissue dysoxia, decreasedlimination due to abnormal liver or kidney function, cat-cholamines, etc).

luid Managementotal body water is increased and there is expansion of the

xtra-cellular space after cardiopulmonary bypass.111 There-

ore, maintenance fluid and sodium requirements are lowerhan usual.

The postoperative course is more often than not accompa-ied by trans-capillary fluid shifts.111 Fluid shifts can be quite

pronounced in neonates if there is a concurrent leakage ofalbumin into the interstitial space. Attempts to maintain in-travascular volume by increasing circulating albumin levelsin such a “leaky” circulation may precipitate pulmonaryedema, particularly in premature infants with lung disease.112

Administration of systemic corticosteroids in the operatingroom and/or in the postoperative period may mitigate “cap-illary leak” but have their risks.113,114 Leakage of fluid into thenterstitial space of tissues and organs can affect function. Forxample, accumulation of fluid in the lung parenchyma,leural space, or chest wall leads to diffusion abnormalities,telectasis, and worsening chest wall compliance.

Spontaneous fluid mobilization from the extracellularpace is accomplished by encouraging lymph flow. Lymphow increases with muscle contraction and spontaneousreathing. It is our institution’s practice to allow early re-umption of spontaneous respiratory and physical activitynd avoidance of muscle relaxation when possible.

espiratory Careeonatal ventilator modes (ie, pressure-limited, time-cycled)

re used at our institution in the postoperative period. Tran-ition to nasal continuous positive airway pressure (CPAP)aintains functional residual capacity, decreases the work of

reathing, and has the advantage of permitting earlier extu-ation. In this institution, extubation to “bubble” CPAP isavored compared with constant pressure ventilator-derivedPAP. Bubble-CPAP enhances gas exchange, lung mechan-

cs, gas mixing efficiency, and lung volume compared withonstant-pressure CPAP.115,116

Prematurity andCongenital Heart DiseaseOne in eight babies in the United States are born before 37completed weeks of gestation and are considered prema-ture.117 Mortality risk increases with declining gestationalage.118 Prematurely born infants who survive are at risk formotor, cognitive, visual, and auditory disabilities.118-121

Congenital heart disease is more common in prematureinfants than those born at full gestational term.122 Interest-ngly, approximately one in five neonates with congenitaleart disease born prematurely.8,122,123 Gestational age is an

mportant contributor to mortality. Crude hospital mortalityates for prematurely born infants with congenital heart dis-ase range from 16.4% in late preterm infants (34 to 36eeks) to twice that in infants born before 34 weeks.8 In very

ow birth weight infants (�1500 g), mortality rates are muchigher.124

Description of the developmental immaturities of the pre-term newborn is beyond the scope of this review. A briefsummary is provided below.

Premature lungs are immature in structure and func-

tion.125,126 Premature infants may be deficient in surfactant

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28 G. Krishnamurthy, V. Ratner, and E. Bacha

requiring exogenous surfactant replacement, oxygen supple-mentation, and, in severe cases, mechanical ventilation.127-130

Premature infants are at risk for apnea of prematurity,chronic lung disease, and ventilator and/or oxygen depen-dence.118,131 Postnatal closure of ductus arteriosus is unusualin extremely low birth weight infants.132 Wide patency cancause congestive cardiac failure and renal insufficiency. Pre-mature neonates also have high insensible water losses andare prone to dehydration and electrolyte abnormalities. Gutimmaturity often prevents establishment of enteral feedings;parenteral nutrition is required for prolonged periods. Pre-mature babies are at high risk for necrotizing enterocolitis,sepsis, and renal failure.118,131 The fragile germinal matrix ofthe premature baby is susceptible to injury. Intraventricularhemorrhage is a potential risk in extremely premature in-fants.118,131

Exposure to high oxygen levels has been implicated in thepathogenesis of retinopathy of prematurity.118,131 Severe ret-nopathy can lead to blindness. Therefore, preterm infantsace multiple challenges that are compounded in the pres-nce of congenital heart disease.

Timing of surgical address for premature babies born withongenital heart disease is unclear. Previously, waiting for anrbitrary optimal weight was favored; the current trend is toperate when able, as waiting is fraught with risks.133-135 Sur-

geries under cardiopulmonary bypass have been performedsuccessfully in patients under 2000 g, and in much smallerbabies by experienced operators.133,134

The functional limitations of the premature baby must berecognized in the operating room and intensive care unit.Exposure to cardiopulmonary bypass may result in surfac-tant dysfunction.136-139 Effects of hemodilution and inflam-

ation are more pronounced in the preterm neonate. Post-perative capillary leak syndrome is more likely in thisatient population. Ventilator strategies favorable to prema-ure lungs and chest wall should be used. High peak inspira-ory or high tidal volumes are particularly injurious to imma-ure lungs. Positive end expiratory pressure stabilizes theighly compliant chest wall and maintains functional resid-al capacity. Oxygen should be used cautiously because itan worsen retinopathy of prematurity and chronic lung dis-ase. The myocardial structural and functional limitationsetailed earlier are more pronounced in premature infants.here are no clear data favoring one inotrope over another,nd choice is driven by institutional practices. Preterm in-ants are more prone to infections; early removal of cathetersnd judicious antibiotic coverage are of benefit.

Finally, maintenance of core temperature is crucial, pre-ature infants are prone to hypothermia because of their thin

kin and a relatively greater body surface area.

Neonatal CardiacCare, A Collaborative ModelThe benefits of specialized units were realized in the 1960s,leading to the establishment of dedicated coronary care

units.140 Quick proliferation of adult cardiac intensive/coro-

nary care units followed.141 A similar pattern is observed incritical care of children. Cardiac intensive care units dedi-cated to the care of children with heart disease have rapidlyflourished. A recent analysis of outcomes based on care mod-els in congenital heart surgery has not demonstrated superioroutcomes in dedicated pediatric cardiac intensive careunits.142 This result lends support to the thesis that although

hysical structural elements of a dedicated unit are impor-ant, human resources and processes involved in deliveringare are more critical.143,144

We believe that term and preterm neonates with congen-ital heart disease benefit from the expertise of personneltrained or experienced in the care of newborns. This shouldinclude pediatric intensivists, cardiologists, neonatologistsand neonatal nurses, and other medical caregivers trained inthe care of the newborn infant. A collaborative model with allcaregivers exhibiting expertise in neonatal cardiac care wouldbe ideal and would meet the specific needs of the newborninfant with congenital heart disease.

In summary, neonates are not just “little children.” Theydiffer from older children not just in weight or height, but inthe physiology of their maturing organ systems. Understand-ing their limitations is the first step in differentiating the caredelivered to them.

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