Anacin

Barbara Abrams DrPH, RD

• Professor of the Graduate School, Epidemiology, Maternal, Child and Adolescent Health, and Public Health Nutrition

https://publichealth.berkeley.edu/people/barbara-abrams/

Disorders of Red Blood Cells Anemia Anemia is defined as a decrease in Hb that is two standard deviations below the mean value for age pain treatment center seattle wa discount anacin 525 mg buy on line. The congenital causes for a microcytic anemia include [3-or a-thalassemia trait pain medication for dogs after being neutered anacin 525 mg order on-line, other forms of thalassemia pain medication for dogs carprofen cheap anacin 525 mg on line, sickle cell combined with thalassemia pain treatment goals discount anacin 525 mg buy on-line, or anemia of chronic disease laser treatment for shingles pain discount anacin 525 mg visa. The reticulocyte count should be used to further classify the anemia into two broad categories of increased or decreased red cell turnover. The reticulocyte count needs to be adjusted for the degree of anemia to determine if it is truly elevated. Patients with congenital or acquired are at increased risk for developing an acquired hemolytic anemia from an increase in shear forces most commonly seen in patients with prosthetic valves. The rationale of this strategy is that a compromised cyanotic patient has limited ability to increase cardiac output to compensate for a low systemic oxygen delivery (13-15). No differences were found in mean or peak arterial lactate, arteriovenous or arteriocerebral oxygen content, or clinical outcomes. It is a multisystem disease characterized by a chronic hemolytic anemia and vaso-occlusive complications resulting in episodes of acute illness and a chronic progression to end-organ damage. In Hb S, an amino acid substitution in the j3-globin gene from glutamic acid to valine ultimately leads to the polymerization of Hb S molecules, causing the red cell "sickling" effect with resultant vascular occlusion and hemolytic anemia. One gene deletion is termed a silent carrier and has no hematologic manifestations. A two-gene deletion is termed a-thalassemia trait; the patient has a mild microcytic hypochromic anemia but is otherwise well with a normal Hb electrophoresis. The presence of a four-gene deletion is termed hydrops fetalis and results in severe anemia in the fetus with intrauterine death. In contrast, the inheritance of two affected f3-globin genes results in a broad spectrum of clinical disease. The clinical phenotype ranges from transfusion dependence (f3-thalassemia major) to a moderate anemia that does not necessitate chronic transfusions (f3-thalassemia intermedia). Treatment of f3-thalassemia major consists of either lifelong chronic red cell transfusions or bone marrow transplant. Chronic red cell transfusions correct the anemia and suppress ineffective erythropoiesis. Transfusions are typically given every 3 to 4 weeks with target nadir Hb of 9 to 10 g/dL. Currently, heart failure is the most common cause of death in patients with f3-thalassemia major. The most common cardiac abnormality in patients with heart failure from iron overload is a biventricular dilated cardiomyopathy, and severe right ventricular cardiomyopathy is evident in advanced disease (41). Iron deposition is greatest in the ventricular walls and less in the atria and the conduction system. Cardiomyocytes are also sensitive to oxidative damage from non-transferrin-bound iron. Pericarditis was common prior to the use of chelation therapy but appears to be decreasing in frequency (42). Paroxysmal atrial fibrillation is common and is typically associated with myocardial dysfunction; restoration of sinus rhythm does not usually reverse the cardiomyopathy (42). First-line chelators currently in use in the United States include deferoxamine, which is given as a 12-hour infusion intravenously or subcutaneously or deferasirox, an oral medication given once daily. Recently, deferiprone was approved as a second-line oral chelator in the United States. An escalation in chelation therapy is imperative for patients with significant cardiac iron loading. Recent studies have demonstrated that deferiprone in combination with an additional chelator has improved cardiac activation (18-20). In general, the heart is usually enlarged and a systolic ejection murmur is found in most patients. Patients can experience a reversal of the iron-induced cardiomyopathy with intensive chelation (42). In primary polycythemia, erythroid progenitors exhibit an excessive response to cytokines secondary to an inherited or acquired genetic mutation. Secondary polycythemia is usually the result of a physiologic response to chronic hypoxia. Barth syndrome is an X-linked recessive mitochondrial disorder that is characterized by a dilated cardiomyopathy with endocardial fibroelastosis, skeletal myopathy, growth retardation, neutropenia, and organic aciduria (48,49). The most common phenotypic features include conotruncal cardiac malformations, immunologic dysfunction, developmental delay, and palate deformities (51). Immunologic dysfunction is the result of thymic aplasia or hypoplasia resulting in a variable T-cell deficiency with a resultant increase in infections and autoimmune disease (52). Decreased regulatory T cells may playa role in the increased incidence of autoimmune disorders (52,53). The holy grail of hemostatic testing would be one test that is rapidly available and adequately reports on all components of hemostasis. Patients with significant polycythemia (hematocrit> 55%) can also have an altered plasma-to-citrate ratio and will have falsely prolonged coagulation assays. In the setting of a bleeding patient, it is imperative that the fibrinogen level is maximized to ensure adequate hemostasis. At this time, there is a limited availability to rapidly assess platelet function. The bleeding time assesses platelet and capillary function but this technique is patient and operator dependent and has fallen out of favor (56). It is insensitive to mild platelet defects and does not consistently predict a bleeding tendency (57). Values measured include R (time necessary for initial clot formation), K (clot kinetics), ex (rate of clot formation), maximum amplitude (maximum strength of the clot), and A-60 to maximum amplitude ratio (fibrinolysis). The thrombocytopenia can improve with phlebotomy especially when the hematocrit is >65% (72). Drug exposure is a common reason for acquired platelet dysfunction or thrombocytopenia. The more commonly used drugs include antibiotics (penicillins, or sulfa-containing antibiotics), anti epileptics (phenytoin, valproate, carbamezepime), H2 agonists (cimetidine or ranitidine), thiazide diuretics, and furosemide. The distribution in the size of these multimers is imperative for hemostatic balance. There have been reports in neonates with patent ductus arteriosus, endocarditis, dysfunctional valve prosthesis, septal defects, and mitral valve prolapse (63,64). Treatment would only be necessary to treat active bleeding that does not resolve with local measures or prior to a significant hemostatic challenge to prevent excessive bleeding. Bernard-Soulier syndrome, a congenital platelet disorder, should be considered when caring for patients with 22q11. Heterozygotes for this condition are clinically normal but may have mild thrombocytopenia and minor platelet function abnormalities (67). It is proposed that the binding of antibodies to this platelet complex results in increased platelet reactivity and thus a prothrombotic state (73). This disorder is characterized by thrombocytopenia and resultant arterial andlor venous thrombosis that can be catastrophic. Multiple scoring systems have been developed and validated in adults but not in pediatric patients (80-82). Unfortunately, it is only performed in a few highly specialized laboratories so is not readily available for most clinicians. Anticoagulation should be initiated with a non-heparin anticoagulant such as a direct thrombin inhibitor. In this setting, warfarin should never be initiated by itself due to an increased risk of skin necrosis and further thrombotic events. These antibodies coat the surface of the platelets and these platelets are cleared through the Fey receptors in the spleen. Treatment can include observation combined with thrombocytopenic precautions or the use of immune-modulating therapies like immune globulin or steroids. In the neonate, immune destruction of platelets can be secondary to a mismatch between the fetal and maternal platelets, termed neonatal alloimmune thrombocytopenia. The mother develops antibodies against antigens on the fetal platelet surface that were inherited from the father. These antibodies cross in the placenta, coat the fetal platelets, and result in significant thrombocytopenia. Too little protamine means heparin is still circulating or excessive unbound protamine has anticoagulant properties (91,92). Primary causes include myeloproliferative disorders that are either inherited (essential thrombocythemia) or acquired (polycythemia vera, leukemia, or myelodysplastic syndrome). Secondary causes are the result of underlying inflammation (infection, rheumatologic disorders, or inflammatory bowel disease), hematologic disorders (hemolytic anemia or iron deficiency), drugs (vinca alkaloids or corticosteroids), or decreased splenic pooling in the setting of asplenia. Clinical factors associated with postoperative bleeding include younger age (<1 year), lower weight «8 kg), cyanosis, prolonged circuit, and deep hypothermia times (8587). One major contributing factor is the degree of hemodilution that occurs in pediatric patients with the institution of cardiac bypass. An adult patient experiences approximately 25% hemodilution with the institution of bypass, while a pediatric patient can experience up to 60% of hemodilution (88). This dilution is further exacerbated by developmental hemostasis in neonates who, at baseline, already have lower procoagulant and anticoagulant proteins (4). Excessive bleeding is a clinical concern that warrants immediate attention and constant vigilance. In the immediate postoperative period, bleeding of <5 mLlkg/h is often associated with minor abnormalities in coagulation status. Red cell transfusion may be necessary to correct a postoperative anemia but blood component administration is rarely necessary. Bleeding 5 to 10 mLlkg/h should prompt notification of the cardiothoracic surgeon and continued evaluation of the patient at the bedside. The patient must be closely monitored for persistence or an increase in the rate of bleeding that may signal the presence of a surgical bleeding site or may be the result of loss of coagulation factors secondary to the ongoing hemorrhage. Bleeding of >10 mLlkg/h that persists or increases will likely result in hemodynamic compromise if not abated. Much work is still needed in the area of diagnosis and treatment and most importantly in defining risk factors so that these potential life-threatening complications can be prevented. The primary end point, time to chest closure, was actually prolonged in the treatment group. No difference was noted in the secondary end points of surgical blood loss or use of blood products (102). The Propensity for Thrombosis in Adolescents and Children with Congenital and Acquired Heart Disease Congenital and acquired heart disease put adolescents and children at risk for thrombosis mainly because the triad of risk factors for thrombosis initially described by Virchow (131) in 1856 is often at play. Turbulent blood flow across abnormal cardiac structures, that is, stenotic valves, can lead directly to platelet activation (132), making "altered blood flow" more applicable to pediatric heart disease than "static blood flow" alone. Therefore, risk factors for thrombus in adolescents and children with heart disease should be expanded to include: 1. Hypercoagulability: Coagulation abnormalities have been identified to include altered coagulation protein levels, decrease endogenous inhibitors of coagulation, and decreased fibrinolytic proteins among others. Such coagulopathies were first identified in children and adolescents with a Fontan circulation but more recently have been found in children through all stages of single-ventricle palliation and also in children with acyanotic and acquired heart disease (121,122,125,126,133-138). Stasis: may occur in dilated heart chambers as well as in dilated native or prosthetic outflow tracts. Turbulent flow: is a flow across stenotic native or prosthetic heart valves, stents, and/or obstructed outflow tracts with increased sheer stress that can result in platelet activation independent of endothelial damage (139). Endothelial disruption: occurs from turbulent flow on endothelial surfaces as well as vessel wall endothelial damage from insertion and persistence of central lines and catheters. Endothelial injury, as discussed previously, exposes tissue factor and subendothelial collagenstimulating platelet aggregation and coagulation at the site of injury. Note, platelets can also be activated by other mechanisms in addition to endothelial injury such as from cytokines release during inflammation (139-141). Thrombosis Thrombosis in Children and Adolescents with Congenital and Acquired Heart Disease Thrombosis has long been recognized as a clinical problem to the clinician caring for adolescents and children with congenital and acquired heart disease. Much work has focused on the diagnosis, treatment, and prevention of thromboses in Kawasaki disease (104-107) and to a lesser extent on the thrombotic complications associated with cardiac catheterization (108-111) or cardiomyopathies (112,113). For the past decade, the single ventricle population has been identified as a particularly high-risk population for thrombosis and their potentially devastating sequelae (119-128). Overall, there is a paucity of information on the true scope of thrombotic complications in children and adolescents With heart disease. Two retrospective studies reviewed thrombotic incidence and risk factors in cardiovascular surgical populations. Deep venous thromboses associated with indwelling central lines were the most common. Wide dose ranges have been reported (17-200,Ug/kg) Lower doses are advisable 4lHiO,Ug/kg Severe bleeding resistant to maximized component therapy. Interestingly, all of the above-mentioned risk factors including coagulation abnormalities, altered blood flow, endothelial damage, and abnormal vascular surfaces are operative. Inflammation and bloodstream infection: Tissue factor has been documented to become accessible via activated monocytes or endothelial cells when stimulated by sepsis or through cytokine production during inflammation (140,142). In recent clinical studies, sepsis was associated with increased thrombus formation especially in the presence of an indwelling central venous catheter (144-146). Consequence of Significant Thrombi in Adolescents and Children with Cyanotic Heart Disease Adolescents and children with cyanotic heart disease are at particular risk of devastating complications from both venous as well as arterial thrombi. Occlusion of systemic-to-pulmonary shunts or Fontan circuits are both lethal without immediate intervention.

Primary antiphospholipid syndrome presenting as chronic thromboembolic pulmonary hypertension pain medication for shingles pain anacin 525 mg line. Pulmonary hypertension in a murine model of the acquired immunodeficiency syndrome dna pain treatment center 525 mg anacin order otc. Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions pain medication for dogs with ear infection anacin 525 mg buy low price. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling pain treatment guidelines purchase generic anacin canada. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32 pain medication for dogs with tumors buy discount anacin 525 mg line. Primary pulmonary hypertension: a case report including electronmicroscopic study. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Epigenetic regulation of the endothelial nitric oxide synthase gene in persistent pulmonary hypertension of the newborn rat. Fibroblast growth factor mediates hypoxiainduced endothelin-a receptor expression in lung artery smooth muscle cells. Development of Crotalaria pulmonary hypertension: hemodynamic and structural study. Pulmonary toxicity of monocrotaline differs at critical periods of lung development. Altered elastin and collagen synthesis associated with progressive pulmonary hypertensin induced by monocrotaline. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Vascular endothelial growth factor coordinates proper development of lung epithelium and vasculature. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. A role for potassium channels in smooth muscle cells and platelets in the etiology of primary pulmonary hypertension. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Currently, diseases are grouped according to similar pathology, pathophysiology, and treatment. In particular, the adult classification does not include abnormalities of alveolar growth and development nor does it account for many of the syndromes seen in pediatric practice, such as Down syndrome. Group 5 consists of miscellaneous disorders that do not fit well into Groups 1 to 4. Due to the difficulties of applying the Dana Point Classification to children, a working group of the Pulmonary Vascular Research Institute developed a unique pediatric classification (Table 67. Other clinical symptoms may include seizures, hemoptysis, chest pain, dizziness, syncope, arrhythmias, or in advanced disease, symptoms of right heart failure, for example, facial edema. In contrast, syncope is a rare presenting symptom in patients with Eisenmenger syndrome. In infants, symptoms are less specific and may involve poor appetite, failure to thrive, lethargy, diaphoresis, tachypnea, tachycardia, and irritability (10-12). Asymmetric lung volumes may suggest either pulmonary arterial or pulmonary venous abnormalities. A unilateral small lung may be seen in unilateral "absence" of a pulmonary artery, scimitar syndrome, or unilateral congenital absence of pulmonary veins. However, the sensitivity is likely higher, especially in combination with a complete physical examination. The chest radiograph may show variable peripheral lung fields, depending on the amount of pulmonary blood flow. The presence of a pericardial effusion is rare in children, but when present, suggests a poor prognosis (27,31). Impedance incorporates the sum of total compliance and resistance of the vascular bed (33-36). Most young children require anesthesia for this procedure, which is an important consideration. The left marker represents the peak early diastolic velocity and the right marker represents the end diastolic velocity of the pulmonary insufficiency Doppler curve. There were no significant adverse events, such as syncope, chest pain, or dizziness, and the study was stopped for fatigue in 53% of patients, leg fatigue in 23%, dyspnea in 21 %, and miscellaneous reasons in 3% (49). It is uncertain if the same definition of vasoreactivity should be applied for adults and children (see Therapy section). Data are shown as histograms and box-and-whiskers plots illustrating the median, 25th and 75th percentile as well as 5th and 95th percentile. Measurements must be obtained when the patient is closest to his/her usual hemodynamic and metabolic state and with a normal pH. Acute vasodilator testing is essential at the baseline diagnostic catheterization to assist in determining the optimal therapeutic regimen, and is described in a subsequent section. Severe hypoxemia is not usually present unless there is either intracardiac shunting via a patent foramen ovale or an open congenital heart defect in patients with Eisenmenger syndrome or severely depressed cardiac output with resultant mixed venous hypoxemia in both conditions. Approximately, 5% to 20% of children with idiopathic disease may have an elevation of antinuclear antibodies as well as evidence of hypothyroidism or hyperthyroidism suggesting an autoimmune association (59-62). Furthermore, children should be screened for evidence of a hypercoagulable state as some may have an underlying coagulopathy such as antiphospholipid antibody syndrome or a lupus anticoagulant. The evaluation should include a liver ultrasound in cases suspected of having portopulmonary hypertension. Many children with genetic syndromes, and in particular Down syndrome, routinely have aspiration. Silent aspiration is of particular concern, as these children do not always cough during aspiration events. In general, treatment of reflux and aspiration should precede treatment with pulmonary vasodilators. Hemodynamics normalized in all children repaired before 9 months of age, regardless of severity of the preoperative Heath-Edwards, morphometric, or hemodynamic changes. The Heath-Edwards changes are heterogeneous, making absolute determination of being inoperable difficult (72). Wedge angiography may provide clues to the severity of pulmonary vascular disease (70,77,78). Reduced penetrance implies that generations of mutation-carrying persons may not express the disease. In families, it may be the child who presents first with severe disease, and then further evaluation of first-degree relatives reveals milder disease in the parents or grandparents (93). It is mandatory that genetic testing be performed in conjunction with experienced genetic counselors before and after the test results (87). The age and type of lesion strongly contribute to the risk of developing irreversible pulmonary vascular disease. Most centers perform early surgical repair in the first months of age to decrease the likelihood of pulmonary vascular disease. Hemodynamics was worse in nonoperated patients than the patients whose defects had been closed. In moderate or large defects, when not operated, clinical parameters tended to worsen with time. A positive preoperative response to oxygen, defined as a fall in the Rp/Rs of 30%, did not correlate with either operative survival or late Rp/Rs (140). Seventy four of these underwent surgery and 12 died or in 275, open without Eisenmenger syndrome in 352, and open with Eisenmenger syndrome in 83. However, several issues arise in the determination of hemodynamics in these patients. These studies are frequently performed under general anesthesia, which frequently leads to a lower systemic blood pressure than the precatheterization condition (58). In patients with single-ventricle anatomy and physiology, additional problems arise. Furthermore, aortopulmonary collaterals are frequent in the single-ventricle patient leading to underestimation of pulmonary blood flow by catheterization. Although many studies have evaluated hemodynamics to determine operability, the precise values that best correlate with early and late outcome remain unclear. The role of longer-term "treatment and repair" or a period of pulmonary artery banding is less well defined but is intriguing (149). Morbidity in Eisenmenger syndrome is common and includes hemoptysis, pulmonary thromboembolism, stroke, and cerebral abscess. An increased risk of death has been shown to be related to noncardiac surgery with general anesthesia. Red blood cell depletion may be utilized in Eisenmenger syndrome to provide temporary relief of major hyperviscosity symptoms or to improve perioperative hemostasis, but should not routinely be performed as this leads to increased stiffness of the red blood cell (161). Treatment of iron deficiency and routine monitoring of hemoglobin level are key elements of treatment and may improve exercise tolerance. Noncardiac operations on Eisenmenger patients are associated with a high mortality rate and should be managed by a multidisciplinary team experienced in the care of patients with this condition. Nocturnal oxygen therapy in Eisenmenger syndrome does not appear to alter long-term outcome (162). Thirty patients (79%) had a good outcome and were asymptomatic at a mean follow-up of 8. Eight patients (21%) had a poor outcome, but there was no significant difference regarding hemodynamic parameters at baseline between those who had a good outcome and those who did not (146). Patients who are under 2 years of age with evidence of pulmonary overcirculation and exclusive left-to-right shunting by echo do not necessarily need to undergo cardiac catheterization prior to surgery. Those patients who are older and have desaturation or bidirectional shunting may benefit from vasodilator testing to stratify risk. An algorithm of preoperative evaluation and management of pediatric patients with congenital cardiac shunts. The routine is not applicable to complex conditions such as the absence of a subpulmonary ventricle (candidates to ca vopulmonary anastomoses). In a separate study, in children on bosentan a progressive decline in exercise capacity was observed from I-year follow-up, whereas in the adults, improvement lasted longer (167). All were females in late childhood or adolescence with idiopathic portal hypertension (177). Proposed theories suggest that these disorders result from a combination of hyperdynamic circulation, increased cardiac output, sheer injury to vascular walls, and an imbalance of circulating vasoactive peptides (178,179). B: Adjusted survival rate curves, based on the propensity scoreadjusted Cox model, of patients within the third propensity score quartile, with and without advanced therapy. Recent studies have highlighted the potential role of vascular endothelial growth factor and hypoxia inducible factor in the development of vascular dilation and arteriovenous malformations (180-184). In children, the initial clinical presentation is subtle with the initial presentation rarely being death from a pulmonary hypertensive crisis (185). Furthermore, these two disorders may be difficult to diagnose and are frequently found at autopsy (217). In both disorders, the definitive diagnosis is usually made by surgical lung biopsy. Due to the findings of myofibroblasts seen in patients with pulmonary vein disorders investigators have attempted use of chemotherapeutic agents with mixed results (218). Despite surgical, medical, and catheter-based attempts, often these therapies are ineffective with recurrence of disease and no cure (229-235). Treatment of cor pulmonale depends on the precise etiology of lung disease, as well as disease severity. Nocturnal oxygen administration may alleviate hypoxia, typically without causing hypercapnia. Left heart disease in adults is common, particularly in the later part of life and is mainly due to left ventricular diastolic dysfunction. Second, there is reflex vasoconstriction of the pulmonary arteries or veins or both. An example of reflex pulmonary vasoconstriction in a 5-year-old patient with restrictive cardiomyopathy. Before vasodilator therapy is started, a complete evaluation of all causes of lung disease and its associated comorbidities should be done (245). Management of children with pulmonary vein stenosis is difficult as catheterbased intervention or surgery has shown poor long-term results and overall survival is poor with the 2-year survival rate from diagnosis of 43% (229). Predisposing factors include antiphospholipid antibody syndrome, bacterial endocarditis, and ventriculoatrial shunt for the treatment of hydrocephalus. A similar approach should be considered for children who develop this condition despite the relative paucity of data on this procedure in the pediatric age group. Therapy in adults is evidence based whereas in children it is based on experience. A positive response is defined by assessing the change in hemodynamic parameters to vasodilators. The younger the child at the time of testing, the greater the likelihood of acute pulmonary vasodilation in response to vasoreactivity testing (81,144,256). Many oral and inhaled vasodilators have been used for testing of vasodilator responsiveness (129,143,144,256-261). Diuretics are used to treat peripheral edema or ascites in the presence of right heart failure; however, excessive diuresis should be avoided. Careful attention to respiratory tract infections is required as this may worsen alveolar hypoxia, and routine influenza vaccination is recommended.

A technique has been described that allows quantitative assessment of abnormalities in a pulmonary wedge angiogram (10) treatment guidelines for shoulder pain order anacin 525 mg fast delivery. An end-hole balloon catheter is directed to the origin of the axial artery of the posterior basal segment of the right lower lobe; the balloon is inflated pain treatment center of illinois new lenox cheap 525 mg anacin with visa, contrast material is injected over the counter pain treatment for dogs order cheap anacin on line, and the injection is filmed on biplane cineangiography pain treatment west plains mo purchase 525 mg anacin mastercard. More abrupt arterial tapering is suggestive of more severe changes in the intraacinar arteries allied pain treatment center inc discount 525 mg anacin otc, assessed both morphometrically and by the Heath-Edwards classification (Table 66. Further studies revealed that there are several pitfalls and limitations in the interpretation of the pulmonary wedge angiogram. Pulmonary stenosis or previous placement of a pulmonary artery band, owing to poststenotic dilation, will give the impression of rapid tapering. With advanced vascular Reactive Pulmonary Circulation A major challenge in pediatric cardiology is to understand and control the reactive pulmonary circulation, which can be particularly problematic in the early postoperative period. The neuroendocrine cells, which are also oxygen sensors, contain bombesin and serotonin, agents known to be potent vasoconstrictors. Because most of the pulmonary hypertensive crises occur while weaning patients from the ventilator, it is tempting to speculate that swings in airway pressure might lead to degranulation of the neuroepithelial cells and release of the vasoconstrictor substances. Moreover, we have observed a striking decrease in lung compliance accompanying the pulmonary hypertensive crisis. In ultrastructural lung-biopsy studies in patients with congenital heart defects and pulmonary hypertension, alterations in endothelial cells support endothelial dysfunction as a cause of heightened pulmonary vascular reactivity and also relate endothelial dysfunction to the pathogenesis of progressive pulmonary vascular disease. On scanning electron microscopy, the endothelial surface of normal thin-walled pulmonary arteries has a "corduroy-like" appearance in that the cells form narrow, even ridges. A: Neuroepithelial bodies (arrowheads) are seen as dark-staining regions (immunoreactive for serotonin) in airway of a newborn infant. B: Tyrosine hydroxylase immunoreactive perivascular nerve fibers (arrow) at the advential-medial border of an alveolar duct artery in a child aged 21/2. A study of nerves containing peptides in the pulmonary vasculature of healthy infants and children and of those with pulmonary hypertension. The hypertensive endothelium may be predisposed to interact abnormally with marginating blood elements, such as platelets and leukocytes. This might result in the release of pulmonary vasoconstrictor substances and smooth muscle mitogens (14). The subendothelium of the muscular arteries is also abnormal in that there appears to be degradation and neosynthesis of the internal elastic lamina. This observation provided an important clue related to the discovery of heightened elastolytic activity in the vessel wall associated with the initiation and progression of pulmonary vascular disease. Further studies were designed to try to identify what the products of increased endothelial metabolism might be. There is evidence from other studies that the neointimal lesions are associated with increased expression of transforming growth factor beta and procollagen in addition to fibronectin (20). It is also proposed that endothelial cell proliferation and a form of angiogenesis are observed with plexiform lesions. The plexiform lesions in pulmonary hypertension appear to be derived from different clonal populations of endothelial cells compared with those observed in primary pulmonary hypertension where a single clone is usually found (21). This could account for the development of platelet fibrin microthrombi in the postoperative period and for abnormal release of vasoactive compounds causing increased vascular reactivity. There also is evidence that production of the vasoconstrictor endothelin also might be increased in patients with pulmonary hypertension and congenital heart defects (18). Almost all patients with high-flow congenital heart defects who are operated upon in a timely fashion, show a fall in pulmonary artery pressure and return to normal resting hemodynamics indicating resolution and regression of pulmonary hypertensive structural changes. This is supported by experimental studies carried out by our group and others as well as by anecdotal reports of resolution of severe pulmonary vascular disease in the remaining lung after single lung transplant. There are, however, a few patients who maintain a high level of pulmonary vascular resistance and are refractory to vasodilator therapy despite what appear to be mild vascular changes on light microscopy (medial hypertrophy), and others who develop rapidly progressive pulmonary vascular disease despite early diagnosis and timely intervention. For these patients, the prognosis may be not much better than for those with unexplained pulmonary hypertension (19). Therapies for the patient with Eisenmenger syndrome have included chronic oxygen, anticoagulants, and palliative surgical procedures, including atrial septal defect creation and intravenous prostacyclin as well as, more recently, aerosolized, nebulized, or oral prostacyclin. In some cases, these measures have improved the quality of life and in others they have served as a bridge to a heart-lung transplant or surgical correction along with single- or double-lung transplant, including living donors. More recent addition of sildenafil and endothelin receptor blockers in this group of patients awaits the results of clinical trials, but is discussed later in this chapter, and in the subsequent chapter, with regard to patients with primary pulmonary hypertension. Experimental Studies Simulating High Flow and Pressure In experimental studies, an aortopulmonary shunt surgically created in a growing piglet results in a progressive increase in pulmonary artery pressure associated with the development of structural changes similar to those seen in the clinical setting. Creation of large aortopulmonary shunts in dogs, particularly into a single pulmonary artery, resulted in more rapidly progressive pulmonary vascular changes. There are several other experimental models of high-flow congenital heart defects such as in sheep or calves after an aortopulmonary lobar anastomosis. Takedown of the shunts during the period of rapid lung growth resulted in regression of both structural changes and pulmonary hypertension (26). Regression of medial hypertrophy and muscularization of distal vessels has been shown in experimental studies following pressure off-loading (27). There are many common features linking the cellular and molecular pathophysiology of pulmonary vascular disease, regardless of etiology, that we have linked to elevated elastase activity and this subject is discussed at the end of the chapter. There is a progressive increase in the deposition of two matrix glycoproteins, tenascin, and fibronectin, in the media and neointima. Progressive pulmonary vascular disease is characterized by a proliferative response related to deposition of tenascin-C and is preceded by subendothelial accumulation of fibronectin. In infants with hypoplastic left heart syndrome, there is such severe medial hypertrophy of the small arteries and veins from birth that it must have developed in utero (29). In both adults and children with rheumatic mitral stenosis, Wagenvoort and Wagenvoort (30) observed increased medial-wall thickness of the pulmonary arteries. In postmortem arteriograms of infants and children with congenital heart defects and elevated pulmonary venous pressure, the axial pulmonary arteries have a reduced lumen diameter throughout their lengths. On microscopic examination of the lung, there is severe extension of muscle into peripheral intra acinar arteries, which are normally nonmuscular, and failure of regression of the fetal musculature of the normally muscular arteries. The vessels, however, appear normal sized and are normal or slightly increased in number. The presence of pulmonary vascular changes in defects with high pulmonary venous pressure and the capacity for these abnormalities to regress with improvement in hemodynamics may be relevant because the Norwood and other various staged surgical procedure for the treatment of hypoplastic left heart syndrome ultimately depend on the success of a bidirectional cavopulmonary shunt and a right atrial-to-pulmonary artery anastomosis or tunnel. Representative photomicrographs Experimental Studies Pulmonary venous hypertension has been created experimentally by banding the pulmonary veins or by elevating left atrial pressure. After 1 week, they observed no change in pulmonary hemodynamics, but there was a striking decrease in compliance of the pulmonary veins. Representative photomicrographs of human lung biopsy tissue after immunoperoxidase staining for S100A4/Mtsl. S100A4/Mtsl was not detected in all cells and appears to be localized in a subpopulation of intimal cells. Immunoreactivity for S100A4/Mtsl was present in the lung parenchyma at a similar level in all grades of pulmonary vascular disease. S100A4/Mtsl produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. By 6 weeks, further progression of pulmonary hypertension was associated with elevated pulmonary venous pressure. By 3 weeks, pulmonary venous hypertension developed and there was already evidence of intimal proliferation. By 6 weeks, there was an increase in collagen in the walls of the pulmonary veins. This study suggested that pulmonary hypertension may be the first sign of pulmonary venous obstruction and that elevation of pulmonary venous pressure is associated with considerable structural remodeling. Studies suggest that the potential for growth of the central pulmonary arteries is correlated with the proportion of elastin in the media, and the same may be true for the intrapulmonary vessels (32). On postmortem arteriograms in patients with decreased pulmonary blood flow, the axial arteries are abnormally narrow in lumen diameter (33). The background haze also may be reduced, as in patients with pulmonary atresia and intact ventricular septum. On microscopic examination of the lung from patients with pulmonary atresia and intact ventricular septum, the intraacinar pulmonary arteries are abnormally thin walled, small, and few in number. In patients with tetralogy of Fallot, these vessels are normal or decreased in muscularity, normal in number, and small (34). Alveolar development is impaired in patients with decreased pulmonary blood flow, and this is reflected mostly by a reduction in alveolar number. Patients with tetralogy of Fallot and associated pulmonary atresia form a special subgroup in which the relative distribution of central pulmonary arteries and aortopulmonary collaterals determines peripheral pulmonary vascular structure. In patients with tricuspid atresia, the structural state of the pulmonary vascular bed is variable, depending on whether pulmonary blood flow is increased or decreased. A: Pulmonary artery pressure (Ppa, upper panel) and pulmonary capillary wedge pressure (Pew, lower panel) in banded and sham-operated piglets at 1, 3, and 6 weeks after banding. The changes in the lung that resulted consisted of diffuse hypoplasia of the musculature of the peripheral pulmonary vessels; those identified were small in caliber and few. In a study by Arias-Stella and Saldana (45), postmortem lung tissue from persons who had been living at high altitudes was compared with that obtained from sea-level dwellers. Children living in Denver (elevation 5,200 feet) have slightly higher mean pulmonary artery pressures than sea-level dwellers, and children living in Moroccocha, Peru (elevation 14,900 feet) have mean pulmonary artery pressures that are twice as high. Moreover, in the high-altitude residents, mean pulmonary artery pressure more than doubles with exercise, whereas it increases by only 50% in sea-level dwellers. There is much variability in individual response to hypoxia; some people hyperventilate and become mildly alkalotic, hardly increasing their pulmonary artery pressure at all, whereas others develop severe pulmonary hypertension with high-altitude pulmonary edema. Endothelial swelling of small arteries occurs in some areas of the lung and causes high resistance, which results in diversion of excessive flow through small vessels, causing edema. Defective fibrinolysis with formation of microemboli has been reported, as has inadequate diuresis (38). There is increased circulating antigenic activity without increased biologic activity, suggesting that the high-molecular-weight components of the molecule may be associated with platelet microaggregates (39). In the rat, the hemodynamic and structural responses of the pulmonary vascular bed to chronic hypoxia were studied. After just 3 days of chronic hypoxia, a sustained elevation in pulmonary artery pressure and resistance was measured even after the rats were kept in room air for several hours. Over the ensuing 2 weeks of hypoxia, mean pulmonary artery pressure progressively rises to double control values (47). This increase is accompanied by right ventricular hypertrophy, further extension of muscle into peripheral arteries, medial hypertrophy of normally muscular arteries, and reduction in arterial related to alveolar concentration. Relative hyporesponsiveness to hypoxia of the female animal has been observed in a number of species. During recovery from chronic hypoxia, mean pulmonary artery pressure returned to near normal in rats exposed as adults but remained 50% above normal in animals exposed during infancy, correlating with more severe residual vascular abnormalities. Ultrastructural and biochemical studies in the rat have shown that regression of smooth muscle hypertrophy following return to room air is accompanied by an increase in the amount of elastin and collagen in the vessel wall (48). Thus, the vessel, although less muscular, is enclosed in a tight sheath, which may interfere with its compliance and its ability to grow. Experimental Studies of Acute Hypoxia Micropuncture has shown that both the small arteries and veins contribute to the acute hypoxic vasoconstrictor response. Recent reports revealed that with hypoxic vasoconstriction there is inhibition of a Ca 2+-activated depolarizing potassium channel. The relationship between acute hypoxic vasoconstriction, the sustained pulmonary hypertension, and structural changes in the pulmonary vascular bed induced by chronic hypoxia is not known. Experimental studies of unilaterally banding the pulmonary artery in chronically hypoxic rats support the hypothesis that some structural changes in hypoxia are influenced by an alteration in the hemodynamics of the pulmonary circulation and others are more direct effects of hypoxia per se (42). There was striking medial hypertrophy and remarkable proliferation of a dense adventitial sheath, which, in large vessels, was sometimes seen to exhibit neovascularization. Further studies showed striking synthesis of elastin in the pulmonary arteries of these neonatal calves. It is believed that these "stem cells" that have characteristics of both fibroblasts and leukocytes (51) migrate into the vessel wall through the angiomata located in the expanding adventitia (52). There is also evidence in this model that epigenetic factors may be controlling the expression of pro inflammatory cytokines in the fibroblasts in this model and that the inflammatory response is critical to the evolution of the disease (54). Studies in transgenic mice suggest that genetic factors might modulate the response to chronic hypoxia. Prostacyclin synthetase overexpression is protective against the hemodynamic and vascular changes of pulmonary hypertension (56). Epigenetic factors also appear to control signaling via Bmpr2 (63) as well as reduced expression of the free radical scavenger superoxide dismutase seen in the fawnhooded rat with pulmonary hypertension (64). We have shown that mice overexpressing the calcium binding protein S100A4/Mts1 have mild pulmonary hypertension under room air conditions. Values are increased over control mice in hypoxia but the remodeling response also appears to be mitigated. We related this to increased production of fibulin-5 and thickening of the elastic laminae (65). Understanding why these compensatory mechanisms fail may be critical in appreciating why some patients develop rapidly progressive pulmonary hypertension. Numerous studies have attempted to show how acute vasoconstriction or a direct hypoxic "injury" initiates the structural changes observed in the pulmonary arteries. There is convincing evidence that the high endothelin levels are causally related to hypoxic vasoconstriction and the subsequent initiation of vascular changes. An artery from the lung of a 2-week-old calf raised at a simulated altitude of 4,300 m from birth.

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