Proventil
Liza J. Enriquez, MD
- Departments of Anesthesiology
- Montefiore Medical Center
- Bronx, New York
Chromaffin cells asthma symptoms stomach pain buy cheapest proventil and proventil, which originate from neural crest asthmatic bronchitis video order proventil 100mcg without a prescription, migrate toward the adrenal cortex around this time and gradually invade the medial aspect of the cortical tissue along its central vein to gain central position asthma score definition order proventil with a visa, forming the adrenal medulla asthmatic bronchitis gluten discount generic proventil uk. However asthma symptoms high blood pressure order 100mcg proventil with visa, encapsulation of the adrenal medulla does not occur until late fetal development asthma forecast order proventil 100mcg on line. Postnatally, the fetal or primitive zone of the adrenal gland rapidly involutes to disappear by approximately 6 months of age (Kempna and Fluck, 2008). Zonation of the cortex, zona glomerulosa, and fasciculata is present at birth, but full differentiation into three separate zones occurs much later, at approximately 3 years of age, when zona reticularis development takes place (Barwick et al, 2005). This chapter focuses on the development, function, and pathophysiology of the steroidogenic adrenal cortex. Histologically, the fetal adrenal cortex consists of a small outer definitive zone, which appears to produce few adrenal steroid hormones until late gestation, and a larger inner fetal zone that produces adrenal steroid hormones throughout gestation. In addition, there is a transitional zone where cortisol production takes place toward the end of fetal development (Mesiano and Jaffe, 1997). At birth, the large fetal zone of the fetal adrenal involutes and disappears by 6 months of age. Concurrently, the definitive zone together with the transitional zone develops into the fully differentiated zona glomerulosa and fasciculata by the age of 3 years. The zona reticularis begins to develop only after 4 years of age and may not be fully differentiated before the age of 15 years. In an adult adrenal gland, these three distinctive zones lie adjacent to one another. The zona glomerulosa is located immediately below the capsule, the zona fasciculata being in the middle, and the innermost zone next to the medulla is the zona reticularis. Three major pathways of mineralocorticoid, glucocorticoid, and androgen synthesis take place mainly in the glomerulosa, fasciculata, and reticularis zones of the cortex, respectively. Aldosterone is the main mineralocorticoid regulating sodium and fluid volume homeostasis; it is under the control of the renin-angiotensin system and blood potassium concentrations (Kuhnle et al, 1981). The prinicipal glucocorticoid in humans is cortisol, with a wide range of roles in regulating body functions, from carbohydrate metabolism, immune system, and acute and chronic stress response to musculoskeletal metabolism. Adrenal androgens have an age-specific secretion profile from adrenarche around the time of puberty and a gradual decrease with aging until andropause (Orentreich et al, 1984). At birth, the adrenals are 10- to 20-fold larger than the adult glands relative to body weight, thereby approximating one third the size of neonatal kidneys (Moore and Persaud, 1998). In late fetal and neonatal phases, the glands predominantly consist of cortex, where active production of glucocorticoids, steroid precursors, estrogens, and progesterone occurs during the third trimester and the first 3 months after birth. Ultrasonographically, the neonatal adrenal gland characteristically has a thin reflective core surrounded by a thick transonic zone. Each of the three biosynthetic pathways take place in different zones: aldosterone biosynthesis in zona glomerulosa, cortisol biosynthesis in zona fasciculata, and androgen production in zona reticularis. The rate of steroid secretion by the fetal adrenal glands may be fivefold that of the adult adrenal glands at rest (Carr and Simpson, 1981). The physiology of human pregnancy involves a continuous supply of relatively increased amount of estrogens. In near term human pregnancy, the rate of estrogen production increases strikingly, reaching concentrations 1000-fold greater than that of nonpregnant women (Carr and Simpson, 1981). During early gestation, the estradiol required to maintain pregnancy is provided by the corpus luteum of the maternal ovary. By the end of pregancy, fetal cortisol is required in preparation for parturition. Maternal cortisol cannot normally reach the fetus because it is oxidized to cortisone, an inactive steroid, by placental 11-hydroxysteroid dehydrogenase type 2 (Wilson et al, 2001). Decreases in vascular volume result in increased secretion of renin by the renal juxtaglomerular apparatus. For example, until at least 1 month postnatally, a large proportion of cortisol and its metabolites are excreted as sulfate esters. This sulfation may serve to inactivate a number of circulating cortisol metabolites during fetal and neonatal life (Ducharme et al, 1970). The variable pattern of decline in the ensuing weeks probably reflects variation in remodeling of the fetal zone and emergence of the zona fasciculata of the definitive zone, the latter being feature of an adult cortex. Plasma aldosterone concentrations tend to be higher in preterm infants than in term infants, both of which in turn are higher than in older children and adults (Doerr et al, 1988; Kotchen et al, 1972). Relative adrenal insufficiency occurs when the hypothalamic-pituitary-adrenal axis produces less than adequate cortisol for the degree of illness or stress. Clinicians are commonly faced with critically ill infants who have cardiovascular insufficiency with hypotension, a condition that has also been associated with adverse consequences. The question often arises as to whether these manifestations reflect underlying glucocorticoid insufficiency. There is increasing evidence that relative adrenal insufficiency may be a cause of hemodynamic instability and hypotension in the crticially ill newborn, but there is definitely a paucity of data in this population. Interestingly, in extremely low-birthweight infants (500 to 999 g) low cortisol concentrations were not predictive of adverse short-term mortality and morbidity. In contrast, high basal cortisols were associated with severe intraventricular hemorrhage, and extremely elevated values were associated with morbidity and death (Aucott et al, 2008). Data associating treatment of adrenal insufficiency with outcomes in the term newborn are limited, and there have been no studies on outcomes beyond the immediate neonatal period. Nonetheless, no adverse events have been attributed to glucocorticoid treatment based on a relatively small number of study subjects. A multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency is currently underway (Aucott et al, 2008). Currently there is insufficient evidence to support the routine use of glucocorticoids in critically ill newborns. On encountering an infant with vasopressorresistant hypotension, accompanied by signs of cardiac hypofunction, the clinician must consider the risk-tobenefit ratio before arriving at the appropiate management. Therapeutic trials with hydrocortisone at the dose of 1 mg per kilogram of body weight have been suggested (Fernandez and Watterberg, 2009) and can be discontinued if there is no clinical improvement or if the pretreatment cortisol level is later observed to be greater than 15 g/dL. Special attention should be paid to the premature newborn who concurrently is receiving indomethacin, because this combination is associated with spontaneous gastrointestinal perforation (Peltoniemi et al, 2005). The enzyme defect also impairs the conversion of progesterone to aldosterone, causing abnormal salt loss (New and Seaman, 1970; New et al, 1966). For newborn males, however, differentiation of the external genitalia is not affected, because the main source of testosterone is the testes and not the adrenal gland. Postnatally, genitalia may continue to virilize because of an excess of adrenal androgens, and pseudoprecocious puberty can occur. In affected adolescent females, signs of hyperandrogenism include facial, axillary, and pubic hair, adult body odor, temporal balding, severe acne, irregular menses, and reduced fertility. Poor control of adrenal androgens in males has been associated with small testes, infertility, and short stature. Infertility occurs because the excess androgens are aromatized peripherally to estrogens, which suppress pituitary gonadotropins and function of the gonads. The high levels of androgens can also accelerate growth in early childhood, producing an unusually tall and muscular child. Resulting hyponatremia, hyperkalemia, high plasma renin activity, and fluid volume depletion are potentially fatal. Studies have demonstrated that there is often a divergence in phenotypes within mutation-identical groups, the reason for which requires further investigation (Chemaitilly et al, 2005; Krone et al, 2000). Thus, further virilization is prevented, allowing normal growth and onset of puberty. The dose of cortisol required is usually 15 to 20 mg/m2/day divided into two to three doses per day (Clayton et al, 2002; New et al, 2006). Hormonal control can be difficult to achieve in many cases, and adrenalectomy may be offered as an alternative therapeutic option in select patients (Gmyrek et al, 2002; New, 1996; Van Wyk et al, 1996). In infancy, patients also require oral salt supplement as in other forms of primary adrenal insufficiency. Prevention of antenatal virilization in affected females is possible with proper prenatal diagnosis and treatment program. There are accurate, compelling data from the largest human studies (Forest et al, 1989; Mercado et al, 1995; New et al, 2001) indicating the benefit of prenatal treatment and that it is safe in the short term for both the fetus and the mother. Preliminary data from long-term studies also support these results (Nimkarn and New, 2009), although long-term follow-up studies are still underway. These mutations include point mutations, small deletions, small insertions, and complex rearrangements of the gene (Stenson et al, 2003). Excess adrenal androgen secretion results in ambiguous genitalia in the affected female fetus. However, hypertension correlates variably with the presence of hypokalemia or with the extent of virilization (Rosler et al, 1982). It is usually not identified until later in childhood or in adolescence, although its appearance in early childhood has been documented. In addition to hormonal therapy, reduced salt intake is often used to reduce fluid volume and hypertension. Maintaining fluid balance in children, however, is often difficult and poses an ongoing challenge to treatment. Affected females suffer from genital ambiguity and may require genital reconstructive surgery after multidisciplinary consultations. Affected individuals cannot produce cortisol but synthesize large amounts of corticosterone (a weak glucocorticoid that mitigates the adrenal insufficiency) and deoxycorticosteroid, which causes hypertension and hypokalemia. Affected females have primary amenorrhea and clinical hypogonadism (Auchus, 2001; Yanase et al, 1991). A large number of cases have been reported in Israel, where the incidence was estimated to be 1 in 5000 to 1 in 7000 births, with a gene frequency of 1 in 71 to 1 in 83. This unexpected clustering of cases was traced to Jewish families of North African origin, particularly from Morocco and Tunisia (Rosler et al, 1992). Clinical Features the typical features of complete deficiency include hypertension and hypokalemia with associated sexual infantilism in genetic females and pseudohermaphroditism and sexual infantilism in genetic males. Nevertheless, there is considerable variability in the clinical and biochemical features, including a few mutations that cause isolated 17,20-lyase deficiency (Auchus, 2001). The age of onset of hypertension and the severity of hypokalemia are highly variable, even among individuals with the same mutations (CostaSantos et al, 2004). Molecular Genetics Two 11-hydroxylase genes have been identified within the human adrenal cortex, each encoding for a different enzyme with distinct enzymatic ability. Epidemiology this disorder has an estimated frequency in most countries of approximately 1 case per 50,000 newborns and accounts worldwide for approximately 1% of all cases of congenital adrenal hyperplasia (Yanase et al, 1991). Founder effects probably explain the high incidence of the disease in other patient populations in the Netherlands and Japan (Costa-Santos et al, 2004). Severity of disease tends to be milder with mutations that retain partial catalytic activity, but the nature of the variability in hypertension and hypokalemia is unclear. Adult genetic males reared as males need surgical correction of the external genitalia and androgen replacement. Mild mutations were also associated with hyperandrogenic symptoms of premature pubic hair development and hirsutism (Mermejo et al, 2005; Pang et al, 2002). Although most males are raised as males and retain the male social sex at puberty (Mendonca et al, 2008), gender identity is an important management issue. Male patients may require testosterone replacement therapy during puberty and adulthood. The aim of the surgical treatment in this condition is to allow development of adequate external genitalia and remove internal structures that are inappropriate for the social sex. Patients must undergo surgical sex reversal procedure preferably before 2 years of age, which is the time when the child becomes aware of his or her genitals and social sex. Two forms of the enzyme have been described in humans: type 1 enzyme expressed in placenta and skin, and type 2 expressed in adrenal glands and gonads. The two forms are closely related in structure and substrate specificity, although the type 1 enzyme has higher substrate affinity and a fivefold greater enzymatic activity than for type 2 (Simard et al, 2005). In females, virilization of external genitalia occurs as a result of the androgen effect from the peripheral conversion of circulating 5 precursors to active 4 steroids; therefore genital ambiguity can result in both sexes. Clinical presentations also include salt wasting crisis, premature pubic hair development, hirsutism, and menstrual disorders (Lutfallah et al, 2002). Affected patients exhibit glucocorticoid and mineralocorticoid deficiencies early in life, and males exhibit undervirilization. It is characterized by lipid droplet accumulation in the cytoplasm of the adrenocortical cells. Presenting in the first decade of life, it is frequently associated with progressive neurologic dysfunction, polyneuropathy, deafness, mental retardation, and hyperkeratosis of palms and soles (Houlden et al, 2002). Manifestations can include ambiguous genitalia in both males and females, primary amenorrhea and enlarged cystic ovaries in females, poor masculinization during puberty in males, and maternal virilization during pregnancy if the fetus is affected. Manifestations of Antley-Bixler syndrome include craniosynostosis; hydrocephalus; distinctive facies; choanal stenosis or atresia; low-set, dysplastic ears with stenotic external auditory canals; skeletal anomalies (radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, clubfeet); renal anomalies (ectopic kidneys, duplication of kidneys, renal hypoplasia, horseshoe kidney, hydronephrosis); and reduction of cognitive function and developmental delay. In moderate cytochrome P450 oxidoreductase deficiency, craniofacial and skeletal anomalies are less severe than in Antley-Bixler syndrome (Scott and Miller, 2008). Mineralocorticoid deficiency usually is not a presentation; therefore aldosterone levels, plasma renin measurements, and serum electrolytes are normal. Among persons of northern or central European ancestry, it has been estimated to range from 1:10,000 to 1:60,000 (Porter, 2000). Adrenal Insufficiency Associated With Other Syndromic Disorders Lysosomal Storage Disorders Complete deficiency of lysosomal esterase can also result in adrenal insufficiency in Wolman disease, a rare autosomal recessive disease. Wolman disease is rare, with only 50 reports of the disease published in the worldwide medical literature. Affected infants exhibit mild mental retardation, hepatosplenomegaly, vomiting, diarrhea, growth failure, and adrenal calcifications. Calcifications that delineate the outline of both adrenals are pathognomonic of this condition (Wolman, 1995). Mitochondrial Disorders Adrenal insufficiency can result from mitochondrial disorders, characterized by chronic lactic acidosis, myopathy, cataracts, and nerve deafness (Bruno et al, 1998; Nicolino et al, 1997). However, in some patients, age of onset is later, up to several years of age and presumably caused by residual functional cortex (Achermann et al, 2001; McCabe, 2000).
The ingestion of any recreational drugs asthma bronchiale kurze definition purchase proventil toronto, alcohol asthma symptoms 4 year old buy proventil in united states online, or medications by the mother during pregnancy should be noted asthma breath sounds buy proventil online now. Particular attention to medications with androgenic or progestational activity is indicated asthma treatment supplements purchase proventil 100 mcg. Medications that affect fetal genital development include cimetidine asthma symptoms hormonal imbalance cheap proventil 100 mcg on line, spironolactone asthma definition 420 buy proventil visa, hydantoin, and progestational agents (Grumbach and Conte, 1998). Superimposed are data for two small-for-gestational age infants (), seven large-forgestational age infants (), and twins (). The physical examination, however, can provide the first clues to the underlying pathology. In addition, the physical examination will provide important information about the degree of virilization of the external genitalia and the presence or absence of palpable gonads. A point to keep in mind is that premature infants have relatively underdeveloped labia majora, so that the clitoris may appear enlarged. A truly enlarged clitoris can be distinguished from a generous clitoral hood by the presence of palpable corporal or erectile tissue. Penis (Phallus) Measurements of the phallic stretch length and middle shaft diameter are important in determining the degree of virilization. The phallus should be stretched and measured from the pubic ramus to the tip of the glans. Measurement of the middle shaft diameter is particularly useful in this circumstance. For term male infants, a normal middle shaft diameter is approximately 1 cm (Feldman and Smith, 1975). A microphallus warrants careful evaluation for the presence of hypopituitarism or growth hormone deficiency, particularly in the presence of hypoglycemia or unexplained Labioscrotal Folds Assessment of the degree of fusion of the labioscrotal folds should be performed. When the infant is exposed to androgens during embryogenesis, fusion of the labioscrotal folds progresses from a posterior to an anterior direction. Is the phallus positioned in the normal superior position relative to the scrotum, or is there a shawl scrotum Asymmetrical external genital development or gonadal descent would be characteristic of mixed gonadal dysgenesis or hermaphroditism. Such abnormalities or multiple congenital anomalies could indicate any of a variety of syndromes associated with ambiguous genitalia (see Box 92-1). The newborn period is a time when the uterus, ovaries, and adrenal glands are optimally visualized (Wright et al, 1995). Ultrasonography can locate undescended testes and determine gonadal size or irregularity, such as an oblong ovotestis. Gonads in the newborn are not always well visualized by ultrasound examination, but that does not necessarily mean they are absent or abnormal. A, There is a mild to moderate degree of virilization, with primarily clitoral hypertrophy and significant fusion of the labia. B, Virilization is moderate, with clitoromegaly, labial fusion, and rugation of labial folds. Examination for the presence of separate urethral and vaginal openings versus a single perineal opening (urogenital sinus) conveys important anatomic information. A urogenital sinus results from failure of the urologic and genital tracts to differentiate completely. In addition, when the urethra enters a urogenital sinus, there is potential for urinary stasis and therefore urinary tract infections. Dysmorphic features suggestive of Turner syndrome indicate the possibility of gonadal dysgenesis or mixed Genitourethrogram A genitourethrogram is a fluoroscopically guided genital dye study that can provide important information on the urethra and internal genital ducts (Wright et al, 1995). Demonstration of the level at which the vagina opens into the urogenital sinus and its relationship to the external sphincter has important surgical implications. Recognition of male or female urethral configurations also may be possible during genitourethrography. The confluence of the vagina with the urogenital sinus is of intermediate severity. The presence of a uterus would be determined radiographically by ultrasound examination, genitourethrogram, or magnetic resonance imaging. Laboratory Investigations Endocrine and genetic laboratory studies are germane in the evaluation of ambiguous genitalia in the newborn. Material for chromosomal studies should optimally be obtained on day 1, as at least 48 to 72 hours are required to complete the study. The presence or absence of a uterus would be determined by radiographic imaging including ultrasound examination, genitourethrogram, or magnetic resonance imaging, as appropriate. Results of these studies should be sent immediately to the appropriate reference laboratory for analysis. Alerting the reference laboratory to the urgent nature of the studies performed will facilitate rapid processing. Serum gonadotropins are often suppressed in the immediate newborn period, so they should be measured after 1 week of life. This time period coincides with the physiologic testosterone surge seen in healthy male infants (Forest et al, 1980). When congenital adrenal hyperplasia is suggested, it is important to check sodium and potassium levels on a daily basis to prevent a salt-wasting crisis. In addition, this methodology allows for the detection of low levels of chromosomal mosaicism, because hundreds of cells can be analyzed rapidly. As a result, results should be interpreted with some degree of caution until confirmation by karyotypic analysis is available. In a small percentage of ambiguous genitalia cases, laparoscopy with gonadal biopsy is necessary to confirm the diagnosis of true hermaphroditism, gonadal dysgenesis, or Leydig cell aplasia. Obtaining a karyotype from gonadal tissue may be helpful when sex chromosome mosaicism is suggested. Occasionally, the presence of excess androgens of maternal origin can result in virilization of the female fetus (Grumbach and Conte, 1998). A unique cause of both maternal and fetal masculinization is placental aromatase deficiency (Conte et al, 1994). The excess production of androgens results in masculinization of the external genitalia of the female fetus, whereas a male infant with 21-hydroxylase deficiency is phenotypically normal. Steroidogenic enzymes are indicated as follows: (1) steroidogenic acute regulatory protein and side chain cleavage, (2) 3-hydroxysteroid dehydrogenase, (3) 17-hydroxylase/17,20lyase, (4) 11-hydroxylase, and (5) 17-hydroxysteroid dehydrogenase. Stage I indicates mild clitoromegaly only; stage V indicates complete masculinization. Finally, 17-hydroxyprogesterone levels rapidly decline after birth, and interpretation of the screening value depends on when the sample was drawn. It has been suggested that using a multitiered method using both birthweight and postnatal age can improve the positive predictive value of the screen (Olgemoller et al, 2003). The diagnosis of 21-hydroxylase deficiency should be suspected in all newborns with ambiguous genitalia (or clitoral hypertrophy) and absent gonads in the labial or scrotal folds. A serum 17-hydroxyprogesterone level obtained after the 1st day of life will often be diagnostic. This convenient test requires only 20 L of blood, obtained by heel stick and blotted on microfilter paper, to provide a reliable diagnostic measurement of l7-hydroxyprogesterone, a cortisol precursor that accumulates in elevated concentrations in 21-hydroxylase deficiency. The simplicity of the test and the ease of transporting the microfilter paper specimens through the mail have facilitated the implementation of many congenital adrenal hyperplasia newborn screening programs in the United States and worldwide (Therrell et al, 1998). There are, however, certain limitations to the screen (Gruneiro-Papendieck et al, 2001; Olgemoller et al, 2003; Therrell et al, 1998; van der Kamp et al, 2005). Second, to maintain good specificity, many cases of the mild nonclassic form will be missed. Third, the cutoff values for a positive screen vary among different countries and among the different states within the United States. Fourth, preterm infants have higher 17-hydroxyprogesterone levels because of immaturity of the adrenal cortex (Hingre et al, 1994), which may present a challenge in determining what is normal. Cutoff values in the United States, Canada, and New Zealand are typically based on birthweight, although reports from Evaluation On presentation to emergency department: infant was well-appearing, weight 2. Levels of androstenedione, testosterone, electrolytes, and plasma renin activity should also be determined. Plasma renin activity is a sensitive indicator of the intravascular volume status of the infant. Impaired sodiumpotassium and sodium-hydrogen exchange owing to aldosterone deficiency in the distal tubule of the kidney results in hyponatremic dehydration, hyperkalemia, and metabolic acidosis. However, the presence of volume overload and hypertension distinguishes this disorder from 21-hydroxylase deficiency (New, 1992). Typically, 11-deoxycortisol (compound S) is elevated and plasma renin activity is suppressed in this disorder. The female infant with this disorder can have clitoromegaly, although such children often are phenotypically normal. Hydrocortisone is the most physiologic form of synthetic glucocorticoids and is less likely to result in unwanted side effects. Hydrocortisone is administered orally at a dose of approximately 25 mg/m2/day (divided into three doses) in the newborn period. No liquid preparation of hydrocortisone is currently available, so tablets must be crushed and administered carefully with formula or food. Mineralocorticoid replacement (fludrocortisone acetate [Florinef]) at a starting dose of 0. Salt-losing crisis and acute adrenal insufficiency should be treated with stress doses of hydrocortisone (100 mg/ m2/day), which can be given either continuously as a drip or divided into equal doses every 6 hours. Intravenous fluids with ample sodium chloride (normal saline for boluses and one-half normal saline for maintenance fluids) are an essential component of treating salt-losing crisis. Hyperkalemia often decreases after sodium chloride and hydrocortisone are provided intravenously, although severe cases of hyperkalemia may require additional therapies. It should be kept in mind that hypertrophy of the clitoris will gradually lessen after medical therapy is instituted; however, complete normalization in the more virilized cases is not likely to occur. In severe cases of clitoral enlargement, clitoral reduction surgery is a treatment option, although suboptimal cosmetic results have been reported in long-term outcome studies. Atrophy or loss of the clitoris or excessive regrowth of clitoral tissue has been described in examinations of adolescent and adult patients who underwent genital surgery in early childhood (Alizai et al, 1999; Creighton et al, 2001). The risk of surgery needs to be balanced against the potential detrimental effects of masculinized genitalia on the development of a poor body image (Meyer-Bahlburg et al, 1996) and of social stigmatization by family or community members (Money et al, 1986). Recently, nerve-sparing ventral clitoroplasty in virilized females has been shown to preserve dorsal nerves for better sensitivity after surgery (Poppas et al, 2007). There is considerable debate about when to perform vaginal exteriorization surgery. The investigators advocate delaying vaginoplasty until puberty or later, when manual dilation can be undertaken by the patient and estrogenization of the vaginal mucosa can help to prevent stricture formation. Others recommend that vaginoplasties be undertaken early in life, because the procedure is technically easier in the first several years of life and the emotional trauma of a major surgery at adolescence is avoided (Donahoe, 1991; Schnitzer, 2001). Problems with loss of sexual sensation and pleasure have been reported in adult patients as a consequence of genital surgery in early life. However, in cases of severe discordance between assigned sex and genital appearance, the psychosocial consequences of uncorrected genital anomalies can be damaging (Money and Ehrhardt, 1972; Money et al, 1986). Participation of the parents in the decision to pursue genital surgery after they have been fully informed of the benefits and risks is perhaps the most judicious approach at this time (Daaboul and Frader, 2001; Lee, 2001; Reiner, 1997). Suggested explanations for reduced fertility included increased anovulatory cycles, low rates of heterosexual activity, inadequate vaginal introitus, and poor compliance with medical treatment (Mulaikal et al, 1987). When properly administered, dexamethasone is effective in preventing ambiguous genitalia in the affected female. The current recommendation is to treat the mother with a pregnancy at risk for 21-hydroxylase deficiency with dexamethasone in a dose of 20 g/kg divided into two or three doses daily (Mercado et al, 1995). The institution of dexamethasone therapy is recommended as soon as pregnancy is confirmed and no later than 9 weeks after the last menstrual period; this will effectively suppress adrenal androgen production, allow normal separation of the vaginal and urethral orifices, and prevent clitoromegaly. The need to initiate at such an early date means that treatment is blind to the sex of the fetus. No significant or enduring side effects were noted in the mothers (other than greater weight gain and a higher incidence of striae and edema than untreated mothers) or the fetuses. There was no statistically significant difference in hypertension or gestational diabetes between treated and untreated mothers. All mothers who took partial or full treatment stated they would take dexamethasone again in the event of a future pregnancy. Amniotic fluid testosterone levels might not be outside the normal range in an affected male (Wilson et al, 1995). In contrast, another study noted some significant maternal side effects, including excessive weight gain, cushingoid facial features, severe striae resulting in permanent scarring, and hyperglycemic response to oral glucose administration (Pang et al, 1992). A long-term follow-up study of 44 children treated prenatally in Scandinavia demonstrated normal prenatal and postnatal growth compared with matched controls (Lajic et al, 1998). Prenatally treated newborns also did not differ in weight, length, or head circumference from untreated, unaffected newborns (Carlson et al, 1999; New et al, 2003). Long-term studies on the psychological development of patients treated prenatally are currently under way. Postpubertal patients have delayed bone maturation, tall stature, and osteopenia (Conte et al, 1994). It should be noted that in 25% to 50% of undermasculinized males, a specific cause cannot be found (Al-Agha et al, 2001; Eil et al, 1984). Other factors such as medications and placental insufficiency may potentially interfere with genital masculinization. Medications such as cimetidine, spironolactone, phenytoin (Dilantin), phenobarbital, medroxyprogesterone, and cyproterone acetate have been associated with altered androgen action or metabolism. Their use during pregnancy may be detrimental to male genital development (Donahoe, 1991; Grumbach and Conte, 1998).
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Classic omphalocele occurs when there is an interruption in lateral fold development asthma 2016 generic proventil 100mcg line, resulting in an abdominal wall defect that lies between the epigastric and hypogastric regions asthma definition zen purchase proventil line. In addition to loops of bowel asthma treatment 9 month old buy cheap proventil on line, liver also may herniate through the abdominal wall defect asthma differential diagnosis purchase proventil 100mcg. The umbilicus arises from an anterior position on the omphalocele asthma treatment plan student discount 100 mcg proventil otc, and the muscular abdominal wall is normal asthma khan academy purchase proventil 100 mcg amex. Human chorionic gonadotropin levels have shown promise in small series in detecting abdominal wall defects (Schmidt et al, 1993). Ultrasound evaluation is not useful during the first trimester, when the midgut is normally herniated. Beyond 14 weeks, however, this modality has a 96% sensitivity (Patel et al, 2009). Once an abdominal wall defect has been identified, ultrasound examination often can distinguish omphalocele from gastroschisis. Because the association of cardiac anomalies and chromosomal disorders is high, fetal echocardiography and amniocentesis should also be performed. Vaginal delivery does not adversely affect outcome; therefore, the need for cesarean section should be based on obstetric indications alone (Segel et al, 2001). If the sac ruptures, the bowel loops may become edematous and matted together, mimicking gastroschisis. Treatment the presence of exteriorized bowel results in heat loss and extravasation of fluid and provides a major portal of entry for bacteria. When the omphalocele is first seen, the sac should be kept moist by wrapping it with gauze sponges that have been soaked in warmed normal saline. Care should be taken to prevent angulation of the sac when the child is prone, to prevent kinking of mesenteric vessels. Alternatively, the infant can be positioned on the side, with the exteriorized bowel in an anterior position. Thereafter, any inspection and manipulation of the abdominal contents should be done with sterile gloves. Operative repair should be undertaken as soon as possible, ideally within 2 to 4 hours of birth. For larger defects, primary repair may cause respiratory failure and abdominal compartment syndrome because the abdominal cavity is too small to accommodate the bowel. Complications of compartment syndrome include renal failure, hypotension from compression of the vena cava, hepatic ischemia, and intestinal ischemia. Final closure can then be achieved after gradual reduction of the bowel into the abdominal cavity over 7 to 10 days (Dunn and Fonkalsrud, 1997). The bag protects the baby from heat and water loss while allowing good visualization of the herniated bowel. This is in fact a small omphalocele, containing only bowel loops in a small sac within the umbilical cord. The fascial defect is relatively small and situated to the right of the umbilical cord and contains exposed bowel (as well as an ovary in this instance). Postoperatively, protracted ileus may occur, necessitating prolonged parenteral nutrition. Attention must also be directed to the diagnosis and management of associated anomalies. In the absence of heart disease, 70% to 90% of infants with omphalocele survive (Forrester and Merz, 1999; Kitchanan et al, 2000). This lesion was traditionally less frequent than omphalocele, but its incidence is increasing worldwide (Srivastava et al, 2009; Vu et al, 2008). The defect appears most common among young mothers and those of low gravidity (Fillingham and Rankin, 2008). Associated anomalies are found in only 15% of patients, the vast majority being intestinal atresias (Stoll et al, 2008). Infants with gastroschisis tend to have intrauterine growth restriction (Santiago-Munoz et al, 2007). This defect arises between the 8th and 10th weeks as a result of failure of closure of the umbilical ring. Cord hernias can be missed at birth, and the intestine can be injured by careless proximal application of the cord clamp. Otherwise, these defects are easily managed by primary closure at birth and have an excellent outcome. Etiology Although the cause of these lesions is not known, many investigators speculate that they may be of vascular origin. Intrauterine interruption of the omphalomesenteric artery has been proposed, an explanation that accounts for many of the clinically observed differences between this lesion and omphalocele (Hoyme et al, 1981). Because the peritoneal sac is absent, the fetal bowel is continuously bathed in amniotic fluid, which results in a significant intestinal "peel," causing poor intestinal motility. As with omphalocele, the need for cesarean section should be restricted to obstetric indications only, despite some evidence that prelabor cesarean section results in better outcome because of the ensuing absence of the fibrous peel (Serra et al, 2008). The entire gastrointestinal tract usually is eviscerated, but unlike with omphalocele, the liver is not exteriorized. The intestinal loops usually are covered by a thick fibrous "peel," which makes them firm, often with a cauliflower-like appearance. Rare complications include intrapartum mesenteric disruption, prenatal volvulus, and closure of the abdominal wall defect around the exteriorized gut. As described for omphalocele, the bowel contents should be kept moist and relatively sterile at birth. Because the abdominal wall defect often is small, vascular compromise occurs more readily, and great care should be taken to position the infant and the exteriorized bowel to prevent kinking of mesenteric vessels. Unlike with omphalocele, primary closure is possible in 90% of patients, but larger defects may require staged repair. A spring-loaded Silastic silo device that can be placed at the bedside allows early closure of the defect and avoids the need for emergency surgery (Jensen et al, 2009; Pastor et al, 2008). Alternatively, simple cases of gastroschisis can be managed with a sutureless bedside technique not requiring general anesthesia (Sandler et al, 2004). All techniques of intestinal protection and abdominal wall closure appear, however, to be equally effective, and only failure to obtain primary closure is associated with significant delays in resuming intestinal function (Weinsheimer et al, 2008). Postoperatively, prolonged ileus often occurs because of intestinal dysmorphology, which often includes the myenteric plexus. Despite this ileus, minimal enteral feeding in the early postoperative period can decrease time to discharge and overall mortality (Walter-Nicolet et al, 2009). Affected infants are at increased risk for necrotizing enterocolitis (Oldham et al, 1988). Intestinal atresias usually are not repaired at the initial procedure because of the fibrous peel and therefore require repair at 3 to 4 weeks of age (Snyder et al, 2001). One third of babies with gastroschisis will experience growth delay in infancy, and prolonged intestinal dysmotility is common (Phillips et al, 2008; South et al, 2008). Prognosis Mortality rates have decreased to 5% to 10% (Fillingham and Rankin, 2008; Kitchanan et al, 2000). Postoperative recovery may be longer in infants undergoing repair of gastroschisis than in those with omphalocele. Enteral feedings may not be established until 2 months after operation, and some infants will require home parenteral nutrition (Molik et al, 2001). In spite of these initial feeding difficulties, most gastroschisis survivors maintain normal growth during infancy and childhood (Davies and Stringer, 1997). Theories include failure in the development of the abdominal wall between the 6th and 8th weeks of gestation and primary urethral obstruction with early bladder distention (Woods and Brandon, 2007). Approximately 20% of patients with prune-belly syndrome die in the neonatal period from renal dysplasia or pulmonary hypoplasia, but of those who survive, 30% develop renal failure during childhood (Burbige et al, 1987). Surgical management of the genitourinary tract remains controversial, with advocates of both watchful waiting and major reconstruction. The latter should be performed only where specialized surgical and anesthesia expertise are available, because the surgery is challenging and postoperative complications are frequent. The undescended testes are corrected in childhood for monitoring and psychological reasons. The incidence of inguinal hernia in lowbirthweight infants varies between 3% for birthweights of 1500 to 2000 g to 42% for birthweights of 500 to 1000 g (Peevy et al, 1986). Additional risk factors for inguinal hernias are cystic fibrosis, congenital dislocation of the hip, presence of a ventriculoperitoneal shunt, and abdominal wall defects. The combined incidence of these complications is as high as 30% (Rowe and Clatworthy, 1970), although it appears to be lower in preterm infants. Most of these incarcerated hernias may be reduced nonoperatively by placing the infant in the Trendelenburg position with sedation and application of an ice pack to the inguinalscrotal area. Successful reduction should be followed by surgical repair in 24 to 48 hours (allowing for resolution of local edema). Nonincarcerated hernias in infants require repair as soon as convenient, preferably within 1 to 2 weeks of diagnosis (Zamakhshary et al, 2008). Premature babies are traditionally operated on just before their discharge from the neonatal intensive care unit, or very soon afterward-although earlier repair may be technically easier for large hernias (Ein et al, 2006). Postoperative apnea occurs in about 5% of preterm infants, particularly those with a history of apneas (Murphy et al, 2008). Postoperative overnight admission for apnea monitoring is therefore indicated for higher-risk outpatients until 48 weeks of postconceptional age. The lowest incidence of apneas occurs with surgery performed using spinal block without sedation (Somri et al, 1998). Other specific postoperative complications include persistent scrotal swelling, recurrence, testicular atrophy, and injury to the vas deferens. Contralateral exploration is probably not indicated in most cases, because the actual risk of a metachronous hernia has been generally estimated at below 10% (Ein et al, 2006; Zamakhshary et al, 2009). The typical hydrocele is noted at or shortly after birth as a unilateral or bilateral swelling in the scrotum, which may fluctuate in size. Differentiation between hydrocele and hernia is critical and may be difficult in the infant. Transillumination is useful, but findings must be interpreted cautiously, because fluid or gas-filled bowel may transilluminate in small infants. The recommended management of a hydrocele is observation during the first 1 or 2 years of life, unless a hernia cannot be excluded. Hydroceles that persist or appear beyond that age are unlikely to resolve spontaneously, and affected infants should therefore undergo elective surgical repair. All varieties of this defect are rare, and treatment is customized to each patient (Galati et al, 2008). Surgical excision of the sinus tract is required if it persists beyond 6 months of life (Galati et al, 2008). Radiopaque contrast material injected into the orifice outlines the urachal tract and fills the bladder. Treatment consists of surgical excision of the umbilicus along with the entire urachus down to the bladder. Cysts may present at birth or may grow slowly and become obvious at any time during infancy or childhood, often through infection. Treatment involves surgical resection, which may be preceded by incision and drainage of the superimposed abscess. As with urachal remnants, presentation and management vary with each type (Snyder, 2007). B, Operative photograph of the urachal remnant with wide attachment to the bladder. The most significant danger with this lesion is evagination (prolapse) of the small bowel through the umbilical orifice, with a significant increase in mortality. Once this lesion is diagnosed, it should be corrected by surgical excision of the umbilicus and the duct. Its distal end usually lies free in the peritoneal cavity, but in some cases it is attached to the umbilicus by a fibrous cord and in a small minority remains patent to the umbilicus (omphalomesenteric fistula). Gentle massage results in the extrusion of mucus, which differentiates this lesion from an umbilical granuloma. Only a small proportion of these diverticula ever become symptomatic, and when they do, this usually happens beyond the age of 4 months. A pancreatic or gastric mass may act as a leading point to produce intussusception. B, Operative picture of wide patent remnant attached to anti-mesenteric side of the ileum. This test is most useful in patients presenting with rectal bleeding-the false-negative rate is high in patients with other symptoms (Menezes et al, 2008). Pentagastrin or cimetidine is useful in enhancing the image of gastric mucosa on subsequent technetium scans. Treatment Resuscitation and blood replacement therapy is the initial treatment regardless of the cause of bleeding. If bleeding ceases, careful observation for recurrence of bleeding is often all that is indicated, because peptic ulcer rarely recurs. A second episode of bleeding, however, strongly suggests that other diagnostic procedures may be needed, including endoscopy, laparoscopy, and laparotomy. Surgical treatment is generally reserved for symptomatic diverticula and those thought to contain ectopic tissue (Snyder, 2007). Note the solid tip of the diverticulum, which probably is filled by ectopic gastric or pancreatic tissue. Hemorrhage is often sudden and catastrophic, causing a precipitous fall in the hematocrit and a shock-like state within a few hours. The first few stools passed may be composed almost entirely of unchanged blood; later, they become burgundy-colored and then tarry.
There are published treatment guidelines for the management of pediatric (including neonatal) thrombosis asthma xolair buy generic proventil on line, but these are based largely on the opinions of a small group of experts asthma 2014 movie generic 100mcg proventil, and most recommendations are based on the lowest level of evidence asthma treatment without medication discount proventil master card. The following discussion should be interpreted in light of this caution asthma in dogs buy proventil in united states online, and the most important recommendation is to solicit the consultation of a pediatric hematologist with a specific interest in pediatric thrombosis refractory asthma definition purchase cheap proventil online. This is of particular importance in neonates because a venous thrombus will likely embolize to the central nervous system because of the patent foramen ovale asthma definition 9 amendment discount proventil 100 mcg line. For example, ascites resulting from a portal vein thrombosis is essentially due to the same physiologic problem. Unless there is a contraindication to anticoagulation, therapy should not be withheld. Once a thrombus is identified, an assessment for acquired risk factors should be performed in order to determine whether any of these factors can be eliminated, such as removing a central line that is no longer needed, or treating dehydration, infections, or an elevated homocysteine level. Regardless of whether such risk factors can be removed or ameliorated, that treatment step is not a substitute for anticoagulation. If there is a temporary contraindication to anticoagulation (planned invasive procedure in the next 1 to 2 days), then therapy can be withheld until the contraindication no longer exists. All three have significant limitations that have been reviewed elsewhere (Young, 2004), and a detailed discussion is beyond the scope of this chapter. Warfarin is the only orally available anticoagulant; however, its numerous drug and food interactions as well as the fact that it cannot be compounded into a liquid reduce its utility in neonates. There is also no available evidence regarding the duration of therapy, although the general recommendation is 3 to 6 months based on extrapolation from adult data. Again, it is recommended that decisions regarding choice of anticoagulant and intensity and duration of therapy be discussed in consultation with a pediatric hematologist with specific expertise in pediatric thrombosis. In selected and severe situations such as superior vena cava syndrome and pulmonary embolism, thrombolysis could be considered, but such therapy should only be performed under the direct supervision of a hematologist (or other physician) with expertise on its use and only after a discussion with the parents regarding the risks and benefits of this approach. With rare exceptions, the results of the thrombophilia evaluation (if it is performed) will not affect the approach to management. First, therapy will need to be initiated before results are generally available, and second, the presence of most of the thrombophilias discussed earlier will not influence the choice, intensity, or duration of anticoagulation. Although two recent studies suggested that there is an increased risk for thrombosis recurrence with deficiencies of proteins C and S and antithrombin and with the prothrombin mutation, it is not clear how this evidence should be translated to treatment (Young et al, 2008). In some circumstances, the results of the thrombophilia evaluation will affect therapy. The most obvious example is that of homozygous protein C or protein S deficiency, in which replacement therapy is mandatory (Thornburg and Pipe, 2006). Historically, replacement therapy was accomplished via frequent infusions of fresh frozen plasma; however, the availability of a protein C concentrate (Ceprotin, Baxter, Westlake Village, Calif. For patients with homozygous protein C deficiency, replacement therapy is required lifelong with infusions administered three times per week. For those with homozygous protein S deficiency, there is no standard approach because there are so few cases reported, and prophylactic replacement with fresh frozen plasma, although feasible, is logistically difficult. Once the initial purpura fulminans is treated, ongoing therapy with anticoagulation can be considered. Although a low antithrombin level in the newborn period may not be diagnostic of a genetic deficiency, the low levels nevertheless could result in heparin resistance such that replacement therapy may be indicated. Last, identification of elevated homocysteine levels, whether moderate or severe, will result in therapy aimed at lowering the levels via vitamin B therapy. Even less is known regarding the outcomes of pulmonary embolism, cerebral sinus thrombosis, portal or renal vein thrombosis, and superior vena cava syndrome. Outcome after neonatal venous thromboembolism is one of the many needed areas for future pediatric thrombosis research. For the purposes of this chapter, stroke is defined as ischemic brain injury resulting from occlusion of the arterial blood supply to or within the brain. In addition to strokes resulting from vascular occlusion, there are a number of metabolic disorders that can result in a clinical scenario similar to stroke and that result from a lack of required nutrients, toxic effects or other mechanisms; however, because these conditions are metabolic in nature, they are covered in other chapters. The neonatal period is one of the most common times for a pediatric patient to present with stroke. It is estimated that from 18 to 43 per 100,000 neonates will have acute ischemic stroke (Bernard and Goldenberg, 2008; Kirton and de Veber, 2009). A number of risk factors have been identified that are associated with stroke in the newborn period. Other risk factors include some thrombophilias such as homozygous protein C deficiency, elevated lipoprotein(a), and hyperhomocysteinemia (Bernard and Goldenberg, 2008). Despite detailed investigations, in many instances no clear cause for stroke is identified. There is a notion that many of these events occur as a result of a perinatal embolic event in which tissue such as amniotic fluid or placental thrombi enter the neonatal venous system, resulting in a paradoxic embolus. It is critical to identify, if possible, the risk factors that led to the stroke, because this will dictate the treatment and assist in formulating a prognosis. For example, the presence of a stroke may unmask a previously undiagnosed heart lesion, a vascular malformation, or a severe thrombophilia. For situations in which risk factors are identified, management of such conditions is an important step toward preventing a second event. One approach to an evaluation for risk factors is first to obtain a detailed history from the parents regarding the pregnancy and family history of thrombotic events. Second is to rule out important causes for stroke such as congenital heart disease and vascular malformations. This evaluation would include an echocardiogram and possibly a cerebral angiogram or cardiac catheterization. The likelihood of a venous thrombus in the absence of a catheter is so remote that such an evaluation is unnecessary unless a venous catheter is present or there is a suspicion for a venous thrombosis based on clinical grounds. From the standpoint of a laboratory evaluation, obtaining a thrombophilia evaluation as described previously remains controversial, especially if other risk factors are identified. In the absence of any identifiable risk factors, a thrombophilia evaluation would be a reasonable course of action. The question is which assays to perform and, importantly, when to perform them, either in the neonatal period or at the age of 6 months or beyond. The advantage of obtaining an evaluation in the newborn period is the possibility of identifying an abnormality that requires treatment such as severe protein C or S deficiency or hyperhomocysteinemia. The disadvantage is that because levels of proteins C and S and antithrombin are physiologically low in the newborn period, it will be necessary to repeat these tests after 6 months of age in order to be sure that normal adult levels have been achieved. Thus, the most prudent approach if one elects to perform a thrombophilia evaluation is to at least obtain protein C and S activity levels, an antithrombin level, and a homocysteine level initially, and to perform the rest of the evaluation when repeating the protein C and S and antithrombin levels at 6 months of age. In addition to the genetic defects described earlier, it is important to evaluate for the antiphospholipid syndrome, because it is possible for the antibodies to be transplacentally transferred from an asymptomatic mother. Clinical Presentation the clinical presentation of neonatal stroke ranges from the dramatic (seizures) to the subtle (poor feeding) to an asymptomatic incidental imaging finding. Approximately half of patients with acute ischemic stroke present with seizures within hours up to a day or two after delivery. Other presenting manifestations include nonspecific respiratory abnormalities such as apnea or grunting and occasionally feeding difficulties. Focal neurologic signs are rare, although occasionally seizures will be focal, at least initially, before becoming generalized. On occasion, central nervous system imaging is obtained for reasons unrelated to the foregoing symptoms, and an infarct is found incidentally with no symptoms. Not infrequently, patients may present months later with what is presumed to be neonatal stroke when they have focal neurologic signs or even seizures without a precipitating event, and imaging demonstrates an old infarct. Last, if at all possible, pathologic examination of the placenta may reveal the presence of thrombi, which could indicate that the stroke was the result of embolization from placental thrombi. Treatment the management of acute ischemic stroke depends largely on the etiology if it can be identified. Obviously, a heart lesion resulting in embolization of thrombi requires rapid correction, as do vascular lesions resulting in ischemia. Severe thrombophilia such as hyperhomocysteinemia or protein C and S deficiency requires specific therapies as previously described. In the more typical situation, however, either no risk factors or more subtle nonspecific risk factors such as infection are present. There are no clinical trials that have evaluated anticoagulation or antiplatelet therapy in a prospective or controlled fashion. If the stroke was felt to be the result of a perinatal embolic event, then the likelihood of a second stroke is essentially zero because, clearly, the risk factor (the birth process and fetal circulation) will never recur. Thus, secondary prevention with anticoagulation or antiplatelet therapy is not required. For those neonates with clear ongoing risk factors such as congenital heart disease or thrombophilia, anticoagulation/ antiplatelet therapy should be considered. Unfortunately, data do not exist to support decisions such as which agent to use, at what intensity, and for what duration. For lesions that are clearly arterial, antiplatelet therapy with aspirin is the most appropriate approach, whereas for venous emboli, anticoagulation is more appropriate. Combining these two therapies is another approach although the risk for bleeding certainly rises in this situation. It is suggested that consultation with a pediatric hematologist and/or neurologist with specific expertise in childhood stroke be sought to assist with therapeutic decisions and for ongoing follow-up after discharge. Other defects such as vision loss, language deficits, and general cognitive impairment may also be noted. It is important to note that the outcomes do not necessarily correlate with the severity of the lesion, making it hard to predict the outcome in any individual patient. It is suggested that the prognosis be discussed in general and broad terms and that parents be made aware that although neurologic sequelae are common, they are not universal, and that their child should have careful monitoring of development such that specific interventions (physical, occupational and speech therapy, for example) begin as early as possible. Fortunately, recurrence is rare in neonatal stroke, except for patients with the specific disorders discussed earlier, and in such cases preventive therapy with antiplatelet or anticoagulant medications presumably reduces the risk of recurrence, although there are no data to support this. It occurs almost exclusively in association with either arterial catheterization or an inadvertent arterial injury during venous catheterization (Aslam et al, 2008). Arterial thrombosis can occur in any vessel that is catheterized; however, because the most common sites for catheterization are the femoral arteries and aorta (umbilical catheters), these would be the most common sites affected. Patients at highest risk are those with congenital heart disease who may undergo multiple catheterizations of the femoral artery, and premature patients in whom umbilical artery catheters are commonly used. On rare occasion, patients my develop thrombosis of the arteries feeding a visceral organ, with renal artery thrombosis being the most common. Even in this setting, it may have resulted from the presence of an umbilical artery catheter. Clinical Presentation Patients with femoral or subclavian/brachial artery thrombosis present with signs of decreased perfusion and ischemia distal to the occlusion. This may include color changes such as pallor or cyanosis, decreased pulses, and eventually tissue necrosis. The presentation of thrombosis in the aorta is usually an incidental finding determined by diagnostic imaging of the abdomen or chest for other reasons. When symptoms are present, they may be subtle, such as differential blood pressures between the upper and lower extremities. Rarely, there may be signs of decreased perfusion distal to the occlusion with symptoms similar to the foregoing. Renal artery thrombosis manifests with hypertension due to disruption of the renin-angiotensin-aldosterone system. Thrombosis of arteries to other organs is extremely rare and will manifests with organ dysfunction. Outcomes Neonates who suffer an overt symptomatic stroke have quite variable and rather unpredictable outcomes. Even those in whom a large area of infarction occurs may have an excellent neurologic outcome, demonstrating the known plasticity of the newborn brain. With this in mind, it is difficult to justify a thrombophilia evaluation in this group of patients, with the exception being the rare patient in whom no cause for the thrombosis can be identified. Treatment the first and most important aspect of therapy is to remove the arterial catheter if it is still in place. Second, determining the degree of obstruction and ischemia is crucial, because this will dictate the aggressiveness of the therapeutic approach. For patients in whom perfusion is relatively maintained, simply removing the catheter may be sufficient. For those with more significant perfusion deficits, such as absent pulses and signs of diminished perfusion (pallor, prolonged capillary refill), anticoagulation therapy with unfractionated heparin is recommended. For those with a complete occlusion or with significant ischemia or signs of necrosis, thrombolysis should be attempted so long as there are no contraindications (Raffini, 2009). If local thrombolysis is feasible, then this has the advantage of using lower doses and directing the thrombolysis at the thrombus. This results in improved safety due to the lower doses used as well as the potential for more rapid resolution. Diagnosis the diagnosis is based on demonstrating arterial occlusion by diagnostic imaging. The most commonly used imaging modality is Doppler ultrasonography, which is sensitive for peripheral arteries as well as the femoral and subclavian arteries and the abdominal aorta. Occasionally, treatment involves catheter-directed thrombolysis (see later discussion), and in such instances, an angiogram is performed before the procedure, which can further define the occlusive lesion. Outcomes the outcome for peripheral arterial thrombosis is fairly straightforward.