Vitamin A

Vitamin A – Deficiency and Toxicity

Vitamin A, in the strictest sense, refers to retinol. However, the oxidized metabolites, retinaldehyde and retinoic acid, are also biologically active compounds. The term retinoids includes all molecules (including synthetic molecules) that are chemically related to retinol. Retinaldehyde (11-cis) is the essential form of vitamin A that is required for normal vision, whereas retinoic acid is necessary for normal morphogenesis, growth, and cell differentiation. Retinoic acid does not function in vision and, in contrast to retinol, is not involved in reproduction. Vitamin A also plays a role in iron utilization, humoral immunity, T cell–mediated immunity, natural killer cell activity, and phagocytosis. Vitamin A is commercially available in esterified forms (e.g., acetate, palmitate) since it is more stable as an ester.

There are more than 600 carotenoids in nature, and approximately 50 of these can be metabolized to vitamin A. β-Carotene is the most prevalent carotenoid in the food supply that has provitamin A activity. In humans, significant fractions of carotenoids are absorbed intact and are stored in liver and fat. It is now estimated that 12 µg or greater of dietary β-carotene is equivalent to 1 µg of retinol, whereas 24 µg or greater of other dietary provitamin A carotenoids (e.g., cryptoxanthin, α-carotene) is equivalent to 1 µg of retinol.

Metabolism

The liver contains approximately 90% of the vitamin A reserves and secretes vitamin A in the form of retinol, which is bound to retinol-binding protein. Once this has occurred, the retinol-binding protein complex interacts with a second protein, transthyretin. This trimolecular complex functions to prevent vitamin A from being filtered by the kidney glomerulus, to protect the body against the toxicity of retinol and to allow retinol to be taken up by specific cell-surface receptors that recognize retinol-binding protein. A certain amount of vitamin A enters peripheral cells even if it is not bound to retinol-binding protein. After retinol is internalized by the cell, it becomes bound to a series of cellular retinol-binding proteins, which function as sequestering and transporting agents as well as co-ligands for enzymatic reactions. Certain cells also contain retinoic acid–binding proteins, which have sequestering functions but also shuttle retinoic acid to the nucleus and enable its metabolism.

Retinoic acid is a ligand for certain nuclear receptors that act as transcription factors. Two families of receptors (RAR and RXR receptors) are active in retinoid-mediated gene transcription. Retinoid receptors regulate transcription by binding as dimeric complexes to specific DNA sites, the retinoic acid response elements, in target genes. The receptors can either stimulate or repress gene expression in response to their ligands. RAR binds all-trans retinoic acid and 9-cis retinoic acid, whereas RXR binds only 9-cis retinoic acid.

The retinoid receptors play an important role in controlling cell proliferation and differentiation. Retinoic acid is useful in the treatment of promyelocytic leukemia and is also used in the treatment of cystic acne because it inhibits keratinization, decreases sebum secretion, and possibly alters the inflammatory reaction. RXRs dimerize with other nuclear receptors to function as coregulators of genes responsive to retinoids, thyroid hormone, and calcitriol. RXR agonists induce insulin sensitivity experimentally, perhaps because RXR is a cofactor for the peroxisome-proliferator-activated receptors (PPARs), which are targets for the thiazolidinedione drugs such as rosiglitazone and troglitazone

Dietary Sources

The retinol activity equivalent (RAE) is used to express the vitamin A value of food. One RAE is defined as 1 µg of retinol (0.003491 mmol), 12 µg of β-carotene, and 24 µg of other provitamin A carotenoids. In older literature, vitamin A was often expressed in international units (IU), with 1 RAE being equal to 3.33 IU of retinol and 20 IU of β-carotene, but these units are no longer in current scientific use.

Liver, fish, and eggs are excellent food sources for preformed vitamin A; vegetable sources of provitamin A carotenoids include dark green and deeply colored fruits and vegetables. Moderate cooking of vegetables enhances carotenoid release for uptake in the gut. Carotenoid absorption is also aided by some fat in a meal. Infants are particularly susceptible to vitamin A deficiency because neither breast nor cow's milk supplies enough vitamin A to prevent deficiency. In developing countries, chronic dietary deficit is the main cause of vitamin A deficiency and is exacerbated by infection. In early childhood, low vitamin A status results from inadequate intakes of animal food sources and edible oils, both of which are expensive, coupled with seasonal unavailability of vegetables and fruits, and lack of marketed fortified food products. Concurrent zinc deficiency can interfere with the mobilization of vitamin A from liver stores. Alcohol interferes with the conversion of retinol to retinaldehyde in the eye by competing for alcohol (retinol) dehydrogenase. Drugs that interfere with the absorption of vitamin A include mineral oil, neomycin, and cholestyramine.

Fig. 1. Carrots, one of vegetables that provide vitamin A

Deficiency

Vitamin A deficiency is endemic where diets are chronically poor, especially in Southern Asia, Sub-Saharan Africa, some areas of Latin America, and the Western Pacific, including parts of China. Vitamin A status is usually assessed by measuring serum retinol [normal range, 1.05–3.50 µmol/L (30–100 µg/dL)] or blood spot retinol or by tests of dark adaptation. Stable isotopic or invasive liver biopsy methods exist to estimate total body stores of vitamin A. Based on deficient serum retinol [<0.70>xerophthalmia. This condition includes milder stages of night blindness and conjunctival xerosis (dryness) with Bitot's spots (white patches of keratinizedepithelium appearing on the sclera) as well as rare, potentially blinding corneal ulceration and necrosis. Keratomalacia (softening of the cornea) leads to corneal scarring that blinds at least a quarter of a million children each year and is associated with a fatality rate of 4–25%. However, vitamin A deficiency at any stage poses an increased risk of mortality from diarrhea, dysentery, measles, malaria, and respiratory disease. Vitamin A deficiency can compromise barrier and innate and acquired immune defenses to infection. Vitamin A supplementation can markedly reduce risk of child mortality (23–34%, on average) where deficiency is widely prevalent. About 10% of pregnant women in undernourished settings also develop night blindness, assessed by history, during the latter half of pregnancy and this moderate vitamin A deficiency is associated with an increased risk of maternal infection and mortality.

Fig 2. Xerophthalmia resulted from vitamin A deficieny

Vitamin A Deficiency: Treatment

Any stage of xerophthalmia should be treated with 60 mg of vitamin A in oily solution, usually contained in a soft-gel capsule. The same dose is repeated 1 and 14 days later. Doses should be reduced by half for patients 6–11 months of age. Mothers with night blindness or Bitot's spots should be given vitamin A orally, either 3 mg daily or 7.5 mg twice a week for 3 months. These regimens are efficacious, and they are less expensive and more widely available than injectable water-miscible vitamin A. A common approach to prevention is to supplement young children living in high-risk areas with 60 mg every 4–6 months, with a half-dose given to infants 6–11 months of age.

Uncomplicated vitamin A deficiency rarely occurs in industrialized countries. One high-risk group, extremely low-birth-weight infants (<1000>

There are no specific deficiency signs or symptoms that result from carotenoid deficiency. It was postulated that β-carotene would be an effective chemopreventive agent for cancer because numerous epidemiologic studies had shown that diets high in β-carotene were associated with lower incidences of cancers of the respiratory and digestive systems. However, intervention studies in smokers found that treatment with high doses of β-carotene actually resulted in more lung cancers than did treatment with placebo. Non–provitamin A carotenoids, such as lutein and zeaxanthin, have been suggested to protect against macular degeneration. The non–provitamin A carotenoid lycopene has been proposed to protect against prostate cancer. However, the effectiveness of these agents has not been proven by intervention studies, and the mechanisms underlying these purported biologic actions are unknown.

Toxicity

Acute toxicity of vitamin A was first noted in Arctic explorers who ate polar bear liver and has also been seen after administration of 150 mg in adults or 100 mg in children. Acute toxicity is manifested by increased intracranial pressure, vertigo, diplopia, bulging fontanels in children, seizures, and exfoliative dermatitis; it may result in death. In children being treated for vitamin A deficiency according to the protocols outlined above, transient bulging of fontanels occurs in 2% of infants, and transient nausea, vomiting, and headache occur in 5% of preschoolers. Chronic vitamin A intoxication is largely a concern in industrialized countries and has been seen in normal adults who ingest 15 mg/d and children who ingest 6 mg/d of vitamin A over a period of several months. Manifestations include dry skin, cheilosis, glossitis, vomiting, alopecia, bone demineralization and pain, hypercalcemia, lymph node enlargement, hyperlipidemia, amenorrhea, and features of pseudotumor cerebri with increased intracranial pressure and papilledema. Liver fibrosis with portal hypertension and bone demineralization may result from chronic vitamin A intoxication. When vitamin A is provided in excess to pregnant women, congenital malformations have included spontaneous abortions, craniofacial abnormalities, and valvular heart disease. In pregnancy, the daily dose of vitamin A should not exceed 3 mg. Commercially available retinoid derivatives are also toxic, including 13-cis-retinoic acid, which has been associated with birth defects. As a result, contraception should be continued for a least 1 year, and possibly longer, in women who have taken 13-cis retinoic acid.

High doses of carotenoids do not result in toxic symptoms but should be avoided in smokers due to an increased risk of lung cancer. Carotenemia, which is characterized by a yellowing of the skin (creases of the palms and soles) but not the sclerae, may be present after ingestion of >30 mg of β-carotene daily. Hypothyroid patients are particularly susceptible to the development of carotenemia due to impaired breakdown of carotene to vitamin A. Reduction of carotenes from the diet results in the disappearance of skin yellowing and carotenemia over a period of 30–60 days.

Testicular cancer

Testicular Cancer

(From Harrison's Principle of Internal Medicine, 17th Ed)

Introduction

Primary germ cell tumors (GCTs) of the testis, arising by the malignant transformation of primordial germ cells, constitute 95% of all testicular neoplasms. Infrequently, GCTs arise from an extragonadal site, including the mediastinum, retroperitoneum, and, very rarely, the pineal gland. This disease is notable for the young age of the afflicted patients, the totipotent capacity for differentiation of the tumor cells, and its curability; about 95% of newly diagnosed patients are cured. Experience in the management of GCTs leads to improved outcome.

Incidence and Epidemiology

In 2007, 7920 new cases of testicular GCT were diagnosed in the United States; the incidence is decreasing after having increased slowly over the past 40 years. The tumor occurs most frequently in men between the ages of 20 and 40. A testicular mass in a male > 50 years should be regarded as a lymphoma until proved otherwise. GCT is at least four to five times more common in white than in African-American males, and a higher incidence has been observed in Scandinavia and New Zealand than in the United States.

Etiology and Genetics

Cryptorchidism is associated with a severalfold higher risk of GCT. Abdominal cryptorchid testes are at a higher risk than inguinal cryptorchid testes. Orchiopexy should be performed before puberty, if possible. Early orchiopexy reduces the risk of GCT and improves the ability to save the testis. An abdominal cryptorchid testis that cannot be brought into the scrotum should be removed. About 2% of men with GCTs of one testis will develop a primary tumor in the other testis. Testicular feminization syndromes increase the risk of testicular GCT, and Klinefelter's syndrome is associated with mediastinal GCT.

An isochromosome of the short arm of chromosome 12 [i(12p)] is pathognomonic for GCT of all histologic types. Excess 12p copy number, either in the form of i(12p) or as increased 12p on aberrantly banded marker chromosomes, occurs in nearly all GCTs, but the gene(s) on 12p involved in the pathogenesis are not yet defined.

Clinical Presentation

A painless testicular mass is pathognomonic for a testicular malignancy. More commonly, patients present with testicular discomfort or swelling suggestive of epididymitis and/or orchitis. In this circumstance, a trial of antibiotics is reasonable. However, if symptoms persist or a residual abnormality remains, then testicular ultrasound examination is indicated.

Ultrasound of the testis is indicated whenever a testicular malignancy is considered and for persistent or painful testicular swelling. If a testicular mass is detected, a radical inguinal orchiectomy should be performed. Because the testis develops from the gonadal ridge, its blood supply and lymphatic drainage originate in the abdomen and descend with the testis into the scrotum. An inguinal approach is taken to avoid breaching anatomic barriers and permitting additional pathways of spread.

Back pain from retroperitoneal metastases is common and must be distinguished from musculoskeletal pain. Dyspnea from pulmonary metastases occurs infrequently. Patients with increased serum levels of human chorionic gonadotropin (hCG) may present with gynecomastia. A delay in diagnosis is associated with a more advanced stage and possibly worse survival.

The staging evaluation for GCT includes a determination of serum levels of fetoprotein (AFP), hCG, and lactate dehydrogenase (LDH). After orchiectomy, a chest radiograph and a CT scan of the abdomen and pelvis should be performed. A chest CT scan is required if pulmonary nodules or mediastinal or hilar disease is suspected. Stage I disease is limited to the testis, epididymis, or spermatic cord. Stage II disease is limited to retroperitoneal (regional) lymph nodes. Stage III disease is disease outside the retroperitoneum, involving supradiaphragmatic nodal sites or viscera. The staging may be "clinical"—defined solely by physical examination, blood marker evaluation, and radiographs—or "pathologic"—defined by an operative procedure.

The regional draining lymph nodes for the testis are in the retroperitoneum, and the vascular supply originates from the great vessels (for the right testis) or the renal vessels (for the left testis). As a result, the lymph nodes that are involved first by a right testicular tumor are the interaortocaval lymph nodes just below the renal vessels. For a left testicular tumor, the first involved lymph nodes are lateral to the aorta (para-aortic) and below the left renal vessels. In both cases, further nodal spread is inferior, contralateral, and, less commonly, above the renal hilum. Lymphatic involvement can extend cephalad to the retrocrural, posterior mediastinal, and supraclavicular lymph nodes. Treatment is determined by tumor histology (seminoma versus nonseminoma) and clinical stage (Table 1).

Table 1 Germ Cell Tumor Staging and Treatment

Treatment Stage Extent of Disease Seminoma Nonseminoma IA Testis only, no vascular/lymphatic invasion (T1) Radiation therapy RPLND or observation IB Testis only, with vascular/lymphatic invasion (T2), or extension through tunica albuginea (T2), or involvement of spermatic cord (T3) or scrotum (T4) Radiation therapy RPLND IIA Nodes <> Radiation therapy RPLND or chemotherapy often followed by RPLND IIB Nodes 2–5 cm Radiation therapy RPLND +/– adjuvant chemotherapy or chemotherapy followed by RPLND IIC Nodes > 5 cm Chemotherapy Chemotherapy, often followed by RPLND III Distant metastases Chemotherapy Chemotherapy, often followed by surgery (biopsy or resecti

Pathology

GCTs are divided into nonseminoma and seminoma subtypes. Nonseminomatous GCTs are most frequent in the third decade of life and can display the full spectrum of embryonic and adult cellular differentiation. This entity comprises four histologies: embryonal carcinoma, teratoma, choriocarcinoma, and endodermal sinus (yolk sac) tumor. Choriocarcinoma, consisting of both cytotrophoblasts and syncytiophoblasts, represents malignant trophoblastic differentiation and is invariably associated with secretion of hCG. Endodermal sinus tumor is the malignant counterpart of the fetal yolk sac and is associated with secretion of AFP. Pure embryonal carcinoma may secrete AFP or hCG, or both; this pattern is biochemical evidence of differentiation. Teratoma is composed of somatic cell types derived from two or more germ layers (ectoderm, mesoderm, or endoderm). Each of these histologies may be present alone or in combination with others. Nonseminomatous GCTs tend to metastasize early to sites such as the retroperitoneal lymph nodes and lung parenchyma. One-third of patients present with disease limited to the testis (stage I), one-third with retroperitoneal metastases (stage II), and one-third with more extensive supradiaphragmatic nodal or visceral metastases (stage III).

Seminoma represents about 50% of all GCTs, has a median age in the fourth decade, and generally follows a more indolent clinical course. Most patients (70%) present with stage I disease, about 20% with stage II disease, and 10% with stage III disease; lung or other visceral metastases are rare. Radiation therapy is the treatment of choice in patients with stage I disease and stage II disease where the nodes are <5>

Tumor Markers

Careful monitoring of the serum tumor markers AFP and hCG is essential in the management of patients with GCT, as these markers are important for diagnosis, as prognostic indicators, in monitoring treatment response, and in the detection of early relapse. Approximately 70% of patients presenting with disseminated nonseminomatous GCT have increased serum concentrations of AFP and/or hCG. While hCG concentrations may be increased in patients with either nonseminoma or seminoma histology, the AFP concentration is increased only in patients with nonseminoma. The presence of an increased AFP level in a patient whose tumor shows only seminoma indicates that an occult nonseminomatous component exists and the patient should be treated for nonseminomatous GCT. LDH levels are not as specific as AFP or hCG but are increased in 50–60% patients with metastatic nonseminoma and in up to 80% of patients with advanced seminoma.

AFP, hCG, and LDH levels should be determined before and after orchiectomy. Increased serum AFP and hCG concentrations decay according to first-order kinetics; the half-life is 24–36 h for hCG and 5–7 days for AFP. AFP and hCG should be assayed serially during and after treatment. The reappearance of hCG and/or AFP or the failure of these markers to decline according to the predicted half-life is an indicator of persistent or recurrent tumor.

Treatment

Stage I Nonseminoma

If, after an orchiectomy (for clinical stage I disease), radiographs and physical examination show no evidence of disease and serum AFP and hCG concentrations are either normal or declining to normal according to the known half-life, patients may be managed by either a nerve-sparing retroperitoneal lymph node dissection (RPLND) or surveillance. The retroperitoneal lymph nodes are involved by GCT (pathologic stage II) in 20–50% of these patients. The choice of surveillance or RPLND is based on the pathology of the primary tumor. If the primary tumor shows no evidence for lymphatic or vascular invasion and is limited to the testis (T1), then either option is reasonable. If lymphatic or vascular invasion is present or the tumor extends into the tunica, spermatic cord, or scrotum (T2 through T4), then surveillance should not be offered. Either approach should cure >95% of patients.

RPLND is the standard operation for removal of the regional lymph nodes of the testis (retroperitoneal nodes). The operation removes the lymph nodes ipsilateral to the primary site and the nodal groups adjacent to the primary landing zone. The standard (modified bilateral) RPLND removes all node-bearing tissue down to the bifurcation of the great vessels, including the ipsilateral iliac nodes. The major long-term effect of this operation is retrograde ejaculation and infertility. Nerve-sparing RPLND, usually accomplished by identification and dissection of individual nerve fibers, may avoid injury to the sympathetic nerves responsible for ejaculation. Normal ejaculation is preserved in ~90% of patients. Patients with pathologic stage I disease are observed, and only the <10%>

RPLND, then a decision regarding adjuvant chemotherapy is made on the basis of the extent of retroperitoneal disease (see below).

Surveillance is an option in the management of clinical stage I disease when no vascular/lymphatic invasion is found (T1). Only 20–30% of patients have pathologic stage II disease, implying that most RPLNDs in this situation are not therapeutic. Surveillance and RPLND lead to equivalent long-term survival rates. Patient compliance is essential if surveillance is to be successful. Patients must be carefully followed with periodic chest radiography, physical examination, CT scan of the abdomen, and serum tumor marker determinations. The median time to relapse is about 7 months, and late relapses (>2 years) are rare. The 70–80% of patients who do not relapse require no intervention after orchiectomy; treatment is reserved for those who do relapse. When the primary tumor is classified as T2 through T4 (extension beyond testis and epididymis or lymphatic/vascular invasion is identified), nerve-sparing RPLND is preferred. About 50% of these patients have pathologic stage II disease and are destined to relapse without the RPLND.

Stage II Nonseminoma

Patients with limited, ipsilateral retroperitoneal adenopathy (nodes usually <3><2>and <6>>50% of patients with "high-volume" metastases (>6 nodes involved, or any involved node >2 cm in largest diameter, or extranodal tumor extension), two cycles of adjuvant chemotherapy should be considered, as it results in cure in >98% of patients. Regimens consisting of etoposide (100 mg/m² daily on days 1–5) plus cisplatin (20 mg/m² daily on days 1–5) with or without bleomycin (30 units per day on days 2, 9, and 16) given at 3-week intervals are effective and well tolerated.

Stages I and II Seminoma

Inguinal orchiectomy followed by retroperitoneal radiation therapy cures ~98% of patients with stage I seminoma. The dose of radiation therapy (2500–3000

cGy) is low and well tolerated, and the in-field recurrence rate is negligible. About 2% of patients relapse with supradiaphragmatic or systemic disease. Surveillance has been proposed as an option, and studies have shown that about 15% of patients relapse. The median time to relapse is 12–15 months, and late relapses (>5 years) may be more frequent than with nonseminoma. The relapse is usually treated with chemotherapy. Surveillance for clinical stage I seminoma is not recommended.

Nonbulky retroperitoneal disease (stage IIA and IIB) is also treated with radiation therapy. Prophylactic supradiaphragmatic fields are not used. Relapses in the anterior mediastinum are unusual. Approximately 90% of patients achieve relapse-free survival with retroperitoneal masses <5>

Chemotherapy for Advanced GCT

Regardless of histology, patients with stage IIC and stage III GCT are treated with chemotherapy. Combination chemotherapy programs based on cisplatin at doses of 100 mg/m² plus etoposide at doses of 500 mg/m² per cycle cure 70–80% of such patients, with or without bleomycin, depending on risk stratification (see below). A complete response (the complete disappearance of all clinical evidence of tumor on physical examination and radiography plus normal serum levels of AFP and hCG for >= 1 month) occurs after chemotherapy alone in ~60% of patients, and another 10–20% become disease-free with surgical resection of residual masses containing viable GCT. Lower doses of cisplatin result in inferior survival rates.

The toxicity of four cycles of the cisplatin/bleomycin/etoposide (BEP) regimen is substantial. Nausea, vomiting, and hair loss occur in most patients, although nausea and vomiting have been markedly ameliorated by modern antiemetic regimens. Myelosuppression is frequent, and symptomatic bleomycin pulmonary toxicity occurs in ~5% of patients. Treatment-induced mortality due to neutropenia with septicemia or bleomycin-induced pulmonary failure occurs in 1–3% of patients. Dose reductions for myelosuppression are rarely indicated. Long-term permanent toxicities include nephrotoxicity (reduced glomerular filtration and persistent magnesium wasting), ototoxicity, and peripheral neuropathy. When bleomycin is administered by weekly bolus injection, Raynaud's phenomenon appears in 5–10% of patients. Other evidence of small blood vessel damage is seen less often, including transient ischemic attacks and myocardial infarction.

Risk-Directed Chemotherapy

Because not all patients are cured and treatment may cause significant toxicities, patients are stratified into "good-risk" and "poor-risk" groups according to

pretreatment clinical features. For good-risk patients, the goal is to achieve maximum efficacy with minimal toxicity. For poor-risk patients, the goal is to identify more effective therapy with tolerable toxicity.

The International Germ Cell Cancer Consensus Group developed criteria to assign patients to three risk groups (good, intermediate, poor) (Table 2). The marker cut-offs have been incorporated into the revised TNM (primary tumor, regional nodes, metastasis) staging of GCT. Hence, TNM stage groupings are now based on both anatomy (site and extent of disease) and biology (marker status and histology). Seminoma is either good or intermediate risk, based on the absence or presence of nonpulmonary visceral metastases. No poor-risk category exists for seminoma. Marker levels play no role in defining risk for seminoma. Nonseminomas have good-, intermediate-, and poor-risk categories based on the site of the primary tumor, the presence or absence of nonpulmonary visceral metastases, and marker levels.

Table 2 IGCCCG Risk Classification for Advanced Germ Cell Tumors

Risk Nonseminoma Seminoma Good Gonadal or retroperitoneal primary site Any primary site Absent nonpulmonary visceral metastases AFP <> Beta-hCG <> LDH <> Absent nonpulmonary visceral metastases Any LDH, hCG Intermediate Gonadal or retroperitoneal primary site Any primary site Absent nonpulmonary visceral metastases AFP 1000–10,000 ng/mL Beta-hCG 5000–50,000 mIU/mL LDH 1.5–10 x ULN Presence of nonpulmonary visceral metastases Any LDH, hCG Poor Mediastinal primary site Presence of nonpulmonary visceral metastases AFP >=10,000 ng/ML Beta-hCG > 50,000 mIU/mL LDH > 10 x ULN No patients classified as poor prognosis

For ~90% of patients with good-risk GCTs, four cycles of etoposide plus cisplatin (EP) or three cycles of BEP produce durable complete responses, with minimal acute and chronic toxicity. Pulmonary toxicity is absent when bleomycin is not used and is rare when therapy is limited to 9 weeks; myelosuppression with neutropenic fever is less frequent; and the treatment mortality rate is negligible. About 75% of intermediate-risk patients and 45% of poor-risk patients achieve durable complete remission with four cycles of BEP, and no regimen has proved superior. More effective therapy is needed.

Postchemotherapy Surgery

Resection of residual metastases after the completion of chemotherapy is an integral part of therapy. If the initial histology is nonseminoma and the marker values have normalized, all sites of residual disease should be resected. In general, residual retroperitoneal disease requires a modified bilateral RPLND. Thoracotomy (unilateral or bilateral) and neck dissection are less frequently required to remove residual mediastinal, pulmonary parenchymal, or cervical nodal disease. Viable tumor (seminoma, embryonal carcinoma, yolk sac tumor, or choriocarcinoma) will be present in 15%, mature teratoma in 40%, and necrotic debris and fibrosis in 45% of resected specimens. The frequency of teratoma or viable disease is highest in residual mediastinal tumors. If necrotic debris or mature teratoma is present, no further chemotherapy is necessary. If viable tumor is present but is completely excised, two additional cycles of chemotherapy are given.

If the initial histology is pure seminoma, mature teratoma is rarely present, and the most frequent finding is necrotic debris. For residual retroperitoneal disease, a complete RPLND is technically difficult owing to extensive postchemotherapy fibrosis. Observation is recommended when no radiographic abnormality exists on CT scan. Positive findings on a positron emission tomography (PET) scan correlate with viable seminoma in residua, and mandate surgical excision or biopsy.

Salvage Chemotherapy

Of patients with advanced GCT, 20–30% fail to achieve a durable complete response to first-line chemotherapy. A combination of cisplatin, ifosfamide, and vinblastine (VeIP) will cure about 25% of patients as a second-line therapy. Substitution of paclitaxel for vinblastine may be more effective in this setting. Patients are more likely to achieve a durable complete response if they had a testicular primary tumor and relapsed from a prior complete remission to first-line cisplatin-containing chemotherapy. In contrast, if the patient failed to achieve a complete response or has a primary mediastinal nonseminoma, then standard-dose salvage therapy is rarely beneficial. Treatment options for such patients include dose-intensive treatment, experimental therapies, and surgical resection.

Chemotherapy consisting of dose-intensive, high-dose carboplatin (>= 1500 mg/m²) plus etoposide (>= 1200 mg/m²), with or without cyclophosphamide, or ifosfamide, with peripheral blood stem cell support, induces a complete response in 25–40% of patients who have progressed after ifosfamide-containing salvage chemotherapy. About one-half of the complete responses will be durable. High-dose therapy is the treatment of choice and standard of care for this patient population. Paclitaxel is also active in previously treated patients and shows promise in high-dose combination programs. Cure is still possible in some relapsed patients.

Extragonadal GCT and Midline Carcinoma of Uncertain Histogenesis

The prognosis and management of patients with extragonadal GCT depends on the tumor histology and site of origin. All patients with a diagnosis of extragonadal GCT should have a testicular ultrasound examination. Nearly all patients with retroperitoneal or mediastinal seminoma achieve a durable complete response to BEP or EP. The clinical features of patients with primary retroperitoneal nonseminoma GCT are similar to those of patients with a primary of testis origin, and careful evaluation will find evidence of a primary testicular GCT in about two-thirds of cases. In contrast, a primary mediastinal nonseminomatous GCT is associated with a poor prognosis; one-third of patients are cured with standard therapy (four cycles of BEP). Patients with newly diagnosed mediastinal nonseminoma are considered to have poor-risk disease and should be considered for clinical trials testing regimens of possibly greater efficacy. In addition, mediastinal nonseminoma is associated with hematologic disorders, including acute myelogenous leukemia, myelodysplastic syndrome, and essential thrombocytosis unrelated to previous chemotherapy. These hematologic disorders are very refractory to treatment. Nonseminoma of any primary site may change into other malignant histologies such as embryonal rhabdomyosarcoma or adenocarcinoma. This is called malignant transformation. i(12p) has been identified in the transformed cell type, indicating GCT clonal origin.

A group of patients with poorly differentiated tumors of unknown histogenesis, midline in distribution, and not associated with secretion of AFP or hCG has been described; a few (10–20%) are cured by standard cisplatin-containing chemotherapy. i(12p) is present in ~25% of such tumors (the fraction that are cisplatin-responsive), confirming their origin from primitive germ cells. This finding is also predictive of the response to cisplatin-based chemotherapy and resulting long-term survival. These tumors are heterogeneous; neuroepithelial tumors and lymphoma may also present in this fashion.

Fertility

Infertility is an important consequence of the treatment of GCTs. Preexisting infertility or impaired fertility is often present. Azoospermia and/or oligospermia are present at diagnosis in at least 50% of patients with testicular GCTs. Ejaculatory dysfunction is associated with RPLND, and germ cell damage may result from cisplatin-containing chemotherapy. Nerve-sparing techniques to preserve the retroperitoneal sympathetic nerves have made retrograde ejaculation less likely in the subgroups of patients who are candidates for this operation. Spermatogenesis does recur in some patients after chemotherapy. However, because of the significant risk of impaired reproductive capacity, semen analysis and cryopreservation of sperm in a sperm bank should be recommended to all patients before treatment.

Tetralogy of Fallot

Tetralogy of Fallot

(from Kliegman Nelson Pediatric 18th Edition, Cyanotic Congenital Heart Lesions: Lesions Associated with Decreased Pulmonary Blood Flow)

Tetralogy of Fallot is one of the conotruncal family of heart lesions in which the primary defect is an anterior deviation of the infundibular septum (the muscular septum that separates the aortic and pulmonary outflows). The consequences of this deviation are (1) obstruction to right ventricular outflow (pulmonary stenosis), (2) ventricular septal defect (VSD), (3) dextroposition of the aorta with override of the ventricular septum, and (4) right ventricular hypertrophy ( Fig. 1 ). Obstruction to pulmonary arterial blood flow is usually at both the right ventricular infundibulum (subpulmonic area) and the pulmonary valve. The main pulmonary artery is often small, and various degrees of branch pulmonary artery stenosis may be present. Complete obstruction of right ventricular outflow (pulmonary atresia with VSD) is classified as an extreme form of tetralogy of Fallot . The degree of pulmonary outflow obstruction varies, with the severity of the obstruction determining the degree of the patient's cyanosis.

Figure 1 Physiology of the tetralogy of Fallot. Circled numbers represent oxygen saturation values. The numbers next to the arrows represent volumes of blood flow (in L/min/m2). Atrial (mixed venous) oxygen saturation is decreased because of the systemic hypoxemia. A volume of 3 L/min/m2 of desaturated blood enters the right atrium and traverses the tricuspid valve. Two liters flows through the right ventricular outflow tract into the lungs, whereas 1 L shunts right to left through the ventricular septal defect (VSD) into the ascending aorta. Thus, pulmonary blood flow is two thirds normal (Qp : Qs [pulmonary-to-systemic blood flow ratio] of 0.7 : 1). Blood returning to the left atrium is fully saturated. Only 2 L of blood flows across the mitral valve. Oxygen saturation in the left ventricle may be slightly decreased because of right-to-left shunting across the VSD. Two liters of saturated left ventricular blood mixing with 1 L of desaturated right ventricular blood is ejected into the ascending aorta. Aortic saturation is decreased, and cardiac output is normal.

PATHOPHYSIOLOGY.

The pulmonary valve annulus may be of nearly normal size or quite small. The valve itself is often bicuspid and, occasionally, is the only site of stenosis. More commonly, the subpulmonic or infundibular muscle, the crista supraventricularis, is hypertrophic, which contributes to the subvalvar stenosis and results in an infundibular chamber of variable size and contour. When the right ventricular outflow tract is completely obstructed (pulmonary atresia), the anatomy of the branch pulmonary arteries is extremely variable; a main pulmonary artery segment may be in continuity with right ventricular outflow, separated by a fibrous but imperforate pulmonary valve, or the entire main pulmonary artery segment may be absent. Occasionally, the branch pulmonary arteries may be discontinuous. In these more severe cases, pulmonary blood flow may be supplied by a patent ductus arteriosus (PDA) and by multiple major aortopulmonary collateral arteries (MAPCAs) arising from the ascending and descending aorta.

The VSD is usually nonrestrictive and large, is located just below the aortic valve, and is related to the posterior and right aortic cusps. Rarely, the VSD may be in the inlet portion of the ventricular septum (atrioventricular septal defect). The normal fibrous continuity of the mitral and aortic valves is usually maintained. The aortic arch is right sided in 20% of cases, and the aortic root is usually large and overrides the VSD to a varying degree. When the aorta overrides the VSD by more than 50% and if there is muscle separating the aortic valve and the mitral annulus (subaortic conus), this defect is usually classified as a form of double-outlet right ventricle; however, the pathophysiology is the same as that of tetralogy of Fallot.

Systemic venous return to the right atrium and right ventricle is normal. When the right ventricle contracts in the presence of marked pulmonary stenosis, blood is shunted across the VSD into the aorta. Persistent arterial desaturation and cyanosis result. Pulmonary blood flow, when severely restricted by the obstruction to right ventricular outflow, may be supplemented by the bronchial collateral circulation (MAPCAs) and, in the newborn, by a PDA. Peak systolic and diastolic pressures in each ventricle are similar and at systemic level. A large pressure gradient occurs across the obstructed right ventricular outflow tract, and pulmonary arterial pressure is normal or lower than normal. The degree of right ventricular outflow obstruction determines the timing of the onset of symptoms, the severity of cyanosis, and the degree of right ventricular hypertrophy. When obstruction to right ventricular outflow is mild to moderate and a balanced shunt is present across the VSD, the patient may not be visibly cyanotic (acyanotic or “pink” tetralogy of Fallot). When obstruction is severe, cyanosis will be present from birth and worsen when the ductus begins to close.

CLINICAL MANIFESTATIONS.

Infants with mild degrees of right ventricular outflow obstruction may initially be seen with heart failure caused by a ventricular-level left-to-right shunt. Often, cyanosis is not present at birth, but with increasing hypertrophy of the right ventricular infundibulum and patient growth, cyanosis occurs later in the 1st yr of life. It is most prominent in the mucous membranes of the lips and mouth and in the fingernails and toenails. In infants with severe degrees of right ventricular outflow obstruction, neonatal cyanosis is noted immediately. In these infants, pulmonary blood flow may be dependent on flow through the ductus arteriosus. When the ductus begins to close in the 1st few hours or days of life, severe cyanosis and circulatory collapse may occur. Older children with long-standing cyanosis who have not undergone surgery may have dusky blue skin, gray sclerae with engorged blood vessels, and marked clubbing of the fingers and toes. Extracardiac manifestations of long-standing cyanotic congenital heart disease are described in Chapter 434 .

Dyspnea occurs on exertion. Infants and toddlers play actively for a short time and then sit or lie down. Older children may be able to walk a block or so before stopping to rest. Characteristically, children assume a squatting position for the relief of dyspnea caused by physical effort; the child is usually able to resume physical activity within a few minutes. These findings occur most often in patients with significant cyanosis at rest.

Paroxysmal hypercyanotic attacks (hypoxic, “blue,” or “tet” spells) are a particular problem during the 1st 2 yr of life. The infant becomes hyperpneic and restless, cyanosis increases, gasping respirations ensue, and syncope may follow. The spells occur most frequently in the morning on initially awakening or after episodes of vigorous crying. Temporary disappearance or a decrease in intensity of the systolic murmur is usual as flow across the right ventricular outflow tract diminishes. The spells may last from a few minutes to a few hours but are rarely fatal. Short episodes are followed by generalized weakness and sleep. Severe spells may progress to unconsciousness and, occasionally, to convulsions or hemiparesis. The onset is usually spontaneous and unpredictable. Spells are associated with reduction of an already compromised pulmonary blood flow, which, when prolonged, results in severe systemic hypoxia and metabolic acidosis. Infants who are only mildly cyanotic at rest are often more prone to the development of hypoxic spells because they have not acquired the homeostatic mechanisms to tolerate rapid lowering of arterial oxygen saturation, such as polycythemia.

Depending on the frequency and severity of hypercyanotic attacks, one or more of the following procedures should be instituted in sequence: (1) placement of the infant on the abdomen in the knee-chest position while making certain that the infant's clothing is not constrictive, (2) administration of oxygen (although increasing inspired oxygen will not reverse cyanosis caused by intracardiac shunting), and (3) injection of morphine subcutaneously in a dose not in excess of 0.2 mg/kg. Calming and holding the infant in a knee-chest position may abort progression of an early spell. Premature attempts to obtain blood samples may cause further agitation and be counterproductive.

Because metabolic acidosis develops when arterial PO₂ is <40 name="4-u1.0-B978-1-4160-2450-7..50432-1--p190">intravenous administration of sodium bicarbonate is necessary if the spell is unusually severe and the child shows a lack of response to the foregoing therapy. Recovery from the spell is usually rapid once the pH has returned to normal. Repeated blood pH measurements may be necessary because rapid recurrence of acidosis may ensue. For spells that are resistant to this therapy, drugs that increase systemic vascular resistance, such as intravenous phenylephrine, can improve right ventricular outflow, decrease the right-to-left shunt, and improve the symptoms. β-Adrenergic blockade by the intravenous administration of propranolol (0.1 mg/kg given slowly to a maximum of 0.2 mg/kg) is also useful.

Growth and development may be delayed in patients with severe untreated tetralogy of Fallot, particularly when oxygen saturation is chronically <70%.>

The pulse is usually normal, as is venous and arterial pressure. The left anterior hemithorax may bulge anteriorly because of right ventricular hypertrophy. The heart is generally normal in size, and a substernal right ventricular impulse can be detected. In about half the cases, a systolic thrill is felt along the left sternal border in the 3rd and 4th parasternal spaces. The systolic murmur is usually loud and harsh; it may be transmitted widely, especially to the lungs, but is most intense at the left sternal border. The murmur is generally ejection in quality at the upper sternal border, but it may sound more holosystolic toward the lower sternal border. It may be preceded by a click. The murmur is caused by turbulence through the right ventricular outflow tract. It tends to become louder, longer, and harsher as the severity of pulmonary stenosis increases from mild to moderate; however, it can actually become less prominent with severe obstruction, especially during a hypercyanotic spell. Either the 2nd heart sound is single, or the pulmonic component is soft. Infrequently, a continuous murmur may be audible, especially if prominent collaterals are present.

DIAGNOSIS.

Roentgenographically, the typical configuration as seen in the anteroposterior view consists of a narrow base, concavity of the left heart border in the area usually occupied by the pulmonary artery, and normal heart size. The hypertrophied right ventricle causes the rounded apical shadow to be uptilted so that it is situated higher above the diaphragm than normal. The cardiac silhouette has been likened to that of a boot or wooden shoe (“coeur en sabot”) ( Fig. 2 ). The hilar areas and lung fields are relatively clear because of diminished pulmonary blood flow or the small size of the pulmonary arteries, or both. The aorta is usually large, and in about 20% of patients it arches to the right, which results in an indentation of the leftward-positioned air-filled tracheobronchial shadow in the anteroposterior view.

Figure 2 Chest x-ray of an 8 yr old boy with the tetralogy of Fallot. Note the normal heart size, some elevation of the cardiac apex, concavity in the region of the main pulmonary artery, right-sided aortic arch, and diminished pulmonary vascularity.

The electrocardiogram demonstrates right axis deviation and evidence of right ventricular hypertrophy. A dominant R wave appears in the right precordial chest leads (Rs, R, qR, qRs) or an RSR′ pattern. In some cases, the only sign of right ventricular hypertrophy may initially be a positive T wave in leads V₃R and V₁. The P wave is tall and peaked or sometimes bifid

Two-dimensional echocardiography establishes the diagnosis ( Fig. 3 ) and provides information about the extent of aortic override of the septum, the location and degree of the right ventricular outflow tract obstruction, the size of the proximal branch pulmonary arteries, and the side of the aortic arch. The echocardiogram is also useful in determining whether a PDA is supplying a portion of the pulmonary blood flow. In a patient without pulmonary atresia, echocardiography usually obviates the need for catheterization before surgical repair.

Figure 3 Echocardiogram in a patient with the tetralogy of Fallot. This parasternal long-axis two-dimensional view demonstrates anterior displacement of the outflow ventricular septum that resulted in stenosis of the subpulmonic right ventricular outflow tract, overriding of the aorta, and an associated ventricular septal defect. Ao, overriding aorta; LA, left atrium; LV, left ventricle; RV, right ventricle

Cardiac catheterization demonstrates a systolic pressure in the right ventricle equal to systemic pressure. If the pulmonary artery is entered, the pressure is markedly decreased, although crossing the right ventricular outflow tract, especially in severe cases, may precipitate a tet spell. Pulmonary arterial pressure is usually lower than normal, in the range of 5–10 mm Hg. The level of arterial oxygen saturation depends on the magnitude of the right-to-left shunt; in “pink tets,” systemic saturation may be normal, whereas in a moderately cyanotic patient at rest, it is usually 75–85%.

Selective right ventriculography best demonstrates the anatomy of the tetralogy of Fallot. Contrast medium outlines the heavily trabeculated right ventricle. The infundibular stenosis varies in length, width, contour, and distensibility ( Fig. 4 ). The pulmonary valve is usually thickened, and the annulus may be small. In patients with pulmonary atresia and VSD, the anatomy of the pulmonary vessels may be extremely complex; for example, there may be discontinuity between the right and left pulmonary arteries. Complete and accurate information regarding the anatomy of the pulmonary arteries and any collateral vessels (MAPCAs) is important when evaluating these children as surgical candidates.

Figure 4 Lateral view of a selective right ventriculogram in a patient with the tetralogy of Fallot. The arrow points to an infundibular stenosis that is below the infundibular chamber (C). The narrowed pulmonary valve orifice is seen at the distal end of the infundibular chamber.

Left ventriculography demonstrates the size of the left ventricle, the position of the VSD, and the overriding aorta; it also confirms mitral-aortic continuity, thereby ruling out a double-outlet right ventricle. Aortography or coronary arteriography outlines the course of the coronary arteries. In 5–10% of patients with the tetralogy of Fallot, an aberrant major coronary artery crosses over the right ventricular outflow tract; this artery must not be cut during surgical repair. Verification of normal coronary arteries is important when considering surgery in young infants who may need a patch across the pulmonary valve annulus. Echocardiography can usually delineate the coronary artery anatomy; angiography is reserved for cases in which questions remain.

COMPLICATIONS.

Before correction, patients with the tetralogy of Fallot are susceptible to several serious complications. Fortunately, most children undergo palliation or, more often, complete repair in infancy, and these complications are rare. Cerebral thromboses, usually occurring in the cerebral veins or dural sinuses and occasionally in the cerebral arteries, are common in the presence of extreme polycythemia and dehydration. Thromboses occur most often in patients younger than 2 yr. These patients may have iron deficiency anemia, frequently with hemoglobin and hematocrit levels in the normal range (but too low for cyanotic heart disease). Therapy consists of adequate hydration and supportive measures. Phlebotomy and volume replacement with albumin or saline are indicated in extremely polycythemic patients who are symptomatic.

Brain abscess is less common than cerebral vascular events and extremely rare when most patients are repaired at young ages. Patients with a brain abscess are usually older than 2 yr. The onset of the illness is often insidious and consists of low-grade fever or a gradual change in behavior, or both. Some patients have an acute onset of symptoms that may develop after a recent history of headache, nausea, and vomiting. Seizures may occur; localized neurologic signs depend on the site and size of the abscess and the presence of increased intracranial pressure. CT or MRI confirms the diagnosis. Antibiotic therapy may help keep the infection localized, but surgical drainage of the abscess is usually necessary (see Chapter 603 ).

Bacterial endocarditis may occur in the right ventricular infundibulum or on the pulmonic, aortic, or, rarely, tricuspid valves. Endocarditis may complicate palliative shunts or, in patients with corrective surgery, any residual pulmonic stenosis or VSD. Antibiotic prophylaxis is essential before and after dental and certain surgical procedures associated with a high incidence of bacteremia (see Chapter 437 ).

Heart failure is not a usual feature in patients with the tetralogy of Fallot. It may occur in a young infant with “pink” or acyanotic tetralogy of Fallot. As the degree of pulmonary obstruction worsens with age, the symptoms of heart failure resolve and eventually the patient experiences cyanosis, often by 6–12 mo of age. These patients are at increased risk for hypercyanotic spells at this time.

ASSOCIATED ANOMALIES.

An associated PDA may be present, and defects in the atrial septum are occasionally seen. A right aortic arch occurs in ≈20% of patients with the tetralogy of Fallot, and other anomalies of the pulmonary arteries and aortic arch may also be seen. Persistence of a left superior vena cava draining into the coronary sinus may be noted. Multiple VSDs are occasionally present and must be diagnosed before corrective surgery. Tetralogy of Fallot may also occur with an atrioventricular septal defect, often associated with Down syndrome.

Congenital absence of the pulmonary valve produces a distinct syndrome that is usually marked by signs of upper airway obstruction (see Chapter 428.1 ). Cyanosis may be absent, mild, or moderate; the heart is large and hyperdynamic; and a loud to-and-fro murmur is present. Marked aneurysmal dilatation of the main and branch pulmonary arteries results in compression of the bronchi and produces stridulous or wheezing respirations and recurrent pneumonia. If the airway obstruction is severe, reconstruction of the trachea at the time of corrective cardiac surgery may be required to alleviate the symptoms.

Absence of a branch pulmonary artery, most often the left, should be suspected if the roentgenographic appearance of the pulmonary vasculature differs on the two sides; absence of a pulmonary artery is often associated with hypoplasia of the affected lung. It is important to recognize the absence of a pulmonary artery because occlusion of the remaining pulmonary artery during surgery seriously compromises the already reduced pulmonary blood flow.

As one of the conotruncal malformations, the tetralogy of Fallot can be associated with the spectrum of lesions known as CATCH 22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia). CATCH 22 includes patients with clinical features of the DiGeorge syndrome (hypocalcemia, thymic hypoplasia, mild facial anomalies) or the Shprintzen velocardiofacial syndrome (abnormal facies, cleft palate). Cytogenetic analysis using fluorescence in situ hybridization demonstrates deletions of a large segment of chromosome 22q11 known as the DiGeorge critical region. Deletion or mutation of the gene encoding the transcription factor Tbx1 has been implicated as a possible cause of DiGeorge syndrome.

TREATMENT.

Treatment of the tetralogy of Fallot depends on the severity of the right ventricular outflow tract obstruction. Infants with severe tetralogy require medical treatment and surgical intervention in the neonatal period. Therapy is aimed at providing an immediate increase in pulmonary blood flow to prevent the sequelae of severe hypoxia. The infant should be transported to a medical center adequately equipped to evaluate and treat neonates with congenital heart disease under optimal conditions. It is critical that oxygenation and normal body temperature be maintained during the transfer. Prolonged, severe hypoxia may lead to shock, respiratory failure, and intractable acidosis and will significantly reduce the chance of survival, even when surgically amenable lesions are present. Cold increases oxygen consumption, which places additional stress on a cyanotic infant, whose oxygen delivery is already limited. Blood glucose levels should be monitored because hypoglycemia is more likely to develop in infants with cyanotic heart disease.

Neonates with marked right ventricular outflow tract obstruction may deteriorate rapidly because, as the ductus arteriosus begins to close, pulmonary blood flow is further compromised. The intravenous administration of prostaglandin E₁ (0.01–0.20 μg/kg/min), a potent and specific relaxant of ductal smooth muscle, causes dilatation of the ductus arteriosus and usually provides adequate pulmonary blood flow until a surgical procedure can be performed. This agent should be administered intravenously as soon as cyanotic congenital heart disease is clinically suspected and continued through the preoperative period and during cardiac catheterization.

Infants with less severe right ventricular outflow tract obstruction who are stable and awaiting surgical intervention require careful observation. Prevention or prompt treatment of dehydration is important to avoid hemoconcentration and possible thrombotic episodes. Paroxysmal dyspneic attacks in infancy or early childhood may be precipitated by a relative iron deficiency; iron therapy may decrease their frequency and also improve exercise tolerance and general well-being. Red blood cell indices should be maintained in the normocytic range. Oral propranolol (0.5–1 mg/kg every 6 hr) had been used more commonly in the past to decrease the frequency and severity of hypercyanotic spells, but with the excellent surgery available, surgical treatment is now indicated as soon as spells begin.

Infants with symptoms and severe cyanosis in the 1st mo of life have marked obstruction of the right ventricular outflow tract or pulmonary atresia. Two options are available in these infants. The first, more common in previous years, is a palliative systemic-to-pulmonary artery shunt performed to augment pulmonary artery blood flow. The rationale for this surgery, previously the only option for these patients, is to decrease the amount of hypoxia and improve linear growth, as well as augment growth of the branch pulmonary arteries. The second option is corrective open heart surgery performed in early infancy and even in the newborn period in critically ill infants. This approach has widespread acceptance with excellent short- and long-term results and carries the theoretical advantage in that early physiologic correction allows for improved growth of the branch pulmonary arteries. In infants with less severe cyanosis who can be maintained with good growth and absence of hypercyanotic spells, primary repair is performed electively at between 4 and 6 mo of age.

The modified Blalock-Taussig shunt is currently the most common aortopulmonary shunt procedure and consists of a Gore-Tex conduit anastomosed side to side from the subclavian artery to the homolateral branch of the pulmonary artery ( Fig. 5 ). Sometimes the shunt is brought directly from the ascending aorta to the main pulmonary artery and in this case is called a central shunt. The Blalock-Taussig operation can be successfully performed in the newborn period with shunts 3–4 mm in diameter and has also been used successfully in premature infants.

Figure 5 Physiology of a Blalock-Taussig shunt in a patient with the tetralogy of Fallot. Circled numbers represent oxygen saturation values. The intracardiac shunting pattern is as described for Figure 430-1 . Blood shunting left to right across the shunt from the right subclavian artery to the right pulmonary artery increases total pulmonary blood flow and results in a higher oxygen saturation than would exist without the shunt

Postoperative complications after a Blalock-Taussig shunt include chylothorax, diaphragmatic paralysis, and Horner syndrome. Chylothorax may require repeated thoracocentesis and, on occasion, reoperation to ligate the thoracic duct. Diaphragmatic paralysis from injury to the phrenic nerve may result in a more difficult postoperative course. Prolonged ventilator support and vigorous physical therapy may be required, but diaphragmatic function usually returns in 1–2 mo unless the nerve was completely divided. Surgical plication of the diaphragm may be indicated. Horner syndrome is usually temporary and does not require treatment. Postoperative cardiac failure may be caused by a large shunt; its treatment is described in Chapter 442 . Vascular problems other than a diminished radial pulse and occasional long-term arm length discrepancy are rarely seen in the upper extremity supplied by the subclavian artery used for the anastomosis.

After a successful shunt procedure, cyanosis diminishes. The development of a continuous murmur over the lung fields after the operation indicates a functioning anastomosis. A good continuous shunt murmur may not be heard until several days after surgery. The duration of symptomatic relief is variable. As the child grows, more pulmonary blood flow is needed and the shunt eventually becomes inadequate. When increasing cyanosis develops, a corrective operation should be performed if the anatomy is favorable. If not possible (because of hypoplastic branch pulmonary arteries) or if the 1st shunt lasts only a brief period in a small infant, a second aortopulmonary anastomosis may be required on the opposite side.

Corrective surgical therapy consists of relief of the right ventricular outflow tract obstruction by removing obstructive muscle bundles and by patch closure of the VSD. If the pulmonary valve is stenotic, a valvotomy is performed. If the pulmonary valve annulus is small or the valve is extremely thickened, a valvectomy may be performed, the pulmonary valve annulus split open, and a transannular patch placed across the pulmonary valve ring. Any previously established systemic-to-pulmonary shunt must be ligated and divided before full repair. The surgical risk of total correction in major centers is <5%.>transatrial-transpulmonary approach is routinely performed to reduce the long-term risks of a right ventriculotomy. Increased bleeding in the immediate postoperative period may be a complicating factor in extremely polycythemic patients.

PROGNOSIS.

After successful total correction, patients are generally asymptomatic and are able to lead unrestricted lives. Uncommon immediate postoperative problems include right ventricular failure, transient heart block, residual VSD with left-to-right shunting, and myocardial infarction from interruption of an aberrant coronary artery. Postoperative heart failure (particularly in patients with a transannular outflow patch) may require diuretics and a positive inotropic agent such as digoxin. The long-term effects of isolated, surgically induced pulmonary valvular insufficiency are unknown, but insufficiency is generally well tolerated. The majority of patients after tetralogy repair and all of those with transannular patch repairs have a to-and-fro murmur at the left sternal border, usually indicative of mild outflow obstruction and mild to moderate pulmonary insufficiency. Patients with more marked pulmonary valve insufficiency also have moderate to marked heart enlargement. Patients with a severe residual gradient across the right ventricular outflow tract may require reoperation, but mild to moderate obstruction is usually present and does not require reintervention.

Follow-up of patients 5–20 yr after surgery indicates that the marked improvement in symptoms is generally maintained. Asymptomatic patients nonetheless have lower than normal exercise capacity, maximal heart rate, and cardiac output. These abnormal findings are more common in patients who underwent placement of a transannular outflow tract patch and may be less frequent when surgery is performed at an early age. As these children move into adolescence and adulthood, some (more commonly those with transannular patches) will develop right ventricular dilation due to severe pulmonary regurgitation. Careful lifelong follow-up by a specialist in adult congenital heart disease is important. Serial echocardiography and magnetic resonance angiography (MRA) are valuable tools for assessing the degree of right ventricular dilation, the presence of right ventricular dysfunction, and the regurgitant fraction. Valve replacement is indicated for those patients with increasing right ventricular pathology.

Conduction disturbances can occur after surgery. The atrioventricular node and the bundle of His and its divisions are in close proximity to the VSD and may be injured during surgery. Permanent complete heart block after surgery is rare. When present, it should be treated by placement of a permanently implanted pacemaker. Even transient complete heart block in the immediate postoperative period is rare; it may be associated with an increased incidence of late-onset complete heart block and sudden death. Right bundle branch block after right ventriculotomy is quite common on the postoperative electrocardiogram. The duration of the QRS interval has been shown to predict both the presence of residual hemodynamic derangement and the long-term risk of sudden death. Research is ongoing to determine the effectiveness of biventricular pacing (in which a pacemaker is used to resynchronize the activation of the right and left ventricles) in improving hemodynamics in those patients with long ventricular conduction delays.

A number of children have premature ventricular beats after repair of the tetralogy of Fallot. These beats are of concern in patients with residual hemodynamic abnormalities; 24-hr electrocardiographic (Holter) monitoring studies should be performed to be certain that occult short episodes of ventricular tachycardia are not occurring. Exercise studies may be useful in provoking cardiac arrhythmias that are not apparent at rest. In the presence of complex ventricular arrhythmias or severe residual hemodynamic abnormalities, prophylactic antiarrhythmic therapy is warranted. Re-repair is indicated if significant residual right ventricular outflow obstruction or severe pulmonary insufficiency is present.