In the past quarter century, two population studies, the New England Regional Infant Cardiac Program ²⁹⁰ and the Baltimore-Washington Infant Study,^263,²⁶⁴ increased understanding of the incidence and etiology of CHD. Recent years have brought the human genome project, advances in molecular biology, and expanded capabilities for chromosomal analysis. Small chromosome deletions and duplications can be identified through fluorescence in situ hybridization (FISH) and, more recently, array comparative genomic hybridization (A-CGH), which opens the door to identification of a greater number of genetic diagnoses. All of these factors combined with the epidemiologic results of the population studies mentioned above are contributing to the identification of genes that cause syndromes as well as isolated congenital heart defects, classification of the pathologic processes of embryology that are triggered by genetic abnormalities, and correlation between genotypes and various phenotypes (the characteristic features).^265,^657,⁶⁹⁹ These methods are enabling identification of chromosome anomalies and gene abnormalities that are a result of new or inherited mutations. These and other new developments are leading to better genetic testing, improved diagnostic and prognostic capabilities, future research opportunities, and enhanced care planning and counseling.⁹³²

Findings about noninherited risk factors for congenital heart disease have also expanded. Knowledge about prescription and nonprescription drugs, environmental influences (chemical, physical, and biologic agents/teratogens), and parental diseases have enhanced our understanding about the etiologies of CHD.

Whether the triggering event is a teratogen, a genetic abnormality, or unknown, the pathogenesis of congenital heart defects follow six mechanisms as proposed by Clark ^181,^182,^506,⁷⁴⁷:

I. Ectomesenchymal tissue migration or neural crest abnormalities, resulting in conotruncal (ventricular outflow) and aortic arch anomalies;

II. Abnormalities of intracardiac blood flow, resulting in hypoplasia of structures through which flow was diminished or absent;

III. Cell death abnormalities, resulting in Ebstein malformation and muscular ventricular septal defects;

IV. Extracellular matrix abnormalities, resulting in anomalous formation of the endocardial cushions (atrioventricular septal and canal defects);

V. Abnormal targeted growth, resulting in anomalies of pulmonary venous and left atrium formation; and

VI. Abnormal situs and looping, resulting in malposition of organs, structures, and vascular connections.

An etiologic event triggers abnormal pathogenesis and each of the preceding pathogenetic mechanisms can cause a spectrum of disorders.

Exploration of anomalies in terms of a common pathogenetic mechanism allows researchers to learn more about familial patterns. As more information about the interaction of genes, environment, and proteins involved in developmental pathways is available, our understanding of the biologic basis of normal and abnormal cardiovascular embryologic development (morphogenesis) will be refined.⁵⁰⁶ Further information on cardiovascular morphogenesis is provided in the section, Fetal Development of the Heart and Great Vessels.

Although most congenital heart disease was previously believed to be of multifactorial etiology (a combination of a number of genetic factors from both parents, environmental influences, and random events), new information has led to the belief that most human CHDs result from single gene defects ⁵⁰⁶ and some from exposure to teratogens. Nevertheless, at this point, for most patients with CHD there is not a precise identifiable cause.⁵⁰⁶ Congenital heart defects are thought to be related to teratogens in 2% to 4%, genetics in 10% (although this is probably underestimated), and unknown in 85% to 90%.^190,²⁷⁷ As discoveries continue, the percentage with unknown cause should decrease.

This section further describes the teratogens and genetics associated with CHDs as an isolated defect or in association with extracardiac anomalies. These are divided into noninherited and inherited risk factors that lead to CHD.

Noninherited Risk Factors for CHD (Many Potentially Modifiable)

Maternal Disorders or Biologic Teratogens

Maternal disorders or biologic teratogens associated with increased incidence of CHD include phenylketonuria (PKU), diabetes, infections, obesity, systemic lupus erythematosus, and epilepsy.²⁷⁷ When a mother has untreated PKU during pregnancy, the fetus may have growth and mental retardation and has a 20% to 25% incidence of CHD. Maternal control of blood phenylalanine concentration and adequate maternal nutrition before and throughout the pregnancy must occur to reduce the risk. All babies conceived when the mother was receiving inadequate nutrition should have an echocardiogram.⁵⁵⁸ The most frequently associated defects are tetralogy of Fallot, ventricular septal defect (VSDs), patent ductus arteriosus (PDA), and single ventricle.⁴¹⁴

Maternal pregestational insulin dependent diabetes increases fetal risk of CHD. The most common defects are malformations with laterality or embryologic heart tube looping defects, transposition of the great arteries, conotruncal defects (e.g., tetralogy of Fallot, interrupted aortic arch, truncus arteriosus), VSDs, atrioventricular septal (AV canal) defects, hypoplastic left heart syndrome, outflow tract defects, PDA, and hypertrophic cardiomyopathy (which may resolve).⁴¹⁴ Less frequently, gestational diabetes also has been associated with CHDs, and these cases may represent women who have undetected type 2 diabetes. Adequate blood sugar control before and during pregnancy does reduce the risk.^414,⁷⁹⁵

Maternal infections have long been associated with CHD. Maternal rubella has been associated with PDA, pulmonary valve abnormalities, peripheral pulmonary stenosis, and VSDs. Immunization of women against rubella can eliminate this risk. More recently other maternal febrile illnesses (such as influenza) in the first trimester have been associated with a variety of heart defects, but it is unknown whether the fever, infectious agent, or medication to treat the fever and infection cause the effect.^190,⁴¹⁴ Although HIV infection in utero increases the risk of dilated cardiomyopathy and left ventricular hypertrophy, it has not been associated with structural cardiac defects.⁴¹⁴

Maternal obesity before pregnancy has been associated with CHD, but findings are inconsistent. The many complex variables with obesity and nutrition make this a difficult area for drawing conclusions.⁴¹⁴ Connective tissue disorders such as systemic lupus erythematosus in women are associated with congenital heart block in infant offspring. Maternal connective tissue disorders have not been associated with structural cardiac malformations.⁴¹⁴

Maternal epilepsy is associated with increased incidence of CHD. The therapy of anticonvulsant drugs and their potential impact on folate metabolism—rather than the seizures themselves—may increase the risk.⁴¹⁴

Maternal Drug Exposure (Chemical Teratogens)

Of note, use of maternal multivitamins and folic acid in the periconceptual period may reduce the risk of CHDs, but the evidence is not yet conclusive. These supplements may reduce the risk of CHD when used with some other agents that are associated with an increased risk of CHD, for example maternal febrile illness. Further studies are needed.⁴¹⁴

Exposure to chemical agents can alter cellular development, and the timing of such exposure can influence the effect on risk. Identification of timing related to fetal vulnerability could help ensure counseling about treatment options to avoid critical exposures for a susceptible embryo.^190,^277,⁴¹⁴ Many therapeutic drugs used preconceptually or during pregnancy have been linked with possible associated risk of congenital heart disease. (The interested reader can find a list on the Evolve Website. Please see Evolve Box 8-1 in the Chapter 8 Supplement on the Evolve Website.) Because much of the evidence is inconclusive and there are always reports from new studies, research and caution is urged before use of any therapeutic drugs during the periconceptual period and pregnancy.

Nontherapeutic drugs used preconceptually and/or during pregnancy that have been associated with increased risk of CHD include: alcohol, cocaine, marijuana, cigarette smoking, and vitamin A in high doses. Again, the evidence is often inconclusive, so actual risks can be difficult to determine. Many other agents have been studied but the data are insufficient to determine risks for cardiac defects.^414,⁷⁵⁴

Environmental Exposures (Chemical, Biologic, and Physical Teratogens) and Influences

Increased risk of a variety of CHDs has been associated with maternal occupational exposure to organic solvents (compositions of solvents can include degreasers, dyes, lacquers, paints, glycol ethers, and mineral oil products); heavy metals; herbicides, pesticides, and rodenticides associated with maternal employment in the agriculture industry; air quality (increased levels of ambient carbon monoxide, ozone, and dioxide); and parental exposure to groundwater contamination with trichloroethylene. There are other environmental exposures, such as hazardous waste sites and occupational exposure to ionized radiation, but no consistent association with CHD has been found.^414,⁸⁶⁶

Evaluation of maternal sociodemographic characteristics has shown that maternal age is not associated with nongenetic CHDs as a group. Some specific defects are more likely with advanced maternal age, and young maternal age is associated with tricuspid atresia.⁴¹⁴ Some studies have shown disparity of incidence between white and black infants, with many defects being more prevalent in white infants, whereas pulmonary stenosis is more prevalent in black infants. Other studies have not shown variations in prevalence of birth defects in general among white, black, and Hispanic infants.⁴¹⁴ Reproductive problems (miscarriage, stillbirth, or preterm birth) have been associated with increased incidence of tetralogy of Fallot, nonchromosomal atrioventricular canal defects, ASDs, and Ebstein’s anomaly, where the association could represent exposure to teratogens or an inherent susceptibility.⁴¹⁴ Maternal stress associated with job loss, divorce, separation, or death of a close relative or friend, especially in mothers who were not high school graduates, was found to be associated with a greater prevalence of conotruncal heart defects.⁴¹⁴

Paternal exposures and factors may also play a role in noninherited cardiac defects. Older fathers have been associated with Marfan syndrome. Studies have suggested that increasing paternal age is associated with ASDs, VSDs, PDA, and tetralogy of Fallot, whereas children of men less than 20 years of age were also at higher risk for septal defects.⁴¹⁴ Other paternal exposures have been investigated in a limited number of studies, with the suggestion or trend toward increased risk of CHD associated with paternal exposure to marijuana, cocaine, cigarette smoking, and alcohol.⁴¹⁴

A unique environmental influence may be present for some monochorionic twins. The smaller twin is more often affected with CHD, which may result from abnormal cord insertion.³⁷³

Prevention of some CHDs may be accomplished by following these recommendations for mothers who wish to become pregnant: Take a multivitamin with folic acid daily, obtain prenatal and preconceptual care for management of maternal disorders associated with increased risk of CHD, discuss use of any drugs with the healthcare provider, avoid contact with people who have the flu or other febrile illnesses, avoid exposure to organic solvents,⁴¹⁴ and follow any employer guidelines established to avoid exposures that may increase risks.

Genetic Factors Associated with CHD

New findings with molecular genetic studies indicate that the genetic contribution to the etiology of CHD has been underestimated. With the rapid changes in this field it is certain that our understanding will be evolving and the identifiable genetic etiologies of CHD will continue to expand.⁷⁰⁰ Review of current literature will always be necessary to have an accurate understanding of these factors.

Humans normally have 46 chromosomes (23 pairs). The first 22 pairs are autosomal (non-sex) chromosomes and the 23rd pair determines gender (XX = female, XY = male). Each chromosome has two arms held together by a centromere—a short arm (p) and a long arm (q). There are more than 35,000 pairs of genes on our chromosomes,¹⁹⁰ and each gene is composed of hundreds or thousands of base pairs. An abnormality in a single base pair can cause a malfunction. Changes in the deoxyribonucleic acid (DNA) sequence (a mutation) in a single gene changes the path of a protein, which is like changing one part of a recipe. (The results can range from asymptomatic to disastrous malformations.) Mutations may occur de novo (a new mutation that is not inherited from a parent) or may result from autosomal-dominant or -negative inheritance. Many gene mutations associated with cardiovascular malformations are now being identified.^190,^277,⁷⁰⁰

Before advanced cytogenetic tests were available, chromosome abnormalities were found in approximately 8% to 13% of neonates with CHD,²⁶³ but with new testing the prevalence of chromosome aberrations is now estimated to be much higher.⁷⁰⁰ These abnormalities can be aneuploidies (abnormal number of chromosomes) such as trisomies (an extra chromosome), or tetrasomies. Other chromosome abnormalities are caused by deletions (a missing piece), duplications (extra genetic material on chromosome), or translocations (genetic material transferred from one chromosome to another).^190,²⁷⁷ Single gene defects have been thought to account for about 3% to 5% of those CHDs with a genetic etiology, but new findings indicate that this range substantially underestimated the problem. Any genetic defect can start an embryonic chain reaction, which can create mild to severe phenotypic expression of the abnormality.⁸⁰³

Inheritance of genetic abnormalities associated with CHD can occur in several ways. Deletions, duplications, and single gene defects can all be the result of a mutation (a sporadic change in DNA sequence triggering abnormalities) or Mendelian inheritance from parents with the same gene anomaly. If both parents must contribute the abnormality it is autosomal recessive—both parents carry the genetic difference, but the parents will only have the disorder if they, too, have two genes with the difference. If the anomaly is inherited when only a single parent is a carrier, the inheritance is autosomal dominant, and in this situation that parent also has the condition.

Cardiovascular malformations can occur as a part of a group or pattern of anomalies. A syndrome, a combination of multiple anomalies occurring together resulting from a single cause (the cause is often a genetic error but the cause may be unknown), is thought to cause about 5% of the CHD. More than 400 genetic syndromes list CHD as a possible manifestation.^651,⁸⁰³ Associations, a group of anomalies that occur in a recurrent pattern, may also involve CHDs. There may be no known genetic basis for an association. Inherited metabolic diseases have a variety of genetic etiologies and may include cardiovascular problems.

For more information on characteristics and etiologies of specific defects and conditions see Tables 8-1 and 8-2. There are hundreds of syndromes and conditions with multiple manifestations that involve cardiovascular malformations. Table 8-2 includes an abbreviated table, and a more comprehensive table with genetic associations is provided in Evolve Table 8-1 in the Chapter 8 Supplement on the Evolve Website.

Table 8-1 Cardiac Defects and Associated Genetics, Teratogens, and Exposures ³²⁸^,⁴¹⁴^,⁷⁰⁰^,⁸⁷¹^,⁹³²

Cardiac Defect	Associated Genetics, Teratogens, and Exposures
Any congenital heart defect	Maternal PKU, pregestational diabetes, febrile illness, influenza, rubella, epilepsy, anticonvulsants, NSAIDS/Ibuprofen, sulfasalazine (antiinflammatory), thalidomide, trimethoprim-sulfonamide, and vitamin A congeners/retinoids. Many illnesses, medical and substance exposures, as well as sociodemographic factors have been studied, but there have been insufficient data to determine risks for CHD with these. Somatic mutations (occur after fertilization and therefore only affect some cells or tissues) are hypothesized to be an important cause of isolated CHDs.
Aortic atresia	See HLHS
Coarctation of the aorta	Turner syndrome. Familial left-sided obstructive heart defects. Deletion of chromosome locus 18p. Duplications in chromosome 4p, 4q, 6q, or 10p. Trisomy 8 or 9. Maternal exposure to organic solvents.
Supravalvular aortic stenosis	Williams-Beuren syndrome. Deletion or translocation (rare) in chromosome locus 7q11. Elastin gene mutations.
Aortic valve or LV outflow tract obstruction	Deletion of chromosome locus 11q or 10q. Trisomy 13 or 18. Duplications of chromosome locus 1q, 2p, 2q, 6q, or 11q. NOTCH 1 gene mutations. Noonan, Turner, or Jacobsen syndromes. Pregestational diabetes. Maternal vitamin A exposure.
Atrial septal abnormalities	Holt Oram, Ellis-van Creveld, Noonan, Rubinstein-Taybi, Kabuki, Williams, Goldenhar, thrombocytopenia-absent radius, Klinefelter, or (rare) Marfan syndrome. Mutations of TBX5 gene on chromosome 12q24.1, NKX2.5 gene on chromosome 5, EVC gene on chromosome 4p16.1, MYH6 gene, or GATA 4 gene. Deletions on chromosome 1, 4, 4p, 5p, 6, 10p, 11,13,17,18, or 22. Trisomy 18 or 21. Pregestational diabetes. Familial ASDs with AV conduction disturbances without extracardiac manifestations (may also have VSD, TOF, and others) has been associated with mutations of NKX2.5 on chromosome 5. Familial ASD without AV conduction disturbances without extracardiac manifestations (may also have VSD and/or PS) has been associated with mutations of GATA 4 gene with variable expression and autosomal dominant inheritance. This condition has also been associated with mutations of NKX2.5 on chromosome 5.
Atrioventricular septal abnormalities/atrioventricular canal/endocardial cushion defects	Trisomy 21, 13 or 18. Deletions of chromosome 3p25, 8p2, or 22q. Duplications of chromosome 10q, 11q, 22q. Holt-Oram, Noonan, Smith-Lemli-Opitz, or Ellis-van Creveld syndrome. Mutation of gene on chromosome 1p21-p31. CRELD1 gene mutations. Chondrodysplasias. Pregestational diabetes. Maternal exposure to organic solvents. Familial AVSD (partial or complete) without extracardiac manifestations has been associated with gene locus on 1p21-p31 mutation with autosomal dominant inheritance.
Bicuspid aortic valve	Turner syndrome. Familial left-sided obstructive heart defects. Deletion of chromosome locus 10p. Duplications in chromosome 6q. Trisomy 13 or 18. BAV without extracardiac manifestations may be associated with other CHDs (especially CoA) and ascending aortic aneurysm is associated with Notch1 gene mutations with autosomal dominant inheritance.
Conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch and others)	Deletion of chromosome 22q11.2. Mutations of NKX2.5 and 2.6. Pregestational diabetes. Maternal exposure to organic solvents.
Double-outlet right ventricle	Trisomy 9, 13, or 18. Duplications on chromosome 2p or 12p. Deletion of 22q11 (rare).
Ebstein anomaly	Most cases are sporadic. Chromosome abnormalities are rare. Has been reported with Trisomy 21, abnormalities of 11q with renal malformation, and Pierre Robin sequence. Familial occurrences are rare but are associated with family members with mitral valve abnormalities or with familial atrial conduction problems. Animal studies are suggestive of a genetic connection with genes on chromosome 17q. Maternal marijuana. Maternal exposure to organic solvents.
Heterotaxy syndromes with complex CHD—laterality and looping abnormalities	Chromosome locus 2 (CFC1 gene encoding CRYPTIC protein), 6q (HTX3 gene), LEFTY A gene, or X-linked q26.2 or Xq24-47 (ZIC3 gene). Pregestational diabetes.
Hypoplastic left heart syndrome	Deletion of chromosome locus 11q (Jacobsen syndrome). Turner or Wolf-Hirschhorn (deletion of 4p) syndromes. Trisomy 13 or 18. Familial left-sided obstructive heart defects. Pregestational diabetes. Maternal exposure to organic solvents.
Interrupted aortic arch	Deletion 22q11.
Left-sided obstructive heart disease—familial—CoA, aortic atresia/HLHS, BAV	Increased occurrence of these lesions in first-degree relatives. Inheritance patterns may be multifactorial, autosomal dominant with reduced penetrance, or autosomal recessive.
Left superior vena cava persistence	60% have other anomalies, 87% have other CHD, and 42% syndromes or other conditions (VACTERL, Down’s syndrome, CHARGE).
Patent ductus arteriosus	Char syndrome. Mutations of TFAP2B. Pregestational diabetes. Indomethacin tocolysis.
PA branch stenosis	Alagille, congenital rubella, Ehlers-Danlos, Noonan, Costello, Cardiofaciocutaneous, LEOPARD, or Williams-Beuren syndromes. Deletions in chromosome locus 20p12. JAG1 gene mutation. Pregestational diabetes. Maternal vitamin A exposure. Maternal exposure to organic solvents.
Pulmonary Valve Obstruction	Noonan, Alagille, Costello, or LEOPARD syndromes. Mutations of PTPN11, KRAS, SOS1, and HRAS genes. Chromosome deletions of 1p, 8p, 10p, or 22q. Chromosome duplications of 6q, 15q, or 19q. Trisomy 8. Maternal vitamin A exposure. Maternal exposure to organic solvents. Maternal rubella.
Tetralogy of Fallot	Deletion of 22q11, 5p or many other chromosomes. Duplication on chromosome 22 and many other chromosomes. Alagille (JAG1 gene), Noonan (PTNP11), Cat-eye, and nearly 50 other syndromes. Trisomy 18 or 21. Partial trisomy 8q. Translocation 1p36. Maternal exposure to organic solvents. Isolated TOF is associated with NKX2.5 mutations.
Total anomalous pulmonary venous return	Most cases are sporadic. Trisomy 8. Familial cases have been reported with familial scimitar syndrome and a chromosome 4p13-q12 abnormality with autosomal dominant inheritance and variable expression (a large Utah-Idaho family). Maternal exposure to organic solvents.
Transposition of great arteries	Rarely associated with chromosome abnormalities or syndromes. Pregestational diabetes. Maternal exposure to organic solvents.
Tricuspid atresia	Most cases are sporadic. Chromosome abnormalities are rare with tricuspid atresia, but deletions of 22q11 and 4p and duplications of chromosome 22 have been reported. Familial occurrences are rare but have been reported. A gene mutation has been associated in mice, which suggests a genetic basis for this disease.
Truncus arteriosus	Deletion on chromosome 22q11 or 10p. Trisomy 8. An autosomal recessive form has been mapped to chromosome 8p21.
Ventricular septal abnormalities	Holt Oram, Rubinstein-Taybi, Goldenhar, Costello, Williams, Kabuki, Cornelia de Lange, Apert, or Carpenter syndrome. VACTERL association. Familial ASD with or without AV conduction disturbances. TBX5 or GATA 4 mutation. Deletions or duplications of many chromosomes. Trisomy 13, 18, or 21. Pregestational diabetes. Maternal marijuana. Maternal exposure to organic solvents. Septal defects without extracardiac manifestations are associated with mutations in MYH6 and CITED2 genes.

ADD, Attention deficit disorder; AS, aortic stenosis; ASD, atrial septal defect; AV, atrioventricular; AVC, atrioventricular canal; AVSD, atrioventricular septal defect; BAV, bicuspid aortic valve; CA, coronary artery; CHD, congenital heart defect; CNS, central nervous system; CoA, coarctation of aorta; CV, cardiovascular; DCM, dilated cardiomyopathy; DORV, double-outlet right ventricle; GI, gastrointestinal; GU, genitourinary; HCM, hypertrophic cardiomyopathy; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; IVC, inferior vena cava; LSVC, persistent left superior vena cava; LV, left ventricular; LVOTO, left ventricular outflow tract obstruction; MV, mitral valve; NSAIDs, nonsteroidal antiinflammatory drugs; PA, pulmonary artery; PAPVR, partial anomalous pulmonary venous return; PAtresia, pulmonary atresia; PDA, patent ductus arteriosus; PKU, phenylketonuria; PPS, peripheral pulmonary stenosis; PS, pulmonary stenosis; RVOTO, right ventricular outflow tract obstruction; SVC, superior vena cava; SVT, supraventricular tachycardia; TAPVR, total anomalous pulmonary venous return; TEF, tracheoesophageal fistula; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

See Table 8-2 for more information on specific genes, syndromes, and conditions.

Table 8-2 Conditions, Cardiac Manifestations, and Genetics

Genetic Testing, Counseling, and Nursing Implications

Genetic testing can reveal important genetic patterns that are critical for identifying other important organ system involvement; gaining prognostic information; learning important reproductive risks for the family; and considering the appropriate testing of other family members.⁷⁰⁰ Genetic testing can be performed on blood lymphocytes, cord blood, skin, amniotic fluid, chorionic villi, and bone marrow. Current genetic tests available to be used in assessing CHD include:

• Standard chromosome analysis—reveals standard karyotype and is used to identify many chromosomal disorders, especially those in which there is an abnormal number of chromosomes.⁷⁰⁰

• High resolution banding—better defines chromosomal structure abnormalities such as duplications, deletions, and translocations of genetic material.⁷⁰⁰

• Fluorescence in situ hybridization (FISH)—specific DNA probes can be used to diagnose more subtle structural abnormalities such as microdeletions, tiny duplications, and/or subtle translocations.⁷⁰⁰

• Array comparative genomic hybridization (A-CGH)—even more sensitive than FISH for testing for tiny structural abnormalities of chromosomes.⁸⁶⁸

• Gene discovery—cloning techniques are used to identify genes that produce a protein associated with cardiogenic gene mutations.⁷⁰⁰

• DNA mutation analysis—identifies changes in the coding sequence of a gene to find small deletions, duplications, or substitutions that alter the resulting protein structure. Once a change is found, it must be determined if it constitutes a disease-causing mutation.⁷⁰⁰

As more etiologic genes are identified, progress can be made in determining mechanisms and interactions that cause various phenotypes. That may lead to the development of targeted therapies for patients and fetuses.⁸⁷¹

Genetic counseling is warranted when there is one major or two minor birth defects and may be employed to attempt to determine exact causes of anomalies in individual situations. Testing must be accurately ordered to direct the proper studies to obtain complete results. Simply ordering a karyotype will not achieve the targeted exploration that can be achieved with FISH or A-CGH studies. Information gathered enables practitioners to counsel the family on problems associated with a condition, allowing them to be proactive in their child’s care. Discussions with the family should be informative but not directive so that parents may make their own decisions.^190,⁶⁵¹

At the very least, preconceptual and prenatal counseling of all women of child-bearing age is important to encourage the use of multivitamins and folic acid supplements, avoiding contact with people with flu or other febrile illnesses, and avoiding exposure to organic solvents during pregnancy. Targeted counseling should be done with women who have specific risk factors to discuss any medications that must be considered with pregnancy. Prenatal testing is also available for some conditions, and early diagnoses can affect care management, morbidity, mortality, and family well-being.

Another feature of genetic counseling is providing recurrence risks. With the exception of possibly teratogen exposures, parents can be counseled that their actions did not cause the condition. For chromosomal deletions, duplications, translocations, and gene anomalies, parental testing may be recommended to determine recurrence risks. In cases of gene anomalies, commercial testing is available for some mutations. Testing capabilities continue to expand so follow-up genetic consultation may be warranted to realize the advantages of new technologies.

Recurrence risks for chromosomal trisomies are low if there are no other birth defects in the family and maternal age is not advanced. For a parent with an autosomal dominant genetic anomaly, there is a 50% risk of recurrence. In parents who have an autosomal negative genetic anomaly (without the evidence of the problem), both parents must have the anomaly to cause the resulting disorder. In these cases the recurrence risk for the couple is 25%. In X-linked recessive anomalies, the risk is 50% for a male to be affected and 50% for a female to be a carrier. In cases of unknown etiology (possibly multifactorial inheritance), if no other child in the family is affected the recurrence risk is presumed to be 3% to 5%, but this changes if a subsequent sibling is affected.^190,⁶⁵¹

Information about genetic conditions is widely available via websites and targeted support groups and associations (e.g., Online Mendelian Inheritance in Man, www.ncbi.nlm.nih.gov/Omim/). Web-based databases and support groups that provide valuable information are provided in the Chapter 8 Supplement on the Evolve Website.

The nursing implications of genetics involvement in congenital heart defects are significant. Nurses who are familiar with the patterns of anomalies can have a heightened index of suspicion when a single malformation is noted and findings can be unmasked. Nursing knowledge can be enhanced by familiarity with the most current scientific statements from the American Heart Association Congenital Heart Defects Committee, Council on Cardiovascular Disease in the Young on both the genetic basis and the noninherited risk factors for congenital heart disease.^414,⁷⁰⁰

Nurses are in a unique position to gather information from families and communicate those findings. Facts about previous pregnancies, parents’ siblings, childhood deaths, other birth defects, exposures, and much more can be revealing. Nurses are also in a unique position to support families through these challenging situations. Nurses must be prepared to provide families with appropriate resources and encourage referrals.

This quote from Joey’s Journey: Our Life with Lissencephaly, at http://lfurlotte.tripod.com expresses how parents may feel when they begin a journey with a child affected by anomalies and the support others can provide: “Life will never be the same again. However, with a little different perspective, life does go on and happiness does return.”⁴¹⁵

Fetal development of the heart and great vessels

Mary Rummell

Formation of the Heart Tube: Day 22

The cardiovascular system is the first system to function in the embryo. The critical period of cardiovascular growth begins at 15 to 18 days of gestation and is initiated by a period of rapid cell proliferation. During this period, the developing heart is most susceptible to teratogens (factors that can be harmful). Early development of the cardiovascular system is necessary because of the increasing need for nutritional and oxygen requirements by the rapidly growing embryo and for elimination of carbon dioxide and waste products. Moore et al.,⁶²⁷ Ransom and Srivastava,⁷²³ and Sander et al.,⁷⁶⁴ describe heart development as involving five primary steps:

1. Migration of precardiac cells from the primitive streak and assembly of paired cardiac crescents at the myocardial plate

2. Coalescence of the cardiac crescents to form the primitive heart tube, an event that establishes the definitive heart

3. Cardiac looping, a complex process that assures proper alignment of the future cardiac chambers

4. Septation and heart chamber formation

5. Development of the cardiac conduction system and coronary vasculature

The primordial heart and vascular system appear in the middle of the third week. The cardiovascular system is primarily derived from embryonic mesoderm and neural crest cells. The precardiac stem cells (mesoderm) migrate to form the cardiac crescents that fuse to form the single heart tube at 22 days (Fig. 8-1).^627,^723,^764,⁹⁰²

Fig. 8-1 Cardiac embryologic development—coiling of the heart tube. At approximately the 21st to 22nd day of fetal life, the two lateral endothelial heart tubes fuse to form a single endocardial tube. A, Between the 22nd and 28th days of life, the heart tube thickens. B, and C, the tube then coils to the right. D, By approximately the 28th day of fetal life, the tube is completely coiled, and major chambers can be identified. At this time, blood is flowing through the heart, and septation of the heart and great vessels can occur.

(Illustration by Marilou Kundemueller.)

At this time (22 days), circulation begins with ebb-and-flow blood flow from the venous to arterial poles. Premyocardial cells and neural crest cells continue to migrate into the region of the heart tube. The regulation of the mesoderm is partially controlled by retinoids, isoforms of vitamin A, that bind to specific nuclear receptors and regulate gene transcription and by extracellular matrix proteins, such as fibronectin, that direct cellular migration. The teratogenic effects caused by interaction of retinoid-like drugs on cell receptors are seen clinically (see Noninherited Risk Factors).⁷⁹

Formation of the Heart Loop: Day 22 to 28

Before and during the looping process, sections of the single heart tube begin to develop specialized cells that will ultimately become the chambers of the mature heart. A cascade of genes is expressed in the anterior (ventricular) and the posterior (atrial) portions of the tube. These genes regulate the cellular processes that transform the heart tube into a four-chambered heart. This transformation occurs through a balance of cell growth, cell differentiation, and cell death (apoptosis). Disruptions in these genetic mechanisms and specific cellular signaling processes result in cardiac malformations seen in congenital heart disease. Problems include defects in cardiac looping, septation, and chamber formation.⁷⁶⁴

The endocardial heart tube begins to expand and elongate and develops areas of dilation: the bulbus cordis (including the truncus arteriosus, conus arteriosus, and conus cordis), ventricle, atrium, and sinus venosus. This expansion and elongation results in coiling of the heart tube anteriorly and to the right (this is referred to as “dextral,” or “D-looping”), with creation of a bulboventricular loop (see Fig. 8-1, B and C).

Because the venous and arterial poles of the heart tube are fixed during this time of coiling, torsion occurs within the anterior portion of the loop, the truncus arteriosus. This torsion will later contribute to the formation of a spiral septum within the truncus. By the 26th day of gestation, a truncus arteriosus is visible in the center of the anterior portion of the heart, and a common atrium and ventricle are recognizable (see Fig. 8-1, D). By day 28 the looping process is complete.

The embryonic heart begins to contract by day 26 to 28, with cycles that are similar to those in mature hearts.⁷² In this “in-series circulation,” blood flows from the morphologically right atrium to the morphologically left atrium, left ventricle, right ventricle and then the truncus arteriosus.⁹⁰²

As the common atrium and ventricle divide into the chambers of the right and left heart, individual chambers are identified by their structure and appearance, or morphology. Structures should be identified by morphology rather than location because the location of the ventricles and great vessels may be abnormal when congenital heart disease is present.

When the ventricles rotate or loop normally to the right, a D-bulboventricular loop has occurred. The anatomic (i.e., morphologic) right ventricle is anterior (and to the right), and the anatomic (i.e., morphologic) left ventricle is posterior (and to the left). Later, normal division of the great vessels will result in location of the aorta posterior and to the right of the pulmonary artery. When the great vessels are in normal position and relationship, they are labeled “d-related great vessels” because the aorta is located to the right (dextral) of the pulmonary artery.

Malrotation during the formation of the ventricular loop may cause various cardiac malpositions (such as dextrocardia) and malformations. As noted, the normal direction for the ventricular loop is to the right, or D-looping. If the ventricles loop to the left instead, L-looping has occurred, so the morphologic left ventricle is located to the right, and the morphologic right ventricle is on the left (Fig. 8-2).

Fig. 8-2 Cardiac loop formation, The primordial heart tube during the fourth week. A, Normal looping (bending) to the right. B, Abnormal looping (bending) to the left.

(From Moore KL, Persaud TVN, Torchia MG: The cardiovascular system. The developing human: clinically oriented embryology, ed 8. Philadelphia, 2008, Saunders Elsevier.)

L-looping of the ventricles frequently is associated with transposed great vessels; this combination commonly is referred to as “corrected transposition of the great arteries.” It is a type of “transposition,” because the aorta lies to the left of the pulmonary artery. The great vessels are transposed: the ascending aorta is anterior and arises from an anatomic (morphologic or structural) right ventricle, sweeping to the left, and the pulmonary artery is posterior and arises from the anatomic (or morphologic or structural) left ventricle. The term “corrected” is appropriate because the hemodynamic pathways are not altered; systemic venous return ultimately enters the pulmonary circulation, and pulmonary venous return enters the systemic circulation. The systemic venous return enters the right atrium, flows through a mitral valve into a morphologic left ventricle, and is then ejected into a posterior pulmonary artery. The pulmonary venous return flows into the left atrium, exits through a tricuspid valve into a structural right ventricle and is then ejected into an anterior aorta. Although the heart is not normal, the child will be asymptomatic unless a complicating heart lesion is present.

Complete congenital heart block, ventricular septal defect, tricuspid valve anomalies, and cardiac malpositions are common among children with l-transposition. It is important to remember that the mitral valve is located with the morphologic left ventricle in corrected transposition, and that these structures receive systemic venous return; the tricuspid valve is associated with the morphologic right ventricle, receiving pulmonary venous return. Therefore if tricuspid atresia is present, obstruction to pulmonary venous return occurs (because the tricuspid valve is located abnormally on the left side). Ebstein’s malformation, an abnormality of the tricuspid valve, produces signs associated with mitral insufficiency (e.g., pulmonary edema). The use of the phrase “ventricular inversion with transposed great vessels” probably would be less confusing than “corrected transposition.”

Formation of Cardiovascular Septation: Day 26 to 49

Cardiac septation occurs after the looping process is complete. During the septation process, septae are formed that ultimately close the ostium primum, the central atrioventricular canal, and the interventricular foramen. At the end of this period, the in-series circulation becomes two parallel circulations.⁹⁰²

Endocardial Cushion Development: Day 26 to 40

Septation begins on day 26 with the ingrowth of large tissue masses, the endocardial cushions. These cushions form on the dorsal and ventral walls of the atrioventricular (AV) canal separating the primordial atrium from the primordial ventricle.⁶²⁷ These cushions contain mesenchymal cells, derived from endocardium, and cardiac jelly, derived from endothelium. The endothelial cells line the atrioventricular canal and conotruncal segments. Neural crest cells migrate into the pharyngeal arches and then to the endocardial cushions, where they play a role in the septation of the cardiac chambers, outflow tracts, and heart valves. From the endocardial cushions, the neural crest cells then invade the myocardium.

Genetic disruptions in neural crest cell development are not fully understood, but patients with DiGeorge, Alagille, and Noonan syndrome have congenital heart defects that are influenced by cardiac neural crest cells.⁷⁶⁴

Defects in the formation of the endocardial cushions can result in an ostium primum atrial septal defect, a ventricular septal defect (that may allow an interventricular shunt, or simply may result in a deficiency of ventricular septal tissue), anomalies of the tricuspid and mitral valves (including tricuspid atresia), or in a complete atrioventricular septal defect (AVSD, also referred to as AV canal).

Atrial Septation: Day 30 to 35

Septation of the atria begins around day 30. Two septae develop and are modified to form a flapped orifice, the foramen ovale as illustrated in Fig. 8-3. The first septum to form is the septum primum, which grows from the anterior, superior portion of the atrium and extends toward the center of the heart. The development of the septum primum leaves a gap, the ostium primum, in the inferior portion of the atrial wall; this gap normally is closed by the fusion of the endocardial cushions. As the ostium primum is closing, perforations produced by apoptosis begin to form in the central portion of the septum primum. These perforations coalesce to create the ostium secundum (see Fig. 8-3, C and D).⁶²⁷

Fig. 8-3 Atrial and ventricular septation. (A-E) Drawings of the developing heart showing partitioning of the atrioventricular canal, primordial atrium and ventricle. A, Sketch showing the plane of the sections. B, Frontal section of the heart during the fourth week (approximately 28 days) showing the early appearance of the septum primum, interventricular septum, and dorsal endocardial cushion. C, Similar section of the heart (approximately 32 days) showing perforations in the dorsal part of the septum primum. D, Section of the heart (approximately 35 days) showing the foramen secundum. E, At approximately 8 weeks, showing the heart after it is partitioned into four chambers. The arrow indicates the flow of well-oxygenated blood from the right to the left atrium. F, Sonogram of a second trimester fetus showing the four chambers of the heart. Note the septum secundum (arrow) and the descending aorta.

(Courtesy of Dr. G. J. Reid, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba, Women’s Hospital, Winnipeg, Manitoba, Canada.) (From Moore KL, Persaud TVN, Torchia MG: The cardiovascular system. The developing human: clinically oriented embryology, ed 8. Philadelphia, 2008, Saunders Elsevier.)

The septum secundum is the second septum to form within the atria. It is a thick crescent-shaped muscular fold that grows immediately adjacent to the septum primum. As it grows, it overlaps the foramen secundum in the septum primum. The atrial partition is incomplete, forming an oval foramen (in Latin, the foramen ovale).⁶²⁷

The portion of the septum primum that is attached to the cranial portion of the atrium gradually disappears. The remaining portion of the primum septum that is attached to the fused endocardial cushions forms the flap of tissue called the valve of the oval foramen.⁶²⁷

Before birth the foramen ovale allows the oxygenated blood from the placenta entering the right atrium via the inferior vena cava to flow to the left atrium and to the fetal brain. (See section, Fetal Circulation that follows.) The flap of the oval foramen normally prevents flow in the opposite direction.⁶²⁷

Atrial septal defects occur when the primum septum or the secundum septum or both do not completely form. Atrial septal defects include an ostium primum, secundum atrial septal defect, or common atrium. An ostium primum atrial septal defect is located near the atrioventricular valves. This defect will not close spontaneously. An ostium secundum atrial septal defect is thought to result from excessive apoptosis of the septum primum, so that a large defect is present in the area of the foramen ovale. Some secundum defects decrease in size and some undergo spontaneous closure.⁷²³

Ventricular Septation: Day 25 to 49

Septation of the ventricles begins around day 25 with protrusions from the inlet (primitive ventricle) and outlet (bulbus cordis) segments of the primordial heart. The muscular intraventricular septum initially grows from the apex of the ventricle and increases with dilation of both ventricles. With rapid proliferation of the myoblasts in the septum, the muscular septum extends toward the center of the heart.^79,⁶²⁷ At first there is a crescent-shaped intraventricular foramen between the septum and endocardial cushions. The right and left bulbar ridges and the fused endocardial cushions join with the intraventricular muscular septum to form the membranous septum, obliterating the intraventricular foramen (refer again to Fig. 8-3, B-E).

As the ventricular cavities develop, the walls form a sponge work of muscular bundles. Some of the bundles become the papillary muscles and the tendinous cords (Latin, chordae tendineae) of the atrioventricular valves.⁶²⁷ Ventricular septal defects can occur in any location in the developing ventricular septum. Some muscular defects will close spontaneously.⁷²³

Septation of the Truncus Arteriosus: Day 26 to 42

Active proliferation of the mesenchymal cells in the walls of the bulbus cordis form the conotruncal or bulbar ridges. Similar ridges form in the truncus arteriosus (Fig. 8-4).

Fig. 8-4 Division of truncus arteriosus into pulmonary artery and aorta. Partitioning of the bulbus cordis and truncus arteriosus. A, Ventral aspect of heart at 5 weeks. The broken lines and arrows indicate the levels of the sections shown in B. B, Transverse sections of the truncus arteriosus and bulbus cordis, illustrating the truncal and bulbar ridges. C, The ventral wall of the heart and truncus arteriosus has been removed to demonstrate these ridges. D, Ventral aspect of heart after partitioning of the truncus arteriosus. The broken lines and arrows indicate the levels of the sections shown in E. E, Sections through the newly formed aorta (A) and pulmonary trunk (PT), showing the aorticopulmonary septum. F, 6 Weeks. The ventral wall of the heart and pulmonary trunk has been removed to show the aorticopulmonary septum. G, Diagram illustrating the spiral form of the aorticopulmonary septum. H, Drawing showing the great arteries (ascending aorta and pulmonary trunk) twisting around each other as they leave the heart.

(From Moore KL, Persaud TVN, Torchia MG: The cardiovascular system. The developing human: clinically oriented embryology, ed 8. Philadelphia, 2008, Saunders Elsevier.)

The mesenchymal cells in these ridges are primarily from neural crest cells. As cell proliferation occurs, the truncal and bulbar ridges create a 180-degree spiraling. This spiraling may be enhanced by the streaming of blood from the ventricles, as illustrated, or may result from passive untwisting as the pulmonary artery passes from the anterior pulmonary valve to the posterior pulmonary bifurcation.⁹⁰²

The spiraling of the conotruncal septum aligns the future pulmonary artery to the anterior and rightward right ventricle, where it joins with the outflow tract (infundibulum) created by incorporation of the bulbus cordis into the right ventricle. The future aorta communicates with the posterior and leftward left ventricle at the aortic vestibule created by incorporation of the bulbus cordis below the aortic valve.⁶²⁷ Differences in cell growth create a separation between the tricuspid and pulmonary valve. Disappearance of this segment below the aortic valve provides fibrous continuity between the mitral and aortic valve.⁷⁹

Defects in the conotruncal and aortic arch development do not close spontaneously. Congenital heart defects that result from defective conotruncal development include: truncus arteriosus, tetralogy of Fallot, pulmonary atresia, double-outlet right ventricle, interrupted aortic arch, and aortopulmonary window. These defects are often associated with genetic deletions of chromosome 22q11 (see section, Genetic Factors Associated with CHD).^627,⁷²³ Failure of appropriate conal reabsorption of the subaortic conus is thought to produce improper truncal rotation and result in d-transposition of the great vessels.

Formation of the Cardiac Valves: Day 34 to 42

The semilunar valves form when truncal septation is nearly complete. They develop from three swellings of subendocardial tissue around the openings of both the aortic and pulmonary trunks. The signaled transformation of endocardial cells to mesenchymal cells creates the differentiation of fibrous valve tissue.³⁰ This fibrous tissue is hollowed out and reshaped to form three thin-walled cusps for each valve.⁶²⁷ Congenital heart defects that result during valve formation include pulmonary valve stenosis or atresia, pulmonary infundibular stenosis, a bicuspid aortic valve, and aortic stenosis.

The atrioventricular valves develop from localized proliferation of tissue around the atrioventricular canals.⁶²⁷ Most of the atrioventricular valve tissue comes from the ventricular myocardium in a process that involves undermining the ventricular walls. This process is asymmetric and positions the tricuspid valve annulus closer to the apex of the heart than the mitral valve annulus. Physical separation of these two valves creates the atrioventricular septum. Absence of this septum is the common defect in children with atrioventricular septal defects. Ebstein anomaly is thought to result from incomplete undermining of the ventricular wall.⁷⁹

Classification of Complex Cardiac Malpositions and Malformations

Complex cardiac malformations and malpositions can be described according to a labeling system proposed by Van Praagh.⁹⁰² This classification included 10 cardiac segments, but three were used most often. The positions of the viscera, the ventricular loop, and the great arteries are all labeled separately, using three letters within curved brackets, such as {A, B, C}.

The cardiac chambers and organ segments are identified by morphology (i.e., structure and appearance); the segments then can be referred to as concordant (consistent in position), or discordant (inconsistent in position). Although this segmental description of congenital heart defects is not used for the most common forms of defects, it is used in the classification of cardiac malpositions (e.g., dextrocardia or dextroversion) and complex transpositions. A variation of the Van Praagh segmental classification has been published recently ³⁴³ using six segments (systemic and pulmonary veins, atrial situs, atrioventricular connection, ventricles and infundibulum, ventricle to artery connection, and great arteries and the ductus arteriosus). The following section identifies the three most commonly used segments for identification.

Development of the Aortic Arch: Day 28 to 49

Two large arteries form at the distal end of the truncus arteriosus during the fourth and fifth weeks of fetal development. Although these original arteries ultimately disappear, they give rise to six pairs of arteries, the six aortic arches. By the end of the fourth week the first two pairs and the fifth pair of aortic arches have disappeared, and the sixth pair of arches now is joined to the pulmonary trunk and contributes to the development of the ductus arteriosus. Ultimately the third aortic arch will form the common carotid artery, the external carotid artery, and part of the internal carotid artery. The fourth aortic arch forms part of the final aortic arch and the proximal portion of the right subclavian artery. The sixth aortic arch provides the proximal segment of both pulmonary arteries and the ductus arteriosus, and a branch develops with the lung buds to provide pulmonary blood flow (see Evolve Fig. 8-1 in the Chapter 8 Supplement on the Evolve Website). Abnormalities in formation of the aortic arches can result in an interrupted aortic arch, aortic atresia, patent ductus arteriosus, vascular rings (including double aortic arches), and aberrant origin of the right subclavian artery.

Development of the Ventricular Myocardium, Conduction System, and Coronary Circulation

After the neural crest cells enter the endocardial cushions, they migrate to the myocardium. The myocardium then develops into a working myocardium and the cardiac conduction system. Originally the atrium acts as the pacemaker of the heart. The sinoatrial node develops during the fifth week. Additional cells from the right atrial wall join with cells from the atrioventricular region to form the atrioventricular node and His bundle located just above the endocardial cushions. Bundle branches are found throughout the ventricular myocardium.⁶²⁷

Additional cells develop from a small, transient organ, the proepicardium, on the dorsal thoracic wall. The proepicardial cells contain mesothelial cells that migrate to the heart and form the epicardium that lines the heart. These cells migrate further and differentiate to form the coronary vasculature and cardiac fibroblasts.⁷⁶⁴

In prenatal life myocardial cells undergo significant changes to increase in number (hyperplasia) and size (hypertrophy). The myocardial cells also change shape from round to cylindrical, become more regular in the orientation of the myofibrils (the contractile element), and have increasing proportions of myofibrils. Developmental changes are also seen in the sarcolemma (plasma membrane) and sarcoplasmic reticulum. Both control the ion channels and transmembrane receptors that regulate cardiac function, depolarization, and repolarization. Maturation of these cells and functions continues into the neonatal period.⁷⁹

Fetal Circulation

Fetal circulation differs anatomically and physiologically from postnatal circulation in several important ways. In the fetus, oxygenation of the blood occurs in the placenta, which is a relatively inefficient oxygenator. The fetus is hypoxemic, with an aortic arterial oxygen tension of approximately 20 to 30 mm Hg; the saturation of fetal hemoglobin is higher at this oxygen tension than is normal hemoglobin, so oxygen saturation is approximately 60% to 70%. The fact that the oxygen tension is normally much lower in the fetus than postnatally may account for the ability of the neonate to tolerate cyanotic heart disease.²⁷⁸ Despite this arterial hypoxemia, the fetus does not have tissue hypoxia because fetal cardiac output is higher than at any other time in life, averaging approximately 400 to 500 mL/kg per minute. Approximately 20% of the normal fetal oxygen consumption of 8 mL/kg per minute is required to develop new tissue.²⁷⁸ Fetal cardiac output is constant (at approximately 400 to 500 mL/kg per minute) at a heart rate greater than 120 to 180/min. Changes in preload result in very little change in cardiac output, and changes in afterload are not well tolerated.²⁷⁸

Fetal circulation is designed to deliver the best-oxygenated and nutrient rich blood from the placenta to the fetal brain and heart (Fig. 8-5). This blood enters the fetus through the umbilical vein. The blood flow splits in the liver with almost half going through the hepatic veins and portal system of the liver and the rest through the ductus venosus, where it joins the inferior vena cava near its junction with the right atrium. In the right atrium the blood from the inferior vena cava (with a PO₂ of 32 to 35 mm Hg and an oxygen saturation of 70%—the highest fetal PO₂) is divided into two streams. About 40% of this blood passes through the foramen ovale into the left atrium, where it joins the small amount of blood from pulmonary venous return. It then passes through the mitral valve to the left ventricle and then to the ascending aorta where it supplies the coronary, carotid, and subclavian arteries. The preferential streaming of this blood results in an ascending aortic arterial oxygen tension (PaO₂) of 26 to 28 mm Hg and an oxygen saturation of 65%.^278,⁶⁸⁶ Ten percent of the blood flow from the left ventricle passes through the aortic arch into the descending aorta, where it joins 90% of the blood leaving the right ventricle. The fetal right ventricle pumps more than two thirds of the combined ventricular output, so the right ventricle is relatively muscular.

Fig. 8-5 Fetal circulation. Fetal blood is oxygenated in the placenta (which is a less efficient oxygenator than the lungs). The oxygenated blood enters the fetus through the umbilical vein and enters the ductus venosus, bypassing the hepatic circulation and flowing into the inferior vena cava. When this blood reaches the right atrium, it is diverted by the crista dividens toward the atrial septum, and flows through the foramen ovale into the left atrium. The blood then passes through the left ventricle and ascending aorta to perfuse the head and upper extremities. This pathway allows the best-oxygenated blood from the placenta to perfuse the fetal brain. Venous blood from the head and upper extremities returns to the fetal heart through the superior vena cava, enters the right atrium and ventricle, and flows into the pulmonary artery. Because pulmonary vascular resistance is high, this blood is diverted through the ductus arteriosus into the descending aorta. Ultimately, much of this blood will return to the placenta through the umbilical arteries.

(Illustration by Marilou Kundemueller.)

Most blood from the right ventricle bypasses the lungs because pulmonary vascular resistance is high; it passes through the ductus arteriosus into the descending aorta. (It provides less resistance to flow than pulmonary vascular resistance.) Only 10% to 15% of the right ventricular blood flow goes to the pulmonary arteries.^278,⁶²⁷ The descending aortic arterial oxygen tension is 20 to 22 mm Hg with an oxygen saturation of 50% to 55%.^278,^681,⁶⁸⁶

Fetal systemic vascular resistance is low. Nearly half of all descending aortic blood flow enters the placenta, which provides little resistance to blood flow. Fetal pulmonary vascular resistance is very high. The fetal lungs are fluid filled, and the resultant alveolar hypoxia contributes to intense pulmonary vasoconstriction. Because pulmonary vascular resistance is high, pulmonary blood flow is minimal (blood flows away from the lungs toward the low-resistance placenta); approximately 10% to 15% of fetal combined ventricular output perfuses the lungs to nourish developing pulmonary tissue.

By approximately week 20 of gestation the major branching pattern of the bronchi and their accompanying pulmonary arteries is complete. All preacinar arteries (those accompanying airways as small as the terminal bronchioles) are formed, and have a thick muscle layer. A muscle layer normally is not present in the vessels accompanying the respiratory bronchioles and the alveolar ducts, or surrounding the alveoli.

During the latter part of gestation the medial muscle layer in the pulmonary arteries thickens. Pulmonary vascular resistance begins to decrease during the last trimester, because small intraacinar arteries (those surrounding alveoli) are forming, and the total cross-sectional area of the pulmonary vascular bed increases.

The oxyhemoglobin dissociation curve for fetal hemoglobin (HbF) has higher affinity for oxygen; it’s P₅₀ (oxygen tension at which 50% of the hemoglobin is saturated with oxygen) is lower than the P₅₀ of normal hemoglobin. Another way to say this is that the HbF oxyhemoglobin dissociation curve is shifted to the left of the normal (postnatal) oxyhemoglobin dissociation curve. This means that at any given PO₂, the fetal hemoglobin will be better saturated than adult hemoglobin would be. Thus, at the same PO₂, oxygen content with fetal hemoglobin will be higher (in mL oxygen/dL blood) than the oxygen content would be with normal hemoglobin. However, because fetal hemoglobin binds more readily to oxygen than normal hemoglobin, fetal hemoglobin does not release oxygen as readily to the tissues. The reason for the difference in oxygen binding is a difference in response to 2,3-diphosphoglycerate (2,3-DPG); in fetal hemoglobin, 2,3-DPG does not alter binding with oxygen, whereas in normal hemoglobin, the 2,3-DPG reduces affinity to oxygen. Fetal hemoglobin normally is replaced by normal hemoglobin within about 3 to 6 months of birth.

Normal perinatal circulatory changes

Important circulatory changes occur at birth when oxygenation in the placenta ceases and the lungs expand and begin to oxygenate the blood. At birth, fetal shunts (the foramen ovale, ductus arteriosus, and ductus venosus) and the umbilical vessels are no longer necessary.

Elimination of the placenta causes an immediate fall in the blood pressure in the inferior vena cava and right atrium. Lung expansion with air that includes oxygen causes a dramatic rise in alveolar oxygenation and a fall in the pulmonary vascular resistance. With the decrease in pulmonary vascular resistance, pulmonary artery pressure falls, and blood flow through the ductus arteriosus is reversed. A rise in arterial oxygen tension and perivascular PO₂ causes vasoconstriction of the ductus arteriosus. This increases pulmonary blood flow, resulting in more pulmonary venous return to the left atrium. This rise in pulmonary venous return increases the left atrial pressure above the inferior vena cava and right atrial pressure and functionally closes the foramen ovale with the flap of the primum septum. Blood pressure increases in the aorta and systemic circulation with removal of the low-resistance placenta from the circulation.^278,^385,^627,⁶⁸⁶

Right ventricular output is reduced to half of the combined ventricular output.²⁷⁸ The increased workload of the right ventricle during fetal life produced a thickened right ventricular wall that is reflected in the increased RV forces on the neonatal electrocardiogram. The thickness of the right ventricular wall regresses over the first postnatal month because the workload of the right ventricle is reduced. With the reverse in workload and increased systemic vascular resistance, the wall of the left ventricle thickens.⁶²⁷

Normal Postnatal Changes in Pulmonary Vascular Resistance

When the lungs fill with air, most of the fluid within the alveoli moves to the pulmonary interstitium, where it is absorbed by the pulmonary capillaries and (to a lesser extent) removed by the lymphatics. As lung fluid is reabsorbed, alveolar hypoxia is eliminated, producing pulmonary vasodilation. Vasoactive substances (including prostaglandins and prostacyclin) mediate pulmonary vasodilation. The medial muscle layer of the pulmonary arteries begins to thin immediately after birth and continues to regress during the first days of life. These changes produce a rapid fall in pulmonary vascular resistance and, consequently, a fall in pulmonary artery pressure.

At sea level, pulmonary vascular resistance falls immediately after birth by approximately 80% and normally reaches near-adult levels during the first weeks of life. Normal pulmonary vascular resistance index (normalized to body surface area) is approximately 7 to 10 Wood units × m² body surface area during the first week of life, but falls to 1 to 3 Wood units × m² body surface area within a few weeks in patients at sea level (Table 8-3). Within 24 hours after birth, mean pulmonary artery pressure has fallen to approximately one half of mean systemic pressure, if the ductus arteriosus has constricted normally. This fall in pulmonary vascular resistance results in a parallel fall in right ventricular systolic and end-diastolic pressure.

Table 8-3 Calculation of Pulmonary Vascular Resistance



Note: This equation yields the PVR in Wood Units (units). Normal values are listed below. To convert these units to units of absolute physical resistance (dynes-sec-cm⁻⁵), multiply the Wood Units by 80.
To normalize PVR for body surface area, Pulmonary Vascular Resistance INDEX Units (PVRI) are calculated. The above equation is utilized, with the substitution of Cardiac Index (L/min per m² BSA). In effect, the PVRI is the PVR (in Wood Units) multiplied by the child’s body surface area. Normal values are listed below.
Age	Absolute PVR (Wood Units)*	PVR Index*
Newborn infant	25-40 Units	7-10 Index units
Child	0.5-4 Units	1-3 Index units

* To convert these units to dynes-s-cm⁻⁵, multiply by 80.

The presence of alveolar hypoxia during the first days of life may delay or prevent the normal fall in pulmonary vascular resistance, because the hypoxia stimulates pulmonary vasoconstriction. Alveolar hypoxia is present in premature neonates with severe respiratory distress syndrome; this may delay the perinatal fall in pulmonary vascular resistance. As long as pulmonary vascular resistance remains high, increased pulmonary blood flow through the ductus arteriosus is prevented. Typically the pulmonary vascular resistance falls when the pulmonary disease resolves. This fall in pulmonary vascular resistance often is heralded by symptoms of a large left-to-right shunt through a patent ductus arteriosus. Other factors that may contribute to pulmonary vasodilation and pulmonary vasoconstriction are listed in Box 8-1.

Closure of Fetal Shunts

The rise in the neonate’s arterial oxygen tension is thought to be the most potent stimulus to ductal constriction; however, many factors contribute to ultimate ductal closure. The rise in the oxygen tension of the blood bathing the ductus (i.e., the perivascular oxygen tension), the fall in endogenous dilating prostaglandins and adenosine levels, and release of circulating vasoactive substances all promote ductal closure.

Constriction of the ductal medial smooth muscle thickens the ductal wall and shortens the ductus, resulting in an infolding of the intima within the ductal lumen. These changes generally produce functional closure of the ductus within 10 to 24 hours following a full-term birth. The ductus then is converted to the ligamentum arteriosus through fibrous infiltration (Fig. 8-6).

Fig. 8-6 Postnatal circulation. Blood is oxygenated in the lungs, and pulmonary vascular resistance is low. Systemic venous (desaturated) blood returns to the heart through the superior and inferior vena cavae. This blood then flows through the right atrium and right ventricle, into the pulmonary artery, and ultimately into the pulmonary circulation. Oxygenated blood from the lungs returns to the left atrium through the pulmonary veins. This blood passes into the left ventricle and flows into the aorta and systemic arteries to perfuse the body.

(Illustration by Marilou Kundemueller.)

Ductal closure may be delayed or prevented in the very premature infant. Failure of ductal constriction results from a combination of factors, including decreased medial muscle within the ductus, decreased constrictive response to oxygen, and increased levels or heightened effects of circulating vasodilating prostaglandins. Ductal closure also may be delayed in patients living at high altitudes (and therefore exposed to low inspired oxygen tension) and neonates with cyanotic heart disease.

When the umbilical cord is tied and cut, the umbilical arteries and vein constrict. Eventually they undergo fibrous infiltration, becoming the medial umbilical ligament and ligamentum teres, respectively. The ductus venosus ultimately becomes the ligamentum venosum.

The flapped atrial opening, the foramen ovale, closes when left atrial pressure exceeds right atrial pressure. The foramen ovale closes by adherence of two portions of the atrial septum; this form of closure is called functional closure of the foramen ovale.

In most individuals the foramen ovale becomes sealed permanently by deposition of fibrin and cell products during the first months of life; this is referred to as anatomic closure of the foramen ovale. In approximately 25% of the population, however, the foramen ovale is not sealed anatomically and remains probe-patent beyond adolescence, so that a catheter can be passed from the right to the left atrium during cardiac catheterization or surgery. Table 8-4 provides a summary of the timing of the closure of the fetal shunts.

Table 8-4 Closure of Fetal Shunts

Unless or until the foramen ovale is sealed anatomically, anything that produces a significant increase in right atrial pressure can reopen the foramen ovale, so that blood can again shunt from the right atrium to the left atrium. In addition, if both atria become dilated, the foramen ovale can be stretched open to allow bidirectional shunting of the blood at the atrial level. Therefore if pulmonary hypertension and right ventricular failure occur or tricuspid atresia is present, the rise in right atrial pressure may produce a right-to-left shunt through the foramen ovale, with resultant cyanosis.

Normal Postnatal Changes in Systemic Vascular Resistance

With separation of the placenta from the circulation the neonate’s systemic vascular resistance begins to rise, and continues to increase during childhood. Normal systemic vascular resistance index is approximately 10 to 15 Wood units × m² body surface area in the young infant, and is approximately 15 to 30 Wood units × m² body surface area in the child and adult (Table 8-5).

Table 8-5 Calculation of Systemic Vascular Resistance



Note: This equation yields the SVR in Wood Units (units). Normal values are listed below. To convert these units to units of absolute physical resistance (dynes-sec-cm⁻⁵), multiply the Wood Units by 80.
To normalize SVR for body surface area, Systemic Vascular Resistance INDEX Units (SVRI) are calculated. The above equation is utilized, with the substitution of Cardiac Index (L/min per m² BSA). In effect, the SVRI is the SVR (in Wood Units) multiplied by the child’s body surface area. Normal values are listed below.
Age	Absolute SVR (Wood Units)*	SVR Index*
Infant	35-50 Units	10-15 Index units
Toddler	25-35 Units	20 Index units
Child	15-25 Units	15-30 Index units

* To convert these units to dynes-s-cm⁻⁵, multiply by 80.

Gross anatomy and function

Mary Fran Hazinski

The Right Side of the Heart

Systemic venous blood returns to the right atrium via the superior and inferior vena cavae. The sinoatrial (SA) node is located near the junction of the superior vena cava and the right atrium, just under the surface of the epicardium. The right atrium lies just under the sternum and forms the right lateral border of the cardiac silhouette on the anterior-posterior chest radiograph. Much of the inside of the right atrium has a trabeculated appearance, resulting from the presence of pectinate muscles that compose the anterior and lateral walls.

The atrial septum forms the posterior border of the right atrium, extending from right to left. The fossa ovalis (remnant of the foramen ovale) usually can be visualized high in the septum. The coronary sinus, which returns coronary venous blood to the heart, normally lies between the inferior vena cava and the tricuspid valve. The atrioventricular (AV) node is located anterior and medial to the coronary sinus and above the tricuspid valve.

Three internodal conduction pathways are thought to provide more rapid conduction between the SA and AV nodes than normal myocardium. Although conduction can occur along any of these three pathways, preferential internodal conduction probably occurs along the anterior internodal pathway, which courses from the sinus node, around the superior vena cava, and along the anterior portion of the atrial septum to the AV node. If these pathways are injured during cardiovascular surgery, AV conduction block can result.

The tricuspid valve is the anterior AV valve. It is positioned so that blood passing through the valve must flow in an anterior, inferior, and leftward direction into the right ventricle. The leaflets of the tricuspid valve are not equal in size, and they are not identifiable immediately as three distinct leaflets. The anterior leaflet extends from the pulmonary infundibulum to the lower anterior portion of the ventricle. The septal (or medial) leaflet attaches to the membranous and muscular portions of the ventricular septum. The posterior leaflet lies along the posterior aspect of the tricuspid ring. Each leaflet is attached to several chordae tendineae, which are in turn attached to one of three papillary muscles in the right ventricle.

The right ventricle is normally the most anterior of the four cardiac chambers, and its inferior border forms much of the left inferior cardiac border on an anteroposterior chest radiograph. The right ventricle receives blood from the right atrium and pumps blood into the low-resistance pulmonary circulation. Because the right ventricle normally generates low pressure, it has a thinner wall and a smaller lumen than the left ventricle. The right ventricle contains muscle bundles, called trabeculations, which give the ventricle a loculated appearance. The moderator band is a larger muscle bundle that traverses the right ventricle from the base of the tricuspid valve papillary muscle and joins the septal band of the septum.

The right ventricle is divided functionally into an inflow and an outflow portion by the crista supraventricularis, a ridge formed by a combination of septal and parietal bands that extends from the lateral wall of the right ventricle to the anterior leaflet of the tricuspid valve; this defines the pulmonary outflow tract. The pulmonary outflow tract also is called the pulmonary infundibulum; blood flows from the right ventricle and is directed posteriorly and superiorly into the pulmonary artery.

The pulmonary valve is a semilunar valve that normally is located above, in front of, and to the left of the aortic valve. Its three cusps are labeled the anterior, right, and left cusps.

Beyond the neonatal period, the pulmonary circulation is normally a low-resistance circulatory pathway that carries systemic venous blood to the lungs and then returns oxygenated pulmonary venous blood to the heart. The typical pulmonary branch artery has a thinner wall (with thinner medial muscle layer) and larger lumen than a comparable systemic artery.

The Left Side of the Heart

Oxygenated blood returns from the lungs through four pulmonary veins to the left atrium. The left atrium is the most posterior of the four cardiac chambers and normally does not contribute to the definition of the cardiac border on the anteroposterior chest radiograph. The left atrium has a slightly thicker and smoother wall than the right atrium. The left atrial appendage, a trabeculated extension of the left atrium, abuts the pulmonary artery.

Pulmonary venous blood flows from the left atrium through the mitral valve and into the left ventricle. The mitral valve consists of two leaflets: the septal leaflet extends from the muscular ventricular septum to the anterior wall of the left ventricle, and the posterior leaflet, the larger of the two leaflets, extends across the remaining portion of the valve annulus. The mitral leaflets attach to several chordae tendineae, which in turn attach to two groups of papillary muscles.

The left ventricle is located behind the right ventricle so that pulmonary venous blood passing through the mitral valve must flow inferiorly and laterally. The left ventricle may not form a distinct part of the cardiac border on the anteroposterior chest radiograph. This ventricle is characterized by a thick wall and a large lumen; its walls appear smoother than the trabeculated walls of the right ventricle. The septal leaflet of the mitral valve divides the left ventricle into an inflow and an outflow chamber. This division is only present when the mitral valve is open; the ventricle functions as a single chamber during systole.

The aorta has a thicker wall and a smaller lumen than the pulmonary artery. The aortic valve is a semilunar valve. Because the coronary arteries arise immediately above the aortic valve, the valve cusps are labeled in reference to the coronary arteries. The cusp immediately below the left coronary artery is called the left coronary cusp; the cusp immediately below the right coronary artery is called the right coronary cusp; and the cusp that is not related to any coronary artery is called the noncoronary cusp.

There are normally two coronary arteries: the left coronary artery, which branches into the left anterior descending and left circumflex arteries, and the right coronary artery. Blood flow from the coronary arteries perfuses the heart from epicardium through the myocardium to the endocardium, then coronary venous blood drains into the anterior cardiac veins or the coronary sinus and then into the right atrium.

A systemic artery has a thicker medial muscle layer, a relatively smaller lumen, and more elastic tissue than a pulmonary artery. Systemic arteries normally carry oxygenated blood under relatively high pressure to the tissues.

Normal cardiac function

The Cardiac Cycle

The heart receives systemic venous blood, ejects it into the lungs, and receives pulmonary venous blood and ejects it into the body. In this serial circulation there is sequential relaxation and contraction of the atria, followed by sequential relaxation and contraction of the ventricles. The circulation on the right side of the heart normally is separated from the circulation on the left side of the heart.

Systemic venous return enters the right atrium through the superior and inferior vena cavae. Oxygen saturation of superior vena caval blood is approximately 70%, which is slightly lower than the saturation of blood in the inferior vena cava (75%). Coronary sinus blood, with an oxygen saturation of approximately 30% to 40%, is then added to this venous return, so the mixed venous saturation (best obtained in the pulmonary artery after mixing is complete) usually is approximately 70% to 75%. This corresponds to a mixed venous oxygen tension (PvO₂) of 38 to 40 mm Hg (Fig. 8-7).

Fig. 8-7 Normal pressures (in mm Hg) and oxygen saturations in the neonatal A, and pediatric B, heart.

During atrial and ventricular diastole the tricuspid valve is open and systemic venous blood flows passively into the right ventricle. Approximately 70% of ventricular filling occurs during this period. Mean right atrial pressure is equal to right ventricular end-diastolic pressure in the absence of tricuspid valve disease. Mean right atrial pressure in spontaneously breathing infants beyond the neonatal period is approximately 0 to 4 mm Hg; mean right atrial pressure in older children during spontaneous breathing is 2 to 6 mm Hg.⁷⁵²

Atrial systole contributes the final 30% of ventricular filling. This volume is not essential for adequate cardiac output in the normal individual. However, loss of atrial systole may compromise stroke volume and cardiac output in a patient with ventricular dysfunction.

The right ventricle fills rapidly at the beginning of ventricular diastole; subsequent ventricular filling is slower until atrial systole occurs (Fig. 8-8, #1). Immediately after atrial contraction, ventricular contraction begins. Initially, ventricular contraction produces only a rise in ventricular pressure (without ejection of blood); this period is called the isovolumetric phase of ventricular systole (see Fig. 8-8, #2).

Fig. 8-8 Phases of the cardiac cycle. 1, Atrial systole. 2, Isovolumetric ventricular contraction. Ventricular volume remains constant as pressure increases rapidly. 3, Ejection. 4, Isovolumetric ventricular relaxation. Both sets of valves are closed, and the ventricles are relaxing. 5, Passive ventricular filling. The atrioventricular (AV) valves are forced open, and the blood rushes into the relaxing ventricles.

(From Patton KT, Thibodeau GA. Anatomy and physiology, ed 7. St Louis, 2010, Mosby).

When right ventricular pressure exceeds right atrial pressure, the tricuspid valve closes and ventricular pressure rises rapidly. Once right ventricular pressure exceeds pulmonary artery pressure, the pulmonary valve opens and blood is ejected into the pulmonary artery. This ejection phase of ventricular contraction is called the isotonic phase of contraction (see Fig. 8-8, #3). Right ventricular systolic pressure is approximately 15 to 25 mm Hg in normal children and adults; it is typically higher in neonates and young infants. Pulmonary artery diastolic pressure is approximately 4 to 12 mm Hg.⁷⁵²

The blood that enters the pulmonary circulation passes through the pulmonary arteries and into the alveolar capillary bed, where it receives oxygen and surrenders carbon dioxide. Oxygenated blood then enters the pulmonary veins and flows into the left atrium. Pulmonary venous blood is normally 97% to 100% saturated with oxygen, unless an intrapulmonary shunt is present. Mean left atrial pressure during spontaneous breathing is normally 3 to 6 mm Hg in infants and 5 to 10 mm Hg in older children.

Because there are no valves between the precapillary pulmonary artery and the left atrium, the pulmonary artery wedge or occlusion pressure (obtained using an end-hole, balloon-tipped, flow-directed pulmonary artery catheter) is roughly equivalent to the left atrial pressure. This assumes that the catheter is placed in a posterior, inferior pulmonary artery branch; the monitoring system is zeroed, leveled, and calibrated correctly; alveolar pressure does not exceed pulmonary end-diastolic pressure (for further information, refer to Chapters 6 and 21); and there is no pulmonary venous constriction or obstruction.

If the mitral valve is normal, left atrial pressure equals left ventricular end-diastolic pressure. Therefore pulmonary artery wedge pressure is approximately equal to left atrial pressure and left ventricular end-diastolic pressure. If pulmonary vascular resistance is normal, pulmonary artery end-diastolic pressure should nearly equal pulmonary artery wedge and left atrial pressures. Conversely, an increased gradient between pulmonary artery end-diastolic pressure and pulmonary artery wedge pressure (or left atrial pressure) indicates that pulmonary vascular resistance is elevated.

As with the right ventricle, left ventricular filling occurs largely during atrial and ventricular diastole (see Fig. 8-8, #5). Left atrial contraction contributes the final 30% of ventricular filling (refer to Fig. 8-8, #1). Immediately after left atrial contraction the left ventricle begins to contract. When left ventricular pressure exceeds left atrial pressure the mitral valve closes; this initial phase of contraction is called isovolumetric contraction (see Fig. 8-8, #2). When left ventricular pressure exceeds aortic pressure the aortic valve opens and blood flows into the aorta and systemic circulation (isotonic contraction occurs; see Fig. 8-8, #3). Left ventricular systolic pressure is approximately equal to the child’s systemic arterial pressure unless left ventricular outflow tract obstruction is present.

The Coronary Circulation

The distribution of coronary arteries is identical in normal infants and adults, although the structure of the arteries changes continually. The right and left coronary arteries perfuse the heart from epicardium through myocardium to endocardium. The epicardial arteries branch into arterioles that perfuse most of the myocardium and then branch further to perfuse the inner portion of the myocardium. The subendocardium is perfused by a plexus of vessels.

Coronary artery flow occurs predominantly during diastole; left ventricular coronary flow occurs only during diastole, whereas right ventricular coronary flow occurs during both systole and diastole. Coronary blood flow constitutes a very small but significant portion of the total cardiac output at rest. Coronary artery flow increases in response to a rise in myocardial oxygen consumption or a significant fall in arterial oxygen content (i.e., severe hypoxemia). Myocardial oxygen supply may be maintained in the presence of compromised flow or reduced oxygen content because oxygen extraction increases; however, this increase in extraction will compensate only for a small reduction in coronary artery flow. Typically the myocardium extracts approximately 50% to 60% of the oxygen delivered; if coronary perfusion is compromised, maximal oxygen extraction is approximately 75% of oxygen delivered.

Coronary artery perfusion pressure is the difference between aortic end-diastolic pressure and the mean right atrial pressure. Therefore, if aortic diastolic pressure falls (as a result of hypotension, aortic insufficiency, extreme vasodilation, or a shunt that allows “run off” from the aorta to the pulmonary artery), or mean right atrial pressure rises (such as occurs during right ventricular failure), coronary artery perfusion pressure can fall.

Unlike adults, pediatric patients rarely suffer from anatomic compromise of coronary artery diameter and flow. An example of compromised flow is caused by congenital anomalous origin of the coronary artery from the pulmonary artery. In this case the “stealing” of myocardial blood flow results when blood from the normal coronary artery (arising from the aorta) flows through a fistula, then retrograde through the anomalous coronary artery and into the pulmonary artery. This creates a shunt from the aorta to the pulmonary artery and prevents effective perfusion of the coronary circulation (see Coronary Artery Anomalies).

A variety of congenital heart defects may produce secondary changes that compromise coronary artery perfusion. Subendocardial tissue ischemia may develop in children with severe aortic stenosis. Massive left ventricular hypertrophy increases the time required to perfuse the subendocardial tissue, yet the resistance to aortic ejection increases the ejection time and compromises the diastolic time. In addition, hypertrophy increases myocardial oxygen consumption, resulting in a mismatch between oxygen supply and oxygen demand that worsens during episodes of tachycardia or increased oxygen demand.

Severe aortic insufficiency reduces coronary artery perfusion pressure because aortic end-diastolic pressure is extremely low and mean right atrial pressure is often elevated. Congestive heart failure, like that occurring with critical aortic stenosis or hypertrophic cardiomyopathy, increases mean right atrial pressure and reduces coronary artery perfusion pressure. These conditions can result in the development of subendocardial ischemia, particularly during episodes of tachycardia, when diastolic time is shortened and myocardial oxygen consumption is increased.

Cellular Physiology

Membrane and Action Potentials

The heart contains muscle, connective tissue, and conductive tissue. Both the myocardium and conductive tissue transmit electrochemical impulses, or current; conductive tissue transmits current more rapidly than does myocardium.

In all tissues of the body there is a difference between intracellular and extracellular concentrations of electrolytes, particularly sodium and potassium. In nerve and muscle cells there is also a difference in electrical charge between the inside and the outside of the cell; the inside of the cell is negatively charged with respect to the outside of the cell (and the outside of the cell is positively charged with respect to the inside of the cell). This difference in electrical charge across the cell membrane is called a membrane potential or a transmembrane potential (see Fig. 8-9).

Fig. 8-9 Sodium-potassium pump and propagation of an action potential. A, Concentration difference of Na⁺ and K⁺ intracellularly and extracellularly. The direction of active transport by the sodium-potassium pump is also shown. B, Top diagram represents the polarized state of a neuronal membrane when at rest. The lower diagrams represent changes in sodium and potassium membrane permeabilities with depolarization and repolarization. (From Thibodeau GA, Patton KT. Anatomy and physiology, ed 6. St Louis, 2007, Mosby.)

The sarcolemma is the membrane surrounding myocardial cells. It maintains the resting membrane potential of the myocardial cell at approximately −75 to −90 mV, but is capable of altering membrane permeability to allow for generation and conduction of a current.

The cardiac resting membrane potential results from concentration gradients for potassium and sodium across the cell membrane, as well as from the relative differences in membrane permeabilities to sodium and potassium (Fig. 8-9, B, top). Changes in membrane permeability to sodium and potassium ions are responsible for the generation of an action potential, a change in electrical charge that occurs when sufficient change in transmembrane potential develops and depolarization of the cell results.

At rest the concentration of potassium is high inside the cell and low outside of the cell; in contrast, the concentration of sodium is low inside the cell and high outside of the cell. Thus, there is a high concentration gradient for potassium to move to the outside of the cell and a concentration gradient for sodium to move to the inside of the cell. An active (energy-requiring) pump moves sodium ions out of the cell and potassium ions into the cell. The hydrolysis of adenosine triphosphate (ATP) provides energy for the pump. For every three sodium ions that are transported out of the cell, two potassium ions are moved into the cell (refer again to Fig. 8-9, A); this active pump generates a current (a net positive charge moves out of the cell). Under resting conditions, sodium moved outside the cell remains outside the cell because the sarcolemma is relatively impermeable to sodium.

As noted, the high concentration of potassium inside of the cell (approximately 100 or more mEq/L) and the relatively low potassium concentration outside of the cell (approximately 3.5 to 5.5 mEq/L) creates a large potassium concentration gradient across the cell membrane. Potassium readily diffuses out of the cell in response to this concentration gradient, because the sarcolemma is relatively permeable to potassium. At the same time, large negatively charged proteins remain trapped in the cell, because the membrane is normally impermeable to these large molecules. The exodus of positively charged ions from the cell coupled with the presence of (negatively charged) captured intracellular proteins creates the negative resting membrane potential. The magnitude of the resting membrane potential is linked most closely to the potassium concentration gradient.

Excitation of the myocardium results in altered sarcolemma permeability to sodium, calcium, and potassium and produces a change in intracellular electrical charge (i.e., an action potential). For an action potential to develop, the cell must be stimulated sufficiently to increase membrane permeability to sodium. At the same time, membrane permeability to potassium is decreased temporarily. Once the cell is stimulated sufficiently to threshold potential (the transmembrane voltage at which an action potential will occur), gating proteins allow sodium ions to enter the cell rapidly through fast channels, producing a current, or flow of electrons (depicted in Fig. 8-9, B, middle). The inside of the cell rapidly becomes positively charged with respect to the outside of the cell. This sodium influx, then, depolarizes the cell.

Depolarization occurs in approximately 300 ms. The fast sodium channels quickly close, but slow channels are then opened that allow calcium to enter the cell. This influx of calcium prolongs the period of time that the inside of the cell is positively charged and prevents immediate repolarization of the cell. The slow calcium channels ultimately close, and membrane permeability to potassium is restored. These two conditions restore the intracellular charge to the negative resting membrane potential.

The development of an action potential is an “all or none” phenomenon—if the cell is stimulated sufficiently (i.e., reaches threshold potential) it will become depolarized. Once membrane permeability to sodium increases at one point in the cell membrane and an action potential is generated, membrane permeability to sodium tends to increase along the length of the cell. This causes a propagation of the action potential throughout the cell. The action potential then spreads from cell to cell in the heart through low-resistance connections, called intercalated discs.

As the outside of the cell becomes negative (or depolarized) with respect to the inside of the cell, a current is generated. This current can be measured on the surface of a nerve or muscle in the laboratory. At the bedside the net electrical effects of the depolarization and repolarization of myocardial cells is detected and represented graphically by the ECG.

The cardiac action potential is a graphic representation over time of changes in the myocardial transmembrane potential of a single myocyte following stimulation. The myocardial action potential is divided into five phases: Phase 0, Phase 1, Phase 2, Phase 3, and Phase 4 (see Fig. 8-10, A), which are related to the changes in the transmembrane ion flow discussed in the preceding paragraphs.^77,^78,⁸⁶³

Phase 0. Fast channels are opened, and sodium rushes into the cell. The intracellular charge becomes progressively less negative, then positive with respect to the outside of the cell. Once the transmembrane potential reaches approximately −30 to −40 mV, slow calcium channels also open, perpetuating the action potential.

Phase 1. A short phase of rapid partial repolarization occurs as the fast channels are closed abruptly. These gates cannot reopen until the cell is repolarized partially during Phase 3, so the cell will be refractory to further excitation until that time. Slow calcium channels remain open at this time.

Phase 2. This plateau is produced when the slow calcium channels remain open, allowing continued diffusion of calcium ions into the cell. This plateau is unique to myocardial cells (it is not a feature of the action potential of skeletal muscle); because it delays repolarization, the plateau lengthens the refractory period of the myocardium, so myocardial tetany cannot occur.

Slow calcium channels not only affect myocardial excitation, they also deliver calcium to the myocardium for contraction and stimulate the sarcoplasmic reticulum to release additional calcium into the intracellular compartment, facilitating contraction. Calcium channels are blocked by specific inhibitor drugs such as verapamil, nifedipine, and diltiazem, and they are activated by sympathomimetic drugs.

Phase 3. Repolarization occurs rapidly when the slow calcium channels close; membrane permeability to potassium is restored. This permeability results in a significant potassium efflux to the outside of the cell.

Phase 4. The resting membrane potential is restored by the sodium-potassium pump and continued potassium efflux from the cell. This phase is the period between two action potentials. In the heart, Phase 4 is characterized by a slow reduction in the magnitude of the transmembrane potential caused by sodium influx; this influx creates prepotential. The prepotential ultimately can bring the transmembrane potential to threshold, so depolarization again occurs. The rate of this Phase 4 depolarization determines the intrinsic pacemaker capacity of the cell (see the following section).

Fig. 8-10 Cardiac action potentials. A, Ventricle. B, Sinoatrial (SA) node. C, Atrium. Sweep velocity in (B) is one half that in (A) or (C)

(Modified from Berne RM, Levy MN. Cardiovascular physiology, ed 8. St Louis, 2001, Mosby.)

Pacemaker Cells and Pacemaker Potentials

Nonpacemaker cells will maintain a membrane potential at the resting level for a prolonged period. All myocardial cells are self-excitable to some degree, however, so they depolarize gradually.

Pacemaker cells spontaneously depolarize at a more rapid rate than typical myocardial cells. The action potential of the pacemaker cells is also different in appearance than the action potential of myocardial cells (Fig. 8-10, B). Pacemaker action potentials can be recognized by the gradual depolarization during Phase 4 (this may be called a prepotential), and the absence of a plateau in Phase 2. The gradual depolarization during Phase 4 allows spontaneous pacemaker excitation, and the absence of a plateau ensures that the cell can be depolarized again within a short period of time.

The resting membrane potential of the pacemaker cell is less negative than the resting membrane potential of a typical myocardial cell. As a result it will reach threshold with a smaller stimulus or smaller change in voltage than a typical myocardial cell. The pacemaker cell is depolarized gradually during Phase 4, initially from the slow inward movement of sodium ions, and then as the result of the opening of slow channels, producing influx of both sodium and calcium ions. Under normal circumstances the pacemaker achieves threshold potential in a shorter period of time than the time needed by other myocardial cells. Once the pacemaker depolarizes, it stimulates other myocardial cells to depolarize.

Potential Alterations in Membrane Potentials and Excitability

Anything that increases the magnitude of the pacemaker membrane potential (makes it more negative) may result in slowing of the heart rate, because it will require a longer period of time for the sodium influx to bring the pacemaker membrane potential to threshold. Overdrive pacing (and resultant stimulation of the sodium-potassium pump) and vagal stimulation may result in “hyperpolarization” of pacemaker cells and a fall in intrinsic pacemaker firing rate.

Because the concentration gradients of sodium, potassium, and calcium affect the magnitude of the membrane potential, alterations in the intracellular and extracellular (including serum) concentrations of these electrolytes can influence myocardial excitability and contractility.

Vagal (parasympathetic) stimulation alters myocardial membrane permeability and reduces the excitability of the cell. Sympathetic nervous system stimulation increases intracellular sodium ion movement so that myocardial cells depolarize more rapidly. In addition, adrenergic stimulation increases the movement of calcium out of the cell at the end of Phase 3; these effects produce an increase in heart rate.

Refractory Periods

Myocardium is absolutely refractory to further electrical stimulation from the time the action potential begins (Phase 0) until significant repolarization has occurred (near the end of Phase 3). This protects the myocardium from tetany (i.e., continuous stimulation).

The myocardium is then relatively refractory to further stimuli from the end of Phase 3 (when the transmembrane potential is approximately −60 mV) until resting membrane potential is nearly reached. During this period a larger stimulus than normal is necessary to depolarize the cell, and conduction of an impulse is not rapid unless fast sodium channels are available.

For a brief period of time before repolarization is complete the myocardium is more susceptible than usual to stimulation and depolarization. During this time, called the supernormal period, a smaller stimulus than usual will generate an action potential.

Myocardial Contraction

Electrical stimulation of the myocardium should result in mechanical contraction. However, electrical depolarization of the myocardium may not result in adequate mechanical function if myocardial dysfunction is present.

The myocardium consists of a woven mesh of interconnected myocardial cells or myocytes. Each myocyte is surrounded by a semipermeable membrane, the sarcolemma. The myocyte contains myofibrils, and the myofibrils, in turn, each contain groups of sarcomeres. The sarcomere is the contractile element of a myocardial cell that contains thin overlapping protein filaments of actin and thicker myosin filaments (Fig. 8-11, A). Coupling of these filaments occurs when intracellular ionized calcium is increased.

Fig. 8-11 Cardiac excitation and contraction. A, Initiation of contraction. Actin and myosin filaments are in the relaxed state, and the sarcoplasmic reticulum contains a store of calcium ions. When depolarization occurs, the wave of excitation is spread rapidly to the inside of the cell via the transverse or “T” tubules. A small amount of free calcium ions then enter the cell from the extracellular space through these T-tubules. The extracellular calcium ion entry alone is not sufficient to produce contraction. B, The intracellular entry of calcium then stimulates the release of large quantities of calcium ions from the intracellular stores in the sarcoplasmic reticulum. Calcium then binds to troponin C, enabling cross-linking of actin and myosin filaments and myocardial contraction. C, With depolarization and contraction, the myocardium generates tension. Initially, the ventricular fibers generate tension and do not shorten; this is a period of isometric contraction, and lasts until the ventricles generate sufficient pressure to open the semilunar valves. Once these valves open, the muscle fibers shorten and blood is ejected. The tangent of the slope of the shortening curve (dl/dt) represents the velocity of initial fiber shortening and can be used as a measure of ventricular contractility.

(A and B by Marilou Kundemueller; C From Berne RM, Levy MN. Cardiovascular physiology, ed 5. St Louis, 1986, Mosby.)

During depolarization of the myocardium, transcellular calcium influx occurs; calcium enters the cell through calcium channels in the sarcolemma and through invaginations in the sarcolemma, called T-tubules (refer, again, to Fig. 8-11, A and B). This calcium entry into the sarcoplasm stimulates further calcium release from the sarcoplasmic reticulum. The free cytoplasmic calcium reacts with troponin, with the resulting formation of cross-linkages between the actin and myosin filaments. As a result of these linkages, the filaments are pulled together, causing shortening of the myocardial fiber (contraction), so the fibers generate tension. Myocardial relaxation results when calcium uptake by the sarcoplasmic reticulum occurs by means of an energy-requiring pump. Exchange of sodium for calcium ions also occurs during diastole.

Tension generated by the myocardium and velocity of myocardial contraction (or shortening) are inversely related. If the myocardium is restrained, isometric contraction will result—the fiber will not shorten, but it will develop tension. If the myocardial fiber is unrestrained, it shortens, or contracts (see Fig. 8-11, B), but it will not develop further tension—this form of contraction is called isotonic contraction. During ventricular systole, both isometric and isotonic contractions occur. Isometric contraction occurs before the opening of the semilunar valves, and isotonic contraction occurs after the semilunar valves open. Stroke volume is determined by the amount of isotonic contraction (or ventricular fiber shortening) that occurs after sufficient tension is developed to overcome resistance to ejection (afterload).^77,^78,⁸⁶³

Myocardial contraction is an energy-requiring process, using ATP and magnesium. Therefore, for contraction to occur, magnesium and effective myocardial aerobic metabolism to generate ATP must be present.

If contraction is to be effective, all myocardial cells must contract in synchrony. This requires efficient calcium release and uptake by the sarcoplasmic reticulum. It also requires rapid transmission of action potentials throughout the heart.

Factors influencing normal ventricular function

Myocardial performance can be affected by changes in many conditions, including oxygenation, perfusion, ionized serum calcium concentration, acid-base and electrolyte balance, and drugs. Each of these factors may impair or enhance cardiac output by altering either heart rate (the number of times the ventricles contract per minute) or ventricular stroke volume (the volume of blood ejected by the ventricles with each contraction).

Stimulation of beta-adrenergic receptors results in increased calcium release and influx, so myocardial contraction is enhanced. In addition, calcium uptake at the end of contraction is more rapid, so relaxation and diastolic filling time is increased, which increases the stroke volume as well as the heart rate. An increase in heart rate, in turn, enhances calcium influx and can improve contractility.

Many of these beta-adrenergic effects are mediated by cyclic adenosine monophosphate (cAMP), an intracellular messenger formed by membrane-bound adenyl cyclase. After contraction, phosphodiesterase converts cAMP into an inactive compound. For this reason, phosphodiesterase inhibitors potentiate adrenergic effects mediated by cAMP. For example, milrinone is a phosphodiesterase inhibitor with inotropic and vasodilatory effects.

Contractility also may be enhanced by other factors that increase intracellular calcium. Alpha-adrenergic stimulation, an increase in extracellular calcium concentration, an increase in heart rate, and administration of cardiac glycosides all increase intracellular ionized calcium.

The intracellular sodium concentration influences free calcium levels in the myocyte because these ions share storage sites and compete for space in the exchange pump. If the intracellular sodium concentration is increased (such as occurs during digitalis therapy), sodium occupies space in the exchange pump, so calcium will accumulate in the myocardial cell. The result is that cardiac contractility is enhanced (see further discussion in the Common Clinical Conditions section, under Congestive Heart Failure).

Effects of changes in heart rate and rhythm are discussed in a subsequent section (Arrhythmias). The following review addresses factors that influence ventricular function and stroke volume.

Three terms have been borrowed from the physiology laboratory to describe factors that influence ventricular stroke volume. These terms—preload, contractility, and afterload—have been defined precisely in the laboratory setting using isolated myocardial muscle strips. However, they are described only generally in the clinical setting with an intact heart, where it usually is impossible to isolate single variables. Therefore a brief review of the clinical interpretation of these factors is provided. This information is also presented in Chapter 6.

Ventricular Preload

The Frank-Starling Law of the Heart

Preload is the amount of myocardial fiber stretch that is present before contraction. Howell (in 1894), Frank (in 1894), and Starling (in 1914) performed experiments using isolated normal myocardial muscle preparations, and observed that normal myocardium generates greater tension during contraction if it is stretched before contraction. The increase in the force of contraction optimizes overlap between actin and myosin filaments in the sarcomere. Their observations became known as the Frank-Starling law of the heart, which states that an increase in ventricular end-diastolic myocardial fiber length (manipulated by increasing ventricular end-diastolic pressure) will produce an increase in ventricular work, systolic tension, and stroke volume. The graphic representation of the relationship between ventricular end-diastolic pressure and stroke volume is the Frank-Starling curve, which is a ventricular (myocardial) function curve (Fig. 8-12).^77,^78,⁸⁶³

Fig. 8-12 Frank-Starling curve. In the laboratory description of the Frank-Starling Law (using isolated normal myocardial fibers), an increase in the end-diastolic myocardial fiber length increased the tension generated by the myocardial fiber. In the clinical setting, measurement of end-diastolic fiber length is impossible, so the ventricular end-diastolic pressure (VEDP) is increased to produce improvement in stroke volume or cardiac output. To a point, an increase in VEDP will produce an improvement in cardiac output (A-B). This increase in VEDP is accomplished through judicious titration of intravenous fluid. The clinician must also recognize that a family of myocardial function curves exists; the patient’s myocardial function may be characterized as normal, dysfunctional, or hyperdynamic. If the myocardium is dysfunctional, it generally requires a higher VEDP than the normal myocardium to maximize cardiac output. In addition, excessive volume administration can produce a decrease in cardiac output and myocardial performance if the ventricle is dysfunctional (B-D). In this case, administration of a diuretic or vasodilator may improve cardiac output (D-B). Correction of acid-base imbalances, reduction in afterload, or administration of inotropic medications may improve myocardial function so that cardiac output increases without need for further increase in VEDP (B and C). If the patient’s myocardial function is hyperdynamic, cardiac output will be high even at low VEDP.

(Illustration courtesy of William Banner Jr.)

The Frank-Starling law of the heart is applicable to dysfunctional as well as normal myocardium, although the appearance (specifically, the position and slope) of each function curve will differ. Optimal stretch of any myocardial fiber should improve myocardial performance. Because myocardial fiber length is not readily measured in the clinical setting, ventricular end-diastolic pressure (VEDP) is monitored as an indirect indication of the stretch placed on the myocardial fibers before contraction. VEDP is increased through intravenous volume administration. The relationship between ventricular end-diastolic volume (and fiber length) and ventricular end-diastolic pressure is not a linear one, however, because it is influenced by ventricular compliance (see discussion of Compliance, below) and venous return; both of these factors may be altered by disease or therapy.

To a point, as ventricular end-diastolic pressure is increased, the force of contraction and myocardial fiber shortening should increase, and stroke volume should rise. If, however, the ventricle is filled beyond a critical point, overlap of actin and myosin filaments is no longer optimal; ventricular dilation can result, and stroke volume can decrease. Extremely high ventricular end-diastolic pressures result in pulmonary and systemic edema, and will compromise coronary and subendocardial blood flow.

If stroke volume or cardiac output can be estimated reliably (e.g., using Doppler, Fick, or thermodilution calculations) a ventricular function curve can be constructed for any patient. Stroke volume (cardiac output divided by heart rate) is plotted on the vertical axis of the graph, and VEDP is plotted on the horizontal axis. As fluid administration is titrated and the stroke volume is determined at various ventricular end-diastolic pressures, the optimal VEDP is identified as the peak point on the curve.

A goal of the treatment of any patient with cardiovascular dysfunction is to maximize stroke volume and cardiac output, while minimizing adverse effects of fluid administration (such as pulmonary edema). An increase in stroke volume and cardiac output can be achieved by moving the patient to the highest point of an individual ventricular function curve (see Fig. 8-12, A to B); this movement may be achieved by judicious fluid administration. Improvement in stroke volume and cardiac output also can be achieved by altering the ventricular compliance, using vasodilator therapy. An increase in stroke volume and cardiac output also can be achieved through improvement in cardiac contractility; this raises the ventricular function curve (see Fig. 8-12, B to C). Such an improvement may be attained by elimination of factors that normally depress myocardial function, or through administration of inotropic agents or vasodilators (see section, Afterload).

Clinical Evaluation of Ventricular Preload

In the clinical setting, ventricular end-diastolic pressure is measured to evaluate ventricular preload. Ventricular end-diastolic volume may also be estimated with echocardiography or nuclear imaging.

Right ventricular end-diastolic pressure (RVEDP) is equal to right atrial pressure unless tricuspid valve stenosis is present. Central venous pressure (CVP) equals right atrial and RVEDP, unless central venous obstruction or positive intrathoracic pressure is present.

RVEDP and CVP often can be estimated with careful clinical assessment of the level of hydration, liver size, palpation of the infant’s fontanelle, determination of presence (or absence) of systemic edema, and evaluation of the cardiac size on chest radiograph. Dry mucous membranes, a sunken fontanelle, and absence of hepatomegaly are findings consistent with normal or low central venous pressure; hepatomegaly and periorbital edema usually are present once the CVP is elevated significantly. Systemic edema also may be noted despite a normal or low CVP if capillary leak or hypoalbuminemia is present. A high RVEDP and heart failure is often associated with cardiac enlargement on chest radiograph.

Left ventricular end-diastolic pressure (LVEDP) is equal to left atrial pressure unless mitral valve disease is present. Reliable estimation of LVEDP is not possible through clinical assessment alone. Although the presence of pulmonary edema frequently is assumed to indicate the presence of a high LVEDP (exceeding 20 to 25 mm Hg), pulmonary edema may be observed at any (even a low) LVEDP if capillary leak is present.

A left atrial catheter or pulmonary artery catheter must be inserted to measure LVEDP, because this pressure cannot reliably be estimated from clinical examination. In the absence of pulmonary venous constriction or obstruction, a pulmonary artery wedge pressure will approximate left atrial pressure; in the absence of mitral valve disease or extreme tachycardia, left atrial pressure should reflect left ventricular end-diastolic pressure. However, the pulmonary artery catheter must be placed appropriately and the transducer must be zeroed, leveled, and calibrated correctly with appropriate consideration of intrapulmonary pressure. (For information about potential errors in use of pulmonary artery catheters, refer to Chapter 21.)

Factors Affecting Ventricular End-Diastolic Pressure (VEDP)

A change in ventricular end-diastolic pressure affects the resting length of the ventricular myocardial cells before contraction. Although VEDP is increased through the administration of intravenous fluids, VEDP is not related linearly to fluid volume administered. VEDP also will be affected by ventricular compliance which is, in turn, affected by ventricular function, ventricular relaxation, wall thickness, ventricular size, pericardial pressures, and heart rate.

Ventricular Compliance

Ventricular compliance refers to the distensibility of the ventricle. It is defined as the change in ventricular volume (in mL) for a given change in pressure (in mm Hg), or ΔV/ΔP, and can be depicted graphically by a ventricular compliance curve (see Fig. 6-3). The opposite of compliance is stiffness (ΔP/ΔV).

If the ventricle is extremely compliant a large volume of fluid may be administered without producing a significant increase in VEDP (see Fig. 6-3, curve B). In contrast, if the ventricle is dysfunctional (as occurs with restrictive cardiomyopathy) or hypertrophied, ventricular compliance usually is reduced (see Fig. 6-3, curve C). In this case, even a small volume of administered intravenous fluids will produce a significant rise in VEDP. The more dysfunctional and noncompliant the ventricle, the higher will be the resting VEDP and the VEDP needed to optimize stroke volume and ventricular performance.

Ventricular compliance is not constant over all ranges of VEDP. Any ventricle is maximally compliant at low filling pressures; as the ventricle is filled, compliance is reduced because ventricular stretch may be maximal. Rapid volume infusion tends to raise VEDP more rapidly than gradual volume infusion. Compliant ventricles usually demonstrate a substantial improvement in stroke volume when intravenous fluid is administered.

Vasodilator therapy will improve ventricular compliance. When these drugs are administered the compliance curve is altered, so a greater end-diastolic volume may be present without a substantial increase in ventricular end-diastolic pressure (see Fig. 6-3). Stroke volume may then be increased without a rise in VEDP.

Compliance also is affected by ventricular size, pericardial space, and heart rate.¹⁴¹ Infants have very small and relatively noncompliant ventricles, so the infant’s VEDP may rise sharply with even small fluid volume administration. If the same volume (on a per kilogram basis) is administered to the older child a smaller change in VEDP will result, because the ventricles are larger and more compliant in the older child.

Constrictive pericarditis and tamponade decrease ventricular compliance because ventricular expansion cannot occur in response to volume administration. Diastolic filling will be impaired and stroke volume often is reduced. Extreme tachycardia (such as supraventricular tachycardia) can produce a rise in VEDP. A rapid heart rate is associated with reduced ventricular diastolic time and incomplete relaxation; as a result the VEDP rises.

Because VEDP is affected by a variety of factors it is important to attempt to determine the VEDP associated with optimal systemic perfusion for each patient. Obviously, this optimal pressure may change frequently during the patient’s clinical course. Throughout therapy, evidence of systemic perfusion always should be assessed as VEDP is manipulated.

Maturational Changes in Response to Preload Manipulation

Many years ago, studies of newborn animals failed to demonstrate an increase in neonatal stroke volume in response to intravenous volume administration. This led to the conclusion that the human neonate is incapable of increasing stroke volume in response to volume administration. However, in each of these studies, secondary changes in hemodynamics occurred that may have affected stroke volume adversely, thus blunting any positive effect of volume administration.

Research now suggests that neonates are capable of increasing stroke volume in response to volume therapy provided aortic pressure does not rise precipitously, ventricular function is adequate, and systemic vascular resistance is not elevated. In the clinical setting it is always necessary to monitor changes in systemic perfusion as VEDP is manipulated, regardless of the age of the patient. If maximal response to volume infusion is to occur, myocardial contractility must be effective and afterload controlled.

Contractility

Definition

The term contractility refers to the strength and efficiency of contraction; it is the force generated by the myocardium, independent of preload and afterload. Contractility is estimated by velocity of fiber shortening; if myocardial function is good the ventricular fibers shorten rapidly. As a result, at the same heart rate, systole will require a smaller portion of the cardiac cycle. If systole requires a smaller portion of each cardiac cycle, there will be a longer time for ventricular filling (diastole) and stroke volume will increase (provided that circulating blood volume is adequate and heart rate and ventricular afterload are unchanged).

Clinical Evaluation of Contractility

Although contractility can be measured in the laboratory it is not easily isolated and measured in the clinical setting. The most common method of evaluating contractility at the bedside is echocardiographic evaluation of fiber-shortening times and measurement of the shortening fraction of left ventricular diameter. Shortening fraction is calculated by determining the difference between the end-diastolic and end-systolic dimensions; this difference is then divided by the end-diastolic dimension (see Box 8-2); the normal shortening fraction is approximately 28% to 44%.

Box 8-2 Echocardiographic Calculation of Left Ventricular Shortening Fraction

If a thermodilution cardiac output pulmonary artery catheter is in place, or if reliable Doppler or other noninvasive cardiac output estimations can be obtained (see Chapters 6 and 21), the nurse may create a ventricular function curve (see Fig. 8-12). If cardiac output improves with no change in VEDP, ventricular contractility or compliance has probably improved.

Other more cumbersome techniques are available to describe ventricular performance (i.e., ventricular function in vivo). Ejection fraction [(end-diastolic volume − end-systolic volume)/end-diastolic volume] can be determined with nuclear imaging, angiocardiography, or echocardiography; normal is 65% to 80%. Velocity of circumferential fiber shortening can be calculated using echocardiography, nuclear imaging, or during cardiac catheterization; however, this velocity is influenced by heart rate, preload, contractility, and afterload. The rate of peak pressure development (ΔP/Δt—peak pressure development over time) also can be measured in the cardiac catheterization laboratory to monitor changes in contractility.

Another good indicator of contractility is the slope of the left ventricular end-systolic pressure/volume curve. This slope is insensitive to changes in preload but accurately reflects changes in myocardial contractility. To determine this slope, end-systolic pressure is estimated from a carotid pulse tracing or the dicrotic notch of a clear arterial waveform tracing, and the left ventricular end-systolic volume (dimension) is determined by echocardiography. These variables are graphed (pressure on the vertical axis and volume on the horizontal axis); the slope of the curve reflects ventricular contractility. Inotropic drugs shift the curve to the left and increase the slope of the curve. When contractility is depressed, the curve is shifted to the right and has a reduced slope.

When contractility is good, ventricular end-diastolic pressure remains low, ventricular systolic pressure rises sharply, and the rate of preejection period/ejection time is low. In comparison, when ventricular contractility is poor, ventricular end-diastolic pressure is high, ventricular pressure rises slowly during systole, and the ratio of preejection period/ejection time lengthens (i.e., the ejection period shortens), because it takes a longer time for the ventricle to generate sufficient pressure to overcome afterload. These differences often can be appreciated when an electrocardiogram and ventricular pressure curve (or intraarterial pressure curve) are examined simultaneously.

The ventricular pressure curve also may provide information regarding ventricular contractility. This ventricular pressure usually must be examined in the cardiac catheterization laboratory; however, the intraarterial pressure curve may be utilized if the catheter is widely patent and vasoconstriction is not present. The area under the pressure curve correlates with stroke volume. If stroke volume and contractility are good, the slope of the systolic upstroke of the waveform will be steep, and a dicrotic notch clearly visible. If contractility is poor and stroke volume is reduced, the waveform will appear dampened, and the slope of the systolic upstroke of the waveform more horizontal (see Chapter 6).

Contractility can be impaired by electrolyte imbalances, acidosis, and hypoxia. Adrenergic stimulation and resultant tachycardia will improve contractility by increasing intracellular calcium concentration.

Maturational Changes in Cardiac Contractility

Neonatal myocardial fibers have a higher water content and fewer contractile elements (per gram of tissue) than adult myocardial fibers. In addition, immature myocardium is able to generate less tension than adult myocardium. These observations are not necessarily indicative of reduced infant myocardial contractility, however, because infant hearts actually have a higher ejection fraction than adult myocardium.

Afterload

Definition

Afterload is the impediment to ventricular ejection. Ventricular afterload is the sum of all forces opposing ventricular emptying and is described as ventricular wall stress. If ventricular wall stress is increased, the afterload of the ventricle and the impediment to ventricular ejection are increased. The parallel of ventricular afterload or wall stress in isolated myocardial fibers is myocardial fiber tension.

Because fiber shortening (isotonic contraction) occurs only when the ventricle has generated sufficient tension to equal its afterload, an increase in ventricular afterload reduces the isotonic contraction time and thus the stroke volume of the ventricle. Even a normal afterload may be excessive when myocardial function is poor. With any increase in afterload, oxygen consumption and the work of the ventricle increase (Fig. 8-13).

Fig. 8-13 Effects of afterload on ventricular function. The normal ventricle maintains stroke volume despite a moderate rise in afterload (such as an increase in systemic vascular resistance). Severe increases in afterload, however, can ultimately compromise ventricular function and result in a fall in stroke volume and cardiac output (see Normal Ventricle Curve). The dysfunctional ventricle will be much more sensitive to an increase in afterload, and even a relatively small increase in afterload may substantially reduce myocardial performance. Administration of vasodilators may reduce afterload sufficiently so that stroke volume and cardiac output increase (see A and B).

(Illustration courtesy of William Banner Jr, MD.)

A simplification of Poiseuille’s law states that pressure is a product of flow and resistance:

From this equation it is clear that an increase in resistance will be associated with a decrease in flow (i.e., cardiac output or stroke volume) unless the driving pressure increases. For example, if aortic stenosis is present, cardiac output will fall unless the left ventricular pressure increases significantly.

The major determinants of afterload or wall stress are: (1) ventricular lumen radius; (2) the thickness of the ventricular wall (hypertrophy decreases afterload); and (3) the ventricular ejection pressure (intracavitary pressure), as indicated in Box 8-3. In the normal patient, left ventricular ejection pressure is equal to systemic arterial pressure, and right ventricular ejection pressure is equal to pulmonary artery pressure; systemic and pulmonary artery pressures, in turn, are determined by blood flow and resistance (Poiseuille’s law). Therefore, in the absence of ventricular outflow tract obstruction or significant alterations in ventricular size or wall thickness, afterload is determined primarily by the impedance provided by the pulmonary and systemic arterial circulations (respectively, the pulmonary and systemic vascular resistances).

Box 8-3 Factors Influencing Ventricular Afterload and Wall Stress

Clinical Evaluation of Afterload

Afterload cannot be measured in the clinical setting. Resistances in the pulmonary and systemic circulation can be calculated if a thermodilution pulmonary artery catheter is in place. Systemic vascular resistance also may be estimated if Doppler or other noninvasive estimates or calculations of cardiac output are available. Pulmonary vascular resistance may be estimated with echocardiography. However, it is important to note that systemic and pulmonary vascular resistances represent calculations or estimations and not direct measurements and each represents one of several factors contributing to right or left ventricular wall stress.

Any calculation of resistance in a circulation is based on Poiseuille’s law, which states that flow through a system is equal to the change in pressure across the system divided by the resistance in the system (flow = change in pressure/resistance). Resistance in the pulmonary or systemic vascular bed is determined by the fall in pressure (ΔP) as blood flows through the circuit, divided by the cardiac output (CO):

*Blood flow can be indexed to Body Surface Area (Cardiac Index instead of Output)

The equations for calculation of pulmonary and systemic vascular resistances are provided in Tables 8-3 and 8-5 (in Normal Perinatal Circulatory Changes). Because calculated or estimated cardiac output is in the denominator of these equations, any error in cardiac output determination results in significant error in calculated resistances. In addition, changes in cardiac output affect calculated resistances. When flow (cardiac output) increases, pressure and calculated resistances in the systemic and pulmonary vascular beds increase, unless dilation of vessels occurs. If cardiac output falls dramatically and blood pressure is unchanged, the calculated SVR and PVR may rise sharply, even in the absence of active vessel constriction. These formulas do not allow determination of cause and effect (i.e., did the cardiac output fall because vascular resistances rose, or did the calculated resistances rise because cardiac output fell?).

Poiseuille’s original equation allowed calculation of the effects of blood viscosity and length of major vessels on resistance to blood flow. As blood viscosity or vessel length increases, resistance to blood flow increases. Because most calculations of SVR and PVR are used for the analysis of patient trends, blood viscosity, and vessel length are assumed to be constant and have been eliminated from the equation. However, if the patient becomes polycythemic or anemic, pulmonary and systemic vascular resistances are altered, yet are not reflected by the calculation of SVR and PVR from the preceding equations.

Poiseuille’s formula also allows consideration of the resistances in all elements of the circulation. The total resistance to flow in a series is the sum of the resistances in the elements of the series. Total pulmonary vascular resistance is the sum of the resistances in all of the pulmonary arteries, pulmonary capillaries, and pulmonary veins.

If the cross-sectional area of a vascular bed increases and flow and vessel radius remain the same, resistance to flow decreases proportionately. An increase in the cross-sectional area allows more flow at the same pressure, or reduces the pressure needed to maintain the same flow.

If, on the other hand, the cross-sectional area of the vascular bed decreases (as occurs in an infant with hypoplastic lungs), the resistance to blood flow increases in the remaining vessels, even if the diameter of the remaining vessels is unchanged. A reduction in the cross-sectional area of a circulation increases the resistance in the circulation and allows less flow at the same pressure or increases the pressure needed to maintain the same flow.

Because the largest number in the numerator of the Poiseuille’s formula is the mean pressure in the vascular bed, changes in that mean pressure often are thought to reflect trends in vascular resistance. For example, if the mean systemic arterial pressure increases, the systemic vascular resistance may be rising. However, such interpretation is subject to error because both mean arterial pressure and mean pulmonary artery pressure are affected by cardiac output, ventricular preload, ventricular contractility, and vascular tone. A better reflection of vascular resistance is the pulmonary or systemic diastolic pressure. Increased vascular tone (i.e., increased pulmonary or systemic vascular resistance) produces a rise in pulmonary or systemic diastolic pressure and a narrowing of the pulse pressure. A fall in pulmonary or systemic vascular resistance produces a fall in pulmonary or systemic diastolic pressure and a widening of the pulse pressure.

Afterload also may be evaluated by determining the velocity of fiber shortening during cardiac catheterization or with echocardiography. This velocity falls in the presence of increased afterload, but also is affected by heart rate, ventricular preload, and ventricular contractility.

Left ventricular end-systolic wall stress can be determined with echocardiography. This determination requires estimation of left ventricular pressure but reflects changes in afterload independent of changes in preload.

The systolic time intervals of a ventricle include the preejection period (PEP), the ventricular ejection time (VET), and the isovolumetric contraction time (ICT); these intervals are determined through echocardiography. The ratio of the preejection period/ventricular ejection time (PEP/VET) correlate linearly with changes in ventricular afterload; the greater the ventricular afterload, the longer the preejection period required for the ventricle to generate sufficient pressure to overcome afterload so that ejection occurs. For example, the ratio of right ventricular preejection period/ventricular ejection time increases in the child who is developing pulmonary vascular disease and pulmonary hypertension.

Maturational Changes in Response to Alterations in Ventricular Afterload

The pediatric ventricle usually can adapt to increases in ventricular afterload provided the increases are not severe or acute. Adaptation may, in fact, be superior to the response of the adult myocardium. For example, if, in the patient with moderate aortic stenosis the left ventricular muscle thickness increases and the diameter of the left ventricular chamber is reduced, wall stress (afterload) may be normalized (refer again to Box 8-3).

If the infant or pediatric myocardium is subjected to extremely high afterload (such as critical aortic stenosis) myocardial dysfunction can quickly develop. Acute increases in afterload, such as reactive pulmonary vasoconstriction, are also poorly tolerated during the neonatal period.

Pulmonary vascular resistance is elevated in the neonate and any child with pulmonary vascular disease. Children with elevated PVR or those with a reactive pulmonary vascular bed may demonstrate pulmonary hypertensive “crises.” These crises seem to be associated with pulmonary vasoconstriction, an acute rise in right ventricular afterload, and sudden deterioration in cardiac output and systemic perfusion. Factors associated with pediatric hypoxic pulmonary vasoconstriction include alveolar hypoxia, acidosis, alveolar overdistention (by high airway pressures), and hypothermia (refer as needed to Box 8-1). These factors may be avoided through administration of supplementary oxygen as needed to prevent alveolar hypoxia, maintenance of a mild serum alkalosis, prevention of excessive airway pressures, and sedation. (For further information the reader is referred to the sections Postnatal Changes in Pulmonary and Systemic; Vascular Resistances earlier in the chapter and the section on Common Clinical Conditions, Pulmonary Hypertension, later in the chapter.)

Oxygen transport, cardiac output, and oxygen consumption

Oxygen Transport

The ultimate function of the heart and lungs is to deliver oxygenated blood to the tissues. Systemic oxygen transport or oxygen delivery (SOT or DO₂) is the volume of oxygen (mL/min per m² body surface area) delivered to the tissues every minute; it is the product of arterial oxygen content (the amount of oxygen [in mL] per deciliter of arterial blood) and the cardiac index (the volume of blood per meter² body surface area delivered to the tissues every minute). Oxygen delivery reflects the quantity of oxygen available to the tissues.

If arterial oxygen content falls, oxygen delivery is maintained only if cardiac output increases commensurately. If cardiac output falls, oxygen delivery falls; SOT often falls in direct correlation to the drop in cardiac output. When SOT falls significantly, there is an attempt to redistribute blood flow to vital organs. In addition, oxygen extraction is increased and anaerobic metabolism results.

Oxygen Content

Oxygen content is the total amount of oxygen (in milliliters) carried in each deciliter of blood. Because oxygen is carried primarily in the form of oxyhemoglobin the arterial oxygen content essentially is determined by the hemoglobin concentration and its saturation.

Factors Affecting Arterial Oxygen Content

Arterial oxygen content will fall in the presence of anemia or if the oxyhemoglobin saturation falls. Anemia should be avoided in the critically ill patient with cardiorespiratory disease because it will compromise arterial oxygen content and may result in a fall in arterial oxygen delivery. Transfusion therapy is one nonventilatory method for improving arterial oxygen content in these patients, and it may improve oxygen delivery. However, the ideal hemoglobin and hematocrit levels for the critically ill patient (and particularly for the critically ill patient with congenital heart disease) have not been determined. Adequate hemoglobin concentration is required to maintain arterial oxygen-carrying capacity and oxygen content; excessive hemoglobin and hematocrit levels, however, increase blood viscosity and resistance to blood flow so that oxygen delivery actually is impaired.

Although the ideal hemoglobin concentration has not been established there are some theoretical differences in the perceived desirable ranges of hemoglobin concentration based on the patient condition. Maintenance of a hemoglobin concentration of 12 to 15 g/dL and a hematocrit of approximately 35% to 40% is probably beneficial for the child with respiratory disease. However, if shock or increased intracranial pressure results in sluggish systemic or cerebral perfusion, a hemoglobin concentration of 10 to 11 g/dL may maintain adequate oxygen content while minimizing blood viscosity.

The child with cyanotic heart disease will require a relatively high hemoglobin concentration to maintain oxygen content in the fact of chronic arterial oxyhemoglobin desaturation. These children generally require hemoglobin of at least 15 g/dL, and anemia will reduce arterial oxygen content. Extreme polycythemia (Hgb concentration >20 g/dL and Hct >55% to 60%) must be avoided, because it will increase blood viscosity and risk of thromboembolic complications.

The oxyhemoglobin saturation will decrease in the presence of an intrapulmonary shunt or a right-to-left intracardiac shunt (cyanotic heart disease); this decrease in saturation will produce a fall in arterial oxygen content and may reduce systemic oxygen transport. If an intrapulmonary shunt is causing hypoxemia, arterial oxygen content can be increased through the administration of supplementary oxygen. Mechanical ventilation with the judicious use of positive end-expiratory pressure also can increase oxyhemoglobin saturation, arterial oxygen content, and oxygen delivery (see Chapter 9).

If a right-to-left (cyanotic) intracardiac shunt produces mild or moderate arterial oxygen desaturation and hypoxemia (i.e., oxyhemoglobin saturation of 85% to 90% and PaO₂ <50 mm Hg), administration of supplementary inspired oxygen is not likely to be beneficial. Oxygen content in these children increases most effectively when hemoglobin concentration increases and pulmonary blood flow and intracardiac mixing improve (refer to the section, Common Clinical Conditions, Hypoxemia).

Oxygen content may improve with oxygen administration in the child with cyanotic heart disease and severe hypoxemia (i.e., oxyhemoglobin saturation of 60% to 75%, and PaO₂ <30-45 mm Hg); in these children any small improvement in arterial oxygen tension achieved by oxygen administration may be associated with a relatively significant increase in oxyhemoglobin saturation and arterial oxygen content.

Clinical Evaluation of Arterial Oxygen Content

The most accurate method of determining arterial oxygen content is through measurement of hemoglobin concentration and its saturation, and arterial oxygen tension. The oxygen content is the product of the hemoglobin concentration, its saturation, and the 1.34 mL (or 1.36 mL according to some sources) of oxygen carried by each gram of saturated hemoglobin per deciliter (see Box 8-4). In addition, a small amount of oxygen is dissolved in the blood; this amount (mL O₂/dL of blood) is calculated by multiplying 0.003 and the arterial oxygen tension (PaO₂). The dissolved oxygen in the blood usually contributes an inconsequential amount to the oxygen content. However, when severe anemia is present this dissolved oxygen may be very important. Normal arterial oxygen content is approximately 18 to 20 mL O₂/dL blood.

Box 8-4 Calculation of Arterial Oxygen Content

Arterial oxygen content is linked most closely to hemoglobin saturation; a pulse oximeter may be used to continuously monitor the oxyhemoglobin saturation. If the hemoglobin concentration is stable the arterial oxygen content is estimated by multiplying the oximeter oxyhemoglobin saturation by the known hemoglobin concentration and 1.34 mL O₂/g of hemoglobin. This estimation will be unreliable if the hemoglobin concentration varies widely (e.g., during hemorrhage or transfusion therapy).

Cardiac Output

Cardiac output is the volume of the blood ejected by the heart in 1 min; it is the product of heart rate and stroke volume. Cardiac output often is recorded in L/min or mL/min, although it may be normalized to body weight (mL/kg body weight per min) or to body surface area (mL/m² body surface area per min). The normal cardiac output averages approximately 200 mL/kg per minute during infancy, 150 mL/kg per minute during childhood, and 100 mL/kg per minute in the adolescent.⁷⁵² Although the cardiac output/kg body weight decreases during childhood, the absolute cardiac output increases as the child grows.

Children of different sizes have different normal ranges of cardiac output, so it is easier to interpret the child’s cardiac index rather than the cardiac output; the typical cardiac index is the same for children of all ages. Cardiac index is equal to the child’s cardiac output divided by the child’s body surface area in m². Normal cardiac index in the child is approximately 3.5-4.5 L/minute per m² body surface area.

Although “normal” ranges of cardiac output and index have been established in children these “normal” ranges may not maintain sufficient oxygen delivery to the tissues. Cardiac output and index always must be evaluated in light of the patient’s clinical condition; the cardiac output or index should be considered as adequate to maintain oxygen and substrate delivery to the tissues, or inadequate, resulting in tissue and organ ischemia. Therapy is directed at restoring cardiac output that is adequate to maintain tissue oxygenation and substrate delivery.

Factors Affecting Cardiac Output

Cardiac output is the product of heart rate and stroke volume. If either component decreases without a commensurate and compensatory increase in the other component, cardiac output falls.

In children the heart rate is rapid and the stroke volume is small. Tachycardia helps to maintain cardiac output during periods of cardiorespiratory distress; any increase in heart rate above normal may improve cardiac output. An extremely rapid heart rate, however, with a ventricular rate exceeding 200 to 220/minute in the infant or 160 to 180/minute in the child results in a compromise in ventricular diastolic filling time and left coronary artery perfusion time, so that stroke volume and cardiac output often fall.

A transient decrease in heart rate may be normal in the infant or child, but significant or sustained bradycardia usually results in a fall in cardiac output or systemic perfusion. Persistent bradycardia may be an ominous clinical finding in the critically ill child and is often associated with hypoxia, or acidosis (refer to Arrhythmias later in this chapter). The bedside nurse should immediately verify that the airway is patent and support oxygenation and ventilation.

Ventricular stroke volume averages approximately 1.5 mL/kg; stroke volume in the 3 kg neonate is approximately 5 mL, and stroke volume in the 50 kg adolescent is approximately 75 mL. Stroke volume is determined by ventricular preload, contractility, and afterload. These factors have been described in the preceding sections. Trends in normal cardiac output and index with age can be found in Chapter 6, Table 6-1.

Clinical Evaluation of Cardiac Output

When cardiac output is inadequate to maintain oxygen and substrate delivery to the tissues, signs of poor systemic perfusion usually are present. Hypotension may not be observed unless acute severe blood loss has occurred or cardiovascular collapse is imminent (see Chapter 6).

The child’s cardiac output may be estimated using Doppler studies of flow through the aorta (Box 8-5), or may be calculated using an artoerial/venous oxygen content difference combined with measured or estimated oxygen consumption (the Fick principle), or with thermodilution techniques. Each of these methods involves the application of physiologic principles to biologic systems, so each has potential sources of error that must be eliminated or at least standardized so the techniques can be used to evaluate trends in the patient’s condition.

Box 8-5 Doppler Cardiac Output Determination

Doppler Cardiac Output Determination

Most Likely Sources of Error

• Determination of area of aorta (estimation of radius or diameter)

• Interobserver and intraobserver variability in determination of velocity

Doppler Echocardiography

Doppler studies use sound waves reflected from red blood cells to evaluate flow velocity; Doppler cardiac output determinations measure the velocity of red blood cells as they pass through the ascending aorta. The diameter of the thoracic aorta is then calculated based on echocardiographic measurement or normative tables. The cardiac output is the product of the mean red blood cell velocity and the area of the aorta (see Box 8-5). Because the diameter is used to determine the radius (radius = 1/2 measured diameter), and the radius is squared to determine the area of the aorta, any error in the measurement of diameter will be magnified in the ultimate cardiac output determination.

Fick Cardiac Output Calculation

The Fick principle states that the flow of a liquid through a system can be determined if a known quantity of indicator (e.g., oxygen) is added to the fluid, and the quantity of the indicator is measured before and after it passes the site of indicator exchange. Therefore if the patient’s oxygen consumption (the amount of oxygen taken up by the body per unit of time) is known and the arterial and venous oxygen content are determined from representative samples, the cardiac output can be calculated.

Calculation of cardiac output using the Fick principle requires calculation, measurement, or estimation of oxygen consumption, careful, simultaneous sampling of arterial and mixed venous blood, and accurate calculation of the arterial and mixed venous oxygen contents (Box 8-6). If the child’s cardiorespiratory function is relatively stable and Fick calculations of cardiac output are used for determining trends, the oxygen consumption can be estimated and assumed to remain constant. However, oxygen consumption may vary widely during the clinical course of the child with cardiorespiratory failure, so such estimations may introduce significant error in the cardiac output calculation.

Box 8-6 Fick Calculation of Cardiac Output

*†

To convert the Fick cardiac output to cardiac index

Most likely sources of error in Fick cardiac output determination

Determination or estimation of oxygen consumption
If right atrial sample used for mixed venous sample, preferential sampling of SVC, IVC, or coronary sinus blood may yield erroneous results
Mathematical error
Intracardiac or great vessel shunt—a left-to-right shunt can raise the mixed venous oxygen saturation and result in falsely high cardiac output calculation

To add dissolved oxygen to these figures, multiply 0.003 × PaO₂ and add to arterial oxygen content and multiply 0.003 × PvO₂ and add to mixed venous oxygen content

^* Determination of oxygen consumption:

• Measurement by calorimeter

• Estimation: 5-8 mL/kg per minute OR 150-160 mL/min per m² for child (and 120-130 mL/min per m² for the young neonate). Child must be in steady state.

^† Calculation of arterial and venous oxygen content:

The venous sample must be representative of mixed systemic venous blood; because the oxygen content varies in the superior and inferior vena cavae and coronary sinus, a central venous or right atrial sample is not ideal for use in this calculation. (Coronary sinus blood has low oxygen content, and inferior vena caval blood has higher oxygen content than superior vena caval blood.) A true mixed venous sample should be obtained from the pulmonary artery. If a central venous or right atrial sample is used consistently for the venous sample, the potential error introduced must be considered. Any intracardiac or great vessel shunt also introduces significant error into the determination of the true mixed venous oxygen content. (A case study demonstration of the Fick cardiac output calculation is included in Evolve Box 8-3 in the Chapter 8 Supplement on the Evolve Website.)

Mixed Venous Oxygen Saturation

The mixed venous oxygen saturation falls when oxygen delivery decreases in the face of constant oxygen consumption. Oxygen delivery can fall if either cardiac output or arterial oxygen content falls. Mixed venous oxygen saturation also falls if oxygen demand increases at a faster rate than oxygen delivery. If arterial oxygen content and oxygen demand are stable, the cardiac output is directly related to the mixed venous oxygen saturation.

Continuous monitoring of mixed venous oxygen saturation is possible using an oximeter placed in the pulmonary artery. These systems analyze the amount of light reflected from hemoglobin (as compared with pulse oximeters, which measure the light actually absorbed by hemoglobin). The SvO₂ falls in the presence of decreased oxygen transport produced by either decreased cardiac output or reduced arterial oxygenation, so the SvO₂ frequently falls despite the presence of a stable cardiac output (see Chapter 21). The superior vena caval (SVC) oxygen saturation (ScvO₂) may be sampled as a surrogate for the mixed venous oxygen saturation level. However, it is important to note that the mixed venous oxygen saturation (normally approximately 75%) obtained in the pulmonary artery reflects the mixture of superior vena caval blood (oxygen saturation about 70% to 75%), inferior vena caval blood (oxygen saturation about 80% to 85%) and coronary sinus blood (oxygen saturation typically less than 50%). ScvO₂ is, therefore, approximately equal to the mixed venous oxygen saturation, but the location of the catheter tip can alter the venous blood sampled and the saturation obtained.

Thermodilution Cardiac Output Calculation

The thermodilution cardiac output calculation is a form of indicator-dilution calculation. This calculation requires insertion of a pulmonary artery catheter containing a thermistor bead. Cold fluid is injected into the right atrium and acts as a thermal indicator. This cold fluid mixes with right ventricular output and is ejected into the pulmonary artery. A thermistor records the temperature change over time in the pulmonary artery, and a computer calculates the area under the time-temperature curve (Box 8-7).

Box 8-7 Thermodilution Cardiac Output

Thermodilution Cardiac Output Calculation

Where:

With thermodilution cardiac output, the cardiac output is inversely related to the area under the time-temperature curve. If the temperature change is large and persists for a relatively long period of time the cardiac output must be small (i.e., only a small volume of blood is ejected by the right ventricle to modify the temperature change produced by the cold injectate). If the temperature change is small and is maintained for only a brief period, the cardiac output must be high. (A large right ventricular output will quickly eliminate any effect of the cold injectate on the temperature in the pulmonary artery.)

For thermodilution cardiac output injections to reflect trends in the patient’s cardiac output or index, the thermal injections must be standardized. The bedside monitor (or performed calculations) must be coded properly for the volume and temperature of the injectate and the size of the catheter. Usually three injections are performed; the calculation resulting from the first injection is typically discarded, because this injection serves to prime the catheter with cold injectate, and the resultant cardiac output calculation is usually erroneously high. The cardiac output calculated from the second and third injections are averaged, provided they do not differ by more than 10%. A strip chart recorder should be used to provide a hard copy of each injection curve, so that inconsistencies in injection technique can be detected.

Sources of error in the thermodilution cardiac output calculation include inaccurate injectate volume or temperature, inaccurate coding of computer (inappropriate calibration constant or coding for catheter size, or volume or temperature of injectate), excessive dead space in injection system (between the syringe and the right atrial port), or warming of injectate by large-volume central venous infusion.

In general, anything that artificially increases the magnitude of the temperature change in the pulmonary artery (e.g., administration of excessive and inaccurate injectate volume, injection of iced saline when computer is coded for room temperature injectate) results in falsely low cardiac output calculations. Anything that artificially reduces the magnitude of the temperature change in the pulmonary artery (e.g., warming of the injectate in the syringe before administration, injection of erroneously small injectate volume, coding of the computer for iced injections when room temperature injectate is used, or insertion of tubing between the injectate syringe and the right atrial catheter port) results in falsely high cardiac output calculations.

Typically, 3 or 5 mL iced injections are required for thermodilution cardiac output calculations using a flow-directed balloon-tipped pulmonary artery catheter. These injection volumes must be added to the child’s total fluid intake. For this reason, injections should be performed only as necessary to calculate the cardiac output, and additional injections to test the temperature of the injectate should be performed into a waste syringe.

Oxygen Consumption

Oxygen consumption (VO₂) is the volume of oxygen consumed by the tissues per unit of time. It is the product of the amount of oxygen extracted from each milliliter of blood and the cardiac output. Oxygen consumption can be calculated, measured, or estimated.

Normally, much more oxygen is delivered to the tissues than is consumed. As a result, mild reductions in oxygen delivery can be tolerated because excess oxygen is available. Oxygen consumption is normally independent of oxygen delivery or supply. Oxygen consumption varies according to need and is increased during fever, exercise, and at times of increased circulating catecholamine levels. If oxygen consumption approaches oxygen delivery, however, or oxygen content falls dramatically, tissue ischemia, anaerobic metabolism, and acidosis can result.

When oxygen delivery is reduced, oxygen consumption may be maintained through an increase in tissue oxygen extraction. If oxygen delivery falls precipitously, however, oxygen consumption also falls. At this point, oxygen consumption becomes transport- or delivery-dependent (for further information, see Chapter 6 and Fig. 6-5).

Oxygen consumption may be reduced through administration of analgesics, sedatives, and neuromuscular blockers (during mechanical ventilation), treatment of fever, or use of hypothermia (intentionally produced during some types of cardiovascular surgery). If the patient is cooled and shivering occurs, oxygen consumption will increase rather than decrease.

Clinical Evaluation of Oxygen Consumption

To calculate oxygen consumption the cardiac output and arterial and mixed venous oxygen saturations must be known. Oxygen consumption is the product of the cardiac output and the difference between arterial and venous oxygen content (Box 8-8). A true mixed-venous oxygen content is determined from a sample of pulmonary artery blood rather than from a central venous or right atrial sample. Normal arteriovenous oxygen content difference is approximately 3 to 5 mL/dL; this is approximately 25% of the total 18 to 20 mL O₂/dL arterial oxygen content.

Box 8-8 Calculation of Oxygen Consumption

Calculation of Oxygen Consumption

Oxygen consumption in infants: 10-14 mL O₂/kg per minute

Oxygen consumption in children: 7-11 mL O₂/kg per minute

Because oxygen consumption is maintained at a fairly constant level over a broad range of clinical conditions, cardiac output is usually inversely proportional to the arteriovenous oxygen difference. When cardiac output is high, little oxygen is extracted from the tissues and the arteriovenous O₂ difference is small. If cardiac output falls a large amount of oxygen must be extracted from each milliliter of blood, so the arteriovenous O₂ difference widens. Frequently the arteriovenous O₂ difference is evaluated on a regular basis to evaluate trends in cardiac output. However, conditions such as sepsis or malignant hyperthermia can alter this relationship (refer to Shock in Common Clinical Conditions in this chapter and Mixed Venous Oxygen Saturation in Chapter 8).

Oxygen consumption also can be estimated from normative data. Oxygen consumption in normal children averages 5 to 8 mL/kg per minute, or 150 to 160 mL/min per m² of body surface area. Oxygen consumption in normal infants less than 2 to 3 weeks of age is approximately 120 to 130 mL/min per m² body surface area.⁷⁵²

Autonomic nervous system

The autonomic nervous system controls visceral functions of the body, including blood pressure, cardiovascular function, gastrointestinal motility, and temperature. Autonomic centers are located in the spinal cord and brain stem. The major autonomic center is located in the hypothalamus. These centers closely maintain homeostasis through a balance of closed reflex loops. Afferent signals are received from chemoreceptors and baroreceptors, and efferent signals are transmitted through two major autonomic divisions; the sympathetic and the parasympathetic nervous systems.

Sympathetic Nervous System

Sympathetic nervous system influences are mediated through nerve fibers or the hormonal influences of circulating catecholamines. Sympathetic nerves originate in the spinal cord, between the first thoracic and second lumbar vertebrae. These spinal nerves pass to the chain of sympathetic ganglion located adjacent to the spinal column; most spinal sympathetic nerves synapse (contact) with other terminal (or postganglionic) neurons. Ultimately the sympathetic signals are transmitted to effector organs such as the heart or the adrenal medulla.

The terminal sympathetic fibers that travel to effector organs produce localized effects. The adrenal medulla, on the other hand, secretes epinephrine and small amounts of norepinephrine into the bloodstream, producing more global effects.

Sympathetic cardiac nerve fibers are distributed in an epicardial plexus to all chambers of the heart. They accompany the branches of the coronary vessels to innervate the myocardium, and they also are located near the SA node. Sympathetic nerve fibers innervate all arterioles in all systemic organs to enable reflex control of blood flow and pressure.

Adrenergic Neurotransmitters

Norepinephrine is the neurotransmitter that is released from the sympathetic nerves and acts locally at the neuromuscular junction. It is synthesized in the sympathetic nerve fiber and is stored in vesicles that are located near the nerve membrane. When an action potential spreads over the terminal sympathetic nerve fiber, norepinephrine is released from the vesicles into the tissue surrounding the effector cells. This norepinephrine normally is active for only a few seconds and then is taken back up by nerve endings, diffuses into other body fluids, or is broken down by enzymes. Norepinephrine release and effects may be modulated by patient condition.

Epinephrine is released chiefly by the adrenal medulla following sympathetic nervous system stimulation; this drug mediates the stress-related metabolic response. The adrenal medulla secretes large quantities of epinephrine and small quantities of norepinephrine into the bloodstream. These circulating neurotransmitters (hormones) produce effects similar to those produced by the terminal nerve fibers (see further discussion later in this section). However, the hemodynamic effects of epinephrine are often more significant and last much longer than the local effects produced by norepinephrine.

The sympathetic nervous system is activated during times of stress, producing a “fight or flight” response; this includes tachycardia, increased cardiac contractility, redistribution of blood flow through arterial vasoconstriction (including peripheral, renal, and splanchnic arterial constriction), diaphoresis, and pupil dilation.

Adrenergic Receptors

Neurotransmitters and exogenous (administered) catecholamines stimulate the effector organs by binding with receptors. Adrenergic receptors are glycoproteins associated with cell membranes. They have high specificity and binding affinity for specific catecholamines.⁹⁶⁸ Activation of the adrenergic receptor alters intracellular function. Effects of adrenergic receptor activation will be determined by both the type of receptor activated and by the density of receptors on the cell surface. Adrenergic receptors generally are divided into alpha, beta, and dopaminergic (DA) types.

Beta Receptors

Beta receptors are further subdivided into beta-1 and beta-2 subtypes. All beta receptors produce intracellular effects by the stimulation of adenyl cyclase, which causes formation of cyclic-AMP. Cyclic-AMP is called a second messenger hormone because it mediates the intracellular effects of hormones.

The beta-1 receptor is the predominant adrenergic receptor in the human heart. Beta-1 receptors are innervated; thus, they are activated preferentially by neuronally released norepinephrine. Beta-1 receptor activation results in an increase in heart rate, atrioventricular conduction velocity, and ventricular contractility.

Beta-2 receptors are not innervated; they are activated only by circulating catecholamines (predominantly epinephrine). Beta-2 receptor activation produces peripheral vasodilation and bronchial dilation.

When norepinephrine is secreted from terminal nerve fibers it stimulates only beta-1 (innervated) receptors. Systemically administered norepinephrine, however, stimulates beta-1, beta-2, and alpha-adrenergic receptors. Circulating epinephrine stimulates both beta-1 and beta-2 receptors, and alpha receptors.

Alpha Receptors

Alpha receptors also have been subdivided into alpha-1 and alpha-2 subtypes. Alpha-1 receptor activation affects intracellular function by increasing transcellular calcium flux. Alpha-2 receptor activation stimulates adenyl cyclase and increases intracellular production of cAMP.

Alpha-receptor stimulation results in constriction of vascular and bronchial smooth muscle. This produces peripheral vasoconstriction, including constriction of the skin and mesenteric and renal arteries; venoconstriction also occurs. In mammals, alpha-adrenergic receptor activation increases cardiac contractility, although in humans this effect seems to be produced chiefly by beta-1 receptor activation. Endogenous epinephrine and norepinephrine stimulate both alpha receptor subtypes, but synthetic catecholamines may demonstrate selective stimulation of these receptors.

Dopaminergic Receptors

Dopamine is an endogenous catecholamine that is present in terminal sympathetic nerves as a precursor of norepinephrine. Exogenous dopamine administration produces both direct and indirect actions because it will activate dopaminergic receptors and will stimulate norepinephrine release. At low doses of administered dopamine (approximately 2-5 mcg/kg per minute), DA effects predominate. At moderate infusion rates (approximately 4-10 mcg/kg per minute), both dopaminergic and beta-adrenergic effects may be seen. At high doses (>10 mcg/kg per minute), alpha-adrenergic effects usually dominate. These dose responses can vary, however.

Activation of dopaminergic receptors will result in renal, coronary, mesenteric, and cerebral vasodilation. As a result of renal dilation the glomerular filtration rate and renal sodium excretion increase. When large doses of dopamine are administered these dopaminergic effects may disappear and alpha-adrenergic receptor activation may result in reduction of renal and mesenteric blood flow.

Dopamine also produces noncardiovascular effects. Administration of exogenous dopamine results in decreased aldosterone secretion, inhibition of thyroid stimulating hormone, and reduction in insulin secretion.⁹⁶⁸ These effects must be considered when dopamine is administered to critically ill patients.

Modulation of Adrenergic Receptor Activation

The density of adrenergic receptors on the cell surface is not static; it is affected by a variety of disease states and conditions. Downregulation of a receptor means that there is a decrease in the number of that type of receptor on the cell surface. For example, downregulation of beta-adrenergic myocardial receptors occurs with chronic severe congestive heart failure, myocardial ischemia, and hypothyroidism. Alpha-adrenergic receptors are downregulated when sepsis is present.⁹⁶⁹ When a beta- or alpha-receptor is down-regulated the cell will be less capable of responding to, respectively, beta- or alpha-adrenergic stimulation from endogenous or exogenous catecholamines.

Upregulation of a receptor means that there is an increase in the number of that type of receptor on the cell surface. For example, upregulation of cardiac beta-receptors occurs in patients with mild heart failure and those with hyperthyroidism. When a receptor is upregulated the cell will be more responsive to stimulation of that receptor by circulating or exogenous catecholamines.

Parasympathetic Nervous System

The parasympathetic nervous system, like the sympathetic nervous system, consists of a series of two to three neurons that begin in the brain or central nervous system and synapse with (contact) other parasympathetic neurons in ganglia located near the spinal cord or effector organs. The cell bodies of the preganglionic parasympathetic nerves are located in the brain stem and in the second, third, and fourth sacral segments of the spinal column. The parasympathetic nerve fibers arise from the third, seventh, ninth, and tenth cranial nerves, and from the second, third, and fourth sacral segments of the spinal cord.

Approximately 75% of all parasympathetic nerve fibers are located in the vagus nerves. Although sympathetic nervous system stimulation typically produces effects consistent with a “fight or flight” response, the parasympathetic effects are more consistent with “rest and repair.” Parasympathetic (cholinergic) stimulation is associated with a decrease in heart rate, an increase in intestinal motility, and increased enzymatic secretion. Bladder contraction and sphincter relaxation also occur with cholinergic stimulation.

Vagal cardiovascular effects are most pronounced in the presence of active adrenergic (sympathomimetic) stimulation. There may be three possible explanations for this observation. Acetylcholine released from parasympathetic nerves may reduce intracellular levels of cAMP, or accelerate its breakdown, thus reducing beta-adrenergic intracellular effects. In addition, acetylcholine release may inhibit norepinephrine release from sympathetic fibers; this effect would be most pronounced at the sinoatrial (SA) node.

Parasympathetic Neurotransmitter

Acetylcholine is the neurotransmitter identified with the parasympathetic nervous system. It is synthesized in the nerve body and transmitted along the axon to vesicles at the end of the nerve fiber. Stimulation of the parasympathetic nerve results in the liberation of acetylcholine, which binds with a receptor site on the membrane of the effector organ and causes altered intracellular function. Acetylcholine is then broken down into acetate and choline by acetylcholinesterase; the choline is transported back into the neuron and is used in the formation of new acetylcholine.

Acetylcholine is also the neurotransmitter released by the presynaptic nerves of the sympathetic nervous system. It is present in skeletal muscle fibers and at neuromuscular junctions.

Cholinergic Receptors

Cholinergic receptors are divided into muscarinic and nicotinic receptors, named after the substances that can activate the specific receptors. Muscarinic receptors are found at all the effector sites of the parasympathetic nervous system, including the heart, viscera, and bladder. Nicotinic receptors are present at the ganglionic junction of preganglionic and terminal (postganglionic) nerves in both the sympathetic and the parasympathetic nervous system. In addition, nicotinic receptors are present in skeletal muscle fibers and at neuromuscular junctions.

Activation of terminal effector cholinergic receptors occurs only following stimulation from a terminal parasympathetic nerve. There are no circulating cholinergic hormones. Parasympathetic stimulation reduces heart rate through a negative chronotropic effect on the sinoatrial node. Cholinergic stimulation has some negative inotropic effect on atrial contractility and a lesser negative inotropic effect on ventricular function.

Common clinical conditions

Congestive heart failure

Ricardo Samson

Pearls

• Both congestive heart failure and shock are conditions of cardiac output that is inadequate to meet the metabolic demands of the body.

• Cardiovascular dysfunction is a continuum with no sharp demarcation between severe congestive heart failure and shock.

Etiology

Congestive heart failure refers to a set of clinical signs and symptoms indicative of myocardial dysfunction and cardiac output that is inadequate to meet the metabolic demands of the body. In children it may be caused by increased cardiac workload (imposed by congenital heart defects that alter cardiac preload or afterload, or by severe anemia), impaired cardiac contractility, or alteration in the sequence or rate of cardiac contraction, or a combination of these factors.

Congenital heart disease is the most common cause of congestive heart failure during childhood, particularly during the first year of life. Severe anemia also may produce congestive heart failure at any age. Likewise, congestive heart failure caused by impaired ventricular function (such as cardiomyopathy) may develop at any period during childhood.

Congenital heart defects that most commonly cause congestive heart failure during the newborn period include severe left ventricular outflow tract obstruction (such as hypoplastic left heart, interrupted aortic arch, critical aortic stenosis, or coarctation of the aorta), large arteriovenous fistula, or combined shunt lesions (such as a ventricular septal defect and patent ductus arteriosus). A large patent ductus arteriosus will produce heart failure in the extremely premature neonate. Isolated septal defects (such as a ventricular septal defect) usually do not produce signs of congestive heart failure until pulmonary vascular resistance falls at approximately 2 to 9 weeks of age,⁵⁹⁷ and hemoglobin concentration falls.^214a

Surgical correction of congenital heart defects may cause congestive heart failure as a result of intraoperative cardiac manipulation and resection, with subsequent alteration in pressure, flow, and resistance relationships. Surgical procedures that require a ventriculotomy incision, conduit insertion, or significant ventricular muscle resection (e.g., correction of tetralogy of Fallot or truncus arteriosus) are likely to be associated with postoperative heart failure.

Congestive heart failure may be associated with high or low cardiac output. High cardiac output failure typically is present in the child with congenital heart disease producing a left-to-right shunt, particularly at the level of the ventricles or within the great vessels. This type of shunt produces high pulmonary blood flow, often at systemic pressure. The increased volume of pulmonary venous return results in a tremendous volume load for the left ventricle.

High cardiac output failure also may be caused by severe anemia, such as that resulting from increased red blood cell destruction (e.g., hemolytic anemia) or reduced red blood cell formation (e.g., aplastic anemia, or other bone marrow failure). Mild anemia may be asymptomatic because cardiac output will increase commensurately to maintain oxygen delivery. Severe anemia, however (with a hemoglobin concentration of less than 5 g/dL and a hematocrit of less than 15%), significantly compromises arterial oxygen-carrying capacity and arterial oxygen content, so that only extremely high levels of cardiac output will maintain oxygen delivery. Frequently the child with severe, chronic anemia maintains a compensated state unless or until conditions develop that require further increase in cardiac output (e.g., fever, sepsis).

Low output congestive heart failure typically is seen in children with severe left heart or aortic obstruction (such as critical aortic stenosis or hypoplastic left heart), cardiomyopathy, or tachyarrhythmias.⁸⁴¹ These children demonstrate signs of decreased left ventricular function and poor systemic perfusion. Low cardiac output also may be present in children with severe congestive heart failure and an extremely large left-to-right shunt. The increased work of breathing in children with congestive heart failure (CHF) results in increased blood flow to respiratory muscles, which effectively “steals” systemic blood flow and may contribute to low cardiac output.

Low output congestive heart failure also may be seen in children with elevated pulmonary artery pressures following a Fontan-type correction of tricuspid atresia, hypoplastic left heart, or other single ventricle lesions (see section, Specific Diseases, Single Functioning Ventricle). In these patients, systemic venous return is routed directly into the pulmonary arteries, flowing passively through the lungs to return to the systemic ventricle to be circulated to the body. High pulmonary or systemic venous pressure may be present for days (or longer) following performance of a Fontan-type procedure. In these patients, low cardiac output is exacerbated by mechanical ventilation with high levels of positive end-expiratory pressure (PEEP) or increased pulmonary vascular resistance.⁹³⁵

Pathophysiology

Biochemical Alterations

Many primary and secondary genetic and biochemical abnormalities have been described in association with impaired ventricular contractility.²⁶¹ In many cases, the final common pathway results in impaired binding or release of calcium or impaired calcium entry into the sarcolemma. These changes lead to abnormalities of excitation-contraction coupling.^438,⁸⁴¹ If oxygen demand increases in the presence of limited myocardial oxygen delivery (particularly in children with aortic stenosis, tachyarrhythmias, or other causes of limited myocardial perfusion, or those with hyperthermia), myocardial perfusion and performance may be inadequate to maintain effective systemic oxygen and substrate delivery. Extreme core hyperthermia may increase oxygen demand significantly. Chronic, severe congestive heart failure also may result in down-regulation (decreased density) of beta-adrenergic receptors.⁹⁶⁹ All of these factors may further compromise myocardial function.

Some patients with congestive heart failure develop enhanced calcium influx, prolonged calcium binding, and impaired calcium uptake. When this occurs, the myocardium generates tension effectively but relaxation is impaired. Impaired relaxation, in turn, compromises diastolic filling, and stroke volume falls.⁴³⁸